Clw@terizclon of tL*Mi. ,1cid in Di&tu',t Pho@dicd Dotuge Fw.d tn ...

DRUG.DRUG INTERACTION STUDIES OF 

CETIRIZIIIE 

THESIS PRESENTED FOR THE DEGREE 

OF 

DOCTOR OT PHILOSOPHY 

BY 

ttr|{nsJa.vaa Ir{,Sc, 

DEPARTMENT OF CIIEMISTRY 

TJNIVERSITY OF KARACH1 

JULY 2009

Deparrnent ofchemisry 

University ofKrrachi 

CERTIFICATE 

Cddtrd rhar Mh3 I.&! sL|t.lra h3 @id out ho B*rt od .,qcrirmrsl rqt d 

thc iopic €trdtld as Drug-Irrug Int rsctioD Sludi€! of Cetliltlm, mdd ou 

suid.!€ 'd rrDcrvki@ i! BFolJ lab I at lh. &!3arcb bsdnn of Pbro@|dcd 

S.i@..+ F&dty of Pt |r@y dd rib 9, D.!rr!la. of Cbc6ify, Unicnrt ofl

llfris tfr-tis is &atcf 

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Hisory 

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Slrrcturc @livity Eldliotrsbip 

Cdi.izi@ .nd @tiond 

Doqge ,41 ./6rnidion 

CONTENTS 

INTRODUCITON 

Calcim cblml block€r 

NoDst rcid.l dti-inflmnarory drugs (NSAID' 

NIDDMS 

EMtid dd Fe eldents 

Immboddalilg &tility 

PEpetion of deioni*d qd.i 

E (PERIMENTA|- 

Uv/vhible sp€cbo$opic ealysis 

PEpdlion of solutioN ofcernizirc 

Conslrwion of lh. calibolro! cw6 of @lirizine 

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CosEucio! ofth. cilibdi@ crc ofi.Lncting dtugt 

1, vtn dailalililie of celiri2iE dihydnhloridc 

Qu itatiotr ofdrugs uing R'P-HPLC tatuiq*s 

Asy ofetnizirc BinS RP- HPLC 

M€rhod dev€lopoat.!d optibizarioo 

DruB- drw intera.don $udi6 

Dng-m€t linr.E tior snrdiq 

sp€crospi. sludis of complqB 

ChflilminesM say 

T

E 

F 

CairiziE witb NSA.ID'3 

Sinuli'eB &ranitudon ofcditiziE lrd NSAIIX by RP- HPLC 

hl.d.rid ofcaniziE wirb NSAID3 

C.tiriziac with eliD.lui.ls 

sihuli!@B d.hiralior of edririe i! p(e@ of utiDLnds 

lft.ddon of cani2i@ qitb etibdr.i.ls 

C.tirizi4 {ilh eftrhDalic drlgt 

Sin'nt.rcoa rLaditrrion of et .izilc in peqe of utunhtulic dt!8r 

l lEtio! !tudre ofErindrl *ith utiadndic ddgt 

C.tiri"j& *itt c4tdorporin! 

Si[uftlFN d.L@i!.lid ofelidziF i! F!s.nc. ofc.pnd69oriB 

l .racnon ofcdni?i!. *itl c.lhrlo.podnj 

Cltirizi!. wilt NIDDMS 

Sinult!@u dcLmindior of eliri2im i! pG.rE of NIDDM3 

bt Elion slldi6 of rlirtjF i! ri!$@ of NIDDM3 

lnt edoi of c.ririzirc witb Bsdrl cl66ts 

Uv-visibL 3pccrrodDlobcty 

HP[,C 

Syn{Bk of drug{ru8 @rdqd 

Synlh6bof d.rivdiv€ of canizi@ 

Ch.Elcrialid of ddiv.tiB 

b-vivo edvity of d.ridivcs 

Orid.tirc bult $dy fd &.lFi! of ROS Dodul.lo6 

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REFERENCES 

159 

180 

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l2 

RESEARCII PUBLICATIONS ANT' PRESENTATTONS 

SulirD N, Any@ MS .d Sl.n t.n g QC@, l, etttu thrdi* 4 fu i'tttuiu b.ts@n 

eti.izie ard E2 rcept@ .tagonhts ai"g Weophotowiy a".l d@rse&phe ,tgL 

p.4@@rc. liqdd.h@logqlV,M.diciNl Clmiliry R.5@h, l.ll. 

Suf|.m N, A6ye MS, N.v6d S md Si.!tn.d g (2@9) ,{.rro, D.wlop,,.,tt ad 

Vali.latid 4 EeliF, ,laa Cluonaogqhi@ 0,.e/za 

Suftm N, An F MS.d Sl..'!.d l| (21,1,9) StD!ta@6 tLio.l D.wlopnzd, 

vdl.ldtor .,t l ln vitrc lden tb6 Sttdif ol Cetuizid ut h PhryIePbiE, CMiJtEsit 

@dl&dr.tdaJr, rouful of Phllrmy dd Pheeuti*l S.i.@s lst?rrrr.4r, 

S!ffi.r. N, AEyn. MS &d Sl.o.'!ii'i12008) Maltdtbvlopwt ofcettrt2ltu lntull 

&ts, dwweuttcal htuulatton a".l utu, w, J. cta. s4c. Pd. JX4). 

Sutt tu N, AnyF MS .nd Sl.@d g lzc,,) )1 RP-HPLC MetM hr h. Sinttu@a 

D.t.rnt@d@ of C.tiritiE in Prcse of Iti$Iotut h Bth Mdoid, Plwwutical 

FMsldtM ard tt@, S.M. Eth atrdl N.rioMl Conf@E Sai.ty ol 

Ph@vigjlre (lNDlA) SoPIC 6 Kd*m Jsu{y } | l. 

Su|!E N, A6yrc MS, Ne S .!!d St|dlrd II (2009) PJyical ad Cl*6tc4l 

Clw@terizclon of tL*Mi. ,1cid in Di&tu',t Pho@dicd Dotuge Fw.d tn 

Stattlt|, Sat liet Un,E Nowl W-EPIC tr rod Eth Amul N.tidl C@f@M Sai.lv 

of Ph.m@vigihne (lNDlA) SoPIC o Koltrr!, .teury ll L 

Suliim N, Anync MS ud S[@W tl Q0O9) Slfrtlt@ou d.Ediaatid oIcarirE, 

Dlhta.n od At' o.lipiE wit:4 R,',futatin I a IN.ml Slat lod t" DoPe. FMlldior 

aul EM *M by W-EPLC 2d InEhlriodl w@khop Cun-Tnining Co@ on 

MoLcul& Mcdicim .d Drus RqEh (MMDR-2) Jxulty 12'15, 2009, l(lrchi. 

Sullr N, Anyn. MS.d S!.D.|.d g (200E) ti4d. Sr4rl,.rJ oJC.n'EiE t$loAes 

Int cdf oi olsdic Sy.rndir. ,e 22, 200E, sod K@. PR- lEo- 

Sulr.E N, Aurs MS id $r.!O.n'npooq Sifitrlt4@4 D.bmitatiu oIcaniziE, 

Ph.,r'LptitiE, C@it{.Esk h,n Mtttulutd Unng RP-EPIE 19 Cod@mi. d. 

Quldiq Dcp.d.n6to dc Qllmio Univ6id.d d. Oricnc Soli.go d. Cuh., 28 M.yo 

2@E. TLmr3. 

SllnE N, Anyn MS rnd Snrolltd I QoOD l" vitu llt Nti6 Sadht of Cei,aE 

\.tth Ea Edpt@ .1d.C@itu Bing Vcnopltutoo"I'y anl RP-HPIE ln|.rrnnl 

Chstrify Conf.llc: Rlqr Adv@3 in Chchislry, LlhoE Coll.!. lor Woh.n 

uiiecBity, L.toF Novobq 2-3. 

Sullrd N, Anle MS ud SLul.n n 1206) t, vItu ttu dio" 9tdi4 of Ceti.i.lte 

vik &*nlial a,td Tw Ele@Nt Uti"g Wcnopl-brcnic and W.EPLC T.clhICEs 

kr Inr.tuli@l Ch.nic.y Cof@@ CC Unir6ity, F.iel.hq4 Ptrisb. Novcnh.r l-1. 

P8 

'lo 

suluD N, AnyG MS 4d Sl|@\d fl l7(M). oPttkbcton d @itatiE aMW oI 

C.EritiE Uti"a Mtltiwiat. Wcnal Calib,atlon tn tuh Dq dd DosC. Fotuulcto 

f l .mdol & lf Mtion l Clstrisrry Conf@M EMlLnl Thrcugn lmv.don 

Dc.mbq 26 - 23, 2(x)7 D.p.rtrd ofch.nisiry, Cmd Unav6ity, D.r ls.il Kne,

ACKNOWLEDCEMENT 

My deet€sr lhelG ges to thc only suprlh. aurhority of thc wholc Univ@, tb. nosr 

b€rcvol€nl {d thc mGl hftitul, rhe foun

ABERf,VIATIONS 

Alnl An odipine PMA Phorbol 12- hfsr.c tl- 

Alor Aroryanad! 

BCP BoncEslpn ple PHA Phyrohodegtulinin 

BPB Bmnoph@lblw PBMC PeripLent blood 

C.l Cdi.izie nomNdd ells 

C.nii Ce&iore Pot Po.""y 

Cip Cipsfloeir NADPH Redu.€dfmof 

CIM Cimetidine d@tilmide adenine 

CNS CentEl ndou systeh din@lolide pnospharc 

Chl Cbloroquine MN Rnirdine 

Conc Conenrarion P€f Refe@cs 

R' Cor€larionc@fIcie RtU Rqdilg pq lminonert 

CPM Coui Fr mi.ure 

CDCL3 Deutenl€d chlorofom ROS R@lile oxyee, sp6ies 

DMSO Dinethylsulfoxide Rec Reov€ry 

Dil Dilti@ RSD Relarive shdard deviation 

EIMS Eleclron ionialion nds Rosu Rosuvaslatin 

sFctos@py RPMI Roswell parknmoriol 

Eno EooEin irodute nedim 

aS E ropy SPAR SpdrflokciD 

FAM Fmolidift SOz s€M opsdnlg zyDos 

AG Gibbs ae €Mry S E. shrl'd mr 

Ou c@fm6ir S.E.E. st nd"xlmrof eslima@ 

HBSS tlmts bol@salt slution Spo Spado@in 

Illd Inrqdly TMs TeFdetbylsiLe 

InEa Indlday EliN Tri.tbylamine 

ISD lmmoglob in E Vet VeFPmil 

ICr Inhibitory@nenElion 

ICH Io€mtional Confffi€. on 

Hmonialion of Technical 

Requimenls fol 

ReSistration of 

Pn@aceuticals for HulM 

Levo bvoflo@in 

McCN Methyl cyeid€ 

No! Norflorein 

NIDDM Non bsulin Dep€trd€trt 

Da,b€ric Mellin! 

NSAIDS Nonsrereidaldtii4flatuurory 

dngs 

NMR Neldnagncriclgme 

Pd Pddiadn

ABSTRACT 

S*ond ee.enrion erihisLmin s N p.glycoprotein subsrdles. Drugs i.nibnine oi induing 

Fglycoprciein nodoldtion day l€ad io drug-dog inierrctions. C€irizine dihydrochbnde. a 

sond c4oation dtihist hiney' b also a potenr substdie ofp,glycoForeins. 

In th€ presenl wort, e attenpl yas madc ro devclop a nunb.r ol HPLC nelhods for 

simullan€ous q@tnalion of c.ti zinc ed orher drugs, ehi.h my posibly be 

coadnirbted. fte lali dqss includ. Hrr€@pror dragooisi Ginetittine, rmolidire and 

miidine), st ris (aloflatatin' Guvalai4 pr.var.rin dd simvsbrin), quinoloie 

etibscterial asotr (lcvonoxacin. o0owin, cip.oflorciD, .@x&ir, sprfloxdin dd 

rcrfloscin), c.lciM chmcl blocreu (dilli@m, v.rpdil. mlodipino, non nmidal etii.flmalory 

drues (ri,tofcn& &id, diclof.n& sodih 0ubiprcfeq ibupofeD. m€f€mic 

&id and ndonm} etimrluiak (prrio.thMine qd cholorcquim), dridrhnadc druss 

Guifencsia phmyl€phiin. &d noncluLsd), ccph.losporitu (@toid@, cphlt xitr ed 

ertuim.) od dtuss ued in non iBulin deFndcnr diab.Ls mllirur (re{omia 

slibeklamid€ ard elqudone, Th. /d.v.toF!l mdhodi *4 validaEd 4d w mpid. 

on@icd and w€E fourt sujratte tor orri"e JJysi"_or d*s druss' iiom 6w nateri.tsphrm@tical 

doss. foru ed ir hltlfu etu. 

GtniziF is 0!e m6t widely pdsibcd drus for allcteic dierd€s ed is .vail.bL in 

@mbinadon with l|ny olhr drugs in mny couries. Due lo rhe po$ibiliiy of cedritne 

ink&don * r othd drugs, dng inr.tuti@r of ednzine r@ sMi.d wi$ atl lhe abov€ 

sLt d dogs. The abore Dstior.d m.rhods w.E appli.d 10 sndy thc po$ible r" rfo 

i erurions Bing uv visible s!E*Aii*c. -o HpLc r.€hiiqoe in sinulated body 

aviremmIs at 3?!c ed ar pH I Gimularins mFy sbhach), pH 4 (sinulatjng tuu 

slol@h), pH 7.4 Gimulatins bl@d pH) dd ar pu 9 Gimuj.tins inrclrinal pH). 

From tn€* inreEtion studies. ir 6 cvidenr $ar rh.rc wss no chsge irff,ailabihy of 

.elin/ine intpRsence ol b, of $.s. drusr cxcept srmv6Etin ud NSA|Ds. Itese 

i erulioE wre futher v.dfied by 3ynrhesizing conptei€s of ceilizie wiln th€s druss 

which llw.hdaderizd by using FT-IR ed |H-NMR. Encryy minimiation studi€s ed 

kindics ofth€e comDl€x€s werc also studicd, 

In orde! lo study lbe struduE elivity relafioNhip, vdious d.logu$ ol cetinzin€ wer€ 

plepded. The rcagenls inchded ph.nyl.n€didi.., phlbalimid., thioacelmide, thioua md

d ephthyldin . Th. rca.tion mh&bm for th. fm.tion of atirizirc d.rivarives follow.d 

nrclophidc subsdtution re&tion3. Th. piodwr. obtrincd wft.hdet ri2.d by FT-IR rH- 

NMR od rc specroi$ 

'll'.$ d.rivativcs w€E furrha subjercd for lh. posibt. etiinU.maiory miiviry .s r€l.s 

of hjri.nift dd podrction of crlotie by mst c.lb {d bephih e thoudt ro b. doely 

inslrcd in Uc p.thog.eeis of .llclgic dis.es. All.Eic dilcdg my involv. irfl'mlrory 

Dediatoa 3rch a hisi.nirc, .ttoLiFs ed msy difIGMr c.ll rtlcs iNludins T c.ttsr oasr 

c.Un bqophils, n umphih, naophagG .r.. An etihist mic sho$ ori,infl.lmliory 

efrecrs at thmp.uric conc.nr.tioN thn ruy nodiry !h€ .fla|3 of idmmabry bedi.roB tt 

r,w at dos @Bp.6ble !o 6os !s.d clinically. Lhiml .nleed chmilMin*r@ @y 

*w F.fodr.d, th. paliniE y $tailg BuX! of wholc blood lnowd rhal .onlouds 

7t4, 119 &fl 121 .xlribn d sigrifimr oxiddiE burn Espo.3. (eri-i.flumarory) !r 

coNotltioB l.rcl of l00, 50, 12.5 F8nLi, Eiell.nr irhibirory &riviri6 of lt!* 

compo@dt wd @.dcd !r t2.5lrghli i... %, 92.5 snd 9t.E Eq.criv.ty. th€* 

@npounds *4 rhm l6rcd for a.dviri6 otr i$ldcd m&Fph.8. elts on liv. @nmr.riotu 

l*L 50,25. 12.5.6.1atd 3.llrgnfr. lr s found lh.r all ddvdrv€{hlv€.ettdr .tr{G 

m nll@ph.e6 .d G nuch |tm potan rha eririzjl. 6c.'r 7l a, Funh6 

phmolosicrl rctiviti.s @old fiMlly d.rmim lhcn.kr mhdism of edon .d .ner 

clrororic &ivni6 th* d.rirdiv.i could rdly povc cGllcfi rh.Epcutic !g6rs in arhm 

Ihc sbitivity of c.&izie ad its dqiEriv6 io r nonllolif.rdis .r!d tmlif.ntiv. BFn$ 

ro r!. ditogsr phrto[.ba€8lurilin (PHA) rad Bilogc.-ilduccd prelif.ati@ of Tlloplers 

M rt$ c!rl@&d. SuppBsiE .fcct of ohFurd 7l4 M obs.d.d o Tslt 

Folife..{o[ simild] 719 $o*!d .xellcnr Tall $ppr6sir &rivides- C@pould ?27 

shoved s int mcdid. !.tiviIy. Th. Gulll fval.d rhn conDounds ?lr, 719 dd 727 

dhibiled dtic.Gr activity .rd @uld b. prcv.d l€ad coopoundr i. th.6p.uic qorld aRcr 

turha srudi6. AnihsrMinic &livi(6 of rh.,Jb96 ompoundi @uld rci be @ndEl€d 

drc !o ler of fei{iry. 

1-,tr& lur'r,

-y,,'11'4"- a1! t n,/-'t;;vL !"t-rtLet,-/--Jv i.t 

'tz ' 

-11!n{,ru.6! rntf \;v L 

tb 

4r e!,'iJi-+ asubstf at€ L,r 4 tr,t 4,! 

*-ft7"'!oth J" 

, 4l qz/ -q t ot d Gta i,,"r - " a i-t,)r?,''i {" li | 

ldJ'J.-+ substmteed, /,4J"t 4{yl/" 't "tc. 

tr $ 

t" d t,'f 

o 1, I !'u.- { {q -e,,t -ts; v4 I }L oe ct t 1,6 I' k J q "t' 

-t!"i- ''2., " ."---tt, t' r6'J r rtlJP =t,!.J-\'"Jv" 

-q Jc -\,t Jtt''t i1,,1 l\),2,'t, N"t l"','tt" Ja,,t/ ia. a, ;Av 

i9 aie L t)t 1 lL'i'$ d,9,! -r ", i u'" 

"'tz z 4 -a't, :i,l- fe t 

+v L F +lz.r€v..-vL!cr-l 4'v'aa,o,)s'!'lt,!'-. f,-, 

;,,iu,,t,.t,;-?Lv,', n,ntA4 J'L -', ett6. -q Lr Jr>\'{ 

-Lt f t; t/e L,iLJ,t oi J\ J,ti!)-. ,-t .' iu-. -Lj,ia Lt)tz -"] 

-t ; v L - L,t \J,v a 2- L o {a1 t! 6 ) /z 1..t Ja t-' I i - - "1, 2 

i" "iJ.:--'J.,','f'f,!* 4cz tr- Ja-.,e.t/a Lb'JtL6ol 

{L.rU"( sttucrurc-Acri\ity Retatio^ship - L ivt{'\ ,t Lt' - 

i' J o: "' j u j' t J E, rlot . t,t g A,"r1,J, ctt I I'v rtur-' v -,.. 

;rlev 6{6 ctfttr{-;lc/-t'r/,t:,!L ' 1,.t * L-ttot-.1Jt: 

i, t q t ; iu" -4 i\ t- rtt lu-, *';tt L L 1 v', v'! -0' r; a t - LV'! 

- a i{J lva $: rlw u d -!'t -(J {r'.1 w o u t, J y. * 

entrtn.:,annarory'ctt t I {. 4r ,! -{/ }} | z- 'Pl - rl r? 

J-!727 ,171s.714. J. /J+" ur, - 6r' iw-* r{i.u ovlt 

!- '-.\f.-)t L 'Jl/ iVV'a 7 -q Jv L df/ Anttinttannato.v 

J. ti.v a',!; - u-z ?;!- c' -r! {./a?-N'|[-v J zts.rtttJ. 7 

-4{tec

INTRODUCTION

II\IRODUCTION 

nisianitu is a subsree thar is widely dktriburcd io body tilsB &d d on k\ 

Elw ftod sronge sites. exen a vriery of phmlod".l "r"* "f ;]* 

,a4,n8 'nknsu) HrtM nesR uru.lb rcspoNibl. ior alkl8r dsod*s,n Y 

th€ body. Il stmulat s the prcdetion of nNN dd .lilafion of blod v.sb. I 

sufra or.11..$/ @osda hi$rnie .fr.crs s r 'lmy nose dd smlLn nael pdesd {l I. 

2 Uin6lr.4.pt4r 

Hislanine bdns3 irs clf@r nmwl rhe e$vnid tw @prors, H, ed H, rtDi ditr rl oi tl)e 

bais oftheii difiering ensiliviry ro agonin od mbgorists, Hr have been foud in b6ii [2] 

Ht rcceptar dtaqonists 

H1 r€cepto. slagonins compelililely bl@k nis@nine at Hr reeptor dd.d b. depicted o 

suhslitut of .lhylmiE @Dpouds. Bov€r &d collabontoB pl ws€ th. fi61 *ho 

disvcFd Hr Gcplor dragonisr* Aner itt disuy mdy @npounds sF fou.d io show 

hi8} ar,sonist pocfty ar this deptor [4 s]. R6ulls ftom @ly snrdid wirh rh* analosou 

dsiwtiv* of cthylcftdidire sueacsEd . clinjc€l potcnlial io. rc.ting .lLrgic ad 

irnallrmb.r di&de6 [6]. 

In rhe b€siMing. thc rctiv€ hi$mine H | @.plor dtaeonists r,s s,6*n by a g.n 6l fomtna 

onFisins two Nmadc sreuF [Dr.d by r shon chlin of 

t" I I 

c atod b ! l.ni.ry Mi@ sreDp. Arr is drlor h.r.re aryl, l-:-i-""'"' 

I 

\tich nay b.6[th.r subslintsl Al is *@na aryt,ingo. 

" ^" 

m aryl netrrl goup. The Mo aryl soup Arr dd Al @y be bnds.d |o fom ticlclic 

derivativ6, X is a sp: or spr hybridized cebon, a niroeen or a spr @bon with d oxyee. 

(€th€t [Dr coMecting the side chain ro the donaiic ringr, C-C r€psents a short chain of 

cabon atom which may b€ sat@ted, uneturaLd, b@ched or fom pan of ring systen. 

\R'R? t g46lly. Gniary dino ercup whi.h my bc pa.t of a nng 3t!i.n. tl ws loud 

dEt activity @!ld b. iftEded nEk dly wiln the iftodwtiotr of a sond mtudc or 

hetemyclic .ing i o rhc $tutur ad ths,ndbq of adlosB wa syndEsird and

€valutcd. The nosl aDnug smup is din rhyl mino {d prrmlidino. Tb€F sEucrws do 

@l hav.. dos ch.mical rcsnblmce lo hblmine exc@t thai thcy do app@ |o she ihc 

f61G of m .lmoniM 6lkyl chaio. It is pr6h.d thal Ihey bind to Ur€ se dionic sne at 

th. @pror,6 dc hisr.siF, but 0B1rLe @nadc ring binds ro a Fa|bya*$ry cgion 

Howvd, th.E N no* lmy @nFuds *hich lhow hgh potdcy jllo nor fit in otrs 

IE Hr elasoniss @ cleitid in b fiBl gmdtiotrjg.6i&d s@nd sq@tion.scnrs 

Fibi g.ndlion dngs e chsedad by srong s.dadng cflels ard nDy ale bl@* 

aubnonic 6epb6. Sonc of lhe dsgs ircluded in thb gFup m cdbihoxoin€. 

dimerhinden€, triprclidine, cl.n&*i&, neobenodin , chloryh.niruine elc. S€cond g.neEtio. 

ag.nts do€s not obllet ly distribule inro $. d!!l moa system srd rh.y e 

cnr@l€dad by $en ls s.daling efaa. Som. of lle dru83 ircluded in this grcup @ 

ebslin., @ilastine, l@itllin., cetizire, astoniale @d m€quit zine €rc [tl]. 

AI of th€ Hr &rrsonhs e s6bl€ uim9 Duing dr lasr d.cad6, dive nebboln€s of 

seEl dtihislnifts hav. b*n us€d G &riv. dngs. Th* agoE @ npidly .bsrH 

followinS oral adhinistradon, wiil pet blood co@traliod @cudi.s in l-2 hou6. They 

ee widely distiibuted ttrough out the body. The Hrseplor elagonisls blGk lhe acions or 

hi$dninc by rcveîble compcdlive ei.gonhn al the Hr @.Ptot. TlBy have ncgliSibl€ 

po&rcy ar rhe H, Gepror sd lid. at fi. Hr @pld [ ]. Hoq.c, ih* dr!$ a onry 

iilibir rhc BpoMs nedis|d by thc El€4 of hjltdift. They ca nol blak ltstuin liom 

Eleding or pGvent hisiMirc len binding lo hisumine (ED @pioi. tho€by blockins th€ 

B 

ceddziie k the founh dddition ro a nry s.nention of audsy m€diation call.d 'non 

*datinC' mlihisr@ine. Thcs. @w dlihisl'nin4 @ clsified s nor-edarins agenls 

b€.ac lh.y caue 163 sedarion lh6 their pnd@sB tBl. c€$ntne displals a sries of 

ad@trg6 over its pEd@so6 s n is Ae of both sjalee ed choliftryic efers ed h6 

poi€ni mlialLtgic aciivily. Howev.r, it is noF sdatilg the lhe olhq non-sedlting

4tihislamic. Cdirizi@ wa mong thoe dNg! $,hich w€E wid.ly pEsrib.d ir EmF for 

aldey befoF it B inrodlc.d in Am.rica. 

Cetirizine dihydrccl ond€ anlain noi les 1h.n 99plo ed not 

hor thcn 100.5% or (R5).2-[2-l+l(a{hbbphcnyltpborl 

tr|I)l)lpiF@iD-l-rllerhoxyl*ric &id dihrdMhbnd(. 

cdculaled qiih Ffe€nce lo dd€d subsl&ce [al. II G@mic compoud) is p'ineily mid 

nel..bolite of hydrexyzir€ tsulting Aom compl.t. on{btion of prib!ry alohol noiety ed is 

auilaue d a vhil€ crrslallin po*der dut is valr-eluble. This onpoud is zwin rionic 

ud elatilely pold &d Zyn* is the br&d nm. of€dnizire [I5]. Th€ drug is isolubl€ it 

eebn€ md in n€thylene chlo.ide, les soluble in lipid, bui soluble in meli'anol having 

mol4dtr s.i8hr of 461.89. Its m.lliog Doi b 218-220 0C &d pH in solnlio. fom is 1.2- 

L8.lt@nrains hslamelal nol moE tbtu l0 ppln, moistN con|c nor moE $d 0.5% w/w 

dd sulphated ah not norc rhd 0,2370 vlx. Cctirizire loss on dryirg is rol moE lhe 0.5% 

dw md 6$y is not l€ss thd 9% w [61. C€tiiizine partly ecouls for lhe i, viw eile.ts 

t Sttctaft..lttitrElorio6,b 

ce&izine hs dboxyl group which h3 reducc &@$ ro th€ e al neoous syst m (CNs) 6 

conpred lo thc hydsxyzin.. \vhs daly3is ws condud€d on thc lipophilicity bchavior of 

cetnizine, pdial inta nol€cula chege naddiation *a obsned in the Gtanol/sater md 

.lode@e/wrd.y$etu. The ionic Fflirion dilgm i.dicaled lhat cdnizie &t 6 a pbid 

rasponer &o$ int rfaces wd.r c@in @ndilions oI pH Il?l ln coEbinaljon Nifi one of 

$e bsic nilroge.s of pipe@i.e ring, rcid fuction.lily tules ihis conpound a very uique 

n terion. Ceboxylic SDup of @tntirc inlttul with th. tsic nitroS.n via folded 

@.fotl'@, thqdolE, il Fsi.ss Elativ.ly hjgh lipopbilicity at physioloei.il pH (LogD- 

1.5). Phmscotin€iics orcelidziDc sisnin@ y dif€$ fiom lho* ofthe baic ed lipophilic 

hydroxyzin . Duc to ryitterionic attuctE dd ils P-gly6prol.in etility. cetiiizin. h4 onch 

low CNS D.netrarion thq hydtuxyzin . Ccliddft display3 dinind a&mlae€s over the 

b6ic hydmrytre in sv.El c.r.gon6 sNh d slow E@ptor diswiaiion ntc, hieb 

sel€cliviq od ncgliSible liv€r enzyG inr.Erio. [r8]. Ih snall sE@tudl cheg6 in 

hydoxlzin l€d to th€ difd€nl phm@kinctb prcnle ed the phtuodr@ic sDectu 

M al$ ch&8.d. In ev€rl i, v,D i61 modcb, c.tirizire prorrd to be poLnl conDourd

wilh l@g le*iDg .ctivily. h I ob*o€d lltrl al dos tblr .lletirrl, bl@l tLe &don of 

httrnift in thc akin ed luB @tuizire ldninisr.tion clicir.d linle or no s€dation or 

el€ct@ocephalosrm {EEc)che8q [19]. 

4 C.fuaru 6d.Nndo6 

C€ririzl!. ii a chir.l dsg ed .Mtion6 @ pE$ot a .&rly l: r nixte. Snrdi.! 6i.d 

on th. n6d r€sist&e b @mwE the €freB of rdmic. R ad S edrizinc indioied thlt S 

€Mtion6 docs mt exl bir anihi$din cfretl N shou by botn @nic .nd R. 

e@tion6. IE emat€ dd R cMrioIM irldbicd histrsi!. ed induced e inclEe i. 

6al rsisra&e, thw irdietilg the andhisi.nine Plopenies of R alirizine 1201. 

CdiriziF hav€ b..n sFtbesizd by vqiour ncihods in licBnre [21-2!], Detk et ar, 

dielo$d th€ p@tical laluolo8y ro. lh. pepetion of (,t)-cdir'ane 2Hcl v,a 

dis€It@letivc orsrnonelallic addilid to x4..r-bui.n6ulfDyl sldiniB [24]. 

r""r 

\4.^." 

tv ru o."- *S**

fY*. 

iO 

h 

s I 

...6., !t f,t 

rvii rot-rcrYn nm 

.4, U z.c c,4/ V c'*y' \t 

r^ria .s\ tlL (fi 

t 

lr'û, 

14ris 

,IrI! 

roalff 

2'C 

tl 

. 

PtlotlIo'Ff 

9 

r-tr 

I 

0 

tl 

"_"oT 

t8t{ , {ior 

a.^fl 

r'l 

6 MdLe {art 

i Spcnoscopic mthods 

IE ain€rioni€ &tihi!Lnine cctirizine sd ib p@nt &[g hyd&xyzin a c&&M 

@nF ad lw @i..d fd U.i! 3D rrirres rrd dr|mie. th. rm b6sic pK! ldues, 

lhc mosl @@or @rfomlrioc for .a.h clatF! sFci* \Nft dlit milcd by molaul{ 

dlMica sinulationr &d €onnmd by NMR h6l!4cnG. Fo @tirizine, lh. re$lls 

d.noBhr.d that tlE eitt ri6 qhicb v@ rh. pr.donimr spe.a6 d r,bsiologic.l pH 

.xilred a foldcd @nfomlts, wh@a irl nomqtiouc sFcic! dtpl.y.d folded @nfom6 

to

sllbiliad by inta holecurd hydrcgd bonds. 'Dr€e fbdines were iD full asdmenr wirh 

pEvious r€sulk on 1he ljpopbilicity behalior of ceirizine in isolropic solvenr syscos ed 

tata roB.rha could explain lhe favorable pbm@kineti. poFni.s of the dde [25] 

C€tinzine ha be.n detmined i. druC, blood &d *tum 6ing fluorimeaic 1261, @bnnert 

[2?] rd crpilldy elsEopnoEsis pbcelws [281. Two siDple ed mpid, ssiile cxr.&tile 

speclrophon€Eic medotls wde dd.loped for the &ntuioation of cedrizine in bulk md in 

phmelticals. TlEs m.thods w.rc bard on fomation oa chlobfom sol ion conplcxed 

bet$q elirjtne with brcm@@l purpl. @CP) or bmnoph.nol bl@ (BPB) ar pH 2.64 

w n e absorydon aI409 ad at 414 m for BCP md BPB. resp@tively. R@clion ondirioro 

wet optinized to obkin ibe Mimh color intensity. The .bsoftoce i.cE6ed lin.dly 

witn d increde in @nc..rarion of cednzine, yhich ws corcboded by lhe catculdled 

corel.tiotr wfrd€m val@. llE sysld ob€yed Bd6 l:w il th. Mge ot l-16 dd t.5-21 

lgnlr lor ACP & BPB, mp.crively. Thc ldiou dalysh pddetes w€rc evaluard 1301. 

With salicylic acid b int€hal srdddd qwrit.rioo wd achieved wilh UV deremination at 

210 m ba.d o. rhc peal n ighl drios. Bd s lar B obey€d in a conce r'rion Ms€ ofl- 

15 lgnl-r qd th. Fgrsio! lirc equlli@ w d*ived wil[ . @tarion @m€ial of 

0,9999. Tle lalidirt ofthe ncihod wa tufthd confift.d usine rle sledad sddirion berhod. 

The popoFd procedu€ ws 3uc@stutly appti.d b tn€ dcreminadon of cainzine in bult 

ald tablet fom, with hien pc.irrge of Ecov..y, good acc@y dd pEision l2?1. 

Cetnnne ws qwdt t d in pEs@ of H, @pror ehgonisis uirg sinult r@u €qulion 

ed derivarive specroeopic teclDiqE [t0]. UV abrorption v6 monilored at 230 nft dd 

oxaridine wa enploy.d as lhe inlmat $mdsd for qedti.arion. (+)c) ccdnzine dd 1he 

dal shrd,rd wm.luiert 6t rslorion lincs of t2, 16 dd t2 mjnuls, rcspe.riv€ly. I.he 

' 

deterion limir ior cetinnhe enetioners ws 4OO ognl-' of uinc. A phs@cokindis srudy 

w6 conducred with rhe h€lp 5 healiby tftale lolules who were adhinistercd lnh a single 

oBl doe of memic eririzinc €@rim.6 ov.r a conenrarion tuge of 2.5 200 rsDL r. 

Tlt. p.!r of lle cxmt d eridziE @rliollB appeEd in the uine sple duilg the 

penod l-2 hous followiry ihe adminttralion of tiE oEt doe. The ex€rcred tevet of i+t 

cdirizi.e was slightly highq thd C) cednzine bu1 lh€ diffcMce was nol s!.tisti.allv 

sisnincdl [3U. In sorher sF.r.ophoiom.rlic n rhod Bels law B obeyed ovq rhe 

@Mn! ron Mge 2.5-20.0 |rgDL' wi$ d lpp@nt mol& aberDtiviry of Lllrlo 4 

L.mol..hrod Sed€lls sensitvny of 0.038 pgcmt. This nedod ws applied lo lhe 

d.tedination of cdinzine in rablers ed based on lhc neutnlizrlion €action. involvi!. rhe 

II

c*boxyl grcup of cctirizilc ad edim hyd@xid. in 6qh6 mediu. Th€ lalidity of lne 

hetlDds M tuiher aertain.d by pdallel detcnninaiion sing 6 Eferenc. melhod md by 

Eorc'l nudiq F2J. Sinplc, prcis &d €cononicd rpelrphoroncEic nelho& *w 

develoD€d ior lhe simulla@s esiimtion ol cefiizift dd mbroxol in t bler fomulaioN. 

The 6d ndhod *6 brsd on th€ B of nultidmpoft mod€ urlysis dd sd nedod 

wa based on fist dailative sp€cual salysis, while lhe thnd Detnod was baed on Qoalysis, 

i... tlp ab$rba@ dlio merhod. Boln druss ob.yed B@"s la* in lhe 6I@!a!io. 

