supplement ii to the japanese pharmacopoeia fifteenth edition - NIHS

SUPPLEMENT IITOTHE JAPANESEPHARMACOPOEIAFIFTEENTH EDITIONOfficial From October 1, 2009English VersionTHE MINISTRY OF HEALTH, LABOUR AND WELFARE

Notice: This English Version of the Japanese Pharmacopoeia is published for the convenienceof users unfamiliar with the Japanese language. When and if any discrepancy arisesbetween the Japanese original and its English translation, the former is authentic.

The Ministry of Health, Labour andWelfare Ministerial Notification No. 425Pursuant to Paragraph 1, Article 41 of the Pharmaceutical Affairs Law (Law No. 145,1960), we hereby revise a part of the Japanese Pharmacopoeia (Ministerial NotificationNo. 285, 2006) as follows*, and the revised Japanese Pharmacopoeia shall come into effecton October 1, 2009. However, in the case of drugs which are listed in the JapanesePharmacopoeia (hereinafter referred to as “previous Pharmacopoeia”) [limited to thoselisted in the Japanese Pharmacopoeia whose standards are changed in accordance withthis notification (hereinafter referred to as “new Pharmacopoeia”)] and drugs which havebeen approved as of October 1, 2009 as prescribed under Paragraph 1, Article 14 of thesame law [including drugs the Minister of Health, Labour and Welfare specifies (theMinistry of Health and Welfare Ministerial Notification No. 104, 1994) as those exemptedfrom marketing approval pursuant to Paragraph 1, Article 14 of the PharmaceuticalAffairs Law (hereinafter referred to as “drugs exempted from approval”)], the Nameand Standards established in the previous Pharmacopoeia (limited to part of the Nameand Standards for the drugs concerned) may be accepted to conform to the Name andStandards established in the new Pharmacopoeia before and on March 31, 2011. In thecase of drugs which are listed in the new Pharmacopoeia (excluding those listed in theprevious Pharmacopoeia) and drugs which have been approved as of October 1, 2009 asprescribed under Paragraph 1, Article 14 of the same law (including those exempted fromapproval), they may be accepted as those being not listed in the new Pharmacopoeia beforeand on March 31, 2011.September 30, 2009Akira NagatsumaThe Minister of Health, Labour and Welfare(The text referred to by the term “as follows” are omitted here. All of them are madeavailable for public exhibition at the Evaluation and Licensing Division, Pharmaceuticaland Food Safety Bureau, Ministry of Health, Labour and Welfare, at each RegionalBureau of Health and Welfare, and at each Prefectural Office in Japan).*The term “as follows” here indicates the contents of Supplement II to the Japanese PharmacopoeiaFifteenth Edition from General Notice to Ultraviolet-visible Reference Spectra (pp. 2041‐2276).

CONTENTSPreface ........................................................................ iSupplement II to The Japanese Pharmacopoeia,Fifteenth Edition ........................................ 2041-2276General Rules for Crude Drugs ........................ 2041General Tests, Process and Apparatus .............. 20431.07 Heavy Metals Limit Test......................... 20431.08 Nitrogen Determination (Semimicro-Kjeldahl Method).................................... 20431.09 Qualitative Tests ..................................... 20442.01 Liquid Chromatography.......................... 20452.04 Amino Acid Analysis of Proteins............ 20463.01 Determination of Bulk and TappedDensities ................................................. 20473.02 Specific Surface Area by Gas Adsorption..........................................................20493.03 Powder Particle Density Determination.. 20523.04 Particle Size Determination .................... 20537.02 Test Methods for Plastic Containers ....... 20579.01 Reference Standards ............................... 20579.41 Reagents, Test Solutions ......................... 20589.42 Solid Supports/Column Packings forChromatography ..................................... 2072Official Monographs ...........................................2073Crude Drugs ....................................................2219Infrared Reference Spectra ...................... 2241-2260Ultraviolet-visible Reference Spectra ...... 2261-2276General Information ...........................................22778. International Harmonization Implemented in theJapanese Pharmacopoeia FifteenthEdition........................................................227914. Mycoplasma Testing for Cell Substrates used forthe Production of Biotechnological/Biological Products....................................228132. Near Infrared Spectrometry .......................228434. System Suitability ......................................229035. Powder Fineness ........................................2291Index .....................................................................2293Index in Latin Name............................................2309Index in Japanese ................................................2311

PREFACEThe 15th Edition of the Japanese Pharmacopoeia(JP) was promulgated by Ministerial Notification No.285 of the Ministry of Health, Labour and Welfare(MHLW) on March 31, 2006.In July 2006, the Committee on JP established thebasic principles for the preparation of the JP 16th Edition,setting out the roles and characteristics of the JP,the definite measures for the revision, and the date ofthe revision.At the above Committee, the five basic principles ofJP, which we refer to as the “five pillars” were establishedas follows: 1) Including all drugs which are importantfrom the viewpoint of health care and medicaltreatment; 2) Making qualitative improvement by introducingthe latest science and technology; 3) Promotinginternationalization; 4) Making prompt partialrevision as necessary and facilitating smooth administrativeoperation; and 5) Ensuring transparency regardingthe revision, and disseminating the JP to thepublic. It was agreed that the Committee on JP shouldmake efforts, on the basis of these principles, to ensurethat the JP is used more effectively in the fields ofhealth care and medical treatment by taking appropriatemeasurements, including getting the understandingand cooperation of other parties concerned.It was agreed that the JP should provide an officialstandard, being required to assure the quality of medicinesin Japan in response to the progress of scienceand technology and medical demands at the time. Itshould define the standards for specifications, as wellas the methods of testing to assure overall quality of alldrugs in principle, and it should have a role in clarifyingthe criteria for quality assurance of drugs that arerecognized to be essential for public health and medicaltreatment.The JP has been prepared with the aid of the knowledgeand experience of many professionals in thepharmaceutical field. Therefore, the JP should have thecharacteristics of an official standard, which might bewidely used by all parties concerned. It should provideinformation and understanding about the quality ofdrugs to the public, and it should be conducive tosmooth and effective regulatory control of the qualityof drugs, as well as promoting and maintaining internationalconsistency and harmonization of technicalrequirements.It was also agreed that JP articles should cover drugs,which are important from the viewpoint of health careand medical treatment, clinical results and frequencyof use, as soon as possible after they reach the market.The target date for the publication of JP 16th Edition(the Japanese edition) was set as April 2011.JP Expert Committees are organized with the followingpanels: Panel on the Principles of Revisions;Sub-committee on the Principles of Revisions; Panelon Medicinal Chemicals; Panel on Antibiotics; Panelon Biologicals; Panel on Crude Drugs; Panel on PharmaceuticalExcipients; Panel on Physico-ChemicalMethods; Panel on Preparations; Panel on PhysicalMethods; Panel on Biological Tests; Panel on Nomenclature;Panel on International Harmonization; Panelon Pharmaceutical Water; and Panel on ReferenceStandards. Furthermore, working groups are establishedunder the Panel on Physico-Chemical Methods,Panel on Preparations and Panel on Biological Tests toexpedite discussion of revision drafts of Monographs.In the Committee on JP, Takao Hayakawa took therole of chairman from July 2003 to September 2009.In addition to the regular revision every five years inline with the basic principles for the preparation of theJP it was agreed that partial revision should be done asnecessary to take account of recent progress of scienceand in the interests of international harmonization.In accordance with the above principles, the panelsinitiated deliberations on selection of articles, and onrevisions for General Notices, General Rules for CrudeDrugs, General Rules for Preparations, General Tests,Monographs and so on.Draft revisions covering subjects in General Rulesfor Crude Drugs, General Tests and Monographs, forwhich discussions were finished between April 2007and March 2009, were prepared for a supplement tothe JP 15. They were examined by the Committee onJP in April 2009, followed by the Pharmaceutical Affairsand Food Sanitation Council (PAFSC) in June2009, and then submitted to the Minister of MHLW.Numbers of discussions in the panels to prepare thesupplement drafts were as follows: Panel on Principlesof Revisions (3); Panel on Medicinal Chemicals (23);Panel on Antibiotics (8); Panel on Biologicals (8);Panel on Crude Drugs (21); Panel on PharmaceuticalExcipients (10): Panel on Physico-Chemical Methods(11, including the working groups); Panel on Preparations(19, including the working groups); Panel onPhysico-Chemical Methods (9): Panel on BiologicalTests (9); Panel on Nomenclature (6); Panel on Inter-i

ii Preface Supplement II, JP XVnational Harmonization (3); and Panel on PharmaceuticalWater (8).It should be noted that in the preparation of thedrafts for the supplement, generous cooperation wasgiven by the Technical Committee of the PharmaceuticalManufacturer’s Association of Osaka and of Tokyo,the Tokyo Crude Drugs Association, the JapanPharmaceutical Excipients Council, the Home MedicineAssociation of Japan, the Japan Kampo MedicineManufacturers’ Association, the Japan Flavor and FragranceMaterials Association, the Japan Medical PlantsFederation, the Japan Parental Drug Association, theJapan Reagent Association, the Japan Oilseeds ProcessorsAssociation, and the Association of MembraneSeparation Technology of Japan.In consequence of this revision, the JP 15th Editioncarries 1673 articles, owing to the addition of 106 articlesand the deletion of 1 article.The principles of description and the salient pointsof the revision in this Supplement are as follows:1. The Supplement II to JP 15th Edition comprisesthe following items, in order: Notification of MHLW;Contents; Preface; General Rules for Crude Drugs;General Tests, Official Monographs; Infrared ReferenceSpectra; and Ultraviolet-visible Reference Spectra;then followed by General Information; and as anappendix a Cumulative Index containing references tothe main volume and the Supplements I and II.2. The articles in General Rules for Preparations,Official Monographs, Infrared Reference Spectra andUltraviolet-visible Reference Spectra are respectivelyplaced in alphabetical order.3. The following items in each monograph are putin the order shown below, except that unnecessaryitems are omitted depending on the nature of the drug:(1) English title(2) Commonly used name(s)(3) Latin title (only for crude drugs)(4) Title in Japanese(5) Structural formula or empirical formula(6) Molecular formula and molecular mass(7) Chemical name(8) Origin(9) Limits of the content of the ingredient(s) and/orthe unit of potency(10) Labeling requirements(11) Method of preparation(12) Description/Description of crude drugs(13) Identification tests(14) Specific physical and/or chemical values(15) Purity tests(16) Loss on drying or ignition, or water(17) Residue on ignition, total ash or acid-insolubleash(18) Tests being required for pharmaceutical preparationsand other special tests(19) Isomer ratio(20) Assay or the content of the ingredient(s)(21) Containers and storage(22) Expiration date(23) Others4. In each monograph, the following physical andchemical values representing the properties and qualityof the drug are given in the order indicated below, exceptthat unnecessary items are omitted depending onthe nature of the drug:(1) Alcohol number(2) Absorbance(3) Congealing point(4) Refractive index(5) Osmolarity(6) Optical rotation(7) Viscosity(8) pH(9) Specific gravity(10) Boiling point(11) Melting point(12) Acid value(13) Saponification value(14) Ester value(15) Hydroxyl value(16) Iodine value5. Identification tests comprise the following items,which are generally put in the order given below:(1) Coloration reactions(2) Precipitation reactions(3) Decomposition reactions(4) Derivatives(5) Infrared and/or ultraviolet-visible absorptionspectrometry(6) Special reactions(7) Cations(8) Anions6. Purity tests comprise the following items, whichare generally put in the order given below, except thatunnecessary items are omitted depending on the natureof the drug:(1) Color(2) Odor(3) Clarity and/or color of solution(4) Acidity or alkalinity(5) Acidity

Supplement II, JP XV Preface iii(6) Alkalinity(7) Chloride(8) Sulfate(9) Sulfite(10) Nitrate(11) Nitrite(12) Carbonate(13) Bromide(14) Iodide(15) Soluble halide(16) Thiocyanide(17) Selenium(18) Cationic salts(19) Ammonium(20) Heavy metals(21) Iron(22) Manganese(23) Chromium(24) Bismuth(25) Tin(26) Aluminum(27) Zinc(28) Cadmium(29) Mercury(30) Copper(31) Lead(32) Silver(33) Alkaline earth metals(34) Arsenic(35) Foreign matter(36) Related substances(37) Residual solvent(38) Other impurities(39) Readily carbonizable substances7. The following articles were newly added to theGeneral Rules for Crude Drugs:(1) Pogostemon Herb(2) Nutmeg(3) Quercus Bark(4) Longan Aril(5) Royal Jelly8. The following article was deleted from theGeneral Rules for Crude Drugs:(1) Rice Starch9. The following item was newly added to theGeneral Tests, Processes and Apparatus:(1) 2.04 Amino Acid Analysis of Proteins10. The following items of the General Tests,Processes and Apparatus were revised:(1) 1.07 Heavy Metals Limit Test(2) 1.08 Nitrogen Determination(Semimicro-Kjeldahl Method)(3) 1.09 Qualitative Tests(4) 2.01 Liquid Chromatography(5) 3.01 Determination of Bulk and TappedDensities(6) 3.02 Specific Surface Area by Gas Adsorption(7) 3.03 Powder Particle Density Determination(8) 3.04 Particle Size Determination(9) 7.02 Test Methods for Plastic Containers11. The following Reference Standards werenewly added:AciclovirCalcitonin (Salmon)DanazolDiflucortolone ValerateDoxazosin MesilateFludrocortisone AcetateFlutamideGefarnateD-GlucuronolactoneIndapamideIpriflavoneLosartan PotassiumPioglitazone HydrochloridePrazosin HydrochlorideProbucolSevofluraneSimvastatinTacrolimus HydrateTazobactamTeprenoneTosulfloxacin Tosilate HydrateTroxipide12. The following Reference Standards wererevised:Amlodipine BesilateAmoxicillinAzathioprineCefalexinCefatrizine Propylene GlycolateCefiximeCefroxadine HydrateCefteram Pivoxil MesitylenesulfonateClomifene CitrateDiethylcarbamazine CitrateEthenzamideFaropenem SodiumGriseofulvinMinocycline HydrochloridePivmecillinam Hydrochloride

iv Preface Supplement II, JP XVProbenecidProchlorperazine MaleateWarfarin Potassium13. English and Latin titles of drugs were based, inprinciple, on the International Nonproprietary Namesfor Pharmaceutical Substances, and the chemicalnames were based on the Rules of the InternationalUnion of Pure and Applied Chemistry (IUPAC).14. Molecular formulas of organic compoundsbegin with C and then H, followed by other involvedelements in the alphabetical order of the symbols of theelements.15. Structural formula of drug represents, as far aspossible, the steric configuration.16. The test procedures in monographs werewritten in full, except within the same monograph andin the monographs for preparation having acorresponding monograph of their principal materialsubstances.17. The following monographs were added:Acemetacin CapsulesAcemetacin TabletsAciclovirL-AlanineAllopurinol TabletsAmiodarone HydrochlorideAmiodarone Hydrochloride TabletsAmlodipine Besilate TabletsAmoxicillin CapsulesAprindine HydrochlorideAprindine Hydrochloride CapsulesArgatroban HydrateAzelastine Hydrochloride GranulesBetaxolol HydrochlorideCadralazineCadralazine TabletsCalcitonin (Salmon)Cefalexin CapsulesCefalexin for SyrupCefatrizine Propylene Glycolate for SyrupCefixime CapsulesCefroxadine for SyrupCefteram Pivoxil TabletsCinoxacinCinoxacin CapsulesClebopride MalateDanazolDibekacin Sulfate Ophthalmic SolutionDiflucortolone ValerateDoxazosin MesilateDroxidopaDroxidopa CapsulesDoroxidopa Fine GranulesEcabet Sodium GranulesEcabet Sodium HydrateEmorfazone TabletsFludrocortisone AcetateFlutamideFlutoprazepamFlutoprazepam TabletsFurosemide InjectionGefarnateGentamicin Sulfate Ophthalmic SolutionGliclazideHeparin CalciumImidapril HydrochlorideImidapril Hydrochloride TabletsIndapamideIndapamide TabletsIpriflavoneIpriflavone TabletsIrsogladine MaleateIrsogladine Maleate Fine GranulesIrsogladine Maleate TabletsIsepamicin Sulfate InjectionKetoconazoleKetoconazole CreamKetoconazole LotionKetoconazole SolutionLevofloxacin HydrateLincomycin Hydrochloride InjectionLosartan PotassiumL-Lysine AcetateMeropenem for InjectionMinocycline Hydrochloride TabletsMosapride Citrate HydrateMosapride Citrate TabletsPimozidePioglitazone HydrochloridePivmecillinam Hydrochloride TabletsPrazosin HydrochloridePrednisolone Sodium PhosphateProbucolPropafenone HydrochloridePropafenone Hydrochloride TabletsRebamipideRebamipide TabletsSevofluraneSimvastatinPurified Sodium HyaluronateSodium Valproate SyrupSodium Valproate Tablets

Supplement II, JP XV Preface vStreptomycin Sulfate for InjectionSulindacTacrolimus HydrateTazobactamTeprenoneTiapride HydrochlorideTiapride Hydrochloride TabletsTosufloxacin Tosilate HydrateTosufloxacin Tosilate TabletsTroxipideTroxipide Fine GranulesTroxipide TabletsUbenimex CapsulesUrsodeoxycholic Acid GranulesUrsodeoxycholic Acid TabletsZolpidem TartrateGoshajinkigan ExtractHachimijiogan ExtractLongan ArilNutmegPogostemon HerbQuercus BarkRoyal JellyShimbuto Extract18. The following monographs were revised:Dried Aluminum Hydroxide Gel Fine GranulesAminophylline InjectionAmoxicillin HydrateAzathioprine TabletsBetamethasone TabletsCarmelloseCarmellose CalciumCarmellose SodiumCefaclor Compound GranulesCellacefateMicrocrystalline CellulosePowdered CelluloseClindamycin HydrochlorideClindamycin Hydrochloride CapsulesClomifene Citrate TabletsCodeine Phosphate TabletsCorn StarchWood CreosoteCroscarmellose SodiumDiethylcarbamazine Citrate TabletsDigoxinDigoxin InjectionDigoxin TabletsDimenhydrinate TabletsDistigmine Bromide TabletsEphedrine Hydrochloride TabletsErgometrine Maleate InjectionErythromycin Enteric-Coated TabletsEstradiol Benzoate Injection (Aqueous Suspension)Estriol Injection (Aqueous Suspension)EthenzamideEthinylestradiolFamotidine PowderFaropenem Sodium for SyrupFaropenem Sodium TabletsFlopropioneFosfomycin Sodium for InjectionGriseofulvin TabletsHeparin SodiumHuman Menopausal GonadotrophinHydralazine Hydrochloride for InjectionHydrocortisone Sodium PhosphateHydroxypropylcelluloseLow Substituted HydroxypropylcelluloseHypromelloseHypromellose PhthalateIndigocarmine InjectionIndometacin SuppositoriesIsoniazid InjectionIsoniazid TabletsIsosorbide Dinitrate TablesJosamycin TabletsAnhydrous LactoseLactose HydrateLidocaine InjectionMeglumine Iotalamate InjectionMeglumine Sodium Amidotrizoate InjectionMepivacaine Hydrochloride InjectionMethylcelluloseMinocycline Hydrochloride for InjectionMorphine Hydrochloride InjectionMorphine Hydrochloride TabletsNicomol TabletsNorethisteronePhenobarbital10% Phenobarbital PowderPhenolsulfonphthalein InjectionPhenytoin PowderPhenytoin TabletsPipemidic Acid HydratePotato StarchProbenecid TabletsProcainamide HydrochlorideProcainamide Hydrochloride InjectionProcainamide Hydrochloride TabletsProchlorperazine Maleate TabletsProgesteroneProgesterone InjectionPropylthiouracil TabletsProtamine Sulfate Injection

vi Preface Supplement II, JP XVRice StarchRokitamycin TabletsSodium Iotalamate InjectionSodium ValproateTeicoplaninTestosterone Enanthate InjectionTestosterone Propionate InjectionTolbutamide TabletsUrsodeoxycholic AcidVasopressin InjectionWarfarin Potassium TabletsWheat StarchZinc Sulfate HydrateApricot KernelAstragalus RootBear BileBupleurum RootCalumbaPowdered CalumbaCardamonCornus FruitDaiokanzoto ExtractEleutherococcus Senticosus RhizomeHochuekkito ExtractJapanese ValerianPowdered Japanese ValerianKakkonto ExtractLithospermum RootLongguNuphar RhizomePeach KernelPowdered Peach KernelPerilla HerbPolygonatum RhizomeSaposhnikovia RootScopolia RhizomeSenegaPowdered SenegaTurmericPowdered TurmericZanthoxylum FruitPowdered Zanthoxylum Fruit19. The following monograph was deleted:Meglumine Amidotrizoate InjectionThose who were engaged in the preparation of SupplementII to JP 15 are as follows:Mitsuo AokiNobuo AoyagiFumiaki AkahoriToshiki AsanoHiroshi AsamaKazuhide AshizawaYukio AsoTeruo AmagasaHiroyuki AraiKeiko ArimotoNobukazu IgoshiMasao IzakiAkiko IshiiKenichi IzutsuShigeru ItaiTakashi ItohYuji ItoKoichi InubushiAtsuhiro UetakeYoshimasa UeharaEriko UchidaKazuichi UmemotoRyozo OishiTadashi OuchiTsuneo OkuboYuko OsumiMasami OtukaAtsuyuki OhtsukiSumiaki ObaKimiya OkazakiSatoshi OkadaMinoru OkadaHaruhiro OkudaShukichi OchiaiKazuhiro OwadaKazuaki KakehiHirohito KatayamaYoshiaki KatoNoriko KatoriTakemine KanaiUrao KawakamiNana KawasakiYoshiaki KawashimaToru KawanishiNobuo KawaharaYoshihiko KawarasakiFumiyuki KiuchiYuuichi KikuchiKeiji KijimaMitikazu KitadaJunko KizuFumiyo KusuTakao KunisadaHiroyuki KuritaMasaaki KuriharaHaruo KuriyamaYukihiro GodaHiroyasu KokuboShigeo KojimaTakashi GotoMasayoshi KohaseKatsuko KomatsuToshifumi KondaKenji KondoSeizo KondoKenji SaikiEiji SakaiYoshikazu SakagamiTomoaki SakamotoTsuguo SasakiTomoko SasakiHiroshi SasakiMotoyoshi SatakeKyoko SatoYasuo ShimadaKesamitsu ShimizuKyoko ShimuraOsamu ShirotaMikio SuzukiKeiichi SudoHisakazu SunadaMichiko SekiguchiSetsuko SekitaTakashi SonobeKunihiro TakaiToshio TakachiKikuo TakateraYoshikazu TakahashiTadahiro TakedaYoshikazu TashiroShinichi TadakiToshihiro TanakaToyoshige TanabeKenichi Tanamoto**Tsuyoshi TanimotoHideya TugeMasafumi TeshigawaraReiko TeraokaKeijiro TerashitaSusumu Terabayashi

Supplement II, JP XV Preface viiYuji TokunagaKiyoshi TomiokaMotowo TomitaHiroyuki TomitsukaMasaaki NaotsukaSinsaku NakagawaHiroaki NagashigeEmi NakajimaTatsumi NakashimaTatsuya NakanoHiroshi NakamuraMasao NasuMitsuo NanauraSingo NiimiYutaka NishiharaHiroshi NishimuraMitsuru Hashida**Rika HatanoRuri HanajiriKentaro HanadaTakao Hayakawa*Masahiro HayashiYoshinori HayashiTakashi BambaKenji HiguchiYukio HiyamaMasashi HyugaFusayoshi HirayamaKiyoshi FukuharaHiroyuki FuchinoKenji HosoyaMasako MaedaMidori MakitaYoshihisa MatsudaMasahiko MarumotoTsuyoshi MiuraEiichi MikamiTakao MitsuhashiTamaki MiyazakiNaoki MiyataHiroto MiyamotoToshimi MuraiMasashi MuroiTakashi MoritaSeiki MorimotoTakehiko YajimaMasato YasuharaTeruhide YamaguchiTakeshi YamazakiToshiyasu YamadaKeiichi YamamotoKeiji YamamotoTosuke YamamotoSumie YoshiokaHikaru YodenEtsuo YonemochiChikako YomotaMasaaki WadaEiji WatanabeHaruo Watanabe*: Chairman, the Committee on JP**: Acting Chairman, the Committee on JP

Supplement II toThe JapanesePharmacopoeiaFifteenth Edition

GENERAL RULES FORCRUDE DRUGSChange the paragraph 1 to read:1. Crude drugs in the monographs include medicinal partsobtained from plants or animals, cell inclusions and secretesseparated from the origins, their extracts, and minerals. GeneralRules for Crude Drugs and Crude Drugs Test are applicable tothe following:Acacia, Achyranthes Root, Agar, Akebia Stem, Alisma Rhizome,Aloe, Alpinia Officinarum Rhizome, Amomum Seed,Anemarrhena Rhizome, Angelica Dahurica Root, Apricot Kernel,Aralia Rhizome, Areca, Artemisia Capillaris Flower, AsiasarumRoot, Asparagus Tuber, Astragalus Root, AtractylodesLancea Rhizome, Atractylodes Rhizome, Bear Bile, BearberryLeaf, Belladonna Root, Benincasa Seed, Benzoin, Bitter Cardamon,Bitter Orange Peel, Bupleurum Root, Burdock Fruit,Calumba, Capsicum, Cardamon, Cassia Seed, Catalpa Fruit,Chrysanthemum Flower, Cimicifuga Rhizome, Cinnamon Bark,Citrus Unshiu Peel, Clematis Root, Clove, Cnidium MonnieriFruit, Cnidium Rhizome, Coix Seed, Condurango, Coptis Rhizome,Cornus Fruit, Corydalis Tuber, Crataegus Fruit, CyperusRhizome, Digenea, Dioscorea Rhizome, Dolichos Seed,Eleutherococcus Senticosus Rhizome, Ephedra Herb, EpimediumHerb, Eucommia Bark, Evodia Fruit, Fennel, ForsythiaFruit, Fritillaria Bulb, Gambir, Gardenia Fruit, Gastrodia Tuber,Gentian, Geranium Herb, Ginger, Ginseng, Glehnia Root, Glycyrrhiza,Gypsum, Hemp Fruit, Honey, Houttuynia Herb, ImmatureOrange, Imperata Rhizome, Ipecac, Japanese AngelicaRoot, Japanese Gentian, Japanese Valerian, Jujube, Jujube Seed,Leonurus Herb, Lilium Bulb, Lindera Root, Lithospermum Root,Longan Aril, Longgu, Lonicera Leaf and Stem, Loquat Leaf,Lycium Bark, Lycium Fruit, Magnolia Bark, Magnolia Flower,Mallotus Bark, Mentha Herb, Moutan Bark, Mulberry Bark,Nelumbo Seed, Notopterygium Rhizome, Nuphar Rhizome,Nutmeg, Nux Vomica, Ophiopogon Tuber, Oriental Bezoar,Oyster Shell, Panax Japonicus Rhizome, PeachKernel, Peony Root, Perilla Herb, Peucedanum Root, PharbitisSeed, Phellodendron Bark, Picrasma Wood, Pinellia Tuber,Plantago Herb, Plantago Seed, Platycodon Root, PogostemonHerb, Polygala Root, Polygonatum Rhizome, Polygonum Root,Polyporus Sclerotium, Poria Sclerotium, Powdered Acacia,Powdered Agar, Powdered Alisma Rhizome, Powdered Aloe,Powdered Amomum Seed, Powdered Atractylodes Lancea Rhizome,Powdered Atractylodes Rhizome, Powdered Calumba,Powdered Capsicum, Powdered Cinnamon Bark, PowderedClove, Powdered Cnidium Rhizome, Powdered Coix Seed,Powdered Coptis Rhizome, Powdered Corydalis Tuber, PowderedCyperus Rhizome, Powdered Dioscorea Rhizome, PowderedFennel, Powdered Gambir, Powdered Gardenia Fruit,Powdered Gentian, Powdered Geranium Herb, Powdered Ginger,Powdered Ginseng, Powdered Glycyrrhiza, Powdered Ipecac,Powdered Japanese Angelica Root, Powdered Japanese Gentian,Powdered Japanese Valerian, Powdered Longgu, PowderedMagnolia Bark, Powdered Moutan Bark, Powdered Oyster Shell,Powdered Panax Japonicus Rhizome, Powdered Peach Kernel,Powdered Peony Root, Powdered Phellodendron Bark, PowderedPicrasma Wood, Powdered Platycodon Root, PowderedPolygala Root, Powdered Polypourus Sclerotium, Powderd PoriaSclerotium, Powdered Processed Aconite Root, PowderedRhubarb, Powdered Rose Fruit, Powdered Scutellaria Root,Powdered Senega, Powdered Senna Leaf, Powdered SmilaxRhizome, Powdered Sophora Root, Powdered Sweet HydrangeaLeaf, Powdered Swertia Herb, Powdered Tragacanth, PowderedTurmeric, Powdered Zanthoxylum Fruit, Processed AconiteRoot, Processed Ginger, Prunella Spike, Pueraria Root, QuercusBark, Red Ginseng, Rehmannia Root, Rhubarb, Rose Fruit,Rosin, Royal Jelly, Safflower, Saffron, Saposhnikovia Root,Sappan Wood, Saussurea Root, Schisandra Fruit, SchizonepetaSpike, Scopolia Rhizome, Scutellaria Root, Senega, Senna Leaf,Sinomenium Stem, Smilax Rhizome, Sophora Root, Sweet HydrangeaLeaf, Swertia Herb, Turmeric, Toad Venom, Tragacanth,Tribulus Fruit, Trichosanthes Root, Uncaria Hook, ZanthoxylumFruit, Zedoary.2041

GENERAL TESTS, PROCESSAND APPARATUSChange the introduction to read:General Tests, Processes and Apparatus includes commonmethods for tests, useful test methods for quality recognition ofdrugs and other articles related to them. Unless otherwise specified,acid-neutralizing capacity determination of gastrointestinalmedicines, alcohol number determination, amino acid analysisof proteins, ammonium determination, arsenic determination,atomic absorption spectrophotometry, boiling point determination,chloride determination, conductivity measurement, congealingpoint determination, determination of bulk and tappeddensities, digestion test, disintegration test, dissolution test, distillingrange determination, endpoint determination in titrimetry,flame coloration, fluorometry, foreign insoluble matter test forinjetcions, foreign insoluble matter test for ophthalmic solutions,gas chromatography, heavy metal determination, infrared spectrophotometry,insoluble particulate matter test for injections,insoluble particulate matter test for ophthalmic solutions, irondetermination, liquid chromatography, loss on drying determination,loss on ignition determination, microbial assay for antibiotics,melting point determination, methanol determination,mineral oil determination, nitrogen determination, nuclearmagnetic resonance spectroscopy, optical rotation determination,osmolarity determination, oxygen flask combustion method,particle size determination, particle size distribution test forpreparations, pH determination, powder particle density determination,qualitative test, refractive index determination, residualsolvents test, residue on ignition determination, specificgravity and density determination, specific surface area determination,sulfate determination, test for bacterial endotoxins,test for glass containers for injections, test for metal particles inophthalmic ointments, test for microbial limit, test for microbiallimit for crude drugs, test for plastic containers, test for pyrogen,test for readily carbonizable substances, test for rubber closurefor aqueous infusions, test for sterility, test for total organiccarbon, test of extractable volume for injection , thermal analysis,thin-layer chromatography, ultraviolet-visible spectrophotometry,uniformity of dosage units (test for content uniformity,mass variation test), viscosity determination, vitamin A assay,water determination, and X-ray powder diffraction are performedas directed in the corresponding articles under the GeneralTests, Processes and Apparatus. The tests for melting pointof fats, congealing point of fatty acids, specific gravity, acidvalue, saponification value, ester value, hydroxyl value,unsaponifiable matter and iodine value of fats and fatty oils areperformed as directed in the corresponding items under Fats andFatty Oils Test, and sampling, preparation of sample for analysis,microscopic examination, purity test, loss on drying, total ash,acid-insoluble ash, extract content, and essential oil content ofcrude drugs are performed as directed in the correspondingitems under Crude Drugs Test.The number of each test method is a category number givenindividually. The number in blackets (< >) appeared inmonograph indicates the number corresponding to the generaltest method.1.07 Heavy Metals Limit TestChange (3) Method 3 under the Preparation oftest solutions and control solutions to read:(3) Method 3Place an amount of the sample, directed in the monograph, ina quartz or porcelain crucible, heat cautiously, gently at first,and then incinerate by ignition between 500ºC and 600ºC. Aftercooling, add 1 mL of aqua regia, evaporate to dryness on a waterbath, moisten the residue with 3 drops of hydrochloric acid, add10 mL of hot water, and warm for 2 minutes. Add 1 drop ofphenolphthalein TS, add ammonia TS dropwise until thesolution develops a pale red color, add 2 mL of dilute acetic acid,filter if necessary, wash with 10 mL of water, transfer the filtrateand washings to a Nessler tube, and add water to make 50 mL.Designate it as the test solution.The control solution is prepared as follows: Evaporate 1 mLof aqua regia to dryness on a water bath. Hereinafter, proceed asdirected for the test solution, and add the volume of StandardLead Solution directed in the monograph and water to make 50mL.1.08 Nitrogen Determination(Semimicro-Kjeldahl Method)Change the following to read:Nitrogen Determination is a method to determine nitrogen inan organic substance in which the nitrogen is converted intoammonia nitrogen by thermal decomposition of the organicsubstance with sulfuric acid, and the ammonia liberated byalkali and trapped by distillation with steam is determined bytitration.1. ApparatusUse the apparatus illustrated in Fig. 1.08-1. It is thoroughlyconstructed of hard glass, and ground glass surfaces may beused for joints. All rubber parts used in the apparatus should beboiled for 10 to 30 minutes in sodium hydroxide TS and for 30to 60 minutes in water, and finally washed thoroughly withwater before use.2043

2044 General Tests, Process and Apparatus Supplement II, JP XVAlternatively, apparatus can be used in which some of theprocedures, such as digestion of organic substances, distillationof the liberated ammonia, and endpoint detection methods intitrimetry (e.g., potentiometric titration or titration bycolorimeter) are automated.A: Kjeldahl flaskB: Steam generator, containing water, to which 2 to 3 drops ofsulfuric acid and fragments of boiling tips for preventingbumping have been addedC: Spray trapD: Water supply funnelE: Steam tubeF: Funnel for addition of alkali solution to flask AG: Rubber tubing with a clampH: A small hole having a diameter approximately equal to thatof the delivery tubeJ: Condenser, the lower end of which is beveledK: Absorption flaskFig. 1.08-12. System suitabilityIf an automated apparatus is used, it is necessary to confirmperiodically the suitability of the apparatus according to thefollowing method:Weigh accurately about 1.7 g of amidosulfuric acid (standardreagent), previously dried in a desiccator (in vacuum, silica gel)for about 48 hours, dissolve in water to make exactly 200 mL.Pipet 2 mL of this solution, and transfer to an digestion flask.When the test is, perform as directed in the instrumentalmanual.: the nitrogen content (%) in amidosulfuric acid shouldbe determined between 14.2% and 14.6%.3. Reagents, Test SolutionsThe figures are in mm.Decomposition Accelerators Unless otherwise specified,use 1 g of a powdered mixture of 10 g of potassium sulfate and1 g of cupper (II) sulfate pentahydrate. The composition andamount of the digestion accelerator may be modified if it isconfirmed that the modified one give almost the same resultsusing the sample as those obtained from the conventionalcatalyst.4. ProcedureUsually, proceed by the following method. Weigh accuratelyor pipet a quantity of the sample corresponding to 2 to 3 mg ofnitrogen (N:14.01), and place in the Kjeldahl flaks A. Add thedecomposition accelerator and wash down any adhering samplefrom the neck of the flask with a small quantity of water. Add 7mL of sulfuric acid, allowing it to flow down the inside wall ofthe flask.Then, while shaking the flask, add cautiously 1 mL ofhydrogen peroxide (30) drop by drop along the inside wall ofthe flask. Heat the flask gradually, then heat so strong that thevapor of sulfuric acid is condensed at the neck of the flask, untilthe solution changes through a blue and clear to a vivid greenand clear, and the inside wall of the flask is free from acarbonaceous material. If necessary, add a small quantity ofhydrogen peroxide (30) after cooling, and heat again. Aftercooling, add cautiously 20 mL of water, cool the solution, andconnect the flask to the distillation apparatus (Fig 1.08-1)washed beforehand by passing stream through it. To theabsorption flask K add 15 mL of boric acid solution (1 in 25), 3drops of bromocresol green-methyl red TS and sufficient waterto immerse the lower end of the condenser tube J. Add 30 mL ofsodium hydroxide solution (2 in 5) through the funnel F, rinsecautiously the funnel with 10 mL of water, lose the clampattached to the rubber tubing G, then begin the distillation withstream, and continue until the distillate measures 80 to 100 mL.Remove the absorption flask from the lower end of thecondenser tube J, rinsing the end part with a small quantity ofwater, and titrate the distillate with 0.005 mol/L sulfuricacid VS until the color of the solution changes from greenthrough pale grayish blue to pale grayish red-purple. Perform ablank determination in the same manner, and make anynecessary correction.Each mL of 0.005 mol/L sulfuric acid VS = 0.1401 mg of NIf an automated apparatus is used, proceed as directed in theinstrumental procedure.1.09 Qualitative TestsChange (2) under the Phosphate(Orthophosphate) to read:Phosphate (Orthophosphate)(2) Acidic solutions in dilute nitric acid of phosphates yielda yellow precipitate with hexaammonium heptamolybdate TS onwarming. The precipitate dissolves upon subsequent addition ofsodium hydroxide TS or ammonia TS.

Supplement II, JP XV General Tests, Process and Apparatus 20452.01 Liquid ChromatographyChange the Apparatus to read:ApparatusBasically, the apparatus required for the liquidchromatographic procedure consists of a pumping system forthe mobile phase, a sample injection port, a column, a detectorand a recorder. A mobile phase component regulator, athermostat for the column, a pumping system for reactionreagents and a chemical reaction chamber are also used, ifnecessary. The pumping system serves to deliver the mobilephase and the reagents into the column and connecting tube at aconstant flow rate. The sample injection port is used to deliver aquantity of the sample to the apparatus with high reproducibility.The column is a tube with a smooth interior, made of inert metal,etc., in which a packing material for liquid chromatography isuniformly packed. A column with a stationary phase chemicallybound on the inside wall instead of the column packed with thepacking material may be used. The detector is used to detect aproperty of the samples which is different from that of themobile phase, and may be an ultraviolet or visiblespectrophotometer, fluorometric detector, differentialrefractometer, electrochemical detector, chemiluminescencedetector, electric conductivity detector, mass spectrophotometer,etc. The output signal is usually proportional to theconcentration of samples at amounts of less than a few µg. Therecorder is used to record the output signals of the detector. Asrequired, a data processor may be used as the recorder to recordor output the chromatogram, retention times or amounts of thecomponents. The mobile phase component regulator is used tovary the ratio of the mobile phase components in a stepwise orgradient fashion.Change the System Suitability to read:System SuitabilitySystem suitability testing is an integral part of test methodsusing chromatography, and is used to ensure that theperformance of the chromatographic systems used is as suitablefor the analysis of the drug as was at the time when theverification of the test method was performed using the system.System suitability testing should be carried out at every series ofdrug analysis. The test procedures and acceptance criteria ofsystem suitability testing must be prescribed in the test methodof drugs. The results of drug analyses are not acceptable unlessthe requirements of system suitability have been met.In system suitability testing of the chromatographic systems,the evaluation of “System performance” and “Systemrepeatability” is usually required. For quantitative purity tests,the evaluation of “Test for required detectability” may also berequired.(1) Test for required detectabilityFor purity tests, when it is confirmed that the target impurityis distinctly detected at the concentration of its specificationlimit, it is considered verified that the system used has adequateperformance to achieve its intended use.For quantitative purity tests, “Test for required detectability”is usually required, and in order to confirm, in some degree, thelinearity of response near its specification limit, the range ofexpected response to the injection of a certain volume of targetimpurity solution at the concentration of its specification limitshould be prescribed. For limit test, “Test for requireddetectability” is not required, if the test is performed bycomparing the response from sample solution with that fromstandard solution at the concentration of its specification limit.“Test for required detectability” is also not required, if it isconfirmed that the impurity can be detected at its specificationlimit by the evaluation of “System repeatability” or some otherprocedure.(2) System performanceWhen it is confirmed that the specificity for determining thetest ingredient is ensured, it is considered verified that thesystem used has adequate performance to achieve its intendeduse.In assay, “System performance” should be defined by theresolution between the test ingredient and a target substance tobe separated (a closely eluting compound is preferable), andwhen appropriate, by their order of elution. In purity tests, boththe resolution and the order of elution between the testingredient and a target substance to be separated (a closelyeluting compound is preferable) should be prescribed. Inaddition, if necessary, the symmetry factor of the test ingredientshould be prescribed together with them. However, if there is nosuitable target substance to be separated, it is acceptable todefine “System performance” using the number of theoreticalplates and the symmetry factor of the test ingredient.(3) System repeatabilityWhen it is confirmed that the degree of variation (precision)of the response of the test ingredient is at a level that meets therequirement of “System repeatability”, it is considered verifiedthat the system used has adequate performance to achieve itsintended use.The allowable limit of “System repeatability” is normallydefined as the relative standard deviation (RSD) of the responseof the test ingredient in replicate injections of standard solution.It is acceptable to confirm the repeatability of the system notonly by replicate injections of standard solution before sampleinjections, but also by divided injections of standard solutionbefore and after sample injections, or by interspersed injectionsof standard solution among sample injections.In principle, total number of replicate injections should be 6.However, in the case that a long time is necessary for oneanalysis, such as the analysis using the gradient method, or theanalysis of samples containing late eluting components, it maybe acceptable to decrease the number of replicate injections byadopting new allowable limit of “System repeatability” whichcan guarantee a level of “System repeatability” equivalent tothat at 6 replicate injections.The allowable limit of “System repeatability” should be set atan appropriate level based on the data when suitability of themethod for the evaluation of quality of the drug was verified,and the precision necessary for the quality test.

2046 General Tests, Process and Apparatus Supplement II, JP XV2.04 Amino Acid Analysisof ProteinsAmino acid analysis of proteins refers to the methodologyused to determine the amino acid composition or content ofproteins, peptides, and other pharmaceutical preparations.Amino acid analysis can be used to quantify protein andpeptides, to determine the identity of proteins or peptides basedon their amino acid composition, to support protein and peptidestructure analysis, to evaluate fragmentation strategies forpeptide mapping, and to detect atypical amino acids that mightbe present in a protein or peptide. It is necessary to hydrolyze aprotein/peptide to its individual amino acid constituents beforeamino acid analysis. Following protein/peptide hydrolysis, theamino acid analysis procedure can be the same as that practicedfor free amino acids in other pharmaceutical preparations. Theamino acid constituents of the test sample are typicallyderivatized for analysis.1. Hydrolysis of Protein and PeptideAcid hydrolysis at 110°C for 24 hours using 6 mol/Lhydrochloric acid containing phenol (Method 1) is the mostcommon method for hydrolyzing protein and samples. Theresult should be analyzed carefully because several amino acidsare chemically modified during the acid hydrolysis and thus notrecovered quantitatively. Tryptophan is destroyed; serine andthreonine are partially destroyed; methionine might undergooxidation; and cysteine is typically recovered as cystine (butcystine recovery is usually poor because of partial destruction orreduction to cysteine). Peptide bonds involving isoleucine andvaline are partially cleaved; and asparagine and glutamine aredeamidated, resulting in aspartic acid and glutamic acid,respectively.The hydrolysis techniques, Methods 2 to 11, are used toaddress these concerns. Some of the hydrolysis techniques,Methods 4 to 11, may cause modifications of cysteine,methionine, asparagines and glutamine to other amino acids.Therefore, the benefits of using a given hydrolysis technique areweighed against the concerns with the technique and are testedadequately before employing a method other than acidhydrolysis by Method 1.(i) Method 1: Hydrolysis using hydrochloric acidcontaining phenol (liquid phase hydrolysis, vapor phasehydrolysis)Prevention of tryptophan oxidation(ii) Method 2: Mercaptoethanesulfonic acid hydrolysis(vapor phase hydrolysis)(iii) Method 3: Hydrolysis using hydrochloric acidcontaining thioglycolic acid (vapor phase hydrolysis)Cysteine-cystine and methionine oxidation(iv) Method 4: Hydrolysis by Method 1 or Method 2 afteroxidation with performic acidCysteine-cystine oxidation(v) Method 5: Hydrolysis using hydrochloric acidcontaining sodium azide (liquid phase hydrolysis)(vi) Method 6: Hydrolysis using hydrochloric acidcontaining dimethylsulfoxide (vapor phase hydrolysis)Cysteine-cystine reduction and alkylation(vii) Method 7: Hydrochloric acid hydrolysis after a vaporphase pyridylethylation reaction(viii) Method 8: Hydrochloric acid hydrolysis after a liquidphase pyridylethylation reaction(ix) Method 9: Hydrochloric acid hydrolysis after a liquidphase carboxymethylation reactionConversion of cysteine-cystine to mixed disulfide(x) Method 10: Hydrochloric acid hydrolysis after areaction with dithiodiglycolic acid or dithiodipropionic acidConversion of asparagine and glutamine(xi) Method 11: Hydrochloric acid hydrolysis after reactionwith bis(1,1-trifuoroacetoxy) iodobenzeneA time-course study is often employed to analyze the startingconcentration of amino acids that are partially destroyed or slowto cleave. An acceptable alternative to the time-course study isto subject an amino acid calibration standard to the samehydrolysis conditions as the test sample. This technique willallow the analyst to account for some residue destruction.Microwave acid hydrolysis has been used and is rapid butrequires special equipment as well as special precautions.Complete proteolysis, using a mixture of proteases, has beenused but can be complicated, requires the proper controls, and istypically more applicable to peptides than proteins.2. Methodologies of Amino Acid AnalysisThe amino acid analysis techniques include the postcolumnderivatization for detection (Methods 1 to 2) after theseparation of the free amino acids by ion-exchangechromatography and the precolumn derivatization of the freeamino acids (Methods 2 to 7) followed by reversed-phaseHPLC.(i) Method l: Ninhydrin(ii) Method 2: o-Phthalaldehyde (OPA)(iii) Method 3: Phenylisothiocyanate (PITC)(iv) Method 4: 6-Aminoquinolyl-N-hydroxysuccinimidylcarbamate (AQC)(v) Method 5: (Dimethylamino)azobenzenesulfonylchloride (DABS-Cl)(vi) Method 6: 9-Fluorenylmethyl chloroformate(FMOC-Cl)(vii) Method 7: 7-Fluoro-4-nitrobenzo-2-oxa-1,3-diazole(NBD-F)Among these methods, ion-exchange chromatography withpostcolumn ninhydrin derivertization is one of the most commonmethods employed for quantitative amino acid analysis.The choice of any one technique often depends on the sensitivityrequired from the assay. Instruments and reagents for theseprocedures are available commercially. Furthermore, manymodifications of these methodologies exist with different reagentpreparations, reaction procedures, chromatographic sys-

Supplement II, JP XV General Tests, Process and Apparatus 2047tems, etc. Specific parameters may vary according to the exactequipment and procedure used.3.01 Determination of Bulkand Tapped DensitiesChange to read:This determination is harmonized with the EuropeanPharmacopoeia and the U.S. Pharmacopeia. The parts of the textthat are not harmonized are marked with symbols ( ◆ ◆).◆ Determination of Bulk and Tapped Densities is a method todetermine the bulk densities of powdered drugs under loose andtapped packing conditions respectively. Loose packing isdefined as the state obtained by pouring a powder sample into avessel without any consolidation, and tapped packing is definedas the state obtained when the vessel containing the powdersample is to be repeatedly dropped a specified distance at aconstant drop rate until the apparent volume of sample in thevessel becomes almost constant. ◆Bulk densityThe bulk density of a powder is the ratio of the mass of anuntapped powder sample and its volume including thecontribution of the interparticulate void volume. Hence, the bulkdensity depends on both the density of powder particles and thespatial arrangement of particles in the powder bed. The bulkdensity is expressed in grams per milliliter (g/mL) although theinternational unit is kilogram per cubic meter (1 g/mL = 1000kg/m 3 ) because the measurements are made using cylinders. Itmay also be expressed in grams per cubic centimeter (g/cm 3 ).The bulking properties of a powder are dependent upon thepreparation, treatment and storage of the sample, i.e. how it washandled. The particles can be packed to have a range of bulkdensities and, moreover, the slightest disturbance of the powderbed may result in a changed bulk density. Thus, the bulk densityof a powder is often very difficult to measure with goodreproducibility and, in reporting the results, it is essential tospecify how the determination was made.The bulk density of a powder is determined by measuring thevolume of a known mass of powder sample, that may have beenpassed through a screen, into a graduated cylinder (Method 1),or by measuring the mass of a known volume of powder that hasbeen passed through a volumeter into a cup (Method 2) or ameasuring vessel (Method 3). Method 1 and Method 3 arefavoured.Method 1: Measurement in a Graduated CylinderProcedurePass a quantity of powder sufficient to complete the testthrough a sieve with apertures greater than or equal to 1.0 mm,if necessary, to break up agglomerates that may have formedduring storage; this must be done gently to avoid changing thenature of the material. Into a dry graduated cylinder of 250 mL(readable to 2 mL), gently introduce, without compacting, approximately100 g of the test sample (m) weighed with 0.1 percent accuracy. Carefully level the powder without compacting,if necessary, and read the unsettled apparent volume (V 0 ) to thenearest graduated unit. Calculate the bulk density in g per mL bythe formula m/V 0 . Generally, replicate determinations are desirablefor the determination of this property.If the powder density is too low or too high, such that the testsample has an untapped apparent volume of either more than250 mL or less than 150 mL, it is not possible to use 100 g ofpowder sample. Therefore, a different amount of powder has tobe selected as test sample, such that its untapped apparentvolume is 150 mL to 250 mL (apparent volume greater than orequal to 60 per cent of the total volume of the cylinder); themass of the test sample is specified in the expression of results.For test samples having an apparent volume between 50 mLand 100 mL a 100 mL cylinder readable to 1 mL can be used;the volume of the cylinder is specified in the expression ofresults.Method 2: Measurement in a VolumeterApparatusThe apparatus (1) (Fig. 3.01-1) consists of a top funnel fittedwith a 1.0 mm sieve. The funnel is mounted over a baffle boxcontaining four glass baffle plates over which the powder slidesand bounces as it passes. At the bottom of the baffle box is afunnel that collects the powder and allows it to pour into a cupmounted directly below it. The cup may be cylindrical (25.00 ±0.05 mL volume with an inside diameter of 30.00 ± 2.00 mm) ora square (16.39 ± 2.00 mL volume with inside dimensions of25.4 ± 0.076 mm).1.0 mm sievePowder funnelLoading funnelBaffle assemblyGlass bafflesSample receiving cupFig. 3.01-1VolumeterStandProcedureAllow an excess of powder to flow through the apparatus intothe sample receiving cup until it overflows, using a minimum of25 cm 3 of powder with the square cup and 35 cm 3 of powderwith the cylindrical cup. Carefully, scrape excess powder fromthe top of the cup by smoothly moving the edge of the blade ofspatula perpendicular to and in contact with the top surface ofthe cup, taking care to keep the spatula perpendicular to preventpacking or removal of powder from the cup. Remove any materialfrom the side of the cup and determine the mass (m) of thepowder to the nearest 0.1 per cent. Calculate the bulk density in

2048 General Tests, Process and Apparatus Supplement II, JP XVg per mL by the formula m/V 0 in which V 0 is the volume of thecup and record the average of 3 determinations using 3 differentpowder samples.(1)The apparatus (the Scott Volumeter) conforms to thedimensions in ASTM 329 90.Method 1ApparatusThe apparatus (Fig. 3.01-3) consists of the following:– a 250 mL graduated cylinder (readable to 2 mL) with amass of 220 ± 44 g.– a settling apparatus capable of producing, in 1 min, eithernominally 250 ± 15 taps from a height of 3 ± 0.2 mm, or nominally300 ± 15 taps from a height of 14 ± 2 mm. The support forthe graduated cylinder, with its holder, has a mass of 450 ± 10 g.Method 3: Measurement in a VesselApparatusThe apparatus consists of a 100 mL cylindrical vessel ofstainless steel with dimensions as specified in Fig. 3.01-2.GraduatedcylinderCylindersupportGraduated part 250 mLnot less than 200 mmTotal heightnot more than 335 mmFig. 3.01-2. Measuring vessel (left) and cap (right)Dimensions in mmProcedurePass a quantity of powder sufficient to complete the testthrough a 1.0 mm sieve, if necessary, to break up agglomeratesthat may have formed during storage and allow the obtainedsample to flow freely into the measuring vessel until itoverflows. Carefully scrape the excess powder from the top ofthe vessel as described for Method 2. Determine the mass (m 0 )of the powder to the nearest 0.1 per cent by subtraction of thepreviously determined mass of the empty measuring vessel.Calculate the bulk density (g/mL) by the formula m 0 /100 andrecord the average of 3 determinations using 3 different powdersamples.Tapped DensityThe tapped density is an increased bulk density attained aftermechanically tapping a container containing the powder sample.The tapped density is obtained by mechanically tapping agraduated measuring cylinder or vessel containing the powdersample. After observing the initial powder volume or mass, themeasuring cylinder or vessel is mechanically tapped, andvolume or mass readings are taken until little further volume ormass change is observed. The mechanical tapping is achievedby raising the cylinder or vessel and allowing it to drop, underits own mass, a specified distance by either of 3 methods asdescribed below. Devices that rotate the cylinder or vesselduring tapping may be preferred to minimize any possibleseparation of the mass during tapping down.AnvilCamFig. 3.01-3.This dimension issuch that the drop1 meets specificationsand that, at thelowest point of thecam, the cylindersupport is sittingfreely on the upperpart of the anvil.ProcedureProceed as described above for the determination of the bulkvolume (V 0 ).Secure the cylinder in the holder. Carry out 10, 500 and 1250taps on the same powder sample and read the correspondingvolumes V 10 , V 500 and V 1250 to the nearest graduated unit. If thedifference between V 500 and V 1250 is less than 2 mL, V 1250 is thetapped volume. If the difference between V 500 and V 1250 exceeds2 mL, repeat in increments such as 1250 taps, until thedifference between succeeding measurements is less than 2 mL.Fewer taps may be appropriate for some powders, whenvalidated. Calculate the tapped density (g/mL) using the formulam/V f in which V f is the final tapped volume. Generally, replicatedeterminations are desirable for the determination of thisproperty. Specify the drop height with the results.If it is not possible to use a 100 g test sample, use a reducedamount and a suitable 100 mL graduated cylinder (readable to 1mL) weighing 130 ± 16 g and mounted on a holder weighing240 ± 12 g. The modified test conditions are specified in theexpression of the results.Method 2ProcedureProceed as directed under Method 1 except that themechanical tester provides a fixed drop of 3 ± 0.2 mm at anominal rate of 250 taps per minute.Method 3ProcedureProceed as described in the method for measuring the bulk

Supplement II, JP XV General Tests, Process and Apparatus 2049density using the measuring vessel equipped with the cap shownin Fig. 3.01-2. The measuring vessel with the cap is lifted 50-60times per minute by the use of a suitable tapped density tester.Carry out 200 taps, remove the cap and carefully scrape excesspowder from the top of the measuring vessel as described inMethod 3 for measuring the bulk density. Repeat the procedureusing 400 taps. If the difference between the 2 masses obtainedafter 200 and 400 taps exceeds 2 per cent, carry out a test using200 additional taps until the difference between succeedingmeasurements is less than 2 per cent. Calculate the tapped density(g/mL) using the formula m f /100 where m f is the mass ofpowder in the measuring vessel. Record the average of 3 determinationsusing 3 different powder samples.Measures of Powder CompressibilityBecause the interparticulate interactions influencing thebulking properties of a powder are also the interactions thatinterfere with powder flow, a comparison of the bulk and tappeddensities can give a measure of the relative importance of theseinteractions in a given powder. Such a comparison is often usedas an index of the ability of the powder to flow, for example theCompressibility Index or the Hausner Ratio.The Compressibility Index and Hausner Ratio are measuresof the propensity of a powder to be compressed as describedabove. As such, they are measures of the powder ability to settleand they permit an assessment of the relative importance ofinterparticulate interactions. In a free-flowing powder, suchinteractions are less significant, and the bulk and tappeddensities will be closer in value. For poorer flowing materials,there are frequently greater interparticulate interactions, and agreater difference between the bulk and tapped densities will beobserved. These differences are reflected in the CompressibilityIndex and the Hausner Ratio.Compressibility Index:V 0 : unsettled apparent volumeV f : final tapped volumeHauser Ratio:100 (V 0 – V f )/V 0V 0 /V fDepending on the material, the compressibility index can bedetermined using V 10 instead of V 0 .3.02 Specific Surface Areaby Gas AdsorptionChange to read:This test is harmonized with the European Pharmacopoeiaand the U.S. Pharmacopoeia. The parts of the text that are notharmonized are marked with symbols ( ◆ ◆).◆ The specific surface area determination method is a methodto determine specific surface area (the total surface area ofpowder per unit mass) of a pharmaceutical powder sample byusing gas adsorption method. ◆ The specific surface area of apowder is determined by physical adsorption of a gas on thesurface of the solid and by calculating the amount of adsorbategas corresponding to a monomolecular layer on the surface.Physical adsorption results from relatively weak forces (van derWaals forces) between the adsorbate gas molecules and the adsorbentsurface of the test powder. The determination is usuallycarried out at the temperature of liquid nitrogen The amount ofgas adsorbed can be measured by a volumetric or continuousflow procedure.1.1 MULTI-POINT MEASUREMENTWhen the gas is physically adsorbed by the powder sample,the following relationship (Brunauer, Emmett and Teller (BET)adsorption isotherm) holds when the relative pressure (P/P 0 ) isin the range of 0.05 to 0.30 for pressure P of the adsorbate gasin equilibrium for the volume of gas adsorbed, V a .1/[V a {(P 0 /P) – 1}] = {(C – 1)/(V m C)} × (P/P 0 ) + 1/(V m C) (1)P: Partial vapour pressure of adsorbate gas in equilibriumwith the surface at -195.8ºC (b.p. of liquid nitrogen), in pascals,P 0 : Saturated pressure of adsorbate gas, in pascals,V a : Volume of gas adsorbed at standard temperature andpressure (STP) [0ºC and atmospheric pressure (1.013 × 10 5 Pa),in milliliters,V m : Volume of gas adsorbed at STP to produce an apparentmonolayer on the sample surface, in milliliters,C: Dimensionless constant that is related to the enthalpy ofadsorption of the adsorbate gas on the powder sample.A value of V a is measured at each of not less than 3 values ofP/P 0 . Then the BET value, 1/[V a {(P 0 /P) – 1}], is plotted againstP/P 0 according to equation (1). This plot should yield a straightline usually in the approximate relative pressure range 0.05 to0.3. The data are considered acceptable if the correlationcoefficient, r, of the linear regression is not less than 0.9975;that is, r 2 is not less than 0.995. From the resulting linear plot,the slope, which is equal to (C – 1)/(V m C), and the intercept,which is equal to 1/(V m C), are evaluated by linear regressionanalysis. From these values, V m is calculated as 1/(slope +intercept), while C is calculated as (slope/intercept) + 1. Fromthe value of V m so determined, the specific surface area, S, inm 2 g -1 , is calculated by the equation:S = (V m Na) / (m × 22400) (2)N: Avogadro constant (6.022 × 10 23 mol -1 ),a: Effective cross-sectional area of one adsorbate molecule, insquare metres (0.162 × 10 -18 m 2 for nitrogen and 0.195 × 10 -18m 2 for krypton),m: Mass of test powder, in grams,22400: Volume, in milliliters, occupied by one mole of theadsorbate gas at STP allowing for minor departures from theideal.A minimum of 3 data points is required. Additional measurementsmay be carried out, especially when non-linearity is ob-

2050 General Tests, Process and Apparatus Supplement II, JP XVtained at a P/P 0 value close to 0.3. Because non-linearity is oftenobtained at a P/P 0 value below 0.05, values in this region arenot recommended. The test for linearity, the treatment of thedata, and the calculation of the specific surface area of the sampleare described above.1.2 SINGLE-POINT MEASUREMENTNormally, at least 3 measurements of V a each at differentvalues of P/P 0 are required for the determination of specificsurface area by the dynamic flow gas adsorption technique(Method I) or by volumetric gas adsorption (Method II). However,under certain circumstances described below, it may beacceptable to determine the specific surface area of a powderfrom a single value of V a measured at a single value of P/P 0such as 0.300 (corresponding to 0.300 mole of nitrogen or0.001038 mole fraction of krypton), using the following equationfor calculating V m :V m = V a {1-(P/P 0 )} (3)The single-point method may be employed directly for a seriesof powder samples of a given material for which the materialconstant C is much greater than unity. These circumstancesmay be verified by comparing values of specific surface areadetermined by the single-point method with that determined bythe multiple-point method for the series of powder samples.Close similarity between the single-point values and multiple-pointvalues suggests that 1/C approaches zero. The single-pointmethod may be employed indirectly for a series ofvery similar powder samples of a given material for which thematerial constant C is not infinite but may be assumed to be invariant.Under these circumstances, the error associated with thesingle-point method can be reduced or eliminated by using themultiple-point method to evaluate C for one of the samples ofthe series from the BET plot, from which C is calculated as (1 +slope/intercept). Then V m is calculated from the single value ofV a measured at a single value of P/P 0 by the equation:V m = V a {(P 0 /P) – 1}[(1/C) + {(C – 1)/C} × (P/P 0 )] (4)2. SAMPLE PREPARATIONBefore the specific surface area of the sample can be determined,it is necessary to remove gases and vapors that may havebecome physically adsorbed onto the surface during storage andhandling. If outgassing is not achieved, the specific surface areamay be reduced or may be variable because some parts of surfacearea are covered with molecules of the previously adsorbedgases or vapors. The outgassing conditions are critical for obtainingthe required precision and accuracy of specific surfacearea measurements on pharmaceuticals because of the sensitivityof the surface of the materials. The outgassing conditionsmust be demonstrated to yield reproducible BET plots, a constantweight of test powder, and no detectable physical orchemical changes in the test powder.The outgassing conditions defined by the temperature, pressureand time should be so chosen that the original surface ofthe solid is reproduced as closely as possible.Outgassing of many substances is often achieved by applyinga vacuum, by purging the sample in a flowing stream of anon-reactive, dry gas, or by applying a desorption-adsorptioncycling method. In either case, elevated temperatures are sometimesapplied to increase the rate at which the contaminantsleave the surface. Caution should be exercised when outgassingpowder samples using elevated temperatures to avoid affectingthe nature of the surface and the integrity of the sample.If heating is employed, the recommended temperature andtime of outgassing are as low as possible to achieve reproduciblemeasurement of specific surface area in an acceptable time.For outgassing sensitive samples, other outgassing methodssuch as the desorption-adsorption cycling method may be employed.The standard technique is the adsorption of nitrogen at liquidnitrogen temperature.For powders of low specific surface area (

Supplement II, JP XV General Tests, Process and Apparatus 2051the desorption peak and obtain the proportion of gas volume perunit peak area.Use a nitrogen/helium mixture for a single-point determinationand several such mixtures or premixing 2 streams of gas fora multiple-point determination. Calculation is essentially thesame as for the volumetric method.A: Flow control valveB: Differential flow controllerC: On-off valveD: Gas inletE: O ring sealsF: Cold trapG: Thermal equilibration tubeH: DetectorI: Digital displayJ: Calibrating septumK: Sample cellL: Self seals quick connectionM: Short path ballastN: DetectorO: Path selection valveP: Long path ballastQ: Flow meterR: Outgassing stationS: Diffusion baffleT: VentFig. 3.02-1Schematic diagram of the dynamic flowmethod apparatus3.2 Method II: the volumetric methodIn the volumetric method (see Fig. 3.02-2), the recommendedadsorbate gas is nitrogen which is admitted into the evacuatedspace above the previously outgassed powder sample to give adefined equilibrium pressure, P, of the gas. The use of a diluentgas, such as helium, is therefore unnecessary, although heliummay be employed for other purposes, such as to measure thedead volume.Since only pure adsorbate gas, instead of a gas mixture, isemployed, interfering effects of thermal diffusion are avoided inthis method.Admit a small amount of dry nitrogen into the sample tube toprevent contamination of the clean surface, remove the sampletube, insert the stopper, and weigh it. Calculate the weight of thesample. Attach the sample tube to the volumetric apparatus.Cautiously evacuate the sample down to the specified pressure(e.g. between 2 Pa and 10 Pa). Alternately, some instrumentsoperate by evacuating to a defined rate of pressure change (e.g.less than 13 Pa/30 s) and holding for a defined period of timebefore commencing the next step.If the principle of operation of the instrument requires the determinationof the dead volume in the sample tube, for example,by the admission of a non-adsorbed gas, such as helium, thisprocedure is carried out at this point, followed by evacuation ofthe sample. The determination of dead volume may be avoidedusing difference measurements, that is, by means of referenceand sample tubes connected by a differential transducer.Raise a Dewar vessel containing liquid nitrogen at -195.8ºCup to a defined point on the sample cell. Admit a sufficientvolume of adsorbate gas to give the lowest desired relativepressure. Measure the volume adsorbed, V a . For multipointmeasurements, repeat the measurement of V a at successivelyhigher P/P 0 values. When nitrogen is used as the adsorbate gas,P/P 0 values of 0.10, 0.20, and 0.30 are often suitable.A: Vacuum gaugeB: Nitrogen reservoirC: Helium reservoirD: Vapour pressure manometerE: Vacuum airF : To cold traps and vacuum pumpsFig. 3.02-2Schematic diagram of the volumetric methodapparatus4. REFERENCE MATERIALSPeriodically verify the functioning of the apparatus using appropriatereference materials of known surface area, such asα-alumina for specific surface area determination, which shouldhave a specific surface area similar to that of the sample to beexamined.

Supplement II, JP XV General Tests, Process and Apparatus 2053to within 0.2%, and calculate the mean of sample volumes (V s ).Finally, unload the test cell, weigh the mass of the test cell, andcalculate the final sample mass (m) by deducting the empty cellmass from the test cell mass. The powder particle density ρ iscalculated by the following equation:ρ = m/V sρ: Powder particle density in g/cm 3 ,m: Final sample mass in g,V s : Sample volume in cm 3If the pycnometer differs in operation or construction fromthe one shown in Fig. 3.03-1, follow the instructions of themanufacturer of the pycnometer. The sample conditioning is indicatedwith the results. For example, indicate whether the samplewas tested as is or dried under specific conditions such asthose described for loss on drying.3.04 Particle Size DeterminationChange the Method 2 to read:Method 2. Analytical Sieving Method◆ The analytical sieving method is a method to estimate theparticle size distribution of powdered pharmaceutical drugs bysieving. The particle size determined by this method is shown asthe size of a minimum sieve opening through which the particlepasses. “Powder” here means a gathering of numerous solidparticles. ◆Sieving is one of the oldest methods of classifying powdersand granules by particle size distribution. When using a wovensieve cloth, the sieving will essentially sort the particles by theirintermediate size dimension (i.e., breadth or width). Mechanicalsieving is most suitable where the majority of the particles arelarger than about 75 µm. For smaller particles, the light weightprovides insufficient force during sieving to overcome the surfaceforces of cohesion and adhesion that cause the particles tostick to each other and to the sieve, and thus cause particles thatwould be expected to pass through the sieve to be retained. Forsuch materials other means of agitation such as air-jet sieving orsonic sifting may be more appropriate. Nevertheless, sieving cansometimes be used for some powders or granules having medianparticle sizes smaller than 75 µm where the method can be validated.In pharmaceutical terms, sieving is usually the method ofchoice for classification of the coarser grades of single powdersor granules. It is a particularly attractive method in that powdersand granules are classified only on the basis of particle size, andin most cases the analysis can be carried out in the dry state.Among the limitations of sieving method are the need for anappreciable amount of sample (normally at least 25 g, dependingon the density of the powder or granule, and the diameter oftest sieves) and difficulty in sieving oily or other cohesive powdersor granules that tend to clog the sieve openings. Themethod is essentially a two-dimensional estimate of size becausepassage through the sieve aperture is frequently more dependenton maximum width and thickness than on length.This method is intended for estimation of the total particlesize distribution of a single material. It is not intended for determinationof the proportion of particles passing or retained onone or two sieves.Estimate the particle size distribution as described under DrySieving Method, unless otherwise specified in the individualmonograph. Where difficulty is experienced in reaching theendpoint (i.e., material does not readily pass through the sieves)or when it is necessary to use the finer end of the sieving range(below 75 µm), serious consideration should be given to the useof an alternative particle-sizing method.Sieving should be carried out under conditions that do notcause the test sample to gain or lose moisture. The relative humidityof the environment in which the sieving is carried outshould be controlled to prevent moisture uptake or loss by thesample. In the absence of evidence to the contrary, analyticaltest sieving is normally carried at ambient humidity. Any specialconditions that apply to a particular material should be detailedin the individual monograph.Principles of Analytical Sieving—Analytical test sieves areconstructed from a woven-wire mesh, which is of simple weavethat is assumed to give nearly square apertures and is sealed intothe base of an open cylindrical container. The basic analyticalmethod involves stacking the sieves on top of one another inascending degrees of coarseness, and then placing the test powderon the top sieve.The nest of sieves is subjected to a standardized period ofagitation, and then the weight of material retained on each sieveis accurately determined. The test gives the weight percentageof powder in each sieve size range.This sieving process for estimating the particle size distributionof a single pharmaceutical powder is generally intended foruse where at least 80% of the particles are larger than 75 µm.The size parameter involved in determining particle size distributionby analytical sieving is the length of the size of theminimum square aperture through which the particle will pass.TEST SIEVESTest sieves suitable for pharmacopoeial tests conform to themost current edition of International Organisation for Standardization(ISO) Specification ISO 3310-1; Testsieves—Technical requirements and testing (see Table 3.04-1).Unless otherwise specified in the monograph, use those ISOsieves listed in the Table 3.04-1 as recommended in the particularregion.Sieves are selected to cover the entire range of particle sizespresent in the test specimen. A nest of sieves having a 2 progressionof the area of the sieve openings is recommended. Thenest of sieves is assembled with the coarsest screen at the topand the finest at the bottom. Use micrometers or millimeters indenoting test sieve openings. [Note—Mesh numbers are providedin the table for conversion purposes only.] Test sieves aremade from stainless steel or, less preferably, from brass or othersuitable non-reactive wire.Calibration and recalibration of test sieves is in accordancewith the most current edition of ISO 3310-1 2) . Sieves should becarefully examined for gross distortions and fractures, especiallyat their screen frame joints, before use. Sieves may be calibrated

2054 General Tests, Process and Apparatus Supplement II, JP XVoptically to estimate the average opening size, and openingvariability, of the sieve mesh. Alternatively, for the evaluation ofthe effective opening of test sieves in the size range of 212 to850 µm, Standard Glass Spheres are available. Unless otherwisespecified in the individual monograph, perform the sieve analysisat controlled room temperature and at ambient relative humidity.Cleaning Test Sieves—Ideally, test sieves should be cleanedusing only an air jet or a liquid stream. If some apertures remainblocked by test particles, careful gentle brushing may be used asa last resort.Test Specimen—If the test specimen weight is not given in themonograph for a particular material, use a test specimen havinga weight between 25 and 100 g, depending on the bulk densityof the material, and test sieves having a 200 mm diameter. For76 mm sieves the amount of material that can be accommodatedis approximately 1/7 th that which can be accommodated on a200 mm sieve. Determine the most appropriate weight for agiven material by test sieving accurately weighed specimens ofdifferent weights, such as 25, 50, and 100 g, for the same timeperiod on a mechanical shaker. [Note—If the test results aresimilar for the 25-g and 50-g specimens, but the 100-g specimenshows a lower percentage through the finest sieve, the 100-gspecimen size is too large.] Where only a specimen of 10 to 25 gis available, smaller diameter test sieves conforming to the samemesh specifications may be substituted, but the endpoint mustbe re-determined. The use of test samples having a smaller mass(e.g. down to 5 g) may be needed. For materials with low apparentparticle density, or for materials mainly comprising particleswith a highly iso-diametrical shape, specimen weights below5 g for a 200 mm screen may be necessary to avoid excessiveblocking of the sieve. During validation of a particularsieve analysis method, it is expected that the problem of sieveblocking will have been addressed.If the test material is prone to picking up or losing significantamounts of water with varying humidity, the test must be carriedout in an appropriately controlled environment. Similarly, if thetest material is known to develop an electrostatic charge, carefulobservation must be made to ensure that such charging is not influencingthe analysis. An antistatic agent, such as colloidalsilicon dioxide and/or aluminum oxide, may be added at a 0.5percent (m/m) level to minimize this effect. If both of the aboveeffects cannot be eliminated, an alternative particle-sizing techniquemust be selected.Agitation Methods—Several different sieve and powder agitationdevices are commercially available, all of which may beused to perform sieve analyses. However, the different methodsof agitation may give different results for sieve analyses andendpoint determinations because of the different types and magnitudeof the forces acting on the individual particles under test.Methods using mechanical agitation or electromagnetic agitation,and that can induce either a vertical oscillation or a horizontalcircular motion, or tapping or a combination of both tappingand horizontal circular motion are available. Entrainmentof the particles in an air stream may also be used. The resultsmust indicate which agitation method was used and the agitationparameters used (if they can be varied), since changes in theagitation conditions will give different results for the sieveanalysis and endpoint determinations, and may be sufficientlydifferent to give a failing result under some circumstances.Endpoint Determination—The test sieving analysis is completewhen the weight on any of the test sieves does not changeby more than 5% or 0.1 g (10% in the case of 76 mm sieves) ofthe previous weight on that sieve. If less than 5% of the totalspecimen weight is present on a given sieve, the endpoint forthat sieve is increased to a weight change of not more than 20%of the previous weight on that sieve.If more than 50% of the total specimen weight is found onany one sieve, unless this is indicated in the monograph, the testshould be repeated, but with the addition to the sieve nest of amore coarse sieve intermediate between that carrying the excessiveweight and the next coarsest sieve in the original nest, i.e.,addition of the ISO series sieve omitted from the nest of sieves.SIEVING METHODSMechanical agitationDry Sieving Method—Tare each test sieve to the nearest 0.1g. Place an accurately weighed quantity of test specimen on thetop (coarsest) sieve, and place the lid. Agitate the nest of sievesfor 5 minutes. Then carefully remove each from the nest withoutloss of material. Reweigh each sieve, and determine the weightof material on each sieve. Determine the weight of material inthe collecting pan in a similar manner. Reassemble the nest ofsieves, and agitate for 5 minutes. Remove and weigh each sieveas previously described. Repeat these steps until the endpointcriteria are met (see Endpoint Determination under Test Sieves).Upon completion of the analysis, reconcile the weights of material.Total losses must not exceed 5% of the weight of the originaltest specimen.Repeat the analysis with a fresh specimen, but using a singlesieving time equal to that of the combined times used above.Confirm that this sieving time conforms to the requirements forendpoint determination. When this endpoint had been validatedfor a specific material, then a single fixed time of sieving maybe used for future analyses, providing the particle size distributionfalls within normal variation.If there is evidence that the particles retained on any sieve areaggregates rather than single particles, the use of mechanical drysieving is unlikely to give good reproducibility, a different particlesize analysis method should be used.Air Entrainment MethodsAir Jet and Sonic Sifter Sieving—Different types of commercialequipment that use a moving air current are available forsieving. A system that uses a single sieve at a time is referred toas air jet sieving. It uses the same general sieving methodologyas that described under the Dry Sieving Method, but with astandardized air jet replacing the normal agitation mechanism. Itrequires sequential analyses on individual sieves starting withthe finest sieve to obtain a particle size distribution. Air jetsieving often includes the use of finer test sieves than used inordinary dry sieving. This technique is more suitable where onlyoversize or undersize fractions are needed.In the sonic sifting method, a nest of sieves is used, and thetest specimen is carried in a vertically oscillating column of air

Supplement II, JP XV General Tests, Process and Apparatus 2055that lifts the specimen and then carries it back against the meshopenings at a given number of pulses per minute. It may benecessary to lower the sample amount to 5 g, when sonic siftingis employed.The air jet sieving and sonic sieving methods may be usefulfor powders or granules when mechanical sieving techniques areincapable of giving a meaningful analysis.These methods are highly dependent upon proper dispersionof the powder in the air current. This requirement may be hardto achieve if the method is used at the lower end of the sievingrange (i.e., below 75 µm), when the particles tend to be morecohesive, and especially if there is any tendency for the materialto develop an electrostatic charge. For the above reasons endpointdetermination is particularly critical, and it is very importantto confirm that the oversize material comprises single particlesand is not composed of aggregates.INTERPRETATIONThe raw data must include the weight of test specimen, thetotal sieving time, and the precise sieving methodology and theset values for any variable parameters, in addition to the weightsretained on the individual sieves and in the pan. It may be convenientto convert the raw data into a cumulative weight distribution,and if it is desired to express the distribution in terms ofa cumulative weight undersize, the range of sieves used shouldinclude a sieve through which all the material passes. If there isevidence on any of the test sieves that the material remaining onit is composed of aggregates formed during the sieving process,the analysis is invalid.1) Additional information on particle size measurement, samplesize, and data analysis is available, for example, in ISO9276.2) International Organization for Standardization (ISO) SpecificationISO 3310-1; Test sieves-Technical requirements andtesting

2056 General Tests, Process and Apparatus Supplement II, JP XVTable 3.04-1. Sizes of Standard Sieve Series in Range of InterestISO Nominal AperturePrincipal sizesSupplementaryUS Sieve Recommended European Sieve JapansizesNo. USP Sieves (microns)No.Sieve No.R 20/3 R 20 40/3 R11.20 mm 11.20 mm 11.20 mm 1120010.00 mm9.50 mm9.00 mm8.00 mm 8.00 mm 8.00 mm7.10 mm6.70 mm6.30 mm5.60 mm 5.60 mm 5.60 mm 5600 3.55.00 mm4.75 mm 44.50 mm4.00 mm 4.00 mm 4.00 mm 5 4000 4000 4.73.55 mm3.35 mm 6 5.53.15 mm2.80 mm 2.80 mm 2.80 mm 7 2800 2800 6.52.50 mm2.36 mm 8 7.52.24 mm2.00 mm 2.00 mm 2.00 mm 10 2000 2000 8.61.80 mm1.70 mm 12 101.60 mm1.40 mm 1.40 mm 1.40 mm 14 1400 1400 121.25 mm1.18 mm 16 141.12 mm1.00 mm 1.00 mm 1.00 mm 18 1000 1000 16900 µm850 µm 20 18800 µm710 µm 710 µm 710 µm 25 710 710 22630 µm600 µm 30 26560 µm500 µm 500 µm 500 µm 35 500 500 30450 µm425 µm 40 36400 µm355 µm 355 µm 355 µm 45 355 355 42315 µm300 µm 50 50280 µm250 µm 250 µm 250 µm 60 250 250 60224 µm212 µm 70 70200 µm180 µm 180 µm 180 µm 80 180 180 83160 µm150 µm 100 100140 µm125 µm 125 µm 125 µm 120 125 125 119112 µm106 µm 140 140100 µm90 µm 90 µm 90 µm 170 90 90 16680 µm75 µm 200 20071 µm63 µm 63 µm 63 µm 230 63 63 23556 µm53 µm 270 28250 µm45 µm 45 µm 45 µm 325 45 45 33040 µm38 µm 38 391

Supplement II, JP XV General Tests, Process and Apparatus 20577.02 Test Methods forPlastic ContainersChange (11) under 2. Polyvinyl chloride containersfor aqueous injections to read:2. Polyvinyl chloride containers for aqueous injections(11) Vinyl chloride—Wash a cut piece of a container withwater, wipe thoroughly with a filter paper, subdivide into piecessmaller than 5-mm square, and place 1.0 g of them in a 20-mLvolumetric flask. Add about 10 mL of tetrahydrofuran for gaschromatography, dissolve by occasional shaking in a cold place,add tetrahydrofuran for gas chromatography, previously cooledin a methanol-dry ice bath, to make 20 mL while cooling in amethanol-dry ice bath, and use this solution as the sample solution.Perform the tests as directed under Gas Chromatography according to the operating conditions 1 and 2, using 10µL each of the sample solution and Standard Vinyl Chloride Solution.The peak height of vinyl chloride from the sample solutionis not more than that from the Standard Vinyl Chloride Solutionunder at least one of the conditions.Operating conditions 1—Detector: A hydrogen flame-ionization detector.Column: A column about 3 mm in inside diameter and 2 to 3m in length, packed with 150 to 180 µm siliceous earth for gaschromatography coated with 15% to 20% polyalkylene glycolmonoether for gas chromatography.Column temperature: A constant temperature of between 60ºCand 70ºC.Carrier gas: NitrogenFlow rate: Adjust the flow rate so that the retention time ofvinyl chloride is about 1.5 minutes.Selection of column: Proceed with 10 µL of Standard VinylChloride Solution under the above operating conditions. Use acolumn from which vinyl chloride and ethanol are eluted in thatorder, with a good resolution between their peaks.Detection sensitivity: Adjust the detection sensitivity so thatthe peak height from 10 µL of the Standard Vinyl Chloride Solutionis 5 to 7 mm.Operating conditions 2—Detector: A hydrogen flame-ionization detector.Column: A column about 3 mm in inside diameter and about1.5 m in length, packed with 150 to 180 µm porous acrylonitrile-divinylbenzenecopolymer for gas chromatography (poresize: 0.06-0.08 µm; 100-200 m 2 /g).Column temperature: A constant temperature of about 120ºC.Carrier gas: NitrogenFlow rate: Adjust the flow rate so that the retention time ofvinyl chloride is about 3 minutes.Selection of column: Proceed with 10 µL of Standard VinylChloride Solution under the above operating conditions. Use acolumn from which vinyl chloride and ethanol are eluted in thatorder, with a good resolution between their peaks.Detection sensitivity: Adjust the detection sensitivity so thatthe peak height from 10 µL of the Standard Vinyl Chloride Solutionis 5 to 7 mm.9.01 Reference StandardsChange the following in (1) to read:*A: AssayD: DissolutionI: IdentificationP: PurityU: Uniformity of dosage units(1) The reference standards which are prepared by those whohave been registered to prepare them by the Minister of Health,Labour and Welfare, according to the Ministerial ordinance establishedby the Minister separately.Reference StandardAmlodipine BesilateAzathioprineClomifene CitrateDiethylcarbamazine CitrateEthenzamideProbenecidProchlorperazine MaleateWarfarin PotassiumIntended Use*I, U, AI, U, AI, U, AU, AI, AI, U, D, AI, U, D, AI, U, D, AChange the following in (2) to read:(2) The reference standards which are prepared by National Instituteof Infectious Diseases.Reference StandardAmoxicillinCefalexinCefatrizine Propylene GlycolateCefiximeCefroxadineCefteram Pivoxil MesityleneSulfonateFaropenem SodiumGriseofulvinMinocycline HydrochloridePivmecillinam HydrochlorideIntended Use*I, D, AU, D, AI, D, AI, P, U, D, AI, U, D, AU, D, AI, P, U, D, AI, P, U, D, AI, P, U, D, AI, P, U, A

2058 General Tests, Process and Apparatus Supplement II, JP XVAdd the following to (1):Reference StandardAciclovirCalcitonin (Salmon)DanazolDiflucortolone ValerateDoxazosin MesilateFludrocortisone AcetateFlutamideGefarnateD-glucuronolactoneIndapamideIpriflavoneLosartan PotassiumPioglitazone HydrochloridePrazosin HydrochlorideProbucolSevofluraneSimvastatinTacrolimusTeprenoneTosufloxacin TosilateTroxipideAdd the following to (2):Reference StandardTazobactamIntended Use*I, AAI, AI, AI, AI, AI, AI, AAI, U, D, AI, AI, AI, AI, AI, AI, AI, AI, AI, AI, U, D, AI, U, D, AIntended Use*I, A9.41 Reagents, Test SolutionsChange the following to read:Benzoylmesaconine hydrochloride for thin-layer chromatographyC 31 H 43 NO 10·HCl·xH 2 O White crystals or crystallinepowder. Soluble in water and in ethanol (99.5) and sparinglysoluble in methanol. Melting point: about 250ºC (withdecomposition).1%Absorbance E 1cm (230 nm): 217 - 231 (5 mg calculatedon the anhydrous basis, methanol, 200 mL)Purity Related substances—Dissolve 1.0 mg of benzoylmesaconinehydrochloride for thin-layer chromatography in exactly1 mL of ethanol (99.5). Perform the test with 5 µL of thissolution as directed in the Identification under Processed AconiteRoot: no spot other than the principal spot at around R f 0.4appears.Bergenin for thin-layer chromatography C 14 H 16 O 9·xH 2 OWhite crystals or crystalline powder. Slightly soluble in ethanol(99.5), very slightly soluble in water, and practically insoluble indiethyl ether.Identification Determine the absorption spectrum of a solutionof bergenin for thin-layer chromatography in methanol (1 in50000) as directed under Ultraviolet-visible Spectrophotometry: it exhibits maxima between 217 nm and 221 nm, andbetween 273 nm, and 277 nm, and a minimum between 241nmand 245 nm.Purity Related substances—Dissolve 1.0 mg of bergenin forthin-layer chromatography in 1 mL of methanol. Perform thetest with 20 µL of this solution as directed in the Identificationunder Mallotus Bark: no spot other than the principal spot at theR f value of about 0.5 appears.(E)-Capsaicin for thin-layer chromatography C 18 H 27 NO 3White crystals, having a strong irritative odor. Very soluble inmethanol, freely soluble in ethanol (95) and in diethyl ether, andpractically insoluble in water.Melting point : 65-70ºC.Purity Related substances—Dissolve 20 mg of(E)-capsaicin for thin-layer chromatography in 2 mL of methanol,and use this solution as the sample solution. Pipet 1 mL ofthis solution, add methanol to make exactly 100 mL, and usethis solution as the standard solution. Perform the test with 10µL each of the sample solution and standard solution as directedin the Identification under Capsicum: any spot other than theprincipal spot at the R f value of about 0.5 from the sample solutionis not more intense than the spot from the standard solution.Add the following:Acemetacin C 21 H 18 ClNO 6 [Same as the namesake monograph]Acemetacin for assay C 21 H 18 ClNO 6 [Same as the monographAcemetacin. When died, it contains no less than 99.5% ofacemetacin (C 21 H 18 ClNO 6 ) meeting the following additionalspecifications.]Purity Dissolve 40 mg of acemetacin for assay in 10 mL ofmethanol, and use this solution as the sample solution. Pipet 1mL of this solution, and add methanol to make exactly 10 mL.Pipet 1 mL of this solution, add methanol to make exactly 20mL, and use this solution as the standard solution. Perform thetest with exactly 10 µL each of the sample solution and standardsolution as directed under Liquid Chromatography accordingto the following conditions. Determine each peak areaof both solutions by the automatic integration method: the areaof each peak other than acemetacin is not larger than 1/2 timesthe peak area of acemetacin obtained from the standard solution,and the total area of the peaks other than the peak of acemetacinis not larger than the peak area of acemetacin from the standardsolution.Operating conditionsDetector, column, column temperature, mobile phase, andflow rate: Proceed as directed in the operating conditions in theAssay under Acemetacin Tablets.Time span of measurement: About 4 times as long as the retentiontime of Acemetacin.System SuitabilityTest for required detectability: Pipet 1 mL of the standard solution,and add methanol to make exactly 20 mL. Confirm thatthe peak area of acemetacin obtained from 10 µL of this solutionis equivalent to 3 to 7% of that of acemetacin from the standardsolution.System performance: Dissolve 75 mg of acemetacin and 75

Supplement II, JP XV General Tests, Process and Apparatus 2059mg of indometacin in 50 mL of methanol. To 4 mL of this solutionadd 1 mL of a solution of hexyl parahydroxybenzoate inmethanol (1 in 250), and add methanol to make 50 mL. Whenthe procedure is run with 10 µL of this solution under the aboveoperating conditions, acemetacin, indometacin and hexyl parahydroxybenzoateare eluted in this order with the resolutionsbetween the peaks of acemetacin and indometacin and betweenthe peaks of indometacin and hexyl parahydroxybenzoate beingnot less than 3, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area ofacemetacin is not more than 1.5%.Acetic acid buffer solution containing 0.1% bovine serumalbumin Dissolve 0.1 g of bovine serum albumin in sodiumacetate trihydrate solution (1 in 100) to make exactly 100 mL,and adjust the pH to 4.0 with 1 mol/L hydrochloric acid TS.Acetic acid-sodium acetate TS, pH 7.0 Dissolve 4.53 g ofsodium acetate trihydrate in water to make 100 mL, and adjustthe pH to 7.0 with diluted acetic acid (100) (1 in 50).Achyranthes root for thin-layer chromatography Aheat-dried, pulverized root of Achyranthes fauriei Leveillé etVaniot (Amaranthaceae) meeting the following additionalspecifications.Identification (1) To 2 g of pulverized achyranthes root forthin-layer chromatography add 10 mL of water, shake for 10minutes, add 5 mL of 1-butanol, shake for 10 minutes, centrifuge,and use the supernatant liquid as the sample solution.Separately, dissolve 1 mg of chikusetsusaponin IV for thin-layerchromatography in 1 mL of methanol, and use this solution asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 10 µLeach of the sample solution and standard solution on a plate ofsilica gel for thin-layer chromatography. Develop the plate witha mixture of ethyl acetate, water and formic acid (5:1:1) to adistance of about 10 cm, and air-dry the plate. Spray evenly dilutesulfuric acid on the plate, and heat the plate at 105ºC for 10minutes: the standard solution shows a deep purplish red spot ataround R f 0.35, and the sample solution shows spots equivalentto those described below:R f valueAround 0Around 0.1Around 0.2Around 0.25Around 0.35Around 0.45Around 0.5Around 0.75Around 0.9Color and shape of the spotA weak spot, blackA weak spot, strong purplish redA weak, tailing spot, strong purplish redA strong spot, deep purplish redA leading spot, deep purplish redA weak spot, dull yellowA weak spot, grayish purplish redA weak spot, grayish redA weak spot, dull red(2) Perform the test as directed in the operating conditionsunder (1), except using a mixture of 1-propanol, ethyl acetateand water (4:4:3) as the developing solvent: the standard solutionshows a deep purplish red spot at around R f 0.45, and thesample solution shows spots equivalent to those described below:R f valueAround 0.25Around 0.25- 0.3Around 0.35Around 0.4Around 0.42Around 0.45Around 0.65Around 0.7Around 0.85Around 0.95Color and shape of the spotA weak spot, strongly purplish redA leading spot or two strong spots, stronglypurplish redA deep purplish red spotA weak spot, dull redA dark red spotA weak spot, grayish redA weak spot, dull greenish yellowA weak spot, grayish redA weak spot, grayish redA weak spot, dull yellow-redAconitum monoester alkaloids standard TS for componentdetermination Weigh accurately about 20 mg of benzoylmesaconinehydrochloride for component determination(separately, determine the water content), about 10 mg of benzoylhypaconinehydrochloride for component determination(separately, determine the water content) and about 20 mg of14-anisoylaconine hydrochloride for component determination(separately, determine the water content), dissolve in a mixtureof phosphate buffer solution for processed aconite root and tetrahydrofuran(183:17) to make exactly 1000 mL. Perform thetest with 20 µL of this solution as directed in the Purity underbenzoylmesaconine hydrochloride for component determination:the peaks of benzoylmesaconine, benzoylhypaconine and14-anisoylaconine appear with a peak area ratio of about 2:1:2.Alcian blue 8 GX C 56 H 68 Cl 14 CuN 16 S 4 Dark blue-purplepowder.Alcian blue staining solution Dissolve 0.5 g of alcian blue8 GX in 100 mL of diluted acetic acid (100) (3 in 100).C 5 H 4 N 4 O [Same as the namesake mono-Allopurinolgraph.]Allopurinol for assay C 5 H 4 N 4 O [Same as the monographAllopurinol. When dried, it contains not less than 99.0% of allopurinol(C 5 H 4 N 4 O).]Alkaline copper (II) TS Dissolve 20 g of anhydrous sodiumcarbonate in dilute sodium hydroxide TS to make 1000mL, and use this solution as solution A. Dissolve 0.5 g of copper(II) sulfate pentahydrate in potassium sodium tartarate tetrahydratesolution (1 in 100) to make 100 mL, and use this solutionas solution B. To 50 mL of solution A add 1 mL of solution B.Prepare before use.Alkaline phosphatase Obtained from bovine small intestine,a white to grayish white or yellow-brown, freeze-driedpowder having no odor.Alkaline phosphatase contains not less than 1 unit per mg andno salts. One unit of alkaline phosphatase indicates an amountof the enzyme which produces 1 µmol of 4-nitrophenol in 1

2060 General Tests, Process and Apparatus Supplement II, JP XVminute at 37ºC and pH 9.8, from 4-nitrophenylphosphate esterused as the substrate.Alkaline phosphatase TS Dissolve 0.1 g of alkaline phosphatasein 10 mL of boric acid-magnesium chloride buffer solution,pH 9.0. Prepare before use.6-Aminoquinolyl-N-hydroxysuccinimidyl carbamateC 14 H 11 N 3 O 4 Prepared for amino acid analysis or biochemistry.2-Aminobenzimidazole C 7 H 7 N 3 White to light yellowcrystals or crystalline powder. Melting point: about 231ºC (withdecomposition).Amiodarone hydrochloride for assay C 25 H 29 I 2 NO 3·HCl[Same as the monograph Amiodarone Hydrochloride. Whendried, it contains not less than 99.5% of amiodarone hydrochloride(C 25 H 29 I 2 NO 3·HCl).]14-Anisoylaconine hydrochloride for component determinationC 33 H 47 NO 11·HCl·xH 2 O White crystalline powderor powder. Freely soluble in methanol, sparingly soluble in waterand in ethanol (99.5). Melting point: about 210ºC (with decomposition).1%Absorbance E 1cm (258 nm): 276 - 294 (5 mg calculatedon the anhydrous basis, methanol, 200 mL).Purity (1) Related substances—To 1.0 mg of14-anisoylaconine hydrochloride for component determinationadd exactly 1 mL of ethanol (99.5). Perform the test with 5 µLof this solution as directed in the Identification under ProcessedAconite Root: no spot other than the principle spot at around R f0.5 appears.(2) Related substances—Dissolve 5.0 mg of14-anisoylaconine hydrochloride for component determinationin 5 mL of the mobile phase, and use this solution as the samplesolution. Pipet 1 mL of this solution, add the mobile phase tomake exactly 50 mL, and use this solution as the standard solution.Perform the test with exactly 20 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area of both solutions by the automatic integrationmethod: the total area of the peaks other than the peak of14-anisoylaconine obtained from the sample solution is not largerthan the peak area of 14-anisoylaconine from the standardsolution.Operating conditionsColumn, column temperature, mobile phase and flow rate:Proceed as directed in the operating conditions in the Assay (3)under Goshajinkigan Extract.Detector: An ultraviolet absorption photometer (wavelength:245 nm).Time span of measurement: About 4 times as long as the retentiontime of 14-anisoylaconine.System suitabilityTest for required detectability: Pipet 1 mL of the standard solution,and add the mobile phase to make exactly 20 mL. Confirmthat the peak area of 14-anisoylaconine obtained from 20µL of this solution is equivalent to 3.5 to 6.5% of that of14-anisoylaconine from 20 µL of the standard solution.System performance: When the procedure is run with 20 µLof aconitum monoester alkaloids standard solution for componentdetermination under the above operating conditions, benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine areeluted in this order with the resolution between these peaks beingnot less than 4.System repeatability: When the test is repeated 6 times with20 µL of aconitum monoester alkaloids standard solution forcomponent determination under the above operating conditions,the relative standard deviations of the peak areas of benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine are notmore than 1.5%, respectively.Aprindine hydrochloride for assay C 22 H 30 N 2·HCl[Same as the monograph Aprindine Hydrochloride. When dried,it contains not less than 99.5% of aprindine hydrochloride(C 22 H 30 N 2·HCl).]Anode solution A for water determination Dissolve 100 gof diethanolamine in 900 mL of a mixture of methanol for waterdetermination and chloroform for water determination (1:1),pass dried sulfur dioxide gas through this solution while coolinguntil the mass increase of the solution reaches 64 g. Then add 20g of iodine, and add water until the color of the solution changesfrom brown to yellow. To 600 mL of this solution add 400 mLof chloroform for water determination.(E)-Asarone C 12 H 16 O 3 White powder. Freely soluble inmethanol and in ethanol (99.5) and practically insoluble in water.Melting point: about 60ºCIdentification Determine the infrared absorption spectrumof (E)-asarone as directed in the potassium bromide disk methodunder Infrared Spectrophotometry , it exhibits absorptionat the wave numbers of about 2990 cm -1 , 2940 cm -1 , 2830 cm -1 ,1609 cm -1 , 1519 cm -1 , 1469 cm -1 , 1203 cm -1 , 1030 cm -1 , 970cm -1 and 860 cm -1 .Purity Related substances—Dissolve 2 mg of (E)-asarone in10 mL of methanol, and use this solution as the sample solution.Pipet 1 mL of this solution, add methanol to make exactly 10mL, and use this solution as the standard solution. Perform thetest with 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions. Determine each peak area of bothsolutions by the automatic integration method: the total area ofthe peaks other than the peak of (E)-asarone obtained from thesample solution is not larger than the peak area of (E)-asaronefrom the standard solution.Operating conditionsDetector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theComponent determination under Perilla Herb.Time span of measurement: About 3 times as long as the retentiontime of (E)-asarone beginning after the solvent peak.System suitabilitySystem performance: Proceed as directed in the system suitabilityin the Component determination under Perilla Herb.Azelastine hydrochloride for assayC 22 H 24 ClN 3 O·HCl

Supplement II, JP XV General Tests, Process and Apparatus 2061[Same as the monograph Azelastine Hydrochloride.]Benz[a]anthracene C 18 H 12 White to yellow crystallinepowder or powder. Practically insoluble in water, in methanoland in ethanol (99.5). Melting point: 158 - 163ºC.Identification Perform the test with benz[a]anthracene asdirected in the Purity: the mass spectrum of the main peakshows a molecular ion peak (m/z 228) and a fragment ion peak(m/z 114).Purity Related substances—Dissolve 3.0 mg ofbenz[a]anthracene in methanol to make 100 mL, and use thissolution as the sample solution. Perform the test with 1 µL ofthis solution as directed under Gas Chromatography , anddetermine each peak area by the automatic integration method.Calculate the amounts of these peaks by the area percentagemethod: the total amount of the peaks other thanbenz[a]anthracene is not more than 2.0%.Operating conditionsDetector: A mass spectrophotometer (EI)Mass scan range:15.00 - 300.00Time of measurement: 12 - 30 minutesColumn: A fused silica column 0.25 mm in inside diameterand 30 m in length, coated inside with 5% diphenyl-95% dimethylpolysiloxanefor gas chromatography in thickness of 0.25- 0.5 µm.Column temperature: Inject at a constant temperature of about45ºC, raise the temperature to 240ºC at a rate of 40ºC per minute,maintain at 240ºC for 5 minutes, raise to 300ºC at a rate of 4ºCper minute, raise to 320ºC at a rate of 10ºC pr minute, andmaintain at 320ºC for 3 minutes.Injection port temperature: At a constant temperature of about250ºC.Interface temperature: At a constant temperature of 300ºC.Carrier gas: HeliumFlow rate: Adjust the flow rate so that the retention time ofbenz[a]anthracene is about 15 minutes.Split ratio: SplitlessSystem suitabilityTest for required detectability: Pipet 1 mL of the sample solution,and add methanol to make exactly 10 mL. Confirm that thepeak area of benz[a]anthracene obtained from 1 µL of this solutionis equivalent to 5 to 15% of that of benz[a]anthracene fromthe standard solution.Benzo[a]pyrene C 20 H 12 Light yellow to green-yellowcrystalline powder or powder. Practically insoluble in water, inmethanol and in ethanol (99.5). Melting point: 176 - 181ºC.Identification Perform the test with benzo[a]pyrene as directedin the Purity: the mass spectrum of the main peak showsa molecular ion peak (m/z 252) and a fragment ion peak (m/z125).Purity Related substances―Dissolve 3.0 mg ofbenzo[a]pyrene in methanol to make 100 mL, and use this solutionas the sample solution. Perform the test with 1 µL of thissolution as directed under Gas Chromatography underthe following conditions, and determine each peak area by theautomatic integration method. Calculate the amounts of thesepeaks by the area percentage method: the total amount of thepeaks other than benzo[a]pyrene is not more than 3.0%.Operating conditionsDetector: A mass spectrophotometer (EI)Mass scan range: 15.00 - 300.00Time of measurement: 12 - 30 minutesColumn: A fused silica column 0.25 mm in inside diameterand 30 m in length, coated inside with 5% diphenyl-95% dimethylpolysiloxanefor gas chromatography in thickness of 0.25- 0.5 µm.Column temperature: Inject at a constant temperature of about45ºC, raise the temperature to 240ºC at a rate of 40ºC per minute,maintain at 240ºC for 5 minutes, raise to 300ºC at a rate of 4ºCper minute, raise to 320ºC at a rate of 10ºC per minute, andmaintain at 320ºC for 3 minutes.Injection port temperature: A constant temperature of about250ºC.Interface temperature: A constant temperature of about 300ºC.Carrier gas: Helium.Flow rate: Adjust the flow rate so that the retention time ofbenzo[a]pyrene is about 22 minutes.Split ratio: Splitless.System suitabilityTest for required detectability: Pipet 1 mL of the sample solution,add methanol to make exactly 10 mL. Confirm that thepeak area of benzo[a]pyrene obtained from 1 µL of this solutionis equivalent to 5 to 15% of that of benzo[a]pyrene from thesample solution.Benzoylhypaconine hydrochloride for component determinationC 31 H 43 NO 9·HCl·xH 2 O White crystals or crystallinepowder. Freely soluble in methanol, soluble in water, andsparingly soluble in ethanol (99.5). Melting point: about 230ºC(with decomposition).1%Absorbance E 1cm (230 nm): 225 - 240 (5 mg calculatedon the anhydrous basis, methanol, 200 mL).Purity (1) Related substances—To 1.0 mg of benzoylhypaconinehydrochloride for component determination add exactly1 mL of ethanol (99.5). Perform the test with 5 µL of thissolution as directed in the Identification under Processed AconiteRoot: no spot other than the principal spot at around R f 0.5appears.(2) Related substance—Dissolve 5.0 mg of benzoylhypaconinehydrochloride for component determination in 5 mL of themobile phase, and use this solution as the sample solution. Pipet1 mL of this solution, add the mobile phase to make exactly 50mL, and use this solution as the standard solution. Perform thetest with exactly 20 µL each of the sample solution and standardsolution as directed under Liquid Chromatography accordingto the following conditions. Determine each peak areaof both solutions by the automatic integration method: the totalarea of the peaks other than the peak of benzoylhypaconine obtainedfrom the sample solution is not larger than the peak areaof benzoylhypaconine from the standard solution.Operating conditionsColumn, column temperature, mobile phase and flow rate:Proceed as directed in the operating conditions in the Assay (3)under Goshajinkigan Extract.Detector: An ultraviolet absorption photometer (wavelength:

2062 General Tests, Process and Apparatus Supplement II, JP XV245 nm).Time span of measurement: About 5 times as long as the retentiontime of benzoylhypaconine.System suitabilityTest for required detectability: Pipet 1 mL of the standard solution,and add the mobile phase to make exactly 20 mL. Confirmthat the peak area of benzoylhypaconine obtained from 20µL of this solution is equivalent to 3.5 to 6.5% of that of benzoylhypaconinefrom the standard solution.System performance: When the procedure is run with 20 µLof aconitum monoester alkaloids standard solution for componentdetermination under the above operating conditions, benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine areeluted in this order with the resolution between these peaks beingnot less than 4, respectively.System repeatability: When the test is repeated 6 times with20 µL of aconitum monoester alkaloids standard solution forcomponent determination under the above operating conditions,the relative standard deviations of the peak areas of benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine are notmore than 1.5%, respectively.Benzoylmesaconine hydrochloride for component determinationBenzoylmesaconine hydrochloride for thin-layerchromatography meeting the following additional specifications.Purity Related substances—Dissolve 5.0 mg of benzoylmesaconinehydrochloride for component determination in 5 mLof the mobile phase, and use this solution as the sample solution.Pipet 1 mL of this solution, add the mobile phase to make exactly50 mL, and use this solution as the standard solution. Performthe test with exactly 20 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area of both solutions by the automatic integration method:the total area of the peaks other than the peak of benzoylmesaconineobtained from the sample solution is not larger than thepeak area of benzoylmesaconine from the standard solution.Operating conditionsColumn, column temperature, mobile phase and flow rate:Proceed as directed in the operating conditions in the Assay (3)under Goshajinkigan Extract.Detector: An ultraviolet absorption photometer (wavelength:245 nm).Time span of measurement: About 6 times as long as the retentiontime of benzoylmesaconine.System suitabilityTest for required detectability: Pipet 1 mL of the standard solution,and add the mobile phase to make exactly 20 mL. Confirmthat the peak area of benzoylmesaconine obtained from 20µL of this solution is equivalent to 3.5 to 6.5% of that of benzoylmesaconinefrom the standard solution.System performance: When the procedure is run with 20 µLof aconitum monoester alkaloids standard solution for componentdetermination under the above operating conditions, benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine areeluted in this order with the resolution between these peaks beingnot less than 4, respectively.System repeatability: When the test is repeated 6 times with20 µL of aconitum ester alkaloids standard solution for componentdetermination under the above operating conditions, therelative standard deviations of the peak areas of benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine are not morethan 1.5%, respectively.C 22 H 18 N 2 [Same as the namesake mono-Bifonazolegraph.]Bis(cis-3,3,5-trimethylcyclohexyl) phthalateC 4 H 4 [COOC 6 H 8 (CH 3 ) 3 ] 2 White crystalline powder.Melting point : 91 - 94ºCBisdemethoxycurcumin C 19 H 16 O 4 Yellow to orangecrystalline powder. Sparingly soluble in methanol, slightly solublein ethanol (99.5), and practically insoluble in water. Meltingpoint: 213 - 217ºC.Identification Determine the absorption spectrum of a solutionof bisdemethoxycurcumin in methanol (1 in 400000) as directedunder Ultraviolet-visible Spectrophotometry : itexhibits a maximum between 413 nm and 417 nm.Purity Related substances (1) Dissolve 4 mg of bisdemethoxycurcuminin 2 mL of methanol, and use this solution as thesample solution. Pipet 1 mL of this solution, add methanol tomake 20 mL, and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 5 µL each of the samplesolution and standard solution on a plate of silica gel forthin-layer chromatography. Develop the plate with a mixture ofdichloromethane and methanol (19:1) to a distance of about 10cm, and air-dry the plate. Examine under ultraviolet light (mainwavelength: 365 nm): the spots other than the principal spot atR f value of about 0.3 obtained from the sample solution are notmore intense than the spot from the standard solution.(2) Dissolve 1.0 mg of bisdemethoxycurcumin in 5 mL ofmethanol, and use this solution as the sample solution. Pipet 1mL of this solution, add methanol to make exactly 20 mL, anduse this solution as the standard solution. Perform the test withexactly 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography under the followingconditions. Determine each peak from both solutions bythe automatic integration method: the total area of the peaksother than the peak of bisdemethoxycurcumin obtained from thesample solution is not larger than the peak area of bisdemethoxycurcuminfrom the standard solution.Operating conditionsColumn, column temperature, mobile phase and flow rate:Proceed as directed in the operating conditions in the Componentdetermination under Turmeric.Detector: A visible absorption photometer (wavelength: 422nm).Time span of measurement: About 4 times as long as the retentiontime of bisdemethoxycurcumin beginning after the solventpeak.System suitabilitySystem performance and system repeatability: Proceed as directedin the operating conditions in the Component determinationunder Turmeric.

Supplement II, JP XV General Tests, Process and Apparatus 2063Test for required detectability: Pipet 1 mL of the standard solution,and add methanol to make exactly 20 mL. Confirm thatthe peak area of bisdemethoxycurcumin obtained from 10 µL ofthis solution is equivalent to 3.5 to 6.5% of that of bisdemethoxycurcuminfrom the standard solution.Bis(1,1-trifluoroacetoxy)iodobenzene C 10 H 5 F 6 IO 4 Preparedfor amino acid analysis or biochemistry.Blood agar medium Sterilize 950 mL of heart infusionagar medium under increased pressure. Allow the media to coolto about 50ºC, add 50 mL of horse or sheep defibrinated blood,dispense in sterilized Petri dishes, and make them as plate media.1% blood suspension Wash a defibrinated animal blood inisotonic solution, and make it into suspension to contain 1 vol%.Prepare before use.Boric acid-magnesium chloride buffer solution, pH 9.0Dissolve 3.1 g of boric acid in 210 mL of dilute sodium hydroxide,and add 10 mL of magnesium chloride hexahydrate (1in 50) and water to make 1000 mL. Adjust the pH to 9.0, if necessary.Cadralazine for assay C 12 H 21 N 5 O 3 [Same as the monographCadralazine. When dried, it contains not less than 99.0%of cadralazine (C 12 H 21 N 5 O 3 ).]Carbazole C 12 H 9 N White to nearly white foliaceous orplate-like crystals or crystalline powder. Freely soluble in pyridineand in acetone, slightly soluble in ethanol (99.5), and practicallyinsoluble in water. It readily sublimes when heated.Melting point : 243 - 245ºCPurity Clarity and color of solution—To 0.5 g of carbazoleadd 20 mL of ethanol (99.5), and dissolve by warming: the solutionis clear.Residue on ignition: Not more than 0.1% (1 g).Carbazole TS Dissolve 0.125 g of carbazole in ethanol(99.5) to make 100 mL.Chlorhexidine hydrochloride C 22 H 30 Cl 2 N 10·2HCl [Sameas the monograph Chlorhexidine Hydrochloride.](2-Chloroethyl) diethylamine hydrochlorideC 6 H 14 ClN·HCl White powder.Content: not less than 95.0%. Assay—Weigh accuratelyabout 0.2 g of (2-chloroethyl)diethylamine hydrochloride, previouslydried at 45ºC for 3 hours under reduced pressure, anddissolve in 15 mL of acetic acid (100). To this solution add 10mL of a mixture of acetic acid (100) and mercury (II) acetate TSfor nonaqueous titration (5:3), and titrate with 0.1 mol/Lperchloric acid VS (potentiometric titration). Perform a blankdetermination in the same manner, and make any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 17.21 mg of C 6 H 14 ClN·HClCinoxacin for assay C 12 H 10 N 2 O 5 [Same as the monographCinoxacin. When dried, it contains not less than 99.0% ofcinoxacin (C 12 H 10 N 2 O 5 )]p-Cresol C 7 H 8 O [K 8306, Special class]Curcumin for component determination C 21 H 20 O 6Yellow to orange crystalline powder. Slightly soluble in methanol,very slightly soluble in ethanol (99.5), and practically insolublein water.1%Absorbance E 1cm (422 nm): 1460 - 1700 (dried for24 hours in a desiccator (in vacuum, silica gel), 2.5 mg, methanol,1000 mL).Melting point : 180 - 184ºC.Purity Related substances—(1) Dissolve 4 mg of curcuminfor component determination in 2 mL of methanol, and usethis solution as the sample solution. Pipet 1 mL of this solution,add methanol to make exactly 50 mL, and use this solution asthe standard solution. Perform the test with these solutions asdirected under Thin-layer chromatography . Spot 5 µLeach of the sample solution and standard solution on a plate ofsilica gel for thin-layer chromatography. Develop the plate witha mixture of dichloromethane and methanol (19:1) to a distanceof about 10 cm, and air-dry the plate. Examine under ultravioletlight (main wavelength: 365 nm): the spots other than the principalspot at the R f value of about 0.5 obtained from the samplesolution are not more intense than the spot from the standardsolution.(2) Dissolve 1.0 mg of curcumin for component determinationin 5 mL of methanol, and use this solution as the samplesolution. Pipet 1 mL of this solution, add methanol to make exactly50 mL, and use this solution as the standard solution. Performthe test with 10 µL each of the sample solution and standardsolution as directed under Liquid Chromatography .Determine each peak from both solutions by the automatic integrationmethod: the total area of the peaks other than the peak ofcurcumin obtained from the sample solution is not larger thanthe peak area of curcumin from the standard solution.Operating conditionsColumn, column temperature, mobile phase and flow rate:Proceed as directed in the operating conditions in the Componentdetermination under Turmeric.Detector: A visible absorption photometer (wavelength: 422nm).Time span of measurement: About 4 times as long as the retentiontime of curcumin beginning after the solvent peak.System suitabilitySystem performance and system repeatability: Proceed as directedin the system suitability in the Component determinationunder Turmeric.Test for required detectability: Pipet 1 mL of the standard solution,add methanol to make exactly 20 mL. Confirm that thepeak area of curcumin obtained from 10 µL of this solution isequivalent to 3.5 to 6.5% of that of curcumin from 10 µL of thestandard solution.Cyanopropylmethylphenylsilicone for gas chromatogra-

2064 General Tests, Process and Apparatus Supplement II, JP XVphy Prepared for gas chromatography.Demethoxycurcumin C 20 H 18 O 5 Yellow to orange crystallinepowder or powder. Sparingly soluble in methanol and inethanol (99.5), and practically insoluble in water. Melting point:166 - 170ºC.Identification Determine the absorption spectrum of a solutionof demethoxycurcumin in methanol (1 in 400000) as directedunder Ultraviolet-visible Spectrophotometry : itexhibits a maximum between 416 nm and 420 nm.Purity Related substances—(1) Dissolve 4 mg of demethoxycurcuminin 2 mL of methanol, and use this solution asthe sample solution. Pipet 1 mL of this solution, add methanol tomake exactly 20 mL, and use this solution as the standard solution.Perform the test as directed under Thin-layer Chromatography. Spot 5 µL each of the sample solution and standardsolution on a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of dichloromethane andmethanol (19:1) to a distance of about 10 cm, and air-dry theplate. Examine under ultraviolet light (main wavelength: 365nm): the spots other than the principal spot at the R f value ofabout 0.3 obtained from the sample solution are not more intensethan the spot from the standard solution.(2) Dissolve 1.0 mg of demethoxycurcumin in 5 mL ofmethanol, and use this solution as the sample solution. Pipet 1mL of this solution, add methanol to make exactly 20 mL, anduse this solution as the standard solution. Perform the test withexactly 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography according tothe following conditions. Determine each peak from both solutionsby the automatic integration method: the total area of thepeaks other than the peak of demethoxycurcumin obtained fromthe sample solution is not larger than the peak area of demethoxycurcuminfrom the standard solution.Operating conditionsColumn, column temperature, mobile phase and flow rate:Proceed as directed in the operating conditions in the Componentdetermination under TurmericDetector: A visible absorption photometer (wavelength: 422nm)Time span of measurement: About 4 times as long as the retentiontime of demethoxycurcumin beginning after the solventpeak.System suitabilitySystem performance and system repeatability: Proceed as directedin the system suitability in the Component determinationunder Turmeric.Test for required detectability: Pipet 1 mL of the standard solution,and add methanol to make exactly 20 mL. Confirm thatthe peak area of demethoxycurcumin obtained from 10 µL ofthis solution is equivalent to 3.5 to 6.5% of that of demethoxycurcuminfrom the standard solution.Dibenz[a,h]anthracene C 22 H 14 Very pale yellow togreen-yellow crystalline powder or powder. Practically insolublein water, in methanol and in ethanol (99.5). Melting point:265 - 270ºC.Identification Perform the test with dibenz[a,h]anthraceneas directed in the Purity: the mass spectrum of the main peakshows a molecular ion peak (m/z 278) and a fragment ion peak(m/z 139).Purity Related substances—Dissolve 3.0 mg ofdibenz[a,h]anthracene in methanol to make 100 mL, and usethis solution as the sample solution. Perform the test with 1 µLof this solution as directed under Gas Chromatography according to the following conditions, and determine each peakarea by the automatic integration method. Calculate the amountsof these peaks by the area percentage method: the total amountof the peaks other than dibenz[a,h]anthracene is not more than7.0%.Operating conditionsDetector: A mass spectrophotometer (EI)Mass scan range: 15.00 - 300.00Time of measurement: 12 - 30 minutesColumn: A fused silica column 0.25 mm in inside diameterand 30 m in length, coated inside with 5% diphenyl-95% dimethylpolysiloxanefor gas chromatography in thickness of 0.25- 0.5 µm.Column temperature: Inject at a constant temperature of about45ºC, raise the temperature to 240ºC at a rate of 40ºC per minute,maintain at 240ºC for 5 minutes, raise to 300ºC at a rate of 4ºCper minute, raise to 320ºC at a rate of 10ºC per minute, andmaintain at 320ºC for 3 minutes.Injection port temperature: A constant temperature of about250ºC.Interface temperature: A constant temperature of about 300ºC.Carrier gas: HeliumFlow rate: Adjust the flow rate so that the reaction time of thepeak of dibenz[a,h]anthracene is about 27 minutes.Split ratio: SplitlessSystem suitabilityTest for required detectability: Pipet 1 mL of the sample solution,and add methanol to make exactly 10 mL. Confirm that thepeak area of dibenz[a,h]anthracene obtained from 1 µL of thissolution is equivalent to 5 to 15% of that ofdibenz[a,h]anthracene from the standard solution.Dibutylamine C 8 H 19 N Colorless, clear liquid.Refractive index n 20D: 1.415 - 1.419Density (20ºC): 0.756 - 0.761 g/mL2,6-Dichloroindophenol sodium-sodium acetate TS Mixequal volumes of 2,6-dichloroindophenol sodium dihydrate solution(1 in 20) and acetic acid-sodium acetate TS, pH 7.0. Preparebefore use.Diisopropylamine [(CH 3 ) 2 CH] 2 NH Colorless, clear liquid,having an amine-like odor. Miscible with water and withethanol (95). The solution in water is alkaline.Refractive index n 20D: 1.391 - 1.394Specific gravity d 2020: 0.715 - 0.722Dimenhydrinate for assay C 17 H 21 NO·C 7 H 7 ClN 4 O 2[Same as the monograph Dimenhydrinate. When dried, it containsnot less than 53.8% and not more than 54.9% of diphen-

Supplement II, JP XV General Tests, Process and Apparatus 2065hydramine (C 17 H 21 NO) and not less than 45.2% and not morethan 46.1% of 8-chlorotheophylline (C 7 H 7 ClN 4 O 2 ).]Dimethoxymethane C 3 H 8 O 2 Colorless, clear and volatileliquid. Miscible with methanol, with ethanol (95) and with diethylether.(Dimethylamino)azobenzenesulfonyl chlorideC 14 H 14 ClN 3 O 2 S Prepared for amino acid analysis or biochemistry.Disodium hydrogen phosphate-citric acid buffer solution,pH 7.5 Dissolve 5.25 g of citric acid monohydrate in water tomake 1000 mL. Add this solution to 1000 mL of 0.05 mol/Ldisodium hydrogen phosphate TS to adjust the pH to 7.5.Dithiodiglycolic acid C 4 H 6 O 4 S 2 Prepared for amino acidanalysis or biochemistry.Dithiodipropionic acid C 6 H 10 O 4 S 2 Prepared for aminoacid analysis or biochemistry.Droxidopa for assay C 9 H 11 NO 5 [Same as the monographDroxidopa. When dried, it contains not less than 99.5% ofdroxidopa (C 9 H 11 NO 5 ).]Ecabet sodium hydrate for assay C 20 H 27 NaO 5 S·5H 2 O[Same as the monograph Ecabet Sodium Hydrate. When dried,it contains not less than 99.5% of ecabet sodium(C 20 H 27 NaO 5 S).]Emorfazone for assay C 11 H 17 N 3 O 3 [Same as the monographEmorfazone. When dried, it contains not less than 99.0%of emorfazone (C 11 H 17 N 3 O 3 ).]9-Fluorenylmethyl chloroformate C 15 H 11 ClO 2 Preparedfor amino acid analysis or biochemistry.7-Fluoro-4-nitrobenzo-2-oxa-1,3-diazole C 6 H 2 FN 3 O 3Prepared for amino acid analysis or biochemistry.Flutoprazepam for assay C 19 H 16 ClFN 2 O [Same as themonograph Flutoprazepam. When dried, it contains not less than99.5% of flutoprazepam (C 19 H 16 ClFN 2 O).]Guaiacol for assay C 7 H 8 O 2 Colorless to yellow clear liquidor colorless crystals with a characteristic, aromatic odor.Miscible with methanol and with ethanol (99.5), and sparinglysoluble in water. Congealing point: 25 - 30ºC.Identification Determine the infrared absorption spectrumof guaiacol for assay as directed in the ATR method under InfraredSpectrophotometry : it exhibits absorption at thewave numbers of about 1595 cm -1 , 1497 cm -1 , 1443 cm -1 , 1358cm -1 , 1255 cm -1 , 1205 cm -1 , 1108 cm -1 , 1037 cm -1 , 1020 cm -1 ,916 cm -1 , 833 cm -1 , and 738 cm -1 .Purity Related substances—Perform the test with 0.5 µL ofguaiacol for assay as directed under Gas Chromatography according to the following conditions. Determine eachpeak area by the automatic integration method: the total area ofthe peaks other than the peak of guaiacol for assay is not morethan 2.0%Operating conditionsDetector: A hydrogen flame-ionization detector.Column: A fused silica column 0.25 mm in inside diameterand 60 m in length, coated inside with polymethylsiloxane forgas chromatography in 0.25 to 0.5 µm in thickness.Column temperature: Raise the temperature from 100ºC to130ºC at a rate of 5ºC per minute, raise to 140ºC at a rate of 2ºCper minute, raise to 200ºC at a rate of 15ºC per minute, andmaintain at 200ºC for 2 minutes.Injection port temperature: 200ºC.Detector temperature: 250ºC.Carrier gas: HeliumFlow rate: Adjust the flow rate so that the retention time ofguaiacol is about 8 minutes.Split ratio: 1:50System suitabilityTest for required detectability: Weigh accurately about 70 mgof guaiacol for assay, add methanol to make exactly 100 mL,and use this solution for the solution for system suitability test.Confirm that the peak area of guaiacol obtained from 1 µL of thesolution for system suitability test is equivalent to 0.08 to 0.16%of that of guaiacol obtained when 0.5 µL of guaiacol for assay isinjected.System performance: When the procedure is run with 1 µL ofthe solution for system suitability test under the above operatingconditions, the number of theoretical plates and the symmetryfactor of the peak of guaiacol are not less than 200000 and notmore than 1.5, respectively.System repeatability: When the test is repeated 6 times with 1µL of the solution for system suitability test under the above operatingconditions, the relative standard deviation of the peakarea of guaiacol is not more than 2.0%.4´-O-Glucosyl-5-O-methylvisamminol for thin-layerchromatography C 22 H 28 O 10 White crystals or crystallinepowder. Freely soluble in methanol and in ethanol (99.5), andsparingly soluble in water.Identification Determine the absorption spectrum of a solutionof 4´-O-glucosyl-5-O-methylvisamminol for thin-layerchromatography in ethanol (1 in 50000) as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximumbetween 286 nm and 290 nm.Purity Related substances—Dissolve 1 mg of4´-O-glucosyl-5-O-methylvisamminol for thin-layer chromatographyin 1 mL of methanol. Perform the test with 5 µL of thissolution directed in the Identification under SaposhnikoviaRoot: no spots other than the principal spot at around R f 0.3 appears.1%1%Guanine C 5 H 5 N 5 O White to pale yellowish white powder.Absorbance Weigh accurately about 10 mg of guanine,dissolve in 20 mL of dilute sodium hydroxide TS, and add2 mL of 1 mol/L hydrochloric acid TS and 0.1 mol/L hydrochloricacid TS to make exactly 1000 mL. Determine the absorbances,E , of this solution at 248 nm and 273 nm: they arebetween 710 and 770, and between 460 and 500, respectively.