6ge of 5-10 ssDL-' for etirizine dd IG60 psml-' for dboxol [3]351. A derivative 

speEopholoneEic m.thod w6 ddcloped for 1h. asy ol thG biMry nixlws of 

pstudo@hedrine with fqofoadirc, cdirizine dd lonladin€, nrc ne6od h bed on $e * 

of lhe nrsl d.dvativ. oflh. qlio spetrM [36]. 

ii HiAhper|almrce thinlarechrudatogtdpll, (HPTLC) 

A Epid od *6itiv. mTLC 6sy had been d.velopcd fo. the m6l!@dl of eririzin€ in 

hmd plasnd dd irs utihy for phmekineics srldy had b€d cvrl@red. In this nelhod 

q@tifi€ on M done vilh ihe h.lp of a d@l wvclcngd TCL @n.r. The prcpoFd 

tElhod had a Ecovery of 9E% an l Ur€ low.sl houl of c.tirizine thal €ould be d.t d.d ws 

50 ne. Thc medod *a applied for tnc d.ldielion of th. plasm lqel ed phjm@kirelic 

pdmeteB of cetrizin€ an€r oral adminidration of lwo na*elcd pr@drtions in h.alhy 

vol@ie4, The detedined merhods eE in agenenl with previocly rcpofted lalucs [37] 

Ps.ld6phdiift dd edrizin @ wid.ly uled in the remot of allergic ihinnjs. A Fpid 

*lecdve &d slability indic.tine HPTLC m€rhod *6 develot d md rElidaled lor then 

sinulrosN dekmimtion in phm@uricalr. The bernod dployed TLC al@inm plaret 

pr€c@ted wilh silica Sel u $e slarioney phse. The elvot syst€m onsisred of EIOAo- 

MCOH-NHj (7:1.5:l). Spetrc

iii High pre$we liquid chtohatogaph, (HPLC) 

Nmb€r of nelho& for th. dermimtion ol ednziG h6 b.cn rcpon.d 6ing HPLC 

tehniquc, Thee nehods dd dEn .l.lails e pEsr€d in rabl€ l. L 

HPLC Mhods o!@tihire 

HyprsilBDS C0(5 A25 cn x 3.9 

mn)@lumn, isriic n d. H,O: 

M.CN:Er,N (61:r7r02) DH 7.t. 

lnensil-C3 (250 x 4.6 mm) 5 FB 

dislill.d Mb, .c.loniril. ud 

l.idny|lnin (a):40:.0.|) pl{ - 3.5 

CtrNovpak@lunn{l50n9nm: 

,tFn) tn6y'Enc & elutid 

:.enibiL (6l:39) pn 2.8 

Novi-P.l{ Ctrcolumi O50 x 39m, 

4lrn) M.CN 0.02 nolLr $dim 

d jhydsSo rldphd.$dryLnin 

Nov!-Pot Cl8 4 m Edial 

@mDE$io oluh|l 5()91 M.CN- 

5eZ phosph& buF6 (pH 1.07) lo 

which 0.011 sol Ll EtlN 

(50:t0,0.15)edO.ol05 noll I 

s.dium dodeyl sdfo@ r.E !ddd. 

HIT€6il BDS C I3, 5 nu column 

i4.5 x 250 mml mobile pl@. of 0.05 

M dihydrcgd Dholphd.: @di'ile: 

hernmol t.hhydrcftnn (12:t:2: l, 

v/v/v/v) .. . pH of 5.5 

I-icht@tb Rl-18 colub4 KHTPO. 

M.CN (55:!5) {v&) 

Lich@|b cr colmi. M9CN 4.01 

moll | 3€diuD hydbgen phoehde. 

002 moll edium h.mlulfo@ 

Sfiin p.cl CLC-ODS @hdn (250x 

4.6 nm), MeCN - 0.01 M KHrmr 

(46:54, tunbiiin! 0.02 M N. 

hept n6ulfon'., pH 6.1) 

sDhdi$rb 5 OD92 olmn (5 mM 

aqt rn buryl @onium phosPn{o - 

nclonol kraa hydb lu@(33:65:2 

Th. irn@e of rnp.|@. .!d El{iv. hrmidiry on rbbiliry of dirizirc dihydrcchbn{b jn etid 

slale wa follos.d bt a HPLC melhod in on€ ofth€ sludy [,t9]. 

12 

,tl 

,18 

ll

Cetirizine is the &1i!e netabolile of htdoxyzine, rirh gr€a$ affiiry fo. Hr @eplor. tcs 

dfinity for elciw chm.ls, a{dr@rsic, D2-dopsDine, stlTt-@ionin dd husinic 

t@prots day deEse plostaglmdirs or leukouioe poduction [s0]. Ir is mpidly abso$ed 

fton sarrloin|sliEl r&t ano or.l adnini$6lio[ pet phsm @nqratior b.irg atuincd 

wi$ jn about I hou. Food dclays rhe rihe to pest ple. @n€dhation but d@s not decrese 

th. u@t ofdrue ab$rbed. Ir is higbiy bodd ro plam prereb rrd ha e .tiniurion half- 

li& ofabout 10 hous. Celidzine is exc€led pinsily i! rhe uin nainly as dchdged.tnB 

dd dG @1 .r'F{ !o frs th. bloo

kela.@n@le withoul ihc incEbed nlk of head iGguldiiies @mo! to 0$6 rcn-sedalins 

&li hLltein* 1561. How*o, MAO irnibiloE ifttte the cfel of synpalbomim.tic 

dires sd may prolong md ifldsiry the.frec' of dlibislanin$. No dde irt @lions had 

bei Eponed wilh th. @ of poa.eihol [57]. Il is hishly $letivc i! tu inrc@tion *irh 

v&ious boooml binding sir6 md hiShly porenr krfenadin€ d well. No wdio roxic eflcrs 

wE ob*ncd wiih rh. nw &ug wncn u*d al its e@m€nded or hi8ns do*s or whd 

adninht€rcd with imidaale ednDeal od n&olide edbiotics. How.ver. orher rypical 

drug inl€rutioro of Hr odnistdire applr 10 eriizine. As.ltirizine is a edalive drug, e il 

should not be talen along wilh alcohols or CNS supprc$ine drugs I58l, 

The ccdnzine l0 ng do noi inte@t wilh al@hol ir two studics bul some dighr addnive 

efects wre .Lt@led in morhd [59-61]. Uha e inrcBction @cured, it appeed lo he due 

to d!. @rbin.d or lddifie enrd neryos d.DMl.ffet5 of both lhc atcohol od th€ 

mdnist.mine 1621. lr had bee. obsened that both c€tilizine t0 mg alone in onbination with 

ni@sulide 100 ng d.c@d wheal !d fle Esrone sisrifi@tly !r 2 hou6 and lhe 

€spose continu€d to decr€ase dll 6 how post dosilg. Th€ d4re6e M nuch hore wh€n 

onbi..ri@ of cetinnne ed nimdulid€ @ 8iyo 3 @mp.Fd lo c.ridt@ alotre. This 

sugSesl€d a synergistic €if*t ot cetirizine ed nimdulid€ therc sd no study reporle'l $ fr 

showing dy phmcody.uic dd ph.@oLin ti6 i e@don beiwcq nin6did. &d 

cetuizjne. PhmMdynmics ine@tion wa noE Dlausible for resulrs oblained 4 

ninesulide h.d ben aponed to hav. borh dli inJldnsrory and $rihi$aninic actilities 

[63]. Dose rDponion l cmd valEs wd€ @hi.ved wirhin I hor of onl adhinist.arion or 

arnizie. CoBisre wit! rbe polr @tur of this @tbxtlic @id dru& l.s th& I tr^ of p.d 

pldna ld€ls had b€en m@rd io th. bmin. Celirirne m.ol €xlosilel! nebboliad ed 

70qlo ofthe l0 ns w6 excrclcd in th€ uin an

&d no dN adj$uned of c€0rizim wa n*ssy. Thc €lecuocddiogdphic eilst ot 

@tirizine w6 studied in l0 HIV subjecls. No parient hod signifimt eleclroctrdiognphic 

chug$ duing cetirizine adninislntion. So, edrizine *s efc &dhislamine drus in palienk 

rEat d wirh ph [65]. Ir€ Ecc .tr@rs of cairizirc wft sludied in nomal subi6.s dd 

a

C Int nctilgdrug! 

Cetinzine is widely prceritEd

static (HMC-coA lldElas irhibibE) @ on. oflnc bcr widely prc$nbed chs of 

.lrugs d&ueholn tb. wodd, b6au. of lheir 4@ll@1 cholor.rolloEirg cffecr &d ov€ratt 

sfely prclile ex@pi for @ but fat l rhabdomyolysh &ising eider dir€ctly or indnedly by 

phdllr@tirdic irl@doN wirh enatu olnq drugs F8l. SrdjE m ptomm€d dlugs rsed 

in th. hcat hdt of hypdlipid@i.. They m f&st posEsing ed 6stn drugs. Siovsi|rilr 

pnvataiin, cdivdrafin fld alorvstad. de sm. oflhe doSs includ€d in this category [79]. 

Nmb.R of inteaciotu of slari$ h.w ben Epon d wirh diff@r

Resfuh on 4{uinolon.-3.carboxyhr€s had l.d to th€ dieovery of a fmily of 6-flum-7, 

pip€ruinyl4-quinolon s &live aeainst bur.ti. i, ytuo s well s ui!@lluld palhosqs ed 

t inethoFin eisl' micrebes tEa9al. Coudrivcly. rh* @Dpouds \,ft called 

fdoquinoloes [E51. 'fte quinoloft adbet!.ials e p|lE to l@y inr.Ecriotu vith other 

&!gs. Quinoloft .beDlion b nEledly Edw.d wnh mrtri& and rh.r.p.uric failw my 

resull. OilM nelallic ion-contaiong drugs 6.ls r€dwe abso+rion. Som. ofue newer 

quinolones inlibned tbe ct1@hrcne P450 systen. 

T.bL l,r 

Qukot B &kd.dJor tiktdiLr I7+1n 

(phs d min6|+fl mF2Jnihydrc3-m€$yl-l014n.rlyl.!pipq@inyt>7oxo-7 

H- pyrido{ l:,3- de l- l,4,b.naEin.-6- 

€lb.r)lic,c'd:( rHrfNo. aprle)elto\orbnShr ' . _ 

t.llow, cryshlline poNder, slightly soluble in wdr€r, 

glioirl reric ei4 slighlly solubl. mdhylere chlolid. 

ItttlopDpyl+nlre l,1.diht de{{xc 7{ | tip.e'nt l) 3{urnon* 

catorylic eid; C'HdNIO I Solubl. in *e. 

ifilil,fr"lt**""'""'cubreisrn' 

l-.lhyl-6-fl uorc-1.4-dihydc4-oxo-7-(l-pipsrinylll,&naghlh yridirc-3- 

@boxylio eidj CTHDFNaOT, il foms cry$ls 

in dhsovnetiyleF chlori(|q tr nelring poirn 

is 220-224"C. 

(cir!5-minGl4rclop'qyu{l,tnindhyll-pip.djnyll6,8iillrcl,4dihyde-4{xc3-quimli'@!6oxylic 

ci4 

CFHlFrNlOr, Y€llow n .dl6 iom 95% 

rl6hol, melling poii 263!C , lolubl. in 

!lk!li.s, hot alcohal, pEoric.lty iMluble in 

I -.thyl-6.fl uorl,4-dihydD-.4{x67{ lpiFEzinyl}3-quinolinobox ylic 

&i4 C6Htr FN: Or, molcult *.ighr irll9.l, 

A Bhit q palcyellow. hyg@pic, 

phd@.sniv., cry$llic po*d.r, v..t sliehdy 

slubl. in tur, slighly s.lubl. in dm and 

l9

Ciptofl(eia @ein rd pc0oeir 6 im|!s rlsphylli!. @nqrllrioN 10 ioxic 

vdB, atrnity of quirolores fq the ga|lddinobItldc &id 6.Fl0r nay indue CNS 

adv* efrets [9sl. Quinolord have beo Epon d ro poss con{Isr &riviry [96-9]. 

4 Cd6M.h.nr.t ukttus 

calciu chonel blockB e a hetercge@s sreup of dres 0lD, r0l I Fp|lgtilg a ldge, 

siMff.lly di!re gbup of chdiqb l|i.13h& lle lbilfty ro inlibil calciu 6ry i o 

nusl. c.ns tnftush &doo on rhe calciw-$l4dve ion llml. Th. ddss inclurted in |hi! 

careso.y re phoylalkylminq (v€Bp.dil), bc@dj.apiE, (dilti@n), dihydopyidinc 

(mlodipire). diarylminopopylmiE (tcpridil) t1031. v@pmil, diltim ed nicardipine 

w fomd to inlibii h.ldic dug-m.t bolizjng .Dr-_ym. SMica on ircE tion b€tw*n 

digoxin ed dlciM.h.@l bl@t6 shoped ihn vdrdil incrled pl.sm digoxile 

@E@hrio6 [r04] Oth* inra!.tioB @udd in prt.ere of @t nu2.pie, cyctGporirc 

and cinelidine have ale b.d rcporr€d 005-rl0l. 

Trbl.l.3 

caL.t@ bbta' vled.nh/ idenctiN l7t11l 

(2S.lSf l r2 dindiylmiRrhyll2.l.4.5-bhhld@2{..ninoxy 

Dh.nyl)4{rel,5-h.nrc diepim 

.3.yle.Lt. h}dehlori&, rnjG, 

crylbllin po*der, solubl. in a.&., 

m.0!rol rnd nedrylo. chldide, 

dishlly slubL in .ttdol, h n.lE 

1 atbul 2llcc with d..onm.ili@. 

Alphllt-l P{ J.{-din.rhdtdEnrlLrhrl lDdnrbhirdprlpyU-J+ 

ndhylaiyl)a.nanaeroniril.;t. 

(3,4ii- 

Ddhox}?herelnyl)Bdhyldinol-2- 

(3,4.dim.dbxyph.nyl>2.i$. 

pFpylvaldnitilqcrH,NP. Flubl. 

ii *d.r dd m.deol, sp.insly 

-v 

(r" 

I - 

2-l{2sinodno(}nndhylH.{2{hlotudbrl}r...dihtdrc-GD.rtyL 

,,5-plddindio6oxylic *id r

3 Notst@idd .ttiJnfunmto,f dr.tt (NSAIDt) 

Irre uLdo8enic popenies ofNSAIDs sr€h fto6 the fact rhat they ft orBei. &id!, which 

@ initat. rhe gsEic nu@e and ale non th€n inhibiiory .frec& on prosLglddir 

biosyntlElb. NSAIDS h8. ben @mi.lly tsilable lior decad.s ed e wll ttum to 

Ed@ pah lDd innMado! [rr] cbD.ic us.s. of rh* drugs h|! b@ assidcd wnt 

lhe poFnlity for sid€ .fi€cts such N gsboint$tiral idilalion ed slppE$ion of Enal 

fiNlion in prn of the popularioi U 12- 1141. 

Ns,lIDs 3.t.tuI Jq i"!@jN Ot11l 

5-benayLa-sedtyl 2rhioDh.n.rc.lic &id. CxHuOls 

of 260.3 & whit micrccryslrllii., insoluble in 

we, n6ly eluble b don., .lohol rd 

2{2,6iic!lr!pt ryl) ditul tq|e @ric 

c l,Cl,NMq. mokcuLr eaghr ir 313- l. 

h is 6indy y.llowish *hirc ro ligl'r b€ige. 

viftdly odod.$, rluble ir wat r, alcohol, 

f,dnyl al@hol diglrtly elubl. in &.1onn 

iNlubL in .d6, chlobfdn ed dilut Gid. 

(9 l. llbiplknylF.dic rid, 2 fl'|l)@.ncrhyl ed (!) 2.(2. 

Aumbiph.nyl-4.y1)prpiaic 

cDHlrFo. ool.culo wigh. is 2rl4.rg, 

whne b dighdy yellop, cryr.ltirc 

Powdr, exirl .r ! tuemt of tho two 

optcal ism.ri irslublc in wrt r, ftely 

sluble ii !l..lbl, .rner, aon.. m.rhmot Md 

rid, CDH'P), Nhir.. .rysllin. 

r'r'-f'-" 

(2i&2-14{2-n.dtlpmpyD phdyupoFmic 

powder or cdoudd .ry$ti Ptuticdly 

irslubl. in Mt r, frly $l!bl. in 

oeloe, m..heol .!d m.thyl.n 

ohldirle, Il di.slves in dild€ &lulions oialt li 

2-(2iniDcrhyl phoyl mjnol b@i. 

eid odl N- (2,3-rylayl) rdlErilie eid 

nolall& rci3hr is 241.1, el Ed 

dnd whit oddl6 micetsdlinc 

pow.r.r, en h4twpiq inslubk in 

hyddides ad @boml4. 

qrter, solubl. in olcohol, nerlyl ilcohol, spannsly iolubl. in dhn md 

Meloxien i! 4-hydrcxy,2.hodyl,N{5,nelhyl-l.Srhiuol2-yD-2 H.1,2bgmrhiuiFlraboxmidcl, 

liioxid. 

havj4 l5l 8 noloLr eiShr Prldi.,lly Frri 

iMlubl. in ldr, :lishrt $tubk in eroft, 

2l

Typical re(tioN includ. cpigbFic pdn, n.u.a voniting, didheo, bleding . 

Frforaion of slomh, sm.ll or lrge i esriD., Fplic ular, hmouhlgc dd Frloniioi. 

Drug resislance in Eal{ia h a vit lly inpor.or public h.alrh concem. E&h ye&, d 

estinatd 0.?-2.7 nillion people die of m.lria. The developm.nt of Esi$ance had d 

siSrinsi influe.e o! thc ofiol of Daldi. in afi.cled @uaid, R6istte. ol pldnotlim 

/aLb@@ to.lnobquin , ! 4uinoqui@lioc, B fi6r oberyed dmn 50 )td ago. Now 

r tlay, chlolquir€ qi5rff. @6 .lD@t iD d€ry EgioD *fi.p P lalcipatun @M, 

Strains of/z/.{Mza pa*ir6 hdd develoFd Fsistalce to mosr of the comonly usd 

edmaldials. incllding sulfadoxine-plrinelhmine (Fssirt r) &d d€floquin 1115-r2ll. 

T.bl.l.7 

tdiNtaials set*t.d fu i@iorc p'n) 

t-(4-oholorophdyl}6.ctlyl-2,4-pyriDidin di.ninc. cDHnclNa, 

practi€lly irsolublc in wder, 

eluhle in etnuol sd dighdy 

$lubl. in cbn , I*t-7.3, 

pdnjon cfficicnr 2.7 in 

!4us ejd od 2.86 in rqllos 

lI -(?-chlosquinolin-1-yllM,lV-diedylp.nr.lr1.4diMin.bisldihydog.n 

phGphd). whiE or nd *nite, 

crysuine po*ds, hygbspicj 6ely $lubl. in wis, slightly 

srubl. in alahol Md 

mdnuol lt dis in 2 fmi 

orc of *hich n.lts .hour 

I95 "C rd .h€ olh.r .t lhour 

218.C. 

7 Antiath.tttL tbust 

Irt cpiBlolt dng rD*cl is domiMcd b, jusr te indiddotuJ 6dn ond chrcnic 

ob.tructjle pulno.lry dis.e. Alth.uel rh* dis.s m rr€.r.d with thc me drugs. rhey 

difci significanlly in th.L sderlyins etiology, Borh & ch@d.dad by loe inflallmtioD. 

tlow.vr, patimrs with arhna suff€r lars.ly fron wdible aidlow obstrurio., wh@d 

padd$ witn chrcnic obsriuclive pulbonary di3.e qpqierce a @Drinuou dslire in lug 

tu ction 6 rhen disc4 P'ogffi [lr]. Asrhm-Elll€d lait' bctud. ctini€l synp{om of 

22

dslhma swh s coughinS, whezing, dd dyspneai bronchial hyp.r.sponsivo*s (BHR) as 

aesd by nedacholift chill€trge lesti $M lgE ldelsj aropy; 6d stopic dermariis. 

motclulosl is l€ulorri.ne modifia. guif.BiD is & qFctom! ph.nylcphdne 

hydr@hlorid. is a dMrgdarr ed a . mydriatic in ophth.lni. appli€tioB [r2]-r251 

T.bl. l, 

,lntilthnatics slect d ht bne@tiots 113-11) 

112'nahoryph.mxyll,2- DdpoEdiol, C'oHkO{ 

crysbllin. po*dsj $lublc in wab, ..hmol, 

cholorolom, insluble in pctol.un ertd, 

ptnioD e@m.i. (@hnotwri.r) 1.4, rquous 

..>

. ihclcri.l sFcrruD .rd sutdi iN al Fcirion 3 of 0E dilydorhi&ire rirs dr.r i[. 

phm(otin.ric! sd m.cbol( pamdeu of rh. dxs It2t] 

c.pktrNpqi$ kb.kd fu MM 11+111 

Disdiqr 6/t,7rt!7-{ltzX2{iiorfi iMr,l-ylIm.6qyinino, Gryll.D'nol 

i\* 

CtrHbNrNilqSr.3%H,, tcly $hhle in *!r.', lplmrly eluble in m.thml, 

q 3liddv $lublc in .thel. 

[6 R .[6,lpha'bad R''ll.?.ltMinophntlr.!ldino]-l.m.rhyr.3-oxo-5. 

lhi!-l-@bicyclo l,t,2.0let2-.n.-2c.rboxylic 

eid; CduNlO.s, 

nol@Lr *i8ht ir 14239, Th. Disq 

or c.rhilcpcin exnibib noF 

biologicol @livity lhd de L-ismq. Ceph.ldin is d€sEd.d by sfons.cid., 

alLli, ulFaviolc lirnt Md Bl.drhs. 

J6 R. [6dDn47bdr Z )ll U('.cryloxrrncrh rl]7{l(2s'nor, 

rhiuolyl)(Dethoxyimino)dlryl jeiDol-8. 

oxo-5rhi.-l@bicycle{4.2.01{cl-2ar-2qboxylic 

rid; C,dl,?\qs:, Bdd 

+.ctum .hird 8.Mior .th.lcp.rin 

dtibi

Hist.oc./melabolic s}t'dmne, which confen a p.diculdly high nsk of cardiovdculd d.aih. 

CeIMlly.tiab€1e e.llitu c.mt b. culd bui only @!iroll.d. Curutly &ailablc glucG 

lowing a8ats v..y @triddally i! th.n .bil y ro rldu e mic@lbdindi4 Tbe 

sullbnyluo sppq to hav. cflet on nidoalbuinuia expEsed d udndy 

alhmidcMtirim Etio, *trile iltc rhi@lidiclioG b.ve sic@ e$dr on rhis isk f&bi 

in pa'all.l qilh dEn ef.cts or iGulir 6isl.@ {rtq. 

NtDDLk yl6t d l* itudiN 11911 

NN- dim.lhylimidodiqrbonimidio dimide, I,l -dim.rhylbraumid.r 

C.HrClNjj FEly slublc in rlc., 

tlighdy elubl. in .Lohol, Fdielly 

inelubl. in &.tonc .nd in m.rhyl.n. 

ohlorid., m.ltin8 poinl is 222 - 226 

l-[a-[2'ft 5+hl@2{rhdybd"iyl)dnino]anylp66ylFulphonyll-3- 

.ycloh.xyluEr, crHrclNrors; wnn. 

or dmosl *hit, ciysrlllire pdwd.r, 

pncriolly iNoluble in w!l.., sparingly 

$lublc in m.tftylec cnbiL, stghly 

slubL in .LdDl dd s.rlml. 

isoquinolyl)chyll 

D E&ltLl ...1 tre .LEdt! 

c'HjNrOlS; *hit. or rlmo{ 

shia po[d.r, pdci€lly iMlublc in 

(96%) &d ir h.rh.!ol, elubL 

i d!':i:C 

rTr-- 

uLr ; dighdy $luble in ethool 

i. .@rc, fi*ly slubl. in 

Mindls esenli{l 10 hcdtb @ inrclv€d in Fifotuing r&ious fiNlioE in body. thcy re 

oslly adhinil&Ed, s wll alonS wilh ditreHt food ddnk or 6 drugs, Tl|n defici.ncr oi 

ex6 My lad ro vsrioE dilrub'l6 b body. Irs. N .bout l?-20 (d.pdding oi dE 

$t@) niffids @Nn|a .ssd.l ro hl||@.utrition. 

Mircds e genmlly clssified ar Major or b.N nimr.k de ond rcfeftd b a 6&ntial 

niadis rquir€d in mouls ol l0{ bg or mrc ps d!t. nE$ @ catcim. chlorid€, 

25

dEgnesim. phosphotus, pot sium, sdim dd sul6n. Mico or tracc mine€k e uoally 

rqlircd io eodts le$ lho 100 ng pq day. n'e$ m €brcmiu, oball, copps. fluoride, 

iodiE, ion, ndrga.e, nolybddh, slaiD &d zim- 

Ultu tre€ mile,als e lhose thar e pobably esential but d required only in hinute 

mouts (l6s th& I ng p€' day) md uually tr be adequlely snppli.d in $e dis wi$out 

add.d $pplel@btior, ft* iftlud. oMiq boml' hromin , @dnim, lad, lirhi@. 

nickel. sili@n. tin ed v&adiM. 

MaAn€sim is the founl oost abuddl nineral in rhe body ed arprcxinal.ly 50elo oi total 

body daen€siu h found in bonc The olhq half is food prcdomiMlly i.side celh of body 

tsls od orsu. Only I % ofm8rEsim is found in blood, brt tbe body *orb vdy hed ro 

kep blood ld€ls of nagn6im .onslaft Ir301 clta vesaabl€s swb as spiMch c good 

ews or m8!€sim, some lesw.s 0e4 ed p€6). nuis ad *e& ed whole. 

'mfDed 

sEiB e de sood $'@s of magciu 0311. Mag!.siM in the body sd.s sreal 

inpo@r metabolic tunctions ad plays a iol. iD the produclion ed tr nspon oI€Mgy. Ir is 

also import nl for the @nirerion ed relMtion of m$l€s Masnesium is involvcd in rhe 

smlhBis of pmr.in od it aisc in lhe n4cdosine of c€rLjn €.zyn r in de body U32l 

Macnesim deficiency ce afed vinually d.ry orSe sys!.b ofth€ body. Wilh rcgdd ro 

skelelal nwle, one Day exFdoe rwilch.r, €rdps, nwle r€mion, nNle soEness. 

including b&k eh€s, reck pair, Lrsion hqdache ed jaw joinl (or TMJ) d'sturclio.. Tn€ 

@htral n.Noa sy$.m nay al$ be nwt€dly atfeted. Synploms includc insomia, &xiery, 

hlT€@tivity and catlc$Bs wiltr onslrrt movd€4 panic atra.ks, ag@phobia dd 

ptn€.srrlal iEitabilig, MagBiM dcfici€dcy synploms involving th. Fdptehl rcdo6 

syslqn include nMbn $, tingling &d otn€r abnotml eostio6, such s zips. aps ed 

vibFlory *Nlio6 o331. 

The nosi aburdrdr din.ral h th. hl!@ bod,, h6 sev€ral inporrel aucions. More thd 

9ryo ofbt.l body cdciM is srocd in tbe boms srd t€el[ wh@ ir nDdiotu ro suppon rhen 

$ruct'e ll34l. nrc Rmainine l% h found rhmughour rbe body in bl@d, nBl. &d 1he 

fluid be$*n celh. Colcim is essntjd for he.llhy bon€s, il is n ed€d for mNle contr&rioq 

harr ato|! blood v*l @trtretion ed exp66ioa nomal blood clolring, t)wo6 syst m 

26

mirlende. rh. sErion of homones ed .nzycs dd sending n€ss8es lhNugh rh€ 

neryols sy$ed [35]. Cal€iw h added to bon6 by ells c.Ued ostoblsts ed is renolcd 

iion bons by *lls called osrclclsB [36]. CrlciM days e inporLnl rcle in a nmbd of 

physiologicd pc6*s a in de qcir.bility of .elemsulr mesblaG. Ir is ale of 

critical importance in excitaiion conuedon @uplinS in musle. Ihe mncenlration of ionic 

calcim ir plam is clGely rcgulal€d ed ilvolv.e onrol of i .srinal ed renal trmpon 

ochdis dd mormqr ben€i bo.e &d ECF 1134. Calcim is a inporiant ctinicd 

pslm.Lr in tlF di.gosis of ihbalaGs in ninsal nerabolim o?ically Miard with 

bone di*ses, di$rdes ol pd.thrroid sle&, Mal failw or cdco [l!El. nE besr f@d 

ews e d.iry pr.ducts, b.$r, @uliflow.r, cg8 yo& nolaer lary g@i reselllki 

*din6, clom md oysr6. Dailr Fquim.ot ofcarcim is E00-t200 me [139]. 

Chrcmim is now @ognir

ld.ls in vidually .ll dieb. R.sadls of brrke, eioals g.n Btty mai sin si.ble dsse 

mdgd€F leveb s a resull of honosblic mehmius that ightly Fgulai. rh€ absorltion 

and .x@tion of this meta.l. Howv€r, high.doe exposG e s6i.r,:d wirh irctted 

liss Mge.F l.vels, €Bing adw E@lo8i.al. ep@ducivc ad rsliElory .flal' In 

hmds, m&ge.s.-ind@d n.wbn€rty is dsilr€d with a mobr dys{ucrion s}nlron , 

comnonly efded b d nalgdism or Pehnsonis, which b of parmout concen ed is 

@aid.Ed ro b. ore ofrhc nolt $6itiE odpoin6 [r4]. Mdg&* is lbelb€d noD lh. 

smdl inresline and th€n F.Npolr.d via blood in rhe tival€ f@ houd lo r baa gtobutin. 

lraomegei!, lt h exceled in th. bil. and thro!€I the inrcatinal wall. Th€ eour.xcr.tcd 

in uir. is v€ty sndl [lrl4]. 

Ircn hs the capeiry ro ecepl ed do&re €Lctrons Eadily, int''rconverlin8 between fdri. 

(Fcr) od re@u (Fe'?) fom. This capabilig @la ft a Btul oopomr of cr{oheDci 

oxygo-binding oolcule .rd nmy ozlm.s. Howr, ire. 6 ale dm!s. tissG by 

cslalyzing thc convesior of hydrog€n pqoxid. io n@-udic.l ios thfi anrck elluld 

hmbr@s! prci.iG ud DNA. Ircn pnbpo.phydD O€be) .d ibn+ultu cluI€s sF. a 

@yme @feloB 0:l5l- 

Each crydmyte @ntaiB billioa.iohs of iren| r norml nEs of 

tllmv{, rnis @Mntrariotr€or..pon& ro d€ iturpoErion of 2 x Ido abN of iM pdday 

0{61. Conseq@ntly, ddia is fie cndinal sign of ircn d€fici.ncy. Mqr of rh€ rnaining 

body ircn is fould i! hepddtts sd Eticulendotb€lisl tuIophagd, which we s srodge 

d.poL. The livd ha firsl-ps.c.* to di€ra.y nurriols a.d @@dily tak up&mour of 

circulaing ircn dit €xc4

e$enrid fuciion ol cob.h is rs a conponenr of vir BD. Cobalt uually @Nid.Ed a nonbnc. 

hower. *!er€ c&.lie failue od some ddths in mm have icsuli.d fron 

ct)llsmflior of legc moun of b€r @ aining 1.2 1.5 pprn @bal104ll. Both exe$ dd a 

deficioc, of obdlt ce irhibn lbt@id activity ed ob6ll s viromin Ba €anses p€nicious 

d6ia. High lweh of cobalr ce pod@ a polycrdcni! in mmy sFcies[lso]. Laee 

uod of @b6ltou ct oride d@B dE producljon of .rtallmttd [r5ll. 

Nickel 6 eliv'l|€ ccnain qzyn s ,r urro. allhouSh lhir ef€cl is mosl preblbly mn 

specific. HisI concenlrldos of Cr md Ni, th.ir fm bindine in nucleic *ids m

dcficimy @ b€ b€st d€teted tbougl a pos'tiv. 6IoM to $ppl.henrllion rridr. Zirc 

supplcm.ntltion h6 ben shom b bav€ a p6iriv..f€.t on tne incidae oadieba ord 

pnemonia md nigh lead lo a da@e in thc incideM of mal&io. Zinc hs de prolen lo 

d€cr€6e lh. duradon ofdiuhea by 15% [1591. ft€ impondce ofzinc for huna hqlin wa 

fist docmentcd in 1963. Duing ttr€ p6l 25 yds, denci€ey of zinc in hhm due 10 

nutritiomlfrctos dd Fvenl dist* sl!l$ h6 now be@ !@cniz!d. Zinc is rcquiFd for 

ndy biologicsl turctioN imlnding DNA synthcais, kll divisiotr ed gde dpcssion. ll is 

r€quircd for th. activny of tIEy.My@s in biologic.l sysrem. R@ studics indicaE th4 

zinc is nad.d for @ll-n dial€d ilmuity. U601, d.ily EquiEne is l0lo l5 h& l0lo40 

% of the di.lary zinc is abe.bed ftom lhc arDll i.Gsti@, the absQtion appea to be 

Mi.r.d wirh nuiilionrl $ars [16l]. Absolprion of ntr ba b@ d€cEa.d wilh rhe 

fomalioD of insoluble mmpldB wilh phrlli. (@rcrlt, calciu, villlnin D, prctcin dd 

fib.r. hc@ed copper inlaks m also suppFss zi.c ab$rplion by @npelition fot albunio 

bindins sites 1162l. It h excEled in the f.ces wirh only tr@s apFding in the uin. sinca th€ 

kidrcys h.v€ liul€ or no rcle in rcsulatins the cont nt ofzi@ in lhe body 0631. 

l0 

CadniM is ! hana meral with a high roxicity, it is loxic ar v.ry lo* qposw lev.ls ed has 

eulc ed chrcnic clfdrs od halll dd dvimmo. CadniM is .ol d€gmdabl. in tutft 

dd will ths, on@ lelq$d lo rhe envirmen|, stay in cionstion. Nw elcss add lo $e 

alaady .xistine d.posis of @dsim in rhc e.vircm.ni. Csdmim tud codniu conpobds 

m, @np@d !o other h€avy b.lals, relatilely MLr sluble. They N th€Efore also noE 

Dobile in €.s. soil, senerolly more bioavailabl. &d t€nd lo bi@mulat€. Chonic @dnim 

exposw produc.s a wi.l€ vdiely of &u. &d ctronic €fsrs in hdm. cadniw 

umulat.s in tlE humm body dd €sFcially in rhc tidn ts [164]. Cadrbim sulphid. ed 

cidniM sdd.tc had betr used for rh€ r,lsl,ndt of stin @ndition &d cy. iritclion, 

Gpetilcly 1165l A suficior @@E tid (200 l1r/s) dabasd ilE Lidney cell, Gultiry in 

preximal ruhle i.juty and Foteinuia U66l- ln rh. GI te! rhe abGotplon of cldniE is 

poo', studies in $e laboFtory einals indiqLd tht enenr of absorydon lo b€ only l.t% 

[167] md limit d sludies in M indlcated d valu. of 6bout 5%. Appoximolely 50vo of$e 

toral body bu.den, aner dhtdbution is foud in lhe liver dd kidneys. Livei dd kidney 

cont ins n.tallolhion€n, which is ind@ible by .xposw $ cadsiM [68]. 

t0

tdd hody kd.a d.r diliihdm ir tutld h dr liE .!d tidE r Liw rd kidDy 

old E t![oltio@4 *hici i, irdu.iblc by deore ro cldoiun [r6t]. 

E Inn.m.d.Ldq ..tirirt 

tfidei.. d€* .!d q,totiD Fo.tud!6 by oa c.{t .rd b..o0tit. & rho!8h !o t 

ilslv.d h t r.dosrori. of.lt .sic dir.r... Ir t8 b€.n ra0ord ttd dlagic didg 

e i!tdt!.d by corylicrrd ibfunc Espord .ad ory iMlve itrtl|noltqy o.dhr.6 &ch 

u HrlrDir. rd.nli&oic.cid uarloli4a crbtin r.!d o.sy dift.ed ccn typ6 

iocldi.g T cd|!' ur ocr4 brrorhr., ialtqbiL\ |tryqt gd a. trral. T cdtr e 

i@h4d i! lh. ''Fr'.i@ .ad ngl!!l[ of .lld8i. intrdn|li@ .!d .Ey phy rotc i. tt 

ctrcoicity of6. dir..$ tltrt r.gdlde tt iDEM .€+@e ro for.ig! t i!€o! od p|nioipCte 

i! it 'Dridr{@ of Fipt...|.!d o..Ld loLr|e [r?1]. A etd.dhl ho

Filuily iNolv.d in inflmato,y dises of $. l@s. Ii hd b€en povcd that lnsldnine is 

d efi@tile siimulus for cx@tlosis ed cyioldne prod@lion nom hlllm lwg merephages, 

h hs also b.en suggelled tnal hislaoi@ nay conidbute to tbe longrm dolltion of lug 

inflal1mrion ed tissre emod.lin8 in allcrgic di*s by nodulating $e pildwion of 

prcinn@torr and imuoEgdatory nedinoF by mrepbasd. tl?51. 

1r' 

0 ., - \J,-J,, ,-! 

: 

".'.t: 

A mild peenc. of inllmolory celb dd ICAM.I deprors oo epirhclidl cell h6 b€en 

demoNtrat€d even during dymploMtic p€riods ih au.leic subje.ts. So lh. comt uearnefi 

ofauergic disordeB should addrcss alle4ic inndmtio. ed notjst $e sydploms. AUersic 

dinjtis ad bbnchial a1hm frequntly co'exist. Thu n is elf{vidcor that alrhoush 

otihislaminB (s@nd g€re61i@ Hl bldtcu) e th€ dost eidcly u!.d lsdrs for t[e 

rrqln@t or alldgic 6ndiio6 0?61. h ws rh. obj4tive of U. p!!sr in@rion ro 

synthesia nov€l sdhbbminic, arni-allcrgic dd dtiinflasnDtory ealogrcs of ccdnzine 

J2

the h@d imw sysid pDi€ct lion dipe, Th€r e tlo typ.s of imuiiy. 

A hrd. 0 no^-tpalft: btun r 

IEEG imuily @mfiis of n€hanicd brri6 &d c[oic€l bdis. Skin,lhe @m of 

th. eyq ed the mcmbffi liniry tle reAi6tory, dig€niv€, ui@y .nd EFoductire tr*at 

do6 not allow nicob6 to Fr€nat 

nno body !d thu acl N m@hdical b.trieF. T@ in 

rhe eyes &rl Fcr€lions in the digestive r&l dd vagina cont iniog eMyms such s lysozrme 

that 6 desiroy b@tciil dd small mol€cule s inlcrf@ft e oI ansidqlbl. importarce in 

pde. on agtoNl Infcdion ed N ampl6 of ch.n'*l bsie^. 

X ds i*ludes ph.g6Ics (MEopbils, @sinophils dd mmcyrdtu bph.g6 in blood ud 

in Dany h.dy li$urs) whic[ @ @gniz. p60Dg6-a!siat d @leulr prrrem rhal m 

pEmt @ mi.bbc! but rcl on hosl cells. Ihc .bility for th€ inrale imuc Fspone to have 

$is Ecognition k on. factor that shos th. clo* Ebtionshjp berweo ih. iMte &d adaptive 

r.spoN. I e.f.'oN md @nmi rila NK cdh) kiu vFD-iDJ*t d ed cmcq *lls. 

Inflmalion aileis lcuk6r16 to th€ inJation sne, *tE innale imu. Gpos6 Mui. 

Irtc eni€ blood c.lls irvolved h @nsDeilic imuiry N mo@ycs (\trich develop ilio 

@Fph,ss), rorropnib, @sitropbils, b€ephik .rd en]6l kill6 elb I lt4. 

Th. €nldgenent md shifring of nonoc)res ftoh blood s[em 10 tissuca duc ro infection @ 

crlled mcrcphag.s, Th.y {e gr&t'les oEt @ nlbd pith eizytrs that h.lp !o dig6t baclerit 

Ncurropbils re pt€e in blood sa.am, Th€y d attet€d lo*{ds b&t ri. rDd ots ri$u€s 

qher they ingest bet ria dd oth€r foreign @lls by a proes rmm a chholaxis. 

Frsinophils e lc$ etive .g.insl b6.icria th6 neuuopbils dd tubphag.s. -IrEn min 

finaior bar be lo .rh.h ro bacraia rd lhs h.lp imobilize rnd ldll p.ruirca. E*hophils 

ale p6nicip.te i, all.lgic Eactio6 ($ch a NthDa). 

l3

iy nLtophiLt url Mt c.lb 

Bsophils ed mst cells inili.t hyF6ensnivny by rclcaing hist nine thal indues 

inilamlion and snoolh nuscl. @nir.crio.. BMphils al$ piodlce substanes lhal attrsl 

n€ulrophils md ssinophils towdds forig. subsidcB in ord€r to phygocytes thm. 

I Notunl Llller c.llt 

Naiual killd (NK) ceUs dc onc typ. of lyhphoctls thrt afix io stmge celh md Elese 

@yns that damage oure! hemb@cs of thar microorgaism. NK cells hill cd.io 

nic@teeisi abnom.l celh dd ells in&d.d by viruFs. 'ftey pdu@ c)iokin6 ihar 

€gdaie $ne of lhe fucrioG of T lymph@rt s, B lyhph@ytA ad l@rcphages. 

B spaifE bM.arr 

Speific o adapiive imnuny is 6.lquiEd imuiry rclpr*nt ai the dne ol binll. ll 

develops a0d ed€ lime of iriliol expcG of ns &d!en od a mnory is fomed. l&t 

cpoIB ro a peviouly 6@ul.iEd eligcn e moE €f.cliv. ed moE npid lh41hN 

g4nt d by i!@L iMuity. T lymphetl.s ,nd Blynphdlte. @ tro bporr! €ll 

i olv€d in a.quiFd im6iy. 

Bone l|r.mw sffit6 B-lynph@rlq hding spccific @For on snich panicdd &tige6 

m bind. \vhm s eligcn amch6 to th.F sitai B lymphdyt s gd nimulslio4 in Bdr 

lbey e coNened irto plas@ ccll ehich pr

u CwrhaealdttutirB 

Whia Dlood ard eruin otlF cdL of dr imu. ry.i.d F!du. crr.ldn€ vba D utiSo 

k d.tet d. Cyrokir6 ed cl|aDkiB e i*gnSd of im@ synd d.y e involEd in 

grewth diffaaniltioo rd *tiyEtio., .k plsy ibpo(rrnr oL in,lLiSic rcrior!. Tb.y 

$irullL qt io vnirc blood clls ro b.com nort ctrccri!€ tillcrs.rd 1o $t-t otha whir. 

bl@d ells 1o . tolblc rpot CtrotiG .i$ priri.ipd. in 3Fific imuity .tn @ b. 

divid.d inio inlaL'ti$ (k), i dftrcG (lf&), @lolr-sdDd.rils n 106 (CSF3) dd 

nloN c$i. f,rro.l (INF!).I!t6&oB iot6fa! vill th l?licdid of vitls lr?1. 

35

EXPERIMENTAL

Raw @&ituls a.d wft of Dtmr.uticd pwily, obhired Aon difi@nr pb@.@tic.l 

but€ds (t bl€ 2.1). ThG Eblcrs rft prc[,$d fon 16.l plrmdy dd B l!h.led. 

NIDDMs 

EXPERJMENIAL 

T.bl.2.l 

D st, b4dt dn M{@t@s 

x- 

Phm&.utio.l irduslry (Lrd.) 

Yugshin Phlmx.{icd Ind. 

50 ahbont b6tro.i6lP.tid.n) 

It 

250 

200 Abbon tihombri.s (Pd,itu) 

Smilh Klin B.rchm 

r50 Beh Phm.€uricak (P{) 

2m 

.:00 

20 

l0 

l0 

.]0 

Atbon lrhoddi6 P.Iitu) 

Brd Hod8s P itu(P{) 

Abbon L.bomtoi6(P itu) 

Bondr Hods$r Palib (Pd) 

36

Analtlical gmde Eagedl3 lle ued during the whole €xFrinenlal prccedws. Melhsol &d 

&.lonitrile w* of (1iILC gtad.) {TEDlAo. USA), OUr€r @gefis included hydrccnbri. 

rcid. nera dd pda pbaelm€diMire, ue!" thiouea, &ewni.le, sodim hydrend€, sdim 

chbnd., polassiu dihy&ogd onlophosphrlc, di$diu hydrDga onhophcphare, 

.@oni@ chlodde, loEo NHr $lutio4 phosphodc @id 85% (Merct, Gmy) Lminol 

(3-oimphhrlhydr@ine) M prchr*

AllD( 500 MHz spetron i.r sing IMS s e ini€hal sllndad, Melting points 1r@ 

ieco.d.d on a Galbnnmp nehing poinr .pp@ru. Cbdilwincsence sd T.Cell 

Foliieration 6ey weE pqfom€d at Pejw&i Cot r for Molcculd Medicine dd Drus 

Rwh. using Lmh6ke RS, A-$intillalion courer (B@knm mutd USA LS 6500). 

'| PEpandoa oJ.lelonlz.d toler 

D.-iodad wter *a pr.pald by pasirg doubl€ disilled wltd brcugb lhc d.ioiid 

(s1de csw 300). while monibinS th. @trdwrs@ ofrle .mu.!r. 

2 PtuNrrtionolbrfiB 

Prepantion of 0.1N hta/ochlorlc 4cld (sinulat d gBttic juice) 

Andlrical gndc (l I N) 9 d[ hydmblodc &id M r.km in ! lil' volumeEic 0ast ed lhc 

volM. w hade up lo thc n rt with deioniz.d s!r.r. 

Papdtutiok ol I M so.litk Mtotid. 

sodim hydrcnde pellers (40 g) were ratd io 1000 nr volMelric fl6k, dislvsd in deionizd 

wllr .rd rbe vdu. w bad. up ro UF Drlt *ith deioniud M!d. 

Prcp@a,ior ot0.2 Mpol8tiw c @id. 

14.91 g po&ssim chloride dilslved in d€-io.ied wler in I L lolMeiric flsh &d ihe 

volud€ made up lo the ddi wilh de-ionizd wa!.r. 

Pnpanion of lM potastim dihydnger uthoph6ph4. 

PotasiM dihydseen onlopholphaE (136.09 g), dislv€d in a litilc

Btf.t pH 7.a (pb''phare btt t) 

0.6 g of poi.siM dihydro8.D orlhophosphrtc, 6,4 g of di$dim hydrog€n orthophosphale 

&d 5.85 g ofedim chlorid. we disslved iD suffici€nl d€-iooized watd 10 prcducc 1000 

rrl- dd th. pH .djusLd if M6sary. 

Batet pH E and g(Mm,na bufet) 

4.98 g of almonim chloiid. M dis$lv. in l00O triL of deionized water ed pH w4 

adjuled qith l0% almonia. 

E Uv/viibh.Frt!@pi..ldtlL 

I Asat ol c..bbhE shts Vl,-tilttd. sp.ctrophotoadda it tod 

P p pa rct io n of s a I ln io h r of c. I tr| z I re 

1 DM solulion of @tnizje w pr4olrd by dislvilg 0.0461 g in 100 ol in 3inul.l€d 

safic jui@ .Id volMe w m.dc up with thc l.rc elv6r |o lh. @L 25 mL of priony 

slution w flnld dilurcd to 250 rI wirh simulated srsiric juice 10 rEl. ih. finrl 

con€mt.lion ofo-l bM, rcsFclively, In a sinild way the solutiore w€r€ Flp!rcd 

Cohntution of ttlt .otibtution c@t of cetui2itu 

in the 

Dif&rent dilulioB rmeins liom 0.01 10 0.I nM wcrc pEpsrEd by diluting the $ock slulions 

(0.1 nM) vilh difrsert buf* ell'ioN oI pH l -9. Fof rhis purpoe 5, 10, 15, 20, 25, 30, 35, 

,lO, 45 .nd 50 6L of slact elidzif slutioo *s eFrr.ly piFn d out in leo diff.Mt 50 

nL voldetric llaks &d dilllld *il[ individusl hfftr $lurio6 up ro lbe b!* to F!pd. 

rhe solulions of 0.01-0.I mM. Ih. ab6o6dce ruim w@ emqd in th€ Esion of 190-700 

m for th.& &lutions agaiNt O. eagent blark. Th€ @ima rlFaFd at 231 M. Gophs 

w ploltld for ab6o$rne asaini @nqr.don dd sniish lin @ obl,.iftd $,hich 

ob€yed Ber lr$err's l3*. Epiilo valB qe ..lcllll€d n@ tF obsemric. 

2 conttra.tlon ofth..atbtutirDc4Molltutuctins.trugs 

To pl€p@ calibdrion cunes of int€@lin8 do8!, difreHt lir€&ity dges wrc seledcd dd 

@ p@r.d i! laue 2.2. Gnphs 9@ plon d for .bsbs. .gd.n @r..lio. .!d ! 

sfaieli lie m ohained enich oberd th. BaR |ry. 

39

T.bl.2l 

LMit rdgd of@lra ob.yirls Bwt lqb.n tre 

NIDDMS 

3 In eUtu awitobititi.s of..tuEii. dthrtltu rbnd. 

0 0t,0 | 

0.0t412 

01405t 

0.1-0.0.6 

0.1-0.6 

0.t4.6 

Th€ i, r,to availabilily sludid of celnizinc dihydncl onde dd NSAIDS were studled 

individualy in sihllared srsic juie (pH l), sinuladn3 frrll stonacn OH a), siDurldnc

loo

solutiors. Con@.nadon tug€3 of all ealytes &e givm in t2bl. 2.3. FEsh etkin8 slntios 

v@ peprEd daily. All $lutioB w fil|.cd (0.45 !n) aDd d.gr$cd ui.g eni€ror 

Clv.ktutdr,b @a.tnitu 

McOH HP 

I 1.2,50 

I I t2-50 

20 l.JJ.ll.l 

50 t0 3.1 I 2 5.t0{ 

75 .18 I 2.5-100 

NIDDMs t0 u 2.4 I 2.5-t00 

2.7 

5 3.2 2.5-100 

70 l0 I 2.5.100 

l0 2.3 2.t100 

Prep@ation oI phqw.e{icat dosee fu n $npls 

Phm@ical fotuulatiotr of lhe Bp€.tiv. b6ds, com.rcially avaiLbl. h Polislar 

w€@ evalutcd. In d€n cde, sreup€ ol lwty i.blels Me individurlly *iel|d &d ff@ly 

povd.tEd in a @i{- W.i8h.d ponio! of 0E po}dd €q!i!al.d b rhe $iilbl€ moud of 

dog (@!ding lo tu lab.lcd cllihed) vs tusfeftd into a 100 mL volwlric 0art. The 

drug m nnly dhelved in nobilc phe drd thcn dilulln wirh thi! $lvdt !p to thc ndlc a 

ponion ofthjs $luton @ lilt Ed tbrcugl a dispoeble 0.45 trm lihd and 1nen inj€cled. 

Ptep@tin of sand@d drug plqru tolutifu 

Blood mplcs elrE sllcred fron h€althy volunim md th.n entriirged ai 3000 Am for 

I0 minutes. The sup@ianl obtained m stor€d at -20oC Aner $rsing, lelm ws 

d@rctiEted by &elonitrile ard spited dlily rith working $lulio6 to Fod@ d6iEd 

o.erhliom of cetntire dihldcnhide md inteEcting drugs. l0 FL rclmc of *h 

mple I irjcct d ed chsmtosraphed ud.r rbove @nditioN. 

2 Mctlodd.v.lopn€ni.ldoptimklrion 

HPLC neuods wre de€lop.d ald opddizd fd @itain pomreE b.foe nelhod 

validatio!. 'ft'. optiniution of rh. erltti.al pFcdw bc b*n @ied our by varyj.g the 

mobile ph6e coiposirioa flow nb, pH of tlr nobile phe, dil@ts of $lutiors md 

42

wveldgth of ealyl.s in ord€r ro &hi.vc aym.tncal p€15 wilh good rcsolulion at 

Ee@ble ret€niioo iime. 

All Blirlatiotr sr.ps wE cMi.d oor eordinS !o dE ICH guid.lirct swh s sysrem 

sunabilitr. *letivny, sFciticiry, lilEity (conelrlrioFdere.lor 6poM rlaio.ship), 

@l@y, pEisior dd sdilivi9 i,e. dctatio! Dd qurifietioa limit. 

Syslem suilability of the medod m evalutcd by &alyzing fiv€ eplicale mlys.s of de 

dru8 .t a sFcific concenftdon for Ep.dabilily, peks slrn€Fy Gy.u.Fy facroO, 

th@rerical pl.l6 of O. @ll@, tululion b.t*an thc pal! of cairizinc dihydr@bloridc 

&d orba d!$, llB disaibutiotr Etio (cap.cig f&tor) rld rcladv. r.rorioi. 

The druBs w* spik d wilh phtueuticrl fomulaiions containing difreient excipienls. 

ft. li@iry of thc h.rhod v6 evalured al dill.Mt @rcdFdtioN in dr. tuS. deib€d in 

t bL 2.l. LilE @rclarion coeficioq itncMpi ad sloF vd6 lft c.lcuhr.d for 

'Ihe &cu€y of th. n.thod @ cal.dded d thE conenlration lwels (80, 100 and 120%) 

by spikj4 hDM q@titis of th€ &!s &dr,L' Dre idetiom of €acb slution weE 

inj€ted b SPLC ayst@ ud % @v.rt sr cdctl.l.d in @h w. 

For th€ p@ision of $. metho

3 Dmg- dru! i .ncriob srndi6 

The D v,r4 intedction srudies of celirizine sd rll tne o-adninisLrcd dlu8s were cdied out 

ar dilfeEnl buffq medims a enpv srom&h (pH l), tull slommh (pH 4), sinulared blood 

(!H ?.4) md simdaicd intesdnal juice (!H 9). For rhis purpo$ I oo rsnl r lrock solnlions of 

aw t r€ial or.etjrizi& .nd oltq &ues (individlrlly) vw pr@d.d and nixed b rEke 

fiml orc.nt?lion oa 5olr8bl-'' fd @h @nnnu.r Th.* l,4 kcpt on ulcr barh for 120 

ninules at lfc. Ar dliquol of 5 DI ws qithdsu a116 every 15 minur.s im€ryals ed an€r 

n kile suitable dilurions wft $med on Uv-visible specirophotomcid. ln the sme 

mamr for sludying inrenctio.s on HPLC, ih. supl.s w@ filt€r€d through 0,45 Fn fill€r 

paper anr mrtirg .ppopriat€ diltjoB rd thE. rsPlicals we injcrad in to the srsrem. 

Th. co@Fation of @h drg rc d.lemined dd % @vdy itr @h c& w6 c.lculal€d. 

4 Dng {.t!l i.rcnctio! rrldid 

l,rr'to availability ofc.ririzine in pEerce of n llh ws detemin d by disslvinS l0 ne of 

c.t izine in 100 mL mixtue of90:10 n€thsol ed wat r. enicated for l0 Fioul$. Sbct 

elulion of th€ inmai sian.hrd, pmpyl peab.n, ws sihilely p@psed. 'nF @e.nl.ation of 

bolh sto.k $tunons ws .quiEtot ro 100 |r8DL'. Slek elurioE of n rab srlc 

(M8cb.6HtO, caclr.2Hro, crc|i6Hro, M'CD.HrO, F.Cl3.6HrO, CoClr.6HrO, Nicl!6tl,o. 

cuclz.2H?o. zich ald CdCl:.Hro) w prcpscd by dislvins 5De ofech in 100 mL of 

de-ionizd water ro gilc @ocntradoc of 50 FgoLr. 

Equivolme slock elutioB of Delal ud @ti.izine wrc nixed togedt r ro give final 

@dcentdion of 50 Fgmlr of edrizine &d 25 lrgnrr of m.tsl salts for dng-neral 

int@tior Th6e elurioB wrc pl&€r! in wdd.ba$ nainbin€d ar l1a 5"C for d hou, rh.n 

lillcEd lbrcugh a 0.45 rrn lihlr @pe ed injered for 4al'sis. 

G SD..rtuopt ltudla oforpld.r 

Cdirizire md its conpld$ weE chlEredzd by FT-IR sp€lrophobD.u in the Egion of 

409000 qr The infftd rpetr! w@ @rdcd s a Dorasim brenid€ dis nellod. 

Polon NMR sludics wF cdied our on a Brukd i$nrnent in deutcrared wrr. m€tnmol 

ed cbloofom uin8 l MS .s d inleml slsdrd.

g Srarn6i! of d.riv.tivd 

I I g of cedrizin€ m reacted Mrh 0.5 8 n€io md pm phoylen.dimine wnh out my 

elvenl at 140.160'C on sd b.th. ItE eclion ws modloEd ai.r.very 30 ninutes by 

applyiq TLC. The prcduct M lh€n c@l€d dd kn for .r'sLlliztio. m

la* dd HBSS+ *s !dd.d to @h wll to oblAi! . 200 pjl volM./wll. 'ft. lhrgoclrosis 

kinelic sludies vc monitored with lminon rd for 50 ninutes in th. Fpeated $tu nod€. 

P€at ad told inl.gral ch.milmiMqce cldin8s w@ .xprcssd in rhc cl.tively liSh un. 

J T-C.[ Foli|intio! ery 

l0 nL blmd E @lletcd by vei! puactw h h.D6rin @drdining lub. nob a n,thy 

volute€r. 50 mL sLdlc hl@n nrb€ m pla.d in stuy.€!ber (.r liditc @ndirio6) to 1nie 

wa added blood, ficoll paque ed RPMI in@mpl.t n€dia iwnho fctll boliie stm) in 

equal lolme. 5 nL li@U paque wa added in rhr@ 15 nL stenb enpty cenrritug€ lub€s md 

enbituged d 4{0xs for 20 minut€s at room reDp.nrN with no brcak. Pqiph.nl blood 

homrEl@ eus (PBMCS) apFared n th! junclion of trc layeF, th. upp6 layd @ 

di$arded ord ln. lowd @d!i!i.g tb€ PBMC5 vs Fesf€d.d ir @lnd slllil. tub., *trs&d 

qnh RPMI ir@hpler! nldia ed @Eifucd $dn sl 300xg for l0 ninults !r 4qC. The 

$pe@lant wa dhddcd dd r€susp€nded pcuct in I DL RPMI in@mpl.i. ncdia ed sroed 

on ie. The viability of the cells @ chect€d by Lyp.n bl@ ed cclls w.e coured by 

hm6'tonEler. 50 pL of 5% conpl€te RPMI w6 add€d into @h qcll of . sterile 96 well 

plate io srdiL cnviom. Bins saf€ry obina follosrcd by spl. dD$ h|ing ln€ 

@Mftrim berw.n 6.25 ed 100 psnl-_r adjcdng dlc fidl wll@ ro 0,1 mL. wlile wlt 

'A @trlained only 5% @npl.a &PMI ro bc u*d a @!irol. 50IL PBMC ells (lxl06hL) 

sF added in !6posion ot 5% onpl.t RPMI ro @h wll €xcept blarl follosed by th€ 

addiiion of 50 !L PHA ex@pi negadv€ @Dtol dd bldk dd volme of well wd nade up lo 

0.2 nl by 5% compl.t RPMI .Ille mixrw wa in ubat€d for 72 ho$ in CO, incubald at 

3?qc. And ircub.tion 25 lll otthldidim *as ad.led in @h wel €icept bl& ard the plsre 

aain ircubared in cq incutoro..t 3?oc for lE hoE. An r incublrion @us wE hdeled 

sing ela 6b.r 6Iq 6d lhe all b.rcnd, In @ll haFdling rhe plar.s \m sash€d witr 

70% ethdol 5 tim.s, fih.r€d .nd leff 6dl $cy \^@ @npl€l€ly dry, thcn dislved in 

sepanle vi.ls using thc scintillador elution md 6cmd by sinrillaiion .ouid.

RESULTS & DISCUSSION

RESULTS AND DISCUSSION 

The possibiliiy of druss ro ini uence each orhos sfety or emecy is tnoM as drug-drug 

ifletudon, Th€ esuhs ofa r€ce.r Egi$ry stldy ildicated thal ar l.st 250,000 Fsos die 

q.h y@ 6 r E dr of @s Eade Btilc thcy e hospnaliad. 'Ilt. hnk of fice do6 

itrvolvcd nbadv€trtws pith lhmpeulic drugs 0E31. Drng i .r.clioB @nnonly @cu 

with multipls medications, may nate drug less e,Iecdve, csuse uncxp.cted side efTects. or 

ilqess lhe action of a panicule dsg. Son. ddg intetutions 6 clen be hmtul dd hay 

bre pl&. due to @ion of dlugs with @h oth.r. This r'rusnrug inre@don my o@ to 

.xF i.n* & uexpelted sidc eff6a Dru-food,bev@g€ intcnctios esuh from dnCr 

Emling wilh fmds o. b€v.rd8cs 0841. Most inte@tioG r€main t!@ognird b€cdue drugs, 

b gei.rrl, havc a wide ndgio of sfety or b€cause the exlenr of chdge in drug leveh is 

sall wh.n compded with vdiadon nomally s6 in clinical thdpy. All drw intcdcions 

hat t phm@kinetic or phmaodylmic b6is [85]. on rh.s€ tes a pmc€duE rc 

adaptcd ro study the - vlz inlerulior olceirizin *irh difreMr @ adnidstqed dDgs. Fo! 

thjs purpose diilftnl sp€clrosopic lechniqu.s w.rc ued md conpoEd. Sinullaneous 

nethod! wer€ als d€v€lop€d dd vali.bt d tor th€ .lelemimtion of ednzine in Pl€eoce of 

dif€E dtues 6ins RP-HPLC lEhniqE. AI tn F n€thods wd late. on used 10 sludy rhe 

p6\iblcr, v,i.o intetulionof erinttr widdificrnt dngs 

A UY-Vilible3p..lolcopy 

aralysis of cdnizin hs b.d snrdi€d qt€6iv.ly by UV spetrcs@py [27-29] blt all $e$ 

n rho

e this wveldgth {a cbos fd ou o,lyric.l 

@ of li.@ rcgEssior fdcdon oblained by 

plonirg @n@ii.tior vesB abcoftdre in lhe 

rorEDg @n@tlrion tuge 

Suiiability of lhe nethod M ch*ked by 

ddynnS lhe li@iiy ai $e 3.r coicefadon 

drgc a pFncd in rable 3. | . Thcs drh sir 

w@ .pplied 10 lirca rcgEssion tunction, ed 

fie r$ulis ohlined @ givd id l.ble 3.2, *hich 

cldly iodica&d thar the n€thod *a sunalb for 

all romulations. ft€ soodms-ortu (i1 wq 

studiB. nis nel[od inrclv.d simullrn@N 

T.bl.3,l 

% R@t ry of dni'k2 h btdza of pH 

1.2 atd 7.1d 23lm 

foud ro b. 0.99E sr pH 1.2 md 0.999 al pH 7.4. In ords b detcmine &cuey of Lhe 

method, kloM qrdtiii€s of ccii.izi@ wd spik d 

sr.nd!.& md wa salyzed in tn@ Epli€a1*. 

It ha bd ohcdlcd $al th. ndlod B dui. 

*i$ io the eivo m8c. The ncinod pds*d fic icst 

for repalability a delemined by Ming six 

epliotB of thc 100% esr $lution @rding ro 

ICH glid.lic. Thc daltticd E$lts oh.jncd 

non thee inv€sligations for both nethorb @ 

sllr)mkld in t!bl. 3,1. ft. ddation linit or 

(LoD) ad linit of qua ihdon (LoQ) lor 

ceriiizi.e *d ch.ck d al two pH l€v€ls i.e. pH 1.2 

&d pH 7.4, LOD for einzine at pH L2 wN foud 

1o bG 0.04 lrgml,'od 0.01 fgnL''ar pH 7.4, For 

Ev na,1erid of ceririzire th. LOQ volc wa 

fowd 10 be 0.14 pgml ' al pH 1.2 ed 0.1 1 pgnl ' 

DHI2 

Lir.o wsiq tNti.w adttEtrs@ .al,Mtat 

9.21 ,9.3 

9t.t8 

I3.57 t03.t6 91.23 

.11.09 107.34 

27.7 | 96.57 93.0E 

t2.tl 100.01 t02.65 l02.ll 

s.E.E.t 

l0l..r2 r01.91 

in the dtug poduct fouowing USP 2009 

r.bh 33 

,awat ad Prchl$ oJth. propaed 

23_09 

LOD LOQ 

2I 0.62 

2ll 0.t2 0_01 0_l I 

l{D.63 

l3_95 102.65 

lo65 

23.06 

21.0t 

.2106 99.83 

)t 07 

.2105 

100.36 

002 

at pH 7.4. Similely thc LoD od LoQ in 

48

s€@ we obs.led to b. 0.04 l!gn[ 'and 0.15 llgnl- ' esp.criv€ly. Equiul.@ sludy w6 

perfomed al difeEnl bmds ol celnizine rablets availdble jn Potjsllr The svajlabihy of 

eii.izinc fion @n@rially wrilablc dosg. fo@ vft ..tculared (rdlc 3,4) dd w 

foud to be in asebot *irh lhe lab.led claim!. 

allco|et! o1(lnitk aJifere lqnulaho8 rn tE 7 4 

r@j 96.23 

t3.9 t008 93..18 97.25 

97 27 92 t2 u.26 t2.t2 

2lL t05 3 t0t.83 t0.2.78 t02.73 

Mo@va, no pturou@d eff€d wo obsred in cG ofpH 1.2 ad 

foud ro b€ pH indeF.denr i..., sc !r pH t.2 ud pH 7.4, The 

on@halion l.vels in pH 7,4 (simulaine btood pH) wft sl€ded 

ldr qwdtador of c.frizine in sfu. I1!. 6ov€ry val@s $ 

obrair.d @ givcn in bble 3.5 idi@tii8 suirability of melhod. Ite 

etulls ofth€ abor nudy indicrd rtu tn dlrhod @utd b€.r,ptied 

to stinale cdirizine in bul* dtue s wI 6 iD d6!s. fomuEioB 

aal in sfu This h€lhod is doe Etiabte thd ot!.i tJv 

speEophorohelric nelhodr &d it en@mgs onc io alply tor oulirc ellsis 

B RP-qPLC reblho. 

.1,2..t1 103,95 

J6_9t 1 ,.2 

HPLC is a *tuitile ed sFcific lahriqu. rhroush which pra@@kn€ric arudi€s ce be 

@alucr.d on a lergc vdi.ty of rh.Ep.uric ag.rrs. ft ce ,le b. u.d foi cli c.t t€s@h and 

for lhdnFuiic drDg monitoriog. A s.lecdve ed Epid HPLC Detnod 16 d.liFd for rhe 

q@ril'rion of c€tntin in &tive, fmulaijoN &d hul@ sm. s,nulr.r€ou HPLC 

nello& of c4irizine in pr6.nce of o ldministdr

ibuFofeD, nefelmic &id dd m.loxicd), dtindeials (pynmdhqile dd choloroquine), 

etuslnmatic dru8s (guifffiin, phdylcphriie md donlehr.n), cephatosporins 

(efriuone, &phalelin ed cofoa{ine) ed druss ued in non iNutin dependot diabetes 

mdh6 (m.domin, glib.ncLmide ad 8tiquidone) wft atso d.veroFd atd lrlidar€d. Tt* 

laii.lal€d merhods ww utili2ld for qqtifiutio. of ddgs i! phameudc.t prcpd!|ioru tud 

m hlM stu, Mo@va, $es. nelhods w.F inlh.r @d ro snrdy rhe in.litro inr.Bcrions 

of etidzirc with l!* .lrues. 

t Opthnh.tion oI ahnMtoetuptic .Mthtians 

In RP-HPLC. compouds stict !o cott!@ in hish aquos nobile phse &d e €lutcd 6on 

@llm in pNne of hiel orgeic nobile ple. h R? HPLC @npobdj e w.reil d@ 

!o rhei hydtuphobic ch@crr [186].'nEre @ iwo nain clals of .olMn: .!oml'sd 

'Evss.d' phd. Mcdr, EvE*d phe @lu|m @ used, p&t€d wft ch.nicrlty bonded 

odad€cylsilyl coEt d silic4 such colum de Efercd io e C_t8 md m very .on-pols 

Other phe olums have @lasityl, cya@Flpyt ard ph€rytsilyt pdtings, t is Epon d rhal 

lhe den on tine of aaltr is clared b llen hydrophobicity ed will be r€idned noe in ihe 

@llm [87]. Hoy€v.r ioniarion ds(t*s rL hydiophobic chdclf aod th€cfoE_ n 

dc|eas Ele ion. Acids looe a lr.bn ott bsE. iotriz.d whs pH irc'las &d b6ss 

gain a proton ed becohe ionikd wnen pH d!cEs*. Ttr@forc, adj$tins pH of1h€ mobilc 

phc using d appiorriar. bufrc' js neccqry in ordr b ehicve r.p.odeible 6utrs ll8al. 

Dtugs woe speded at low pH b6ause at hi8ne, plt the ptubl€o of p€ok bbadening tud 

f.ilirg lNw .o@ur.Ed 6 eidic dtogs jnt @Ld et@6ric.lty ro sibtrot gllups. 

TheEIoE. oper.ting al . low pH @duces ft Enoves d.tetenous s@pE,suppolt nr,acrDDq 

&d Foduced *.ll,shapcd, drcw psll fd host spl6. A3 eall1.s wrc lipophilic dd 

ionic in dt@ rh€ eidic mobitc pba ptuvid.d besl pak shrp.s dd aptuducible $D.ation 

ofconponeors lor long cnain alkyt bonded-phse cotLms. Nuber ofdaSs could be besl 

E$tvel by 25 d long cot@ dd 5 l1h panicle size p,ovided @m!te qprciry f&to. In 

ord.r to scl*t a popq mobil. ph$ for alt rhe nethodj hocraric elution sb appli€d. Th€ 

mbil€ ph!$ uscd vilh B€E d p[G mllms e Etarirely pola,, c.s. MGOwHZO Th. 

hoE pold coDponenh of a nixr@ eluie fisr, since these padjtion Eladv€ly unlsvorably on 

rh. hiENy mn-pot& p.ctdn8. tel$ils tne potdig of the $lvat mcE6.d rhe rctotion 

time ofd patticlk @npon@i Acid is Eed io inpreve rhe ct onabgmphic pel sh.pe od 

lo pmydc a sol@ ofprerom in Ev@ phc [189j, Mobil. phe composition is dr most 

50

povatul My of optinizing sel*dvny \neM tempente hs a mi.or .ffecr dd would 

o.ly ehiae mll slcliviiy ch&lg€s. pH *illort, signfi@rty afrer ih. rcrdtion of w€ll 

scids and b*s. Oprinum coididoff to ad€qulely r€llin all ealtlcsi thal is, to e.s@ thal 

rc an ltt ha a c€p.city f&!or of les lhe 0.5 (!oor raorioo could 6ult in pert 

ovdlalping) ad rc ealtle h.s a ccpaciry f&!or gEatr ih.n lo-t5 (€xa$ive r.l€ jon 

lads 10 lolg s.lysis 1im. md br@d Fals wirl poo' dere!6bility) Il90]. Affq seestul 

@hpl€ti@ of merhod dd€lopm€nt ir *s vdid,cd a@rdjng ro lhe euide ft6 e1 by 

Intemrional CodfeEnc. on Hhoni?nion tt9tl. 

Acc@y n€aues lh€ closen€$ of rh. .xFinenral rcsut8 to ihe trn€ vdue. A{uacy 

sudies for dng slbslsnc. ed drug prodNt e ft@nhended to be D.rfo@.d al l4t @h in 

rr'plislc dt rhe 80, l0O ad l2@/o lev.ls of t.bel claim. An u!@y 1e$ ats Ev.,ls the 

speifcily ofthc hethod in prcene of the eicipiats udd nre chroDabgEphic @oditions, 

Th. 0,6RSD of $. rcpli@rai ale prcvid6 de balysis prcision *t ch h@ws tb€ cto$res 

of dala for a nubd of meswdars bdq thc tue eal',1ical oadilions. pFcisions should 

b. esrimt.d bt thr @npomnts E!.alllitjry, irr.media@ p@isiotr ad EprodEibitiry. 