2066 General Tests, Process and Apparatus Supplement II, JP XVLoss on drying : Not more than 1.5% (0.5 g, 105ºC, 4hours).Heart infusion agar medium Prepared for biochemicaltests.Heptyl parahydroxybenzoate C 14 H 20 O 3 White crystalsor crystalline powder.Melting point : 45 - 50ºC.Content: Not less than 98.0% Assay—Weigh accuratelyabout 3.5 g of heptyl parahydroxybenzoate, dissolve in 50 mL ofdiluted N,N-dimethylformamide (4 in 5), and titrate with1 mol/L sodium hydroxide VS (potentiometric titration). Performa blank determination in the same manner, and make anynecessary correction.Each mL of 1 mol/L sodium hydroxide VS= 236.3 mg of C 14 H 20 O 3Hexyl parahydroxybenzoate C 13 H 18 O 3 White crystals orcrystalline powder.Melting point : 49 - 53ºCContent: Not less than 98.0%. Assay—Proceed as directedin the Assay under Ethyl Parahydroxybenzoate.Each mL of 1 mol/L sodium hydroxide VS= 222.3 mg of C 13 H 18 O 3Hyodeoxycholic acid for thin-layer chromatographyC 24 H 40 O 4 White to pale brown crystalline powder or powder.Freely soluble in methanol an in ethanol (99.5), and practicallyinsoluble in water.Identification Determine the infrared absorption spectrumof hyodeoxycholic acid for thin-layer chromatography as directedin the potassium bromide disk method under InfraredSpectrophotometry : it exhibits absorption at the wavenumbers of about 2940 cm -1 , 2840 cm -1 , 2360 cm -1 , 1740 cm -1 ,1460 cm -1 , 1340 cm -1 , 1200 cm -1 , 1160 cm -1 , 1040 cm -1 and 600cm -1 .Optical rotation [α] 20D: +7 - +10º (0.4 g, ethanol(99.5), 20 mL, 100 mm).Melting point : 198 - 205ºCPurity Related substances—Dissolve 20 mg of hyodeoxycholicacid for thin-layer chromatography in 1 mL of methanol,and use this solution as the sample solution. Pipet 0.2 mL of thissolution, add methanol to make exactly 10 mL, and use this solutionas the standard solution. Perform the test as directed underThin-layer Chromatography . Spot 5 µL each of thesample solution and standard solution on a plate of silica gel forthin-layer chromatography. Develop the plate with a mixture ofchloroform, acetone and acetic acid (100) (7:2:1) to a distanceof about 10 cm, and air-dry the plate. Splay evenly dilute sulfuricacid on the plate, and heat at 105ºC for 10 minutes: the spotsother than the principal spot at the R f value of about 0.3 obtainedfrom the sample solution are not more intense than thespot from the standard solution.10-Hydroxy-2-(E)-decenoic acid for component determination10-hydroxy-2-(E)-decenoic acid for thin-layer chromatographymeeting the following additional specifications.Purity Related substances—Dissolve 10 mg of10-hydroxy-2-(E)-decenoic acid for component determination in100 mL of methanol, and use this solution as the sample solution.Pipet 1 mL of this solution, add methanol to make exactly100 mL, and use this solution as the standard solution. Performthe test with exactly 10 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak from both solutions by the automatic integration method:the total area of the peaks other than the peak of10-hydroxy-2-(E)-decenoic acid is not larger than the peak areaof 10-hydroxy-2-(E)-decenoic acid from the standard solution.Operating conditionsDetector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theComponent determination under Royal Jelly.Time span of measurement: About 4 times as long as the retentiontime of 10-hydroxy-2-(E)-decenoic acid beginning afterthe solvent peak.System suitabilitySystem performance and system repeatability: Proceed as directedin the system suitability in the Component determinationunder Royal Jelly.Test for required detectability: Pipet 1 mL of the standard solution,and add methanol to make exactly 20 mL. Confirm thatthe peak area of 10-hydroxy-2-(E)-decenoic acid obtained from10 µL of this solution is equivalent to 3.5 to 6.5% of that of10-hydroxy-2-(E)-decenoic acid from the standard solution.10-Hydroxy-2-(E)-decenoic acid for thin-layer chromatographyC 10 H 18 O 3 White crystalline powder. Very solublein methanol, freely soluble in ethanol (99.5), soluble in diethylether, and slightly soluble in water.Identification Determine the absorption spectrum of a solutionof 10-hydroxy-2-(E)-decenoic acid for thin-layer chromatographyin ethanol (99.5) (1 in 125000) as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximumbetween 206 nm and 210 nm.Melting point : 63 - 66ºC.Purity Related substances—Dissolve 5.0 mg of10-hydroxy-2-(E)-decenoic acid for thin-layer chromatographyin 1 mL of diethyl ether. Perform the test with 20 µL of this solutionas directed in the Identification under Royal Jelly: no spotother than the principal spot at around R f 0.5 appears.Imidapril hydrochloride C 20 H 27 N 3 O 6·HCl [Same as themonograph Imidapril Hydrochloride.]Imidapril hydrochloride for assay C 20 H 27 N 3 O 6·HCl[Same as the monograph Imidapril Hydrochloride. When dried,it contains not less than 99.0% of imidapril hydrochloride(C 20 H 27 N 3 O 6·HCl).]Irsogladine maleate C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 [Same as themonograph Irsogladine Maleate.]Irsogladine maleate for assay C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 [Same

Supplement II, JP XV General Tests, Process and Apparatus 2067as the monograph Irsogladine Maleate. When dried, it containsnot less than 99.5% of irsogladine maleate(C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ).]Isosorbide dinitrate for assay C 6 H 8 N 2 O 8 [Same as themonograph Isosorbide Dinitrate. It contains not less than 99.0%of isosorbide dinitrate (C 6 H 8 N 2 O 8 ) meeting the following additionalspecifications.]Purity Related substances—Dissolve 50 mg of isosorbidedinitrate for assay in 50 mL of a mixture of water and methanol(1:1), and use this solution as the sample solution. Pipet 1 mL ofthis solution, add a mixture of water and methanol (1:1) to makeexactly 200 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography, and determine each peak area of both solutions by theautomatic integration method: the total area of the peaks otherthan the peak of isosorbide dinitrate obtained from the samplesolution is not larger than the peak area of isosorbide dinitratefrom the standard solution.Operating conditionsDetector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating procedures in theAssay under Isosorbide Dinitrate Tablets.Time span of measurement: About 2 times as long as the retentiontime of isosorbide dinitrate beginning after the solventpeak.System suitabilityTest for required detectability: Pipet 5 mL of the standard solution,and add a mixture of water and methanol (1:1) to makeexactly 50 mL. Confirm that the peak area of isosorbide dinitrateobtained from 10 µL of this solution is equivalent to 7 to13% of that of isosorbide dinitrate from the standard solution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of isosorbide dinitrate are not less than 3000 and not morethan 1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of isosorbidedinitrate is not more than 2.0%.Ketoconazolemonograph.]C 26 H 28 Cl 2 N 4 O 4 [Same as the namesakeKetoconazole for assay C 26 H 28 Cl 2 N 4 O 4 [Same as themonograph Ketoconazole. When dried, it contains not less than99.5% of ketoconazole (C 26 H 28 Cl 2 N 4 O 4 ).]4-methoxybenzaldehyde-sulfuric acid-acetic acid-ethanolTS for spray To 9 mL of ethanol (95) add 0.5 mL of4-methoxybenzaldehyde, mix gently, add gently 0.5 mL of sulfuricacid and 0.1 mL of acetic acid (100) in this order, and mixwell.Loganin for component determination Loganin forthin-layer chromatography meeting the following additionalspecifications.1%Absorbance E 1cm (235 nm): 275 - 303 (dried in adesiccator (silica gel) for 24 hours, 5 mg, methanol, 500 mL).Purity Related substances—Dissolve 2 mg of loganin forcomponent determination in 5 mL of the mobile phase, and usethis solution as the sample solution. Pipet 1 mL of this solution,add the mobile phase to make exactly 100 mL, and use this solutionas the standard solution. Perform the test with exactly 10µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions. Determine each peak area of both solutions bythe automatic integration method: the total area of the peaksother than the peak of loganin is not larger than the peak area ofloganin from the standard solution.Operating conditionsDetector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay (1) under Goshajinkigan Extract.Time span of measurement: About 3 times as long as the retentiontime of loganin.System suitabilitySystem performance and system repeatability: Proceed as directedin the system suitability in the Assay (1) under GoshajinkiganExtract.Test for required detectability: Pipet 1 mL of the standard solution,and add the mobile phase to make exactly 20 mL. Confirmthat the peak area of loganin obtained from 10 µL of thissolution is equivalent to 3.5 to 6.5% of that of loganin from thestandard solution.Lovastatin C 24 H 36 O 5 White crystals or crystalline powder.Soluble in acetonitrile and in methanol, sparingly soluble inethanol (99.5), and practically insoluble in water.Optical rotation [α] 20D: +325 - +340º (50 mg calculatedon the anhydrous basis, acetonitrile, 10 mL, 100 mm).Loss on drying : Not more than 1.0% (1 g, under reducedpressure not exceeding 0.67 kPa, 60ºC, 3 hours).Mebendazole C 16 H 13 N 3 O 3 White powder. Practically insolublein water and in ethanol (95).Mercaptoethanesulfonic acid C 2 H 6 O 3 S 2 Prepared foramino acid analysis or biochemistry.2-Methoxy-4-methylphenol C 8 H 10 O 2 Colorless to paleyellow liquid. Miscible with methanol and with ethanol (99.5),and slightly soluble in water. Congealing point: 3 - 8ºC.Identification Determine the infrared absorption spectrumof 2-methoxy-4-methylphenol as directed in the ATR methodunder Infrared Spectrophotometry : it exhibits absorptionat the wave numbers of about 1511 cm -1 , 1423 cm -1 , 1361 cm -1 ,1268 cm -1 , 1231 cm -1 , 1202 cm -1 , 1148 cm -1 , 1120 cm -1 , 1031cm -1 , 919 cm -1 , 807 cm -1 and 788 cm -1 .Purity Related substances—Perform the test with 0.2 µL of2-methoxy-4-methylphenol as directed under Gas Chromatography according to the following conditions. Determineeach peak by the automatic integration method: the total area ofthe peaks other than the peak of 2-methoxy-4-methylphenol is

2068 General Tests, Process and Apparatus Supplement II, JP XVnot more than 3.0%.Operating conditionsDetector: A hydrogen flame-ionization detector.Column: A fused silica column 0.25 mm in inside diameterand 60 m in length, coated inside with polymethylsiloxane forgas chromatography in 0.25 to 0.5 µm in thickness.Column temperature: Inject at a constant temperature of about100ºC, raise the temperature to 130ºC at a rate of 5ºC per minute,raise to 140ºC at a rate of 2ºC per minute, raise to 200ºC at arate of 15ºC per minute, and maintain at 200ºC for 2 minutes.Injection port temperature: 200ºC.Detector temperature: 250ºC.Carrier gas: HeliumFlow rate: Adjust the flow rate so that the retention time of2-methoxy-4-methylphenol is about 10 minutes.Split ratio: 1:50System suitabilitySystem performance: Dissolve 60 mg of2-methoxy-4-methylphenol in methanol to make 100 mL, anduse this solution as the solution for system suitability test. Proceedwith 1 µL of the solution for system suitability test underthe above operating conditions: the symmetry factor of the peakof 2-methoxy-4-methylphenol is not more than 1.5.System repeatability: When the test is repeated 6 times with 1µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of2-methoxy-4-methylphenol is not more than 2.0%.Methyl acetate CH 3 COOCH 3[K 8382, Special class]Mosapride citrate for assay C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7·2H 2 O[Same as the monograph Mosapride Citrate Hydrate. It containsnot less than 99.0% of mosapride citrate(C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 ) calculated on the anhydrous basis.]Myristicin for thin-layer chromatography C 11 H 12 O 3Colorless, clear liquid, having a characteristic odor. Misciblewith ethanol (95), and practically insoluble in water.Identification Determine the infrared absorption spectrumof myristicin for thin-layer chromatography as directed in theliquid film method under Infrared Spectrophotometry : itexhibits absorption at the wave numbers of about 3080 cm -1 ,2890 cm -1 , 1633 cm -1 , 1508 cm -1 , 1357 cm -1 , 1318 cm -1 , 1239cm -1 , 1194 cm -1 , 1044 cm -1 , 994 cm -1 , 918 cm -1 , 828 cm -1 and806 cm -1 .Purity Related substances—Dissolve 20 mg of myristicinfor thin-layer chromatography in 1 mL of ethanol (95), and usethis solution as the sample solution. Pipet 0.5 mL of this solution,add ethanol (95) to make exactly 25 mL, and use this solutionas the standard solution. Perform the test with 5 µL each ofthe sample solution and standard solution as directed in theIdentification under Nutmeg: the spots other than the principlespot at the R f value of about 0.4 obtained from the sample solutionare not more intense than the spot from the standard solution.C 18 H 20 FN 3 O 4 [Same as the namesake mono-Ofloxacingraph.]Perillaldehyde for component determination Perillaldehydefor thin-layer chromatography meeting the followingspecifications.1%Absorbance E 1cm (230 nm): 850 - 950 (10 mg,methanol, 2000 mL).Purity Related substances—Dissolve 10 mg of perillaldehydein 250 mL of methanol, and use this solution as the samplesolution. Pipet 1 mL of this solution, add methanol to make exactly50 mL, and use this solution as the standard solution. Performthe test with exactly 10 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak from both solutions by the automatic integration method:the total area of the peaks other than the peak of perillaldehydeis not larger than the peak of perillaldehyde from the standardsolution.Operating conditionsDetector, column, column temperature, mobile phase andflow rate: proceed as directed in the operating conditions in theComponent determination under Perilla Herb.Time span of measurement: About 3 times as long as the retentiontime of perillaldehyde beginning after the solvent peak.System suitabilitySystem performance and system repeatability: Proceed as directedin the system suitability in the Component determinationunder Perilla Herb.Test for required detectability: Pipet 1 mL of the standard solution,and add methanol to make exactly 20 mL. Confirm thatthe peak area of perillaldehyde obtained from 10 µL of this solutionis equivalent to 3.5 to 6.5% of that of perillaldehyde fromthe standard solution.Perillaldehyde for thin-layer chromatography C 10 H 14 OColorless to light brown transparent liquid, having a characteristicodor. Miscible with methanol and with ethanol (99.5), andvery slightly soluble in water.Identification Determine the infrared absorption spectrumof perillaldehyde for thin-layer chromatography as directed inthe liquid film method under Infrared Spectrophotometry: it exhibits absorption at the wave numbers of about3080 cm -1 , 2930 cm -1 , 1685 cm -1 , 1644 cm -1 , 1435 cm -1 and 890cm -1 .Purity Related substances—Dissolve 1.0 mg of perillaldehydefor thin-layer chromatography in 10 mL of methanol, andperform the test with 10 µL of this solution as directed in theIdentification under Perilla Herb: no spot other than the principalspot at around R f 0.5 appears.Phenyl isothiocyanate C 7 H 5 NS Prepared for amino acidanalysis or biochemistry.Phenobarbital for assaymonograph Phenobarbital.]C 12 H 12 N 2 O 3 [Same as thePhenytoin for assay C 15 H 12 N 2 O 2 [Same as the monographPhenytoin meeting the following additional specifications.]Purity Related substances—Dissolve 25 mg of phenytoin

Supplement II, JP XV General Tests, Process and Apparatus 2069for assay in 50 mL of the mobile phase, and use this solution asthe sample solution. Pipet 1 mL of this solution, add the mobilephase to make exactly 200 mL, and use this solution as thestandard solution. Perform the test with exactly 10 µL each ofthe sample solution and standard solution as directed under LiquidChromatography . Determine each peak from bothsolutions by the automatic integration method: the total area ofthe peaks other than the peak of phenytoin obtained from thesample solution is not larger than the peak area of phenytoinfrom the standard solution.Operating conditionsColumn, column temperature and flow rate: Proceed as directedin the operating conditions in the Assay under PhenytoinTablets.Detector: An ultraviolet absorption photometer (wavelength:220 nm)Mobile phase: A mixture of 0.02 mol/L phosphate buffer solution,pH 3.5, and acetonitrile for liquid chromatography(11:9).Time span of measurement: About 5 times as long as the retentiontime of phenytoin beginning after the solvent peak.System suitabilityTest for required detectability: Pipet 2 mL of the standard solution,and add the mobile phase to make exactly 20 mL. Confirmthat the peak area of phenytoin obtained from 10 µL of thissolution is equivalent to 8 to 12% of that of phenytoin from thestandard solution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of phenytoin are not less than 6000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of phenytoinis not more than 2.0%.Plantago seed for thin-layer chromatography [Same asthe monograph Plantago Seed meeting the following additionalspecifications.]Identification (1) To 1 g of pulverized plantago seed forthin-layer chromatography add 3 mL of methanol, and warm ona water bath for 3 minutes. After cooling, centrifuge, and use thesupernatant liquid as the sample solution. Perform the test withthis solution as directed under Thin-layer Chromatography. Spot 10 µL of the sample solution on a plate of silicagel for thin-layer chromatography. Develop the plate with amixture of acetone, ethyl acetate, water and acetic acid (100)(10:10:3:1) to a distance of about 10 cm, and air-dry the plate.Splay evenly 4-methoxybenzaldehyde-sulfuric acid TS on theplate, heat at 105ºC for 10 minutes: spots equivalent to thosedescribed below appear.R f valueAround 0Around 0.08Around 0.1 - 0.2Around 0.25Around 0.35Around 0.45Around 0.50Around 0.6Around 0.85Around 0.9 - 0.95Color and shape of the spotA strong spot, very dark blueA very dark blue spotA leading spot, very dark blueA strong spot, deep blue (correspondingto plantagoguanidinic acid)A strong spot, dark grayish blue (correspondingto geniposidic acid)A weak spot, grayish yellowish greenA strong spot, deep yellow-green(corresponding to acteoside)A weak spot, light blueA deep blue spotA tailing spot, grayish blue(2) Proceed as directed in the operating conditions under (1),except using a mixture of ethyl acetate, water and formic acid(6:1:1) as developing solvent: spots equivalent to those describedbelow appear.R f valueAround 0Around 0.05Around 0.2Around 0.25Around 0.35Around 0.4 - 0.45Around 0.45Around 0.5Around 0.95Around 0.97Color and shape of the spotA yellow-greenish dark gray spotA weak spot, dark grayish yellow-greenA weak spot, dark greenA strong spot, dark reddish purple(corresponding to geniposidic acid)A weak spot, bright blueA weak tailing spot, dull greenish blueA strong spot, deep yellow-green(corresponding to acteoside)A strong spot, deep blue (correspondingto plantagoguanidinic acid)A strong spot, dark grayish blue-greenA dark grayish blue-green spotPolyethylene glycol 2-nitroterephthalate for gas chromatographyPrepared for gas chromatography.Polymethylsiloxane for gas chromatography Prepared forgas chromatography.(E)-2-methoxycinnamaldehyde for thin-layer chromatographyC 10 H 10 O 2 White to yellow crystalline powder orpowder. Freely soluble in methanol and in ethanol (99.5), andpractically insoluble in water. Melting point: 44 - 50ºC.Identification (1) Determine the absorption spectrum of(E)-2-methoxycinnamaldehyde for thin-layer chromatographyas directed under Ultraviolet-visible Spectrophotometry :it exhibits maxima between 282 nm and 286 nm, and between331 nm and 335 nm.(2) Determine the infrared absorption spectrum of(E)-2-methoxycinnamaldehyde for thin-layer chromatographyas directed in the potassium bromide disk method under InfraredSpectrophotometry : it exhibits absorption at the wavenumbers of about 1675 cm -1 , 1620 cm -1 , 1490 cm -1 , 1470 cm -1 ,1295 cm -1 , 1165 cm -1 , 1130 cm -1 , 1025 cm -1 and 600 cm -1 .Purity Related substances—Dissolve 10 mg of

2070 General Tests, Process and Apparatus Supplement II, JP XV(E)-2-methoxycinnamaldehyde for thin-layer chromatography in5 mL of methanol, and use this solution as the sample solution.Pipet 1 mL of this solution, add methanol to make exactly 50mL, and use this solution as the standard solution. Perform thetest with 5 µL each of the sample solution and standard solutionas directed in the Identification (5) (ii) under Goshajinkigan Extract:the spots other than the principal spot at the R f value ofabout 0.4 obtained from the sample solution are not more intensethan the spot from the standard solution.0.01 mol/L Potassium dihydrogen phosphate TS, pH 4.0Dissolve 1.4 g of potassium dihydrogen phosphate in 1000 mLof water, and adjust the pH to 4.0 with phosphoric acid.Pig bile powder for thin-layer chromatography A yellow-grayto yellow-brown powder, having a characteristic odorand a bitter taste. It is practically insoluble in water, in methanoland in ethanol (99.5)Identification To 0.1 g of pig bile powder for thin-layerchromatography in a screw-capped test tube, add 1 mL of sodiumhydroxide solution (3 in 25), and shake. Heat the tube inan oil bath at 120ºC for 4 hours, allow to cool to a lukewarmtemperature, add 2 mL of 3 mol/L hydrochloric acid TS and 2mL of ethyl acetate, shake at 50ºC for 30 minutes, and separateethyl acetate layer as the sample solution. Separately, dissolve10 mg of hyodeoxycholic acid for thin-layer chromatography in5 mL of methanol, and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 2 µL each of the samplesolution and standard solution on a plate of silica gel forthin-layer chromatography. Develop the plate with a mixture ofchloroform, acetone and acetic acid (100) (7:2:1) to a distanceof about 10 cm, and air-dry the plate. Spray evenly dilute sulfuricacid on the plate, and heat the plate at 105ºC for 10 minutes:one of the several spots obtained from the sample solutionshows the same color tone and the same R f value as the spotfrom the standard solution.Propafenone hydrochloride for assay C 21 H 27 NO 3·HCl[Same as the monograph Propafenone Hydrochloride. Whendried, it contains not less than 99.0% of propafenone hydrochloride(C 21 H 27 NO 3·HCl). When proceed as directed in the Purity(2), the total area of the peaks other than the peak ofpropafenone is not larger than 3 times the peak area ofpropafenone from the standard solution.]0.2 mol/L Pyridine-formic acid buffer solution, pH 3.0To 15.82 g of pyridine add 900 mL of water, shake well, adjustthe pH to 3.0 with diluted formic acid (1 in 2), and add water tomake 1000 mL.Rebamipide for assay C 19 H 15 ClN 2 O 4 [Same as themonograph Rebamipide. When dried, it contains not less than99.5% of rebamipide (C 19 H 15 ClN 2 O 4 ).]Sodium Azide NaN 3 [K 9501, Special class]0.2 mol/L Sodium chloride TS Dissolve 11.7 g of sodiumchloride in water to make 1000 mL.Sodium glycocholate for thin-layer chromatographyC 26 H 42 NNaO 6·xH 2 O White to pale brown crystalline powderor powder. Freely soluble in water and in methanol, and slightlysoluble in ethanol (99.5). Melting point: about 260ºC (with decomposition).Identification Determine the infrared absorption spectrumof sodium glycocholate for thin-layer chromatography as directedin the potassium bromide disk method under InfraredSpectrophotometry , it exhibits absorption at the wavenumbers of about 2940 cm -1 , 1640 cm -1 , 1545 cm -1 , 1450 cm -1 ,1210 cm -1 , 1050 cm -1 , and 600 cm -1 .Optical rotation [α] 20D: +25 - +35º (60 mg, methanol,20 mL, 100 mm).Purity Related substances—Dissolve 5 mg of sodium glycocholatefor thin-layer chromatography in 1 mL of methanol,and use this solution as the sample solution. Pipet 0.2 mL of thissolution, add methanol to make exactly 10 mL, and use this solutionas the standard solution. Perform the test with these solutionsas directed under Thin-layer Chromatography .Proceed with 5 µL each of the sample solution and standard solutionas directed in the Identification under Bear Bile: the spotsother than the principal spot at the R f value of about 0.2 obtainedfrom the sample solution are not more intense than thespot from the standard solution.Sodium 1-nonanesulfonate CH 3 (CH 2 ) 8 SO 3 Na Whitecrystalline powder. Freely soluble in water.Loss on drying : Not more than 1.0% (1 g, 105ºC, 3hours).Residue on ignition : 30 - 32% (0.5 g).Sodium tauroursodeoxycholate for thin-layer chromatographyC 26 H 44 NNaO 6 S·xH 2 O White to pale brown crystallinepowder or powder. Freely soluble in methanol, soluble in water,and sparingly soluble in ethanol (99.5).Identification Determine the infrared absorption spectrumof sodium tauroursodeoxycholate for thin-layer chromatographyas directed in the potassium bromide disk method under InfraredSpectrophotometry : it exhibits the absorption at thewave numbers of about 2940 cm -1 , 1600 cm -1 , 1410 cm -1 , 1305cm -1 , 1195 cm -1 , 1080 cm -1 , 1045 cm -1 , 980 cm -1 , 950 cm -1 , 910cm -1 and 860 cm -1 .Optical rotation [α] 20D: +40 - +50º (40 mg, methanol,20 mL, 100 mm)Purity Related substances—Dissolve 10 mg of sodiumtauroursodeoxycholate for thin-layer chromatography in 1 mLof methanol, and use this solution as the sample solution. Pipet0.2 mL of this solution, add methanol to make exactly 10 mL,and use this solution as the standard solution. Perform the testwith these solutions as directed under Thin-layer Chromatography. Perform the test as directed in the Identificationunder Bear Bile: the spots other than the principal spot at the R fvalue of about 0.2 obtained from the sample solution are notmore intense than the spot from the standard solution.Sodium tetraborate-sulfuric acid TS To 9.5 g of sodiumtetraborate decahydrate add 1000 mL of purified sulfuric acid,

Supplement II, JP XV General Tests, Process and Apparatus 2071and dissolve by shaking for a night.Sodium valproate for assay C 8 H 15 NaO 2 [Same as themonograph Sodium Valproate. When dried, it contains not lessthan 99.0% of sodium valproate (C 8 H 15 NaO 2 ).]Strontium TS Dissolve 76.5 g of strontium chloride in waterto make exactly 500 mL. Pipet 20 mL of this solution, andadd water to make exactly 1000 mL (1000 ppm).Testosterone C 19 H 28 O 2 White crystals or crystallinepowder.Identification Determine the infrared absorption spectrumof testosterone as directed in the potassium bromide diskmethod under Infrared Spectrophotometry : it exhibitsthe absorption at the wave numbers of about 3530 cm -1 , 3380cm -1 , 1612 cm -1 , 1233 cm -1 , 1067 cm -1 and 1056 cm -1 .Theophylline for assay C 7 H 8 N 4 O 2 [Same as the monographTheophylline meeting the following additional specifications.]Purity Related substances—Dissolve 50 mg of theophyllinefor assay in water to make 100 mL, and use this solution as thesample solution. Pipet 1 mL of this solution, add water to makeexactly 200 mL, and use this solution as the standard solution.Perform the test with exactly 20 µL of the sample solution andstandard solution as directed under Liquid Chromatography. Determine each peak from both solutions by the automaticintegration method: the total area of peaks other than thepeak of theophylline obtained from the sample solution is notlarger than the peak area of theophylline from the standard solution.Operating conditionsDetector: An ultraviolet absorption photometer (wavelength:270 nm)Column: A stainless steel column 6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of diluted acetic acid (100) (1 in100) and methanol (4:1).Flow rate: Adjust the flow rate so that the retention time oftheophylline is about 10 minutes.Time span of measurement: About 3 times as long as the retentiontime of theophylline.System suitabilityTest for required detectability: Pipet 5 mL of the standard solution,and add water to make exactly 25 mL. Confirm that thepeak area of theophylline obtained from 20 µL of this solution isequivalent to 15 to 25% of that of theophylline from the standardsolution.System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of theophylline are not less than 3000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of theophyllineis not more than 3.0%.Tiapride hydrochloride for assay C 15 H 24 N 2 O 4 S·HCl[Same as the monograph Tiapride Hydrochloride.]1% Triethylamine-phosphate buffer solution, pH 3.0Dissolve 10 g of triethylamine in 950 mL of water, adjust the pHto 3.0 with phosphoric acid, and make exactly 1000 mL.Tris(4-t-butylphenyl)phosphate [(CH 3 ) 3 CC 6 H 4 O] 3 POWhite crystals or crystalline powder.Melting point : 100 - 104ºCUbenimex for assay C 16 H 24 N 2 O 4 [Same as the monographUbenimex. When dried, it contains not less than 99.0% ofubenimex (C 16 H 24 N 2 O 4 ).]Ursodeoxycholic acid for assay C 24 H 40 O 4 [Same as themonograph Ursodeoxycholic Acid. However, when dried, itcontains not less than 99.0% of ursodeoxycholic acid(C 24 H 40 O 4 ) meeting the following additional specifications.]Purity Related substances—Dissolve 0.15 g of ursodeoxycholicacid in 5 mL of methanol for liquid chromatography, anduse this solution as the sample solution. Pipet 2 mL of this solutionand add methanol for liquid chromatography to make exactly50 mL. Pipet 2.5 mL of this solution, add methanol for liquidchromatography to make exactly 20 mL, and use this solutionas the standard solution. Perform the test with exactly 5 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions. Determine each peak area of both solutions bythe automatic integration method: the area of the peak, havingthe relative retention time of about 2.5 with respect to ursodeoxycholicacid, obtained from the sample solution is not largerthan the peak area of ursodeoxycholic acid from the standardsolution, and the area of the peak, having the relative retentiontime of about 5.5, obtained from the sample solution is not largerthan 1/5 times the peak area of ursodeoxycholic acid fromthe standard solution. Furthermore, the total area of the peaksother than the peak of ursodeoxycholic acid and other than thepeaks mentioned above is not larger than 1/5 times the peak areaof ursodeoxycholic acid from the standard solution.Operating conditionsDetector: An ultraviolet absorption photometer (wavelength:210 nm).Column: A stainless steel column 3 mm in inside diameterand 7.5 cm in length, packed with octylsilanized silica gel forliquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of methanol for liquid chromatography,diluted phosphoric acid (1 in 1000) and acetonitrile forliquid chromatography (96:69:35).Flow rate: Adjust the flow rate so that the retention time ofursodeoxycholic acid is about 2.3 minutes.Time span of measurement: About 7 times as long as the retentiontime of ursodeoxycholic acid.System suitability—Test for required detectability: Pipet 2 mL of the standard so-

2072 General Tests, Process and Apparatus Supplement II, JP XVlution, and add methanol for liquid chromatography to makeexactly 20 mL. Confirm that the peak area of ursodeoxycholicacid obtained from 5 µL of this solution is equivalent to 8 to12% of that of ursodeoxycholic acid from the standard solution.System performance: To 30 mg of chenodeoxycholic acid forthin-layer chromatography and 30 mg of lithocholic acid forthin-layer chromatography, add 1 mL of the sample solution,dissolve in methanol for liquid chromatography to make 50 mL.When the procedure is run with 5 µL of this solution under theabove operating conditions, ursodeoxycholic acid, chenodeoxycholicacid, and lithocholic acid are eluted in this order withthe resolution between these peaks being not less than 7, respectively.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above conditions, the relativestandard deviation of the peak area of ursodeoxycholic acidis not more than 2.0%.9.42 Solid Supports/ColumnPackings for ChromatographyAdd the following:Sulfonamide group bound to hexadecylsilanized silica gel forliquid chromatography Prepared for column chromatography.

Official MonographsAdd the following:Acemetacin CapsulesアセメタシンカプセルAcemetacin Capsules contain not less than 93.0%and not more than 107.0% of the labeled amount ofacemetacin (C 21 H 18 ClNO 6 : 415.82).Method of preparation Prepare as directed under Capsules,with Acemetacin.Identification To an amount of powdered contents ofAcemetacin Capsules, equivalent to 0.1 g of Acemetacin accordingto the labeled amount, add 100 mL of methanol, shakewell, and filter. Take 10 mL of the filtrate, and distil the methanolunder reduced pressure. To the residue add 1 mL of methanol,shake well, centrifuge, and use the supernatant liquid as thesample solution. Separately, dissolve 10 mg of acemetacin in 1mL of methanol, and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 2 µL each of the samplesolution and standard solution on a plate of silica gel withfluorescent indicator for thin-layer chromatography. Develop theplate with a mixture of hexane, 4-methyl-2-pentanone and aceticacid (100) (3:2:1) to a distance of about 10 cm, and air-dry theplate. Examine under ultraviolet light (main wavelength: 254nm): the spots obtained from the sample solution and standardsolution show the same R f value.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.Take out the contents of 1 capsule of Acemetacin Capsules,add 40 mL of methanol, shake well, and add methanol to makeexactly V mL so that each mL contains about 0.6 mg ofacemetacin (C 21 H 18 ClNO 6 ). Filter this solution, discard the first10 mL of the filtrate, pipet 5 mL of the subsequent filtrate, addexactly 2 mL of the internal standard solution, add methanol tomake 50 mL, and use this solution as the sample solution. Proceedas directed in the Assay.Amount (mg) of acemetacin (C 21 H 18 ClNO 6 )= W S × (Q T /Q S ) × (V/50)W S : Amount (mg) of acemetacin for assayInternal standard solution—A solution of hexyl parahydroxybenzoatein methanol (1 in 1000)Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of 2nd fluid for dissolution test as the dissolutionmedium, the dissolution rate in 30 minutes ofAcemetacin Capsules is not less than 70%.Start the test with 1 capsule of Acemetacin Capsules, withdrawnot less than 20 mL of the medium at the specified minuteafter starting the test, and filter through a membrane filter with apore size not exceeding 0.45 µm. Discard the first 10 mL of thefiltrate, pipet V mL of the subsequent filtrate, add 2nd fluid fordissolution test to make exactly V´ mL so that each mL containsabout 33 µg of acemetacin (C 21 H 18 ClNO 6 ) according to the labeledamount, and use this solution as the sample solution.Separately, weigh accurately about 17 mg of acemetacin for assay,previously dried at 105ºC for 2 hours, dissolve in the dissolutionmedium to make exactly 100 mL. Pipet 4 mL of this solution,add the dissolution medium to make exactly 20 mL, anduse this solution as the standard solution. Determine the absorbances,A T and A S , of the sample solution and standard solutionat 319 nm as directed under Ultraviolet-visible Spectrophotometry.Dissolution rate (%) with respect to the labeled amount ofacemetacin (C 21 H 18 ClNO 6 )= W S × (A T / A S ) × (V´/V) × (1/C) × 180W S : Amount (mg) of acemetacin for assayC: Labeled amount (mg) of acemetacin (C 21 H 18 ClNO 6 ) in 1capsuleAssay Take out the contents of not less than 20 AcemetacinCapsules, weigh accurately the mass of the contents, and powder.Weigh accurately a portion of the powder, equivalent toabout 30 mg of acemetacin (C 21 H 18 ClNO 6 ), add 40 mL ofmethanol, shake well, and add methanol to make exactly 50 mL.Filter this solution, discard the first 10 mL of the filtrate, pipet 5mL of the subsequent filtrate, add exactly 2 mL of the internalstandard solution, add methanol to make 50 mL, and use thissolution as the sample solution. Separately, weigh accuratelyabout 30 mg of acemetacin for assay, previously dried at 105ºCfor 2 hours, and dissolve in methanol to make exactly 50 mL.Pipet 5 mL of this solution, add exactly 2 mL of the internalstandard solution, add methanol to make 50 mL, and use thissolution as the standard solution. Perform the test with 20 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and calculate the ratios, Q T and Q S , of the peakarea of acemetacin to that of the internal standard.Amount (mg) of acemetacin (C 21 H 18 ClNO 6 )= W S × (Q T /Q S )W S : Amount (mg) of acemetacin for assayInternal standard solution—A solution of hexyl parahydroxybenzoatein methanol (1 in 1000)Operating Conditions—2073

2074 Official Monographs Supplement II, JP XVDetector: An ultraviolet absorption photometer (wavelength254 nm)Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To 6 g of acetic acid (100) add water to make1000 mL, and adjust the pH to 3.2 with a solution of 1.36 g ofsodium acetate trihydrate in 100 mL of water. To 200 mL of thissolution add 300 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofacemetacin is about 7 minutes.System suitability—System performance: Dissolve 75 mg of acemetacin and 75mg of indometacin in 50 mL of methanol. To 2 mL of this solutionadd 2 mL of the internal standard solution, and add methanolto make 50 mL. When the procedure is run with 20 µL ofthis solution under the above operating conditions, acemetacin,indometacin and the internal standard are eluted in this orderwith the resolutions between the peaks of acemetacin and indometacinand between the peaks of indometacin and the internalstandard being not less than 3, respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof acemetacin to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Add the following:Acemetacin Tabletsアセメタシン 錠Acemetacin Tablets contain not less than 93.0% andnot more than 107.0% of the labeled amount ofacemetacin (C 21 H 18 ClNO 6 : 415.82).Method of preparation Prepare as directed under Tablets,with Acemetacin.Identification To a quantity of powdered Acemetacin Tablets,equivalent to 0.1 g of Acemetacin according to the labeledamount, add 100 mL of methanol, shake well, and filter. Take 10mL of the filtrate, and distil the methanol under reduced pressure.Dissolve the residue in 1 mL of methanol, centrifuge, anduse the supernatant liquid as the sample solution. Separately,dissolve 10 mg of acemetacin in 1 mL of methanol, and use thissolution as the standard solution. Perform the test with these solutionsas directed under Thin-layer Chromatography .Spot 2 µL each of the sample solution and standard solution on aplate of silica gel with fluorescent indicator for thin-layer chromatography.Develop the plate with a mixture of hexane,4-methyl-2-pentanone and acetic acid (100) (3:2:1) to a distanceof about 10 cm, and air-dry the plate. Examine under ultravioletlight (main wavelength: 254 nm): the spots obtained from thesample solution and standard solution show the same R f value.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Acemetacin Tablets add 3 mL of water, andshake until the tablet is disintegrated. Add 15 mL of methanol,shake for 20 minutes, and add methanol to make exactly V mLso that each mL contains about 1.2 mg of acemetacin(C 21 H 18 ClNO 6 ). Centrifuge this solution, filter the supernatantliquid, discard the first 10 mL of the filtrate, pipet 5 mL of thesubsequent filtrate, add exactly 1 mL of the internal standardsolution, add methanol to make 50 mL, and use this solution asthe sample solution. Proceed as directed in the Assay.Amount (mg) of acemetacin (C 21 H 18 ClNO 6 )= W S × (Q T /Q S ) × (V/25)W S : Amount (mg) of acemetacin for assayInternal standard solution—A solution of hexyl parahydroxybenzoatein methanol (1 in 250)Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof 2nd fluid for dissolution test as the dissolution medium, thedissolution rate in 45 minutes of Acemetacin Tablets is not lessthan 80%.Start the test with 1 tablet of Acemetacin Tablets, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add the dissolutionmedium to make exactly V´ mL so that each mL contains about33 µg of acemetacin (C 21 H 18 ClNO 6 ) according to the labeledamount, and use this solution as the sample solution. Separately,weigh accurately about 17 mg of acemetacin for assay, previouslydried at 105ºC for 2 hours, dissolve in the dissolution mediumto make exactly 100 mL. Pipet 4 mL of this solution, addthe dissolution medium to make exactly 20 mL, and use this solutionas the standard solution. Determine the absorbances, A Tand A S , of the sample solution and standard solution at 319 nmas directed under Ultraviolet-visible Spectrophotometry .Dissolution rate (%) with respect to the labeled amount ofacemetacin (C 21 H 18 ClNO 6 )= W S × (A T / A S ) × (V´/V) × (1/C) × 180W S : Amount (mg) of acemetacin for assayC: Labeled amount (mg) of acemetacin (C 21 H 18 ClNO 6 ) in 1tabletAssay Weigh accurately the mass of not less than 20Acemetacin Tablets, and powder. Weigh accurately a portion ofthe powder, equivalent to about 0.6 g of acemetacin(C 21 H 18 ClNO 6 ), add 120 mL of methanol, shake for 20 minutes,and add methanol to make exactly 200 mL. Centrifuge this solution,filter the supernatant liquid, discard the first 10 mL of thefiltrate, pipet 2 mL of the subsequent filtrate, add exactly 1 mL

Supplement II, JP XV Official Monographs 2075of the internal standard solution, add methanol to make 50 mL,and use this solution as the sample solution. Separately, weighaccurately about 30 mg of acemetacin for assay, previouslydried at 105ºC for 2 hours, and dissolve in methanol to makeexactly 25 mL. Pipet 5 mL of this solution, add exactly 1 mL ofthe internal standard solution, add methanol to make 50 mL, anduse this solution as the standard solution. Perform the test with10 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions, and calculate the ratios, Q T and Q S , of thepeak area of acemetacin to that of the internal standard.Amount (mg) of acemetacin (C 21 H 18 ClNO 6 )= W S × (Q T /Q S ) × 20W S : Amount (mg) of acemetacin for assayInternal standard solution—A solution of hexyl parahydroxybenzoatein methanol (1 in 250)Operating Conditions—Detector: An ultraviolet absorption photometer (wavelength254 nm)Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To 6 g of acetic acid (100) add water to make1000 mL, and adjust the pH to 3.2 with a solution of 1.36 g ofsodium acetate trihydrate in 100 mL of water. To 200 mL of thissolution add 300 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofacemetacin is about 7 minutes.System suitability—System performance: Dissolve 75 mg of acemetacin and 75mg of indometacin in 50 mL of methanol. To 4 mL of this solutionadd 1 mL of the internal standard solution, and add methanolto make 50 mL. When the procedure is run with 10 µL ofthis solution under the above operating conditions, acemetacin,indometacin and the internal standard are eluted in this orderwith the resolutions between the peaks of acemetacin and indometacinand between the peaks of indometacin and the internalstandard being not less than 3, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof acemetacin to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Add the following:AciclovirアシクロビルC 8 H 11 N 5 O 3 : 225.202-Amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one [59277-89-3]Aciclovir contains not less than 98.5 and not morethan 101.0% of C 8 H 11 N 5 O 3 , calculated on the anhydrousbasis.Description Aciclovir occurs as a white to pale yellowishwhite crystalline powder.It is slightly soluble in water and very slightly soluble inethanol (99.5).It dissolves in 0.1 mol/L hydrochloric acid TS and in dilutesodium hydroxide TS.Identification (1) Determine the absorption spectrum of asolution of Aciclovir in 0.1 mol/L hydrochloric acid TS (1 in100000) as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the Reference Spectrumor the spectrum of Aciclovir Reference Standard: bothspectra exhibit similar intensities of absorption at the samewavelengths.(2) Determine the infrared absorption spectrum of Acicloviras directed in the potassium bromide disk method under InfraredSpectrophotometry , and compare the spectrum with theReference Spectrum or the spectrum of Aciclovir ReferenceStandard: both spectra exhibit similar intensities of absorption atthe same wave numbers.Purity (1) Clarity and color of solution—Dissolve 0.5 g ofAciclovir in 20 mL of dilute sodium hydroxide TS: the solutionis clear and is not more colored than the following control solution.Control solution: To 2.5 mL of Matching Fluid for Color Fadd diluted dilute hydrochloric acid (1 in 10) to make 100 mL.(2) Heavy metals —Proceed with 1.0 g of Acicloviraccording to Method 2, and perform the test. Prepare the controlsolution with 1.0 mL of Standard Lead Solution (not more than10 ppm).(3) Related substances—Use the sample solution obtainedin the Assay as the sample solution. Separately, weigh accuratelyabout 25 mg of guanine, dissolve in 50 mL of dilute sodiumhydroxide TS, and add the mobile phase to make exactly100 mL. Pipet 2 mL of this solution, add the mobile phase tomake exactly 100 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the samplesolution and standard solution as directed under Liquid Chro-

2076 Official Monographs Supplement II, JP XVmatography according to the following conditions. Determinethe peak areas of guanine, A T and A S , and calculate theamount of guanine by the following equation: it is not more than0.7%. Determine each peak area from the sample solution by theautomatic integration method, and calculate the amount of eachrelated substance other than aciclovir and guanine by the areapercentage method: it is not more than 0.2%. Furthermore, thesum of the amount of guanine calculated above and the amountsof related substances determined by the area percentage methodis not more than 1.5%.Amount (%) of guanine = (W S /W T ) × (A T /A S ) × (2/5)W S : Amount (mg) of guanineW T : Amount (mg) of AciclovirOperating Conditions—Detector, column, column temperature, mobile phase, andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 8 times as long as the retentiontime of aciclovir beginning after the solvent peak.System suitability—System performance: Proceed as directed in the system suitabilityin the Assay.Test for required detectability: Pipet 1 mL of the sample solution,add the mobile phase to make exactly 100 mL, and use thissolution as the solution for system suitability test. Pipet 1 mL ofthe solution for system suitability test, and add the mobile phaseto make exactly 10 mL. Confirm that the peak area of aciclovirobtained from 10 µL of this solution is equivalent to 7 to 13% ofthat from the solution for system suitability test.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of guanineis not more than 2.0%.(4) Residual solvent—Being specified separately.Water Not more than 6.0% (50 mg, potentiometric titration).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 20 mg each of Aciclovir andAciclovir Reference Standard (separately determine the water in the same manner as Aciclovir), dissolve each in 1 mLof dilute sodium hydroxide TS, add the mobile phase to makeexactly 20 mL each, and use these solutions as the sample solutionand standard solutions, respectively. Perform the test with10 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions, and determine the peak areas, A T and A S ,of aciclovir in each solution.Amount (mg) of C 8 H 11 N 5 O 3 = W S × (A T /A S )Ws: Amount (mg) of Aciclovir Reference Standard, calculatedon the anhydrous basisOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm)Column: A stainless steel column 4.6 mm in inside diameterand 10 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 20ºC.Mobile phase: Dissolve 1.0 g of sodium 1-decanesulfonateand 6.0 g of sodium dihydrogen phosphate dihydrate in 1000mL of water, and adjust the pH to 3.0 with phosphoric acid. Tothis solution add 40 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofaciclovir is about 3 minutes.System suitability—System performance: Dissolve 0.1 g of Aciclovir in 5 mL ofdilute sodium hydroxide TS, add 2 mL of a solution of guaninein dilute sodium hydroxide TS (1 in 4000), and add the mobilephase to make 100 mL. When the procedure is run with 10 µL ofthis solution under the above operating conditions, aciclovir andguanine are eluted in this order with the resolution betweenthese peaks being not less than 17.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of acicloviris not more than 1.0%.Containers and storage Containers—Well-closed containers.Add the following:L-AlanineL‐アラニンC 3 H 7 NO 2 : 89.09(2S)-2-Aminopropanoic acid [56-41-7]L-Alanine, when dried, contains not less than 98.5%and not more than 101.0% of C 3 H 7 NO 2 .Description L-Alanine occurs as white crystals or crystallinepowder. It has a slightly sweet taste.It is freely soluble in water and in formic acid, and practicallyinsoluble in ethanol (99.5).It dissolves in 6 mol/L hydrochloric acid TS.Identification Determine the infrared absorption spectrum ofL-Alanine as directed in the potassium bromide disk methodunder Infrared Spectrophotometry , and compare thespectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.Optical rotation [α] 20D: +13.5 - +15.5º (after drying,2.5 g, 6 mol/L hydrochloric acid TS, 25 mL, 100 mm).pH Dissolve 1.0 g of L-Alanine in 20 mL of water: thepH of the solution is between 5.7 and 6.7.

Supplement II, JP XV Official Monographs 2077Purity (1) Clarity and color of solution—Dissolve 1.0 g ofL-Alanine in 10 mL of water: the solution is clear and colorless.(2) Chloride —Perform the test with 0.5 g ofL-Alanine. Prepare the control solution with 0.30 mL of 0.01mol/L hydrochloric acid VS (not more than 0.021%).(3) Sulfate —Perform the test with 0.6 g ofL-Alanine. Prepare the control solution with 0.35 mL of 0.005mol/L sulfuric acid VS (not more than 0.028%).(4) Ammonium —Perform the test with 0.25 g ofL-Alanine. Prepare the control solution with 5.0 mL of StandardAmmonium Solution (not more than 0.02%).(5) Heavy metals —Proceed with 1.0 g of L-Alanineaccording to Method 1, and perform the test. Prepare the controlsolution with 1.0 mL of Standard Lead Solution (not more than10 ppm).(6) Iron —Prepare the test solution with 1.0 g ofL-Alanine according to Method 1, and perform the test accordingto Method A. Prepare the control solution with 1.0 mL ofStandard Iron Solution (not more than 10 ppm).(7) Related substances—Weigh accurately about 0.5 g ofL-Alanine, dissolve in 0.5 mL of hydrochloric acid and water tomake exactly 100 mL. Pipet 5 mL of this solution, add 0.02mol/L hydrochloric acid TS to make exactly 50 mL, and use thissolution as the sample solution. Separately, accurately measure2.5 mmol amounts of L-aspartic acid, L-threonine, L-serine,L-glutamic acid, glycine, L-alanine, L-valine, L-cystine,L-methionine, L-isoleucine, L-leucine, L-tyrosine,L-phenylalanine, L-lysine hydrochloride, ammonium chloride,L-histidine hydrochloride monohydrate, and L-arginine, dissolvein 0.1 mol/L hydrochloric acid TS to make exactly 1000 mL,and use this solution as the standard stock solution. Pipet 5 mLof this solution, add 0.02 mol/L hydrochloric acid TS to makeexactly 100 mL. Pipet 2 mL of this solution, add 0.02 mol/L hydrochloricacid TS to make exactly 50 mL, and use this solutionas the standard solution. Perform the test with 20 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions.Based on the peak heights obtained from the sample solutionand standard solution, determine the mass of the amino acidsother than alanine contained in 1 mL of the sample solution, andcalculate the mass percent: the amount of each amino acid otherthan alanine is not more than 0.1%.Operating conditions—Detector: A visible spectrophotometer (wavelength: 570 nm)Column: A stainless steel column 4.6 mm in inside diameterand 8 cm in length, packed with strongly acidic ion-exchangeresin for liquid chromatography (sodium type) composed with asulfonated polystyrene copolymer (3 µm in particle diameter).Column temperature: A constant temperature of about 57ºC.Chemical reaction bath temperature: A constant temperatureof about 130ºC.Reaction time: About 1 minute.Mobile phase: Prepare mobile phases A, B, C, D and E accordingto the following table, and add 0.1 mL of capric acid toeach mobile phase.Mobile phase A Mobile phase B Mobile phase C Mobile phase D Mobile phase ECitric acid monohydrate 19.80 g 22.00 g 12.80 g 6.10 g -Trisodium citrate dihydrate 6.19 g 7.74 g 13.31 g 26.67 g -Sodium chloride 5.66 g 7.07 g 3.74 g 54.35 g -Sodium hydroxide - - - - 8.00 gEthanol (99.5) 260 mL 20 mL 4 mL - 100 mLThiodiglycol 5 mL 5 mL 5 mL - -Benzyl alcohol - - - 5 mL -Lauromacrogol solution (1 in 4) 4 mL 4 mL 4 mL 4 mL 4 mLWaterAppropriateamountAppropriateamountAppropriateamountAppropriateamountAppropriateamountTotal volume 2000 mL 1000 mL 1000 mL 1000 mL 1000 mLChanging mobile phases: When the procedure is run with 20µL of the standard solution under the above operating conditions,switchover to mobile phase A, mobile phase B, mobile phase C,mobile phase D and mobile phase E, in sequence so that asparticacid, threonine, serine, glutamic acid, glycine, alanine, valine,cystine, methionine, isoleucine, leucine, tyrosine, phenylalanine,lysine, ammonia, histidine, and arginine are eluted in this orderwith the resolution between the peaks of isoleucine and leucinebeing not less than 1.2.Reaction reagents: Dissolve 407 g of lithium acetate dehydratein water, add 245 mL of acetic acid (100) and 801 mL of1-methoxy-2-propanol, and water to make 2000 mL, introducenitrogen for 10 minutes, and use this solution as solution (I).Separately, add 77 g of ninhydrin to 1957 mL of1-methoxy-2-propanol, introduce nitrogen for 5 minutes, add0.134 g of sodium borohydride, and introduce nitrogen for 30minutes. To 12 volumes of this solution add 13 volumes of solution(I). Prepare before use.Flow rate of mobile phase: 0.32 mL per minute.Flow rate of reaction reagent: 0.30 mL per minute.

2078 Official Monographs Supplement II, JP XVSystem suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the resolution between the peaks of glycine and alanine is notless than 1.5.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviations of the peak height and retentiontime of each amino acid obtained from the standard solutionare not more than 5.0% and not more than 1.0%, respectively.Loss on drying Not more than 0.3% (1 g, 105ºC, 3hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 90 mg of L-Alanine, previouslydried, dissolve in 3 mL of formic acid, add 50 mL of acetic acid(100), and titrate with 0.1 mol/L perchloric acid VS (potentiometrictitration). Perform a blank determination in thesame manner, and make any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 8.909 mg of C 3 H 7 NO 2Containers and storage Containers—Tight containers.Add the following:Allopurinol Tabletsアロプリノール 錠Allopurinol Tablets contain not less than 93.0% andnot more than 107.0% of the labeled amount of allopurinol(C 5 H 4 N 4 O: 136.11).Method of preparation Prepare as directed under Tablets,with Allopurinol.Identification (1) Determine the absorption spectrum of thesample solution obtained in the Assay as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximumbetween 248 nm and 252 nm.(2) To a quantity of powdered Allopurinol Tablets, equivalentto 0.1 g of Allopurinol according to the labeled amount, add5 mL of a solution of diethylamine (1 in 10), shake well, add 5mL of methanol, centrifuge, and use the supernatant liquid asthe sample solution. Separately, dissolve 0.1 g of allopurinol in5 mL of a solution of diethylamine (1 in 10), add 5 mL ofmethanol, and use this solution as the standard solution. Performthe test with these solutions as directed under Thin-layer Chromatography. Spot 2.5 µL each of the sample solutionand standard solution on a plate of silica gel with fluorescent indicatorfor thin-layer chromatography. Develop the plate with amixture of 2-butanone, ammonia solution (28) and2-methoxyethanol (3:1:1) to a distance of about 10 cm, andair-dry the plate. Examine under ultraviolet light (main wavelength:254 nm): the principal spots obtained from the samplesolution and standard solution show the same R f value.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Allopurinol Tablets add V/10 mL of 0.05 mol/Lsodium hydroxide TS, shake well, and treat with ultrasonicwaves for 10 minutes. After cooling, add 0.1 mol/L hydrochloricacid TS to make exactly V mL so that each mL contains about0.5 mg of allopurinol (C 5 H 4 N 4 O), and filter through a membranefilter with a pore size not exceeding 0.8 µm. Discard thefirst 10 mL of the filtrate, pipet 2 mL of the subsequent filtrate,add 0.1 mol/L of hydrochloric acid TS to make exactly 100 mL,and use this solution as the sample solution. Separately, weighaccurately about 50 mg of allopurinol for assay, previously driedat 105ºC for 4 hours, dissolve in 10 mL of 0.05 mol/L sodiumhydroxide TS, and add 0.1 mol/L hydrochloric acid TS to makeexactly 100 mL. Pipet 2 mL of this solution, add 0.1 mol/L hydrochloricacid TS to make exactly 100 mL, and use this solutionas the standard solution. Determine the absorbances, A T andA S , of the sample solution and standard solution at 250 nm asdirected under Ultraviolet-visible Spectrophotometry .Amount (mg) of allopurinol (C 5 H 4 N 4 O)= W S × (A T /A S ) × (V/100)W S : Amount (mg) of allopurinol for assayDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Allopurinol Tablets is not less than 80%.Start the test with 1 tablet of Allopurinol Tablets, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.8 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to make exactlyV´ mL so that each mL contains about 11 µg of allopurinol(C 5 H 4 N 4 O) according to the labeled amount, and use this solutionas the sample solution. Separately, weigh accurately about11 mg of allopurinol for assay, previously dried at 105ºC for 4hours, and dissolve in water to make exactly 100 mL. Pipet 5mL of this solution, add water to make exactly 50 mL, and usethis solution as the standard solution. Determine the absorbances,A T and A S , of the sample solution and standard solution at250 nm as directed under Ultraviolet-visible Spectrophotometry.Dissolution rate (%) with respect to the labeled amount ofallopurinol (C 5 H 4 N 4 O)= W S × (A T /A S ) × (V´/V) × (1/C) × 90W S : Amount (mg) of allopurinol for assayC: Labeled amount (mg) of allopurinol (C 5 H 4 N 4 O) in 1 tabletAssay Weigh accurately the mass of not less than 20 AllopurinolTablets, and powder. Weigh accurately a portion of thepowder, equivalent to about 0.1 g of allopurinol (C 5 H 4 N 4 O), add

Supplement II, JP XV Official Monographs 207920 mL of 0.05 mol/L sodium hydroxide TS, shake well, andtreat with ultrasonic waves for 10 minutes. After cooling, add0.1 mol/L hydrochloric acid TS to make exactly 200 mL, andfilter through a membrane filter with a pore size not exceeding0.8 µm. Discard the first 10 mL of the filtrate, pipet 2 mL of thesubsequent filtrate, add 0.1 mol/L hydrochloric acid TS to makeexactly 100 mL, and use this solution as the sample solution.Separately, weigh accurately about 0.1 g of allopurinol for assay,previously dried at 105ºC for 4 hours, dissolve in 20 mL of 0.05mol/L sodium hydroxide TS, and add 0.1 mol/L hydrochloricacid TS to make exactly 200 mL. Pipet 2 mL of this solution,add 0.1 mol/L hydrochloric acid TS to make exactly 100 mL,and use this solution as the standard solution. Determine theabsorbances, A T and A S , of the sample solution and standard solutionat 250 nm as directed under Ultraviolet-visible Spectrophotometry.Amount (mg) of allopurinol (C 5 H 4 N 4 O) = W S × (A T /A S )W S : Amount (mg) of allopurinol for assayContainers and storage Containers—Well-closed containers.Dried Aluminum Hydroxide GelFine Granules乾 燥 水 酸 化 アルミニウムゲル 細 粒Change the Method of preparation to read:Method of preparation Prepare to finely granulated form asdirected under Powders, with Dried Aluminum Hydroxide Gel.= W S × (A T /A S )W S : Amount (mg) of theophylline for assayOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:270 nm).Column: A stainless steel column 6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of diluted acetic acid (100) (1 in100) and methanol (4:1).Flow rate: Adjust the flow rate so that the retention time oftheophylline is about 5 minutes.System suitability—System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions, thenumber of theoretical plates and the symmetry factor of the peakof theophylline are not less than 3000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of theophyllineis not more than 1.0%.Add the following:Amiodarone Hydrochlorideアミオダロン 塩 酸 塩Add the following next to the Identification:Particle size It meets the requirement.Aminophylline Injectionアミノフィリン 注 射 液Change the Assay (1) to read:Assay (1) Theophylline—Pipet a volume of AminophyllineInjection, equivalent to about 39.4 mg of theophylline(C 7 H 8 N 4 O 2 ) (about 50 mg of Aminophylline Hydrate), add waterto make exactly 50 mL, and use this solution as the samplesolution. Separately, weigh accurately about 40 mg of theophyllinefor assay, previously dried at 105ºC for 4 hours, dissolve inwater to make exactly 50 mL, and use this solution as the standardsolution. Perform the test with exactly 5 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak areas, A T and A S , of theophylline in eachsolution.Amount (mg) of theophylline (C 7 H 8 N 4 O 2 )C 25 H 29 I 2 NO 3·HCl: 681.77(2-Butylbenzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl}methanone monohydrochloride [19774-82-4]Amiodarone Hydrochloride, when dried, containsnot less than 98.5% and not more than 101.0% ofC 25 H 29 I 2 NO 3·HCl.Description Amiodarone Hydrochloride occurs as awhite to pale yellowish white crystalline powder.It is very soluble in water at 80ºC, freely soluble in dichloromethane,soluble in methanol, sparingly soluble inethanol (95), and very slightly soluble in water.Melting point: about 161ºC (with decomposition).Identification (1) Determine the absorption spectrum of asolution of Amiodarone Hydrochloride in ethanol (95) (1 in100000) as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the Reference Spectrum:both spectra exhibit similar intensities of absorption at thesame wavelengths.

2080 Official Monographs Supplement II, JP XV(2) Determine the infrared absorption spectrum of AmiodaroneHydrochloride as directed in the potassium bromide diskmethod under Infrared Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) To 0.1 g of Amiodarone Hydrochloride add 10 mL ofwater, dissolve by warming at 80ºC, and cool: the solution respondsto the Qualitative Tests (2) for chloride.pH To 1.0 g of Amiodarone Hydrochloride add 20 mLof freshly boiled and cooled water, dissolve by warming at 80ºC,and cool: the pH of this solution is between 3.2 and 3.8.Purity (1) Clarity and color of solution—Dissolve 0.5 g ofAmiodarone Hydrochloride in 10 mL of methanol: the solutionis clear, and is not more colored than the following control solutions(1) and (2).Control solution (1): To a mixture of 1.0 mL of Cobalt (II)Chloride Colorimetric Stock Solution, 2.4 mL of Iron (III)Chloride Colorimetric Stock Solution and 0.4 mL of Copper (II)Sulfate Colorimetric Stock Solution, add diluted hydrochloricacid (1 in 40) to make 10.0 mL. To 2.5 mL of this solution adddiluted hydrochloric acid (1 in 40) to make 20 mL.Control solution (2): To 3.0 mL of a mixture of 0.2 mL ofCobalt (II) Chloride Colorimetric Stock Solution, 9.6 mL of Iron(III) Chloride Colorimetric Stock Solution and 0.2 mL of Copper(II) Sulfate Colorimetric Stock Solution, add diluted hydrochloricacid (1 in 40) to make 100 mL.(2) Iodine—To 1.50 g of Amiodarone Hydrochloride add 40mL of water, dissolve by warming at 80ºC, cool, add water tomake exactly 50 mL, and use this solution as the sample stocksolution. Pipet 15 mL of this solution, add exactly 1 mL of 0.1mol/L hydrochloric acid TS and exactly 1 mL of a solution ofpotassium iodate (107 in 10000), add water to make exactly 20mL, and use this solution as the sample solution. Separately, pipet15 mL of the sample stock solution, add exactly 1 mL of 0.1mol/L hydrochloric acid TS, exactly 1 mL of a solution of potassiumiodide (441 in 5000000) and exactly 1 mL of a solutionof potassium iodate (107 in 10000), add water to make exactly20 mL, and use this solution as the standard solution. Separately,pipet 15 mL of the sample stock solution, add exactly 1 mL of0.1 mol/L hydrochloric acid TS, add water to make exactly 20mL, and use this solution as the control solution. Allow thesample solution, standard solution and control solution to standin a dark place for 4 hours. Perform the test with the sample solutionand standard solution as directed under Ultraviolet-visibleSpectrophotometry , using the control solution as theblank: the absorbance of the sample solution at 420 nm is notlarger than 1/2 times the absorbance of the standard solution.(3) Heavy metals —Proceed with 1.0 g of AmiodaroneHydrochloride according to Method 4, and perform the test.Prepare the control solution with 2.0 mL of Standard Lead Solution(not more than 20 ppm).(4) Related substance 1—Dissolve 0.5 g of AmiodaroneHydrochloride in 5 mL of dichloromethane, and use this solutionas the sample solution. Separately, dissolve 10 mg of2-chloroethyl diethylamine hydrochloride in 50 mL of dichloromethane,and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 5 µL each of the samplesolution and standard solution on a plate of silica gel withfluorescent indicator for thin-layer chromatography. Develop theplate with a mixture of dichloromethane, methanol and formicacid (17:2:1) to a distance of about 15 cm, and air-dry the plate.Splay evenly bismuth subnitrate TS and then hydrogen peroxideTS: the spot obtained from the sample solution corresponding tothe spot from the standard solution is not more intense than thespot from the standard solution.(5) Related substance 2—Dissolve 0.125 g of AmiodaroneHydrochloride in 25 mL of a mixture of water and acetonitrilefor liquid chromatography (1:1), and use this solution as thesample solution. Pipet 2 mL of this solution, and add a mixtureof water and acetonitrile for liquid chromatography (1:1) tomake exactly 50 mL. Pipet 1 mL of this solution, add a mixtureof water and acetonitrile for liquid chromatography (1:1) tomake exactly 20 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area by the automatic integration method: thearea of any peak other than amiodarone obtained from the samplesolution is not larger than the peak area of amiodarone fromthe standard solution, and the total area of the peaks other thanthe peak of amiodarone from the sample solution is not largerthan 2.5 times the peak area of amiodarone from the standardsolution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:240 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 30ºC.Mobile phase: To 800 mL of water add 3.0 mL of acetic acid(100), adjust the pH to 4.95 with ammonia solution (28), andadd water to make 1000 mL. To 300 mL of this solution add 400mL of acetonitrile for liquid chromatography and 300 mL ofmethanol for liquid chromatography.Flow rate: Adjust the flow rate so that the retention time ofamiodarone is about 24 minutes.Time span of measurement: About 2 times as long as the retentiontime of amiodarone.System suitability—Test for required detectability: Pipet 5 mL of the standard solution,and add a mixture of water and acetonitrile for liquidchromatography (1:1) to make exactly 25 mL. Confirm that thepeak area of amiodarone obtained from 10 µL of this solution isequivalent to 14 to 26% of that of amiodarone from the standardsolution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amiodarone are not less than 5000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with

Supplement II, JP XV Official Monographs 208110 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of amiodaroneis not more than 1.0%.(6) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, reducedpressure not exceeding 0.3 kPa, 50ºC, 4 hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.6 g of Amiodarone Hydrochloride,previously dried, dissolve in 40 mL of a mixture ofacetic anhydride and acetic acid (100) (3:1), and titrate with 0.1 mol/L perchloric acid VS (potentiometric titration).Perform a blank determination in the same manner, and makeany necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 68.18 mg of C 25 H 29 I 2 NO 3·HClContainers and storage Containers—Tight containers.Storage—Light-resistant.Add the following:Amiodarone Hydrochloride Tabletsアミオダロン 塩 酸 塩 錠Amiodarone Hydrochloride Tablets contain not lessthan 93.0% and not more than 107.0% of the labeledamount of amiodarone hydrochloride(C 25 H 29 I 2 NO 3·HCl: 681.77).Method of preparation Prepare as directed under Tablets,with Amiodarone Hydrochloride.Identification To 1 mL of the sample stock solution obtainedin the Assay add the mobile phase to make 50 mL. Determinethe absorption spectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximumbetween 239 nm and 243 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Amiodarone Hydrochloride Tablets add 160 mLof the mobile phase, treat with ultrasonic waves for 10 minutes,add the mobile phase to make exactly 200 mL, and centrifuge.Pipet V mL of the supernatant liquid, equivalent to about 1 mgof amiodarone hydrochloride (C 25 H 29 I 2 NO 3·HCl), add the mobilephase to make exactly 50 mL, and use this solution as thesample solution. Separately, weigh accurately about 25 mg ofamiodarone hydrochloride for assay, previously dried at 50ºCfor 4 hours under reduced pressure not exceeding 0.3 kPa, anddissolve in the mobile phase to make exactly 50 mL. Pipet 2 mLof this solution, add the mobile phase to make exactly 50 mL,and use this solution as the standard solution. Perform the testwith exactly 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions, and determine the peak areas,A T and A S , of amiodarone in each solution.Amount (mg) of amiodarone hydrochloride(C 25 H 29 I 2 NO 3·HCl)= W S × (A T /A S ) × (8/V)W S : Amount (mg) of amiodarone for assayOperating conditions—Proceed as directed in the operating conditions in the Assay.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amiodarone are not less than 5000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of amiodaroneis not more than 1.0%.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof acetic acid-sodium acetate buffer solution, pH 4.0, as thedissolution medium, the dissolution rate in 30 minutes ofAmiodarone Hydrochloride Tablets is not less than 80%.Start the test with 1 tablet of Amiodarone Hydrochloride Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membranefilter with a pore size not exceeding 0.45 µm. Discard the first10 mL of the filtrate, pipet V mL of the subsequent filtrate, addmethanol to make exactly V´ mL so that each mL contains about11 µg of amiodarone hydrochloride (C 25 H 29 I 2 NO 3·HCl) accordingto the labeled amount, and use this solution as the samplesolution. Separately, weigh accurately about 28 mg of amiodaronehydrochloride for assay, previously dried at 50ºC for 4hours under reduced pressure not exceeding 0.3 kPa, and dissolvein methanol to make exactly 50 mL. Pipet 2 mL of thissolution, add exactly 10 mL of the dissolution medium, addmethanol to make exactly 100 mL, and use this solution as thestandard solution. Determine the absorbances, A T and A S , of thesample solution and standard solution at 241 nm as directed underUltraviolet-visible Spectrophotometry , using a solution,prepared by adding methanol to 2 mL of the dissolutionmedium to make 20 mL, as the blank.Dissolution rate (%) with respect to the labeled amount ofamiodarone hydrochloride (C 25 H 29 I 2 NO 3·HCl)= W S × (A T /A S ) × (V´/V) × (1/C) × 36W S : Amount (mg) of amiodarone for assayC: Labeled amount (mg) of amiodarone hydrochloride(C 25 H 29 I 2 NO 3·HCl) in 1 tabletAssay Weigh accurately the mass of not less than 20 AmiodaroneHydrochloride Tablets, and powder. Weigh accurately aportion of the powder, equivalent to about 50 mg of amiodarone

2082 Official Monographs Supplement II, JP XVhydrochloride (C 25 H 29 I 2 NO 3·HCl), add 80 mL of the mobilephase, treat with ultrasonic waves for 10 minutes, and add themobile phase to make exactly 100 mL. Centrifuge this solution,and use the supernatant liquid as the sample stock solution. Pipet2 mL of this solution, add 2 mL of the internal standard solution,add the mobile phase to make 50 mL, and use this solutionas the sample solution. Separately, weigh accurately 25 mgof amiodarone hydrochloride for assay, previously dried at 50ºCfor 4 hours under reduced pressure not exceeding 0.3 kPa, anddissolve in the mobile phase to make exactly 50 mL. Pipet 2 mLof this solution, add exactly 2 mL of the internal standard solution,add the mobile phase to make 50 mL, and use this solutionas the standard solution. Perform the test with 10 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of amiodaroneto that of the internal standard.Amount (mg) of amiodarone hydrochloride(C 25 H 29 I 2 NO 3·HCl)= W S × (Q T /Q S ) × 2W S : Amount (mg) of amiodarone hydrochloride for assayInternal standard solution—A solution of chlorhexidine hydrochloridein the mobile phase (1 in 2500)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:242 nm)Column: A stainless steel column 4 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 50ºC.Mobile phase: A mixture of acetonitrile for liquid chromatography,a solution of sodium laurylsulfate (1 in 50) and phosphoricacid (750:250:1).Flow rate: Adjust the flow rate so that the retention time ofamiodarone is about 7 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the internal standard and amiodarone are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof amiodarone to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Storage—Light-resistant.Add the following:Amlodipine Besilate Tabletsアムロジピンベシル 酸 塩 錠Amlodipine Besilate Tablets contain not less than95.0% and not more than 105.0% of the labeledamount of amlodipine besilate(C 20 H 25 ClN 2 O 5·C 6 H 6 O 3 S: 567.05).Method of preparation Prepare as directed under Tablets,with Amlodipine Besilate.Identification To a quantity of powdered Amlodipine BesilateTablets, equivalent to 2.5 mg of Amlodipine Besilate accordingto the labeled amount, add 100 mL of 0.01 mol/L hydrochloricacid-methanol TS, shake vigorously, and filter. Determine theabsorption spectrum of the filtrate as directed under Ultraviolet-visibleSpectrophotometry : it exhibits maxima between235 nm and 239 nm, and between 358 nm and 362 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Amlodipine Besilate Tablets add 10 mL of waterto disintegrate, disperse with the aid of ultrasonic waves withoccasional shaking, add the mobile phase to make exactly V mLso that each mL contains about 69 µg of amlodipine besilate(C 20 H 25 ClN 2 O 5·C 6 H 6 O 3 S), and shake for 60 minutes. Centrifugethis solution, pipet 10 mL of the supernatant liquid, add exactly5 mL of the internal standard solution, add the mobile phase tomake 25 mL, and use this solution as the sample solution. Proceedas directed in the Assay.Amount (mg) of amlodipine besilate(C 20 H 25 ClN 2 O 5·C 6 H 6 O 3 S)= W S × (Q T /Q S ) × (V/500)W S : Amount (mg) of Amlodipine Besilate Reference Standard,calculated on the anhydrous basisInternal standard solution—A solution of isobutyl parahydroxybenzoatein the mobile phase (3 in 20000)Dissolution Being specified separately.Assay To 20 Amlodipine Besilate Tablets add 100 mL of waterto disintegrate, disperse with the aid of ultrasonic waves withoccasional shaking, add the mobile phase to make exactly 1000mL, and shake for 60 minutes. Centrifuge this solution, pipet avolume of the supernatant liquid, equivalent to about 0.7 mg ofamlodipine besilate (C 20 H 25 ClN 2 O 5·C 6 H 6 O 3 S), add exactly 5 mLof the internal standard solution, add the mobile phase to make25 mL, and use this solution as the sample solution. Separately,weigh accurately about 35 mg of Amlodipine Besilate ReferenceStandard (separately, determine the water in the samemanner as Amlodipine Besilate), and dissolve in the mobilephase to make exactly 250 mL. Pipet 5 mL of this solution, add

Supplement II, JP XV Official Monographs 2083exactly 5 mL of the internal standard solution, add the mobilephase to make 25 mL, and use this solution as the standard solution.Perform the test with 20 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of amlodipine to that of theinternal standard.Amount (mg) of amlodipine besilate(C 20 H 25 ClN 2 O 5·C 6 H 6 O 3 S)= W S × (Q T /Q S ) × (1/50)W S : Amount (mg) of Amlodipine Besilate Reference Standard,calculated on the anhydrous basisInternal standard solution—A solution of isobutyl parahydroxybenzoatein the mobile phase (3 in 20000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:237 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of methanol and potassium dihydrogenphosphate (41 in 10000) (13:7)Flow rate: Adjust the flow rate so that the retention time ofamlodipine is about 8 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,amlodipine and the internal standard are eluted in this order withthe resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratios of the peakarea of amlodipine to that of the internal standard is not morethan 1.0%.Containers and storage Containers—Well-closed containers.Add the following:Amoxicillin CapsulesアモキシシリンカプセルAmoxicillin Capsules contain not less than 92.0%and not more than 105.0% of the labeled potency ofAmoxicillin (C 16 H 19 N 3 O 5 S: 365.40).Method of preparation Prepare as directed under Capsules,with Amoxicillin Hydrate.Identification Take out the contents of Amoxicillin Capsules,to a quantity of the contents, equivalent to 8 mg (potency) ofAmoxicillin Hydrate according to the labeled amount, add 2 mLof 0.01 mol/L hydrochloric acid TS, shake for 30 minutes, filter,and use the filtrate as the sample solution. Separately, dissolvean amount equivalent to 8 mg (potency) of Amoxicillin ReferenceStandard in 2 mL of 0.01 mol/L hydrochloric acid TS, anduse this solution as the standard solution. Perform the test withthese solutions as directed under Thin-layer Chromatography. Spot 5 µL each of the sample solution and standard solutionon a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of tetrahydrofuran, water andformic acid (50:5:2) to a distance of about 10 cm, and air-drythe plate. Spray evenly a solution of ninhydrin in ethanol (95) (1in 20) on the plate, and heat the plate at 110ºC for 15 minutes:the principal spot obtained from the sample solution and thestandard solution show a red-purple color and the same R f value.Purity Related substances— Take out the contents of AmoxicillinCapsules, to a quantity of the contents, equivalent to 0.1 g(potency) of Amoxicillin Hydrate according to the labeledamount, add 30 mL of a solution of boric acid (1 in 200), shakefor 15 minutes, and add a solution of boric acid (1 in 200) tomake 50 mL. Centrifuge this solution, and use the supernatantliquid as the sample solution. Pipet 1 mL of this solution, add asolution of boric acid (1 in 200) to make exactly 100 mL, anduse this solution as the standard solution. Perform the test withexactly 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography according tothe following conditions. Determine each peak area of both solutionsby the automatic integration method: the area of eachpeak other than amoxicillin obtained from the sample solution isnot larger than the peak area of amoxicillin from the standardsolution.Operating conditions—Proceed as directed in the operating conditions in the Purity(3) under Amoxicillin Hydrate.System suitability—Test for required detectability and system repeatability: Proceedas directed in the system suitability in the Purity (3) underAmoxicillin Hydrate.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amoxicillin is not less than 2500 and not more than 1.5,respectively.Water Not more than 15.0% (0.1 g, volumetric titration,direct titration).Uniformity of dosage units It meets the requirementof the Mass variation test.Dissolution When the test is performed at 100 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of water as the dissolution medium, thedissolution rate in 60 minutes of Amoxicillin Capsules is notless than 75%.Start the test with 1 capsule of Amoxicillin Capsules, withdrawnot less than 20 mL of the medium at the specified minuteafter starting the test, and filter through a membrane filter with apore size not exceeding 0.45 µm. Discard the first 10 mL of the

2084 Official Monographs Supplement II, JP XVfiltrate, pipet V mL of the subsequent filtrate, add water to makeexactly V´ mL so that each mL contains about 56 µg (potency)of Amoxicillin Hydrate according to the labeled amount, anduse this solution as the sample solution. Separately, weigh accuratelyan amount equivalent to about 28 mg (potency) of AmoxicillinReference Standard, dissolve in water to make exactly100 mL. Pipet 5 mL of this solution, add water to make exactly25 mL, and use this solution as the standard solution. Performthe test with exactly 50 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions, and determine thepeak areas, A T and A S , of amoxicillin in each solution.Dissolution rate (%) with respect to the labeled amount ofamoxicillin (C 16 H 19 N 3 O 5 S)= W S × (A T /A S ) × (V´/V) × (1/C) × 180W S : Amount [mg (potency)] of Amoxicillin Reference StandardC: Labeled amount [mg (potency)] of amoxicillin(C 16 H 19 N 3 O 5 S) in 1 capsuleOperating conditions—Proceed as directed in the operating conditions in the Assayunder Amoxicillin Hydrate.System suitability—System performance: When the procedure is run with 50 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amoxicillin are not less than 2500 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with50 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of amoxicillinis not more than 1.5%.Assay Weigh accurately the mass of not less than 10 AmoxicillinCapsules, take out the contents, and weigh accurately themass of the emptied shells. Weigh accurately an amountequivalent to about 0.1 g (potency) of Amoxicillin Hydrate accordingto the labeled amount, add 70 mL of water, shake for 15minutes, and add water to make exactly 100 mL. Centrifuge thissolution, and use the supernatant liquid as the sample solution.Separately, weigh accurately an amount equivalent to about 20mg (potency) of Amoxicillin Reference Standard, dissolve inwater to make exactly 20 mL, and use this solution as the standardsolution. Perform the test with exactly 10 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak areas, A T and A S , of amoxicillin in eachsolution.Amount [mg (potency)] of amoxicillin (C 16 H 19 N 3 O 5 S)= W S × (A T /A S ) × 5W S : Amount [mg (potency)] of Amoxicillin Reference StandardOperating conditions—Column temperature, mobile phase, and flow rate: Proceed asdirected in the operating conditions in the Assay under AmoxicillinHydrate.Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4 mm in inside diameterand 30 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (10 µm in particle diameter).System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amoxicillin are not less than 2500 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of peak areas of amoxicillinis not more than 1.0%.Containers and storage Containers—Tight containers.Amoxicillin Hydrateアモキシシリン 水 和 物Change the Purity (3) to read:Purity (3) Related substances—Dissolve 0.10 g of AmoxicillinHydrate in 50 mL of a solution of boric acid (1 in 200),and use this solution as the sample solution. Pipet 1 mL of thesample solution, add a solution of boric acid (1 in 200) to makeexactly 100 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area of both solutions by the automatic integration method:the area of each peak other than amoxicillin obtained from thesample solution is not larger than the peak area of amoxicillinfrom the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4 mm in inside diameterand 30 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (10 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: Dissolve 1.36 g of sodium acetate trihydrate in750 mL of water, adjust the pH to 4.5 with acetic acid (31), andadd water to make 1000 mL. To 950 mL of this solution add 50mL of methanol.Flow rate: Adjust the flow rate so that the retention time ofamoxicillin is about 8 minutes.Time span of measurement: About 4 times as long as the retentiontime of amoxicillin.System suitability—Test for required detectability: To exactly 1 mL of the standardsolution add a solution of boric acid (1 in 200) to makeexactly 10 mL. Confirm that the peak area of amoxicillin ob-

Supplement II, JP XV Official Monographs 2085tained from 10 µL of this solution is equivalent to 7 to 13% ofthat of amoxicillin from the standard solution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amoxicillin are not less than 2500 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of amoxicillinis not more than 1.0%.Add the following:Aprindine Hydrochlorideアプリンジン 塩 酸 塩C 22 H 30 N 2·HCl: 358.95N-(2,3-Dihydro-1H-inden-2-yl)-N´,N´-diethyl-N-phenylpropane-1,3-diamine monohydrochloride[33237-74-0]Aprindine Hydrochloride, when dried, contains notless than 98.5% and not more than 101.0% ofC 22 H 30 N 2·HCl.Description Aprindine Hydrochloride occurs as a white topale yellowish white crystalline powder. It has a bitter taste,numbing the tongue.It is very soluble in water, methanol and in acetic acid (100),and freely soluble in ethanol (99.5).It gradually turns brown on exposure to light.Identification (1) Dissolve 10 mg of Aprindine Hydrochloridein a solution of hydrochloric acid in diluted ethanol (1 in 2)(1 in 125) to make 50 mL. Determine the absorption spectrumof this solution as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the ReferenceSpectrum: both spectra exhibit similar intensities of absorptionat the same wavelengths.(2) Determine the infrared absorption spectrum ofAprindine Hydrochloride as directed in the potassium chloridedisk method under Infrared Spectrophotometry , andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavenumbers.(3) To 5 mL of a solution of Aprindine Hydrochloride (1 in50) add 1 mL of dilute nitric acid: this solution responds to theQualitative Tests for chloride.pH Dissolve 1.0 g of Aprindine Hydrochloride in50 mL of water: the pH of the solution is between 6.4 and 7.0.Melting point 127-131ºCPurity (1) Clarity and color of solution—Dissolve 1.0 g ofAprindine Hydrochloride in 10 mL of methanol: the solution isclear, and its absorbance at 420 nm determined as directed underUltraviolet-visible Spectrophotometry is not more than0.10.(2) Heavy metals —Proceed with 1.0 g of AprindineHydrochloride according to Method 2, and perform the test.Prepare the control solution with 1.0 mL of Standard Lead Solution(not more than 10 ppm).(3) Related substances—Dissolve 25 mg of Aprindine Hydrochloridein 10 mL of the mobile phase, and use this solutionas the sample solution. Pipet 1 mL of this solution, add the mobilephase to make exactly 100 mL, and use this solution as thestandard solution. Perform the test with exactly 10 µL each ofthe sample solution and standard solution as directed under LiquidChromatography according to the following conditions.Determine each peak area of both solutions by the automaticintegration method: the area of the peak other thanaprindine obtained from the sample solution is not larger than1/10 times the peak area of aprindine from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 3.40 g of potassium dihydrogenphosphate in 500 mL of water, and adjust the pH to 3.0 with hydrochloricacid. To 500 mL of this solution add 500 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofaprindine is about 6 minutes.Time span of measurement: About 4 times as long as the retentiontime of aprindine.System suitability—Test for required detectability: Pipet 1 mL of the standard solution,and add the mobile phase to make exactly 10 mL. Confirmthat the peak area of aprindine obtained from 10 µL of thissolution is equivalent to 7 to 13% of that of aprindine from thestandard solution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of aprindine are not less than 3000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area ofaprindine is not more than 1.5%.(4) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, in vacuum,60ºC, 4 hours).

2086 Official Monographs Supplement II, JP XVResidue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.5 g of Aprindine Hydrochloride,previously dried, dissolve in 80 mL of acetic acid (100),and titrate with 0.1 mol/L perchloric acid VS (potentiometrictitration). Perform a blank determination in the samemanner, and make any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 35.90 mg of C 22 H 30 N 2·HClContainers and storage Containers—Well-closed containersStorage—Light-resistant.Add the following:Aprindine Hydrochloride Capsulesアプリンジン 塩 酸 塩 カプセルAprindine Hydrochloride Capsules contain not lessthan 95.0% and not more than 105.0% of the labeledamount of aprindine hydrochloride (C 22 H 30 N 2·HCl:358.95).Method of preparation Prepare as directed under Capsules,with Aprindine Hydrochloride.Identification Determine the absorption spectrum of the samplesolution obtained in the Assay as directed under Ultraviolet-visibleSpectrophotometry , it exhibits maxima between264 nm and 268 nm, and between 271 nm and 275 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.Take out the contents of 1 capsule of Aprindine HydrochlorideCapsules, add 30 mL of a solution of hydrochloric acid indiluted ethanol (1 in 2) (1 in 125), shake vigorously for 20 minutes,add a solution of hydrochloric acid in diluted ethanol (1 in2) (1 in 125) to make exactly V mL so that each mL containsabout 0.2 mg of aprindine hydrochloride (C 22 H 30 N 2·HCl), andfilter. Discard the first 5 mL of the filtrate, and use the subsequentfiltrate as the sample solution. Proceed as directed in theAssay.Amount (mg) of aprindine hydrochloride (C 22 H 30 N 2·HCl)= W S × (A T /A S ) × (V/250)W S : Amount (mg) of aprindine hydrochloride for assayDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of water as the dissolution medium, thedissolution rate in 15 minutes of Aprindine Hydrochloride Capsulesis not less than 80%.Start the test with 1 capsule of Aprindine HydrochlorideCapsules, withdraw not less than 20 mL of the medium at thespecified minute after starting the test, and filter through amembrane filter with a pore size not exceeding 0.45 µm. Discardthe first 10 mL of the filtrate, pipet V mL of the subsequentfiltrate, add water to make exactly V´ mL so that each mL containsabout 11 µg of aprindine hydrochloride (C 22 H 30 N 2·HCl)according to the labeled amount, and use this solution as thesample solution. Separately, weigh accurately about 28 mg ofaprindine hydrochloride for assay, previously dried in vacuum at60ºC for 4 hours, and dissolve in water to make exactly 100 mL.Pipet 2 mL of this solution, add water to make exactly 50 mL,and use this solution as the standard solution. Perform the testwith exactly 20 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions, and determine the peak areas,A T and A S , of aprindine in each solution.Dissolution rate (%) with respect to the labeled amount ofaprindine hydrochloride (C 22 H 30 N 2·HCl)= W S × (A T /A S ) × (V´/V) × (1/C) × 36W S : Amount (mg) of aprindine hydrochloride for assayC: Labeled amount (mg) of aprindine hydrochloride(C 22 H 30 N 2·HCl) in 1 capsuleOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 3.40 g of potassium dihydrogenphosphate in 500 mL of water, and adjust the pH to 3.0 with hydrochloricacid. To 500 mL of this solution add 500 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofaprindine is about 6 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of aprindine are not less than 3000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area ofaprindine is not more than 1.5%.Assay Take out the contents of not less than 20 Aprindine HydrochlorideCapsules, weigh accurately the mass of the contents,and powder. Weigh accurately a portion of the powder, equivalentto about 0.1 g of aprindine hydrochloride (C 22 H 30 N 2·HCl),add 60 mL of a solution of hydrochloric acid in diluted ethanol(1 in 2) (1 in 125), shake vigorously for 20 minutes, and add asolution of hydrochloric acid in diluted ethanol (1 in 2) (1 in125) to make exactly 100 mL. Pipet 10 mL of this solution, adda solution of hydrochloric acid in diluted ethanol (1 in 2) (1 in125) to make exactly 50 mL, and filter, Discard the first 5 mL of

Supplement II, JP XV Official Monographs 2087the filtrate, and use the subsequent filtrate as the sample solution.Separately, weigh accurately about 50 mg of aprindine hydrochloridefor assay, previously dried in vacuum at 60ºC for 4hours, and dissolve in a solution of hydrochloric acid in dilutedethanol (1 in 2) (1 in 125) to make exactly 50 mL. Pipet 10 mLof this solution, add a solution of hydrochloric acid in dilutedethanol (1 in 2) (1 in 125) to make exactly 50 mL, and use thissolution as the standard solution. Determine the absorbances, A Tand A S , of the sample solution and standard solution at 265 nmas directed under Ultraviolet-visible Spectrophotometry .Amount (mg) of aprindine hydrochloride (C 22 H 30 N 2·HCl)= W S × (A T /A S ) × 2W S : Amount (mg) of aprindine hydrochloride for assayContainers and storage Containers—Tight containers.Storage—Light-resistant.Add the following:Argatroban Hydrateアルガトロバン 水 和 物and epimer at C*C 23 H 36 N 6 O 5 S·H 2 O: 526.65(2R,4R)-4-Methyl-1-((2S)-2-{[(3RS)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl]sulfonyl}amino-5-guanidinopentanoyl)piperidine-2-carboxylic acidmonohydrate [141396-28-3]Argatroban Hydrate contains not less than 98.5%and not more than 101.0% of argatroban(C 23 H 36 N 6 O 5 S: 508.63), calculated on the anhydrousbasis.Description Argatroban Hydrate occurs as white crystals orcrystalline powder. It has a bitter taste.It is freely soluble in acetic acid (100), sparingly soluble inmethanol, slightly soluble in ethanol (99.5), and very slightlysoluble in water.It is gradually decomposed on exposure to light.Identification (1) Determine the absorption spectrum of asolution of Argatroban Hydrate in ethanol (99.5) (1 in 20000) asdirected under Ultraviolet-visible Spectrophotometry ,and compare the spectrum with the Reference Spectrum: bothspectra exhibit similar intensities of absorption at the samewavelengths.(2) Determine the infrared absorption spectrum of ArgatrobanHydrate as directed in the potassium bromide disk methodunder Infrared Spectrophotometry , and compare thespectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.Optical rotation [α] 20D: +175 - +185º (0.2 g calculatedon the anhydrous basis, methanol, 25 mL, 100 mm).Purity (1) Heavy metals —Proceed with 2.0 g ofArgatroban Hydrate according to Method 2, and perform the test.Prepare the control solution with 2.0 mL of Standard Lead Solution(not more than 10 ppm).(2) Arsenic —Incinerate 2.0 g of Argatroban Hydrateaccording to Method 4. After cooling, add 10 mL of dilute hydrochloricacid to the residue, dissolve by warming on a waterbath, and perform the test using this solution as the test solution.Add 10 mL of a solution of magnesium nitrate hexahydrate inethanol (95) (1 in 10), then add 1.5 mL of hydrogen peroxide(30), and fire to burn (not more than 1 ppm).(3) Related substance 1—Dissolve 50 mg of ArgatrobanHydrate in 40 mL of methanol, add water to make 100 mL, anduse this solution as the sample solution. Perform the test with 10µL of the sample solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area from the sample solution by the automatic integrationmethod, and calculate the amount of them by the areapercentage method: the amount of each peak other than argatrobanis not more than 0.1%.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 45ºC.Mobile phase A: To 2.5 mL of acetic acid (100) add water tomake 1000 mL, and adjust the pH to 5.0 with ammonia TS. To500 mL of this solution add 500 mL of methanol.Mobile phase B: To 2.5 mL of acetic acid (100) add water tomake 1000 mL, and adjust the pH to 5.0 with ammonia TS. To200 mL of this solution add 800 mL of methanol.Flowing of the mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injectionof sample(min)0-55-35Mobile phase A(vol%)Mobile phase B(vol%)1000100→50→95Flow rate: About 1.0 mL per minute.Time span of measurement: About 1.5 times as long as theretention time of argatroban beginning after the solvent peak.System suitability—Test for required detectability: To 1 mL of the sample solutionadd the mobile phase A to make 100 mL, and use this solutionas the solution for system suitability test. Pipet 1 mL of the solutionfor system suitability test, and add the mobile phase A to

2088 Official Monographs Supplement II, JP XVmake exactly 10 mL. Confirm that the peak area of argatrobanobtained from 10 µL of this solution is equivalent to 7 to 13% ofthat of argatroban from the solution for system suitability test.System performance: Dissolve 5 mg of Argatroban Hydrateand 5 µL of methyl benzoate in 40 mL of methanol, and addwater to make 100 mL. To 5 mL of this solution add 40 mL ofmethanol and water to make 100 mL. When the procedure is runwith 10 µL of this solution under the above operating conditions,methyl benzoate and argatroban are eluted in this order with theresolution between these peaks being not less than 3.System repeatability: When the test is repeated 6 times with10 µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the peakarea of argatroban is not more than 2.0%.(4) Related substance 2— Dissolve 0.10 g of ArgatrobanHydrate in 10 mL of methanol, and use this solution as the samplesolution. Pipet 3 mL of this solution, and add methanol tomake exactly 100 mL. Pipet 5 mL of this solution, add methanolto make exactly 50 mL, and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 10 µL each of thesample solution and standard solution on a plate of silica gelwith fluorescent indicator for thin-layer chromatography. Developthe plate with a mixture of methanol, ethyl acetate andwater (10:10:1) to a distance of about 10 cm, and air-dry theplate. Examine under ultraviolet light (main wavelength: 254nm): the number of spots other than the principal spot obtainedfrom the sample solution is not more than 2, and they are notmore intense than the spot from the standard solution.(5) Residual solvent—Being specified separately.Water 2.5 - 4.5% (0.2 g, volumetric titration, direct titration).Residue on ignition Not more than 0.1% (1 g).Isomer ratio Dissolve 50 mg of Argatroban Hydrate in 50 mLof methanol, add water to make 100 mL, and use this solution asthe sample solution. Perform the test with 10 µL of the samplesolution as directed under Liquid Chromatography accordingto the following conditions. Determine the areas of twoadjacent peaks, A a and A b , having the retention times of about 40minutes, where A a is the peak area of shorter retention time andA b is the peak area of longer retention time: A b /(A a + A b ) is between0.30 and 0.40.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 6.0 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To 500 mL of water add 500 mL of methanol,13 mL of diluted 40% tetrabutylammonium hydroxide TS (1 in4) and 0.68 mL of phosphoric acid, and adjust the pH to 6.8 withammonia TS and diluted ammonia solution (28) (1 in 20).Flow rate: Adjust the flow rate so that the retention time ofthe peak having the shorter retention time of the two peaks ofargatroban is about 40 minutes.System suitability—System performance: When the procedure is run with 10 µLof the sample solution under the above operating conditions, theresolution between the two peaks is not less than 1.2.System repeatability: When the test is repeated 6 times with10 µL of the sample solution under the above operating conditions,the relative standard deviation of the total area of the twoseparate peaks of argatroban is not more than 2.0%.Assay Weigh accurately about 0.5 g of Argatroban Hydrate,dissolve in 20 mL of acetic acid for nonaqueous titration, add 40mL of acetone for nonaqueous titration, and titrate with0.1 mol/L perchloric acid VS (potentiometric titration). Performa blank determination in the same manner, and make any necessarycorrection.Each mL of 0.1 mol/L perchloric acid VS= 50.86 mg of C 23 H 36 N 6 O 5 SContainers and storage Containers—Tight containers.Storage—Light-resistant.Azathioprine Tabletsアザチオプリン 錠Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Azathioprine Tablets add 1 mL of dimethylsulfoxidefor ultraviolet-visible spectrophotometry per 5 mg ofAzathioprine (C 9 H 7 N 7 O 2 S), shake well, add 0.1 mol/L hydrochloricacid TS to make exactly V mL so that each mL containsabout 0.2 mg of azathioprine (C 9 H 7 N 7 O 2 S), and filter. Discardthe first 20 mL of the filtrate, pipet 3 mL of the subsequent filtrate,add 0.1 mol/L hydrochloric acid TS to make exactly 100mL, and use this solution as the sample solution. Proceed as directedin the Assay.Amount (mg) of azathioprine (C 9 H 7 N 7 O 2 S)= W S × (A T /A S ) × (V/500)W S : Amount (mg) of Azathioprine Reference Standard

Supplement II, JP XV Official Monographs 2089Add the following:Azelastine Hydrochloride Granulesアゼラスチン 塩 酸 塩 顆 粒Azelastine Hydrochloride Granules contain not lessthan 93.0% and not more than 107.0% of the labeledamount of azelastine hydrochloride(C 22 H 24 ClN 3 O·HCl: 418.36).Method of preparation Prepare as directed under Granules,with Azelastine Hydrochloride.Identification To a quantity of Azelastine HydrochlorideGranules, equivalent to 2 mg of Azelastine Hydrochloride accordingto the labeled amount, add 30 mL of 0.1 mol/L hydrochloricacid TS, and treat with ultrasonic waves for 30 minutes.After cooling, add 0.1 mol/L hydrochloric acid TS to make 50mL, and centrifuge. Determine the absorption spectrum of thesupernatant liquid as directed under Ultraviolet-visible Spectrophotometry: it exhibits a maximum between 283 nmand 287 nm.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof 0.05 mol/L acetic acid-sodium acetate buffer solution, pH 4.0,as the dissolution medium, the dissolution rate in 45 minutes ofAzelastine Hydrochloride Granules is not less than 80%.Start the test with accurately weighed amount of AzelastineHydrochloride Granules, equivalent to about 1 mg of azelastinehydrochloride (C 22 H 24 ClN 3 O·HCl) according to the labeledamount, withdraw not less than 20 mL of the medium at thespecified minute after starting the test, and filter through amembrane filter with a pore size not exceeding 0.5 µm. Discardthe first 10 mL of the filtrate, and use the subsequent filtrate asthe sample solution. Separately, weigh accurately about 50 mgof azelastine hydrochloride for assay, previously dried at 105ºCfor 2 hours, and dissolve in the dissolution medium to make exactly250 mL. Pipet 1 mL of this solution, add the dissolutionmedium to make exactly 200 mL, and use this solution as thestandard solution. Perform the test with exactly 50 µL each ofthe sample solution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak areas, A T and A S , of azelastine ineach solution.Dissolution rate (%) with respect to the labeled amount ofazelastine hydrochloride (C 22 H 24 ClN 3 O·HCl)= (W S /W T ) × (A T /A S ) × (1/C) × (9/5)W S : Amount (mg) of azelastine hydrochloride for assayW T : Amount (g) of Azelastine Hydrochloride GranulesC: Labeled amount (mg) of azelastine hydrochloride(C 22 H 24 ClN 3 O·HCl) in 1 gOperating conditions—Proceed as directed in the Assay.System suitability—System performance: When the procedure is run with 50 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of azelastine are not less than 2000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with50 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of azelastineis not more than 2.0%.Particle size It meets the requirement.Assay Weigh accurately an amount of Azelastine HydrochlorideGranules, equivalent to about 2 mg of azelastine hydrochloride(C 22 H 24 ClN 3 O·HCl), add 50 mL of 0.1 mol/L hydrochloricacid TS, treat with ultrasonic waves for 20 minutes, add 40 mLof ethanol (99.5), add exactly 5 mL of the internal standard solution,and add ethanol (99.5) to make 100 mL. Centrifuge thissolution, and use the supernatant liquid as the sample solution.Separately, weigh accurately about 50 mg of azelastine hydrochloridefor assay, previously dried at 105ºC for 2 hours, anddissolve in water to make exactly 50 mL. Pipet 10 mL of thissolution, and add 0.1 mol/L hydrochloric acid TS to make exactly50 mL. Pipet 10 mL of this solution, add 40 mL of 0.1mol/L hydrochloric acid TS and 40 mL of ethanol (99.5), addexactly 5 mL of the internal standard solution, add ethanol(99.5) to make 100 mL, and use this solution as the standardsolution. Perform the test with 20 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of azelastine to that of theinternal standard.Amount (mg) of azelastine hydrochloride(C 22 H 24 ClN 3 O·HCl)= W S × (Q T /Q S ) × (1/25)W S : Amount (mg) of azelastine hydrochloride for assayInternal standard solution—Dissolve 0.2 g of 2-ethylhexylparahydroxybenzoate in ethanol (99.5) to make 100 mL.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:285 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of acetonitrile and a solution of sodiumlauryl sulfate in diluted acetic acid (100) (1 in 250) (1 in500) (11:9).Flow rate: Adjust the flow rate so that the retention time ofazelastine is about 6 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,azelastine and the internal standard are eluted in this order withthe resolution between these peaks being not less than 2.0.System repeatability: When the test is repeated 6 times with

2090 Official Monographs Supplement II, JP XV20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof azelastine to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Add the following:Betaxolol Hydrochlorideベタキソロール 塩 酸 塩Betamethasone Tabletsベタメタゾン 錠Change the Uniformity of dosage units to read:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Betamethasone Tablets add V mL of water sothat each mL contains about 50 µg of betamethasone(C 22 H 29 FO 5 ). Add exactly 2 V mL of the internal standard solution,shake vigorously for 10 minutes, centrifuge, and use thesupernatant liquid as the sample solution. Separately, weigh accuratelyabout 20 mg of Betamethasone Reference Standard,previously dried for 4 hours in a desiccator (in vacuum, phosphorus(V) oxide), dissolve in acetonitrile to make exactly 200mL. Pipet 5 mL of this solution, add exactly 20 mL of the internalstandard solution, add 5 mL of water, and use this solutionas the standard solution. Perform the test with 20 µL each of thesample solution and standard solution as directed under LiquidChromatography , and calculate the ratios, Q T and Q S , ofthe peak area of betamethasone to that of the internal standard.Amount (mg) of betamethasone (C 22 H 29 FO 5 )= W S × (Q T /Q S ) × (V/400)W S : Amount (mg) of Betamethasone Reference StandardInternal standard solution—A solution of butyl parahydroxybenzoatein acetonitrile (1 in 40000)Operating conditions—Proceed as directed in the operating conditions in the Assay.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,betamethasone and the internal standard are eluted in this orderwith the resolution between these peaks being not less than 10.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof betamethasone to that of the internal standard is not morethan 1.0%.C 18 H 29 NO 3·HCl: 343.89(2RS)-1-{4-[2-(Cyclopropylmethoxy)ethyl]phenoxy}-3-[(1-methylethyl)amino]propan-2-ol monohydrochloride[63659-19-8]Betaxolol Hydrochloride, when dried, contains notless than 99.0% and not more than 101.0% ofC 18 H 29 NO 3·HCl.Description Betaxolol Hydrochloride occurs as white crystalsor crystalline powder.It is very soluble in water, and freely soluble in methanol,ethanol (99.5) or acetic acid (100).Dissolve 1.0 g of Betaxolol Hydrochloride in 50 mL of water:the pH of the solution is between 4.5 and 6.5.A solution of Betaxolol Hydrochloride (1 in 100) shows nooptical rotation.Identification (1) Determine the absorption spectrum of asolution of Betaxolol Hydrochloride in ethanol (99.5) (1 in10000) as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the Reference Spectrum:both spectra exhibit similar intensities of absorption at thesame wavelengths.(2) Determine the infrared absorption spectrum of BetaxololHydrochloride as directed in the potassium chloride disk methodunder Infrared Spectrophotometry , and compare thespectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) A solution of Betaxolol Hydrochloride (1 in 10) respondsto the Qualitative Tests (2) for chloride.Melting point 114-117ºCPurity (1) Clarity and color of solution—Dissolve 1.0 g ofBetaxolol Hydrochloride in 10 mL of water: the solution is clearand colorless.(2) Heavy metals —Proceed with 2.0 g of BetaxololHydrochloride according to Method 4, and perform the test.Prepare the control solution with 2.0 mL of Standard Lead Solution(not more than 10 ppm).(3) Arsenic —Prepare the test solution with 2.0 g ofBetaxolol Hydrochloride according to Method 3, and performthe test (not more than 1 ppm).(4) Related substance I—Dissolve 0.10 g of Betaxolol Hydrochloridein 10 mL of methanol, and use this solution as thesample solution. Pipet 3 mL of this solution, and add methanolto make exactly 50 mL. Pipet 1 mL of this solution, add methaandenantiomer

Supplement II, JP XV Official Monographs 2091nol to make exactly 20 mL, and use this solution as the standardsolution. Perform the test with these solutions as directed underThin-layer Chromatography . Spot 10 µL each of thesample solution and standard solution on a plate of silica gel forthin-layer chromatography. Develop the plate with a mixture ofethyl acetate, water and acetic acid (100) (10:3:3) to a distanceof about 10 cm, and air-dry the plate. Allow the plate to stand iniodine vapor for 1 hour: the number of the spots other than theprincipal spot obtained from the sample solution is not morethan three, and they are not more intense than the spot from thestandard solution.(5) Related substance II—Dissolve 0.10 g of Betaxolol Hydrochloridein 50 mL of the mobile phase, and use this solutionas the sample solution. Pipet 1 mL of this solution, add the mobilephase to make exactly 200 mL, and use this solution as thestandard solution. Perform the test with exactly 10 µL each ofthe sample solution and standard solution as directed under LiquidChromatography according to the following conditions.Determine each peak area of both solutions by the automaticintegration method: the area of the peak other than betaxololobtained from the sample solution is not larger than thepeak area of betaxolol from the standard solution, and the totalarea of the peaks other than the peak of betaxolol obtained fromthe sample solution is not larger than 2 times the peak area ofbetaxolol from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:273 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of diluted 0.05 mol/L potassium dihydrogenphosphate TS (1 in 2) with the pH adjusted to 3.0 with1 mol/L hydrochloric acid TS, acetonitrile and methanol(26:7:7).Flow rate: Adjust the flow rate so that the retention time ofbetaxolol is about 9 minutes.Time span of measurement: About 2 times as long as the retentiontime of betaxolol beginning after the solvent peak.System suitability—Test for required detectability: Pipet 4 mL of the standard solution,and add the mobile phase to make exactly 20 mL. Confirmthat the peak area of betaxolol obtained from 10 µL of thissolution is equivalent to 14 to 26% of that of bataxolol from thestandard solution.System performance: Dissolve 50 mg of Betaxolol Hydrochlorideand 5 mg of 2-naphthol in 200 mL of the mobile phase.When the procedure is run with 10 µL of this solution under theabove operating conditions, betaxolol and 2-naphthol are elutedin this order with the resolution between these peaks being notless than 10.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of betaxololis not more than 2.0%.(6) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 4hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.3 g of Betaxolol Hydrochloride,previously dried, dissolve in 30 mL of acetic acid (100),add 30 mL of acetic anhydride, and titrate with 0.1mol/L perchloric acid VS (potentiometric titration). Perform ablank determination in the same manner, and make any necessarycorrection.Each mL of 0.1 mol/L perchloric acid VS= 34.39 mg of C 18 H 29 NO 3·HClContainers and storage Containers—Tight containers.Add the following:Cadralazineカドララジンand enantiomerC 12 H 21 N 5 O 3 : 283.33Ethyl 3-(6-{ethyl[(2RS)-2-hydroxypropyl]amino}pyridazin-3-yl)carbazate [64241-34-5]Cadralazine, when dried, contains not less than98.5% and not more than 101.0% of C 12 H 21 N 5 O 3 .Description Cadralazine occurs as a pale yellow to light yellowcrystalline powder.It is freely soluble in acetic acid (100), soluble in methanol,sparingly soluble in ethanol (99.5), and slightly soluble in water.It dissolves in 0.05 mol/L sulfuric acid TS.A solution of Cadralazine in methanol (1 in 40) shows no opticalrotation.Melting point: about 165ºC (with decomposition).Identification (1) Determine the absorption spectrum of asolution of Cadralazine in 0.05 mol/L sulfuric acid TS (1 in125000) as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the Reference Spectrum:both spectra exhibit similar intensities of absorption at thesame wavelengths.(2) Determine the infrared absorption spectrum of Cadralazine,previously dried, as directed in the potassium bromidedisk method under Infrared Spectrophotometry , andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavenumbers.Purity (1) Chloride —Dissolve 0.40 g of Cadralazine

2092 Official Monographs Supplement II, JP XVin 15 mL of methanol, add 6 mL of dilute nitric acid and waterto make 50 mL. Perform the test using this solution as the testsolution. Prepare the control solution with 0.40 mL of 0.01mol/L hydrochloric acid VS by adding 15 mL of methanol, 6mL of dilute nitric acid, and water to make 50 mL (not morethan 0.036%).(2) Heavy metals —Proceed with 1.0 g of Cadralazineaccording to Method 4, and perform the test. Prepare thecontrol solution with 2.0 mL of Standard Lead Solution (notmore than 20 ppm).(3) Related substances—Dissolve 50 mg of Cadralazine in20 mL of 0.05 mol/L sulfuric acid TS, add water to 100 mL, anduse this solution as the sample solution. Pipet 1 mL of this solution,add water to make exactly 200 mL, and use this solution asthe standard solution. Perform the test with exactly 10 µL eachof the sample solution and standard solution as directed underLiquid Chromatography according to the following conditions.Determine each peak area of both solutions by theautomatic integration method: the area of the peak, having therelative retention time of about 2.1 with respect to cadralazine,obtained from the sample solution is not larger than the peakarea of cadralazine from the standard solution, and the area ofthe peak other than cadralazine and other than the peak mentionedabove is not larger than 2/5 times the peak area of cadralazinefrom the standard solution. Furthermore, the total area ofthe peaks other than cadralazine obtained from the sample solutionis not larger than 2 times the peak area of cadralazine fromthe standard solution. For this calculation, use the areas of thepeaks, having the relative retention time of about 0.49 and about2.1 with respect to cadralazine, after multiplying by their relativeresponse factors, 0.65 and 1.25, respectively.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:250 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 13.6 g of sodium acetate trihydrate in800 mL of water, adjust the pH to 5.8 with dilute acetic acid,and add water to make 1000 mL. To 860 mL add 140 mL ofacetonitrile.Flow rate: Adjust the flow rate so that the retention time ofcadralazine is about 10 minutes.Time span of measurement: About 3 times as long as the retentiontime of cadralazine.System suitability—Test for required detectability: Pipet 5 mL of the standard solution,and add water to make exactly 25 mL. Confirm that thepeak area of cadralazine obtained from 10 µL of this solution isequivalent to 15 to 25% of that of cadralazine from the standardsolution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of cadralazine are not less than 4000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of cadralazineis not more than 4.0%.(4) Residual solvent—Being specified separately.Loss on drying Not more than 1.0% (1 g, 105ºC, 3hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.5 g of Cadralazine, previouslydried, dissolve in 50 mL of acetic acid (100), and titrate with 0.1 mol/L perchloric acid VS (potentiometric titration).Perform a blank determination in the same manner, andmake any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 28.33 mg of C 12 H 21 N 5 O 3Containers and storage Containers—Well-closed containers.Add the following:Cadralazine Tabletsカドララジン 錠Cadralazine Tablets contain not less than 95.0% andnot more than 105.0% of the labeled amount of cadralazine(C 12 H 21 N 5 O 3 : 283.33).Method of preparation Prepare as directed under Tablets,with Cadralazine.Identification To a quantity of powdered Cadralazine Tablets,equivalent to 20 mg of Cadralazine according to the labeledamount, add 50 mL of 0.05 mol/L sulfuric acid TS, shake well,and centrifuge. To 1 mL of the supernatant liquid add 0.05mol/L sulfuric acid TS to make 50 mL. Determine the absorptionspectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximumbetween 247 nm and 251 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Cadralazine Tablets add 30 mL of 0.05 mol/Lsulfuric acid TS, shake well to disintegrate, and add 0.05 mol/Lsulfuric acid TS to make exactly 50 mL. Centrifuge this solution,pipet 3 mL of the supernatant liquid, add 0.05 mol/L sulfuricacid TS to make exactly V mL so that each mL contains about 6µg of cadralazine (C 12 H 21 N 5 O 3 ), and use this solution as thesample solution. Separately, weigh accurately about 20 mg ofcadralazine for assay, previously dried at 105ºC for 3 hours, anddissolve in 0.05 mol/L sulfuric acid TS to make exactly 100 mL.Pipet 3 mL of this solution, add 0.05 mol/L sulfuric acid TS tomake exactly 100 mL, and use this solution as the standard solution.Determine the absorbances, A T and A S , of the sample so-

Supplement II, JP XV Official Monographs 2093lution and standard solution at 249 nm as directed under Ultraviolet-visibleSpectrophotometry .Amount (mg) of cadralazine (C 12 H 21 N 5 O 3 )= W S × (A T /A S ) × (V/200)W S : Amount (mg) of cadralazine for assayDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Cadralazine Tablets is not less than 80%.Start the test with 1 tablet of Cadralazine Tablets, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.5 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to make exactlyV´ mL so that each mL contains about 5.6 µg of cadralazine(C 12 H 21 N 5 O 3 ) according to the labeled amount, and use this solutionas the sample solution. Separately, weigh accurately about30 mg of cadralazine for assay, previously dried at 105ºC for 3hours, and dissolve in water to make exactly 200 mL. Pipet 4mL of this solution, add water to make exactly 100 mL, and usethis solution as the standard solution. Determine the absorbances,A T and A S , of the sample solution and standard solution at254 nm as directed under Ultraviolet-visible Spectrophotometry.Dissolution rate (%) with respect to the labeled amount ofcadralazine (C 12 H 21 N 5 O 3 )= W S × (A T /A S ) × (V´/V) × (1/C) × 18W S : Amount (mg) of cadralazine for assayC: Labeled amount (mg) of cadralazine (C 12 H 21 N 5 O 3 ) in 1tabletAssay To 10 Cadralazine Tablets add 70 mL of 0.05 mol/Lsulfuric acid TS, shake well to disintegrate, add 0.05 mol/L sulfuricacid to make exactly 200 mL. Centrifuge this solution, pipeta volume of the supernatant liquid, equivalent to about 2.5mg of cadralazine (C 12 H 21 N 5 O 3 ), add exactly 5 mL of the internalstandard solution, add water to make 25 mL, and use thissolution as the sample solution. Separately, weigh accuratelyabout 25 mg of cadralazine for assay, previously dried at 105ºCfor 3 hours, and dissolve in 0.05 mol/L of sulfuric acid TS tomake exactly 50 mL. Pipet 5 mL of this solution, add exactly 5mL of the internal standard solution, add water to make 25 mL,and use this solution as the standard solution. Perform the testwith 5 µL each of the sample solution and standard solution asdirected under Liquid Chromatography according to thefollowing conditions, and calculate the ratios, Q T and Q S , of thepeak area of cadralazine to that of the internal standard.Amount (mg) of cadralazine (C 12 H 21 N 5 O 3 )= W S × (Q T /Q S ) × (1/10)W S : Amount (mg) of cadralazine for assayInternal standard solution—A solution of p-toluenesulfonamidein acetonitrile (1 in 50)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:250 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 13.6 g of sodium acetate trihydrate in800 mL of water, adjust the pH to 5.8 with dilute acetic acid,and add water to make 1000 mL. To 860 mL of this solution add140 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofcadralazine is about 10 minutes.System suitability—System performance: When the procedure is run with 5 µL ofthis solution under the above operating conditions, cadralazineand the internal standard are eluted in this order with the resolutionbetween these peaks being not less than 3.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofcadralazine to that of the internal standard is not more than1.0%.Containers and storage Containers—Well-closed containers.Add the following:Calcitonin (Salmon)カルシトニン(サケ)┌─────┐CSNLSTCVLG KLSQELHKLQ TYPRTNTGSG TP-NH 2C 145 H 240 N 44 O 48 S 2 : 3431.85[47931-85-1]Calcitonin (Salmon) is a synthetic polypeptide consistingof 32 amino acid residues. It is a hormone witha blood calcium lowering effect.It contains not less than 4000 Units of calcitonin(salmon) per 1 mg of peptide.Description Calcitonin (Salmon) occurs as a white powder.It is freely soluble in water.It dissolves in dilute acetic acid.Dissolve 20 mg of Calcitonin (Salmon) in 2 mL of water: thepH of the solution is between 5.0 and 7.0.It is hygroscopic.Identification Dissolve 1 mg of Calcitonin (Salmon) in 1 mLof dilute acetic acid. Determine the absorption spectrum of thissolution as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the Reference Spectrum:both spectra exhibit similar intensities of absorption at thesame wavelengths.