Rep€mbility cM be s*ssed by injectins mutdpte ,utu of homoeenou smDte md th€n 

c.lcul,rins lhe % RSD. trren diare pEcision cm b. cei€d our by catcutarjng rhe % RSD of 

the sples on nulripl. days, by diffeht dstys$ &d insrrmenls elc, R€producibility 

qprcs3 th€ pEcision b.tq€m t.bodlories 6 in coll.bontiv. $!di€s. 

Detediot and quantitdion tinit 

Dcre.don limi is tne bw€sl cooenrrqrion ofe anatyr. in a tude lhat cfl be dete€l€d. bur 

nol M€srily b. q@rihted wdq 0!. sral€d.xFringt l @ftlitioE. e@titadon linir i3 

thc lor€si onc.nr'aiion of daltle in a spl€ lhar @ bc det mineil wirh acceprable 

pFisor ed dl@y hdq th. $ard exFrimdtsl @ndiroN. 

Liftaily Ual ob.ys Be',s Law is depcndd on ln. conpoud being ealyzd &d th. kind of 

d.rector Ned, qorting htle conefilation e{i mplcs teslld for a@cy sboutd b. in thc 

l'r@ mge. Rage is lhc int€rvat h€rw..n the hisn md bw levcls ofdalvle sfudi€d. 

5l

RobusuEs c& b. ssssd by m.&ing delibrar€ chme6 in rhe ncrhod p.:usrm, IE 

nelho2) is a nBW of sep@tion b€tw@n n o !slG. 

The dum.y of q@drlrion @dd trol be mhicved wirh incr.le i. Fak laiting. ThoEtiql 

plate nMbd is a d€aue ol @lum .ffi€i€ey U9l, l9l. 

iit Me,ho.t dNlopwtt an t wtddnn o!..ti,ht . sins Rp-EpLC 

Nmbss of HPLC mcrlbds of c.tnitrc hare b.€n eponed in litqalE (rdt. t.l). Z.spte 

.? u1.. [39] dcleloped a sidpte tsr ed p@ise Rp HPLC m€thod for th. sinllt n6us 

dchiDtion ofcedntF and psud@pheddE in abt.s A hrT.Eit BDS Ctr (5 U. 25 €b x 

3.9 m) ollm in i$@tic Dode. wjth ihe nobil€ ph6e H,O-MeCNB-EiN (631?:0.21dd 

pH adjwred to 7.5 witn 5% pnosphoric eid w€E us.d d 2j4 M. The floq nl. ws r 

nlminr ed |td.

m. xrcjD ., d. t{31 dd€lop.d d R!-HPLC m.rhod fo. the d€r.miuior ofetdzine in 

sine uiry Nova-Pal Cr 6ll@ wirh a hobitc I'has of 50oZ M.CN-50% phosphat buifo 

in lo which EtrN dd sodih dodccyl sutfoEt! were .lso ,rtded. Thc dd.ctor *as opqlred at 

Uv 229 m, wnn &doxinn 6 e i emal $ddatd wality .r 4t. [27] d€rmined ! simple 

HPLC say of etiiizirc in pr$nce of one of it5 synrheti. precues (hy.rroxrzine Hc0. 

Bondapal C l8 colum ws u*d wilh a mobile phae of .c.bnftit€ dd almoniu 

dihydtuger sulfde al a flow rr. of 2 nLbjn r. L ord.r to dct.mirc sinulr,n@Bly, (+) & (" 

) etirizin i! hulM uine, choi tud coulbodros l3ll dev€tor.d a chirar $pedon method 

by HPLC. A chiEl srarioEy phe of alphat -&id gtyoprerein, . AGp-CSp, ws ued 10 

eparare tnc .ndtromeB. Mobil. pI4 @Bisr€d of phospbac btfer 4d erodrite for 

u'rc ssys. Jelinsta {4Sl ad CowotkeB develoFd ed validsled &o1h€, HPLC nelhod for 

fie

stsftl,rd w6 4.2 ninut s Estectively. The sylt m suiLbility of the nethod ss esr.blished 

by injddrs six Fpli@r.s of ! edd.rd slurion dd nNitre r[. BFBS (!6t a6) of 

The Elative sl$dard d.viation ofd. six pek Espon$s ws nol foud gEaler rbe 2% 

vrhich colfimed tte suitrbility of ihe mrbod. SFciflciry of ttE m€rhod ws d.boBilaet by 

gerdtlg rcprelcniarive .hrcmdoerms (Iigre 3.1) ro lhow ihal rhe othe. conDoncnh thai 

@uld b. p@nl in r[. mdc mrit @ @tv.d tm de p.mt edyc. 

No signifiHr cheges in AUC or rcre ion rine of ttE d{8s in p,.sncc &d abence of 

.xcipients clorly indic.lcd rbd specificiry of rh€ De$od. For limairy siudi€e. dle *ri6 of 

@nqlra$o6 of the d$g in t. mge 3.12-50 lrgbt L w€E prcpard, calibotion cwe fol 

Ors m8. w$ dal@ted, Th. tin@ Eg6sion .q@rion foud for 1his mg. ws y = l0o89x 

+ 19100 ed lild @mcis1 valE b foud ro be 0.999. Thc del[od peision w 

p.rfom.d by fou iepaFdalive s@plcs on c&h of 2 days, The ..rimaled prection (toi.l 

vdation) non virhin day qFd|Mr h ob*d€d io bc ls rhd 2% RSD. Th. nerhod 

p6s.d lhe lest for rcpealabiliry N derenin d by 0/oRSD of $e rca of rbe peaks of six 

Gpliclr. inj€.rioB d t00/. t s c()l@r{ion hbte 3.6. nle csutts of intedcdiare pRisio, 

Aeu@y of the ndhod *s cv.turd 

thc ditrtul indepod.nl onadrdions 

i,c. 8, 10. 12 !g EIr for dl 0E degs 

(n=6) by drlting lnom q@rili$ of rhe 

.ubL io rhe drug Pl0der Th. 6ult of 

a€'@y (llble 3.7) Ev€sled lhat ft€ 

h.tl'od vs det€ for all oSoE pu.pos. 

w.E der.mircd (rlbte 3.7). 

l0 25 20 3t2 

0.22 1.05 

0.62 088 

Icbl.' (q"RsDJ 021 065 

0.25 t12 0ll 

t02.45 

8f, 

l9Der and e8n^ ity ohh. n.thad 

%RSD LOD L()() 

0.8.1 

019 

0_22 

ne LOD dd LOQ v.tks for drllftnr drnes

Ruggedrs ol ihc medod @ hld.!.d by dcr.miling rbe 

which ws deiemin€d bt injectins lhe srandlrd md Mple 

*.c rcrd 6 Fat ea. In sotution ws 

allowed !o s&nd ar mbicnt remp€raiue for 24 

ho6 md th6 lhe slurions were daly&d 

r8ai4I ihe nEshly pEpoEd 3lad!rd. Ille 

aveFge value of lhe ag.d elurions r.spoNs 

tsl lB) E obad.d ro aeE with rhe 

ii€sn sbtior rcspotuca, wiihb r3%. IrE 

d.velop.d Dahod @ appli.d for rhe 

d.leni&rion of dilf€Ent dng @otcnB ir 

st biliry ofd. &alyt elurioa 

solulions ed detector Espon$s 

m&teldl fomulado$. The 6!ay esltl3 shoh in lable 1.6, denonstFred lhe $itabitity of 

ne6od. Sihil&ly rhe %t@vqi6 od R, of dtugs jn PI€ge of stu (bblc 3.6) F€ded 

th. applicability of nedod for lh.raleuric pu'loses. 

C Dngdrug ila.mrio! rrrdi6 lritr, ,pernFopi. .!d Rp_HpLC ictliqr6 

Seod dd rhird somtion alihi$.dines ft FSly@pbr€in subsrat€s. If Fslycopbtein is 

iolibited or i.du@d by othq drues, deceasad emc&y or enldced side ef€crs of$cond or 

tbitd g.ieotio. erihirteiB my c lt93l. Modutarion of p-cty@Plorei. tbtuugh 

i.Iibition or inducdon @ lsd io drug-dtug inte@lios by alr,ering intestinal, CNS. rnal or 

biliary emu [9{]. Tlc nor-ed.rina erilislanin6 shov a divcsiry of fa1es in lhe b.dy &d 

$e tMent dngs ed netabolites Eay .lifio in rhei biologic.t prcpeni6. Clinically 

significdt ini@clios with iriibitoE of cyl@hrlne p45O hlvc b€a repon€d pnn{ity for 

lerfenadioc [1951. P-glycopbr.in irnibhoE, al$ cdled .e!c6al agcnE o. Fgly@petein 

nodulato$, thcy modulab P-glycoprct in turcdon by comFring with $e bindins aid 

tespon ofth. dhs o. ilrcugh nor@hpetitivc binding [r96.t9Si_ p-slyopbreh i.hjbils a 

wtde @ge of cobpounds, includinS hydrophobic dphipathic drugs, catcim chM€l 

bl@k6, dtilislanitus, Ffljde ad st€Dj4s [r99l. C€{dzire bcing . Fglycopretein 

substrale ce lleEforc i e6cr with a nmbq of o-adminisLrld &u8s. In rh€ p@sdl wort 

@tiritn. w qMtiriii.d in pEs@e of orbd co@only co ldminis&rcd dnss Fbn th. 

sLach& it is €!id6t thai edrizine show.n I@ly all rcrls of possiblc rmsiriG o. &out 

of pr€scc of rcniary mino 8rclp &d @boryl grcup whicn g, 

55

n-n. bMsilions. Since ode of the @mtic rjry is disubslitut .t wirh bod el4ron donaring 

erelp i... Cgr ed chlodre (with pd! snbslitulior), Knd of dnel Es@e inaEdon 

@cs b€rw€eh subsriiucnl grcups. As methyl and chlorine both 4t s autrttrones lhey 

it|l,te @njleation. Sin e chlorin po3s ushffid d6aoo pan, Iw.4c int @rior of 

thjs lof peir with double bond incl€es th€ l.ngth of @njugabd syscD. So s a Esutt Oc 

non-bondine eletron beon€s psn of r lyst m of noleuld o.bilal inci*ing iB t.ngrh b, I 

dtb orbilal. In l[€ similar fathioD, nethyt grcu9 do nor he uslrFd elenon rhc 

is thoughr ro r€sult fom olcilop of CH bonding 

'nler&lioo 

odilal wirh r sysrem rcsulting in 

nt?€Mnjugarion. *dich culrt in exI. ion oar synms. So E @ slre @ d@ bsij 

rhlt de ctuohophoG group i! dlis ce may be dtubsliluled b@ne riry shoying ,-r. 

lrssition. The lvo t chniqws w€E ed fo, inteelion srudi.s i,.. spet ospy art Rp. 

HPLC. The spetrophobm.r.ic asy of dngs @ty involvee rhe n€lj@m.fi of ab$rbde 

of smpl.s .onraininS onty on ibsrbinS conpondr. The ba.is ofalt rh€ sp.cnopboloneuic 

IahrjqB fd mltioEpoMt $Dd* is rbe FoFrry oEr ar dt Mvcldstbl, the a!&rba@ 

of a solurion is lhe suD of abslbece of tr€ individurl omponors o! rhe n*@d 

absrb6ft. is rh. ditrccne h.rvH rhc tor.t abelbdrce of |he eluiio, in 0E sDte ett 

ed llal oflhe $lutio! ir the cfeEnce cell [200]. 

In odq to q@tiry cedrizi@ ir Fche of oth.r cea.!,ninister.d dru$ rm difeF.t 

@uarc, prer$ tud @enicd appm&hs \@ us.d for th. cstimtior. 

I Siddrrr€ous €quadon 

2 Daivarivc spetrlspy 

A* {tlhultanfu .qutuN 

A helhod ws designed on Uv-vhibt. sre.rrophoroneter to sinullan@sty nesw g. 

q!.!rni6 of cririzin€ in pEqe of cmonly @.dhidnq.d ttrugs pEhr in th. @c 

soluto!! without Fp@ring dEn. lor thic pu.pos . D.rhmaricd rctadoship wE! Ds.d 

which gav. Oe corc@rlrioa of r*o ddgs sinulbn€ouly. wh.n m€auEd ar th.ir ab$rprion 

c!= 

56

Hce, b = lldr logth of $e ell ( I cn in ou *pcrinmts), c = @Denration of$lurion. 

However sihdlan@us equrioft could ontt bc applied wh€n 1n. ofthe two dnes e 

lE&nauy disinild dd ln. rs! drugs do ,ot in!.Ect ch@icaut ^f,_ 

lh.Eby n.gatng dE 

innid ssMprion that lhc rot l sbsbae is rhc sm ofthe individual also,bma [20tl. For 

lne 6say of cetirizine, stock soluioru of I nM \r@ p,epe€.t in bu'Ic6 nnSing &oh pH I -9 

dd dilu&d to @ratrFalion 6gc of 0.09,0.t nM uing rlE M€ slvor &d sDFd in th€ 

rcgion of 200-700 m dgaiGt $c reagar bla,L Th. abs$ee .t Lu vas rc@rd€tl (rable 

3.8) ed caiibation wcs of ab@lbaM ag.iBt .oft.lr"tion wcE plon d Bhicn ob.ycd 

B4fs law in {E orco&ltion rdg. of O.O9-O.I mM. Mole aberltiviris \@ also 

cd.ulat d ed wd la&r in catculalioc. 

otphon at utni,in. EJcr.4. std,lad at wba ,11 

2 0.129 0..155 

0.112 0.155 0.2 0.164 

0.595 

5 0.828 0.861 0.134 

0.912 L0.]l 

0.462 

133 1.209 1.031 |.072 r.133 

r..,93 I t3l t.lt t.2.16 t.251 t.142 t.2M I t45 

9 t..148 1.371 tl76 1.361 I 568 I 16l 

l0 l.6l I 482 | 501 t.5t9 t.481 t.6.12 

D€riladve sp.cFophorom.hy in the Uv-visibl. €Cjon is a etul techniqw for qudnadve 

dd q@turiv. 3rudy of ov.rtlpping bands of the mlfes &.1 inrerfeEnces. Und€r 

ahputer controllcd irs[uaradoA ddivari!€ speci.ophoroDcEy is playing a v..y 

important rcl€ b ihe nutli.coDponor eatr3is ofnixrG by Uv/vhibte spetrophobm€try. 

It coBisE in difie@dari4 nomat sF.dun by @th€naricd dq5fotmt@ of qecrnr 

cwc inro 6 drivarile (n'sl or highd dcdvativ6). nft bchnique implov$ r€siution beds, 

.lieimies rh. idluc@ of baclqro@d and prcvjdq nor d.fbed fineerprin8 lii& di@t 

esorumce specra. Derivadvc lr&sfomali@ F@itl di$.inierion .s.ins b@dbad 

nlerf.ron s eising lion brctSFbd abso+rioo md n tends ro enphdia sublte sDecrm 

fal@, allowing lhe ennM.nr of dE s4irivity. Denvadve UV spedrospy ha ben 

51

witdt d.d s . tool br f .di-riE &lytir ch.|.|dianon !d 

!8.ioh!r.l, phr.rfiqnicd &d U6h.dicd ffelds. This dndrndi& 

l@lbiq6 ha @iv6.t in@ing 

&alib in !'irgl. .id @lri- 

@trpd.nt q@rlii|riE afilysiq 

.4@irlly in w-$5bin8 ndic6 

[202] vriae daiv ivg of 

cairtir. re pr.p€r.d ir tb. 

b!6.6 ofptl l, 4, 7.4 .nt 9 

I C.{.6. rtr X, Hoddr 

I SitutttpM.btmh,edofetiririE inprewqH,wpte aqqisrs 

Ir Dod ofrb. .{dgic di!..s Onat .d flrr! unidit {d daEdognpnim), @.oEir&r 

&tninidntion ofe Hr .-.Fd lrlrgdic with 

a rI1 Gc.p(f d.gdilr B raEd b b. Ie 

.trdiw tls di. adDini.h.li@ of !n Hdi.sdin 

c e rL ld.gdie &E ErL206l 

FunlEDoE, n w.! .to o66arc{t ttlrl @bbincd 

FtLtut with & Dd tlr {r.gai!& @!.d . 

gcda innibirion of hinminciaduc€d nud 

R.sENt6 thdtdd an le&Mt, oJ 

|,oA LOD 

0103 0.031 

0.132 

0.0t4 

bloc&.g. tlu did Hr drgois .foe [262011. tr qpaB ltlr !ff&d, 6GH,4tl 

pf|lnmy I cpdriblc ao. th. 6itu t i.!.1 btoc*rg., luggdling e@ d.A@ of itrtqldion 

ba*a th. E &d rL d.dulat !d[*ry! I2raj. Fd ddi€,n E d@id.ddt &.fcaiw 

.

nin'mM detectable linit of 5 lenl, r, fte c@fiicienh of vdiation of thh nerlod for i.t€r 

ed ilFanly ey wrc fobtl ro b€ ls 6an E%- 

Radolph {2151 dsoibed d H?Lc hedod for rhe 

cxt &1ion of cindidine, ton whole blood dd 

uine, nrc method neasurd concenlrarioB of 

cimelidinc s loq s 0.05 ug nL r. A rlpid. Fnlilive 

dd rcbust rcv.F pha HPLC h.thod wilh 

collnm swirchiig t*hniqw for the dermination of 

fdotidine ir hMd plsha B d*rib.d by 

znons md Yeh [216]. 'nE inftd.y @emdeiK of 

tl3!F 3,,r: R.prcs@iv. chrnnosm 

wialion !r all @n@na on lw.k t* L$ ihtu tQplo, Thc linir of o@iinodor for 

f@otidioe h hwd plama ws I n8DLr, How.rer, no m.thod foi siDulla.@Ds 

nlnin r. RepEeoradle chrc@toglrm w€r€ gm€rat€d lo show rhat o1h€r conponenrs lnat 

@uld be presit in rhe sple tuEix e Fsolvcd ftom the p@ni edlyte. No sisniticmt 

ch.!g6 b AUC d rreltion rihe of rh. dr!8s in ptls.G &d ab*e of pbDtllohb.n 

(int.dl iudard) cldly indic.Ld lF speifci9 of rhe mdlod (6grc ].5). 

Fof lim&ity srudi* 6 ditrdd cotr@rftdoB (33,33, 16.66, u.33, 10, 6,66.l,3l |lgDL-') 

of 6 mixl@ ofeach dtu& ii presnce ol ituenal sandard wer asaycd. TIE line&it otlh€ 

nelho

The develoted nelhod M lppli.d tor rh. d.tmimdon of difl@nt dng con!.nt in 

ndkeled fomulaiios, The say resulb show iD labte 3.32, dchorstftled th€ suilsbitiiy of 

th€ m.thod. Sidildly th. o4@ved6 ed R' of Ih. drugs in pB.k of sfu shou in 

utblc l.ll Ev.,l.d rhc .!'pl'c!bility of @edod for rhonpedic purFs. 

rrbb JJI 

'6 Rtcowia ofAlid bnnat 

1.t., 10t.93 12,0J t04_3 10_t2 31.72 34.45 

102.32 r6 t5 96.t,2 tr.2t 102.13 t5.25 l7.ll 

B.l t2.5 ll.Jl 13.19 

10053 10.62 lm.3 9.71 105 t9 9.49 

I00.2.2 6.59 6,3 

l.t6 

25 20 I5 5 n: 

99.24 10t.65 t(M I 

96.91 t0t_19 t02.5 

95.52 l0l.t3 102.15 

t01.75 r0t.t! 

It l,tret@tion studies ofcetiri2i@ with H, bloctzrs 

Fmotidilc allEs ro bc a P-glycopbteh lub6ra1ei th@ is posibitiry of ili.tutioc 

rhmud irlibiriotr or indErion of this raspond [2r4_ rr hs .bo ben repon d rh.r 

Mitidirc dd cindidin cs act 6 eb€rrares lor rhis pnlein. tr hs bed susis€sled rh.r rhe 

balec. b.tw€en absQtiv. md sret ry mehehhs 6 a fdlor in dermining inreslihal 

absorytim Blds to b€ a ourire @Niddtotr 4€n fd @mpoudr exFcred ro hav. a 

Fdmiir ly elluld llloDriotr rcule d lh. msl of dnsr ab$lb€d by s{ft bui. I2tEl. 

6I

Th! .bsrbuce mdim of ciociidire al &idic pH i... I &d 4 \|@ foud 10 be 218 M 

whft 4,.r pH 7.4 n 6 217 ed ar pH 

9, 216 m. Simulk@6 equatio! B 

.lplied fo. lhe deremiMtion of 

ikmrd@dtu M^ 

c.dridr in pes.tB of cindidiE, 

Th. .Filon vatB of llc drugs d th.ir 

10393.31 

tfi42.95 

186t t29 

E F.tiE cf@ and on th€ 

int eting drugs Efelt@s ar v&ioq 

t6350 10371.91 

16350 r0t68 l4l5l.05 

pH lcv€h (i.ble 1.34) wft calcdsled dd !i.d for cslculgrins the o/dvailabilily of dsss aftei 

thc i, lito interadions. The % e@very of cdirizin ed cimetidine at all pH leveh mg€d 

bels.a 97-l04yo, This itrdi€aled th.r bo$ the &usr @ available rnd oone inrdfered wilb 

TrbLlJs 

IM.M rceib of etiitirc vth e ielAiw N Uy tpectophuowty ed 

HPLC 

pHl 

HPLC HPL' HPI-C HPI-c 

ttn27 100.t2 100,45 98,/tl _u lmi6 

l5 99.52 l0o,4J loo.t3 96.f2 98.54 t@?8 r0o.r2 

99.57 98.45 100.74 91.25 94.t2 t0t.14 

97.25 t0l.6l 97.33 

t0056 r0082 100.31 

99.t4 101.98 93.12 

l0t.2l 99.12 100.46 

I05 100.87 102.t4 99.6J 10071 

t20 100 t.] l00,ll l0l.ll t00.81 98.9 t01.46 I01.39 100.39 

105 

100.24 r04.l8 91.12 

t0l.t2 91.07 98.78 101.33 

t00.70 93.33 

98.32 r00.62 t02.45 9431 l0r ll 

94.41 99_t7 t00tl t01.65 10058 t00.23 

94.55 l0o.J4 9.t6 100.9 t@?8 101.34 

l0o.7l tot.62 10t.37 tmiT 

t20 t01.62 r00.J2 Im.03 I0t.39 

62

Irr &nltri.al nsim for feotidirc .t stomh pH i,c. I sd 4 w fou[d 10 b.266 m 

vh.@, .t blood ad int4tinli pH it wB !r 284 m. Sinc. th. spccr! of f.sotidirc did nor 

intcrfdc wilh thc ruin. of cdnizirc 

h@e 3imllllEoa cqulrion w6 

.p!li.d to qutit t thc rrc dru$ in 

th. mixtuF. Th. .pilotr vdB lr@ 

€lcol.t d a pBdt d in rh. rdL 

1.36, 

pHl t6t0o QN 761.6 

l3t0() 3I4I 625.51 

16350 755t.91 1718 l|lt.56 

pH9 l6rr0 7157_99 5565 186.59 

T.!h ljt 

na I W q*bopletoNtr dd EPLC 

tl PH 

HPLC HPI.C HPt' HPLC 

9E,n 10t.9 t00,2 99,,1t l0t.? tm.7 tott 

It 96_51 9.52 91.52 t0t,7 t01,3 9E.54 91.5,t 

JO t02.0 9t.05 t00,6 98,J' t00.4 

Ll n.25 10t.3 91.12 9.tl 98_n to2t 

r@.6 9,23 98.31 9n7 9t.75 

15 t00.5 t00.2 I0t.9 93.t9 99.t! 98A2 

90 9.28 l0t.l 94,61 t00,3 9t,57 100.3 99.55 

t05 r(x).8 100.4 r0t.l ,9E3 9E,t2 100.7 I00.3 

r20 t00.! t0t,4 roo.5 (x).O 9.0t t00.7 91.25 

0 9,,52 100.7 tot.9 .12 

It 94.67 100,8 9tt 9t.09 t0t,6 9t.6t t00.6 

30 9,12 l0o,l 9t.u, t00,8 9t.12 t00.8 

99.24 9.12 91.4! 99.65 l0!.t 

6o t00,6 98.?l 100.., 9.t0 99t8 

97,00 9t.l! 98.,16 rm_8 I00.7 !00.1 99,2t 99l0 

98.2t 100.2 t00.8 t0t-7 tt.52 t00.7 

105 l03J t00.5 t0o,? t00.t roo_t 

t2o 100.1 I00.3 100,3 tl.il5 99,71 I(x}JI t0t_8 

Ihe in dcti6 sfu(|i$ p.rfodiFd on W spoctup[otomcrry .nd HPLC (r!bt. 3.]r) ddty 

irdiorcddr.tceri.izin w!v.il.bt.upio97-104%in.Id!.buflcrn di@.Inrh.e. 

hy t[. wailalility of fo&otidir. E fould io h. 96- 103% by uling borb rb. t chdqrcs. 

6l

'nE .citm mvcblgt[ d pn I *u 2Z ud 313 M wls! s .,t ,tl thc orlE mdilm 

Os 4, 7-4 .!d e) l[. ffiidr r@ bund lo b.228 |ntl 313 M. A. rra I dp 'is!.I .tD6 

lna.pplyitrB fird d6ivdiv. lor odirizino rnd nnitidi@ ww 224.84 rd A1.26 m 

.atp€.liEly. Al pH 4, 74 ud 9, 22E.43 rd 3!6.93 n|! qr obEvcd for c.ri.iriE r.d 

l|E aa: DlndiE.t .ti. ordnni! rrrtib 

rxl 

lur tattdq ofdtlr*t atdMrlM 

tll7.4 

pll9 ,- l! !7lr-0.0t01 0.996 

pl|l 

pH7a 

I!. i!t6!.lion @lr rbos! in rlbL 3.t9 cldly indicrod rhrt m i!n€.!.ri@ o€utld 

b€.96 it $l.oi.d ddg!_ Tt t@v.ry ofcdniziF .l dl ptl t v6l, rw 6t d lo b. itr tls 

tuge of9A-l0l7o. Itr rlF !'m w|y ttF i.coy..y rdw of miridiio s@ ftold to b.9?- 

101% i'di6!i.g @ E tioo b.t*6 Gt d.tga 

t'

tbh aS9 

Ituftti@ r.s,Ls otethxiE with MiltliE N w speciophdmt.y a'd ttprc 

pHl pH4 

HPLC HPLC HPLC HPLC 

9.60 l@,45 98.56 

98.56 tm95 I00.14 

93.Il t8.45 Lt2 99.8t 93.21 93L] 

45 1rr.26 9,92 t@.78 100.?5 10t93 

93.72 98.!' 100.85 100.21 

r00.78 ,9.t2 tol.64 93.17 

r00.82 100.6r 93.33 

10t.72 99.22. 

10t.35 t00.24 

I00,62 

r00,.ll 99,96 98.78 100.33 98.7J 

99.39 t00.75 99.U 99. r0 99.32 

93.45 9.11 t.6l 9992 

97.13 93.31 93,3t 

93.12 

100.88 l0o.l1 100)2 93.52 

l0t 99.t3 98,65 100.89 lm,l 9a_16 

lt0 1m29 t0t.6l t00.36 

I SinulteeoB detemination ofc.tuiziw inpres.nce oftatirc 

A badirl of ce rporrs of irr!€sNiliviiy io seriE havc appe.rd in ihe lft@nre. Ihe 

@lio.s h.v. includ€d stin @tiois, joinl pe!!, egio-@d€na left vatricute 

dysru.tionl pullMary srrprons (@ugh, dyspdo€. dDd pnel@litit [2r9]. st tiN d. rhe 

nolt colmo! ttF of cbol6iebl-loking drugr us.d in clini.at pr&rice. R4a16emh 

sugS.sl€d lnat liiey may also have &ri-inflffidory prep.nies ir psaicul& by iohibidor of 

d inportal inflamabry cell .alled ! T lynphoc',t . Th€* fmdinss d@Btrared th. 

th.nFuric potendal ofsrdin-*tuitiv. p.thways in.lldgic aiMF djsee [220]. Ir @rher 

3ttdy, it @ ale oncluded th,r st tiB havc dli,inimro., dd IEWprcr@Uv. 

Fop.ni6 vtich my b. beneficirl ir rhc rla[rcnr of mulripL sLmsis 6 w[ s orlFr 

@16l idou sls.d (cNs) n 'rod.sffiliv. di!..s [r2r]. 

65

NilBh [222] rL$rib.d e RP-mLc m€rhod for 3imulrar@u eningliotr or sinvs!.rin 8d 

cz.linibe i! onbined &eAc fm. Th. mcrhod s loud ro b. Iilk in th. mge ot l-50 

pgnlr Mth m@ @ovcry of 99.21% foi simvaiaiin ed 99.50plo for czlinibe. Ihe 

@Fclriion ceffici€nls for.ll @mDonmte 4 €los to L Shah.r al, [223] dev€lop.d 

sinult.mu Deihod on RP-HPLC lor the d.t mimdotr oI atosNtarh calcim erd Gpirin 

in opsuL doegc foms. Th. @te ion rin€s of.tonasratin cddu ed sDifin weE 5.4 dd 

1.4 ninu6, 6Fcriv.ly. TIE liMity tur doryBtati! c.lcim dd s?irh wtr in th. BnB. 

of0.5-4 ard 5-25 nsml ', 6p€1iv€ly. Lsa .r al, [224] doelop.d sindl.'rcoN belhod for 

thc dd€mimtion of thc bcia.blekG (alenolol, sot lol, meropblol, bisoprelol, proptuolol 

dd ceedilol), calcim{haDel elasonkis (dih@, dlodipine ed vmpmil), 

rngiotqsinli d|gonbis (losn & irbddtan, ulefian dd r€thisarr{) ond rh. 

ddery$nic dns (Rcritri.lc) itr stole blood sple &m fomic auoFi6. wirh 0E 

.x@ptio! or dlodipift' de linit of qhificlrion @ve!d lov lh.r.p.ulic @Ilqrrlrim 

l.v.ls for all lhe mmpouds. zrltn dd Ucal(uk [225] develop.

et dt. [22E] q@rifi.d rhe sinvlsrlrin dd p,o{ihydoxysid simvslarin libehtcd ftom 

sinvarad( The nethod ws chd&tdized by good liMity ovq th. n .iuM.nl rsg€ oI 

Hower, i. order to d.t€mine ed qhit for the 

fi$r tine efirizine in pr.s.m of stliils n€e m.thod 

6 dry.lop.d and vali&led- For anlinine oFiniz.d 

@ndition of lhe ncthod veious rados ol n $uol: 

wrer (90:10,85:15,80:20) wre lii.rt. lt M 

ob6dld lh.l i@ in lL. m.lhMl 6lio of tbe 

nobile pbse r€sulled i. pmr $laniion betwd 

Ju--'l 

chM&sm of €in a rh.rurD, 

c.lirizin. rnd aloNsralin ad incGe in tb.6tio of 

Ba&I Brhcd ii tailing and lda c|cntio dnc of dogs. H.@. a rew ol84ic elrcnt m 

irnoduc.d inio the sFGm. DiffeFnr nixtud of &c4loniFil., n thdol &d watd (5,E0:15, 

10:70:15,20r60:lt,20:50:20,20145125, v/v/v) q@ iried. ln dl iGr.nc€s, sotr of iobil€ 

phas caull.d in For *?aEtid sd i! enc thc p.ar slmEy w6 disbncd- 

%RSD 

o.l5 10019 

0.13 I00.23 

0.33 

o.24 

0.53 

0.25 

101.25 

t.2l 103.35 

t2v/. 1.52 t04.17 

Ho@, only &etonihiL: Mrq wa |an€d 4 lh. nohle pbe, lt B obefl€d thrl tt: 25 

*.eroniEil.: wats gavc lhe besr Esults with pop€r *p6Fri@ of.€tirizin , aloryst tin, 

61

osuvsrarjn &d sihBraril Howvd, evd at this mobil. pha* pnv.slarin colld not b. 

$?!Et d in pEse bsuvaeatin e pEratltin m tu ep€Ei.ly ?nolg with ceririzine. 

IbuFo&n wa chosen as & inletul slardard. It m.lso obswed d.t all slalins w€e pH 

ldilive ad h€de pH 2.8 va $l4tcd givinr lhc b6t tglution rrd symccy of peals. 

The El€nlion tine of 4tirizioe, aroweladn, rosuvadad.! phvslstir dd sinvasLlh wr€ 

found to be 2.05,3.45,4.45 md l0 biNles, EsD.ciively. 

Mctlo

Intudide pr*iriN of the Ntho.l 

% RSD %RSD 9'RSD 

II t2 II t2 II t2 II t2 tl t2 

2.25 05, LI3 Lf2 0.t6 t.t7 

0.24 08t 0.3 1.55 t.2 

t, 0.82 0.71 0.34 0.56 0 l.I 0.99 

,:0 02t 0.ll l.l2 0.13 0.91 t.87 

0.59 0.87 o.16 0.12 

50 0.03 0.4 0_87 

The % RSD ed found was calculqled in .&h cs, The above validared delhod w used fot 

all lhe drug. asy detemimtion in rhc phMudc.l ttp@lion. TIE %@ov.ri6 of all 

tE dng! wd found ro b. with h l[e a.pr.blc mgq1l!. sFcificiry of the m.1hod ws 

al$ cdfn.d in rhii t!).mr a m id.rGr.r.. tom ih. ddDidrs ct@lv indicd.d rn 

sFcifi city of thc method. 

I0l l 2.51 106.8 2,67 

1026 5.13 t0l.l 4.n 97.22 5.42 

t5 100.8 I5.ll 98,16 102.6 

20.96 I9.97 96 t6 20.01 100.8 20.1? 

103.6 25.91 u.25 25.19 21.91 

50.39 9333 

91.16 10t.2 101.2 101.7 

R@very of c.tnizin€ B al$ p€rfo@ed in ffi sine spiked drus-E€€ seM st five 

diffdnl cot@ttlrioB. Th. y.|@vai6 in 5fu for aI rhc dru$ wE fould ro b. in the 

@A. of 97.55-108.94% thu irdi€ri.g rl€ .pplicirion of rlE mrhod for dEnp.utic 

pnrpoes, MoE over thh .pplhation onc. .gsin irdicaLd th. 3peificiry ofd. n.$od in 

rclafion lo endogdou @npon€nrs.

2 5 l5 20 25 

t00.!.t 103 99 10159 tot.32 l0l.2l 

t0o.t 99 33 l@ 7l t01.45 

91.66 106.7,1 

n.55 l0? 5 

l05..ll 102 65 

It lttqd

tbn ct .[dtttEadtu 

r=ll3!7i+0.0017 

R. 

0 9925 

DH 9.0 0.9808 

pH 1.0 

pll9.0 

0 9993 

o.t 62 

.4do4 t t'rd ofdi@ dh atot1,.tui,6 W t 

DHI Dll9 

HPt' HPLC rflc HPI' 

t00.10 99,6 93.24 9t.t5 96.30 

l5 93.t4 99.62 t0!.21 l0l.12 

3{' 103.t6 98.50 t0013 91.6t 

r02.E2 98.66 lm 5t _12 lol.33 t01.78 22 

60 lm_73 t0178 105 76 9{.79 99.22 Ll9 

15 9t.ta 94.72 t03.66 100.n l@.L tm 5a 

90 lm.7t l02.2l t0t.76 9l.l0 

l0J ,t.53 9.62 vt 62 

t2t) 101.32 tt2.69 f3 rcj_71 1m.69 t00.25 

t(n.!l t@.91 t9 3l t0t.5J 

l5 100.92 97.01 93.62 

30 100.92 

10t.33 l0o.t3 l0t.t2 !*21 

l@.6s l0l tt l@,69 96.2t t0t.42 100.97 

15 10163 t01.90 96.2E l0o.7r 101,45 98.46 97.62 

t0t.95 r@.4t 93.5t 93.r7 t00.73 99.t0 

93.11 10t.88 lm 32 t00.t2 

120 t00 56 t05.52 t04.3, 95.51 loi_u t(D.t6 

Th..Elydc.l !i8dh o6.avd d try {c.rrt 

6. .ll tlt ptt E di!tu sw fdrd b b. d 

21o M. Abelot vdE of ddivriv. rig6t. 

fo. eti.izin a pII t,4 ?4 ud 9 9@ 

nlstld !1 221.9,24059,24t.36 std 

223.01 m. In rt mc dy $. ddir,|rirc 

7l

c$!6r.rin.i pH l. 4, ?.4 md 9 \r@ 51 23t.33, 210.81, 230.95, 230.E6 M, Esp41i!ely. 