2094 Official Monographs Supplement II, JP XVAbsorbance acetic acid, 1 mL).1%E 1cm (275 nm): 3.3 - 4.0 (1 mg, diluteOptical rotation [α] 20D: –24 - –32º (25 mg, dilutedacetic acid (100) (1 in 2), 10 mL, 100 mm).Constituent amino acids Weigh accurately about 1 mg ofCalcitonin (Salmon), put in a test tube for hydrolysis, dissolve in0.5 mL of diluted hydrochloric acid (1 in 2), freeze in a dryice-acetone bath, seal the tube under reduced pressure, and heatat 110 ± 2ºC for 24 hours. After cooling, open the tube, evaporatethe hydrolyzate to dryness under reduced pressure, dissolvethe residue in exactly 5 mL of 0.02 mol/L hydrochloric acid TS,and use this solution as the sample solution. Separately, weighaccurately about 27 mg of L-aspartic acid, about 24 mg ofL-threonine, about 21 mg of L-serine, about 29 mg of L-glutamicacid, about 23 mg of L-proline, about 15 mg of glycine, about 18mg of L-alanine, about 23 mg of L-valine, about 48 mg ofL-cystine, about 30 mg of methionine, about 26 mg ofL-isoleucine, about 26 mg of L-leucine, about 36 mg ofL-tyrosine, about 33 mg of phenylalanine, about 37 mg ofL-lysine hydrochloride, about 42 mg of L-histidine hydrochloridemonohydrate and about 42 mg of L-arginine hydrochloride,dissolve them in 10 mL of 1 mol/L hydrochloric acid TS, andadd water to make exactly 100 mL. Pipet 5 mL of this solution,add 0.02 mol/L hydrochloric acid TS to make exactly 50 mL,and use this solution as the standard solution. Perform the testwith exactly 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions: 13 peaks of amino acidsappear on the chromatogram obtained from the sample solution,and their respective molar ratios with respect to leucine (=5) are1.9 – 2.3 for lysine, 0.8 – 1.1 for histidine, 0.9 – 1.1 for arginine,1.9 – 2.1 for aspartic acid, 4.5 – 4.9 for threonine, 3.2 – 3.8 forserine, 2.8 – 3.1 for glutamic acid, 1.9 – 2.4 for proline, 2.7 –3.3 for glycine, 1.5 – 2.5 for 1/2 cystine, 0.9 – 1.0 for valine,and 0.8 – 1.0 for tyrosine.Operating conditions—Detector: A visible spectrophotometer (wavelength: 440 nmand 570 nm)Column: A stainless steel column 4.6 mm in inside diameterand 6 cm in length, packed with strongly acidic ion–exchangeresin for liquid chromatography (sodium type) composed with asulfonated polystyrene copolymer (3 µm in particle diameter).Column temperature: A constant temperature of about 57ºC.Chemical reaction bath temperature: A constant temperatureof about 130ºC.Color developing time: About 1 minute.Mobile phase: Prepare mobile phases A, B, C, D and E accordingto the following table.Mobile phase A Mobile phase B Mobile phase C Mobile phase D Mobile phase ECitric acid monohydrate 19.80 g 22.00 g 12.80 g 6.10 g –Trisodium citrate dihydrate 6.19 g 7.74 g 13.31 g 26.67 g –Sodium hydroxide – – – – 8.00 gSodium chloride 5.66 g 7.07 g 3.74 g 54.35 g –Ethanol (99.5) 130.0 mL 20.0 mL 4.0 mL – 100.0 mLBenzyl alcohol – – – 5.0 mL –Thiodiglycol 5.0 mL 5.0 mL 5.0 mL – –Lauromacrogol solution (1 in 4) 4.0 mL 4.0 mL 4.0 mL 4.0 mL 4.0 mLCaprylic acid 0.1 mL 0.1 mL 0.1 mL 0.1 mL 0.1 mLWatera sufficientamounta sufficientamounta sufficientamounta sufficientamounta sufficientamountTotal volume 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Supplement II, JP XV Official Monographs 2095Flowing of the mobile phase: Control the gradient by mixing the mobile phases A, B, C, D and E as directed in the following table.Time after injection ofsample (min)Mobile phase A(vol%)Mobile phase B(vol%)Mobile phase C(vol%)Mobile phase D(vol%)Mobile phase E(vol%)0 – 1.5 100 0 0 0 01.5 – 4 0 100 0 0 04 – 12 0 0 100 0 012 – 26 0 0 0 100 026 – 30 0 0 0 0 100Reaction reagent: Mix 407 g of lithium acetate dihydrate, 245mL of acetic acid (100) and 801 mL of 1–methoxy–2–propanol,add water to make 2000 mL, stir for 10 minutes while passingnitrogen, and use this solution as solution A. Separately, to 1957mL of 1–methoxy–2–propanol add 77 g of ninhydrin and 0.134g of sodium borohydride, stir for 30 minutes while passing nitrogen,and use this solution as solution B. Mix solution A andsolution B before use.Flow rate of mobile phase: About 0.4 mL per minute.Flow rate of reaction reagent: About 0.35 mL per minute.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,aspartic acid, threonine, serine, glutamic acid, proline, glycine,alanine, cystine, valine, methionine, isoleucine, leucine, tyrosine,phenylalanine, lysine, histidine and arginine are eluted in thisorder with the resolutions between the peaks of threonine andserine, glycine and alanine, and isoleucine and leucine being notless than 1.2, 1.0 and 1.2, respectively.System repeatability: When the test is repeated 3 times with10 µL of the standard solution under the above operating conditions,the relative standard deviations of the peak areas of asparticacid, proline, valine and arginine are not more than 2.0%,respectively.Peptide content Calculate the peptide content in Calcitonin(Salmon) by the following equation using amino acid analysisvalues (µmol/mL) obtained in the Constituent amino acids: it isnot less than 80.0%.Peptide content (%) = 3431.85 × (5/W) × (A/11) × 100A: Total (µmol/mL) of the amino acid analysis values ofvaline, leucine, glycine and prolineW: Amount (µg) of sample11: Total of the theoretical residue numbers of valine, leucine,glycine and proline per one mole of calcitonin (salmon)Purity (1) Acetic acid—Weigh accurately about 10 mg ofCalcitonin (Salmon), dissolve in water to make exactly 10 mL,and use this solution as the sample solution. Separately, weighaccurately about 1 g of acetic acid (100), and dissolve in waterto make exactly 100 mL. Pipet 2 mL of this solution, add waterto make exactly 200 mL, and use this solution as the standardsolution. Perform the test with exactly 100 µL each of the samplesolution and standard solution as directed under LiquidChromatography according to the following conditions.Determine the peak areas, A T and A S , of acetic acid in each solution,and calculate the amount of acetic acid by the followingequation: the amount of acetic acid is not more than 7.0%.Amount (%) of acetic acid (CH 3 COOH)= (W S /W T ) × (A T /A S ) × (1/10)W S : Amount (mg) of acetic acid (100)W T : Amount (mg) of Calcitonin (Salmon)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:210 nm)Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase A: To 0.7 mL of phosphoric acid add 900 mL ofwater, adjust the pH to 3.0 with 8 mol/L sodium hydroxide TS,and add water to make 1000 mL.Mobile phase B: MethanolFlowing of the mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 – 5 95 55 – 10 95→50 5→5010 – 20 50 5020 – 22 50→95 50→522 – 30 95 5Flow rate: Adjust the flow rate so that the retention time ofacetic acid is about 4 minutes.System suitability—System performance: When the procedure is run with 100 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of acetic acid are not less than 3000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with100 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak areas of ace-

2096 Official Monographs Supplement II, JP XVtic acid is not more than 2.0%.(2) Related substances—Dissolve 2 mg of Calcitonin(Salmon) in 2 mL of dilute acetic acid, and use this solution asthe sample solution. Perform the test with 20 µL of this solutionas directed under Liquid Chromatography according tothe following conditions. Determine each peak area from thesample solution by the automatic integration method, and calculatethe amount of them by the area percentage method: thetotal amount of the peaks other than calcitonin (salmon) is notmore than 3%.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:210 nm)Column: A stainless steel column 3.9 mm in inside diameterand 30 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (10 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of 1% trimethylamine–phosphatebuffer solution, pH 3.0, and acetonitrile (27:13).Flow rate: Adjust the flow rate so that the retention time ofcalcitonin (salmon) is about 9 minutes.Time span of measurement: About 2 times as long as the retentiontime of calcitonin (salmon) beginning after the solventpeak.System suitability—Test for required detectability: Pipet 1 mL of the sample solution,add the mobile phase to make exactly 100 mL, and use thissolution as the solution for system suitability test. Pipet 1 mL ofthe solution for system suitability test, and add the mobile phaseto make exactly 10 mL. Confirm that the peak area of calcitonin(salmon) obtained from 20 µL of this solution is equivalent to 5to 15% of that of calcitonin (salmon) from the solution for systemsuitability test.System performance: Dissolve 5 mg of methyl parahydroxybenzoateand 7 mg of ethyl parahydroxybenzoate in 100 mL ofacetonitrile. When the procedure is run with 20 µL of this solutionunder the above operating conditions methyl parahydroxybenzoateand ethyl parahydroxybenzoate are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with20 µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the peakareas of calcitonin (salmon) is not more than 2.0%.(3) Residual solvent—Being specified separately.Water Not more than 10.0% (5 mg, coulometric titration).Assay (i) Test animals: Select healthy albino rats weighingbetween 55 and 180 g, fasted for 24 hours before the test but allowedto drink water ad libitum..(ii) Standard solutions: Dissolve a quantity of Calcitonin(Salmon) Reference Standard in acetic acid buffer solution containing0.1% bovine serum albumin, and prepare a high–dosestandard solution S H and a low–dose standard solution S L containingexactly 0.050 and 0.025 Units per mL, respectively.(iii) Sample solutions: According to the labeled units, weighaccurately a suitable amount of Calcitonin (Salmon), and dissolvein acetic acid buffer solution containing 0.1% bovine serumalbumin, and prepare a high–dose sample solution T H andthe low–dose sample solution T L having Units equal to thestandard solutions in equal volumes, respectively.(iv) Dose for injection: Inject 0.3 mL per animal.(v) Procedure: Divide the test animals at random into 4groups, A, B, C and D, with not less than 8 animals and equalnumbers in each group. Inject S H , S L , T H and T L into the tailvein or subcutaneously into the neck of each animal of the respectivegroups. At 1 hour after the injection, collect blood fromthe abdominal aorta in a way that minimizes the suffering of theanimals, allow the blood samples to stand at room temperaturefor about 30 minutes, and centrifuge at 3000 revolutions perminute for 10 minutes to separate serum.(vi) Serum calcium determination: Pipet 0.1 mL of the serum,add exactly 6.9 mL of strontium TS, mix well, and use thissolution as the sample solution for calcium determination.Separately, pipet a suitable volume of Standard Calcium Solutionfor Atomic Absorption Spectrophotometry, dissolve instrontium TS to make a solution so that each mL contains 0.2 to3 µg of calcium (Ca: 40.08), and use this solution as the standardsolution for calcium determination. Perform the test as directedunder Atomic Absorption Spectrometry accordingto the following conditions, and calculate the calcium content ofthe sample solution for calcium determination from the calibrationcurve obtained from the absorbance of the standard solutionfor calcium determination.Amount (mg) of Calcium (Ca) in 100 mL of the serum= Calcium content (ppm) in the sample solution for calciumdetermination × 7Gas: Combustible gas—AcetyleneSupporting gas—AirLamp: Calcium hollow–cathode lampWavelength: 422.7 nm(vii) Calculation: Amounts of calcium in the serum obtainedwith S H , S L , T H and T L are symbolized as y 1 , y 2 , y 3 and y 4 , respectively.Sum up y 1 , y 2 , y 3 and y 4 on each set to obtain Y 1 , Y 2 ,Y 3 and Y 4 , respectively.Units per mg of peptide = antilog M × (b/a) × (1/c) × 5M = 0.3010 × (Y a /Y b )Y a = – Y 1 – Y 2 + Y 3 + Y 4Y b = Y 1 – Y 2 + Y 3 – Y 4a: Amount (mg) of Calcitonin (Salmon)b: Total volume (mL) of the high–dose sample solution preparedby dissolving Calcitonin (Salmon) in acetic acidbuffer solution containing 0.1% bovine serum albumin.c: Peptide content (%)F´ computed by the following equation should be smallerthan F 1 shown in the table against n with which s 2 is calculated.Calculate L (P=0.95) by use of the following equation: L shouldbe not more than 0.20. If F´ exceeds F 1 , or if L exceeds 0.20,repeat the test, increasing the number of animals or arrangingthe assay conditions so that F´ is not more than F 1 and L is not

Supplement II, JP XV Official Monographs 2097more than 0.20.F´ = (– Y 1 + Y 2 + Y 3 – Y 4 ) 2 /4fs 2f: Number of the test animals of each group.s 2 = {Σy 2 – (Y/f)}/nΣy 2 : The sum of squares of y 1 , y 2 , y 3 and y 4 in each group.Y = Y 1 2 + Y 2 2 + Y 3 2 + Y 42n = 4(f – 1)L = 2 (C – 1)(CM 2 + 0.09062)C = Y b 2 /(Y b 2 – 4fs 2 t 2 )t 2 : Value shown in the following table against n used to calculates 2 .n t 2 = F 1 n t 2 = F 1 n t 2 = F 11 161.45 13 4.667 25 4.2422 18.51 14 4.600 26 4.2253 10.129 15 4.543 27 4.2104 7.709 16 4.494 28 4.1965 6.608 17 4.451 29 4.1836 5.987 18 4.414 30 4.1717 5.591 19 4.381 40 4.0858 5.318 20 4.351 60 4.0019 5.117 21 4.325 120 3.92010 4.965 22 4.301 ∞ 3.84111 4.844 23 4.27912 4.747 24 4.260Containers and storage Containers—Hermetic containers.Storage—Light–resistant, not exceeding 10ºC.CarmelloseカルメロースAdd the following next to the Japanese title:[9000-11-7]Carmellose CalciumカルメロースカルシウムAdd the following next to the Japanese title:[9050-04-8]Carmellose SodiumカルメロースナトリウムAdd the following next to the Japanese title:[9004-32-4]Cefaclor Compound Granulesセファクロル 複 合 顆 粒Change the Purity to read:Purity Related substances—Take out the total contents of notless than 5 packs of Cefaclor Compound Granules, add a smallamount of 0.1 mol/L phosphate buffer solution, pH 4.5, grind,add 0.1 mol/L phosphate buffer solution, pH 4.5, shake vigorouslyfor 10 minutes, and add 0.1 mol/L phosphate buffer solution,pH 4.5, to make exactly V mL so that each mL containsabout 5 mg (potency) of Cefaclor according to the labeled totalpotency. Pipet 10 mL of this solution, add 0.1 mol/L phosphatebuffer solution, pH 4.5, to make exactly 25 mL, and filterthrough a membrane filter with a pore size not exceeding 0.45µm. Discard the first 1 mL of the filtrate, and use the subsequentfiltrate as the sample solution. Separately, weigh accurately anamount of Cefaclor Reference Standard, equivalent to about 20mg (potency), and dissolve in 0.1 mol/L phosphate buffer solutions,pH 4.5, to make exactly 20 mL. Pipet 2 mL of this solution,add 0.1 mol/L phosphate buffer solutions, pH 4.5, to makeexactly 100 mL, and use this solution as the standard solution.Perform the test with exactly 50 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and determineeach peak area of both solutions by the automatic integrationmethod. Calculate the amount of each related substance by thefollowing equation: the amount of each related substance is notmore than 0.6%, and the total amount of the related substancesis not more than 2.8%. If necessary, correct the fluctuation ofthe base line by performing the test in the same way with 50 µLof 0.1 mol/L phosphate buffer solution, pH 4.5.Amount (%) of each related substance= W S × (A T /A S ) × (V/4) × {1/(C × T)}Total amount (%) of the related substances= W S × (ΣA T /A S ) × (V/4) × {1/(C × T)}W S : Amount [mg (potency)] of Cefaclor Reference StandardA T : Area of each peak other than cefaclor, solvent and excipientfrom the sample solutionΣA T : Total area of the peaks other than cefaclor, solvent andexcipient from the sample solutionA S : Peak area of cefaclor from the standard solutionC: Labeled total potency [mg (potency)] of Cefaclor in 1 packT: Number (pack) of sampleOperating conditions—Proceed as directed in the operating conditions in the Purity(3) under Cefaclor.System suitability—Test for required detectability: Pipet 1 mL of the standard solution,and add 0.1 mol/L phosphate buffer solution, pH 4.5, tomake exactly 20 mL. Confirm that the peak area of cefaclor obtainedfrom 50 µL of this solution is equivalent to 3.5 to 6.5% ofthat of cefaclor from the standard solution.System performance: When the procedure is run with 50 µL

2098 Official Monographs Supplement II, JP XVof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of cefaclor are not less than 40000, and between 0.8 and1.3, respectively.System repeatability: When the test is repeated 3 times with50 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of cefacloris not more than 2.0%.Add the following:Cefalexin CapsulesセファレキシンカプセルCefalexin Capsules contain not less than 93.0% andnot more than 107.0% of the labeled potency of cefalexin(C 16 H 17 N 3 O 4 S: 347.39).Method of preparation Prepare as directed under Capsules,with Cefalexin.Identification Take out the contents of Cefalexin Capsules, toa quantity of the contents, equivalent to 70 mg (potency) of Cefalexinaccording to the labeled amount, add 25 mL of water,shake vigorously for 5 minutes, and filter. To 1 mL of the filtrateadd water to make 100 mL. Determine the absorption spectrumof this solution as directed under Ultraviolet-visible Spectrophotometry: it exhibits a maximum between 260 nm and264 nm.Water Not more than 10.0% (0.2 g, volumetric titration,back titration)Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.Open 1 capsule of Cefalexin Capsules, add 3V/5 mL of 0.1mol/L phosphate buffer solution, pH 4.5, shake vigorously for10 minutes, add 0.1 mol/L phosphate buffer solution, pH 4.5, tomake exactly V mL so that each mL contains about 1.25 mg(potency) of Cefalexin. Centrifuge this solution, pipet 2 mL ofthe supernatant liquid, add exactly 10 mL of the internal standardsolution, add 0.1 mol/L phosphate buffer solution, pH 4.5,to make 100 mL, and use this solution as the sample solution.Separately, weigh accurately an amount of Cefalexin ReferenceStandard, equivalent to about 25 mg (potency), dissolve in 0.1mol/L phosphate buffer solution, pH 4.5, to make exactly 100mL. Pipet 10 mL of this solution, add exactly 10 mL of the internalstandard solution, add 0.1 mol/L phosphate buffer solution,pH 4.5, to make 100 mL, and use this solution as the standardsolution. Perform the test with 10 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions, andcalculate the ratios, Q T and Q S , of the peak area of cefalexin tothat of the internal standard in each solution.Amount [mg (potency)] of cefalexin (C 16 H 17 N 3 O 4 S)= W S × (Q T /Q S ) × (V/20)W S : Amount [mg (potency)] of Cefalexin Reference StandardInternal standard solution—A solution ofm-hydroxyacetophenone in 0.1 mol/L phosphate buffer solution,pH 4.5 (1 in 15000)Operating conditions—Proceed as directed in the operating conditions in the Assay.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,cefalexin and the internal standard substance are eluted in thisorder with the resolution between these peaks being not lessthan 8.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof cefalexin to that of the internal standard substance is notmore than 1.0%.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rates in 30minutes of 125-mg (potency) capsules and in 60 minutes of250-mg (potency) capsules are not less than 75% and 80%, respectively.Start the test with 1 capsule of Cefalexin Capsules, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.5 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to make exactlyV´ mL so that each mL contains about 22 µg (potency) of Cefalexinaccording to the labeled amount, and use this solution asthe sample solution. Separately, weigh accurately an amount ofCefalexin Reference Standard, equivalent to about 22 mg (potency),and dissolve in water to make exactly 50 mL. Pipet 5 mLof this solution, add water to make exactly 100 mL, and use thissolution as the standard solution. Perform the test with the samplesolution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine the absorbances,A T and A S , at 262 nm.Dissolution rate (%) with respect to the labeled amount ofcefalexin (C 16 H 17 N 3 O 4 S)= W S × (A T /A S ) × (V´/V) × (1/C) × 90W S : Amount [mg (potency)] of Cefalexin Reference StandardC: Labeled amount [mg (potency)] of cefalexin(C 16 H 17 N 3 O 4 S) in 1 capsuleAssay Take out the contents of not less than 20 capsules ofCefalexin Capsules, weigh accurately the mass of the contents,and powder. Weigh accurately a portion of the powder, equivalentto about 0.1 g (potency) of Cefalexin, add 60 mL of 0.1mol/L phosphate buffer solution, pH 4.5, shake vigorously for10 minutes, add 0.1 mol/L phosphate buffer solution, pH 4.5, tomake exactly 100 mL, and centrifuge. Pipet 2 mL of the supernatantliquid, add exactly 10 mL of the internal standard solu-

Supplement II, JP XV Official Monographs 2099tion, add 0.1 mol/L phosphate buffer solution, pH 4.5, to make100 mL, and use this solution as the sample solution. Separately,weigh accurately an amount of Cefalexin Reference Standard,equivalent to about 20 mg (potency), dissolve in 0.1 mol/Lphosphate buffer solution, pH 4.5, to make exactly 100 mL. Pipet10 mL of this solution, add exactly 10 mL of the internalstandard solution, add 0.1 mol/L phosphate buffer solution, pH4.5, to make 100 mL, and use this solution as the standard solution.Perform the test with 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of cefalexin to that of the internalstandard in each solution.Amount [mg (potency)] of cefalexin (C 16 H 17 N 3 O 4 S)= W S × (Q T /Q S ) × 5W S : Amount [mg (potency)] of Cefalexin Reference StandardInternal standard solution—A solution ofm-hydroxyacetophenone in 0.1 mol/L phosphate buffer solution,pH 4.5 (1 in 15000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 3.0 mm in inside diameterand 7.5 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: Dissolve 2.72 g of potassium dihydrogenphosphate in 1000 mL of water, and adjust the pH to 3.0 withdiluted phosphoric acid (3 in 500). To 800 mL of this solutionadd 200 mL of methanol.Flow rate: Adjust the flow rate so that the retention time ofcefalexin is about 6 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,cefalexin and the internal standard are eluted in this order withthe resolution between these peaks being not less than 8.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof cefalexin to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Add the following:Cefalexin for Syrupシロップ 用 セファレキシンCefalexin for Syrup is a preparation for syrup, whichis dissolved or suspended before use.It contains not less than 90.0% and not more than110.0% of the labeled potency of cefalexin(C 16 H 17 N 3 O 4 S: 347.39).Method of preparation Prepare as directed under Syrup, withCefalexin.Identification Dissolve a quantity of Cefalexin for Syrup,equivalent to 3 mg (potency) of Cefalexin according to the labeledamount, in water to make 100 mL. Determine the absorptionspectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximumbetween 260 nm and 264 nm.Water Not more than 5.0% (0.4 g, volumetric titration,back titration)Uniformity of dosage units Perform the test accordingto the following method: Cefalexin for Syrup in single-unitcontainers meets the requirement of the Content uniformity test.Take out the total contents of 1 pack of Cefalexin for Syrup,add 3V/5 mL of 0.1 mol/L phosphate buffer solution, pH 4.5,shake vigorously for 10 minutes, add 0.1 mol/L phosphatebuffer solution, pH 4.5, to make exactly V mL so that each mLcontains about 1 mg (potency) of Cefalexin, and centrifuge. Pipet2 mL of the supernatant liquid, add exactly 10 mL of the internalstandard solution, add 0.1 mol/L phosphate buffer solution,pH 4.5, to make 100 mL, and use this solution as the samplesolution. Then, proceed as directed in the Assay.Amount [mg (potency)] of cefalexin (C 16 H 17 N 3 O 4 S)= W S × (Q T /Q S ) × (V/20)W S : Amount [mg (potency)] of Cefalexin Reference StandardInternal standard solution—A solution ofm-hydroxyacetophenone in 0.1 mol/L phosphate buffer solution,pH 4.5 (1 in 15000)Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 15minutes of Cefalexin for Syrup is not less than 80%.Start the test with an accurately weighed amount of Cefalexin,equivalent to about 0.25 g (potency) of Cefalexin for Syrup accordingto the labeled amount, withdraw not less than 20 mL ofthe medium at the specified minute after starting the test, andfilter through a membrane filter with a pore size not exceeding0.5 µm. Discard the first 10 mL of the filtrate, pipet 2 mL of thesubsequent filtrate, add water to make exactly 25 mL, and usethis solution as the sample solution. Separately, weigh accuratelyan amount of Cefalexin Reference Standard, equivalent to

2100 Official Monographs Supplement II, JP XVabout 22 mg (potency), and dissolve in water to make exactly 50mL. Pipet 5 mL of this solution, add water to make exactly 100mL, and use this solution as the standard solution. Perform thetest with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , and determinethe absorbances, A T and A S , at 262 nm.Dissolution rate (%) with respect to the labeled amount ofcefalexin (C 16 H 17 N 3 O 4 S)= (W S /W T ) × (A T /A S ) × (1/C) × 1125W S : Amount [mg (potency)] of Cefalexin Reference StandardW T : Amount (g) of Cefalexin for SyrupC: Labeled amount [mg (potency)] of cefalexin(C 16 H 17 N 3 O 4 S) in 1 gAssay Powder Cefalexin for Syrup, if necessary, and weighaccurately a portion of the powder, equivalent to about 0.1 g(potency) of Cefalexin, add 60 mL of 0.1 mol/L phosphatebuffer solution, pH 4.5, shake vigorously for 10 minutes, add0.1 mol/L phosphate buffer solution, pH 4.5, to make exactly100 mL, and centrifuge. Pipet 2 mL of the supernatant liquid,add exactly 10 mL of the internal standard solution, add 0.1mol/L phosphate buffer solution, pH 4.5, to make 100 mL, anduse this solution as the sample solution. Separately, weigh accuratelyan amount of Cefalexin Reference Standard, equivalent toabout 20 mg (potency), dissolve in 0.1 mol/L phosphate buffersolution, pH 4.5, to make exactly 100 mL. Pipet 10 mL of thissolution, add exactly 10 mL of the internal standard solution,add 0.1 mol/L phosphate buffer solution, pH 4.5, to make 100mL, and use this solution as the standard solution. Perform thetest with 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions, and calculate the ratios, Q T and Q S ,of the peak area of cefalexin to that of the internal standard ineach solution.Amount [mg (potency)] of cefalexin (C 16 H 17 N 3 O 4 S)= W S × (Q T /Q S ) × 5W S : Amount [mg (potency)] of Cefalexin Reference StandardInternal standard solution—A solution ofm-hydroxyacetophenone in 0.1 mol/L phosphate buffer solution,pH 4.5 (1 in 15000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 3.0 mm in inside diameterand 7.5 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: Dissolve 2.72 g of potassium dihydrogenphosphate in 1000 mL of water, and adjust the pH to 3.0 withdiluted phosphoric acid (3 in 500). To 800 mL of this solutionadd 200 mL of methanol.Flow rate: Adjust the flow rate so that the retention time ofcefalexin is about 6 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,cefalexin and the internal standard are eluted in this order withthe resolution between these peaks being not less than 8.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof cefalexin to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Storage—Light-resistant.Add the following:Cefatrizine Propylene Glycolatefor Syrupシロップ 用 セファトリジンプロピレングリコールCefatrizine Propylene Glycolate for Syrup is apreparation for syrup, which is dissolved before use.It contains not less than 90.0% and not more than105.0% of the labeled potency of Cefatrizine(C 18 H 18 N 6 O 5 S 2 : 462.50).Method of preparation Prepare as directed under Syrup, withCefatrizine Propylene Glycolate.Identification Powder Cefatrizine Propylene Glycolate forSyrup, weigh a portion of the powder, equivalent to 10 mg (potency)of Cefatrizine Propylene Glycolate according to the labeledamount, and dissolve in 10 mL of water. To 2 mL of thissolution add water to make 100 mL. Determine the absorptionspectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits maxima between 225 nmand 229 nm, and between 266 nm and 271 nm.pH Take an amount of Cefatrizine Propylene Glycolatefor Syrup, equivalent to 0.4 g (potency) of Cefatrizine PropyleneGlycolate according to the labeled amount, and suspendin 10 mL of water: the pH of this suspension is between 4.0 and6.0.Purity Related substances—Use the sample solution obtainedin the Assay as the sample solution. Pipet 1 mL of the samplesolution, add water to make exactly 100 mL, and use this solutionas the standard solution. Perform the test with exactly 10 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions. Determine each peak area of both solutions bythe automatic integration method: the area of each peak otherthan cefatrizine obtained from the sample solution is not largerthan the peak area of cefatrizine from the standard solution, andthe total area of the peaks other than the peak of cefatrizine obtainedfrom the sample solution is not larger than 2 times thepeak area of cefatrizine from the standard solution.Operating conditions—

Supplement II, JP XV Official Monographs 2101Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay under Cefatrizine Propylene Glycolate.Time span of measurement: About 2.5 times as long as theretention time of cefatrizine, beginning after the solvent peak.System suitability—System performance: Proceed as directed in the system suitabilityin the Assay under Cefatrizine Propylene Glycolate.Test for required detectability: Pipet 2 mL of the standard solution,and add water to make exactly 10 mL. Confirm that thepeak area of cefatrizine obtained from 10 µL of this solution isequivalent to 15 to 25% of that of cefatrizine from the standardsolution.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of cefatrizineis not more than 2.0%.Uniformity of dosage units Cefatrizine PropyleneGlycolate for Syrup in single-unit containers meets the requirementof the Mass variation test.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 15minutes of Cefatrizine Propylene Glycolate for Syrup is not lessthan 85%.Start the test with an accurately weighed amount of CefatrizinePropylene Glycolate for Syrup, equivalent to about 0.1 g(potency) of Cefatrizine Propylene Glycolate, withdraw not lessthan 20 mL of the medium at the specified minute after startingthe test, and filter through a membrane filter with a pore size notexceeding 0.45 µm. Discard the first 10 mL of the filtrate, anduse the subsequent filtrate as the sample solution. Separately,weigh accurately an amount of Cefatrizine Propylene GlycolateReference Standard, equivalent to about 28 mg (potency), anddissolve in water to make exactly 50 mL. Pipet 5 mL of this solution,add water to make exactly 25 mL, and use this solutionas the standard solution. Perform the test with exactly 10 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and determine the peak areas of cefatrizine, A Tand A S , of both solution.Dissolution rate (%) with respect to the labeled amount ofcefatrizine (C 18 H 18 N 6 O 5 S 2 )= (W S /W T )× (A T /A S ) × (1/C) × 360W S : Amount [mg (potency)] of Cefatrizine Propylene GlycolateReference StandardW T : Amount (g) of Cefatrizine Propylene Glycolate for SyrupC: Labeled amount [mg (potency)] of cefatrizine propyleneglycolate (C 18 H 18 N 6 O 5 S 2·C 3 H 8 O 2 ) in 1 gOperating conditions—Detector, column and column temperature: Proceed as directedin the operating conditions in the Assay under CefatrizinePropylene Glycolate.Mobile phase: A mixture of a solution of potassium dihydrogenphosphate (17 in 12500) and methanol (4:1).Flow rate: Adjust the flow rate so that the retention time ofcefatrizine is about 8 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of cefatrizine are not less than 3000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of cefatrizineis not more than 1.0%.Assay Powder Cefatrizine Propylene Glycolate for Syrup,weigh accurately a portion of the powder, equivalent to about0.1 g (potency) of Cefatrizine Propylene Glycolate, dissolve inwater to make exactly 500 mL, and use this solution as the samplesolution. Separately, weigh accurately an amount of CefatrizinePropylene Glycolate Reference Standard, equivalent toabout 20 mg (potency), dissolve in water to make exactly 100mL, and use this solution as the standard solution. Then, proceedas directed in the Assay under Cefatrizine Propylene Glycolate.Amount [mg (potency)] of cefatrizine (C 18 H 18 N 6 O 5 S 2 )= W S × (A T /A S ) × 5W S : Amount [mg (potency)] of Cefatrizine Propylene GlycolateReference StandardContainers and storage Containers—Tight containers.Add the following:Cefixime CapsulesセフィキシムカプセルCefixime Capsules contain not less than 90.0% andnot more than 105.0% of the labeled potency of cefixime(C 16 H 15 N 5 O 7 S 2 : 453.45).Method of preparation Prepare as directed under Capsules,with Cefixime.Identification Take out the contents of Cefixime Capsules, toa quantity of the contents of Cefixime Capsules, equivalent to70 mg (potency) of Cefixime according to the labeled amount,add 100 mL of 0.1 mol/L phosphate buffer solution, pH 7.0,shake for 30 minutes, and filter. Pipet 1 mL of the filtrate, andadd 0.1 mol/L phosphate buffer solution, pH 7.0, to make 50 mL.Determine the absorption spectrum of this solution as directedunder Ultraviolet-visible Spectrophotometry : it exhibitsa maximum between 286 nm and 290 nm.Purity Related substances—Take out the contents of CefiximeCapsules, to a quantity of the contents of Cefixime Capsules,equivalent to 0.1 g (potency) of Cefixime according to the la-

2102 Official Monographs Supplement II, JP XVbeled amount, add 100 mL of 0.1 mol/L phosphate buffer solution,pH 7.0, shake for 30 minutes, filter, and use the filtrate asthe sample solution. Perform the test with 10 µL of the samplesolution as directed under Liquid Chromatography accordingto the following conditions. Determine each peak areafrom the sample solution by the automatic integration method,and calculate the amount of them by the area percentagemethod: the amount of each peak other than cefixime is notmore than 1.0%, and the total amount of the peaks other thancefixime is not more than 2.5%.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay under Cefixime.Time span for measurement: Proceed as directed in the operatingconditions in the Purity under Cefixime.System suitability—Test for required detectability: Pipet 1 mL of the sample solution,and add 0.1 mol/L phosphate buffer solution, pH 7.0, tomake exactly 100 mL, and use this solution as the solution forsystem suitability test. Pipet 1 mL of the solution for systemsuitability test, and add 0.1 mol/L phosphate buffer solution, pH7.0, to make exactly 10 mL. Confirm that the peak area of cefiximeobtained from 10 µL of this solution is equivalent to 7 to13% of that of cefixime from the solution for system suitabilitytest.System performance: When the procedure is run with 10 µLof the solution for system suitability test under the above operatingconditions, the number of theoretical plates and the symmetryfactor of the peak of cefixime are not less than 4000 andnot more than 2.0, respectively.System repeatability: When the test is repeated 6 times with10 µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the peakarea of cefixime is not more than 2.0%.Water Not more than 12.0% (0.1 g of the contents,volumetric titration, direct titration)Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.Take out the contents of 1 capsule of Cefixime Capsules, and tothe contents and the capsule shells add 7V/10 mL of 0.1 mol/Lphosphate buffer solution, pH 7.0, shake for 30 minutes, andadd 0.1 mol/L phosphate buffer solution, pH 7.0, to make exactlyV mL so that each mL contains about 1 mg (potency) ofCefixime. Centrifuge this solution, pipet 10 mL of the supernatantliquid, add 0.1 mol/L phosphate buffer solution, pH 7.0,to make exactly 50 mL, and use this solution as the sample solution.Separately, weigh accurately an amount of Cefixime ReferenceStandard, equivalent to about 20 mg (potency), dissolvein 0.1 mol/L phosphate buffer solution, pH 7.0, to make exactly100 mL, and use this solution as the standard solution. Then,proceed as directed in the Assay under Cefixime.Amount [mg (potency)] of cefixime (C 16 H 15 N 5 O 7 S 2 )= W S × (A T /A S ) × (V/20)W S : Amount [mg (potency)] of Cefixime Reference StandardDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of disodium hydrogen phosphate-citricacid buffer solution, pH 7.5, as the dissolution medium, the dissolutionrates in 60 minutes of 50-mg (potency) capsules and in90 minutes of 100-mg (potency) capsules are not less than 80%,respectively.Start the test with 1 capsule of Cefixime Capsules, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.5 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add the dissolution mediumto make exactly V´ mL so that each mL contains about 56µg (potency) of Cefixime according to the labeled amount, anduse this solution as the sample solution. Separately, weigh accuratelyan amount of Cefixime Reference Standard, equivalent toabout 28 mg (potency), and dissolve in the dissolution mediumto make exactly 100 mL. Pipet 4 mL of this solution, add thedissolution medium to make exactly 20 mL, and use this solutionas the standard solution. Perform the test with exactly 20 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and determine the peak areas, A T and A S , of cefiximein each solution.Dissolution rate (%) with respect to the labeled amount ofcefixime (C 16 H 15 N 5 O 7 S 2 )= W S × (A T /A S ) × (V´/V) × (1/C) × 180W S : Amount [mg (potency)] of Cefixime Reference StandardC: Labeled amount [mg (potency)] of Cefixime in 1 capsuleOperating conditions—Proceed as directed in the operating conditions in the Assayunder Cefixime.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of cefixime are not less than 4000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of cefiximeis not more than 2.0%.Assay Take out the contents of not less than 20 CefiximeCapsules, weigh accurately the mass of the contents, and powder.Weigh accurately a portion of the powder, equivalent toabout 0.1 g (potency) of Cefixime, add 70 mL of 0.1 mol/Lphosphate buffer solution, pH 7.0, and shake for 30 minutes,add 0.1 mol/L phosphate buffer solution, pH 7.0, to make exactly100 mL. Centrifuge this solution, pipet 10 mL of the supernatantliquid, add 0.1 mol/L phosphate buffer solution, pH7.0, to make exactly 50 mL, and use this solution as the samplesolution. Separately, weigh accurately an amount of CefiximeReference Standard, equivalent to about 20 mg (potency), dis-

Supplement II, JP XV Official Monographs 2103solve in 0.1 mol/L phosphate buffer solution, pH 7.0, to makeexactly 100 mL, and use this solution as the standard solution.Then, proceed as directed in the Assay under Cefixime.Amount [mg (potency)] of cefixime (C 16 H 15 N 5 O 7 S 2 )= W S × (A T /A S ) × 5W S : Amount [mg (potency)] of Cefixime Reference StandardContainers and storage Containers—Tight containers.Add the following:Cefroxadine for Syrupシロップ 用 セフロキサジンCefroxadine for Syrup is a preparation for syrup,which is suspended before use.It contains not less than 93.0% and not more than107.0% of the labeled potency of cefroxadine(C 16 H 19 N 3 O 5 S: 365.40).Method of preparation Prepare as directed under Syrup, withCefroxadine Hydrate.Identification Powder Cefroxadine for Syrup, if necessary. Toa portion of the powder, equivalent to 2 mg (potency) of CefroxadineHydrate according to the labeled amount, add 100 mLof 0.001 mol/L hydrochloric acid TS, shake well, and filter. Determinethe absorption spectrum of this filtrate as directed underUltraviolet-visible Spectrophotometry : it exhibits amaximum between 267 nm and 271 nm.Water Not more than 4.5% (0.1 g, volumetric titration,direct titration).Uniformity of dosage units Perform the test accordingto the following method: Cefroxadine for Syrup in single-unitcontainers meets the requirement of the Content uniformitytest.Take out the total contents of 1 pack of Cefroxadine for Syrup,add 4V/5 mL of a mixture of dilute acetic acid and phosphoricacid (500:1), shake well for 15 minutes, add exactly 5 mL of theinternal standard solution per 50 mg (potency) of CefroxadineHydrate, and add a mixture of dilute acetic acid and phosphoricacid (500:1) to make V mL so that each mL contains 0.25 mg(potency) of Cefroxadine Hydrate. Filter this solution through amembrane filter with pore size of not exceeding 0.45 µm, anduse the filtrate as the sample solution. Separately, weigh accuratelyan amount of Cefroxadine Reference Standard, equivalentto about 50 mg (potency), dissolve in a mixture of dilute aceticacid and phosphoric acid (500:1), add exactly 5 mL of the internalstandard solution, add a mixture of dilute acetic acid andphosphoric acid (500:1) to make 200 mL, and use this solutionas the standard solution. Then, proceed as directed in the Assayunder Cefroxadine Hydrate.Amount [mg (potency)] of cefroxadine (C 16 H 19 N 3 O 5 S)= W S × (Q T /Q S ) × (V/200)W S : Amount [mg (potency)] of Cefroxadine Reference StandardInternal standard solution—Dissolve 1.6 g of vanillin in 5 mLof methanol, and add a mixture of dilute acetic acid and phosphoricacid (500:1) to make 100 mL.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 15minutes of Cefroxadine for Syrup is not less than 85%.Start the test with an accurately weighed amount of Cefroxadinefor Syrup, equivalent to about 0.1 g (potency) of CefroxadineHydrate according to the labeled amount, withdrawnot less than 10 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.8 µm. Discard the first 5 mL of the filtrate,pipet 4 mL of the subsequent filtrate, add 0.1 mol/L hydrochloricacid TS to make exactly 20 mL, and use this solution as thesample solution. Separately, weigh accurately an amount of CefroxadineReference Standard, equivalent to about 22 mg (potency),and dissolve in 0.1 mol/L hydrochloric acid TS to makeexactly 100 mL. Pipet 5 mL of this solution, add 10 mL of water,add 0.1 mol/L hydrochloric acid TS to make exactly 50 mL, anduse this solution as the standard solution. Perform the test withthe sample solution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine theabsorbances, A T and A S , at 267 nm.Dissolution rate (%) with respect to the labeled amount ofcefroxadine (C 16 H 19 N 3 O 5 S)= (W S /W T ) × (A T /A S ) × (1/C) × 450W S : Amount [mg (potency)] of Cefroxadine Reference StandardW T : Amount (g) of Cefroxadine for SyrupC: Labeled amount [mg (potency)] of cefroxadine(C 16 H 19 N 3 O 5 S) in 1 gAssay Powder Cefroxadine for Syrup, if necessary, weigh accuratelya portion of the powder, equivalent to about 50 mg(potency) of Cefroxadine Hydrate, add 160 mL of a mixture ofdilute acetic acid and phosphoric acid (500:1), shake well for 15minutes, add exactly 5 mL of the internal standard solution, andadd a mixture of dilute acetic acid and phosphoric acid (500:1)to make 200 mL. Filter this solution through a membrane filterwith a pore size not exceeding 0.45 µm, and use the filtrate asthe sample solution. Separately, weigh accurately an amount ofCefroxadine Reference Standard, equivalent to about 50 mg(potency), dissolve in a mixture of dilute acetic acid and phosphoricacid (500:1), add exactly 5 mL of the internal standardsolution, add a mixture of dilute acetic acid and phosphoric acid(500:1) to make 200 mL, and use this solution as the standardsolution. Proceed as directed in the Assay under CefroxadineHydrate.Amount [mg (potency)] of cefroxadine (C 16 H 19 N 3 O 5 S)

2104 Official Monographs Supplement II, JP XV= W S × (Q T /Q S )W S : Amount [mg (potency)] of Cefroxadine Reference StandardInternal standard solution—Dissolve 1.6 g of vanillin in 5 mLof methanol, and add a mixture of dilute acetic acid and phosphoricacid (500:1) to make 100 mL.Containers and storage Containers—Tight containers.Add the following:Cefteram Pivoxil Tabletsセフテラム ピボキシル 錠Cefteram Pivoxil Tablets contain not less than 90.0% and notmore than 110.0% of the labeled amount of cefteram(C 16 H 17 N 9 O 5 S 2 : 479.49).Method of preparation Prepare as directed under Tablets,with Cefteram Pivoxil.Identification To a quantity of powdered Cefteram PivoxilTablets, equivalent to 0.1 g (potency) of Cefteram Pivoxil accordingto the labeled amount, add 20 mL of methanol, shakewell, and filter. To 1 mL of the filtrate add 0.05 mol/L hydrochloricacid-methanol TS to make 500 mL. Determine the absorptionspectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximumbetween 262 nm and 266 nm.Purity Related substances—To a quantity of powderedCefteram Pivoxil Tablets, equivalent to 0.1 g (potency) ofCefteram Pivoxil according to the labeled amount, add dilutedacetonitrile (1 in 2) to make 100 mL. Disperse this solution withultrasonic waves, filter, and use the filtrate as the sample solution.Pipet 1 mL of this solution, add the mobile phase to makeexactly 50 mL and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area of both solutions by the automatic integration method:the area of the peak, having the relative retention time of about0.9 with respect to cefteram pivoxil, obtained from the samplesolution is not larger than 1.75 times the peak area of cefterampivoxil from the standard solution, and the area of the peak,having the relative retention time of about 0.1 with respect tocefteram pivoxil, obtained from the sample solution is not largerthan 17/25 times the peak area of cefteram pivoxil from thestandard solution. Furthermore, the total area of the peaks otherthan cefteram pivoxil from the sample solution is not larger than3.7 times the peak area of cefteram pivoxil from the standardsolution. For this calculation, use the area of the peak, havingthe relative retention time of about 0.1 with respect to cefterampivoxil, after multiplying by the relative response factor,0.74.relative responseOperating conditions—Proceed as directed in the operating conditions in the Purity(3) under Cefteram Pivoxil.System suitability—Proceed as directed in the system suitability in the Purity (3)under Cefteram Pivoxil.Water Not more than 4.0% (a quantity equivalent to0.2 g (potency) of powdered Cefteram Pivoxil Tablets, volumetrictitration, direct titration).Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Cefteram Pivoxil Tablets add exactly 5 mL ofthe internal standard solution per 50 mg (potency) of CefteramPivoxil, and add diluted acetonitrile (1 in 2) to make V mL sothat each mL contains about 1 mg (potency) of Cefteram Pivoxil.Disperse this solution with ultrasonic waves, filter through amembrane filter with pore size of not exceeding 0.45 µm, discardthe first 10 mL of the filtrate, and use the subsequent filtrateas the sample solution. Separately, weigh accurately anamount of Cefteram Pivoxil Mesitylene Sulfonate ReferenceStandard, equivalent to about 50 mg (potency), dissolve in 20mL of diluted acetonitrile (1 in 2), add exactly 5 mL of the internalstandard solution, add diluted acetonitrile (1 in 2) to make50 mL, and use this solution as the standard solution. Then,proceed as directed in the Assay under Cefteram Pivoxil.Amount [mg (potency)] of cefteram (C 16 H 17 N 9 O 5 S 2 )= W S × (Q T /Q S ) × (V/50)W S : Amount [mg (potency)] of Cefteram Pivoxil MesityleneSulfonate Reference StandardInternal standard solution—A solution of methyl parahydroxybenzoatein diluted acetonitrile (1 in 2) (1 in 1000)Dissolution When the test is performed at 75 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Cefteram Pivoxil Tablets is not less than 75%.Start the test with 1 tablet of Cefteram Pivoxil Tablets, withdrawnot less than 20 mL of the medium at the specified minuteafter starting the test, and filter through a membrane filter with apore size not exceeding 0.45 µm. Discard the first 10 mL of thefiltrate, pipet V mL of the subsequent filtrate, add water to makeexactly V´ mL so that each mL contains about 22 µg (potency)of Cefteram Pivoxil according to the labeled amount, and usethis solution as the sample solution. Separately, weigh accuratelyan amount of Cefteram Pivoxil Mesitylene SulfonateReference Standard, equivalent to about 22 mg (potency), anddissolve in 20 mL of methanol, and add water to make exactly50 mL. Pipet 5 mL of this solution, add water to make exactly100 mL, and use this solution as the standard solution. Performthe test with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , usingwater as the blank, and determine the absorbances, A T andA S , at 300 nm.

Supplement II, JP XV Official Monographs 2105Dissolution rate (%) with respect to the labeled amount ofcefteram (C 16 H 17 N 9 O 5 S 2 )= W S × (A T /A S ) × (V´/V) × (1/C) × 90W S : Amount [mg (potency)] of Cefteram Pivoxil MesityleneSulfonate Reference StandardC: Labeled amount [mg (potency)] of cefteram(C 16 H 17 N 9 O 5 S 2 ) in 1 tabletAssay To a number of tablet of Cefteram Pivoxil Tablets,equivalent to about 1.0 g (potency) of Cefteram Pivoxil, add 120mL of diluted acetonitrile (1 in 2), disperse with ultrasonicwaves, and add diluted acetonitrile (1 in 2) to make exactly 200mL. Centrifuge this solution, pipet 10 mL of the supernatantliquid, add exactly 5 mL of the internal standard solution, adddiluted acetonitrile (1 in 2) to make 50 mL, filter through amembrane filter with pore size not exceeding 0.45 µm, discardthe first 3 mL of the filtrate, and use the subsequent filtrate asthe sample solution. Separately, weigh accurately an amount ofCefteram Pivoxil Mesitylene Sulfonate Reference Standard,equivalent to about 50 mg (potency), dissolve in 20 mL of dilutedacetonitrile (1 in 2), add exactly 5 mL of the internal standardsolution, add diluted acetonitrile (1 in 2) to make 50 mL,and use this solution as the standard solution. Then, proceed asdirected in the Assay under Cefteram Pivoxil.Amount [mg (potency)] of cefteram (C 16 H 17 N 9 O 5 S 2 )= W S × (Q T /Q S ) × 20W S : Amount [mg (potency)] of Cefteram Pivoxil MesityleneSulfonate Reference StandardInternal standard solution—A solution of methyl parahydroxybenzoatein diluted acetonitrile (1 in 2) (1 in 1000)Containers and storage Containers—Tight containers.Storage—Light-resistant.CellacefateセラセフェートChange the Chemical name to read:[9004-38-0]Microcrystalline Cellulose結 晶 セルロースAdd the following next to the Japanese title:[9004-34-6, Cellulose]Powdered Cellulose粉 末 セルロースAdd the following next to the Japanese title:[9004-34-6, Cellulose]Add the following:CinoxacinシノキサシンC 12 H 10 N 2 O 5 : 262.225-Ethyl-8-oxo-5,8-dihydro[1,3]dioxolo[4,5-g]cinnoline-7-carboxylic acid [28657-80-9]Cinoxacin, when dried, contains not less than 98.0%and not more than 101.0% of C 12 H 10 N 2 O 5 .Description Cinoxacin occurs as a white to pale yellow crystallinepowder. It is odorless or has a slight, characteristic odor.It has a bitter taste.It is slightly soluble in N,N-dimethylformamide or acetone,very slightly soluble in ethanol (99.5), and practically insolublein water.It dissolves in sodium hydroxide TS.Melting point: about 265ºC (with decomposition).Identification (1) Dissolve 30 mg of Cinoxacin in 10 mL ofdilute sodium hydroxide TS, and add water to make 100 mL. To1 mL of this solution add 0.1 mol/L hydrochloric acid TS tomake 50 mL. Determine the absorption spectrum of this solutionas directed under Ultraviolet-visible Spectrophotometry ,and compare the spectrum with the Reference Spectrum: bothspectra exhibit similar intensities of absorption at the samewavelengths.(2) Determine the infrared absorption spectrum of Cinoxacinas directed in the potassium bromide disk method under InfraredSpectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similar intensitiesof absorption at the same wave numbers.Purity (1) Sulfate —Dissolve 0.20 g of Cinoxacin in10 mL of dilute sodium hydroxide TS, add 20 mL of 0.1 mol/Lhydrochloric acid TS, shake, filter, and add water to the filtrateto make 50 mL. Perform the test using this solution as the testsolution. Prepare the control solution with 0.20 mL of 0.005mol/L sulfuric acid by adding 10 mL of dilute sodium hydroxideTS, 20 mL of 0.1 mol/L hydrochloric acid TS, and water tomake 50 mL (not more than 0.048%).(2) Heavy metals —Proceed with 1.0 g of Cinoxacin

2106 Official Monographs Supplement II, JP XVaccording to Method 2, and perform the test. Prepare the controlsolution with 2.0 mL of Standard Lead Solution (not more than20 ppm).(3) Related substances—Dissolve 10 mg of Cinoxacin in 10mL of acetone, and use this solution as the sample solution. Pipet1 mL of this solution, add acetone to make exactly 200 mL,and use this solution as the standard solution. Perform the testwith these solutions as directed under Thin-layer Chromatography. Spot 10 µL each of the sample solution and standardsolution on a plate of silica gel with fluorescent indicatorfor thin-layer chromatography. Develop the plate with a mixtureof acetonitrile, water and ammonia solution (28) (14:4:1) to adistance of about 10 cm, and air-dry the plate. Examine underultraviolet light (main wavelength: 254 nm): the spots other thanthe principal spot obtained from the sample solution are notmore intense than the spot from the standard solution.(4) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 1hour).Residue on ignition Not more than 0.2% (1 g).Assay Weigh accurately about 0.4 g of Cinoxacin, previouslydried, add 60 mL of a mixture of acetic anhydride and aceticacid (100) (7:3), and dissolve by warming. After cooling, titrate with 0.1 mol/L perchloric acid VS (potentiometric titration).Perform a blank determination in the same manner, andmake any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 26.22 mg of C 12 H 10 N 2 O 5Containers and storage Containers—Tight containers.Add the following:Cinoxacin CapsulesシノキサシンカプセルCinoxacin Capsules contain not less than 95.0% andnot more than 105.0% of the labeled amount of cinoxacin(C 12 H 10 N 2 O 5 : 262.22).Method of preparation Prepare as directed under Capsules,with Cinoxacin.Identification To a quantity of the contents of CinoxacinCapsules, equivalent to 10 mg of Cinoxacin according to the labeledamount, add 20 mL of acetone, shake well, and centrifuge.To 3 mL of the supernatant liquid add acetone to make 10 mL,and use this solution as the sample solution. Separately, dissolve10 mg of cinoxacin for assay in 20 mL of acetone. To 3 mL ofthis solution add acetone to make 10 mL, and use this solutionas the standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 10 µLeach of the sample solution and standard solution on a plate ofsilica gel with fluorescent indicator for thin-layer chromatography.Develop the plate with a mixture of acetonitrile, water andammonia solution (28) (14:4:1) to a distance of about 10 cm,and air-dry the plate. Examine under ultraviolet light (mainwavelength: 254 nm): the principal spot obtained from the samplesolution and the spot from the standard solution show ablue-purple color and the same R f value.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 capsule of Cinoxacin Capsules add 40 mL of dilute sodiumhydroxide TS, and dissolve the capsule in lukewarm waterwith occasional shaking. After cooling, add water and shakewell, add water to make exactly V mL so that each mL containsabout 1 mg of cinoxacin (C 12 H 10 N 2 O 5 ), and filter. Discard thefirst 20 mL of the filtrate, pipet 1 mL of the subsequent filtrate,add 0.1 mol/L hydrochloric acid TS to make exactly 100 mL,and use this solution as the sample solution. Separately, weighaccurately about 0.2 g of cinoxacin for assay, previously dried at105ºC for 1 hour, dissolve in 40 mL of dilute sodium hydroxideTS, and add water to make exactly 200 mL. Pipet 1 mL of thissolution, add 0.1 mol/L of hydrochloric acid TS to make exactly100 mL, and use this solution as the standard solution. Performthe test with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , anddetermine the absorbances, A T and A S , at 354 nm.Amount (mg) of cinoxacin (C 12 H 10 N 2 O 5 )= W S × (A T /A S ) × (V/200)W S : Amount (mg) of cinoxacin for assayDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of 2nd solution for dissolution test as thedissolution medium, the dissolution rate in 90 minutes of CinoxacinCapsules is not less than 70%.Start the test with 1 capsule of Cinoxacin Capsules, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add the dissolutionmedium to make exactly V´ mL so that each mL contains about11 µg of cinoxacin (C 12 H 10 N 2 O 5 ) according to the labeledamount, and use this solution as the sample solution. Separately,weigh accurately about 22 mg of cinoxacin for assay, previouslydried at 105ºC for 1 hour, and dissolve in the dissolution mediumto make exactly 100 mL. Pipet 5 mL of this solution, addthe dissolution medium to make exactly 100 mL, and use thissolution as the standard solution. Perform the test with the samplesolution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine the absorbances,A T and A S , at 351 nm.Dissolution rate (%) with respect to the labeled amount ofcinoxacin (C 12 H 10 N 2 O 5 )= W S × (A T /A S ) × (V´/V) × (1/C) × 45W S : Amount (mg) of cinoxacin for assay

Supplement II, JP XV Official Monographs 2107C: Labeled amount (mg) of cinoxacin (C 12 H 10 N 2 O 5 ) in 1capsuleAssay Weigh accurately the mass of not less than 20 CinoxacinCapsules, take out the contents, and powder. Wash the capsuleshells with a small amount of diethyl ether, allow to standat room temperature to vaporize the diethyl ether, weigh accuratelythe mass of the capsule shells, and calculate the mass ofthe contents. Weigh accurately a portion of the powder, equivalentto about 50 mg of cinoxacin (C 12 H 10 N 2 O 5 ), add 10 mL ofdilute sodium hydroxide TS, shake, add water to make exactly100 mL, and filter. Discard the first 20 mL of the filtrate, pipet 1mL of the subsequent filtrate, add 0.1 mol/L hydrochloric acidTS to make exactly 50 mL, and use this solution as the samplesolution. Separately, weigh accurately about 50 mg of cinoxacinfor assay, previously dried at 105ºC for 1 hour, dissolve in 10mL of dilute sodium hydroxide TS, and add water to make exactly100 mL. Pipet 1 mL of this solution, add 0.1 mol/L hydrochloricacid TS to make exactly 50 mL, and use this solution asthe standard solution. Perform the test with the sample solutionand standard solution as directed under Ultraviolet-visible Spectrophotometry, and determine the absorbances, A T andA S , at 354 nm.Amount (mg) of cinoxacin (C 12 H 10 N 2 O 5 )= W S × (A T /A S )W S : Amount (mg) of cinoxacin for assayContainers and storage Containers—Well-closed containers.Add the following:Clebopride Malateクレボプリドリンゴ 酸 塩C 20 H 24 ClN 3 O 2·C 4 H 6 O 5 : 507.964-Amino-N-(1-benzylpiperidin-4-yl)-5-chloro-2-methoxybenzamide mono-(2RS)-malate[57645-91-7]and enantiomerClebopride Malate, when dried, contains not lessthan 98.5% and not more than 101.0% ofC 20 H 24 ClN 3 O 2·C 4 H 6 O 5 .Description Clebopride Malate occurs as a white crystallinepowder.It is freely soluble in acetic acid (100), soluble in methanol,sparingly soluble in water, and slightly soluble in ethanol (99.5).A solution of Clebopride Malate in methanol (1 in 25) showsno optical rotation.Identification (1) Determine the absorption spectrum of asolution of Clebopride Malate in methanol (1 in 80000) as directedunder Ultraviolet-visible Spectrophotometry , andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of CleboprideMalate, previously dried, as directed in the potassiumbromide disk method under Infrared Spectrophotometry ,and compare the spectrum with the Reference Spectrum: bothspectra exhibit similar intensities of absorption at the same wavenumbers.(3) Perform the test with Clebopride Malate under FlameColoration Test (2): a green color appears.Purity (1) Chloride —Dissolve 1.0 g of CleboprideMalate in 20 mL of acetic acid (100), add 6 mL of dilute nitricacid and water to make 50 mL. Perform the test using this solutionas the test solution. Prepare the control solution with 0.25mL of 0.01 mol/L hydrochloric acid VS by adding 20 mL ofacetic acid (100), 6 mL of dilute nitric acid and water to make50 mL (not more than 0.009%).(2) Heavy metals —Proceed with 2.0 g of CleboprideMalate according to Method 2, and perform the test. Preparethe control solution with 2.0 mL of Standard Lead Solution(not more than 10 ppm).(3) Related substances—Dissolve 0.10 g of CleboprideMalate in 10 mL of the mobile phase, and use this solution asthe sample solution. Pipet 0.2 mL of this solution, add the mobilephase to make 100 mL, and use this solution as the standardsolution. Perform the test with exactly 10 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area of both solutions by the automatic integrationmethod: the total area of the peaks other than the peak ofclebopride obtained from the sample solution is not larger thanthe peak area of clebopride from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:240 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (7 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: Dissolve 3.85 g of ammonium acetate in waterto make 500 mL, and filter through a membrane filter with apore size not exceeding 0.5 µm. To 400 mL of the filtrate add600 mL of methanol.Flow rate: Adjust the flow rate so that the retention time ofclebopride is about 15 minutes.Time span of measurement: About 2 times as long as the retentiontime of clebopride.System suitability—Test for required detectability: Pipet 10 mL of the standardsolution, and add water to make exactly 100 mL. Confirm thatthe peak area of clebopride obtained from 10 µL of this solutionis equivalent to 7 to 13% of that of clebopride from the standardsolution.

2108 Official Monographs Supplement II, JP XVSystem performance: Dissolve 30 mg Clebopride Malate and5 mg of propyl parahydroxybenzoate in the mobile phase tomake 100 mL. When the procedure is run with 10 µL of this solutionunder the above operating conditions, propyl parahydroxybenzoateand clebopride are eluted in this order with theresolution between these peaks being not less than 3.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of cleboprideis not more than 2.5%.(4) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 4hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.5 g of Clebopride Malate,previously dried, dissolve in 30 mL of acetic acid (100), and titrate with 0.1 mol/L perchloric acid VS (potentiometrictitration). Perform a blank determination in the same manner,and make any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 50.80 mg of C 20 H 24 ClN 3 O 2·C 4 H 6 O 5Containers and storage Containers—Tight containers.Clindamycin Hydrochlorideクリンダマイシン 塩 酸 塩Change the Origin/limits of content and Assay toread:Clindamycin Hydrochloride is the hydrochloride of a derivativeof lincomycin.It contains not less than 838 µg (potency) and not more than940 µg (potency) per mg, calculated on the anhydrous basis. Thepotency of Clindamycin Hydrochloride is expressed as mass(potency) of clindamycin (C 18 H 33 ClN 2 O 5 S: 424.98).Assay Weigh accurately an amount of Clindamycin Hydrochlorideand an amount of Clindamycin Hydrochloride ReferenceStandard, equivalent to about 20 mg (potency), dissolveeach in the mobile phase to make exactly 20 mL, and use thesesolutions as the sample solution and standard solution, respectively.Perform the test with exactly 20 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions, anddetermine the peak areas, A T and A S , of clindamycin in each solution.Amount [µg (potency)] of clindamycin (C 18 H 33 ClN 2 O 5 S)= W S × (A T /A S ) × 1000W S : Amount [mg (potency)] of Clindamycin HydrochlorideReference StandardOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:210 nm)Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: To 0.05 mol/L potassium dihydrogen phosphateTS add 8 mol/L potassium hydroxide TS to adjust the pHto 7.5. To 550 mL of this solution add 450 mL of acetonitrile forliquid chromatography.Flow rate: Adjust the flow rate so that the retention time ofclindamycin is about 10 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of clindamycin are not less than 6000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of clindamycinis not more than 1.0%.Clindamycin HydrochlorideCapsulesクリンダマイシン 塩 酸 塩 カプセルChange the Origin/limits of content, Uniformity ofdosage units and Assay to read:Clindamycin Hydrochloride Capsules contains notless than 93.0% and not more than 107.0% of the labeledpotency of clindamycin (C 18 H 33 ClN 2 O 5 S:424.98).Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 capsule of Clindamycin Hydrochloride Capsules add asuitable amount of the mobile phase, shake for 30 minutes, andadd the mobile phase to make exactly V mL so that each mLcontains about 0.75 mg (potency) of Clindamycin Hydrochloride.Centrifuge this solution, and use the supernatant liquid asthe sample solution. Then, proceed as directed in the Assay.Amount [mg (potency)] of clindamycin (C 18 H 33 ClN 2 O 5 S)= W S × (A T /A S ) × (V/100)W S : Amount [mg (potency)] of Clindamycin HydrochlorideReference StandardAssay Take out the contents of not less than 20 ClindamycinHydrochloride Capsules, weigh accurately the mass of the contents,and powder. Weigh accurately a portion of the powder,equivalent to about 75 mg (potency) of Clindamycin Hydro-

Supplement II, JP XV Official Monographs 2109chloride, add the mobile phase, shake for 30 minutes, and addthe mobile phase to make exactly 100 mL. Centrifuge this solution,and use the supernatant liquid as the sample solution.Separately, weigh accurately about 75 mg (potency) of ClindamycinHydrochloride Reference Standard, dissolve in the mobilephase to make exactly 100 mL, and use this solution as thestandard solution. Perform the test with exactly 20 µL each ofthe sample solution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the peak areas, A T and A S , of clindamycin ineach solution.Amount [mg (potency)] of clindamycin (C 18 H 33 ClN 2 O 5 S)= W S × (A T /A S )W S : Amount [mg (potency)] of Clindamycin HydrochlorideReference StandardOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:210 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To 0.05 mol/L of potassium dihydrogen phosphateTS add 8 mol/L potassium hydroxide TS to adjust the pHto 7.5. To 550 mL of this solution add 450 mL of acetonitrile forliquid chromatography.Flow rate: Adjust the flow rate so that the retention time ofclindamycin is about 7 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of clindamycin are not less than 3000 and not more than2.0, respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of clindamycinis not more than 1.0%.Clomifene Citrate Tabletsクロミフェンクエン 酸 塩 錠Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Clomifene Citrate Tablets add 10 mL of water,and shake until the tablets are disintegrated. To this solution add50 mL of methanol, shake for 10 minutes, and add methanol tomake exactly 100 mL. Centrifuge this solution, pipet 4 mL ofthe supernatant liquid, add methanol to make exactly V mL sothat each mL contains about 20 µg of clomifene citrate(C 26 H 28 ClNO·C 6 H 8 O 7 ), and use this solution as the sample solution.Proceed as directed in the Assay.Amount (mg) of clomifene citrate (C 26 H 28 ClNO·C 6 H 8 O 7 )= W S × (A T /A S ) × (V/100)W S : Amount (mg) of Clomifene Citrate Reference StandardCodeine Phosphate Tabletsコデインリン 酸 塩 錠Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Codeine Phosphate Tablets add 3V/25 mL ofwater to disintegrate, add 2V/25 mL of diluted dilute sulfuricacid (1 in 20), and treat with ultrasonic waves for 10 minutes. Tothis solution add exactly 2V/25 mL of the internal standard solution,add water to make V mL so that each mL contains about0.2 mg of codeine phosphate hydrate (C 18 H 21 NO 3·H 3 PO 4·½H 2 O),filter, and use the filtrate as the sample solution. Separately,weigh accurately about 50 mg of codeine phosphate for assay(separately, determine the water content in the samemanner as Codeine Phosphate Hydrate), and dissolve in water tomake exactly 100 mL. Pipet 10 mL of this solution, add exactly2 mL of the internal standard solution, add water to make 25 mL,and use this solution as the standard solution. Proceed as directedin the Assay.Amount (mg) of codeine phosphate hydrate(C 18 H 21 NO 3·H 3 PO 4·½H 2 O)= W S × (Q T /Q S ) × (V/250) × 1.023W S : Amount (mg) of codeine phosphate for assay, calculatedon the anhydrous basisInternal standard solution—A solution of ethylefurin hydrochloride(3 in 2000)Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Codeine Phosphate Tablets is not less than 80%.Start the test with 1 tablet of Codeine Phosphate Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard the first 10mL of the filtrate, pipet V mL of the subsequent filtrate, add waterto make exactly V´ mL so that each mL contains about 5.6 µgof codeine phosphate hydrate (C 18 H 21 NO 3·H 3 PO 4·½H 2 O) accordingto the labeled amount, and use this solution as the samplesolution. Separately, weigh accurately about 28 mg of codeinephosphate for assay (separately, determine the water content in the same manner as Codeine Phosphate Hydrate),dissolve in water to make exactly 100 mL. Pipet 2 mL of thissolution, add water to make exactly 100 mL, and use this solu-

2110 Official Monographs Supplement II, JP XVtion as the standard solution. Perform the test with exactly 100µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and determine the peak areas, A T and A S , of codeinein each solution.Dissolution rate (%) with respect to the labeled amount ofcodeine phosphate hydrate (C 18 H 21 NO 3·H 3 PO 4·½H 2 O)= W S × (A T /A S ) × (V´/V) × (1/C) × 18 × 1.023W S : Amount (mg) of codeine phosphate for assay, calculatedon the anhydrous basisC: Labeled amount (mg) of codeine phosphate hydrate(C 18 H 21 NO 3·H 3 PO 4·½H 2 O) in 1 tabletOperating procedures—Proceed as directed in the Assay.System suitability—System performance: When the procedure is run with 100 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of codeine are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with100 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of codeineis not more than 2.0%.Corn StarchトウモロコシデンプンChange the Identification (1) to read:Identification (1) Under a microscope , using amixture of water and glycerin (1:1), Corn Starch appears as eitherangular polyhedral granules of irregular sizes with diametersranging from about 2 µm to about 23 µm or as rounded orspheroidal granules of irregular sizes with diameters rangingfrom about 25 µm to about 35 µm. The central hilum consists ofa distinct cavity or two- to five-rayed cleft, and there are noconcentric striations. Between orthogonally oriented polarizingplates or prisms, the starch granules show a distinct black crossintersecting at the hilum.Add the following next to the Purity (3):Purity ◆ (4) Foreign matter—Under a microscope ,Corn Starch does not contain starch granules of any other origin.It may contain a minute quantity, if any, of fragments of the tissueof the original plant. ◆Change to read:Wood Creosote木 クレオソートWood Creosote is a mixture of phenols obtainedfrom by using wood tar derived from dry distillation ofstems and branches of various plants of genus Pinus(Pinaceae), genus Cryptomeria (Taxodiaceae), genusFagus (Fagaceae), genus Afzelia (genus Intsia);(Leguminosae), genus Shorea (Dipterocarpaceae) orgenus Tectona (Verbenaceae), followed by distillationand collection at 180 to 230°C, then further purificationand then re-distillation.Wood Creosote contains not less than 23.0% and notmore than 35 % of guaiacol (C 7 H 8 O 2 :124.14).Description Wood Creosote is a colorless or pale yellow,clear liquid. It has a characteristic odor.It is slightly soluble in water.It is miscible with methanol or ethanol (99.5).Its saturated solution is acidic.It is highly refractive.It gradually changes in color by light or by air.Identification The sample solution for assay is used as thesample solution. Separately dissolve 0.1 g of phenol, p-cresol,guaiacol and 2-methoxy-4-methylphenol in methanol respectively,to prepare 100 mL of solutions. Take 10 mL of each solutionand add methanol to prepare 50 mL of solutions, whichare used as Standard Solution (1), Standard Solution (2), StandardSolution (3) and Standard Solution (4). The perform testwith 10 µL each of the sample solution, Standard Solution (1),Standard Solution (2), Standard Solution (3) and Standard Solution(4) as directed under liquid chromatography accordingto the following conditions: the main peaks show thesame retention times with those obtained with the Standard Solution(1-4).Operating conditions—It meets test requirements directed in the assay.Specific gravity d 2020: Not less than 1.076.Purity (1) Coal Creosote Accurately measure 10 mL ofthis Coal Creosote, add methanol to prepare exactly 20 mL ofthe solution, which is used as the standard solution. Separatelyprepare exactly 1 mg each of benzo[a]pyrene,benz[a]anthracene and dibenz[a, h]anthracene, dissolve ethylacetate as needed and add methanol to prepare a 100 mL solution.Take 1 mL of this solution and add methanol to prepare100 mL of the standard solution. Perform the test with exactly 1µL each of sample solution and standard solution as directedunder gas chromatography according to the followingconditions: No peaks are detected for retention times that correspondto benzo[a]pyrene, benz[a]anthracene and dibenz[a,h]anthracene. Change these conditions if any peak is detectedfor retention times that correspond to benzo[a]pyrene,benz[a]anthracene or dibenz[a, h]anthracene, to verify that such

Supplement II, JP XV Official Monographs 2111a peak does not belong to benzo[a]pyrene, benz[a]anthracene ordibenz[a, h]anthracene.Operating conditions—Detector: Mass spectrometer (EI).Monitored ions:Benz[a]anthracene: Molecular ion m/z228, Fragment ion m/z 114Benzo[a]pyrene: Molecular ion m/z 252,Fragment ion m/z 125Dibenz[a, h]anthracene: Molecular ionm/z 278, Fragment ion m/z 139About 14 to 20minutesAbout 20 to 25minutesAbout 25 to 30minutesColumn: A quartz tube 0.25 mm in inside diameter and 30 min length, with internal coating 0.25 – 0.5 µm in thickness madeof 5% diphenyl and 95% dimethyl polysiloxane for gas chromatography.Column temperature: Perform injection at constant temperaturein vicinity of 45°C, then raise temperature by 40°C eachtime to 240°C, maintain the temperature at 240°C for 5 minutes,then raise temperature by 4°C per minute until it reaches 300°C,then raise the temperature by 10°C each minute until it reaches320°C, then maintain temperature at 320°C for 3 minutes.Injection port temperature: Constant temperature in vicinityof 250°C.Interface temperature: Constant temperature in vicinity of300°C.Carrier gas: Helium.Flow rate: Adjust the flow rate so that the retention time ofbenzo [a]pyrene is about 22 minutes.Split ratio: Splitless.System suitability—Test for required deectability: Accurately measure 1 mL ofstandard solution and add methanol to prepare exactly 10 mL ofthe solution for system suitability test. When the test is performedwith conditions described above for 1 µL of the solutionfor system suitability test, the S/N ratio of each substance is notless than 3.System performance: When the procedure is run with conditionsdescribed above for 1 µL of the solution for system suitabilitytest, the elution takes place in order of benz[a]anthracene,benzo[a]pyrene and then dibenz[a, h]anthracene.System repeatability: When the test is repeated 6 times with 1µL of the solution for system suitability test under the aboveconditions, the relative standard deviation of the peak area ofbenzo[a]pyrene, benz[a]anthracene and dibenz[a, h]anthraceneis respectively not more than 10 %.(2) AcenaphtheneAdd methanol to 0.12 g of Wood Creosote to prepare 50 mLof the sample solution. Separately dissolve 25 mg of acenaphthenein methanol to prepare a 50 mL of solution. Take 5mL of this solution and add methanol to prepare 20 mL of solution.Take 2 mL of this solution and add methanol to prepare100 mL of standard solution. Perform the test with exactly 1 µLeach of sample solution and standard solution as directed undergas chromatography according to the following conditions:No peaks are detected with sample solution for the retentiontime corresponding to acenaphthene of the standard solution.Change these conditions if any peak is detected for the retentiontime corresponding to acenaphthene, to verify that sucha peak does not belong to athenaphthene.Operating conditions—Detector: A hydrogen flame-ionization detector.Column: A fused silica tube 0.25 mm inside diameter and 60m in length, with internal coating 0.25 – 0.5 µm in thicknessmade of polymethylsiloxane for gas chromatography.Column temperature: Perform injection at a constant temperaturein vicinity of 45°C, then raise the temperature by11.5°C per minute until reaching 160°C, then raise the temperatureby 4°C per minute until reaching 180°C, then raise thetemperature by 8°C until reaching 270°C, then maintain temperatureat 270°C for 3 minutes.Injection port temperature: 250°C.Detector temperature: 250°C.Carrier gas: Helium.Flow rate: Adjust the flow rate so that the retention time ofacenaphthene is about 18 minutes.Split ratio: Splitless.System suitability—Test for required detectability: Accurately measure 1 mL ofthis solution, add methanol to prepare exactly 10 mL of the solutionfor system suitability test. When the procedure is run withconditions described above for 1 µL of solution for system suitabilitytest, the S/N ratio of acenaphthene is not less than 3.System repeatability: When the test is repeated 6 times with 1µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the peakarea of acenaphthene is not more than 6.0 %.(3) Other impuritiesAdd 2 mL of petroleum benzin to 1.0 mL of Wood Creosote,then add 2 mL of barium hydroxide test solution, agitate to mixand allow to stand. No blue or muddy brown color develops inthe upper layer of the mixture. Furthermore, no red color developsin the lower layer.Distilling range 200 – 220°C, not less than 85 vol%.Assay Add methanol to exactly 0.1 g of Wood Creosote toprepare exactly 50 mL of the solution. Add methanol to exactly10 mL of this solution to prepare 50 mL of sample solution.Separately add methanol to about 30 mg of accurately measuredguaiacol for assay to prepare exactly 50 mL of the solution.Accurately measure 10 mL of this solution, add methanol toprepare exactly 50 mL of the standard solution. Perform the testwith 10 µL each of sample solution and standard solution as directedunder liquid chromatography according to thefollowing conditions, and calculate the peak areas, A T and A S , ofthe guaiacol for each solution.The amount of guaiacol (C 7 H 8 O 2 ) (mg)= W S × (A T / A S )W S : Amount of guaiacol for assay (mg)Operating conditions—Detector: Ultraviolet absorption detector (detected wavelength:275 nm).

2112 Official Monographs Supplement II, JP XVColumn: Fill a stainless steel tube with internal diameter of4.6 mm and length of 15 cm with 5 µm of octadecylsilanizedsilica gel for gas chromatography.Column temperature: Constant temperature in vicinity of40°C.Mobile phase: Mixture of water and acetonitrile (4:1).Flow rate: Adjust the flow rate so that the retention time ofguaiacol is about 9 minutes.System suitability—System performance: Dissolve 2 mg each of guaiacol andphenol to obtain 10 mL of solution. The procedure is run withconditions described above for 10 µL of this solution, the elutiontakes place in order of phenol then guaiacol, with the degreein separation of not less than 2.5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of guaiacolis not more than 1.5 %.Containers and storage Containers— Tight containers.Storage—Light-resistant.Croscarmellose SodiumクロスカルメロースナトリウムAdd the following next to the Japanese title:[74811-65-7]Add the following:DanazolダナゾールC 22 H 27 NO 2 : 337.4617α-Pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol[17230-88-5]Danazol, when dried, contains not less than 98.5%and not more than 101.0% of C 22 H 27 NO 2 .Description Danazol occurs as a white to pale yellow crystallinepowder.It is soluble in acetone, sparingly soluble in ethanol (99.5),and practically insoluble in water.Melting point: about 225ºC (with decomposition).Identification (1) Determine the absorption spectrum of asolution of Danazol in ethanol (95) (1 in 50000) as directed underUltraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrum of asolution of Danazol Reference Standard prepared in the samemanner as the sample solution: both spectra exhibit similar intensitiesof absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Danazolas directed in the potassium bromide disk method under InfraredSpectrophotometry , and compare the spectrum with theReference Spectrum or the spectrum of a solution of DanazolReference Standard prepared in the same manner as the samplesolution: both spectra exhibit similar intensities of absorption atthe same wave numbers.Optical rotation [α] 20D: +8 - +11º (after drying, 0.25 g,ethanol (99.5), 50 mL, 100 mm).Purity (1) Chloride —To 2.0 g of Danazol add 80mL of water, shake well, and boil for 5 minutes. After cooling,add water to make 100 mL, and filter through a glass filter (G4).Discard the first 30 mL of the filtrate, take 40 mL of the subsequentfiltrate, and add 6 mL of dilute nitric acid and water tomake 50 mL. Perform the test using this solution as the test solution.Prepare the control solution with 0.25 mL of 0.01 mol/Lhydrochloric acid VS (not more than 0.011%).(2) Heavy metals —Proceed with 2.0 g of Danazolaccording to Method 2, and perform the test. Prepare the controlsolution with 2.0 mL of Standard Lead Solution (not more than10 ppm).(3) Related substances—Dissolve 0.20 g of Danazol in 4mL of acetone, and use this solution as the sample solution. Pipet2 mL of this solution, add acetone to make exactly 200 mL.Pipet 4 mL of this solution, add acetone to make exactly 20 mL,and use this solution as the standard solution. Perform the testwith these solutions as directed under Thin-layer Chromatography. Spot 5 µL each of the sample solution and standardsolution on a plate of silica gel with fluorescent indicator forthin-layer chromatography. Develop the plate with a mixture ofcyclohexane and ethyl acetate (3:2) to a distance of about 15 cm,and air-dry the plate. Examine under ultraviolet light (mainwavelength: 254 nm): the spots other than the principal spot andother than the spot at the starting point obtained from the samplesolution are not more intense than the spot from the standardsolution.(4) Residual solvent—Being specified separately.Loss on drying Not more than 0.2% (1 g, in vacuum,phosphorous (V) oxide, 60ºC, 4 hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 25 mg each of Danazol andDanazol Reference Standard, previously dried, dissolve separatelyin ethanol (95) to make exactly 50 mL. Pipet 2 mL eachof these solutions, add ethanol (95) to make exactly 50 mL, anduse these solutions as the sample solution and standard solution,respectively. Perform the test with the sample solution andstandard solution as directed under Ultraviolet-visible Spectrophotometry, and determine the absorbances, A T and A S ,at 285 nm.

Supplement II, JP XV Official Monographs 2113Amount (mg) of danazol (C 22 H 27 NO 2 )= W S × (A T /A S )W S : Amount (mg) of Danazol Reference StandardContainers and storage Containers—Well-closed containers.Storage—Light-resistant.Add the following:Dibekacin Sulfate OphthalmicSolutionジベカシン 硫 酸 塩 点 眼 液Dibekacin Sulfate Ophthalmic Solution is an aqueousophthalmic solution.It contains not less than 90.0% and not more than110.0% of the labeled potency of dibekacin(C 18 H 37 N 5 O 8 : 451.52).Method of preparation Prepare as directed under OphthalmicSolution, with Dibekacin Sulfate.Description Dibekacin Sulfate Ophthalmic Solution is a clear,colorless liquid.Identification To a volume of Dibekacin Sulfate OphthalmicSolution add water so that each mL contains about 2.5 mg (potency)of Dibekacin Sulfate according to the labeled amount,and use this solution as the sample solution. Separately, dissolvean amount of Dibekacin Sulfate Reference Standard, equivalentto 5 mg (potency), in 2 mL of water, and use this solution as thestandard solution. Perform the test with these solutions as directedunder Thin-layer Chromatography . Spot 10 µLeach of the sample solution and standard solution on a plate ofsilica gel for thin-layer chromatography. Proceed as directed inthe Identification (1) under Dibekacin Sulfate.pH 6.5 - 7.5Foreign insoluble matter It meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay Perform the test according to the Cylinder-plate methodas directed under Microbial Assay for Antibiotics accordingto the following conditions.(i) Test organism, culture medium and standard solutions—Proceedas directed in the Assay under Dibekacin Sulfate.(ii) Sample solutions—Pipet a volume of Dibekacin SulfateOphthalmic Solution, equivalent to about 12 mg (potency), andadd water to make exactly 30 mL. Pipet a suitable volume ofthis solution, add 0.1 mol/L phosphate buffer solution, pH 8.0,to make solutions so that each mL contains 20 µg (potency) and5 µg (potency), and use these solutions as the high concentrationsample solution and low concentration sample solution, respectively.Containers and storage Containers—Tight containers.Diethylcarbamazine Citrate Tabletsジエチルカルバマジンクエン 酸 塩 錠Change the Origin/limits of content and Identificationto read:Diethylcarbamazine Citrate Tablets contain not lessthan 95.0% and not more than 105.0% of the labeledamount of diethylcarbamazine citrate(C 10 H 21 N 3 O·C 6 H 8 O 7 : 391.42).Identification To a quantity of the powdered DiethylcarbamazineCitrate Tablets, equivalent to 0.1 g of DiethylcarbamazineCitrate according to the labeled amount, add 10 mL ofwater, shake well, and filter. To the filtrate add 1 mL ofReinecke salt TS: a light red precipitate is formed.Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Diethylcarbamazine Citrate Tablets add 70 mLof the mobile phase, shake vigorously for 10 minutes, add themobile phase to make exactly 100 mL, and filter through amembrane filter with a pore size not exceeding 0.45 µm. Discardthe first 3 mL of the filtrate, pipet V mL of the subsequentfiltrate, equivalent to about 2.5 mg of diethylcarbamazine citrate(C 10 H 21 N 3 O·C 6 H 8 O 7 ), add exactly 5 mL of the internal standardsolution, add the mobile phase to make 50 mL, and use this solutionas the sample solution. Proceed as directed in the Assay.Amount (mg) of diethylcarbamazine citrate(C 10 H 21 N 3 O·C 6 H 8 O 7 )= W S × (Q T /Q S ) × (10/V)W S : Amount (mg) of Diethylcarbamazine Citrate ReferenceStandardInternal standard solution—A solution of 2-aminobenzimidazolin the mobile phase (1 in 12500)Change the Assay to read:Assay Weigh accurately the mass of not less than 20 DiethylcarbamazineCitrate Tablets, and powder. Weigh accurately aportion of the powder, equivalent to about 50 mg of diethylcarbamazinecitrate (C 10 H 21 N 3 O·C 6 H 8 O 7 ), add 70 mL of the mobilephase, shake vigorously for 10 minutes, add the mobile phase tomake exactly 100 mL, and filter through a membrane filter witha pore size not exceeding 0.45 µm. Discard the first 3 mL of the

2114 Official Monographs Supplement II, JP XVfiltrate, pipet 5 mL of the subsequent filtrate, add exactly 5 mLof the internal standard solution, add the mobile phase to make50 mL, and use this solution as the sample solution. Separately,weigh accurately about 25 mg of Diethylcarbamazine CitrateReference Standard, previously dried at 105ºC for 4 hours, dissolvein the mobile phase to make exactly 50 mL. Pipet 5 mL ofthis solution, add exactly 5 mL of the internal standard solution,add the mobile phase to make 50 mL, and use this solution asthe standard solution. Perform the test with 20 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of diethylcarbamazineto that of the internal standard.Amount (mg) of diethylcarbamazine citrate(C 10 H 21 N 3 O·C 6 H 8 O 7 )= W S × (Q T /Q S ) × 2W S : Amount (mg) of Diethylcarbamazine Citrate ReferenceStandardInternal standard solution—A solution of2-aminobenzimidazole in the mobile phase (1 in 12500)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:220 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To 0.05 mol/L potassium dihydrogen phosphateTS add phosphoric acid to adjust the pH to 2.5. To 950 mLof this solution add 50 mL of methanol.Flow rate: Adjust the flow rate so that the retention time ofdiethylcarbamazine is about 14 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,diethylcarbamazine and the internal standard are eluted in thisorder with the resolution between these peaks being not lessthan 2.5.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof diethylcarbamazine to that of the internal standard is notmore than 1.0%.Add the following:Diflucortolone Valerateジフルコルトロン 吉 草 酸 エステルC 27 H 36 F 2 O 5 : 478.576α,9-Difluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 21-pentanate[59198-70-8]Diflucortolone Valerate contains not less than 98.0%and not more than 102.0% of C 27 H 36 F 2 O 5 , calculatedon the dried basis.Description Diflucortolone Valerate occurs as white crystalsor crystalline powder.It is sparingly soluble in methanol and in ethanol (99.5), andpractically insoluble in water.Identification (1) Prepare the test solution by proceedingwith 10 mg of Diflucortolone Valerate according to the OxygenFlask Combustion Method , using a mixture of 0.5 mL of0.01 mol/L sodium hydroxide TS and 20 mL of water as the absorbingliquid: the test solution responds to the Qualitative Tests for fluoride.(2) Determine the absorption spectrum of a solution ofDiflucortolone Valerate in methanol (3 in 200000) as directedunder Ultraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrumof a solution of Diflucortolone Valerate Reference Standardprepared in the same manner as the sample solution: both spectraexhibit similar intensities of absorption at the same wavelengths.(3) Determine the infrared absorption spectrum of DiflucortoloneValerate as directed in the potassium bromide diskmethod under Infrared Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrum ofDiflucortolone Valerate Reference Standard: both spectra exhibitsimilar intensities of absorption at the same wave numbers.Optical rotation [α] 20D: +110 - +115º (0.1 g calculatedon the dried basis, ethanol (99.5), 10 mL, 100 mm).Melting point 200 - 204ºCPurity (1) Heavy metals —Proceed with 2.0 g ofDiflucortolone Valerate in a platinum crucible according toMethod 2, and perform the test. Prepare the control solutionwith 2.0 mL of Standard Lead Solution (not more than 10 ppm).Carbonize and incinerate as directed under Residue on Ignition

Supplement II, JP XV Official Monographs 2115.(2) Related substances—Perform the test with 10 µL of thesample solution obtained in the Assay as directed under LiquidChromatography according to the following conditions.Determine each peak area of both solutions by the automatic integrationmethod, and calculate the amounts of these peaks bythe area percentage method: the amount of each peak of flucortolonevalerate, 12α diflucortolone valerate and ∆4 diflucortolonevalerate, having the relative retention times of about 0.97,1.03 and 1.05 with respect to diflucortolone valerate, respectively,is not more than 0.6%, respectively; the amount of thepeak of clocortolone valerate, having the relative retention timeof about 1.09 with respect to diflucortolone valerate, is not morethan 0.3%; and the amount of each peak other than those mentionedabove is not more than 0.1%. Furthermore, the totalamount of the peaks other than the peak of diflucortolone valerateis not more than 2.0%.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 1.4 times as long as theretention time of diflucortolone valerate, beginning after thesolvent peak.System suitability—System performance and system repeatability: Proceed as directedin the system suitability in the Assay.Test for required detectability: Pipet 0.1 mL of the samplesolution, add a mixture of water and acetonitrile (1:1) to makeexactly 10 mL, and use this solution as the solution for systemsuitability test. Pipet 1 mL of the solution for system suitabilitytest, and add a mixture of water and acetonitrile (1:1) to makeexactly 20 mL. Confirm that the peak area of diflucortolone valerateobtained from 10 µL of this solution is equivalent to 3.5 to6.5% of that of diflucortolone valerate from the solution forsystem suitability test.(3) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 3hours).Residue on ignition Not more than 0.1% (1 g, platinumcrucible).Assay Weigh accurately about 5 mg each of DiflucortoloneValerate and Diflucortolone Valerate Reference Standard (separately,determine the loss on drying in the same manneras Diflucortolone Valerate), dissolve each in a mixture of waterand acetonitrile (1:1) to make exactly 10 mL, and use these solutionsas the sample solution and standard solution, respectively.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and determine thepeak areas, A T and A S , of diflucortolone valerate in each solution.Amount (mg) of diflucortolone valerate (C 27 H 36 F 2 O 5 )= W S × (A T /A S )W S : Amount (mg) of Diflucortolone Valerate Reference Standard,calculated on dried basis.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:238 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with sulfonamide group bound tohexadecylsilanized silica gel for liquid chromatography (5 µm inparticle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase A: To 0.02 mol/L potassium dihydrogen phosphateTS add phosphoric acid to adjust the pH to 3.0. Mix thissolution with acetonitrile for liquid chromatography (11:9).Mobile phase B: Acetonitrile for liquid chromatography.Flowing of the mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 – 10 100 → 90 0 → 1010 – 25 90 1025 – 45 90 → 35 10 → 6545 – 50 35 65Flow rate: 1.0 mL per minute.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of diflucortolone valerate are not less than 10000 and notmore than 1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of diflucortolonevalerate is not more than 1.0%.Containers and storage Containers—Tight containers.DigoxinジゴキシンChange the System suitability in the Purity (2)Related substances to read:Purity (2) Related substancesSystem suitability—Test for required detectability: Dissolve 25 mg of Digoxin in50 mL of warm ethanol (95), cool, and add ethanol (95) to make100 mL. To 10 mL of this solution add 10 mL of water and diluteethanol to make 50 mL, and use this solution as the solutionfor system suitability test. Pipet 2 mL of the solution for system

2116 Official Monographs Supplement II, JP XVsuitability test, and add dilute ethanol to make exactly 100 mL.Pipet 5 mL of this solution, and add dilute ethanol to make exactly100 mL. Confirm that the peak area of digoxin obtainedfrom 10 µL of this solution is equivalent to 0.07 to 0.13% of thatfrom the solution for system suitability test.System performance: Dissolve 25 mg of Digoxin in 50 mL ofwarm ethanol (95), cool, and add ethanol (95) to make 100 mL.To 10 mL of this solution add 5 mL of a solution of propylparahydroxybenzoate in ethanol (95) (1 in 4000), 10 mL of waterand dilute ethanol to make 50 mL. When the procedure is runwith 10 µL of this solution under the above operating conditions,digoxin and propyl parahydroxybenzoate are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the peakarea of digoxin is not more than 2.5%.Digoxin Injectionジゴキシン 注 射 液Change the Method of preparation to read:Method of preparation Prepare as directed under Injections,with a solution of Digoxin in 10 to 50 vol% ethanol.Add the following next to the Identification:Alcohol number 0.8 - 1.2 (Method 1).Purity Related substances—To a volume of Digoxin Injection,equivalent to 2.5 mg of Digoxin according to the labeledamount, add dilute ethanol to make 50 mL, and use this solutionas the sample solution. Perform the test with 10 µL of the samplesolution as directed under Liquid Chromatography according to the following conditions. Determine each peak areaof the sample solution by the automatic integration method andcalculate the amounts of these peaks: the total amount of thepeaks other than digoxin is not more than 5%.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 4 times as long as the retentiontime of digoxin, beginning after the solvent peak.System suitability—Test for required detectability: Dissolve 25 mg of digoxin in50 mL of warm ethanol (95), cool, add ethanol (95) to make 100mL. To 10 mL of this solution add 10 mL of water and diluteethanol to make 50 mL, and use this solution as the solution forsystem suitability test. Pipet 2 mL of the solution for systemsuitability test, and add dilute ethanol to make exactly 100 mL.Pipet 5 mL of this solution, and add dilute ethanol to make exactly100 mL. Confirm that the peak area of digoxin obtainedfrom 10 µL this solution is equivalent to 0.07 to 0.13% of that ofdigoxin from the solution for system suitability test.System performance: Dissolve 25 mg of digoxin in 50 mL ofwarm ethanol (95), cool, and add ethanol (95) to make 100 mL.To 10 mL of this solution add 5 mL of a solution of propylparahydroxybenzoate in ethanol (95) (1 in 4000), 10 mL of waterand dilute ethanol to make 50 mL. When the procedure is runwith 10 µL of this solution under the above operating conditions,digoxin and propyl parahydroxybenzoate are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the peakarea of digoxin is not more than 2.5%.Digoxin Tabletsジゴキシン 錠Add the following next to the Identification:Purity Related substances—Powder not less than 20 DigoxinTablets. Weigh a portion of the powder equivalent to 2.5 mg ofDigoxin according to the labeled amount, add 30 mL of diluteethanol, treat with ultrasonic waves for 20 minutes, and shakefor 5 minutes. After cooling, add dilute ethanol to make 50 mL,filter, and use the filtrate as the sample solution. Perform the testwith 10 µL of the sample solution as directed under LiquidChromatography according to the following conditions.Determine each peak area of the sample solution by the automaticintegration method and calculate the amount of thesepeaks by the area percentage method: the total amount of thepeaks other than digoxin is not more than 5%.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 4 times as long as the retentiontime of digoxin, beginning after the solvent peak.System suitability—Test for required detectability: Dissolve 25 mg of digoxin in50 mL of warm ethanol (95), cool, add ethanol (95) to make 100mL. To 10 mL of this solution add 10 mL of water and diluteethanol to make 50 mL, and use this solution as the solution forsystem suitability test. Pipet 2 mL of the solution for systemsuitability test, and add dilute ethanol to make exactly 100 mL.Pipet 5 mL of this solution, and add dilute ethanol to make exactly100 mL. Confirm that the peak area of digoxin obtainedfrom 10 µL of this solution is equivalent to 0.07 to 0.13% of thatof digoxin from the solution for system suitability test.System performance: Dissolve 25 mg of digoxin in 50 mL ofwarm ethanol (95), cool, and add ethanol (95) to make 100 mL.To 10 mL of this solution add 5 mL of a solution of propylparahydroxybenzoate in ethanol (95) (1 in 4000), 10 mL of waterand dilute ethanol to make 50 mL. When the procedure is runwith 10 µL of this solution under the above operating conditions,digoxin and propyl parahydroxybenzoate are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the solution for system suitability test under the above

Supplement II, JP XV Official Monographs 2117operating conditions, the relative standard deviation of the peakarea of digoxin is not more than 2.5%.Dimenhydrinate Tabletsジメンヒドリナート 錠Add the following next to the Identification:Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 15minutes of Dimenhydrinate Tablets is not less than 85%.Start the test with 1 tablet of Dimenhydrinate Tablets, withdrawnot less than 20 mL of the medium at the specified minuteafter starting the test, and filter through a membrane filter with apore size not exceeding 0.45 µm. Discard the first 10 mL of thefiltrate, pipet V mL of the subsequent filtrate, add water to makeexactly V´ mL so that each mL contains about 28 µg of dimenhydrinate(C 17 H 21 NO·C 7 H 7 ClN 4 O 2 ) according to the labeledamount, and use this solution as the sample solution. Separately,weigh accurately about 28 mg of dimenhydrinate for assay, previouslydried in vacuum over phosphorous (V) oxide for 24hours, and dissolve in water to make exactly 50 mL. Pipet 5 mLof this solution, add water to make exactly 100 mL, and use thissolution as the standard solution. Determine the absorbances, A Tand A S , of the sample solution and standard solution at 276 nmas directed under Ultraviolet-visible Spectrophotometry .Dissolution rate (%) with respect to the labeled amount ofdimenhydrinate (C 17 H 21 NO·C 7 H 7 ClN 4 O 2 )= W S × (A T /A S ) × (V´/V) × (1/C) × 90W S : Amount (mg) of dimenhydrinate for assayC: Labeled amount (mg) of dimenhydrinate(C 17 H 21 NO·C 7 H 7 ClN 4 O 2 ) in 1 tabletDistigmine Bromide TabletsW S : Amount (mg) of distigmine bromide for assay, calculatedon the anhydrous basisDissolution When the test is performed at 75 revolutionsper minute according to the Paddle method using 500 mLof water as the dissolution medium, the dissolution rate in 30minutes of Distigmine Bromide Tablets is not less than 80%.Start the test with 1 tablet of Distigmine Bromide Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.8 µm. Discard the first 10mL of the filtrate, pipet V mL of the subsequent filtrate, add waterto make exactly V´ mL so that each mL contains about 10 µgof distigmine bromide (C 22 H 32 Br 2 N 4 O 4 ) according to the labeledamount, and use this solution as the sample solution. Separately,weigh accurately about 50 mg of distigmine bromide for assay(separately, determine the water content in the samemanner as Distigmine Bromide), and dissolve in water to makeexactly 100 mL. Pipet 10 mL of this solution, add water to makeexactly 500 mL, and use this solution as the standard solution.Perform the test with the sample solution and standard solutionas directed under Ultraviolet-visible Spectrophotometry ,and determine the absorbances, A T1 and A S1 , at 270 nm, and A T2and A S2 , at 350 nm.Dissolution rate (%) with respect to the labeled amount ofdistigmine bromide (C 22 H 32 Br 2 N 4 O 4 )= W S × {(A T1 – A T2 ) / (A S1 – A S2 )} × (V´/V) × (1/C) × 10W S : Amount (mg) of distigmine bromide for assay, calculatedon the anhydrous basisC: Labeled amount (mg) of distigmine bromide(C 22 H 32 Br 2 N 4 O 4 ) in 1 tabletAdd the following:Doxazosin Mesilateドキサゾシンメシル 酸 塩ジスチグミン 臭 化 物 錠Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Distigmine Bromide Tablets add 30 mL of 0.1mol/L hydrochloric acid TS, shake for 1 hour, add 0.1 mol/Lhydrochloric acid TS to make exactly 50 mL, and filter. Discardthe first 20 mL of the filtrate, pipet V mL of the subsequent filtrate,and add 0.1 mol/L hydrochloric acid TS to make exactlyV´ mL so that each mL contains about 30 µg of distigmine bromide(C 22 H 32 Br 2 N 4 O 4 ), and use this solution as the sample solution.Proceed as directed in the Assay.Amount (mg) of distigmine bromide (C 22 H 32 Br 2 N 4 O 4 )= W S × {(A T2 – A T1 ) / (A S2 – A S1 )} × (V´/V) × (1/20)Description Doxazosin Mesilate occurs as a white to yellowandenantiomerC 23 H 25 N 5 O 5·CH 4 O 3 S: 547.581-(4-Amino-6,7-dimethoxyquinazolin-2-yl)-4-{[(2RS)-2,3-dihydro-1,4-benzodioxin-2-yl]carbonyl}piperazinemonomethansulfonate [77883-43-3]Doxazosin Mesilate, when dried, contains not lessthan 98.0% and not more than 102.0% ofC 23 H 25 N 5 O 5·CH 4 O 3 S.

2118 Official Monographs Supplement II, JP XVish white crystalline powder.It is freely soluble in dimethylsulfoxide, slightly soluble inwater and in methanol, and very slightly soluble in ethanol(99.5).A solution of Doxazosin Mesilate in dimethylsulfoxide solution(1 in 20) shows no optical rotation.Melting point: about 272ºC (with decomposition).Identification (1) Determine the absorption spectrum of asolution of Doxazosin Mesilate in 0.01 mol/L hydrochloricacid-methanol TS (1 in 200000) as directed under Ultraviolet-visibleSpectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of a solutionof Doxazosin Mesilate Reference Standard prepared in the samemanner as the sample solution: both spectra exhibit similar intensitiesof absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of DoxazosinMesilate as directed in the potassium bromide diskmethod under Infrared Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrum ofDoxazosin Mesilate Reference Standard: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) 30 mg of Doxazosin Mesilate responds to the QualitativeTests (2) for mesilate.Purity (1) Heavy metals —Proceed with 1.0 g ofDoxazosin Mesilate according to Method 2, and perform the test.Prepare the control solution with 2.0 mL of Standard Lead Solution(not more than 20 ppm).(2) Related substances—Dissolve 20 mg of Doxazosin Mesilatein 5 mL of a mixture of methanol and acetic acid (100)(1:1), and use this solution as the sample solution. Pipet 1 mL ofthis solution, add a mixture of methanol and acetic acid (100)(1:1) to make exactly 100 mL. Pipet 5 mL of this solution, add amixture of methanol and acetic acid (100) (1:1) to make exactly10 mL, and use this solution as the standard solution. Performthe test with these solutions as directed under Thin-layer Chromatography. Spot 5 µL each of the sample solution andstandard solution on a plate of silica gel with fluorescent indicatorfor thin-layer chromatography. Develop the plate with anupper layer of a mixture, prepared by adding 1 volume of waterand 1 volume of acetic acid (100) to 2 volumes of4-methyl-2-pentanon and shaking, to a distance of about 10 cm,and air-dry the plate. Examine under ultraviolet light (mainwavelength: 254 nm): the spot at the R f value of about 0.15 obtainedfrom the sample solution is not more intense than the spotfrom the standard solution, and no spots other than the principalspot and other than the spots mentioned above appear from thesample solution.(3) Residual solvent—Being specified separately.Loss on drying Not more than 1.0% (1 g, 105ºC, 4hours).Residue on ignition Not more than 0.2% (1 g).Assay Weigh accurately about 25 mg each of Doxazosin Mesilateand Doxazosin Mesilate Reference Standard, previouslydried, dissolve separately in methanol to make exactly 50 mL.Pipet 3 mL each of these solutions, add the mobile phase tomake exactly 100 mL, and use these solutions as the sample solutionand standard solution, respectively. Perform the test withexactly 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography according tothe following conditions, and determine the peak areas, A T andA S , of doxazosin in each solution.Amount (mg) of doxazosin mesilate (C 23 H 25 N 5 O 5·CH 4 O 3 S)= W S × (A T /A S )W S : Amount (mg) of Doxazosin Mesilate Reference StandardOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:246 nm)Column: A stainless steel column 3.9 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (4 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of 0.05 mol/L potassium dihydrogenphosphate TS, pH 3.0, methanol and acetonitrile (12:8:3).Flow rate: Adjust the flow rate so that the retention time ofdoxazosin is about 5 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of doxazosin are not less than 2000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of doxazosinis not more than 1.0%.Containers and storage Containers—Tight containers.Add the following:DroxidopaドロキシドパC 9 H 11 NO 5 : 213.19(2S,3R)-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid [23651-95-8]Droxidopa, when dried, contains not less than 99.0%and not more than 101.0% of C 9 H 11 NO 5 .Description Droxidopa occurs as white to light brown crystalsor crystalline powder.

Supplement II, JP XV Official Monographs 2119It is slightly soluble in water and practically insoluble inethanol (99.5).It dissolves in 0.1 mol/L hydrochloric acid TS.Identification (1) Determine the absorption spectrum of asolution of Droxidopa in 0.1 mol/L hydrochloric acid TS (1 in25000) as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the Reference Spectrum:both spectra exhibit similar intensities of absorption at thesame wavelengths.(2) Determine the infrared absorption spectrum of Droxidopaas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similar intensitiesof absorption at the same wave numbers.Optical rotation [α] 20D: –38 - –43º (after drying, 0.1 g,0.1 mol/L hydrochloric acid TS, 20 mL, 100 mm).Purity (1) Chloride —Dissolve 0.40 g of Droxidopain 6 mL of dilute nitric acid, and add water to make 50 mL.Perform the test using this solution as the test solution. Preparethe control solution with 0.40 mL of 0.01 mol/L hydrochloricacid VS (not more than 0.036%).(2) Heavy metals —Proceed with 2.0 g of Droxidopaaccording to Method 2, and perform the test. Prepare the controlsolution with 2.0 mL of Standard Lead Solution (not more than10 ppm).(3) Arsenic —Prepare the test solution with 1.0 g ofDroxidopa according to Method 3, and perform the test (notmore than 2 ppm).(4) Related substances—To 0.10 g of Droxidopa add 50 mLof 0.1 mol/L hydrochloric acid TS, dissolve by shaking whilecooling in an ice bath, and use this solution as the sample solution.Pipet 1 mL of this solution, add 0.1 mol/L hydrochloricacid TS to make exactly 100 mL. Pipet 5 mL of this solution,add 0.1 mol/L hydrochloric acid TS to make 50 mL, and use thissolution as the standard solution. Perform the test with exactly10 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions. Determine each peak area of both solutionsby the automatic integration method: the area of each peakother than droxidopa obtained from the sample solution is notlarger than the peak area of droxidopa from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:220 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: Dissolve 1.0 g of sodium 1-heptanesulfonateand 1.36 g of potassium dihydrogen phosphate in 1000 mL ofwater, and adjust the pH to 2.0 with phosphoric acid. To 930 mLof this solution add 70 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofdroxidopa is about 5 minutes.Time span of measurement: About 12 times as long as the retentiontime of droxidopa, beginning after the solvent peak.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of droxidopa are not less than 10000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of droxidopais not more than 2.0%.(5) Residual solvent—Being specified separately.Loss on drying Not more than 0.1% (1 g, in vacuum,60ºC, 3 hours).Residue on ignition Not more than 0.2% (1 g).Assay Weigh accurately about 0.3 g of Droxidopa, previouslydried, dissolve in exactly 20 mL of 0.1 mol/L perchloric acid VS,add 50 mL of acetic acid (100), and titrate the excessperchloric acid with 0.1 mol/L sodium acetate VS (potentiometrictitration). Perform a blank determination in the same manner,and make any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 21.32 mg of C 9 H 11 NO 5Containers and storage Containers—Well-closed containers.Add the following:Droxidopa CapsulesドロキシドパカプセルDroxidopa Capsules contain not less than 93.0% andnot more than 107.0% of the labeled amount of droxidopa(C 9 H 11 NO 5 : 213.19).Method of preparation Prepare as directed under Capsules,with Droxidopa.Identification (1) To an amount of the contents of DroxidopaCapsules, equivalent to 50 mg of Droxidopa according tothe labeled amount, add 50 mL of water, shake for 10 minutes,and filter. To 5 mL of the filtrate add 1 mL of ninhydrin TS, andheat in a water bath for 3 minutes: a blue-purple color develops.(2) To an amount of the contents of Droxidopa Capsules,equivalent to 20 mg of Droxidopa according to the labeledamount, add 20 mL of diluted acetic acid (100) (1 in 500), shakefor 10 minutes, and filter. To 1 mL of the filtrate add 4 mL ofwater and 1 drop of iron (III) chloride TS: a deep green color isproduced, and it gradually changes to light brown.(3) To an amount of the contents of Droxidopa Capsules,equivalent to 50 mg of Droxidopa according to the labeledamount, add 50 mL of 0.1 mol/L hydrochloric acid TS, shakewell, add 0.1 mol/L hydrochloric acid TS to make 100 mL, and

2120 Official Monographs Supplement II, JP XVfilter. Discard the first 10 mL of the filtrate, and to 2 mL of thesubsequent filtrate add 0.1 mol/L hydrochloric acid TS to make25 mL. Determine the absorption spectrum of this solution asdirected under Ultraviolet-visible Spectrophotometry : itexhibits a maximum between 278 nm and 282 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To the contents of 1 capsule of Droxidopa Capsules, add 100mL of 0.1 mol/L hydrochloric acid TS, shake well, and add 0.1mol/L hydrochloric acid TS to make exactly V mL so that eachmL contains about 0.5 mg of droxidopa (C 9 H 11 NO 5 ). Filter thissolution, discard the first 10 mL of the filtrate, pipet 2 mL of thesubsequent filtrate, add 0.1 mol/L hydrochloric acid TS to makeexactly 25 mL, and use this solution as the sample solution.Separately, weigh accurately about 50 mg of droxidopa for assay,previously dried in vacuum at 60ºC for 3 hours, dissolve in 0.1mol/L hydrochloric acid TS to make exactly 100 mL. Pipet 2mL of this solution, add 0.1 mol/L hydrochloric acid TS to makeexactly 25 mL, and use this solution as the standard solution.Perform the test with the sample solution and standard solutionas directed under Ultraviolet-visible Spectrophotometry ,and determine the absorbances, A T and A S , at 280 nm.Amount (mg) of droxidopa (C 9 H 11 NO 5 )= W S × (A T /A S ) × (V/100)W S : Amount (mg) of droxidopa for assayDissolution When the test is performed at 75 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of water as the dissolution medium, thedissolution rate in 90 minutes of Droxidopa Capsules is not lessthan 70%.Start the test with 1 capsule of Droxidopa Capsules, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to makeexactly V´ mL so that each mL contains about 56 µg of droxidopa(C 9 H 11 NO 5 ) according to the labeled amount, and use thissolution as the sample solution. Separately, weigh accuratelyabout 28 mg of droxidopa for assay, previously dried in vacuumat 60ºC for 3 hours, dissolve in water to make exactly 100 mL.Pipet 4 mL of this solution, add water to make exactly 20 mL,and use this solution as the standard solution. Perform the testwith the sample solution and standard solution as directed underUltraviolet-visible Spectrophotometry , and determinethe absorbances, A T1 and A S1 , at 280 nm, and A T2 and A S2 , at 350nm.Dissolution rate (%) with respect to the labeled amount ofdroxidopa (C 9 H 11 NO 5 )= W S × {(A T1 – A T2 ) / (A S1 – A S2 )} × (V´/V) × (1/C) × 180W S : Amount (mg) of droxidopa for assayC: Labeled amount (mg) of droxidopa (C 9 H 11 NO 5 ) in 1 capsuleAssay Take out the contents of not less than 20 DroxidopaCapsules, weigh accurately the mass of the contents, and mixuniformly. Weigh accurately an amount equivalent to about 50mg of droxidopa (C 9 H 11 NO 5 ), add 50 mL of 0.1 mol/L hydrochloricacid TS, shake well, add 0.1 mol/L hydrochloric acid TSto make exactly 100 mL, and filter. Discard the first 10 mL ofthe filtrate, pipet 2 mL of the subsequent filtrate, add 0.1 mol/Lhydrochloric acid TS to make exactly 25 mL, and use this solutionas the sample solution. Separately, weigh accurately about50 mg of droxidopa for assay, previously dried in vacuum at60ºC for 3 hours, dissolve in 0.1 mol/L hydrochloric acid TS tomake exactly 100 mL. Pipet 2 mL of this solution, add 0.1mol/L hydrochloric acid TS to make exactly 25 mL, and use thissolution as the standard solution. Perform the test with the samplesolution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine the absorbances,A T and A S , at 280 nm.Amount (mg) of droxidopa (C 9 H 11 NO 5 )= W S × (A T /A S )W S : Amount (mg) of droxidopa for assayContainers and storage Containers—Tight containers.Add the following:Droxidopa Fine Granulesドロキシドパ 細 粒Droxidopa Fine Granules contain not less than93.0% and not more than 107.0% of droxidopa(C 9 H 11 NO 5 : 213.19).Method of preparation Prepare fine granules as directed underPowders, with Droxidopa.Identification (1) To a quantity of powdered DroxidopaFine Granules, equivalent to 50 mg of Droxidopa according tothe labeled amount, add 50 mL of water, shake for 10 minutes,and filter. To 5 mL of the filtrate add 1 mL of ninhydrin TS, heatin a water bath for 3 minutes: a blue-purple color develops.(2) To a quantity of powdered Droxidopa Fine Granules,equivalent to 20 mg of Droxidopa according to the labeledamount, add 20 mL of diluted acetic acid (100) (1 in 500), shakefor 10 minutes, and filter. To 1 mL of the filtrate add 4 mL ofwater and 1 drop of iron (III) chloride TS: a deep green color isproduced, and it gradually changes to light brown.(3) To a quantity of powdered Droxidopa Fine Granules,equivalent to 50 mg of Droxidopa according to the labeledamount, add 50 mL of 0.1 mol/L hydrochloric acid TS, shakewell, add 0.1 mol/L hydrochloric acid TS to make 100 mL, andfilter. Discard the first 10 mL of the filtrate, to 2 mL of the subsequentfiltrate add 0.1 mol/L hydrochloric acid TS to make 25mL. Determine the absorption spectrum of this solution as directedunder Ultraviolet-visible Spectrophotometry : itexhibits a maximum between 278 nm and 282 nm.

Supplement II, JP XV Official Monographs 2121Dissolution When the test is performed at 75 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 45minutes of Droxidopa Fine Granules is not less than 70%.Start the test with an accurately weighed amount of DroxidopaFine Granules, equivalent to about 0.1 g of droxidopa(C 9 H 11 NO 5 ), according to the labeled amount, withdraw not lessthan 20 mL of the medium at the specified minute after startingthe test, and filter through a membrane filter with a pore size notexceeding 0.45 µm. Discard the first 10 mL of the filtrate, pipet5 mL of the subsequent filtrate, add exactly 5 mL of water, anduse this solution as the sample solution. Separately, weigh accuratelyabout 28 mg of droxidopa for assay, previously dried invacuum at 60ºC for 3 hours, dissolve in water to make exactly100 mL. Pipet 4 mL of this solution, add water to make exactly20 mL, and use this solution as the standard solution. Performthe test with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , anddetermine the absorbances, A T1 and A S1 , at 280 nm, and A T2 andA S2 , at 350 nm.Dissolution rate (%) with respect to the labeled amount ofdroxidopa (C 9 H 11 NO 5 )= (W S /W T ) × {(A T1 – A T2 ) / (A S1 – A S2 )} × (1/C) × 360W S : Amount (mg) of droxidopa for assayW T : Amount (g) of Droxidopa Fine GranulesC: Labeled amount (mg) of droxidopa (C 9 H 11 NO 5 ) in 1 gParticle size It meets the requirement.Assay Powder not less than 20 g of Droxidopa Fine Granules.Weigh accurately a portion of the powder, equivalent to about50 mg of droxidopa (C 9 H 11 NO 5 ), add 50 mL of 0.1 mol/L hydrochloricacid TS, shake well, add 0.1 mol/L hydrochloric acidTS to make exactly 100 mL, and filter. Discard the first 10 mLof the filtrate, pipet 2 mL of the subsequent filtrate, add 0.1mol/L hydrochloric acid TS to make exactly 25 mL, and use thissolution as the sample solution. Separately, weigh accuratelyabout 50 mg of droxidopa for assay, previously dried in vacuumat 60ºC for 3 hours, dissolve in 0.1 mol/L hydrochloric acid TSto make exactly 100 mL. Pipet 2 mL of this solution, add 0.1mol/L hydrochloric acid TS to make exactly 25 mL, and use thissolution as the standard solution. Perform the test with the samplesolution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine the absorbances,A T and A S , at 280 nm.Amount (mg) of droxidopa (C 9 H 11 NO 5 )= W S × (A T /A S )W S : Amount (mg) of droxidopa for assayContainers and storage Containers—Tight containers.Add the following:Ecabet Sodium Granulesエカベトナトリウム 顆 粒Ecabet Sodium Granules contain not less than95.0% and not more than 105.0% of the labeledamount of ecabet sodium hydrate(C 20 H 27 NaO 5 S·5H 2 O: 492.56).Method of preparation Prepare as directed under Granules,with Ecabet Sodium Hydrate.Identification To a quantity of Ecabet Sodium Granules,equivalent to 50 mg of Ecabet Sodium Hydrate according to thelabeled amount, add 25 mL of dilute sodium hydroxide TS,shake, and filter. Discard the first 10 mL of the filtrate, and to 3mL of the subsequent filtrate add dilute sodium hydroxide TS tomake 20 mL. Determine the absorption spectrum of this solutionas directed under Ultraviolet-visible Spectrophotometry :it exhibits maxima between 269 nm and 273 nm, and between278 nm and 282 nm.Uniformity of dosage units Perform the test accordingto the following method: Ecabet Sodium Granules in single-unitcontainers meets the requirement of the Content uniformitytest.Take out the total contents of 1 pack of Ecabet Sodium Granules,add 70 mL of dilute sodium hydroxide TS, treat with ultrasonicwaves for 5 minutes with occasional shaking, add dilutesodium hydroxide TS to make exactly V mL so that each mLcontains about 10 mg of ecabet sodium hydrate(C 20 H 27 NaO 5 S·5H 2 O), and filter. Discard the first 10 mL of thefiltrate, pipet 2 mL of the subsequent filtrate, add water to makeexactly 50 mL, and use this solution as the sample solution.Separately, weigh accurately about 20 mg of ecabet sodium hydratefor assay (separately, determine the water content in the same manner as Ecabet Sodium Hydrate), dissolve in 2mL of dilute sodium hydroxide TS, add water to make exactly50 mL, and use this solution as the standard solution. Determinethe absorbances, A T and A S , of the sample solution and standardsolution at 271 nm as directed under Ultraviolet-visible Spectrophotometry, using water as the blankAmount (mg) of ecabet sodium hydrate (C 20 H 27 NaO 5 S·5H 2 O)= W S × (A T /A S ) × (V/2) × 1.224W S : Amount (mg) of ecabet sodium hydrate for assay, calculatedon the anhydrous basis.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Ecabet Sodium Granules is not less than 80%.Start the test with an accurately weighed amount of EcabetSodium Granules, equivalent to about 1 g (potency) of EcabetSodium Hydrate according to the labeled amount, withdraw notless than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the fil-

2122 Official Monographs Supplement II, JP XVtrate, pipet 2 mL of the subsequent filtrate, add water to makeexactly 10 mL, and use this solution as the sample solution.Separately, weigh accurately about 22 mg of ecabet sodium hydratefor assay (separately, determine the water content in the same manner as Ecabet Sodium Hydrate), dissolve in 1mL of methanol, add water to make exactly 100 mL, and usethis solution as the standard solution. Determine the absorbances,A T and A S , at 271 nm of the sample solution and standardsolution as directed under Ultraviolet-visible Spectrophotometry, using water as the blankDissolution rate (%) with respect to the labeled amount ofecabet sodium hydrate (C 20 H 27 NaO 5 S·5H 2 O)= (W S /W T ) × (A T /A S ) × (1/C) × 4500 × 1.224W S : Amount (mg) of ecabet sodium hydrate for assay, calculatedon the anhydrous basisW T : Amount (g) of Ecabet Sodium GranulesC: Labeled amount (mg) of ecabet sodium hydrate(C 20 H 27 NaO 5 S·5H 2 O) in 1 gParticle size It meets the requirement.Assay Weigh accurately an amount of Ecabet Sodium Granules,equivalent to about 30 mg of ecabet sodium hydrate(C 20 H 27 NaO 5 S·5H 2 O), add exactly 5 mL of the internal standardsolution, add 25 mL of diluted methanol (1 in 2), shake vigorouslyfor 20 minutes, and filter through a membrane filter with apore size not exceeding 0.45 µm. Discard the first 5 mL of thefiltrate, to 3 mL of the subsequent filtrate add the mobile phaseto make 50 mL, and use this solution as the sample solution.Separately, weigh accurately about 30 mg of ecabet sodium hydratefor assay (separately, determine the water content in the same manner as Ecabet Sodium Hydrate), add exactly 5mL of the internal standard solution, and dissolve in dilutemethanol (1 in 2) to make 30 mL. To 3 mL of this solution addthe mobile phase to make 50 mL, and use this solution as thestandard solution. Perform the test with 20 µL each of the samplesolution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of ecabet tothat of the internal standard.Amount (mg) of ecabet sodium hydrate (C 20 H 27 NaO 5 S·5H 2 O)= W S × (Q T /Q S ) × 1.224W S : Amount (mg) of ecabet sodium hydrate for assay, calculatedon the anhydrous basisInternal standard solution—A solution of ethyl parahydroxybenzoatein diluted methanol (1 in 2) (3 in 400)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:225 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To 0.1 mol/L potassium dihydrogen phosphateTS add phosphoric acid to adjust the pH to 3.0. To 730 mL ofthis solution add 270 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofecabet is about 8 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,ecabet and the internal standard are eluted in this order with theresolution between these peaks being not less than 6.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ecabet to that of the internal standard is not more than 1.0%.Containers and storage Containers—Well-closed containers.Add the following:Ecabet Sodium Hydrateエカベトナトリウム 水 和 物C 20 H 27 NaO 5 S·5H 2 O: 492.56(1R,4aS,10aS)-1,4a-Dimethyl-7-(1-methylethyl)-6-sodiosulfonato-1,2,3,4,4a,9,10,10aoctahydrophenanthrene-1-carboxylicacid pentahydrate[219773-47-4]Ecabet Sodium Hydrate contains not less than98.5% and not more than 101.5% of ecabet sodium(C 20 H 27 NaO 5 S: 402.48), calculated on the anhydrousbasis.Description Ecabet Sodium Hydrate is white crystals.It is freely soluble in methanol, and slightly soluble in waterand in ethanol (99.5).It dissolves in sodium hydroxide TS.Dissolve 1.0 g of Ecabet Sodium Hydrate in 200 mL of water:the pH of the solution is about 3.5.Identification (1) Determine the absorption spectrum of asolution of Ecabet Sodium Hydrate in dilute sodium hydroxideTS (3 in 10000) as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the ReferenceSpectrum: both spectra exhibit similar intensities of absorptionat the same wavelengths.(2) Determine the infrared absorption spectrum of EcabetSodium Hydrate as directed in the potassium bromide diskmethod under Infrared Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.

Supplement II, JP XV Official Monographs 2123(3) Place 1 g of Ecabet Sodium Hydrate in a porcelain crucible,and carbonize. After cooling, add 0.5 mL of nitric acid,heat gradually to incinerate, and dissolve the residue in 10 mLof water: the solution responds to the Qualitative Tests for sodium salt.Optical rotation [α] 20D: +69 - +76º (0.25 g calculatedon the anhydrous basis, methanol, 25 mL, 100 mm).Purity (1) Heavy metals —Proceed with 2.0 g ofEcabet Sodium Hydrate according to Method 2, and perform thetest. Prepare the control solution with 2.0 mL of Standard LeadSolution (not more than 10 ppm).(2) Related substances—Dissolve 10 mg of Ecabet SodiumHydrate in 10 mL of the mobile phase, and use this solution asthe sample solution. Pipet 2 mL of this solution, add the mobilephase to make exactly 20 mL. Pipet 1 mL of this solution, addthe mobile phase to make exactly 100 mL, and use this solutionas the standard solution. Perform the test with exactly 20 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions. Determine each peak area of both solutions bythe automatic integration method: the area of each peak otherthan ecabet obtained from the sample solution is not larger thanthe peak area of ecabet from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:225 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To 0.1 mol/L potassium dihydrogen phosphateTS add phosphoric acid to adjust the pH to 3.0. To 730 mL ofthis solution add 270 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofecabet is about 8 minutes.Time span of measurement: About 2 times as long as the retentiontime of ecabet, beginning after the solvent peak.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of ecabet are not less than 5000 and not more than 1.5, respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of ecabetis not more than 2.0%.(3) Residual solvent—Being specified separately.Water 17.3 - 19.2% (0.2 g, volumetric titration, directtitration).Assay Weigh accurately about 1.2 g of Ecabet Sodium Hydrate,dissolve in 30 mL of methanol, add 30 mL of water, andtitrate with 0.1 mol/L sodium hydroxide VS (indicator: 4drops of phenolphthalein TS). Perform a blank determination inthe same manner, and make any necessary correction.Each mL of 0.1 mol/L sodium hydroxide VS= 40.25 mg of C 20 H 27 NaO 5 SContainers and storage Containers—Well-closed containers.Add the following:Emorfazone Tabletsエモルファゾン 錠Emorfazone Tablets contain not less than 95.0% andnot more than 105.0% of the labeled amount of emorfazone(C 11 H 17 N 3 O 3 : 239.27).Method of preparation Prepare as directed under Tablets,with Emorfazone.Identification To a quantity of powdered Emorfazone Tablets,equivalent to 0.1 g of Emorfazone according to the labeledamount, add 100 mL of water, shake well, and centrifuge. Filterthe supernatant liquid, and to 1 mL of the filtrate add water tomake 100 mL. Determine the absorption spectrum of this solutionas directed under Ultraviolet-visible Spectrophotometry: it exhibits maxima between 237 nm and 241 nm, andbetween 310 nm and 314 nm, and a shoulder between 288 nmand 298 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Emorfazone Tablets add methanol to make exactlyV mL so that each mL contains about 4 mg of emorfazone(C 11 H 17 N 3 O 3 ), and shake well to disintegrate. Centrifuge thissolution, pipet 2 mL of the supernatant liquid, add exactly 10mL of the internal standard solution, add methanol to make 50mL, and use this solution as the sample solution. Proceed as directedin the Assay.Amount (mg) of emorfazone (C 11 H 17 N 3 O 3 )= W S × (Q T /Q S ) × (V/5)W S : Amount (mg) of emorfazone for assayInternal standard solution—A solution of2,4-dinitrophenylhidrazine in methanol (3 in 2000). Prepare beforeuse.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 45minutes of Emorfazone Tablets is not less than 80%.Start the test with 1 tablet of Emorfazone Tablets, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to make

2124 Official Monographs Supplement II, JP XVexactly V´ mL so that each mL contains about 11 µg of emorfazone(C 11 H 17 N 3 O 3 ) according to the labeled amount, and usethis solution as the sample solution. Separately, weigh accuratelyabout 28 mg of emorfazone for assay, previously dried invacuum at 60ºC for 4 hours, and dissolve in water to make exactly100 mL. Pipet 4 mL of this solution, add water to makeexactly 100 mL, and use this solution as the standard solution.Determine the absorbances, A T and A S , of the sample solutionand standard solution at 239 nm as directed under Ultraviolet-visibleSpectrophotometry Dissolution rate (%) with respect to the labeled amount ofemorfazone (C 11 H 17 N 3 O 3 )= W S × (A T /A S ) × (V´/V) × (1/C) × 36W S : Amount (mg) of emorfazone for assayC: Labeled amount (mg) of emorfazone (C 11 H 17 N 3 O 3 ) in 1tabletAssay To 10 tablets of Emorfazone Tablets add 200 mL ofmethanol, shake well to disintegrate, add methanol to make exactly250 mL, and centrifuge. Pipet a volume of the supernatant,equivalent to about 8 mg of emorfazone (C 11 H 17 N 3 O 3 ), add exactly10 mL of the internal standard solution, add methanol tomake 50 mL, and use this solution as the sample solution.Separately, weigh accurately about 20 mg of emorfazone for assay,previously dried in vacuum at 60ºC for 4 hours, and dissolvein methanol to make exactly 25 mL. Pipet 10 mL of thissolution, add exactly 10 mL of the internal standard solution,add methanol to make 50 mL, and use this solution as the standardsolution. Perform the test with 20 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions, andcalculate the ratios, Q T and Q S , of the peak area of emorfazoneto that of the internal standard.Amount (mg) of emorfazone (C 11 H 17 N 3 O 3 )= W S × (Q T /Q S ) × (2/5)W S : Amount (mg) of emorfazone for assayInternal standard solution—A solution of2,4-dinitrophenylhidrazine in methanol (3 in 2000). Prepare beforeuse.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:313 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of water and methanol (11:10)Flow rate: Adjust the flow rate so that the retention time ofemorfazone is about 5 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,emorfazone and the internal standard are eluted in this orderwith the resolution between these peaks being not less than 2.5.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof emorfazone to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Storage—Light-resistant.Ephedrine Hydrochloride Tabletsエフェドリン 塩 酸 塩 錠Add the following next to the Uniformity of dosageunits:Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Ephedrine Hydrochloride Tablets is not less than80%.Start the test with 1 tablet of Ephedrine Hydrochloride Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard the first 10mL of the filtrate, and use the subsequent filtrate as the samplesolution. Separately, weigh accurately about 28 mg of ephedrinehydrochloride for assay, previously dried at 105ºC for 3 hours,and dissolve in water to make exactly 100 mL. Pipet 5 mL ofthis solution, add water to make exactly 50 mL, and use this solutionas the standard solution. Perform the test with exactly 10µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and determine the peak areas , A T and A S , ofephedrine in each solution.Dissolution rate (%) with respect to the labeled amount ofephedrine hydrochloride (C 10 H 15 NO·HCl)= W S × (A T /A S ) × (1/C) × 90W S : Amount (mg) of ephedrine hydrochloride for assayC: Labeled amount (mg) of ephedrine hydrochloride(C 10 H 15 NO·HCl) in 1 tabletOperating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in thePurity (4) under Ephedrine Hydrochloride.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of ephedrine are not less than 10000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of ephedrineis not more than 2.0%.

Supplement II, JP XV Official Monographs 2125Ergometrine Maleate Injectionエルゴメトリンマレイン 酸 塩 注 射 液Add the following next to the Identification:Bacterial endotoxins Less than 1500 EU/mg.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Erythromycin Enteric-CoatedTabletsエリスロマイシン 腸 溶 錠Change the Disintegration to read:Disintegration It meets the requirement. For the testwith 2nd fluid for disintegration test, use the disk.Estradiol Benzoate Injection(Aqueous Suspension)エストラジオール 安 息 香 酸 エステル 水 性 懸 濁 注 射 液Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: no readily detectable foreign insoluble matters areobserved.Sterility Perform the test according to the Directmethod: it meets the requirement.Estriol Injection(Aqueous Suspension)エストリオール 水 性 懸 濁 注 射 液Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: no readily detectable foreign insoluble matters areobserved.Sterility Perform the test according to the Directmethod: it meets the requirement.EthenzamideエテンザミドChange the following to read:Description Ethenzamide occurs as white crystals or crystallinepowder.It is soluble in methanol, in ethanol (95), and in acetone, andpractically insoluble in water.It begins to sublime slightly at about 105ºC.Identification (1) Determine the absorption spectrum of asolution of Ethenzamide in methanol (1 in 100000) as directedunder Ultraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrumof a solution of Ethenzamide Reference Standard prepared in thesame manner as the sample solution: both spectra exhibit similarintensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Ethenzamide,previously dried, as directed in the potassium bromidedisk method under Infrared Spectrophotometry , andcompare the spectrum with the Reference Spectrum or the spectrumof Ethenzamide Reference Standard: both spectra exhibitsimilar intensities of absorption at the same wave numbers.EthinylestradiolエチニルエストラジオールChange the following to read:Optical rotation [α] 20D: –26 - –31º (after drying, 0.1 g,pyridine, 25 mL, 100 mm).Famotidine Powderファモチジン 散Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: Famotidine Powder in single-unitcontainers meets the requirement of the Content uniformity test.Take out the total contents of 1 pack of Famotidine Powder,add 10 mL of water per 10 mg of famotidine (C 8 H 15 N 7 O 2 S 3 ),shake well, add 10 mL of methanol, shake well, add methanol tomake exactly V mL so that each mL contains about 0.4 mg offamotidine (C 8 H 15 N 7 O 2 S 3 ), and centrifuge. Pipet 5 mL of thesupernatant liquid, add exactly 2 mL of the internal standard solution,add the mobile phase to make 20 mL, and use this solutionas the sample solution. Proceed as directed in the Assay.

2126 Official Monographs Supplement II, JP XVAmount (mg) of famotidine (C 8 H 15 N 7 O 2 S 3 )= W S × (Q T /Q S ) × (V/250)W S : Amount (mg) of famotidine for assayInternal standard solution—To 5 mL of a solution of methylparahydroxybenzoate in methanol (1 in 500) add water to make50 mL.Faropenem Sodium for Syrupシロップ 用 ファロペネムナトリウムAdd the following next to the Uniformity of dosageunit:Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 15minutes of Faropenem Sodium for Syrup is not less than 85%.Start the test with an accurately weighed amount of FaropenemSodium for Syrup, equivalent to about 50 mg (potency)of Faropenem Sodium Hydrate according to the labeled amount,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard the first 10mL of the filtrate, and use the subsequent filtrate as the samplesolution. Separately, weigh accurately an amount of FaropenemSodium Reference Standard, equivalent to about 18 mg (potency),and dissolve in water to make exactly 100 mL. Pipet 5mL of this solution, add water to make exactly 20 mL, and usethis solution as the standard solution. Perform the test with thesample solution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine the absorbances,A T and A S , at 306 nm.Dissolution rate (%) with respect to the labeled amount offaropenem (C 12 H 15 NO 5 S)= (W S /W T ) × (A T /A S ) × (1/C) × 225W S : Amount [mg (potency)] of Faropenem Sodium ReferenceStandardW T : Amount (g) of Faropenem Sodium for SyrupC: Labeled amount [mg (potency)] of faropenem(C 12 H 15 NO 5 S) in 1 gFaropenem Sodium Tabletsファロペネムナトリウム 錠Delete the Disintegration and add the followingnext to the Uniformity of dosage unit:Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Faropenem Sodium Tablets is not less than 85%.Start the test with 1 tablet of Faropenem Sodium Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard the first 10mL of the filtrate, pipet V mL of the subsequent filtrate, add waterto make exactly V´ mL so that each mL contains about 56 µg(potency) of Faropenem Sodium Hydrate according to the labeledamount, and use this solution as the sample solution.Separately, weigh accurately an amount of Faropenem SodiumReference Standard, equivalent to about 18 mg (potency), anddissolve in water to make exactly 100 mL. Pipet 5 mL of thissolution, add water to make exactly 20 mL, and use this solutionas the standard solution. Perform the test with the sample solutionand standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine the absorbances, A Tand A S , at 306 nm.Dissolution rate (%) with respect to the labeled amount offaropenem (C 12 H 15 NO 5 S)= W S × (A T /A S ) × (V´/V) × (1/C) × 225W S : Amount [mg (potency)] of Faropenem Sodium ReferenceStandardC: Labeled amount [mg (potency)] of faropenem(C 12 H 15 NO 5 S) in 1 tabletFlopropioneフロプロピオンChange the Origin/limits of content, Description,Identification and Purity to read:Flopropione contains not less than 98.0% and notmore than 101.0% of C 9 H 10 O 4 , calculated on the anhydrousbasis.Description Flopropione occurs as a white to pale yellow-browncrystalline powder.It is very soluble in N,N-dimethylformamide, freely soluble inmethanol and in ethanol (99.5), and practically insoluble in water.Identification (1) Determine the absorption spectrum of asolution of Flopropione in ethanol (99.5) (1 in 200000) as directedunder Ultraviolet-visible Spectrophotometry , andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Flopropioneas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similarintensities of absorption at the same wave numbers.Purity (1) Heavy metals —Proceed with 1.0 g ofFlopropione according to Method 4, and perform the test. Preparethe control solution with 2.0 mL of Standard Lead Solution(not more than 20 ppm).

Supplement II, JP XV Official Monographs 2127(2) Related substances—Dissolve 50 mg of Flopropione in50 mL of the mobile phase, and use this solution as the samplesolution. Pipet 1 mL of this solution, add the mobile phase tomake exactly 100 mL, and use this solution as the standard solution.Perform the test with exactly 20 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area of both solutions by the automatic integrationmethod: the area of each peak other than the peak offlopropione obtained from the sample solution is not larger than1/10 times the peak area of flopropione from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:267 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 35ºC.Mobile phase: A mixture of acetonitrile, water and phosphoricacid (114:86:1)Flow rate: Adjust the flow rate so that the retention time offlopropione is about 3 minutes.Time span of measurement: About 7 times as long as the retentiontime of flopropione.System suitability—Test for required detectability: Pipet 1 mL of the standard solution,and add the mobile phase to make exactly 10 mL. Confirmthat the peak area of flopropione obtained from 20 µL ofthis solution is equivalent to 7 to 13% of that of flopropionefrom the standard solution.System performance: Dissolve 25 mg of ethyl parahydroxybenzoatein 30 mL of acetonitrile, and add the mobile phase tomake 50 mL. To 2.5 mL of this solution add 2 mL of the samplesolution and the mobile phase to make 50 mL. When the procedureis run with 20 µL of this solution under the above operatingconditions, flopropione and ethyl parahydroxybenzoate areeluted in this order with the resolution between these peaks beingnot less than 2.0.System repeatability: When the test is repeated 6 times with 20µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of flopropione isnot more than 1.0%.Add the following:Fludrocortisone Acetateフルドロコルチゾン 酢 酸 エステルC 23 H 31 FO 6 : 422.499-Fluoro-11β,17,21-trihydroxypregn-4-ene-3,20-dione21-acetate [514-36-3]Fludrocortisone Acetate, when dried, contains notless than 97.5% and not more than 102.5% ofC 23 H 31 FO 6 .Description Fludrocortisone Acetate occurs as a white to paleyellow crystals or crystalline powder.It is soluble in acetone, sparingly soluble in ethanol (95), andpractically insoluble in water.Melting point: about 220ºC (with decomposition).Identification (1) Prepare the test solution by proceedingwith 10 mg of Fludrocortisone Acetate according to the OxygenFlask Combustion Method , using 0.5 mL of 0.01 mol/Lsodium hydroxide VS as the absorbing liquid: the test solutionresponds to the Qualitative Tests for fluoride.(2) Determine the absorption spectrum of a solution ofFludrocortisone Acetate in ethanol (95) (1 in 100000) as directedunder Ultraviolet-visible Spectrophotometry , andcompare the spectrum with the Reference Spectrum or the spectrumof a solution of Fludrocortisone Acetate Reference Standardin the same manner as the sample solution: both spectraexhibit similar intensities of absorption at the same wavelengths.(3) Determine the infrared absorption spectrum of FludrocortisoneAcetate, previously dried, as directed in the potassiumbromide disk method under Infrared Spectrophotometry ,and compare the spectrum with the Reference Spectrum or thespectrum of Fludrocortisone Acetate Reference Standard, previouslydried: both spectra exhibit similar intensities of absorptionat the same wave numbers.Optical rotation [α] 20D: +131 - +138º (after drying,0.1 g, acetone, 20 mL, 100 mm).Purity (1) Heavy metals —Proceed with 0.5 g ofFludrocortisone Acetate according to Method 2, and perform thetest. Prepare the control solution with 1.5 mL of Standard LeadSolution (not more than 30 ppm).(2) Related substances—Dissolve 20 mg of FludrocortisoneAcetate in 10 mL of the mobile phase, and use this solution asthe sample solution. Pipet 1 mL of this solution, add the mobilephase to make exactly 50 mL, and use this solution as the stan-

2128 Official Monographs Supplement II, JP XVdard solution. Perform the test with exactly 20 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions.Determine each peak area of both solutions by the automatic integrationmethod: the area of each peak other than the peak offludrocortisone acetate obtained from the sample solution is notlarger than 1/4 times the peak area of fludrocortisone acetatefrom the standard solution, and the total area of the peaks otherthan the peak of fludrocortisone acetate obtained from the samplesolution is not larger than 1/2 times the peak area of fludrocortisoneacetate from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4.6 mm in inside diameterand 20 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of water and tetrahydrofuran (13:7)Flow rate: Adjust the flow rate so that the retention time offludrocortisone acetate is about 10 minutes.Time span of measurement: About 2 times as long as the retentiontime of fludrocortisone acetate, beginning after the solventpeak.System suitability—Test for required detectability: Pipet 5 mL of the standard solution,and add the mobile phase to make exactly 100 mL. Confirmthat the peak area of fludrocortisone acetate obtained from20 µL of this solution is equivalent to 4.0 to 6.0% of that offludrocortisone acetate from the standard solution.System performance: Dissolve 2 mg each of FludrocortisoneAcetate and hydrocortisone acetate in 50 mL of the mobilephase. When the procedure is run with 20 µL of this solutionunder the above operating conditions, hydrocortisone acetateand fludrocortisone acetate are eluted in this order with theresolution between these peaks being not less than 1.5.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of fludrocortisoneacetate is not more than 2.0%.(3) Residual solvent—Being specified separately.Loss on drying Not more than 1.0% (1 g, in vacuum,100ºC, 2 hours).Residue on ignition Not more than 0.1% (1 g, platinumcrucible).Assay Weigh accurately about 25 mg each of FludrocortisoneAcetate and Fludrocortisone Acetate Reference Standard, previouslydried, and dissolve separately in ethanol (95) to makeexactly 100 mL. Pipet 4 mL each of these solutions, add ethanol(95) to make exactly 100 mL, and use these solutions as thesample solution and standard solution, respectively. Perform thetest with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , and determinethe absorbances, A T and A S , at 238 nm.Amount (mg) of fludrocortisone acetate (C 23 H 31 FO 6 )= W S × (A T /A S )W S : Amount (mg) of Fludrocortisone Acetate ReferenceStandardContainers and storage Containers—Well-closed containers.Storage—Light-resistant.Add the following:FlutamideフルタミドC 11 H 11 F 3 N 2 O 3 : 276.212-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide[13311-84-7]Flutamide, when dried, contains not less than 98.5%and not more than 101.5% of C 11 H 11 F 3 N 2 O 3 .Description Flutamide occurs as a light yellow crystallinepowder.It is freely soluble in methanol and in ethanol (95), and practicallyinsoluble in water.Identification (1) Determine the absorption spectrum of asolution of Flutamide in ethanol (95) (1 in 50000) as directedunder Ultraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrumof a solution of Flutamide Reference Standard prepared in thesame manner as the sample solution: both spectra exhibit similarintensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Flutamideas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of Flutamide ReferenceStandard: both spectra exhibit similar intensities of absorptionat the same wave numbers.Melting point 109 - 113ºCPurity (1) Heavy metals —Proceed with 2.0 g ofFlutamide according to Method 2, and perform the test. Preparethe control solution with 2.0 mL of Standard Lead Solution (notmore than 10 ppm).(2) Related substances—Dissolve 40 mg of Flutamide in 50mL of methanol, and use this solution as the sample solution.Perform the test with exactly 10 µL of the sample solution asdirected under Liquid Chromatography according to thefollowing conditions. Determine each peak area of the samplesolution by the automatic integration method and calculate the

Supplement II, JP XV Official Monographs 2129amounts of them by the area percentage method: the amount ofeach peak other than flutamide is not more than 0.3%, and thetotal amount of the peaks other than flutamide is not more than0.5%.Operating conditions—Column, column temperature, mobile phase and flow rate:Proceed as directed in the operating conditions in the Assay.Detector: An ultraviolet absorption photometer (wavelength:230 nm).Time span of measurement: About 2 times as long as the retentiontime of flutamide, beginning after the solvent peak.System suitability—System performance: Proceed as directed in the system suitabilityin the Assay.Test for required detectability: Pipet 1 mL of the standard solution,add methanol to make exactly 100 mL, and use this solutionas the solution for system suitability test. Pipet 2 mL of thesolution for system suitability test, and add methanol to makeexactly 20 mL. Confirm that the peak area of flutamide obtainedfrom 10 µL of this solution is equivalent to 7 to 13% of that offlutamide from the solution for system suitability test.System repeatability: When the test is repeated 6 times with10 µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the peakarea of flutamide is not more than 2.0%.(3) Residual solvent—Being specified separately.Internal standard solution—A solution of testosterone inmethanol (9 in 10000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 3.9 mm in inside diameterand 30 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (10 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of methanol and 0.05 mol/L potassiumdihydrogen phosphate (7:4)Flow rate: Adjust the flow rate so that the retention time offlutamide is about 12 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,flutamide and the internal standard are eluted in this order withthe resolution between these peaks being not less than 2.0.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of flutamideis not more than 1.0%.Containers and storage Containers—Tight containers.Add the following:FlutoprazepamフルトプラゼパムLoss on drying Not more than 0.5% (0.5 g, in vacuum, phosphorus (V) oxide, 60ºC, 3 hours).Residue on ignition Not more than 0.1% (1 g, platinumcrucible).Assay Weigh accurately about 40 mg each of Flutamide andFlutamide Reference Standard, and dissolve separately inmethanol to make exactly 25 mL. Pipet 5 mL each of these solutions,add 5 mL of the internal standard solution, add methanolto make 50 mL, and use these solutions as the sample solutionand standard solution, respectively. Perform the test with 10 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and calculate the ratios, Q T and Q S , of the peakarea of flutamide to that of the internal standard, respectively.Amount (mg) of flutamide (C 11 H 11 F 3 N 2 O 3 )= W S × (Q T /Q S )W S : Amount (mg) of Flutamide Reference StandardC 19 H 16 ClFN 2 O: 342.797-Chloro-1-cyclopropylmethyl-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one [25967-29-7]Flutoprazepam, when dried, contains not less than99.0% and not more than 101.0% of C 19 H 16 ClFN 2 O.Description Flutoprazepam occurs as a white to light yellowcrystals or crystalline powder.It is freely soluble in ethyl acetate, soluble in ethanol (99.5)and in acetic anhydride, and practically insoluble in water.Identification (1) Dissolve 2 mg of Flutoprazepam in 200mL of a solution of sulfuric acid in ethanol (99.5) (3 in 1000).Determine the absorption spectrum of this solution as directedunder Ultraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Flutoprazepamas directed in the potassium bromide disk methodunder Infrared Spectrophotometry , and compare thespectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) Perform the test with Flutoprazepam as directed underFlame Coloration Test (2): a green color appears.Melting point 118 - 122ºC

2130 Official Monographs Supplement II, JP XVPurity (1) Chloride —To 1.0 g of Flutoprazepam add50 mL of water, allow to stand for 1 hour with occasional shaking,and filter. Pipet 20 mL of the filtrate, add 6 mL of dilute nitricacid and water to make 50 mL. Perform the test using thissolution as the test solution. Prepare the control solution with0.40 mL of 0.01 mol/L hydrochloric acid VS (not more than0.036%).(2) Heavy metals —Proceed with 1.0 g of Flutoprazepamaccording to Method 2, and perform the test. Preparethe control solution with 1.0 mL of Standard Lead Solution (notmore than 10 ppm).(3) Related substances—Dissolve 0.10 g of Flutoprazepamin 20 mL of ethyl acetate, and use this solution as the samplesolution. Pipet 1 mL of this solution, and add ethyl acetate tomake exactly 50 mL. Pipet 1 mL of this solution, add ethyl acetateto make exactly 20 mL, and use this solution as the standardsolution. Perform the test with these solutions as directed underThin-layer Chromatography . Spot 10 µL each of thesample solution and standard solution on a plate of silica gelwith fluorescent indicator for thin-layer chromatography. Developthe plate with a mixture of ethyl acetate and hexane (3:2)to a distance of about 12 cm, and air-dry the plate. Examine underultraviolet light (main wavelength: 254 nm): the spots otherthan the principal spot obtained from the sample solution are notmore intense than the spot from the standard solution.(4) Residual solvent—Being specified separately.Loss on drying Not more than 0.20% (1 g, 105ºC, 2hours).Residue on ignition Not more than 0.1% (1 g, platinumcrucible).Assay Weigh accurately about 0.5 g of Flutoprazepam, previouslydried, dissolve in 70 mL of acetic anhydride, and titrate with 0.1 mol/L perchloric acid VS (potentiometric titration).Perform a blank determination in the same manner, andmake any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 34.28 mg of C 19 H 16 ClFN 2 OContainers and storage Containers—Well-closed containers.Add the following:Flutoprazepam Tabletsフルトプラゼパム 錠Flutoprazepam Tablets contain not less than 93.0%and not more than 107.0% of the labeled amount offlutoprazepam (C 19 H 16 ClFN 2 O: 342.79).Method of preparation Prepare as directed under Tablets,with Flutoprazepam.Identification To a quantity of powdered Flutoprazepam Tablets,equivalent to 10 mg of Flutoprazepam according to the labeledamount, add 20 mL of a solution of sulfuric acid in ethanol(99.5) (3 in 1000), shake well, and add a solution of sulfuricacid in ethanol (99.5) (3 in 1000) to make 100 mL. Centrifugethis solution, pipet 10 mL of the supernatant liquid, and add asolution of sulfuric acid in ethanol (99.5) (3 in 1000) to make100 mL. Determine the absorption spectrum of this solution asdirected under Ultraviolet-visible Spectrophotometry : itexhibits maxima between 240 nm and 244 nm, between 279 nmand 285 nm, and between 369 nm and 375 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Flutoprazepam Tablets add 60 mL of the mobilephase, shake for 15 minutes to disintegrate, disperse the particlewith the aid of ultrasonic waves, and add the mobile phase tomake exactly V mL so that each mL contains about 20 µg offlutoprazepam (C 19 H 16 ClFN 2 O). Filter this solution through amembrane filter with a pore size not exceeding 0.45 µm, discardthe first 5 mL of the filtrate, and use the subsequent filtrate asthe sample solution. Proceed as directed in the Assay.Amount (mg) of flutoprazepam (C 19 H 16 ClFN 2 O)= W S × (A T /A S ) × (V/1000)W S : Amount (mg) of flutoprazepam for assayDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 90minutes of Flutoprazepam Tablets is not less than 70%.Start the test with 1 tablet of Flutoprazepam Tablets, withdrawnot less than 20 mL of the medium at the specified minuteafter starting the test, and filter through a membrane filter with apore size not exceeding 0.45 µm. Discard the first 10 mL of thefiltrate, pipet V mL of the subsequent filtrate, add water to makeexactly V´ mL so that each mL contains about 2.2 µg of flutoprazepam(C 19 H 16 ClFN 2 O) according to the labeled amount, anduse this solution as the sample solution. Separately, weigh accuratelyabout 22 mg of flutoprazepam for assay, previously driedat 105ºC for 2 hours, and dissolve in methanol to make exactly100 mL. Pipet 1 mL of this solution, add water to make exactly100 mL, and use this solution as the standard solution. Performthe test with exactly 20 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions, and determine thepeak areas of flutoprazepam, A T and A S , of both solution.Dissolution rate (%) with respect to the labeled amount offlutoprazepam (C 19 H 16 ClFN 2 O)= W S × (A T /A S ) × (V´/V) × (1/C) × 9W S : Amount (mg) of flutoprazepam for assayC: Labeled amount (mg) of flutoprazepam (C 19 H 16 ClFN 2 O) in1 tabletOperating conditions—Proceed as directed in the operating conditions in the Assay.System suitability—

Supplement II, JP XV Official Monographs 2131System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of flutoprazepam are not less than 4000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of flutoprazepamis not more than 1.0%.Assay Weigh accurately not less than 20 Flutoprazepam Tablets,and powder. Weigh accurately a portion of the powder,equivalent to about 2 mg of flutoprazepam (C 19 H 16 ClFN 2 O),add 60 mL of the mobile phase, shake for 15 minutes, and addthe mobile phase to make exactly 100 mL. Filter this solutionthrough a membrane filter with a pore size not exceeding 0.45µm. Discard the first 5 mL of the filtrate, and use the subsequentfiltrate as the sample solution. Separately, weigh accuratelyabout 20 mg of flutoprazepam for assay, previously dried at105ºC for 2 hours, and dissolve in the mobile phase to makeexactly 100 mL. Pipet 2 mL of this solution, add the mobilephase to make exactly 20 mL, and use this solution as the standardsolution. Perform the test with exactly 20 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak areas , A T and A S , of flutoprazepam ineach solution.Amount (mg) of flutoprazepam (C 19 H 16 ClFN 2 O)= W S × (A T /A S ) × (1/10)W S : Amount (mg) of flutoprazepam for assayOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:230 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of methanol and water (3:1)Flow rate: Adjust the flow rate so that the retention time offlutoprazepam is about 5 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of flutoprazepam are not less than 4000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of flutoprazepamis not more than 1.0%.Containers and storage Containers—Well-closed containers.Fosfomycin Sodium for Injection注 射 用 ホスホマイシンナトリウムChange the Identification (2) and Water to read:Identification (2) To 2 mL of a solution of Fosfomycin Sodiumfor Injection (1 in 250) add 1 mL of perchloric acid and 2mL of 0.1 mol/L sodium periodate solution, and heat in a waterbath for 10 minutes. After cooling, add 1 mL of hexaammoniumheptamolybdate-sulfuric acid TS and 1 mL of1-amino-2-naphtol-4-sulfonic acid TS, and allow to stand for 30minutes: a blue color develops.Water Not more than 4.0% (0.1 g, coulometric titration).Add the following:Furosemide Injectionフロセミド 注 射 液Furosemide Injection is an aqueous solution for injection.It contains not less than 95.0% and not more than105.0% of the labeled amount of furosemide(C 12 H 11 ClN 2 O 5 S: 330.74).Method of preparation Prepare as directed under Injection,with Furosemide.Description Furosemide Injection is a colorless, clear liquid.Identification (1) To a volume of Furosemide Injection,equivalent to 2.5 mg of Furosemide according to the labeledamount, add 10 mL of 2 mol/L hydrochloric acid TS, heat undera reflux condenser on a water bath for 15 minutes. After cooling,render the solution slightly acid with 18 mL of sodium hydroxideTS: the solution responds to the Qualitative Tests forprimary aromatic amines. The color of the solution is red tored-purple.(2) To a volume of Furosemide Injection, equivalent to 20mg of Furosemide according to the labeled amount, add water tomake 100 mL. Pipet 2 mL of this solution, add 0.01 mol/L sodiumhydroxide TS to make 50 mL. Determine the absorptionspectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits maxima between 227 nmand 231 nm, between 269 nm and 273 nm, and between 330 nmand 336 nm.Osmotic pressure ratio Being specified separately.pH Being specified separately.Purity Pipet a volume of Furosemide Injection, equivalent to40 mg of Furosemide according to the labeled amount, add 30mL of acetone, shake well, and add acetone to make exactly 50mL. Centrifuge this solution, to 1.0 mL of the supernatant liquid

2132 Official Monographs Supplement II, JP XVadd 3.0 mL of water, cool in a ice bath, add 3.0 mL of dilute hydrochloricacid and 0.15 mL of sodium nitrite TS, shake, andallow to stand for 1 minute. To this solution add 1.0 mL of ammoniumamidosulfate TS, shake well, allow to stand for 3 minutes,add 1.0 mL of N,N-diethyl-N´-1-naphtylethylenediamineoxalate TS, shake well, and allow to stand for 5 minutes. Determinethe absorbance of this solution at 530 nm as directedunder Ultraviolet-visible Spectrophotometry using a solution,prepared in the same manner with 1.0 mL of acetone, asthe blank: the absorbance is not more than 0.10.Bacterial endotoxins Less than 1.25 EU/mg.Extractable volume It meets the requirement.Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay To an exactly measured volume of Furosemide Injection,equivalent to about 20 mg of Furosemide (C 12 H 11 ClN 2 O 5 S),add water to make exactly 100 mL. Pipet 3 mL of this solution,add 0.01 mol/L sodium hydrochloride TS to make exactly 100mL, and use this solution as the sample solution. Separately,weigh accurately about 20 mg of Furosemide Reference Standard,previously dried at 105ºC for 4 hours, add 0.01 mol/L sodiumhydroxide TS to make exactly 100 mL. Pipet 3 mL of thissolution, add 0.01 mol/L sodium hydroxide TS to make exactly100 mL, and use this solution as the standard solution. Performthe test with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , anddetermine the absorbances, A T and A S , at 271 nm.Amount (mg) of furosemide (C 12 H 11 ClN 2 O 5 S)= W S × (A T /A S )W S : Amount (mg) of Furosemide Reference StandardContainers and storage Containers—Hermetic containers.Storage—Light-resistant.Add the following:GefarnateゲファルナートC 27 H 44 O 2 : 400.64(2E)-3,7-Dimethylocta-2,6-dienyl(4E,8E)-5,9,13-trimethyltetradeca-4,8,12-trienoate[51-77-4, 4E isomer]Gefarnate is a mixture of 4E geometrical isomer.It contains not less than 98.0% and not more than101.0% of C 27 H 44 O 2 .Description Gefarnate is a light yellow to yellow, clear oilyliquid.It is miscible with acetonitrile, with ethanol (99.5) and withcyclohexane.It is practically insoluble in water.Identification Determine the infrared absorption spectrum ofGefarnate as directed in the liquid film method under InfraredSpectrophotometry , and compare the spectrum with theReference Spectrum or the spectrum of Gefarnate ReferenceStandard: both spectra exhibit similar intensities of absorption atthe same wave numbers.Specific gravity d 2020: 0.906 - 0.914Purity (1) Acidity—To 1.0 g of Gefarnate add 30 mL ofneutralized ethanol. To this solution add 1 drop of phenolphthaleinTS and 0.40 mL of 0.1 mol/L sodium hydroxide VS: ared color develops.(2) Heavy metals —Proceed with 2.0 g of Gefarnateaccording to Method 2, and perform the test. Prepare the controlsolution with 2.0 mL of Standard Lead Solution (not more than10 ppm).(3) Related substances—Use a solution of Gefarnate inacetonitrile (1 in 500) as the sample solution. Pipet 2 mL of thissolution, add acetonitrile to make exactly 100 mL, and use thissolution as the standard solution. Perform the test with exactly 2µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions. Determine each peak area of both solutions bythe automatic integration method: the area of each peak otherthan the peak of gefarnate obtained from the sample solution isnot larger than 1/2 times the peak area of gefarnate from thestandard solution, and the total area of the peaks other than thepeak of gefarnate obtained from the sample solution is not largerthan the peak area of gefarnate from the standard solution.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay.

Supplement II, JP XV Official Monographs 2133Time span of measurement: About 2 times as long as the retentiontime of gefarnate, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 2 mL of the standard solution,add acetonitrile to make exactly 20 mL. Confirm that thepeak area of gefarnate obtained from 2 µL of this solution isequivalent to 7 to 13% of that of gefarnate from the standardsolution.System performance: When the procedure is run with 2 µL ofthe standard solution under the above operating conditions, thenumber of theoretical plates and the symmetry factor of the peakof gefarnate are not less than 4000, and between 0.9 and 1.2,respectively.System repeatability: When the test is repeated 6 times with 2µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of gefarnate isnot more than 1.0%.Isomer ratio To 1 mL of Gefarnate add 100 mL of ethanol(99.5), and use this solution as the sample solution. Perform thetest with 4 µL of the sample solution as directed under GasChromatography according to the following conditions.Determine the areas of two adjacent peaks, A a and A b , havingthe retention time of about 37 minutes, where Aa is the peakarea of shorter retention time and A b is the peak area of longerretention time: A a /(A a + A b ) is between 0.2 and 0.3.Operating conditions—Detector: A hydrogen flame-ionization detector.Column: A glass column 3 mm in inside diameter and 160 cmin length, packed with polyethylene glycol 20M for gas chromatographycoated at the ratio of 5% on acid-treated and silanizedsiliceous earth for gas chromatography (149 to 177 µm inparticle diameter).Column temperature: A constant temperature of about 210ºC.Carrier gas: Nitrogen.Flow rate: Adjust the flow rate so that the reaction time of thepeak showing earlier elution of the two peaks of gefarnate isabout 35 minutes.System suitability—System performance: When the procedure is run with 4 µL ofthe sample solution under the above conditions: the resolutionbetween the two peaks of gefarnate is not less than 1.0.System repeatability: When the test is repeated 6 times with 4µL of the sample solution under the above operating conditions:the relative standard deviation of the peak area of gefarnate withthe shorter retention time of the two peaks is not more than2.0%.Assay Weigh accurately about 50 mg each of Gefarnate andGefarnate Reference Standard, add exactly 5 mL of the internalstandard solution and 20 mL of acetonitrile, and use these solutionsas the sample solution and standard solution. Perform thetest with 2 µL each of the sample solution and standard solutionas directed under Liquid Chromatography according tothe following conditions, and calculate the ratios, Q T and Q S , ofthe peak area of gefarnate to that of the internal standard.Amount (mg) of gefarnate (C 27 H 44 O 2 ) = W S × (Q T /Q S )W S : Amount (mg) of Gefarnate Reference StandardInternal standard solution—A solution of tris (4-t-butylphenyl)phosphate in acetonitrile (1 in 400)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:220 nm)Column: A stainless steel column 4 mm in inside diameterand 30 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (10 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of acetonitrile for liquid chromatography,water and phosphoric acid (700:300:1).Flow rate: Adjust the flow rate so that the retention time ofgefarnate is about 19 minutes.System suitability—System performance: When the procedure is run with 2 µL ofthe standard solution under the above operating conditions, theinternal standard and gefarnate are eluted in this order with theresolution between these peaks being not less than 2.0.System repeatability: When the test is repeated 6 times with 2µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofgefarnate to that of the internal standard is not more than 1.0%.Containers and storage Containers—Tight containers.Storage—Light-resistant, and under nitrogen atmosphere.Add the following:Gentamicin Sulfate OphthalmicSolutionゲンタマイシン 硫 酸 塩 点 眼 液Gentamicin Sulfate Ophthalmic Solution is an aqueous ophthalmicsolutionIt contains not less than 90.0% and not more than 110.0% ofthe labeled potency of expressed as mass of gentamicin C 1(C 21 H 43 N 5 O 7 : 477.60).Method of preparation Prepare as directed under OphthalmicSolution, with Gentamicin Sulfate.Description Gentamicin Sulfate Ophthalmic Solution is aclear, colorless or pale yellow liquid.Identification To a volume of Gentamicin Sulfate OphthalmicSolution, equivalent to 10 mg (potency) of Gentamicin Sulfateaccording to the labeled amount, add water to make 5 mL, anduse this solution as the sample solution. Separately, dissolve anamount of Gentamicin Sulfate Reference Standard, equivalent to10 mg (potency), in 5 mL of water, and use this solution as thestandard solution. Perform the test with these solutions as directedunder Thin-layer Chromatography . Spot 5 µLeach of the sample solution and standard solution on a plate ofsilica gel for thin-layer chromatography. Develop the plate withthe lower layer of a mixture of chloroform, ammonia solution

2134 Official Monographs Supplement II, JP XV(28) and methanol (2:1:1) to a distance of about 15 cm, andair-dry the plate. Spray evenly 0.2% ninhydrin-water saturated1-butanol TS on the plate, and heat the plate at 100ºC for 5 minutes:three principal spots obtained from the sample solution arethe same with the corresponding spots from the standard solutionin color tone and the R f value, respectively.pH 5.5 - 7.5Foreign insoluble matter It meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay Perform the test according to the Cylinder-plate methodas directed under Microbial Assay for Antibiotics accordingto the following conditions.(i) Test organism, agar media for seed and base layer, agarmedium for transferring test organism, and standard solutions—Proceed as directed in the Assay under Gentamicin Sulfate.(ii) Sample solutions—Pipet a volume of Gentamicin SulfateOphthalmic Solution, equivalent to about 12 mg (potency)of Gentamicin Sulfate, add 0.1 mol/L phosphate buffer solution,pH 8.0, to make a solution so that each mL contains about 1 mg(potency). Pipet a suitable volume of this solution, add 0.1mol/L phosphate buffer solution, pH 8.0, to make solutions sothat each mL contains 4 µg (potency) and 1 µg (potency), anduse these solutions as the high concentration sample solutionand low concentration sample solution, respectively.Containers and storage Containers—Tight containers.Expiration date 24 months after preparation.Add the following:GliclazideグリクラジドC 15 H 21 N 3 O 3 S: 323.411-(Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-[(4-methylphenyl)sulfonyl]urea [21187-98-4]Gliclazide, when dried, contains not less than 98.5%and not more than 101.0% of C 15 H 21 N 3 O 3 S.Description Gliclazide is a white crystalline powder.It is sparingly soluble in acetonitrile and in methanol, slightlysoluble in ethanol (99.5) and practically insoluble in water.Identification (1) Determine the absorption spectrum of asolution of Gliclazide in methanol (1 in 62500) as directed underUltraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Gliclazideas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similar intensitiesof absorption at the same wave numbers.Melting point 165 - 169ºC.Purity (1) Heavy metals —Proceed with 2.0 g of Gliclazideaccording to Method 2, and perform the test. Prepare thecontrol solution with 2.0 mL of Standard Lead Solution (notmore than 10 ppm).(2) Related substances—Conduct this procedure within 2hours after preparation of the sample solution. Dissolve 50 mgof Gliclazide in 23 mL of acetonitrile, add water to make 50 mL,and use this solution as the sample solution. Pipet 1 mL of thissolution, and add a mixture of water and acetonitrile (11:9) tomake exactly 100 mL. Pipet 10 mL of this solution, add a mixtureof water and acetonitrile (11:9) to make exactly 100 mL,and use this solution as the standard solution. Perform the testwith exactly 20 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions. Determine each peak areaof both solutions by the automatic integration method: the areaof each peak other than gliclazide obtained from the sample solutionis not larger than the peak area of gliclazide from thestandard solution, and the total area of the peaks other than thepeak of gliclazide obtained from the sample solution is not largerthan 3 times the peak area of gliclazide from the standardsolution. For this calculation, use the area of the peak, havingthe relative retention time of about 0.9 with respect to gliclazide,after multiplying by their relative response factor, 5.65.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:235 nm).Column: A stainless steel column 4.0 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (4 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of water, acetonitrile, triethylamineand trifluoroacetic acid (550:450:1:1)Flow rate: Adjust the flow rate so that the retention time ofgliclazide is about 14 minutes.Time span of measurement: About 2 times as long as the retentiontime of gliclazide, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 4 mL of the standard solution,and add a mixture of water and acetonitrile (11:9) tomake exactly 20 mL. Confirm that the peak area of gliclazideobtained from 20 µL of this solution is equivalent to 10 to 30%of that of gliclazide from the standard solution.System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,

Supplement II, JP XV Official Monographs 2135the number of theoretical plates and the symmetry factor of thepeak of gliclazide are not less than 8000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of gliclazideis not more than 2.0%.(3) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 2hours).W S : Amount [mg (potency)] of Griseofulvin Reference StandardC: Labeled amount [mg (potency)] of griseofulvin(C 17 H 17 ClO 6 ) in 1 tabletAdd the following:Heparin CalciumヘパリンカルシウムResidue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.3 g of Gliclazide, previouslydried, dissolve in 30 mL of a mixture of acetic anhydride andacetic acid (100) (7:3), and titrate with 0.1 mol/L perchloricacid VS (potentiometric titration). Perform a blank determinationin the same manner, and make any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 32.34 mg of C 15 H 21 N 3 O 3 SContainers and storage Containers—Well-closed containers.Griseofulvin Tabletsグリセオフルビン 錠Delete the Disintegration and add the followingnext to the Uniformity of dosage units:Dissolution When the test is performed at 100 revolutionsper minute according to the Paddle method using 900 mLof a solution of sodium laurylsulfate (1 in 100) as the dissolutionmedium, the dissolution rate in 120 minutes of GriseofulvinTablets is not less than 70%.Start the test with 1 tablet of Griseofulvin Tablets, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to makeexactly V´ mL so that each mL contains about 6.9 µg (potency)of Griseofulvin according to the labeled amount, and use thissolution as the sample solution. Separately, weigh accurately anamount of Griseofulvin Reference Standard, equivalent to about28 mg (potency), and dissolve in ethanol (95) to make exactly200 mL. Pipet 5 mL of this solution, add 5 mL of the dissolutionmedium and water to make exactly 100 mL, and use this solutionas the standard solution. Determine the absorbances, A T andA S , at 295 nm of the sample solution and standard solution asdirected under Ultraviolet-visible Spectrophotometry ,using water as the blankDissolution rate (%) with respect to the labeled amount ofgriseofulvin (C 17 H 17 ClO 6 )= W S × (A T /A S ) × (V´/V) × (1/C) × (45/2)R 1 , R 3 , R 4 = SO - 3 or HR 2 = SO - 3 orR 5 = CO - 2 , R 6 = HorR 5 = H, R 6 -= CO 2[37270-89-6]Heparin Calcium is the calcium salt of sulfated glycosaminoglycanscomposed of disaccharide units ofD-glucosamine and uronic acid (L-iduronic acid orD-glucuronic acid) obtained from the intestinal mucosaof healthy edible swine.Heparin Calcium prolongs the clotting time of blood.It contains not less than 150 Heparin Units per mg.Heparin Calcium, calculated on the dried basis,contains not less than 90% and not more than 110% ofthe labeled Units, and not less than 8.0% and not morethan 12.0% of calcium (Ca: 40.08).Description Heparin Calcium occurs as a white to grayishbrown powder or grains. It is freely soluble in water, and practicallyinsoluble in ethanol (99.5).It is hygroscopic.Identification (1) Dissolve 10 mg of Heparin Calcium in 5mL of water. To this solution add 0.1 mL of 1 mol/L hydrochloricacid TS and 5 mL of a solution of toluidine blue O (1 in20000): a purple to red-purple color develops.(2) Dissolve 50 mg of Heparin Calcium in 5 mL of water:the solution responds to the Qualitative Tests for calciumsalt.pH Dissolve 1.0 g of Heparin Calcium in 100 mL ofwater: the pH of the solution is between 6.0 and 8.0.Purity (1) Clarity and color of solution—Dissolve 0.5 g ofHeparin Calcium in 20 mL of water: the solution is clear. De-

2136 Official Monographs Supplement II, JP XVtermine the absorbance of this solution at 400 nm as directedunder Ultraviolet-visible Spectrophotometry : the absorbanceis not more than 0.05.(2) Chloride —Perform the test with 0.5 g of HeparinCalcium. Prepare the control solution with 0.30 mL of 0.01mol/L hydrochloric acid VS (not more than 0.021%).(3) Heavy metals —Proceed with 0.5 g of HeparinCalcium according to Method 2, and perform the test. Preparethe control solution with 1.5 mL of Standard Lead Solution (notmore than 30 ppm).(4) Barium—Dissolve 30 mg of Heparin Calcium in 3.0 mLof water, and use this solution as the sample solution. To 1.0 mLof the sample solution add 3 drops of dilute sulfuric acid, andallow to stand for 10 minutes: no turbidity is produced.(5) Residual solvent—Being specified separately.(6) Total nitrogen—Weigh accurately about 0.1 g of HeparinCalcium, previously dried, and perform the test as directedunder Nitrogen Determination : the amount of nitrogen(N: 14.01) is not more than 3.0%.(7) Protein—To 1.0 mL of the sample solution obtained in(4) add 5 drops of a solution of trichloroacetic acid (1 in 5):neither a precipitate nor turbidity is produced.(8) Oversulfated chondroitin sulfate—Dissolve 20 mg ofHeparin Calcium in 0.60 mL of a solution of sodium3-trimethylsilylpropionate-d 4 for nuclear magnetic resonancespectroscopy in heavy water for nuclear magnetic resonancespectroscopy (1 in 10000), and use this solution as the samplesolution. Determine the spectrum of the sample solution, usingsodium 3-trimethylsilylpropionate-d 4 for nuclear magneticresonance spectroscopy as an internal reference compound, asdirected under Nuclear Magnetic Resonance Spectroscopy ( 1 H) in accordance with the following conditions, usingspectrometer (1) with a proton resonance frequency of not lessthan 400 MHz: no signal occurs from the N-acetyl proton ofoversulfated chondroitin sulfate between δ 2.13 ppm and δ 2.23ppm.Operating conditions—Temperature: 25ºCSpinning: OffNumber of data points: 32,768Spectral range: ±6.0 ppm with the DHO signal at the centerFlip angle: 90ºDelay time: 20 secondsNumber of dummy scans: 4Number of scans: Repeat until the S/N ratio of the signal ofN-acetyl proton of heparin is not less than 200.Window function: Exponential function (Line broadeningfactor = 0.2 Hz)System suitability—Dissolve 0.10 mg of Oversulfated Chondroitin Sulfate ReferenceStandard in 0.60 mL of a solution of sodium3-trimethylsilylpropionate-d 4 for nuclear magnetic resonancespectroscopy in heavy water for nuclear magnetic resonancespectroscopy (1 in 10000), and use this solution as the standardsolution. Dissolve about 20 mg of heparin calcium in 0.60 mLof the standard solution, and use this solution as the solution forsystem suitability test. Proceed under the above operating conditions:Signals occur from the N-acetyl protons of heparin andoversulfated chondroitin sulfate at δ 2.02 – 2.06 ppm and at δ2.13 – δ 2.23 ppm, respectively.Loss on drying Not more than 8% (50 mg, in vacuum,60ºC, 3 hours).Bacterial endotoxins Less than 0.0030 EU/heparinUnit.Assay (1) Heparin(i) Substrate solution: Dissolve 15 mg ofN-benzoyl-L-isoleucyl-L-glutamyl(γ-OR)-glycyl-L-arginyl-p-nitroanilide hydrochloride in 20 mL of water.(ii) Activated blood coagulation factor X solution: Dissolvebovine activated blood coagulation factor X in water to make asolution containing 0.426 Unit per mL.(iii) Buffer solution: Dissolve 6.06 g of2-amino-2-hydroxymethyl-1,3-propanediol in 750 mL of water,adjust the pH to 8.4 with 1 mol/L hydrochloric acid TS, and addwater to make 1000 mL.(iv) Reaction stop solution: To 20 mL of acetic acid (100)add water to make 40 mL.(v) Heparin standard solutions: Dissolve Heparin SodiumReference Standard in isotonic sodium chloride solution tomake a solution containing 10 Units per mL. To 100 µL of thissolution add buffer solution to make exactly 5 mL, and use thissolution as the standard stock solution. Prepare the heparinstandard solutions (1), (2), (3), (4) and (5) by addition of antithrombinIII TS, human normal plasma and the buffer solutionto the standard solution as directed in the following table.Heparin standard solutionAntithrombin III TS Human normalHeparin concentration(Unit/mL)Buffer solution (µL)No.(µL)plasma (µL)Standard solution (µL)(1) 0 800 100 100 0(2) 0.02 700 100 100 100(3) 0.04 600 100 100 200(4) 0.06 500 100 100 300(5) 0.08 400 100 100 400(vi) Sample solution: Weigh accurately an adequate amountof Heparin Calcium, dissolve in isotonic sodium chloride solutionso that each mL contains about 0.5 Units according to thelabeled amount. To 100 µL of this solution add 100 µL of antithrombinIII TS, 100 µL of human normal plasma and 700 µL ofthe buffer solution, and use this solution as the sample solution.

Supplement II, JP XV Official Monographs 2137(vii) Procedure: Transfer 400 µL of the sample solution to atest tube, and warm at 37ºC for 4 minutes. To this solution add200 µL of the activated blood coagulation factor X solution, mixwell, warm at 37ºC for exactly 30 seconds, add 400 µL of thesubstrate solution, previously warmed at 37ºC, and mix well.Warm this solution at 37ºC for exactly 3 minutes, add 600 µL ofthe reaction stop solution, and mix immediately. Determine theabsorbance at 405 nm as directed under Ultraviolet-visibleSpectrophotometry , using the blank solution prepared byaddition of 600 µL of the reaction stop solution and 600 µL ofwater to 400 µL of the sample solution. Proceed the same waywith the heparin standard solution (1), the heparin standard solution(2), the heparin standard solution (3), the heparin standardsolution (4) and the heparin standard solution (5), and determinetheir absorbances.(viii) Calculation: Plot the absorbances of the standard solutionsand their heparin concentrations to prepare a calibrationcurve. Determine the heparin concentration, C, of the samplesolution, and calculate heparin Units per mg of Heparin Calciumfrom the following formula.Units per mg of Heparin Calcium = C × 10 × (b/a)a: Amount of sample (mg)b: Total volume (mL) of isotonic sodium chloride solutionused to dissolve the sample to make the solution containingabout 0.5 Units per mL(2) Calcium Weigh accurately about 50 mg of HeparinCalcium, dissolve in 20 mL of water, add 2 mL of 8 mol/L sodiumhydroxide TS, allow to stand for 3 to 5 minutes with occasionalshaking, add 0.1 g of NN indicator, and immediately titrate with 0.1 mol/L disodium dihydrogen ethylenediaminetetraacetate VS until the color of the solution changes fromred-purple to blue.Each mL of 0.01 mol/L disodium dihydrogen ethylenediaminetetraacetate VS= 0.4008 mg of CaContainers and storage Containers—Tight containers.Heparin SodiumヘパリンナトリウムAdd the following next to the Japanese title:R 1 , R 3 , R 4 = SO 3 Na or HR 2 = SO 3 Na orR 5 = CO 2 Na, R 6 = HorR 5 = H, R 6 = CO 2 Na[9041-08-1]Change the Origin/limits of content to read:Heparin Sodium is the sodium salt of sulfated glycosaminoglycanscomposed of disaccharide units of D-glucosamine anduronic acid (L-iduronic acid or D-glucuronic acid) obtained fromthe livers, the lungs and the intestinal mucosa of healthy edibleanimals. It prolongs the clotting time of blood. Heparin Sodiumobtained from the livers and the lungs contains not less than 110Heparin Units per mg, and that obtained from the intestinalmucosa contains not less than 130 Heparin Units per mg.Heparin Sodium, calculated on the dried basis, contains notless than 90% and not more than 110% of the labeled Units.Label the name of the organ used as the starting material.Human Menopausal Gonadotrophinヒト 下 垂 体 性 性 腺 刺 激 ホルモンChange the Purity to read:Purity Interstitial cell-stimulating hormone—Perform the testaccording to the following method: the ratio of the unit of interstitialcell-stimulating hormone (luteinizing hormone) to that offollicle-stimulating hormone is not more than 1. The luteinizingactivity of the hormone is determined by the seminal vesicleweight assay or ovarian ascorbic acid depletion assay. Theseminal vesicle weight assay may be used when the ratio of theunit of interstitial cell-stimulating hormone to that of follicle-stimulatinghormone is not more than 1 and not less than0.10.1. Seminal vesicle weight assay(i) Test animals—Select healthy male albino rats weighingabout 45 to 65 g.

2138 Official Monographs Supplement II, JP XV(ii) Standard solutions—Weigh accurately a suitable amountof Human Menopausal Gonadotrophin Reference Standard, anddissolve in bovine serum albumin-sodium chloride-phosphatebuffer solution, pH 7.2, to prepare three kinds of solutions, containing10, 20 and 40 interstitial cell-stimulating hormone (luteinizinghormone) units per 1.0 mL, respectively. Inject thesesolutions into three groups consisting of five test animals each,and weigh their seminal vesicles as directed in (iv). Accordingto the result of the test, designate the concentration of the referencestandard, which will make the mass of the seminal vesicle20 to 35 mg, as the high-dose standard solution, S H . Dilute theS H to 1.5 to 2.0 times the initial volume with the bovine serumalbumin-sodium chloride-phosphate buffer solution, pH 7.2, anddesignate this solution as the low-dose standard solution, S L .Store these solutions at 2 - 8ºC.(iii) Sample solutions—According to the labeled units,weigh accurately a suitable amount of Human Menopausal Gonadotrophin,and dissolve in the bovine serum albumin-sodiumchloride-phosphate buffer solution, pH 7.2, to prepare thehigh-dose sample solution, T H and the low-dose sample solution,T L , so that their concentrations are similar to those of the correspondingstandard solutions, respectively. Store these solutionsat 2 - 8ºC.(iv) Procedure—Divide the test animals at random into 4groups, A, B, C and D, with not less than 10 animals and equalnumbers in each group. Inject subcutaneously once every day0.2 mL each of S H , S L , T H and T L to each animal in the respectivegroups for five days. On the sixth day, excise the seminalvesicles, remove extraneous tissue, remove fluid adhering to thevesicles and the contents of the vesicles by lightly pressing betweenfilter papers, and weigh the vesicles.(v) Calculation—Proceed as directed in (v) in the Assay bychanging the mass of ovaries to the mass of seminal vesicles toread.2. Ovarian ascorbic acid depletion assay(i) Test animals—Select healthy female albino rats weighingabout 45 to 65 g.(ii) Standard solutions—Dissolve Human Menopausal GonadotrophinReference Standard in bovine serum albumin-sodiumchloride-phosphate buffer solution, pH 7.2, to preparefour kinds of solutions, containing 2, 4, 8 and 16 interstitialcell-stimulating hormone (luteinizing hormone) units per 1.0mL, respectively. Inject these solutions into four groups consistingof five test animals each, and determine the amount ofovarian ascorbic acid. Separately, inject bovine serum albumin-sodiumchloride-phosphate buffer solution, pH 7.2, to acontrol group of animals. According to the result of the test,designate the concentration of the reference standard, which willmake the amount of ovarian ascorbic acid 0.80 to 0.85 timesthat in the control group, as the concentration for the low-dosestandard solution, and 4 to 6 times that as the concentration forthe high-dose standard solution. Dissolve Human MenopausalGonadotrophin Reference Standard in bovine serum albumin-sodiumchloride-phosphate buffer solution, pH 7.2, to preparethe high-dose standard solution and low-dose standard solutionto contain the concentrations described above, and designatethem as S H and S L , respectively.(iii) Sample solutions—According to the labeled units,weigh accurately a suitable amount of Human Menopausal Gonadotrophin,and dissolve in the bovine serum albumin-sodiumchloride-phosphate buffer solution, pH 7.2, to prepare thehigh-dose sample solution and low-dose sample solution tocontain units equal to those of the high-dose standard solutionand low-dose standard solution, and designate them as T H andT L , respectively.(iv) Procedure—Inject subcutaneously to each animal 80units of serum gonadotrophin dissolved in 0.5 mL of isotonicsodium chloride solution. At 56 to 72 hours after the injection,inject subcutaneously to each animal 40 units of human chorionicgonadotrophin dissolved in 0.5 mL of isotonic sodiumchloride solution. On 6 to 9 days after the last injection, dividethe test animals at random into 4 groups, A, B, C and D, withnot less than 10 animals and equal numbers in each group. Inject1 mL each of S H , S L , T H and T L into the tail vein of each animalin groups A, B, C and D, respectively. At 2 to 4 hours after theinjection, excise the both ovaries, remove the fat and other unwantedtissues attached to the ovaries, weigh, add a prescribedvolume between 5 and 15 mL of metaphosphoric acid solution(1 in 40), homogenize with a homogenizer on ice, and centrifuge.To 0.5 to 1 mL (1 mL in principle. 0.5 mL may be usedwhen the absorbance is not more than 0.1) of the supernatantliquid, add 1.5 mL of metaphosphoric acid solution (1 in 40) and2.5 mL of 2,6-dichloroindophenol sodium-sodium acetate TS,mix the solution, and immediately determine the absorbance ofthe solution at 520 nm as directed under Ultraviolet-visibleSpectrophotometry . Separately, weigh accurately 10.0mg of Ascorbic Acid Reference Standard, and add water tomake exactly 100 mL. Pipet 5 mL of this solution, and add waterto make exactly 50 mL. Pipet a suitable volume of this solution,and add metaphosphoric acid solution (1 in 40) to make asolution so that each mL contains 2.0 to 10.0 µg of ascorbic acid(C 6 H 8 O 6 : 176.12). To 2.5 mL of this solution, add 2.5 mL of2,6-dichloroindophenol sodium-sodium acetate TS, mix the solution,immediately determine the absorbance in the same manneras mentioned above, and prepare the calibration curve. Fromthe calibration curve of ascorbic acid, determine the amount(mg) of ascorbic acid in 100 g of ovary.(v) Calculation—Proceed as directed in (v) in the Assay bychanging the mass of ovaries to the amount of ascorbic acid toread.Hydralazine Hydrochloride forInjection注 射 用 ヒドララジン 塩 酸 塩Add the following next to the pH:Bacterial endotoxins Less than 5.0 EU/mg.Uniformity of dosage units It meets the requirementof the Mass variation test. (T: 106.0%)Foreign insoluble matter Perform the test according

Supplement II, JP XV Official Monographs 2139to Method 2: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Hydrocortisone Sodium Phosphateヒドロコルチゾンリン 酸 エステルナトリウムDelete the Loss on drying and change the Origin/limitsof content, Optical rotation and Purity(5) to read:Hydrocortisone Sodium Phosphate contains not lessthan 96.0% and not more than 102.0% ofC 21 H 29 Na 2 O 8 P, calculated on the anhydrous basis.Optical rotation [α] 20D: +123 - +131º (1 g, calculatedon the anhydrous basis, phosphate buffer solution, pH 7.0, 100mL, 100 mm).Purity (5) Free phosphoric acid—Weigh accurately about0.25 g of Hydrocortisone Sodium Phosphate, dissolve in waterto make exactly 100 mL, and use this solution as the sample solution.Pipet 5 mL each of the sample solution and StandardPhosphoric Acid Solution into separate 25-mL volumetric flasks,add 2.5 mL of hexaammonium heptamolybdate-sulfuric acid TSand 1 mL of 1-amino-2-naphthol-4-sulfonic acid TS, shake, addwater to make exactly 25 mL, and allow to stand at 20 ± 1ºC for30 minutes. Perform the test with these solutions as directedunder Ultraviolet-visible Spectrophotometry , using asolution prepared with 5 mL of water in the same manner as theblank. Determine the absorbances, A T and A S , at 740 nm of thesample solution and Standard Phosphoric Acid Solution: theamount of free phosphoric acid is not more than 1.0%.Content (%) of free phosphoric acid (H 3 PO 4 )= (A T /A S ) × (1/W) × 258.0W: Amount (mg) of Hydrocortisone Sodium Phosphate, calculatedon the anhydrous basis.Add the following next to the Purity:Water Not more than 5.0% (30 mg. coulometric titration).Change the Assay to read:Assay Weigh accurately about 20 mg each of HydrocortisoneSodium Phosphate and Hydrocortisone Sodium Phosphate ReferenceStandard (previously determine the water content in the same manner as Hydrocortisone Sodium Phosphate), dissolveeach in 50 mL of the mobile phase, add exactly 10 mL ofthe internal standard solution, then add the mobile phase tomake 200 mL, and use these solutions as the sample solutionand the standard solution, respectively. Perform the test with 20µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and calculate the ratios, Q T and Q S , of the peakarea of hydrocortisone phosphate to that of the internal standard,respectively.Amount (mg) of hydrocortisone sodium phosphate(C 21 H 29 Na 2 O 8 P ) = W S × (Q T /Q S )W S : Amount (mg) of Hydrocortisone Sodium Phosphate ReferenceStandard, calculated on the anhydrous basisInternal standard solution—A solution of isopropyl parahydroxybenzoatein the mobile phase (3 in 5000).Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (7 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of 0.05 mol/L sodium dihydrogenphosphate TS, pH 2.6 and methanol (1:1).Flow rate: Adjust the flow rate so that the retention time ofhydrocortisone phosphate is about 10 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,hydrocortisone phosphate and the internal standard are eluted inthis order with the resolution between these peaks being not lessthan 8.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratios of the peakarea of hydrocortisone phosphate to that of the internal standardis not more than 1.0%.HydroxypropylcelluloseヒドロキシプロピルセルロースAdd the following next to the Japanese title:[9004-64-2]Low SubstituteHydroxypropylcellulose低 置 換 度 ヒドロキシプロピルセルロースAdd the following next to the Japanese title:[9004-64-2, Hydroxypropylcellulose]

2140 Official Monographs Supplement II, JP XVHypromelloseヒプロメロースChange the Chemical name to read:[9004-65-3]Hypromellose Phthalateヒプロメロースフタル 酸 エステルChange the Chemical name to read:[9050-31-1]Add the following:Imidapril Hydrochlorideイミダプリル 塩 酸 塩C 20 H 27 N 3 O 6·HCl: 441.91(4S)-3-{(2S)-2-[(1S)-1-Ethoxycarbonyl-3-phenylpropylamino]propanoyl}-1-methyl-2-oxoimidazolidine-4-carboxylic acid monohydrochloride[89396-94-1]Imidapril Hydrochloride, when dried, contains notless than 98.5% and not more than 101.0% ofC 20 H 27 N 3 O 6·HCl.Description Imidapril Hydrochloride occurs as a white crystals.It is freely soluble in methanol, soluble in water, and sparinglysoluble in ethanol (99.5).Dissolve 1.0 g of Imidapril Hydrochloride in 100 mL of water:the pH of the solution is about 2.Melting point: about 203ºC (with decomposition).Identification (1) To 3 mL of a solution of Imidapril Hydrochloride(1 in 50) add 5 drops of Reinecke salt TS: a light redprecipitate is formed.(2) Determine the infrared absorption spectrum of ImidaprilHydrochloride as directed in the potassium chloride disk methodunder Infrared Spectrophotometry , and compare thespectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) A solution of Imidapril Hydrochloride (1 in 50) respondsto the Qualitative Tests for chloride.Optical rotation [α] 20D: –65.0 - –69.0º (after drying,0.1 g, methanol, 10 mL, 100 mm).Purity (1) Heavy metals —Proceed with 2.0 g ofImidapril Hydrochloride according to Method 4, and performthe test. Prepare the control solution with 2.0 mL of StandardLead Solution (not more than 10 ppm).(2) Related substances—Dissolve 25 mg of Imidapril Hydrochloridein 50 mL of the mobile phase, and use this solutionas the test solution. Pipet 1 mL of this solution, add the mobilephase to make exactly 100 mL, and use this solution as thestandard solution. Perform the test with exactly 20 µL each ofthe sample solution and standard solution as directed under LiquidChromatography according to the following conditions.Determine each peak area of both solutions by the automaticintegration method: the area of the peak having the relativeretention time of about 0.45 with respect to imidapril, obtainedfrom the sample solution, is not larger than 2/5 times thepeak area of imidapril from the standard solution, and the areaof each peak other than the peaks of imidapril and other thanthose mentioned above from the sample solution is not largerthan 1/5 times the peak area of imidapril from the standard solution.Furthermore, the total area of the peaks other than imidaprilfrom the sample solution is not larger than 1/2 times thepeak area of imidapril from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:215 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 1.36 g of potassium dihydrogenphosphate in 1000 mL of water, and adjust the pH to 2.7 withphosphoric acid. To 600 mL of this solution add 400 mL ofmethanol.Flow rate: Adjust the flow rate so that the retention time ofimidapril is about 8 minutes.Time span of measurement: About 2 times as long as the retentiontime of imidapril, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 2 mL of the standard solution,and add the mobile phase to make exactly 20 mL. Confirmthat the peak area of imidapril obtained from 20 µL of thissolution is equivalent to 7 to 13% of that of imidapril from thestandard solution.System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of imidapril are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of imidaprilis not more than 2.0%.(3) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 3

Supplement II, JP XV Official Monographs 2141hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.4 g of Imidapril Hydrochloride,previously dried, dissolve in 70 mL of water, and titrate with 0.1 mol/L sodium hydroxide VS from the firstequivalent point to the second equivalent point (potentiometrictitration).Each mL of 0.1 mol/L sodium hydroxide VS= 44.19 mg of C 20 H 27 N 3 O 6·HClContainers and storage Containers—Well-closed containers.Add the following:Imidapril Hydrochloride Tabletsイミダプリル 塩 酸 塩 錠Imidapril Hydrochloride Tablets contain not lessthan 95.0% and not more than 105.0% of the labeledamount of Imidapril Hydrochloride (C 20 H 27 N 3 O 6·HCl:441.91).Method of preparation Prepare as directed under Tablets,with Imidapril Hydrochloride.Identification Weigh accurately an amount of powdered ImidaprilHydrochloride Tablets, equivalent to 25 mg of ImidaprilHydrochloride, add 5 mL of ethanol (99.5), shake well, filter,and use the filtrate as the sample solution. Separately, dissolve25 mg of imidapril hydrochloride in 5 mL of ethanol (99.5), anduse this solution as the standard solution. Perform the test withthese solutions as directed under Thin-layer Chromatography. Spot 10 µL each of the sample solution and standardsolution on a plate of silica gel with fluorescent indicator forthin-layer chromatography. Develop the plate with a mixture of1-butanol, ethyl acetate, water, ethanol (99.5) and acetic acid(100) (16:16:7:2:2) to a distance of about 13 cm, and air-dry theplate. Examine under ultraviolet light (main wavelength: 254nm): the principal spot obtained from the sample solution hasthe same R f value as the spot from the standard solution.Purity Related substances— To a quantity of powdered ImidaprilHydrochloride Tablets, equivalent to 25 mg of ImidaprilHydrochloride according to the labeled amount, add 40 mL ofdiluted methanol (2 in 5), shake vigorously for 10 minutes, adddiluted ethanol (2 in 5) to make 50 mL, and filter through amembrane filter with a pore size not exceeding 0.45 µm. Discardthe first 2 mL of the filtrate, and use the subsequent filtrateas the sample solution. Pipet 1 mL of this solution, add dilutedmethanol (2 in 5) to make exactly 100 mL, and use this solutionas the standard solution. Perform the test with exactly 20 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions. Determine each peak area of both solutions bythe automatic integration method: the area of the peak havingthe relative retention time of about 0.45 with respect to imidapril,obtained from the sample solution, is not larger than thepeak area of imidapril from the standard solution; the area of thepeak having the relative retention time of about 0.8 with respectto imidapril from the sample solution is not larger than 7/10times the peak area of imidapril from the standard solution; andthe area of each peak other than the peak of imidapril and otherthan those mentioned above from the sample solution is not largerthan 3/10 times the peak area of imidapril from the standardsolution. Furthermore, the total area of the peaks other than thepeak of imidapril from the sample solution is not larger than 1.5times the peak area of imidapril from the standard solution.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 2 times as long as the retentiontime of imidapril, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 2 mL of the standard solution,and add diluted methanol (2 in 5) to make exactly 20 mL.Confirm that the peak area of imidapril obtained from 20 µL ofthis solution is equivalent to 7 to 13% of that of imidapril fromthe standard solution.System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of imidapril are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of imidaprilis not more than 2.0%.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Imidapril Hydrochloride Tablets add 2V/5 mLof water, shake vigorously for 10 minutes, add diluted methanol(2 in 3) to make exactly V mL so that each mL contains about0.1 mg of imidapril hydrochloride (C 20 H 27 N 3 O 6·HCl), filterthrough a membrane filter with a pore size not exceeding 0.45µm. Discard the first 2 mL of the filtrate, and use the subsequentfiltrate as the sample solution. Separately, weigh accuratelyabout 10 mg of imidapril for assay, previously dried at 105ºCfor 3 hours, dissolve in diluted methanol (2 in 5) to make exactly100 mL, and use this solution as the standard solution.Perform the test with exactly 20 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and determine thepeak areas , A T and A S , of imidapril in each solution.Amount (mg) of imidapril hydrochloride (C 20 H 27 N 3 O 6·HCl)= W S × (A T /A S ) × (V/100)W S : Amount (mg) of imidapril hydrochloride for assayOperating conditions—

2142 Official Monographs Supplement II, JP XVProceed as directed in the operating conditions in the AssaySystem suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of imidapril are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of imidaprilis not more than 1.0%.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 45minutes of Imidapril Hydrochloride Tablets is not less than85%.Start the test with 1 tablet of Imidapril Hydrochloride Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard the first 10mL of the filtrate, pipet V mL of the subsequent filtrate, add waterto make exactly V´ mL so that each mL contains about 2.8 µgof imidapril hydrochloride (C 20 H 27 N 3 O 6·HCl) according to thelabeled amount, and use this solution as the sample solution.Separately, weigh accurately about 28 mg of imidapril hydrochloridefor assay, previously dried at 105ºC for 3 hours, anddissolve in water to make exactly 100 mL. Pipet 2 mL of thissolution, add water to make exactly 200 mL, and use this solutionas the standard solution. Perform the test with exactly 50 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and determine the peak areas, A T and A S , of imidaprilin each solution.Dissolution rate (%) with respect to the labeled amount ofimidapril hydrochloride (C 20 H 27 N 3 O 6·HCl)= W S × (A T /A S ) × (V´/V) × (1/C) × 9W S : Amount (mg) of imidapril hydrochloride for assayC: Labeled amount (mg) of imidapril hydrochloride(C 20 H 27 N 3 O 6·HCl) in 1 tabletOperating conditions—Proceed as directed in the operating conditions in the Assay.System suitability—System performance: When the procedure is run with 50 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of imidapril are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with50 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of imidaprilis not more than 2.0%.(C 20 H 27 N 3 O 6·HCl), add 30 mL of diluted methanol (2 in 5) andexactly 5 mL of the internal standard solution, shake vigorouslyfor 10 minutes, add diluted methanol (2 in 5) to make 50 mL,and filter through a membrane filter with a pore size not exceeding0.45 µm. Discard the first 2 mL of the filtrate, pipet 5mL of the subsequent filtrate, add diluted methanol (2 in 5) tomake 20 mL, and use this solution as the sample solution.Separately, weigh accurately about 20 mg of imidapril hydrochloridefor assay, previously dried at 105ºC for 3 hours, dissolvein 5 mL of the internal standard solution, add dilutedmethanol (2 in 5) to make 50 mL. Pipet 5 mL of this solution,add diluted methanol (2 in 5) to make 20 mL, and use this solutionas the standard solution. Perform the test with 20 µL each ofthe sample solution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area ofimidapril to that of the internal standard.Amount (mg) of imidapril hydrochloride (C 20 H 27 N 3 O 6·HCl)= W S × (Q T /Q S )W S : Amount (mg) of imidapril hydrochloride for assayInternal standard solution—A solution of ethyl parahydroxybenzoatein diluted methanol (2 in 5) (1 in 500)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:215 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 1.36 g of potassium dihydrogenphosphate in 1000 mL of water, and adjust the pH to 2.7 withphosphoric acid. To 600 mL of this solution add 400 mL ofmethanol.Flow rate: Adjust the flow rate so that the retention time ofimidapril is about 8 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,imidapril and the internal standard are eluted in this order withthe resolution between these peaks being not less than 4.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof imidapril to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Assay Weigh accurately not less than 20 Imidapril HydrochlorideTablets, and powder. Weigh accurately a portion of thepowder, equivalent to about 20 mg of imidapril hydrochloride

Supplement II, JP XV Official Monographs 2143Add the following:IndapamideインダパミドC 16 H 16 ClN 3 O 3 S: 365.834-Chloro-N-[(2RS)-2-methyl-2,3-dihydro-1H-indol-1-yl]-3-sulfamoylbenzamide [26807-65-8]Indapamide contains not less than 98.5% and notmore than 101.5% of C 16 H 16 ClN 3 O 3 S, calculated onthe dried basis.Description Indapamide occurs as a white crystalline powder.It is freely soluble in ethanol (99.5), and practically insolublein water.A solution of Indapamide in ethanol (99.5) (1 in 10) shows nooptical rotation.Identification (1) Determine the absorption spectrum of asolution of Indapamide in ethanol (99.5) (1 in 100000) as directedunder Ultraviolet-visible Spectrophotometry , andcompare the spectrum with the Reference Spectrum or the spectrumof a solution of Indapamide Reference Standard preparedin the same manner as the sample solution: both spectra exhibitsimilar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Indapamideas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of IndapamideReference Standard: both spectra exhibit similar intensities ofabsorption at the same wave numbers.(3) Perform the test with Indapamide as directed underFlame Coloration Test (2): a green color appears.Melting point 167 - 171ºC.and enantiomerPurity (1) Chloride —To 1.5 g of Indapamide add 50mL of water, shake for 15 minutes, allow to stand in an ice bathfor 30 minutes, and filter. To 30 mL of the filtrate add 6 mL ofdilute nitric acid and water to make 50 mL. Perform the test usingthis solution as the test solution. Prepare the control solutionwith 0.25 mL of 0.01 mol/L hydrochloric acid VS (not morethan 0.01%).(2) Heavy metals —Proceed with 2.0 g of Indapamideaccording to Method 2, and perform the test. Prepare thecontrol solution with 2.0 mL of Standard Lead Solution (notmore than 10 ppm).(3) Related substances— Conduct this procedure usinglight-resistant vessels. Dissolve 0.10 g of Indapamide in 5 mL ofethanol (99.5), and use this solution as the sample solution. Pipet1 mL of this solution, add ethanol (99.5) to make exactly200 mL, and use this solution as the standard solution (1). Pipet5 mL of this solution, add ethanol (99.5) to make exactly 10 mL,and use this solution as the standard solution (2). Perform thetest with these solutions as directed under Thin-layer Chromatography. Spot 10 µL each of the sample solution, standardsolution (1) and standard solution (2) on a plate of silicagel with fluorescent indicator for thin-layer chromatography.Immediately develop the plate with a mixture of ethyl acetate,cyclohexane and acetic acid (100) (100:80:1) to a distance ofabout 10 cm, and air-dry the plate. Examine under ultravioletlight (main wavelength: 254 nm): the spots other than the principalspot obtained from the sample solution are not more intensethan the spot from the standard solution (1), and the totalamount of these related substances, calculated by comparisonwith the spots from the standard solutions (1) and (2), is notmore than 2.0%.(4) Residual solvent—Being specified separately.Loss on drying Not more than 3.0% (0.5 g, reducedpressure not exceeding 0.67 kPa, phosphorus (V) oxide, 110ºC,2 hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 20 mg each of Indapamide andIndapamide Reference Standard (separately, determine the losson drying in the same manner as Indapamide), and dissolveeach in a mixture of water and ethanol (99.5) (1:1) tomake exactly 100 mL. Pipet 10 mL each of these solutions, addexactly 2 mL of the internal standard solution and a mixture ofwater and ethanol (99.5) (1:1) to make 20 mL, and use thesesolutions as the sample solution and standard solution, respectively.Perform the test with 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of indapamide to that of theinternal standard.Amount (mg) of indapamide (C 16 H 16 ClN 3 O 3 S)= W S × (Q T /Q S )W S : Amount (mg) of Indapamide Reference Standard, calculatedon the dried basisInternal standard solution—A solution of isopropyl parahydroxybenzoatein a mixture of water and ethanol (99.5) (1:1) (3in 1000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:287 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of diluted phosphoric acid (1 in1000), acetonitrile and methanol (6:3:1).Flow rate: Adjust the flow rate so that the retention time of

2144 Official Monographs Supplement II, JP XVindapamide is about 6 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,indapamide and the internal standard are eluted in this orderwith the resolution between these peaks being not less than 4.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of indapamideis not more than 1.0%.Containers and storage Containers—Tight containers.Storage—Light-resistant.Add the following:Indapamide Tabletsインダパミド 錠Indapamide Tablets contain not less than 93.0% andnot more than 103.0% of the labeled amount of indapamide(C 16 H 16 ClN 3 O 3 S: 365.83).Method of preparation Prepare as directed under Tablets,with Indapamide.Identification To an amount of powdered Indapamide Tablets,equivalent to 10 mg of Indapamide according to the labeledamount, add 5 mL of ethyl acetate, shake for 10 minutes, centrifuge,and use the supernatant liquid as the sample solution.Separately, dissolve 10 mg of Indapamide Reference Standard in5 mL of ethyl acetate, and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 10 µL each of thesample solution and standard solution on a plate of silica gelwith fluorescent indicator for thin-layer chromatography. Developthe plate with a mixture of ethyl acetate, cyclohexane andacetic acid (100) (100:80:1) to a distance of about 10 cm, andair-dry the plate. Examine under ultraviolet light (main wavelength:254 nm): the spots from the sample solution and thestandard solution show a blue-purple color and have the same R fvalue.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Indapamide Tablets add exactly V/10 mL of theinternal standard solution, and add a mixture of water and ethanol(99.5) (1:1) to make V mL so that each mL contains about0.1 mg of indapamide (C 16 H 16 ClN 3 O 3 S), shake to disintegrate,treat with ultrasonic waves for 10 minutes, shake again for 10minutes, centrifuge, and use the supernatant liquid as the samplesolution. Proceed as directed in the Assay.Amount (mg) of indapamide (C 16 H 16 ClN 3 O 3 S)= W S × (Q T /Q S ) × (V/200)W S : Amount (mg) of Indapamide Reference Standard, calculatedon the dried basisInternal standard solution—A solution of isopropyl parahydroxybenzoatein a mixture of water and ethanol (99.5) (1:1) (3in 1000)Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rates in 45minutes of 1-mg tablets and in 90 minutes of 2-mg tablets arenot less than 70%, respectively.Start the test with 1 tablet of Indapamide Tablets, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to makeexactly V´ mL so that each mL contains about 1.1 µg of indapamide(C 16 H 16 ClN 3 O 3 S) according to the labeled amount, and usethis solution as the sample solution. Separately, weigh accuratelyabout 20 mg of Indapamide Reference Standard (separately,determine the loss on drying in the same manneras Indapamide), and dissolve in ethanol (99.5) to make exactly50 mL. Pipet 5 mL of this solution, and add water to make exactly100 mL. Pipet 5 mL of this solution, add water to makeexactly 100 mL, and use this solution as the standard solution.Perform the test with exactly 50 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and determine thepeak areas , A T and A S , of indapamide in each solution.Dissolution rate (%) with respect to the labeled amount ofindapamide (C 16 H 16 ClN 3 O 3 S)= W S × (A T /A S ) × (V´/V) × (1/C) × (9/2)W S : Amount (mg) of Indapamide Reference Standard, calculatedon the dried basisC: Labeled amount (mg) of indapamide (C 16 H 16 ClN 3 O 3 S) in 1tabletOperating conditions—Proceed as directed in the operating conditions in the Assayunder Indapamide.System suitability—System performance: When the procedure is run with 50 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of indapamide are not less than 3500 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with50 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of indapamideis not more than 1.5%.Assay To 20 Indapamide Tablets add 80 mL of a mixture ofwater and ethanol (99.5) (1:1), shake well to disintegrate, andtreat with ultrasonic waves for 10 minutes. Shake the solutionfor 10 minutes, and add a mixture of water and ethanol (99.5)(1:1) to make exactly 100 mL. Pipet a volume of indapamide

Supplement II, JP XV Official Monographs 2145(C 16 H 16 ClN 3 O 3 S), equivalent to about 2 mg, and add exactly 2mL of the internal standard solution and a mixture of water andethanol (99.5) (1:1) to make exactly 20 mL. Centrifuge this solution,and use the supernatant liquid as the sample solution.Separately, weigh accurately about 20 mg of Indapamide ReferenceStandard (separately, determine the loss on drying in the same manner as Indapamide), and dissolve in amixture of water and ethanol (99.5) (1:1) to make 100 mL. Pipet10 mL of this solution, add exactly 2 mL of the internal standardsolution and a mixture of water and ethanol (99.5) (1:1) to make20 mL, and use this solution as the standard solution. Proceed asdirected in the Assay under Indapamide.Amount (mg) of indapamide (C 16 H 16 ClN 3 O 3 S)= W S × (Q T /Q S ) × (1/10)W S : Amount [mg (potency)] of Indapamide Reference Standard,calculated on the dried basisInternal standard solution—A solution of isopropyl parahydroxybenzoatein a mixture of water and ethanol (99.5) (1:1) (3in 1000)Containers and storage Containers—Tight containers.equivalent to about 2 mg of indometacin (C 19 H 16 ClNO 4 ), add amixture of methanol and acetic acid (100) (200:1) to make exactly50 mL, and use this solution as the sample solution. Separately,weigh accurately about 0.1 g of Indometacin ReferenceStandard, previously dried at 105ºC for 4 hours, and dissolve ina mixture of methanol and acetic acid (100) (200:1) to makeexactly 100 mL. Pipet 4 mL of this solution, add a mixture ofmethanol and acetic acid (100) (200:1) to make exactly 100 mL,and use this solution as the standard solution. Perform the testwith the sample solution and standard solution as directed underUltraviolet-visible Spectrophotometry , and determinethe absorbances, A T and A S , at 320 nm.Amount (mg) of indometacin (C 19 H 16 ClNO 4 )= W S × (A T /A S ) × (2/V)W S : Amount (mg) of Indometacin Reference StandardAdd the following:IpriflavoneイプリフラボンIndigocarmine Injectionインジゴカルミン 注 射 液Add the following next to the Identification:Bacterial endotoxins Less than 7.5 EU/mg.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter Perform the test accordingto Method 2: it meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Indometacin Suppositoriesインドメタシン 坐 剤Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 suppository of Indometacin Suppositories add 80 mL ofa mixture of methanol and acetic acid (100) (200:1), dissolve bywarming, add a mixture of methanol and acetic acid (100)(200:1) to make exactly 100 mL. Pipet V mL of this solution,C 18 H 16 O 3 : 280.327-(1-Methylethyl)oxy-3-phenyl-4H-chromen-4-one[35212-22-7]Ipriflavone, when dried, contains not less than98.5% and not more than 101.0% of C 18 H 16 O 3 .Description Ipriflavone occurs as white to yellowish whitecrystals or crystalline powder.It is soluble in acetonitrile, sparingly soluble in methanol andin ethanol (99.5), and practically insoluble in water.It gradually turns yellow on exposure to light.Identification (1) Determine the absorption spectrum of asolution of Ipriflavone in methanol (1 in 200000) as directedunder Ultraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrumof a solution of Ipriflavone Reference Standard prepared in thesame manner as the sample solution: both spectra exhibit similarintensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Ipriflavoneas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of IpriflavoneReference Standard: both spectra exhibit similar intensities ofabsorption at the same wave numbers.Melting point 116 - 119ºC.Purity (1) Heavy metals —Proceed with 1.0 g of

2146 Official Monographs Supplement II, JP XVIpriflavone according to Method 2, and perform the test. Preparethe control solution with 1.0 mL of Standard Lead Solution (notmore than 10 ppm).(2) Arsenic —Prepare the test solution with 1.0 g ofIpriflavone according to Method 4, and perform the test. Preparethe test solution with 10 mL of dilute hydrochloric acid insteadof using 3 mL of hydrochloric acid. Prepare the standard colorwith 1.0 mL of Standard Arsenic Solution (not more than 1ppm).(3) Related substances—Dissolve 30 mg of Ipriflavone in50 mL of acetonitrile. To 5 mL of this solution add acetonitrileto make 50 mL, and use this solution as the sample solution.Pipet 1 mL of this solution, add acetonitrile to make exactly 100mL, and use this solution as the standard solution. Perform thetest with exactly 20 µL each of the sample solution and standardsolution as directed under Liquid Chromatography accordingto the following conditions. Determine each peak areaof both solutions by the automatic integration method: the areaof each peak other than the peak of ipriflavone obtained fromthe sample solution is not larger than 1/2 times the peak area ofipriflavone from the standard solution, and the total area of thepeaks other than the peak of ipriflavone obtained from the samplesolution is not larger than the peak area of ipriflavone fromthe standard solution.Operating conditions—Detector, column, column temperature and flow rate: Proceedas directed in the operating conditions in the Assay.Time span of measurement: About 2 times as long as the retentiontime of ipriflavone, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 2 mL of the standard solution,and add acetonitrile to make exactly 20 mL. Confirm thatthe peak area of ipriflavone obtained from 20 µL of this solutionis equivalent to 7 to 13% of that of ipriflavone from the standardsolution.System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of ipriflavone are not less than 2000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ipriflavone to that of the internal standard is not more than2.0%.(4) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 2hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 30 mg each of Ipriflavone andIpriflavone Reference Standard, previously dried, dissolveseparately in acetonitrile to make exactly 50 mL. Pipet 5 mLeach of these solutions, add exactly 5 mL of the internal standardsolution and acetonitrile to make 50 mL, and use these solutionsas the sample solution and standard solution, respectively.Perform the test with 20 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of ipriflavone to that of theinternal standard.Amount (mg) of ipriflavone (C 18 H 16 O 3 )= W S × (Q T /Q S )W S : Amount (mg) of Ipriflavone Reference StandardInternal standard solution—A solution of di-n-butyl phthalate inacetonitrile (1 in 100)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:280 nm)Column: A stainless steel column 4 mm in inside diameterand 15 cm in length, packed with octylsilanized silica gel forliquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of acetonitrile and water (3:2)Flow rate: Adjust the flow rate so that the retention time ofipriflavone is about 6 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,ipriflavone and the internal standard are eluted in this order withthe resolution between these peaks being not less than 3.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ipriflavone to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Storage—Light-resistant.Add the following:Ipriflavone Tabletsイプリフラボン 錠Ipriflavone Tablets contain not less than 95.0% andnot more than 105.0% of the labeled amount of ipriflavone(C 18 H 16 O 3 : 280.32).Method of preparation Prepare as directed under Tablets,with Ipriflavone.Identification To a quantity of powdered Ipriflavone Tablets,equivalent to 11 mg of Ipriflavone according to the labeledamount, add 100 mL of methanol, shake vigorously for 10 minutes,and centrifuge. To 5 mL of the supernatant liquid addmethanol to make 100 mL. Determine the absorption spectrumof this solution as directed under Ultraviolet-visible Spectrophotometry: it exhibits maxima between 247 nm and251 nm, and between 297 nm and 301 nm.

Supplement II, JP XV Official Monographs 2147Uniformity of dosage units It meets the requirementof the Mass variation test.Dissolution Being specified separately.Assay Weigh accurately the mass of not less than 20 IpriflavoneTablets, and powder. Weigh accurately a portion of thepowder, equivalent to about 30 mg of ipriflavone (C 18 H 16 O 3 ),add 30 mL of acetonitrile, shake vigorously for 15 minutes, addacetonitrile to make exactly 50 mL, and centrifuge. Pipet 5 mLof the supernatant liquid, add exactly 5 mL of the internal standardsolution. add acetonitrile to make 50 mL, and use this solutionas the sample solution. Separately, weigh accurately about30 mg of Ipriflavone Reference Standard, previously dried at105ºC for 2 hours, and dissolve in acetonitrile to make exactly50 mL. Pipet 5 mL of this solution, add exactly 5 mL of the internalstandard solution and acetonitrile to make 50 mL, and usethis solution as the standard solution. Proceed as directed in theAssay under Ipriflavone.Amount (mg) of ipriflavone (C 18 H 16 O 3 )= W S × (Q T /Q S )W S : Amount (mg) of Ipriflavone Reference StandardInternal standard solution—A solution of di-n-butyl phthalate inacetonitrile (1 in 100)Containers and storage Containers—Tight containers.Storage—Light-resistant.Add the following:Irsogladine Maleateイルソグラジンマレイン 酸 塩C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 : 372.166-(2,5-Dichlorophenyl)-1,3,5-triazine-2,4-diaminemonomaleate [84504-69-8]Irsogladine Maleate, when dried, contains not lessthan 99.0% and not more than 101.0% ofC 9 H 7 Cl 2 N 5·C 4 H 4 O 4 .Description Irsogladine Maleate occurs as white crystals orcrystalline powder. It has a slightly bitter taste.It is sparingly soluble in acetic acid (100) and in ethyleneglycol,slightly soluble in methanol and in ethanol (99.5), andpractically insoluble in water.Identification (1) Dissolve 20 mg of Irsogladine Maleate inmethanol to make 20 mL. Take 2 mL of this solution, and addwater to make 20 mL. To 2 mL of this solution add water tomake 50 mL. Determine the absorption spectrum of this solutionas directed under Ultraviolet-visible Spectrophotometry ,and compare the spectrum with the Reference Spectrum: bothspectra exhibit similar intensities of absorption at the samewavelengths.(2) Determine the infrared absorption spectrum of IrsogladineMaleate as directed in the potassium bromide diskmethod under Infrared Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) Dissolve 10 mg of Irsogladine Maleate in 1 mL of dilutehydrochloric acid and 4 mL of water, and add 3 drops of potassiumpermanganate TS: the color of the solution is dischargedimmediately.Purity (1) Heavy metals —Proceed with 2.0 g of IrsogladineMaleate according to Method 4, and perform the test.Prepare the control solution with 2.0 mL of Standard Lead Solution(not more than 10 ppm).(2) Related substances—Dissolve 50 mg of IrsogladineMaleate in 10 mL of ethyleneglycol, and use this solution as thesample solution. Pipet 1 mL of this solution, add ethyleneglycolto make exactly 100 mL, and use this solution as the standardsolution. Perform the test with exactly 5 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area of both solutions by the automatic integrationmethod: the area of each peak other than the peaks ofmaleic acid and irsogladine obtained from the sample solution isnot larger than 1/10 times the peak area of irsogladine from thestandard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:250 nm).Column: A stainless steel column 4.6 mm in inside diameterand 7.5 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of methanesulfonic acid solution (1in 1000) and methanol (4:1)Flow rate: Adjust the flow rate so that the retention time ofirsogladine is about 8 minutes.Time span of measurement: About 3 times as long as the retentiontime of irsogladine, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 1 mL ofthe standard solution, and add ethyleneglycol to make exactly10 mL. Confirm that the peak area of irsogladine obtained from5 µL of this solution is equivalent to 7 to 13% of that of irsogladinefrom the standard solution.System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions, thenumber of theoretical plates and the symmetry factor of the peakof irsogladine are not less than 3000 and not more than 1.5, respectively.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of irsogladine is

2148 Official Monographs Supplement II, JP XVnot more than 2.0%.(3) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 4hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.3 g of Irsogladine Maleate,previously dried, dissolve in 25 mL of acetic acid (100), add 25mL of acetic anhydride, and titrate with 0.05 mol/L perchloricacid VS (potentiometric titration). Perform a blank determinationin the same manner, and make any necessary correction.Each mL of 0.05 mol/L perchloric acid VS= 18.61 mg of C 9 H 7 Cl 2 N 5·C 4 H 4 O 4Containers and storage Containers—Well-closed containers.Add the following:Irsogladine Maleate Fine Granulesイルソグラジンマレイン 酸 塩 細 粒Irsogladine Maleate Fine Granules contain not lessthan 93.0% and not more than 107.0% of irsogladinemaleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 : 372.16).Method of preparation Prepare fine granules as directed underPowders, with Irsogladine Maleate.Identification To a quantity of powdered Irsogladine MaleateFine Granules, equivalent to 2 mg of Irsogladine Maleate accordingto the labeled amount, add 5 mL of methanol, shake for10 minutes, centrifuge, and use the supernatant liquid as thesample solution. Separately, dissolve 2 mg of irsogladinemaleate in 5 mL of methanol, and use this solution as the standardsolution. Perform the test with these solutions as directedunder Thin-layer Chromatography . Spot 10 µL each ofthe sample solution and standard solution on a plate of silica gelwith fluorescent indicator for thin-layer chromatography. Developthe plate with a mixture of petroleum ether, acetone andacetic acid (100) (12:4:1) to a distance of about 10 cm, andair-dry the plate. Examine under ultraviolet light (main wavelength:254 nm): the spot from the sample solution has the sameR f value as the spot from the standard solution.Uniformity of dosage units Perform the test accordingto the following method: Irsogladine Maleate Fine Granulesin single-unit containers meet the requirement of the Contentuniformity test.Take out the total contents of 1 pack of Irsogladine MaleateFine Granules, add 2 mL of water, add 2 mL methanol per mg ofirsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ), treat with ultrasonicwaves for 10 minutes with occasional shaking, and add water tomake exactly V mL so that each mL contains about 40 µg of irsogladinemaleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ). Centrifuge this solution,pipet 1 mL of the supernatant liquid, and add water to make exactly20 mL. Filter this solution through a membrane filter witha pore size not exceeding 0.5 µm, discard the first 10 mL of thefiltrate, and use the subsequent filtrate as the sample solution.Separately, weigh accurately about 20 mg of irsogladine maleatefor assay, previously dried at 105ºC for 4 hours, dissolve inmethanol to make exactly 20 mL. Pipet 2 mL of this solution,add water to make exactly 20 mL. Pipet 2 mL of this solution,add water to make exactly 100 mL, and use this solution as thestandard solution. Perform the test with the sample solution andstandard solution as directed under Ultraviolet-visible Spectrophotometry, using water as the blank, and determine theabsorbances, A T and A S , at 210 nm.Amount (mg) of irsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 )= W S × (A T /A S ) × (V/500)W S : Amount (mg) of irsogladine maleate for assayDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Irsogladine Maleate Fine Granules is not less than70%.Start the test with an accurately weighed amount of IrsogladineMaleate Fine Granules, equivalent to about 4 mg of irsogladinemaleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ), withdraw not less than 20mL of the medium at the specified minute after starting the test,and filter through a membrane filter with a pore size not exceeding0.5 µm. Discard the first 10 mL of the filtrate, and usethe subsequent filtrate as the sample solution. Separately, weighaccurately about 40 mg of irsogladine maleate for assay, previouslydried at 105ºC for 4 hours, and dissolve in methanol tomake exactly 20 mL. Pipet 2 mL of this solution, and add waterto make exactly 20 mL. Pipet 2 mL of this solution, add water tomake exactly 100 mL, and use this solution as the standard solution.Perform the test with the sample solution and standardsolution as directed under Ultraviolet-visible Spectrophotometry, using water as the blank, and determine the absorbances,A T and A S , at 210 nm.Dissolution rate (%) with respect to the labeled amount ofirsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 )= (W S /W T ) × (A T /A S ) × (1/C) × 9W S : Amount (mg) of irsogladine maleate for assayW T : Amount (g) of Irsogladine Maleate Fine GranulesC: Labeled amount (mg) of irsogladine maleate(C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ) in 1 gParticle size It meets the requirement.Assay Weigh accurately an amount of powdered IrsogladineMaleate Fine Granules, equivalent to about 5 mg of irsogladinemaleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ), add exactly 5 mL of the internalstandard solution, shake until it is dispersed, and add 5 mL ofwater. To the solution add 25 mL of ethyleneglycol, treat withultrasonic waves for 10 minutes with occasional shaking, andadd ethyleneglycol to make 50 mL. Filter this solution through a

Supplement II, JP XV Official Monographs 2149membrane filter with a pore size not exceeding 0.5 µm, discardthe first 10 mL of the filtrate, and use the subsequent filtrate asthe sample solution. Separately, weigh accurately about 25 mgof irsogladine maleate for assay, previously dried at 105ºC for 4hours, and dissolve in ethyleneglycol to make exactly 25 mL.Pipet 5 mL of this solution, add exactly 5 mL of the internalstandard solution, add 5 mL of water and ethyleneglycol tomake 50 mL, and use this solution as the standard solution.Perform the test with 5 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of irsogladine to that of theinternal standard.Amount (mg) of irsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 )= W S × (Q T /Q S ) × (1/5)W S : Amount (mg) of irsogladine maleate for assayInternal standard solution—A solution of ethyl parahydroxybenzoatein methanol (1 in 2500)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:250 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of water, acetonitrile and acetic acid(100) (750:250:3)Flow rate: Adjust the flow rate so that the retention time ofirsogladine is about 9 minutes.System suitability—System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions, irsogladineand the internal standard are eluted in this order withthe resolution between these peaks being not less than 10.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofirsogladine to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Add the following:Irsogladine Maleate Tabletsイルソグラジンマレイン 酸 塩 錠Irsogladine Maleate Tablets contain not less than93.0% and not more than 107.0% of the labeledamount of irsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 :372.16).Method of preparation Prepare as directed under Tablets,with Irsogladine Maleate.Identification To a quantity of powdered Irsogladine MaleateTablets, equivalent 2 mg of Irsogladine Maleate according to thelabeled amount, add 5 mL of methanol, shake for 10 minutes,centrifuge, and use the supernatant liquid as the sample solution.Separately, dissolve 2 mg of irsogladine maleate in 5 mL ofmethanol, and use this solution as the standard solution. Performthe test with these solutions as directed under Thin-layer Chromatography. Spot 10 µL each of the sample solution andstandard solution on a plate of silica gel with fluorescent indicatorfor thin-layer chromatography. Develop the plate with amixture of petroleum ether, acetone and acetic acid (100)(12:4:1) to a distance of about 10 cm, and air-dry the plate.Examine under ultraviolet light (main wavelength: 254 nm): thespot from the sample solution has the same R f value as the spotfrom the standard solution.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Irsogladine Maleate Tablets add 2 mL of water,add 2 mL of methanol per mg of irsogladine maleate(C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ), treat with ultrasonic waves for 10 minuteswith occasional shaking, add water to make exactly V mL sothat each mL contains about 40 µg of irsogladine maleate(C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ). Centrifuge this solution, pipet 1 mL of thesupernatant liquid, and add water to make exactly 20 mL. Filterthis solution through a membrane filter with a pore size not exceeding0.5 µm, discard the first 10 mL of the filtrate, and usethe subsequent filtrate as the sample solution. Separately, weighaccurately about 20 mg of irsogladine maleate for assay, previouslydried at 105ºC for 4 hours, and dissolve in methanol tomake exactly 20 mL. Pipet 2 mL of this solution, and add waterto make exactly 20 mL. Pipet 2 mL of this solution, add water tomake exactly 100 mL, and use this solution as the standard solution.Perform the test with the sample solution and standardsolution as directed under Ultraviolet-visible Spectrophotometry, using water as the blank, and determine the absorbances,A T and A S , at 210 nm.Amount (mg) of irsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 )= W S × (A T /A S ) × (V/500)W S : Amount (mg) of irsogladine maleate for assayDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Irsogladine Maleate Tablets is not less than 80%.Start the test with 1 tablet of Irsogladine Maleate Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.5 µm. Discard the first 10mL of the filtrate, pipet V mL of the subsequent filtrate, add waterto make exactly V´ mL so that each mL contains about 2.2 µgof irsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ) according to thelabeled amount, and use this solution as the sample solution.Separately, weigh accurately about 20 mg of irsogladine maleatefor assay, previously dried at 105ºC for 4 hours, and dissolve in

2150 Official Monographs Supplement II, JP XVmethanol to make exactly 20 mL. Pipet 2 mL of this solution,and add water to make exactly 20 mL. Pipet 2 mL of this solution,add water to make exactly 100 mL, and use this solution asthe standard solution. Perform the test with the sample solutionand standard solution as directed under Ultraviolet-visible Spectrophotometry, using water as the blank, and determinethe absorbances, A T and A S , at 210 nm.Dissolution rate (%) with respect to the labeled amount ofirsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 )= W S × (A T /A S ) × (V´/V) × (1/C) × 9W S : Amount (mg) of irsogladine maleate for assayC: Labeled amount (mg) of irsogladine maleate(C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ) in 1 tabletAssay Weigh accurately the mass of not less than 20 IrsogladineMaleate Tablets, and powder. Weigh accurately a portionof the powder, equivalent to about 5 mg of irsogladinemaleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 ), add exactly 5 mL of the internalstandard solution, shake until it is dispersed, and add 5 mL ofwater. To this solution add 25 mL of ethyleneglycol, treat withultrasonic waves for 10 minutes with occasional shaking, andadd ethyleneglycol to make 50 mL. Filter this solution through amembrane filter with a pore size not exceeding 0.5 µm, discardthe first 10 mL of the filtrate, and use the subsequent filtrate asthe sample solution. Separately, weigh accurately about 25 mgof irsogladine maleate for assay, previously dried at 105ºC for 4hours, and dissolve in ethyleneglycol to make exactly 25 mL.Pipet 5 mL of this solution, add exactly 5 mL of the internalstandard solution, add 5 mL of water and ethyleneglycol tomake 50 mL, and use this solution as the standard solution.Perform the test with 5 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of irsogladine to that of theinternal standard.Amount (mg) of irsogladine maleate (C 9 H 7 Cl 2 N 5·C 4 H 4 O 4 )= W S × (Q T /Q S ) × (1/5)W S : Amount (mg) of irsogladine maleate for assayInternal standard solution—A solution of ethyl parahydroxybenzoatein methanol (1 in 2500)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:250 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of water, acetonitrile and acetic acid(100) (750:250:3)Flow rate: Adjust the flow rate so that the retention time ofirsogladine is about 9 minutes.System suitability—System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions, irsogladineand the internal standard are eluted in this order withthe resolution between these peaks being not less than 10.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofirsogladine to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Add the following:Isepamicin Sulfate Injectionイセパマイシン 硫 酸 塩 注 射 液Isepamicin Sulfate Injection is an aqueous injection.It contains not less than 90.0% and not more than110.0% of the labeled potency of isepamicin(C 22 H 43 N 5 O 12 : 569.60).Method of preparation Prepare as directed under Injections,with Isepamicin Sulfate.Description Isepamicin Sulfate Injection is a clear, colorlessliquid.Identification To a volume of Isepamicin Sulfate Injection,equivalent to 20 mg (potency) of Isepamicin Sulfate accordingto the labeled amount, add water to make 10 mL, and use thissolution as the sample solution. Separately, dissolve an amountof Isepamicin Sulfate Reference Standard, equivalent to 20 mg(potency) in 10 mL of water, and use this solution as the standardsolution. Proceed with these solutions as directed in theIdentification (2) under Isepamicin Sulfate.Osmotic pressure ratio Being specified separately.pH 5.5 - 7.5Purity Related substances—Perform the test with 5 µL of thesample solution obtained in the Assay as directed under LiquidChromatography according to the following conditions.Determine each peak area of the sample solution by the automaticintegration method and calculate the amounts of thesepeaks by the area percentage method: the amount of isoserine,having the relative retention time of about 0.3 with respect toisepamicin, is not more than 2.0%, and the amount of gentamicinB, having the relative retention time of about 1.3 withrespect to isepamicin, is not more than 4.0%. For this calculation,use the peak area of gentamicin B after multiplying by therelative response factor, 1.11.Operating conditions—Apparatus, detector, column, column temperature, reactioncoil, mobile phase, reaction reagent, reaction temperature, flowrate of the mobile phase, and flow rate of the reaction reagent:Proceed as directed in the operating conditions in the Assay underIsepamicin Sulfate.Time span of measurement: About 2 times as long as the re-

Supplement II, JP XV Official Monographs 2151tention time of isepamicin.System suitability—System performance and system repeatability: Proceed as directedin the Assay under Isepamicin Sulfate.Test for required detectability: To 1 mL of the sample solutionadd water to make 10 mL, and use this solution as the solutionfor system suitability test. Pipet 1 mL of the solution for systemsuitability test, and add water to make exactly 10 mL. Confirmthat the peak area of isepamicin obtained from 5 µL of this solutionis equivalent to 7 to 13% of that of isepamicin from the solutionfor system suitability test.Bacterial endotoxins Less than 0.50 EU/mg (potency).Extractable volume It meets the requirement.Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay Pipet a volume of Isepamicin Sulfate Injection, equivalentto about 0.2 g (potency) of Isepamicin Sulfate, add water tomake exactly 100 mL. Pipet 10 mL of this solution, add water tomake exactly 100 mL, and use this solution as the sample solution.Separately, weigh accurately an amount of Isepamicin SulfateReference Standard, equivalent to about 20 mg (potency),dissolve in water to make exactly 100 mL, and use this solutionas the standard solution. Proceed as directed in the Assay underIsepamicin Sulfate.Amount [mg (potency)] of isepamicin (C 22 H 43 N 5 O 12 )= W S × (A T /A S ) × 10W S : Amount [mg (potency)] of Isepamicin Sulfate ReferenceStandardContainers and storage Containers—Hermetic containers.Expiration date 24 months after preparation.Isoniazid Injectionイソニアジド 注 射 液Add the following next to the Identification:Bacterial endotoxins Less than 0.50 EU/mg.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Isoniazid Tabletsイソニアジド 錠Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Isoniazid Tablets add exactly V mL of water sothat each mL, contains about 0.5 mg of isoniazid (C 6 H 7 N 3 O),and shake well to disintegrate. Filter this solution, discard thefirst 10 mL of the filtrate, pipet 5 mL of the subsequent filtrate,add the mobile phase to make exactly 50 mL, and use this solutionas the sample solution. Proceed as directed in the Assay.Amount (mg) of isoniazid (C 6 H 7 N 3 O)= W S × (A T /A S ) × (V/100)W S : Amount (mg) of isoniazid for assayIsosorbide Dinitrate Tablets硝 酸 イソソルビド 錠Change the Origin/limits of content to read:Isosorbide Dinitrate Tablets contain not less than93.0% and not more than 107.0% of the labeledamount of isosorbide dinitrate (C 6 H 8 N 2 O 8 : 236.14).Add the following next to the Purity:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Isosorbide Dinitrate Tablets add 1 mL of water,and shake to disintegrate. To this solution add a mixture of waterand methanol (1:1) to make exactly V mL so that each mLcontains about 0.1 mg of isosorbide dinitrate (C 6 H 8 N 2 O 8 ), andshake for 10 minutes. Centrifuge this solution, and use the supernatantliquid as the sample solution. Proceed as directed inthe Assay.Amount (mg) of isosorbide dinitrate (C 6 H 8 N 2 O 8 )= W S × (A T /A S ) × V × (1/500)W S : Amount (mg) of isosorbide dinitrate for assay, calculatedon the anhydrous basis

2152 Official Monographs Supplement II, JP XVChange the Assay to read:Assay Weigh accurately the mass of not less than 20 tablets ofIsosorbide Dinitrate Tablets, and powder. Weigh accurately aportion of the powder, equivalent to about 5 mg of isosorbidedinitrate tablets (C 6 H 8 N 2 O 8 ), add a mixture of water andmethanol (1:1) to make exactly 50 mL, and shake for 10 minutes.Centrifuge this solution, and use the supernatant liquid asthe sample solution. Separately, weigh accurately about 50 mgof isosorbide dinitrate for assay (separately, determine the watercontent in the same manner as Isosorbide Dinitrate),dissolve in a mixture of water and methanol (1:1) to make exactly100 mL. Pipet 10 mL of this solution, add a mixture ofwater and methanol (1:1) to make exactly 50 mL, and use thissolution as the standard solution. Perform the test with exactly10 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions, and determine the peak areas, A T and A S ,of isosorbide dinitrate in each solution.Amount (mg) of isosorbide dinitrate (C 6 H 8 N 2 O 8 )= W S × (A T /A S ) × (1/10)W S : Amount (mg) of isosorbide dinitrate for assay, calculatedon the anhydrous basisOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:220 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of water and methanol (11:9)Flow rate: Adjust the flow rate so that the retention time ofisosorbide dinitrate is about 6 minutes.System suitability—System performance: When the procedure is run with10 µL ofthe standard solution under the above operating conditions, thenumber of theoretical plates and the symmetry factor of the peakof isosorbide dinitrate are not less than 3000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of isosorbidedinitrate is not more than 1.0%.Josamycin Tabletsジョサマイシン 錠Change the Disintegration to read:Disintegration Perform the test using the disk, itmeets the requirement.Add the following:KetoconazoleケトコナゾールC 26 H 28 Cl 2 N 4 O 4 :531.431-Acetyl-4-(4-{[(2RS,4SR)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine [65277-42-1]Ketoconazole, when dried, contains not less than99.0% and not more than 101.0% of C 26 H 28 Cl 2 N 4 O 4 .Description Ketoconazole occurs as a white to light yellowishwhite powder.It is soluble in methanol, sparingly soluble in ethanol (99.5),and practically insoluble in water.A solution of Ketoconazole in methanol (1 in 20) shows nooptical rotation.Identification (1) Determine the absorption spectrum of asolution of Ketoconazole in methanol (3 in 100000) as directedunder Ultraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Ketoconazoleas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similarintensities of absorption at the same wave numbers.(3) Perform the test with Ketoconazole as directed underFlame Coloration Test (2): a green color appears.Melting point 148 - 152ºC.and enantiomerPurity (1) Heavy metals —Proceed with 1.0 g ofKetoconazole according to Method 2, and perform the test. Preparethe control solution with 1.0 mL of Standard Lead Solution(not more than 10 ppm).(2) Related Substances Dissolve 0.10 g of Ketoconazolein 10 mL of methanol, and use this solution as the sample solution.Pipet 5 mL of this solution, and add methanol to make exactly100 mL. Pipet 1 mL of this solution, add methanol to makeexactly 10 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area of both solutions by the automatic integration method:

Supplement II, JP XV Official Monographs 2153the area of each peak other than the peak of ketoconazole obtainedfrom the sample solution is not larger than 2/5 times thepeak area of ketoconazole from the standard solution, and thetotal area of the peaks other than the peak of ketoconazole obtainedfrom the sample solution is not larger than the peak areaof ketoconazole from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:220 nm).Column: A stainless steel column 4.6 mm in inside diameterand 10 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase A: Acetonitrile for liquid chromatography.Mobile phase B: A solution of tetrabutylammonium hydrogensulfate(17 in 5000).Flowing of the mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 – 10 5 → 50 95 → 5010 – 15 50 50Flow rate: 2.0 mL per minute.Time span of measurement: Beginning after the solvent peakto 15 minutes after injection.System suitability—Test for required detectability: Pipet 2 mL of the standard solution,and add methanol to make exactly 20 mL. Confirm thatthe peak area of ketoconazole obtained from 10 µL of this solutionis equivalent to 7 to 13% of that of ketoconazole from thestandard solution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of ketoconazole are not less than 40000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of ketoconazoleis not more than 2.5%.(3) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 4hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.2 g of Ketoconazole, previouslydried, dissolve in 70 mL of a mixture of 2-butanone andacetic acid (100) (7:1), and titrate with 0.1 mol/L perchloricacid VS (potentiometric titration). Perform a blank determinationin the same manner, and make any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 26.57 mg of C 26 H 28 Cl 2 N 4 O 4Containers and storage Containers—Tight containers.Storage—Light-resistant.Add the following:Ketoconazole CreamケトコナゾールクリームKetoconazole Cream contains not less than 95.0%and not more than 105.0% of the labeled amount ofketoconazole (C 26 H 28 Cl 2 N 4 O 4 :531.43)Method of preparation Prepare as directed under Ointments,with Ketoconazole.Identification To a quantity of Ketoconazole Cream, equivalentto 0.1 g of Ketoconazole according to the labeled amount,add 20 mL of 2-propanol, shake for 20 minutes, centrifuge, anduse the supernatant liquid as the sample solution. Separately,dissolve 25 mg of ketoconazole in 5 mL of 2-propanol, and usethis solution as the standard solution. Perform the test with thesesolutions as directed under Thin-layer Chromatography .Spot 5 µL each of the sample solution and standard solution on aplate of silica gel with fluorescent indicator for thin-layer chromatography.Develop the plate with a mixture of ethyl acetate,hexane, methanol, water and ammonia solution (28)(40:40:25:2:1) to a distance of about 12 cm, and air-dry the plate.Examine under ultraviolet light (main wavelength: 254 nm): theprincipal spot obtained from the sample solution has the same R fvalue as the spot from the standard solution.Assay Weigh accurately an amount of Ketoconazole Cream,equivalent to about 25 mg of ketoconazole (C 26 H 28 Cl 2 N 4 O 4 ),dissolve in methanol to make exactly 100 mL. Pipet 10 mL ofthis solution, add exactly 4 mL of the internal standard solution,add methanol to make 50 mL, and use this solution as the samplesolution. Separately, weigh accurately about 25 mg of ketoconazolefor assay, previously dried at 105ºC for 4 hours, anddissolve in methanol to make exactly 50 mL. Pipet 5 mL of thissolution, add exactly 4 mL of the internal standard solution, addmethanol to make 50 mL, and use this solution as the standardsolution. Perform the test with 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of ketoconazole to that of theinternal standard.Amount (mg) of ketoconazole (C 26 H 28 Cl 2 N 4 O 4 )= W S × (Q T /Q S )W S : Amount (mg) of ketoconazole for assayInternal standard solution—A solution of xanthone in methanol(1 in 10000)Operating conditions—

2154 Official Monographs Supplement II, JP XVDetector: An ultraviolet absorption photometer (wavelength:230 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To ammonium acetate solution (1 in 200) addacetic acid (100) to adjust the pH to 5.0. To 250 mL of this solutionadd 750 mL of methanol.Flow rate: Adjust the flow rate so that the retention time ofketoconazole is about 8 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the internal standard and ketoconazole are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ketoconazole to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Add the following:Ketoconazole LotionケトコナゾールローションKetoconazole Lotion is an emulsion lotion.It contains not less than 93.0% and not more than107.0% of the labeled amount of ketoconazole(C 26 H 28 Cl 2 N 4 O 4 :531.43).Method of preparation Prepare as directed under Lotions,with Ketoconazole.Description Ketoconazole Lotion occurs as a white emulsion.Identification Shake well and take an amount of KetoconazoleLotion, equivalent to 0.1 g of Ketoconazole according tothe labeled amount, add 20 mL of 2-propanol, shake for 20 minutes,centrifuge, and use the supernatant liquid as the samplesolution. Separately, dissolve 25 mg of ketoconazole in 5 mL of2-propanol, and use this solution as the standard solution. Performthe test with these solutions as directed under Thin-layerChromatography . Spot 5 µL each of the sample solutionand standard solution on a plate of silica gel with fluorescent indicatorfor thin-layer chromatography. Develop the plate with amixture of ethyl acetate, hexane, methanol, water and ammoniasolution (28) (40:40:25:2:1) to a distance of about 12 cm, andair-dry the plate. Examine under ultraviolet light (main wavelength:254 nm): the principal spot obtained from the samplesolution has the same R f value as the spot from the standard solution.Assay Shake well and weigh accurately an amount of KetoconazoleLotion, equivalent to about 25 mg of ketoconazole(C 26 H 28 Cl 2 N 4 O 4 ), dissolve in methanol to make exactly 100 mL.Pipet 10 mL of this solution, add exactly 4 mL of the internalstandard solution, add methanol to make 50 mL, and use thissolution as the sample solution. Separately, weigh accuratelyabout 25 mg of ketoconazole for assay, previously dried at105ºC for 4 hours, dissolve in methanol to make exactly 50 mL.Pipet 5 mL of this solution, add exactly 4 mL of the internalstandard solution, add methanol to make 50 mL, and use thissolution as the standard solution. Perform the test with 10 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and calculate the ratios, Q T and Q S , of the peakarea of ketoconazole to that of the internal standard.Amount (mg) of ketoconazole (C 26 H 28 Cl 2 N 4 O 4 )= W S × (Q T /Q S )W S : Amount (mg) of ketoconazole for assayInternal standard solution—A solution of xanthone in methanol(1 in 10000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:230 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: To ammonium acetate solution (1 in 200) addacetic acid (100) to adjust the pH to 5.0. To 250 mL of this solutionadd 750 mL of methanol.Flow rate: Adjust the flow rate so that the retention time ofketoconazole is about 8 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the internal standard and ketoconazole are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ketoconazole to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.

Supplement II, JP XV Official Monographs 2155Add the following:Ketoconazole Solutionケトコナゾール 液Ketoconazole Solution is a liquid for external use.Ketoconazole Solution contains not less than 95.0%and not more than 105.0% of the labeled amount ofketoconazole (C 26 H 28 Cl 2 N 4 O 4 :531.43).Method of preparation Prepare as directed under Solutionswith Ketoconazole.Description Ketoconazole Solution is a clear liquid.Identification To a volume of Ketoconazole Solution,equivalent to 10 mg of Ketoconazole according to the labeledamount, add methanol to make 10 mL, and use this solution asthe sample solution. Separately, dissolve 10 mg of ketoconazolein 10 mL of methanol, and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 5 µL each of the samplesolution and standard solution on a plate of silica gel withfluorescent indicator for thin-layer chromatography. Develop theplate with a mixture of ethyl acetate, hexane, methanol, waterand ammonia solution (28) (40:40:30:2:1) to a distance of about10 cm, and air-dry the plate. Examine under ultraviolet light(main wavelength: 254 nm): the principal spot obtained fromthe sample solution has the same R f value as the spot from thestandard solution.pH Being specified separately.Assay Weigh accurately an amount of Ketoconazole Solution,equivalent to about 10 mg of ketoconazole (C 26 H 28 Cl 2 N 4 O 4 ),add exactly 5 mL of the internal standard solution, and add 15mL of methanol. To 1 mL of this solution add methanol to make25 mL, and use this solution as the sample solution. Separately,weigh accurately about 50 mg of ketoconazole for assay, previouslydried at 105ºC for 4 hours, and dissolve in methanol tomake exactly 50 mL. Pipet 10 mL of this solution, add exactly 5mL of the internal standard solution, add methanol to make 20mL. Take 1 mL of this solution, add methanol to make 25 mL,and use this solution as the standard solution. Perform the testwith 20 µL each of the sample solution and standard solution asdirected under Liquid Chromatography according to thefollowing conditions, and calculate the ratios, Q T and Q S , of thepeak area of ketoconazole to that of the internal standard.Amount (mg) of ketoconazole (C 26 H 28 Cl 2 N 4 O 4 )= W S × (Q T /Q S ) × (1/5)W S : Amount (mg) of ketoconazole for assayInternal standard solution—A solution of bifonazole in methanol(3 in 2000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:240 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of a solution of diisopropylamine inmethanol (1 in 500), ammonium acetate solution (1 in 200) andacetic acid (100) (1800:600:1).Flow rate: Adjust the flow rate so that the retention time ofketoconazole is about 11 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,ketoconazole and the internal standard are eluted in this orderwith the resolution between these peaks being not less than 3.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ketoconazole to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Anhydrous Lactose無 水 乳 糖Change the Purity (2) and Isomer ratio to read:Purity (2) Acidity or alkalinity—Dissolve 6 g of AnhydrousLactose by heating in 25 mL of freshly boiled and cooled water,and after cooling, add 0.3 mL of phenolphthalein TS: the solutionis colorless, and not more than 0.4 mL of 0.1 mol/L sodiumhydroxide VS is required to produce a pale red color or redcolor.Isomer ratio Place 1 mg of Anhydrous Lactose in a 5-mLscrew capped reaction vial for gas chromatography, add 0.45mL of dimethylsulfoxide, stopper, and shake well. Add 1.8 mLof a mixture of pyridine and trimethylsilylimidazole (18:7), sealthe vial tightly with a screw cap, and mix gently. Allow to standfor 20 minutes, and use this solution as the sample solution.Perform the test with 2 µL of the sample solution as directedunder Gas Chromatography according to the followingconditions. Determine the peak areas of α-lactose derivateiveand β-lactose derivateive, A a and A b , and calculate the contents(%) of α-lactose derivateive and β-lactose derivateive in AnhydrousLactose by the following equations.Content (%) of α-lactose = [A a / (A a + A b )] × 100Content (%) of β-lactose = [A b / (A a + A b )] × 100Operating conditions—Detector: A hydrogen flame-ionization detector.Injection port temperature: A constant temperature of about 275ºCDetector temperature: A constant temperature of about 275ºC.Column: A glass column 4 mm in inside diameter and 90 cmin length, packed with siliceous earth for gas chromatographycoated at the ratio of 3% with 25% phenyl-25% cyanopro-

2156 Official Monographs Supplement II, JP XVpyl-methylsilicone polymer for gas chromatography.Column temperature: A constant temperature of about 215ºC.Carrier gas: HeliumFlow rate: A constant flow rate of about 40 mL per minute.System suitability—System performance: Prepare a solution with 1 mg of a mixtureof α-lactose and β-lactose (1:1) in the same manner as forpreparing the sample solution, and proceed with 2 µL of this solutionunder the above operating conditions, and determine theretention times of the peaks of α-lactose derivative and β-lactosederivative: the relative retention time of α-lactose derivativewith respect to that of β-lactose derivative is about 0.7 with theresolution between these peaks being not less than 3.0.Lactose Hydrate乳 糖 水 和 物Change the Purity (2) to read:Purity (2) Acidity or alkalinity—Dissolve 6 g of LactoseHydrate by heating in 25 mL of freshly boiled and cooled water,and after cooling, add 0.3 mL of phenolphthalein TS: the solutionis colorless, and not more than 0.4 mL of 0.1 mol/L sodiumhydroxide VS is required to produce a pale red color or redcolor.Add the following:Levofloxacin Hydrateレボフロキサシン 水 和 物C 18 H 20 FN 3 O 4·½H 2 O: 370.38(3S)-9-Fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate [138199-71-0]Levofloxacin Hydrate contains not less than 99.0%and not more than 101.0% of levofloxacin(C 18 H 20 FN 3 O 4 : 361.37), caluculated on the anhydrousbasis.Description Levofloxacin Hydrate occurs as light yellowishwhite to yellowish white crystals or crystalline powder.It is freely soluble in acetic acid (100), sparingly soluble inwater and in methanol, and slightly soluble in ethanol (99.5).It dissolves in 0.1 mol/L hydrochloric acid TS.It gradually turns dark light yellowish white on exposure tolight.Melting point: about 226ºC (with decomposition).Identification (1) Determine the absorption spectrum of asolution of Levofloxacin Hydrate in 0.1 mol/L hydrochloric acidsolution (1 in 150000) as directed under Ultraviolet-visibleSpectrophotometry , and compare the spectrum with theReference Spectrum: both spectra exhibit similar intensities ofabsorption at the same wavelengths.(2) Determine the infrared absorption spectrum ofLevofloxacin Hydrate as directed in the potassium bromide diskmethod under Infrared Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.Optical rotation [α] 20D: –92 - –99º (0.1 g calculatedon the anhydrous basis, methanol, 10 mL, 100 mm).Purity (1) Heavy metals —Proceed with 2.0 g ofLevofloxacin Hydrate according to Method 4, and perform thetest. Prepare the control solution with 2.0 mL of Standard LeadSolution (not more than 10 ppm).(2) Related substances—Conduct this procedure usinglight-resistant vessels. Dissolve 50 mg of Levofloxacin Hydratein 10 mL of a mixture of water and methanol (1:1), and use thissolution as the sample solution. Pipet 1 mL of this solution, andadd a mixture of water and methanol (1:1) to make exactly 10mL. Pipet 1 mL of this solution, add a mixture of water andmethanol (1:1) to make exactly 10 mL, and use this solution asthe standard solution. Perform the test with exactly 10 µL eachof the sample solution and standard solution as directed underLiquid Chromatography according to the following conditions.Determine each peak area of both solutions by theautomatic integration method: the area of the peak having therelative retention time of about 1.2 with respect to levofloxacinobtained from the sample solution is not larger than 2/5 timesthe peak area of levofloxacin from the standard solution, and thearea of each peak other than the peak of levofloxacin and otherthan the peak having the relative retention time of about 1.2with respect to levofloxacin from the sample solution is not largerthan 1/5 times the peak area of levofloxacin from the standardsolution. Furthermore, the total area of the peaks other thanthe peak of levofloxacin and other than the peak having the relativeretention time of about 1.2 with respect to levofloxacinfrom the sample solution is not larger than 3/10 times the peakarea of levofloxacin from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:340 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 45ºC.Mobile phase: Dissolve 1.76 g of L-valine, 7.71 g of ammoniumacetate and 1.25 g of Copper (II) sulfate pentahydrate inwater to make 1000 mL. To this solution add 250 mL of methanol.Flow rate: Adjust the flow rate so that the retention time oflevofloxacin is about 22 minutes.

Supplement II, JP XV Official Monographs 2157Time span of measurement: About 2 times as long as the retentiontime of levofloxacin, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 1 mL of the standard solution,and add a mixture of water and methanol (1:1) to makeexactly 20 mL. Confirm that the peak area of levofloxacin obtainedfrom 10 µL of this solution is equivalent to 4 to 6% ofthat of levofloxacin from the standard solution.System performance: Dissolve 10 mg of ofloxacin in 20 mLof a mixture of water and methanol (1:1). To 1 mL of this solutionadd a mixture of water and methanol (1:1) to make 10 mL.When the procedure is run with 10 µL of th is solution under theabove operating conditions, the resolution between the peak oflevofloxacin and the peak having the relative retention time ofabout 1.2 with respect to levofloxacin is not less than 3.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area oflevofloxacin is not more than 3.0%.(3) Residual solvent—Being specified separately.Water 2.1 - 2.7% (0.5 g, volumetric titration, direct titration).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.3 g of Levofloxacin Hydrate,dissolve in 100 mL of acetic acid (100), and titrate with0.1 mol/L perchloric acid VS (potentiometric titration). Performa blank determination in the same manner, and make any necessarycorrection.Each mL of 0.1 mol/L perchloric acid VS= 36.14 mg of C 18 H 20 FN 3 O 4Containers and storage Containers—Tight containers.Storage—Light-resistant.Lidocaine Injectionリドカイン 注 射 液Delete the Pyrogen and add the following next tothe Identification:Bacterial endotoxins Less than 1.0 EU/mg.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Add the following:Lincomycin HydrochlorideInjectionリンコマイシン 塩 酸 塩 注 射 液Lincomycin Hydrochloride Injection is an aqueousinjection.It contains not less than 93.0% and not more than107.0% of the labeled potency of lincomycin(C 18 H 34 N 2 O 6 S: 406.54).Method of preparation Prepare as directed under Injections,with Lincomycin Hydrochloride Hydrate.Description: Lincomycin Hydrochloride Injection is a clear,colorless liquid.Identification To a volume of Lincomycin Hydrochloride Injection,equivalent to 30 mg (potency) of Lincomycin HydrochlorideHydrate, add 30 mL of water, and use this solution asthe sample solution. Separately, dissolve 10 mg (potency) ofLincomycin Hydrochloride Reference Standard in 10 mL ofwater, and use this solution as the standard solution. Perform thetest with these solutions as directed under Thin-layer Chromatography. Spot 5 µL each of the sample solution andstandard solution on a plate of silica gel for thin-layer chromatography.Dissolve 150 g of ammonium acetate in 800 mL ofwater, adjust the pH to 9.6 with ammonia solution (28), and addwater to make 1000 mL. To 80 mL of this solution add 40 mL of2-propanol and 90 mL of ethyl acetate, shake, develop the platewith the upper layer of this solution to a distance of about 15 cm,and air-dry the plate. Spray evenly a solution of potassium permanganate(1 in 1000) on the plate: the principal spots from thesample solution and the standard solution show the same R fvalue.pH 3.5 - 5.5Bacterial endotoxins Less than 0.50 EU/mg (potency).Extractable volume It meets the requirement.Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay Pipet a volume of Lincomycin Hydrochloride Injection,equivalent to about 0.3 g (potency) of Lincomycin HydrochlorideHydrate, add the mobile phase to make exactly 30 mL. Pipet2 mL of this solution, add the mobile phase to make exactly20 mL, and use this solution as the sample solution. Separately,weigh accurately an amount of Lincomycin Hydrochloride Ref-

2158 Official Monographs Supplement II, JP XVerence Standard, equivalent to 20 mg (potency), dissolve in themobile phase to make exactly 20 mL, and use this solution asthe standard solution. Then, proceed as directed in the Assayunder Lincomycin Hydrochloride Hydrate.Amount [mg (potency)] of lincomycin (C 18 H 34 N 2 O 6 S)= W S × (A T /A S ) × 15W S : Amount [mg (potency)] of Lincomycin HydrochlorideReference StandardContainers and storage Containers—Hermetic containers.Add the following:Losartan PotassiumロサルタンカリウムC 22 H 22 ClKN 6 O: 461.00Monopotassium 5-{[4´-(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]biphenyl-2-yl}-1H-tetrazol-1-ide[124750-99-8]Losartan Potassium contains not less than 98.5%and not more than 101.0% of C 22 H 22 ClKN 6 O, calculatedon the anhydrous basis.Description Losartan Potassium occurs as a white crystallinepowder.It is very soluble in water, and freely soluble in methanol andin ethanol (99.5).Identification (1) Determine the absorption spectrum of asolution of Losartan Potassium in methanol (1 in 100000) as directedunder Ultraviolet-visible Spectrophotometry , andcompare the spectrum with the Reference Spectrum or the spectrumof a solution of Losartan Potassium Reference Standardprepared in the same manner as the sample solution: both spectraexhibit similar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of LosartanPotassium as directed in the potassium bromide disk methodunder Infrared Spectrophotometry , and compare thespectrum with the Reference Spectrum or the spectrum ofLosartan Potassium Reference Standard: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) Losartan Potassium responds to the Qualitative Tests (1) for potassium salt.(4) Perform the test with Losartan Potassium as directed underFlame Coloration Test (2): a green color appears.Purity (1) Heavy metals —Proceed with 2.0 g ofLosartan Potassium according to Method 2, and perform the test.Prepare the control solution with 2.0 mL of Standard Lead Solution(not more than 10 ppm).(2) Related substances—Dissolve 30 mg of Losartan Potassiumin 100 mL of methanol, and use this solution as the samplesolution. Pipet 1 mL of this solution, add methanol to make exactly100 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area of both solutions by the automatic integration method:the area of each peak other than the peaks of solvent and losartanobtained from the sample solution is not larger than 1/10times the peak area of losartan from the standard solution, andthe total area of the peaks other than the peak of losartan fromthe sample solution is not larger than 3/10 times the peak area oflosartan from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:220 nm).Column: A stainless steel column 4 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase A: Diluted phosphoric acid (1 in 1000).Mobile phase B: Acetonitrile.Flowing of the mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 – 25 75 → 10 25 → 9025 – 35 10 90Flow rate: 1.0 mL per minute.Time span of measurement: 35 minutes after injection of thesample.System suitability—Test for required detectability: Pipet 1 mL of the standard solution,and add methanol to make exactly 10 mL. Confirm thatthe peak area of losartan obtained from 10 µL of this solution isequivalent to 7 to 13% of that of losartan from the standard solution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of losartan are not less than 10000 and not more than 1.3,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of losartanis not more than 2.0%.

Supplement II, JP XV Official Monographs 2159(3) Residual solvent—Being specified separately.Water Not more than 0.5% (0.25 g, volumetric titration,direct titration)Assay Weigh accurately about 25 mg each of Losartan Potassiumand Losartan Potassium Reference Standard (separately,determine the water content in the same manner asLosartan Potassium), dissolve separately in methanol to makeexactly 100 mL, and use these solutions as the sample solutionand standard solution, respectively. Perform the test with exactly10 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions, and calculate the peak areas, A T and A S , oflosartan in each solution.Amount (mg) of losartan potassium (C 22 H 22 ClKN 6 O)= W S × (A T /A S )W S : Amount (mg) of Losartan Potassium Reference Standard,calculated on the anhydrous basis.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 35ºC.Mobile phase: A mixture of diluted phosphoric acid (1 in1000) and acetonitrile (3:2)Flow rate: Adjust the flow rate so that the retention time oflosartan is about 6 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of losartan are not less than 5500 and not more than 1.4,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of losartanis not more than 1.0%.Containers and storage Containers—Tight containers.Add the following:L-Lysine AcetateL‐リジン 酢 酸 塩C 6 H 14 N 2 O 2·C 2 H 4 O 2 : 206.24(2S)-2,6-Diaminohexanoic acid monoacetate[57282-49-2]L-Lysine Acetate, when dried, contains not less than98.5% and not more than 101.0% ofC 6 H 14 N 2 O 2·C 2 H 4 O 2 .Description L-Lysine Acetate occurs as white crystals orcrystalline powder. It has a characteristic odor and a slightlyacid taste.It is very soluble in water, freely soluble in formic acid, andpractically insoluble in ethanol (99.5).It is deliquescent.Identification (1) Determine the infrared absorption spectrumof L-Lysine Acetate as directed in the potassium bromidedisk method under Infrared Spectrophotometry , andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavenumbers.(2) A solution of L-Lysine Acetate (1 in 20) responds to theQualitative Tests (2) for acetate.Optical rotation [α] 20D: +8.5 - +10.0º (after drying,2.5 g, water, 25 mL, 100 mm).pH Dissolve 1.0 g of L-Lysine Acetate in 10 mL ofwater: the pH of the solution is between 6.5 and 7.5.Purity (1) Clarity and color of solution—Dissolve 1.0 g ofL-Lysine Acetate in 10 mL of water: the solution is colorless andclear.(2) Chloride —Perform the test with 0.5 g ofL-Lysine Acetate. Prepare the control solution with 0.30 mL of0.01 mol/L hydrochloric acid VS (not more than 0.021%).(3) Sulfate —Perform the test with 0.6 g of L-LysineAcetate. Prepare the control solution with 0.35 mL of 0.005mol/L sulfuric acid VS (not more than 0.028%).(4) Ammonium —Perform the test with 0.25 g ofL-Lysine Acetate. Prepare the control solution with 5.0 mL ofStandard Ammonium Solution (not more than 0.02%).(5) Heavy metals —Proceed with 1.0 g of L-LysineAcetate according to Method 4, and perform the test. Preparethe control solution with 1.0 mL of Standard Lead Solution (notmore than 10 ppm).(6) Iron —Prepare the test solution with 1.0 g ofL-Lysine Acetate according to Method 1, and perform the testaccording to Method A. Prepare the control solution with 1.0

2160 Official Monographs Supplement II, JP XVmL of Standard Iron Solution (not more than 10 ppm).(7) Related substances—Weigh accurately about 0.5 g ofL-Lysine Acetate, dissolve in 0.5 mL of hydrochloric acid andwater to make exactly 100 mL. Pipet 5 mL of this solution, add0.02 mol/L hydrochloric acid to make exactly 50 mL, and usethis solution as the sample solution. Separately, weigh accurately2.5 mmol amounts of L-aspartic acid, L-threonine,L-serine, L-glutamic acid, glycine, L-alanine, L-valine, L-cystine,L-methionine, L-isoleucine, L-leucine, L-tyrosine,L-phenylalanine, L-lysine hydrochloride, ammonium chloride,L-histidine hydrochloride monohydrate and L-arginine, dissolvein 0.1 mol/L hydrochloric acid TS to make exactly 1000 mL,and use this solution as the standard stock solution. Pipet 5 mLof this solution, add 0.02 mol/L hydrochloric acid to make exactly100 mL, Pipet 2 mL of this solution, add 0.02 mol/L hydrochloricacid to make exactly 50 mL, and use this solution asthe standard solution. Perform the test with exactly 20 µL eachof the test solution and standard solution as directed under LiquidChromatography according to the following conditions.Based on the peak heights of the amino acids obtainedfrom the sample solution and standard solution, determine themass of the amino acids other than lysine contained in 1 mL ofthe sample solution, and calculate the mass per cent: the amountof each amino acids other than lysine is not more than 0.1%.Operating conditions—Detector: A visible spectrophotometer (wavelength: 570 nm)Column: A stainless steel column 4.6 mm in inside diameterand 8 cm in length, packed with strongly acidic ion-exchangeresin for liquid chromatography (sodium type) composed with asulfonated polystyrene copolymer (3 µm in particle diameter).Column temperature: A constant temperature of about 57ºC.Chemical reaction bath temperature: A constant temperatureof about 130ºC.Color developing time: About 1 minute.Mobile phase: Prepare mobile phases A, B, C, D and E accordingto the following table, and to each phase add 0.1 mL ofcapric acid.Mobile phase A Mobile phase B Mobile phase C Mobile phase D Mobile phase ECitric acid monohydrate 19.80 g 22.00 g 12.80 g 6.10 g -Trisodium citrate dihydrate 6.19 g 7.74 g 13.31 g 26.67 g -Sodium chloride 5.66 g 7.07 g 3.74 g 54.35 g -Sodium hydroxide - - - - 8.00 gEthanol (99.5) 260 mL 20 mL 4 mL - 100 mLThiodiglycol 5 mL 5 mL 5 mL - -Benzyl alcohol - - - 5 mL -Lauromacrogol solution (1 in 4) 4 mL 4 mL 4 mL 4 mL 4 mLWaterAppropriateamountAppropriateamountAppropriateamountAppropriateamountAppropriateamountTotal volume 2000 mL 1000 mL 1000 mL 1000 mL 1000 mLChanging mobile phases: Proceed with 20 µL of the standardsolution under the above operating conditions: aspartic acid,threonine, serine, glutamic acid, glycine, alanine, valine, cystine,methionine, isoleucine, leucine, tyrosine, phenylalanine, lysine,ammonia, histidine and arginine are eluted in this order.Switchover the mobile phases A, B, C, D and E in sequence sothat the resolution between the peaks of isoleucine and leucineis not less than 1.2.Reaction reagents: Dissolve 407 g of lithium acetate dihydratein water, and add 245 mL of acetic acid (100), 801 mLof 1-methoxy-2-propanol, and water to make 2000 mL, gas withnitrogen for 10 minutes, and use this solution as the solution (I).Separately, to 1957 mL of 1-methoxy-2-propanol add 77 g ofninhydrin, gas with nitrogen for 5 minutes, add 0.134 g of sodiumborohydride, and gas the solution with nitrogen for 30minutes. To this solution add the solution (I) (12:13).Mobile phase flow rate: 0.32 mL per minute.Reaction reagent flow rate: 0.30 mL per minute.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the resolution between the peaks of glycine and alanine is notless than 1.5.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak height of eachamino acid in the standard solution is not more than 5.0%, andthe relative standard deviation of the retention time is not morethan 1.0%.Loss on drying Not more than 0.3% (1 g, 80ºC, 3hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.1 g of L-Lysine Acetate, previouslydried, dissolve in 3 mL of formic acid, add 50 mL ofacetic acid (100), and titrate with 0.1 mol/L perchloricacid VS (potentiometric titration). Perform a blank determinationin the same manner, and make any necessary correction.

Supplement II, JP XV Official Monographs 2161Each mL of 0.1 mol/L perchloric acid VS= 10.31 mg of C 6 H 14 N 2 O 2·C 2 H 4 O 2Containers and storage Containers—Tight containers.Meglumine Iotalamate Injectionイオタラム 酸 メグルミン 注 射 液Delete the Bacterial endotoxins and add the followingnext to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Meglumine Sodium AmidotorizoateInjectionアミドトリゾ 酸 ナトリウムメグルミン 注 射 液Delete the Pyrogen and change the Method ofpreparation to read:Mepivacaine HydrochlorideInjectionメピバカイン 塩 酸 塩 注 射 液Change the Origin/limits of content, Descriptionand Identification to read:Mepivacaine Hydrochloride Injection is an aqueoussolution for injection.It contains not less than 95.0% and not more than105.0% of the labeled amount of mepivacaine hydrochloride(C 15 H 22 N 2 O·HCl: 282.81).Description Mepivacaine Hydrochloride Injection is a clear,colorless liquid.Identification To a volume of Mepivacaine HydrochlorideInjection, equivalent to 20 mg of Mepivacaine Hydrochlorideaccording to the labeled amount, add 1 mL of sodium hydroxideTS, and extract with 20 mL of hexane. To 8 mL of the hexaneextract add 20 mL of 1 mol/L hydrochloric acid TS, shake vigorously,and determine the absorption spectrum of the waterlayer separated as directed under Ultraviolet-visible Spectrometry: it exhibits maxima between 261 nm and 265 nm,and between 270 nm and 273 nm.Add the following next to the IdentificationpHBeing specified separately.Method of preparation(1)Amidotorizoic Acid (anhydrous)Sodium HydroxideMeglumineWater for Injection(2)Amidotorizoic Acid (anhydrous)Sodium HydroxideMeglumineWater for Injection471.78 g5.03 g125.46 ga sufficient quantityTo make 1000 mL597.30 g6.29 g159.24 ga sufficient quantityTo make 1000 mLBacterial endotoxins Less than 0.6 EU/mg.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Change the Assay to read:Prepare as directed under Injections, with the above ingredients(1) or (2).Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay Pipet a volume of Mepivacaine Hydrochloride Injection,equivalent to about 40 mg of Mepivacaine Hydrochloride(C 15 H 22 N 2 O·HCl) according to the labeled amount, add exactly4 mL of the internal standard solution and 0.001 mol/L hydrochloricacid TS to make 20 mL, and use this solution as thesample solution. Separately, weigh accurately about 40 mg ofmepivacaine hydrochloride for assay, previously dried at 105ºCfor 3 hours, dissolve in 0.001 mol/L hydrochloric acid TS, addexactly 4 mL of the internal standard solution and 0.001 mol/Lhydrochloride TS to make 20 mL, and use this solution as thestandard solution. Perform the test with 5 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions, andcalculate the ratios, Q T and Q S , of the peak area of mepivacaine

2162 Official Monographs Supplement II, JP XVto that of the internal standard.Amount (mg) of mepivacaine hydrochloride(C 15 H 22 N 2 O·HCl)= W S × (Q T /Q S )W S : Amount (mg) of mepivacaine hydrochloride for assayInternal standard solution—A solution of benzophenone inmethanol (1 in 4000).Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (10 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: Dissolve 2.88 g of sodium lauryl sulfate in1000 mL of a mixture of 0.02 mol/L phosphate buffer solution,pH 3.0, and acetonitrile (11:9).Flow rate: Adjust the flow rate so that the retention time ofmepivacaine is about 6 minutes.System suitability—System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions, mepivacaineand the internal standard are eluted in this order withthe resolution between these peaks being not less than 6.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofmepivacaine to that of the internal standard is not more than1.0%.Add the following:Meropenem for Injection注 射 用 メロペネムMeropenem for Injection is a preparation for injection,which is dissolved before use.It contains not less than 93.0% and not more than107.0% of the labeled potency of meropenem(C 17 H 25 N 3 O 5 S: 383.46).Method of preparation Prepare as directed under Injections,with Meropenem Hydrate.Description Meropenem for Injection occurs as a white tolight yellow crystalline powder.Identification Determine the infrared absorption spectrum ofMeropenem for Injection as directed in the potassium bromidedisk method under Infrared Spectrophotometry : it exhibitsabsorption at the wave numbers of about 3410 cm -1 , 1750cm -1 , 1655 cm -1 , 1583 cm -1 and 1391 cm -1 .pH Dissolve an amount of Meropenem for Injection,equivalent to 0.25 g (potency) of Meropenem Hydrate accordingto the labeled amount, in 5 mL of water: the pH of the solutionis between 7.3 and 8.3.Purity (1) Clarity and color of solution—Dissolve anamount of Meropenem for Injection, equivalent to 1.0 g (potency)of Meropenem Hydrate according to the labeled amount,in 20 mL of water: the solution is clear and is not more intenselycolored than the following matching fluid.Matching fluid: To a mixture of 0.3 mL of Cobalt (II) ChlorideColorimetric Stock Solution and 1.2 mL of Iron (III) ChlorideColorimetric Stock Solution add 18.5 mL of diluted hydrochloricacid (1 in 40).(2) Related substances—Being specified separately.Loss on drying 9.5 - 12.0% (0.1 g, reduced pressurenot exceeding 0.67 kPa, 60ºC, 3 hours).Bacterial endotoxins Less than 0.12 EU/mg (potency).Uniformity of dosage units It meets the requirementof the Mass variation test.Foreign insoluble matter Perform the test accordingto Method 2: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay Weigh accurately the mass on the contents of not lessthan 10 containers of Meropenem for Injection. Weigh accuratelyan amount of the contents, equivalent to about 50 mg(potency) of Meropenem Hydrate, dissolve in exactly 10 mL ofthe internal standard solution, add triethylamine-phosphatebuffer solution, pH 5.0, to make 100 mL, and use this solutionas the sample solution. Separately, weigh accurately an amountof Meropenem Reference Standard, equivalent to about 50 mg(potency), dissolve in exactly 10 mL of the internal standard solution,add triethylamine-phosphate buffer solution, pH 5.0, tomake 100 mL, and use this solution as the standard solution.Perform the test with 5 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of meropenem to that of theinternal standard.Amount [mg (potency)] of meropenem (C 17 H 25 N 3 O 5 S)= W S × (Q T /Q S )W S : Amount [mg (potency)] of Meropenem Reference StandardInternal standard solution—A solution of benzyl alcohol intriethylamine-phosphate buffer solution, pH 5.0 (1 in 300)Operating conditions—Proceed as directed in the operating conditions in the Assayunder Meropenem Hydrate.

Supplement II, JP XV Official Monographs 2163System suitability—System performance: Proceed as directed in the system suitabilityin the Assay under Meropenem Hydrate.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofmeropenem to that of the internal standard is not more than1.0%.Containers and storage Containers—Hermetic containers.Plastic containers for aqueous injections may be used.MethylcelluloseメチルセルロースChange the Chemical name to read:[9004-67-5]Minocycline Hydrochloridefor Injection注 射 用 ミノサイクリン 塩 酸 塩Change the Assay to read:Assay Weigh accurately the mass of the contents of not lessthan 10 containers of Minocycline Hydrochloride for Injection.Weigh accurately an amount of the contents, equivalent to about0.1 g (potency) of Minocycline Hydrochloride, dissolve in themobile phase to make exactly 100 mL. Pipet 25 mL of this solution,add the mobile phase to make exactly 50 mL, and use thissolution as the sample solution. Separately, weigh accurately anamount of Minocycline Hydrochloride Reference Standard,equivalent to about 25 mg (potency), dissolve in the mobilephase to make exactly 50 mL, and use this solution as the standardsolution. Perform the test with exactly 20 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak area of minocycline, A T and A S , of eachsolution.Amount [mg (potency)] of minocycline (C 23 H 27 N 3 O 7 )= W S × (A T /A S ) × 4W S : Amount [mg (potency)] of Minocycline HydrochlorideReference StandardOperating conditions—Detector, column, column temperature, and flow rate: Proceedas directed in the operating conditions in the Assay underMinocycline Hydrochloride.Mobile phase: Adjust the pH to 6.5 of a mixture of ammoniumoxalate monohydrate solution (7 in 250),N,N-dimethylformamide and 0.1 mol/L disodium dihydrogenethylenediamine tetraacetate TS (11:5:4) with tetrabutylammoniumhydroxide TS.System suitability—System performance: Dissolve 50 mg of minocycline hydrochloridein water to make 25 mL. Heat 5 mL of this solution ona water bath for 60 minutes, and add water to make 25 mL.When the procedure is run with 20 µL of this solution under theabove operating conditions, epiminocycline and minocycline areeluted in this order with the resolution between these peaks beingnot less than 2.0.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of minocyclineis not more than 1.0%.Add the following:Minocycline Hydrochloride Tabletsミノサイクリン 塩 酸 塩 錠Minocycline Hydrochloride Tablets contain not lessthan 90.0% and not more than 110.0% of the labeledpotency of Minocycline (C 23 H 27 N 3 O 7 : 457.48).Method of preparation Prepare as directed under Tablets,with Minocycline Hydrochloride.Identification To a quantity of powdered Minocycline HydrochlorideTablets, equivalent to 10 mg (potency) of MinocyclineHydrochloride according to the labeled amount, add 625mL of a solution of hydrochloric acid in methanol (19 in 20000),shake well, and filter. Determine the absorption spectrum of thefiltrate as directed under Ultraviolet-visible Spectrophotometry: it exhibits maxima between 221 nm and 225 nm, between261 nm and 265 nm, and between 354 nm and 358 nm.Purity Related substances—Conduct this procedure rapidlyafter preparation of the sample solution. Powder not less than 5Minocycline Hydrochloride Tablets. Weigh accurately a portionof the powder, equivalent to 50 mg (potency) of MinocyclineHydrochloride according to the labeled amount, add 60 mL ofthe mobile phase, shake vigorously, and add the mobile phase tomake 100 mL. Centrifuge this solution, and use the supernatantliquid as the sample solution. Perform the test with 20 µL of thesample solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area from both solutions by the automatic integrationmethod. Calculate the amounts of these peaks by the area percentagemethod: the amount of the peak of epiminocycline,having the relative retention time of 0.83 with respect to minocycline,is not more than 2.0%.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 2.5 times as long as theretention time of minocycline, beginning after the solvent peak.