Tb. i,-rrto irctution Bdls of eririui* Mth Mwlsraiin r all pH d*igmred thd 

atniziE did @l intcrf@ with oslBl.rin ,r rcidic or bsic pH. Thc 96!sil.biuli6 of 

@tniziE at .lf buff.Ed nedims v@ foud ro tE i^ the tugE of 9.60-IM.WA 

(detemioed by Uv speftpboton t r) ald 95.60-101.22% Oy HPLC). 

R.wih tu1aict of c.tlzire @'d rctwMin 

pH 1.0 

srnB olati.iziN ,ith rdue.lcE d W r 

0.gvn 

HPIC HPIC HPLC 

10068 r00.4t 9.8r 93.35 r00.48 t00.0t 

94.24 99..10 lot 0 96.82 98.26 

l0 95.21 98.?l 1007: 

99.48 100.69 9t,24 100.22 

99 6l 101.32 101.61 r0r.85 97..:.1 10.1.57 99.69 

15 102.69 101.62 95.61 99.12 I01.23 l0l.3l 

90 97.EE 101.87 I01.69 97.0E I0o.l2 101.87 

105 t02.t5 94.2\ 93_7.] 98.2' 102_70 100.85 t0o.0i 

r20 r00.6l 102.1t 104.9 

94.62 9922 t01.22 tm.7l 99.29 

t5 97.28 99.21 t01.29 93.t' 

l0\,26 10,0.73 

98.06 

60 100.64 95.E1 100,69 104,78 t00.64 

15 99.61 100.91 98,?0 9,80 9.72 I0070 

90 97.82 10t.23 98,90 t00.62 98.18 100.91 100.75 

I0t 9.87 102.18 98.47 

120 10t.35 I00.73 100.48 %,70 r03.48 99.' 

12

Tr! Mid risr.l ohriBt ftr l[. Fw.drli! w 

fqnd b b.235 @ i! .[ d. b.dil@. rlolffi, 

&.ivdiE dg!.k cb€ for o.anni!. rdd 

F.v.tain.r pH I ed 4 pa! 235.55 |nd 2t9.tl 

4 F.p..riidy si@ildly r. pH 7.:t od 9 rtE 

|IlFl'rr: DdidiE@d 

dntbdFd.i. 

dgrdr rd.a.d 9@ ?9 Dd 219.()? d ir cai.izim ed Fng.ti, ,!.p..ridy (6CE 

3.1D. 

pH 1.0 

pHta 

cr r.0 

td ofetun4 dn wtui, 

y- |.652r - 0.02ln 

t.Db l!2 

iMMelttdd@ sitwddiu W tsd@htu@at tEprc 

II l9 

rlPlc HPI,C qna HPT' 

.24 99.28 l@.42 91.67 

l5 93.73 t00.45 10t.54 97.31 98.r8 

JO 105 63 Lt0 100.41 100.73 lm.6l 

9.24 10t.22 103,4 100.61 1m.73 qm vt.4 

9931 t01.34 t01.44 lc2 56 lm 

15 l0l-5,t tot_17 t01.9 99.rr 99.62 vt.2l 

l0l.8l l0l.09 m42 

q_n t(D_32 q_12 tmjl 10163 

l2l) 101.68 10t.63 9t.62 qt t0l.t] t@.84 

100.25 r02.96 99.25 96..11 103.21 

l5 n73 too.a l0t.a2 rcL2t 99?9 98.3t 

l{, ltD.05 r3.t0 l0l3a 9_20 9913 

96 t9 l('2.35 9t.9 too R t00.@ 9lL t0o.2t 

t01.36 too.t3 9t.96 

99.t I Im.3l t0?..n lo2_t9 

rcl.t1 99 3l 99 75 t0163 

9a f2 9.62 9J.60 10176 100.3t 

t20 l@.56 10165 9913 

73

Tb E rl a icdi@

l :l 

&rF1(,: Chudo'u.of iGdon .r Ct a,7.a d r Etd N rr.tdd srt ddind|cin 

T.D|.lL 

I"t @iM@tt ofetttun etk ttMdt d ul/tp@ebyot t 

pH4 ellT 4 

HPI4 HPLC HPT,C 

9!.75 912l 93.U 95 22 

l5 92.t3 9.5' 92.99 9512 9r_51 

8t.t5 I10,12 ||5.89 119.32 

|2.42 1t7.9 t2o.?3 120.lrl 

t6.90 4532 1t6.8, ll9vt tzt_1t t26.ll 

15 35ll $.9 12064 t22.t9 t3192 lJo_t2 

tt.5.l t2a_15 t23.92 ttgs7 lJ5_J5 

105 n.a2 |]3 t3 t43.33 l.lt 35 

120 ,l_n 7J.tl t3t.al t15.72 

4.23 a).tl 53 45 

l5 !{2r 33.46 @13 53I n.lr 

lo 6t.t6 54.26 6t 05 70.22 7l tl 

{5 51.23 6l.tl 5a.l I 65.t' 61t2 

53.99 53.()7 63.22 6t)] 

6t_66 

50.n 52.61 J3.3a 

t05 40.!l q.32 55 {l 

120 41.t4 rt5.28 lan 50.n 

DosHa€@r irt qdi@ @ t fod of lddhiod qdio.. thlt do mr nr lbd.I rut6 of 

v.ldy t!'o!@E, pr!(ird! 6y odl. ooly in rolnion fo.u rr .qitibiub wir[ rh. 

.oqod mhods laxrl. T!. lifdinc of dl. cdglq (rotri@ of dotr! rd a.c.otor5) 

d|c bo sdretrly dort B. |i-Iftlddrlld (B-rD e..hod i. t ' .rr u..d 4pN.6 for 

ddqDilirg lh. I.i.iin .'y ud .quilihi@ 6or.d. of @ hood.d itrrd!.tis $ticb i! 

b.td 6 rt 6@'lin lbr wt6.irh.. @ of dt .a.ri. (hod d s!.!r) ir FE d i! 

d.d leld. oq lle orha rad.d, tt dr..dqidic .t 0rl'.@ ,!@r. of lt. ortd 

15

anot eill b. trstrFor i. dE @lleriv. .butdcc/.||issio! tugc oflbc E$1io 3Frm 

[234]. It 6 h. cdclld.d uing dF foll ins €qlrdo. 

tDlo/Ah = (l/talo) ( lr

3 C.dddr. rttt qrbolon6 

I Shrtt@Bd.tmttutionoletbbltu tnF.nrc.ofqrtnlms 

Cdidnrc is @nlnintuldld with quinoloB in nubq of c.g howE; .!'rg-irduc.d 

ulti*ia hls bei Fron d *ith r wi& d|8c of dru$ &d v@iB NSAIDs dd edbiotie 

e dE dru$ don @oly .ssoci.r.d wnh unic{i., .lrlDugD rltirbtc d.tji nDm 

prlrpcdirly @noollcd sfudiB i! $!n 12351. QrimlG eribiodcs ind@ mBp6cifc 

hid.mirc El.itc t2361. lt E rF sdl cpotu of d$phyt-tic rliN eirh 

cipFflonin. n&y *ilh ti61 hoM cxpoG, which 3ronSly $88.3rt M-imlF 

n di.t d hi$.mitu El.a [234. h ha d$ b€n FFd.d dt t mo.r D.ddrs wit buttipt 

dnlg dld$, sydllm &d hoG rh.D @ dnd of eubj.cb with . hidory ofhypa*Niriviry 

!, . lilglc adih..idid dng w@ ch.Eariad by l[c F€4! of ciFut.rirS hturinic 

cl€dig f*loB enich bi8ht DIry . relc ir &lS-idrxrd ldw.s erioB ob*ry.d ii Oasc 

p.tidis t23tl. Monova,0F ldhinilE ti@ of e@t drl83 (six HrE lror btoctcr+ ffi 

baMdmrgic etlgonll!, fou d'dg6icr lctr diuraie sd fw guinoloi!) whi.t modutdc 

lh. turctid of P-slycoprelcin lo pdriftt3 may ldllely afan rhc onul ftndid of rhi! 

.mu pmp rtrd Dy oe dngnDs itrr.drim indu.d sidc.re|3 1239!. Oi. of tE 

sndi.s confncd tbc polani.l fdrility hlzlds of @only $.d druss tuh $ Hr Fcpror 

e!.8ding eric?il.ptics {d edbioriB I!,t01. P.ria|! rrli!8 ciplolloreir @ cully 

tdvk d to pbtccr 6.ir s*itr froD di@r iu!'li8hr l2,ltl. 

O. lhb b8b n b*{E lpp.Mr ro &rclop &d latidal! for rI. fir$ rirc . nErhod fd 

3iDulr.M{a d.idEilatid of ccririd4 in p|!*. of quildoB Mait! e, ar, [r,a2] 

dcEl@ . siDplc. siriv. isi.lic ndhod for tlt d.larion ud oMdfic.too of 

.iFotld&i! in plalm lrd qiE. Thc osy conrisrld of twB.d-Dle HPLC with 

ulE viola

H&id! ?r ar, [246] develop.d d HPLC n rhod. for th. say of gatifloxrcb h aw tuaterial 

aid tableb. M€$od wa linw ftom 4-14 FgDLn. Thc i cr sd ild"day p@isio. w6 less 

rha 1,05%. Bne a al. [24?] d.v.lop.d md 

wlidoled HPLC method for th. detlmining 

golifloxein @ncnlradons in selw sd uin 

by nem ofcl8 Ev€re-pha!. colhn wirh a 

nobile phde coshing of l0 mM SDS, l0 

nrM TBAA ad 25 nM citiic acid wirh 5070 

aebninile ir d€ioni4d w.t r at 293 ft. Thc 

LOQ B lo0 nsnl-i ir sfu dd I pgnlr 

lltun 314: R.pFenndv. chmabsm 

otquirclon., cainzin. ed int h.l tuddd 

Howvq, no n€tLod for sioulLn@u &r.dii.rion of quinolo!.r D pBae of c.ririzift 

w FF.led. HenG h th. pFent &* a n4hod ws &rclop

Rerendon line obw.rl for ouinoton.s. atnizinc dd int€nal .rd.rd ws foud to b€ 2.5. 

3-5 md 9.5 minutcs, BFctivcly, 

Corbli@ @etrcio& od s.nsilivny of 

dE Delhod e pr€*nt d in rsbt. 3.56. 

The 3p€cilicily ed rcbuln6s of lh. 

m€rhod ws also stablished. It was foud 

that lne prcposed m.thod p&scd the r€sl 

Ior mbuires dd sp€cit:city, Th. 

EsFcliv€ chrcm.togm d.mostFtcd 

dar dE nerhod m speific. TIE 

chrcmlogtm obtaired fion sLn

Th &.uey &d pEbion of lh. EElhod d. pBat d in trbl. 1,57. For er€tu.rio! of thc 

inm-diy pacbion s.yins spl.r s@ F.p.rcd at six l4.k ofconc€ r.tid on difrd€n 

d.ys, Th. Eladr. srandrd ddi.ti6 otr ah dBy wa cslculard .nd foud @.DLblc with i! 

'6 

T.bL3ll 

tu$E ld. pebt tt of tb Ntlbd 

RSD 2.5 t It 20 50 

0.29 0.19 0.ll 0,75 t,2l 

0.lt 0,59 0,56 0,96 1.55 0.62 

o,t9 L09 0.12 0.t 

0.67 0.2t t.r6 0.89 093 1.03 

0.54 0.13 0.lt 

0.55 l.2l I.]I Lt, 

o-008 0,1 0.m5 t.2 

0.12 0,16 0,25 0.lt t.t 0.89 

0.tl 0,17 0.03 0.15 

0.12 0.5,t 0,92 t.2 t.5 

t,27 0-37 oa) o.16 0,15 0,22 

2.0t o.8l 0.96 t.23 1.09 

o.5l oxn 0.95 0.82 071 

0.n 0,92 t,01 t,05 t.7t 

xR@i.trtMciN 

2 t5 20 

t05.21 100.9 to2t7 9t.tl 

2.tt 5,m t5.t4 b.19 2t.53 

tol.2, r04,5J t04.22 l0l.?il 95.J6 

2.02 t6,2t 20.!5 2t.u 

t00,25 t0t.54 to2.15 t00.t? too.t2 

2.01 t.o8 lt.4l m,t1 ,t.0.' 

t00lt 99.45 99.0' 

1.95 1,82 t5,oJ t9.89 

9t.5J 99,15 t00.02 l00.ll 100.45 

197 I5 20.o1 25.t1 

99,33 96.25 t00,04 t0t.57 

2 4_86 20.01 25.J9 

97,t2 9.62 100.26 10t.45 

L'4 4,9J 20,05 25.16 

80

LaLt al 

t*tdhl nattqedtur dh lo@t6 Wtpdnb*iy.nHptE 

Dll l !H 1.1 rll9 

HPI' H''T.c H?L HPLC 

9t.14 9.15 tm.@ ,4.22 ,.n 94.t2 

IJ 99.t v,.2 ta.z 96.u 12l tl,0.3a t01.23 

30 9.21 96.32 tot.aJ cr_l l0t,5a tm.t 

tt.r1 r01.32 9i. 9.0t 10l,.,5 r0i}.al 

60 9t.r I 9,t5 t@,5a 96_ll 96?l 99.ni, tm.t3 

,5 99.11 l|n.23 t00_?r 9r.t ll|o.tJ 96.t1 9a.ra 

too_0, l0t_ta lr9.3t 9t:l l@.ll l0lJa 9.ta 521 

t0J l(x).65 td,.75 q_12 99.6 tm.69 1029| 9..6 q.25 

t20 l0o.7t l@.49 ,t.tl 1@.n t0l.ta t0o.t5 96 

0 951' 9?.aa t0.?5 too,t2 9.11 9t.65 t0o.ll t0l 

t5 99.I1 t0l}.ol 965 9t.3 LX q.25 94.7J 

30 96.32 tm.2J .rt,72 l@_la ttt.6 98.?a 

,tt yt.tl tol.|l 90.t lB.$ ltD_tl tq,.t6 

,2.11 to2,75 99.5! loo.06 9ljt l(D_o1 lot.22 r0l,5t 

,5 ltD.lt ,4.1J l(D.tB l0t.I9 rn33 

9l.tt l@.06 t6.u 9t_57 totJt l0ll' l(l).,1{ 

l0t 99.11 lto ItlJ tuJ.69 102 lot.52 

ta) lo0.l2 ,24 It 3.65 t00,3t lx.t7 to0.7J 

Sililr rr r E!oigr.d oI|I,l. i.a tt lu|E ofc.iririB r4.d laE 95.!llol.tay{ 

rt.r tt ralr.t v.t|. 6. tcvlfod. d r[ dI v.t! od W 

r9..lt rtdd.. |ld Bn s!! tud io b. in r!. os. of 92.|l-lo5.t7%. Th. nda. 

cldiy idict .rld c.irizi!. it ltiLaL i! rt rF ic c.|Fr*roo ft. n phE .otoriol 

dtoo i! Fr.@ of ldldordc 

Nqfor&n r- r Y.ris rH [.Ert s 

d.@i!.4 n pfl | n E tu&d io b.3t5.5 .!d 

T,, @\a dla3*trs d|n 6.arlr1.a 

192t34213 o,',25 M.dn ps 9b b.3 

315, 32!, 2tl dd A 1.00 d E! rqrd.il 

lir rkivaiE rp..'orqy e.r r!.d lo 

olorlr. tt % raqi.. of elgr r ir zdo 

drl6 l!. l|vdagtl olcatidD s. oQtady 

ovtttPilg li. no.foEdn pat .d n E 6r 

Fnibb to d.a.dn n by .in .6l| oqrdid 

tlF! t |!l Dsidrr F oacnirt 

Al pH l, a, ?.a .d 9 rh. qldagtt 

82

el@t€d for eririzi.e \|@ 242.6r,240.81, 226.50 ed 240 M, resFcriv€ly &d rh€ 

walelcigrh for mrooein ]6 2A.14,2a7,40, 284.A7 ed 2AI m, Est@tively (fisu€ 

Llt. 

The EgIKion nadstiG for ln. applicd d.nv!d!. spocrsspic rechriqE @ Fegr.d in 

rable 1.63. Frcn ilt @rion cut! (labl. l.6a) obnb.d by uing tw tecbriqs i_e. UV 

spetophoronet y ard llPL. lt wa clid.nl rh.t tu irt.n tior muft€d berwd rbe ddss. 

Thc @very mg6 fo. cairiziG .r dl pH lcv.ls v@ fould to b. 91.5G 108.0ry, Sinjlrly 

mrfloxein E8.d betw@ 9l.77105.I f4. 

Ikt.$io, tdiatu af.4inirc ad no lor 

v=00121r+00007 

srtd dettiiE wilh"trllw u W @rcDlttwtu 

942l 

HPLC 

99.16 98.2t 

HPT' 

t0ol7 lOO.],1 

HlT 

t00. l0l.2l 

HPIC 

I00, 

l5 r00.20 

l0t.tl 

91.t0 

95.41 

9t.26 

100.13 

l0l.6l 97_29 

9308 

100.30 100.76 

91.50 99.82 93.43 

l0t.7l 

97.2\ 99,10 

t00,63 

98,52 

97,22 99.t3 

93.20 99.21 

t01.26 10t.66 

l0t.25 r00.18 100.18 100.t0 

t20 t00.19 98,17 9E 5l t02.66 t00.12 

t00,:1 98.t1 t00.22 99.1.1 

l0 I00.20 r00,03 

l0l.6J 9818 

15 

93.25 

ttn.62 

t00.72 

106.82 

98_24 

91.20 

993\ 

100,98 

I0l.2l 93.93 

t03.c2 

102_66 

t0{_n 

10t.52 102.08 9a_62 t00_01 I00.33 

94.12 

t00.25 

I20 105 19 r00.87 r00.2t 

83

ft. r* ofofotuin .t pH I w fold ro 

b 29a urd t6 n4 a f,l 4 w 32n, 29a 

..d 227 oo. d pH 7.4 X* $., d 324 

291 .d 27.00 m |nd .r plt 9 i1 w 

@ d,3az 244.255, uE d nE 

m. TrE nv.logth. Fl.dd for 

cdirizile ud o0oMrin .td agptirg fftlr 

(kiv.tirc lp€dm!.opy !r ptl I 9@ 

226.49 d 2a2.@ .t6, t fll 4 td 1,4 

ww 227.00 rd 102.30 m .nrt .! ptl 9 

c{r drl 

ftc l.IC Ddivd4 e.da oa.dnizi& ad 

otrMt 

r* 226.8? ed 276 ni, Fec.ti\llly (fu@ 3.16). Tb % |lcosy ofc..irizinc i, Fg& 

of ofoei! @tt..d..a.d qelaSlt ! dt pH t vdt uiig boat tt lctuiqud rc bu.d 

b b. ir ib. r!qg. of9.6O-lOZ55% r o.dior.d h nDlo 3_65_ Si,litrty ib |Fv..y v.l6 

orddr.in d .[ tlf bvd. !y fra (kivniv. !..ld{! 9w foq,.t ro b. ct.4?-103.48%. 

ltlir .nt !y ujlg tt. rs a.cLiq8 cLdy tbsEit tu o in6.db! 

drr0 

dra.0 

pg ?.4 

pH 4.0 

9fl t.4 

y=0.01r +5&l? 

u

od 

ry..elt, ntdtt 4n Ernth oltur,6 w tsd,@t tuE 

pr 1.4 

HPT' xPtc HPI,C HPIC 

cr,tt ,t.11 l0l.'7 td,.8J v2.& 9ttt t00.0t 

l5 E.1l 9a_a lra,6 101.36 95.8t 96.82 

JO 95.23 99.!O 99_59 t@.62 98.66 

a5 ct.90 Ln tm.25 99.tt t0l.a5 1m.22 

9.53 t0l.t2 too,tt 96.61 r('o.9a t00.6t yt.u 

10t.62 t0t.62 9t,41 10t.0 t00.90 r0l.3t 94.24 

9o loo.6, r06.56 99.61 tm.l2 Ln 9j1 

105 tgt.55 9t.21 Im.al 97.t18 r0o.t6 

120 rot.6, 99.f2 LA t(D_2t 9,.r0 l0l,.,lr Im.t tm.6l 

ln52 loo.t6 l(x).?t t@ lr9.x l(D.4 99.8 

IJ vt zl ,t.la 94.6a t00.tB tm.7l 

30 c5.6t 9..65 t0l.tt 

n.7t 9t.30 1m.71 t0o.?0 

9.21 t0,J,72 t0t.59 91.4 l0l./A 

75 1,0.91 too, Itrr,Tl t00., tol5 

,t.2t 10t.2, yr,tl lot.t7 '9.0 ,t.10 r@.t5 tm.qt t@.1t 

t@.?' l0t.u tn269 

ln' t0l.t5 1t2.99 l03.al 99 5l 

Es..ttr tbecd n! 1- in rtdb di|d ! 

3{,, 266 !d 219 m. b tb !c uy tt lr 

otri.d b. doufi ir rae.t .d b.dc 

6.dim ''@ !46, 265 d 2E @, 

'tl pll 7.4 rd q l!. Fl of .odrn 

octqg.d rlE rp..n ofcaiirrE.!d i s 

Dr FdbL ro c.lotd. th. ffiid of 

er &!g qil dr id6fr.@ 6.tbr! wc 

lppiied fi.d dda d..irdiE t (tlrcopy ft' 

ftn 3.lt: Dqivriw p.dr- d 

dl d.diM.. Ar pH I tlF rt tinS Bst.lsrt br c..iriri!. .nd .!|oeia !n . {otyins ffi 

d.iivairc {e 232.74 r.d 257.2he. r..p.dirdy. A ptl 4 catundrc w .rdr"rcd d 22!.57 

m .!d .twin !r 276,64 d TL urd.oatb clc b.c.t!i.js .t oll z4 w 223.57 

.d .r pH 9 w 226.62 m wn*.{ &r s|Ni! rt pH 7.4 e&Etd$i pr.tur.d w 27664 

dtl d prl 9 r|! 2?7 d4 clpGdiv.ly (69@ !. | 7). 

E5

Rcg$sion sbdnics re sboh in tablc 

3.6?. IrF o/dqilalilig lrlEs of 

cairizine {d ooEin in diffffil 

buff6 neditm cl@ly indiored lhal 

drugs e nor eff*red by drc prele of 

this qd@l(E a wll dd quiNlo!. 

did nol inte.f@ rhe dislibulion ed 

abs+don of drug .| ey body 

mvircmentol nedim (1abl€ 3.68). 'ne 

@ovcry yalu6 of €.tifizile io .tll rhe 

m€dims on uV sp4trephoton€ny reg.d 

lwvery vals w@ 97. l9n 0l.96%. 

Trble 3. 67 

RtsE tion $distics oldiEire aad enMir 

0.9982 

0 086.4 

bciwcd 96,48-106.78% dd o. HILC lh. 

.tturu Etdb ol@luh.,4,.nodh on w secnnhdon tu a'd I 

I 

xptr HPLC HPI.C HPLC 

101.26 99.E1 I03.43 

91.22 t00.31 97.t1 

30 t0t.72 105.89 t&_21 

t02.69 99.24 10i.72 9t.12 tot 55 10t.25 

l@52 t00.43 

97.10 tol 58 lo0.2l 

yt.l2 100.80 105.t2 

105 l0l.4t t01.22 

t20 tm. t01.26 I00.20 

91.25 t01.78 97.88 t0o.t2 

l5 93.6.1 97.21 105.54 98.29 101.32 97.31 100.58 

l0 103.26 99.61 99.62 10265 

101.53 l01.l.l 98.12 102.57 

10J.72 98.26 IOI36 r00 85 I01.33 

99.62 101.0 l0l.3t 100.91 

l00.r.I 

105 99.32 I0l.N7 98.94 

1.20 I01.32 r02.36 100.52 99tl 

Tlrc I* obsed lor cipmllokin !l pH I ed 4 € found to b€ 3 15 ad 277 M. Simitdly 

.r pH 7.4 sd 9 6e liE obrlincd we 314, 1t,27t &d 227 M, Bp6riv.ly. The 

weclcDgtts pFtu for cdnizi4 ed ciprotloxa.h an4 .pplyiq frn ddiv.tiw r@llliqE 

^ pH I w 2)9.20 &d 2a1 .61 d! a1 pH 4 w choh .r 222.t 5 ed 230.9 rD, rr DH 7.4 

86

obwe,l d, 224.72 tl 2@.91 M lad ft pH 9 ir 

w *let d !r 22t .!d 262 nn! rcll'.diEly (fig. 

3 19) 

Th. Egrcsion 3t ridi$ lffi .Eludcd ($to 

3.69). The 'svtry dudk of cairizin in 

pl!g@ of ciprofloeh indiot€d m cbtrg. in 

.vlil.bilitt vdu6 of borh !h. dtug!. TtE/. 

Ewil.lility of .tftizi@ in F.!.M of 

ciprof,oeia d .[ pH la.lt 

ru foud to b. b.t9a 

9425-t05.61%. SiDilrly ttk 

% adihlility of ciFofoxt itr 

d .[ pll l4k B ot6/.it 

to b. ir tlE 6!9. of 9.& 

cip 

fi.rE 3.rt: rr.ridiE qcfu orccniziE 

eitcinooein 

t8ttfu ttdnka ofsw an d 

fltE ottuw,It ctptulMn d Uv t4rDd,t em6tI EPLC 

Dlt I 

t5 

t0 

9a.u 

t02.n 

XPLC 

tot 77 

l00.Jl 

93.09 

101.00 

t04.32 

t05.6.! 

t00.37 

HPI-C 

t@.to 

99 53 

.21 

10t.36 

t(x).al 

vt.u 

HPI,C 

.n 

l(x) ?3 

93 39 

HPIC 

99n 

l0t.5a 100.61 99t0 99 7l 

120 

0 

l5 

94.25 

9412 

99.8! 

102.35 

97.21 

99 tO 

too.30 

93.26 

t00.77 

9at2 

9t.62 

t0l.t9 

98 40 

t@.n 

10t.33 

10t.76 

104.35 

101.09 

t@t3 

t03 6t 

to.t.2J 

1m.73 

t01.4.2 

t00.t3 

99.31 

t03.21 

93.30 

9962 

t(x)73 

t01.36 

10t.53 100.02 

10t.65 10t.66 

t00.92 102.96 

10t.22 9.2t 100.05 100.25 

t01.33 100.82 100.98 99.64 

93?t 

100.68 

tm12 

100 73 101.9 

l(x)3l 

105 

93.7E 99.3 | 98.79 tm.55 

120 99.t I 99.31 100,71 100.42 101.63 

a7

T1E r'- of 3pd0oeir at pH I w'16I, 296 

ald 224 at pH 4 w obs&d io bc .t 368, 298 

ttd 232 n\ Gp.ctircly. TIF odtricd 

ww.ldgtb cho6 an6 .pplying 6.!t dlriv.lirr 

4.drc@pic ahdi.r for clttizin .nd 

3p&Soein rt pII I ll@ el.dd ! 224.t4 Dd 

8r,s6, rt pH 4 w fotdl ro b. |r 245.57 |nd 

287.46 d\ d pH 7.4 w ob6lrd ! 2A.l4.nrt 

300 m..d n plt 9 qr foli ro t! 24.46 |nd tot Er cedrivdy (6ge 3.20). m. 

FgBi'..ql|nid ud Rltd6 @.hom in idL 3.7l. Tl|. qddlr @fici@it turftl 

b.l[. iatod w oh.in d i6 tlF r!9. of 0.98O?-0.99j7. 

&Fs46 'd1'd6 oJatn E @d 'i,tt@t R: 

dr1 

Dtl7.a 

pll9 

ptll 

rH4 

htdldid lndilr f,i.d orrt ! wici! hfta. rdi,r'nr rtonEd drla io ida.dioor , ey of 

Ite plt lcvd!. TlD.AEiLbiliry ofetniri@ ! dl rlE pB lcv.! d W !rc.t optoton i.y 

rDg.d b.*sq 92.41-10!.86% sd d tlp|-c I fqfit ro bG b.rl6 96 Eo-t01.42% 

'h€rcfor., n w 6n lud.d rh cdirizii. outd b. dcty u!.d yith flu.oquiDloei .od 

tlF. fu.oqli@l{lG did et iflct !d wirh ir, ditr.ihdid or $e.ptidj, ior d.ttyqt l[.n 

rd..& io brb &y !o.t of|.lr, 

33

H?LC HPLC H?tc 

100.5 | 9ll3 t0t.66 96 80 

l5 101.78 qt.62 99n2 tm.56 

30 99.t2 t0r.36 98.50 93.33 

98.66 98.71 108)8 r0r.88 98_22 

9.68 I00. t0 10092 

99.23 98.06 92,41 

t02.66 I01.33 93.14 95.63 

105 9815 t00,32 

120 99.24 100.25 

0 93.45 100 2.1 100.54 99.22 101.42 

t5 t01.35 100 l.l 98.61 

.t0 91.25 

9a_29 t01.7, 95.02 91.65 t00_1] 

96.11 t02.42 100.68 101,45 10t.73 

75 99.69 lot m 96.28 9612 100.91 

100.41 tol.54 94.27 10t,63 93.46 

t05 I0t.29 98.t1 t05.76 99.86 10042 t00.1.2 

t20 10{.78 100.52 t04.tt l00m 93.09 

4 Cedrnir. ritb qLi@ .hun.l blo.k E 

I Sihtlt@B d.t minatin of ethbttu in ws@ ot@lcim chael bl@te6 

C.lciw iotu @ cntcr dE en lhsueh volragc dcpodot chdn ls .nd rh. povo€tim of 

brolchosp€sn with oewoENiner acetylcholirc eotonin or hhramirc nay &tivar 

speific rcalos ibat opeo c.lcim chmels [250]. Calcim-chmel bl@kcF w.rc loud io 

ptud$e Eiobl. innibilory etrecb on all.Aic ard non-all€rgic hisdift krelion [251]. 

Mo@q,fihitir B ale found to h. stonlly eirr.d with sys:rolic blood pllss@ aad 

hrFr.Bion b mr t2521. ln tulbs rtl

M .@onim @tate. aceroniuile and l'ielhyleine (2:2:l:0.04 v/v/v). dete.don linit ws 

ls tha E ngbln lo. atl @mpounds , *irb ctrrciots of wi.rion lN thD 19o (for inbed 

i ra.day) ovd lh€ co.c.nrration rtus€ of I-IOOO ngmln, MBtaf.1216l develop.d ed 

vrlidared HPLC ncthod for th. simultaFu aDtysis of mlodipi@ ed v.lsrna in mpls 

for liv€r p€rfisiod s1udi6. This Eerhod ws foud to bc li.@ within ih. rug! of0,05 !o 60 

!snI--I, LOD ed LOQ v.lu6 \re 0.02 snd o.o5 llgnrr for bolh lDlodipire ed v.isdt n. 

VoE and kdav [251 daclop€d R.P-H]LC nethod for sinultlmu d.lediution of 

bispelol fiddaL dd ulodipine bBylale in i.bleis, Lin@ity wa e$ablished in lhe arse 

of 8-31 ,!8DL-r. Md l@very w6 9.1% ed 98-6yo for bisoFotol fr||]qt .!d 

drnodipine b€sylsL, r€sperively. chaldh6i ,/ at, I25El desib.d e RP.HPLC method foi 

thc sinul|InoE .stimdon of aroMqatin ed dlodipift fibh th€n cmbiInios dn8 

prcdDct. A sability indicadng RP-HPLC metnod h6 bcn da.loped ard s$lequatly 

vdid.t d for simultllHB .siination of mlodipim pEnt s lnlodipin b6ylar. ed 

h..mpril ny&ochlorid€ frcn fien @nbinarion Dtuducr. The d.sqib.d n thod ws Un€e 

ovc . ran8. of G l4 pgnLi for sblo

lgnl-n for sll drugs wcE sinulileouly prpsed. All $lutio6 @ntailcd 5 !gml--' of 

F$$t!th (int @l standard). Ee[ ehrion m id.ded in tdplior€. C.tibBlion c@es 

lNft @dlrnctcd by plonirg @!@tnlio! v.ts dtu p.d( ag dio. Ihe @retadon 

c@6ci.nts wrc calcular.d (bble Ltl) 6d lintu Egc$ion .qutio.e found fd v€rapenil 

B y = 2l0J4x + 10493, dilrian B 

y = 7918 8x + 41587, ulodipinc re y = l8ltox 

+ 27?31 &d cairizirc B t-l6l45i+58960. 

'Ibe sleciticity of e daltlical method @y b. 

d.6,€d a th€ lbitty to ureqlilRlUy &redie 

lh. anallte in pFse of additional coDporcnis 

swh a inpuities. degndarioi pldrcrs. 

SF.incig, B evalul.d by pFFring $e 

ealltic.l spik d mpl.s &d it @ o.fid.d 

tul Oe rie.al m6u€d 6 @ue€d onty by rh. 

malytes, Tn€ FpEsnutive chtl)mtogllm did 

not slow oy od.r F.lc, which @ med lhe 

specificity of thc helnod. 

Lltunenke Fdirie oltJt @ba 

8W. l.l8 98.12 

l0t.5l 

O.JJ] 

80y. t_6t 

tuo/. 

9. RSD %RSD %RSD 

2.5 0.21 0.98 0.99 0.1 055 

5 01t 0.t2 

l5 0.t2 

Lll 

t.t5 

033 

1.59 

|.47 0.23 

l.l I l.t5 

0_92 

0.35 0.t2 t.0l l.t6 

t2@/, 0.t2 

l,0l 9a.n 

0.82t l0l 

t00.]9 

t.l9 

Aeley (&}|. 3.74) rtudy *s pdfmed by spiti.g 80, IOO &d I20yo of e*ins 

slandsd. The pr.cision of rh. hethod lru sdsfadory s c/oRSD w6 nol mor $e 2%, 

Rsfl3 indicjr.d tb!. r[. hdividu.l @ecry of .I it dngs mgld t't'w6 9E,72-tOl.r2%. 

PFcisioa (bble 3.74 ed 3,75) @ nBWd in r.ms of rcpeahbiliry ot.ppti@rion ed 

D4ll@or. -nE iner{ay p@isi@ dala $!F obrain d by .gyilg @plca prEplld ar 

9l

ihe ld.b of co@manon o. difrer d.F. Rlpealability of sr.idad appticarion B 

ffi.d our Bilg sir Gpliqrs of ilE t00./.ld $tutiotr. nE y,RSD of Del !16 foraI Oe 

.hes wa foud 1o be vdy low. 

Thc bbultnss dd rugs€.L.ss of rhe hcrhod M €6rabtish.d s the yd.vilrion iom m.d 

ey valE- It *6 tur€d dw m degndlrio of &, dng blrt ecuftd in rh€ @nccd 

fdnuLtion l!.1 9@ &dtys.d by Ihir ncIhod (l!U. 3.?6). IF low %RSD ul@ indiclt d 

the suitability of lht m€6od for butin halyris of aI drugs in phmaceuliql dosge fom. 

Th. l@rcri6 of dru8! ir pE*nc€ of s@ fd dt tn. ddgs qd r6r€d for Dcm@ of 

.ldos€ooB @npordrs rtdch hiShr inr.rf.E wiit rhe drgs b.i,g oalr2.d (labl. 3.?7). 

Cl[onsroSrms of blel plMa ed a pta3tu @plc spiked wiih all ile drugs wce 

@mp@d to show rh. 3peificity .!d $Lcrivit of th. FoFed p@!dw. 

% ?c@wn6 oldg?ad bnn& 

l02.tl 99.52 

5 98,97 to5_21 s.02 

l5 104.u r0r.2 lt.l8 95.14 1412 

t02.11 t9,97 19.E6 

25 t0t.l? 25.29 24.6J 

r0l.2r t00 25 44.29 

2 20 25 

93.52 l0t.2l 93.75 100.12 

95.26 96.1t 96,53 

93.65 t03_54 

100,16 lor.02 102.66 r00.88 

ll C. rizia. tnieraction studie, with catciw chtuet btute| 

oIE ofrlE msl srudi.d 6isr,@ nehqis b m.did€d by p_8tyoDrerein, which ce,t$ 

be noddated b, .atciuh chanel bl@lc6 12601. Ddss such o dilri@h ad v@p€n e 

nodulators ofborh CYP3A4 ed p-glycoprctein. Horev€r, ilE roL ofp_gtycopoteh i! rh*e 

speifi. d$s inl.o.nod mdc wl€.r 12291. vmpaDit tuy ord phan@ caidane. 