2164 Official Monographs Supplement II, JP XVSystem suitability—System performance: Proceed as directed in the system suitabilityin the Assay.Test for required detectability: To 2 mL of the sample solutionadd the mobile phase to make 100 mL, and use this solution asthe solution for system suitability test. Pipet 5 mL of the solutionfor system suitability test, and add the mobile phase tomake exactly 100 mL. Confirm that the peak area of minocyclineobtained from 20 µL of this solution is equivalent to 3.5to 6.5% of that of minocycline from 20 µL of the solution forsystem suitability test.System repeatability: When the test is repeated 6 times with20µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the peakarea of minocycline is not more than 2.0%.Water Not more than 12.0% (0.5 g of powdered MinocyclineHydrochloride Tablets, volumetric titration, back titration)Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Minocycline Hydrochloride Tablets add 60 mLof the mobile phase, treat with ultrasonic waves for 15 minutes,and add the mobile phase to make exactly V mL so that each mLcontains about 0.5 mg (potency) of Minocycline Hydrochloride.Centrifuge this solution, and use the supernatant liquid as thesample solution. Then, proceed as directed in the Assay.Amount [mg (potency)] of minocycline (C 23 H 27 N 3 O 7 )= W S × (A T /A S ) × (V/50)W S : Amount [mg (potency)] of Minocycline HydrochlorideReference StandardDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Minocycline Hydrochloride Tablets is not less than85%.Start the test with 1 tablet of Minocycline HydrochlorideTablets, withdraw not less than 20 mL of the medium at thespecified minute after starting the test, and filter through amembrane filter with a pore size not exceeding 0.45 µm. Discardthe first 10 mL of the filtrate, pipet V mL of the subsequentfiltrate, add water to make exactly V´ mL so that each mL containsabout 9 µg (potency) of Minocycline Hydrochloride accordingto the labeled amount, and use this solution as the samplesolution. Separately, weigh accurately an amount of MinocyclineHydrochloride Reference Standard, equivalent to about30 mg (potency), and dissolve in water to make exactly 100 mL.Pipet 4 mL of this solution, add water to make exactly 100 mL,and use this solution as the standard solution. Perform the testwith the sample solution and standard solution as directed underUltraviolet-visible Spectrophotometry , and determinethe absorbances, A T and A S , at 348 nm.minocycline (C 23 H 27 N 3 O 7 )= W S × (A T /A S ) × (V´/V) × (1/C) × 36W S : Amount [mg (potency)] of Minocycline HydrochlorideReference StandardC: Labeled amount [mg (potency)] of minocycline(C 23 H 27 N 3 O 7 ) in 1 tabletAssay To a number of Minocycline Hydrochloride Tablets,equivalent to about 1 g (potency) of Minocycline Hydrochloride,add 120 mL of the mobile phase, treat with ultrasonic waves for15 minutes, and add the mobile phase to make exactly 200 mL.Centrifuge this solution, pipet 5 mL of the supernatant liquid,add the mobile phase to make exactly 50 mL, and use this solutionas the sample solution. Separately, weigh accurately anamount of Minocycline Hydrochloride Reference Standard,equivalent to about 25 mg (potency), dissolve in the mobilephase to make exactly 50 mL, and use this solution as the standardsolution. Perform the test with exactly 20 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak areas, A T and A S , of minocycline in eachsolution.Amount [mg (potency)] of minocycline (C 23 H 27 N 3 O 7 )= W S × (A T /A S ) × 40W S : Amount [mg (potency)] of Minocycline HydrochlorideReference StandardOperating conditions—Detector, column, column temperature and flow rate: Proceedas directed in the operating conditions in the Assay under MinocyclineHydrochloride.Mobile phase: Adjust the pH to 6.5 of a mixture of ammoniumoxalate monohydrate solution (7 in 250),N,N-dimethylformamide and 0.1 mol/L disodium dihydrogenethylenediamine tetraacetate TS (11:5:4) with tetrabutylammoniumhydroxide TS.System suitability—System performance: Dissolve 50 mg of minocycline hydrochloridein 25 mL of water. Heat 5 mL of this solution on a waterbath for 60 minutes, and add water to make 25 mL. When theprocedure is run with 20 µL of this solution under the above operatingconditions, epiminocycline and minocycline are elutedin this order with the resolution between these peaks being notless than 2.0.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of minocyclineis not more than 1.0%.Containers and storage Containers—Tight containers.Storage—Light-resistant.Dissolution rate (%) with respect to the labeled amount of

Supplement II, JP XV Official Monographs 2165Morphine Hydrochloride Injectionモルヒネ 塩 酸 塩 注 射 液Add the following next to the Identification:Bacterial endotoxins Less than 1.5 EU/mg.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Morphine Hydrochloride Tabletsモルヒネ 塩 酸 塩 錠Add the following next to the Uniformity of dosageunits:Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 15minutes of Morphine Hydrochloride Tablets is not less than85%.Start the test with 1 tablet of Morphine Hydrochloride Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard the first 10mL of the filtrate, and use the subsequent filtrate as the samplesolution. Separately, weigh accurately about 28 mg of morphinehydrochloride for assay (separately, determine the water content in the same manner as Morphine Hydrochloride Hydrate),and dissolve in water to make exactly 100 mL. Pipet 2mL of this solution, add water to make exactly 50 mL, and usethis solution as the standard solution. Perform the test with exactly25 µL each of the sample solution and standard solution asdirected under Liquid Chromatography according to thefollowing conditions, and determine the peak areas , A T and A S ,of morphine in each solution.Dissolution rate (%) with respect to the labeled amount ofmorphine hydrochloride hydrate (C 17 H 19 NO 3·HCl·3H 2 O)= W S × (A T /A S ) × (1/C) × 36 × 1.168W S : Amount (mg) of morphine hydrochloride for assay, calculatedon the anhydrous basisC: Labeled amount (mg) of morphine hydrochloride hydrate(C 17 H 19 NO 3·HCl·3H 2 O) in 1 tabletOperating conditions—Proceed as directed in the operating conditions in the Assay.System suitability—System performance: When the procedure is run with 25 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of morphine are not less than 5000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with25 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of morphineis not more than 2.0%.Add the following:Mosapride Citrate Hydrateモサプリドクエン 酸 塩 水 和 物and enantiomerC 21 H 25 ClFN 3 O 3·C 6 H 8 O 7·2H 2 O: 650.054-Amino-5-chloro-2-ethoxy-N-{[(2RS)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}benzamidemonocitrate dihydrate [636582-62-2]Mosapride Citrate Hydrate contains not less than98.5% and not more than 101.0% of mosapride citrate(C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 : 614.02), calculated on theanhydrous basis.Description Mosapride Citrate Hydrate occurs as a white toyellowish white crystalline powder.It is freely soluble in N,N-dimethylformamide and in aceticacid (100), sparingly soluble in methanol, slightly soluble inethanol (99.5), and practically insoluble in water.A solution of Mosapride Citrate Hydrate inN,N-dimethylformamide (1 in 20) shows no optical rotation.Identification (1) Determine the absorption spectrum of asolution of Mosapride Citrate Hydrate in methanol (1 in 50000)as directed under Ultraviolet-visible Spectrophotometry ,and compare the spectrum with the Reference Spectrum: bothspectra exhibit similar intensities of absorption at the samewavelengths.(2) Determine the infrared absorption spectrum ofMosapride Citrate Hydrate as directed in the potassium bromidedisk method under Infrared Spectrophotometry , andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavenumbers.(3) A solution of Mosapride Citrate Hydrate inN,N-dimethylformamide (1 in 10) responds to the QualitativeTests (1) for citrate.Purity (1) Heavy metals —Proceed with 1.0 g ofMosapride Citrate Hydrate in a platinum crucible according to

2166 Official Monographs Supplement II, JP XVMethod 4, and perform the test. Prepare the control solutionwith 2.0 mL of Standard Lead Solution (not more than 20 ppm).(2) Related substances—Dissolve 0.10 g of Mosapride CitrateHydrate in 50 mL of methanol, and use this solution as thesample solution. Pipet 1 mL of this solution, and add methanolto make exactly 50 mL. Pipet 1 mL of this solution, add methanolto make exactly 20 mL, and use this solution as the standardsolution. Perform the test with exactly 5 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area of both solutions by the automatic integrationmethod: the area of the peak having the relative retentiontime of about 0.47 with respect to mosapride from the samplesolution is not larger than 3 times the peak area of mosapridefrom the standard solution, and the area of each peak other thanthe peak of mosapride and other than the peak mentioned abovefrom the sample solution is not larger than the peak area ofmosapride from the standard solution. Furthermore, the totalarea of the peaks other than the peak of mosapride from thesample solution is not larger than 5 times the peak area ofmosapride from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:274 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase A: Dissolve 8.82 g of trisodium citrate dihydratein 800 mL of water, adjust the pH to 4.0 with dilute hydrochloricacid, and add water to make 1000 mL.Mobile phase B: AcetonitrileFlowing of the mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 – 35 80 → 45 20 → 55Flow rate: 1.0 mL per minuteTime span of measurement: Beginning after the solvent peakto 35 minutes after injection.System suitability—Test for required detectability: Pipet 4 mL of the standard solution,and add methanol to make exactly 20 mL. Confirm thatthe peak area of mosapride obtained from 5 µL of this solution isequivalent to 15 to 25% of that of mosapride from the standardsolution.System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions, thenumber of theoretical plates and the symmetry factor of the peakof mosapride are not less than 40000 and not more than 1.5, respectively.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of mosapride isnot more than 5.0%.(3) Residual solvent—Being specified separately.Water 5.0 - 6.5% (0.5 g, volumetric titration, back titration).Residue on ignition Not more than 0.1% (1 g, platinumcrucible).Assay Weigh accurately 0.5 g of Mosapride Citrate Hydrate,dissolve in 70 mL of acetic acid (100), and titrate with0.1 mol/L perchloric acid VS (potentiometric titration). Performa blank determination in the same manner, and make any necessarycorrection.Each mL of 0.1 mol/L perchloric acid VS= 61.40 mg of C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7Containers and storage Containers—Well-closed containers.Add the following:Mosapride Citrate Tabletsモサプリドクエン 酸 塩 錠Mosapride Citrate Tablets contain not less than95.0% and not more than 105.0% of the labeledamount of mosapride citrate (C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 :614.02).Method of preparation Prepare as directed under Tablets,with Mosapride Citrate Hydrate.Identification (1) To an amount of powdered MosaprideCitrate Tablets, equivalent to 10 mg of mosapride citrate(C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 ), add 10 mL of dilute acetic acid,shake for 10 minutes, and filter. To 5 mL of the filtrate add 0.3mL of Dragendorff’s TS: an orange precipitate is formed.(2) Determine the absorption spectrum of the sample solutionobtained in the Assay as directed under Ultraviolet-visibleSpectrophotometry : it exhibits maxima between 271 nmand 275 nm, and between 306 nm and 310 nm.Purity Related substances—Powder not less than 20 tablets ofMosapride Citrate Tablets. Moisten a portion of the powder,equivalent to 10 mg of mosapride citrate(C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 ) according to the labeled amount, with1 mL of water. Add 9 mL of methanol, shake for 20 minutes,centrifuge, and use the supernatant liquid as the sample solution.Pipet 1 mL of this solution, add methanol to make exactly 20mL. Pipet 2 mL of this solution, add methanol to make exactly20 mL, and use this solution as the standard solution. Performthe test with exactly 10 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area of both solutions by the automatic integration method:the area of the peaks having the relative retention times of about0.60 and about 0.85 with respect to mosapride from the samplesolution is not larger than the peak area of mosapride from the

Supplement II, JP XV Official Monographs 2167standard solution, and the area of each peak other than the peakof mosapride and other than those mentioned above from thesample solution is not larger than 2/5 times the peak area ofmosapride from the standard solution. Furthermore, the totalarea of the peaks other than mosapride from the sample solutionis not larger than 2 times the peak area of mosapride from thestandard solution.Operating conditions—Detector, column, column temperature, mobile phase A, mobilephase B, and flow rate: Proceed as directed in the operatingconditions in the Purity (2) under Mosapride Citrate Hydrate.Flowing of the mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 – 40 85 → 45 15 → 55Time span of measurement: Beginning after the solvent peakto 40 minutes after injection.System suitability—Test for required detectability: Pipet 1 mL of the standard solution,and add methanol to make exactly 25 mL. Confirm thatthe peak area of mosapride obtained from 10 µL of this solutionis equivalent to 3.0 to 5.0% of that of mosapride from the standardsolution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of mosapride are not less than 40000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area ofmosapride is not more than 3.0%.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Mosapride Citrate Tablets add 5 mL of water,and shake well to disintegrate. Add 20 mL of methanol, shakefor 20 minutes, and add methanol to make exactly 50 mL. Centrifugethis solution, pipet V mL of the supernatant liquid, addmethanol to make exactly V´ mL so that each mL contains about20 µg of mosapride citrate (C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 ), and usethis solution as the sample solution. Proceed as directed in theAssay.Amount (mg) of mosapride citrate (C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 )= W S × (A T /A S ) × (V´/V) × (1/50)W S : Amount (mg) of mosapride citrate for assay, calculatedon the anhydrous basisDissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of 2nd fluid for dissolution test as the dissolutionmedium, the dissolution rate in 45 minutes ofMosapride Citrate Tablets is not less than 80%.Start the test with 1 tablet of Mosapride Citrate Tablets, withdrawnot less than 20 mL of the medium at the specified minuteafter starting the test, and filter through a membrane filter with apore size not exceeding 0.45 µm. Discard the first 10 mL of thefiltrate, pipet V mL of the subsequent filtrate, add the dissolutionmedium to make exactly V´ mL so that each mL contains about2.8 µg of mosapride citrate (C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 ) accordingto the labeled amount, and use this solution as the sample solution.Separately, weigh accurately about 30 mg of mosapridecitrate for assay (separately, determine the water content in the same manner as Mosapride Citrate Hydrate), and dissolvein the mobile phase to make exactly 100 mL. Pipet 2 mL of thissolution, add the mobile phase to make exactly 200 mL, and usethis solution as the standard solution. Perform the test with exactly50 µL each of the sample solution and standard solution asdirected under Liquid Chromatography according to thefollowing conditions, and determine the peak areas , A T and A S ,of mosapride in each solution.Dissolution rate (%) with respect to the labeled amount ofmosapride citrate (C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 )= W S × (A T /A S ) × (V´/V) × (1/C) × 9W S : Amount (mg) of mosapride citrate for assay, calculatedon the anhydrous basisC: Labeled amount (mg) of mosapride citrate(C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 ) in 1 tabletOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:274 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 8.82 g of trisodium citrate dihydratein 800 mL of water, adjust the pH to 3.3 with dilute hydrochloricacid, and add water to make 1000 mL. To 240 mL of this solutionadd 90 mL of methanol and 70 mL of acetonitrileFlow rate: Adjust the flow rate so that the retention time ofmosapride is about 9 minutes.System suitability—System performance: When the procedure is run with 50 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of mosapride are not less than 4000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with50 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area ofmosapride is not more than 2.0%.Assay Weigh accurately the mass of not less than 20Mosapride Citrate Tablets, and powder. Weigh accurately a portionof the powder, equivalent to about 10 mg of mosapride citrate(C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 ), and moisten with 2 mL of water.

2168 Official Monographs Supplement II, JP XVAdd 70 mL of methanol, shake for 20 minutes, add methanol tomake exactly 100 mL, and centrifuge. Pipet 10 mL of the supernatantliquid, add methanol to make exactly 50 mL, and usethis solution as the sample solution. Separately, weigh accuratelyabout 53 mg of mosapride citrate for assay (separately,determine the water content in the same manner asMosapride Citrate Hydrate), and dissolve in methanol to makeexactly 100 mL. Pipet 2 mL of this solution, add methanol tomake exactly 50 mL, and use this solution as the standard solution.Perform the test with the sample solution and standard solutionas directed under Ultraviolet-visible Spectrophotometry, and determine the absorbances, A T and A S , at 273 nm.Amount (mg) of mosapride citrate (C 21 H 25 ClFN 3 O 3·C 6 H 8 O 7 )= W S × (A T /A S ) × (1/5)W S : Amount (mg) of mosapride citrate for assay, calculatedon the anhydrous basis.Containers and storage Containers—Tight containers.Nicomol Tabletsニコモール 錠Add the following next to the Identification:Uniformity of dosage units It meets the requirementof the Mass variation test.NorethisteroneノルエチステロンChange the following to read:Description Norethisterone occurs as a white to pale yellowishwhite crystalline powder. it has no odor.It is sparingly soluble in ethanol (95), in acetone, and in tetrahydrofuran,slightly soluble in diethyl ether, and very slightlysoluble in water.It is affected by light.Optical rotation [α] 20D: –32 - –37º (after drying, 0.25g, acetone, 25 mL, 100 mm).PhenobarbitalフェノバルビタールChange the Origin/limits of content and Identificationto read:Phenobarbital, when dried, contains not less than99.0% and not more than 101.0% of C 12 H 12 N 2 O 3 .Identification (1) Determine the absorption spectrum of asolution of Phenobarbital in boric acid-potassium chloride-sodiumhydrochloride buffer solution, pH 9.6 (1 in 100000)as directed under Ultraviolet-visible Spectrophotometry ,and compare the spectrum with the Reference Spectrum: bothspectra exhibit similar intensities of absorption at the samewavelengths.(2) Determine the infrared absorption spectrum of Phenobarbitalas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similar intensitiesof absorption at the same wave numbers.10% Phenobarbital Powderフェノバルビタール 散 10%Change the Identification to read:Identification (1) Determine the absorption spectrum of thesample solution obtained in the Assay as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximumbetween 238 nm and 242 nm.(2) To 6 g of 10% Phenobarbital Powder add 150 mL ofethanol, shake well, and filter. Condense the filtrate in a waterbath to about 5 mL, filter with about 50 mL of water to collectthe crystals, and dry them at 105ºC for 2 hours. Determine theinfrared absorption spectrum of the crystals as directed in thepotassium bromide disk method under Infrared Spectrophotometry, and compare the spectrum with the ReferenceSpectrum: both spectra exhibit similar intensities of absorptionat the same wave numbers.Add the following next to the Identification:Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of 10% Phenobarbital Powder is not less than 80%.Start the test with an accurately weighted about 0.3 g of 10%Phenobarbital Powder, withdraw not less than 20 mL of the mediumat the specified minute after starting the test, and filterthrough a membrane filter with a pore size not exceeding 0.45µm. Discard the first 10 mL of the filtrate, pipet 5 mL of thesubsequent filtrate, add exactly 10 mL of boric acid-potassiumchloride-sodium hydroxide buffer solution, pH 9.6, and use this

Supplement II, JP XV Official Monographs 2169solution as the sample solution. Separately, weigh accuratelyabout 17 mg of phenobarbital for assay, previously dried at105ºC for 2 hours, and dissolve in water to make exactly 100mL. Pipet 5 mL of this solution, and add water to make exactly25 mL. Pipet 5 mL of this solution, add exactly 10 mL of boricacid-potassium chloride-sodium hydroxide buffer solution, pH9.6, and use this solution as the standard solution. Perform thetest with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , using amixture of boric acid-potassium chloride-sodium hydroxidebuffer solution, pH 9.6, and water (2:1) as the blank, and determinethe absorbances, A T and A S , at 240 nm.Dissolution rate (%) with respect to the labeled amount ofphenobarbital (C 12 H 12 N 2 O 3 )= (W S /W T ) × (A T /A S ) × (1/C) × 180W S : Amount (mg) of phenobarbital for assayW T : Amount (g) of 10% Phenobarbital PowderC: Labeled amount (mg) of phenobarbital (C 12 H 12 N 2 O 3 ) in 1gParticle size It meets the requirement.Change the Assay to read:Assay Weigh accurately about 0.2 g of 10% PhenobarbitalPowder, dissolve in a boric acid-potassium chloride-sodium hydroxidebuffer solution, pH 9.6 to make exactly 100 mL. Pipet 5mL of this solution, add a boric acid-potassium chloride-sodiumhydroxide buffer solution, pH 9.6 to make exactly 100 mL, anduse this solution as the sample solution. Separately, weigh accuratelyabout 20 mg of phenobarbital for assay, previously driedat 105ºC for 2 hours, and add a boric acid-potassium chloride-sodiumhydroxide buffer solution, pH 9.6 to make exactly100 mL. Pipet 5 mL of this solution, add a boric acid-potassiumchloride-sodium hydroxide buffer solution, pH 9.6 to make exactly100 mL, and use this solution as the standard solution.Perform the test with the sample solution and standard solutionas directed under Ultraviolet-visible Spectrophotometry ,using a boric acid-potassium chloride-sodium hydroxide buffersolution, pH 9.6 as the blank, and determine the absorbances, A Tand A S , at 240 nm.Amount (mg) of phenobarbital (C 12 H 12 N 2 O 3 )= W S × (A T /A S )W S : Amount (mg) of phenobarbital for assayPhenolsulfonphthalein Injectionフェノールスルホンフタレイン 注 射 液Add the following next to the pH:Bacterial endotoxins Less than 7.5 EU/mg.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter Perform the test accordingto Method 2: it meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Phenytoin Powderフェニトイン 散Change the Origin/limits of content and Assay toread:Phenytoin Powder contains not less than 95.0% andnot more than 105.0% of the labeled amount ofphenytoin (C 15 H 12 N 2 O 2 : 252.27).Assay Weigh accurately an amount of Phenytoin Powder,equivalent to about 50 mg of phenytoin (C 15 H 12 N 2 O 2 ), add 30mL of methanol, treat with ultrasonic waves for 15 minutes withoccasional shaking, shake for another 10 minutes, and addmethanol to make exactly 50 mL. Centrifuge this solution, pipet5 mL of the supernatant liquid, add exactly 5 mL of the internalstandard solution, and use this solution as the sample solution.Separately, weigh accurately about 25 mg of phenytoin for assay,previously dried at 105ºC for 2 hours, and dissolve in methanolto make exactly 25 mL. Pipet 5 mL of this solution, add exactly5 mL of the internal standard solution, and use this solution asthe standard solution. Perform the test with 10 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of phenytointo that of the internal standard.Amount (mg) of phenytoin (C 15 H 12 N 2 O 2 )= W S × (Q T /Q S ) × 2W S : Amount (mg) of phenytoin for assayInternal standard solution—A solution of propyl parahydroxybenzoatein the mobile phase (1 in 25000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:258 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silicagel for liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about40ºC.Mobile phase: A mixture of methanol and 0.02 mol/Lphosphate buffer solution, pH 3.5 (11:9)Flow rate: Adjust the flow rate so that the retention time of

2170 Official Monographs Supplement II, JP XVphenytoin is about 5 minutes.System suitability—System performance: When the procedure is run with 10µL of the standard solution under the above operating conditions,phenytoin and the internal standard are eluted in thisorder with the resolution between these peaks being not lessthan 8.System repeatability: When the test is repeated 6 timeswith 10 µL of the standard solution under the above operatingconditions, the relative standard deviation of the ratio of thepeak area of phenytoin to that of the internal standard is notmore than 1.0%.Phenytoin Tabletsフェニトイン 錠Change the Origin/limits of content and Identificationto read:Phenytoin Tablets contain not less than 95.0% andnot more than 105.0% of the labeled amount ofphenytoin (C 15 H 12 N 2 O 2 : 252.27).Identification Weigh a portion of powdered Phenytoin Tablets,equivalent to about 0.3 g of Phenytoin, transfer to a separator,and add 1 mL of dilute hydrochloric acid and 10 mL of water.Extract with 100 mL of diethyl ether, then with four 25-mL potionsof diethyl ether. Combine the extracts, evaporate the diethylether in a water bath, and dry the residue at 105ºC for 2hours. Proceed with the residue as directed in the Identificationunder Phenytoin.Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Phenytoin Tablets add 3V/5 mL of a mixture ofwater and acetonitrile (1:1), treat with ultrasonic waves for 15minutes with occasional shaking, shake for another 10 minutes,and add a mixture of water and acetonitrile (1:1) to make exactlyV mL so that each mL contains about 1 mg of phenytoin(C 15 H 12 N 2 O 2 ). Centrifuge this solution, pipet 5 mL of the supernatantliquid, add exactly 5 mL of the internal standard solution,and use this solution as the sample solution. Proceed as directedin the Assay.Assay Weigh accurately the mass of not less than 20 PhenytoinTablets, and powder in an agate mortar. Weigh accurately aportion of the powder, equivalent to about 50 mg of phenytoin(C 15 H 12 N 2 O 2 ), add 30 mL of a mixture of water and acetonitrile(1:1), treat with ultrasound waves for 15 minutes with occasionalshaking, shake for another 10 minutes, and add a mixtureof water and acetonitrile (1:1) to make exactly 50 mL. Centrifugethis solution, pipet 5 mL of the supernatant liquid, add exactly5 mL of the internal standard solution, and use this solutionas the sample solution. Separately, weigh accurately about25 mg of phenytoin for assay, previously dried at 105ºC for 2hours, and dissolve in a mixture of water and acetonitrile (1:1)to make exactly 25 mL. Pipet 5 mL of this solution, add exactly5 mL of the internal standard solution, and use this solution asthe standard solution. Perform the test with 10 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of phenytointo that of the internal standard.Amount (mg) of phenytoin (C 15 H 12 N 2 O 2 ) = W S × (Q T /Q S ) × 2W S : Amount (mg) of phenytoin for assayInternal standard solution—A solution of propyl parahydroxybenzoatein the mobile phase (1 in 25000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:258 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of methanol and 0.02 mol/L phosphatebuffer solution, pH 3.5 (11:9)Flow rate: Adjust the flow rate so that the retention time ofphenytoin is about 5 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,phenytoin and the internal standard are eluted in this order withthe resolution between these peaks being not less than 8.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof phenytoin to that of the internal standard is not more than1.0%.Amount (mg) of phenytoin (C 15 H 12 N 2 O 2 )= W S × (Q T /Q S ) × (V/25)W S : Amount (mg) of phenytoin for assayInternal standard solution—A solution of propyl parahydroxybenzoatein the mobile phase (1 in 25000)Change the Assay to read:

Supplement II, JP XV Official Monographs 2171Add the followingPimozideピモジドC 28 H 29 F 2 N 3 O: 461.551-{1-[4,4-Bis(4-fluorophenyl)butyl]piperidin-4-yl}-1,3-dihydro-2H-benzoimidazol-2-one [2062-78-4]Pimozide contains not less than 98.5% and not morethan 101.0% of C 28 H 29 F 2 N 3 O.Description Pimozide occurs as a white to pale yellowishwhite powder.It is freely soluble in acetic acid (100), slightly soluble inmethanol and in ethanol (99.5), and practically insoluble in water.Identification (1) Determine the absorption spectrum of asolution of Pimozide in methanol (1 in 25000) as directed underUltraviolet-visible Spectrophotometry , and compare thespectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Pimozideas directed in the potassium bromide disk method under InfraredSpectrophotometry , and compare the spectrum with theReference Spectrum: both spectra exhibit similar intensities ofabsorption at the same wave numbers.Melting point 216 - 220ºC.Purity (1) Heavy metals —Proceed with 2.0 g ofPimozide according to Method 2, and perform the test. Preparethe control solution with 2.0 mL of Standard Lead Solution byusing 5 mL of sulfuric acid (not more than 10 ppm).(2) Arsenic —Prepare the test solution with 1.0 g ofPimozide according to Method 3, and perform the test (not morethan 2 ppm).(3) Related substances—Dissolve 0.10 g of Pimozide in 10mL of methanol, and use this solution as the sample solution.Pipet 1 mL of this solution, add methanol to make exactly 200mL, and use this solution as the standard solution. Perform thetest with exactly 10 µL each of the sample solution and standardsolution as directed under Liquid Chromatography accordingto the following conditions. Determine each peak areaof both solutions by the automatic integration method: the areaof the peak other than the peak of pimozide from the samplesolution is not lager than the peak area of pimozide from thestandard solution, and the total area of the peaks other than thepeak of pimozide from the sample solution is not larger than 1.5times of the peak area of pimozide from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:280 nm).Column: A stainless steel column 4.6 mm in inside diameterand 10 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase A: Dissolve 2.5 g of ammonium acetate and 8.5g of tetrabutylammonium hydrogensulfate in water to make1000 mL.Mobile phase B: AcetonitrileFlowing of the mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 – 10 80 → 70 20 → 3010 – 15 70 30Flow rate: 2.0 mL per minute.Time span of measurement: 1.5 times as long as the retentiontime of pimozide.System suitability—Test for required detectability: Pipet 1 mL of the standard solution,and add methanol to make exactly 10 mL. Confirm thatthe peak area of pimozide obtained from 10 µL of this solutionis equivalent to 8 to 12% of that of pimozide from the standardsolution.System performance: Dissolve 5 mg of Pimozide and 2 mg ofmebendazole in methanol to make 100 mL. When the procedureis run with 10 µL of this solution under the above operatingconditions, mebendazole and pimozide are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of pimozideis not more than 2.0%.(4) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, 105ºC, 3hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 70 mg of dried Pimozide, dissolvein 25 mL of acetic acid for nonaqueous titration, and titrate with 0.02 mol/L perchloric acid VS (indicator: 2drops of crystal violet TS). Perform a blank determination in thesame manner, and make any necessary correction.Each mL of 0.02 mol/L perchloric acid VS= 9.231 mg of C 28 H 29 F 2 N 3 OContainers and storage Containers—Well-closed containers.

2172 Official Monographs Supplement II, JP XVAdd the following:Pioglitazone Hydrochlorideピオグリタゾン 塩 酸 塩C 19 H 20 N 2 O 3 S·HCl: 392.90(5RS)-5-{4-[2-(5-Ethylpyridin-2-yl)ethoxy]benzyl}thiazolidine-2,4-dionemonohydrochloride [112529-15-4]and enantiomerPioglitazone Hydrochloride contains not less than99.0% and not more than 101.0% of C 19 H 20 N 2 O 3 S·HCl,calculated on the anhydrous basis.Description Pioglitazone Hydrochloride occurs as whitecrystals or crystalline powder.It is soluble in N,N-dimethylformamide and in methanol,slightly soluble in ethanol (99.5), and practically insoluble inwater.It dissolves in 0.1 mol/L hydrochloric acid TS.A solution of Pioglitazone Hydrochloride inN,N-dimethylformamide (1 in 20) shows no optical rotation.Identification (1) Determine the absorption spectrum of asolution of Pioglitazone Hydrochloride in 0.1 mol/L hydrochloricacid TS (1 in 50000) as directed under Ultraviolet-visibleSpectrophotometry , and compare the spectrum with theReference Spectrum or the spectrum of a solution of PioglitazoneHydrochloride Reference Standard prepared in the samemanner as the sample solution: both spectra exhibit similar intensitiesof absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of PioglitazoneHydrochloride as directed in the potassium bromide diskmethod under Infrared Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrum ofPioglitazone Hydrochloride Reference Standard: both spectraexhibit similar intensities of absorption at the same wave numbers.(3) Dissolve 50 mg of Pioglitazone Hydrochloride in 1 mLof nitric acid, and add 4 mL of dilute nitric acid: the solutionresponds to the Qualitative Tests (2) for chloride.Purity (1) Heavy metals —Proceed with 1.0 g ofPioglitazone Hydrochloride according to Method 4, and performthe test. After incineration, use 3 mL of hydrobromic acid insteadof 3 mL of hydrochloric acid. Prepare the control solutionwith 1.0 mL of Standard Lead Solution (not more than 10 ppm).(2) Related substances—Dissolve 20 mg of PioglitazoneHydrochloride in 20 mL of methanol, add the mobile phase tomake 100 mL, and use this solution as the sample solution. Pipet1 mL of this solution, add the mobile phase to make exactly200 mL, and use this solution as the standard solution. Performthe test with exactly 40 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area of both solutions by the automatic integration method:the area of the peaks, having the relative retention times ofabout 0.7, about 1.4 and about 3.0 with respect to pioglitazonefrom the sample solution, is not larger than 2/5 times the peakarea of pioglitazone from the standard solution, and the area ofeach peak other than the peak of pioglitazone and other thanthose mentioned above is smaller than 1/5 times the peak area ofpioglitazone from the standard solution. Furthermore, the totalarea of the peaks other than the peak of pioglitazone is not largerthan the peak area of pioglitazone from the standard solution.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 4 times as long as the retentiontime of pioglitazone, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 1 mL of the standard solution,and add the mobile phase to make exactly 10 mL. Confirmthat the peak area of pioglitazone obtained from 40 µL ofthis solution is equivalent to 7 to 13% of that of pioglitazonefrom the standard solution.System performance: Dissolve 50 mg of Pioglitazone Hydrochloridein 10 mL of a solution of benzophenone in methanol(1 in 750), and add methanol to make 100 mL. To 1 mL of thissolution add the mobile phase to make 20 mL. When the procedureis run with 40 µL of this solution under the above operatingconditions, pioglitazone and benzophenone are eluted in thisorder with the resolution between these peaks being not lessthan 10.System repeatability: When the test is repeated 6 times with40 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of pioglitazoneis not more than 2.0%.(3) Residual solvent—Being specified separately.Water Not more than 0.2% (0.5 g, coulometric titration).For anolyte solution, use anolyte solution for water determinationA.Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 50 mg each of PioglitazoneHydrochloride and Pioglitazone Hydrochloride Reference Standard(separately, determine the water content in thesame manner as Pioglitazone Hydrochloride), add exactly 10mL of the internal standard solution and methanol to make 100mL. Pipet 2 mL each of these solutions, add the mobile phase tomake 20 mL, and use these solutions as the sample solution andstandard solution, respectively. Perform the test with 20 µL eachof the sample solution and standard solution as directed underLiquid Chromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of

Supplement II, JP XV Official Monographs 2173pioglitazone to that of the internal standard.Amount (mg) of pioglitazone hydrochloride (C 19 H 20 N 2 O 3 S·HCl)= W S × (Q T /Q S )W S : Amount (mg) of Pioglitazone Hydrochloride ReferenceStandard, calculated on the anhydrous basisInternal standard solution—A solution of benzophenone inmethanol (1 in 750)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:269 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of ammonium acetate solution (77in 10000), acetonitrile and acetic acid (100) (25:25:1)Flow rate: Adjust the flow rate so that the retention time ofpioglitazone is about 7 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,pioglitazone and the internal standard are eluted in this orderwith the resolution between these peaks being not less than 10.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of pioglitazoneis not more than 1.0%.Containers and storage Containers—Well-closed containers.Pipemidic Acid Hydrateピペミド 酸 水 和 物Delete the Loss on drying and change the Origin/limitsof content and Purity (1) and (2) to read:Pipemidic Acid Hydrate contains not less than98.5% and not more than 101.0% of pipemidic acid(C 14 H 17 N 5 O 3 : 303.32), calculated on the anhydrous basis.Description Pipemidic Acid Hydrate occurs as a pale yellow,crystalline powder.It is freely soluble in acetic acid (100), very slightly soluble inwater and in ethanol (99.5), and practically insoluble in methanol.It dissolves in sodium hydroxide TS.It is gradually colored on exposure to light.Melting point: about 250ºC (with decomposition).Purity (1) Chloride —Dissolve 1.0 g of PipemidicAcid Hydrate in 35 mL of water and 10 mL of sodium hydroxideTS, shake well with 15 mL of dilute nitric acid, and filterthrough a glass filter (G3). To 30 mL of the filtrate add 6 mL ofdilute nitric acid and water to make 50 mL. Perform the test usingthis solution as the test solution. Prepare the control solutionas follows: to 0.30 mL of 0.01 mol/L hydrochloric acid VS add5 mL of sodium hydroxide TS, 13.5 mL of dilute nitric acid andwater to make 50 mL (not more than 0.021%).(2) Sulfate —Dissolve 1.0 g of Pipemidic Acid Hydratein 35 mL of water and 10 mL of sodium hydroxide TS,shake well with 15 mL of dilute hydrochloric acid, and filterthrough a glass filter (G3). To 30 mL of the filtrate add water tomake 50 mL. Perform the test using this solution as the test solution.Prepare the control solution as follows: to 0.50 mL of0.005 mol/L sulfuric acid VS add 5 mL of sodium hydroxide TS,7.5 mL of dilute hydrochloric acid and water to make 50 mL(not more than 0.048%).Add the following next to the Purity:Water 14.5 - 16.0% (20 mg, coulometric titration)Change the Assay to read:Assay Weigh accurately about 0.35 g of Pipemidic Acid Hydrate,dissolve in 40 mL of acetic acid (100), and titrate with 0.1 mol/L perchloric acid VS (potentiometric titration).Perform a blank determination in the same manner, and makeany necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 30.33 mg of C 14 H 17 N 5 O 3Add the following:Pivmecillinam HydrochlorideTabletsピブメシリナム 塩 酸 塩 錠Pivmecillinam Hydrochloride Tablets contains notless than 93.0% and not more than 107.0% of the labeledpotency of mecillinam (C 15 H 23 N 3 O 3 S: 325.43).Method of preparation Prepare as directed under Tablets,with Pivmecillinam Hydrochloride.Identification Powder Pivmecillinam Hydrochloride Tablets,dissolve a portion of the powder, equivalent to 35 mg (potency)of Pivmecillinam Hydrochloride according to the labeledamount, in 4 mL of a mixture of acetonitrile and acetic acid(100) (97:3), and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 2 mL of the filtrate,and use the subsequent filtrate as the sample solution. Separatelydissolve 25 mg of Pivmecillinam Hydrochloride ReferenceStandard in 2 mL of a mixture of acetonitrile and aceticacid (100) (97:3), and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 2 µL each of the samplesolution and standard solution on a plate of silica gel forthin-layer chromatography, and immediately develop the plate

2174 Official Monographs Supplement II, JP XVwith a mixture of acetone, water and acetic acid (100) (10:1:1)to a distance of about 12 cm, and air-dry the plate. Allow theplate to stand in iodine vapor for 10 minutes: the principal spotobtained from the sample solution has the same R f value as thespot from the standard solution.Water Not more than 3.0% (1g of powdered PivmecillinamHydrochloride Tablets, volumetric titration, direct titration).Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Pivmecillinam Hydrochloride Tablets add 40mL of the mobile phase, shake vigorously for 10 minutes, andadd the mobile phase to make exactly 50 mL. Pipet V mL,equivalent to about 10 mg (potency) of Pivmecillinam Hydrochloride,add exactly 5 mL of the internal standard solution andthe mobile phase to make 50 mL, filter through a membrane filterwith a pore size not exceeding 0.45 µm, discard the first 10mL of the filtrate, and use the subsequent filtrate as the samplesolution. Separately, weigh accurately an amount of PivmecillinamHydrochloride Reference Standard, equivalent to about 20mg (potency), dissolve in the mobile phase, add exactly 10 mLof the internal standard solution, add the mobile phase to make100 mL, and use this solution as the standard solution. Then,proceed as directed in the Assay under Pivmecillinam Hydrochloride.Amount [mg (potency)] of mecillinam (C 15 H 23 N 3 O 3 S)= W S × (Q T /Q S ) × (25/V)W S : Amount [mg (potency)] of Pivmecillinam HydrochlorideReference StandardInternal standard solution—A solution of diphenyl in the mobilephase (1 in 12500)Disintegration Perform the test using the disk: itmeets the requirement.Assay Weigh accurately the mass of not less than 20 PivmecillinamHydrochloride Tablets, and powder. Weigh accurately aportion of the powder, equivalent to about 0.1 g (potency) ofPivmecillinam Hydrochloride, add 50 mL of the mobile phase,shake vigorously for 10 minutes, and add the mobile phase tomake exactly 100 mL. Pipet 10 mL of this solution, add exactly5 mL of the internal standard solution and the mobile phase tomake 50 mL, filter through a membrane filter with a pore sizenot exceeding 0.45 µm, discard the first 10 mL of the filtrate,and use the subsequent filtrate as the sample solution. Separately,weigh accurately an amount of Pivmecillinam HydrochlorideReference Standard, equivalent to about 20 mg (potency), dissolvein the mobile phase, add exactly 10 mL of the internalstandard solution, add the mobile phase to make 100 mL, anduse this solution as the standard solution. Then, proceed as directedin the Assay under Pivmecillinam Hydrochloride.Amount [mg (potency)] of mecillinam (C 15 H 23 N 3 O 3 S)= W S × (Q T /Q S ) × 5W S : Amount [mg (potency)] of Pivmecillinam HydrochlorideReference StandardInternal standard solution—A solution of diphenyl in the mobilephase (1 in 12500)Containers and storage Containers—Tight containers.Potato StarchバレイショデンプンChange the Identification to read:Identification (1) Examined under a microscope using a mixture of water and glycerin (1:1), Potato Starch presentsgranules, either irregularly shaped, ovoid or pear-shaped,usually 30-100 µm in size but occasionally exceeding 100 µm,or rounded, 10-35 µm in size. There are occasional compoundgranules having two to four components. The ovoid andpear-shaped granules have an eccentric hilum and the roundedgranules acentric or slightly eccentric hilum. All granules showclearly visible concentric striations. Between orthogonally orientedpolarizing plates or prisms, the granules show a distinctblack cross intersecting at the hilum.Add the following next to Purity (3):Purity ◆ (4) Foreign matter—Under a microscope ,Potato Starch does not contain starch granules of any other origin.It may contain a minute quantity, if any, of fragments of thetissue of the original plant. ◆Add the following:Prazosin Hydrochlorideプラゾシン 塩 酸 塩C 19 H 21 N 5 O 4·HCl: 419.861-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-4-(2-furoyl)piperazine monohydrochloride [19237-84-4]Prazosin Hydrochloride, when dried, contains notless than 97.0% and not more than 103.0% ofC 19 H 21 N 5 O 4·HCl.Description Prazosin Hydrochloride occurs as a white crystallinepowder.

Supplement II, JP XV Official Monographs 2175It is slightly soluble in methanol, very slightly soluble inethanol (99.5) and practically insoluble in water.It gradually turns pale yellowish white on exposure to light.Melting point: about 270ºC (with decomposition).Identification (1) Determine the absorption spectrum of asolution of Prazosin Hydrochloride in 0.01 mol/L hydrochloricacid-methanol TS (1 in 200000) as directed under Ultraviolet-visibleSpectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of a solutionof Prazosin Hydrochloride Reference Standard prepared in thesame manner as the sample solution: both spectra exhibit similarintensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of PrazosinHydrochloride as directed in the potassium chloride disk methodunder Infrared Spectrophotometry , and compare thespectrum with the Reference Spectrum or the spectrum of PrazosinHydrochloride Reference Standard: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) To 0.1 g of Prazosin Hydrochloride add 5 mL of waterand 1 mL of ammonia TS, shake, allow to stand for 5 minutes,and filter. Render the filtrate acid with acetic acid (100): the solutionresponds to the Qualitative Tests for chloride.Purity (1) Heavy metals —Proceed with 1.0 g ofPrazosin Hydrochloride according to Method 4, and perform thetest. Prepare the control solution with 1.0 mL of Standard LeadSolution (not more than 10 ppm).(2) Related substances—Dissolve 20 mg of Prazosin Hydrochloridein 20 mL of the mobile phase, and use this solutionas the sample solution. Pipet 1 mL of this solution, and add themobile phase to make exactly 100 mL. Pipet 1 mL of this solution,add the mobile phase to make exactly 10 mL, and use thissolution as the standard solution. Perform the test with exactly20 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions. Determine each peak area of both solutionsby the automatic integration method: the area of each peakother than the peak of prazosin from the sample solution is notlarger than 2 times the peak area of prazosin from the standardsolution, and the total area of the peaks other than the peak ofprazosin from the sample solution is not larger than 5 times thepeak area of prazosin from the standard solution.Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: Dissolve 3.484 g of sodium 1-pentane sulfonateand 18 mL of tetramethylammonium hydroxide in 900mL of water, adjust the pH to 5.0 with acetic acid (100), and addwater to make 1000 mL. To this solution add 1000 mL ofmethanolFlow rate: Adjust the flow rate so that the retention time ofprazosin is about 9 minutes.Time span of measurement: About 6 times as long as the retentiontime of prazosin.System suitability—Test for required detectability: Pipet 5 mL of the standard solution,and add the mobile phase to make exactly 10 mL. Confirmthat the peak area of prazosin obtained from 20 µL of thissolution is equivalent to 35 to 65% of that of prazosin from thestandard solution.System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of prazosin are not less than 4000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of prazosinis not more than 2.0%.(3) Residual solvent—Being specified separately.Loss on drying Not more than 1.0% (1 g, 105ºC, 2hours).Residue on ignition Not more than 0.2% (1 g).Assay Weigh accurately about 25 mg each of Prazosin Hydrochlorideand Prazosin Hydrochloride Reference Standard,previously dried, and dissolve each in methanol to make exactly50 mL. Pipet 3 mL each of these solutions, and add a mixture ofmethanol and water (7:3) to make exactly 100 mL, and use thesesolutions as the sample solution and standard solution, respectively.Perform the test with exactly 10 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions, andcalculate the peak areas, A T and A S , of prazosin in each solution.Amount (mg) of prazosin hydrochloride (C 19 H 21 N 5 O 4·HCl)= W S × (A T /A S )W S : Amount (mg) of Prazosin Hydrochloride ReferenceStandardOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm)Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with silica gel for liquid chromatography(5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of methanol, water, acetic acid (100)and diethylamine (3500: 1500: 50:1)Flow rate: Adjust the flow rate so that the retention time ofprazosin is about 8 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of prazosin are not less than 5000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of prazosin

2176 Official Monographs Supplement II, JP XVis not more than 1.0%.Containers and storage Containers—Well-closed containers.Storage—Light-resistant.Add the following:Prednisolone Sodium Phosphateプレドニゾロンリン 酸 エステルナトリウムC 21 H 27 Na 2 O 8 P: 484.39Disodium 11β,17,21-trihydroxypregna-1,4-diene-3,20-dione 21-phosphate [125-02-0]Prednisolone Sodium Phosphate contains not lessthan 97.0% and not more than 103.0% ofC 21 H 27 Na 2 O 8 P, calculated on the anhydrous basis.Description Prednisolone Sodium Phosphate occurs as awhite to pale yellow powder.It is freely soluble in water, soluble in methanol, and practicallyinsoluble in ethanol (99.5).It is hygroscopic.Identification (1) Moisten 1.0 g of Prednisolone SodiumPhosphate with a small amount of sulfuric acid, and graduallyheat to incinerate. After cooling, dissolve the residue in 10 mLof dilute nitric acid, and heat in a water bath for 30 minutes. Aftercooling, filter if necessary. This solution responds to theQualitative Tests for phosphate.(2) Dissolve 2 mg of Prednisolone Sodium Phosphate in 2mL of sulfuric acid, and allow to stand for 2 minutes: a deep redcolor, without fluorescence, develops.(3) Determine the absorption spectrum of a solution ofPrednisolone Sodium Phosphate (1 in 50000) as directed underUltraviolet-visible Spectrophotometry , and compare thespectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wavelengths.(4) Determine the infrared absorption spectrum of PrednisoloneSodium Phosphate as directed in the potassium bromidedisk method under Infrared Spectrophotometry , andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavenumbers.(5) The solution obtained in (1) responds to the QualitativeTests for sodium salt.Optical rotation [α] 20D: +96 - +103º (1 g, calculatedon the anhydrous basis, phosphate buffer solution, pH 7.0, 100mL, 100 mm).pH Dissolve 1.0 g of Prednisolone Sodium Phosphatein 100 mL of water: the pH of the solution is between 7.5 and9.0.Purity (1) Clarity and color of solution—Dissolve 1.0 g ofPrednisolone Sodium Phosphate in 10 mL of water: the solutionis clear and not more colored than the following control solutionControl solution: To a mixture of 3.0 mL of Cobalt (II) ChlorideColorimetric Stock Solution, 3.0 mL of Iron (III) ChlorideColorimetric Stock Solution and 2.4 mL of Copper (II) SulfateColorimetric Stock Solution add diluted hydrochloric acid (1 in40) to make 10 mL. To 2.5 mL of this solution add diluted hydrochloricacid (1 in 40) to make 100 mL.(2) Heavy metals —Proceed with 0.5 g of PrednisoloneSodium Phosphate according to Method 3, and perform thetest. Prepare the control solution with 2.0 mL of Standard LeadSolution (not more than 40 ppm).(3) Free phosphoric acid—Weigh accurately about 0.25 g ofPrednisolone Sodium Phosphate, dissolve in water to make exactly100 mL, and use this solution as the sample solution. Pipet5 mL of the sample solution and Phosphoric Acid Standard Solution,add 2.5 mL of hexaammonium heptamolybdate-sulfuricacid TS and 1 mL of 1-amino-2-naphtol-4-sulfonic acid TS,shake, add water to make exactly 25 mL, and allow to stand at20±1ºC for 30 minutes. Perform the test with these solutions asdirected under Ultraviolet-visible Spectrophotometry ,using a solution prepared with 5 mL of water in the same manneras the blank. Determine the absorbances, A T and A S , of eachsolution from the sample solution and standard solution at 740nm: the content of free phosphoric acid is not more than 1.0%Content (%) of free phosphoric acid (H 3 PO 4 )= (1/W) × (A T /A S ) × 257.8W: Amount (mg) of Prednisolone Sodium Phosphate, calculatedon the anhydrous basis.(4) Related substances—Dissolve 10 mg of PrednisoloneSodium Phosphate in 100 mL of the mobile phase, and use thissolution as the sample solution. Pipet 2 mL of this solution, addthe mobile phase to make exactly 100 mL, and use this solutionas the standard solution. Perform the test with exactly 20 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions. Determine each peak area of both solutions bythe automatic integration method: the area of each peak otherthan the peak of prednisolone phosphate from the sample solutionis not larger than 1.5 times the peak area of prednisolonephosphate from the standard solution, and the total area of thepeaks other than the peak of prednisolone phosphate from thesample solution is not larger than 2.5 times the peak area ofprednisolone phosphate from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:245 nm)Column: A stainless steel column 4.6 mm in inside diameterand 10 cm in length, packed with octadecylsilanized silica gel

Supplement II, JP XV Official Monographs 2177for liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 6.80 g of potassium dihydrogenphosphate in water to make 1000 mL, and adjust the pH to 2.5with phosphoric acid. To 1000 mL of this solution add 250 mLof acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofprednisolone phosphate is about 7 minutes.Time span of measurement: About 4 times as long as the retentiontime of prednisolone phosphate.System suitability—Test for required detectability: Pipet 5 mL of the standard solution,and add the mobile phase to make exactly 50 mL. Confirmthat the peak area of prednisolone phosphate obtained from20 µL of this solution is equivalent to 7 to 13% of that of prednisolonephosphate from the standard solution.System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of prednisolone phosphate are not less than 3000 and notmore than 2.0, respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of prednisolonephosphate is not more than 2.0%.(5) Residual solvent—Being specified separately.Water Not more than 8.0% (0.1 g, volumetric titration,direct titration).Assay Weigh accurately about 0.1 g of Prednisolone SodiumPhosphate, and dissolve in water to make exactly 100 mL. Pipet2 mL of this solution, add 1 mL of alkaline phosphatase TS, andallow to stand for 2 hours with occasional shaking. To this solutionadd exactly 20 mL of 1-octanol, and shake vigorously. Centrifugethis solution, pipet 10 mL of the 1-octanol layer, add1-octanol to make exactly 50 mL, and use this solution as thesample solution. Separately, weigh accurately about 25 mg ofPrednisolone Reference Standard, previously dried at 105ºC for3 hours, and dissolve in 1-octanol to make exactly 100 mL. Pipet6 mL of this solution, add a solution prepared by adding 1mL of alkaline phosphatase TS to 2 mL water and being allowedto stand for 2 hours with occasional gentle shaking, add exactly14 mL of 1-octanol, and shake vigorously. Proceed in the samemanner as the sample solution to make the standard solution.Perform the test with the sample solution and standard solutionas directed under Ultraviolet-visible Spectrophotometry ,using 1-octanol as the blank, and determine the absorbances, A Tand A S , at 245 nm.Amount (mg) of prednisolone sodium phosphate(C 21 H 27 Na 2 O 8 P)= W S × (A T /A S ) × 3 × 1.3439W S : Amount (mg) of Prednisolone Reference StandardContainers and storage Containers—Tight containers.Probenecid Tabletsプロベネシド 錠Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Probenecid Tablets add 30 mL of water and 2mL of 1 mol/L hydrochloric acid TS, treat with ultrasonic waveswith occasional shaking to disintegrate the tablet completely,and add ethanol (99.5) to make exactly 100 mL. Centrifuge thissolution, pipet 3 mL of the supernatant liquid, and add 1 mL of 1mol/L hydrochloric acid TS and ethanol (99.5) to make exactly50 mL. Pipet 5 mL of this solution, and add ethanol (99.5) tomake exactly V mL so that each mL contains about 15 µg ofprobenecid (C 13 H 19 NO 4 S), and use this solution as the samplesolution. Separately, weigh accurately about 0.125 g of ProbenecidReference Standard, previously dried at 105ºC for 4hours, dissolve in 15 mL of water, 1 mL of 1 mol/L hydrochloricacid TS and ethanol (99.5) to make exactly 50 mL. Pipet 3 mLof this solution, and add 1 mL of 1 mol/L hydrochloric acid TSand ethanol (99.5) to make exactly 50 mL. Pipet 5 mL of thissolution, add ethanol (99.5) to make exactly 50 mL, and use thissolution as the standard solution. Perform the test with the samplesolution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , using a solution, preparedby adding ethanol (99.5) to 1 mL of 0.1 mol/L hydrochloric acidTS to make exactly 50 mL, as the blank, and determine the absorbances,A T and A S , at 248 nm.Amount (mg) of probenecid (C 13 H 19 NO 4 S)= W S × (A T /A S ) × (V/25)W S : Amount (mg) of Probenecid Reference StandardAdd the following:ProbucolプロブコールC 31 H 48 O 2 S 2 : 516.844,4´-[Propan-2,2-diylbis(sulfandiyl)]bis[2,6-bis(1,1-dimethylethyl)phenol] [23288-49-5]Probucol, when dried, contains not less than 98.5%and not more than 101.0% of C 31 H 48 O 2 S 2 .Description Probucol occurs as a white crystalline powder.

2178 Official Monographs Supplement II, JP XVIt is very soluble in tetrahydrofuran, freely soluble in ethanol(99.5), soluble in methanol, and practically insoluble in water.It gradually turns light yellow on exposure to light.Identification (1) Determine the absorption spectrum of asolution of Probucol in methanol (1 in 100000) as directed underUltraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum or the spectrum of asolution of Probucol Reference Standard prepared in the samemanner as the sample solution: both spectra exhibit similar intensitiesof absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Probucolas directed in the potassium bromide disk method under InfraredSpectrophotometry , and compare the spectrum with theReference Spectrum or the spectrum of Probucol ReferenceStandard: both spectra exhibit similar intensities of absorption atthe same wave numbers.Melting point 125 - 128ºC.Purity (1) Heavy metals —Proceed with 2.0 g ofProbucol according to Method 2, and perform the test. Preparethe control solution with 2.0 mL of Standard Lead Solution (notmore than 10 ppm).(2) Related substances—Conduct this procedure usinglight-resistant vessels. Dissolve 0.40 g of Probucol in 5 mL ofethanol (99.5), add the mobile phase to make 20 mL, and usethis solution as the sample solution. Pipet 1 mL of this solution,and add the mobile phase to make exactly 50 mL. Pipet 1 mL ofthis solution, add the mobile phase to make exactly 100 mL, anduse this solution as the standard solution. Perform the test withexactly 5 µL each of the sample solution and standard solutionas directed under Liquid Chromatography according tothe following conditions. Determine each peak area of both solutionsby the automatic integration method: the area of the peakhaving the relative retention time of about 0.9 with respect toprobucol from the sample solution is not larger than the peakarea of probucol from the standard solution; the area of peakhaving the relative retention time of about 1.9 with respect toprobucol from the sample solution is no larger than 25 times thepeak area of probucol from the standard solution; and the areaof each peak other than the peak of probucol and other than thepeaks mentioned above is not larger than 5 times the peak areaof probucol from the standard solution. Furthermore, the totalarea of the peaks other than probucol from the sample solutionis not larger than 50 times the peak area of probucol from thestandard solution. For this calculation, use the areas of the peaks,having the relative retention times of about 0.9 and about 1.9with respect to probucol, after multiplying by their relative responsefactors, 1.2 and 1.4, respectively.Operating conditions—Detector, column, column temperature, mobile phase andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 3 times as long as the retentiontime of probucol, beginning after the solvent peak, excludingthe peak having the relative retention time of about 0.5with respect to probucol.System suitability—Test for required detectability: Pipet 2 mL of the standard solution,and add the mobile phase to make exactly 10 mL. Confirmthat the peak area of probucol obtained from 5 µL of thissolution is equivalent to 14 to 26% of that of probucol from thestandard solution.System performance: To 1 mL of the sample solution add themobile phase to make 50 mL. To 1 mL of this solution add 1 mLof a solution of phthalic acid bis(cis-3,3,5-trimethylcyclohexyl)in the mobile phase (1 in 1000), 5 mL of ethanol (99.5), and themobile phase to make 20 mL. When the procedure is run with 5µL of this solution under the above operating conditions,phthalic acid bis(cis-3,3,5-trimethylcyclohexyl) and probucolare eluted in this order with the resolution between these peaksbeing not less than 6.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of probucol isnot more than 5%.(3) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g, in vacuum,80ºC, 1 hour).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 60 mg each of Probucol andProbucol Reference Standard, previously dried, dissolve each in5 mL of tetrahydrofuran, and add the mobile phase to make exactly50 mL. Pipet 5 mL each of these solutions, add exactly 5mL of the internal standard solution and the mobile phase tomake 100 mL, and use these solutions as the sample solutionand standard solution. Perform the test with 10 µL each of thesample solution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of probucolto that of the internal standard.Amount (mg) of probucol (C 31 H 48 O 2 S 2 )= W S × (Q T /Q S )W S : Amount (mg) of Probucol Reference StandardInternal standard solution—Dissolve 0.2 g of phthalic acidbis(cis-3,3,5-trimethylcyclohexyl) in 1 mL of tetrahydrofuran,and add the mobile phase to make 50 mL.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:242 nm)Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of acetonitrile and water (93:7)Flow rate: Adjust the flow rate so that the retention time ofprobucol is about 13 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,

Supplement II, JP XV Official Monographs 2179the internal standard solution and probucol are eluted in this orderwith the resolution between these peaks being not less than6.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof probucol to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Storage—Light-resistant.Procainamide Hydrochlorideプロカインアミド 塩 酸 塩Change the Origin/limits of contents, Description,Identification, Purity and Loss on drying to read:Procainamide Hydrochloride, when dried, containsnot less than 98.0% and not more than 101.0% ofC 13 H 21 N 3 O·HCl.Description Procainamide Hydrochloride occurs as a white tolight yellow crystalline powder.It is very soluble in water and soluble in ethanol (99.5).It is hygroscopic.Identification (1) Determine the infrared absorption spectrumof Procainamide Hydrochloride, previously dried, as directedin the potassium chloride disk method under InfraredSpectrophotometry , and compare the spectrum with theReference Spectrum: both spectra exhibit similar intensities ofabsorption at the same wave numbers.(2) A solution of Procainamide Hydrochloride (1 in 20) respondsto the Qualitative Tests for chloride.Purity (1) Clarity and color of solution—Dissolve 1.0 g ofProcainamide Hydrochloride in 10 mL of water: the solution isclear and colorless.(2) Heavy metals —Proceed with 2.0 g of ProcainamideHydrochloride according to Method 2, and perform thetest. Prepare the control solution with 2.0 mL of Standard LeadSolution (not more than 10 ppm).(3) Arsenic —Prepare the test solution with 1.0 g ofProcainamide Hydrochloride according to Method 1, and performthe test (not more than 2 ppm).(4) Related substances—Dissolve 50 mg of ProcainamideHydrochloride in 100 mL of the mobile phase, and use this solutionas the sample solution. Pipet 1 mL of this solution, and addthe mobile phase to make exactly 50 mL. Pipet 2 mL of this solution,add the mobile phase to make exactly 20 mL, and usethis solution as the standard solution. Perform the test with exactly10 µL each of the sample solution and standard solution asdirected under Liquid Chromatography according to thefollowing conditions. Determine each peak area of both solutionsby the automatic integration method: the total area of thepeaks other than procainamide from the sample solution is notlarger than the peak area of procainamide from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:270 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of 0.02 mol/L phosphate buffer solution,pH 3.0 and methanol (9:1)Flow rate: Adjust the flow rate so that the retention time ofprocainamide is about 9 minutes.Time span of measurement: About 2 times as long as the retentiontime of procainamide.System suitability—Test for required detectability: Pipet 10 mL of the standardsolution, and add the mobile phase to make exactly 20 mL.Confirm that the peak area of procainamide obtained from 10 µLof this solution is equivalent to 40 to 60% of that of procainamidefrom the standard solution.System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of procainamide are not less than 10000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of procainamideis not more than 2.0%.Loss on drying Not more than 0.3% (2 g, 105ºC, 4hours).Procainamide HydrochlorideInjectionプロカインアミド 塩 酸 塩 注 射 液Change the Origin/limits of content and Identificationto read:Procainamide Hydrochloride Injection is an aqueoussolution for injection.It contains not less than 95.0% and not more than105.0% of the labeled amount of procainamide hydrochloride(C 13 H 21 N 3 O·HCl: 271.79).Identification (1) To a volume of Procainamide HydrochlorideInjection, equivalent to 10 mg of Procainamide Hydrochlorideaccording to the labeled amount, add 1 mL of dilute hydrochloricacid and water to make 5 mL: the solution responds tothe Qualitative Tests (1) for primary aromatic amines.(2) To a volume of Procainamide Hydrochloride Injection,equivalent to 0.1 g of Procainamide Hydrochloride according tothe labeled amount, add water to make 100 mL. To 1 mL of thissolution add water to make 100 mL. Determine the absorption

2180 Official Monographs Supplement II, JP XVspectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximum between 277nm and 281 nm.(3) Procainamide Hydrochloride Injection responds to theQualitative Tests (2) for chloride.Add the following next to the Identification:Bacterial endotoxins Less than 0.30 EU/mg.Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Procainamide HydrochlorideTabletsプロカインアミド 塩 酸 塩 錠Change the Origin/limits of content and Identificationto read:Procainamide Hydrochloride Tablets contain not lessthan 95.0% and not more than 105.0% of the labeledamount of procainamide hydrochloride(C 13 H 21 N 3 O·HCl: 271.79).Identification To a quantity of powdered Procainamide HydrochlorideTablets, equivalent to 1.5 g of Procainamide Hydrochlorideaccording to the labeled amount, add 30 mL of water,shake well, filter, and use the filtrate as the sample solution.To 0.2 mL of the sample solution add 1 mL of dilute hydrochloricacid and 4 mL of water: the solution responds to the QualitativeTests for primary aromatic amines.Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Procainamide Hydrochloride Tablets add 3V/5mL of 0.02 mol/L phosphate buffer solution, pH 3.0, treat withultrasonic waves to disintegrate the tablet completely, add 0.02mol/L phosphate buffer solution, pH 3.0, to make exactly V mLso that each mL contains about 2.5 mg of procainamide hydrochloride(C 13 H 21 N 3 O·HCl), and shake for 5 minutes. Centrifugethis solution, pipet 1 mL of the supernatant liquid, add 0.02mol/L phosphate buffer solution, pH 3.0, to make 250 mL, anduse this solution as the sample solution. Proceed as directed inthe Assay.Amount (mg) of procainamide hydrochloride(C 13 H 21 N 3 O·HCl)= W S × (A T /A S ) × (V/20)W S : Amount (mg) of procainamide hydrochloride for assayChange the Dissolution and Assay to read:Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Procainamide Hydrochloride Tablets is not less than80%.Start the test with 1 tablet of Procainamide HydrochlorideTablets, withdraw not less than 30 mL of the medium at thespecified minute after starting the test, and filter through amembrane filter with a pore size not exceeding 0.8 µm. Discardthe first 10 mL of the filtrate, pipet V mL of the subsequent filtrate,add 2nd fluid for dissolution test to make exactly V´ mL sothat each mL contains about 7 µg of procainamide hydrochloride(C 13 H 21 N 3 O·HCl) according to the labeled amount, and use thissolution as the sample solution. Separately, weigh accuratelyabout 0.125 g of procainamide hydrochloride for assay, previouslydried at 105ºC for 4 hours, and dissolve in water to makeexactly 1000 mL. Pipet 5 mL of this solution, add 2nd fluid fordissolution test to make exactly 100 mL, and use this solution asthe standard solution. Perform the test with the sample solutionand standard solution as directed under Ultraviolet-visible Spectrophotometry, and determine the absorbances, A T andA S , at 278 nm.Dissolution rate (%) with respect to the labeled amount ofprocainamide hydrochloride (C 13 H 21 N 3 O·HCl)= W S × (A T /A S ) × (V´/V) × (1/C) × (9/2)W S : Amount (mg) of procainamide hydrochloride for assayC: Labeled amount (mg) of procainamide hydrochloride(C 13 H 21 N 3 O·HCl) in 1 tabletAssay To 10 Procainamide Hydrochloride Tablets add 300 mLof 0.02 mol/L phosphate buffer solution, pH 3.0, and treat withultrasonic waves to disintegrate the tablets completely. To thissolution add 0.02 mol/L phosphate buffer solution, pH 3.0, tomake exactly 500 mL, and stir for 5 minutes. Centrifuge thissolution, pipet V mL of the supernatant liquid, and add 0.02mol/L phosphate buffer solution, pH 3.0, to make V´ mL so thateach mL contains about 10 µg of procainamide hydrochloride(C 13 H 21 N 3 O·HCl). Filter this solution through a membrane filterwith a pore size not exceeding 0.45 µm, discard the first 10 mLof the filtrate, and use the subsequent filtrate as the sample solution.Separately, weigh accurately about 50 mg of procainamidehydrochloride for assay, previously dried at 105ºC for 4 hours,dissolve in 0.02 mol/L phosphate buffer solution, pH 3.0, tomake exactly 100 mL. Pipet 2 mL of this solution, add 0.02mol/L phosphate buffer solution, pH 3.0, to make 100 mL, anduse this solution as the standard solution. Perform the test withexactly 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography according tothe following conditions, and calculate the peak areas, A T and A S ,of procainamide in each solution.Amount (mg) of procainamide hydrochloride(C 13 H 21 N 3 O·HCl)

Supplement II, JP XV Official Monographs 2181= W S × (A T /A S ) × (V´/V) × (1/10)W S : Amount (mg) of procainamide hydrochloride for assayOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:270 nm)Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of 0.02 mol/L phosphate buffer solution,pH 3.0, and methanol (9:1)Flow rate: Adjust the flow rate so that the retention time ofprocainamide is about 9 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of procainamide are not less than 10000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of procainamideis not more than 1.0%.Prochlorperazine Maleate Tabletsプロクロルペラジンマレイン 酸 塩 錠Add the following next to the Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.Conduct this procedure using light-resistant vessels. To 1tablet of Prochlorperazine Maleate Tablets add 3V/5 mL of amixture of dilute phosphoric acid (1 in 500) and ethanol (99.5)(1:1), treat with ultrasonic waves until the tablet is disintegrated,and shake vigorously for 10 minutes. Add exactly V/20 mL ofthe internal standard solution, and a mixture of dilute phosphoricacid (1 in 500) and ethanol (99.5) (1:1) to make V mL so thateach mL contains about 80 µg of prochlorperazine maleate(C 20 H 24 ClN 3 S·2C 4 H 4 O 4 ), and use this solution as the samplesolution. Centrifuge this solution, and use the supernatant liquidas the sample solution. Proceed as directed in the Assay.Amount (mg) of prochlorperazine maleate(C 20 H 24 ClN 3 S·2C 4 H 4 O 4 )= W S × (Q T /Q S ) × (V/250)W S : Amount (mg) of Prochlorperazine Maleate ReferenceStandardInternal standard solution—A solution of butyl parahydroxybenzoatein a mixture of diluted phosphoric acid (1 in 500) andethanol (99.5) (1:1) (1 in 1000).Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of 2nd fluid for dissolution test as the dissolutionmedium, the dissolution rate in 45 minutes of ProchlorperazineMaleate Tablets is not less than 75%.Start the test with 1 tablet of Prochlorperazine Maleate Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membranefilter with a pore size not exceeding 0.45 µm. Discard the first10 mL of the filtrate, pipet V mL of the subsequent filtrate, addthe dissolution medium to make exactly V´ mL so that each mLcontains about 9 µg of prochlorperazine maleate(C 20 H 24 ClN 3 S·2C 4 H 4 O 4 ) according to the labeled amount, anduse this solution as the sample solution. Separately, weigh accuratelyabout 18 mg of prochlorperazine maleate for assay, previouslydried at 105ºC for 3 hours, and dissolve in methanol tomake exactly 100 mL. Pipet 5 mL of this solution, add the dissolutionmedium to make exactly 100 mL, and use this solutionas the standard solution. Perform the test with the sample solutionand standard solution as directed under Ultraviolet-visibleSpectrophotometry , using the dissolution medium as theblank, and determine the absorbances, A T and A S , at 255 nm.Dissolution rate (%) with respect to the labeled amount ofprochlorperazine maleate (C 20 H 24 ClN 3 S·2C 4 H 4 O 4 )= W S × (A T /A S ) × (V´/V) × (1/C) × 45W S : Amount (mg) of Prochlorperazine Maleate ReferenceStandardC: Labeled amount (mg) of prochlorperazine maleate(C 20 H 24 ClN 3 S·2C 4 H 4 O 4 ) in 1 tabletChange the Assay to read:Assay Conduct this procedure using light-resistant vessels.Weigh accurately the mass of not less than 20 ProchlorperazineMaleate Tablets, and powder in an agate mortar. Weigh accuratelya portion of the powder, equivalent to about 8 mg of prochlorperazinemaleate (C 20 H 24 ClN 3 S·2C 4 H 4 O 4 ), add 60 mL of amixture of diluted phosphoric acid (1 in 500) and ethanol (99.5)(1:1), and shake vigorously for 10 minutes. Add exactly 5 mL ofthe internal standard solution, and add a mixture of dilutedphosphoric acid (1 in 500) and ethanol (99.5) (1:1) to make 100mL. Centrifuge this solution, and use the supernatant liquid asthe sample solution. Separately, weigh accurately about 20 mgof Prochlorperazine Maleate Reference Standard, previouslydried at 105ºC for 3 hours, and dissolve in a mixture of dilutedphosphoric acid (1 in 500) and ethanol (99.5) (1:1) to make exactly25 mL. Pipet 10 mL of this solution, add exactly 5 mL ofthe internal standard solution and a mixture of diluted phosphoricacid (1 in 500) and ethanol (99.5) (1:1) to make 100 mL, anduse this solution as the standard solution. Perform the test with 5µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and calculate the ratios, Q T and Q S , of the peakarea of prochlorperazine to that of the internal standard.Amount (mg) of prochlorperazine maleate(C 20 H 24 ClN 3 S·2C 4 H 4 O 4 )= W S × (Q T /Q S ) × (2/5)

2182 Official Monographs Supplement II, JP XVW S : Amount (mg) of Prochlorperazine Maleate ReferenceStandardInternal standard solution—A solution of butyl parahydroxybenzoatein a mixture of diluted phosphoric acid (1 in 500) andethanol (99.5) (1:1) (1 in 1000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:257 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: A mixture of diluted 0.05 mol/L sodium dihydrogenphosphate TS (1 in 2) and acetonitrile (11:9)Flow rate: Adjust the flow rate so that the retention time ofprochlorperazine is about 5 minutes.System suitability—System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions,prochlorperazine and the internal standard are eluted in this orderwith the resolution between these peaks being not less than10.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofprochlorperazine to that of the internal standard is not more than1.0%.ProgesteroneプロゲステロンChange the Description, Identification, Opticalrotation, Melting point, Purity and Assay to read:Description Progesterone occurs as white crystals or a whitecrystalline powder.It is soluble in methanol and in ethanol (99.5), and practicallyinsoluble in water.Identification (1) Determine the absorption spectrum of asolution of Progesterone in ethanol (99.5) (1 in 100000) as directedunder Ultraviolet-visible Spectrophotometry , andcompare the spectrum with the Reference Spectrum or the spectrumof a solution of Progesterone Reference Standard preparedin the same manner as the sample solution: both spectra exhibitsimilar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Progesteroneas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of ProgesteroneReference Standard: both spectra exhibit similar intensities ofabsorption at the same wave numbers. If any difference appearsbetween the spectra, dissolve Progesterone and ProgesteroneReference Standard in ethanol (95), respectively, then evaporatethe ethanol to dryness, and repeat the test on the residues.Optical rotation [α] 20D: +184 - +194º (after drying,0.2 g, ethanol (99.5), 10 mL, 100 mm).Melting point 128 - 133ºC or 120 - 122ºC.Purity Related substances—Dissolve 80 mg of Progesteronein 2 mL of methanol, and use this solution as the sample solution.Pipet 1 mL of this solution, add methanol to make exactly100 mL, and use this solution as the standard solution. Performthe test with these solutions as directed under Thin-layer Chromatography. Spot 5 µL each of the sample solution andstandard solution on a plate of silica gel with fluorescent indicatorfor thin-layer chromatography. Develop the plate with amixture of diethyl ether and diethylamine (19:1) to a distance ofabout 15 cm, and air-dry the plate. Examine under ultravioletlight (main wavelength: 254 nm): the spots other than the principalspot obtained from the sample solution is not more intensethan the spot from the standard solution.Assay Weigh accurately about 10 mg each of Progesteroneand Progesterone Reference Standard, previously dried, anddissolve each in ethanol (99.5) to make exactly 100 mL. Pipet 5mL each of these solutions, add ethanol (99.5) to make exactly50 mL, and use these solution as the sample solution and standardsolution, respectively. Determine the absorbances, A T andA S , of the sample solution and standard solution at the wavelengthof maximum absorption at about 241 nm as directed underUltraviolet-visible Spectrophotometry .Amount (mg) of progesterone (C 21 H 30 O 2 ) = W S × (A T /A S )W S : Amount (mg) of Progesterone Reference StandardProgesterone Injectionプロゲステロン 注 射 液Change the Origin/limits of content and Identificationto read:Progesterone Injection is an oily solution for injection.It contains not less than 95.0% and not more than105.0% of the labeled amount of progesterone(C 21 H 30 O 2 : 314.46).Identification To 1 mL of Progesterone Injection add 1 mL ofdiluted ethanol (9 in 10), shake well, take the ethanol layer,shake well with 1 mL of petroleum benzin, and use the ethanollayer as the sample solution. Separately, dissolve about 5 mg ofProgesterone Reference Standard in 1 mL of ethanol (99.5), anduse this solution as the standard solution. Perform the test withthese solutions as directed under Thin-layer Chromatography. Spot 2 µL each of the sample solution and standard solutionon a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of diethyl ether and diethylamine(19:1) to a distance of about 10 cm, and air-dry the plate.Spray evenly sulfuric acid on the plate, and heat the plate at105ºC for 10 minutes: the principal spot obtained from the sam-

Supplement II, JP XV Official Monographs 2183ple solution has the same R f value as the spot from the standardsolution.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.progesterone to that of the internal standard is not more than1.0%.Add the following:Propafenone Hydrochlorideプロパフェノン 塩 酸 塩Sterility Perform the test according to the Directmethod: it meets the requirement.Change the Assay to read:Assay Measure the specific gravity of Progesterone Injection.Weigh accurately the mass of Progesterone Injection, equivalentto about 1 mL, mix with 2 mL of tetrahydrofuran, and addethanol (99.5) to make exactly V mL so that each mL containsabout 0.5 mg of progesterone (C 21 H 30 O 2 ). Pipet 2 mL of this solution,add exactly 10 mL of the internal standard solution andethanol (99.5) to make 20 mL, and use this solution as the samplesolution. Separately, weigh accurately about 10 mg of ProgesteroneReference Standard, previously dried in vacuum for 4hours using phosphorus (V) oxide as the desiccant, dissolve in 2mL of tetrahydrofuran, and add ethanol (99.5) to make exactly20 mL. Pipet 2 mL of this solution, add exactly 10 mL of the internalstandard solution and ethanol (99.5) to make 20 mL, anduse this solution as the standard solution. Perform the test with 5µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and calculate the ratios, Q T and Q S , of the peakarea of progesterone to that of the internal standard.Amount (mg) of progesterone (C 21 H 30 O 2 )= W S × (Q T /Q S ) × (V/20)W S : Amount (mg) of Progesterone Reference StandardInternal standard solution—A solution of testosterone propionatein ethanol (99.5) (1 in 4000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:241 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 35ºC.Mobile phase: A mixture of acetonitrile and water (7:3)Flow rate: Adjust the flow rate so that the retention time ofprogesterone is about 6 minutes.System suitability—System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions,progesterone and the internal standard are eluted in this orderwith the resolution between these peaks being not less than 9.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofand enantiomerC 21 H 27 NO 3·HCl: 377.901-{2-[(2RS)-2-Hydroxy-3-(propylamino)propyloxy]phenyl}-3-phenylpropan-1-one monohydrochloride [34183-22-7]Propafenone Hydrochloride, when dried, containsnot less than 98.5% and not more than 101.0% ofC 21 H 27 NO 3·HCl.Description Propafenone Hydrochloride occurs as whitecrystals or a white crystalline powder.It is freely soluble in formic acid, sparingly soluble in methanol,and slightly soluble in water and in ethanol (99.5).A solution of Propafenone Hydrochloride in methanol (1 in100) shows no optical rotation.Identification (1) Dissolve 0.1 g of Propafenone Hydrochloridein 20 mL of water by warming. After cooling, to 3 mLof this solution add water to make 500 mL. Determine the absorptionspectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similarintensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum ofPropafenone Hydrochloride as directed in the potassium chloridedisk method under Infrared Spectrophotometry , andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavenumbers.(3) Dissolve 0.1 g of Propafenone Hydrochloride in 20 mLof water by warming. After cooling, to 10 mL of this solutionadd 1 mL of dilute nitric acid, and filter to separate formed precipitate: the filtrate responds to the Qualitative Tests (2)for chloride.Melting point 172 - 175ºC.Purity (1) Heavy metals —Proceed with 1.0 g ofPropafenone Hydrochloride according to Method 4, and performthe test. Prepare the control solution with 2.0 mL of StandardLead Solution (not more than 20 ppm).(2) Related substances—Dissolve 0.10 g of PropafenoneHydrochloride in 20 mL of the mobile phase in the operatingconditions 1, and use this solution as the sample solution. Pipet2 mL of this solution, and add the mobile phase in the operatingconditions 1 to make exactly 50 mL. Pipet 2.5 mL of this solu-

2184 Official Monographs Supplement II, JP XVtion, add 2.5 mL of a solution of diphenyl phthalate in methanol(1 in 2000), add the mobile phase in the operating conditions 1to make exactly 100 mL, and use this solution as the standardsolution. Perform the test with exactly 10 µL each of the samplesolution and standard solution as directed under Liquid Chromatography according to the following conditions 1 and2. Determine each peak area of both solutions by the automaticintegration method: the area of each peak other than the peak ofpropafenone from the sample solution is not larger than the peakarea of propafenone from the standard solution.Operating conditions 1—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 4.6 g of sodium 1-nonanesulfonateand 2.3 g of phosphoric acid in water to make 1000 mL, and filterthrough a membrane filter with a pore size not exceeding0.45 µm. To 900 mL of the filtrate add 600 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofdiphenyl phthalate is about 39 minutes.Time span of measurement: Beginning after the solvent peakto the retention time of diphenyl phthalate.System suitability 1—System performance: Dissolve 12 mg of Propafenone Hydrochlorideand 50 mg of isopropyl benzoate in 100 mL ofmethanol. When the procedure is run with 10 µL of this solutionunder the above operating conditions 1, propafenone and isopropylbenzoate are eluted in this order with the resolution betweenthese peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions1, the relative standard deviation of the peak area ofpropafenone is not more than 2.0%.Operating conditions 2—Detector, column and column temperature: Proceed as directedin the operation conditions 1.Mobile phase: Dissolve 7.33 g of sodium 1-decanesulfonateand 2.3 g of phosphoric acid in water to make 1000 mL, and filterthrough a membrane filter with a pore size not exceeding0.45 µm. To 700 mL of the filtrate add 700 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofdiphenyl phthalate is about 11 minutes.Time span of measurement: About 2.5 times as long as theretention time of diphenyl phthalate.System suitability 2—System performance: Dissolve 12 mg of Propafenone Hydrochlorideand 50 mg of isopropyl benzoate in 100 mL ofmethanol. When the procedure is run with 10 µL of this solutionunder the above operating conditions 2, propafenone and isopropylbenzoate are eluted in this order with the resolution betweenthese peaks being not less than 21.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions2, the relative standard deviation of the peak area ofpropafenone is not more than 2.0%.(3) Residual solvent—Being specified separately.Loss on drying Not more than 0.5% (1 g,105ºC, 2hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.3 g of Propafenone Hydrochloride,previously dried, dissolve in 2 mL of formic acid, add50 mL of acetic anhydride, and titrate with 0.05 mol/Lperchloric acid VS (potentiometric titration). Perform a blankdetermination in the same manner, and make any necessary correction.Each mL of 0.05 mol/L perchloric acid VS = 18.90 mg ofC 21 H 27 NO 3·HCl.Containers and storage Containers—Well-closed containers.Add the following:Propafenone Hydrochloride Tabletsプロパフェノン 塩 酸 塩 錠Propafenone Hydrochloride Tablets contain not lessthan 96.0% and not more than 104.0% of the labeledamount of propafenone hydrochloride(C 21 H 27 NO 3·HCl: 377.90).Method of preparation Prepare as directed under Tablets,with Propafenone Hydrochloride.Identification To a quantity of Propafenone HydrochlorideTablets, equivalent to 0.3 g of Propafenone Hydrochloride accordingto the labeled amount, add 60 mL of water, and disintegrateby warming. After cooling, centrifuge, and to 3 mL of thesupernatant liquid add water to make 500 mL. Determine theabsorption spectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits maxima between247 nm and 251 nm, and between 302 nm and 306 nm.Separately, determine the both maximal absorbances, A 1 and A 2 ,of the solution,: the ratio of A 1 /A 2 is between 2.30 and 2.55.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Propafenone Hydrochloride Tablets add 30 mLof a mixture of water and acetonitrile (1:1), shake well to disintegrate,add a mixture of water and acetonitrile (1:1) to makeexactly 50 mL, and centrifuge. Pipet V mL of the supernatantliquid, equivalent to about 6 mg of propafenone hydrochloride(C 21 H 27 NO 3·HCl), add exactly 5 mL of the internal standard solution,add methanol to make 50 mL, and use this solution as thesample solution. Proceed as directed in the Assay.Amount (mg) of propafenone hydrochloride(C 21 H 27 NO 3·HCl)

Supplement II, JP XV Official Monographs 2185= W S × (Q T /Q S ) × (10/V)W S : Amount (mg) of propafenone hydrochloride for assayInternal standard solution—A solution of isopropyl benzoate inmethanol (1 in 200)Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Propafenone Hydrochloride is not less than 75%.Start the test with 1 tablet of Propafenone HydrochlorideTablets, withdraw not less than 20 mL of the medium at thespecified minute after starting the test, and filter through amembrane filter with a pore size not exceeding 0.5 µm. Discardthe first 10 mL of the filtrate, pipet V mL of the subsequent filtrate,add water to make exactly V´ mL so that each mL containsabout 67 µg of propafenone hydrochloride (C 21 H 27 NO 3·HCl)according to the labeled amount, and use this solution as thesample solution. Separately, weigh accurately about 13 mg ofpropafenone hydrochloride for assay, previously dried at 105ºCfor 2 hours, dissolve in water to make exactly 200 mL, and usethis solution as the standard solution. Determine the absorbances,A T and A S , of the sample solution and standard solution at305 nm as directed under Ultraviolet-visible Spectrophotometry.Dissolution rate (%) with respect to the labeled amount ofpropafenone hydrochloride (C 21 H 27 NO 3·HCl)= W S × (A T /A S ) × (V´/V) × (1/C) × 450W S : Amount (mg) of propafenone hydrochloride for assayC: Labeled amount (mg) of propafenone hydrochloride(C 21 H 27 NO 3·HCl) in 1 tabletAssay To a quantity of Propafenone Hydrochloride Tablets,equivalent to 1.5 g of propafenone hydrochloride(C 21 H 27 NO 3·HCl), add 70 mL of a mixture of water and acetonitrile(1:1), shake well to disintegrate, shake well for another 5minutes, add a mixture of water and acetonitrile (1:1) to makeexactly 100 mL, and centrifuge. Pipet 4 mL of the supernatantliquid, and add methanol to make exactly 50 mL. Pipet 5 mL ofthe solution, add exactly 5 mL of the internal standard solution,add methanol to make 50 mL, and use this solution as the samplesolution. Separately, weigh accurately about 30 mg ofpropafenone hydrochloride for assay, previously dried at 105ºCfor 2 hours, and dissolve in methanol to make exactly 50 mL.Pipet 10 mL of this solution, add exactly 5 mL of the internalstandard solution, add methanol to make 50 mL, and use thissolution as the standard solution. Perform the test with 10 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and calculate the ratios, Q T and Q S , of the peakarea of propafenone to that of the internal standard.Amount (mg) of propafenone hydrochloride(C 21 H 27 NO 3·HCl)= W S × (Q T /Q S ) × 50W S : Amount (mg) of propafenone hydrochloride for assayInternal standard solution—A solution of isopropyl benzoate inmethanol (1 in 200)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 4.6 g of sodium 1-nonanesulfonateand 2.3 g of phosphoric acid in water to make 1000 mL, and filterthrough a membrane filter with a pore size not exceeding0.45 µm. To 900 mL of the filtrate add 600 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofpropafenone is about 8 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,propafenone and the internal standard are eluted in this orderwith the resolution between these peaks being not less than 5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof propafenone to that of the internal standard is not more than1.0%.Containers and storage Containers—Tight containers.Propylthiouracil Tabletsプロピルチオウラシル 錠Add the following next to Identification:Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Propylthiouracil Tablets add 3V/4 mL of 2ndfluid for dissolution test, treat with ultrasonic waves until thetablet is disintegrated, and add 2nd fluid for dissolution test tomake exactly V mL so that each mL contains about 0.25 mg ofpropylthiouracil (C 7 H 10 N 2 OS). Filter this solution through amembrane filter with a pore size not exceeding 0.45 µm, discardthe first 5 mL of the filtrate, pipet 2 mL of the subsequent filtrate,add 2nd fluid for dissolution test to make exactly 100 mL,and use this solution as the sample solution. Proceed as directedin the Assay.Amount (mg) of propylthiouracil (C 7 H 10 N 2 OS)= W S × (A T /A S ) × (V/200)W S : Amount (mg) of propylthiouracil for assay

2186 Official Monographs Supplement II, JP XVChange the Dissolution and Assay to read:Dissolution When the test is performed at 75 revolutionsper minute according to the Paddle method using 900 mLof 2nd fluid for dissolution test as the dissolution medium, thedissolution rate in 30 minutes of Propylthiouracil Tablets is notless than 80%.Start the test with 1 tablet of Propylthiouracil Tablets, withdrawnot less than 20 mL of the medium at the specified minuteafter starting the test, and filter through a membrane filter with apore size not exceeding 0.8 µm. Discard the first 10 mL of thefiltrate, pipet 5 mL of the subsequent filtrate, add the dissolutionmedium to make exactly 50 mL, and use this solution as thesample solution. Separately, weigh about 50 mg of propylthiouracilfor assay, previously dried at 105ºC for 2 hours, anddissolve in the dissolution medium to make exactly 1000 mL.Pipet 5 mL of this solution, add the dissolution medium to make50 mL, and use this solution as the standard solution. Proceed asdirected in the Assay.Dissolution rate (%) with respect to the labeled amount ofpropylthiouracil (C 7 H 10 N 2 OS)= W S × (A T /A S ) × (1/C) × 90W S : Amount (mg) of propylthiouracil for assayC: Labeled amount (mg) of propylthiouracil (C 7 H 10 N 2 OS) in1 tabletAssay Weigh accurately the mass of not less than 20 PropylthiouracilTablets, and powder. Weigh accurately a portion of thepowder, equivalent to about 50 mg of propylthiouracil(C 7 H 10 N 2 OS), add 150 mL of 2nd fluid for dissolution test, dispersefinely the particles with the aid of ultrasonic waves, andadd 2nd fluid for dissolution test to make exactly 200 mL. Filterthis solution through a membrane filter with a pore size not exceeding0.45 µm, discard the first 5 mL of the filtrate, pipet 2mL of the subsequent filtrate, add 2nd fluid for dissolution testto make exactly 100 mL, and use this solution as the sample solution.Separately, weigh accurately about 50 mg of propylthiouracilfor assay, previously dried at 105ºC for 2 hours, anddissolve in 2nd fluid for dissolution test to make exactly 200 mL.Pipet 2 mL of this solution, add 2nd fluid for dissolution test tomake 100 mL, and use this solution as the standard solution.Determine the absorbance at 274 nm, A T and A S , of the samplesolution and standard solution as directed under Ultraviolet-visibleSpectrophotometry .Amount (mg) of propylthiouracil (C 7 H 10 N 2 OS)= W S × (A T /A S )W S : Amount (mg) of propylthiouracil for assayProtamine Sulfate Injectionプロタミン 硫 酸 塩 注 射 液Delete the Purity and Heparin-binding capacity,and change the Origin/limits of content to read:Protamine Sulfate Injection is an aqueous solutionfor injection.It contains not less than 92.0% and not more than108.0% of the labeled amount of Protamine Sulfate. Itbinds with not less than 100 Units of heparin per mg ofthe labeled amount.Identification (1) Dilute a volume of Protamine Sulfate Injection,equivalent to 1 mg of Protamine Sulfate according tothe labeled amount, with water to make 2 mL, and proceed asdirected in the Identification (1) under Protamine Sulfate.(2) Dilute a volume of Protamine Sulfate Injection, equivalentto 5 mg of Protamine Sulfate according to the labeledamount, with water to make 1 mL, and proceed as directed inthe Identification (2) under Protamine Sulfate.Add the following next to the pH:Bacterial endotoxins Less than 6.0 EU/mg.Add the following next to the Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay (1) Protein—Pipet a volume of Protamine Sulfate Injection,equivalent to about 10 mg of Protamine Sulfate, transferto a Kjeldahl flask, evaporate on a water bath to dryness withthe aid of a current of air, determine the nitrogen as directedunder Nitrogen Determination , and calculate the amountof protein by converting 0.24 mg of nitrogen (N: 14.01) to 1 mgof protein.(2) Heparin-binding activity—Proceed the test as directedin the Heparin-binding capacity under Protamine Sulfate,changing the sample solution (a) as below, and determine theamount of heparin bound to 1 mg of protein by dividing by theamount of protein.(i) Sample solution (a)—Pipet a volume of Protamine SulfateInjection, equivalent to 15.0 mg of Protamine Sulfate accordingto the labeled amount, and add water to make exactly100 mL. Repeat this procedure two more times, and designatethe solutions so obtained as the sample solutions (a 1 ), (a 2 ) and(a 3 ).

Supplement II, JP XV Official Monographs 2187Add the following:RebamipideレバミピドC 19 H 15 ClN 2 O 4 : 370.79(2RS)-2-(4-Chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid [90098-04-7]and enantiomerRebamipide, when dried, contains not less than99.0% and not more than 101.0% of C 19 H 15 ClN 2 O 4 .Description Rebamipide occurs as a white crystalline powder,and has a bitter taste.It is soluble in N,N-dimethylformamide, very slightly solublein methanol and in ethanol (99.5), and practically insoluble inwater.A solution of Rebamipide in N,N-dimethylformamide (1 in20) shows no optical rotation.Melting point: about 291ºC (with decomposition).Identification (1) Determine the absorption spectrum of asolution of Rebamipide in methanol (7 in 100000) as directedunder Ultraviolet-visible Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Rebamipideas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similarintensities of absorption at the same wave numbers.(3) Perform the test with Rebamipide as directed under FlameColoration Test (2): a green color appears.Purity (1) Chloride —Dissolve 0.5 g of Rebamipidein 40 mL of N,N,-dimethylformamide, and add 6 mL of dilutenitric acid and water to make 50 mL. Perform the test using thissolution as the test solution. Prepare the control solution as follows: To 0.40 mL of 0.01 mol/L hydrochloric acid VS add 40mL of N,N,-dimethylformamide, 6 mL of dilute nitric acid andwater to make 50 mL (not more than 0.028%).(2) Heavy metals —Proceed with 2.0 g of Rebamipideaccording to Method 2, and perform the test. Prepare thecontrol solution with 2.0 mL of Standard Lead Solution (notmore than 10 ppm).(3) Rebamipide m-chloro isomer Dissolve 40 mg of Rebamipidein a mixture of water, 0.05 mol/L phosphate buffersolution, pH 6.0, and methanol (7:7:6) to make 100 mL, and usethis solution as the sample solution. Pipet 2 mL of this solution,and add a mixture of water, 0.05 mol/L phosphate buffer solution,pH 6.0 and methanol (7:7:6) to make exactly 20 mL. Pipet2 mL of this solution, add a mixture of water, 0.05 mol/L phosphatebuffer solution, pH 6.0 and methanol (7:7:6) to make exactly50 mL, and use this solution as the standard solution. Performthe test with exactly 10 µL each of the sample solution andstandard solution as directed under Liquid Chromatography according to the following conditions. Determine eachpeak area of both solutions by the automatic integration method:the area of the peak of rebamipide m-chloro isomer, having therelative retention time of about 0.95 with respect to rebamipide,from the sample solution, is not larger than 3/8 times the area ofthe peak of rebamipide from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:222 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: To 300 mL of phosphate buffer solution, pH 6.2,add 750 mL of water. To 830 mL of this solution add 170 mL ofacetonitrile.Flow rate: Adjust the flow rate so that the retention time ofrebamipide is about 20 minutes.System suitability—Test for required detectability: Pipet 5 mL of the standard solution,and add a mixture of water, 0.05 mol/L phosphate buffersolution, pH 6.0 and methanol (7:7:6) to make exactly 25 mL.Confirm that the peak area of rebamipide obtained from 10 µLof this solution is equivalent to 15 to 25% of that of rebamipidefrom 10 µL of the standard solution.System performance: To 1 mL of the sample solution add amixture of water, 0.05 mol/L phosphate buffer solution, pH 6.0and methanol (7:7:6) to make 100 mL. When the procedure isrun with 10 µL of this solution under the above operating conditions,the number of theoretical plates and the symmetry factorof the peak of rebamipide are not less than 11000 and not morethan 1.2, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of rebamipideis not more than 2.0%.(4) Related substances— Perform the test with exactly 10µL each of the sample solution and standard solution obtained in(3) as directed under Liquid Chromatography accordingto the following conditions. Determine each peak area of bothsolutions by the automatic integration method: each area of thepeaks of rebamipide o-chloro isomer and debenzoylated isomer,having the relative retention times of about 0.5 and about 0.7,respectively, with respect to rebamipide from the sample solution,is not larger than 3/8 times the peak area of rebamipidefrom the standard solution, the area of each peak other than thepeak mentioned above is not larger than 1/4 times the peak areaof rebamipide from the standard solution, and the total area ofthe peaks other than rebamipide from the sample solution is notlarger than the peak area of rebamipide from the standard solution.For the calculation, use the peak area of rebamipide

2188 Official Monographs Supplement II, JP XVo-chloro isomer, after multiplying by the response factor, 1.4.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength :232 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: Dissolve 2.44 g of sodium 1-decanesulfonatein 1000 mL of water and to this solution add 1000 mL ofmethanol and 10 mL of phosphoric acid.Flow rate: Adjust the flow rate so that the retention time ofrebamipide is about 12 minutes.Time span of measurement: About 3 times as long as the retentiontime of rebamipide, beginning after the solvent peak.System suitability—Test for required detectability: Pipet 5 mL of the standard solution,and add a mixture of water, 0.05 mol/L phosphate buffersolution, pH 6.0, and methanol (7:7:6) to make exactly 50 mL.Confirm that the peak area of rebamipide obtained from 10 µLof this solution is equivalent to 7 to 13% of that of rebamipidefrom 10 µL of the standard solution.System performance: Dissolve 20 mg of 4-chlorobenzoate inmethanol to make 50 mL. To 5 mL each of this solution and thesample solution add a mixture of water, 0.05 mol/L phosphatebuffer solution, pH 6.0, and methanol (7:7:6) to make 50 mL.When the procedure is run with 10 µL of this solution under theabove operating conditions, rebamipide and 4-chlorobenzoateare eluted in this order with the resolution between these peaksbeing not less than 8.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of rebamipideis not more than 2.0%.relative response(5) Residual solvent—Being specified separately.Loss on drying Not more than 3.0% (1 g, 105ºC, 2hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.6 g of Rebamipide, previouslydried, dissolve in 60 mL of N,N-dimethylformamide, andtitrate with 0.1 mol/L potassium hydroxide VS until thecolor of the solution changes from pale yellow to colorless(indicator:2 drops of phenol red TS). Perform a blank determinationin the same manner, and make any necessary correction.Each mL of 0.1 mol/L potassium hydroxide VS= 37.08 mg of C 19 H 15 ClN 2 O 4Containers and storage Containers—Well-closed containers.Storage—Light-resistant.Add the following:Rebamipide Tabletsレバミピド 錠Rebamipide Tablets contain not less than 95.0% andnot more than 105.0% of the labeled amount of rebamipide(C 19 H 15 ClN 2 O 4 : 370,79).Method of preparation Prepare as directed under Tablets,with Rebamipide.Identification To a quantity of powdered Rebamipide Tablets,equivalent to 30 mg of Rebamipide according to the labeledamount, add 5 mL of a mixture of methanol and ammonia solution(28) (9:1), shake for 10 minutes, centrifuge, and use thesupernatant liquid as the sample solution. Separately, dissolve30 mg of rebamipide for assay in 5 mL of a mixture of methanoland ammonia solution (28) (9:1), and use this solution as thestandard solution. Perform the test with these solutions as directedunder Thin-layer Chromatography . Spot 5 µLeach of the sample solution and standard solution on a plate ofsilica gel with fluorescent indicator for thin-layer chromatography.Develop the plate with a mixture of ethyl acetate, methanoland formic acid (75:25:2) to a distance of about 10 cm, andair-dry the plate. Examine under ultraviolet light (main wavelength:254 nm): the principal spot obtained from the samplesolution has the same R f value as the spot from the standard solution.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Rebamipide Tablets add 10 mL of water, shakewell for 10 minutes, add exactly 10 mL of the internal standardsolution, add 10 mL of N,N-dimethylformamide, shake well for5 minutes, and add N,N-dimethylformamide to make 50 mL.Centrifuge this solution, pipet V mL of the supernatant liquid,equivalent to 3 mg of rebamipide (C 19 H 15 ClN 2 O 4 ), and add 20mL of N,N-dimethylformamide and water to make 50 mL. Filterthis solution through a membrane filter with a pore size not exceeding0.5 µm, discard the first 1 mL of the filtrate, and use thesubsequent filtrate as the sample solution. Separately, weighaccurately about 0.1 g of rebamipide for assay, previously driedat 105ºC for 2 hours, dissolve in N,N-dimethylformamide, andadd exactly 10 mL of the internal standard solution andN,N-dimethylformamide to make 50 mL. Pipet 1.5 mL of thissolution, add 20 mL of N,N-dimethylformamide, add water tomake 50 mL, and use this solution as the standard solution.Proceed as directed in the Assay.Amount (mg) of rebamipide (C 19 H 15 ClN 2 O 4 )= W S × (Q T /Q S ) × (3/2V)W S : Amount (mg) of rebamipide for assayInternal standard solution—A solution of acetanilide inN,N-dimethylformamide (1 in 150)

Supplement II, JP XV Official Monographs 2189Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using 900 mLof diluted disodium hydrogen phosphate-citric acid buffer solution(1 in 4), pH 6.0, as the dissolution medium, the dissolutionrate in 60 minutes of Rebamipide Tablets is not less than 75%.Start the test with 1 tablet of Rebamipide Tablets, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add the dissolutionmedium to make exactly V´ mL so that each mL contains about22 µg of rebamipide (C 19 H 15 ClN 2 O 4 ) according to the labeledamount, and use this solution as the sample solution. Separately,weigh accurately about 50 mg of rebamipide for assay, previouslydried at 105ºC for 2 hours, and dissolve inN,N-dimethylformamide to make exactly 25 mL. Pipet 2 mL ofthis solution, add the dissolution medium to make exactly 200mL, and use this solution as the standard solution. Perform thetest with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , using thedissolution medium as the blank, and determine the absorbances,A T and A S , at 326 nm.Dissolution rate (%) with respect to the labeled amount ofrebamipide (C 19 H 15 ClN 2 O 4 )= W S × (A T /A S ) × (V´/V) × (1/C) × 36W S : Amount (mg) of rebamipide for assayC: Labeled amount (mg) of rebamipide (C 19 H 15 ClN 2 O 4 ) in 1tabletAssay To 10 Rebamipide Tablets add exactly V/5 mL of theinternal standard solution and 50 mL of N,N-dimethylformamide,and disintegrate the tablets with the aid of ultrasonic waves.Shake this solution for 5 minutes, add N,N-dimethylformamideto make V mL so that each mL contains about 10 mg of rebamipide(C 19 H 15 ClN 2 O 4 ). Centrifuge this solution, and to 5 mLof the supernatant liquid add N,N-dimethylformamide to make50 mL. To 2 mL of this solution add 20 mL ofN,N-dimethylformamide and water to make 50 mL. Filter, ifnecessary, through a membrane filter with a pore size not exceeding0.5 µm, and use the filtrate as the sample solution.Separately, weigh accurately about 0.1 g of rebamipide for assay,previously dried at 105ºC for 2 hours, dissolve inN,N-dimethylformamide, and add exactly 2 mL of the internalstandard solution and N,N-dimethylformamide to make 100 mL.To 2 mL of this solution, add 20 mL of N,N-dimethylformamideand water to make 50 mL, and use this solution as the standardsolution. Perform the test with 20 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of rebamipide to that of theinternal standard.Amount (mg) of rebamipide (C 19 H 15 ClN 2 O 4 )= W S × (Q T /Q S ) × (V/100)W S : Amount (mg) of rebamipide for assayInternal standard solution—A solution of acetanilide inN,N-dimethylformamide (1 in 20)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25ºC.Mobile phase: To 300 mL of phosphate buffer solution, pH6.2, add 750 mL of water. To 830 mL of this solution add 170mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofrebamipide is about 20 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the internal standard and rebamipide are eluted in this order withthe resolution between these peaks being not less than 8.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof rebamipide to that of the internal standard is not more than1.0%.Containers and storage Containers—Well-closed containers.Rice StarchコメデンプンDelete the Description and Total ash, and changethe Definition to read:This monograph is harmonized with the European Pharmacopoeiaand the U.S. Pharmacopoeia. The parts of the text thatare not harmonized are marked with symbols ( ◆ ◆).Rice starch consists of the starch granules obtained from thecaryopsis of Oryza sativa Linné (Gramineae).Add the following next to Definition:◆ Description Rice Starch occurs as a white mass or powder.It is practically insoluble in water and in ethanol (99.5). ◆Change the Identification to read:Identification (1) Examined under a microscope using a mixture of water and glycerin (1:1), Rice Starch presentspolyhedral, simple grains 1-10 µm, mostly 4-6 µm, in size.These simple grains often gather in ellipsoidal, compoundgrains 50-100 µm in diameter. The granules have a poorly visiblecentral hilum and there are no concentric striations. Betweenorthogonally orientated polarizing plates or prisms, the starchgranules show a distinct black cross intersecting at the hilum.(2) To 1 g of Rice Starch add 50 mL of water, boil for 1minute, and allow to cool: a thin, cloudy mucilage is formed.(3) To 1 mL of the mucilage obtained in (2) add 0.05 mL of

2190 Official Monographs Supplement II, JP XVdiluted iodine TS (1 in 10): an orange-red to dark-blue color isproduced which disappears on heating.Add the following next to the Identification:pH To 5.0 g of Rice Starch add 25 mL of freshlyboiled and cooled water, and mix gently for 1 minute to achievesuspension. Allow to stand for 15 minutes: the pH of the solutionis 5.0 to 8.0.Change the Purity and Loss on drying to read:Purity (1) Iron—To 1.5 g of Rice Starch add 15 mL of 2mol/L hydrochloric acid TS, mix, filter, and use the filtrate asthe test solution. To 2.0 mL of Standard Iron Solution add waterto make 20 mL, and use this solution as the control solution. Put10 mL each of the test solution and the control solution in testtubes, add 2 mL of a solution of citric acid (1 in 5) and 0.1 mLof mercapto acetic acid, and mix. Add ammonia solution (28) tothese solutions until the color of a litmus paper to change fromred to blue, add water to make 20 mL, and mix. Transfer 10 mLeach of these solutions into test tubes, allow to stand for 5 minutes,and compare the color of these solutions against a whitebackground: the color of the test solution is not more intensethan that of the control solution (not more than 10 ppm).(2) Oxidizing substances—To 4.0 g of Rice Starch add 50mL of water, shake for 5 minutes, and centrifuge. To 30 mL ofthe supernatant liquid add 1 mL of acetic acid (100) and 0.5 to1.0 g of potassium iodide, shake, and allow to stand for 25 to 30minutes in the dark. Add 1 mL of starch TS, and titrate with 0.002 mol/L sodium thiosulfate VS until the starch-iodinecolor disappears. Perform a blank determination in the samemanner, and make any necessary correction. Not more than 1.4mL of 0.002 mol/L sodium thiosulfate VS is required (not morethan 20 ppm, calculated as H 2 O 2 ).(3) Sulfur dioxide—(i) Apparatus Use as shown in the figure.hydrogen peroxide-sodium hydroxide TS in the test-tube. After15 minutes, remove the funnel without interrupting the streamof carbon dioxide, and introduce through the opening into theflask about 25 g of Rice Starch, accurately weighed, with the aidof 100 mL of water. Apply tap grease to the outside of the connectionpart of the funnel, and load the funnel. Close the tap ofthe funnel, pour 80 mL of 2 mol/L hydrochloric acid TS into thefunnel, open the tap to introduce the hydrochloric acid into theflask, and close the tap while several mL of the hydrochloricacid remains, in order to avoid losing sulfur dioxide. Place theflask in a water bath, and heat the mixture for 1 hour. Open thetap of the funnel and stop the flow of carbon dioxide and alsothe heating and the cooling water. Transfer the contents of thetest-tube with the aid of a little water to a wide-necked conicalflask. Heat on a water-bath for 15 minutes and allow to cool.Add 0.1 mL of bromophenol blue TS, and titrate with0.1 mol/L sodium hydroxide VS until the color changes fromyellow to violet-blue lasting for at least 20 seconds. Perform ablank determination in the same manner, and make any necessarycorrection. Calculate the amount of sulfur dioxide by applyingthe following formula: it is not more than 50 ppm.Amount (ppm) of sulfur dioxide = (V/W) × 1000 × 3.203W: Amount (g) of the sampleV: Amount (mL) of 0.1 mol/L sodium hydroxide VS consumed◆ (4) Foreign matter—Under a microscope , RiceStarch does not contain starch granules of any other origin. Itmay contain a minute quantity, if any, of fragments of the tissueof the original plant. ◆Loss on drying Not more than 15.0% (1 g, 130ºC, 90minutes).Add the following next to the Loss on drying:Residue on ignition Not more than 0.6% (1 g).A: Boiling flask (500 mL)B: Funnel (100 mL)C: CondenserD: Test tube◆Containers and storage Containers—Well-closed containers.◆Rokitamycin Tabletsロキタマイシン 錠Carbon dioxideAdd the following next to Containers and storage:Expiration date: 24 months after preparation.The figures are in mm.(ii) Procedure Introduce 150 mL of water into the boilingflask, close the tap of the funnel, and pass carbon dioxidethrough the whole system at a rate of 100 ± 5 mL per minute.Pass cooling water through the condenser, and place 10 mL of

Supplement II, JP XV Official Monographs 2191Add the following:SevofluraneセボフルランC 4 H 3 F 7 O:200.051,1,1,3,3,3-Hexafluoro-2-(fluoromethoxy)propane[28523-86-6]Sevoflurane contains not less than 99.0% and notmore than 101.0% of C 4 H 3 F 7 O, calculated on the anhydrousbasis.Description Sevoflurane is a clear, colorless, and mobile liquid.It is very slightly soluble in water.It is miscible with ethanol (99.5).It is volatile and inflammable.Refractive index n 20D: 1.2745 – 1.2760Boiling point: about 58.6°CIdentification Transfer about 1 µL of Sevoflurane to a gas cellhaving light path 10 cm in length, and determine the infraredabsorption spectrum as directed in the gas sampling method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of SevofluraneReference Standard: both spectra exhibit similar intensitiesof absorption at the same wave numbers.Specific gravity d 2020: 1.510 - 1.530Purity (1) Acidity or alkalinity— To 50 mL of Sevofluranewith 50 mL of freshly boiled and cooled water vigorously for 3minutes. Separate the water layer and use this solution as thesample solution. To 20 mL of the sample solution add 1 drop ofbromocresol purple TS and 0.10 mL of 0.01 mol/L sodium hydroxideVS: a red-purple color develops. To 20 mL of the samplesolution add 1 drop of bromocresol purple TS and 0.6 mL of0.01 mol/L hydrochloric acid VS: a yellow color is produced.(2) Soluble fluoride—To 6 g of Sevoflurane add 12 mL ofdiluted 0.01 mol/L sodium hydroxide TS (1 in 20), and shakefor 10 minutes. Transfer 4.0 mL of diluted 0.01 mol/L sodiumhydroxide solution (1 in 20) layer into a Nessler tube. Add 30mL of a mixture of alizarin complexone TS, aceticacid-potassium acetate buffer solution, pH4.3 and cerium (III)nitrate TS (1:1:1), add water to make 50 mL, allow to stand for60 minutes, and use this solution as the sample solution. Separately,transfer 0.2 mL of the fluorine standard solution and 4.0mL of diluted 0.01 mol/L sodium hydroxide TS (1 in 20) into aNessler tube, and add 30 mL of a mixture of alizarin complexoneTS, acetic acid-potassium acetate buffer solution, pH4.3 andcerium (III) nitrate TS (1:1:1). Proceed in the same manner asdirected for the preparation of the sample solution, and use thissolution as the standard solution. Determine the absorbances ofthe sample solution and standard solution at 600 nm as directedunder Ultraviolet-visible Spectrophotometry , using asolution, prepared with 4.0 mL of diluted 0.01 mol/L sodiumhydroxide TS (1 in 20) in the same manner, as the blank: theabsorbance of the sample solution is not more than that of thestandard solution (not more than 1 ppm).Fluorine standard solution: Dissolve exactly 2.21 g of sodiumfluoride in water to make exactly 1000 mL. Pipet 10 mL of thissolution and add water to make exactly 1000 mL. Each mL ofthis solution contains 0.01 mg of fluorine (F).(3) Related substances—Perform the test with 2 µL of Sevofluraneas directed under Gas Chromatography accordingto the following conditions. Determine each peak areaby the automatic integration method and calculate the amount ofthem by the area percentage method: the amount of the peak ofhexafluoroisopropyl methyl ether, having the relative retentiontime of about 0.84 with respect to sevoflurane, is not more than0.005%, the amount of each peak other than the peaks of sevofluraneand hexafluoroisopropyl methyl ether is not more than0.0025%, and the total amount of the peaks other than the peaksof sevoflurane and hexafluoroisopropyl methyl ether is not morethan 0.005%.Operating conditions—Detector, column, injection port temperature, detector temperature,carrier gas and split ratio: Proceed as directed in theoperating conditions in the Assay.Column temperature: Inject at a constant temperature of about40°C, maintain the temperature for 10 minutes, raise at a rate of10°C per minute to 200°C, and maintain at a constant temperatureof about 200ºC.Flow rate: Adjust the flow rate so that the retention time ofsevoflurane is about 7 minutes.Time span of measurement: About 6 times as long as the retentiontime of sevoflurane.System suitability―Test for required detectability: To 20 µL of Sevoflurane addo-xylene to make 20 mL. To 1 mL of this solution add o-xyleneto make 20 mL, and use this solution as the solution for systemsuitability test. Pipet 1 mL of the solution for system suitabilitytest and add o-xylene to make exactly 10 mL. Confirm that thepeak area of sevoflurane obtained from 2 µL of this solution isequivalent to 7 to 13% of the peak area of sevoflurane from thesolution for system suitability test.System performance: When the procedure is run with 2 µL ofthe solution for system suitability test under the above operatingconditions, the number of theoretical plates and symmetry factorof the peak of sevoflurane are not less than 6000 and not morethan 1.5, respectively.System repeatability: When the test is repeated 6 times with 2µL of the solution for system suitability test under the above operatingconditions, the relative standard deviation of the peakarea of Sevoflurane is not more than 5.0%.(4) Residual solvent―Being specified separately.(5) Residue on evaporation―Evaporate 10 mL of Sevoflurane,exactly measured, on a water bath to dryness, and dry at105°C for 2 hours: the mass of the residue is not more than 1.0mg.

2192 Official Monographs Supplement II, JP XVWater 0.04 - 0.2 w/v% (5 mL, volumetric titration,direct titration).Assay Pipet 5 mL each of Sevoflurane and SevofluraneReference Standard (separately determine the water content using the same manner as Sevoflurane), to each add exactly5 mL of dimethoxymethane as an internal standard, anduse these solutions as the sample solution and standard solution,respectively. Perform the test with 1 µL each of the sample solutionand standard solution as directed under Gas Chromatography according to the following conditions, and calculatethe ratios, Q T and Q S , of the peak area of sevoflurane to that ofthe internal standard.Amount (mg) of sevoflurane (C 4 H 3 F 7 O)= V S × (Q T / Q S ) × 1000 × 1.521V S : Amount (mL) of Sevoflurane Reference Standard, calculatedon the anhydrous basis.1.521: Specific gravity of Sevoflurane (d 2020)Operating conditions—Detector: A hydrogen flame-ionization detector.Column: A fused silica column 0.32 mm in inside diameterand 30 m in length, coated inside with cyanopropyl methylphenylsilicone for gas chromatography in 1.8 µm thickness.Column temperature: 40°CInjection port temperature: A constant temperature of about200°C.Detector temperature: A constant temperature of about 225°C.Carrier gas: Helium.Flow rate: Adjust the flow rate so that the retention time ofSevoflurane is about 3 minutes.Split ratio: 1:20.System suitability―System performance: When the procedure is run with 1 µL ofthe standard solution under the above operating conditions, sevofluraneand the internal standard are eluted in this order withthe resolution between these peaks being not less than 3.System repeatability: When the test is repeated 6 times with 1µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area ofsevoflurane to that of the internal standard is not more than1.0 %.Containers and storageContainers―Tight containers.Add the following:SimvastatinシンバスタチンC 25 H 38 O 5 :418.57(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl2,2-dimethylbutanoate [79902-63-9]Simvastatin contains not less than 98.0% and notmore than 101.0% of C 25 H 38 O 5, calculated on the driedbasis.It may contain a suitable antioxidant.Description Simvastatin occurs as a white, crystalline powder.It is freely soluble in acetonitrile, in methanol and in ethanol(99.5), and practically insoluble in water.Identification (1) Determine the absorption spectrum of asolution of Simvastatin in acetonitrile (1 in 100000) as directedunder Ultraviolet-visible Spectrophotometry and comparethe spectrum with the Reference Spectrum or the spectrumof a solution of Simvastatin Reference Standard prepared in thesame manner as the sample solution: both spectra exhibit similarintensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Simvastatinas directed in the potassium bromide disk method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of SimvastatinReference Standard: both spectra exhibit similar intensities ofabsorption at the same wave numbers.Optical rotation [a] 20D: +285 - +300º (50 mg calculatedon the dried basis, acetonitrile, 10 mL, 100 mm).Purity (1) Clarity and color of solution—Dissolve 1 g ofSimvastatin in 10 mL of methanol: the solution is clear. Performthe test with this solution as directed under Ultraviolet-visibleSpectrophotometry : the absorbance at 440 nm is notmore than 0.10.(2) Heavy metals —To 1.0 g of Simvastatin add 2mL of sulfuric acid, and heat gently to carbonize. After cooling,add 2 mL of nitric acid and 1 mL of sulfuric acid, heat gentlyuntil the white fumes no more evolve, and heat to incinerate at500 to 600°C. If the incineration is not accomplished, add 0.5mL of nitric acid, heat in the same manner as above, and igniteat 500 to 600°C to incinerate completely. After cooling, add 2mL of hydrochloric acid, proceed with this solution according toMethod 2, and perform the test. Prepare the control solution by

Supplement II, JP XV Official Monographs 2193using the same quantities of the same reagents as directed forthe preparation of the test solution, and add 2.0 mL of StandardLead solution and water to make 50 mL (not more than 20ppm).(3) Related substances―Dissolve 30 mg of Simvastatin in20 mL of a mixture of acetonitrile and 0.01 mol/L potassiumdihydrogen phosphate TS, pH 4.0, (3:2), and use this solution asthe sample solution. Perform the test with 5 µL of the samplesolution as directed under Liquid Chromatography accordingto the following conditions. Determine each peak areafrom the sample solution by the automatic integration method,and calculate the amount of them by the area percentagemethod: the amounts of the peaks , having the relative retentiontimes of about 0.45, about 0.80, about 2.42, and about 3.80 withrespect to simvastatin are not more than 0.2%, respectively; theamount of the peak wsith a relative retention time of about 2.38is not more than 0.3%; the amount of the peak with a relativeretention time of about 0.60 is not more than 0.4%; and theamount of each peak other than simvastatin and other than thepeaks mentioned above is not more than 0.1%. Furthermore, thetotal amount of the peaks other than simvastatin and other thanthe peak with relative retention time of about 0.60 with respectto simvastatin is not more than 1.0 %.Operating conditions—Detector, column, and column temperature: Proceed as directedin the operating conditions in the Assay.Mobile phase A: A mixture of diluted phosphoric acid (1 in1000) and acetonitrile for liquid chromatography (1:1).Mobile phase B: A solution of phosphoric acid in acetonitrilefor liquid chromatography (1 in 1000).Flowing of mobile phase: Control the gradient by mixing themobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 - 4.5 100 04.5 - 4.6 100 → 95 0 → 54.6 - 8.0 95 → 25 5 → 758.0 - 11.5 25 75Flow rate: 3.0 mL per minute.Time span of measurement: About 5 times as long as the retentiontime of simvastatin.System suitability―Proceed as directed in the system suitability in the Assay.Test for required detectability: Pipet 0.5 mL of the samplesolution, add a mixture of acetonitrile and 0.01 mol/L potassiumdihydrogen phosphate TS, pH 4.0 (3:2), to make exactly 100mL, and use this solution as the solution for system suitabilitytest. Pipet 2 mL of the solution for system suitability test, add amixture of acetonitrile and 0.01 mol/L potassium dihydrogenphosphate TS, pH 4.0 (3:2), to make exactly 10 mL. Confirmthat the peak area of simvastatin obtained from 5 µL of this solutionis equivalent to 16 to 24% of the peak area of simvastatinin the solution for system suitability test.System performance: Proceed as directed in the system suitabilityin the Assay.System repeatability: When the test is repeated 6 times with 5µL of the solution for system suitability test under the aboveconditions, the relative standard deviation of the peak area ofsimvastatin is not more than 1.0 %.(4) Residual solvent―Being specified separately.Loss on drying Not more than 0.5% (1 g, in vacuumnot exceeding 0.67 kPa, 60°C, 3 hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 30 mg each of Simvastatin andSimvastatin Reference Standard (previously determine the losson drying in the same manner as Simvastatin), dissolveeach in a mixture of acetonitrile and 0.01 mol/L potassium dihydrogenphosphate TS, pH 4.0, (3:2) to make exactly 20 mL,and use these solutions as the sample solution and the standardsolution, respectively. Perform the test with exactly 5 µL each ofthe sample solution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak areas, A T and A S , of simvastatinfor each solution.Amount (mg) of simvastatin (C 25 H 38 O 5 ) = W S × (A T / A S )W S : Amount (mg) of Simvastatin Reference Standard , calculatedon the dried basisOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:238 nm).Column: A stainless steel column 4.6 mm in inside diameterand 33 mm in length, packed with octadecylsilanized silica gelfor liquid chromatography (3 µm in particle diameter).Column temperature: A constant temperature of about 25°C.Mobile phase: A mixture of diluted phosphoric acid (1 in1000) and acetonitrile for liquid chromatography (1:1).Flow rate: Adjust the flow rate so that the retention time ofsimvastatin is about 3 minutes.System suitability―System performance: Dissolve 3 mg of lovastatin in 2 mL ofthe standard solution. When the procedure is run with 5 µL ofthis solution under the above operating conditions, lovastatinand simvastatin are eluted in this order with the resolution betweenthese peaks being not less than 3.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of simvastatin isnot more than 1.0 %.Containers and storage Containers―Tight containers.Storage—Under nitrogen atmosphere.

2194 Official Monographs Supplement II, JP XVAdd the following:Purified Sodium Hyaluronate精 製 ヒアルロン 酸 ナトリウム(C 14 H 20 NNaO 11 ) n[9067-32-7]Purified Sodium Hyaluronate is the sodium salt ofglycosaminoglycans composed of disaccharide units ofD-glucuronic acid and N-acetyl-D-glucosamine obtainedfrom cockscomb or microorganisms.It contains not less than 90.0% and not more than105.5% of sodium hyaluronate (C 14 H 20 NNaO 11 ) n , calculatedon the dried basis.It is composed of an average molecular mass of thesodium salt of hyaluronic acid between 500,000 and1,200,000 or between 1,500,000 and 3,900,000.The average molecular mass of Purified SodiumHyaluronate should be labeled.Description Purified Sodium Hyaluronate occurs as whitepowder, granules or fibrous masses.It is sparingly soluble in water, and practically insoluble inethanol (99.5).It is hygroscopic.Identification (1) Determine the infrared absorption spectrumof Purified Sodium Hyaluronate, previously dried, as directedin the potassium bromide disk method under InfraredSpectrophotometry , and compare the spectrum with theReference Spectrum: both spectra exhibit similar intensities ofabsorption at the same wave numbers.(2) A solution of Purified Sodium Hyaluronate (1 in 1000)responds to the Qualitative Tests (1) for sodium salt.Viscosity Weigh accurately an amount of Purified SodiumHyaluronate so that the downflowing time of its solutionin 100 mL of 0.2 mol/L sodium chloride TS is 2.0 to 2.4 timeslonger than that of 0.2 mol/L sodium chloride TS, dissolve in0.2 mol/L sodium chloride TS to make exactly 100 mL, and usethis solution as the sample solution (1). Pipet 16 mL, 12 mL and8 mL of the sample solution (1), to each add 0.2 mol/L sodiumchloride TS to make exactly 20 mL, and use these solutions asthe sample solutions (2), (3) and (4), respectively. Perform thetest with the sample solutions (1), (2), (3) and (4) as directedunder Method 1 at 30 ± 0.1ºC using a Ubbelohde-type viscometerin which the downflowing time for 0.2 mol/L sodium chlorideis 200 to 300 seconds: the maximum viscosity calculated onthe dried basis is between 10.0 and 19.5 dL/g or between 25.0and 55.0 dL/g.Purity (1) Clarity and color of solution—Dissolve 0.10 g ofPurified Sodium Hyaluronate in 10 mL of water: the solution isclear and colorless.(2) Chloride —Dissolve 0.20 g of Purified SodiumHyaluronate in 15 mL of water, add 6 mL of dilute nitric acid,and heat on a water bath for 30 minutes. After cooling, add waterto make 50 mL. Perform the test using this solution as thetest solution. Prepare the control solution with 0.70 mL of 0.01mol/L hydrochloric acid VS (not more than 0.124%).(3) Heavy metals —Proceed with 1.0 g of PurifiedSodium Hyaluronate according to Method 2, and perform thetest. Prepare the control solution with 2.0 mL of Standard LeadSolution (not more than 20 ppm).(4) Residual solvent—Being specified separately.(5) Protein—Weigh accurately about 20 mg of Purified SodiumHyaluronate, calculated on the dried basis, dissolve in 1.0mL of dilute sodium hydroxide TS, and use this solution as thesample solution. Separately, weigh accurately about 10 mg ofbovine serum albumin, dissolve in dilute sodium hydroxide TSto make exactly 1000 mL, and use this solution as the standardsolution. To 1.0 mL each of the sample solution and standardsolution add 5.0 mL of alkaline copper TS (2), immediately stir,allow to stand at room temperature for 10 minutes, add 0.5 mLof diluted Folin’s TS (1 in 2), immediately stir, and allow tostand at room temperature for 30 minutes. Perform the test withthese solutions as directed under Ultraviolet-visible Spectrophotometry, using a solution, prepared with 1.0 mL ofdilute sodium hydrochloride in the same manner, as the blank:the absorbance of the sample solution at 750 nm does not exceedthe absorbance of the standard solution (not more than0.05%).(6) Nucleic acid— Determine the absorbance of a solutionof 0.10 g Purified Sodium Hyaluronate in 50 mL of water as directedunder Ultraviolet-visible Spectrophotometry , usingwater as the blank: the absorbance at 260 nm is not morethan 0.02.(7) Other acidic mucopolysaccharides—(In the case ofchicken-derived samples) Dissolve 0.25 g of Purified SodiumHyaluronate in 100 mL of water, and use this solution as thesample solution. Immerse a cellulose acetate membrane 6 cm inlength in 0.2 mol/L pirydine-formic acid buffer solution, pH 3.0.Take out the membrane and remove excessive buffer solutionusing a filter paper. Place the membrane in an electrophoresisvessel saturated with 0.2 mol/L pyridine-formic acid buffer solution,pH 3.0, and run at 0.5 mA/cm for 1 minute. Apply 2 µLof the sample solution to the membrane in an area 1 cm in widthat 1.5 cm from the anode. Carry out electrophoresis at 0.5mA/cm for 1 hour. After the electrophoresis, stain the membraneby immersing it in Alcian blue staining solution for 10 to 20minutes. After staining, decolorize sufficiently with diluted aceticacid (100) (3 in 100): no bands other than the principal bandappears.(8) Hemolytic streptococci—(In the case of microorganism-derivedsamples) Dissolve 0.5 g of Purified Sodium Hyalu-

Supplement II, JP XV Official Monographs 2195ronate in sterile isotonic sodium chloride solution to make exactly100 mL. Take 0.5 mL of this solution, apply to 2 bloodagar plates, respectively, using a Conradi stick, and incubate at37ºC for 48 hours: no hemolytic colonies appear, or if any, nostreptococci are observed in the colony under a microscope.(9) Hemolysis—(In the case of microorganism-derivedsamples) Dissolve 0.40 g of Purified Sodium Hyaluronate insterile physiological saline to make exactly 100 mL. To 0.5 mLof this solution add 0.5 mL of 1% blood suspension, mix, allowto stand at 37ºC for 2 hours, and, if necessary, centrifuge at 3000revolutions per minute for 10 minutes: the erythrocytes precipitateand the supernatant liquid is clear as in a blank determinationperformed in the same manner using 0.5 mL of isotonic sodiumchloride as the blank and 0.5 mL of sterile purified wateras the positive control.Loss on drying Not more than 15.0% (0.1 g, reducedpressure not exceeding 0.67 kPa, phosphorus (V) oxide, 60ºC, 5hours).Microbial limit The allowable limits of the total aerobicmicrobial count and of the total combined yeasts/moldscount for Purified Sodium Hyaluronate are 10 2 CFU/g and 10 1CFU/g, respectively.Average molecular mass (1) In the case of the labeled averagemolecular mass of between 500,000 and 1,200,000Calculate the average molecular mass of Purified Sodium Hyaluronateaccording to the following equation: it is between500,000 and 1,200,000. For [η], use the maximum viscosity underViscosity Determination.Average molecular mass = ([η] × 10 5 / 36) 1/0.78(2) In the case of the labeled average molecular mass ofbetween 1,500,000 and 3,900,000Calculate the average molecular mass of Purified SodiumHyaluronate according to the following equation: it is between1,500,000 and 3,900,000. For [η], use the maximum viscosityunder Viscosity Determination.Average molecular mass = ([η] × 10 5 / 22.8) 1/0.816Assay Weigh accurately about 50 mg of Purified SodiumHyaluronate, and dissolve in water to make exactly 50 mL. Pipet1 mL of this solution, add water to make exactly 20 mL, anduse this solution as the sample solution. Separately, weigh accuratelyabout 20 mg of D-Glucuronolactone Reference Standard,previously dried (under reduced pressure not exceeding 0.67kPa, silica gel, 24 hours), and dissolve in water to make exactly100 mL. Pipet 1 mL of this solution, add water to make exactly10 mL, and use this solution as the standard solution. Pipet 1 mLeach of the sample solution and standard solution, gently addinto the 5.0 mL of sodium tetraborate-sulfuric acid TS, previouslycooled in ice water, stir while cooling, heat in a water bathfor 10 minutes, and cool in ice water. To each solution add 0.2mL of carbazole TS, stir well, heat in a water bath for 15 minutes,and cool in ice water to room temperature. Determine theabsorbances, A T and A S , of the sample solution and standard solutionat the wavelength of maximum absorption at 530 nm asdirected under Ultraviolet-visible Spectrophotometry ,using a solution, prepared with 1 mL of water in the same manner,as the blank.Amount (mg) of sodium hyaluronate [(C 14 H 20 NNaO 11 ) a ]= W S × (A T /A S ) × 2.2786W S : Amount (mg) of D-Glucuronolactone Reference StandardContainers and storage Containers—Tight containers.Storage—Light-resistant, at not exceeding 15ºC.Sodium Iotalamate Injectionイオタラム 酸 ナトリウム 注 射 液Add the following next to Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Directmethod: it meets the requirement.Sodium Valproateバルプロ 酸 ナトリウムChange the Origin/limits of content, Description,Identification and Purity to read:Sodium Valproate, when dried, contains not lessthan 98.5% and not more than 101.0% of C 8 H 15 NaO 2 .Description Sodium Valproate occurs as a white, crystallinepowder.It is very soluble in water, freely soluble in ethanol (99.5) andin acetic acid (100). It is hygroscopic.Identification (1) To 5mL of a solution of Sodium Valproate(1 in 20) add 1 mL of a solution of cobalt (II) nitratehexahydrate (1 in 20) and warm on a water bath: a purple precipitateis formed.(2) Dissolve 0.5 g of Sodium Valproate in 5 mL of water,add 5 mL of diethyl ether and 1 mL of 2 mol/L hydrochloricacid TS, and shake vigorously for 1 minute. Separate the diethylether layer, dehydrate with anhydrous sodium sulfate, and filter.Evaporate the solvent of the filtrate, determine the infraredspectrum of the residue as directed in the liquid film methodunder Infrared Spectrophotometry , and compare thespectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) A solution of Sodium Valproate (1 in 10) responds tothe Qualitative Tests for sodium salt.