92

Fli.d| toF of in9ltrtd d4rc cdd dE b n! lor.did pdy.op{cadn itbibir,o., efcd! 

[r6t]. 

vd|lrnil rhortd ir n|xit|M $!ort.e d 27E Dd 229 m in dl lrudi.d pB 6€

.5t lt9 

Itur@tt@ wltt ofqd^nN db tnp,tt u W tp.noptoown, a,t 

HPI,C HPIC rfLc urrr 

99.25 91.65 99 6l 

It 99.62 94.74 992t 

lo 98.12 98.t2 93.2 lm 06 97.24 lo0 5 

100.r t0t.2 

9ta 102 105.5 yr.t5 

15 t03 1(B6 10t.3 

1027 l0l t00.J8 l0l t(x).2 

105 l0t 9i3 10t.7 98.63 

tm 98.73 100.2 t03 l0l t6 98.69 94.72 l@.3 

0 102.7 t03.J4 9t.l I !03.3 9ta 

t5 l0l9 l0l toz.vl lot 3 

to2 lm37 98.t5 lo0 I 

t0l 933 l0t.t I0t.2 

fi ct,t5 t03 l0l3 100.7 lm7 

15 t01.96 t02.1 9947 t0lJ to2_a 

tm.l 100 53 104 %32 100 2 

l0J 99_ra tg2 tm.7 

l.t0 100.3 y, t7 l0l l0t 3 

Ia.I t!. hlfr*d Ddiutu (r,H t, { 7. !d 9) s&.ragtn Dryitu of il|n,.5 E 

ob!..v!d ro bc at 236 M. So in dda ro r@tve d,. c Et ppD8 lIErrA of .aniziE od 

dihtu&m th. frn dajldjE Bpons 

I pH I r@ rBt&d d 223.43 .d 

Sibilrly rt cponB d pH d Z.a 

&d 9 fo. eridt4 B4 224.14 

223.77 .rd 216 9a n4 c.p..riEly. 

Fo diti.zcm rhe !!rtri@t 

hEr@gtb4 !.t dcd fo. qu.btrdd 

e6. 219.34,2t6-9t Dd 2lr.oo orr r6!.direty. Tt ,/d@vay of canizie .@..t 

b.twn Ll5.lot 7s% wtFE { rhd of ditt.*d E foud ro be in dx 6,rse of 9.};5.

t05.65% Th. |@rst ddic. of bo$ rt drug' clarty stow.d rt|tt d inra.dion.r |Iy pH 

bv.h Ou! both {E dosr c@ld bc d.ly 6.tnini!tq!d. 

DI 

t4ktu 4nnt oJ 4dtur rhh dtt@- tu w tp.dtupteto&nr @d EpLa 

pH9 

HPLC HPII HPLC urrr 

%.la 

t5 98 35 97.42 

l@.02 101.22 99 55 

105.75 l(x) 96 r@.03 l@tl 101.43 

92.t5 t02.65 10016 l03.la 

93 5t lm 5.t 

t00.69 9t.36 t0t.23 l0l.2l 

t05 102.15 9a l'l 

120 y, t5 r@.J6 93.13 101.37 t(D.63 

0 Iot .}t tm.9l 93. t3 rot.n 

t5 1m.56 100.87 l0l 16 1m.85 9t.36 101.23 

t01.26 22 I02 35 

102.5a 100.68 %.tJ 

l&99 96.1,t l@31 yr.t2 l@ 33 

15 102.54 l0l.2l 10t.57 100 36 93.41 

l0l. q_tl rct.n tot.92 

t00.03 100.26 

tm 9125 

Th. Niru6 3pc.r..l ri8fi,tr fo..blodipi@.t dl 

th. pn le obkEd b be !r 366 !|d 236m. 

IIde h ordr io strc rh. ddiqtiv. sp€r. of 

cdiri2i@ .rd .Dtodipin it|. fiis &ivdiE 

lp€ro@pic t€hriq@ wa .ppli.d. A,.lrricd 

ng..|3 n6!r&d 1 pH 1 fo. cai.izi@ &d 

mroi'F4 rc.! 225.t 19.d 23r a3 @. r pn 

ll - !/a\ 

n..E 3.2rr DeridtiE Srcn dcc .Dd r,il 

4,2ta.M @ 2t9.tZ, tt pttT.4 rhe .DtFicrl esrct.tgrt Fl.dd *$ 22.9t at! 210.74 m 

!,.t .r plt 9 ir $.! d 224.95 ud 2t9.53 m (fi8@ 3 24). Th. Gg.eion r.ri!ri..! e 

- 

95

.pfstd ttdiei3 ol c.tizitu dd z'todiDi4 

pHl 

0j9r 

o-9956 

'fte 6ult5 (la!I. 3.83) of anlodipinq showed rhlr no interedon dt oy pH lclels. The rry 

sF.iropnobtErcric valus of eririzjE rnd dlodipirc ar all pH l*ls @8ed b.rven 90l0l% 

md 95- 109%. rspecti!.ly md on HPLC rtuged belw@n 9t- l Ot "/o for bolh th€ dru8s. 

r.b|. 313 

In@E iM /6ulB oJdirizke vith an!.dipin on UV tpzcnoplotmtry dd 

EPLC 

PH9 

HDLC HPLC HPT' HPLC 

97.24 99.82, 98.45 91.20 98.82 

I5 91.20 9.25 

l0 98,15 t00.5) I00.3t 96.J4 t00 7l 93_62 

100 8.1 t00.?.1 93.19 r00.90 

94.42 t00.41 

98.48 93.33 93,51 

90 99.07 99.52 101.65 98.71 100.41 97.84 

95.16 t00.3t 9l.ill 

99.42 93.55 l0t.5l 

99.1| r00.31 

I5 99.11 93.t5 9n 89 t00.42 rol & 

t0 95.0E r00.9t 96.2t 9,78 r0o,7l 

99.20 96.54 97.49 93.92 t01.4 | 

97_t8 100.61 93_3J 

91.51 99.43 

99.85 94.71 100.08 100.89 99.85 

105 l{x)91 100.62 t0t.65 98,72 100.26 97.O1 

Cdniri!. ri.n NSAID'! 

98.54 100.37 96.88 100.86 

Sinuhdtuow zleterkituioa of@tirlzltu ihyeMA@ ofNSA|DS b, Rp- H.LC 

96

It hs ben 6bblish.d drt s'n.rgisli. €tre.t ws .xlibit€d by th. .ombired e of c*nizim 

wilh ni@didc [262] dd in clinic,l triats cctirizire had b6 saf€ly adDilbl.r.d wjlh 

NSAID9 12631, Topial dlihist minic agenls not ody povirL f&rrer od suFrior ctief thd 

syslenic etihistmines, bu1 th.y hay also ,osses a longd dualion of@lion rhan orler 

.lNs i.cluding vMoffificlo6, lul cell 31$ilisea, NSAIDS ed coni@st€roids. M&y 

&tihi$mircs hve eliinllamatory pnFni.t s rell. Som. ol6rs dli.iif{M.tory 

.tra1 s6 with 'pw dnhi$lhiG pE C.v@lbastine ed mcd.srine) nay b. diE tly 

.nribnl€d lo rh. bl@king of th. hislaniie rcccptor ihar hs been shom to dom rcgulat€ 

int@lllld .dh$ion noLcul..l expEsion &d in nn4 liajr chemoiaxis of infl&rnarory 

elh. Ym ed Ju [264] dcvclopcd a siriv. &d yd siopl. RP-IiPLC o.rhod for tbe 

d€l€mimlion of ibuprcfed in b.agle doeh plMa by 6ine $lid phae €xlticrion. Avd.ge 

qbelnle @overies w€E 88% for ibuoofen dd 96% Ior inremal slanddd. N.soji [265], 

d.velop.d a 3impl€. *letiv€, Epi4 peis ud .@nonic.l rcv.e phAe HPLC 6€lhod for 

simulr{oE .srim.rion of nindulide dd diclofeMc $diu 6!n eesul6. Thc lin@ 

dtMic tu8. lor bod nib.sulide md diclof.ne edim ws 0,5,30 psnl-_' 

dd 2.0-lO Agml-r Especlilcly by lhis 

m.rhod. l'l@lanol *a @.t 6 m 

intqml st afd. Heelala d a/., [2d6] 

d€sib€d a sihple, sp.cinc, &cuar€ 

4d pei* RP-HPLC method for th€ 

siDdr.ms detemiedon of 

nin sulide ed riaitline froD |!ble!s. 

Coefici.nts of cod€lolion obr.ined for 

ninesulide &d tiai

ft. n€thod for rh€ dcimination of 

cetiiizift (slion B-iii) B seleted lo 

qudt NSAIDS in &1i!., ph'Mnlical 

pr.te.liom dd in tu. Rehrion rirc of 

clt rizin., tiapofen@ &id, fllrlirofen, 

iblprcfcn ed nefendic acid \^@ 

sibllr.!@Bly de|emined elnling our .r 

2.5, 3.E, 4.8, 5.10, and 7.1 minnt s, 

Gp

t1M 

%RSD 

0_52 

I01.72 

9.62 

l0l.l I 

to0.8,r 

0.1,t 9.8.] 

t02..,6 

96.15 

93.|l 

t0l-55 

lO,l.87 

t20% 0.33 t0'4.t2 

0.12 t02,66 

100,22 

101.99 

to0_2 | 

0.21 93.77 

0.8? 

tn@t"edii@ sei:;ta oltlz nethd 

%RSD YORSD 

I l.I 2.25 l.t3 o.97 0.7., t.72 

6.25 o.21 0.r6 0.t6 t.55 

12.5 0,&2 0.ll 0.62 0.11 

t0 0.2 | 0Jl5 It2 0.88 018 

)5 0.t99 0.21 0.29 o., 

0.82 0.72 

99

mon dtd. pra*tu oftlz nhd 

%RSD 

0.16 Ll 0.45 t.t2 

0.lt t.6 0.37 t.2 r12 

t2.5 0.56 0.t2 l.l,l 

20 0_91 1.37 l.2l 

0_t2 0.55 0.17 

l0 0.37 087 

M.thod bb6hs with Fgld to vdi.tiotr in wav.Lngth ir lh. slgc of 230,240 M ws 

$dic.l. P.!l a6 lrd Et ntion tire chdg6 l4 ob*nEd. R6uhs ctdly indidr.d rhrr 

Frr c rd6 lrw irflEnccd lN, up to 2% fd .ll rbe d gs .seyed- Momh, rh. 

epeation M foud ro bc sulficidt. Th. m.thod B suc6stuUy applisbL for pla.rical 

ue, To cv.lule ihe i.ledivity of developcd m.rhod for ihe aEl$is of fomulat d prodwrs. 

c.tidzinc, tilpbfen c si4 nuhprefea ibuprefqr m.fendic @id ed @toxi@ rablcrs 

rw &dyz.d .!d c!rcDtogtu v@ dp.rtd *ir[ de $.Dd'd etution of rh* dtugs 

*IFF m irterf@ne ofcxcipidts B ob{.F.d, 

wecowh, ol dltete4, b@'ds 

102.13 lt9 LI 10t.78 Ll3 

6.25 6.2C t02.13 98.2X 93.25 

12.5 12.61 101.45 t2.93 t2.45 96..]6 12.05 

N 99.88 19.93 20,3t t01.99 98.48 

x 21J9 25.67 10.,78 

l0 96.21 24.45 29_41 28,10 r03.65 ILl 

t02,44 5t.22 t0.1.65 5t.El 98,21 49.11 105.15 52.]J 

I00

%Rwn* oldtf.Eit bru,& 

It) t05.25 3.24 I02.12 Ll9 107,88 1.37 

98.32 107J, I02.t6 

t2.5 12.02 105 22 ll l5 12.63 

r0136 20.21 100.23 

102.69 

l0l.2l 97.6t 

96.21 

IrF sFcincig of th€ n.Ood qs also ddonsraled by spiking $tm smpl.s in fik 

dif.Ht @netreadoN qd calculatiry th. lwrcr, (r.ble 1.93), which for .tt the drugr M 

found b b. in lhe @g. 92.45- 107.45 showirg th. fi.Epartic siglli@ce oflh. Ddnod, 

ll Interactiobofcetbizire thNMtDs 

t.t2 6.25 12,5 20 25 

10t.54 

t$.22 t0t.99 102.66 r00.29 

I03.57 98.6t 98,64 

,9 t2 101.44 I0l 

10521 96.21 96ll l03 

107.23 99.21 97.65 

92.45 9a.D 

NSAIDS may eflst P-glycopol€in expE$ion [258], ir qs foud thai both celecoxib ed 

diclo&@ haE tn lDr.oli.l ro inlibn rh. tunction ot p-gtyopot in ir ECC 6i,s 

Aodqi.c !p&le sd .flu ,sF [269]. 

Thc ab$rption lmima of risprfemc &id a1 pH 4 wd foud b b€ 3 I I nr! howwer at pH?.4 

md 9, it w at 315m. Simulr.nos €qutioD ws lpplied o qu&rilate the two dtug! in 

$lulioq in0.drion ruults cldly iDrlic$cd th.r % availabiliry of cctirizift M ml.dly 

rffc.tcd ir F€..@ of riapof.m &id. ft. yc lv.ilabitiry of eririzire wa foud lo b€ 

168.l5-748,93 ed 121.46.128.8? % by Lry sp.clrcsopy ald HPLC eFctively. 

t0l

Epsilaau c wiw t'ft^ 

15100 t29\7 

t68t0 ]65t t4742 

l6lt0 l5r0 tlotl 

TIF % avaihbiliry orcdirizi!. in pBace ofri.prcf@ eid ys nor fodd looyo. Sinitdly 

ti.prcfoe rcid b also sf&ctcd in presc. of c.liiizi!.. D!. Esults al vebs DH lev.h 

a peeld in ubl€ 3.95 cldly indicat€d th. @tid bellrg thc two drugs. 

Tianbfon& 

qPl! HPI,c HPLC 

t02 100 t03.t6 9.68 I02.91 

It 90,05 93.1 l0E.5o t01,92 36.36 33.66 

l0 9t.60 l0o 84 t0{.95 3I 

1t5 80 5.61 lt42t 1t609 11218 I I9.96 

0. t2 |1.7 I t3.64 t\6.97 10886 I I0.t6 

II9.t2 l r8.62 ll6.15 I I7.tt 102l) I Ia.t7 

I26.tl t29.43 I20.66 t25)1 1t5,63 

105 r30,9 I2l.3l t2t.75 t21.99 llt.57 Il3.4l 

I15.20 r21,34 I15.70 \25.42 t20,69 

t04.J9 100 1084 98.48 115.53 |l9.68 

t5 93_lt t06.3 t09.21 t06.6 

9l.lt 109.3 107.59 t02.3 t00.2t 

1t5,95 |2.52 ro7.9l ll2.l3 I t3. r.l 

l6t,.t' ll6.5l 8.r4 r08,7 D1.24 

t25.1t I I3.6.] |1,17 2t5.97 I19.07 

l50i.l t20.19 20o.ll tr0,8l t20.ll 

105 12t.3 t24_62 122.61 

120 t6t It t21.46 r28.87 244.91 r28.81 

i Diclofe@ sotliu 

'ft. absrption lwiM ofdiclofcn c ediu .t DH 4 ald 7,4 qd fourd ro bc n 27lm ud 

al pH 9 al 276M, Th€ inI@lion study of c.tiriziE @ p6fom.d in pt€ge of di.lofen& 

sdim cing simulia!@s equdons, The eplilon vd!6 w. cdt llared dd 6e D6e.led 

t02

Thc intmctlon rcsuh oI c€tinzinc 

in pFs€M of diclof.N $dim 

cldly indic.Ld thd @tion 

@oE!d al sll rhc pH la€k. Il 

w obswed that rvailability of 

diclofcu. $dih (@id€obly deElsed i! pt*re of etirizire. TIE iolc6.rioD Mg€ 

obercd for didof@ $diu .r.il dE bufld n diu tug.d b.r@ 26,2&56.1070 on 

Uv -lisible spectrophotomelq, sinild rend was obsw€d on HPLC, which w6 5o.EE- 

7E.45% I! lhc s. my, tbc itr&cdon Bults for c€tniziF .i .ll pH lcrcb wE ir lh. 

tu9. of 157.13- | 61.94% d uv-visiblc sp.ctrqhorom.&r &d E0,45-2t 0,03% on HPLC. 

T.bL 3,!, 

Epiton wtt6 d wio6 b,I.B 

D 

t5100 9237 

16850 l0l7l I t57 

pHo 16350 10t35 9804 .l l7 

HPLC HPI' HPLC 

IM lod.t2 t0().t5 

It 67.95 93.91 96.91 9!.86 

l0 72.59 26.62 8?.88 4.1.0J 37.52 

65.92 24.20 35.24 t3.69 88.i8 

5524 54.U 20.62 n.1a 54.29 91.54 

75 5E.77 Itol 16_t5 

53.00 t4|l 1068 3l7l 

t2.17 681 5t.61 

120 t0.88 2626 69.89 

|l0.t3 95.3) 9n.18 93.1| 

r5 35 

16986 8.t.]6 87.35 31.19 

130.24 r85.51 46.12 88.5J lIl.36 31.72 

|l5.]6 |1.66 37.t9 

I5 t70.92 187,2t |r1_t t25.83 3713 

90 170.31 192.\4 10.08 t29.27 34.33 

l0t l98.ll 5.33 81.16 3t.69 

r20 2ro.0l t2n.76 5t.tt 

ftc MimM .r.lyticd sign l ob@ed for flubipreIer w !r 246 m ir all pH bedi@. 

H.M limiramB .qu.rio! B lppli.d to. th. q@riialion of I[* drugs in 

l0l

Ite ini.@rion reeultr of nubiprof€n at veiou pH l*ls indic.lcd s inct€e in availabiliry 

of flubiprefd whi.h 6dged b.twen 125.I I'l68.9t % or UV spenosly ed o. HPLC. In 

tb. 9m v!y, .vaiLhlfty of cdnizi@ ift@s.d dEsrioly in p|!$M of Rutbipbfto b lLe 

tuEe o:I 25 1.y2444. | 5yd.. 

Epitn uot4s d was btfus 

J286 l4r.l 

16350 2t94 

16150 .21650 

il H 

4 

HPLI HPLC HPLC 

9t.10 

l5 95 5.] 98.i 91.13 91.t6 

100.48 94..t5 

Il1.33 98.16 99.02 9t.32 

ttt.24 147.8' |5_27 t02,98 

15 |]6.50 150.71 102.t7 II5J3 103.31 

154_42 l26.ll t20.55 I I8. t9 

t0t 146.t9 159.84 lll.46 I21.58 l]6..:0 12t.96 

120 I55.96 168.9r 112.90 \25.67 112.46 I25.ll 

t00.t5 t00 I.]I 97.26 22J_6 Imil 

r5 t0,.9 2242\ t03.tt 

9t.2t, I l t.44 97.1E 110.69 

121.5r tot42 2@.59 102.17 .I13.76 

341.14 26t.74 90l9 

]69.r1 15988 nn_27 I|0.91 93.31 

.]89,01 143.28 5.67 98.72 

105 ll8.46 250.93 

29432 lr0 8l

Th. iaitutiotr srurlr of c€rnizirc 6 Frfom.d i! prls€re of ticpofe@ &id 6ins 

sinulLn@B equtioBi €psilon vdG l@ cilculded dd @ prcml.d in lable 3, t00, The 

irt€@tion resulls of cdirinre in 

Fel.re of ibDprcf.n ihos thd 

d. Eaclion ccued !t all th. pU 

lw€h ed ihe % availability of 

both thc drngs @Nid€Ebly 

Eprtlo, vdus d woa bSe6 

333 

16350 t 7|l2 254 

t0012 

% mihbilitr of ilru6 .r wis DH lo.l 

H' 

H?LC HPL,c HPLC 

100.16 t00.88 100.01 93.63 t01.69 

t5 l0o.3l 65.37 23t.45 lt2_14 

88,97 98i6 27t.ll t2t.03 

269.a4 l15 43 

I26.94 261.21 t2a 11 125_75 

12089 42t.66 t42.41 

t35.39 t22.11 

t05 145.78 116.78 411.88 123.7 

120 150.69 140.33 419.45 129.4J 

98..]6 

l5 r02.89 t06.13 93.61 \02.26 

120 219.77 

115.96 92.t5 120.46 t64.'l 106.54 96 82 

t2o.5a | 70ll t2E_11 192.47 I I3.43 

l]8.9 101.09 It9.37 82 68 

t30.2) 

r37.61 t94..33 211.87 113.44 

218.15 I35.43 288_12 

'rlE .b$rptiotr l|uim. of tuftui. &id B fould ro b. st 285@ h.e sinutr$os 

eqution sa usd to q@tit r€ th. rvo dnss in pEstre of @h orher (iabl€ 3.102). 

105

Th. % availability of ednzie 

ra4.d bdwco 44,73-45.tt9 Y. on 

UV rp.clrophotorc&r &d 66.26- 

?3.58 % @ tlPLC. Sinildly 

@isi.Loble dtit B ob6dcd for 

Eps on r:dw d wiN btd.A 

16350 tt2l0 1219 105 

15ll r27 

n.f.Mic rcid wherc availability indEs.d up r,o 124.25.135.84% on Uv spcct opholob.ily 

.r1d 265.9G27A-1Po on IIPLC, 

tlr. nwimm si8tul at all ih. pH 

lels for oebncd M foud to b. 

ai 162 m h.ne sinulr.ncoE 

eq@iid 6 alpli.d io qMritlr. the 

tw dnrgs in nixtw (bbl. 3.104). 

% llro .btti, oldt zt a wios tE L|.b t9 

HPI' HPLC 

I5 31.71 870l 97.15 

l0 23,50 8t.39 25.44 

8t.72 lt_57 37_95 

60 87.19 35.71 3,1.19 

75 87.43 18.29 

90 41.18 

7t98 12.69 

t20 7t.54 6_26 

0 93.25 t00 99.18 

97.56 105.59 106.89 

t0 7938 t22.lt u3.20 

t64.31 

t21.16 t70.86 2t0.39 

t26.62 t92_11 r5t,78 220.96 

90 tu.74 l9t.m 157.69 267.28 

r0t t2t_52 210 135.56 

l20 115.34 265.96 t21.25 278.n 

Eryilon w|tur d wnw btli\ 

11904 22 

t2152 

t\54 

t06

For cctirizin€ th€ o/dv.jlability ieged berwan 120.96182.11 % sd I15.62-191.?3 % by 

UV spebophotoneter ed H?LC Esp€ctiv.ly, Thc % avanatiliq ofmcbn@ ir pr.se 

of ccti.irift dsased 10 c aignif@t qr.!! N.ihlilirt of c.ririAft @ 2_06{6.2e W 

lJv-vi3ible stFtophoromacry and 42.6t68.49.a bJ HILC. 

I.bl.3J05 

tr4 t9 

HPI' HPt,c 

t0o.t2 91_Zl .r9.39 

I5 91tl t2_6 88.15 36.71 6l.tl aJ6 

30 57.11 l5 34 39. t9 

27.47 56.23 

19i 35.49 102.5 65.67 

2.11 33.11 64.67 78 88 

2.25 63.9t 7t.tt 

105 63.It 

r20 

100 10008 96,59 

l5 2.9 I10.99 l0l24 110.25 1t2.55 

30 t30.16 79.33 103.07 |]0.62 ll6.2l 

t2t.t1 tu.32 105.13 I6t.5? 

\t2.17 l.l4.tJ t24.t6 I09.21 l1t_62 

7t 113.6 ltt.78 115.84 t06.41 141.3 

I14,06 r40.88 t26.62 1t0.87 

r05 I17.63 178 6 112.88 143.9 149.32 

t20 t20 96 I9l.7l t2t.75 ll5 62 l82.rt 

Inl @lion nudi6 s@ fsnhd supponed by th.modynmic d!t!. lt ws obsd.d ftom 

themodyMi€ dal, thai sponhrcous qcrio. have ocared be$e€n NSAIDS ad etirizine, 

6 dl itr. Cibbs Ge o65, vdu6 \'@ fo6d 10 b€ rcg.tivc.In s simild ey, helI 6nLnr 

vdB *w .lso fould to b. eg.tiv., *I|icn shoved rh.r @hdd fotuio! is duc b 

cb.l.li@. En$oDy val6 for all de ini.*ti@s *w fourd ro b. positiw qc.pr for 

b.loxicM in pH 4 at all thrc. r€mFEtc. N.gaiive €ntopy v.luca of meloxi.m indic.red 

doror eepbr mnpl€x forrutio. due lo hydrcgc. bondiq dd ch.larion. 

107

* 

i 

t 

I 

o! 

I ',.! 

i; 

s 

is P 

E 

3 I 

q 

s .? .r 

i d E I e R 

J 

T T E € 

2 E 8 E € e 

I 1 

2 s 

.1 J a 

F s 

F a i R e s T 

? .t e .t 

Y 

t 

s E F 

E t Y I E E I F € 

? 

a 

i 

'a 

.6 

F 

F 

R 

5 

e 

a

6 C.tirizib. ritb r imrl.d.lt 

I SintLa@ts deteminatiok oIcefthift l, preleace ofantltularlah 

In om of thc an|di6 a ce of d.l.y.d Fss@ urtiwi. w p@l.d in whjch 

,dihistuiG g+ rct efedre. tlo**r, drrbddid E found 10 prldue positiv€ 

imF.i [270]. In eolhd .& or aut uiidia dd algio€dqE onl etihisrabiB showed 

no dier of sydploos. rbwv.r, 06l chlobquine shoqed ! .lrmatic inpovtuot in 

patie condition t2?ll. ln solr uniceio dimalrial tptrn€ M .fiecdve [2?2]. nE 

ddotdtids, c oroquin*, hydnxychlooquin€. ed quim.nn€ e usd prihdily lot 

maldia but th.y cd b. b.n ficial for c!ran6$ lupu dtlhmatoss (LE), pollmoQhoB 

liclt duptioo, el& uni@i! &d Frph"ia cur8@ I'd. t273l. siftc etmldi.is e efely 

coadoinislcEd dnSs in pEpM of erin2irc .d haw shoM . poitivc cull in dr 

l@rndt of liliwi. hene a nov€l &P-HPLC F.thod m develop€d [o simultaMuly 

q@dry cdnitn in presm of mlinaldials. Nu€rcN RP-HPLC h.thods have b€a 

Fported for the d€teminadon of dtiDalaials. B.ll a ar, [2?4] dev€lop.rl HPLC melhod for 

th€ qu.ndrsdr! detcrnilalio! of @mon etimaldials, they q@tificd stdfadoine, 

pyrimlb@i@, chlorcqui!.c, dodirqui& &d .16.:thyldodiaquift lion wbol€ blo.d. 

Cdibdion crc wcc lin@ (rL0-9t in dE MS6 5 l0O llSnl-], 5O-IOOO, 150 1500, 

100 1000 and 100-1000 ngml r for sutfadorirc, p}Tindhtuift, chlobquiE, dodiaquift 

ed desihylmodiaquire. Esp€.tively. ,&. dr 4t, [2?5] de$ib.d mcilFd for ihe 

d€t mi@lion of pyrimethdine, sulfadieinc sd its melaboliL N-acdyl-lllf.diuiE in 

plama mpl.! fom rconals, s@ple tftp@tion wa bded on proreio pdipitadon. The 

dalysis s perfofr.d usila HPLC with UV md ns spet onmic dcEcrion. 

Ii tbe plffir *ort, ! w merbod B 

dcvelopcd .rd $lidn

sym€F of p€ali. The reteition tin.s of pydh€$mine, cflotoqui@ ed eririzine at rhis 

mbil. phe 6 foud to be 2.5, 3.6 md 6.2 njlurcs, 6F.rively, TLe d.r..rior ws 

perf@ed.r 210 M with 1.5 mLnitir. Rosuvslalir ws choq to be & inl€h.l slandlrd 

elutinS ou1 at 9.3 niml6. Itu Fp6dt tive lin@ cqudoB fo. plrin lhdiF. 

chlooquioe dd c€tirizine w.E foud ro h€ y =80262x-24975, y = 54715x + 5861l8 &d y 

= 6622?x -200861, Esl,e.iiEly. Th. corelidon @ffici€nls, LOD nd LOO Elc @ 

PzgtstN id6tLt @d kBt\'ly oI th. n4hod 

LOQ toD 

0 999 0.00r 

0,04t 0.0800 

Th. $tinEt d p@isiotr (torsl laialion) EDh wilhin dNy expsjn€ w ob$Ned 6 l6s 

thd 2%. Thc m.rbod p6s€d th€ r6t for etc.Lbiliry a d.r.min d by %RSD ofd. d.a of 

t& peks of six rcplic.tE iljadoc.r toop/o rs1@lc.nEation (raue LtO8). ,nE Esulr, ot 

inrmcdiare p@ision @ s[M ir labtc 3.109. The lKti of a@@y (r..bL ]. | 0s) Ev..l.d 

lhil lbe meurod wN ecwte for .I abov€ purpoFs. 

ccttt dnd wisiM olrtE netbd 

% RSD 

100.t4 

0.ll I00.12 

t0ty4 I.23 t0l 

tle/. 98.75 

l@ 12 

99.11 

t2e/o 100.t9 

ll0

Iir'4ne.Iitte p4bid oJth. h.tkd 

50 0|l 0.78 

y.RSD %RSD 

25 0.15 0.26 0.01 

t2.5 25 0.05 

o,072 0.75 0.08] IJ6 

2.5 0.92 

0.12 ) 0.61 

t5 0.21 1.25 0.032 

fte av€Es. v.lws of thc ag€d $lution 6poB6 (!eal d6) sed obseFed ro be asE d 

wnh tne Alsh $turid sFls, within i2%. Tlle 7o rccoEns of tue, h pr6e@ of 

s@ (bble 3,I l0) reveal.d the applicabiliry of |nelnod for rhemFrric &d clinicd pu+osg 

ll tn ranio, of c.ftlzire vith @timl@iats 

t2.5 

to2_34 t01.37 95_1a 

50 25 2 

I00.ll 

t0115 t0t.u r00.85 

P-8ly@prctci, honologw I (?Bhl), noddaL s@irivity io a tuge of eiiftat&iat 

@npouds. In th€ sc atudy, mdloquin ws shoM ro be . Fi.nr irhibftc of p- 

glycoprobin tespon acdvity, incrcsing the sositivity of drus{esistdftmoi c.ll li@s to 

cfotonc agdts [276]. Mc0oquift hlve both pFiosty b.e! sbou ro bird diFrty to p- 

glycopret i4 alrhowh it des e with rhigha.6nity rh{ vP I2?4. TtF e.tsi! D€ruit 's 

P-glycopDbin hobolog!., iDllMe d. sitiviry of malqia p@ircs to a div* tuge ol 

&tiDaldiai druss bul lh. Mhetum by which n do6 e hs @i!cd obs@ [2?s]. 

Mdim of pyrihethmic dt aI pH \N* obedql !r 272 {rd 223 m. And .gplying 661 

d.dv.tiw techniq@ th. i&lttical wvelagth Ft{red for dI pH t.v.ls \r@ obee€d ro be 

.l 240,53 m for cdnizbc sd 224,84 M fd pyribelldii*. 

|ll

R.snt@ lotiurs ol.attN dA pnn4tmme 

pHl 

y-0.026r+00007 

Thc int.rerion Esulis shou in tlble 3.I|2 d.moBrar€d rhd nudied druF did nor i erfft 

with *h otb.s qwtitaion in .ombinrdod, C.riririre E avaihble in E tuse of 95.EE- 

l0l.35clo and 97,16-100.98% by both the t chriqB. Sihil{ly pydmcilmine awilabiliry 

a 97.l0-l 12.86010 lrd 9?.2G 100.82% uilg sp.clropnotoh.try 6d H!LC. 

Irnk 3.112 

hteretih nsths oJdnbiv eah N@tttunke d W tp.ctrcptn!@try o.d 

EPLC 

HPI.C HPIf HPI' 

9932 Im_76 td).2a IOIiI 

93.66 lo0 78 91.t6 100.58 l0o.8r 

94.72 98.42 98.71 9a.29 99.41 

95.88 93.99 93.36 

93.32 99.8.] 98.79 

$.q) I00.43 

100.7J 

r0l.lt 99.69 

120 9348 98..t? 

l@.65 lm.at 100.02 94,51 94.96 t00.61 

l5 100,98 93.11 I@ 7l l00.ll 2.86 98.69 

I00,69 r00 8.r 10t.74 98.66 97.42 

t0t.93 t01.65 100.84 91.t6 

100.99 t00,.]l 10t.87 t(x).63 97.31 

99.1I 

99,82 100.69 

105 100.68 I00.72 93.36 yt.42 

120 %.42 t00.t9 r@.86 100.32 

ll2

Th. .bdliE tuiD of cuoroqli4 d ptl I *@ 

d 342, 237 aA 223 M hd. dqirdi$ 

{od@Py e.! {rli.d ft. il, al32 m fd 

€lirizin dd 219.39 m r€r! d@tr tur cnbFquie 

lftq fiBt ddi$ti@ t6nniqu. Tle iddciim r$!h 

I 

l|arr Jl': DqirriE .0ds ordlr! 

.r pB I idi.!.d rbd o ida..rid @n!d Bod tt drugr w@ .nit.u. |rc.rd t6, 

lo@,t thugh cit dr. oqqilt rnd ooddni@ (irbl. l. I l4), 

6 tffid dtenhtEdn 

Ri 

pll I 0.9181 

Pl|| y=1552x-0.0208 

r.U.!.t!l 

ht Md6 Enltt deiM* Nnth.rto,t4tdre q Wtp.tot',tolonhyda 

'LC 

ctl 

t5 15 10, tm 

9r.t 93.12 10t.7! 

rtrta 93.t7 100.17 100.73 101.37 

,s_tl lu).54 100.35 95.t I 101.82 

ltPL l@-,rr l0()..t7 94.24 1m.42 100.03 t00.16 

C.drld@ rto ..d.xlE.d. dat 

$@tbEtu .Len,tdld dedtidE h pew olo taatiAt azgs 

It .di.inneidory lrd |di{rhric .6icr of .#hiirds td b6 ddut d in 

prri.d. wirh bodr dlrSic |.!hM ,'d lhinhi! t279l. Cliridt bsrdit| of II, r.c.oror 

dr.gooid *4 +F qr i! 6od.rd! tdor t2tol. n hd d.o b€ rss.|t.d ih.airLtu. 

drld b. u.dl &r 6. !!6.d of oitd ro Eoddd..tttD rrd .q &. rt Flv.din of 

lh. di&4 t2rl1. Co rlhpy of u.dihi{miF *ir! ! t.utoii@ 6.910r .l|l.eoiin w 

tuid ro Flde Srcdq dti{.bDrb.r.d du rhlr of.iths ds8 gim aroD t2r9} 

Adilir.riq or 6ly FEvldtd tt Fog(5iE ofdtae, ha rb.y E! ftod ro db4 

d! .frdry pta @dinql *irh loLdiiF rd.g6id. t2r2l. r! rdtm rx{d.i, 

@nDiE srpy of Hr a|rrgoixi ietudi.g .rnizin wnh r6!iE!dy ddg! sh s 

I t.,

guinfenesir dd hont€lntal weE nostly €o'mon [28!]. Momw, etinzine is rlso 

.lailable in coftbimtion wirh rcspirabry drugs such 6 pFudoephedrirc [2E4] ed elhedrin. 