2196 Official Monographs Supplement II, JP XVPurity (1) Heavy metals ―Dissolve 2.0 g of SodiumValproate in 44 mL of water, shake with 6 mL of dilute hydrochloricacid, allow to stand for 5 minutes, and filter. Discard thefirst 5 mL of the filtrate, neutralize the subsequent 25 mL withammonia TS, and add 2 mL of dilute acetic acid and water tomake 50 mL. Perform the test using this solution as the test solution.Prepare the control solution as follows: to 2.0 mL ofStandard Lead Solution add 2 mL of dilute acetic acid and waterto make 50 mL (not more than 20 ppm).(2) Related substances―Dissolve 0.10 g of Sodium Valproatein 10 mL of a mixture of formic acid and methyl acetate(1:1), and use this solution as the sample solution. Pipet 1 mL ofthe sample solution, add a mixture of formic acid and methylacetate (1:1) to make exactly 200 mL, and use this solution asthe standard solution. Perform the test with exactly 2 µL each ofthe sample solution and standard solution as directed under GasChromatography according to the following conditions.Determine each peak area of both solutions by automatic integrationmethod: the total area of the peaks other than the peak ofvalproic acid from the sample solution is not more than the peakarea of valproic acid from the standard solution.Operating conditions—Detector: A hydrogen flame-ionization detector.Column: A glass column 3 mm in diameter and 2 m in length,packed with siliceous earth for gas chromatography (150 to 180µm in particle diameter) coated with diethylene glycol adipateester for gas chromatography and phosphoric acid at the ratiosof 5% and 1%, respectively.Column temperature: A constant temperature of about 145°C.Carrier gas: Nitrogen.Flow rate: Adjust the flow rate so that the retention time ofvalproic acid is about 7 minutes.Time span of measurement: About 2 times as long as the retentiontime of valproic acid, beginning after the solvent peak.System suitability―System performance: To 2 mL of the sample solution and 8µL of n-valerianic acid, add a mixture of formic acid and methylacetate (1:1) to make 10 mL. When the procedure is run with 2µL of this solution under the above operating conditions,n-valerianic acid and valproic acid are eluted in this order withthe resolution between these peaks being not less than 5.System repeatability: Pipet 2 mL of the standard solution andadd a mixture of formic acid and methyl acetate (1:1) to makeexactly 10 mL. When the test is repeated 6 times with 2 µL ofthis solution under the above operating conditions, the relativestandard deviation of the peak area of valproic acid is not morethan 5.0%.Add the following:Sodium Valproate Syrupバルプロ 酸 ナトリウムシロップSodium Valproate Syrup contains not less than95.0% and not more than 105.0% of the labeledamount of sodium valproate (C 8 H 15 NaO 2 : 166.19).Method of preparation Prepare as directed under Syrups,with Sodium Valproate.Identification To a volume of Sodium Valproate Syrup,equivalent to 50 mg of Sodium Valproate according to the labeledamount, add water to make 10 mL. To 5 mL of this solutionadd 1 mL of a solution of cobalt (II) nitrate hexahydrate (1in 20) and warm on a water bath: a purple precipitate is formed.Microbial Limit Test Acceptance criteria for the totalaerobic microbial count and the total combined yeasts andmoulds are 10 2 CFU and 10 1 CFU per mL of Sodium ValproateSyrup, respectively, with no Escherichia coli present.Assay Pipet a volume of Sodium Valproate Syrup, equivalentto about 0.1 g of sodium valproate (C 8 H 15 NaO 2 ) and add waterto make exactly 100 mL. Pipet 20 mL of this solution, add exactly5 mL of internal standard solution, and use this solution asthe sample solution. Separately, weigh accurately about 50 mgof sodium valproate for assay , previously dried at 105°C for 3hours, dissolve in water to make exactly 50 mL. Pipet 20 mL ofthis solution, add exactly 5 mL of the internal standard solution,and use this solution as the standard solution. Perform the testwith 10 µL each of the sample solution and standard solution asdirected under Liquid Chromatography according to thefollowing conditions, and calculate the ratios, Q T and Q S , of thepeak area of valproic acid to that of the internal standard.Amount (mg) of sodium valproate (C 8 H 15 NaO 2 )= W S × (Q T / Q S ) × 2W S : Amount (mg) of sodium valproate for assayInternal standard solution—A solution of ethyl parahydroxybenzoatein the mobile phase (1 in 50000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:210 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25°C.Mobile phase: A mixture of 0.05 mol/L sodium dihydrogenphosphateTS, pH 3.0 and acetonitrile (1:1).Flow rate: Adjust the flow rate so that the retention time ofvalproic acid is about 6 minutes.System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the internal standard and valproic acid are eluted in this orderwith the resolution between these peaks being not less than 7.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof valproic acid to that of the internal standard is not more than1.0%.Containers and storage Containers―Tight containers.

Supplement II, JP XV Official Monographs 2197Add the following:Sodium Valproate Tabletsバルプロ 酸 ナトリウム 錠Sodium Valproate Tablets contain not less than95.0% and not more than 105.0% of the labeledamount of sodium valproate (C 8 H 15 NaO 2 : 166.19).Method of preparation Prepare as directed under Tablets,with Sodium Valproate.Identification To a quantity of powdered Sodium ValproateTablets, equivalent to 0.5 g of Sodium Valproate according tothe labeled amount, add 10 mL of water, shake well, and centrifuge.To 5 mL of the supernatant liquid add 1 mL of a solutionof cobalt (II) nitrate hexahydrate (1 in 20) and warm on a waterbath: a purple precipitate is formed.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Sodium Valproate Tablets add 7 V/10 mL ofthe mobile phase, shake vigorously, add the mobile phase tomake exactly V mL so that each mL contains about 1 mg of sodiumvalproate (C 8 H 15 NaO 2 ), and centrifuge. Filter the supernatantliquid, pipet 20 mL of the filtrate, add exactly 5 mL ofthe internal standard solution, shake vigorously, and use thissolution as the sample solution. Proceed as directed in the Assay.Amount (mg) of sodium valproate (C 8 H 15 NaO 2 )= W S × (Q T / Q S ) × (V / 100)W S : Amount (mg) of sodium valproate for assayInternal standard solution―A solution of ethyl parahydroxybenzoatein the mobile phase (1 in 50000)Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of water as the dissolution medium, thedissolution rate in 30 minutes of Sodium Valproate Tablets isnot less than 85%.Start the test with 1 tablet of Sodium Valproate Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard the first 10mL of the filtrate, pipet V mL of the subsequent filtrate, addwater to make exactly V´ mL so that each mL contains about0.11 mg of sodium valproate (C 8 H 15 NaO 2 ), according to the labeledamount, and use this solution as the sample solution.Separately, weigh accurately about 0.11 mg of sodium valproatefor assay, previously dried at 105°C for 3 hours, and dissolve inwater to make exactly 50 mL. Pipet 5 mL of this solution, addwater to make exactly 50 mL of the solution, and use this solutionas the standard solution. Perform the test with exactly 50 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and determine the peak areas, A T and A S , of thevalproic acid in each solution.Dissolution rate (%) with respect to the labeled amount ofsodium valproate (C 8 H 15 NaO 2 )= W S × (A T / A S )×(V ´/ V )×(1 / C)× 180W S : Amount (mg) of sodium valproate for assayC: Labeled amount (mg) of sodium valproate (C 8 H 15 NaO 2 ) in1 tablet.Operating conditions—Proceed as directed in the Assay.System suitability―System performance: When the procedure is run with 50 µLof the standard solution under the above operating conditions,the number of theoretical plates and symmetry factor of the peakof valproic acid are not less than 3000 and not more than 2.0,respectively.System repeatability: When the test is repeated 6 times with50 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of valproicacid is not more than 1.5%.Assay Weigh accurately the mass of not less than 20 SodiumValproate Tablets, and powder. Weigh accurately a portion ofthe powder, equivalent to about 0.2 g of sodium valproate(C 8 H 15 NaO 2 ), add about 160 mL of the mobile phase, shakewell, add the mobile phase to make exactly 200 mL, and centrifuge.Filter the supernatant liquid, pipet 20 mL of the filtrate,add exactly 5 mL of the internal standard solution, and use thissolution as the sample solution. Separately, weigh accuratelyabout 0.1 g of sodium valproate for assay, previously dried at105°C for 3 hours, and dissolve in the mobile phase to makeexactly 100 mL. Pipet 20 mL of this solution, add exactly 5 mLof the internal standard solution, and use this solution as thestandard solution. Perform the test with 10 µL each of the samplesolution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of valproicacid to that of the internal standard.Amount (mg) of sodium valproate (C 8 H 15 NaO 2 )= W S × (Q T / Q S ) × 2W S : Amount (mg) of sodium valproate for assayInternal standard solution―A solution of ethyl parahydroxybenzoatein the mobile phase (1 in 50000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:210 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25°CMobile phase: A mixture of 0.05 mol/L sodium dihydrogenphosphateTS, pH 3.0 and acetonitrile (1:1).Flow rate: Adjust the flow rate so that the retention time of

2198 Official Monographs Supplement II, JP XVvalproic acid is about 6 minutes.System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the internal standard and valproic acid are eluted in this orderwith the resolution between these peaks being not less than 7.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof valproic acid to that of the internal standard is not more than1.0%.Containers and storageAdd the following:Containers―Tight containers.Streptomycin Sulfate for Injection注 射 用 ストレプトマイシン 硫 酸 塩Streptomycin Sulfate for Injection is a preparationfor injection, which is dissolved before use.It contains not less than 90.0% and not more than110.0% of the labeled potency of streptomycin(C 21 H 39 N 7 O 12 : 581.57).Method of preparation Prepare as directed under Injections,with Streptomycin Sulfate.Description Streptomycin Sulfate for Injection occurs as awhite or light yellowish white masses or powder.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Assay Perform the test according to the Cylinder-plate methodas directed under Microbial Assay for Antibiotics accordingto the following conditions.(i) Test organisms, culture medium and standard solutions—Proceedas directed in the Assay under StreptomycinSulfate.(ii) Sample solution Take 10 containers of StreptomycinSulfate for Injection, and weigh accurately the mass of the contents.Weigh accurately an amount of the contents, equivalent to1 g (potency) of Streptomycin Sulfate, and dissolve in water tomake exactly 200 mL. Take exactly a suitable amount of thissolution, add 0.1 mol/L phosphate buffer solution, pH 8.0, tomake a solutions so that each mL contains 8 µg (potency) and 2µg (potency), and use these solutions as the high concentrationsample solution and the low concentration sample solution, respectively.Containers and storageAdd the following:SulindacスリンダクContainers―Hermetic containers.Identification Peform the test as directed in the Identification(2) under Streptomycin Sulfate.Osmotic pressure ratioBeing specified separately.pH The pH of a solution prepared by dissolving anamount of Streptomycin Sulfate for Injection, equivalent to 2.0g (potency) of Streptomycin Sulfate according to the labeledamount, in 10 mL of water is 5.0 to 7.0.Purity Clarity and color of solution—Dissolve an amount ofStreptomycin Sulfate for Injection, equivalent to 1.0 g (potency)of Streptomycin Sulfate according to the labeled amount, in 3mL of water: The solution is clear, and the absorbance of thissolution at 400 nm, determined as directed under Ultraviolet-visibleSpectrophotometry , is not more than 0.50.Loss on drying Not more than 4.0 % (0.5 g, reducedpressure not exceeding 0.67 kPa, 60°C, 3 hours).Bacterial endotoxins Less than 0.10 EU/mg (potency).Uniformity of dosage units It meets the requirementof the Mass Variation Test.Foreign insoluble matter Perform the test accordingto Method 2: it meets the requirement.and enantiomerC 20 H 17 FO 3 S:356.41(1Z)-(5-Fluoro-2-methyl-1-{4-[(RS)-methylsulfinyl]benzylidene}-lH-inden-3-yl)acetic acid[38194-50-2]Sulindac, when dried, contains not less than 99.0%and not more than 101.0% of C 20 H 17 FO 3 S.Description Sulindac occurs as a yellow, crystalline powder.It is sparingly soluble in methanol and in ethanol (99.5), andpractically insoluble in water.A solution of Sulindac in methanol (1 in 100) shows no opticalrotation.Melting point: about 184°C (with decomposition).Identification (1) Dissolve 15 mg of Sulindac in 1000 mLof a solution of hydrochloric acid in methanol (1 in 120). Determinethe absorption spectrum of this solution as directed underthe Ultraviolet-visible Spectrophotometry andcompare the spectrum with the Reference Spectrum: both spectraexhibit similar intensities of absorption at the same wave-

2200 Official Monographs Supplement II, JP XVtitration).Residue on ignition Not more than 0.1% (1 g).Isomer Being specified separately.Assay Weigh accurately about 25 mg each of Tacrolimus Hydrateand Tacrolimus Reference Standard (separately determinethe water content in the same manner as TacrolimusHydrate) and dissolve each in 15 mL of ethanol (99.5), to eachadd exactly 10 mL of the internal standard, add 25 mL of water,allow to stand for 6 hours, and use these solutions as the samplesolution and standard solution, respectively. Perform the testwith 10 µL each of the sample solution and standard solution asdirected under Liquid Chromatography according to thefollowing conditions, and calculate the ratios, Q T and Q S , of thepeak area of tacrolimus to that of the internal standard.Amount (mg) of tacrolimus (C 44 H 69 NO 12 ) = W S × (Q T / Q S )W S : Amount (mg) of Tacrolimus Reference Standard, calculatedon the anhydrous basis.Internal standard solution―A solution of heptyl parahydroxybenzoatein ethanol (99.5) (3 in 4000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:220 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 50°C.Mobile phase: A mixture of water, 2-propanol for liquidchromatography and tetrahydrofuran for liquid chromatography(5:2:2).Flow rate: Adjust the flow rate so that the retention time oftacrolimus is about 10 minutes.System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,tacrolimus and the internal standard are eluted in this order withthe resolution between these peaks being not less than 6.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof tacrolimus to that of internal standard is not more than 1.0%.Containers and storageContainers―Well-closed containers.Add the following:TazobactamタゾバクタムC 10 H 12 N 4 O 5 S: 300.29(2S,3S,5R)-3-Methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 4,4-dioxide [89786-04-9]Tazobactam contains not less than 980 µg and notmore than 1020 µg (potency) per 1 mg, calculated onthe anhydrous basis. The potency of Tazobactam isexpressed as mass (potency) of C 10 H 12 N 4 O 5 S.Description Tazobactam occurs as a white to pale yellowishwhite, crystalline powder.It is freely soluble in dimethylsulfoxide and in N,N-dimethylformamide, and slightly soluble in water, in methanoland in ethanol (99.5).It dissolves in a solution of sodium hydrogen carbonate (3 in100).Identification (1) Determine the infrared absorption spectrumof Tazobactam as directed in the potassium bromide diskmethod under the Infrared Spectrophotometry , andcompare the spectrum with the Reference Spectrum or the spectrumof Tazobactam Reference Standard: both spectra exhibitsimilar intensities of absorption at the same wave numbers.(2) Determine the spectrum of a solution of Tazobactam indeuterated dimethylsulfoxide for nuclear magnetic resonancespectroscopy (1 in 35) as directed under the Nuclear MagneticResonance Spectroscopy ( 1 H), using tetramethylsilanefor nuclear magnetic resonance spectroscopy as an internal referencecompound: it exhibits a single signal A at around δ 1.3ppm, and double signals, B and C, at around δ 7.8 ppm and ataround δ 8.1 ppm. The ratio of the integrated intensity of eachsignal, A:B:C, is about 3:1:1.Optical rotation 20[α] D: +162 − +167º (1 g calculatedon the anhydrous basis, N, N-dimethylformamide, 100 mL, 100mm).Purity (1) Clarity and color of solution-Dissolve 1.0 g ofTazobactam in 10 mL of sodium hydrogen carbonate (3 in 100) :the solution is clear. Perform the test with the solution as directedunder Ultraviolet-visible Spectrophotometry : theabsorbance at 420 nm is not more than 0.14.(2) Heavy metals -Proceed with 1.0 g of Tazobactamaccording to Method 2, and perform the test. Prepare thecontrol solution with 1.0 mL of Standard Lead Solution (notmore than 10 ppm).(3) Related substances-This operation must be performedquickly. Dissolve 50 mg of Tazobactam in 20 mL of the mobile

Supplement II, JP XV Official Monographs 2201phase, and use this solution as the sample solution. Pipet 1 mLof the sample solution, add the mobile phase to make exactly100 mL, and use this solution as the standard solution (1). Pipet1 mL of the standard solution (1), add the mobile phase to makeexactly 10 mL, and use this solution as the standard solution (2).Perform the test with exactly 50 µL each of the sample solution,the standard solution (1) and the standard solution (2) as directedunder the Liquid Chromatography according tothe following conditions. Determine each peak area form thesesolutions by the automatic integration method: the area of thepeak, having the relative retention time of about 0.17 with respectto tazobactam, obtained from the sample solution is notlarger than 4/5 times the peak area of tazobactam from the standardsolution (1), the peak area other than the peak of tazobactamand the peak having the relative retention time of about 0.17with respect to tazobactam from the sample solution is not largerthan the peak area of tazobactam from the standard solution(2), and the total area of the peaks other than the peak of tazobactamand the peak having the relative retention time of about0.17 with respect of tazobactam from the sample solution is notlarger than 2 times the peak area of tazobactam from the standardsolution (2).Operating conditions-Detector, column, column temperature, mobile phase, andflow rate: Proceed as directed in the operating conditions in theAssay.Time span of measurement: About 3 times as long as the retentiontime of tazobactam.System suitability-Test for required detectability: Pipet 1 mL of the standard solution(1), and add the mobile phase to make exactly 20 mL.Confirm that the peak area of tazobactam obtained from 50 µLof this solution is equivalent to 3 to 7% of that of tazobactamfrom the standard (1).System performance: When the procedure is run with 50 µLof the standard solution (1) under the above operating conditions,the number of theoretical plates and the symmetry factorof the peak of tazobactam are not less than 2000 and 0.8 -1.2,respectively.System repeatability: When the test is repeated 6 times with 50µL of the standard solution (1) under the above operating conditions,the relative standard deviations of the peak area of tazobactamis not more than 1.0%.(4) Residual solvent Being specified separately.Water Not more than 0.5% (1 g, volumetric titration,direct titration. Use a mixture of formamide for water determinationand methanol for water determination (3:1) instead ofmethanol for water determination).Residue on ignition Not more than 0.1% (1 g).Bacterial endotoxins Less than 0.04 EU/mg (potency).Assay Weigh accurately an amount of Tazobactam and TazobactamReference Standard, equivalent to about 50 mg (potency),dissolve in exactly 10 mL of the internal standard solution,add water to make 100 mL, and use these solutions as thesample solution and the standard solution, respectively. Performthe test with 10 µL each of the sample solution and the standardsolution as directed under the Liquid Chromatography according to the following conditions, and determine the ratios,Q T and Q S , of the peak areas of tazobactam to that of the internalstandard.Amount [µg (potency)] of tazobactam (C 10 H 12 N 4 O 5 S)= Ws×(Q T /Q S )×1000Ws: Amount [mg (potency)] of Tazobactam Reference StandardInternal standard solution-A solution of phenylalanine (1 in400).Operating conditions-Detector: An ultraviolet absorption photometer (wavelength:210 nm).Column: A stainless steel column 4.6 mm in inside diameterand 25 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (10 µm in particle diameter).Column temperature: A constant temperature of about 25°C.Mobile phase: Disssolve 1.32 g of diammonium hydrogenphosphate in 750 mL of water, adjust the pH to 2.5 with phosphoricacid, add water to make 1000 mL, and add 25 mL ofacetonitrile.Flow rate: Adjust the flow rate so that the retention time oftazobactam is about 10 minutes.System suitability-System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the internal standard, the internal standard and tazobactam areeluted in this order with the resolution between these peaks beingnot less than 4.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratios of the peakarea of tazobactam to that of the internal standard is not morethan 1.0%.Containers and storageExpiration dateTeicoplaninテイコプラニンContainers―Tight containers.24 months after preparation.Change the Origin/limits of content to read:Teicoplanin is a mixture of glycopeptide substanceshaving antibacterial activity produced by the growth ofActinoplanes teichomyceticus.It contains not less than 900 µg (potency) and notmore than 1120 µg (potency) per 1 mg, calculated onthe anhydrous, de-sodium chloride and de-residualsolvents basis. The potency of Teicoplanin is expressedas mass (potency) of teicoplanin (C 72~89 H 68~99Cl 2 N 8~9 O 28~33 ).

2202 Official Monographs Supplement II, JP XVAdd the following:TeprenoneテプレノンC 23 H 38 O:330.55(5E,9E,13E)-6,10,14,18-Tetramethylnonadeca-5,9,13,17-tetraen-2-one(5Z,9E,13E)-6,10,14,18-Tetramethylnonadeca-5,9,13,17-tetraen-2-one[6809-52-5]Teprenone contains not less than 97.0% and notmore than 101.0% of C 23 H 38 O.Teprenone is comprised of mono-cis and all-transisomers, with their ratio being about 2:3.Description Teprenone occurs as a colorless to slightly yellowishclear oily liquid, with slight, characteristic odor.It is miscible with ethanol (99.5), with ethyl acetate and withhexane.It is practically insoluble in water.It is oxidized by air, and gradually turns yellow.Identification (1) To 2 mL of a solution of Teprenone inethanol (99.5) (1 in 100) add 1 mL of a solution of phosphomolybdicacid n-hydrate in acetic acid (100) (1 in 100), heat in awater bath for 5 minutes, and continue heating with addition of5 to 6 drops of sulfuric acid: blue to bluish green color develops.(2) To 2 mL of a solution of Teprenone in ethanol (99.5) (1in 100) add 2 mL of 2,4-dinitrophenylhydrazine TS, and shake:a yellow to orange-yellow precipitate is formed.(3) Determine the infrared absorption spectrum of Teprenoneas directed in the liquid film method under InfraredSpectrophotometry , and compare the spectrum with theReference Spectrum or the spectrum of Teprenone ReferenceStandard: both spectra exhibit similar intensities of absorption atthe same wave numbers.Refractive index n 20D: 1.485 – 1.491Specific gravity d 2020: 0.882 – 0.890Purity (1) Clarity and color of solution―To 1.0 mL of Teprenoneadd 9 mL of ethanol (99.5) and shake: the solution isclear, and its absorbance at 400 nm determined as directed underUltraviolet-visible Spectrophotometry is not morethan 0.02.(2) Heavy metals ―Proceed with 1.0 g of Teprenoneaccording to Method 2 and perform the test. Prepare thecontrol solution with 2.0 mL of Standard Lead Solution (notmore than 20 ppm).(3) Related substances―Dissolve 30 mg of Teprenone in 6mL of hexane, and use this solution as the sample solution. Performthe test with 3 µL of the sample solution as directed underGas Chromatography according to the following conditions.Determine each peak area from the sample solution by theautomatic integration method and calculate the amounts of themby the area percentage method: the peak area of the di-cis isomerof teprenone, having the relative retention time of about 0.8with respect to the all-trans isomer of teprenone, is not morethan 0.5%, and each area of the peaks for the mono-cis andall-trans isomers of the teprenone and for those other than mentionedabove is not more than 0.2 %. Furthermore, the total areaof the peaks other than the mono-cis, all-trans and di-cis isomersof teprenone is not more than 1.0 %.Operating conditions—Detector, column, column temperature, carrier gas and flowrate: Proceed as directed in the operating conditions in the Assay.Time span of measurement: About 2 times as long as the retentiontime for the all-trans isomer of teprenone beginning afterthe solvent peak.System suitability―Test for required detectability: To 1 mL of the sample solutionadd hexane to make 100 mL, and use this solution as thesolution for system suitability test. Pipet 1 mL of the solutionfor system suitability test, and add hexane to make exactly 10mL. Confirm that the sum of the peak areas of the mono-cis andall-trans isomers of teprenone obtained from 3 µL of this solutionis 7 to 13% of the peak areas of the mono-cis and all-transisomers of teprenone from the solution for system suitabilitytest.System performance: When the procedure is run with 3 µL ofthe solution for system suitability test under the above operatingconditions, the mono-cis and all-trans isomers of teprenone areeluted in this order with the resolution between these peaks beingnot less than 1.1.System repeatability: When the test is repeated 6 times with 3µL of the solution for system suitability test under the aboveoperating conditions, the relative standard deviation of the sumof the peak areas of the mono-cis and all-trans isomers of teprenoneis not more than 3.0%.(4) Residual solvent―Being specified separately.Residue on ignition Not more than 0.1% (1 g).Isomer ratio Dissolve 30 mg of Teprenone in 6 mL of hexane,and use this solution as the sample solution. Perform the testwith 3 µL of the sample solution as directed under Gas Chromatography according to the following conditions. Determinethe areas of two adjacent peaks, A a and A b , having retentiontimes of about 18 minutes, where A a is the peak of themono-cis isomer, having the shorter retention time, and A b is thepeak area of the all-trans isomer, having the longer retentiontime: A a /A b is 0.60 to 0.70.Operating conditions—Proceed as directed in the Assay.System suitability―Proceed as directed in the system suitability in the Purity (3).

Supplement II, JP XV Official Monographs 2203Assay Weigh accurately about 50 mg each of Teprenone andTeprenone Reference Standard, dissolve each in exactly 5 mL ofthe internal standard solution, add ethyl acetate to make 50 mL,and use these solutions as the sample solution and standard solution,respectively. Perform the test with 3 µL each of the samplesolution and standard solution as directed under Gas Chromatography according to the following conditions, andcalculate the ratios, Q T and Q S , of the peak area of teprenone(sum of the peak areas of mono-cis and all-trans isomers) to thatof the internal standard.Amount (mg) of teprenone (C 23 H 38 O) = W S × (Q T /Q S )W S : Amount (mg) of Teprenone Reference StandardInternal standard solution—A solution of di-n-butyl phthalate inethyl acetate (1 in 100)Operating conditions—Detector: A hydrogen flame-ionization detector.Column: A glass column 4 mm in inside diameter and 2 m inlength, packed with 149 to 177 µm siliceous earth for gas chromatographycoated in 5% with polyethylene glycol2-nitroterephthalate.Column temperature: Constant temperature of about 210°C.Carrier gas: Nitrogen or helium.Flow rate: Adjust the flow rate so that the retention time ofthe peak of the all-trans isomer of teprenone, the larger of thetwo main peaks, having the retention time about 18 minutes,becomes 19 minutes.System suitability―System performance: When the procedure is run with 3 µL ofthe standard solution under the above operating conditions, theinternal standard and the mono-cis and all-trans isomers of teprenoneare eluted in this order with the resolution between themono-cis and all-trans isomers being not less than 1.1.System repeatability: When the test is repeated 6 times with 3µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the sum of the peakareas of the mono-cis and all-trans isomers of teprenone to thatof the internal standard is not more than 1.0%.Containers and storage Containers—Tight Containers.Storage conditions―Under Nitrogen atmosphere at 2 to 8°C.Testosterone Enanthate Injectionテストステロンエナント 酸 エステル 注 射 液Add the following next to Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter Perform the test accordingto Method 2: it meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Testosterone Propionate Injectionテストステロンプロピオン 酸 エステル 注 射 液Add the following next to Foreign insolublematter:Insoluble particulate matter Perform the test accordingto Method 2: it meets the requirement.Add the following:Tiapride Hydrochlorideチアプリド 塩 酸 塩C 15 H 24 N 2 O 4 S·HCl: 364.89N-[2-(Diethylamino)ethyl]-2-methoxy-5-(methylsulfonyl)benzamide monohydrochloride[51012-33-0]Tiapride Hydrochloride, when dried, contains notless than 99.0% and not more than 101.0% ofC 15 H 24 N 2 O 4 S·HCl.Description Tiapride Hydrochloride occurs as a white toslightly yellowish white crystal or crystalline powder.It is very soluble in water, freely soluble in acetic acid (100),soluble in methanol, slightly soluble in ethanol (99.5) and veryslightly soluble in acetic anhydride.It dissolves in 0.1 mol/L hydrochloric acid TS.Identification (1) Determine the absorption spectrum of asolution of Tiapride Hydrochloride in 0.1 mol/L hydrochloricacid TS (1 in 10000) as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the ReferenceSpectrum: both spectra exhibit similar intensities of absorptionat the same wavelengths.(2) Determine the infrared absorption spectrum of TiaprideHydrochloride as directed in the potassium chloride disk methodunder Infrared Spectrophotometry : both spectra exhibitsimilar intensities of absorption at the same wave numbers.(3) A solution of Tiapride Hydrochloride (1 in 20) respondsto Qualitative Tests for chloride.Purity (1) Heavy metals ―Proceed with 1 g ofTiapride Hydrochloride according to Method 1 and perform thetest. Prepare the control solution with 2.0 mL of Standard LeadSolution (not more than 20 ppm).(2) Related substances―Dissolve 0.20 g of Tiapride Hydrochloridein 10 mL of methanol and use this solution as the

2204 Official Monographs Supplement II, JP XVsample solution. Pipet 1 mL of the sample solution, and addmethanol to make exactly 100 mL. Pipet 1 mL of this solution,add methanol to make exactly 10 mL, and use this solution asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot rapidly10µL each of the sample solution and standard solution on aplate of silica gel with fluorescent indicator for thin-layer chromatographyunder a stream of nitrogen. Develop the plate with amixture of water, 1-butanol and acetic acid (100) (2:2:1) to adistance of about 10 cm, and air-dry, and then dry the plate at80°C for 30 minutes. Examine under ultraviolet light (mainwavelength: 254 nm): the spots other than the principal spotfrom the sample solution are not more intense than the spotfrom the standard solution.(3) Residual solvent―Being specified separately.Loss on drying Not more than 0.5% (1 g, 105°C, 2hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.4 g of Tiapride Hydrochloride,previously dried, dissolve in 50 mL of a mixture of aceticanhydride and acetic acid (100) (7:3), and titrate with0.1 mol/L perchloric acid VS (potentiometric titration). Performa blank determination in the same manner, and make any necessarycorrection.Each mL of 0.1 mol/L perchloric acid VS= 36.49 mg of C 15 H 24 N 2 O 4 S·HClContainers and storage Containers―Well-closed containers.Add the following:Tiapride Hydrochloride Tabletsチアプリド 塩 酸 塩 錠Tiapride Hydrochloride Tablets contain not less than95.0% and not more than 105.0% of the labeledamount of tiapride (C 15 H 24 N 2 O 4 S: 328.43)Method of preparation Prepare as directed under Tablets,with Tiapride Hydrochloride.Identification To a quantity of powdered Tiapride HydrochlorideTablets, equivalent to 10 mg of tiapride (C 15 H 24 N 2 O 4 S)according to the labeled amount, add 100 mL of 0.1 mol/L hydrochloricacid TS, shake well, and filter. Determine the absorptionspectrum of the filtrate as directed under Ultraviolet-visibleSpectrophotometry : it exhibits a maximum between 286nm and 290 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Tiapride Hydrochloride Tablets add V/10 mL of0.1 mol/L hydrochloric acid TS, treat with ultrasonic waves untilthe tablet is disintegrated, and add 4V/10 mL of methanol. Tothis solution add exactly V/10 mL of the internal standard solution,shake for 30 minutes, and add methanol to make V mL sothat each mL contains about 1 mg of tiapride (C 15 H 24 N 2 O 4 S).Centrifuge this solution for 10 minutes, and use the supernatantliquid as the sample solution. Proceed as directed in the Assay.Amount (mg) of tiapride (C 15 H 24 N 2 O 4 S)= W S × (Q T /Q S ) × (V/100) × 0.900W S : Amount (mg) of tiapride hydrochloride for assayInternal standard solution—A solution of methyl parahydroxybenzoatein methanol (1 in 500)Dissolution Being specified separately.Assay Weigh accurately the mass of not less than 20 TiaprideHydrochloride Tablets and powder. Weigh accurately a portionof the powder, equivalent to about 0.1 g of tiapride(C 15 H 24 N 2 O 4 S), add about 10 mL of 0.1 mol/L hydrochloricacid TS and 40 mL of methanol, add exactly 10 mL of the internalstandard solution, shake for 30 minutes, and add methanolto make 100 mL. Centrifuge this solution and use the supernatantliquid as the sample solution. Separately, weigh accuratelyabout 0.11 g of tiapride chloride for assay, previouslydried at 105°C for 2 hours, dissolve in 10 mL of 0.1 mol/L hydrochloricacid TS, add exactly 10 mL of the internal standardsolution, add methanol to make 100 mL, and use this solution asthe standard solution. Perform the test with 5 µL each of thesample solution and standard solution as directed under liquidchromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of Tiaprideto that of the internal standard.Amount (mg) of tiapride (C 15 H 24 N 2 O 4 S)= W S × (Q T /Q S ) × 0.900W S : Amount (mg) of tiapride chloride for assayInternal standard solution—A solution of methyl parahydroxybenzoatein methanol (1 in 500)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel column 4 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 25°C.Mobile phase: Dissolve 11.2 g of sodium perchlorate in 800mL of water, add 5 mL of diluted perchloric acid (17 in 2000).To 800 mL of this solution add 200 mL of acetonitrile.Flow rate: Adjust the flow rate so that the retention time oftiapride is about 8 minutes.System suitability―System performance: When the procedure is run with 5 µL ofthe standard solution under the above operating conditions,tiapride and the internal standard are eluted in this order withthe resolution between these peaks being not less than 8.

Supplement II, JP XV Official Monographs 2205System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak area oftiapride to that of the internal standard is not more than 1.0%.Containers and storage Containers―Well-closed containers.Add the following:Tosufloxacin Tosilate Hydrateトスフロキサシントシル 酸 塩 水 和 物Tolbutamide Tabletsトルブタミド 錠Add the following next to Identification:Uniformity of dosage units It meets the requirementof the Mass variation test.Change the Dissolution to read:Dissolution When the test is performed at 100 revolutionsper minute according to the Paddle method, using 900 mLof phosphate buffer solution, pH 7.4, as the dissolution medium,the dissolution rate in 30 minutes of Tolbutamide Tablets is notless than 80%.Start the test with 1 tablet of Tolbutamide Tablets, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.8 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to make exactlyV´ mL so that each mL contains about 10 µg of tolbutamide(C 12 H 18 N 2 O 3 S) according to the labeled amount, and use thissolution as the sample solution. Separately, weigh accuratelyabout 50 mg of Tolbutamide Reference Standard, previouslydried at 105°C for 3 hours, dissolve in 10 mL of methanol, andadd the dissolution medium to make exactly 100 mL. Pipet 2mL of this solution, add water to make exactly 100 mL, and usethis solution as the standard solution. Perform the test with thesample solution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine theabsorbances, A T and A S , at 226 nm.Dissolution rate (%) with respect to the labeled amount oftolbutamide (C 12 H 18 N 2 O 3 S)= W S × (A T /A S )× (V´/V ) × (1/C) × 18W S : Amount (mg) of Tolbutamide Reference StandardC: Labeled amount (mg) of tolbutamide (C 12 H 18 N 2 O 3 S) in 1tabletand enantiomerC 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S·H 2 O: 594.567-[(3RS)-3-Aminopyrrolidin-1-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid monotosylate monohydrate [115964-29-9, anhydride]Tosufloxacin Tosilate Hydrate contains not less than98.5% and not more than 101.0% of tosufloxacin tosilate(C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S: 576.54), calculated onthe anhydrous basis.Description Tosufloxacin Tosilate Hydrate occurs as a whiteto pale yellowish white, crystalline powder.It is freely soluble in N,N-dimethylformamide, sparinglysoluble in methanol, and practically insoluble in water and inethanol (99.5).A solution of Tosufloxacin Tosilate Hydrate in methanol (1 in100) shows no optical rotation.Melting point: about 254°C (with decomposition).Identification (1) Tosufloxacin Tosilate Hydrate shows alight bluish-white fluorescence under ultraviolet light (mainwavelength 254 nm).(2) Proceed 10 mg of Tosufloxacin Tosilate Hydrate as directedunder Oxygen Flask Combustion Method , using amixture of 0.5 mL of 0.01 mol/L sodium hydroxide TS and 20mL of water as the absorbing liquid: the solution responds to theQualitative Tests (2) for fluoride.(3) Determine the absorption spectrum of a solution of TosufloxacinTosilate Hydrate in a mixture of methanol and sodiumhydroxide TS (49:1) (1 in 100000) as directed under Ultraviolet-visibleSpectrophotometry , and compare thespectrum with the Reference Spectrum or the spectrum of a solutionof Tosufloxacin Tosilate Hydrate Reference Standardprepared in the same manner as the sample solution: both spectraexhibit similar intensities of absorption at the same wavelengths.(4) Determine the infrared absorption spectrum of TosufloxacinTosilate Hydrate as directed in the paste method underInfrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of TosufloxacinTosilate Hydrate Reference Standard: both spectra exhibit similarintensities of absorption at the same wave numbers.

2206 Official Monographs Supplement II, JP XVPurity (1) Chloride ―Dissolve 1.0 g of TosufloxacinTosilate Hydrate in 40 mL of N,N-dimethylformamide, and add6 mL of dilute nitric acid and N,N-dimethylformamide to make50 mL. Perform the test using this solution as the test solution.Prepare the control solution with 0.20 mL of 0.01 mol/L hydrochloricacid VS, 6 mL of dilute nitric acid andN,N-dimethylformamide to make 50 mL (not more than0.007%).(2) Heavy metals ―Proceed with 1.0 g of TosufloxacinTosilate Hydrate according to Method 4, and performthe test. Prepare the control solution with 2.0 mL of StandardLead Solution (not more than 20 ppm).(3) Arsenic ―Prepare the test solution with 1.0 g ofTosufloxacin Tosilate Hydrate according to Method 4, and performthe test under the condition of the ignition temperature beingbetween 750 and 850°C, and add 10 mL of diluted hydrochloricacid to residue (not more than 2 ppm).(4) Related substances―Dissolve10 mg of TosufloxacinTosilate Hydrate in 12 mL of mobile phase B, add water tomake 25 mL, and use this solution as the sample solution. Pipet5 mL of this solution, and add mobile phase A to make exactly100 mL. Pipet 2 mL of this solution, add mobile phase A tomake exactly 50 mL, and use this solution as the standard solution.Perform the test with exactly 20 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area of both solutions by automatic integrationmethod: the area of each peak other than the peaks of tosylicacid and tosufloxacin from the sample solution is not more than3/4 of the peak area of tosufloxacin from the standard solution,and the total area of the peaks other than those of tosylic acidand tosufloxacin from the sample solution is not larger than 2.5times the peak area of tosufloxacin from the standard solution.Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:272 nm).Column: A stainless steel column 3.0 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 35ºCMobile phase A: To 300 to 500 mL of water add slowly 100mL of methanesulfonic acid under ice-cooling, add slowly 100mL of triethylamine under ice-cooling too, and add water tomake 1000 mL. To 10 mL of this solution add 143 mL of water,40 mL of acetonitrile and 7 mL of 1 mol/L dipotassium hydrogenphosphate TS for buffer solution.Mobile phase B: To 300 to 500 mL of water add slowly 100mL of methanesulfonic acid under ice-cooling, add slowly 100mL of triethylamine under ice-cooling too, and add water tomake 1000 mL. To 10 mL of this solution add 100 mL of acetonitrile,83 mL of water and 7 mL of 1 mol/L dipotassium hydrogenphosphate TS for buffer solution.Flowing of mobile phase: Control the gradient by mixing themobile phases A and B as directed in the following table.Time after injectionof sample(min)Mobile phase A(vol%)Mobile phase B(vol%)0 - 1 100 01 - 16 100 → 0 0 → 10016 - 35 0 100Flow rate: 0.5 mL per minute.Time span of measurement: About 5 times as long as the retentiontime of tosufloxacin.System suitability―Test for required detectability: Pipet 5 mL of the standard solution,and add mobile phase A to make exactly 20 mL. Confirmthat the peak area of tosufloxacin obtained from 20 µL of thissolution is equivalent to 18 to 32% of the peak area of tosufloxacinfrom the standard solution.System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,the number of theoretical plates and symmetry factor of the peakof tosufloxacin are not less than 10000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of tosufloxacinis not more than 2.0%.(5) Residual solvent Being specified separately.Water 2.5 – 3.5% (30 mg, coulometric titration).Assay Weigh accurately about 30 mg each of TosufloxacinTosilate Hydrate and Tosufloxacin Tosilate Hydrate ReferenceStandard (separately determine the water content in thesame manner as Tosufloxacin Tosilate Hydrate), and dissolveeach in methanol to make exactly 100 mL. Pipet 20 mL each ofthese solutions, to each add exactly 4 mL of the internal standardsolution and methanol to make 100 mL, and use these solutionsas the sample solution and standard solution, respectively.Perform the test with 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of tosufloxacin to that of theinternal standard.Amount (mg) of tosufloxacin tosilate(C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S)= W S × (Q T /Q S )W S : Amount (mg) of Tosufloxacin Tosilate Reference Standard,calculated on the anhydrous basis.Internal standard solution—A solution of methyl parahydroxybenzoatein methanol (1 in 800)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:270 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 40ºC.

Supplement II, JP XV Official Monographs 2207Mobile phase: To a mixture of 0.02 mol/L phosphate buffersolution, pH 3.5, and a solution of dibutylamine in methanol (1in 2500) (3:1) add diluted phosphoric acid (1 in 10) to adjust thepH to 3.5.Flow rate: Adjust the flow rate so that the retention time oftosufloxacin is about 20 minutes.System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the internal standard and tosufloxacin are eluted in this orderwith the resolution between these peaks being not less than 2.5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof tosufloxacin to that of the internal standard is not more than1.0%.Containers and storage Containers―Tight containers.Add the following:Tosufloxacin Tosilate Tabletsトスフロキサシントシル 酸 塩 錠Tosufloxacin Tosilate Tablets contain not less than95.0% and not more than 105.0% of the labeledamount of tosuflozacin tosilate hydrate(C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S·H 2 O: 594.56).Method of preparation Prepare as directed under Tablets,with Tosufloxacin Tosilate Hydrate.Identification To a quantity of powdered Tosufloxacin TosilateTablets, equivalent to 75 mg of Tosufloxacin Tosilate Hydrateaccording to the labeled amount, add 200 mL of a mixtureof methanol and sodium hydroxide TS (49:1), shake well, andcentrifuge. To 2 mL of the supernatant liquid add 100 mL of amixture of methanol and sodium hydroxide TS (49:1). Determinethe absorption spectrum of this solution as directed underUltraviolet-visible Spectrophotometry : it exhibitsmaxima between 260 nm and 264 nm, between 341 nm and 345nm, and between 356 nm and 360 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Tosufloxacin Tosilate Tablets add V/10 mL ofwater and shake until the tablet is disintegrated. Add methanolto make exactly V mL so that each mL contains about 1.5 mg oftosufloxacin tosilate hydroxide (C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S·H 2 O).Shake this solution for 10 minutes, and centrifuge. Pipet 4 mLof the supernatant liquid, add exactly 4 mL of the internal standardsolution and methanol to make 100 mL, and use this solutionas the sample solution. Proceed as directed in the Assay.Amount (mg) of tosufloxacin tosilate hydrate(C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S·H 2 O)= W S × (Q T /Q S )× (V/20) × 1.031W S : Amount (mg) of Tosufloxacin Tosilate Reference Standard,calculated on the anhydrous basis.Internal standard solution—A solution of methyl parahydroxybenzoatein methanol (1 in 800)Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 90minutes of Tosufloxacin Tosilate Tablets is not less than 65%.Start the test with 1 tablet of Tosufloxacin Tosilate Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.5 µm. Discard the first 10mL of the filtrate, pipet V mL of the subsequent filtrate, add0.05 mol/L acetic acid-sodium acetate buffer solution, pH 4.0,to make exactly V´ mL so that each mL contains about 17 µg oftosufloxacin tosilate hydrate (C 19 H 15 F 3 N 4 O 3·7H 8 O 3 S·H 2 O) accordingto the labeled amount, and use this solution as the samplesolution. Separately, weigh accurately about 21 mg of TosufloxacinTosilate Reference Standard (separately determine thewater content in the same manner as Tosufloxacin TosilateHydrate), and dissolve in N,N-dimethylformamide to makeexactly 25 mL. Pipet 2 mL of this solution, add 0.05 mol/L aceticacid-sodium acetate buffer solution, pH 4.0, to make exactly100 mL, and use this solution as the standard solution. Performthe test with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , using0.05 mol/L acetic acid-sodium acetate buffer solution, pH4.0, as the blank, and determine the absorbances, A T and A S, at346 nm.Dissolution rate (%) with respect to the labeled amount oftosufloxacin tosilate hydrate (C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S·H 2 O)= W S × (A T /A S ) × (V´/V) × (1/C) × 72 × 1.031W S : Amount (mg) of Tosufloxacin Tosilate Reference Standard,calculated on the anhydrous basis.C: Labeled amount (mg) of tosufloxacin tosilate hydrate(C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S·H 2 O) in 1 tabletAssay Weigh accurately the mass of not less than 20 TosufloxacinTosilate Tablets, and powder. Weigh accurately a portionof the powder, equivalent to about 0.15 g of tosufloxacintosilate hydrate (C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S·H 2 O), add 10 mL ofwater and methanol to make exactly 100 mL, shake for 10 minutes,and centrifuge. Pipet 4 mL of the supernatant liquid, addexactly 4 mL of the internal standard solution and methanol tomake 100 mL, and use this solution as the sample solution.Separately, weigh accurately about 30 mg of Tosufloxacin TosilateReference Standard (separately determine the water content in the same manner as Tosufloxacin Tosilate Hydrate),add 2 mL of water, and dissolve in methanol to makeexactly 100 mL. Pipet 20 mL of this solution, add exactly 4 mLof the internal standard solution and methanol to make 100 mL,and use this solution as the standard solution. Perform the testwith 10 µL each of the sample solution and standard solution as

2208 Official Monographs Supplement II, JP XVdirected under Liquid Chromatography according to thefollowing conditions, and calculate the ratios, Q T and Q S , of thepeak area of tosufloxacin to that of the internal standard.Amount (mg) of tosufloxacin tosilate hydrate(C 19 H 15 F 3 N 4 O 3·C 7 H 8 O 3 S·H 2 O)= W S × (Q T /Q S )× 5 × 1.031W S : Amount (mg) of Tosufloxacin Tosilate Reference Standard,calculated on the anhydrous basis.Internal standard solution—A solution of methyl parahydroxybenzoatein methanol (1 in 800)Operating conditions—Proceed as directed in the operating conditions in the Assayunder Tosufloxacin Tosilate.System suitability―Proceed as directed in the system suitability in the Assay underTosufloxacin Tosilate.Containers and storage Containers―Well-closed containers.Add the following:Troxipideトロキシピドand enantiomerC 15 H 22 N 2 O 4 : 294.353,4,5-Trimethoxy-N-[(3RS)-piperidin-3-yl]benzamide[30751-05-4]Troxipide, when dried, contains not less than 98.5%and not more than 101.0% of C 15 H 22 N 2 O 4.Description Troxipide occurs as a white, crystalline powder.It is freely soluble in acetate (100), soluble in methanol,sparingly soluble in ethanol (99.5) and slightly soluble in water.It dissolves in 0.1 mol/L hydrochloric acid TS.A solution of Troxipide in 1 mol/L hydrochloric acid TS (1 in5) shows no optical rotation.Identification (1) Determine the absorption spectrum of asolution of Troxipide in 0.1 mol/L hydrochloric acid TS (1 in62500) as directed under Ultraviolet-visible Spectrophotometry, and compare the spectrum with the Reference Spectrumor the spectrum of a solution of Troxipide Reference Standardprepared in the same manner as the sample solution: both spectraexhibit similar intensities of absorption at the same wavelengths.(2) Determine the infrared absorption spectrum of Troxipideas directed in the potassium bromide disk method under InfraredSpectrophotometry , and compare the spectrumwith the Reference Spectrum or the spectrum of Troxipide ReferenceStandard: both spectra exhibit similar intensities of absorptionat the same wave numbers.Melting point 177‐181°CPurity (1) Chloride ―Dissolve 1.0 g of Troxipide in30 mL of methanol, and add 6 mL of dilute nitric acid and waterto make 50 mL. Perform the test using this solution as the testsolution. Prepare the control solution as follows: to 0.25 mL of0.01 mol/L hydrochloric acid VS add 30 mL of methanol, 6 mLof dilute nitric acid and water to make 50 mL (not more than0.009%).(2) Heavy metals ―Moisten 2.0 mg of Troxipidewith 1 mL of sulfuric acid, and gently heat until charred. Aftercooling, add 2 mL of nitric acid, carefully heat until whitefumes are no longer evolved, and perform the test according toMethod 2. Prepare the control solution as follows: evaporate 1mL of sulfuric acid, 2 mL of nitric acid and 2 mL of hydrochloricacid on a water bath and then on a sand bath to dryness, andmoisten the residue with 3 drops of hydrochloric acid. Proceedin the same manner for the preparation of the test solution, andadd 2.0 mL of Standard Lead Solution and water to make 50 mL(not more than 10 ppm).(3) Related substances―Dissolve 0.20 g of Troxipide in 10mL of methanol, and use this solution as the sample solution.Pipet 2 mL of this solution, and add methanol to make exactly100 mL. Pipet 2 mL of this solution, add methanol to make exactly20 mL, and use this solution as the standard solution. Performthe test with these solutions as directed under Thin-layerChromatography . Spot 5 µL each of the sample solutionand standard solution on a plate of silica gel with fluorescent indicatorfor thin-layer chromatography. Develop the plate with amixture of methanol, ethyl acetate, water, hexane and ammoniawater (28) (20:20:5:5:1) to a distance of about 10 cm, andair-dry the plate. Examine under ultraviolet light (main wavelength:254 nm): the number of the spots other than the principalspot obtained from the sample solution is not more than three,and they are not more intense than the spot from the standardsolution.(4) Residual solvent―Being specified separately.Loss on drying Not more than 1.0% (1 g, 105°C, 2hours).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.6 g of Troxipide, previouslydried, dissolve in 40 mL of acetic acid (100), and titrate with 0.1 mol/L perchloric acid VS (potentiometric titration).Perform a blank determination in the same manner, and makeany necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 29.44 mg of C 15 H 22 N 2 O 4Containers and storage Containers―Tight containers.

Supplement II, JP XV Official Monographs 2209Add the following:Troxipide Fine Granulesトロキシピド 細 粒Tiapride Fine Granules contain not less than 93.0%and not more than 107.0% of the labeled amount oftroxipide (C 15 H 22 N 2 O 4 : 294.35).Method of preparation Prepare as directed under Powders,with Troxipide.Identification To a quantity of Troxipide Fine Granules,equivalent to 20 mg of Troxipide according to the labeledamount, add 100 mL of 0.1 mol/L hydrochloric acid TS, stir,and filter. To 4 mL of the filtrate add 0.1 mol/L hydrochloricacid TS to make 50 mL. Determine the absorption spectrum ofthis solution as directed under Ultraviolet-visible Spectrophotometry: it exhibits a maximum between 256 nm and260 nm.Uniformity of dosage units Perform the test accordingto the following method: Tiapride Fine Granules in single-unitcontainers meet the requirement of the Content uniformitytest.Take out the entire content of 1 pack of Troxipide Fine Granules,add 80 mL of 0.1 mol/L hydrochloric acid TS, stir for 10minutes, and add 0.1 mol/L hydrochloric acid TS to make exactlyV mL so that each mL contains about 1 mg of troxipide(C 15 H 22 N 2 O 4 ). Centrifuge this solution, pipet 2 mL of the supernatantliquid, add exactly 3 mL of the internal standard solution,add water to make 100 mL, and use this solution as thesample solution. Proceed as directed in the Assay.Amount (mg) of troxipide (C 15 H 22 N 2 O 4 )= W S × (Q T /Q S ) × (V/25)W S : Amount (mg) of Troxipide Reference StandardInternal standard solution—A solution of 4-aminoacetophenonein 0.1 mol/L hydrochloric acid TS (3 in 2000).Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 60minutes of Troxipide Fine Granules is not less than 85%.Weigh accurately an amount of Troxipide Fine Granules,equivalent to about 0.1 g of Troxipide (C 15 H 22 N 2 O 4 ) accordingto the labeled amount, start the test, withdraw not less than 20mL of the medium at the specified minute, and filter through amembrane filter with a pore size not exceeding 0.8 µm. Discardthe first 10 mL of the filtrate, pipet 4 mL of the subsequent filtrate,add water to make exactly 20 mL, and use this solution asthe sample solution. Separately, weigh accurately about 20 mgof Troxipide Reference Standard, previously dried at 105°C for2 hours, and dissolve in water to make exactly 200 mL. Pipet 4mL of this solution, add water to make exactly 20 mL, and usethis solution as the standard solution. Perform the test with thesample solution and standard solution as directed under Ultraviolet-visibleSpectrophotometry , and determine theabsorbances, A T and A S, at 258 nm.Dissolution rate (%) with respect to the labeled amount oftroxipide (C 15 H 22 N 2 O 4 )= (W S /W T ) × (A T /A S ) × (1/C) × 450W S : Amount (mg) of Troxipide standard for assayW T : Amount (mg) of Troxipide for AssayC: Labeled amount (mg) of troxipide (C 15 H 22 N 2 O 4 ) in 1 gParticle Size It meets the requirement.Assay Weigh accurately an amount of Troxipide Fine Granules,equivalent to about 0.5 g of troxipide (C 15 H 22 N 2 O 4 ), add200 mL of 0.1 mol/L hydrochloric acid TS, stir for 10 minutes,and add 0.1 mol/L hydrochloric acid TS to make exactly 250mL. Centrifuge this solution, pipet 5 mL of the supernatant liquid,add 0.1 mol/L hydrochloric acid TS to make exactly 10 mL.Pipet 2 mL of this solution, add exactly 3 mL of the internalstandard solution, add water to make 100 mL, and use this solutionas the sample solution. Separately, weigh accurately about25 mg of Troxipide Reference Standard, previously dried at105°C for 2 hours, and dissolve in 0.1 mol/L hydrochloric acidTS to make exactly 25 mL. Pipet 2 mL of this solution, add exactly3 mL of the internal standard solution, add water to make100 mL, and use this solution as the standard solution. Performthe test with 20 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions, and calculate the ratios, Q Tand Q S , of the peak area of troxipide to that of the internal standard.Amount (mg) of troxipide (C 15 H 22 N 2 O 4 )= W S × (Q T /Q S ) × 20W S : Amount (mg) of Troxipide Reference StandardInternal standard solution—A solution of 4-aminoacetophenonein 0.1 mol/L hydrochloric acid TS (3 in 2000).Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:258 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 30ºC.Mobile phase: To diluted phosphoric acid (1 in 500) add diethylamineto adjust the pH to 3.0. To 1500 mL of this solutionadd 100 mL of methanol and 50 mL of tetrahydronfuran.Flow rate: Adjust the flow rate so that the retention time oftroxipide is about 7 minutes.System suitability―System performance: When the procedure is run with 20 µLof standard solution under the above operating conditions,troxipide and the internal standard are eluted in this order withthe resolution between these peaks being not less than 3.System repeatability: When the test is repeated 6 times with

2210 Official Monographs Supplement II, JP XV20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof troxipide to that of the internal standard is not more than1.0%.Containers and storage Containers―Tight containers.Add the following:Troxipide Tabletsトロキシピド 錠Troxipide Tablets contain not less than 95.0% andnot more than 105.0% of the labeled amount of troxipide(C 15 H 22 N 2 O 4 : 294.35).Method of preparation Prepare as directed under Tablets,with Troxipide.Identification Weigh accurately an amount of powderedTroxipide Tablets, equivalent to 0.1 g of Troxipide according tothe labeled amount, add 250 mL of 0.1 mol/L hydrochloric acidTS, shake, and filter. To 4 mL of the filtrate add 0.1 mol/L hydrochloricacid TS to make 100 mL. Determine the absorptionspectrum of this solution as directed under Ultraviolet-visibleSpectrophotometry : it exhibits maximum between 256nm and 260 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 tablet of Troxipide Tablets add 90 mL of 0.1 mol/L hydrochloricacid TS, shake well to disintegrate, shake for another10 minutes, and add 0.1 mol/L hydrochloric acid TS to makeexactly V mL so that each mL contains about 1 mg of troxipide(C 15 H 22 N 2 O 4 ). Pipet 2 mL of the supernatant liquid, add exactly3 mL of the internal standard solution, add water to make 100mL, and use this solution as the sample solution. Proceed as directedin the Assay.Amount (mg) of troxipide (C 15 H 22 N 2 O 4 )= W S × (Q T /Q S ) × (V/25)W S : Amount (mg) of Troxipide Reference StandardInternal standard solution—A solution of 4-aminoacetophenonein 0.1 mol/L hydrochloric acid TS (3 in 2000).Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rate in 30minutes of Troxipide Tablets is not less than 70%.Start the test with 1 tablet of Troxipide Tablets, withdraw notless than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.8 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add water to make exactlyV´ mL so that each mL contains about 22 µg of troxipide(C 15 H 22 N 2 O 4 ) according to the labeled amount, and use this solutionas the sample solution. Separately weigh accurately about20 mg of Troxipide Reference Standard, previously dried at105°C for 2 hours, and dissolve in water to make exactly 200mL. Pipet 4 mL of this solution, add water to make exactly 20mL, and use this solution as the standard solution. Perform thetest with the sample solution and standard solution as directedunder Ultraviolet-visible Spectrophotometry , and determinethe absorbances, A T and A S , at 258 nm.Dissolution rate (%) with respect to the labeled amount oftroxipide (C 15 H 22 N 2 O 4 )= W S × (A T /A S ) × (V´/V ) × (1/C) × 90W S : Amount (mg) of Troxipide Reference StandardC: Labeled amount (mg) of Troxipide (C 15 H 22 N 2 O 4 ) in 1 tabletAssay Weigh accurately the mass of not less than 20 TroxipideTablets, and powder. Weigh accurately a portion of thepowder, equivalent to about 1 g of troxipide (C 15 H 22 N 2 O 4 ), add150 mL of 0.1 mol/L hydrochloric acid TS, shake for 30 minutes,add 0.1 mol/L hydrochloric acid TS to make exactly 250mL. Centrifuge this solution, pipet 5 mL of the supernatant liquid,and add 0.1 mol/L hydrochloric acid TS to make exactly 20mL. Pipet 2 mL of this solution, add exactly 3 mL of the internalstandard solution and water to make 100 mL, and use thissolution as the sample solution. Separately, weigh accuratelyabout 25 mg of Troxipide Reference Standard, previously driedat 105°C for 2 hours, and dissolve in 0.1 mol/L hydrochloricacid TS to make exactly 25 mL. Pipet 2 mL of this solution, addexactly 3 mL of the internal standard solution and water to make100 mL, and use this solution as the standard solution. Performthe test with 20 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions, and calculate the ratios, Q Tand Q S , of the peak area of troxipide to that of the internal standard.Amount (mg) of troxipide (C 15 H 22 N 2 O 4 )= W S × (Q T /Q S ) × 40W S : Amount (mg) of Troxipide Reference StandardInternal standard solution—A solution of 4-aminoacetophenonein 0.1 mol/L hydrochloric acid TS (3 in 2000).Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:258 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 30 °C.Mobile phase: To 1500 mL of diluted phosphoric acid (1 in500) add diethylamine to adjust the pH to 3.0. To this solutionadd 100 mL of methanol and 50 mL of tetrahydronfuran.Flow rate: Adjust the flow rate so that the retention time oftroxipide is about 7 minutes.System suitability―

Supplement II, JP XV Official Monographs 2211System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,troxipide and the internal standard are eluted in this order withthe resolution between these peaks being not less than 3.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof troxipide to that of the internal standard is not more than1.0%.Containers and storage Containers―Tight containers.Add the following:Ubenimex CapsulesウベニメクスカプセルUbenimex Capsules contain not less than 93.0% andnot more than 107.0% of the labeled amount of ubenimex(C 16 H 24 N 2 O 4 : 308.37).Method of preparation Prepare as directed under Capsules,with Ubenimex.Identification To a quantity of the contents of UbenimexCapsules, equivalent to 25 mg of Ubenimex according to thelabeled amount, add water to make 50 mL, shake well, and filter.Determine the absorption spectrum of the filtrate as directedunder Ultraviolet-visible Spectrophotometry : it exhibitsmaxima between 250 nm and 254 nm, between 255 nm and 259nm, and between 261 nm and 265 nm.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.To 1 capsule of Ubenimex Capsules add 30 mL of a mixtureof water and acetonitrile (7:3), shake well for 30 minutes, andadd a mixture of water and acetonitrile (7:3) to make exactly 50mL. Centrifuge this solution and filter the supernatant liquidthrough a membrane filter with a pore size not exceeding 0.45µm. Discard the first 5 mL of the filtrate, pipet V mL of thesubsequent filtrate, equivalent to about 3 mg of ubenimex(C 16 H 24 N 2 O 4 ), add exactly 4 mL of the internal standard solution,add a mixture of water and acetonitrile (7:3) to make 50mL, and use this solution as the sample solution. Separately,weigh accurately about 20 mg of ubenimex for assay, previouslydried at 80°C for 4 hours under reduced pressure, and dissolvein a mixture of water and acetonitrile (7:3) to make exactly 100mL. Pipet 15 mL of this solution, add exactly 4 mL of the internalstandard solution, add a mixture of water and acetonitrile(7:3) to make 50 mL, and use this solution as the standard solution.Perform the test with 20 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and calculate theratios, Q T and Q S , of the peak area of ubenimex to that of theinternal standard.Amount (mg) of ubenimex (C 16 H 24 N 2 O 4 S)= W S × (Q T / Q S ) × (1 / V) × (15 / 2)W S : Amount (mg) of ubenimex for assayInternal standard solution—A solution of ethyl parahydroxybenzoatein a mixture of water and acetonitrile (7:3) (1 in 2000)Operating conditions—Proceed as directed in the Assay.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,ubenimex and the internal standard are eluted in this order withthe resolution between these peaks being not less than 10.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ubenimex to that of the internal standard is not more than2.0%.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method using thesinker, using 900 mL of water as the dissolution medium, thedissolution rate in 30 minutes of Ubenimex Capsules is not lessthan 70 %.Start the test with 1 capsule of Ubenimex Capsules, withdrawnot less than 20 mL of the medium at the specified minute afterstarting the test, and filter through a membrane filter with a poresize not exceeding 0.45 µm. Discard the first 10 mL of the filtrate,pipet V mL of the subsequent filtrate, add a mixture ofwater and acetonitrile (7:3) to make exactly V´ mL so that eachmL contains about 11 µg of ubenimex (C 16 H 24 N 2 O 4 ) accordingto labeled amount, and use this solution as the sample solution.Separately, weigh accurately about 22mg of ubenimex for assay,previously dried in vacume at 80°C for 4 hours, and dissolve ina mixture of water and acetonitrile (7:3) to make exactly 100mL. Pipet 5 mL of this solution, add a mixture of water andacetonitrile (7:3) to make exactly 100 mL, and use this solutionas the standard solution. Perform the test with exactly 50 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and determine the peak areas, A T and A S , ofubenimex in each solution.Dissolution rate (%) with respect to the labeled amount ofubenimex (C 16 H 24 N 2 O 4 )= W S × (A T / A S ) ×(V ′/ V ) × (1 / C) × 45W S : Amount (mg) of ubenimex for assayC: Labeled amount (mg) of ubenimex (C 16 H 24 N 2 O 4 ) in 1capsuleOperating conditions—It meets test requirements directed in the assay.System suitability—System performance: When the procedure is run with conditionsdescribed above for 50 µL of the standard solution, thenumber of theoretical plates and symmetry factor for Ubenimexare not less than 3000 and not more than 2.0, respectively.

2212 Official Monographs Supplement II, JP XVSystem repeatability: When the test is repeated 6 times with50 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of Ubenimexis not more than 2.0%.Assay To 10 Ubenimex capsules add 140 mL of a mixture ofwater and acetonitrile (7:3), shake well for 30 minutes, and adda mixture of water and acetonitrile (7:3) to make exactly 200mL. Centrifuge this solution, and filter. Discard the first 20 mLof the filtrate, pipet a volume of the subsequent filtrate, equivalentto about 7.5 mg of ubenimex (C 16 H 24 N 2 O 4 ), add exactly 10mL of the internal standard solution, add a mixture of water andacetonitrile (7:3) to make 50 mL, and use this solution as thesample solution. Separately, weigh accurately about 30 mg ofubenimex for assay, previously dried at 80°C for 4 hours underreduced pressure, dissolve in a mixture of water and acetonitrile(7:3) to make exactly 20 mL. Pipet 5 mL of this solution, addexactly 10 mL of the internal standard solution, add a mixture ofwater and acetonitrile (7:3) to make 50 mL, and use this solutionas the standard solution. Perform the test with 20 µL each of thesample solution and standard solution as directed under liquidchromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of ubenimexto that of the internal standard.Amount (mg) of ubenimex (C 16 H 24 N 2 O 4 S)= W S × (Q T / Q S ) × (1 / 4)W S : Amount (mg) of ubenimex for assayInternal standard solution—A solution of ethyl parahydroxybenzoatein mixture of water and acetonitrile (7:3) (1 in2000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:200 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 30 °C.Mobile phase: A mixture of diluted phosphoric acid and acetonitrilefor liquid chromatography (83:17) (1 in 100).Flow rate: Adjust the flow rate so that the retention time ofubenimex is about 8 minutes.System suitability—System performance: When the procedure is run with 20 µLof the standard solution under the above operating conditions,ubenimex and the internal standard are eluted in this order withthe resolution between these peaks being not less than 10.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ubenimex to that of the internal standard is not more than1.0%.Containers and storageContainers―Tight containers.Ursodeoxycholic Acidウルソデオキシコール 酸Change the Origin/limits of content, Description,Identification, and Purity and Assay to read:Ursodeoxycholic Acid, when dried, contains not lessthan 98.5% and not more than 101.0% of C 24 H 40 O 4.Description Ursodeoxycholic Acid occurs as a white crystalor powder, with bitter taste.It is freely soluble in methanol, in ethanol (99.5) and in aceticacid (100), and practically insoluble in water.Identification Determine the infrared absorption spectrum ofUrsodeoxycholic Acid as directed in the potassium bromide diskmethod under Infrared Spectrophotometry , and comparethe spectrum with the Reference Spectrum: both spectra exhibitsimilar intensities of absorption at the same wave numbers.Purity (1) Sulfate —Dissolve 2.0 g of UrsodeoxycholicAcid in 20 mL of acetic acid (100), add water to make200 mL, and allow to stand for 10 minutes. Filter this solution,discard the first 10 mL of the filtrate, and use the subsequent filtrateas the sample solution. To 40 mL of the sample solutionadd 1 mL of dilute hydrochloric acid and water to make 50 mL.Perform the test using this solution as the test solution. Preparethe control solution with 0.40 mL of 0.005 mol/L sulfuric acidby adding 4 mL of acetic acid (100), 1 mL of dilute hydrochloricacid and water to make 50 mL (not more than 0.048%).(2) Heavy metal —Proceed with 1.0 g of UrsodeoxycholicAcid according to Method 2 and perform the test.Prepare the control solution with 2.0 mL of Standard Lead Solution(not more than 20 ppm).(3) Barium—To 2.0 g of Ursodeoxychollic Acid add 100mL of water and 2 mL of hydrochloric acid, boil for 2 minutes,allow it to cool, filter, and wash the filter with water until to get100 mL of the filtrate. To 10 mL of the filtrate add 1 mL of dilutesulfuric acid: no turbidity is appeared.(4) Related substances—Dissolve 0.10 g of UrsodeoxycholicAcid in 1 mL of methanol, add acetone to make exactly10 mL, and use this solution as the sample solution. Pipet 1 mLof this solution, and add acetone to make exactly 100 mL. Pipet1 mL and 2 mL of this solution, to each add acetone to makeexactly 20 mL, and use these solutions as the standard solution(A) and standard solution (B), respectively. Separately, dissolve50 mg of chenodeoxycholic acid for thin-layer chromatographyin 5 mL of methanol, add acetone to make exactly 50 mL. Pipet2 mL of this solution, add acetone to make exactly 20 mL, anduse this solution as the standard solution (1). Furthermore, dissolve25 mg of lithocholic acid for thin-layer chromatography in5 mL of methanol, and add acetone to make exactly 50 mL. Pipet2 mL of this solution, and add acetone to make exactly 20mL. Pipet 2 mL of this solution, add acetone to make exactly 10mL, and use this solution as standard solution (2). Perform thetest with these solutions as directed under Thin-layer Chromatography. Spot 10µL each of the sample solution, stan-

Supplement II, JP XV Official Monographs 2213dard solution (1), standard solution (2), standard solution (A)and standard solution (B) on a plate of silica gel for thin-layerchromatography. Develop the plate with a mixture of isooctane,ethanol (99.5), ethyl acetate and acetic acid (100) (10:6:3:1) to adistance of about 15 cm, and air-dry the plate. Dry the platefurther at 120°C for 30 minutes, and immediately spray evenlythe solution which was prepared by dissolving 5 g of phosphomolybdicacid n-hydrate in about 50 mL of ethanol (99.5), towhich 5 mL of sulfuric acid is dropped in and add ethanol (99.5)to make 100 mL, and heat at 120°C for 3 to 5 minutes: the spotsfrom the sample solution corresponding to the spots obtainedfrom the standard solution (1) and (2) are not more intense thanthe spots from the standard solutions (1) and (2), the spots otherthan the principal spot from the sample solution and other thanthose mentioned above are not intense than the spots obtainedfrom the standard solution (B), and the total amount of the spotsother than the principal spot from the sample solution and otherthan those mentioned above, which is calculated by the comparisonwith the spots obtained from the standard solutions (A)and (B), is not more than 0.25%.Assay Weigh accurately about 0.5 g of Ursodeoxycholic Acid,previously dried, dissolve in 40 mL of ethanol (95) and 20 mLof water, and titrate with 0.1 mol/L sodium hydroxideVS (potentiometric titration). Perform a blank determination inthe same manner, and make any necessary correction.Each mL of 0.1 mol/L sodium hydroxide VS= 39.26 mg of C 24 H 40 O 4Add the following:Ursodeoxycholic Acid Granulesウルソデオキシコール 酸 顆 粒Ursodeoxycholic Acid Granules contain not lessthan 95.0% and not more than 105.0% of the labeledamount of ursodeoxycholic acid (C 24 H 40 O 4 : 392.57).Method of preparation Prepare as directed under Granules,with Ursodeoxycholic Acid.Identification To a quantity of powdered UrsodeoxycholicAcid Granules, equivalent to 20 mg of Ursodeoxycholic Acidaccording to the labeled amount, add 10 mL of methanol, andshake for 20 minutes. Centrifuge this solution, pipet 4 mL of thesupernatant liquid, and distil under reduced pressure. To theresidue add 4 mL of acetone, disperse with ultrasonic waves,centrifuge, and use the supernatant liquid as the sample solution.Separately, dissolve 10 mg of ursodeoxycholic acid in 5 mL ofacetone, and use this solution as the standard solution. Performthe test with these solutions as directed under Thin-layer Chromatography. Spot 10 µL of the sample solution andstandard solution on a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of isooctane, ethanol(99.5), ethyl acetate and acetic acid (100) (10:6:3:1) to a distanceof about 15 cm, and air-dry the plate. Dry the plate furtherat 120°C for 30 minutes, immediately splay evenly a solution ofphosphomolybdic acid n-hydrate in ethanol (99.5) (1 in 5), andheat at 120ºC for 3 to 5 minutes: the principle spot obtainedfrom the sample solution and the spot from the standard solutionshow a blue color and the same R f value.Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof the 2nd fluid for dissolution test as the test solution, the dissolutionrate in 15 minutes of Ursodeoxycholic Acid Granules isnot less than 80 %.Start the test by taking the exact amount that correspond toabout 50 mg of ursodeoxycholic acid (C 24 H 40 O 4 ) according tolabeled amount and withdraw not less than 20 mL of the mediumat the specified time, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard first 10 mL ofthe filtrate, then use the subsequent filtrate as the sample solution.Separately, weigh accurately about 22 mg of ursodeoxycholicacid for array, previously dried at 105°C for 2 hours, anddissolve in acetonitrile to make exactly 100 mL of the solution.Pipet 5 mL of this solution, add test solution to prepare exactly20 mL of standard solution. Perform the test with 100 µL eachof sample solution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak areas, A T and A S , of ursodeoxycholicacid in each solution.Dissolution rate (%) with respect to the labeled amount ofursodeoxycholic acid (C 24 H 40 O 4 )= (W S / W T ) × (A T / A S ) × (1 / C) × 225W S : Amount (mg) of ursodeoxycholic acid for assayW T : Amount (g) of Ursodeoxycholic Acid GlanulesC: Labeled amount (mg) of ursodeoxycholic acid (C 24 H 40 O 4 )in 1 gOperating conditions—Proceed as directed in the Assay.System suitability—System performance: When the procedure is run with 100 µLof the standard solution under the above operating conditions,the number of theoretical plates and symmetry factor of the peakof ursodeoxycholic acid are not less than 3000 and not morethan 2.0, respectively.System repeatability: When the test is repeated 6 times with100 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of ursodeoxycholicacid is not more than 2.0 %.Particle Size It meets the requirement.Assay Weigh accurately an amount of powdered UrsodeoxycholicAcid Granules, equivalent to about 0.1 g of ursodeoxycholicacid (C 24 H 40 O 4 ) according to labeled amount, add exactly20 mL of the internal standard solution, shake for 10 minutes,and centrifuge. Filter the supernatant liquid through a membranefilter with a pore size not exceeding 0.45 µm, and use the filtrateas the sample solution. Separately, weigh accurately about 0.1 g

2214 Official Monographs Supplement II, JP XVof ursodeoxycholic acid for assay, previously dried at 105°C for2 hours, dissolve in 20 mL of the internal standard solution, anduse this solution as the standard solution. Perform the test with10 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions, and calculate the ratios, Q T and Q S , of thepeak area of ursodeoxycholic acid to that of the internal standard.Amount (mg) of ursodeoxycholic acid (C 24 H 40 O 4 )= W S × (Q T / Q S )W S : Amount (mg) of ursodeoxycholic acid for assayInternal standard solution— A solution of ethyl parahydroxybenzoatein diluted methanol (4 in 5) (7 in 200000).Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:210 nm).Column: A stainless steel column 4.6 mm in inside diameter and15 cm in length, packed with octadecylsilanized silica gel forliquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 40 °C.Mobile phase: A mixture of diluted phosphoric acid (1 in 500)and acetonitrile for liquid chromatography (11:9).Flow rate: Adjust the flow rate so that the retention time ofursodeoxycholic acid is about 6 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,ursodeoxycholic acid and the internal standard are eluted in thisorder with the resolution between these peaks being not lessthan 8.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ursodeoxycholic acid to that of the internal standard is notmore than 1.0%.Containers and storageAdd the following:Containers—Tight containers.Ursodeoxycholic Acid Tabletsウルソデオキシコール 酸 錠Ursodeoxycholic Acid Tablets contain not less than95.0% and not more than 105.0% of the labeledamount of Ursodeoxycholic Acid (C 24 H 40 O 4 : 392.57).Method of preparation Prepare as directed under Tablets,with Ursodeoxycholic Acid.Identification To a quantity of powdered UrsodeoxycholicAcid Tablets, equivalent to 20 mg of Ursodeoxycholic Acid accordingto the labeled amount, add 10 mL of methanol, andshake for 20 minutes. Centrifuge this solution, pipet 4 mL of thesupernatant liquid, and distil under reduced pressure. To theresidue add 4 mL of acetone, disperse with ultrasonic waves,centrifuge, and use the remaining supernatant liquid as the samplesolution. Separately, dissolve 10 mg of ursodeoxycholic acidin 5 mL of acetone, and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 10 µL each of thesample solution and standard solution on a plate of silica gel forthin-layer chromatography. Develop the plate with a mixture ofisooctane, ethanol (99.5), ethyl acetate and acetic acid (100)(10:6:3:1) to a distance of about 15 cm, and air-dry the plate.Dry the plate further at 120°C for 30 minutes, and immediatelysplay evenly a solution of phosphomolybdic acid n-hydrate inethanol (95) (1 in 5) on the plate, and heat at 120ºC for 3 to 5minutes: the principal spot obtained from the sample solutionand the spot from the standard solution show a blue color andthe same R f value.Uniformity of dosage units Perform the test accordingto the following method: it meets the requirement of theContent uniformity test.Take 1 tablet of Ursodeoxycholic Acid Tablets and add exactlyV mL of the internal standard solution so that each mLcontains about 5 mg of ursodeoxycholic acid (C 24 H 40 O 4 ), disperseit with ultrasonic waves, then agitate to mix for 10 moreminutes and then centrifuge. Filter the clear supernatant solutionthrough a membrane filter with a pore size not exceeding 0.45µm, and use this filtrate as the sample solution.Proceed as directed in the operating conditions in the AssayAmount (mg) of ursodeoxycholic acid (C 24 H 40 O 4 )= W S × (Q T / Q S ) × (V / 20)W S : Amount (mg) of ursodeoxycholic acid for assayInternal standard solution—A solution of ethyl parahydroxybenzoatein diluted methanol (4 in 5) (7 in 200000).Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof the 2nd fluid for dissolution test as the dissolution medium,the dissolution rate of a 50-mg Ursodeoxycholic Acid tablet in30 minutes and a 100-mg tablet in 45 minutes are not less than80% and not less than 70%, respectively.Start the test with one tablet of Ursodeoxycholic Acid Tablets,withdraw not less than 20 mL of the medium at the specifiedtime after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard 10 mL of thefirst filtrate and pipet V mL of the subsequent filtrate. Add dissolutionmedium to make exactly V´ mL so that each mL containsabout 56 µg of ursodeoxycholic acid (C 24 H 40 O 4 ) accordingto the labeled amount, and use the solution as the sample solution.Separately weigh accurately about 22 mg of ursodeoxycholicacid for assay, previously dried at 105°C for 2 hours, anddissolve in acetonitrile to make exactly 100 mL. Pipet 5 mL ofthis solution, add dissolution medium to make exactly 20 mL,and use this solution as the standard solution. Perform the testwith exactly 100 µL each of sample solution and standard solu-

Supplement II, JP XV Official Monographs 2215tion as directed under Liquid Chromatography accordingto the following conditions, and determine the peak areas,A T and A S , of ursodeoxycholic acid in each solution.Dissolution rate (%) with respect to the labeled amount ofursodeoxycholic acid (C 24 H 40 O 4 )= W S × (A T / A S ) + (V ′/ V ) + (1 / C) × 225W S : Amount (mg) of ursodeoxycholic acid for assayC: Labeled amount (mg) of ursodeoxycholic acid in 1 tablet(C 24 H 40 O 4 )Operating conditions—Proceed as directed in the operating conditions in the Assay.System suitability—System performance: When the procedure is run with 100 µLof the standard solution under the above operating condition, thenumber of theoretical plates and symmetry factor of the peak ofursodeoxycholic acid are not less than 3000 and not more than2.0, respectively.System repeatability: When the test is repeated 6 times with100 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of ursodeoxycholicacid is not more than 2.0 %.Assay Weigh accurately the mass of not less than 20 UrsodeoxycholicAcid Tablets, and powder. Weigh accurately a portionof the powder, equivalent to about 0.1 g of ursodeoxycholic acid(C 24 H 40 O 4 ), add exactly 20 mL of the internal standard solution,shake for 10 minutes, and centrifuge. Filter the supernatant liquidthrough a membrane filter with a pore size not exceeding0.45 µm, and use the filtrate as the sample solution. Separately,weigh accurately about 0.1 g of ursodeoxycholic acid for assay,previously dried at 105°C for 2 hours, dissolve in exactly 20 mLof the internal standard solution, and use this solution as thestandard solution. Perform the test with 10 µL each of the samplesolution and standard solution as directed under LiquidChromatography according to the following conditions,and calculate the ratios, Q T and Q S , of the peak area of ursodeoxycholicacid to that of the internal standard.Amount (mg) of ursodeoxycholic acid (C 24 H 40 O 4 )= W S × (Q T / Q S )W S : Amount (mg) of ursodeoxycholic acid for assayInternal standard solution—A solution of ethyl parahydroxybenzoatein diluted methanol (4 in 5) (7 in 200000).Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:210 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: Constant temperature of about 40°C.Mobile phase: A mixture of diluted phosphoric acid (1 in500) and acetonitrile for liquid chromatography (11:9).Flow rate: Adjust the flow rate so that the retention time ofursodeoxycholic acid is about 6 minutes.System suitability—System performance: When the procedure is run with 10 µLof the standard solution according to the above operating conditions,ursodeoxycholic acid and the internal standard are elutedin this order with the resolution between these peaks being notless than 8.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof ursodeoxycholic acid to that of the internal standard is notmore than 1.0%.Containers and storageVasopressin Injectionバソプレシン 注 射 液Containers—Tight containers.Add the following next to Purity:Bacterial endotoxins Less than 15 EU / VasopressinunitAdd the following next to Extractable volume:Foreign insoluble matter Perform the test accordingto Method 1: it meets the requirement.Insoluble particulate matter It meets the requirement.Sterility Perform the test according to the Membranefiltration method: it meets the requirement.Warfarin Potassium Tabletsワルファリンカリウム 錠Add the following next to Uniformity of dosageunits:Dissolution When the test is performed at 50 revolutionsper minute according to the Paddle method, using 900 mLof water as the dissolution medium, the dissolution rates of0.5-mg, 1-mg and 2-mg tablets in 15 minutes and of 5-mg tabletsin 30 minutes are not less than 80%.Start the test with 1 tablet of Warfarin Potassium Tablets,withdraw not less than 20 mL of the medium at the specifiedminute after starting the test, and filter through a membrane filterwith a pore size not exceeding 0.45 µm. Discard the first 10mL of the filtrate, pipet V mL of the subsequent filtrate, addwater to make exactly V´ mL so that each mL contains about0.56 µg of warfarin potassium (C 19 H 15 KO 4 ) according to the labeledamount, and use this solution as the sample solution.Separately, weigh accurately about 22 mg of Warfarin PotassiumReference Standard, previously dried at 105°C for 3 hours,and dissolve in water to make exactly 100 mL. Pipet 5 mL ofthis solution, and add water to make exactly 100 mL. Pipet 5mL of this solution, add water to make exactly 100 mL, and use

2216 Official Monographs Supplement II, JP XVthis solution as the standard solution. Perform the test with 100µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions, and determine the peak areas, A T and A S , of warfarinfrom each solution.Dissolution rate (%) with respect to the labeled amount ofwarfarin potassium (C 19 H 15 KO 4 )= W S × (A T / A S ) × (V ′/ V ) × (1 / C) × (9 / 4)W S : Amount (mg) of Warfarin Potassium Reference StandardC: Labeled amount (mg) of warfarin potassium (C 19 H 15 KO 4 )in 1 tabletOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:283 nm).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 35°C.Mobile phase: A mixture of methanol, water and phosphoricacid (700:300:1).Flow rate: Adjust the flow rate so that the retention time ofwarfarin is about 6 minutes.System suitability—System performance: When the procedure is run with 100 µLof the standard solution under the above conditions, the numberof theoretical plates and the symmetry factor of the peak ofwarfarin are not less than 2000 and not more than 2.0, respectively.System repeatability: When the test is repeated 6 times with100 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of warfarinis not more than 2.0%.Wheat StarchコムギデンプンChange the Origin/limits of content and the Identification(1) to read:Wheat Starch consists of the starch granules obtainedfrom caryopsis of wheat, Triticum aestivum Linné(Gramineae).cross intersecting at the hilum.Add the following next to item (3) in the sectionon Purity.Purity ◆ (4) Foreign matter—Under a microscope ,Wheat Starch does not contain starch granules of any other origin.◆Zinc Sulfate Hydrate硫 酸 亜 鉛 水 和 物Change the Description and Identification toread:Description Zinc Sulfate Hydrate occurs as colorless crystalsor white crystalline powder.It is very soluble in water, and very slightly soluble in ethanol(99.5).It effloresces in dry air.Identification (1) A solution of Zinc Sulfate Hydrate (1 in20) responds to the Qualitative Tests for zinc salt.(2) A solution of Zinc Sulfate Hydrate (1 in 20) responds tothe Qualitative Tests for sulfate.Add the following next to the Identification:pH Dissolve 1.0 g of Zinc Sulfate Hydrate in 20 mLof water: the pH of the solution is between 4.4 and 6.0.Change the Purity (1) to read:Purity (1) Clarity and color of solution―Dissolve 0.25 g ofZinc Sulfate Hydrate in 5 mL of water: the solution is clear andcolorless.Add the following next to the Purity:Loss on drying Not less than 35.5% and not morethan 38.5% (1 g, 105°C, 3 hours).Identification (1) Examine under a microscope usinga mixture of water and glycerinol (1:1), Wheat Starch presentslarge and small granules, and, very rarely, intermediatesizes. The large granules, usually 10-60 µm in diameter, arediscoid or, more rarely, reniform when seen face-on. The centralhilum and striations are invisible or barely visible and the granulessometimes show cracks on the edges. Seen in profile, thegranules are elliptical and fusiform and the hilum appears as aslit along the main axis. The small granules, rounded or polyhedral,are 2-10 µm in diameter. Between orthogonally orientedpolarizing plates or prisms, the granules show a distinct black

Supplement II, JP XV Official Monographs 2217Add the following:Zolpidem Tartrateゾルピデム 酒 石 酸 塩(C 19 H 21 N 3 O) 2·C 4 H 6 O 6 :764.87N,N,6–Trimethyl–2–(4–methylphenyl)imidazo[1,2–a]pyridine–3-acetamidehemi–(2R,3R)–tartrate [99294–93–6]Zolpidem Tartrate contains not less than 98.5% andnot more than 101.0% of zolpidem tartrate[(C 19 H 21 N 3 O) 2·C 4 H 6 O 6 )], calculated on the anhydrousbasis.Description Zolpidem Tartrate occurs as a white, crystallinepowder.It is freely soluble in acetic acid (100), soluble inN,N-dimethylformamide and in methanol, sparingly soluble inwater, and slightly soluble in ethanol (99.5) and in acetic anhydride.It dissolves in 0.1 mol/L hydrochloric acid TS.It gradually changes to yellow in color on exposure to light.Optical rotation [α] 20D: About +1.8° (1 g,N,N-dimethylformamide, 20 mL, 100 mm).Identification (1) Dissolve 50 mg of Zolpidem Tartrate in 5mL of acetic acid (100) and add 3 drops of Dragendorff’s TS: anorange precipitate is formed.(2) Determine the absorption spectrum of a solution of ZolpidemTartrate in 0.1 mol/L hydrochloric acid TS (1 in 100000)as directed under Ultraviolet-visible Spectrophotometry ,and compare the spectrum with the Reference Spectrum: bothspectra exhibit similar intensities of absorption at the samewavelengths.(3) Determine the infrared absorption spectrum of ZolpidemTartrate as directed in the potassium bromide disk method underthe Infrared Spectrophotometry , and compare the spectrumwith the Reference Spectrum: both spectra exhibit similarintensities of absorption at the same wave numbers.(4) A solution of Zolpidem Tartrate in methanol (1 in 10)responds to the Qualitative Tests (3) for tartrate.Purity (1) Heavy metals —Proceed with 2.0 g ofZolpidem Tartrate according to Method 4, and perform the test.Prepare the control solution with 2.0 mL of Standard Lead Solution(not more than 10 ppm).(2) Related substances—Dissolve 10 mg of Zolpidem Tartratein 20 mL of methanol and use this solution as the samplesolution. Pipet 1 mL of this solution, and add methanol to makeexactly 100 mL. Pipet 2 mL of this solution, add methanol tomake exactly 20 mL, and use this solution as the standard solution.Perform the test with exactly 5 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions. Determineeach peak area of both solutions by the automatic integrationmethod: each area of the peak other than the peak of zolpidemfrom the sample solution is not more than the peak area of zolpidemfrom the standard solution.Operating conditions—Detector: A ultraviolet absorption photometer (wavelength:254 nm).Column: A stainless steel tube 4.6 mm in inside diameter and7.5 cm in length, packed with octadecylsilanized silica gel forliquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 25°C.Mobile phase: To 4.9 g of phosphoric acid add 1000 mL ofwater, and adjust the pH to 5.5 with triethylamine. To 11 volumesof this solution add 5 volumes of methanol and 4 volumesof acetonitrile.Flow rate: Adjust the flow rate so that the retention time ofzolpidem is about 5 minutes.Time span of measurement: About 5 times as long as the retentiontime of zolpidem.System suitability—System performance: Dissolve 10 mg each of Zolpidem Tartrateand benzyl parahydroxybenzoate in 100 mL of methanol.When the procedure is run with 5 µL of this solution under theabove operating conditions, zolpidem and benzyl parahydroxybenzoateare eluted in this order with the resolution betweenthese peaks being not less than 9.System repeatability: When the test is repeated 6 times with 5µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of zolpidem isnot more than 5.0%.(3) Residual solvent―Being specified separately.Water Not more than 3.0% (0.5 g, volumetric titration,direct titration).Residue on ignition Not more than 0.1% (1 g).Assay Weigh accurately about 0.4 g of Zolpidem Tartrate,dissolve in 100 mL of a mixture of acetic anhydride and aceticacid (100) (7:3) and titrate with 0.1 mol/L perchloricacid VS (potentiometric titration). Perform a blank determinationin the same manner, and make any necessary correction.Each mL of 0.1 mol/L perchloric acid VS= 38.24 mg of (C 19 H 21 N 3 O) 2·C 4 H 6 O 6Containers and storage Containers—Tight containersStorage conditions―Light-resistant

Crude DrugsApricot KernelキョウニンChange the Origin to read:Apricot Kernel is the seed of Prunus armeniacaLinné or Prunus armeniaca Linné var. ansu Maximowicz(Rosaceae).It contains not less than 2.0% of amygdalin, calculatedon the basis of dried material.Add the following next to the Purity:Loss on drying Not more than 7.0% (6 hours).Component determination Weigh accurately 0.5 g of groundApricot Kernel, add 40 mL of diluted methanol (9 in 10), heatimmediately under a reflux condenser on a water bath for 30minutes, and cool. Filter the mixture, add diluted methanol (9 in10) to make exactly 50 mL. Pipet 5 mL of this solution, add waterto make exactly 10 mL, filter, and use the filtrate as the samplesolution. Separately, weigh accurately about 10 mg ofamygdalin for component determination, previously dried in adesiccator (silica gel) for not less than 24 hours, dissolve in dilutedmethanol (1 in 2) to make exactly 50 mL, and use this solutionas the standard solution. Perform the test with 10 µL eachof the sample solution and standard solution as directed underLiquid Chromatography according to the following conditions,and determine the peak areas, A T and A S , of amygdalinin each solution.Amount (mg) of amygdalin = W S × (A T /A S ) × 2W S : Amount (mg) of amygdalin for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:210 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilianized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 45°C.Mobile phase: A mixture of 0.05 mol/L sodium dihydrogenphosphate TS and methanol (5:1).Flow rate: 0.8 mL per minute (the retention time of amygdalinis about 12 minutes).System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amygdalin are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of amygdalinis not more than 1.5%.Astragalus RootオウギAdd the following next to Description:Identification Put 1 g of pulverized Astragalus Root in aglass-stoppered centrifuge tube, add 5 mL of potassium hydroxideTS and 5 mL acetonitrile, and stop the vial tightly. Aftershaking this for 10 minutes, centrifuge, and use the upper layeras the sample solution. Separately, dissolve 1 mg of astragalosideIV for thin-layer chromatography in 2 mL of methanol,and use this solution as the standard solution. Perform the testwith these solutions as directed under Thin-layer Chromatography. Spot 10 µL of the sample solution and standard solutionon a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of ethyl acetate, methanol andwater (20:5:4) to a distance of about 10 cm, and air-dry the plate.Spray evenly diluted sulfuric acid on the plate, heat at 105°C for5 minutes, and examine under ultraviolet light (main wavelength:365 nm): one of the spot among the several spots fromthe sample solution has the same color tone and R f value withthe brownish yellow fluorescent spot from the standard solution.Bear BileユウタンChange the Identification to read:Identification To 0.1 g of pulverized Bear Bile, add 5 mL ofmethanol, heat on a water bath for 10 minutes, centrifuge aftercooling, and use the supernatant liquid as the sample solution.Separately, dissolve 10 mg of sodium tauroursodeoxycholate forthin-layer chromatography in 5 mL of methanol, and use this asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 5 µLeach of the sample solution and standard solution on a plate ofsilica gel for thin-layer chromatography. Develop the plate witha mixture of acetic acid (100), toluene and water (10:10:1) to adistance of about 10 cm, and air-dry the plate. Spray evenly dilutedsulfuric acid on the plate, and heat at 105°C for 10 minutes:one of the spot among the several spots from the samplesolution has the same color tone and R f value with the spot fromthe standard solution.2219

2220 Crude Drugs Supplement II, JP XVAdd the following next to the Identification:Purity Other animal biles—Use the sample solution obtainedin the Identification as the sample solution. Separately, dissolve10 mg of sodium glycocholate for thin-layer chromatographyand 20 mg of powdered porcine bile for thin-layer chromatographyin 5 mL of methanol, and use these solutions as the standardsolution (1) and standard solution (2) respectively. Performthe test with these solutions as directed in the Identification:Spots from the sample solution correspond to neither the spot ofglycocholic acid from the standard solution (1) nor thegray-brown to black spot of powdered porcine bile at around R f0.3 from the standard solution (2).Powdered Calumbaコロンボ 末Change the Purity to read:Purity (1) Heavy metals Proceed with 3.0 g ofPowdered Calumba according to Method 3, and perform the test.Prepare the control solution with 3.0 mL of Standard Lead Solution(not more than 10 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofPowdered Calumba according to Method 4, and perform the test(not more than 5 ppm).Bupleurum RootサイコChange the Identification (2) to read:Identification (2) To 1.0 g of the pulverized BupleurumRoot, add 10 mL of methanol, and boil gently under a refluxcondenser on a water bath for 15 minutes. After cooling, centrifuge,and use the filtrate as the sample solution. Separately, dissolve1 mg of saikosaponin a for thin-layer chromatography in 1mL of methanol, and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 10 µL each of thesample solution and standard solution on a plate of silica gel forthin-layer chromatography. Develop the plate with a mixture ofethyl acetate, ethanol (99.5) and water (8:2:1) to a distance ofabout 10 cm, and air-dry the plate. Spray evenly4-dimethylaminobenzaldehyde TS on the plate, and heat at105°C for 5 minutes: one of the spot among the several spotsfrom the sample solution has the same color tone and R f valuewith the gray-brown spot from the standard solution, accompaniedby the adjacent yellow-red spot above.CalumbaコロンボChange the Purity to read:Purity (1) Heavy metals Proceed with 3.0 g ofpulverized Calumba according to Method 3, and perform thetest. Prepare the control solution with 3.0 mL of Standard LeadSolution (not more than 10 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofpulverized Calumba according to Method 4, and perform thetest (not more than 5 ppm).CardamonショウズクChange the another title in Japanese of themonograph as follows:小 豆 宼小 豆 蔲Cornus FruitサンシュユChange the Origin to read:Cornus Fruit is the pulp of the pseudocarp of Cornusofficinalis Siebold et Zuccarini (Cornaceae).It contains not less than 0.4% of loganin, calculatedon the basis of dried material.Add the following next to Extract Content:Component determination Weigh accurately about 1 g offine cuttings of Cornus Fruit (separately determine the loss ondrying ), put in a glass-stoppered centrifuge tube, suspendin 30 mL of diluted methanol (1 in 2), shake for 20 minutes,centrifuge, and separate the supernatant liquid. To theresidue, add 30 mL of diluted methanol (1 in 2), and repeat theabove process twice more. Combine all the extracts, add dilutedmethanol (1 in 2) to make exactly 100 mL, and use this solutionas the sample solution. Separately, weigh accurately about 10mg of loganin for component determination, previously dried ina desiccator (silica gel) for 24 hours, dissolve in diluted methanol(1 in 2) to make exactly 100 mL, and use this solution as thestandard solution. Perform the test with 10 µL each of the samplesolution and standard solution as directed under LiquidChromatography according to the following conditions,and determine the peak areas, A T and A S , of loganin in each solution.Amount (mg) of loganin = W S × (A T /A S )

Supplement II, JP XV Crude Drugs 2221W S : Amount (mg) of loganin for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:238 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilianized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 50°C.Mobile phase: A mixture of water, acetonitrile and methanol(55:4:1).Flow rate: Adjust the flow rate so that the retention time ofloganin is about 25 minutes.System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of loganin are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of loganinis not more than 1.5%.Daiokanzoto Extract大 黄 甘 草 湯 エキスChange the Origin to read:Daiokanzoto Extract contains not less than 3.5 mg ofsennoside A (C 42 H 38 O 20 : 862.74) and not less than 9mg and not more than 27 mg (for preparation prescribed1 g of Glycyrrhiza) or not less than 18 mg andnot more than 54 mg (for preparation prescribed 2 g ofGlycyrrhiza) of glycyrrhizic acid (C 42 H 62 O 16 : 822.93)per the extract prepared as directed in the Method ofpreparation.Eleutherococcus SenticosusRhizomeシゴカAdd the following next to Identification:Purity (1) Heavy metals Proceed with 3.0 g ofpulverized Eleutherococcus Senticosus Rhizome according toMethod 3, and perform the test. Prepare the control solutionwith 3.0 mL of Standard Lead Solution (not more than 10 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofpulverized Eleutherococcus Senticosus Rhizome according toMethod 4, and perform the test (not more than 5 ppm).Add the following:Goshajinkigan Extract牛 車 腎 気 丸 エキスGoshajinkigan Extract contains not less than 4 mg and notmore than 16 mg of loganin, not less than 6 mg and not morethan 18 mg of peoniflorin (C 23 H 28 O 11 : 480.46), and not less than0.2 mg (for preparation prescribed Powdered Processed AconiteRoot 1) of total alkaloids (as benzoylmesaconine hydrochlorideand 14-anisoylaconine hydrochloride, or as benzoylmesaconinehydrochloride and benzoylhypaconine hydrochloride) or not lessthan 0.1 mg (for preparation prescribed Powdered ProcessedAconite Root 2) of total alkaloids (as benzoylmesaconine hydrochlorideand benzoylhypaconine hydrochloride) per the extractprepared as directed in the Method of preparation.Method of preparation Prepare a dry extract or viscous extractas directed under Extracts, with 5 g of Rehmannia Root, 3g of Cornus Fruit, 3 g of Dioscorea Rhizome, 3 g of AlismaRhizome, 3 g of Poria Sclerotium, 3 g of Moutan Bark, 1 g ofCinnamon Bark, 1 g of Powdered Processed Aconite Root 1 orPowdered Processed Aconite Root 2 of “Powdered ProcessedAconite Root”, 3 g of Achyranthes Root and 3 g of PlantagoSeed.Description Goshajinkigan Extract occurs as brown toblack-brown powder or viscous extract. It has slightly a characteristicodor and a slightly acid taste.Identification (1) To 1.0 g of the dry extract (or 3.0 g of theviscous extract), add 10 mL of water, shake, then add 30 mL ofmethanol, shake, centrifuge, and use the supernatant liquid asthe sample solution. Perform the test with the sample solution asdirected under Thin-layer Chromatography . Spot 5 µL ofthe sample solution on a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of water, methanoland 1-butanol (1:1:1) to a distance of about 10 cm, andair-dry the plate. Spray evenly 4-methoxybenzaldehyde-sulfuricacid TS on the plate, heat at 105°C for 5 minutes, and allow tocool; a dark-green spot is observed at around R f 0.6 (RehmanniaRoot).(2) To 2.0 g of the dry extract (or 6.0 g of the viscous extract),add 10 mL of water, shake, then add 5 mL of 1-butanol,shake, centrifuge, and use the supernatant liquid as the samplesolution. Separately, dissolve 1 mg of loganin for thin-layerchromatography in 1 mL of methanol, and use the solution asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 10 µLof the sample solution and 2 µL of the standard solution on aplate of silica gel for thin-layer chromatography. Develop theplate with a mixture of ethyl acetate, water and formic acid(6:1:1) to a distance of about 10 cm, and air-dry the plate. Sprayevenly 4-methoxybezaldehyde-sulfuric acid TS on the plate, andheat at 105°C for 2 minutes: one of the spot among the severalspots from the sample solution has the same color tone and R fvalue with the purple spot from the standard solution (CornusFruit).

2222 Crude Drugs Supplement II, JP XV(3) To 2.0 g of the dry extract (or 6.0 g of the viscous extract),add 10 mL of sodium carbonate TS, shake, then add 10mL of diethyl ether, shake, centrifuge, and use the supernatantliquid as the sample solution. Separately, dissolve 1 mg of AlisolA for thin-layer chromatography in 1 mL of methanol, and usethe solution as the standard solution. Perform the test with thesesolutions as directed under Thin-layer Chromatography .Spot 20 µL of the sample solution and 2µL of the standard solutionon a plate of silica gel for thin-layer chromatography. Developthe plate with a mixture of ethyl acetate, hexane and aceticacid (100)(10:10:3) to a distance of about 10 cm, and air-drythe plate. Spray evenly vanillin-sulfuric acid TS on the plate,heat at 105°C for 5 minutes, and allow to cool: one of the spotamong the several spots from the sample solution has the samecolor tone and R f value with the purple spot from the standardsolution (Alisma Rhizome).(4) To 2.0 g of the dry extract (or 6.0 g of the viscous extract),add 10 mL of water, shake, then add 5 mL of diethyl ether,shake, centrifuge, and use the supernatant liquid as the samplesolution. Separately, dissolve 1 mg of paeonol for thin-layerchromatography in 1 mL of methanol, and use the solution asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 20 µLof the sample solution and 2µL of the standard solution on aplate of silica gel for thin-layer chromatography. Develop theplate with a mixture of hexane and diethyl ether (5:3) to a distanceof about 10 cm, and air-dry the plate. Spray evenly4-methoxybezaldehyde-sulfuric acid TS on the plate, and heat at105°C for 5 minutes: one of the spot among the several spotsfrom the sample solution has the same color tone and R f valuewith the orange spot from the standard solution (Moutan Bark).(5) Perform the test according to the following (i) or (ii)(Cinnamon Bark).(i) Put 10 g of the dry extract (or 30 g of the viscous extract)in a 300 mL hard-glass flask, add 100 mL of water and 1mL of silicone resin, connect the apparatus for essential oil determination,and heat to boil under a reflux condenser. Thegraduated tube of the apparatus is to be previously filled withwater to the standard line, and 2 mL of hexane is added to thegraduated tube. After heating under reflux for 1 hour, separate 1mL of the hexane layer, add 0.5 mL of sodium hydroxide TS,shake, centrifuge, and use the supernatant liquid as the samplesolution. Separately, dissolve 1 mg of (E)-cinnamaldehyde forthin-layer chromatography in 1 mL of methanol, and use thissolution as the standard solution. Perform the test with these solutionsas directed under Thin-layer Chromatography .Spot 50 µL of the sample solution and 2 µL of the standard solutionon a plate of silica gel for thin-layer chromatography. Developthe plate with a mixture of hexane, diethyl ether andmethanol (15:5:1) to a distance of about 10 cm, and air-dry theplate. Spray evenly 2,4-dinitrophenylhydrazine TS on the plate:one of the spot among the several spots from the sample solutionhas the same color tone and R f value with the yellow-orangespot from the standard solution.(ii) To 2.0 g of dry extract (or 6.0 g of the viscous extract),add 10 mL of water, shake, then add 5 mL of hexane, shake,centrifuge, and use the supernatant liquid as the sample solution.Separately, dissolve 1 mg of (E)-2-methoxycinnamaldehyde forthin-layer chromatography in 1 mL of methanol, and use thissolution as the standard solution. Perform the test with these solutionsas directed under Thin-layer Chromatography .Spot 20 µL of the sample solution and 2 µL of the standard solutionon a plate of silica gel for thin-layer chromatography. Developthe plate with a mixture of hexane and ethyl acetate (2:1)to a distance of about 10 cm, and air-dry the plate. Examine underultraviolet light (main wavelength: 365 nm): one of the spotamong several spots from the sample solution has the samecolor tone and R f value with the bluish white fluorescent spotfrom the standard solution.(6) To 3.0 g of the dry extract (or 9.0 g of the viscous extract),add 20 mL of diethyl ether and 2 mL of ammonia TS,shake for 10 minutes, centrifuge, and evaporate the supernatantliquid under reduced pressure. Add 1 mL of acetonitrile to theresidue, and use this solution as the sample solution. Separately,dissolve 1 mg of benzoylmesaconine hydrochloride forthin-layer chromatography in 10 mL of ethanol (99.5), and usethis solution as the standard solution. Perform the test with thesesolutions as directed under Thin-layer Chromatography .Spot 20 µL of the sample solution and 10 µL of the standard solutionon a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of 1-butanol, water and aceticacid (100)(4:2:1) to a distance of about 10 cm, and air-dry theplate. Spray evenly Dragendorff’s TS for spraying on the plate,and air-dry the plate. Then spray evenly sodium nitrite TS on theplate: one of the spot among the several spots from the samplesolution has the same color tone and R f value with the yellow-brownspot from the standard solution (Powdered ProcessedAconite Root).(7) To 2.0 g of the dry extract (or 6.0 g of the viscous extract),add 10 mL of water, shake, then add 5 mL of 1-butanol,shake, centrifuge, and use the supernatant liquid as the samplesolution. Separately, to 0.3 g of pulverized Plantago Seed forthin-layer chromatography, add 1 mL of methanol, heat on awater bath for 3 minutes, centrifuge after cooling, and use thesupernatant liquid as the standard solution. Perform the test withthese solutions as directed under Thin-layer Chromatography. Spot 10 µL each of the sample solution and standardsolution on a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of acetone, ethyl acetate, waterand acetic acid (100) (10:10:3:1) to a distance of about 10 cm,and air-dry the plate. Spray evenly4-methoxybezaldehyde-sulfuric acid TS on the plate, and heat at105°C for 5 minutes: one of the spot among the several spotsfrom the sample solution has the same color tone and R f value(around 0.3) with the deep blue spot from the standard solution(Plantago Seed).(8) To 2.0 g of the dry extract (or 6.0 g of the viscous extract),add 10 mL of water, shake, then add 5 mL of 1-butanol,shake, centrifuge, and use the supernatant liquid as the samplesolution. Separately, to 2 g of Achyranthes Root for thin-layerchromatography, add 10 mL of water, shake, then add 10 mL of1-butanol, shake, centrifuge, and use the supernatant liquid asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 20 µL

Supplement II, JP XV Crude Drugs 2223each of the sample solution and standard solution on a plate ofsilica gel for thin-layer chromatography. Develop the plate witha mixture of 1-propanol, ethyl acetate and water (4:4:3) to adistance of about 10 cm, and air-dry the plate. Spray evenly dilutedsulfuric acid on the plate and heat at 105°C for 5 minutes:one of the spot among the several spots from the sample solutionhas the same color tone and R f value (around 0.4) with thedark red spot from the standard solution (Achyranthes Root).Purity (1) Heavy metals Prepare the test solutionwith 1.0 g of the dry extract (or an amount of the viscous extract,equivalent to 1.0 g of the dried substance) as directed in the Extracts(4) under General Rules for Preparations, and perform thetest (not more than 30 ppm).(2) Arsenic Prepare the test solution with 0.67 g ofthe dry extract (or an amount of the viscous extract, equivalentto 0.67 g of the dried substance) according to Method 3, andperform the test (not more than 3 ppm).(3) Aconitum diester alkaloids (aconitine, jesaconitine, hypaconitineand mesaconitine)— Weigh accurately 1.0 g of thedry extract (or an amount of the viscous extract, equivalent to1.0 g of the dried substance), add 20 mL of diethyl ether, shake,then add 3.0 mL of 0.1 mol/L hydrochloric acid TS and shakefor 10 minutes. Centrifuge this solution, remove the upper layer,then add 20 mL of diethyl ether, proceed in the same manner asdescribed above, and remove the upper layer. To the water layer,add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shakefor 30 minutes, centrifuge, and take the supernatant liquid. Tothe water layer, add 1.0 mL of ammonia TS and 20 mL of diethylether, and repeat the above process twice more. Combineall the supernatant liquids, and evaporate to dryness under reducedpressure. Dissolve the residue with exactly 10 mL of amixture of phosphate buffer solution for processed aconite rootand acetonitrile (1:1). Centrifuge this solution, and use the supernatantliquid as the sample solution. Separately, pipet 1 mLof aconitum diester alkaloids standard solution for purity, add amixture of phosphate buffer solution for processed aconite rootand acetonitrile (1:1) to make exactly 10 mL, and use this solutionas the standard solution. Perform the test with exactly 40 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions: the heights of the peaks corresponding to aconitine,jesaconitine, hypaconitine and mesaconitine from thesample solution are not higher than the respective heights correspondingto aconitine, jesaconitine, hypaconitine and mesaconitinefrom the standard solution.Operating conditions―Detector: An ultraviolet absorption photometer (wavelength:231 nm for aconitine, hypaconitine and mesaconitine; 254 nmfor jesaconitine).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40°C.Mobile phase: A mixture of phosphate buffer for processedaconite root and tetrahydrofuran (183:17).Flow rate: 1.0 mL per minute (the retention time of mesaconitineis about 31 minutes).System suitability―System performance: When the procedure is run with 20 µLof aconitum diester alkaloids standard solution for purity underthe above operating conditions, using 254 nm, mesaconitine,hypaconitine, aconitine and jesaconitine are eluted in this order,and each resolution between their peaks is not less than 1.5 respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,using 231 nm, the relative standard deviation of the peakheight of mesaconitine is not more than 1.5%.Loss on drying The dry extract: Not more than 9.0%(1 g, 105°C, 5 hours).The viscous extract: Not more than 66.7% (1 g, 105°C, 5hours).Total ash Not more than 9.0%, calculated on the driedbasis.Assay (1) Loganin―Weigh accurately about 0.5 g of the dryextract (or an amount of the viscous extract, equivalent to about0.5 g of the dried substance), add exactly 50mL of dilutedmethanol (1 in 2), shake for 15 minutes, filter, and use the filtrateas the sample solution. Separately, weigh accurately 10 mgof loganin for component determination, previously dried in adesiccator (silica gel) for not less than 24 hours, and dissolve indiluted methanol (1 in 2) to make exactly 100 mL, and use thissolution as the standard solution. Perform the test with exactly10 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions, and determine the peak areas, A T and A S ,of loganin.Amount (mg) of loganin = W S × (A T / A S ) × (1/2)W S : Amount (mg) of loganin for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:238 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 50°C.Mobile phase: A mixture of water, acetonitrile and methanol(55:4:1).Flow rate: 1.2 mL per minute (the retention time of loganin isabout 25 minutes).System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and symmetry factor of the peakof loganin are not less than 5000 and not more than 1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of loganinis not more than 1.5%.(2) Peoniflorin―Weigh accurately about 0.5 g of the dry

2224 Crude Drugs Supplement II, JP XVextract (or an amount of the viscous extract, equivalent to about0.5 g of the dried substance), add exactly 50 mL of dilutedmethanol (1 in 2), shake for 15 minutes, filter, and use the filtrateas the sample solution. Separately, weigh accurately about10 mg of Peoniflorin Reference Standard (separately determinethe water), and dissolve in diluted methanol (1 in 2) to makeexactly 100 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and determine thepeak areas, A T and A S , of peoniflorin.Amount (mg) of peoniflorin (C 23 H 28 O 11 )= W S × (A T / A S ) × (1/2)W S : Amount (mg) of Peoniflorin Reference Standard, calculatedon the anhydrous basisOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:232 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 20°C.Mobile phase: A mixture of water, acetonitrile and phosphoricacid (850:150:1).Flow rate: 1.0 mL per minute (the retention time of peoniflorinis about 9 minutes).System suitability―System performance: Dissolve 1 mg each of Peoniflorin ReferenceStandard and albiflorin in diluted methanol (1 in 2) tomake 10 mL. When the procedure is run with 10 µL of this solutionunder the above operating conditions, albiflorin andpeoniflorin are eluted in this order with the resolution betweenthese peaks being not less than 2.5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area ofpeoniflorin is not more than 1.5%.(3) Total alkaloids―Weigh accurately about 1 g of the dryextract (or an amount of the viscous extract, equivalent to about1 g of the dried substance), add 20 mL of diethyl ether, shake,then add 3.0 mL of 0.1 mol/L hydrochloric acid TS, and shakefor 10 minutes. Centrifuge this solution, remove the upper layer,then add 20 mL of diethyl ether, proceed in the same manner asdescribed above, and remove the upper layer. To the water layer,add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shakefor 30 minutes, centrifuge, and take the supernatant liquid. Tothe water layer, add 1.0 mL of ammonia TS and 20 mL of diethylether, and repeat the above process twice more. Combineall the supernatant liquids, and evaporate to dryness under reducedpressure. Dissolve the residue with a mixture of phosphatebuffer solution for processed aconite root and acetonitrile(1:1) to make exactly 10 mL. Centrifuge this solution, and usethe supernatant liquid as the sample solution. Perform the testwith exactly 20 µL each of the sample solution and the aconitummonoester alkaloids standard solution TS for component determinationas directed under Liquid Chromatography accordingto the following conditions. Determine the peak areas ofbenzoylmesaconine, benzoylhypaconine and 14-anisoylaconine,A TM and A SM , A TH and A SH , as well as A TA and A SA , in each solution,respectively.Amount (mg) of benzoylmesaconine hydrochloride= C SM × (A TM / A SM ) × 10Amount (mg) of benzoylhypaconine hydrochloride= C SH × (A TH / A SH ) × 10Amount (mg) of 14-anisoylaconine hydrochloride= C SA × (A TA / A SA ) × 10C SM : Concentration (mg/mL) of benzoylmesaconine hydrochloridefor component determination in aconitummonoester alkaloids standard solution TS for componentdeterminationC SH : Concentration (mg/mL) of benzoylhypaconine hydrochloridefor component determination in aconitummonoester alkaloids standard solution TS for componentdeterminationC SA : Concentration (mg/mL) of 14-anisoylaconine hydrochloridefor component determination in aconitummonoester alkaloids standard solution TS for componentdeterminationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:231 nm for benzoylhypaconine and benzoylmesaconine; 254 nmfor 14-anisoylaconine).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40°C.Mobile phase: A mixture of phosphate buffer solution forprocessed aconite root and tetrahydrofuran (183:17).Flow rate: 1.0 mL per minute (the retention time of benzoylmesaconineis about 15 minutes).System suitability―System performance: When the procedure is run with 20 µLof the aconitum monoester alkaloids standard solution TS forcomponent determination under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of benzoylmesaconine are not less than 5000 and not morethan 1.5, respectively.System repeatability: When the test is repeated 6 times with20 µL of the aconitum monoester alkaloids standard solution TSfor component determination under the above operating conditions,the relative standard deviation of the peak areas of benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine isnot more than 1.5%.Container and storage Containers―Tight containers.

Supplement II, JP XV Crude Drugs 2225Add the following:Hachimijiogan Extract八 味 地 黄 丸 エキスHachimijiogan Extract contains not less than 4 mg and notmore than 16 mg of loganin, not less than 6 mg and not morethan 18 mg (for preparation prescribed 3 g of Moutan Bark) ornot less than 5 mg and not more than 15 mg (for preparationprescribed 2.5 g of Moutan Bark) of peoniflorin (C 23 H 28 O 11 :480.46), and not less than 0.7 mg (for preparation prescribed 1 gof Processed Aconite Root 1) of total alkaloids (as benzoylmesaconinehydrochloride and 14-anisoylaconine hydrochloride),or not less than 0.2 mg (for preparation prescribed 1 g of PowderedProcessed Aconite Root 1) of total alkaloids (as benzoylmesaconinehydrochloride and 14-anisoylaconine hydrochloride,or as benzoylmesaconine hydrochloride and benzoylhypaconinehydrochloride), or not less than 0.1 mg (for preparation prescribed1 g of Powdered Processed Aconite Root 2) of total alkaloids(as benzoylmesaconine hydrochloride and benzoylhypaconinehydrochloride), or not less than 0.1 mg (for preparationprescribed 0.5 g of Powdered Processed Aconite Root 1) oftotal alkaloids (as benzoylmesaconine hydrochloride and14-anisoylaconine hydrochloride, or as benzoylmesaconine hydrochlorideand benzoylhypaconine hydrochloride) per the extractprepared as directed in the Method of preparation.Method of preparation Prepare a dry extract or viscous extractas directed under Extracts, with 5 g of Rehmannia Root, 3g of Cornus Fruit, 3 g of Dioscorea Rhizome, 3 g of AlismaRhizome, 3 g of Poria Sclerotium, 3 g of Moutan Bark, 1 g ofCinnamon Bark, and 1 g of Processed Aconit Root 1 of “ProcessedAconit Root” or Powdered Processed Aconit Root 1 orPowdered Processed Aconit Root 2 of “Powdered ProcessedAconit Root”, or with 6 g of Rehmannia Root, 3 g of CornusFruit, 3 g of Dioscorea Rhizome, 3 g of Alisma Rhizome, 3 g ofPoria Sclerotium, 2.5 g of Moutan Bark, 1 g of Cinnamon Bark,and 0.5 g of Powdered Processed Aconit Root 1 of “PowderedProcessed Aconit Root”.Description Hachimijiogan Extract occurs as grayish brownto black-brown powder or viscous extract. It has a characteristicodor and a slightly bitter and acid taste.Identification (1) To 1.0 g of the dry extract (or 3.0 g of theviscous extract), add 10 mL of water, shake, then add 30 mL ofmethanol, shake, centrifuge, and use the supernatant liquid asthe sample solution. Perform the test with these solutions as directedunder Thin-layer Chromatography . Spot 5 µL ofthe sample solution on a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of water, methanoland 1-butanol (1:1:1) to a distance of about 10 cm, andair-dry the plate. Spray evenly 4-methoxybezaldehyde-sulfuricacid TS on the plate, heat at 105ºC for 5 minutes, and allow tocool; a dark-green spot is observed at around R f 0.6 (RehmanniaRoot).(2) To 2.0 g of the dry extract (or 6.0 g of the viscous extract),add 10 mL of water, shake, then add 5 mL of 1-butanol,shake, centrifuge, and use the supernatant liquid as the samplesolution. Separately, dissolve 1 mg of loganin for thin-layerchromatography in 1 mL of methanol, and use the solution asthe standard solution. Perform the test with the sample solutionand standard solution as directed under Thin-layer Chromatography. Spot 10 µL of the sample solution and 2 µL of thestandard solution on a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of ethyl acetate, waterand formic acid (6:1:1) to a distance of about 10 cm, andair-dry the plate. Spray evenly 4-methoxybezaldehyde-sulfuricacid TS on the plate, and heat at 105ºC for 2 minutes: one of thespot among the several spots from the sample solution has thesame color tone and R f value with the purple spot from thestandard solution (Cornus Fruit).(3) To 2.0 g of the dry extract (or 6.0 g of the viscous extract),add 10 mL of sodium carbonate TS, shake, then add 10mL of diethyl ether, shake, centrifuge, and use the supernatantliquid as the sample solution. Separately, dissolve 1 mg of AlisolA for thin-layer chromatography in 1 mL of methanol, and usethe solution as the standard solution. Perform the test with thesesolutions as directed under Thin-layer Chromatography .Spot 20 µL of the sample solution and 2µL of the standard solutionon a plate of silica gel for thin-layer chromatography. Developthe plate with a mixture of ethyl acetate, hexane and aceticacid (100) (10:10:3) to a distance of about 10 cm, and air-drythe plate. Spray evenly vanillin-sulfuric acid TS on the plate,heat at 105ºC for 5 minutes, and allow to cool: one of the spotamong the several spots from the sample solution has the samecolor tone and R f value with the purple spot from the standardsolution (Alisma Rhizome).(4) To 2.0 g of the dry extract (or 6.0 g of the viscous extract),add 10 mL of water, shake, then add 5 mL of diethyl ether,shake, centrifuge, and use the supernatant liquid as the samplesolution. Separately, dissolve 1 mg of paeonol for thin-layerchromatography in 1 mL of methanol, and use the solution asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 20 µLof the sample solution and 2 µL of the standard solution on aplate of silica gel for thin-layer chromatography. Develop theplate with a mixture of hexane and diethyl ether (5:3) to a distanceof about 10 cm, and air-dry the plate. Spray evenly4-methoxybezaldehyde-sulfuric acid TS on the plate, and heat at105ºC for 5 minutes: one of the spot among the several spotsfrom the sample solution has the same color tone and R f valuewith the orange spot from the standard solution (Moutan Bark ).(5) Perform the test according to the following (i) or (ii)(Cinnamon Bark).(i) Put 10 g of the dry extract (or 30 g of the viscous extract)in a 300 mL hard-glass flask, add 100 mL of water and 1mL of silicone resin, connect the apparatus for essential oil determination,and heat to boil under a reflux condenser. Thegraduated tube of the apparatus is to be previously filled withwater to the standard line, and 2 mL of hexane is added to thegraduated tube. After heating under reflux for 1 hour, separate 1mL of the hexane layer, add 0.5 mL of sodium hydroxide TS,shake, centrifuge, and use the supernatant liquid as the samplesolution. Separately, dissolve 1 mg of (E)-cinnamaldehyde for

2226 Crude Drugs Supplement II, JP XVthin-layer chromatography in 1 mL of methanol, and use thissolution as the standard solution. Perform the test with these solutionsas directed under Thin-layer Chromatography .Spot 50 µL of the sample solution and 2 µL of the standard solutionon a plate of silica gel for thin-layer chromatography. Developthe plate with a mixture of hexane, diethyl ether andmethanol (15:5:1) to a distance of about 10 cm, and air-dry theplate. Spray evenly 2,4-dinitrophenylhydrazine TS on the plate:one of the spot among the several spots from the sample solutionhas the same color tone and R f value with the yellow-orangespot from the standard solution.(ii) To 2.0 g of dry extract (or 6.0 g of the viscous extract),add 10 mL of water, shake, then add 5 mL of hexane, shake,centrifuge, and use the supernatant liquid as the sample solution.Separately, dissolve 1 mg of (E)-2-methoxycinnamaldehyde forthin-layer chromatography in 1 mL of methanol, and use thissolution as the standard solution. Perform the test with these solutionsas directed under Thin-layer Chromatography .Spot 20 µL of the sample solution and 2 µL of the standard solutionon a plate of silica gel for thin-layer chromatography. Developthe plate with a mixture of hexane and ethyl acetate (2:1)to a distance of about 10 cm, and air-dry the plate. Examine underultraviolet light (main wavelength: 365 nm): one of the spotamong several spots from the sample solution has the samecolor tone and R f value with the bluish white fluorescent spotfrom the standard solution.(6) To 3.0 g of the dry extract (or 9.0 g of the viscous extract),add 20 mL of diethyl ether and 2 mL of ammonia TS,shake for 10 minutes, centrifuge, and evaporate the supernatantliquid under reduced pressure. Add 1 mL of acetonitrile to theresidue, and use this solution as the sample solution. Separately,dissolve 1 mg of benzoylmesaconine hydrochloride forthin-layer chromatography in 10 mL of ethanol (99.5), and usethis solution as the standard solution. Perform the test with thesesolutions as directed under Thin-layer Chromatography .Spot 20 µL of the sample solution and 10 µL of the standard solutionon a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of 1-butanol, water and aceticacid (100) (4:2:1) to a distance of about 10 cm, and air-dry theplate. Spray evenly Dragendorff’s TS for spraying on the plate,and air-dry the plate. Then spray evenly sodium nitrite TS on theplate : one of the spot among the several spots from the samplesolution has the same color tone and R f value with the yellow-brownspot from the standard solution (Processed AconiteRoot or Powdered Processed Aconite Root).Purity (1) Heavy metals Prepare the test solutionwith 1.0 g of the dry extract (or an amount of the viscous extract,equivalent to 1.0 g of the dried substance) as directed in the Extracts(4) under General Rules for Preparations, and perform thetest (not more than 30 ppm).(2) Arsenic Prepare the test solution with 0.67 g ofthe dry extract (or an amount of the viscous extract, equivalentto 0.67 g of the dried substance) according to Method 3, andperform the test (not more than 3 ppm).(3) Aconitum diester alkaloids (aconitine, jesaconitine, hypaconitineand mesaconitine)— Weigh accurately 1.0 g of thedry extract (or an amount of the viscous extract, equivalent to1.0 g of the dried substance), add 20 mL of diethyl ether, shake,then add 3.0 mL of 0.1 mol/L hydrochloric acid TS and shakefor 10 minutes. Centrifuge this solution, remove the upper layer,then add 20 mL of diethyl ether, proceed in the same manner asdescribed above, and remove the upper layer. To the water layer,add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shakefor 30 minutes, centrifuge, and take the supernatant liquid. Tothe water layer, add 1.0 mL of ammonia TS and 20 mL of diethylether, and repeat the above process twice more. Combineall the supernatant liquids, and evaporate to dryness under reducedpressure. Dissolve the residue with exactly 10 mL of amixture of phosphate buffer solution for processed aconite rootand acetonitrile (1:1). Centrifuge this solution, and use the supernatantliquid as the sample solution. Separately, pipet exactly1 mL of aconitum diester alkaloids standard solution for purity,add a mixture of phosphate buffer solution for processed aconiteroot and acetonitrile (1:1) to make exactly 10 mL, and use thissolution as the standard solution. Perform the test with exactly40 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions: the heights of the peaks corresponding toaconitine, jesaconitine, hypaconitine and mesaconitine from thesample solution are not higher than the respective heights correspondingto aconitine, jesaconitine, hypaconitine and mesaconitinefrom the standard solution.Operating conditions―Detector: An ultraviolet absorption photometer (wavelength:231 nm for aconitine, hypaconitine and mesaconitine; 254 nmfor jesaconitine).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of phosphate buffer for processedaconite root and tetrahydrofuran (183:17).Flow rate: 1.0 mL per minute (the retention time of mesaconitineis about 31 minutes).System suitability―System performance: When the procedure is run with 20 µLof aconitum diester alkaloids standard solution for purity underthe above operating conditions, using 254 nm, mesaconitine,hypaconitine, aconitine and jesaconitine are eluted in this order,and each resolution between their peaks is not less than 1.5 respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,using 231 nm, the relative standard deviation of the peakheight of mesaconitine is not more than 1.5 %.Loss on drying The dry extract: Not more than 8.5 %(1 g, 105ºC, 5 hours).The viscous extract: Not more than 66.7% (1 g, 105ºC, 5hours).Total ash Not more than 10.0%, calculated on thedried basis.Assay (1) Loganin―Weigh accurately about 0.5 g of the dry

Supplement II, JP XV Crude Drugs 2227extract (or an amount of the viscous extract, equivalent to about0.5 g of the dried substance), add exactly 50 mL of dilutedmethanol (1 in 2), shake for 15 minutes, filter, and use the filtrateas the sample solution. Separately, weigh accurately 10 mgof loganin for component determination, previously dried in adesiccator (silica gel) for not less than 24 hours, and dissolve indiluted methanol (1 in 2) to make exactly 100 mL, and use thissolution as the standard solution. Perform the test with exactly10 µL each of the sample solution and standard solution as directedunder Liquid Chromatography according to thefollowing conditions, and determine the peak areas, A T and A s ,of loganin.Amount (mg) of loganin = W S × (A T / A s ) × (1/2)W S : Amount (mg) of loganin for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:238 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 50ºC.Mobile phase: A mixture of water, acetonitrile and methanol(55:4:1).Flow rate: 1.2 mL per minute (the retention time of loganin isabout 25 minutes).System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and symmetry factor of the peakof loganin are not less than 5000 and not more than 1.5, respectively.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of loganinis not more than 1.5%.(2) Peoniflorin―Weigh accurately about 0.5 g of the dry extract(or an amount of the viscous extract, equivalent to about0.5 g of the dried substance), add exactly 50 mL of dilutedmethanol (1 in 2), shake for 15 minutes, filter, and use the filtrateas the sample solution. Separately, weigh accurately about10 mg of Peoniflorin Reference Standard (separately determinethe water), and dissolve in diluted methanol (1 in 2) to makeexactly 100 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and determine thepeak areas, A T and A s , of peoniflorin.Amount (mg) of peoniflorin (C 23 H 28 O 11 )= W S × (A T / A S ) × (1/2)W S : Amount (mg) of Peoniflorin Reference Standard, calculatedon the anhydrous basisOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:232 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 20ºC.Mobile phase: A mixture of water, acetonitrile and phosphoricacid (850:150:1).Flow rate: 1.0 mL per minute (the retention time of peoniflorinis about 9 minutes).System suitability―System performance: Dissolve 1 mg each of Peoniflorin ReferenceStandard and albiflorin in diluted methanol (1 in 2) tomake 10 mL. When the procedure is run with 10 µL of this solutionunder the above operating conditions, albiflorin andpeoniflorin are eluted in this order with the resolution betweenthese peaks being not less than 2.5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area ofpeoniflorin is not more than 1.5%.(3) Total alkaloids―Weigh accurately about 1 g of the dryextract (or an amount of the viscous extract, equivalent to about1 g of the dried substance), add 20 mL of diethyl ether, shake,then add 3.0 mL of 0.1 mol/L hydrochloric acid TS, and shakefor 10minutes. Centrifuge this solution, remove the upper layer,then add 20 mL of diethyl ether, proceed in the same manner asdescribed above, and remove the upper layer. To the water layer,add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shakefor 30 minutes, centrifuge, and take the supernatant liquid. Tothe water layer, add 1.0 mL of ammonia TS and 20 mL of diethylether, and repeat the above process twice more. Combineall the supernatant liquids, and evaporate to dryness under reducedpressure. Dissolve the residue with a mixture of phosphatebuffer solution for processed aconite root and acetonitrile(1:1) to make exactly 10 mL. Centrifuge this solution, and usethe supernatant liquid as the sample solution. Perform the testwith exactly 20 µL each of the sample solution and the aconitummonoester alkaloids standard solution TS for component determinationas directed under Liquid Chromatography accordingto the following conditions. Determine the peak areas ofbenzoylmesaconine, benzoylhypaconine and 14-anisoylaconine,A TM and A SM , A TH and A SH , as well as A TA and A SA , in each solution,respectively.Amount (mg) of benzoylmesaconine hydrochloride= C SM × (A TM / A SM ) × 10Amount (mg) of benzoylhypaconine hydrochloride= C SH × (A TH / A SH ) × 10Amount (mg) of 14-anisoylaconine hydrochloride= C SA × (A TA / A SA ) × 10C SM : Concentration (mg/mL) of benzoylmesaconine hydrochloridefor component determination in aconitummonoester alkaloids standard solution TS for componentdeterminationC SH : Concentration (mg/mL) of benzoylhypaconine hydrochloridefor component determination in aconitum

2228 Crude Drugs Supplement II, JP XVmonoester alkaloids standard solution TS for componentdeterminationC SA : Concentration (mg/mL) of 14-anisoylaconine hydrochloridefor component determination in aconitummonoester alkaloids standard solution TS for componentdeterminationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:231 nm for benzoylhypaconine and benzoylmesaconine; 254 nmfor 14-anisoylaconine).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40ºC.Mobile phase: A mixture of phosphate buffer solution forprocessed aconite root and tetrahydrofuran (183:17).Flow rate: 1.0 mL per minute (the retention time of benzoylmesaconineis about 15 minutes).System suitability―System performance: When the procedure is run with 20 µLof the aconitum monoester alkaloids standard solution TS forcomponent determination under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of benzoylmesaconine are not less than 5000 and not morethan 1.5, respectively.System repeatability: When the test is repeated 6 times with20 µL of the aconitum monoester alkaloids standard solution TSfor component determination under the above operating conditions,the relative standard deviation of the peak areas of benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine isnot more than 1.5%.Container and storage Containers-Tight containers.Hochuekkito Extract補 中 益 気 湯 エキスChange the Origin to read:Hochuekkito Extract contains not less than 16 mgand not more than 64 mg of hesperidin, not less than0.3 mg and not more than 1.2 mg (for preparation prescribed1 g of Bupleurum Root) or not less than 0.6 mgand not more than 2.4 mg (for preparation prescribed 2g of Bupleurum Root) of saikoponin b 2 , and not lessthan12 mg and not more than 36 mg of grycyrrhizicacid (C 42 H 62 O 16 : 822.93) per the extract prepared asdirected in the Method of preparation.Japanese ValerianカノコソウChange the Purity to read:Purity (1) Heavy metals Proceed with 3.0 g ofpulverized Japanese Valerian according to Method 3, and performthe test. Prepare the control solution with 3.0 mL of StandardLead Solution (not more than 10 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofpulverized Japanese Valerian according to Method 4, and performthe test (not more than 5 ppm).Powdered Japanese Valerianカノコソウ 末Change the Purity to read:Purity (1) Heavy metals Proceed with 3.0 g ofPowdered Japanese Valerian according to Method 3, and performthe test. Prepare the control solution with 3.0 mL of StandardLead Solution (not more than 10 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofPowdered Japanese Valerian according to Method 4, and performthe test (not more than 5 ppm).Kakkonto Extract葛 根 湯 エキスChange the Origin to read:Kakkonto Extract contains not less than 9 mg andnot more than 27 mg (for preparation prescribed 3 g ofEphendra Herb) or not less than 12 mg and not morethan 36 mg (for preparation prescribed 4 g of EphendraHerb) of total alkaloids [ephedrine (C 10 H 15 NO: 165.23)and pseudoephedrine (C 10 H 15 NO: 165.23)], not lessthan 14 mg and not more than 56 mg (for preparationprescribed 2 g of Peony Root) of peoniflorin(C 23 H 28 O 11 : 480.46) or not less than 21 mg and notmore than 84 mg (for preparation prescribed 3 g ofPeony Root), and not less than 19 mg and not morethan 57 mg of glycyrrhizic acid (C 42 H 62 O 16 : 822.93)per the extract prepared as directed in the Method ofpreparation.