[2t51. N@@s HPLC melho& have ben rporred ror th€ d.himtior or rhe spinrory 

drurs. Phoylephirinc ed rropicuide lN* sihltrad@uly dclemitrd n€thod in nl|l@ 

aqueus hmor by HPLC Sepetion w6 p€rfon€d o. d CN coll)m wi$ 0.01 M Pic 88 

(ochne sulfonic acid)-rcelo.nrib (65:15, v/v) s mobile phe. The stdddd cwes weE 

Un@ in th. ddad@ tuge Tn Feisio! of O. melhod (.xpta*d by Glariv€ srandlrd 

ddiatior) ed th. sccuocy (m.e €mr in per c.o0 w*

Tl@foe, a 3inple @u.& od p@ie HPLC 

mlhod for situlllM6 delgbiEtion of rh.s 

drues ws dt loFd. 115 rhc* drugs &e 

availabl€ in coDbinalion ed e nostly @ 

dmiNler.d $ a medod wb Foposd lor $. 

simdran@s deLmimtion of de drugs in Fw 

materials, dosg. fom'nalionr ed in b@4 

elm usinS ibuprofen as e i eml staidald. 

Ihe d€velop€d ne6od w6 foud lo b€ wid.ly 

lppli€ble trd @dd be usd for U.r@utic Dd clinicd purp.*r. 

ChM.rogm of dnas, r= 

Fsuoifd.sin, c=etinzirc, 

Ssi6 of exlqimmis w@ .ondu€i€d lo .srablish d. oFimM hlE of rh. &allric.l 

vdiabl6- 'Ir,e pam.LB optimizd imludcd mobile pl@ vdietions dd $me physical 

v&iau6, ircludins th€ fiow 8L &d the s!1. lolue adjuun€rt oI pH. MoE over. ir 

B obscd lhar lolg th. conccnF.rior of w{€r ln. shonq Uc rererlio! rim. of rl de 

dDgs esuhing in overlapping of peaks. hcr€se in oMnlration ot wate. upro l? triL, 

Gsulted in fal.r 6d b€tLr s.p@lion of p€.ks of atl lhe drugs. However, DoF incMe in 

orenFatior ol *arq 6uhd in very lorg fr.nlon dne for no el&6t. HeMfonl\ th. 

optinm @hFsilion ofd. nobile pb& w.chided ir a otio of 17 vateij 4 ebdrrite 

ed 75 neteol fo! shdp ed well Fsolv.d p.ats. Acardin8ly, the flow or. q6 ale 

adjuled e thai lor lbe drugs it w6 sr al L I hlniri' dd for monteluk6l ir w6 et ar L5 

ml-min'r. ThG oPliru @nposition ofde nobilc ph* @sisr.d ofmetheol: *eronirriL: 

sre (79:4:17) drd s pE 2.7, sdjusred by orrlophcphdic &id for mpid dd wlfEelv€d 

peets ofall lhe drugs, Ac@rdingly,lhe gradie nowmle system wd utiliad fornonitoring 

of chMulogms by intodrcinr ptugllmin8 in sftwe. So lh. flow Ele wd adjuled in 

srch . uy rhat for th@ drugs i... cdnizin , phayl.phni!. a.d erdnfdEsio n *s l l 

mlmir'r dd for monteluld it *6 1.5 Dlninr. The !€r61ion (mes of rb. druss w@ 

foud lo bd 2.5 Dinutes for phenyl€phldne, I minules for gui.f€n€sin, 3.6 miNtes fo! 

c€lirizi@, l0 minulB for @orclulsl dd ibupofo (ini.mal stadd&d) €luring out al 7.2 

hinut s. Thc Uv spetE ofildividud drugs vw @ord.d ald @mFld in lhe wv.L.sth 

tuse non 200 ro 400 m. Th. choice lo w isb€stic Fid sa ar 230 M B .onsidd€d 

satisfacbry, p€milting the dekcrion of all dogs wirh adequre eosiliviry. 

ll5

IlF rhtive $andard &virtion of th€ six FaI F6DDNs wu lot found grater th& 2%. Ihe 

rc$luljon p,@elea w.E found for phayl.thirift lo be 2.58, guitrfeGin 2.00, cainzin 

2.20 tnd fdmor&l ai 1.98. 

No signiflcor cfi"ngd ir ftd uorLx cw. or rcLtlti@ li@ of th. dngs in preeo@ ed 

abenc. of ercipidls cl€arly th. 

qEiliciiy of the me6od. 

'ndicared 

Th. re!resdrativ. 

li!@.quati6 in de @n@dr.ri@ @ge of 

2.5-100 |rgDl,r 

(2-5, 5, 15, 20, 25, 50, IOO) 

for c.tirizirc 16 foud to b. t-17955x + 

52233. for guifoesin wa r-22164x + 

5,1&19. ph@yhtkin w6 r

dt t die Ntitio, olrk tuthod 

%RSD %RSD 

2 0.35 t5l 

0.ll 021 0.1 Ll8 

t5 015 416 0.25 051 76.25 0.t2 

20 0. r8 0.52 0. r5 6.08 It 

t.0l 

IlE sv€88. v.lres of the aecd slurion Bpos.s Geak als) w.re ob66rd ro .€!re with 

lhe f.$h slution respons8, within 13%. Since montelutsi i! lighl sGitive d.ug hence it 

M stor.d in tidtly qppcd n.sk pEpp.d ii alminm foil. Tlrc develo!.d mcdbd s 

lppli€d for th€ de&miMdon of difrmr dog @nreor in ph.@udcal fomut.lioro. Th. 

4sy sulls shom in l:blc 3.118 demoNtrat d lhe suirabilily oi nedod, Simildly the 

o/ofcoverid dd @ftlation co.fiicie or dru8s in pmence of !e@ {bble 3.119) Eveal€d 

dE appli€biuty ofmedDd fo. the.nleudc &d clinical purps6. 

IkcoEn i" tt@wdkot hn'tuIotiM 

93.63 t.91 209 

8.75 tm.9l lo.4.I 5.l,l 

2,6.25 101.73 15.57 

35 t9l3 

26.6 22.71 

87.t t0.t.02 

25 20 t5 5 2.5 

102.14 t01.87 

I(x).31 

t02.45 10t.24 

1.5 3.75 2625 t5 4.t.t5 87.5 

t04.21 lot 73 100,J4 

027 

|1

It beraato., e@.s dedtutu vih qd$tlnadc dagt 

A'|tIh. ir u idl$rlddy di|.& lyopr.d & FeE of coqgb 6 siajtrt' !d !n 

,p.ci6qly dlctic wlEing or iodn l d€h Bitl C..p di&!tdc.. Cdtuizin. i. r pot6. 

od long{.1irg ..cond-g.s.lion Iftt 6i@ HFre.lror &r!gni!r u!€d br rh. relrndr of 

.ll6si. di-rq rlrl s dirsic ,lti!ftn .nd c&oric ilio!.ttic unnrh rdd e. |lh.' doa 

d in ..it'dio. rit[ ortd di{dDri. 6 .di dlasic d!gr. A th-+a!ic.lt, .fic(riF 

.anot of ..tiriri& ir u!.d to F!i!d d drd @!.r of x .tu! drd. It doag. 

d.padt ds.idly d tt .p..ifE n tt d of .doiniltnlbn !d @ ttc purDoc of {|e 

Flonr|dn t2tl. Ir r.. ford tu !l-*A dyoogrd.io Ftf6!di.[y ilitiEd lt. 

pndykrhirei.dEd cod.did ttt3l 

AI .li pll l.edt tt lqio of 8u.ie{ai! w 

obhEd rt 2?3 rd 27j @ lI.@ d.[ !.din! 

lh. ddivdiv. lign l ctos for c.rnizirc ws 

223.11 M ud for @ift!6in w 230.69 m. Tb. 

ttgGio Gqldid Tb. idq.dlF Bl of 

canira i. FE.@ ofgurifaxio rlbrEd rh.. rh. 

rqihbihy of dogs a uqFcd.d in pr.6.icc of 

oh otbd. IlE ./. .Eihbilhy of @ri.izi.. pd 

frrd to b. in l[. rug. of 9cl0l% brh64 

sy gqrif.dat! w eiLU. in 6. rug! 96.1+ 

l0l.98P, by lriig both thc rclniq@r. 

ttc rx: Dqn?riE rdr d 

!HI0 

Plt40 

pll7 a 0.9945 

l18

T.lb3.lll 

ttt6cttn Eturtt tedtueith gtdf8n @ WtPdft'fuMo 

pHl pH,l pH t.a !x9 

HPI,C HPIC HPI' tfLc 

lm.2l 100.53 94.25 .47 9t tl 

l5 99.23 9.25 99 63 

93.15 9_A 9.6 t00.59 9t.15 9.6., 93 at 

99.62 t00.?3 t0o.ol 96ll 93.15 

@ t(D 3t 95.3t 

15 93 35 l0l3t 100.75 9t.87 t00.06 9ai5 99ll 

10145 99.57 9.ll lm 30 100.08 

10t.6, 93.t7 94.2i lm.fl 

t20 10175 

tm15 93.1t lmft 99.a1 93.47 

l5 98.51 t0t.67 t00.73 91.9 t00.0, 99 5l 99.1! 

.73 101.93 9t.7t lm36 

100 7l 

93.1,4 l0l.,ll 

100.t6 .91 9a.15 9t.6! 1013, 

93l4 10175 LA1 9911 t00.t3 

105 100.t0 l(n 09 

l!o t0o.5r 

Ar pH I dd a dE @na of Phatl.?hri* 6 

&!d to b. d 214 !d 27] @ lbqlE .t pH ?.4 .od 

pH q th. .qiu *@ ob@cd tl ,8 and 273 m. 

Daiv.tis ecdD..ogt w rfPli.d to E$lv. tlE 

ochpooS FL' 23761 m ft). c.tirizi@ !6d 

283 07 m for ph..tl.pbnft q@ chos for rn. 

qulditdioo a! edrc pH rt@ a.. pll ?.4 !d 9, 

240.61 br cantc ttd 2a3.66 m tu 

phaybftinc vtr! cto!.n (fgurc 3.31). 

dr l d{a 

L.

(ztxi@ twiiiu .lr.tiniw ad Dhpnv:|. 

0.998' 

y - 0.1258x+0.0153 0.9987 

0.9959 

'ft. Tdvailability ofc.tilizine in all butre ws obw€d to be in th. rug€ of96-10l% by 

sing boih lh€ l€chniqucs, In the sm€ wy phcnylephrin€ w6 9?-loto/o avaitabt. ai ihc cnd 

of cxFri|Mt *trich slowld dlr l[e dn$ did aor ifierfec qi0r .&h otLa. 

lnbdiontuuhof.ahi.iEenhde.rkplrk q W tp.cttupldMtl @t t ITPLC 

HPI,C HPLC ljv HPT,c HPI-c 

94.23 99.38 98.11 98..12 100.54 9j6 93.t6 

It 94.67 100 5l 93.53 

roo.8? 9a_27 94.29 

9388 

9lo 98.24 I00,53 97.49 100.81 

75 93.37 t00.85 98.16 t00.56 t00.79 r00.63 

90 91.45 98.68 94.25 I00.46 93.26 

t20 t(x)_31 

99.51 t0091 9t 8) 98.t0 

I5 I00.76 93.37 98. t6 91.24 

t0 100.42 99 l.] 98.01 I00.63 93.t1 

60 t00.55 98.89 l00.ll I00.91 l(x).87 99.58 93.14 

r0l. t9.97 98.87 10t.47 

I00.15 908 94.26 

l0t tm.63 98.1t 93.03 

t20 100.88 98.73 101.43 99.10 l00.tl 

120

Mdima of montcluksr ar pH 9 s€E 

folrd lo be ai 145, 328 ed 28lm 

espcliwly- Sinuhar@u equdd m 

applicd to q@dt{€ eririzinc &d 

monlelulal h ih. nixrE. The 

16150 I9103.67 294.0952 

awiht'ility ofc.tilizirc 6 foud ro be in (h. Elge of96.9 . Molelutln @ avaihbL 

it lh. Dng. of 90.87-99.437.. However @6t.nr d€cEe in rlE lwitabilirv of mo ehbsr 

M ohw.d which is anributed lo irs brable behavior. 

hrtu6A ts oJariuN vth Mtdut6! 6 W tpectophanty ad HPLC d pH g 

l5 30 15 r20 

93.33 93.21 94.12 91.32 

91.t2 93.93 

97.17 

HPLC 9t l.] 94.t2 91.12 9J 22 92.47 

E C.airi.ir. vitn cpn brporiu 

I Sinultatuous d2temiNtio, olcetuizire in prcserce d ceplvlosryi8 

c€ririzin ha bc.n safelr adhiiilte&d qith @phalosporic [294]. However, r tue insriM 

of @ntrcI-tyF unidia sullinS fion d a.guiFd sdirizrion lo @tbdcpolin @nlDund. 

in . chenist lab M Epod.d t29t. In arcrhr sludy admi.ieririon of c@batothin, 

c@hal*i4 celedrcxil od cefdalih in rEnicillin{tlergic t6tients E ssociated wior a 

si8lifi@l itrcr€4 in the 61e of all€rgic arctioN shc@ adnitrifiadon of afDDzil, 

eturcxin€, e&odoxi@, eneidime ard eftrido@ did nor. on rhis bsis ! tr .d fo. 

simult reoN d.lhod qa f€X which could b. ed irnh.r ro snrdy th. possible a v,ltu 

ut @tioc of @tirizire i! pretue o{ @.dminisrrd 4phrlospori6. Sqml HPLC 

aaho& har hdn Epolt.d for @ph,lospdiB. A hid Fsft liquid chmbatosE hic 

ncthod B deenbcd fo. the ad.lysc of a wid. @gc ofcphalosporin con8.n6, uils only 

th@ Faeots for extnclion ed drug alalFis, Compoud. sn lyzd included @phalcxin, 

e&mandole c.lhdothi[ @fotaxine, ef@li4 €th.loddire, efoxitii! efelor, 

aplt pirin ad efopa@lq Esh anribioli. &mstrated cxette li@ny rhroughoul thc 

)21

Lalence [29?] developed s HPLC techniqud involvinS a radial @mpqsion hodule for 

nesuring chlormphoicol md five cephaloslori. mlibiotics: efotarine. cefelin, 

ccforiin, cephapinn, md efdodol. Sbndard cwes \l@ lina 10 at l6t tOO n8ur. The 

lbsorb&c€ of chiompn€li@l wa nooitoEd ar 254 and 280 M. Ydututu er ,1., [29E] 

4pli.d 

HPLC nethod for ile tLt @iErion of Bidlsl €pbdcporiG i! b.Gf nea. Th. 

'@!ai.s vw ar levels of 78.3 ro 91.6%. A6ync .r al, [299] dev.lop.d e emte 

*6niw &d l@l lime @smin8 RP-HPLC ncrhod for lbe 6:tiD,tion of efpiomc in rh€ 

pr*ic. of €slial ed tae mdal. The d.rfttion linir of c.bimn @ tO ng. nrce 

srudies w@ rcpon€d lo b€ b€n ficial lor deEminine rhe ddg in dEnpedic concod{ion3 

ituid. hlll@ body d w€I 6 ns complexalion wilh n t l calions. Shinde e, a/., I3O0l 

d.v.lo!.d a simple, priF md taDid, RP-HPLC mdnod fo.1he simulranos dermiBtion 

of.ephdexin ed prcbdeid ir t bteis, The minihm d.t€clion linit obrained for borh th. 

dngs Ns 2 F8nLr. 

In this melhod nifedipine !s lsed 6 m inr€nal srardtrd. 

In ord.r to develop a dovel RP-HPLC method for the d€l€mimlior oI elnizire in prcsdce 

of c@hdGporic Eiou mobile phe @mbiEtioru wF tied. For ihe $pdtion, Cl8 

@lum a us€d since th. cn @tdistic rinS s1rucrw ed ioaizble side gbup6 of 

eph.lsporiB tulG r[d id.d edidales for Ev.e pn4 mLC. The lipophitic Mrw of 

c.phal6porins ormd ex@U.or areftior on Gv.M-phe coll|lM porl. 

Prclinindy €xF ineo!3 indicaled lhdr Bing 

dif.am corcsrrariotu of neth{ot and war' ir 

was nol posible to sp&at€ the rEals oa 

ein'zine dd ceph.losporiN or to ohain suillbl. 

rercn$oh md lFal shap€. In orde lo abi€ve 

&celkblc peak shaFs ed perform dc 

ep@ion or a suirable tu rine ed b kep ihc 

n Iho

T!. chrcdatosm obrliftd toB slandad $lurid w idori@l eirh rhx oblliEt tm 

spik d solution cont jninS m .quivalot co.centnlion. Th€ cprcmradv. chematogms 

(ngw 3.22) show.d no olhd pe.Is on fi€ Fteniion rihe of..tirizin€ dd cQhrlospotiB ih. 

eidtion tih6 did m| clang.. A@.dinely, rb. proFsd tulhod @ b. @ili&Ed 

sl€ctiv€. Th€ coGlarion c@fficimls (!blc 3,126) 

detcmined Ior ell the degs denoNtr4r.d .xcell@r 

lintuig in th. tugc of 2-50 ,rghl r. 

y=@856x 66123 

y=11909x+59194 

y=l7l22x+19A92 

y=l392Jr+65711 

kge$im stdinix @1d tNitirit! 

LOa t,oD 

0.211 

00t6 

0.012 

Th. cnsirivity of rh. meinod w.s.valnated (rablc Ll26) by ddmining the LOD md LOQ 

fot dl lhe druSs asyed. The LOD eslisaied s ihe mowi ofdtugs fdjrhing a siglal thra 

r rbe $c noi$ (s^=3/l) and LOQ 6 @cidd.d s tbe low*r @m!iri@ 

lin6 sFt 

a!.lyad widr @.piahL @ufuy md 

pFction (20olo) for all th. ealyes. 

Psision M n4ued in tcm of 

GF.ralility of appliedon {d 

n.!ll@@1. A.cur&t dd pEcision \m 

dct mined six iines per concarra,liod 

(r.blc 3.127). within- ard b.r*qiay 

pEcisior rElre! e giv6 in r.bl€ 3.128. 

%R.cov€nes ed %RSD valEs weE used 

10 .xpB @l@y &d P@ision. stad:rd 

addition and @ovat €xFircnrs wG 

al$.ond@ted !o dehine the accuacy of 

lh. pFst medod for the q@rific*ion of 

cairiziE, cephalqin, efotaxitr dd etoidorc. 

aewet @d paniu of tlf tulod 

0.23 

l2@/, 100.1 

968 

t2tt% 

0.61 

0.ll 

0.21 

LI5 100.! 

0.34 

0.73 100.21 

Mcthod mbwlls! md ruggedncls w@ deremincd by dat,zirS sm€ smple ar mmal 

op€Btitrg @ndilio6 &d also by ch&ging son opd.liDg analtlical conditioff s*h Es 

qv.laglh, oobil. ptas @npositiol! llow '!1e, i.srul@r .nd a!.tr!r IlE Ehrire 

staftiad devi.riotr ir @h ce es foud mr norc rhd 42yo. IrE n.rhod @ fttthd 

0.001 

t23

nbi..r.d to l! r!.llrir i! F@ (r.btc 3.129). Tt b!$od w tudd io be $ir!bt. for 

httcri.dtu ptdtton oftb *th'.l 

II D II lt II a n u 

0.31 0.@ o.a2 t.7 0.93 LlI 

2..13 2.63 0.t t.23 I 0t6 

t5 o21 l1l on 

0.u23 013 1.35 2.O1 0.72 0.79 

25 0.47 0.87 0.87 t13 0.81 0.36 

LbL3.lr9 

100 02 104.37 95.56 95,05 

ll Itu ttlid olennth. eib @pt arrsrt8 

n.42 103.09 94.12 93.31 98.67 

yr_2t 

9t_6t 101.53 

t03.!2 l0lia 10t.25 

C.phdolporii! e . flnily of kmi .y hdh rtibiodo!, sm of rhich htw 3uucrul 

fc.tru .!d4n qnh rlbi.d6 br i!. Nti ddg !&,po,ta, p-Stycoprdtir s.tu ofrh. 

c+[.lo.pori! .dilioti€ .h!! ,tiudrd cbsrinils vil[ .g.d! bom ro oodd.r. in 

!!Ei!8 @l|ii dug cid.@ tL2l 

l'-. otc.nrimre.t dl pg l.Ek wd fouDd io b..r 

2al d q.€pr d pH I which w{ n 262 @. Horlg, 

d.gc of otqlapi"g w ot€6,rd itr dE 23t no 

l.gin 0- ofoaiizie). So it s .t5 dotv.d by 

.pplyinS ilqivdire .p.do@pic t ctliqE Dqirii€ 

r'8trlk cho@ fo. €tirizim lNd etoidoE .t DH I 

rq! 215.2t 3!d 231.3t m. Sioildt |t .t ri. dtd 

pH l.!€b ri8!.k ldcd.d e.! 2a1.85 d 6. eririziE 

.!.1 230.84 m 6r eftit:@ 

:l 

50 

lu

.p.sw ednks oletitiae ad celtidine 

!= 1652r'0.0208 

R' 

0.9942 

'fu % availability of @ddzine in pEsence of celfuidore ws foud lo be in $e mgc 94.I2- 

102.54% by Uv-visiblc lp.clro@py dd 96.87-101.32% by II?LC. The q/dvlilaliliry of 

enridor i! aI thc buft6 ws i! the tuge of 96.36-103.65% lad 93.56-lol.58t6 by UV- 

viliblc .nd HPLC, ctFrirclt. ft ss did.nr hom lle 6drs 6rr m inia&lion @ur.d ai 

sut4 ofcatnzke \|ith.trno|n an W ttec 

PH 9 

HPIC HPI' 

95.1| 

t5 98.21 100.31 I0l.l2 100.5t 9a_D 

99.31 

100.14 100.73 9C.22 98.28 96,25 100.85 1007E 

96.21 100.69 102.54 91.64 96.1\ 

l00.lJ 97.11 96.r8 100.13 

r00.73 t0l.t2 l00.ll t0t.39 

I00.17 94,22 t3.25 

tlt tm.06 tfi.t2 ntl 94.2\ 

t00.It 96.28 98.6' I00.1I r0l 

l5 96.36 102,96 101.69 99.25 

l0 102.98 93.25 98.12 100.14 98,66 

94.58 93.1 101.29 105.37 91.69 

99.61 91.56 I0l.t7 tot.22 I01.58 

tm.0l ro0 29 

tol 2.1 

10t.23 t01.58 98.t5 t02 

I20 100.26 

nD int Ectiotr of@li.i2i* vith efo|axim &picr.d e c&ang6 jn .v.ilalifty elc of rh. 

two dnlgs, Elotl rbe dngs rft avaihblc wirh in d. Mae of 9t. I n 01.72% in a[ ttc bufcnd 

t25

Trbl.3.ll2 

HPLC HPLC HPI' Hptc 

97.tt 91.54 

I5 9t.73 100.09 99.87 

99.E2 lot.63 97.82 r00.76 

45 r00.06 91.63 98.63 97,6t1 

60 9.62 95.71 98.66 9E.t2 

97.n 91,81 t00.tt 

r{,0.56 t00,69 91.6t 100.06 

105 98.48 t00,43 

t20 r0t..]l tol.72 97_l 

r00.46 96.r6 97_46 

I5 96.18 10t,96 91.24 97.81 

JO 97.42 r00.16 ,8.76 98.87 

r00,59 97.18 t01,48 

60 96.12 t00.63 l00.ot 

,8.71 

94,21 93.t9 99.]' 

t05 r00.2 | l0o.o5 99,61 94,71 

120 100,3 r00_16 roo_09 99.42 

T!. Rrlri rt wi@ pH lcEL .r 3?qC indic.rd no ch..gcs i! % .EiLbitili6 oflhe &ss, 

bol[ d.ugs }e avtil&|. lp io 96.02-102.76%, stich sheld tlt c€tiriziF 6 h. !.f.ty 

{udniniilnd *ith c.phalqin. 

T.n|. J.||t 

rtuion telB oldttltie vfi, c. 

gprr HPLC HPI' HPLC 

9,62 t00,81 ro0_, 

t5 91.U t0l.64 9.6 99.6r 

30 96.3' 98.42 t0o.l 

97.11 91.2E t0t.58 

60 t0o.o9 t0lzl 98.3r 

to0.7l 100.63 91,1t 91,E 

l0r.r8 91.54 93.t5 9!.71 

100,9? 97,52 97.42 93.1 

t20 9l.lt 98.t1 9E.45 99.6r 

0 99.36 97.I 91,4E 

l5 91.t9 t00-55 94.52 98.42 

l0 I00.09 91.t1 91,63 

to0.tr 97_21 98.11 98.,1 

t00.25 %.t6 99.78 99r8 

r01.96 r{,0.09 

90 I01.69 tot,12 101.9 

99.21 102,3, 100,t2 

t20 96,02 t02,74 t02.ll 

t26

9 C.dridn. ritn MDDMS 

I SituLtuous.letemiMtion otcetuxire in preprce of NIDDl,lt 

Tl}tph@t16 may prcfmntially ditr@ i.t€ lo*srds a Thl ebBF, which b thowht ro b€ 

involvcd in th. autoimre .spets ofdiabd.r or a In2 subtt!., whjch is thought ro d.dial€ 

aueryic dbeses [3{3]. orc of the sudies 

@nfim.d $. skin ndifesLtions of 

diab€Es n llits to b. a co@on 

@u!r!@ 'lquiring a sios appr@h &d 

Ednar It w Eval€d tbar pEv.L4 of 

diab.l6 Fllitu rclatcd stir disr

I! th. deib.d pc.d!n, sp{rtio of ildieidud 

NIDDMT t!qui!.d oodifi.tlid of th. 

hlf.r/oryeic aolvcd r.lio. Ho*vq, no mahod for siEult.FB d.t@i..lio of edririd 

i! plBdc of NIDDMS w nudi.d ro fr. 

InlI|? p|!s.! vqt..d RP-HPLC mdhod 

for siDull{|ds catitutioo of caidnrc in 

F*@ of mcdmiA sliquidom d|d 

glibcelcni& a dcElopcd. In th 

Fllininry qrdimnrs difrst tr.ri6 of dE 

iiobil. p[e *E t6r.d. h B ob.dcd rhll 

ntio @tukrins of (90:10) mrhdDl: qard 

R.8@bn notbls ct l witb r of tb 

8!E @ sf.rolioE of F.ri b.t96 c.ttti4 dd Dcrftdi!. HG@ o{hd ddo! vw.l$ 

ti.d. TL &:20 su!.d in good symaricd F.lr wiu -api.bL 3?.mi6 .bons dl 

&ugi Hos.lq, dcBioe rhc &mul of hcihlsl fidtd in th. nobil. pt|'!c Bttrd ir 

itsgscd raqnio dDc for sliguidorc. H.ncc, r*o conpolrcd FobiL pha w chos.n for 

tE 3ndy. t w'! .le ob.dvcd d .djusi.s 0F pH of mbib plw ro 2.E Bltr.d i! 

oltr@d {.ltlc paL ryt|Way and 

!6oluti@ for ltl tb. .!s.ycd druss. Th. 

r.cn{on liB for mdomill cctirizi@, 

slibqFlui& ed gliqlidoc wc 

foud b b. 2.5, l,t, 5,5 rrd t2 niNt 3" 

n$.ctislr. ln lhk retlod diclolqE 

3odtue q,!! r!.d a e inrdnrl lrllddd 

cluliog ord .r 7.5 rninqt6. Th. 

..libr$ion crw6 for .ll dE dn$ wE 

@6h&Ld ud.r o?dhu @nditi@ 

&d dF li|Eiry of d! mthod w6 

erBt d by Frfo.niq injetiom.l 

toa toD 

o.2r3 

0,95 0.t69 o.26 

0.01 0,(x)3 

0.393 0.|l7 

r|lLJ,Dj 

%RSD 

o.12 91,88 

0,56 t0l_22 

o.52 91,3t 

807. 0.3 to2.1J 

l00tt 0.16 106.1 

t20x 0.tl 10t,78 

wl 0J,l 102.36 

t@'4 0,6 l0t.8t 

0.65 t0t.7'l 

80tr o.52 t0t.t8 

l00ra 0_J6 9,94 

t20rl l00.l,a 

*q difr@nt con @lEtid l*b in thc lind mgc ov.r 2 diffctqr d.rs. Ttu D.d( !n$ 

of dl th. doa3 wa plo!.d lgrinsr lh. @FsFodi!8 lmiol @nc.oL|ri@ io obr.in 

cdibdrion gtlph. Th. @blion @mci@ls oad tt sitivity of dl dE ddSs v4 

e!r.bli!h.d od e p@ncd h l!U. 3. | 14, Th. FgBid .qurriou obtdrEd for ncdmit! 

elniziE, slib@cbni& md sliqddo@ lw y-E0609(+38188, r=332E9x-t tEt6, 

F58303x-12E27 ald r {390x+51842, Fg.crisly. Thc sitivhy of lk &.t}ri.!t 

t2E

nethod wa.v.lu&d by.letemiline thc limir! of dete.lion ard q@tiLtion. nF signalro 

@ie nti6 of I rl ard l0: I Ec lato 6 LOD ed LOQ EsP€ctircly- Th. Fpcsulrire 

%RSD %RSD 

II t2 II tz l t2 II t2 

2.25 05t It3 t7t 

25 035 0. t6 0.3 0.1I 

20 0.32 0ll 0.71 0.56 

t5 l. t2 0.13 0.91 |.87 

5 0.599 022 0.t2 0.t5 

2.5 0.3? 0.87 

cbmd,roSe i! ihou b 8gw 1.24 showing th. speificity of1h. m.dod. No Gndog.@u 

@mpon€ i intdf.n.8 wilh alalttes ed rhe inr.mrl siardards wrc foud i. rhe 

chrcmtoslams oblained. Prccision dd a@dey were 6*sed in @nju.tion wi$ the 

liEeit !tudid uils thre sliked shplca at €a.h of thre @M ratios (E, l0 and 12 

!srnln). PFlion ws asss€d in t ds of%RSD. Accu!.y *s d.L@itFd li@ th. bis 

R@vqy tclr in fmul.lioG -@ pe.fmcd by $c drlda.d additioo d.thod .r six difeMr 

@lmtaio6 for delfomiq c.lirizift. glib.nclmide ar(l gliquidonc, In dl c!s, dE 

@overy P€tcn!A8. values raged b€tw€m 92.01 6d lu954% with el.live slandard 

deviation

23 m t0 l5 5 

t01., 97.58 lfi 55 

9t.38 1o2.35 

t01.36 105.33 t03 56 

98.22 t03.54 t06.98 t0? 33 93,5 

+t.d lauo io dE f..d p..l !A f|ths of .quivrleot ,4l|de iaitrrd &tuti$. 

Speciioity in lBlirid lo.ndog@u cmpomnr! w$ d.rcrlrdt d by aEblis of i sia of 

tutlonJt 3d.d.d ddg-&* @|n mpt.| (rrbtc 3. | 38). 

B. bnereli@ stubes of @tirt.te tn Ws@ INDDMS 

Th. rcdble gly@pFtdn PGI innibir.d iiriin rccdor tyui@ tile .id pt y.d . ole 

.. L.d io p..t in l[. iulin .sii.rd. of NIDDM. Alrhough ir. .n l pnyiiotoeiol mte 

llMitturho*q imd.'r in 8ly@prddn rc-l ir aqir8 nlidly' b@E of it3 Dodibl. ti.j( 

si|[ lt Fthog@ir of di.t'..6 .rl olg. P@iM nootr. @at d lh bdt|@ 

glycoprddtr I€-l ldiviry *i..ldra.d in qdn!.d ftrott dt too NIDDM D.ri.d! qitb 

i&lin Gn!.@ t3ro, trr} 

At tII I th. '4i@ of E rftrDh w 

hrldto be.r 205 m &d r. pH 4, ?.4 ai 

9 $. n'nni of bcthmir s rlco8t d b 

be d ,3 m. Fd ridlhElt 

dcamifttim of .dnizin. rd @rfmii 

ddivatic !q.d.o!co9ic t cl'liqE v.! 

ptl I pg1 

appli.d by *l€ding 212.88 m for odirizirc 

ed 219.34 M for m.tbmin. Ito*€vd d 

pr I dr*lcrcdurctaglhw2%02m forc.&izim.d2ta99mfor'ft.foE n 

- 

l -/-- J\ ---t\'!-i': 

pll1.4 pH9 

rIa.E Lrt DciEliE rp..iE d dntiE dit 

130

.@tt iaitat d r.thzn. ai N 

pH7.4 

Ih* inrdr.rion 3tudid show€d tu i qacrio bd*@ D€trmin ,!d ciririrc ar &y pH 

ldels. Ir'e dv.ilabiliy of cdnizin. rt rll pH lcvcls 6ged bet$an 97.17100.98%. 

Sinildly th. % w.ilabili9 of mefomin tug.d bctwEn 97,1+101,59y., Th€$ resuhs 

indic.t d rhat th. availability of.eridtne is uitrar.d in Desoe of nerfomin. 

Trbl.3.133 

I'x@io, witt of etntire wxh NfMk on w qtuphdoret, aha 

pH9 

HPI.C HPT,c HPTC HPTC 

0 IU).93 

I5 93..I1 I00.36 9_t7 94.f9 

l0 98.26 100.69 9851 98.81 99.19 

t00.81 93.39 

93.t4 99.14 

15 98.89 r00.87 93.53 9'l3 

Ll0 98.38 93.63 97.52 

105 98 75 99.63 9E18 97.t7 

t20 91.21 t00.75 93.11 9E.19 

98 29 

EPLC 

91,24 99.31 

98.16 99.63 

60 100.23 100.78 100.76 99,t2 98.73 

100.4J 100,J8 96_U I00.43 100.72 

100.37 93.06 97.24 I00.45 98,57 

lmil 93,|l 9'.3t 

l3l

fi. l4itu of gliquido* d pH 9 a obsEd ro b. d 

225 m .ad 2l8 m Afta rtplying ffin odd dqitltirc 

th. lfuiru oldl€d for cai.idn. dd gliquidm (fullft 

3-26) 1@ 210.01 i.d 230.9 .b, r.!p.di!dt Th. 

r.gcaid rnbi6 .la llPlyhg ddivni€ r..hiq6 

@ dDM in nbL 3,138. Tb. id6.dioi 3bdy of 

gliquidonc with c.tnizin w @i.d on & pll 9. No 

ftE3.x: D6il|liF E eor 

.6.rg6 in Tt uiLbility of dr d.rgr s! obFad i' prq.c or *h olta (t bL 

Lll9). Ita % MiLbility ofo.ridrin *.. b@d to b. i! tlE ds. of 97.51-1m.98./a 

'nnc 

v. $ril.bilhy ofSlhuid@ irs found lo b. b l[. tu8! of9E.0l-100.EE r'o. 

uI@ tundq of*d,ttE dn t 

dt9 

!H9 

tu an@ wnt oIdlruEvii 

I5 15 lm 

93J? 100 65 100.98 99.42 t00.42 

HPI' 9t.88 98.t6 93.32 t@.42 l00.al 9E.{l 

94 53 9.t5 94.74 98.03 

HPT' lo0.(' 93 55 1m.6, to0.,r 

TIp $lorption maiM of glib@ldid. w$ otdred 10 

b t 22a n wnich a ovalrppiiS lt. .p..16 of 

ritiri?ie lttr E lb |qs rld daitdiE tttuioa I 

u!.d ro sl€ rh. ddt p9in8 !F.1a b3,2s n 2219.52 

m wft sl6Ld 8). c.tirizir. &d slibtuluid. a 

tlaE 3|? : Dqn/riw s.6 

.!drri6l dt!.h of fnt &.ivdiB. Th. .@t of 

Slitdldid. d !H 9 3h',!d th drug' did tr.r iddfcld 

vitl @t otlE !.d w@ .dLble in rh.6ngc of 97 5&100,85%. Th.'/dwl.lility of 

c€drizb. wa rvlilrbl. in lh. fi€. &gaalloDA3%.

sitD tdi\iB olaiziE @d qlib.rct 

T.bt 3.l,|o 

Lttukn B,/B of et 12itu vith stibmt^rle u w spdnophdomtry ad EpLc 

o l5 15 105 t20 

tm.9l 93.61 t00.08 98.51 .1t 9aAl 100.73 

HPI-C lm_41 t00.oo 99,61 9t.88 99,31 

93.32 99.4t 97.58 9.92 100.72 99.6t 

93.63 93.14 98,19 100.78 100,7r 100.35 

InLEctiDr of .diii!i. q t *qti.l .|.ndii 

W- in . W.ctrophotod.lr! 