Supplement II, JP XV Crude Drugs 2229Lithospermum RootシコンChange the Purity to read:Purity (1) Heavy metals Proceed with 3.0 g ofpulverized Lithospermum Root according to Method 3, andperform the test. Prepare the control solution with 3.0 mL ofStandard Lead Solution (not more than 10 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofpulverized Lithospermum Root according to Method 4, andperform the test (not more than 5 ppm).Add the following:Longan ArilLongan ArillusリュウガンニクLongan Aril is the aril of Euphoria longana Lamarck(Sapindaceae).Description Depressed ellipsoidal aril, 1 - 2 cm in length,about 1 cm in width; yellowish red-brown to blackish brown;soft in texture and mucous; when immersed in water,bell-shaped, with the tip split in several parts.Odor, characteristic; taste, sweet.Under a microscope , a transverse section reveals theoutmost layer composed of a single-layered epidermis, beneaththis observed parenchyma consisting of depressed parenchymacells; the innermost layer composed of slightly thick-walledepidermis; parenchyma contains red-brown to brown contents aswell as solitary crystals, amorphous crystals and sand crystals ofcalcium oxalate.Identification To 1 g of coarse cuttings of Longan Aril, add10 mL of water, shake thoroughly, and filter. To 3 mL of the filtrate,add 3 mL of Fehling solution, and heat on a water bath: ared precipitate is produced.Total ash Not more than 5.0%.Extract content Dilute ethanol-soluble extract: Notless than 75.0%.LongguリュウコツChange (2) of the Identification and (1) of the Purityto read:Identification (2) The turbid solution obtained in (1) has acharacteristic odor. Filtrate this solution and neutralize withammonia TS: this solution responds to the Qualitative Tests (1), (2) and (3) for calcium salt.Purity (1) Heavy metals To 2.0 g of pulverizedLonggu, add 5 mL of water, shake, add gradually 6 mL of hydrochloricacid, evaporate on a water bath to dryness, dissolvethe residue in 50 mL of water, and filter. To 25 mL of the filtrate,add 2 mL of dilute acetic acid, 1 drop of ammonia TS and waterto make 50 mL. Perform the test with this solution as the testsolution. Separately, evaporate 3 mL of hydrochloric acid on awater bath to dryness, add 2 mL of dilute acetic acid, 2.0 mL ofStandard Lead Solution and water to make 50 mL, and use thissolution as the control solution (not more than 20 ppm).When being shown as extracts, infusions and decoctions onthe label, the procedure and the limit are as follows.To 20.0 g of pulverized Longgu, add 80 mL of water, shakeoccasionally on a water bath, heat to make about 40 mL, allowto cool, and filter. Proceed with this solution according toMethod 3, and perform the test. To the control solution, add 1.0mL of Standard Lead Solution (not more than 0.5 ppm).Nuphar RhizomeセンコツChange the Purity to read:Purity (1) Petiole―The amount of the petioles contained inNuphar Rhizome does not exceed 3.0%.(2) Heavy metals Proceed with 3.0 g of pulverizedNuphar Rhizome according to Method 3, and perform the test.Prepare the control solution with 3.0 mL of Standard Lead Solution(not more than 10 ppm).(3) Arsenic Prepare the test solution with 0.4 g ofpulverized Nuphar Rhizome according to Method 4, and performthe test (not more than 5 ppm).(4) Foreign matter The amount of foreign matterother than the petioles is not more than 1.0%.Add the following:NutmegMyristicae SemenニクズクNutmeg is the seed of Myristica fragrans Houttuyn(Myristicaceae), usually from which the seed coat hasbeen removed.Description Ovoid-globose to ellipsoidal seeds, 1.5 - 3.0 cmin length, 1.3 - 2.0 cm in diameter; externally grayish brown,with wide and shallow longitudinal furrows and fine wrinkles;usually, grayish white to grayish yellow and slightly protrudinghilum at one end, grayish brown to dark brown and slightlyconcave chalaza at the other end; cross section has a marble-likeappearance with the dark brown thin perisperm extending ir-

2230 Crude Drugs Supplement II, JP XVregularly into the light yellowish white to light brown endosperm.Odor, characteristic and strong; taste, acrid and slightly bitter.Under a microscope , a transverse section reveals perispermcomposed of outer and inner layers, the outer layercomposed of parenchyma containing dark red-brown contentsand the inner layer composed of parenchyma containingred-brown contents with a number of large oil cells and scatteredvascular bundles; in parenchyma cells of endosperm, simpleor compound starch grains and aleurone grains observed.Identification To 1 g of pulverized Nutmeg, add 5 mL ofmethanol, allow to stand for 10 minutes with occasional shaking,filtrate, and use the filtrate as the sample solution. Separately,dissolve 2 mg of myristicin for thin-layer chromatography in 1mL of ethanol (95), and use this solution as the standard solution.Perform the test with these solutions as directed underThin-layer Chromatography . Spot 5 µL each of the samplesolution and standard solution on a plate of silica gel forthin-layer chromatography. Develop the plate with a mixture ofhexane and acetone (9:1) to a distance of about 10 cm, andair-dry the plate. Spray evenly diluted sulfuric acid on the plate,and heat at 105°C for 5 minutes: one of the spot among the severalspots from the sample solution has the same color tone andR f value with the red-purple spot from the standard solution.Loss on drying Not more than 16.0% (6 hours).Total ash Not more than 2.5%.Essential oil content When the test is performed with10.0 g of pulverized Nutmeg, the essential oil content is not lessthan 0.5 mL.Peach KernelトウニンChange the Origin to read:Peach Kernel is the seed of Prunus persica Batschor Prunus persica Batsch var. davidiana Maximowicz(Rosaceae).It contains not less than 1.2% of amygdalin, calculatedon the basis of dried material.Add the following next to the Purity:Loss on drying Not more than 8.0% (6 hours).Component determination Weigh accurately 0.5 g of groundPeach Kernel, add 40 mL of diluted methanol (9 in 10), heatimmediately under a reflux condenser on a water bath for 30minutes, and cool. Filter the mixture, add diluted methanol (9 in10) to make exactly 50 mL. Pipet 5 mL of this solution, add waterto make exactly 10 mL, filter, and use the filtrate as the samplesolution. Separately, weigh accurately about 10 mg ofamygdalin for component determination, previously dried in adesiccator (silica gel) for not less than 24 hours, dissolve in dilutedmethanol (1 in 2) to make exactly 50 mL, and use this solutionas the standard solution. Perform the test with 10 µL eachof the sample solution and standard solution as directed underLiquid Chromatography according to the following conditions,and determine the peak areas, A T and A S , of amygdalinin each solution.Amount (mg) of amygdalin = W S × (A T /A S ) × 2W S : Amount (mg) of amygdalin for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:210 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilianized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 45°C.Mobile phase: A mixture of 0.05 mol/L sodium dihydrogenphosphate TS and methanol (5:1).Flow rate: 0.8 mL per minute (the retention time of amygdalinis about 12 minutes).System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amygdalin are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with 10µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of amygdalin isnot more than 1.5%.Powdered Peach Kernelトウニン 末Change the Origin to read:Powdered Peach Kernel is the powder of PeachKernel.It contains not less than 1.2% of amygdalin, calculatedon the basis of dried material.Add the following next to the Acid-insoluble ash:Component determination Weigh accurately 0.5 g of PowderedPeach Kernel, add 40 mL of diluted methanol (9 in 10),heat immediately under a reflux condenser on a water bath for30 minutes, and cool. Filter the mixture, add diluted methanol (9in 10) to make exactly 50 mL. Pipet 5 mL of this solution, addwater to make exactly 10 mL, filter, and use the filtrate as thesample solution. Separately, weigh accurately about 10 mg ofamygdalin for component determination, previously dried in adesiccator (silica gel) for not less than 24 hours, dissolve in dilutedmethanol (1 in 2) to make exactly 50 mL, and use this solutionas the standard solution. Perform the test with 10 µL eachof the sample solution and standard solution as directed under

Supplement II, JP XV Crude Drugs 2231Liquid Chromatography according to the following conditions,and determine the peak areas, A T and A S , of amygdalinin each solution.Amount (mg) of amygdalin = W S × (A T /A S ) × 2W S : Amount (mg) of amygdalin for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:210 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilianized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 45°C.Mobile phase: A mixture of 0.05 mol/L sodium dihydrogenphosphate TS and methanol (5:1).Flow rate: 0.8 mL per minute (the retention time of amygdalinis about 12 minutes).System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of amygdalin are not less than 5000 and not more than 1.5,respectively.System repeatability: When the test is repeated 6 times with 10µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of amygdalin isnot more than 1.5%.Perilla HerbソヨウDelete the Essential oil content and change theOrigin and the Identification to read:Perilla Herb is the leaves and the tips of branches ofPerilla frutescens Britton var. acuta Kudo or Perillafrutescens Britton var. crispa Decaisne (Labiatae).It contains not less than 0.08% of perillaldehyde,calculated on the basis of dried material.Identification To 0.6 g of pulverized Perilla Herb, add 10 mLof diethyl ether, shake for 15 minutes, filter, and use the filtrateas the sample solution. Separately, dissolve 1 mg of perillaldehydefor thin-layer chromatography in 10 mL of methanol, anduse this solution as the standard solution. Perform the test withthese solutions as directed under Thin-layer Chromatography. Spot 10 µL each of the sample solution and standardsolution on a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of hexane and ethyl acetate(3:1) to a distance of about 10 cm, and air-dry the plate. Sprayevenly 4-methoxybenzaldehyde-sulfuric acid-acetic acid-ethanolTS for spray on the plate, and heat at 105°C for 2 minutes: oneof the spot among the several spots from the sample solution hasthe same color tone and R f value with the red-purple spot fromthe standard solution.Add the following next to the Acid-insoluble ash:Component determination Weigh accurately about 0.2 g offreshly prepared pulverized Perilla Herb, put in aglass-stoppered centrifuge tube, add 20 mL of methanol, shakefor 10 minutes, centrifuge, and separate the supernatant liquid.To the residue, add 20 mL of methanol, and proceed in the samemanner. Combine all the extracts, add methanol to make exactly50 mL, and use this solution as the sample solution. Separately,weigh accurately about 10 mg of perillaldehyde for componentdetermination, and dissolve in methanol to make exactly 100mL. Weigh accurately 10 mL of this solution, add methanol tomake exactly 100 mL, and use this solution as the standard solution.Perform the test with 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and determine thepeak areas, A T and A S , of perillaldehyde in each solution.Amount (mg) of perillaldehyde = W S × (A T / A S ) × (1/20)W S : Amount (mg) of perillaldehyde for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:230 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40°C.Mobile phase: A mixture of water and acetonitrile (13:7).Flow rate: 1.0 mL per minuteSystem suitability―System performance: Dissolve 1 mg of (E)-asarone in thestandard solution to make exactly 50 mL. When the procedure isrun with 10 µL of this solution under the above operating conditions,perillaldehyde and (E)-asarone are eluted in this orderwith the resolution between these peaks being not less than 1.5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of perillaldehydeis not more than 1.5%.Add the following:Pogostemon HerbPogostemoni HerbaカッコウPogostemon Herb is the terrestrial part of Pogostemoncablin Bentham (Labiatae).Description Stems with opposite leaves, leaves wrinkled andshriveled. When smoothed by immersion in water, leaves areobovate to ovate-oblong, 2.5-10 cm in length, 2.5-7 cm in width,with obtusely serrate margins and petioles at the cuneate bases;the upper surface of leaves dark brown, the lower surface gray-

2232 Crude Drugs Supplement II, JP XVish brown, both sides covered densely with hairs. Stems aresquare, solid, grayish green, covered with grayish to yellowishwhite hairs; the pith broad, whitish, spongy. Under a magnifyingglass, leaf reveales hairs, glandular hairs and glandular scales.Odor, distinct; taste, slightly bitter.Under a microscope , a transverse section of petiolereveals central portion of the adaxial side protruding remarkably,with collenchyma cells beneath epidermis; vascular bundles atthe center divided into two groups. Under a microscope ,a transverse section of the midvein of lamina reveals the adaxialside protruding remarkably, with collenchyma cells beneathepidermis; vascular bundles at the center arranged in fan-shape.Under a microscope , a transverse section of stem revealsseveral-cells-layered collenchyma beneath epidermis, occasionallywith cork layer developed; beneath cortex, collateral vascularbundles arranged in a circle, phloem fibers in groups observedat the outer portion of phloem; oil droplets observed inparenchymat cells of cortex,, needle, solitary or columnar crystalsof calcium oxalate in parenchyma cells of pith.Identification To 0.5 g of pulverized Pogostemon Herb, add 5mL of methanol, shake for 3 minutes, filter, and use the filtrateas the sample solution. Perform the test with the sample solutionas directed under Thin-layer Chromatography . Spot 5 µLof the sample solution on a plate of silica gel for thin-layerchromatography, develop the plate with a mixture of hexane andacetone (9:1) to a distance of about 10 cm, and air-dry the plate.Spray evenly vanillin-sulfuric acid TS on the plate, and heat at105°C; a red spot appears at around R f 0.4.Loss on drying Not more than 15.0% (6 hours).Total ash Not more than 13.0%.Acid-insoluble ash Not more than 3.0%.Essential oil content When the test is performed with50.0 g of pulverized Pogostemon Herb in a flask with 1 mL ofsilicon resin added, the essential oil content is not less than 0.3mL.Polygonatum RhizomeオウセイAdd the following next to Identification:Quercus BarkQuercus CortexボクソクQuercus Bark is the bark of Quercus acutissimaCarruthers, Quercus serrata Murray, Quercus mongolicaFischer ex Ledebour var. crispula Ohashi orQuercus variabilis Blume (Fagaceae).Description Plate-like or semi-tubular pieces of bark, 5 - 15mm in thickness; externally grayish brown to dark brown, withthick periderm and longitudinal coarse splits; internally brownto light brown, with longitudinal ridges, the transverse sectionbrown to light brown, white small spots composed of stone cellsin groups observed sporadically.Almost odorless, tasteless.Under a microscope , a transverse section reveals acork layer with scattered cork stone cells; in secondary cortexfiber bundles lined almost stepwide, large groups of stone cellsarranged irregularly; in parenchyma aggregate crystals of calciumoxalate scattered; adjacent to stone cells and fiber cells,cells containing solitary crystals of calcium oxalate observed,and these cells form crystal cell rows in a longitudinal section.Identification To 2 g of pulverized Quercus Bark, add 10 mLof ethyl acetate, shake for 10 minutes, and centrifuge to removeethyl acetate. Add 10 mL of acetone to the residue, shake for 10minutes, centrifuge, and use the supernatant liquid as the samplesolution. Perform the test with this solution as directed underThin-layer Chromatography . Spot 10 µL of the samplesolution on a plate of silica gel for thin-layer chromatography,develop the plate with a mixture of ethyl acetate, methanol andwater (7:2:1) to a distance of about 10 cm, and air-dry the plate.Examine under ultraviolet light (main wavelength: 365 nm):Two consecutive fluorescent spots in different colors are observedat around R f 0.4. Then, spray evenly diluted sulfuric acidon the plate, heat at 105ºC. Examine under ultraviolet light(main wavelength: 365 nm): one of these spots produces fluorescence.Loss on drying Not more than 11.0% (6 hours).Total ash Not more than 8.5%.Acid-insoluble ash Not more than 0.5%.Purity (1) Heavy metals Proceed with 3.0 g ofpulverized Polygonutum Rhizome according to Method 3, andperform the test. Prepare the control solution with 3.0 mL ofStandard Lead Solution (not more than 10 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofpulverized Polygonutum Rhizome according to Method 4, andperform the test (not more than 5 ppm).

Supplement II, JP XV Crude Drugs 2233Add the following:Royal JellyApilacローヤルゼリーRoyal Jelly is the viscous liquid or its dried substancesecreted by the secreting gland on the head ofApis mellifera Linné or Apis cerana Fabricius (Apidae).It contains not less than 4.0% and not more than8.0% of 10-hydroxy-2-(E)-decenoic acid, calculated onthe basis of dried material.Description Slightly viscous liquid or powder, milky white tolight yellow in color. Odor, characteristic; taste, astringent andacid.Identification To a portion of Royal Jelly, equivalent to 0.2 gof dried substance, add 5 mL of water, 1 mL of dilute hydrochloricacid and 10 mL of diethyl ether, shake for 15 minutes,and centrifuge. Take the diethyl ether layer, evaporate under reducedpressure, dissolve the residue in 5 mL of methanol, anduse this solution as the sample solution. Separately, dissolve 2mg of 10-hydroxy-2-(E)-decenoic acid for thin-layer chromatographyin 1 mL of methanol, and use this solution as the standardsolution. Perform the test with these solutions as directedunder Thin-layer Chromatography . Spot 20 µL each ofthe sample solution and standard solution on a plate of silica gelwith fluorescent indicator for thin-layer chromatography, developthe plate with a mixture of 1-propanol and ammonia solution(28) (7:3) to a distance of about 10 cm, and air-dry the plate.Examine under ultraviolet light (main wavelength: 254 nm): thespot from the sample solution has the same color tone and R fvalue with the dark purple spot from the standard solution.Purity (1) Heavy metals Proceed with a portion ofRoyal Jelly, equivalent to 1.0 g of the dried substance, accordingto Method 3, and perform the test. Prepare the control solutionwith 3.0 mL of Standard Lead Solution (not more than 30 ppm).(2) Arsenic Prepare the test solution with anamount of Royal Jelly, equivalent to 0.40 g of the dried substanceaccording to Method 3, and perform the test (not morethan 5 ppm).Loss on drying The slightly viscous liquid: Not lessthan 57.0% and not more than 77.0% (6 hours).The powder: Not less than 7.0% and not more than 13.0% (6hours)Component determination Weigh a portion of Royal Jelly,equivalent to 0.2 g of the dried substance, add 20 mL of methanol,treat with ultrasonic waves for 30 minutes, and add methanolto make exactly 50 mL. Centrifuge this solution, take exactly2 mL of the supernatant liquid, add exactly 2 mL of the internalstandard solution, then add 25 mL of water and methanolto make exactly 50 mL, and use this solution as the sample solution.Separately, weigh accurately about 10 mg of10-hydroxy-2-(E)-decenoic acid for component determination,dissolve in methanol to make exactly 100 mL. To exactly 3 mLof this solution, add exactly 2 mL of the internal standard solution,then add 25 mL of water and methanol to make exactly 50mL, and use this solution as the standard solution. Perform thetest with 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions, and calculate the ratios, Q T and Q S ,of the peak area of 10-hydroxy-2-(E)-decenoic acid to that ofthe internal standard.Amount (mg) of 10-hydroxy-2-(E)-decenoic acid= W S × (Q T /Q S ) × (3/4)W S : Amount (mg) of 10-hydroxy-2-(E)-decenoic acid forcomponent determinationInternal standard solution—A solution of propyl parahydroxybenzoatein methanol (1 in 5000)Operating conditions—Detector: An ultraviolet absorption photometer (wavelength:215 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 50°C.Mobile phase: A mixture of water, methanol and phosphoricacid (550:450:1)Flow rate: Adjust the flow rate so that the retention time of10-hydroxy-2-(E)-decenoic acid is about 10 minutes.System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,10-hydroxy-2-(E)-decenoic acid and the internal standard areeluted in this order with the resolution between these peaks beingnot less than 6.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the ratio of the peak areaof 10-hydroxy-2-(E)-decenoic acid to that of the internal standardis not more than 1.0%.Container and storage Containers―Tight containers.Storage―At not exceeding 10°CTotal ash Not more than 4.0%, calculated on the driedbasis.Acid-insoluble ash Not more than 0.5%, calculated onthe dried basis.

2234 Crude Drugs Supplement II, JP XVSaposhnikovia RootボウフウAdd the following next to the Description:Identification To 1 g of pulverized Saposhnikovia Root, add 5mL of methanol, shake for 10 minutes, filter, and use the filtrateas the sample solution. Separately, dissolve 1 mg of4´-O-glucosyl-5-O-methylvisamminol for thin-layer chromatographyin 1 mL of methanol, and use this solution as the standardsolution. Perform the test with these solutions as directedunder Thin-layer Chromatography . Spot 5 µL each ofthe sample solution and standard solution on a plate of silica gelwith fluorescent indicator for thin-layer chromatography, developthe plate with a mixture of ethyl acetate, methanol andwater (10:2:1) to a distance of about 10 cm, and air-dry the plate.Examine under ultraviolet light (main wavelength: 254 nm): oneof the spot among several spots from the sample solution has thesame color tone and R f value with the blue spot from the standardsolution.Scopolia RhizomeロートコンChange the Purity to read:Purity (1) Heavy metals Proceed with 3.0 g ofpulverized Scopolia Rhizome according to Method 3, and performthe test. Prepare the control solution with 4.5 mL of StandardLead Solution (not more than 15 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofpulverized Scopolia Rhizome according to Method 4, and performthe test (not more than 5 ppm).SenegaセネガChange the Purity to read:Purity (1) Stem—The amount of the stems contained inSenega does not exceed 2.0%.(2) Heavy metals Proceed with 3.0 g of pulverizedSenega according to Method 3, and perform the test. Prepare thecontrol solution with 3.0 mL of Standard Lead Solution (notmore than 10 ppm).(3) Arsenic Prepare the test solution with 0.40 g ofpulverized Senega according to Method 4, and perform the test(not more than 5 ppm).(4) Foreign matter The amount of foreign matterother than the stems is not more than 1.0%.Powdered Senegaセネガ 末Change the Purity to read:Purity (1) Heavy metals Proceed with 3.0 g ofPowdered Senega according to Method 3, and perform the test.Prepare the control solution with 3.0 mL of Standard Lead Solution(not more than 10 ppm).(2) Arsenic Prepare the test solution with 0.40 g ofPowdered Senega according to Method 4, and perform the test(not more than 5 ppm).(3) Foreign matter―Under a microscope , stonecells, starch grains or crystals of calcium oxalate are not observed.Add the following:Shimbuto Extract真 武 湯 エキスShimbuto Extract contains not less than 26 mg and not morethan 78 mg of peoniflorin (C 23 H 28 O 11 : 480.46), not less than 0.5mg and not more than 2.0 mg (for preparation prescribed 0.8 gof Ginger) or not less than 0.6 mg and not more than 2.4 mg (forpreparation prescribed 1 g of Ginger) or not less than 0.9 mgand not more than 3.6 mg (for preparation prescribed 1.5 g ofGinger) of [6]-gingerol, and not less than 0.7 mg (for preparationprescribed 1 g of Processed Aconite Root 1) of total alkaloids(as benzoylmesaconine hydrochloride and14-anisoylaconine hydrochloride) or not less than 0.2 mg (forpreparation prescribed 1 g of Powdered Processed Aconite Root1) of total alkaloids (as benzoylmesaconine hydrochloride and14-anisoylaconine hydrochloride, or as benzoylmesaconine hydrochlorideand benzoylhypaconine hydrochloride) or not lessthan 0.1 mg (for preparation prescribed 1 g of Powdered ProcessedAconite Root 2) of total alkaloids (as benzoylmesaconinehydrochloride and 14-benzoylhypacomine hydrochloride) or notless than 0.1 mg (for preparation prescribed 0.5 g of PowderedProcessed Aconite Root 1) of total alkaloids (as benzoylmesaconinehydrochloride and 14-anisoylaconine hydrochloride, oras benzoylmesaconine hydrochloride and benzoylhypaconinehydrochloride) per the extract prepared as directed in theMethod of preparation.Method of preparation Prepare a dry extract or viscous extractas directed under Extracts, with 5 g of Poria Sclerotium, 3g of Paeony Root, 3 g of Atractylodes Rhizome, 1 g of Gingerand 1 g Processed Aconit Root 1 of “Processed Aconit Root”, orwith 5 g of Poria Sclerotium, 3 g of Paeony Root, 3 g of AtractylodesLancea Rhizome, 1 g of Ginger and 1 g of PowderedProcessed Aconit Root 1 of “Powdered Processed Aconit Root”,or with 5 g of Poria Sclerotium, 3 g of Paeony Root, 3 g ofAtractylodes Rhizome, 0.8 g of Ginger and 1 g of PowderedProcessed Aconit Root 2 of “Powdered Processed Aconit Root”,

Supplement II, JP XV Crude Drugs 2235or with 4 g of Poria Sclerotium, 3 g of Paeony Root, 3 g ofAtractylodes Lancea Rhizome, 1.5 g of Ginger and 0.5 g ofPowdered Processed Aconit Root 1 of “Powdered ProcessedAconit Root”.Description Shimbuto Extract occurs as light yellow-brown tobrown powder. It has slightly a characteristic odor and a hot andbitter taste.Identification (1) To 2.0 g of Shimbuto Extract, add 10 mLof water, shake, then add 5 mL of 1-butanol, shake, centrifuge,and use the supernatant liquid as the sample solution. Separately,dissolve 1 mg of Peoniflorin Reference Standard in 1 mL ofmethanol, and use this solution as the standard solution. Performthe test with these solutions as directed under Thin-layer Chromatography. Spot 5 µL each of the sample solution andstandard solution on a plate of silica gel for thin-layer chromatography.Develop the plate with a mixture of ethyl acetate,methanol and water (20:3:2) to a distance of about 10 cm, andair-dry the plate. Spray evenly 4-methoxybezaldehyde-sulfuricacid TS on the plate, and heat at 105°C for 5 minutes: one of thespot among the several spots from the sample solution has thesame color tone and R f value with the purple spot from thestandard solution (Peony Root).(2) (For preparation prescribed Atractylodes Rhizome) To1.0 g of Shimbuto Extract, add 10 mL of water, shake, then add25 mL of diethyl ether, and shake. Take the diethyl ether layer,evaporate the layer under reduced pressure, add 2 mL of diethylether to the residue, and use this solution as the sample solution.Separately, dissolve 1 mg of atractylenolide III for thin-layerchromatography in 2 mL of methanol, and use this solution asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 5 µLeach of the sample solution and standard solution on a plate ofsilica gel for thin-layer chromatography. Develop the plate witha mixture of ethyl acetate and hexane (1:1) to a distance ofabout 10 cm, and air-dry the plate. Spray evenly diluted sulfuricacid on the plate, heat at 105°C for 5 minutes, and examine underultraviolet light (main wavelength: 365 nm): one of the spotamong the several spots from the sample solution has the samecolor tone and R f value with the bluish white fluorescent spotfrom the standard solution (Atractylodes Rhizome).(3) (For preparation prescribed Atractylodes Lancea Rhizome)To 2.0 g of Shimbuto Extract, add 10 mL of water,shake, then add 25 mL of hexane, and shake. Take the hexanelayer, add anhydrous sodium sulfate to dry, and filter. Evaporatethe filtrate under reduced pressure, add 2 mL of hexane to theresidue, and use this solution as the sample solution. Performthe test with the sample solution as directed under Thin-layerChromatography . Spot 20 µL of the sample solution on aplate of silica gel with fluorescent indicator for thin-layer chromatography,develop the plate with a mixture of hexane andacetone (7:1) to a distance of about 10 cm, and air-dry the plate.Examine under ultraviolet light (main wavelength: 254 nm): adark purple spot is observed at around R f 0.4. The spot shows agreenish brown color after being sprayed evenly4-dimethylaminobenzaldehyde TS for spraying, heated at 105°Cfor 5 minutes and allowed to cool (Atractylodes Lancea Rhizome).(4) To 1.0 g of Shimbuto Extract, add 10 mL of water, shake,then add 25 mL of diethyl ether, and shake. Take the diethylether layer, evaporate the layer under reduced pressure, add 2mL of diethyl ether to the residue, and use this solution as thesample solution. Separately, dissolve 1 mg of [6]-gingerol forthin-layer chromatography in 1 mL of methanol, and use thissolution as the standard solution. Perform the test with these solutionsas directed under Thin-layer Chromatography .Spot 10 µL of the sample solution and 5 µL of the standard solutionon a plate of silica gel for thin-layer chromatography. Developthe plate with a mixture of ethyl acetate and hexane (1:1)to a distance of about 10 cm, and air-dry the plate. Spray evenly4-dimethylaminobenzaldehyde TS for spraying on the plate,heated at 105°C for 5 minutes and allowed to cool: one of thespot among the several spots from the sample solution has thesame color tone and R f value with the blue-green spot from thestandard solution (Ginger).(5) To 3.0 g of Shimbuto Extract, add 20 mL of diethylether and 2 ml of ammonia TS, shake for 10 minutes, centrifuge,and take the supernatant liquid. Evaporate the supernatant liquidunder reduced pressure, add 1 mL of acetonitrile to the residue,and use this solution as the sample solution. Separately, dissolve1 mg of benzoylmesaconine hydrochloride for thin-layer chromatographyin 10 mL of ethanol (99.5), and use this solution asthe standard solution. Perform the test with these solutions asdirected under Thin-layer Chromatography . Spot 20 µLof the sample solution and 10 µL of the standard solution on aplate of silica gel for thin-layer chromatography. Develop theplate with a mixture of 1-butanol, water and acetic acid (100)(4:2:1) to a distance of about 10 cm, and air-dry the plate. Sprayevenly Dragendorff’s TS for spraying on the plate, and air-drythe plate. Then spray evenly sodium nitrite TS on the plate: oneof the spot among the several spots from the sample solution hasthe same color tone and R f value with the yellow-brown spotfrom the standard solution (Processed Aconite Root or PowderedProcessed Aconite Root).Purity (1) Heavy metals Prepare the test solutionwith 1.0g of Shimbuto Extract as directed in the Extracts (4)under General Rules for Preparations, and perform the test (notmore than 30 ppm).(2) Arsenic Prepare the test solution with 0.67 g ofShimbuto Extract according to Method 3, and perform the test(not more than 3 ppm).(3) Aconitum diester alkaloids (aconitine, jesaconitine, hypaconitineand mesaconitine)—Weigh accurately 1.0 g ofShimbuto Extract, add 20 mL of diethyl ether, shake, then add3.0 mL of 0.1 mol/L hydrochloric acid TS and shake for 10minutes. Centrifuge this solution, remove the upper layer, thenadd 20 mL of diethyl ether, proceed in the same manner as describedabove, and remove the upper layer. To the water layer,add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shakefor 30 minutes, centrifuge, and take the supernatant liquid. Tothe water layer, add 1.0 mL of ammonia TS and 20 mL of diethylether, and repeat the above process twice more. Combineall the supernatant liquids, and evaporate to dryness under reducedpressure. Dissolve the residue with exactly 10 mL of a

2236 Crude Drugs Supplement II, JP XVmixture of phosphate buffer solution for processed aconite rootand acetonitrile (1:1). Centrifuge this solution, and use the supernatantliquid as the sample solution. Separately, pipet 1 mLof aconitum diester alkaloids standard solution for purity, add amixture of phosphate buffer solution for processed aconite rootand acetonitrile (1:1) to make exactly 10 mL, and use this solutionas the standard solution. Perform the test with exactly 40 µLeach of the sample solution and standard solution as directedunder Liquid Chromatography according to the followingconditions: the heights of the peaks corresponding to aconitine,jesaconitine, hypaconitine and mesaconitine from thesample solution are not higher than the respective heights correspondingto aconitine, jesaconitine, hypaconitine and mesaconitinefrom the standard solution.Operating conditions―Detector: An ultraviolet absorption photometer (wavelength:231 nm for aconitine, hypaconitine and mesaconitine; 254 nmfor jesaconitine).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40°C.Mobile phase: A mixture of phosphate buffer for processedaconite root and tetrahydrofuran (183:17).Flow rate: 1.0 mL per minute (the retention time of mesaconitineis about 31 minutes).System suitability―System performance: When the procedure is run with 20 µLof aconitum diester alkaloids standard solution for purity underthe above operating conditions, using 254 nm, mesaconitine,hypaconitine, aconitine and jesaconitine are eluted in this order,and each resolution between their peaks is not less than 1.5 respectively.System repeatability: When the test is repeated 6 times with20 µL of the standard solution under the above operating conditions,using 231 nm, the relative standard deviation of the peakheight of mesaconitine is not more than 1.5%.Loss on drying Not more than 7.0% (1 g, 105°C, 5hours).Total ash Not more than 10.0%.Assay (1) Peoniflorin―Weigh accurately about 0.5 g ofShimbuto Extract, add exactly 50 mL of diluted methanol (1 in2), shake for 15 minutes, filter, and use the filtrate as the samplesolution. Separately, weigh accurately about 10 mg of PeoniflorinReference Standard (separately determine the water), anddissolve in diluted methanol (1 in 2) to make exactly 100 mL,and use this solution as the standard solution. Perform the testwith exactly 10 µL each of the sample solution and standard solutionas directed under Liquid Chromatography accordingto the following conditions, and determine the peak areas,A T and A S , of peoniflorin.Amount (mg) of peoniflorin (C 23 H 28 O 11 )= W S × (A T / A S ) × (1/2)W S : Amount (mg) of Peoniflorin Reference Standard, calculatedon the anhydrous basisOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:232 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 20°C.Mobile phase: A mixture of water, acetonitrile and phosphoricacid (850:150:1).Flow rate: 1.0 mL per minute (the retention time of peoniflorinis about 9 minutes).System suitability―System performance: Dissolve 1 mg each of Peoniflorin ReferenceStandard and albiflorin in diluted methanol (1 in 2) tomake 10 mL. When the procedure is run with 10 µL of thisstandard solution under the above operating conditions, albiflorinand peoniflorin are eluted in this order with the resolutionbetween these peaks being not less than 2.5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area ofpeoniflorin is not more than 1.5%.(2) [6]-gingerol―Weigh accurately about 0.5 g of ShimbutoExtract, add exactly 50 mL of diluted methanol (7 in 10), shakefor 15 minutes, filter, and use the filtrate as the sample solution.Separately, weigh accurately about 10 mg of [6]-gingerol forcomponent determination, dissolve in diluted methanol to makeexactly 100 mL. Pipet 5 mL of this solution, add methanol tomake exactly 50 mL, and use this solution as the standard solution.Perform the test with exactly 10 µL each of the sample solutionand standard solution as directed under Liquid Chromatography according to the following conditions, and determinethe peak areas, A T and A S , of [6]-gingerol.Amount (mg) of [6]-gingerol = W S × (A T / A S ) × (1/20)W S : Amount (mg) of [6]-gingerol for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:282 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 30°C.Mobile phase: A mixture of water, acetonitrile and phosphoricacid (620:380:1).Flow rate: 1.0 mL per minute (the retention time of[6]-gingerol is about 15 minutes).System suitability―System performance: When the procedure is run with 10 µLof the standard solution under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of [6]-gingerol are not less than 5000 and not more than1.5, respectively.System repeatability: When the test is repeated 6 times with

Supplement II, JP XV Crude Drugs 223710 µL of the standard solution under the above operating conditions,the relative standard deviation of the peak area of[6]-gingerol is not more than 1.5%.(3) Total alkaloids―Weigh accurately about 1 g of ShimbutoExtract, add 20 mL of diethyl ether, shake, then add 3.0 mLof 0.1 mol/L hydrochloric acid TS, and shake for 10 minutes.Centrifuge this solution, remove the upper layer, then add 20mL of diethyl ether, proceed in the same manner as describedabove, and remove the upper layer. To the water layer, add 1.0mL of ammonia TS and 20 mL of diethyl ether, shake for 30minutes, centrifuge, and take the supernatant liquid. To the waterlayer, add 1.0 mL of ammonia TS and 20 mL of diethyl ether,and repeat the above process twice more. Combine all the supernatantliquids, and evaporate to dryness under reduced pressure.Dissolve the residue with a mixture of phosphate buffersolution for processed aconite root and acetonitrile (1:1) tomake exactly 10 mL. Centrifuge this solution, and use the supernatantliquid as the sample solution. Perform the test withexactly 20 µL each of the sample solution and the aconitummonoester alkaloids standard solution TS for component determinationas directed under Liquid Chromatography accordingto the following conditions. Determine the peak areas ofbenzoylmesaconine, benzoylhypaconine and 14-anisoylaconine,A TM and A SM , A TH and A SH , as well as A TA and A SA , in each solution,respectively.Amount (mg) of benzoylmesaconine hydrochloride= C SM × (A TM / A SM ) × 10Amount (mg) of benzoylhypaconine hydrochloride= C SH × (A TH / A SH ) × 10Amount (mg) of 14-anisoylaconine hydrochloride= C SA × (A TA / A SA ) × 10C SM : Concentration (mg/mL) of benzoylmesaconine hydrochloridefor component determination in aconitummonoester alkaloids standard solution TS for componentdeterminationC SH : Concentration (mg/mL) of benzoylhypaconine hydrochloridefor component determination in aconitummonoester alkaloids standard solution TS for componentdeterminationC SA : Concentration (mg/mL) of 14-anisoylaconine hydrochloridefor component determination in aconitummonoester alkaloids standard solution for TS componentdeterminationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:231 nm for benzoylhypaconine and benzoylmesaconine; 254 nmfor 14-anisoylaconine).Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilanized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40°C.Mobile phase: A mixture of phosphate buffer solution forprocessed aconite root and tetrahydrofuran (183:17).Flow rate: 1.0 mL per minute (the retention time of benzoylmesaconineis about 15 minutes).System suitability―System performance: When the procedure is run with 20 µLof the aconitum monoester alkaloids standard solution TS forcomponent determination under the above operating conditions,the number of theoretical plates and the symmetry factor of thepeak of benzoylmesaconine are not less than 5000 and not morethan 1.5, respectively.System repeatability: When the test is repeated 6 times with20 µL of the aconitum monoester alkaloids standard solution TSfor component determination under the above operating conditions,the relative standard deviation of the peak areas of benzoylmesaconine,benzoylhypaconine and 14-anisoylaconine isnot more than 1.5%.Container and storage Containers-Tight containers.TurmericウコンChange the Origin and the identification to read:Turmeric is the rhizome of Curcuma Longa Linné(Zingiberaceae) with or without cork layers, usuallywith the application of blanching.It contains not less than 1.0% and not more than5.0% of total curcuminoids (curcumin, demethoxycurcuminand bisdemethoxycurcumin), calculated on thebasis of dried material.Identification (1) To 0.5 g of pulverized Turmeric, add 20mL of methanol, shake for 15 minutes, filter, and use the filtrateas the sample solution. Perform the test with the sample solutionas directed under Thin-layer Chromatography . Spot 5 µLof the sample solution on a plate of silica gel for thin-layerchromatography. Develop the plate with a mixture of ethyl acetate,hexane and acetic acid (100) (70:30:1) to a distance about10 cm, and air-dry the plate: a yellow spot appears at around R f0.4.(2) To 0.2 g of pulverized Turmeric, add 25 mL of a mixtureof methanol and acetic acid (100) (99:1), centrifuge after shakingfor 20 minutes, and separate the supernatant liquid. Performthe test as directed in the Component Determination, and measurethe peak areas of curcumin, demethoxycurcumin and bisdemethoxycurcumin:the peak area of curcumin is larger thanthe peak area of demethoxycurcumin and is larger than 0.69times the peak area of bisdemethoxycurcumin.Add the following next to Extract Content:Component determination Weigh accurately about 0.2 g ofpulverized Turmeric, add 25 mL of a mixture of methanol andacetic acid (100) (99:1), shake for 20 minutes, centrifuge, andseparate the supernatant liquid. To the residue, add 25 mL of amixture of methanol and acetic acid (100) (99:1), and proceed inthe same manner as described above. Combine all the extracts,

2238 Crude Drugs Supplement II, JP XVadd methanol to make exactly 50 mL, and use this solution asthe sample solution. Separately, weigh accurately about 10 mgof curcumin for component determination, and dissolve inmethanol to make exactly 50 mL. Weigh accurately 10 mL ofthis solution, add methanol to make exactly 50 mL, and use thissolution as the standard solution. Perform the test with exactly10 µL each of the sample solution and standard solution as describedunder Liquid Chromatography according to thefollowing conditions, and determine the peak areas, A TC , A TDand A TD of curcumin, demethoxycurcumin and bisdemethoxycurcuminin the sample solution as well as the peak area A S ofcurcumin in the standard solution.Amount (mg) of total curcuminoids (curcumin, demethoxycurcuminand bisdemethoxycurcumin)= W S × {( A TC + A TD + A TB × 0.69) / A S } × (1 / 5)W S : Amount (mg) of curcumin for component determinationOperating conditions―Detector: An ultraviolet absorption photometer (wavelength:245 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilianized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40°C.Mobile phase: A mixture of water, acetonitrile and acetic acid(100) (56:43:1).Flow rate: 1.0 mL per minute (the retention time of curcuminis about 11 minutes).System suitability―System performance: Dissolve 1 mg each of curcumin, demethoxycurcuminand bisdemethoxycurcumin for componentdetermination in methanol to make 5 mL. When the procedure isrun with 10 µL of this solution under the above operating conditions,bisdemethoxycurcumin, demethoxycurcumin and curcuminare eluted in this order with the resolution among thesepeaks being not less than 1.5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of curcumin is not morethan 1.5%.Powdered Turmericウコン 末Change the Origin and the Identification to read:Powdered Turmeric is the powder of Turmeric.It contains not less than 1.0% and not more than5.0% of total curcuminoids (curcumin, demethoxycurcuminand bisdemethoxycurcumin), calculated on thebasis of dried material.Identification (1) To 0.5 g of Powdered Turmeric, add 20mL of methanol, shake for 15 minutes, filter, and use the filtrateas the sample solution. Perform the test with the sample solutionas directed under Thin-layer Chromatography . Spot 5 µLof the sample solution on a plate of silica gel for thin-layerchromatography. Develop the plate with a mixture of ethyl acetate,hexane and acetic acid (100) (70:30:1) to a distance about10 cm, and air-dry the plate: a yellow spot appears at around R f0.4.(2) To 0.2 g of Powdered Turmeric, add 25 mL of a mixtureof methanol and acetic acid (100) (99:1), centrifuge after shakingfor 20 minutes, and separate the supernatant liquid. Performthe test as directed in the Component Determination, and measurethe peak areas of curcumin, demethoxycurcumin and bisdemethoxycurcumin:the peak area of curcumin is larger thanthe peak area of demethoxycurcumin and is larger than 0.69times the peak area of bisdemethoxycurcumin.Add the following next to Extract Content:Component determination Weigh accurately about 0.2 g ofPowdered Turmeric, add 25 mL of a mixture of methanol andacetic acid (100) (99:1), shake for 20 minutes, centrifuge, andseparate the supernatant liquid. To the residue, add 25 mL of amixture of methanol and acetic acid (100) (99:1), and proceed inthe same manner as described above. Combine all the extracts,add methanol to make exactly 50 mL, and use this solution asthe sample solution. Separately, weigh accurately about 10 mgof curcumin for component determination, and dissolve inmethanol to make exactly 50 mL. Weigh accurately 10 mL ofthis solution, add methanol to make exactly 50 mL, and use thissolution as the standard solution. Perform the test with exactly10 µL each of the sample solution and standard solution as describedunder Liquid Chromatography according to thefollowing conditions, and determine the peak areas, A TC , A TDand A TB of curcumin, demethoxycurcumin and bisdemethoxycurcuminin the sample solution as well as the peak area A S ofcurcumin in the standard solution.Amount (mg) of total curcuminoids (curcumin, demethoxycurcuminand bisdemethoxycurcumin= W S ×{( A TC + A TD + A TB × 0.69) / A S } × (1 / 5)W S : Amount (mg) of curcumin for component determinationOperating conditions—Detector: An ultraviolet absorption photometer (wavelength:245 nm)Column: A stainless steel column 4.6 mm in inside diameterand 15 cm in length, packed with octadecylsilianized silica gelfor liquid chromatography (5 µm in particle diameter).Column temperature: A constant temperature of about 40°C.Mobile phase: A mixture of water, acetonitrile and acetic acid(100) (56:43:1).Flow rate: 1.0 mL/per minute (the retention time of curcuminis about 11 minutes).System suitability―System performance: Dissolve 1 mg each of curcumin, demethoxycurcuminand bisdemethoxycurcumin for componentdetermination in methanol to make 5 mL. When the procedure isrun with 10 µL of this solution under the above operating conditions,bisdemethoxycurcumin, demethoxycurcumin and curcu-

Supplement II, JP XV Crude Drugs 2239min are eluted in this order with the resolution among thesepeaks being not less than 1.5.System repeatability: When the test is repeated 6 times with10 µL of the standard solution under the above operating conditions,the relative standard deviation of curcumin is not morethan 1.5%.Zanthoxylum FruitサンショウChange the Total ash to read:Total ash Not more than 8.0%.Powdered Zanthoxylum Fruitサンショウ 末Change the Total ash to read:Total ash Not more than 8.0%

InfraredReference Spectra

Supplement II, JP XV Infrared Reference Spectra 2243Change to read the following Infrared Reference Spectrum:L-Arginine

2244 Infrared Reference Spectra Supplement II, JP XVAdd the following 51 spectra:AciclovirL-AlanineAmiodarone Hydrochloride

Supplement II, JP XV Infrared Reference Spectra 2245Aprindine HydrochlorideArgatroban HydrateBetaxolol Hydrochloride

2246 Infrared Reference Spectra Supplement II, JP XVCadralazineCinoxacinClebopride Malate

Supplement II, JP XV Infrared Reference Spectra 2247DanazolDiflucortolone ValerateDoxazosin Mesilate

2248 Infrared Reference Spectra Supplement II, JP XVDroxidopaEcabet Sodium HydrateEthenzamide

Supplement II, JP XV Infrared Reference Spectra 2249FlopropioneFludrocortisone AcetateFlutamide

2250 Infrared Reference Spectra Supplement II, JP XVFlutoprazepamGefarnateGliclazide

Supplement II, JP XV Infrared Reference Spectra 2251Imidapril HydrochlorideIndapamideIpriflavone

2252 Infrared Reference Spectra Supplement II, JP XVIrsogladine MaleateKetoconazoleLevofloxacin Hydrate

Supplement II, JP XV Infrared Reference Spectra 2253Losartan PotassiumL-Lysine AcetateMosapride Citrate Hydrate

2254 Infrared Reference Spectra Supplement II, JP XVPhenobarbitalPimozidePioglitazone Hydrochloride

Supplement II, JP XV Infrared Reference Spectra 2255Prazosin HydrochloridePrednisolone Sodium PhosphateProbucol

2256 Infrared Reference Spectra Supplement II, JP XVProcainamide HydrochloridePropafenone HydrochlorideRebamipide

Supplement II, JP XV Infrared Reference Spectra 2257SevofluraneSimvastatinPurified Sodium Hyaluronate

2258 Infrared Reference Spectra Supplement II, JP XVSulindacTacrolimus HydrateTazobactam

Supplement II, JP XV Infrared Reference Spectra 2259TeprenoneTiapride HydrochlorideTosufloxacin Tosilate Hydrate

2260 Infrared Reference Spectra Supplement II, JP XVTroxipideUrsodeoxycholic AcidZolpidem Tartrate

Ultraviolet-visible Reference Spectra

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2263Add the following 41 spectra:AciclovirAmiodarone HydrochlorideAprindine Hydrochloride

2264 Ultraviolet-visible Reference Spectra Supplement II, JP XVArgatroban HydrateBetaxolol HydrochlorideCadralazine

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2265Calcitonin(Salmon)CinoxacinClebopride Malate

2266 Ultraviolet-visible Reference Spectra Supplement II, JP XVDanazolDiflucortolone ValerateDoxazosin Mesilate

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2267DroxidopaEcabet Sodium HydrateEthenzamide

2268 Ultraviolet-visible Reference Spectra Supplement II, JP XVFludrocortisone AcetateFlutamideFlutoprazepam

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2269GliclazideIndapamideIpriflavone

2270 Ultraviolet-visible Reference Spectra Supplement II, JP XVIrsogladine MaleateKetoconazoleLevofloxacin Hydrate

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2271Losartan PotassiumMosapride Citrate HydratePhenobarbital

2272 Ultraviolet-visible Reference Spectra Supplement II, JP XVPimozidePioglitazone HydrochloridePrazosin Hydrochloride

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2273Prednisolone Sodium PhosphateProbucolProgesterone

2274 Ultraviolet-visible Reference Spectra Supplement II, JP XVPropafenone HydrochlorideRebamipideSimvastatin

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2275SulindacTiapride HydrochlorideTosufloxacin Tosilate Hydrate

2276 Ultraviolet-visible Reference Spectra Supplement II, JP XVTroxipideZolpidem Tartrate

General Information

Add the following:GENERAL INFORMATION8. International Harmonization Implemented in the JapanesePharmacopoeia Fifteenth EditionJune 2008 (Rev.1)Harmonized items JP15 (Supplement II) RemarksBulk Density and Tapped Density ofPowdersBulk densityMethod 1: Measurement in a graduatedcylinderProcedureMethod 2: Measurement in a volumeterApparatusProcedureMethod 3: Measurement in a vesselApparatusProcedureTapped density3.01 Determination of Bulk and TappedDensities(Introduction)Bulk densityMethod 1: Measurement in a GraduatedCylinderProcedureMethod 2: Measurement in a VolumeterApparatusProcedureMethod 3: Measurement in a VesselApparatusProcedureTapped densityJP’s particular description: Explanation ofthis test method.Method 1 Method 1ApparatusProcedureApparatusProcedureMethod 2 Method 2ProcedureProcedureMethod 3 Method 3ProcedureMeasures of powder compressibilityProcedureMeasures of powder compressibility2279

2280 General Information Supplement II, JP XVMay 2007Harmonized items JP15 (Supplement II) RemarksGas Pycnometric Density of Solids3.03 Powder Particle Density Determination.(Introduction) (Introduction) JP’s particular description: application ofthis test methodApparatus1. ApparatusCalibration of apparatusThe range of temperature during themeasurement is described in the Procedure.MethodExpression of the results2. Procedure2. ProcedureOctober 2006Harmonized items JP15 (Supplement II) RemarksRice StarchDefinitionRice StarchDefinitionIdentification A Identification (1)Identification B Identification (2)Identification C Identification (3)pHIronLoss on dryingSulphated ashOxidising substancesSulphur dioxidepHPurity (1) IronLoss on dryingResidue on ignitionPurity (2) Oxidizing substancesPurity (3) Sulfur dioxideMay 2007Harmonized items JP15 (Supplement II) RemarksGENERAL INFORMATIONPowder FinenessPowder Fineness

Supplement II, JP XV General Information 2281Change to read:14. Mycoplasma Testing for CellSubstrates used for the Productionof Biotechnological/BiologicalProductsThis document describes the currently available methods ofmycoplasma testing that should be performed for cell substratesthat are used in the manufacture of biotechnological/biologicalproducts.Methods suggested for detection of mycoplasma are, A. culturemethod, B. indicator cell culture method, and C. polymerasechain reaction (PCR) method.Mycoplasma testing should be performed on the master cellbank (MCB) and the working cell bank (WCB), as well as onthe cell cultures used during the manufacturing process of theproduct. For the assessment of these cells, mycoplasma testingshould be performed using both methods A and B. Method B,however, does not detect only DNA derived from mycoplasma.Therefore, if a positive result is obtained only from method B,method C can be used to determine whether mycoplasma is actuallypresent. When method C is used, it is necessary to demonstratethe rationale for determining a negative result. In such acase, the sensitivity and specificity of the method, the appropriatenessof the sample preparation, and the suitability of the selectionof the test method, including selection of reagents, reactionconditions and primers should be taken into account.Prior to mycoplasma testing, the sample should be tested todetect the presence of any factors inhibiting the growth of mycoplasma.If such growth-inhibiting factors are detected theyshould be neutralized or eliminated by an appropriate method,such as centrifugation or cell passage.If the test will be performed within 24 hours of obtaining thesample, the sample should be stored at a temperature between2ºC and 8ºC. If more than 24 hours will elapse before the test isperformed, the sample should be stored at –60ºC or lower.If mycoplasma is detected, additional testing to identify thespecies may be helpful in determining the source of contamination.A. Culture Method1. Culture MediumBoth agar plates and broth are used. Each lot of agar andbroth medium should be free of antibiotics except for penicillin.Refer to the Minimum Requirements for Biological Productsregarding selection of the culture media. Other culture mediamay be used if they fulfill the requirements described in the followingsection 2.2. Suitability of Culture MediumEach lot of medium should be examined for mycoplasmagrowth-promoting properties. To demonstrate the capacity of themedia to detect known mycoplasma, each test should includecontrol cultures of at least two known species or strains of mycoplasma,one of which should be a dextrose fermenter (i.e., M.pneumoniae ATCC15531 or equivalent species or strains) andone of which should be an arginine hydrolyser (i.e., M. oraleATCC23714 or equivalent species or strains). The mycoplasmastrains used for the positive control tests should be those with alow number of passages obtained from an official or suitablyaccredited agency, and handled appropriately. Inoculate the culturemedium with 100 colony-forming units (CFU) or 100color-changing units (CCU) or less.3. Culture and Observation1) Inoculate no less than 0.2 mL of test sample (cell suspension)in evenly distributed amounts over the surface of each oftwo or more agar plates. After the surfaces of the inoculatedplates are dried, the plates should be incubated under microaerophilicconditions in an atmosphere of nitrogen containing5 to 10 percent carbon dioxide and adequate humidity at 36± 1ºC for no less than 14 days.2) Inoculate no less than 10 mL of the test sample (cell suspension)into each of one or more vessels containing 100 mL ofbroth medium, and incubate at 36 ± 1ºC.If the culture medium for the sample cells contains anygrowth-inhibiting factors, such as antibiotics, these factors mustbe removed. A method such as centrifugation is recommendedfor this purpose. Refer to the Validation tests forgrowth-inhibiting factors described in the Minimum Requirementsfor Biological Products for the detection ofgrowth-inhibiting factors.3) Subculture 0.2 mL of broth culture from each vessel onthe 3 rd , 7 th , and 14 th days of incubation onto two or more agarplates. The plates should be incubated microaerophilically at 36± 1ºC for no less than 14 days.4) Examination of all plates for mycoplasma coloniesshould be done microscopically on the 7 th and 14 th day at 100times magnification or greater.B. Indicator Cell Culture MethodUsing Vero cell culture substrate, pretest the suitability of themethod using an inoculum of 100 CFU or 100 CCU or less of M.hyorhinis (ATCC29052, ATCC17981 or equivalent species orstrains) and M. orale (ATCC23714 or equivalent species orstrains).An equivalent indicator cell substrate and suitable mycoplasmastrains may be acceptable if data demonstrate at leastequal sensitivity for the detection of known mycoplasma contaminants.The mycoplasma strains should be those with a lownumber of passages obtained from an official or suitably accreditedagency, and handled appropriately, and the unit of inoculationshould be determined before use. The cell substrate usedshould be obtained from a qualified cell bank and certified to bemycoplasma free. The acquired cells should be carefully culturedand propagated, and sufficient volumes of seed stockshould be prepared with the proper precautions to avoid mycoplasmacontamination. The stock should be tested for mycoplasmacontamination using at least one of the methods describedin this document, then frozen for storage. For each test anew container from the stock should be thawed and used within6 passages.Indicator cell cultures should be grown on cover slips sub-

2282 General Information Supplement II, JP XVmerged in culture dishes or equivalent containers for one day.Inoculate no less than 1 mL of the test sample (cell culture supernatant)into two or more of the culture dishes.The test should include a negative (non-infected) control andtwo positive mycoplasma controls, such as M. hyorhinis(ATCC29052, ATCC17981 or equivalent species or strains) andM. orale (ATCC23714 or equivalent species or strains). Use aninoculum of 100 CFU or 100 CCU or less for the positive controls.Incubate the cell cultures for 3 to 6 days at 36 ± 1ºC in an atmosphereof air containing 5 percent carbon dioxide.Examine the cell cultures after fixation for the presence ofmycoplasma by epifluorescence microscopy (400 to 600 timesmagnification or greater) using a DNA-binding fluorochrome,such as bisbenzimidazole or an equivalent stain. Compare themicroscopical appearance of the test cultures with that of thenegative and positive controls.Procedure1) Aseptically place a sterilized glass cover slip into eachcell culture dish (35 mm diameter).2) Prepare Vero cell suspension in Eagle’s minimum essentialmedium containing 10 percent bovine calf serum at a concentrationof 1 × 10 4 cells per 1 mL. The bovine calf serumshould be tested and confirmed to be free from mycoplasmaprior to use.3) Inoculate aliquots of 2 mL of the Vero cell suspensioninto each culture dish. Ensure that the cover slips are completelysubmerged, and not floating on the surface of the culture medium.Incubate the cultures at 36 ± 1ºC in an atmosphere of aircontaining 5 percent carbon dioxide for one day, so that the cellsare attached to the glass cover slip.4) Replace 2 mL of the culture medium with fresh medium,then add 0.5 mL of the test sample (cell culture supernatant) toeach of two or more culture dishes. Perform the same procedurefor the positive (2 types of mycoplasma, such as M. hyorhinis(ATCC29052, ATCC17981 or equivalent species or strains) andM. orale (ATCC23714 or equivalent species or strains)) andnegative controls.5) Incubate the cultures for 3 to 6 days at 36 ± 1ºC in anatmosphere of air containing 5 percent carbon dioxide.6) Remove the culture medium from the culture dishes, andadd 2 mL of a mixture of acetic acid (100) and methanol (1:3)(fixative) to each dish; then, allow them to stand for 5 minutes.7) Remove the fixative from each dish, then add the sameamount of fixative again, and leave the dishes to stand for 10minutes.8) Remove the fixative and then completely air-dry all thedishes.9) Add 2 mL of bisbenzamide fluorochrome staining solutionto each culture dish. Cover the dishes and let them stand atroom temperature for 30 minutes.10) Aspirate the staining solution and rinse each dish with 2mL of distilled water 3 times. Take out the glass cover slips anddry them.11) Mount each cover slip with a drop of a mounting fluid.Blot off surplus mounting fluid from the edges of the coverslips.12) Examine by epifluorescence microscopy at 400 to 600times magnification or greater.13) Compare the microscopic appearance of the test samplewith that of the negative and positive controls.14) The test result is judged to be positive if there are morethan 5 cells per 1000 (0.5%) that have minute fluorescent spotsthat appear to surround, but are outside, the cell nucleus.C. Polymerase Chain Reaction (PCR) Detection MethodThe PCR method is a highly specific method that enables thedetection of trace amounts of mycoplasma DNA, and has cometo be widely used in recent years as a means of detecting mycoplasmacontamination. However, the sensitivity and specificitydepend on the procedure employed, and a positive resultfrom PCR does not always indicate the presence of viable mycoplasma.The PCR method is based on amplifying DNA extracted fromthe cell culture with specific primers so that the presence of thetarget DNA is detected. A two-step PCR (nested PCR) is recommendedin order to increase sensitivity and specificity. Thetests should include both a positive control (such as M. hyorhinis(ATCC29052, ATCC17981 or equivalent species orstrains) of 100 CFU or 100 CCU or less) and a negative control.Mycoplasma DNA from the sample of cells or cell cultures isamplified using primers which should be able to amplify somecommon conserved mycoplasma DNA sequence. The amplificationshould be performed using an appropriate heat-resistantDNA polymerase, and suitable conditions. The amplified DNAcan be identified after agarose gel electrophoresis, followed byethidium bromide staining and UV irradiation of the gel.For this method, it is important to use primers that are specificto mycoplasma by choosing base sequences that arewell-conserved for a wide range of mycoplasma species, forexample, the spacer region between the 16S-23S ribosomegenes.It is recommended that a two-step PCR using nested primersshould be performed to increase the sensitivity and specificity, ifthe one-step PCR is negative.The primers to be selected for the second stage of a two-stepPCR are nested primers from the inner portion of the sequence.The outer and inner primers should have proven effectivenessand specificity as described in publications or be validated experimentally.It is possible to increase the accuracy of the detection of mycoplasmaDNA by performing PCR tests after cultivation ofmycoplasma that may be present in samples using Vero cells.The following is an example of a two-step PCR procedure.The reagents and reaction conditions in this example are not exclusive.If the suitability of other reagents and conditions isverified, they may be used. If another procedure is used, theprocedure should be justified and documented in detail, and theinformation provided should include the sensitivity and specificityof the method.Example Procedure1. Preparation of template1) Place 600 µL of the test cell suspension (if necessary,subcultured with Vero cells) in a tube and dissolve the cells with

Supplement II, JP XV General Information 22830.1% SDS or an equivalent. Add an equal volume (600 µL) ofTE (10 mmol/L tris-hydrochloric acid (pH 8.0), 1 mmol/LEDTA) buffer-saturated phenol, and mix.2) Centrifuge at 15,000 min -1 for 5 minutes at roomtemperature.3) Transfer 400 µL of the supernatant to another tube, andadd 10 µL of 3 mol/L sodium acetate.4) Add 1 mL (2.5 volumes) of ethanol (95) and stir thoroughly.Ice the mixture for 15 minutes, then centrifuge at 15,000min -1 for 10 minutes at 4ºC.5) Discard the supernatant and rinse the precipitate once ortwice with 200 to 300 µL of 80% ethanol. Remove the rinse solutionusing a pipet. Centrifuge at 15,000 min -1 for 10 minutes at4ºC, then remove the supernatant thoroughly and dry up theprecipitate.6) Dissolve the precipitate in 40 µL of distilled water.2. Perform the same procedure for the positive and negativecontrols3. First stage of a two-step PCR1) Make a mixture of the heat-resistant DNA polymerase,dNTP solution, outer primer, and reaction buffer solution (includingMg ions), and place 90 µL in each tube.2) Add 10 µL of the template prepared as above to eachtube containing the first stage PCR solution (90 µL).3) Perform the DNA amplification by repeating 30 cycles ofdenaturation at 94ºC for 30 seconds, annealing at an appropriatetemperature for the primer (55ºC for the primer in this example),and elongation at 72ºC for 2 minutes.4. Second stage of a two-step PCR1) Make a mixture of the heat-resistant DNA polymerase,dNTP solution, inner primer, and reaction buffer solution (includingMg ions), and place 99 µL in each tube.2) Add 1 µL of the first stage PCR product from each tubeto a tube containing the second stage PCR solution (99 µL).3) Perform the DNA amplification by repeating 30 cycles ofdenaturation at 94ºC for 30 seconds, annealing at an appropriatetemperature for the primer (55ºC for the primer in this example),and elongation at 72ºC for 2 minutes.5. Agarose gel electrophoresis1) Mix 10 µL of each of the first stage and second stagePCR products with 2 µL of an appropriate dye as a migrationmarker, and perform 1% agarose gel electrophoresis.2) Stain the gel with ethidium bromide and take a photographunder UV irradiation.3) The test is judged to be positive if a DNA band is detected.[An Example of Primer]For mycoplasma detectionOuter primerF1:5´-ACACCATGGGAG(C/T)TGGTAAT-3´R1:5´-CTTC(A/T)TCGACTT(C/T)CAGACCCAAGG-CAT-3´Inner primerF2:5´-GTG(G/C)GG(A/C)TGGATCACCTCCT-3´R2:5´-GCATCCACCA(A/T)A(A/T)AC(C/T)CTT-3´( ) indicates a mixture.[PCR reaction solution] [First stage] [Second stage]dNTP solution (1.25 mol each) 16 µL 16 µLPrimer (10 pmol/µL) F1 2 µL F2 2 µLPrimer (10 pmol/µL) R1 2 µL R2 2 µLHeat-resistant DNA polymerase (1 U/µL) 2 µL 2 µLReaction buffer solution25 mmol/L magnesium chloride hexahydrate 8 µL 8 µL10-fold buffer solution* 10 µL 10 µLSterile distilled water 50 µL 59 µL*Composition of 10-fold buffer solution2-amino-2-hydroxymethyl-1,3-propanediolhydrochloricacid (pH 8.4)100 mmol/LPotassium chloride500 mmol/LMagnesium chloride hexahydrate 20 mmol/LGelatin0.1 g/L[Method of cultivating mycoplasma within Vero cells]1) Use at least two cell culture dishes for each of the testsample, positive control and negative control.2) Into each cell culture dish (35 mm diameter), inoculate 2mL of the Vero cell suspension (1 × 10 4 cells per 1 mL) in Eagle’sminimum essential medium containing 10 percent bovinecalf serum (tested in advance using the PCR method to verifythat it does not contain any detectable mycoplasma DNA). Incubatethe cultures at 36 ± 1ºC in an atmosphere of air containing5 percent carbon dioxide for one day.3) Replace the culture media with fresh media, and add 0.5mL of the test sample (cell culture supernatant) to each of two ormore Vero cell culture dishes. Perform the same procedure forthe positive (such as 100 CFU or 100 CCU or less of M. hyorhinis(ATCC29052, ATCC17981 or equivalent species orstrains)) and negative controls.4) Incubate the Vero cell culture dishes for the test sample,positive and negative controls for 3 to 6 days at 36 ± 1ºC in anatmosphere of air containing 5 percent carbon dioxide.

2284 General Information Supplement II, JP XVAdd the following:32. Near Infrared SpectrometryNear infrared spectrometry (NIR) is one of spectroscopicmethods used to qualitatively and quantitatively evaluate substancesfrom analysis of data obtained by determining their absorptionspectrum of light in the near-infrared range.The near-infrared range lies between the visible light and infraredlight, typically of wavelengths (wave numbers) between750 and 2500 nm (13333 – 4000 cm -1 ). The absorption ofnear-infrared light occurs due to harmonic overtones from normalvibration or combination tones in the infrared range (4000to 400 cm -1 ), primarily absorption of O-H, N-H, C-H and S-Hthat involve hydrogen atoms, in particular. For instance theasymmetrical stretching vibration of N-H occurs in the vicinityof 3400 cm -1 , but the absorption due to the first harmonic overtoneoccurs in the vicinity of 6600 cm -1 (wavelength 1515 nm),which is near double 3400 cm -1 .Absorption in the near-infrared range is far weaker than absorptiondue to normal vibration that occurs in the infraredrange. Furthermore, in comparison with visible light,near-infrared light has longer wavelength, which makes it possiblefor the light to penetrate to a depth of several mm intosolid specimens, including fine particles. This method is oftenutilized as a nondestructive analysis, as changes occurring withabsorbed light spectrum (transmitted light or reflected light) inthis process provide physical and chemical information pertainingto specimens.Conventional spectrometry, such as calibration curve method,is used as a method for analyzing near-infrared absorption spectrumwhenever applicable. Ordinarily, however, chemometricsmethods are used for analysis. Chemometrics ordinarily involvequantification of chemical data, as well as numerical and statisticalprocedures for computerization of information. Chemometricsfor near-infrared spectrometry includes various types ofmultivariate analysis such as multiple regression analysis, toperform qualitative or quantitative evaluation of active substances.Near-infrared spectrometry is used as a rapid and nondestructivemethod of analysis that replaces conventional and establishedanalysis methods for water determinations or substanceverifications. It is necessary to perform a comparison test toevaluate this method against an existing analysis method, toverify that this method is equivalent to such existing analysismethod, before using this analysis method as a quality evaluationtest method in routine tests.Applications of near-infrared spectrometry in the pharmaceuticalfield include qualitative or quantitative evaluation of ingredients,additives or water contents of active substances orpreparations. Furthermore, near-infrared spectrometry can alsobe used for evaluation of physical conditions of substances, suchas crystal forms, crystallinity, particle diameters. It is also possibleto perform spectrometry on samples that are located in aremote location away from equipment main units, without sampling,by using optical fibers. It can therefore be used as an effectivemeans to perform pharmaceutical manufacturing processcontrol online.1. EquipmentNear-infrared spectrophotometers can either be a distributednear-infrared spectrophotometer or a Fourier transformnear-infrared spectrophotometer 1) . Interference filter-typenear-infrared spectrophotometers that use interference filter inthe spectrometry section are also available, however, this typeof equipment is hardly used in the field of pharmaceutical qualitycontrol.1.1 Distributed near-infrared spectrophotometerThis equipment is comprised of light source section, samplesection, spectrometry section, photometry section, signal processingsection, data processing section, display-record-outputsection. Halogen lamps, tungsten lamps, light emitting diodesand other such devices that can emit high intensity near-infraredlight in a stable manner are used in the light source section. Thesample section is comprised of a sample cell and a sampleholder. Equipment that have an optical fiber section that iscomprised of optical fibers and a collimator are equipped with afunction for transmitting light to sample section, which is remotelylocated away from the spectrophotometer main unit.Quartz is ordinarily used as material for optical fibers.The spectrometry section is intended to extract light of requiredwavelength, using dispersive devices and is comprised ofslits, mirrors and dispersive devices. Potential dispersive devicesinclude prisms, diffraction grating, acousto-optical tunablefilters (AOTF), or liquid crystal tunable filters (LCTF).The photometry section is comprised of detectors and amplifiers.Sensors include semiconductor detectors (silicon, lead sulfide,indium-gallium-arsenic, indium-antimony), as well asphotomultiplier tubes. Detecting methods that use semiconductordetectors generally perform detections with single elements,but there are also occasions where array-type detectors that usemultiple elements are used. Such detectors are capable of simultaneouslydetecting multiple wavelengths (wave numbers).The signal processing section separates signals required formeasurements from output signals fed by amplifiers and thenoutputs such isolated signals. The data processing section performsdata conversions and spectral analysis, etc. The display-record-outputsection outputs data, analysis results and dataprocessing results to a printer.1.2 Fourier transform near-infrared spectrophotometerThe configuration of the equipment is fundamentally same asthat of the distributed-type equipment described in Section 1.1,except for the spectrometry section and the signal processingsection.The spectrometry section is comprised of interferometers,sampling signal generators, detectors, amplifiers, A/D conversiondevices, etc. Interferometers include Michelson interferometers,transept interferometers and polarization interferometers.The signal processing section is equipped with functionsthat are required for spectrometer, as well as a function fortranslating acquired interference waveform (interferogram) intoabsorption spectrum by Fourier transformation.

Supplement II, JP XV General Information 22852. DeterminationThere are three types of measurement methods that are usedwith near-infrared spectrometry: transmittance method, diffusereflectance method and transmittance reflectance method. Theselection of measurement methods relies on the shape of samplesand applications. The transmittance method or diffuse reflectancemethod is used for solid samples, including fine particles.The transmittance method or transmittance reflectancemethod is used for liquid samples.2.1 Transmittance methodThe degree of decay for incident light intensity as the lightfrom a light source passes through a sample, is represented astransmittance rate T (%) or absorbance A with the transmittancemethod.A sample is placed in the light path between a light source and adetector, the arrangement of which is ordinarily same as that ofthe spectroscopic method.T = 100 tT = I / I 0 = 10 -αclI 0 : Incident light intensityI: Transmitted light intensityα: Absorptivityc: Solution concentrationl: Layer length (sample thickness)A = -log t = log (1 / t) = log (I 0 / I) = αclThis method is applied for taking measurements of samplesthat are liquids and solutions. Quartz glass cells and flow cellsare used, with the layer length of 1 – 5 mm along. Furthermore,this method can also be applied for taking measurements ofsamples that are solids, including fine particles. It is also knownas diffuse transmittance method. Selecting appropriate layerlength is critical for this method, since the transmitted light intensityvaries depending on grain sizes and surface conditions ofsamples.2.2 Diffuse reflectance methodThe ratio of the reflection light intensity I, emitted from thesample in a wide reflectance range and a control reflection lightintensity I r emitted from surface of a substance, is expressed asreflectance R (%) with the diffuse reflectance method. Thenear-infrared light penetrates to a depth of several mm into solidsamples, including fine particles. In that process, transmission,refraction, reflection and dispersion are repeated, and diffusiontakes place, but a portion of the diffused light is emitted againfrom the surface of the sample and captured by a detector. Thespectrum for the diffuse reflectance absorbance (A r ) can ordinarilybe obtained by plotting logarithm of inverse numbers for reflectance(1/r) against wavelengths (wave numbers).R = 100 rr= I / I rI: Reflection light intensity of light, diffuse reflected off thesampleI r : Control reflection light intensity of light emitted from surfaceof reference substanceA r = log (1 / r) = log (I r / I)The intensity of diffuse reflectance spectrum can also be expressedwith the Kubelka-Munk (K-M) function. The K-Mfunction is derived, based on the existence of a sample with sufficientthickness, and expressed in terms of light scattering coefficient,which is determined by absorptivity, grain size, shapeand fill condition (compression).This method is applied to solid samples, including fine particles,and requires a diffuse reflector.2.3 Transmittance reflectance methodThe transmittance reflectance method is a combination of thetransmittance method and reflectance method. A mirror is usedto re-reflect a light that has passed through a sample in order totake a measurement of transmittance reflectance rate, T* (%).Light path must be twice the thickness of the sample. On theother hand, the light reflected off a mirror and enters into a detectoris used as the control light. When this method is appliedto suspended samples, however, a metal plate or a ceramic reflectorwith rough surface that causes diffuse reflectance is usedinstead of a mirror.Transmittance reflectance absorbance (A*) is obtained by thefollowing formula with this method:T * = 100 t *t * = I / I TI: Intensity of transmitted and reflected light, in cases wherea sample is placedl T : Intensity of reflected light, in cases where is no sampleA * = log (1 / t * )This is a method that is applied to solid samples, includingfine particles, as well as liquids and suspended samples. Thethickness of a sample must be adjusted when applying thismethod to a solid sample. Ordinarily adjustment is made by settingabsorbance to 0.1 – 2 (transmittance of 79 – 1%), whichprovides the best linearity and S/N ratio of detector. A cell withappropriate layer length, according to the grain size of the fineparticle, must be selected when applying the method to a fineparticle sample.3. Factors that affect spectrumFollowing items must be considered as factors that can affectspectrum when applying near-infrared spectrometry, particularlywhen conducting quantitative analysis.3.1 Sample temperatureA significant change (wavelength shift, for example) can occurwhen the temperature varies by a several degree (°C). Caremust be taken, particularly when the sample is a solution orcontains water.3.2 Water or residual solventWater or residual solvent contents of a sample, as well aswater (humidity) in the environment wherein measurements aretaken, can potentially significantly affect absorption band of thenear-infrared range.3.3 Sample thicknessThe thickness of a sample is a factor for spectral changes and

2286 General Information Supplement II, JP XVtherefore needs to be controlled at a certain thickness. A samplemay be considered to be of adequate thickness for the diffusereflectance method, however, if the thickness is less than a certainamount, for example, the sample may have to be placed ona support plate with high reflectance to take measurements bythe transmittance reflectance method.3.4 Fill condition of sampleThe condition of sample fill can potentially affect spectrum,when taking measurements of samples that are solids or fineparticles. Care must be taken when filling samples in a cell, toensure that a certain amount is filled through a specific procedure.3.5 Optical characteristics of samplesWhen a sample is physically, chemically or optically uneven,relatively large beam size must be used, multiple samples mustbe used, measurements must be taken at multiple points on thesame sample, or a sample must be pulverized to ensure averagingof the sample. Grain size, fill condition, as well as roughnessof surface can also affect fine particle samples.3.6 Crystal formsVariations in crystal structures (crystal forms) can also affectspectrumIn cases where multiple crystal forms exist, it is necessary tohave consideration for characteristics of samples to be consideredand care must be taken to ensure that even standard samplesfor calibration curve method have diversified distributionssimilar to that of samples that are subject to analysis.3.7 Temporal changes in characteristics of samplesSamples can potentially undergo chemical, physical or opticalproperty changes, due to passing of time or storage after sampling,and such changes affect spectrum in a subtle manner. Forinstance even with identical samples, if elapsed times differ,then their characteristics of near-infrared spectrum can vary significantly.In creating calibration curves, therefore, measurementsmust be taken offline in a laboratory or online in manufacturingprocess (or inline) and samples for calibration curvesmust be prepared with adequate considerations for the passingof time before measurements are taken.2, 3)4 Control of equipment performance4.1 Accuracy of wavelengths (wave numbers)The accuracy of wavelengths (wave numbers) of an equipmentis derived from the deviation of substances for which peakabsorption wavelengths (wave numbers) have been defined,such as polystyrene, mixture of rare earth oxides (dysprosium,holmium and erbium; 1:1:1) or steam, from the figures indicatedon the equipment. Tolerance figures in the vicinity of 3 peaksare ordinarily set in the following manner:1200 ± 1 nm (8300 ± 8 cm -1 )1600 ± 1 nm (6250 ± 4 cm -1 )2000 ± 1.5 nm (5000 ± 4 cm -1 )Since the location of absorption peaks vary, depending on thesubstance used as reference, absorption peaks of wavelengths(wave numbers) that are closest to the above 3 peaks are selectedfor suitability evaluations. A mixture of rare earth oxides,for instance, would indicate characteristic absorption peaks at1261 nm, 1681 nm and 1971 nm.Absorption peaks at 1155 nm, 1417 nm, 1649 nm, 2352 nm(layer length: 1.0 mm) can be used, when taking measurementswith transmittance method that involve the use of dichloromethaneas reference. The absorption peak of steam at 7306.7cm -1 can be used with a Fourier transformation-type spectrophotometer,as its wave number resolution ability is high.Other substances can also be used as reference, so long astheir adequacy for the purpose can be verified.4.2 Spectroscopic linearityAppropriate standard plates, such as plate-shaped polymerimpregnated with varying concentrations of carbon (carbon-dopedpolymer standards), can be used to evaluate spectroscopiclinearity. In order to verify linearity, however, standardplates with no less than 4 levels of concentration within the reflectanceof 10 – 90% must be used. When measurements areexpected to be taken with absorbance of no less than 1.0, it isnecessary to add standard plates with reflectance of either 2% or5% or both.In order to plot absorbance (A OBS ) of such standard plates atlocations in the vicinity of wavelengths 1200 nm, 1600 nm and2000 nm against absorbance (A REF ) assigned to each standardplate, verifications must be made to ensure that the gradient oflinearity obtained are within the range 1.0±0.05 for each ofthese wavelengths and 0±0.05 for ordinate intercept.4.3 Spectrophotometric noiseThe spectrophotometric noise of the equipment can bechecked using appropriate reflectance standard plates, such aswhite-colored reflecting ceramic tiles or reflective thermoplasticresin (such as polytetrafluoroethylene).4.3.1 High flux noiseSpectrophotometric noise is evaluated by using standardplates with high reflectance, such as reflectance of 99%. Standardplates are used to take measurements for both samples andcontrol samples. The average value obtained from calculation ofmean square root (RMS) of noise for each 100 nm segments inthe wavelength range of 1200 – 2200 nm must not be more than0.3 x 10 -3 and individual values must not exceed 0.8 x 10 -3 .RMS = {1 / N • Σ (A i - A m ) 2 } 1 / 2N: Number of measurement points per segmentA i : Absorbance at each measurement point of segmentA m : Average absorbance for segment4.3.2 Low flux noiseSpectrophotometric noise is evaluated by using standardplates with low reflectance, such as reflectance of 10%, whenthe amount of light is low. In such cases, light source, opticalsystem, detector and electronic circuit systems all have someimpact on noise. Similar to the cases of high flux noise, the averagevalue obtained from calculation of RMS for each 100 nmsegments in the wavelength range of 1200 – 2200 nm must notbe more than 1.0 x 10 -3 and individual values must not exceed2.0 x 10 -3 .5. Application to qualitative or quantitative analysisUnlike in the infrared range, mainly harmonic overtones andcombinations manifest as spectrum in the near-infrared range.Such absorbance spectrums are often observed as overlay of

Supplement II, JP XV General Information 2287absorption bands of functional groups and atomic groups. Thenear-infrared spectrometry, therefore, differs from conventionalanalysis methods and it is usually necessary to establish analysismethods that correspond to each application, by preparingmodel analysis methods using methodologies of chemometrics,such as multivariate analysis.Characteristics of near-infrared absorption spectrum must beemphasized and effects of complexities of spectrums, as well asoverlay of absorption bands must be reduced by performingmathematical preprocesses, such as primary or secondary spectraldifferentiation processes or normalizations, which becomesone of vital procedures in establishing analysis methods that usemethodologies of chemometrics. While there are manychemometrics methodologies and mathematical preprocessingmethods for data, appropriate combinations must be selectedthat suit the purposes of intended analysis.Evaluation of validity based on analysis parameters is ordinarilyrequired for the analysis validation when establishing anear-infrared analysis method. Selection of parameters that areappropriate for applications must be made for its intended use.Furthermore, following issues must be considered, in conformitywith attributes of the near-infrared spectrometry.(i) Whether or not wavelengths (wave numbers) intendedfor the particular analysis method, are suitable for evaluation ofcharacteristics of a sample in performing analysis under givenconditions.(ii) Whether or not the method is adequately robust to dealwith variables such as handling of samples (for instance fillcondition for fine particle samples, etc.) and configuration matrix.(iii) Whether or not about the same level of accuracy orprecision can be obtained, in comparison with the existing andestablished analysis methods, which are available as standards.(iv) Sustaining and managing performance of an analysismethod, once established, are critical. Continuous and systematicmaintenance and inspection work must therefore be implemented.Furthermore, it must be determined whether or not appropriateevaluation procedures are available to deal withchange controls or implementation of re-validation on changesmade in manufacturing processes or raw materials, as well aschanges arising from replacement of major components inequipment.(v) Whether or not there are appropriate evaluation proceduresin place to verify validity of transferring implementationof an analysis, which presupposes the use of a specific equipment,from such originally intended equipment to anotherequipment (model transfer) for the purpose of sharing the analysismethod.5.1 Qualitative analysisQualitative analysis, such as verification of substances, isperformed after preparing a reference library that includes inter-lotvariations within tolerance range and chemometricsmethodologies, such as multivariate analysis, have been established.Minute quality characteristic variations between lots canalso be estimated by using this method.Furthermore, multivariate analysis includes direct analysismethods that consider wavelengths (wave numbers) and absorptionsas variables, such as wavelength correlation method, residualsum of squares, range sum of squares, along with factoranalysis method, cluster analysis method, discriminant analysismethod, as well as SIMCA (soft independent modeling of classanalogy).It is also possible to consider the overall near-infrared absorptionspectrum as a single pattern and to identify parameters obtainedby applying multivariate analysis methods or characteristicwavelength (wave number) peaks of the sample substance asindices for monitoring, for the purpose of manufacturing processcontrol for active substances or preparations.5.2 Quantitative analysisQuantitative analysis uses spectrums of sample groups andanalysis values obtained through the existing and establishedanalysis methods, to obtain quantitative models with methodologiesof chemometrics. These are used to calculate concentrationsof individual ingredients and material values of samplesbeing measured, using conversion formulas. Chemometricsmethodologies for obtaining quantitative models include multipleregression analysis method, main ingredient regressionanalysis method and PLS (partial least squares) regressionanalysis method.In cases where the composition of a sample is simple, concentrationsof ingredients in the sample that are subject toanalysis can be calculated, by plotting a calibration curve usingthe absorbance of a specific wavelength (wave number) or thecorrelating relationship between the parameters and concentration,using samples for preparation of calibration curves withknown concentrations (calibration curve method).Reference1) General Rules for Near-infrared SpectrophotometricAnalysis, JIS K 0134 (2002), Japanese Industrial Standards2) Near-infrared Spectrophotometry, 2.2.40, European Pharmacopoeia5.0 (2005)3) Near-infrared Spectrophotometry, , US Pharmacopoeia30 (2007)Add the following:33. Rapid counting of microbesusing fluorescent stainingThis chapter provides rapid methods using fluorescencestaining for the quantitative estimation of viable microorganisms.Incubation on an agar medium has been widely used forquantitative estimation of viable microorganisms, but a numberof environmental microorganisms of interest are not easy togrow in culture under usual conditions, thus new microbial detectionmethods based on fluorescence or luminescence havebeen developed. In the fluorescence staining method, microorganismsare stained with fluorescent dye, and can easily be detectedand counted with various sorts of apparatus, such as afluorescence microscope or flow cytometer. Methods are availableto detect total microorganisms, including both dead andviable cells, or to detect only cells with a specified bioactivity

2288 General Information Supplement II, JP XVby choosing the dye reagent appropriately. Nucleic acid stainingreagents, which bind with DNA or RNA, detect all cells containingnucleic acids, whether they are live or dead. This techniqueis the most fundamental for the fluorescence stainingmethod. On the other hand, fluorescent vital staining methodstarget the respiratory activity of the microorganism and the activityof esterase, which is present universally in microorganisms.In the microcolony method, microcolonies in the earlystage of colony formation are counted. The CFDADAPI doublestaining method and the microcolony method are described below.These methods can give higher counts than the other techniques,because these rapid and accurate techniques providequantitative estimation of viable microorganisms based on avery specific definition of viability, which may be differentfrom that implicit in other methods. The procedures of thesemethods described here may be changed as experience with themethods is accumulated. Therefore, other reagents, instrumentsand apparatus than those described here may also be used ifthere is a valid reason for so doing.1. CFDADAPI double staining methodFluorescein diacetate (FDA) reagents are generally used forthe detection of microorganisms possessing esterase activity.These reagents are hydrolyzed by intracellular esterase, and thehydrolyzed dye exhibits green fluorescence under blue excitationlight (about 490 nm). Modified FDAs such as carboxyfluoresceindiacetate (CFDA) are used because of the low stainabilityof gramnegative bacteria with FDA. The principle of theCFDADAPI double staining method, which also employs a nucleicacid staining reagent, 4´,6-diamidino-2-phenylindole(DAPI), is as follows.The nonpolar CFDA penetrates into the cells and is hydrolyzedto fluorescent carboxyfluorescein by intracellular esterase.The carboxyfluorescein is accumulated in the living cells due toits polarity, and therefore green fluorescence due to carboxyfluoresceinoccurs when cells possessing esterase activity areilluminated with blue excitation light. No fluorescent carboxyfluoresceinis produced with dead cells, since they are unable tohydrolyze CFDA. On the other hand, DAPI binds preferentiallyto the adenine and thymine of DNA after penetration into bothviable and dead microorganisms, and consequently all of theorganisms containing DNA exhibit blue fluorescence under ultravioletexcitation light. Therefore, this double staining methodenables to count specifically only live microorganisms possessingesterase activity under blue excitation light, and also to determinethe total microbial count (viable and dead microorganisms)under ultraviolet excitation light.1.1 Apparatus1.1.1 Fluorescence microscope or fluorescence observationapparatus . Various types of apparatus for counting fluorescencestainedmicroorganisms are available. Appropriate filtersare provided, depending on the fluorescent dye reagents used. Afluorescence microscope, laser microscope, flow cytometer, andvarious other types of apparatus may be used for fluorescenceobservation.1.2 Instruments(i) Filtering equipment (funnels, suction flasks, suctionpumps)(ii) Membrane filters (poresize: 0.2 µm); A suitable filter thatcan trap particles on the surface can be used such as polycarbonatefilter, alumina filter, etc.(iii) Glass slide(iv) Cover glass(v) Ocular micrometer for counting (with 10 x 10 grids)1.3 ProcedureAn example of the procedure using fluorescence microscope isdescribed below.1.3.1 Preparation of samplesPrepare samples by ensuring that microbes are dispersed evenlyin the liquid (water or buffer solution).1.3.2 FiltrationSet a membrane filter (poresize: 0.2 µm) on the funnel of thefiltering equipment. Filter an appropriate amount of sample totrap microbes in the sample on the filter.1.3.3 StainingPour sufficient amount of buffer solution for CFDA staining,mixed to provide final concentration of 150 µg/mL of CFDAand 1 µg/mL of DAPI, into the funnel of the filtering equipmentand allow staining in room temperature for 3 minutes, then filterthe liquid by suction. Pour in sufficient amount of aseptic water,suction filter and remove excess fluorescent reagent left on thefilter. Thoroughly dry the filter.1.3.4 Slide preparationPut one drop of immersion oil for fluorescence microscope onthe glass slide. Place the air dried filter over it, with the filteringside on the top. Then put one drop of immersion oil for fluorescencemicroscope on the surface of the filter, place a cover glass.Put another drop of immersion oil for fluorescence microscopeon the cover glass when using an oilimmersion objective lens.1.3.5 CountingObserve and count under fluorescence microscope, with 1000magnification. In case of CFDADAPI double staining method,count the microorganisms (with esterase activity) exhibitinggreen fluorescence under the blue excitation light first to avoidcolor fading by the ultraviolet light, then count the microorganisms(with DNA) exhibiting blue fluorescence under the ultravioletexcitation light in the same microscopic field. Count theorganisms exhibiting fluorescence on more than 20 randomlyselected fields among 100 grids observed through an ocular micrometerof the microscope, and calculate the total number oforganisms using the following formula. The area of the microscopicfield should be previously determined with the ocularand objective micrometers. The amount of the sample to be filteredmust be adjusted so that the cell number per field is between10 and 100. It might be necessary to reprepare the samplein certain instances. (In such case that the average count numberis not more than 2 organisms per field, or where more than 5fields are found which have no organism per field, it is assumedthat the microorganism count is below the detection limit.).Number of microbes (cells/mL)= {(average number of microbes per visual field) x (area offiltration)} / {( amount (mL) of sample filtered) x ( area ofone microscopic field)}1.4 Reagents and test solutions

Supplement II, JP XV General Information 2289(i) Aseptic waterFilter water through a membrane filter with 0.2 µm pore size toremove particles, then sterilize it by heating in an autoclave at121ºC for 15 minutes. Water for injection may be used.(ii) CFDA solution, 10 mg/mLDissolve 50 mg of CFDA in dimethylsulfoxide to prepare a 5mL solution. Store at -20°C in light shielded condition.(iii) Buffer solution for CFDA stainingMix 5 g of sodium chloride with 0.5 mL of 0.1 mol/L ethylenediaminetetraaceticaciddisodium dihydrogen test solutionand diluted disodium hydrogen phosphate test solution (1 in 3)to prepare 100 mL of solution. Add sodium dihydrogen phosphatedihydrate solution (1 in 64) to adjust the pH level to 8.5.Filter the solution through a membrane filter with a pore size of0.2 µm.(iv) DAPI solution, 10 µg/mLDissolve 10 gm of DAPI in 100 mL of aseptic water. Dilutethis solution 10 times with aseptic water and filter through amembrane filter with a pore size of 0.2 µm. Store at 4°C in lightshielded condition.(v) Immersion oil for fluorescence microscope2. Microcolony methodMicrocolonies, which are in early stages of colony formation,are fluorescently stained, then observed and counted underfluorescence microscope or other suitable systems. This methodenables to count the number of proliferative microorganisms,with short incubation time. In this method, the organisms aretrapped on a membrane filter, the filter is incubated on a mediumfor a short time, and the microcolonies are counted. Bythis method, even colonies which are undetectable with the nakedeye can be identified, so viable organisms can be countedrapidly and with high precision.Various nucleic acid staining reagents can be used for stainingof microcolonies.2.1 Apparatus2.1.1 Fluorescence microscope or fluorescence observationapparatus.Various types of apparatus for counting fluorescencestainedmicroorganisms are available. Appropriate filters are provided,depending on the fluorescence dye reagents used. A fluorescencemicroscope, laser microscope and various other types ofapparatus may be used for fluorescence observation.2.2 Instruments(i) Filtering equipment (funnels, suction flasks, suctionpumps)(ii) Membrane filters (pore size: 0.2 µm); A suitable filter thatcan trap particles on the surface can be used such as polycarbonatefilter, alumina filter, etc.(iii) Glass slide(iv) Cover glass(v) Filter paper (No. 2)(vi) Ocular micrometer for counting (with 10 x 10 grids)2.3 ProcedureAn example of the procedure using a fluorescence microscopeis described below.2.3.1 Preparation of samplesPrepare samples by ensuring that microbes are dispersed evenlyin the liquid (water or buffer solution).2.3.2 FiltrationSet a membrane filter (pore size: 0.2 µm)on the funnel of thefiltering equipment. Filter an appropriate amount of sample totrap microbes in the sample on the filter.2.3.3 IncubationRemove the filter from the filtering equipment and place itwith filtering side facing up on a culture medium avoiding formationof airbubbles between the filter and the medium. Incubateat a suitable temperature for appropriate hours in a darkplace. It should be noted that the appropriate incubation conditions(such as medium, incubation temperature and/or incubationtime) are different, depending on the sample.2.3.4 FixationSoak filter paper with an appropriate amount of neutral bufferedformaldehyde test solution, then place the filter that hasbeen removed from the culture medium on top with filteringside up, and allow to remain at room temperature for more than30 minutes to fix the microcolonies.2.3.5 StainingSoak filter paper with an appropriate amount of staining solution(such as1 µg/mL of DAPI, 2% polyoxyethylenesorbitanmonolaurate), then place the filter on top with filtering side up,and then leave at room temperature, light shielded for 10 minutesto stain microcolonies. Wash the filter by placing it with thefiltering side facing up on top of a filter paper soaked with asepticwater for 1 minute. Thoroughly air dry the filter.2.3.6 Slide preparationPut one drop of immersion oil for fluorescence microscope onthe slide glass. Place an air dried filter over it, with the filteringside on the top. Then, put one drop of immersion oil for fluorescencemicroscope on top, place a cover glass.2.3.7 CountingCount the organisms exhibiting fluorescence on more than 20randomly selected fields among the 100 grids observed throughan ocular micrometer of the microscope, and calculate the totalnumber of organisms using the following formula. The area ofthe microscopic field should be previously determined with theocular and objective micrometers.(In such case that the average count number is not more than 2microcolonies per field, or where more than 5 fields are foundwhich have no microcolony per field, it is assumed that the microorganismcount is below the detection limit.).Number of microcolonies (cells/mL)= {(average number of microcolonies per visual field) x (areaof filtration)} / {( amount (mL) of sample filtered) x (area ofone microscopic field)}2.4 Reagents and test solutions(i) Aseptic waterFilter water through a membrane filter with 0.2 µm pore sizeto remove particles, and sterilize it by heating in an autoclave at121ºC for 15 minutes. Water for injection may be used.(ii) Staining solutionDissolve 10 gm of DAPI in 100 mL of aseptic water. Dilutethe solution 10 times with aseptic water and filter through amembrane filter with pore size of 0.2 µm. Store at 4°C in light

2290 General Information Supplement II, JP XVshielded condition. Dissolve polyoxyethylene sorbitanmonolaurate to the final concentration of 2%, when using.(iii) Neutral buffered formaldehyde solution (4w/v% formaldehydesolution; neutrally buffered).(iv) Immersion oil for fluorescence microscope34. System SuitabilityIn order to ensure the reliability on the results of drug analyses,it is essential to verify that the test method to be applied tothe test, including the method prescribed in the Japanese Pharmacopoeia(JP), can give the results adequate for its intendeduse using the analytical system in the laboratory in which thetest is to be performed, then to carry out system suitability testingfor confirming that the analytical system maintains the statesuitable for the quality test.1. Definition and role of system suitability“System Suitability” is the concept for ensuring that the performanceof the analytical system is as suitable for the analysisof the drug as was at the time when the verification of the testmethod was performed using the system.Usually, system suitability testing should be carried out atevery series of drug analysis. The test procedures and acceptancecriteria of system suitability testing must be prescribed inthe test methods of drugs. The results of drug analyses are notacceptable unless the requirements of system suitability havebeen met.System suitability testing is an integral part of test methodsusing analytical instruments, and based on the concept that theequipments, electronic data processing systems, analytical operations,samples to be analyzed and operators constitute an integralsystem that can be evaluated, when the test proceduresand acceptance criteria of system suitability testing are prescribedin the test methods.2. Points to consider in setting system suitabilityParameters of system suitability testing to be prescribed in thetest method depend on the intended use and type of analyticalmethod. Since system suitability testing is to be carried out in aroutine manner, it is preferable to select the parameters necessaryfor ensuring that the analytical system maintains the statesuitable for the analysis of the drug and to prescribe its test procedureable to carry out easily and rapidly.For example, in the case of quantitative purity tests using liquidchromatography or gas chromatography, the evaluation ofparameters such as “System performance” (to confirm the abilityto analyze target substance specifically), “System repeatability”(to confirm that the degree of variation in the analytical resultsof target substance in replicate injections is within the allowablelimit) and “Test for required detectability” (to confirmthe linearity of chromatographic response around the specificationlimit) are usually required.The followings are supplements to the section of systemsuitability prescribed in “Liquid Chromatography”.(1) Allowable limit of system repeatabilityIt is described in the section of system suitability in “LiquidChromatography” that “In principle, total number of replicateinjections should be 6.”, and “The allowable limit of “Systemrepeatability” should be set at an appropriate level based on thedata when suitability of the method for the evaluation of qualityof the drug was verified, and the precision necessary for thequality test.”Based on the above description, an allowable limit of systemrepeatability for 6 replicate injections should be set in considerationwith the following descriptions. However, in the casethat the test method prescribed in the JP monograph is used forthe test, the allowable limit of system repeatability prescribed inthe monograph should be applied.Assay for drug substance (for drug substance with the contentnearby 100%): An adequate allowable limit should beset at the level that the chromatographic system is able togive the precision suitable for the evaluation of variation inthe content of active ingredient within and among thebatches of drug substance. For example, the allowablelimit of “not more than 1.0%” is usually recommended forthe drug substances whose width of content specificationare not more than 5%, as is in the case of content specificationof 98.0-102.0% which is often observed in the assayusing liquid chromatography.Assay for drug products: An adequate allowable limit shouldbe set considering the width of content specification of thedrug product and the allowable limit prescribed in the assayof drug substance (when the drug product is analyzedby a method with the same chromatographic conditions asthose used for the analysis of drug substance).Purity test for related substances: An adequate allowablelimit should be set considering the concentration of activeingredients in the solution used for the system suitabilitytesting. In the case that a solution with active ingredientconcentration of 0.5-1.0% is used for the test of systemrepeatability, an allowable limit of “not more than 2.0%” isusually recommended.Recommendations for allowable limits described aboveshould not be applicable to gas chromatography.(2) Method for decreasing the number of replicate injectionswithout losing the quality of system repeatability testingIt is described in the section of system suitability in “LiquidChromatography” that “In principle, total number of replicateinjections should be 6. However, in the case that a long time isnecessary for one analysis, such as the analysis using the gradientmethod, or the analysis of samples containing late elutingcomponents, it may be acceptable to decrease the number ofreplicate injections by adopting new allowable limit of “Systemrepeatability” which can guarantee a level of “System repeatability”equivalent to that at 6 replicate injections.”In consideration of the above description, a method for decreasingthe number of replicate injections without losing the

Supplement II, JP XV General Information 2291quality of system repeatability testing is adopted. One can setthe test for system repeatability with reduced number of replicateinjections by utilizing this method, if necessary, and canalso apply it as an alternative for the method prescribed in amonograph.The following table shows the allowable limits to be attainedin the test at 3-5 replicate injections (n=3-5) to keep the qualityof test equivalent to that of test at n=6.However, it should be kept in mind that since decrease in thenumber of replicate injections results in increase in the weightof each injection, it becomes more important to perform the testby the experienced operator, and to maintain the equipment in asuitable state.Table Allowable limits to be attained in the test at 3-5 replicate injections (n=3-5)to keep the quality of test equivalent to that of test at n=6 *Allowable limit (RSD)Allowable limitprescribed in the testof n=61% 2% 3% 4% 5% 10%Allowablelimit tobe attainedn=5 0.88% 1.76% 2.64% 3.52% 4.40% 8.81%n=4 0.72% 1.43% 2.15% 2.86% 3.58% 7.16%n=3 0.47% 0.95% 1.42% 1.89% 2.37% 4.73%* The probability for inadequate analytical systems to meet the requirements of system suitability testing, is supposed to be 5%.3. Points to consider at the change of analytical system(Change control of analytical system)When the test method and analytical system verified is continuouslyused for the quality test without any change, it is sufficientto confirm the compliance to the requirements of systemsuitability at every series of drug analysis.However, when the test is performed for a long period, asituation in which some changes in the analytical system are inevitable,may occur. These changes don’t affect the quality ofthe product itself, but they affect the scale in the evaluation ofproduct quality. If the change in the analytical system may inducea significant deviation of the scale, it may lead to the acceptanceof products with inadequate quality and/or the rejectionof products with adequate quality. Thus, at the time ofchange in the analytical system, it is necessary to check whetherthe change is appropriate or not, to avoid the deviation of thescale in the evaluation of product quality.In the case of the change of test method, it is required to performan adequate validation depending on the extent of thechange.On the other hand, in the case of the change of analytical systemin a laboratory, such as renewal of apparatus or column ofliquid chromatography, and the change of operator, it is necessaryto perform at least system suitability testing using the systemafter change, and to confirm that the equivalency of the resultsbefore and after change.In the case that equivalent results would not be obtained afterchange, for example, when a renewal of column of liquid chromatographmay induce a significant change of elution pattern,such as the reversal of elution order between target ingredient ofthe test and substance for checking resolution, it is required toperform a revalidation of the analytical system for the test usingnew column, since it is uncertain whether the specificity and/orother validation characteristics necessary for estimating targetingredient is kept or not.35. Powder FinenessThis classification is harmonized with the European Pharmacopoeiaand the U.S. Pharmacopoeia.A simple descriptive classification of powder fineness is providedin this chapter. Sieving is most suitable where a majorityof the particles are larger than about 75 µm, although it can beused for some powders having smaller particle sizes where themeth——od can be validated. Light diffraction is also a widelyused technique for measuring the size of a wide range of particles.Where the cumulative distribution has been determined byanalytical sieving or by application of other methods, particlesize may be characterized in the following manner:x 90 : particle size corresponding to 90% of the cumulative undersizedistributionx 50 : median particle size (ie: 50% of the particles are smallerand 50% of the particles are larger)x 10 : particle size corresponding to 10% of the cumulative undersizedistributionIt is recognized that the symbol d is also widely used to designatethese values. Therefore, the symbols d 90 , d 50 , d 10 may beused.The following parameters may be defined based on the cumulativedistribution.Q r (x): cumulative distribution of particles with a dimension lessthan or equal to x where the subscript r reflects the distributiontype

2292 General Information Supplement II, JP XVrDistribution Type0 Number1 Length2 Area3 VolumeQ r (x) = 0.90 when x = x 90Q r (x) = 0.50 when x = x 50Q r (x) = 0.10 when x = x 10An alternative but less informative method of classifying powderfineness is by use of the descriptive terms in the followingtable.Therefore, by definition:Classification of Powders by FinenessDescriptive Term x 50 (µm) Cumulative Distribution by volume basis, Q 3 (x)Coarse >355 Q 3 (355)

INDEXPage citations refer to the pages of the Supplement II, to the pages of the SupplementI, and to the pages of the JP XV main volume, including those where the textbeing revised in the Supplements originally appeared. This Supplement II commenceswith page 2041 and succeeding Supplements will continue to be paged insequence.1 - 1788 Main Volume of JP XV1789 - 2040 Supplement I2041 - 2322 Supplement IIAAbsorptive Ointment, 265Acacia, 1251Powdered, 1251Acebutolol Hydrochloride, 265Aceglutamide Aluminum, 266Acemetacin, 1825Capsules, 2073Tablets, 2074Acetaminophen, 267Acetazolamide, 268Acetic Acid, 268Glacial, 269Acetohexamide, 269Acetylcholine Chloride for Injection,271, 1825Acetylsalicylic Acid, 318Tablets, 319Achyranthes Root, 1252Aciclovir, 2075Aclarubicin Hydrochloride, 272Acrinoland Zinc Oxide Oil, 273and Zinc Oxide Ointment, 274Hydrate, 274Actinomycin D, 275Adrenaline, 276Injection, 276Solution, 277AdsorbedDiphtheria-Purified Pertussis-TetanusCombined Vaccine, 596Diphtheria-Tetanus Combined Toxoid,596Diphtheria Toxoid for Adult Use,596Habu-venom Toxoid, 716Hepatitis B Vaccine, 716Purified Pertussis Vaccine, 980Tetanus Toxoid, 1156Afloqualone, 277Agar, 1252Powdered, 1253Ajmaline, 278Tablets, 279, 1826Akebia Stem, 1253Alacepril, 279Tablets, 280L-Alanine, 2076Albumin Tannate, 282Alcohol, 638Dehydrated, 639for Disinfection, 640Aldioxa, 282Alimemazine Tartrate, 283Alisma Rhizome, 1253Powdered, 1253Allopurinol, 284Tablets, 2078Alminoprofen, 1826Tablets, 1827Aloe, 1254Powdered, 1255Alpinia Officinarum Rhizome, 1256,1937Alprazolam, 284Alprenolol Hydrochloride, 285Alprostadil, 286Alfadex, 287Injection, 1828Alum, 292Solution, 293AluminumAcetylsalicylate, 319Hydroxide Gel, Dried, 288Hydroxide Gel Fine Granules, Dried,289, 2079Monostearate, 291Potassium Sulfate, Dried, 292Potassium Sulfate Hydrate, 292Silicate, Natural, 289Silicate, Synthetic, 290Sucrose Sulfate Ester, 1118Amantadine Hydrochloride, 293Ambenonium Chloride, 294Amidotrizoic Acid, 295Amikacin Sulfate, 296Injection, 1830Aminoacetic Acid, 704Aminobenzylpenicillin, 307Anhydrous, 306Hydrate, 307Sodium, 308AminophyllineHydrate, 297Injection, 297, 1831, 2079Amiodarone Hydrochloride, 2079Tablets, 2081Amitriptyline Hydrochloride, 298Tablets, 299, 1831Amlexanox, 1831Tablets, 1833Amlodipine Besilate, 1834Tablets, 2082Ammonia Water, 299Amobarbital, 300Sodium for Injection, 300Amomum Seed, 1256Powdered, 1256Amorphous Insulin Zinc Injection(Aqueous Suspension), 764Amosulalol Hydrochloride, 1835Tablets, 1836Amoxapine, 301AmoxicillinCapsules, 2083Hydrate, 302, 2085Amphotericin B, 303for Injection, 304Syrup, 305Tablets, 305AmpicillinAnhydrous, 306Ethoxycarbonyloxyethyl Hydrochloride,329Hydrate, 307Sodium, 308Sodium for Injection, 1838Ampicillinphthalidyl Hydrochloride,11382293

2294 Index Supplement II, JP XVAmyl Nitrite, 309Anemarrhena Rhizome, 1256, 1937Anesthamine, 644Anesthetic Ether, 641Angelica Dahurica Root, 1257, 1937AnhydrousAminobenzylpenicillin, 306Ampicillin, 306Caffeine, 386Citric Acid, 514Dibasic Calcium Phosphate, 396,1874Ethanol, 639Lactose, 802, 1900Antipyrine, 310Apricot Kernel, 1257, 1937, 2219Water, 1257Aprindine Hydrochloride, 2085Capsules, 2086Aralia Rhizome, 1937Arbekacin Sulfate, 311Injection, 312Areca, 1258Argatroban Hydrate, 2087L-Arginine, 313Hydrochloride, 313Hydrochloride Injection, 314, 1839Aromatic Castor Oil, 415Arotinolol Hydrochloride, 314Arsenical Paste, 315Arsenic Trioxide, 316Arsenous Acid, 316Artemisia Capillaris Flower, 1258Ascorbic Acid, 316Injection, 317, 1839Powder, 317Asiasarum Root, 1259, 1938Asparagus Tuber, 1259, 1938L-Aspartic Acid, 318Aspirin, 318Aluminum, 319Tablets, 319Aspoxicillin Hydrate, 320Astragalus Root, 1260, 2219Astromicin Sulfate, 322Atenolol, 323AtractylodesLancea Rhizome, 1260Lancea Rhizome, Powdered, 1260Rhizome, 1261, 1938Rhizome, Powdered, 1261, 1939Atropine SulfateHydrate, 324Injection, 324Azathioprine, 325Tablets, 326, 2088Azelastine Hydrochloride, 1839Granules, 2089Azithromycin Hydrate, 327Aztreonam, 328for Injection, 1840BBacampicillin Hydrochloride, 329Bacitracin, 330Baclofen, 331Tablets, 332, 1841Bamethan Sulfate, 333Barbital, 333Barium Sulfate, 334Bear Bile, 1262, 2219Bearberry Leaf, 1262Beclometasone Dipropionate, 335Beef Tallow, 336BeeswaxWhite, 336Yellow, 336Bekanamycin Sulfate, 337BelladonnaExtract, 1263, 1939Root, 1263Benidipine Hydrochloride, 338Tablets, 339Benincasa Seed, 1264Benoxinate Hydrochloride, 951Benserazide Hydrochloride, 340Bentonite, 341Benzalkonium Chloride, 342Concentrated Solution 50, 343Solution, 342Benzbromarone, 343Benzethonium Chloride, 344Solution, 345Benzocaine, 644Benzoic Acid, 345Benzoin, 1265BenzylAlcohol, 346Benzoate, 347BenzylpenicillinBenzathine Hydrate, 348Potassium, 349Potassium for Injection, 1841BerberineChloride Hydrate, 351Tannate, 352Betahistine Mesilate, 353, 1842Tablets, 354Betamethasone, 355Dipropionate, 358Sodium Phosphate, 359Tablets, 356, 2090Valerate, 360Valerate and Gentamicin SulfateCream, 361Valerate and Gentamicin SulfateOintment, 362Bethanechol Chloride, 363Betaxolol Hydrochloride, 2090Bezafibrate, 364Sustained Release Tablets, 365Bifonazole, 366Biotin, 1842Biperiden Hydrochloride, 366Bisacodyl, 367Suppositories, 368, 1843BismuthSubgallate, 368Subnitrate, 369Bisoprolol Fumarate, 1843Tablets, 1844BitterCardamon, 1265Orange Peel, 1265Tincture, 1266BleomycinHydrochloride, 370Sulfate, 372Boric Acid, 374Bromazepam, 374Bromhexine Hydrochloride, 375Bromocriptine Mesilate, 376Bromovalerylurea, 377Bucillamine, 377Tablets, 1845Bucumolol Hydrochloride, 378Bufetolol Hydrochloride, 379Bufexamac, 380Cream, 380Ointment, 381Buformin Hydrochloride, 1846Enteric-coated Tablets, 1847Tablets, 1849Bumetanide, 382Bunazosin Hydrochloride, 383Bupleurum Root, 1266, 2220Bupranolol Hydrochloride, 383Buprenorphine Hydrochloride, 1850Burdock Fruit, 1267Burnt Alum, 292Busulfan, 384Butropium Bromide, 385Butyl Parahydroxybenzoate, 386CCacao Butter, 386Cadralazine, 2091Tablets, 2092Caffeineand Sodium Benzoate, 388Anhydrous, 386Hydrate, 387Calciferol, 624Calcitonin (Salmon), 2093CalciumCarbonate, Precipitated, 389Chloride Hydrate, 390Chloride Injection, 390, 1851Folinate, 391, 1851Gluconate Hydrate, 391Hydroxide, 392Lactate Hydrate, 393Leucovorin, 391Oxide, 393

Supplement II, JP XV Index 2295Pantothenate, 394Paraaminosalicylate Granules, 394Paraaminosalicylate Hydrate, 395Polystyrene Sulfonate, 398Stearate, 400Calumba, 1267, 1939, 2220Powdered, 1268, 1939, 2220Camellia Oil, 400Camostat Mesilate, 400, 1852d-Camphor, 401dl-Camphor, 402Capsicum, 1268and Salicylic Acid Spirit, 1270Powdered, 1269Tincture, 1269Capsules, 403CapsulesAcemetacin, 2073Amoxicillin, 2083Aprindine Hydrochloride, 2086Cefaclor, 416Cefadroxil, 1852Cefalexin, 2098Cefdinir, 435Cefixime, 2101Cinoxacin, 2106Clindamycin Hydrochloride, 520,2018Clofibrate, 526Clorazepate Dipotassium, 1869Doxifluridine, 604Droxidopa, 2119Flopropione, 667Flurazepam, 678Indometacin, 756, 1893Nizatidine, 1913Rifampicin, 1065Roxatidine Acetate HydrochlorideExtended-release, 1071Sodium Iodide ( 123 I), 1103Sodium Iodide ( 131 I), 1103Sulpiride, 1132Tranexamic Acid, 1192Ubenimex, 2211Vitamin A, 1230Vitamin A Oil, 1230Captopril, 403Carbamazepine, 404Carbazochrome Sodium SulfonateHydrate, 405Carbetapentane Citrate, 974Carbetapentene Citrate, 974Carbidopa Hydrate, 406L-Carbocisteine, 407Carbolic Acid, 985for Disinfection, 986Liquefied, 986Carbon Dioxide, 407Carboxymethylcellulose, 408Calcium, 409Sodium, 410Cardamon, 1271, 2220Carmellose, 408Calcium, 409, 2097Sodium, 410, 2097Carmofur, 411Carnauba Wax, 411Carteolol Hydrochloride, 412Carumonam Sodium, 412Cassia Seed, 1271Castor Oil, 414Aromatic, 415Catalpa Fruit, 1271Cefaclor, 415Capsules, 416Compound Granules, 419, 2097Fine Granules, 417Cefadroxil, 421Capsules, 1852for Syrup, 1853Cefalexin, 422Cefalotin Sodium, 423, 1854Cefapirin Sodium, 424Cefatrizine Propylene Glycolate, 425,1854Cefazolin Sodium, 426for Injection, 1854Hydrate, 428Cefbuperazone Sodium, 429Cefcapene Pivoxil HydrochlorideFine Granules, 432Hydrate, 430Tablets, 433Cefdinir, 434Capsules, 435Fine Granules, 436Cefaclor Compound Granules, 2097CefalexinCapsules, 2098for Syrup, 2099Cefatrizine Propylene Glycolate forSyrup, 2100Cefditoren Pivoxil, 437Fine Granules, 438Tablets, 438Cefepime Dihydrochloridefor Injection, 441Hydrate, 439Cefixime, 442Capsules, 2101Cefmenoxime Hydrochloride, 443Cefmetazole Sodium, 445for Injection, 1855Cefminox Sodium Hydrate, 446Cefodizime Sodium, 447Cefoperazone Sodium, 448Cefotaxime Sodium, 449Cefotetan, 451CefotiamHexetil Hydrochloride, 453Hydrochloride, 455Hydrochloride for Injection, 456Cefozopran Hydrochloride, 457for Injection, 458Cefpiramide Sodium, 458Cefpirome Sulfate, 460Cefpodoxime Proxetil, 461Cefroxadinefor Syrup, 2103Hydrate, 462Cefsulodin Sodium, 464Ceftazidimefor Injection, 1856Hydrate, 466Cefteram Pivoxil, 468Fine Granules, 469Tablets, 2104Ceftibuten Hydrate, 470Ceftizoxime Sodium, 471Ceftriaxone Sodium Hydrate, 472CefuroximeAxetil, 474Sodium, 476Cellacefate, 480, 2105CelluloseMicrocrystalline, 477, 2105Powdered, 480, 2105Celmoleukin (Genetical Recombination),481Cetanol, 484Cetirizine Hydrochloride, 1856Tablets, 1857Cetraxate Hydrochloride, 485Chenodeoxycholic Acid, 486Chloral Hydrate, 487Chloramphenicol, 487Palmitate, 488Sodium Succinate, 489Chlordiazepoxide, 490Powder, 491Tablets, 492, 1858ChlorhexidineGluconate Solution, 493Hydrochloride, 493Chlorinated Lime, 494Chlormadinone Acetate, 494Chlorobutanol, 495Chlorphenesin Carbamate, 496, 1858Tablets, 1859Chlorpheniramineand Calcium Powder, 497Maleate, 498Maleate Injection, 499Maleate Powder, 499Maleate Tablets, 500d-Chlorpheniramine Maleate, 501Chlorpromazine Hydrochloride, 502Injection, 503, 1860Tablets, 503, 1861Chlorpropamide, 504Tablets, 505, 1861Cholecalciferol, 506Cholera Vaccine, 506Cholesterol, 507Chorionic Gonadotrophin, 707for Injection, 708Chrysanthemum Flower, 1271Cibenzoline Succinate, 1861Tablets, 1862

2296 Index Supplement II, JP XVCiclacillin, 507Ciclosporin, 509A, 509Cilastatin Sodium, 509CilazaprilHydrate, 1863Tablets, 1864Cilostazol, 511Tablets, 512, 1866Cimetidine, 513Cimicifuga Rhizome, 1272, 1939Cinchocaine Hydrochloride, 569CinnamonBark, 1272Bark, Powdered, 1273Oil, 1273Cinoxacin, 2105Capsules, 2106Cisplatin, 513Citric AcidAnhydrous, 514Hydrate, 515Citrus Unshiu Peel, 1273Clarithromycin, 516Tablets, 517Clebopride Malate, 2107Clemastine Fumarate, 519Clematis Root, 1274, 1939Clindamycin Hydrochloride, 519,2108Capsules, 520, 2108Clindamycin Phosphate, 521Injection, 1866Clinofibrate, 522Clobetasol Propionate, 1867Clocapramine Hydrochloride Hydrate,523Clofedanol Hydrochloride, 524Clofibrate, 525Capsules, 526Clomifene Citrate, 526Tablets, 527, 2109Clomipramine Hydrochloride, 528Clonazepam, 528Clonidine Hydrochloride, 529Cloperastine Hydrochloride, 530Clorazepate Dipotassium, 1868Capsules, 1869Clotiazepam, 531Clotrimazole, 532Clove, 1274Oil, 1275Powdered, 1274Cloxacillin Sodium Hydrate, 533Cloxazolam, 534CMC, 408Calcium, 409Sodium, 410CnidiumMonnieri Fruit, 1275Rhizome, 1275, 1939Rhizome, Powdered, 1276, 1940Cocaine Hydrochloride, 535Coconut Oil, 535Codeine PhosphateHydrate, 536Powder, 1%, 536Powder, 10%, 537Tablets, 537, 2109Cod Liver Oil, 538Coix Seed, 1276Powdered, 1276Colchicine, 538ColistinSodium Methanesulfonate, 540Sulfate, 541Colophonium, 1347CompoundAcrinol and Zinc Oxide Oil, 273Diastase and Sodium BicarbonatePowder, 567Hycodenone Injection, 952Iodine Glycerin, 770Methyl Salicylate Spirit, 879Oxycodone and Atropine Injection,953Oxycodone Injection, 952Phellodendron Powder for Cataplasm,1332Rhubarb and Senna Powder, 1346Salicylic Acid Spirit, 1080Scopolia Extract and Diastase Powder,1355Thianthol and Salicylic Acid Solution,1165Vitamin B Powder, 1230ConcentratedGlycerin, 703Glycerol, 703Condurango, 1276Fluidextract, 1277, 1940Coptis Rhizome, 1277, 1940Powdered, 1278, 1940CornOil, 542Starch, 542, 2110Cornus Fruit, 1279, 2220Cortisone Acetate, 543Corydalis Tuber, 1279, 1940Powdered, 1940Crataegus Fruit, 1941Creosote, 544, 1870Wood, 2110Cresol, 544Solution, Saponated, 545Croconazole Hydrochloride, 546Croscarmellose Sodium, 546, 2112Crude Glycyrrhiza Extract, 1297, 1943Crystalline Insulin Zinc Injection(Aqueous Suspension), 765Crystal Violet, 881Cyanamide, 548Cyanocobalamin, 548, 1870Injection, 549, 1871Cyclopentolate Hydrochloride, 549Cyclophosphamide Hydrate, 550Cycloserine, 551Cyperus Rhizome, 1280, 1942Powdered, 1280, 1942Cyproheptadine Hydrochloride Hydrate,551L-Cysteine, 1871Hydrochloride Hydrate, 1872Cytarabine, 552DDaiokanzoto Extract, 1280, 2221Danazol, 2112Dantrolene Sodium Hydrate, 553Daunorubicin Hydrochloride, 553Deferoxamine Mesilate, 554, 1873Dehydrated Alcohol, 639Dehydrocholate Sodium Injection, 557Dehydrocholic Acid, 556Injection, 557, 1873Purified, 556Demethylchlortetracycline Hydrochloride,558DentalAntiformin, 310Iodine Glycerin, 771Paraformaldehyde Paste, 969Phenol with Camphor, 987Sodium Hypochlorite Solution, 310Triozinc Paste, 1210Dermatol, 368Deslanoside, 559Injection, 560, 1873Dexamethasone, 560Dextran40, 561, 187340 Injection, 56270, 563Sulfate Sodium Sulfur 5, 564Sulfate Sodium Sulfur 18, 565Dextrin, 565Dextromethorphan HydrobromideHydrate, 566Diagnostic Sodium Citrate Solution,1100Diastase, 567and Sodium Bicarbonate Powder,567Diazepam, 567DibasicCalcium Phosphate, Anhydrous, 396,1874Calcium Phosphate Hydrate, 396,1875Sodium Phosphate Hydrate, 568Dibekacin Sulfate, 569Ophthalmic Solution, 2113Dibucaine Hydrochloride, 569Dichlorphenamide, 571Tablets, 572Diclofenac Sodium, 570Diclofenamide, 571

Supplement II, JP XV Index 2297Tablets, 572Dicloxacillin Sodium Hydrate, 573Diethylcarbamazine Citrate, 574Tablets, 574, 2113Diethylstilbestrol Diphosphate, 683Tablets, 684Difenidol Hydrochloride, 575Diflucortolone Valerate, 2114Digenea, 1280Digitoxin, 576Tablets, 576Digoxin, 578, 2115Injection, 579, 2116Tablets, 580, 2116Dihydrocodeine Phosphate, 581Powder, 1%, 582Powder, 10%, 582Dihydroergotamine Mesilate, 583Dihydroergotoxine Mesilate, 584Dilazep Hydrochloride Hydrate, 586Diltiazem Hydrochloride, 586DiluteHydrochloric Acid, 726Iodine Tincture, 769Diluted Opium Powder, 940Dimemorfan Phosphate, 588Dimenhydrinate, 588Tablets, 589, 2117Dimercaprol, 590Injection, 590Dimorpholamine, 591Injection, 591Dinoprost, 592Dionin, 648Dioscorea Rhizome, 1282, 1942Powdered, 1282, 1942Diphenhydramine, 593and Bromovalerylurea Powder, 593Hydrochloride, 594,Phenol and Zinc Oxide Liniment,595Tannate, 595Diphenylhydantoin, 991Powder, 992Sodium for Injection, 92Tablets, 992DiphtheriaTetanus Combined Toxoid, 596Toxoid, 596Dipyridamole, 597Disodium Edetate Hydrate, 598Disopyramide, 598Distigmine Bromide, 599Tablets, 600, 2117Disulfiram, 600Dobutamine Hydrochloride, 601Dolichos Seed, 1282Domperidone, 1876Dopamine Hydrochloride, 602Injection, 602, 1877Dover's Powder, 1324Doxapram Hydrochloride Hydrate,603Doxazosin Mesilate, 2117Doxifluridine, 604Capsules, 604Doxorubicin Hydrochloride, 605for Injection, 1877Doxycycline Hydrochloride Hydrate,606DriedAluminum Hydroxide Gel, 288Aluminum Hydroxide Gel Fine Granules,289Aluminum Potassium Sulfate, 292Sodium Carbonate, 1096Sodium Sulfite, 1109Thyroid, 1171Yeast, 1241Droperidol, 608Droxidopa, 2118Capsules, 2119Fine Granules, 2120Dydrogesterone, 609Tablets, 610EEcabet SodiumGranules, 2121Hydrate, 2122Ecarazine Hydrochloride, 1185Ecothiopate Iodide, 610Edrophonium Chloride, 611Injection, 612, 1878EDTA Sodium Hydrate, 598Elcatonin, 612Eleutherococcus Senticosus Rhizome,1283, 2221Emorfazone, 1878Tablets, 2123Enalapril Maleate, 1879Tablets, 1880Enflurane, 615Enoxacin Hydrate, 616Enviomycin Sulfate, 616Eperisone Hydrochloride, 618Ephedra Herb, 1283Ephedrine Hydrochloride, 619Injection, 619, 1882Powder, 620Powder, 10%, 620Tablets, 621, 1882, 2124Epimedium Herb, 1284Epinephrine, 276Injection, 276Solution, 277Epirizole, 621Epirubicin Hydrochloride, 622Ergocalciferol, 624Ergometrine Maleate, 625Injection, 625, 2125Tablets, 626Ergotamine Tartrate, 627Erythromycin, 627Enteric-Coated Tablets, 1882, 2125Ethylsuccinate, 629Lactobionate, 629Stearate, 630Estazolam, 631Estradiol Benzoate, 631Injection, 632Injection (Aqueous Suspension),633, 2125Estriol, 633Injection (Aqueous Suspension),634, 2125Tablets, 635Etacrynic Acid, 636Tablets, 636Ethacridine Lactate, 274Ethambutol Hydrochloride, 637Ethanol, 638Anhydrous, 639for Disinfection, 640Ethenzamide, 640, 2125Ether, 641Anesthetic, 641Ethinylestradiol, 642, 2125Tablets, 642Ethionamide, 643Ethosuximide, 644Ethoxybenzamide, 640EthylAminobenzoate, 644Cysteine Hydrochloride, 645L-Cysteine Hydrochloride, 645Icosapentate, 646Parahydroxybenzoate, 647Ethylenediamine, 648Ethylmorphine Hydrochloride Hydrate,648Etidronate Disodium, 649Tablets, 650Etilefrine Hydrochloride, 650Tablets, 651Etizolam, 652Fine Granules, 1883Tablets, 1884Etodolac, 653Etoposide, 653Eucalyptus Oil, 654Eucommia Bark, 1284Evodia Fruit, 1285Exsiccated Gypsum, 1298ExtractBelladonna, 1263, 1939Daiokanzoto, 1280, 2221Glycyrrhiza, 1296, 1943Goshajinkigan, 2221Crude Glycyrrhiza, 1297, 1943Hachimijiogan, 2225Hangekobokuto, 1943Hochuekkito, 1298, 1945Kakkonto, 1308, 1950, 2228Kamishoyosan, 1310, 1952Keishibukuryogan, 1955Nux Vomica, 1322, 1960

2298 Index Supplement II, JP XVRyokeijutsukanto, 1347, 1965Saireito, 1349Scopolia, 1353, 1967Shimbuto, 2234FFamotidine, 655for Injection, 656, 1885Powder, 657, 2125Tablets, 657Faropenem Sodiumfor Syrup, 659, 1886, 2126Hydrate, 658, 1885Tablets, 660, 1886, 2126Felbinac, 1887Fenbufen, 660Fennel, 1285Oil, 1286Powdered, 1285Fentanyl Citrate, 661Ferrous Sulfate Hydrate, 661Fine GranulesCefaclor, 417Cefcapene Pivoxil Hydrochloride,432Cefdinir, 436Cefditoren Pivoxil, 438Cefteram Pivoxil, 469Dried Aluminum Hydroxide Gel,289, 2079Droxidopa, 2120Etizolam, 1883Irsogladine Maleate, 2148Troxipide, 2209Flavin Adenine Dinucleotide Sodium,662Flavoxate Hydrochloride, 664Flomoxef Sodium, 664for Injection, 666Flopropione, 667, 2126Capsules, 667Flucytosine, 668Fludiazepam, 669Fludrocortisone Acetate, 2127FluidextractCondurango, 1277, 1940Platycodon, 1334, 1962Uva Ursi, 1371, 1969Flunitrazepam, 670Fluocinolone Acetonide, 670Fluocinonide, 672Fluorescein Sodium, 673Fluorometholone, 673Fluorouracil, 674Fluoxymesterone, 675Fluphenazine Enanthate, 676Flurazepam, 677Capsules, 678Hydrochloride, 678Flurbiprofen, 679Flutamide, 2128Flutoprazepam, 2129Tablets, 2130Foeniculated Ammonia Spirit, 1286Folic Acid, 680Injection, 681, 1888Tablets, 681, 1888Formalin, 681Water, 682Formoterol Fumarate Hydrate, 682Forsythia Fruit, 1286Fosfestrol, 683, 1888Tablets, 684, 1888FosfomycinCalcium Hydrate, 685Sodium, 686Sodium for Injection, 687, 2131Fradiomycin Sulfate, 688Freeze-driedBCG Vaccine (for Percutaneous Use),335Botulism Antitoxin, Equine, 374Diphtheria Antitoxin, Equine, 596Habu Antivenom, Equine, 716Inactivated Tissue Culture RabiesVaccine, 1054Japanese Encephalitis Vaccine, 786Live Attenuated Measles Vaccine,843Live Attenuated Mumps Vaccine,902Live Attenuated Rubella Vaccine,1074Mamushi Antivenom, Equine, 841Smallpox Vaccine, 1091Smallpox Vaccine Prepared in CellCulture, 1091Tetanus Antitoxin, Equine, 1156Fritillaria Bulb, 1287, 1942Fructose, 689Injection, 689, 1888Furosemide, 690Injection, 2131Tablets, 691Fursultiamine Hydrochloride, 692GGabexate Mesilate, 693, 1889β-Galactosidase(Aspergillus), 694(Penicillium), 695Gallium (67Ga) Citrate Injection, 696Gambir, 1287Powdered, 1287Gardenia Fruit, 1288Powdered, 1288Gas Gangrene Antitoxin, Equine, 696Gastrodia Tuber, 1289, 1943Gefarnate, 2132Gelatin, 696Purified, 697Gentamicin Sulfate, 698Ophthalmic Solution, 2133Gentian, 1290, 1943and Sodium Bicarbonate Powder,1290Japanese, 1306, 1949Powdered, 1290, 1943Powdered, Japanese, 1306, 1949Geranium Herb, 1291Powdered, 1291Ginger, 1291Powdered, 1292Ginseng, 1292Powdered, 1293Glacial Acetic Acid, 269Glehnia Root, 1294, 1943Glibenclamide, 699Gliclazide, 2134Glucose, 700Injection, 701, 1889L-Glutamine, 1889Glutathione, 701Glycerin, 702and Potash Solution, 704Concentrated, 703Glycerol, 702Concentrated, 703Glyceryl Monostearate, 704Glycine, 704Glycyrrhiza, 1295Extract, 1296, 1943Extract, Crude, 1297, 1943Powdered, 1296Gonadorelin Acetate, 705GonadotrophinChorionic, 707for Injection, Chorionic, 708for Injection, Human Chorionic, 708Human Chorionic, 707Human Menopausal, 708Serum, 710for Injection, Serum, 711Goshajinkigan Extract, 2221Gramicidin, 712GranulesAzelastine Hydrochloride, 2089Calcium Paraaminosalicylate, 394Cefaclor Compound, 419, 2097Ecabet Sodium, 2121Ursodeoxycholic Acid, 2213Pas-calcium Granules, 394Griseofulvin, 713Tablets, 1890, 2135Guaiacol Glyceryl Ether, 714Guaifenesin, 714Guanabenz Acetate, 715Guanethidine Sulfate, 716Gypsum, 1297HHachimijiogan Extract, 2225Haloperidol, 717

Supplement II, JP XV Index 2299Tablets, 718Halothane, 719Haloxazolam, 719Hangekobokuto Extract, 1943Hemp Fruit, 1298Heparin Calcium, 2135Heparin Sodium, 721, 2137Injection, 722Hochuekkito Extract, 1298, 1945,2228Homatropine Hydrobromide, 722Homochlorcyclizine Hydrochloride,723Honey, 1301Houttuynia Herb, 1302HumanChorionic Gonadotrophin, 707Chorionic Gonadotrophin for Injection,708Menopausal Gonadotrophin, 708,2137Normal Immunoglobulin, 724Hycoato Injection, 953Hydralazine Hydrochloride, 724for Injection, 724, 2138Powder, 725Tablets, 725, 1890Hydrochloric Acid, 725Dilute, 726Lemonade, 727Hydrochlorothiazide, 727Hydrocortisone, 728Acetate, 729and Diphenhydramine Ointment,730Butyrate, 730Sodium Phosphate, 731, 2139Sodium Succinate, 732Succinate, 733Hydrocotarnine HydrochlorideHydrate, 734Hydrogenated Oil, 735HydrophilicOintment, 735Petrolatum, 981Hydrous Lanolin, 807Hydroxocobalamin Acetate, 736Hydroxypropylcellulose, 736, 2139Low Substituted, 2139Hydroxypropylmethylcellulose, 741HydroxyzineHydrochloride, 739Pamoate, 739Hymecromone, 740Hypromellose, 741, 2140Phthalate, 743, 1891, 2140Ibudilast, 1892Ibuprofen, 744Ichthammol, 744IIdarubicin Hydrochloride, 745for Injection, 746Idoxuridine, 747Ophthalmic Solution, 747, 1893Ifenprodil Tartrate, 748Imidapril Hydrochloride, 2140Tablets, 2141Imipenemand Cilastatin for Injection, 750Hydrate, 749Imipramine Hydrochloride, 751Tablets, 752, 1893Immature Orange, 1302Imperata Rhizome, 1302, 1949Indapamide, 2143Tablets, 2144Indenolol Hydrochloride, 753Indigocarmine, 754Injection, 755, 2145Indium ( 111 In) Chloride Injection, 755Indometacin, 755Capsules, 756, 1893Suppositories, 757, 2145Influenza HA Vaccine, 758InjectionAcetylcholine Chloride for, 271,1825Adrenaline, 276Alprostadil, 1828Amikacin Sulfate, 1830Aminophylline, 297, 1831, 2079Amobarbital Sodium for, 300Amphotericin B for, 304Ampicillin Sodium for, 1838Estradiol Benzoate, (AqueousSuspension), 633, 2125Estriol, (Aqueous Suspension), 634,2125Insulin Zinc, (Aqueous Suspension),763Insulin Zinc, Amorphous, (AqueousSuspension), 764Insulin Zinc, Crystalline, (AqueousSuspension), 765Insulin Zinc Protamine, (AqueousSuspension), 766Isophane Insulin, (Aqueous Suspension),762Arbekacin Sulfate, 312L-Arginine Hydrochloride, 314,1839Ascorbic Acid, 317, 1839Atropine Sulfate, 324Aztreonam for, 1840Benzylpenicillin Potassium for, 1841Calcium Chloride, 390, 1851Cefazolin Sodium for, 1854Cefepime Dihydrochloride for, 441Cefmetazole Sodium for, 1855Cefotiam Hydrochloride for, 456Cefozopran Hydrochloride for, 458Ceftazidime for, 1856Chlorpheniramine Maleate, 499Chlorpromazine Hydrochloride, 503,1860Chorionic Gonadotrophin for, 708Clindamycin Phosphate, 1866Cyanocobalamin, 549, 1871Dehydrocholate Sodium, 557Dehydrocholic Acid, 557, 1873Deslanoside, 560, 1873Dextran 40, 562Digoxin, 579, 2116Dimercaprol, 590Dimorpholamine, 591Diphenylhydantoin Sodium for, 992Dopamine Hydrochloride, 602, 1877Doxorubicin Hydrochloride for,1877Edrophonium Chloride, 612, 1878Ephedrine Hydrochloride, 619, 1882Epinephrine, 276Ergometrine Maleate, 625, 2125Estradiol Benzoate, 632Famotidine for, 656, 1885Flomoxef Sodium for, 666Folic Acid, 681, 1888Fosfomycin Sodium for, 687, 2131Fructose, 689, 1888Furosemide, 2131Gallium ( 67 Ga) Citrate, 696Glucose, 701, 1889Heparin Sodium, 722Human Chorionic Gonadotrophin for,708Hycoato, 953Hycodenone, Compound, 952Hydralazine Hydrochloride for, 724,2138Idarubicin Hydrochloride for, 746Imipenem and Cilastatin for, 750Indigocarmine, 755, 2145Indium ( 111 In) Chloride, 755Insulin, 762Iodinated ( 131 I) Human Serum Albumin,768Isepamicin Sulfate Injection, 2150Isoniazid, 781, 2151Isotonic Sodium Chloride, 1098Levallorphan Tartrate, 814, 1900Lidocaine, 818, 2157Lidocaine Hydrochloride, 818, 2157Magnesium Sulfate, 839, 1900D-Mannite, 842D-Mannitol, 842, 1903Meglumine Amidotrizoate, 851Meglumine Iotalamate, 852, 2161Meglumine Sodium Amidotrizoate,853, 2161Meglumione Sodium Iodamide, 854Mepivacaine Hydrochloride, 860,2161Meropenem for, 2162Metenolone Enanthate, 866Minocycline Hydrochloride for,1904, 2163

2300 Index Supplement II, JP XVMitomycin C for, 1905Morphine and Atropine, 899Morphine Hydrochloride, 901, 2165Neostigmine Methylsulfate, 910,1912Nicardipine Hydrochloride, 912,1912Nicotinic Acid, 921, 1912Noradrenaline, 931, 1915Noradrenaline Hydrochloride, 931Norepinephrine, 931Norepinephrine Hydrochloride, 931Operidine, 981Opium Alkaloids and Atropine, 942Opium Alkaloids and Scopolamine,943Opium Alkaloids Hydrochlorides, 942Oxycodone and Atropine, Compound,953Oxycodone, Compound, 952Oxytocin, 960Ozagrel Sodium for, 1917Papaverine Hydrochloride, 965,1918Peplomycin Sulfate for, 1918Pethidine Hydrochloride, 981, 1918Phenolsulfonphthalein, 988, 2169Phenytoin Sodium for, 992Piperacillin Sodium for, 998Prednisolone Sodium Succinate for,1025, 1921Procainamide Hydrochloride, 1029,2179Procaine Hydrochloride, 1030Progesterone, 1034, 2182Protamine Sulfate, 1042, 1922, 2186Pyridoxine Hydrochloride, 1048,1922Reserpine, 1056, 1922Riboflavin Phosphate, 1062Riboflavin Sodium Phosphate, 1062,1922Serum Gonadotrophin for, 711Sodium Bicarbonate, 1094, 19250.9% Sodium Chloride, 109810% Sodium Chloride, 1098, 1925Sodium Chromate ( 51 Cr), 1099Sodium Citrate, for Transfusion,1099, 1926Sodium Iodohippurate ( 131 I), 1103Sodium Iotalamate, 1103, 2195Sodium Pertechnetate ( 99m Tc), 1105Sodium Thiosulfate, 1110, 1927Streptomycin Sulfate for, 2198Sulfobromophthalein Sodium, 1130Sulpyrine, 1134, 1927Suxamethonium Chloride for, 1137,1928Suxamethonium Chloride, 1138,1928Teceleukin for, (Genetical Recombination),1148, 1929Testosterone Enanthate, 1154, 2203Testosterone Propionate, 1155, 2203Thallium ( 201 Tl) Chloride, 1158Thiamine Chloride Hydrochloride,1161, 1930Thiamylal Sodium for, 1164Thiopental Sodium for, 1167, 1930Tobramycin, 1930Tranexamic Acid, 1193Tubocurarine Chloride Hydrochloride,1213, 1931Tubocurarine Hydrochloride, 1213Vancomycin Hydrochloride for,1223Vasopressin, 1223, 2215Vinblastine Sulfate for, 1227Vitamin B 1 Hydrochloride, 1161Vitamin B 2 Phosphate Ester, 1062Vitamin B 6 , 1048Vitamin B 12 , 549Vitamin C, 317Water for, 1235, 1934Weak Opium Alkaloids and Scopolamine,945Xylitol, 1241, 1935Insulin, 758Human (Genetical Recombination),760Injection, 762Zinc Injection (Aqueous Suspension),763Amorphous, 764Crystalline, 765Zinc Protamine Injection (AqueousSuspension), 766Iodamide, 767Iodinated ( 131 I) Human Serum AlbuminInjection, 768Iodine, 768Salicylic Acid and Phenol Spirit,772Tincture, 769Iodoform, 773Iopamidol, 773Iotalamic Acid, 774Iotroxic Acid, 775Ipecac, 1303, 1949Powdered, 1303, 1949Syrup, 1304Ipratropium Bromide Hydrate, 776Ipriflavone, 2145Tablets, 2146Iproveratril Hydrochloride, 1225Ilsogladine Maleate, 2147Fine Granules, 2148Tablets, 2149Isepamicin Sulfate, 777Injection, 2150Isoflurane, 778L-Isoleucine, 780Isoniazid, 780Injection, 781, 2151Tablets, 781, 2151Isophane Insulin Injection (AqueousSuspension), 762l-Isoprenaline Hydrochloride, 782Isopropanol, 783Isopropyl Alcohol, 783Isopropylantipyrine, 783Isosorbide, 784Dinitrate, 785Dinitrate Tablets, 786, 2151IsotonicSalt Solution, 1098Sodium Chloride Injection, 1098Sodium Chloride Solution,1098,1893Isoxsuprine Hydrochloride, 1894Tablets, 1895Itraconazole, 1896JapaneseAngelica Root, 1305Angelica Root, Powdered, 1305Encephalitis Vaccine, 786Encephalitis Vaccine, Freeze-dried,786Gentian, 1306, 1949Gentian, Powdered, 1306, 1949Valerian, 1306, 1950, 2228Valerian, Powdered, 1307, 1950,2228Josamycin, 786Propionate, 788Tablets, 1897, 2152Jujube, 1307Seed, 1307JKKainic Acidand Santonin Powder, 790Hydrate, 789Kakkonto Extract, 1308, 1950, 2228Kallidinogenase, 790Kamishoyosan Extract, 1310, 1952KanamycinMonosulfate, 793Sulfate, 794Kaolin, 795Keishibukuryogan Extract, 1955Ketamine Hydrochloride, 795Ketoconazole, 2152Cream, 2153Lotion, 2154Solution, 2155Ketoprofen, 796Ketotifen Fumarate, 797Kitasamycin, 798Acetate, 799Tartrate, 800

Supplement II, JP XV Index 2301LLabetalol Hydrochloride, 1898Tablets, 1899Lactic Acid, 801Lactose, 803Anhydrous, 802, 1900, 2155Hydrate, 803, 2156Lactulose, 804Lanatoside C, 805Tablets, 806LanolinHydrous, 807Purified, 808Lard, 808Latamoxef Sodium, 809Lauromacrogol, 810LemonadeHydrochloric Acid, 727Lenampicillin Hydrochloride, 810Leonurus Herb, 1958L-Leucine, 812Leucomycin, 798Acetate, 799Tartrate, 800Levallorphan Tartrate, 813Injection, 814, 1900Levodopa, 814Levofloxacin Hydrate, 2156Levomepromazine Maleate, 815Levothyroxine SodiumHydrate, 816Tablets, 817Lidocaine, 818Hydrochloride Injection, 818Injection, 818, 2157LightAnhydrous Silicic Acid, 1087Liquid Paraffin, 967Lilium Bulb, 1958Limaprost Alfadex, 819LinimentDiphenhydramine, Phenol and ZincOxide, 595Lincomycin HydrochlorideHydrate, 820Injection, 2157Lindera Root, 1313, 1959Liothyronine Sodium, 821Tablets, 822LiquefiedCarbolic Acid, 986Phenol, 986Liquid Paraffin, 966LisinoprilHydrate, 823Tablets, 824Lithium Carbonate, 826Lithospermum Root, 1313, 1959, 2228Live Oral Poliomyelitis Vaccine, 1005Longan Aril, 2229Longgu, 1313, 2229Lonicera Leaf and Stem, 1314Loquat Leaf, 1314Lorazepam, 827Losartan Potassium, 2158LotionKetoconazole, 2154Sulfur and Camphor, 1130Low Substituted Hydroxypropylcellulose,738, 2139Loxoprofen Sodium Hydrate, 828LyciumBark, 1315, 1959Fruit, 1315Lysine Hydrochloride, 829L-Lysine Acetate, 2159L-Lysine Hydrochloride, 829Lysozyme Hydrochloride, 830MMacrogol400, 8301500, 8314000, 8326000, 83220000, 833Ointment, 833MagnesiumCarbonate, 834Oxide, 835Silicate, 836Stearate, 837Sulfate Hydrate, 838Sulfate Injection, 839, 1900Sulfate Mixture, 839MagnoliaBark, 1315, 1959Bark, Powderd, 1316, 1959Flower, 1317Mallotus Bark, 1317Maltose Hydrate, 840Manidipine Hydrochloride, 1900Tablets, 1902D-Mannite Injection, 842D-Mannitol, 841Injection, 842, 1903Maprotiline Hydrochloride, 842Meclofenoxate Hydrochloride, 843Mecobalamin, 844Medazepam, 845, 1903MedicinalCarbon, 845Soap, 846Mefenamic Acid, 847Mefloquine Hydrochloride, 848Mefruside, 849Tablets, 849, 1903Meglumine, 850Amidotrizoate Injection, 851Iotalamate Injection, 852, 2161Sodium Amidotrizoate Injection,853, 2161Sodium Iodamide Injection, 854Melphalan, 855Menatetrenone, 855MenthaHerb, 1317Oil, 1318Water, 1318dl-Menthol, 856l-Menthol, 857Mepenzolate Bromide, 857Mepirizole, 621Mepitiostane, 858Mepivacaine Hydrochloride, 859Injection, 860, 2161Mequitazine, 861Merbromin, 862Solution, 863Mercaptopurine Hydrate, 861Mercurochrome, 862Solution, 863Meropenemfor Injection, 2162Hydrate, 863Mestranol, 864MetenoloneAcetate, 865Enanthate, 866Enanthate Injection, 866Metformin Hydrochloride, 867Tablets, 867Methamphetamine Hydrochloride, 868L-Methionine, 869Methotrexate, 869Methoxsalen, 870Methylbenactyzium Bromide, 871Methylcellulose, 871, 2163MethyldopaHydrate, 873Tablets, 874, 1903dl-Methylephedrine Hydrochloride,875Powder, 876Powder, 10%, 876Methylergometrine Maleate, 876Tablets, 877MethylParahydroxybenzoate, 878Salicylate, 881Methylprednisolone, 879Succinate, 880Methylrosanilinium Chloride, 881Methyltestosterone, 882Tablets, 883Meticrane, 884Metildigoxin, 885Metoclopramide, 886Tablets, 886Metoprolol Tartrate, 887Tablets, 888Metronidazole, 889Tablets, 889Metyrapone, 890Mexiletine Hydrochloride, 891

2302 Index Supplement II, JP XVMiconazole, 892Nitrate, 893Microcrystalline Cellulose, 477Micronomicin Sulfate, 893Midecamycin, 894Acetate, 895Migrenin, 896Minocycline Hydrochloride, 897for Injection, 1904, 2163Tablets, 2163Mitomycin C, 898for Injection, 1905Mizoribine, 1906Tablets, 1907Monobasic Calcium PhosphateHydrate, 397Monosodium Trichloroethyl Phosphate,1202Syrup, 1203Morphineand Atropine Injection, 899Hydrochloride Hydrate, 900Hydrochloride Injection, 901, 2165Hydrochloride Tablets, 902, 1908,2165Mosapride CitrateHydrate, 2165Tablets, 2166Moutan Bark, 1318Powdered, 1319Mulberry Bark, 1320, 1960Mupirocin Calcium Hydrate, 902NNabumetone, 1908Tablets, 1910Nadolol, 904Nafamostat Mesilate, 1911Nalidixic Acid, 905Naloxone Hydrochloride, 906Naphazolineand Chlorpheniramine Solution, 906Hydrochloride, 907Nitrate, 908Naproxen, 908Narcotine, 936Hydrochloride, 937Natamycin, 994Natural Aluminum Silicate, 289Nelumbo Seed, 1320Neomycin Sulfate, 688Neostigmine Methylsulfate, 909Injection, 910, 1912Netilmicin Sulfate, 910Nicardipine Hydrochloride, 911Injection, 912, 1912Nicergoline, 913Powder, 914Tablets, 915Niceritrol, 916Nicomol, 917Tablets, 918, 2168Nicorandil, 919, 1912Nicotinamide, 919Nicotinic Acid, 920Injection, 921, 1912Nifedipine, 922Nilvadipine, 923Tablets, 924Nitrazepam, 925Nitrendipine, 926Tablets, 927Nitrogen, 928Nitroglycerin Tablets, 928Nitrous Oxide, 929Nizatidine, 1912Capsules, 1913Noradrenaline, 930Hydrochloride Injection, 931Injection, 931, 1915Norepinephrine, 930Hydrochloride Injection, 931Injection, 931Norethisterone, 932, 2168Norfloxacin, 932Norgestrel, 933and Ethinylestradiol Tablets, 934Nortriptyline Hydrochloride, 935Noscapine, 936Hydrochloride Hydrate, 937Notopterygium Rhizome, 1321, 1960Nuphar Rhizome, 1321, 1960, 2229Nutmeg, 2229Nux Vomica, 1321Extract, 1322, 1960Extract Powder, 1323Tincture, 1323Nystatin, 937OOfloxacin, 938OintmentAbsorptive, 265Acrinol and Zinc Oxide, 274Betamethasone Valerate and GentamicinSulfate, 362Bufexamac, 381Ointment (continued)Hydrocortisone and Diphenhydramine,730Hydrophilic, 735Macrogol, 833Polyethylene Glycol, 833Simple, 1089Sulfur, Salicylic Acid and Thianthol,1131White, 1238Zinc Oxide, 1246Olive Oil, 939Omeprazole, 1915Operidine, 980Injection, 981Ophiopogon Tuber, 1324Ophthalmic SolutionDibekacin Sulfate, 2113Gentamicin Sulrate, 2133Idoxuridine, 747, 1893Silver Nitrate, 1088Zinc Sulfate, 1247OpiumIpecac Powder, 1324Powdered, 939Tincture, 940Opium Alkaloidsand Atropine Injection, 942and Scopolamine Injection, 943Hydrochlorides, 941Hydrochlorides Injection, 942OrangeOil, 946Peel Syrup, 1325Peel Tincture, 1325Orciprenaline Sulfate, 946Oriental Bezoar, 1325Oxapium Iodide, 947Oxaprozin, 948Oxazolam, 948Oxetacaine, 949Oxethazaine, 949Oxprenolol Hydrochloride, 950Oxybuprocaine Hydrochloride, 951Oxycodone Hydrochloride Hydrate,951Oxydol, 954Oxygen, 955Oxymetholone, 956Oxytetracycline Hydrochloride, 956Oxytocin, 958Injection, 960Oyster Shell, 1326Powdered, 1326Ozagrel Sodium, 1916for Injection, 1917PPanax Japonicus Rhizome, 1326, 1960Powdered, 1327, 1960Pancreatin, 961Pancuronium Bromide, 962Panipenem, 962Pantethine, 964Papaverine Hydrochloride, 965Injection, 965, 1918Paracetamol, 267Paraffin, 966Light Liquid, 967Liquid, 966Paraformaldehyde, 968Parnaparin Sodium, 969Pas-calciumGranules, 394Hydrate, 395

Supplement II, JP XV Index 2303PasteArsenical, 315Paraformaldehyde, Dental, 969Triozinc, Dental, 1210Peach Kernel, 1327, 1961, 2230Powdered, 1327, 1961, 2230Peanut Oil, 971Penbutolol Sulfate, 972Penicillin G Potassium, 349Pentazocine, 972Pentobarbital Calcium, 973Pentoxyverine Citrate, 974Peony Root, 1328Powdered, 1329Peplomycin Sulfate, 975for Injection, 1918Perilla Herb, 1329, 1961, 2231Perphenazine, 977Maleate, 978Maleate Tablets, 979Tablets, 977Pethidine Hydrochloride, 980Injection, 981, 1918PetrolatumHydrophilic, 981White, 981Yellow, 982Petroleum Benzin, 982Peucedanum Root, 1961Pharbitis Seed, 1330Phellodendron,Albumin Tannate and Bismuth SubnitratePowder, 1332Bark, 1330Bark, Powdered, 1331Phenazone, 310Phenethicillin Potassium, 983Phenobarbital, 984, 2168Powder, 985Powder, 10%, 985, 2168Phenol, 985and Zinc Oxide Liniment, 987for Disinfection, 986Liquefied, 986Phenolated Water, 987for Disinfection, 987Phenolsulfonphthalein, 988Injection, 988, 2169L-Phenylalanine, 989Phenylbutazone, 990Phenylephrine Hydrochloride, 990Phenytoin, 991Powder, 992, 2169Sodium for Injection, 992Tablets, 992, 2170Phytomenadione, 993Phytonadione, 993Picrasma Wood, 1333Powdered, 1333Pilocarpine Hydrochloride, 994Pimaricin, 994Pimozide, 2171Pindolol, 995Pinellia Tuber, 1333Pioglitazone Hydrochloride, 2172Pipemidic Acid Hydrate, 996, 2173PiperacillinHydrate, 1919Sodium, 997Sodium for Injection, 998PiperazineAdipate, 999Phosphate Hydrate, 999Phosphate Tablets, 1000Pirarubicin, 1000Pirenoxine, 1001Pirenzepine Hydrochloride Hydrate,1002Piroxicam, 1003Pivmecillinam Hydrochloride, 1004Tablets, 2173PlantagoHerb, 1334Seed, 1334PlatycodonFluidextract, 1334, 1962Root, 1334Root, Powdered, 1335Polyethylene Glycol400, 8301500, 8314000, 8326000, 83220000, 833Ointment, 833Pogostemon Herb, 2231Polygala Root, 1335, 1962Powdered, 1335, 1962Polygonatum Rhizome, 1336, 2232Polygonum Root, 1336, 1962Polymixin B Sulfate, 1006Polyoxyethylene Lauryl Alcohol Ether,810Polyoxyl 40 Stearate, 1007Polyporus Sclerotium, 1336, 1962Powdered, 1337, 1963Polysorbate 80, 1007Polyvidone, 1015Polyvinylpyrrolidone, 1015Poria Sclerotium, 1337Powdered, 1337Potash Soap, 1007PotassiumBromide, 1008Canrenoate, 1008Carbonate, 1009Chloride, 1009Clavulanate, 1010Hydroxide, 1012Iodide, 1013Permanganate, 1013Sulfate, 1014Potato Starch, 1014, 2174Povidone, 1015Iodine, 1017PowderAscorbic Acid, 317Chlordiazepoxide, 491Chlorpheniramine and Calcium, 497Chlorpheniramine Maleate, 499Codeine Phosphate, 1%, 536Codeine Phosphate, 10%, 537Diastase and Sodium Bicarbonate,567Diastase and Sodium Bicarbonate,Compound, 567Dihydrocodeine Phosphate, 1%, 582Dihydrocodeine Phosphate, 10%, 582Diluted Opium, 940Diphenhydramine andBromovalerylurea, 593Diphenylhydantoin, 992Dover's, 1324Ephedrine Hydrochloride, 620Ephedrine Hydrochloride, 10%, 620Famotidine, 657, 2125Gentian and Sodium Bicarbonate,1290Hydralazine Hydrochloride, 725Kainic Acid and Santonin, 790dl-Methylephedrine Hydrochloride,876dl-Methylephedrine Hydrochloride,10%, 876Nicergoline, 914Nux Vomica Extract, 1323Opium Ipecac, 1324Phellodendron, Albumin Tannateand Bismuth Subnitrate, 1332Phenobarbital, 985Phenobarbital, 10%, 985, 2168Phenytoin, 992, 2169Reserpine, 1057Reserpine, 0.1%, 1057Rhubarb and Senna, Compound, 1346Riboflavin, 1060Salicylated Alum, 1078Scopolia Extract, 1354Scopolia Extract and Carbon, 1355Scopolia Extract and Diastase, Compound,1355Scopolia Extract and EthylAminobenzoate, 1355Scopolia Extract, Paparerine andEthyl Aminobenzoate, 1356Swertia and Sodium Bicarbonate,1367Thiamine Chloride Hydrochloride,1162Vitamin B, Compound, 1230Vitamin B1 Hydrochloride, 1162Vitamin B2, 1060Vitamin C, 317Zinc Oxide Starch, 1246PowderedAcacia, 1251Agar, 1253Alisma Rhizome, 1253

2304 Index Supplement II, JP XVAloe, 1255Amomum Seed, 1256Atractylodes Lancea Rhizome, 1260Atractylodes Rhizome, 1261, 1939Calumba, 1268, 1939, 2220Capsicum, 1269Cellulose, 480, 2105Cinnamon Bark, 1273Clove, 1274Cnidium Rhizome, 1276, 1940Coix Seed, 1276Coptis Rhizome, 1278, 1940Corydalis Tuber, 1940Cyperus Rhizome, 1280, 1942Dioscorea Rhizome, 1282, 1942Fennel, 1285Gambir, 1287Gardenia Fruit, 1288Gentian, 1290, 1943Geranium Herb, 1291Ginger, 1292Ginseng, 1293Glycyrrhiza, 1296Ipecac, 1303, 1949Japanese Angelica Root, 1305Japanese Gentian, 1306, 1949Japanese Valerian, 1307, 1950, 2228Magnolia Bark, 1316, 1959Moutan Bark, 1319Opium, 939Oyster Shell, 1326Panax Japonicus Rhizome,1327,1960Peach Kernel, 1327, 1961, 2230Peony Root, 1329Phellodendron Bark, 1331Picrasma Wood, 1333Platycodon Root, 1335Polygala Root, 1335, 1962Polyporus Sclerotium, 1337, 1963Poria Sclerotium, 1337Processed Aconite Root, 1339,1963Rhubarb, 1345Rose Fruit, 1346Scutellaria Root, 1359, 1967Senega, 1361, 1968, 2234Senna Leaf, 1362Smilax Rhizome, 1364, 1968Sophora Root, 1364, 1969Sweet Hydrangea Leaf, 1365Swertia Herb, 1366Tragacanth, 1369Turmeric, 1969, 2238Zanthoxylum Fruit, 1371, 2239Pranoprofen, 1018Pravastatin Sodium, 1018Prazepam, 1020Tablets, 1021Prazosin Hydrochloride, 2174Precipitated Calcium Carbonate, 389Prednisolone, 1021Acetate, 1023Sodium Succinate for Injection,1025, 1921Sodium Phosphate, 2176Succinate, 1024Tablets, 1022Primidone, 1026Probenecid, 1027Tablets, 1027, 2177Probucol, 2177Procainamide Hydrochloride, 1028,2179Injection, 1029, 2179Tablets, 1029, 2180Procaine Hydrochloride, 1030Injection, 1030Procarbazine Hydrochloride, 1031Procaterol Hydrochloride Hydrate,1032ProcessedAconite Root, 1338, 1963Aconite Root, Powdered, 1339, 1963Ginger, 1341, 1964Prochlorperazine Maleate, 1033Tablets, 1033, 2181Progesterone, 1034, 2182Injection, 1034, 2182Proglumide, 1035Promethazine Hydrochloride, 1036Propafenone Hydrochloride, 2183Tablets, 2184Propantheline Bromide, 1036Propranolol Hydrochloride, 1037Tablets, 1038Propyl Parahydroxybenzoate, 1039Propylene Glycol, 1039Propylthiouracil, 1040Tablets, 1040, 2185Propyphenazone, 783ProstaglandinE 1 , 286E 1 α-Cyclodextrin ClathrateCompound, 287F 2α , 592Protamine Sulfate, 1041, 1921Injection, 1042, 1922, 2186Prothionamide, 1042Protirelin, 1043Tartrate Hydrate, 1044Prunella Spike, 1341Pueraria Root, 1341Pullulan, 1045PurifiedDehydrocholic Acid, 556Gelatin, 697Lanolin, 808Shellac, 1085Sodium Hyaluronate, 2194Water, 1236Water, Sterile, 1236Pyrantel Pamoate, 1045Pyrazinamide, 1046Pyridostigmine Bromide, 1047Pyridoxine Hydrochloride, 1047Injection, 1048, 1922Pyroxylin, 1049Pyrrolnitrin, 1049QQuercus Bark, 2232Quick Lime, 393Quinidine Sulfate Hydrate, 1050QuinineEthyl Carbonate, 1051Hydrochloride Hydrate, 1052Sulfate Hydrate, 1053RRanitidine Hydrochloride, 1054Rape Seed Oil, 1055Rebamipide, 2187Tablets, 2188Red Ginseng, 1342Rehmannia Root, 1343, 1964Reserpine, 1055Injection, 1056, 1922Powder, 1057Powder, 0.1%, 1057Tablets, 1057RetinolAcetate, 1058Palmitate, 1059Rhubarb, 1344Powdered, 1345Riboflavin, 1059Butyrate, 1060Rice Starch, 2189Phosphate, 1061Phosphate Injection, 1062Powder, 1060Sodium Phosphate, 1061Sodium Phosphate Injection, 1062,1922Ribostamycin Sulfate, 1063Rice Starch, 1346Rifampicin, 1064Capsules, 1065Ringer's Solution, 1066, 1922Ritodrine Hydrochloride, 1067Tablets, 1068Rokitamycin, 1069Tablets, 1923, 2190Rose Fruit, 1346Powdered, 1346Rosin, 1347Roxatidine Acetate Hydrochloride,1070Extended-release Capsules, 1071Roxithromycin, 1073, 1923Royal Jelly, 2233Ryokeijutsukanto Extract, 1347, 1965

Supplement II, JP XV Index 2305SSaccharated Pepsin, 1074Saccharin, 1075Sodium, 1076Sodium Hydrate, 1076Safflower, 1348Saffron, 1349Saireito Extract, 1349Salazosulfapyridine, 1077Salbutamol Sulfate, 1078Salicylated Alum Powder, 1078Salicylic Acid, 1079, 1924Plaster, Adhesive, 1080Spirit, 1080Santonin, 1081Saponated Cresol Solution, 545Saposhnikovia Root, 1352, 1966, 2234Sappan Wood, 1352Saussurea Root, 1352, 1966Schisandra Fruit, 1352Schizonepeta Spike, 1353ScopolamineButylbromide, 1082Hydrobromide Hydrate, 1083Scopolia Extract, 1353, 1967and Carbon Powder, 1355and Ethyl Aminobenzoate Powder,1355and Tannic Acid Suppositories,1357,Papaverine and Ethyl AminobenzoatePowder, 1356Powder, 1354Rhizome, 1357, 1967, 2234Scutellaria Root, 1358, 1967Powdered, 1359, 1967Senega, 1360, 1968, 2234Powdered, 1361, 1968, 2234Syrup, 1361Senna Leaf, 1361Powdered, 1362L-Serine, 1925Serrapeptase, 1083Serum Gonadotrophin, 710for Injection, 711Sesame Oil, 1084Sevoflurane, 2191ShellacPurified, 1085Shimbuto Extract, 2234Siccanin, 1086SilverNitrate, 1088Nitrate Ophthalmic Solution, 1088Protein, 1088Protein Solution, 1089SimpleOintment, 1089Syrup, 1089Simvastatin, 2192Sinomenium Stem, 1363Sisomicin Sulfate, 1090Slaked Lime, 392Smilax Rhizome, 1364, 1968Powdered, 1364, 1968SodiumAcetate Hydrate, 1091Aurothiomalate, 1092Benzoate, 1093Bicarbonate, 1093Bicarbonate and Bitter TinctureMixture, 1364Bicarbonate Injection, 1094, 1925Bisulfite, 1094Borate, 1095Bromide, 1095Carbonate, Dried, 1096Carbonate Hydrate, 1096Chloride, 1097Chloride Injection, 0.9%, 1098Chloride Injection, 10%, 1098, 1925Chloride Solution, Isotonic, 1098,1893Chromate ( 51 Cr) Injection, 1099Citrate Hydrate, 1099Citrate Injection for Transfusion,1099, 1926Citrate Solution, Diagnostic, 1100Cromoglicate, 1100Fusidate, 1101Hyaluronate, Purified, 2194Hydrogen Sulfite, 1094Hydroxide, 1101Iodide, 1102Iodide ( 123 I) Capsules, 1103Iodide ( 131 I) Capsules, 1103Iodide ( 131 I) Solution, 1103Iodohippurate ( 131 I) Injection, 1103Iotalamate Injection, 1103, 2195Lauryl Sulfate, 1104Metabisulfite, 1108Pertechnetate ( 99m Tc) Injection,1105Picosulfate Hydrate, 1105Polystyrene Sulfonate, 1106Prasterone Sulfate Hydrate, 1107Pyrosulfate, 1108Salicylate, 1108Starch Glycolate, 1926Sulfite, Dried, 1109Thiosulfate Hydrate, 1109Thiosulfate Injection, 1110, 1927Valproate, 1110, 2195Valproate Syrup, 2196Valproate Tablets, 2197SolutionAdrenaline, 277Alum, 293Benzalkonium Chloride, 342Benzethonium Chloride, 345Chlorhexidine Gluconate, 493Cresol, 545Dental Sodium Hypochlorite, 310Diagnostic Sodium Citrate, 1100Epinephrine, 277Glycerin and Potash, 704Isotonic Salt, 1098Isotonic Sodium Chloride, 1098,1893Ketoconazole, 2155Merbromin, 863Mercurochrome, 863Naphazoline and Chlorpheniramine,906Ringer's, 1066, 1922Saponated Cresol, 545Silver Protein, 1089Sodium Citrate, Diagnostic, 1100Sodium Iodide ( 131 I), 1103D-Sorbitol, 1113Thianthol and Salicylic Acid, Compound,1165Tolnaftate, 1189Sophora Root, 1364, 1968Powdered, 1364, 1969Sorbitan Sesquioleate, 1111D-Sorbitol, 1112Solution, 1113Soybean Oil, 1113Spectinomycin Hydrochloride Hydrate,1114Spiramycin Acetate, 1114SpiritCapsicum and Salicylic Acid, 1270Foeniculated Ammonia, 1286Iodine Salicylic Acid and Phenol,772Methyl Salicylate, Compound, 879Salicylic Acid, 1080Salicylic Acid, Compound, 1080Spironolactone, 1116StarchCorn, 542, 2110Glycolate, Sodium, 1926Potato, 1014, 2174Rice, 1346, 2189Wheat, 1237, 2216Stearic Acid, 1116Stearyl Alcohol, 1117Sterile Purified Water, 1236Streptomycin Sulfate, 1117for Injection, 2198Sucralfate Hydrate, 1118Sucrose, 1120Sulbactam Sodium, 1122, 1927Sulbenicillin Sodium, 1123Sulfadiazine Silver, 1124Sulfafurazole, 1128Sulfamethizole, 1125Sulfamethoxazole, 1126Sulfamonomethoxine Hydrate, 1126Sulfasalazine, 1077Sulfinpyrazone, 1127, 1927Tablets, 1128, 1927Sulfisomezole, 1126Sulfisoxazole, 1128Sulfobromophthalein Sodium, 1129

2306 Index Supplement II, JP XVInjection, 1130Sulfur, 1130and Camphor Lotion, 1130Salicylic Acid and Thianthol Ointment,1131Sulindac, 2198Sulpiride, 1131Capsules, 1132Tablets, 1132SulpyrineHydrate, 1133Injection, 1134, 1927Sultamicillin Tosilate Hydrate,1134,1927Sultiame, 1136SuppositoriesBisacodyl, 368, 1843Indometacin, 757, 2145Scopolia Extract and Tannic Acid,1357Suxamethonium Chloridefor Injection, 1137, 1928Hydrate, 1137Injection, 1138, 1928Sweet Hydrangea Leaf, 1365Powdered, 1365Swertiaand Sodium Bicarbonate Powder,1367Herb, 1365Herb, Powdered, 1366SyntheticAluminum Silicate, 290Camphor, 402SyrupAmphotericin B, 305Cefadroxil for, 1853Cefalexin, 2099Cefatrizine Propylene Glycolate for,2100Cefroxadine for, 2103Faropenem Sodium for, 659, 1886,2126Ipecac, 1304Monosodium Trichloroethyl Phosphate,1203Orange Peel, 1325Senega, 1361Simple, 1089Sodium Valproate, 2196Triclofos Sodium, 1203TTabletsAcemetacin, 2074Acetylsalicylic Acid, 319Ajmaline, 279, 1826Alacepril, 280Allopurinol, 2078Alminoprofen, 1827Amiodarone Hydrochloride, 2081Amitriptyline Hydrochloride, 299,1831Amlexanox, 1833Amlodipine Besilate, 2082Amosulalol Hydrochloride, 1836Amphotericin B, 305Aspirin, 319Azathioprine, 326, 2088Baclofen, 332, 1841Benidipine Hydrochloride, 339Betahistine Mesilate, 354Betamethasone, 356, 2090Bezafibrate Sustained Release, 365Bisoprolol Fumarate, 1844Bucillamine, 1845Buformine Hydrochloride, 1849Buformine HydrochlorideEntericcoated, 1847Cadralazine, 2092Cefcapene Pivoxil Hydrochloride,433Cefditoren Pivoxil, 438Cefteram Pivoxil, 2104Cetirizine Hydrochloride, 1857Chlordiazepoxide, 492, 1858Chlorphenesin Carbamate, 1859Chlorpheniramine Maleate, 500Chlorpromazine Hydrochloride, 503,1861Chlorpropamide, 505, 1861Cibenzoline Succinate, 1862Cilazapril, 1864Cilostazol, 512, 1866Clarithromycin, 517Clomifene Citrate, 527, 2109Codeine Phosphate, 537, 2109Dichlorphenamide, 572Diclofenamide, 572Diethylcarbamazine Citrate, 574,2113Diethylstilbestrol Diphosphate, 684Digitoxin, 576Digoxin, 580, 2116Dimenhydrinate, 589, 2117Diphenylhydantoin, 992Distigmine Bromide, 600, 2117Dydrogesterone, 610Emorfazone, 2123Enalapril Maleate, 1880Ephedrine Hydrochloride, 621, 1882,2124Ergometrine Maleate, 626Erythromycin Enteric-Coated, 1882,2125Estriol, 635Etacrynic Acid, 636Ethinylestradiol, 642Etidronate Disodium, 650Etilefrine Hydrochloride, 651Etizolam, 1884Famotidine, 657Faropenem Sodium, 660, 1886, 2126Flutoprazepam, 2130Folic Acid, 681, 1888Fosfestrol, 684, 1888Furosemide, 691Griseofulvin, 1890, 2135Haloperidol, 718Hydralazine Hydrochloride, 725,1890Imidapril Hydrochloride, 2141Imipramine Hydrochloride, 752,1893Indapamide, 2144Ipriflavone, 2146Irsogladine Maleate, 2149Isoniazid, 781, 2151Isosorbide Dinitrate, 786, 2151Isoxsuprine Hydrochloride, 1895Josamycin, 1897, 2152Labetalol Hydrochloride, 1899Lanatoside C, 806Levothyroxine Sodium, 817Liothyronine Sodium, 822Lisinopril, 824Manidipine Hydrochloride, 1902Mefruside, 849, 1903Metformin Hydrochloride, 867Methyldopa, 874, 1903Methylergometrine Maleate, 877Methyltestosterone, 883Metoclopramide, 886Metoprolol Tartrate, 888Metronidazole, 889Minocycline Hydrochloride, 2163Mizoribine, 1907Morphine Hydrochloride, 902, 1908,2165Mosapride Citrate, 2166Nabumetone, 1910Nicergoline, 915Nicomol, 918, 2168Nilvadipine, 924Nitrendipine, 927Nitroglycerin, 928Norgestrel and Ethinylestradiol, 934Perphenazine, 977Perphenazine Maleate, 979Phenytoin, 992, 2170Piperazine Phosphate, 1000Pivmecillinam Hydrochloride, 2173Prazepam, 1021Prednisolone, 1022Probenecid, 1027, 2177Procainamide Hydrochloride, 1029,2180Prochlorperazine Maleate, 1033,2181Propafenone Hydrochloride, 2184Propranolol Hydrochloride, 1038Propylthiouracil, 1040, 2185Rebamipide, 2188Reserpine, 1057Ritodrine Hydrochloride, 1068Rokitamycin, 1923, 2190Sodium Valproate, 2197

Supplement II, JP XV Index 2307Sulfinpyrazone, 1128, 1927Sulpiride, 1132Thiamazole, 1160Tiapride Hydrochloride, 2204Tiaramide Hydrochloride, 1172Tipepidine Hibenzate, 1177, 1930Tolbutamide, 1188, 2205Tosufloxacin Tosilate, 2207Tranexamic Acid, 1193Trichlormethiazide, 1199Trihexyphenidyl Hydrochloride,1204Trimetazidine Hydrochloride, 1207Trimethadione, 1209Troxipide, 2210Ursodeoxycholic Acid, 2214Verapamil Hydrochloride, 1226Voglibose, 1232Warfarin Potassium, 1234, 2215Zaltoprofen, 1243Tacrolimus Hydrate, 2199Talampicillin Hydrochloride, 1138Talc, 1139, 1928Tamsulosin Hydrochloride, 1140Tannic Acid, 1141Tartaric Acid, 1141Taurine, 1142Tazobactam, 2200Teceleukinfor Injection (Genetical Recombination),1148, 1929(Genetical Recombination), 1143Tegafur, 1149Teicoplanin, 1150, 2201Teprenone, 2202Terbutaline Sulfate, 1153TestosteroneEnanthate, 1154Enanthate Injection, 1154, 2203Propionate, 1155Propionate Injection, 1155, 2203Tetracaine Hydrochloride, 1156Tetracycline Hydrochloride, 1157Thallium ( 201 Tl) Chloride Injection,1158Theophylline, 1158Thiamazole, 1159Tablets, 1160ThiamineChloride Hydrochloride, 1160Chloride Hydrochloride Injection,1161, 1930Chloride Hydrochloride Powder,1162Nitrate, 1162Thiamylal Sodium, 1163for Injection, 1164Thianthol, 1165Thiopental Sodium, 1166for Injection, 1167, 1930Thioridazine Hydrochloride, 1168Thiotepa, 1168L-Threonine, 1169Thrombin, 1170Thymol, 1170Tiapride Hydrochloride, 2203Tablets, 2204Tiaramide Hydrochloride, 1171Tablets, 1172Ticlopidine Hydrochloride, 1173Timepidium Bromide Hydrate, 1174Timolol Maleate, 1174TinctureBitter, 1266Capsicum, 1269Iodine, 769Iodine, Dilute, 769Nux Vomica, 1323Opium, 940Orange Peel, 1325Tinidazole, 1175Tipepidine Hibenzate, 1176Tablets, 1177, 1930Titanium Oxide, 1178Tizanidine Hydrochloride, 1179Toad Venom, 1368Tobramycin, 1180Injection, 1930Tocopherol, 1181Acetate, 1182Calcium Succinate, 1183Nicotinate, 1184dl-α-Tocopherol, 1181Acetate, 1182Nicotinate, 1184Todralazine Hydrochloride Hydrate,1185Tofisopam, 1186Tolazamide, 1187Tolbutamide, 1188Tablets, 1188, 2205Tolnaftate, 1189Solution, 1189Tolperisone Hydrochloride, 1190Tosufloxacin TosilateHydrate, 2205Tablets, 2207Tragacanth, 1369Powdered, 1369Tranexamic Acid, 1191Capsules, 1192Injection, 1193Tablets, 1193Trapidil, 1194Trepibutone, 1195Tretoquinol Hydrochloride, 1209Triamcinolone, 1195Acetonide, 1196Triamterene, 1197Tribulus Fruit, 1369Trichlormethiazide, 1198Tablets, 1199Trichomycin, 1201Trichosanthes Root, 1369Triclofos Sodium, 1202Syrup, 1203Trihexyphenidyl Hydrochloride, 1204Tablets, 1204Trimebutine Maleate, 1206Trimetazidine Hydrochloride, 1207,1931Tablets, 1207Trimethadione, 1208Tablets, 1209Trimetoquinol Hydrochloride Hydrate,1209Tropicamide, 1211Troxipide, 2208Fine Granules, 2209Tablets, 2210L-Tryptophan, 1211Tubocurarine Chloride HydrochlorideHydrate, 1212, 1931Injection, 1213, 1931Tubocurarine Hydrochloride, 1212Injection, 1213Tulobuterol Hydrochloride, 1213Turmeric, 1367, 1969, 2237Powdered, 1969, 2238Turpentine Oil, 1214L-Tyrosine, 1931UUbenimex, 1932Capsules, 2211Ubidecarenone, 1214Ulinastatin, 1215Uncaria Hook, 1370Urapidil, 1217Urea, 1218Urokinase, 1219Ursodeoxycholic Acid, 1220, 2212Granules, 2213Tablets, 2214Uva Ursi Fluidextract, 1371, 1969VVaccineBCG, Freeze-dried, (for PercutaneousUse), 335Cholera, 506Diphtheria-Purified Pertussis-TetanusCombined, Adsorbed, 596Hepatitis B, Adsorbed, 716Inactivated Tissue Culture Rabies,Freeze-dried, 1054Influenza HA, 758Japanese Encephalitis, 786Japanese Encephalitis, Freeze-dried,786Live Attenuated Measles,Freeze-dried, 843Live Attenuated Mumps, Freeze-dried,902Live Attenuated Rubella, Freeze-dried,1074

2308 Index Supplement II, JP XVLive Oral Poliomyelitis, 1005Purified Pertussis, Adsorbed, 980Smallpox, Freeze-dried, 1091Smallpox, Freeze-dried, Prepared inCell Culture, 1091Weil's Disease and Akiyami Combined,1237L-Valine, 1221Vancomycin Hydrochloride, 1221for Injection, 1223Vasopressin Injection, 1223, 2215Verapamil Hydrochloride, 1225Tablets, 1226Vinblastine Sulfate, 1226for Injection, 1227Vincristine Sulfate, 1228, 1933Vitamin AAcetate, 1058Capsules, 1230Oil, 1229Oil Capsules, 1230Palmitate, 1059Vitamin B 1Hydrochloride, 1160Hydrochloride Injection, 1161Hydrochloride Powder, 1162Nitrate, 1162Vitamin B 2 , 1059Phosphate Ester, 1061Phosphate Ester Injection, 1062Powder, 1060Vitamin B 6 , 1047Injection, 1048Vitamin B 12 , 548Injection, 549Vitamin C, 316Injection, 317Powder, 317Vitamin D 2 , 624Vitamin D 3 , 506Vitamin E, 1181Acetate, 1182Calcium Succinate, 1183Nicotinate, 1184Vitamin K 1 , 993Voglibose, 1231Tablets, 1232WWarfarin Potassium, 1233Tablets, 1234, 2215Water, 1235for Injection, 1235, 1934Purified, 1236Sterile Purified, 1236Weak Opium Alkaloids and ScopolamineInjection, 945Weil's Disease and Akiyami CombinedVaccine, 1237Wheat Starch, 1237, 2216WhiteBeeswax, 336Ointment, 1238Petrolatum, 981Shellac, 1085Soft Sugar, 1121Whole Human Blood, 1238Wine, 1238Wood Creosote, 1870, 2110XXylitol, 1240Injection, 1241, 1935YYellowBeeswax, 336Petrolatum, 982ZZaltoprofen, 1242Tablets, 1243Zanthoxylum Fruit, 1371, 2239Powdered, 1371, 2239Zedoary, 1372, 1969Zidovudine, 1935ZincChloride, 1244Oxide, 1245Oxide Oil, 1245Oxide Ointment, 1246Oxide Starch Powder, 1246Sulfate Hydrate, 1246, 2216Sulfate Ophthalmic Solution, 1247Zinostatin Stimalamer, 1247Zolpidem Tartrate, 2217

INDEX IN LATIN NAMEAAchyranthis Radix, 1252AdepsLanae Rurificatus, 808Suillus, 808Agar, 1252Pulveratum, 1253Akebiae Caulis, 1253Alismatis Rhizoma, 1253Pulveratum, 1253Aloe, 1254Pulverata, 1255AlpiniaeFructus, 1265Officinari Rhizoma, 1256Amomi Semen, 1256Pulveratum, 1256AmylumMaydis, 542Oryzae, 1346Solani, 1014Tritici, 1237Anemarrhenae Rhizoma, 1256Angelicae Radix, 1305Pulverata, 1305Apilac, 2233Araliae Cordatae Rhizoma, 1937Arctii Fructus, 1267Arecae Semen, 1258Armeniacae Semen, 1257Artemisiae Capillaris Flos, 1258Asiasari Radix, 1259Asparagi Tuber, 1259Astragali Radix, 1260AtractylodisLanceae Rhizoma, 1260Lanceae Rhizoma Pulveratum, 1260Rhizoma, 1261Rhizoma Pulveratum, 1261AurantiiBobilis Pericarpium, 1273Fructus Immaturus, 1302Pericarpium, 1265BBelladonnae Radix, 1263Benincasae Semen, 1264Benzoinum, 1265Bezoar Bovis, 1325Bufonis Venenum, 1368Bupleuri Radix, 1266CCalumbae Radix, 1267Pulverata, 1268Cannabis Fructus, 1298Capsici Fructus, 1268Pulveratus, 1269Cardamomi Fructus, 1271Carthami Flos, 1348Caryophylli Flos, 1274Pulveratus, 1274Cassiae Semen, 1271Catalpae Fructus, 1271CeraAlba, 336Carnauba, 411Flava, 336Chrysanthemi Flos, 1271Cimicifugae Rhizoma, 1272Cinnamomi Cortex, 1272Pulveratus, 1273Clematidis Radix, 1274CnidiiMonnieris Fructus, 1275Rhizoma, 1275Rhizoma Pulveratum, 1276Coicis Semen, 1276Pulveratum, 1276Condurango Cortex, 1276Coptidis Rhizoma, 1277Pulveratum, 1278Corni Fructus, 1279Corydalis Tuber, 1279Pulveratum, 1940Crataegi Fructus, 1941Crocus, 1349Curcumae Rhizoma, 1367Purveratum, 1969Cyperi Rhizoma, 1280Pulveratum, 1280DDigenea, 1280Dioscoreae Rhizoma, 1282Pulveratum, 1282Dolichi Semen, 1282EEleutherococci senticosi Rhizoma,1283Ephdrae Herba, 1283Epimedii Herba, 1284Eriobotryae Folium, 1314Eucommiae Cortex, 1284Evodiae Fructus, 1285Extractum Belladonnae, 1263FFel Ursi, 1262Foeniculi Fructus, 1285Pulveratus, 1285Forsythiae Fructus, 1286Fossilia Ossis Mastodi, 1313Fritillariae Bulbus, 1287GGambir, 1287Pulveratum, 1287Gardeniae Fructus, 1288Pulveratus, 1288Gastrodiae Tuber, 1289GentianaeRadix, 1290Radix Pulverata, 1290Scabrae Radix, 1306Scabrae Radix Pulverata, 1306Geranii Herba, 1291Pulverata, 1291Ginseng Radix, 1292Pulverata, 1293Rubra, 1342Glehniae Radix cum Rhizoma, 1294Glycyrrhizae Radix, 1295Pulverata, 1296Gummi Arabicum, 1251Pulveratum, 1251GypsumExsiccatum, 1298Fibrosum, 1297HHouttuyniae Herba, 1302Hydrangeae Dulcis Folium, 1365Pulveratum, 1365Imperatae Rhizoma, 1302Ipecacuanhae Radix, 1303Pulverata, 1303ILLeonuri Herba, 1958Lilii Bulbus, 1958Linderae Radix, 1313Lithospermi Radix, 1313Lonicerae Folium Cum Caulis, 1314Longan Arillus, 2229Lycii2309

2310 Index in Latin Name Supplement II, JP XVCortex, 1315Fructus, 1315MMagnoliaeCortex, 1315Cortex Pulveratus, 1316Flos, 1317Malloti Cortex, 1317Mel, 1301Menthae Herba, 1317Mori Cortex, 1320Moutan Cortex, 1318Pulveratus, 1319Myristicae Semen, 2229NNelumbis Semen, 1320Notopterygii Rhizoma, 1321Nupharis Rhizoma, 1321OOleumArachidis, 971Aurantii, 946Cacao, 386Camelliae, 400Caryophylli, 1275Cinnamomi, 1273Cocois, 535Eucalypti, 654Foeniculi, 1286Maydis, 542Menthae Japonicae, 1318Olivae, 939Rapae, 1055Ricini, 414Sesami, 1084Sojae, 1113Terebinthinae, 1214Ophiopogonis Tuber, 1324Opium Pulveratum, 939Ostreae Testa, 1326Pulverata, 1326PPaeoniae Radix, 1328Pulverata, 1329Panacis Japonici Rhizoma, 1326Pulveratum, 1327Perillae Herba, 1329Persicae Semen, 1327Pulveratum, 1327Peucedani Radix, 1961Pharbitidis Semen, 1330Phellodendri Cortex, 1330Pulveratus, 1331Picrasmae Lignum, 1333Pulveratum, 1333Pinelliae Tuber, 1333PlantaginisHerba, 1334Semen, 1334Platycodi Radix, 1334Pulverata, 1335Pogostemoni Herba, 2231Polygalae Radix, 1335Pulverata, 1335Polygonati Rhizoma, 1336Polygoni Multiflori Radix, 1336Polyporus, 1336Pulveratus, 1337Poria, 1337Pulveratum, 1337Processi Aconiti Radix, 1338Pulverata, 1339Prunellae Spica, 1341Puerariae Radix, 1341QQuercus Cortex, 2232RRehmanniae Radix, 1343Resina Pini, 1347Rhei Rhizoma, 1344Pulveratum, 1345Rosae Fructus, 1346Pulveratus, 1346SSaposhnikoviae Radix, 1352Sappan Lignum, 1352Saussureae Radix, 1352Schisandrae Fructus, 1352Schizonepetae Spica, 1353Scopoliae Rhizoma, 1357Scutellariae Radix, 1358Pulverata, 1359Senegae Radix, 1360Pulverata, 1361Sennae Folium, 1361Pulveratum, 1362Sevum Bovinum, 336Sinomeni Caulis et Rhizoma, 1363Smilacis Rhizoma, 1364Pulveratum, 1364Sophorae Radix, 1364Pulverata, 1364Strychni Semen, 1321Swertiae Herba, 1365Pulverata, 1366SyrupusIpecacuanha, 1304Senegae, 1361TTinctura Amara, 1266Tragacantha, 1369Pulverata, 1369Tribuli Fructus, 1369Trichosanthis Radix, 1369UUncariae Uncis Cum Ramulus, 1370Uvae Ursi Folium, 1262VValerianae Radix, 1306Pulverata, 1307ZZanthoxyli Fructus, 1371Pulveratus, 1371Zedoariae Rhizoma, 1372ZingiberisProcessum Rhizoma, 1341Rhizoma, 1291Rhizoma Pulveratum, 1292ZizyphiFructus, 1307Semen, 1307

INDEX IN JAPANESEア亜 鉛 華 デンプン 1246亜 鉛 華 軟 膏 1246アカメガシワ 1317アクチノマイシン D 275アクラルビシン 塩 酸 塩 272アクリノール・ 亜 鉛 華 軟 膏 274アクリノール 水 和 物 274アクリノール・チンク 油 273アシクロビル 2075アザチオプリン 325アザチオプリン 錠 326, 2088亜 酸 化 窒 素 929アジスロマイシン 水 和 物 327アジマリン 278 アジマリン 錠 279,1826亜 硝 酸 アミル 309アスコルビン 酸 316アスコルビン 酸 散 317アスコルビン 酸 注 射 液 317, 1839アズトレオナム 328アストロマイシン 硫 酸 塩 322L-アスパラギン 酸 318アスピリン 318アスピリンアルミニウム 319アスピリン 錠 319アスポキシシリン 水 和 物 320アセグルタミドアルミニウム 266アセタゾラミド 268アセトアミノフェン 267アセトヘキサミド 269アセブトロール 塩 酸 塩 265アセメタシン 1825アセメタシンカプセル 2073アセメタシン 錠 2074アゼラスチン 塩 酸 塩 1839アゼラスチン 塩 酸 塩 顆 粒 2089アセンヤク 1287アセンヤク 末 1287アテノロール 323アドレナリン 276アドレナリン 液 277アドレナリン 注 射 液 276アトロピン 硫 酸 塩 水 和 物 324アトロピン 硫 酸 塩 注 射 液 324アプリンジン 塩 酸 塩 2085アプリンジン 塩 酸 塩 カプセル 2086亜 ヒ 酸 パスタ 315アフロクアロン 277アヘンアルカロイド・アトロピン 注射 液 942アヘンアルカロイド 塩 酸 塩 941アヘンアルカロイド 塩 酸 塩 注 射 液942アヘンアルカロイド・スコポラミン注 射 液 943アヘン 散 940アヘンチンキ 940アヘン・トコン 散 1324アヘン 末 939アマチャ 1365アマチャ 末 1365アマンタジン 塩 酸 塩 293アミオダロン 塩 酸 塩 2079アミオダロン 塩 酸 塩 錠 2081アミカシン 硫 酸 塩 296アミカシン 硫 酸 塩 注 射 液 1830アミドトリゾ 酸 295アミドトリゾ 酸 ナトリウムメグルミン 注 射 液 853, 2161アミドトリゾ 酸 メグルミン 注 射 液851アミトリプチリン 塩 酸 塩 298アミトリプチリン 塩 酸 塩 錠299,1831アミノ 安 息 香 酸 エチル 644アミノフィリン 水 和 物 297アミノフィリン 注 射 液 297, 1831アムホテリシン B 303アムホテリシン B 錠 305アムホテリシン B シロップ 305アムロジピンベシル 酸 塩 1834アムロジピンベシル 酸 塩 錠 2082アモキサピン 301アモキシシリンカプセル 2083アモキシシリン 水 和 物 302, 2084アモスラロール 塩 酸 塩 1835アモスラロール 塩 酸 塩 錠 1836アモバルビタール 300アラセプリル 279アラセプリル 錠 280L-アラニン 2076アラビアゴム 1251アラビアゴム 末 1251アリメマジン 酒 石 酸 塩 283アルガトロバン 水 和 物 2087亜 硫 酸 水 素 ナトリウム 1094L-アルギニン 313L-アルギニン 塩 酸 塩 313L-アルギニン 塩 酸 塩 注 射 液314,1839アルジオキサ 282アルプラゾラム 284アルプレノロール 塩 酸 塩 285アルプロスタジル 286アルプロスタジルアルファデクス287アルプロスタジル 注 射 液 1828アルベカシン 硫 酸 塩 311アルベカシン 硫 酸 塩 注 射 液 312アルミノプロフェン 1826アルミノプロフェン 錠 1827アロエ 1254アロエ 末 1255アロチノロール 塩 酸 塩 314アロプリノール 284アロプリノール 錠 2078安 息 香 酸 345安 息 香 酸 ナトリウム 1093安 息 香 酸 ナトリウムカフェイン388安 息 香 酸 ベンジル 347アンソッコウ 1265アンチピリン 310アンピシリン 水 和 物 307アンピシリンナトリウム 308アンベノニウム 塩 化 物 294アンモニア・ウイキョウ 精 1286アンモニア 水 299アンレキサノクス 1831アンレキサノクス 錠 1833イイオウ 1130イオウ・カンフルローション 1130イオウ・サリチル 酸 ・チアントール 軟膏 1131イオタラム 酸 774イオタラム 酸 ナトリウム 注 射 液1103, 2195イオタラム 酸 メグルミン 注 射 液852, 2161イオトロクス 酸 775イオパミドール 773イクタモール 744イコサペント 酸 エチル 646イセパマイシン 硫 酸 塩 777イセパマイシン 硫 酸 塩 注 射 液 2150イソクスプリン 塩 酸 塩 1894イソクスプリン 塩 酸 塩 錠 1895イソソルビド 784イソニアジド 780イソニアジド 錠 781, 2151イソニアジド 注 射 液 781, 2151イソフェンインスリン 水 性 懸 濁 注 射液 762イソフルラン 778l-イソプレナリン 塩 酸 塩 782イソプロパノール 783イソプロピルアンチピリン 783L-イソロイシン 780イダルビシン 塩 酸 塩 745イドクスウリジン 747イドクスウリジン 点 眼 液 747, 1893イトラコナゾール 1896イフェンプロジル 酒 石 酸 塩 748イブジラスト 1892イブプロフェン 744イプラトロピウム 臭 化 物 水 和 物2311

2312 Index in Japanese Supplement II, JP XV776イプリフラボン 2145イプリフラボン 錠 2146イミダプリル 塩 酸 塩 2140イミダプリル 塩 酸 塩 錠 2141イミプラミン 塩 酸 塩 751イミプラミン 塩 酸 塩 錠 752, 1893イミペネム 水 和 物 749イルソグラジンマレイン 酸 塩 2147イルソグラジンマレイン 酸 塩 細 粒2148イルソグラジンマレイン 酸 塩 錠2149イレイセン 1274, 1939インジゴカルミン 754インジゴカルミン 注 射 液 755, 2145インスリン 758インスリン 亜 鉛 水 性 懸 濁 注 射 液763インスリン 注 射 液 762インダパミド 2143インダパミド 錠 2144インチンコウ 1258インデノロール 塩 酸 塩 753インドメタシン 755インドメタシンカプセル 756, 1893インドメタシン 坐 剤 757, 2145インフルエンザ HA ワクチン 758インヨウカク 1284ウウイキョウ 1285ウイキョウ 末 1285ウイキョウ 油 1286ウコン 1367, 1969, 2237ウコン 末 1969, 2238ウベニメクス 1932ウベニメクスカプセル 2211ウヤク 1313, 1959ウラピジル 1217ウリナスタチン 1215ウルソデオキシコール 酸 2212ウルソデオキシコール 酸 錠 2214ウルソデオキシコール 酸 顆 粒 185,1220, 2213ウロキナーゼ 1219ウワウルシ 1262ウワウルシ 流 エキス 1371, 1969エエイジツ 1346エイジツ 末 1346液 状 フェノール 986エコチオパートヨウ 化 物 610エスタゾラム 631エストラジオール 安 息 香 酸 エステル631エストラジオール 安 息 香 酸 エステル水 性 懸 濁 注 射 液 633, 2125エストラジオール 安 息 香 酸 エステル注 射 液 632エストリオール 633エストリオール 錠 635エストリオール 水 性 懸 濁 注 射 液634, 2125エタクリン 酸 636エタクリン 酸 錠 636エタノール 638エタンブトール 塩 酸 塩 637エチオナミド 643エチゾラム 652エチゾラム 細 粒 1883エチゾラム 錠 1884エチドロン 酸 二 ナトリウム 649エチドロン 酸 二 ナトリウム 錠 650エチニルエストラジオール 642,2125エチニルエストラジオール 錠 642L-エチルシステイン 塩 酸 塩 645エチルモルヒネ 塩 酸 塩 水 和 物 648エチレフリン 塩 酸 塩 650エチレフリン 塩 酸 塩 錠 651エチレンジアミン 648エデト 酸 ナトリウム 水 和 物 598エーテル 641エカベトナトリウム 顆 粒 2121エカベトナトリウム 水 和 物 2121エテンザミド 640, 2125エトスクシミド 644エトドラク 653エトポシド 653エドロホニウム 塩 化 物 611エドロホニウム 塩 化 物 注 射 液 612,1878エナラプリルマレイン 酸 塩 1879エナラプリルマレイン 酸 塩 錠 1880エノキサシン 水 和 物 616エピリゾール 621エピルビシン 塩 酸 塩 622エフェドリン 塩 酸 塩 619エフェドリン 塩 酸 塩 散 10% 620エフェドリン 塩 酸 塩 錠 621, 1882,2124エフェドリン 塩 酸 塩 注 射 液619,1882エペリゾン 塩 酸 塩 618エモルファゾン 1878エモルファゾン 錠 2123エリスロマイシン 627エリスロマイシンエチルコハク 酸 エステル 629エリスロマイシンステアリン 酸 塩630エリスロマイシン 腸 溶 錠 1882,2125エリスロマイシンラクトビオン 酸 塩629エルカトニン 612エルゴカルシフェロール 624エルゴタミン 酒 石 酸 塩 627エルゴメトリンマレイン 酸 塩 625エルゴメトリンマレイン 酸 塩 錠626エルゴメトリンマレイン 酸 塩 注 射 液625, 2125塩 化 亜 鉛 1244塩 化 インジウム( 111 In) 注 射 液 755塩 化 カリウム 1009塩 化 カルシウム 水 和 物 390塩 化 カルシウム 注 射 液 390, 1851塩 化 タリウム( 201 Tl) 注 射 液 1158塩 化 ナトリウム 109710% 塩 化 ナトリウム 注 射 液1098,1925エンゴサク 1279, 1940エンゴサク 末 1940塩 酸 725塩 酸 リモナーデ 727エンビオマイシン 硫 酸 塩 616エンフルラン 615オオウギ 1260, 2219オウゴン 1358, 1967オウゴン 末 1359, 1967黄 色 ワセリン 982オウセイ 1336, 2232オウバク 1330オウバク・タンナルビン・ビスマス 散1332オウバク 末 1331オウレン 1277, 1940オウレン 末 1278, 1940オキサゾラム 948オキサピウムヨウ 化 物 947オキサプロジン 948オキシコドン 塩 酸 塩 水 和 物 951オキシテトラサイクリン 塩 酸 塩956オキシトシン 958オキシトシン 注 射 液 960オキシドール 954オキシブプロカイン 塩 酸 塩 951オキシメトロン 956オキセサゼイン 949オクスプレノロール 塩 酸 塩 950オザグレルナトリウム 1916オフロキサシン 938オメプラゾール 1915オリブ 油 939オルシプレナリン 硫 酸 塩 946オレンジ 油 946オンジ 1335, 1962オンジ 末 1335, 1962カカイニン 酸 ・サントニン 散 790カイニン 酸 水 和 物 789カオリン 795カカオ 脂 386加 香 ヒマシ 油 415

Supplement II, JP XV Index in Japanese 2313カゴソウ 1341カシュウ 1336, 1962ガジュツ 1372, 1969加 水 ラノリン 807ガスえそウマ 抗 毒 素 696カッコウ 2231カッコン 1341葛 根 湯 エキス 1308, 1950, 2228カドララジン 2091カドララジン 錠 2092過 テクネチウム 酸 ナトリウム( 99m Tc)注 射 液 1105果 糖 689果 糖 注 射 液 689, 1888カナマイシン 一 硫 酸 塩 793カナマイシン 硫 酸 塩 794カノコソウ 1306, 1950, 2228カノコソウ 末 1307, 1950, 2228カフェイン 水 和 物 387カプセル 403カプトプリル 403ガベキサートメシル 酸 塩 693, 1889過 マンガン 酸 カリウム 1013加 味 逍 遙 散 エキス 1310, 1952カモスタットメシル 酸 塩 400, 1852b-ガラクトシダーゼ(アスペルギルス) 694b-ガラクトシダーゼ(ペニシリウム)695カリジノゲナーゼ 790カリ 石 ケン 1007カルシトニン(サケ) 2093カルテオロール 塩 酸 塩 412カルナウバロウ 411カルバゾクロムスルホン 酸 ナトリウム 水 和 物 405カルバマゼピン 404カルビドパ 水 和 物 406L-カルボシステイン 407カルメロース 408, 2097カルメロースカルシウム 409, 2097カルメロースナトリウム 410, 2097カルモナムナトリウム 412カルモフール 411カロコン 1369カンキョウ 1341, 1964乾 燥 亜 硫 酸 ナトリウム 1109乾 燥 甲 状 腺 1171乾 燥 酵 母 1241乾 燥 細 胞 培 養 痘 そうワクチン 1091乾 燥 ジフテリアウマ 抗 毒 素 596乾 燥 弱 毒 生 おたふくかぜワクチン902乾 燥 弱 毒 生 風 しんワクチン 1074乾 燥 弱 毒 生 麻 しんワクチン 843乾 燥 水 酸 化 アルミニウムゲル 288乾 燥 水 酸 化 アルミニウムゲル 細 粒289, 2079乾 燥 組 織 培 養 不 活 化 狂 犬 病 ワクチン1054乾 燥 炭 酸 ナトリウム 1096乾 燥 痘 そうワクチン 1091乾 燥 日 本 脳 炎 ワクチン 786乾 燥 破 傷 風 ウマ 抗 毒 素 1156乾 燥 はぶウマ 抗 毒 素 716乾 燥 BCG ワクチン 335乾 燥 ボツリヌスウマ 抗 毒 素 374乾 燥 まむしウマ 抗 毒 素 841乾 燥 硫 酸 アルミニウムカリウム292カンゾウ 1295カンゾウエキス 1296, 1943カンゾウ 粗 エキス 1297, 1943カンゾウ 末 1296カンテン 1252カンテン 末 1253含 糖 ペプシン 1074d-カンフル 401dl-カンフル 402肝 油 538カンレノ 酸 カリウム 1008キ希 塩 酸 726キキョウ 1334キキョウ 末 1335キキョウ 流 エキス 1334, 1962キクカ 1271キササゲ 1271キジツ 1302キシリトール 1240キシリトール 注 射 液 1241, 1935キタサマイシン 798キタサマイシン 酢 酸 エステル 799キタサマイシン 酒 石 酸 塩 800キニジン 硫 酸 塩 水 和 物 1050キニーネエチル 炭 酸 エステル 1051キニーネ 塩 酸 塩 水 和 物 1052キニーネ 硫 酸 塩 水 和 物 1053牛 脂 336吸 水 軟 膏 265キョウカツ 1321, 1960キョウニン 1257, 1937, 2219キョウニン 水 1257希 ヨードチンキ 769金 チオリンゴ 酸 ナトリウム 1092クグアイフェネシン 714グアナベンズ 酢 酸 塩 715グアネチジン 硫 酸 塩 716グアヤコールスルホン 酸 カリウム1011クエン 酸 ガリウム( 67 Ga) 注 射 液 696クエン 酸 水 和 物 515クエン 酸 ナトリウム 水 和 物 1099クコシ 1315クジン 1364, 1968クジン 末 1364, 1969苦 味 重 曹 水 1364苦 味 チンキ 1266クラブラン 酸 カリウム 1010グラミシジン 712クラリスロマイシン 516クラリスロマイシン 錠 517グリクラジド 2134グリシン 704グリセオフルビン 713グリセオフルビン 錠 1890, 2135グリセリン 702グリセリンカリ 液 704クリノフィブラート 522グリベンクラミド 699クリンダマイシン 塩 酸 塩 519, 2108クリンダマイシン 塩 酸 塩 カプセル520, 2108クリンダマイシンリン 酸 エステル521クリンダマイシンリン 酸 エステル 注射 液 1866グルコン 酸 カルシウム 水 和 物 391グルタチオン 701L-グルタミン 1889クレオソート 544クレゾール 544クレゾール 水 545クレゾール 石 ケン 液 545クレボプリドリンゴ 酸 塩 2107クレマスチンフマル 酸 塩 519クロカプラミン 塩 酸 塩 水 和 物 523クロキサシリンナトリウム 水 和 物533クロキサゾラム 534クロコナゾール 塩 酸 塩 546クロスカルメロースナトリウム546, 2112クロチアゼパム 531クロトリマゾール 532クロナゼパム 528クロニジン 塩 酸 塩 529クロフィブラート 525クロフィブラートカプセル 526クロフェダノール 塩 酸 塩 524クロベタゾールプロピオン 酸 エステル 1867クロペラスチン 塩 酸 塩 530クロミフェン 塩 酸 塩 錠 2109クロミフェンクエン 酸 塩 526クロミフェンクエン 酸 塩 錠 527クロミプラミン 塩 酸 塩 528クロム 酸 ナトリウム( 51 Cr) 注 射 液1099クロモグリク 酸 ナトリウム 1100クロラゼプ 酸 二 カリウム 1868クロラゼプ 酸 二 カリウムカプセル1869クロラムフェニコール 487クロラムフェニコールコハク 酸 エステルナトリウム 489クロラムフェニコールパルミチン 酸エステル 488クロルジアゼポキシド 490クロルジアゼポキシド 散 491クロルジアゼポキシド 錠 492, 1858クロルフェニラミン・カルシウム 散

2314 Index in Japanese Supplement II, JP XV497クロルフェニラミンマレイン 酸 塩498d-クロルフェニラミンマレイン 酸 塩501クロルフェニラミンマレイン 酸 塩 散499クロルフェニラミンマレイン 酸 塩 錠500クロルフェニラミンマレイン 酸 塩 注射 液 499クロルフェネシンカルバミン 酸 エステル 496, 1858クロルフェネシンカルバミン 酸 エステル 錠 1859クロルプロパミド 504クロルプロパミド 錠 505, 1861クロルプロマジン 塩 酸 塩 502クロルプロマジン 塩 酸 塩 錠503,1861クロルプロマジン 塩 酸 塩 注 射 液503,1860クロルヘキシジン 塩 酸 塩 493クロルヘキシジングルコン 酸 塩 液493クロルマジノン 酢 酸 エステル 494クロロブタノール 495ケケイガイ 1353経 口 生 ポリオワクチン 1005ケイ 酸 マグネシウム 836軽 質 無 水 ケイ 酸 1087軽 質 流 動 パラフィン 967桂 枝 茯 苓 丸 エキス 1955ケイヒ 1272ケイヒ 末 1273ケイヒ 油 1273ケタミン 塩 酸 塩 795結 晶 性 インスリン 亜 鉛 水 性 懸 濁 注 射液 765結 晶 セルロース 477, 2105血 清 性 性 腺 刺 激 ホルモン 710ケツメイシ 1271ケトコナゾール 2152ケトコナゾール 液 2155ケトコナゾールクリーム 2153ケトコナゾールローション 2154ケトチフェンフマル 酸 塩 797ケトプロフェン 796ケノデオキシコール 酸 486ゲファルナート, 105, 2132ケンゴシ 1330ゲンタマイシン 硫 酸 塩 698ゲンタマイシン 硫 酸 塩 点 眼 液 2133ゲンチアナ 1290, 1943ゲンチアナ・ 重 曹 散 1290ゲンチアナ 末 1290, 1943ゲンノショウコ 1291ゲンノショウコ 末 1291ココウカ 1348硬 化 油 735コウジン 1342合 成 ケイ 酸 アルミニウム 290コウブシ 1280, 1942コウブシ 末 1280, 1942コウボク 1315, 1959コウボク 末 1316, 1959ゴオウ 1325コカイン 塩 酸 塩 535ゴシツ 1252牛 車 腎 気 丸 エキス 2221ゴシュユ 1285コデインリン 酸 塩 散 1% 536コデインリン 酸 塩 散 10% 537コデインリン 酸 塩 錠 537, 2109コデインリン 酸 塩 水 和 物 536ゴナドレリン 酢 酸 塩 705ゴボウシ 1267ゴマ 油 1084ゴミシ 1352コムギデンプン 1237, 2216コメデンプン 1346, 2189コリスチンメタンスルホン 酸 ナトリウム 540コリスチン 硫 酸 塩 541コルチゾン 酢 酸 エステル 543コルヒチン 538コレカルシフェロール 506コレステロール 507コレラワクチン 506コロンボ 1267, 1939, 2220コロンボ 末 1268, 1939, 2220コンズランゴ 1276コンズランゴ 流 エキス 1277, 1940ササイクロセリン 551サイコ 1266, 2220サイシン 1259, 1938柴 苓 湯 エキス 1349酢 酸 268酢 酸 ナトリウム 水 和 物 1091サッカリン 1075サッカリンナトリウム 水 和 物 1076サフラン 1349サラシ 粉 494サラシミツロウ 336サラゾスルファピリジン 1077サリチル 酸 1079, 1924サリチル 酸 精 1080サリチル 酸 ナトリウム 1108サリチル 酸 絆 創 膏 1080サリチル 酸 メチル 881サリチル・ミョウバン 散 1078ザルトプロフェン 1242ザルトプロフェン 錠 1243サルブタモール 硫 酸 塩 1078酸 化 亜 鉛 1245酸 化 カルシウム 393酸 化 チタン 1178酸 化 マグネシウム 835サンキライ 1364, 1968サンキライ 末 1364, 1968サンザシ 1941三 酸 化 ヒ 素 316サンシシ 1288サンシシ 末 1288サンシュユ 1279, 2220サンショウ 1371, 2239サンショウ 末 1371, 2239酸 素 955サンソウニン 1307サントニン 1081サンヤク 1282, 1942サンヤク 末 1282, 1942シジアスターゼ 567ジアスターゼ・ 重 曹 散 567ジアゼパム 567シアナミド 548シアノコバラミン 548, 1870シアノコバラミン 注 射 液 549, 1871ジエチルカルバマジンクエン 酸 塩574, 2113ジエチルカルバマジンクエン 酸 塩 錠574ジオウ 1343, 1964歯 科 用 アンチホルミン 310歯 科 用 トリオジンクパスタ 1210歯 科 用 パラホルムパスタ 969歯 科 用 フェノール・カンフル 987歯 科 用 ヨード・グリセリン 771ジギトキシン 576ジギトキシン 錠 576シクラシリン 507ジクロキサシリンナトリウム 水 和 物573シクロスポリン 508ジクロフェナクナトリウム 570ジクロフェナミド 571ジクロフェナミド 錠 572シクロペントラート 塩 酸 塩 549シクロホスファミド 水 和 物 550シゴカ 1283, 2221ジゴキシン 578, 2115ジゴキシン 錠 580, 2116ジゴキシン 注 射 液 579, 2116ジコッピ 1315, 1959シコン 1313, 1959, 2228次 硝 酸 ビスマス 369ジスチグミン 臭 化 物 599ジスチグミン 臭 化 物 錠 600, 2117L-システイン 1871L-システイン 塩 酸 塩 水 和 物 1872シスプラチン 513ジスルフィラム 600

Supplement II, JP XV Index in Japanese 2315ジソピラミド 598シソマイシン 硫 酸 塩 1090シタラビン 552シッカニン 1086シツリシ 1369ジドブジン 1935ジドロゲステロン 609ジドロゲステロン 錠 610シノキサシン 2105シノキサシンカプセル 2106ジノスタチンスチマラマー 1247ジノプロスト 592ジヒドロエルゴタミンメシル 酸 塩583ジヒドロエルゴトキシンメシル 酸 塩584ジヒドロコデインリン 酸 塩 581ジヒドロコデインリン 酸 塩 散 1%582ジヒドロコデインリン 酸 塩 散 10%582ジピリダモール 597ジフェニドール 塩 酸 塩 575ジフェンヒドラミン 593ジフェンヒドラミン 塩 酸 塩 594ジフェンヒドラミン・バレリル 尿 素散 593ジフェンヒドラミン・フェノール・ 亜鉛 華 リニメント 595ジブカイン 塩 酸 塩 569ジフテリアトキソイド 596ジフテリア 破 傷 風 混 合 トキソイド596ジフルコルトロン 吉 草 酸 エステル2114シプロヘプタジン 塩 酸 塩 水 和 物551ジベカシン 硫 酸 塩 569ジベカシン 硫 酸 塩 点 眼 液 2113シベンゾリンコハク 酸 塩 1861シベンゾリンコハク 酸 塩 錠 1862シメチジン 513ジメモルファンリン 酸 塩 588ジメルカプロール 590ジメルカプロール 注 射 液 590ジメンヒドリナート 588ジメンヒドリナート 錠 589, 2117次 没 食 子 酸 ビスマス 368ジモルホラミン 591ジモルホラミン 注 射 液 591弱 アヘンアルカロイド・スコポラミン 注 射 液 945シャクヤク 1328シャクヤク 末 1329ジャショウシ 1275シャゼンシ 1334シャゼンソウ 1334臭 化 カリウム 1008臭 化 ナトリウム 1095ジュウヤク 1302シュクシャ 1256シュクシャ 末 1256酒 石 酸 1141ショウキョウ 1291ショウキョウ 末 1292硝 酸 イソソルビド 785硝 酸 イソソルビド 錠 786, 2151硝 酸 銀 1088硝 酸 銀 点 眼 液 1088常 水 1235ショウズク 1271, 2220焼 セッコウ 1298消 毒 用 エタノール 640消 毒 用 フェノール 986消 毒 用 フェノール 水 987ショウマ 1272, 1939ジョサマイシン 786ジョサマイシン 錠 1897, 2152ジョサマイシンプロピオン 酸 エステル 788シラザプリル 錠 1864シラザプリル 水 和 物 1863シラスタチンナトリウム 509ジラゼプ 塩 酸 塩 水 和 物 586ジルチアゼム 塩 酸 塩 586シロスタゾール 511シロスタゾール 錠 512, 1866シロップ 用 セファトリジンプロピレングリコール 2100シロップ 用 セファドロキシル 1853シロップ 用 セファレキシン 2099シロップ 用 セフロキサジン 2103シロップ 用 ファロペネムナトリウム2126シロップ 用 ファロペネムナトリウム659, 1886シンイ 1317親 水 軟 膏 735親 水 ワセリン 981診 断 用 クエン 酸 ナトリウム 液 1100シンバスタチン 2192真 武 湯 エキス 2234ス水 酸 化 カリウム 1012水 酸 化 カルシウム 392水 酸 化 ナトリウム 1101スキサメトニウム 塩 化 物 水 和 物1137スキサメトニウム 塩 化 物 注 射 液1138, 1928スクラルファート 水 和 物 1118スコポラミン 臭 化 水 素 酸 塩 水 和 物1083ステアリルアルコール 1117ステアリン 酸 1116ステアリン 酸 カルシウム 400ステアリン 酸 ポリオキシル 40 1007ステアリン 酸 マグネシウム 837ストレプトマイシン 硫 酸 塩 1117スピラマイシン 酢 酸 エステル 1114スピロノラクトン 1116スペクチノマイシン 塩 酸 塩 水 和 物1114スリンダク 2198スルタミシリントシル 酸 塩 水 和 物1134, 1927スルチアム 1136スルバクタムナトリウム 1122, 1927スルピリド 1131スルピリドカプセル 1132スルピリド 錠 1132スルピリン 水 和 物 1133スルピリン 注 射 液 1134, 1927スルファジアジン 銀 1124スルファメチゾール 1125スルファメトキサゾール 1126スルファモノメトキシン 水 和 物1126スルフイソキサゾール 1128スルフィンピラゾン 1127, 1927スルフィンピラゾン 錠 1128, 1927スルベニシリンナトリウム 1123スルホブロモフタレインナトリウム1129スルホブロモフタレインナトリウム注 射 液 1130セ成 人 用 沈 降 ジフテリアトキソイド596精 製 水 1236精 製 ゼラチン 697精 製 セラック 1085精 製 デヒドロコール 酸 556精 製 白 糖 1120精 製 ヒアルロン 酸 ナトリウム 2194精 製 ラノリン 808生 理 食 塩 液 1098, 1893石 油 ベンジン 982セタノール 484セチリジン 塩 酸 塩 1856セチリジン 塩 酸 塩 錠 1857セッコウ 1297セトラキサート 塩 酸 塩 485セネガ 1360, 1968, 2234セネガシロップ 1361セネガ 末 1361, 1968, 2234セファクロル 415セファクロルカプセル 416セファクロル 細 粒 417セファクロル 複 合 顆 粒 419, 2097セファゾリンナトリウム 426セファゾリンナトリウム 水 和 物428セファトリジンプロピレングリコール 425, 1854セファドロキシル 421セファドロキシルカプセル 1852セファピリンナトリウム 424セファレキシン 422セファレキシンカプセル 2098セファロチンナトリウム 423, 1854セフィキシム 442セフィキシムカプセル 2101

2316 Index in Japanese Supplement II, JP XVセフェピム 塩 酸 塩 水 和 物 439セフォジジムナトリウム 447セフォゾプラン 塩 酸 塩 457セフォタキシムナトリウム 449セフォチアム 塩 酸 塩 455セフォチアムヘキセチル 塩 酸 塩453セフォテタン 451セフォペラゾンナトリウム 448セフカペンピボキシル 塩 酸 塩 細 粒432セフカペンピボキシル 塩 酸 塩 錠433セフカペンピボキシル 塩 酸 塩 水 和 物430セフジトレンピボキシル 437セフジトレンピボキシル 細 粒 438セフジトレンピボキシル 錠 438セフジニル 434セフジニルカプセル 435セフジニル 細 粒 436セフスロジンナトリウム 464セフタジジム 水 和 物 466セフチゾキシムナトリウム 471セフチブテン 水 和 物 470セフテラムピボキシル 468セフテラムピボキシル 細 粒 469セフテラムピボキシル 錠 2104セフトリアキソンナトリウム 水 和 物472セフピラミドナトリウム 458セフピロム 硫 酸 塩 460セフブペラゾンナトリウム 429セフポドキシムプロキセチル 461セフミノクスナトリウム 水 和 物446セフメタゾールナトリウム 445セフメノキシム 塩 酸 塩 443セフロキサジン 水 和 物 462セフロキシムアキセチル 474セフロキシムナトリウム 476セボフルラン 2191セラセフェート 480, 2105ゼラチン 696セラペプターゼ 1083L-セリン 1925セルモロイキン( 遺 伝 子 組 換 え)481センキュウ 1275, 1939センキュウ 末 1276, 1940ゼンコ 1961センコツ 1321, 1960, 2229センソ 1368センナ 1361センナ 末 1362センブリ 1365センブリ・ 重 曹 散 1367センブリ 末 1366ソウジュツ 1260ソソウジュツ 末 1260ソウハクヒ 1320, 1960ソボク 1352ソヨウ 1329, 1961, 2231ソルビタンセスキオレイン 酸 エステル 1111ゾルピデム 酒 石 酸 塩 2217D-ソルビトール 1112D-ソルビトール 液 1112タダイオウ 1344大 黄 甘 草 湯 エキス 1280, 2221ダイオウ 末 1345ダイズ 油 1113タイソウ 1307ダウノルビシン 塩 酸 塩 553タウリン 1142タクシャ 1253タクシャ 末 1253タクロリムス 水 和 物 2199タゾバクタム 2200ダナゾール 2112タムスロシン 塩 酸 塩 1140タランピシリン 塩 酸 塩 1138タルク 1139, 1928炭 酸 カリウム 1009炭 酸 水 素 ナトリウム 1093炭 酸 水 素 ナトリウム 注 射 液1094,1925炭 酸 ナトリウム 水 和 物 1096炭 酸 マグネシウム 834炭 酸 リチウム 826単 シロップ 1089ダントロレンナトリウム 水 和 物553単 軟 膏 1089タンニン 酸 1141タンニン 酸 アルブミン 282タンニン 酸 ジフェンヒドラミン595タンニン 酸 ベルベリン 352チチアプリド 塩 酸 塩 176, 2203チアプリド 塩 酸 塩 錠 177, 2204チアマゾール 1159チアマゾール 錠 1160チアミラールナトリウム 1163チアミン 塩 化 物 塩 酸 塩 1160チアミン 塩 化 物 塩 酸 塩 散 1162チアミン 塩 化 物 塩 酸 塩 注 射 液 1161,1930チアミン 硝 化 物 1162チアラミド 塩 酸 塩 1171チアラミド 塩 酸 塩 錠 1172チアントール 1165チオテパ 1168チオペンタールナトリウム 1166チオリダジン 塩 酸 塩 1168チオ 硫 酸 ナトリウム 水 和 物 1109チオ 硫 酸 ナトリウム 注 射 液 1110,1927チクセツニンジン 1326, 1960チクセツニンジン 末 1327, 1960チクロピジン 塩 酸 塩 1173チザニジン 塩 酸 塩 1179窒 素 928チニダゾール 1175チペピジンヒベンズ 酸 塩 1176チペピジンヒベンズ 酸 塩 錠1177,1930チメピジウム 臭 化 物 水 和 物 1174チモ 1256, 1937チモール 1170チモロールマレイン 酸 塩 1174注 射 用 アズトレオナム 1840注 射 用 アセチルコリン 塩 化 物 271,1825注 射 用 アムホテリシン B 304注 射 用 アモバルビタールナトリウム300注 射 用 アンピシリンナトリウム1838注 射 用 イダルビシン 塩 酸 塩 746注 射 用 イミペネム・シラスタチンナトリウム 750注 射 用 オザグレルナトリウム 1917注 射 用 血 清 性 性 腺 刺 激 ホルモン 711注 射 用 水 1235, 1934注 射 用 スキサメトニウム 塩 化 物1137, 1928注 射 用 ストレプトマイシン 硫 酸 塩2198注 射 用 セファゾリンナトリウム1854注 射 用 セフェピム 塩 酸 塩 441注 射 用 セフォゾプラン 塩 酸 塩 458注 射 用 セフォチアム 塩 酸 塩 456注 射 用 セフタジジム 1856注 射 用 セフメタゾールナトリウム1855注 射 用 チアミラールナトリウム1164注 射 用 チオペンタールナトリウム1167, 1930注 射 用 テセロイキン( 遺 伝 子 組 換 え)1148, 1929注 射 用 ドキソルビシン 塩 酸 塩 1877注 射 用 バンコマイシン 塩 酸 塩 1223注 射 用 ヒト 絨 毛 性 性 腺 刺 激 ホルモン708注 射 用 ヒドララジン 塩 酸 塩 724,2138注 射 用 ピペラシリンナトリウム998注 射 用 ビンブラスチン 硫 酸 塩 1227注 射 用 ファモチジン 656, 1885注 射 用 フェニトインナトリウム992注 射 用 プレドニゾロンコハク 酸 エステルナトリウム 1025, 1921

Supplement II, JP XV Index in Japanese 2317注 射 用 フロモキセフナトリウム666注 射 用 ペプロマイシン 硫 酸 塩 1918注 射 用 ベンジルペニシリンカリウム1841注 射 用 ホスホマイシンナトリウム687, 2131注 射 用 マイトマイシン C 1905注 射 用 ミノサイクリン 塩 酸 塩 1904,2163注 射 用 メロペネム 2162チョウジ 1274チョウジ 末 1274チョウジ 油 1275チョウトウコウ 1370チョレイ 1336, 1962チョレイ 末 1337, 1963L-チロジン 1931チンク 油 1245沈 降 ジフテリア 破 傷 風 混 合 トキソイド 596沈 降 精 製 百 日 せきジフテリア 破 傷 風混 合 ワクチン 596沈 降 精 製 百 日 せきワクチン 980沈 降 炭 酸 カルシウム 389沈 降 破 傷 風 トキソイド 1156沈 降 はぶトキソイド 716沈 降 B 型 肝 炎 ワクチン 716チンピ 1273ツツバキ 油 400ツボクラリン 塩 化 物 塩 酸 塩 水 和 物1212, 1931ツボクラリン 塩 化 物 塩 酸 塩 注 射 液1213, 1931ツロブテロール 塩 酸 塩 1213テテイコプラニン 1150, 2201低 置 換 度 ヒドロキシプロピルセルロース 738, 2139テオフィリン 1158テガフール 1149デキサメタゾン 560デキストラン 40 561, 1873デキストラン 40 注 射 液 562デキストラン 70 563デキストラン 硫 酸 エステルナトリウムイオウ 5 564デキストラン 硫 酸 ナトリウムイオウ18 565デキストリン 565デキストロメトルファン 臭 化 水 素 酸塩 水 和 物 566テストステロンエナント 酸 エステル1154テストステロンエナント 酸 エステル注 射 液 1154, 2203テストステロンプロピオン 酸 エステル 1155テストステロンプロピオン 酸 エステル 注 射 液 1155, 2203デスラノシド 559デスラノシド 注 射 液 560, 1873テセロイキン( 遺 伝 子 組 換 え) 1143テトラカイン 塩 酸 塩 1156テトラサイクリン 塩 酸 塩 1157デヒドロコール 酸 556デヒドロコール 酸 注 射 液 557, 1873デフェロキサミンメシル 酸 塩554,1873テプレノン 2202デメチルクロルテトラサイクリン 塩酸 塩 558テルブタリン 硫 酸 塩 1153テレビン 油 1214天 然 ケイ 酸 アルミニウム 289デンプングリコール 酸 ナトリウム1926テンマ 1289, 1943テンモンドウ 1259, 1938トトウガシ 1264トウガラシ 1268トウガラシ・サリチル 酸 精 1270トウガラシチンキ 1269トウガラシ 末 1269トウキ 1305トウキ 末 1305トウニン 1327, 1961, 2230トウニン 末 1327, 1961, 2230トウヒ 1265トウヒシロップ 1325トウヒチンキ 1325トウモロコシデンプン 542, 2110トウモロコシ 油 542ドキサゾシンメシル 酸 塩 2117ドキサプラム 塩 酸 塩 水 和 物 603ドキシサイクリン 塩 酸 塩 水 和 物606ドキシフルリジン 604ドキシフルリジンカプセル 604ドキソルビシン 塩 酸 塩 605ドクカツ 1937トコフェロール 1181トコフェロールコハク 酸 エステルカルシウム 1183トコフェロール 酢 酸 エステル 1182トコフェロールニコチン 酸 エステル1184トコン 1303, 1949トコンシロップ 1304トコン 末 1303, 1949トスフロキサシントシル 酸 塩 錠179, 2207トスフロキサシントシル 酸 塩 水 和 物178, 2205トチュウ 1284トドララジン 塩 酸 塩 水 和 物 1185ドパミン 塩 酸 塩 602ドパミン 塩 酸 塩 注 射 液 602, 1877トフィソパム 1186ドブタミン 塩 酸 塩 601トブラマイシン 1180トブラマイシン 注 射 液 1930トラガント 1369トラガント 末 1369トラザミド 1187トラネキサム 酸 1191トラネキサム 酸 カプセル 1192トラネキサム 酸 錠 1193トラネキサム 酸 注 射 液 1193トラピジル 1194トリアムシノロン 1195トリアムシノロンアセトニド 1196トリアムテレン 1197トリクロホスナトリウム 1202トリクロホスナトリウムシロップ1203トリクロルメチアジド 1198トリクロルメチアジド 錠 1199トリコマイシン 1201L-トリプトファン 1211トリヘキシフェニジル 塩 酸 塩 1204トリヘキシフェニジル 塩 酸 塩 錠1204トリメタジオン 1208トリメタジオン 錠 1209トリメタジジン 塩 酸 塩 1207, 1931トリメタジジン 塩 酸 塩 錠 1207トリメトキノール 塩 酸 塩 水 和 物1209トリメブチンマレイン 酸 塩 1206トルナフタート 1189トルナフタート 液 1189トルブタミド 1188トルブタミド 錠 1188, 2205トルペリゾン 塩 酸 塩 1190L-トレオニン 1169トレピブトン 1195ドロキシドパ 2118ドロキシドパカプセル 2119ドロキシドパ 細 粒 2120トロキシピド 2208トロキシピド 細 粒 2209トロキシピド 錠 2210トロピカミド 1211ドロペリドール 608トロンビン 1170豚 脂 808ドンペリドン 1876ナナイスタチン 937ナタネ 油 1055ナドロール 904ナファゾリン 塩 酸 塩 907ナファゾリン・クロルフェニラミン液 906

2318 Index in Japanese Supplement II, JP XVナファゾリン 硝 酸 塩 908ナファモスタットメシル 酸 塩 1911ナブメトン 1908ナブメトン 錠 1910ナプロキセン 908ナリジクス 酸 905ナロキソン 塩 酸 塩 906ニニガキ 1333ニガキ 末 1333ニカルジピン 塩 酸 塩 911ニカルジピン 塩 酸 塩 注 射 液912,1912ニクズク 2229ニコチン 酸 920ニコチン 酸 アミド 919ニコチン 酸 注 射 液 921, 1912ニコモール 917ニコモール 錠 918, 2168ニコランジル 919, 1912ニザチジン 1912ニザチジンカプセル 1913二 酸 化 炭 素 407ニセリトロール 916ニセルゴリン 913ニセルゴリン 散 914ニセルゴリン 錠 915ニトラゼパム 925ニトレンジピン 926ニトレンジピン 錠 927ニトログリセリン 錠 928ニフェジピン 922日 本 脳 炎 ワクチン 786乳 酸 801乳 酸 カルシウム 水 和 物 393乳 糖 水 和 物 803, 2156尿 素 1218ニルバジピン 923ニルバジピン 錠 924ニンジン 1292ニンジン 末 1293ニンドウ 1314ネネオスチグミンメチル 硫 酸 塩 909ネオスチグミンメチル 硫 酸 塩 注 射 液910, 1912ネチルマイシン 硫 酸 塩 910ノ濃 グリセリン 703濃 ベンザルコニウム 塩 化 物 液 50343ノスカピン 936ノスカピン 塩 酸 塩 水 和 物 937ノルアドレナリン 930ノルアドレナリン 注 射 液 931, 1915ノルエチステロン 932, 2168ノルゲストレル 933ノルゲストレル・エチニルエストラジオール 錠 934ノルトリプチリン 塩 酸 塩 935ノルフロキサシン 932ハバイモ 1287, 1942バカンピシリン 塩 酸 塩 329白 色 セラック 1085白 色 軟 膏 1238白 色 ワセリン 981白 糖 1121バクモンドウ 1324バクロフェン 331バクロフェン 錠 332, 1841バシトラシン 330バソプレシン 注 射 液 1223, 2215八 味 地 黄 丸 エキス 2225ハチミツ 1301ハッカ 1317ハッカ 水 1318ハッカ 油 1318パップ 用 複 方 オウバク 散 1332パニペネム 962パパベリン 塩 酸 塩 965パパベリン 塩 酸 塩 注 射 液 965, 1918ハマボウフウ 1294, 1943バメタン 硫 酸 塩 333パラアミノサリチル 酸 カルシウム 顆粒 394パラアミノサリチル 酸 カルシウム 水和 物 395パラオキシ 安 息 香 酸 エチル 647パラオキシ 安 息 香 酸 ブチル 386パラオキシ 安 息 香 酸 プロピル 1039パラオキシ 安 息 香 酸 メチル 878パラフィン 966パラホルムアルデヒド 968L-バリン 1221パルナパリンナトリウム 969バルビタール 333バルプロ 酸 ナトリウム 1110, 2195バルプロ 酸 ナトリウムシロップ2196バルプロ 酸 ナトリウム 錠 2197バレイショデンプン 1014, 2173ハロキサゾラム 719ハロタン 719ハロペリドール 717ハロペリドール 錠 718パンクレアチン 961パンクロニウム 臭 化 物 962ハンゲ 1333半 夏 厚 朴 湯 エキス 1943バンコマイシン 塩 酸 塩 1221パンテチン 964パントテン 酸 カルシウム 394ヒピオグリタゾン 塩 酸 塩 2172ビオチン 1842ピコスルファートナトリウム 水 和 物1105ビサコジル 367 ビサコジル 坐 剤 368,1843ビソプロロールフマル 酸 塩 1843ビソプロロールフマル 酸 塩 錠 1844ビタミン A 油 1229ビタミン A 油 カプセル 1230ヒトインスリン( 遺 伝 子 組 換 え)760ヒト 下 垂 体 性 性 腺 刺 激 ホルモン708, 2137ヒト 絨 毛 性 性 腺 刺 激 ホルモン 707人 全 血 液 1238人 免 疫 グロブリン 724ヒドララジン 塩 酸 塩 724ヒドララジン 塩 酸 塩 散 725ヒドララジン 塩 酸 塩 錠 725, 1890ヒドロキシジン 塩 酸 塩 739ヒドロキシジンパモ 酸 塩 739ヒドロキシプロピルセルロース736, 2139ヒドロキソコバラミン 酢 酸 塩 736ヒドロクロロチアジド 727ヒドロコタルニン 塩 酸 塩 水 和 物734ヒドロコルチゾン 728ヒドロコルチゾンコハク 酸 エステル733ヒドロコルチゾンコハク 酸 エステルナトリウム 732ヒドロコルチゾン 酢 酸 エステル729ヒドロコルチゾン・ジフェンヒドラミン 軟 膏 730ヒドロコルチゾン 酪 酸 エステル730ヒドロコルチゾンリン 酸 エステルナトリウム 731, 2139ピブメシリナム 塩 酸 塩 1004ピブメシリナム 塩 酸 塩 錠 2173ヒプロメロース 741, 2140ヒプロメロースフタル 酸 エステル743, 1891, 2140ピペミド 酸 水 和 物 996, 2173ピペラシリン 水 和 物 1919ピペラシリンナトリウム 997ピペラジンアジピン 酸 塩 999ピペラジンリン 酸 塩 錠 1000ピペラジンリン 酸 塩 水 和 物 999ビペリデン 塩 酸 塩 366ビホナゾール 366ヒマシ 油 414ピマリシン 994ヒメクロモン 740ピモジド 2171ビャクゴウ 1958

Supplement II, JP XV Index in Japanese 2319ビャクシ 1257, 1937ビャクジュツ 1261, 1938ビャクジュツ 末 1261, 1939氷 酢 酸 269ピラジナミド 1046ピラルビシン 1000ピランテルパモ 酸 塩 1045ピリドキシン 塩 酸 塩 1047ピリドキシン 塩 酸 塩 注 射 液1048,1922ピリドスチグミン 臭 化 物 1047ピレノキシン 1001ピレンゼピン 塩 酸 塩 水 和 物 1002ピロ 亜 硫 酸 ナトリウム 1108ピロカルピン 塩 酸 塩 994ピロキシカム 1003ピロキシリン 1049ピロールニトリン 1049ビワヨウ 1314ビンクリスチン 硫 酸 塩 1228, 1933ピンドロール 995ビンブラスチン 硫 酸 塩 1226ビンロウジ 1258フファモチジン 655ファモチジン 散 657, 2125ファモチジン 錠 657ファロペネムナトリウム 錠660,1886, 2126ファロペネムナトリウム 水 和 物658,1885フィトナジオン 993フェニトイン 991フェニトイン 散 992, 2169フェニトイン 錠 992, 2170L-フェニルアラニン 989フェニルブタゾン 990フェニレフリン 塩 酸 塩 990フェネチシリンカリウム 983フェノバルビタール 984, 2168フェノバルビタール 散 10% 985,2168フェノール 985フェノール・ 亜 鉛 華 リニメント 987フェノール 水 987フェノールスルホンフタレイン988フェノールスルホンフタレイン 注 射液 988, 2169フェルビナク 1887フェンタニルクエン 酸 塩 661フェンブフェン 660複 方 アクリノール・チンク 油 273複 方 オキシコドン・アトロピン 注 射液 953複 方 オキシコドン 注 射 液 952複 方 サリチル 酸 精 1080複 方 サリチル 酸 メチル 精 879複 方 ジアスターゼ・ 重 曹 散 567複 方 ダイオウ・センナ 散 1346複 方 チアントール・サリチル 酸 液1165複 方 ビタミン B 散 1230複 方 ヨード・グリセリン 770複 方 ロートエキス・ジアスターゼ 散1355ブクモロール 塩 酸 塩 378ブクリョウ 1337ブクリョウ 末 1337ブシ 1338, 1963フシジン 酸 ナトリウム 1101ブシ 末 1339, 1963ブシラミン 377ブシラミン 錠 1845ブスルファン 384ブチルスコポラミン 臭 化 物 1082ブドウ 酒 1238ブドウ 糖 700ブドウ 糖 注 射 液 701, 1889ブトロピウム 臭 化 物 385ブナゾシン 塩 酸 塩 383ブフェキサマク 380ブフェキサマククリーム 380ブフェキサマク 軟 膏 381ブフェトロール 塩 酸 塩 379ブプラノロール 塩 酸 塩 383ブプレノルフィン 塩 酸 塩 1850ブホルミン 塩 酸 塩 1846ブホルミン 塩 酸 塩 錠 1849ブホルミン 塩 酸 塩 腸 溶 錠 1847ブメタニド 382フラジオマイシン 硫 酸 塩 688プラステロン 硫 酸 エステルナトリウム 水 和 物 1107プラゼパム 1020プラゼパム 錠 1021プラゾシン 塩 酸 塩 2174プラノプロフェン 1018プラバスタチンナトリウム 1018フラビンアデニンジヌクレオチドナトリウム 662フラボキサート 塩 酸 塩 664プリミドン 1026フルオキシメステロン 675フルオシノニド 672フルオシノロンアセトニド 670フルオレセインナトリウム 673フルオロウラシル 674フルオロメトロン 673フルジアゼパム 669フルシトシン 668フルスルチアミン 塩 酸 塩 692フルタミド 2128フルトプラゼパム 2129フルトプラゼパム 錠 2130フルドロコルチゾン 酢 酸 エステル2127フルニトラゼパム 670フルフェナジンエナント 酸 エステル676フルラゼパム 677フルラゼパム 塩 酸 塩 678フルラゼパムカプセル 678プルラン 1045フルルビプロフェン 679ブレオマイシン 塩 酸 塩 370ブレオマイシン 硫 酸 塩 372プレドニゾロン 1021プレドニゾロンコハク 酸 エステル1024プレドニゾロン 酢 酸 エステル 1023プレドニゾロンリン 酸 エステルナトリウム 2176プレドニゾロン 錠 1022プロカインアミド 塩 酸 塩 1028,2179プロカインアミド 塩 酸 塩 錠 1029,2180プロカインアミド 塩 酸 塩 注 射 液1029, 2179プロカイン 塩 酸 塩 1030プロカイン 塩 酸 塩 注 射 液 1030プロカテロール 塩 酸 水 和 物 1032プロカルバジン 塩 酸 塩 1031プログルミド 1035プロクロルペラジンマレイン 酸 塩1033プロクロルペラジンマレイン 酸 塩 錠1033, 2181プロゲステロン 1034, 2182プロゲステロン 注 射 液 1034, 2182フロセミド 690フロセミド 錠 691フロセミド 注 射 液 2131プロタミンインスリン 亜 鉛 水 性 懸 濁注 射 液 766プロタミン 硫 酸 塩 1041, 1921プロタミン 硫 酸 塩 注 射 液 1042,1922, 2186プロチオナミド 1042プロチレリン 1043プロチレリン 酒 石 酸 塩 水 和 物 1044プロテイン 銀 1088プロテイン 銀 液 1089プロパフェノン 塩 酸 塩 2183プロパフェノン 塩 酸 塩 錠 2184プロパンテリン 臭 化 物 1036プロピルチオウラシル 1040プロピルチオウラシル 錠 1040,2185プロピレングリコール 1039プロブコール 2177プロプラノロール 塩 酸 塩 1037プロプラノロール 塩 酸 塩 錠 1038フロプロピオン 667, 2126フロプロピオンカプセル 667プロベネシド 1027プロベネシド 錠 1027, 2177ブロマゼパム 374ブロムヘキシン 塩 酸 塩 375プロメタジン 塩 酸 塩 1036フロモキセフナトリウム 664ブロモクリプチンメシル 酸 塩 376ブロモバレリル 尿 素 377粉 末 セルロース 480, 2105

2320 Index in Japanese Supplement II, JP XVヘベカナマイシン 硫 酸 塩 337ベクロメタゾンプロピオン 酸 エステル 335ベザフィブラート 364ベザフィブラート 徐 放 錠 365ベタキソロール 塩 酸 塩 2090ベタネコール 塩 化 物 363ベタヒスチンメシル 酸 塩 353, 1842ベタヒスチンメシル 酸 塩 錠 354ベタメタゾン 355ベタメタゾン 吉 草 酸 エステル 360ベタメタゾン 吉 草 酸 エステル・ゲンタマイシン 硫 酸 塩 クリーム 361ベタメタゾン 吉 草 酸 エステル・ゲンタマイシン 硫 酸 塩 軟 膏 362ベタメタゾンジプロピオン 酸 エステル 358ベタメタゾン 錠 356, 2090ベタメタゾンリン 酸 エステルナトリウム 359ペチジン 塩 酸 塩 980ペチジン 塩 酸 塩 注 射 液 981, 1918ベニジピン 塩 酸 塩 338ベニジピン 塩 酸 塩 錠 339ヘパリンカルシウム 2135ヘパリンナトリウム 721, 2137ヘパリンナトリウム 注 射 液 722ペプロマイシン 硫 酸 塩 975ベラドンナエキス 1263, 1939ベラドンナコン 1263ベラパミル 塩 酸 塩 1225ベラパミル 塩 酸 塩 錠 1226ペルフェナジン 977ペルフェナジン 錠 977ペルフェナジンマレイン 酸 塩 978ペルフェナジンマレイン 酸 塩 錠979ベルベリン 塩 化 物 水 和 物 351ベンザルコニウム 塩 化 物 342ベンザルコニウム 塩 化 物 液 342ベンジルアルコール 346ベンジルペニシリンカリウム 349ベンジルペニシリンベンザチン 水 和物 348ヘンズ 1282ベンズブロマロン 343ベンゼトニウム 塩 化 物 344ベンゼトニウム 塩 化 物 液 345ベンセラジド 塩 酸 塩 340ペンタゾシン 972ペントキシベリンクエン 酸 塩 974ベントナイト 341ペントバルビタールカルシウム973ペンブトロール 硫 酸 塩 972ボウイ 1363ホボウコン 1302, 1949ホウ 酸 374ホウ 砂 1095抱 水 クロラール 487ボウフウ 1352, 1966, 2234ボクソク 2232ボグリボース 1231ボグリボース 錠 1232ホスフェストロール 683, 1888ホスフェストロール 錠 684, 1888ホスホマイシンカルシウム 水 和 物685ホスホマイシンナトリウム 686ボタンピ 1318ボタンピ 末 1319補 中 益 気 湯 エキス 1298, 1945, 2228ポビドン 1015ポビドンヨード 1017ホマトロピン 臭 化 水 素 酸 塩 722ホミカ 1321ホミカエキス 1322, 1960ホミカエキス 散 1323ホミカチンキ 1323ホモクロルシクリジン 塩 酸 塩 723ポリスチレンスルホン 酸 カルシウム398ポリスチレンスルホン 酸 ナトリウム1106ポリソルベート 80 1007ホリナートカルシウム 391, 1851ポリミキシン B 硫 酸 塩 1006ホルマリン 681ホルマリン 水 682ホルモテロールフマル 酸 塩 水 和 物682ボレイ 1326ボレイ 末 1326ママイトマイシン C 898マオウ 1283マーキュロクロム 862マーキュロクロム 液 863マクリ 1280マクロゴール 400 830マクロゴール 1500 831マクロゴール 4000 832マクロゴール 6000 832マクロゴール 20000 833マクロゴール 軟 膏 833マシニン 1298麻 酔 用 エーテル 641マニジピン 塩 酸 塩 1900マニジピン 塩 酸 塩 錠 1902マプロチリン 塩 酸 塩 842マルトース 水 和 物 840D-マンニトール 841D-マンニトール 注 射 液 842, 1903ミミグレニン 896ミクロノマイシン 硫 酸 塩 893ミコナゾール 892ミコナゾール 硝 酸 塩 893ミゾリビン 1906ミゾリビン 錠 1907ミツロウ 336ミデカマイシン 894ミデカマイシン 酢 酸 エステル 895ミノサイクリン 塩 酸 塩 897ミノサイクリン 塩 酸 塩 錠 2163ミョウバン 水 293ム無 晶 性 インスリン 亜 鉛 水 性 懸 濁 注 射液 764無 水 アンピシリン 306無 水 エタノール 639無 水 カフェイン 386無 水 クエン 酸 514無 水 乳 糖 802, 1900, 2155無 水 リン 酸 水 素 カルシウム396,1874ムピロシンカルシウム 水 和 物 902メメキシレチン 塩 酸 塩 891メキタジン 861メグルミン 850メクロフェノキサート 塩 酸 塩 843メコバラミン 844メシル 酸 塩 ガベキサート 693メストラノール 864メダゼパム 845, 1903メタンフェタミン 塩 酸 塩 868L-メチオニン 869メチクラン 884メチラポン 890dl-メチルエフェドリン 塩 酸 塩 875dl-メチルエフェドリン 塩 酸 塩 散 10%876メチルエルゴメトリンマレイン 酸 塩876メチルエルゴメトリンマレイン 酸 塩錠 877メチルジゴキシン 885メチルセルロース 871, 2163メチルテストステロン 882メチルテストステロン 錠 883メチルドパ 錠 874, 1903メチルドパ 水 和 物 873メチルプレドニゾロン 879メチルプレドニゾロンコハク 酸 エステル 880メチルベナクチジウム 臭 化 物 871メチルロザニリン 塩 化 物 881滅 菌 精 製 水 1236

Supplement II, JP XV Index in Japanese 2321メテノロンエナント 酸 エステル866メテノロンエナント 酸 エステル 注 射液 866メテノロン 酢 酸 エステル 865メトキサレン 870メトクロプラミド 886メトクロプラミド 錠 886メトトレキサート 869メトプロロール 酒 石 酸 塩 887メトプロロール 酒 石 酸 塩 錠 888メトホルミン 塩 酸 塩 867メトホルミン 塩 酸 塩 錠 867メトロニダゾール 889メトロニダゾール 錠 889メナテトレノン 855メピチオスタン 858メピバカイン 塩 酸 塩 859メピバカイン 塩 酸 塩 注 射 液 860,2161メフェナム 酸 847メフルシド 849メフルシド 錠 849, 1903メフロキン 塩 酸 塩 848メペンゾラート 臭 化 物 857メルカプトプリン 水 和 物 861メルファラン 855メロペネム 水 和 物 863dl-メントール 856l-メントール 857モ木 クレオソート 1870, 2110モクツウ 1253モサプリドクエン 酸 塩 錠 2166モサプリドクエン 酸 塩 水 和 物 2165モッコウ 1352, 1966モノステアリン 酸 アルミニウム291モノステアリン 酸 グリセリン 704モルヒネ・アトロピン 注 射 液 899モルヒネ 塩 酸 塩 錠 902, 1908, 2165モルヒネ 塩 酸 塩 水 和 物 900モルヒネ 塩 酸 塩 注 射 液 901, 2165ヤクチ 1265ヤクモソウ 1958薬 用 石 ケン 846薬 用 炭 845ヤシ 油 535ヤユユウタン 1262, 2219ユーカリ 油 654輸 血 用 クエン 酸 ナトリウム 注 射 液1099, 1926ユビデカレノン 1214ヨヨウ 化 カリウム 1013ヨウ 化 ナトリウム 1102ヨウ 化 ナトリウム( 123 I)カプセル1103ヨウ 化 ナトリウム( 131 I) 液 1103ヨウ 化 ナトリウム( 131 I)カプセル1103ヨウ 化 人 血 清 アルブミン( 131 I) 注 射 液768ヨウ 化 ヒプル 酸 ナトリウム( 131 I) 注 射液 1103葉 酸 680葉 酸 錠 681, 1888葉 酸 注 射 液 681, 1888ヨウ 素 768ヨクイニン 1276ヨクイニン 末 1276ヨーダミド 767ヨーダミドナトリウムメグルミン 注射 液 854ヨード・サリチル 酸 ・フェノール 精772ヨードチンキ 769ヨードホルム 773ララウリル 硫 酸 ナトリウム 1104ラウロマクロゴール 810ラクツロース 804ラタモキセフナトリウム 809ラッカセイ 油 971ラナトシド C 805ラナトシド C 錠 806ラニチジン 塩 酸 塩 1054ラベタロール 塩 酸 塩 1898ラベタロール 塩 酸 塩 錠 1899リリオチロニンナトリウム 821リオチロニンナトリウム 錠 822リシノプリル 錠 824リシノプリル 水 和 物 823L-リジン 塩 酸 塩 829L-リジン 酢 酸 塩 2159リゾチーム 塩 酸 塩 830リドカイン 818リドカイン 注 射 液 818, 2157リトドリン 塩 酸 塩 1067リトドリン 塩 酸 塩 錠 1068リファンピシン 1064リファンピシンカプセル 1065リボスタマイシン 硫 酸 塩 1063リボフラビン 1059リボフラビン 散 1060リボフラビン 酪 酸 エステル 1060リボフラビンリン 酸 エステルナトリウム 1061リボフラビンリン 酸 エステルナトリウム 注 射 液 1062, 1922リマプロストアルファデクス 819リュウガンニク 2229リュウコツ 2229リュウコツ 1313硫 酸 亜 鉛 水 和 物 1246, 2216硫 酸 亜 鉛 点 眼 液 1247硫 酸 アルミニウムカリウム 水 和 物292硫 酸 カリウム 1014硫 酸 鉄 水 和 物 661硫 酸 バリウム 334硫 酸 マグネシウム 水 839硫 酸 マグネシウム 水 和 物 838硫 酸 マグネシウム 注 射 液 839, 1900リュウタン 1306, 1949リュウタン 末 1306, 1949流 動 パラフィン 966リョウキョウ 1256, 1937苓 桂 朮 甘 湯 エキス 1347, 1965リンゲル 液 1066, 1922リンコマイシン 塩 酸 塩 水 和 物 820リンコマイシン 塩 酸 塩 注 射 液 2157リン 酸 水 素 カルシウム 水 和 物396,1875リン 酸 水 素 ナトリウム 水 和 物 568リン 酸 二 水 素 カルシウム 水 和 物397レレセルピン 1055レセルピン 散 0.1% 1057レセルピン 錠 1057レセルピン 注 射 液 1056, 1922レチノール 酢 酸 エステル 1058レチノールパルミチン 酸 エステル1059レナンピシリン 塩 酸 塩 810レバミピド 2187レバミピド 錠 2188レバロルファン 酒 石 酸 塩 813レバロルファン 酒 石 酸 塩 注 射 液814,1900レボチロキシンナトリウム 錠 817レボチロキシンナトリウム 水 和 物816レボドパ 814レボフロキサシン 水 和 物 2156レボメプロマジンマレイン 酸 塩815レンギョウ 1286レンニク 1320ロL-ロイシン 812ロキサチジン 酢 酸 エステル 塩 酸 塩1070ロキサチジン 酢 酸 エステル 塩 酸 塩 徐

2322 Index in Japanese Supplement II, JP XV放 カプセル 1071ロキシスロマイシン 1073, 1923ロキソプロフェンナトリウム 水 和 物828ロキタマイシン 1069ロキタマイシン 錠 1923, 2190ロサルタンカリウム 2158ロジン 1347ロートエキス 1353, 1967ロートエキス・アネスタミン 散1355ロートエキス・カーボン 散 1355ロートエキス 散 1353ロートエキス・タンニン 坐 剤 1357ロートエキス・パパベリン・アネスタミン 散 1356ロートコン 1357, 1967, 2234ロラゼパム 827ローヤルゼリー 2233ワワイル 病 秋 やみ 混 合 ワクチン 1237ワルファリンカリウム 1233ワルファリンカリウム 錠 1234,2215