Mci.Uic salts e involved in F.foming vdoc nndion3 

dninjsr.r.d, 6 w[ .long with diffdent food drinl$ 

or a drugs. Then d.ffci.ncy or .xc6 @t l.!d to 

vdiou disluba@s itr Ihc body and D6r of the 

m.tals @ inyolv..l in @ting wioN kindr of 

all€rgic readioN [312-3151. A h4othsir @ 

led{y pul foNBrd ttal diffurion of pbsm 

hirtrnic i.lo tlE dvit|mdrl rissB, in e,ldch lhc 

m.diaior b €labolizd. nighl oro pssivety in thc 

fod of zinchisidin€{ysteimle @mpLx. It 

in body. They e o6Uy 

% ,lwdan iD o[caiEw d 37C 

0 52.2 

l5 9t.2 89.4 365 

97.0 54.1 93.1 

95.2 a7_2 53.4 10t.7 

9l_0 t02.1 

33.7 1l.2 r05.1 

accordoc. wirh ftb hypoitEsis, dy padn r ligaod 

for zi@ ad hisLnirc in $,lrich nisiig pLsa 

@Mneltior Nuld .ntail . bend mbilialion of bist'oiF into @ral dimtsiblc ftl'l 

onpLxq wdd al$ favor thc hisldjnc 6r.bolisF. Metal io6 phy a vilal rele duing rhc 

biological pM$ of drug utiliaiid in de body, In rhe trE tn€nl of emi4 iron is oElly 

adminbl@d 'tile zirc, copptr ed tulee de peqt in nullivir.min mixtws, 

t316Jrtl. Hower, in on of rhe studis etnizin. B inre@r.d *irh d.l!b in preec. of 

diclofc@ $diu od n a @lcluded lbll only dicloferc sodiu h.d lh. alilit, for ncial 

t03.4 

I05 93.5 9l.l 9.1.8 101,1 

I20 94.7 t09.2

inding. Cctirizire sinply dbpl.c.d the net l ions ad its Cl- ion neuraliad ilE positive 

c.rt . of $. rclal iNolv.d. MoHE, n m ale @&l!d.d thar d@ to dr. pl€ge ot 

eith€r lwo or tlue moleuLs of diclof€E sdiu, stdic hndme efrcts Dmhibil€d ihe 

inter&1ion of nor tho ooe etnizjn€ molccule [3r8]. So ir b€cde appMr io inleret 

etiizine with individual n€llls in ords 10 krow ih€ deg@ of.omplexation. nr€ objet of 

pretrr puL *a ro obanc lle lNibl. ctr@t! of mg.6iM, calcid. chFniub, 

nanedeF, ircn, 6bal! nickel, cupFr, zinc dd cadn'm on ltE ,tvir, .v.ilabiliry of 

celirizine alooe ed h lheir pr*M sd d€t mimlion of rh.ir @nplq6 by RP-HPLC. 

Metal mnpl.x6 of c.tilizim e of grc.l importae for udeBtandins drug-metal 

inreadiotr and for th.n F|.nrial pb.m@logicrl E. L y ro El€s of c.tirizim aloE 

(iable 3.141) sd i! pse@ of meral i@ .$oiisl ro hul@ body like nrgn.sim. .alciu, 

chrcmim, neSese,Idic, fenou, cobalt, nick€I, apper, nnc &d cadhim studies Bins 

BP 2007 disolulion t61 aprenB weE srrdj.d in dpty sto@h pH, n $oo&h pH, blood 

pH dd iri.sliul pH al37C, It m okwed thsl avlilabilig ofcdnizire a unafi€drd in 

pEs@ ofall th. neials erd cedrizi!. did nor bind silh dy ofthc studi€d hel'l!. 

N EPLC 

validal€d @thod

i : 

B 

t 

b 

! 

F 

.E 

E E 4 3 

E 

I 

E 

3 

€ 

a 

n g S 

a 

.€ a F 

a 

n 

a B 

a 

b 3s 

E 

t 

E 

\ 

E 

E 

E 

E 

E 

E 

E 

3 

s 

E 

F 

F 

i a 

a 

a 

F 

t E 

e 

E e a 

a 

E 

d s 

a 

F I 

i

i 

t s 

.! 

€ 

! 

a 

3 

.E 

E 

E 

E 

E 

F 

g E 

E 3 e $ I 

a 

R 

I 

a 

: 

e 

s 

a 

R 

I 

F x Ei 

a 

a 

E 

b 

i 

.3 

I 

t 

I 

s 

E 

E 

a 

s 

e 

j It 

E

E Sydh6l! oldrugirg oupL!6 

Ir ha b€n di$us.d in *rio! C (2 &d 8) drar eftiziG inr€tuled *ilh NSAID'S dd 

nnvaiatin Bulling chdges in % availabililies of dn8s. Hoe e attempi hd b€en h6d€ lo 

synihaiz€ the conpl€x.s of ini@tiDg dru8s in pEs@ of @tirizine. ItE* .onplexes 

9@ synth$iz.d in meth4ol for rte hoN .rd th.n GrFralliud, Tb. synlhAiz.d 

cmplqs *E ch,rut{ized by {ren physi.rl p.@.&F s sll s by thc techniqes of IR 

dd NMR. 

The Nigmats of lR ba|ds \N* md. by @Dpdine d. 3Fctn of rhe p@ d$g ed 

ini@ijng sFcics Mlh lhe @Dplq6, mjor aberptior bdds for the innzred ftcquenci.s 

dd ihe @mponding asigmdll e diicus.d. 

In rcpon€d speti or e&izir, OH s[n hing nbde of wr.r.nd oH dimd of 0!. mine 

@hoxylic eid @ ob*ryeif al 1417.6 &d 262a.8 2354.9 cb-r. Gtetively. B@d bdd 

obsred al (3110 3000 cm r) md 2985.6 2914,2 cn ' is 6sign.d io Oe eoaric CH dd 

.liphlric CHr 8tuup, EsFcrircly. Tlte qu,t duiy nirogen atom srelch obsded al -30?0 

cn-' dd a vlry slak t6!d at 2216.1 d I b sigD€d to hytlrochlodde. The OH diF. is 

shou b bc ! nono-$bsrituti@ to a C&crlOCHr by th. ?58 or. Sbiffs rr 84F808.1 

.n ' showed the peme of tso sdj@i boa. rir8s. TIF cdboxylic C-O bond frcquncy 

]6 obwed ar 1456.2- 1319,2 ed 1214.9-1242.1 n1 , bdo8.n substitulion ( l?39.? cn ') 

appe6 s a ho@-$bstnrdon d | 078- I 6 ' ir rh. p@Gposition wilh ! rirS sr,lrch bcrren 

1650-14q.? cm-t teqE&y tuBe. Aliphalic chrjn C-O bond in CHTCHTOCHTCOOH 

app@ ar r 186.1 and ar 740 cnr I!r9, ?61. 

DLloleM 3Fc!u showed dE NH ffihins band al l2?6.8cmr ud NH,,,O bad or 

inta'noladd hydng.n bodhg .1 3421.5 @-r [r2o]. s€v.dl splir boG lilm 1604.? ro 

1388-7cm' e si$ed to the slb.liruied ph.nyl grcup6. Brnds at 1454.2 ed 869.8 

621cn ' 

indicaied a dihalogeMtcd substituted bemne ring ed ittr€e adj@nt hydbga 

6toms. Al 1604.? mi band b sigled to d ofrro-disuh6{ilution, .1 1234-Ll20l.6 @r and 

682.916.6.m-r is shou 1.2+ulsinnid ir thc s@!d.ing. TIE o.lbnyl sdup arFa6 

bdwtr l8OO lrd l95O cn I s a ee!} ahaorbe@ dd again s th. neurraliad .ntiiy of $e 

wboxylic acid in rhe @s6 l610-1554.s ed t 409.9-1292 .mr [3r9 ]- 

tJ7

The !R spccta ol nubiprofd showed chucr.dstic brcad p€a& h the nnec 2500 10 3500 

cn ' dE to hydmsa bordils. The p€I! .l 1698 ald 290 cm-' vft d@ b orbonyt ed 

hytltoxyl sf achils, espelilely [32r]. 

Mebnc@ show.d chdictciislic psks at t 620 cn-r (C.O strcrchine), 3292 cnr (econdary 

-NH or -OH) dnd sne ploni&nr b.!ds su.h s 84656? d-r (.cH emlric rins bading 

dd [.1soNm.d6) and 1346 io I 163 cb:' G=O 3rachirg) [32t]. 

Mcf@mi. &id shos€d Fdls ar 3300 cmr (N-H srdch). 1647 cn ' (C=O sEetch), t 572 cn 

| (N-H b€nding), l5O4 cmi (c{ sterh),757 cm | (e@dc str.!ch) [32!]. 

IR s!€trn of ibl4bfd @ntritu a stoog sbslptid bond at t7O8 di dE to erboxyl 

Creup dd thc btds @ntstodiDg 1o vibdtioN of the NEtrc ring &d dF i$bntyl 

ftagne s(1608,1512, r044, ed 1020 mj) t3241. 

Sin6lriD show€d petl ^r 3546 d4 1422 @'r of &c ed eiated O-H slretch, 

Fsp.criwly. It sbowd p6k .l l0l I d_' of otcnnic C-H irctch. 'Ihe Ffs ob@ed ar 

2969.2929,2811 ard 1459 .D r wft d@ ro Ihe psoe of mcihyl C-H 6)1Mclric od 

slmetric afttch. Simwlarin showed checr.rishc p€aks at 1261 dtd 1225 ch't iue ro 

prsce of lrcrole C.OC aGl.h The p.its d lTOl dd I 106 ch' we egn d b eG 

C{ and 6td C.O-C stErch, Bpdrirely- Th. F k ar l3E9 .!d 1369 cm'' E signed ro 

ihep6en@ of gm{im€thyl C-H st€tchard .r 1056. 870 &d5?0cD' wft of $@rdary 

slcohol, tri substituted oLfinic C-H ed cis olelinic C-E sr.etch$, rerpecdvely F251. 

In the infFrcd sp@t|u of lh. c@pl.x foded bet*q cdnizift ed dicloforc 

sodiu, th! Ng di@ of mim &id Aon 2?0G2.100 m-r diepFaEd ed dF qutorty 

nitrogs alom siretching 3hin.d froh 30?0 to 3040 cnI, Simildly ihe mmtic CH and 

aliphati. CHr lbsrltion ban& shin d Aom 3l10-3000 ad 2985.6 2914.2 |o1165 j024 

tld 2v25.11-2847.61 d-1 Bpetir€ly. NH rftr.bin8 bdd snd de carboiyl gour iD 

diclof@ shii.d Aob 3276,8 ard l8OG.l95O co:r ro 3320.1 rid at 1315.32-1147 ,19 ffi-t . 

A nodifi€d b&d appad.t l63E.l4 mj stich bdiated n ur.siiati@ of itE {boxylic 

Stoup i.to a carbolyl gFup, Th. &bendinS c&bonyl nodc shincd fton 1421,57-1200.91 

cDj b 1409.31-123?.68 mi, Fon lbe aborc 6&s, n !s bd @clurled rls! kak 

chrg€ E&sfd i erE rion qtE bcl9@ 6e doubly charged pipc@im noiery in eiinzine 

dd diclofdrc, Cetirizine er a @ elst on ac€ptor [319], C.tirizinenubiprofcn comtlex 

sho*.d th.t lhc quat€nsry nntu8.n aioE streichng sbii€d fron 3O7O 10 3O4l cm-'. Th€ NH 

diffi of mino aid non 270G2,100 m- ap!.ir€d a . xik sig.al with cFd ro 

138

cciirizine, Ch&&lensd€ broad p.alc in lhe rege of 2500-3500 ed 2920 cm' due io 

hydrcgen bonding dd hydroxyl slr.lchiq diepFed whfta cdrtonyl peal shined lion 

| 698 lo 1654 cn-' wit! diminbhcd inlensity. 

Conplex fomed betw@n cdirizile dd ncloxicd shosed quar€mary liitogd atom 

stFlching at 3070 cm I md NH dintu of Mino eid in rh. r€gion of 2700-2400 cb_l 

coDplelely di$ppc&rd with EslEt ro dntiDa Cb@Ldnic F.rs ofmdoxi@ d 1620 

dd 3292 m-r foi C{ ed s@lda.y ,NH or -OH strsrchirg disllFir€d whil., otho ers 

In tlE conplex of mefe@ic &id NH dind of uilo &id ed lhe quateddy niEosetr atom 

sftLhitrg nom 270G2400 m-' and 3070 ro 3040 d ' dieppdr€d. ShininA of somc 

meswd peek werc obsNcd wilh r€sp.d ro m€feMic acid, p€.Is of neutnliad 

.ntiiy oI0!e wboxylic acid shiftcd liom 16l0-1554.5ed 1409.9-1292.2 cn-rlo 1654-158t 

IR 3pefu of elnizirc-ibuFof@ prcved th|t th. quar.nary litroga arom stFtching ard 

NH diner of mino rcid f@m 2?00-2400 cnir md 3070J040 cm I conpleicly dhappearcd. 

Srong absorption beds drc lo wboxyl grcu! shii€d fion l70E !o 1768.90 cn r, 

IR sFn.rdn of eti.izine*imlardid @mpl.x pmv€d that rhe qurtury ntuogd atom 

$elchiry nd NH dimr of mi@ &id at -30?O cE ' ed 270G2400 cn I rclF€rively, 

dhdppedd sill] Espar to @tirizin€- Ch{erqblic Fab of l&1ore C-O-C arr.tching of 

3iFvasladn shincd froo 1267 srd 1225 qr ro l24l cn'. Sihil&ly fiftire of 6r€r C=O 

ard csrcr {4C sterchins toil Tot ad | 166 chr !o 1728 6d I135 mr !p?.dtd. orhq 

s4! of siCnals we sme. 

'It. rU NMR sFcoa of eririzine @.6ned th. abov€ Gulls. The srgrrh of c€tnizine 

sholEd a singl.i ai d 2,8 dd at 4,09 ppn deliSraddg tsr poto6 for lhe CH, attached ro N 

iD the NCHTCH,O grelp ed t$! polo6 of the CH, adjeelt ro lhe ceboxylic acid, 

$perivel, Th. Dirog.n prclon in pipepjn w6 obtrn€d .t , 121 3.47 ppd. A rripLl 

B ob6n€d a1 d 3.65 3.86 pPn for i& pdro6 i! 6e CH, nd ilE O in CHrCIlrO. ItE 

pdlon oflhe CH in lhe n€thyl diphdyl ercup showed a bro.d si.gld ol d 4.6 ppm. fte 

nultiplel ar d ?.1 ?.6 ppD @ drc to nile prctoB of the enatic.i!es ard.t d 10,8 ppd a 

el bbad singl.t 6 shoM for @ pDton of ih. e|boxylic eid IroW. 

l]9

The deshi€ldin! efl*t ws .x.ned in @npl.xes on l!€ somalic NH pmior via inrdnolsula 

chrge n4Gr euing lhe @M@ ro b€ do$rft€td shifled to d ?.6 ppn. nN, 

lhis prelon app€tEd in the troad nullipl€r b.$@ , 6.27 &rd 7.56 ppn shoving sixreq 

aomdt CH pDloN dd thc t$b Ntf pnlons. A singlel qs ob&ned ar d 3.3 ppm for 

nethyl diphenyl CH proion, Triple! al ,3.7t ppm ws obviou dE to fou prctoos on rhe 

&yclic CH, Sbups adj&ot to NH- in $e piF@ire riDe md at , 3.16 DpD @ obsdcd for 

the grclps .dja.enr to lhe nftogd hydebbnde dnfty. A dou-fietd ob$n€d for acyctic 

oliphalic CH, in NII'CHTCHTO from d 2.8 ro 3.4 ppn d irs proror w6 ir ihe plee of lh€ 

cdbonyl grcup. Anothd singlei .t d 3.61 ppn with tM prctons w6 shoM for iie CE, in 

CH,CHIO.ntily, The CE? in th€ CHTCOOH gdu! a9peFd s ! siDgLt,l.7t ppn. A very 

aEt singlcr B Dltgt ar d 10.8 ppd for ri. oF pmroD of th. o.tFxylic eid grcup In 

sp€ct? of ncfcn4ic scid coDplq, dosrfi.ld lhifr w obsacd lor emaric pbro6. 

Tnpbts at d 3.16 ed l.5l pph obswed for proioB on the &yclic CH, g@ups adj&enl ro 

NIf ir the pipc@ire ring. Singl€r .l d 10.8 pln ws presr for one pbron of lhe cdboxylic 

&id greup. Simild 6u! *s obs.ird tur @dn?inc,flurbiprof.n 6rplq ir, singlel of 

@boxylic gtuup pbton mincd ai, lo.E mn &d domfield shin obered for Nmatic 

poio6. nF piotoN of pip@in w@ obs€n.

7ll \< a "e 

722 

7t2 

70E 

710 

?ll 

ftnbl.l43 

Posibl shat@ ad clsetqianifu ol@wba 

n";A-* Fral 

n 

0,.-s_4-*e,e"{-, 

'}rti*-* 

2t0"c 

?25"C 

siclttly I t2"C

F Synrb6ir of d..lr.tivs ol.dirlrim 

In !l6t y6 l€s€ah wrt ha ben cei.d oul for $e strtheis of potent @Dpouds 

vhich codd b€ uwd to tFat all€rei. ed innmmtory di$ideB sinultlmuly [3t6, 32?], 

t M! .t a/, Il2El lnrcd tu lisllnire Hr@pror er.gdi$ cdntine to No{el6ing 

spe* ercups, 'ft. Hrbinding $lffolds of@titizirc, eflednzine, erl lodr.dine werc linted 

to a lilbpbilic N-hydroxyE4 th! 5-LO inhibitils noiay of ziLuton [329]- Nubs of 

ddiEtiw of .ltnizie wE pFpsrd io lMif6l llc dli-irtldmlo.y !.tiviry of c*nizire. 

Duc 10 laat of Gaili1i6, etihistaminic activity of cetirizin€ could dot b€ esbblhhed. Ibe 

@mpou& elel.d D lhis ce vw cbos oD tb€ bsis of lh€n dtiiofldabry elivities 

such 4 thiolM t3301, @taeide [331], phdyLnqdiui* [$2], n phthyltoin. [3$]. 

Th€ re&tion n€chmis for ihe fomalion of etrizirc ddivatives poc..ded via ait .t by lh. 

loft p6is peol d niEogo of thiour.a $i@.tdi&. phcylenedi@in , MPhthyldie 

ed pthaldidc, njtogcn @ts s . nEl@phjl. ed aneks rhe catboxyl wbon of the acid 

vhich lads to th! fmtion of e akonde ioi Gi.! 1). A3 a o$dl@M, a poto! 's losl 

8!b d NH: g6up (step 2). An nslurld d6!u pan on th. altqid. oxygd ion moB in 

to h.lp disple. dr l.lving gbup Gtep 3). th. r4tion follows th. NU'l .lclophillic 

G_-,O *t'r:i 

:{ -6 i- 'i' ,f*- 

(--"-_,-t n . _ 

.9.\'/- 

-2!H'R 

L'r :dF 

-,,"---::s, 

->-q-/& 

I 

-t? 

.Fp 

-'c(:r 

cdH 

\_"-ifi* 

t-"..-.H",. i_"_ -il 

i, 

7r. R{rfl'N(nrt6yr.n d!hi*) 72J R-qHls CIr @id.) 

719 R=clHrNcpbdlldodilmh.) 7A R-CsrNsaftiourc.) 

12 r R{r}t No:(phrt.linido 727 R=€d4(Drpbu'ybnin ) 

,f 

t42

Thjs D.lhod.!lov!d Uc idrodudid of . v&i.ty of subslir@r! sEh a c-naptbyldift, m' 

phm.Lndimin , p-phoelddimirc, lhio@s, thioacetadi.lc ad phth.lini& into tle core 

sirucrw ofeiirizin.,.t carbo*ylic ercup, in ! quick and simpL way, Funn r oor, n 3l3o 

.lloq.d 6e sFlh*is with s hieh y.[d foanmbd ofedoS!* in thc sFt m. 

Chs..rdhati

M6iqn dat updQn47U 

'y1 .^"-"-r" * 

\.- a l.n_., -,-"*:r I 

@ .-"""_____"-* [a._ a*] 

|"ry:l---{"rl

Trbl.l.l44 

?hrsical ahd spe.E^copic .lata ofcompothd 7 t4 

N{4-miroph.nyl}2{2{4{(44hlorcptdyDonenylFcthyl)pipquinr 

1742\ 

o 

'0-'"x 

.173.(2.?D, 388,1(4.06), 301,(3.01), 2tl4.l(5.22) 201,0(100 0) 

T$le 3.145 

Physical and tp.cnMopi. dato oJ conpound 719 

N-(4trinorhoyl!2-{2{4{(4{hldoDh.nylxplsyl)tn.lhylhipdzin-l 

47421 

aN--.vcr,-c-NH 

N-2 -/, 

478,1(2 ?tr, l'&l(1.06), ]01.\l.olr, 244 l(5.12).201.0(100 0l 

c=O ofdidd appe.ed in lLe tum ofi e8ificd pat al I?Il69m_'i.c. itte dymclrical 

3trrching whilc 6'1mehcd esler stRhing appercd al l5o7cm lh. mturic chtur 

is Dw! moE ptunidr !t 3182.75c6i qbilc N.C apFaed s! l273cm' md lh@ *s no 

!..1 tur c{toxylic s@p. 

Th€ Eoction iite is dboxylic grcup ofcctlizim s in NMR sPecl&m ofcoFpoud 721 th€e 

B rc p€al at lo.8ppm ald .dditiord fou pdoa of pbth.linid. noi.ty.ptor.d b trc 

fom of muttiplcr al ?.83-?.86 ppb wfil€ mbatic Folou of eftizinc noieiy opp.d€d at 

t45

7,21-7.7 ppm, Pre1on for th€ CII, sft&hed io N h NCH,CH2O goup app€@d al 1.54 and 

3.4 ppn, tLc pblon ofpipeFiG !i!g app€e.d .i 2.50!'pm. 

Mas fasm,tdtid patted oJ72 ! 

c "'^ o 

oô o^c--rr 

! 

_.!-.--\ 

r-- r'Y"\,-\, 

\,i\-2 " 

T|bL 3.la6 

Pttsiql ond tp.cttMopic eb ofanpoud 121 

2-(2-(2-(4-benzhydrylpip@in-l 

143.22 

25r(r 22), r68.09\r2 t9),92.06(19.19) 

_yl).thoxv)a@lvl)isoindoline_ I 

Tlr F6de of Fsk al 3350 &d l300otrt iddic$.d i!. Pt..4. of Fhtrv dim *nich 

lFongly @nfm.d th€ stret@3 of @bFuad 4d ole .vi&M M the shiiing of C=O 

p.ats lov:rd the lower 8eqrcNy i... ar l6oocm r. Asmalic grcup ahsorh€d at 3l50cd ' with 

ituifed fom .!d dplEtic cb,@rq @Fe!d d 2850co r' 

146

Si.elel of NHt apptud at 2.49 ppm, {ni|. signrl for s@dsry @ir6 ,pFed ai 6.3ppn. 

'fte Foto! of piFmzie risg .ppcrEd !l 1,83 .!d .t 4.67 ppD. A rripLt obsd ar 3.?4, 

3,?9 ppn for tB! FotoE in th. CH, ar rh! O ir CHTCHTO. ]h. prc1on of CH in lhe 

nelhyldiph.nyl group is shoM by ! broad but vslt singlet at 5.6ppb. nF enaiic nine 

proloB app@d ai 7.14-7.32 ppn whil€ tb€rc b lot sileL 1 at 610.8ppm fd th. .aboxylic 

&id goup thd coDnriEd the 3it of@ctioo. 

M6t ltustu,ttdtio, pdtEm oJ 72J 

C-JY\-* 

r -- r'r 

!-_\ r-\ 

-n4.- 

) 

r'n--r 

T.bL!.147 

Physical or.l specn@copic data olco pornd 723 

,v{3{2{+bcnrhydylpip.@i& l-ylFlhoxy)-2{xopopylFthddhrmi 

l17C 

25r(' rl, r6809(r.0t, ?3.0J(9 86) 

The FoIs at 3358 ed 3lO?,25 mj dE to slrctchinS of NH: we ob6.sed which b slrong 

indicadd of a c@pl.x G thi F* is a!.dt in U. plr€nr obpound. The Nmric ch@le. 

r47

k meh Fonin !t at 3145.9? di , dipbdic chlin is obedcd at 2913 @r .nd C=O bond 

ot6.(!d ar 159?-28 mn. Th. €k ab$btion fo. es obs€d al2030 d'' v6 drc ro 

h.aw weidt of sulphu grup. C=O stdching w obeped at loM fr€quency a conpcd 

to p.Mt &!g i... ar 1597,28 m''. 

Sinelct of^'tl, apFared .t 2,49 ppm, etile signrl for s@nddy dircs sppened !t 6.3ppm. 

Th. ptoton of pipeEin. nng app€.red d 3-83 and at 467 ppn. A t ipld obs.d€d at 3.84l.9t 

ppo for t$o preront ir dE Cft M dt O i! cH2CtUO. Th. Foron of cH thc 

ncinyldilh.nyl grup is shoM by ! broad bul *$l singl.t *tnch app.!r.d al5 4lPpn. Th€ 

ehad. Dift protos appqlld at 7.147.32 ppi while O.F is m sinelci at 6l0jppm for 

th. cdboxylic eid eroup llrl c@68.d th! sa of @dio! 

Ma ttugtuntation spectw ofTU 

G^CT 

TrbL 3JlE 

P|r*tcal and spectscopic daa olconPound n4 

l.(2{2{+b.n2hrdrrlpiFEin- | -yl/.lhoxyF@tyllhio@ 

412.5t 

lTfc 

l9?.r 3(1.36, 133.2(6.32), 2tr.r5(16.21). 

148

Boad budi ot6ad, 3l lO-3000 .!d 29E5,6-2914.2 d-' e sigtEd to ih. @tic 

CH ald alip[rlic CtL sro,4, r!.p.cliEly. Th! C{ of mid6 4percd i! tlF fm of 

inleEifi.d bed at 1620 cn' whil€ emltio lb$rb€d .t 3l5O wilh ircNided fofr &d 

alphalic ch.@t* app{€d at 2E50, 

'IrE tH NMR sF.r6 of @Dto@d 727 w .@Fr€d *ith lhe speftn of lhe fiF drug. 

Pip€@ine, chlob beMre ed Nrrtic Foton! lhowd no dl4t, a singlct @curcd !t 6 8.0 

pPm Epca.nlilg ih. Pl.@ of ffii& goup. 

M6s Jragneitation pattfl of 727 

a]r 

Y r.".N, \--' 

Emrs ninnnbdiN .elalatiM oldtMtvt 

B.E. 

.1.9106 t4 2425 2_7159 

7t9 29.95 J.9516 21202 

121 65.1523 20,t l6a 

21.3498 4.3015 0.7113 2.5182 

124 21.691 2.4131 

121 t0.5525 -2.677 .2.1 780 0.653r ,.6.]16 

G In-yt@ acdrtt otd.nElbs 

Ii is w.ll knoM rhat remtive oxygo spc.i6 (ROS) @ inlimal.ty rclevdr lo ihe induction of 

inJlamation. Tle Ros geD@red io tucDph.g6 m) pDdue pcE2, No, €yrotine (lLr0, 

II--6, TNI{), l.adilg ro tbe dd€loptMr ot i!flalrmtion 13341. F@ Fdicds d€riwd from 

m.cbolites of unsnrIld fdty &ids or moDhift \r@ sbou ro indrce hisidnjre at6e 

ton rat @t cells [33s,336]. Evid.@ suge.sred dat 1h. conrin@t El%e of hisianire 

lirD ludg cells of astbna pari€nts @y @ntiburc to lqe iis@ bfl€|rmii@ ,nd 

lmodeline, dd @y af*r ltoph@tr.s, monoctlcs, ba&phils, .pirhetisl elts, &d 

Mbphag6 by moduldiDg rh. El€e of pohfllmdory ed imuoEgutalory n€dilroE 

dd .y1okjrcr [337], IIE eri-infl@atory &riviris of *coi.l &d rhhd_genc@tio! Hr 

l@pio. atagonisis h.ve bc! daluli.d t vt o_ Irre studis sho*.d tbr n ny s@nd_ 

8o@lion Hr-Ecepror anrlgonisls aad thnd-ge@rion HFrec@to, dtasodsr. innibited 

relea d g€rcution of Dulriplc iD{.rnD,rory hediatoB, including IL-4, IL{, IL8. .d tL 

l3j PGD2; LTC4j tt?lae; hktaminq dd lhe TNF-d.induc€d chemokine RAIITES. s wU 

a @sinoplil .hmonxis rld adb6i@ [331. S€od dd Oid-s*anid odbisruj*s 

ll@ afreted on rhe all€ryic irisDnaiory r€spo$e ar hign ddg con .drlrioB 133&!401, 

Fd .@tic, oE t yrm sludy of lle *end-g€rcntior drug cdnizi!. otr tb. inhiltton of 

Il-s{.pended @sircphit swi}€.I EquiRd s concmrtirion of rhe deg (l0O umoll.r) rhat 

E nrch highr rhar rhat u*d ctidcaly t3401. 

t50

', I 

TT 

lrrndEF€,!.i{erU'dEi'0E r!t) 

l! 

l.!A6.6us,.@ 

Il 

rl3uE r,T1. Espinlory hfltudory .@da ftin|ly aiNly .. utt rcspoft6 ro dldgdr gdeEs 

!.rritu dd ritld diviriG eEn ! .6iDo9hit 'bi|IM Dd D'difdiA 'nodis 

lldpho.y6, dd deEnljilio ofddr crb l3atl. 

of IsE by B 

Aldgic aiMy ElpoNs ielud.d rt tldirn m dd hfiL.rid of rH2+ lFpt@'rex B 

lymphocttcs, tut c€Is, b6ephil!, ard osi&phits, c&h 

of enich degmrlrr€d q ws a.tiv.tcd to Et@e 

b€{tiato6, crlotincs, ald cnenokiB tbsr @lrdbrncd 10 

Bpihlory inflamErion. AriihiflaDin6 that slD*ld 

dti-iro@rErory .tr6t3 !t rb.r4.uric ct)!@tradotu 

Day modiry the .fl@ts of in0al)@bry Dediaros u vivo 

ar dls @n|r@bl. b rlt@ us.d ctioi.dly [3a21. h rhe 

lighl oI lbove faa8 wc srnd4i4d a nMbd of ddivarivB in or.l€r io ielle 0!. 

inflmtory adivity of clritizirc dd rhftfoiq w did nor Frfon .nrihislminic elivity of 

ddivltive bur D@ opbsiad d bd-inrn.m'lory md imuohodulrlory adviijs of 

Mdonv ba6. sttqlo. @'!rt& oJ ROS tu lrt to6 

This rd allo{€d ddmiDrio! of tetoc'r onddiE hrn in ncpsioizd enob bloo

€stosiblc for prcd@i!8 sup@xidc aio!, which w6 quickly @Nen d to hydogen 

Forid. ad hldDryl Edic.k. AbnoDAliti6 in lhe @Bdt@t p4tidd of tb€ NADPH 

oxiddc ozyme Bysth lead to dy!functros chand€tistic ofCGD, N€urrophils ton CGD 

p{dot! fliled to podw a 3iedfi@t oxidatirc busl following stimulation. n. oxidalive 

bu61 of gruuloclr.s s inpsird in laspler€d palicnis ald patierrs with AIDS on th€ 

orher hmd. li wa highly .Lv.i.d in inflaMatory dierd6. veios imuomodulaloa 

G.e., cytokia (GM-CSF, G.CSF, dd TNFo) or doss) !.@ to hN. effdrs or rhe oxidqriv€ 

bu.si. Siimulaiory compouds @uld hare oppon$ity of being i@uomodulale or dhmce 

imle imm 6pon* o. Uc oiltq hld $ppcsiog @mpou& @ h. us.d eitha edinflMatory 

or im@suppr*$vq The test prinople M dEl ph.goctrosis by polymoryh- 

Gnrcld Eutrophib, non@t16 &d t'r,@phlgs @nsrhr.d a stial e of hosl 

defense agaidsi beterial or irgal iof.ctio6. The phagoc,,tic prcc.$ e be s@a.tcd ir o 

*vEE1 mjd sLs6; ch@ouxjs (Eisrltid of phagayes to irnmtubit sit s), .nehndl 

of paniclcs to thc ccl suf&e of phaeocltes, ing.stion (ph.sayt6b) and intlellule killiq 

by oxyscn{epoddi (onddivc b!d) lnd oxys*inde!.nderl m..hmis. Upon 

stimulalior, g6ul@tas &d mo@yt6 prod@d l@tirc oxyg€n mddohd in calde of 

eM$ si.ded with p.oduction of luFbxid€s, sup.oxide &ion, hydrogo pcDxide. 

hno.NobG, eid wbich ddrcy€d b&tei, iEide rhe phlsoeme Fodadon of th. @ctiE 

oriddL dring the ond.tiv€ bubl car be DoritoEd by tlE addirion of ldinol or lucigenir 

In su@!ry, ph.goclrosis &d rbe 3ubs€q@r digdrion e a nutisr.p ed mDllifeldial 

Ldiml cda|8l cbenilhil].s@ 'sy lw F.fod€d s deib€d by Hered [18r] 

ed Eakld sr zr, [182]. Ilte prcliDindy sFnins @ulB of whole blood showed th.t 

@nDouds 714, ?19 8d ?2? cxl bited ligninqr ondadve bursr BF@ (etiinflamatory) 

at concentilioB Lv.lof 100,50. 12,5 Fgor'' wilh ICe < 12,5 !gnt'. 

Exellent inlibitory a.rivitis ofth.* obpollds *F t@ded at 12.5!gmli i.e, 96,92,6 

dd 94.E rcsp..tivcly (i.bl. LI50). nEs onpouds *ft thcn t6t d for acdlnis on 

isldlttl drrepbsge @Is on fiw concat6i6levek 50,25, 12.5,6.3 ed 3.l|l8rnlr &d 

Mph,s6 a@ &iiEd by SOz 0uiEl-b3s€d) (l!bL 3.l5l). Ir a found $at all 

ddjvativca hale *€elenl€il4rs otr @rcphrgB aid aF nuch mo€ potent thd @tirizine 

dcpl ?19. IEe @.deourds posssed vsy lN ICs vnich lN* 6.6, 11.3,

cylcioxio raivitiQ tl* d.dvdiq q rally Fwo s@lb.t tlsrpodc !g.ds i! alrhma 

T.U.3.13) 

s.enh8 ofdhnre @d t d.,lwdw ldnE vtbt. bktdJu chatrl/n!@ @nit 

26.5 191.9 yt.t 

12.5 50 t2.5 

23.8 3tl 335 5 97.5 926 

721 1206 623.f l6a5 -t7.1 

n1 224.7 3t7 12.9 

rc50 

lSD 

33.4 214.5 12l I 92.8 29.3 

m 2t.0 1J5.2 u.5

T.U.3Jl 

*n6tttc of eniziu atd iE t r1!tE t .d d.nnnw Ldns M4rec., tn tbir @hidlaMdr 

719 

nl 

.7zx! 

I 

drso 

RIU 

lc 50 

+sD NLU 

4629 am.2 

&||I 25.O 3L2 

t2.s lr5 

6.ZS t3l4J 1105 0 

3l 21225 12.6!4.1 ll16.0 

23 

lt.5 

35.1 

2(bJ 

721 

250 

125 

20r.3 

625 

3l t2625 

10r5.0 

1t70.5 

x 25.0 

t53.' 

t63.1 

lL3 nl 

12.5 62,5 4 51.5t4.4 l2.J 6512 

+sD 

t293.0 to26.l 

3.1 16t5.5 ll 2t48.5 ll.&13 

50 83.r{t.J 

I2.5 

711.2 

tc 50 

1SD 

122

ft. $Bitivit of eftizirc &d ia (kivatiB lo s Mp'olif@tirc dd prolif.nrire 6poe 

!o thc nitogo phttohem.gglutidn (PHA) &d mitogen-induccd ttulifsenio. of T- 

lynph@,r6 wE w.lulr.d. Polif.Elir E po@ @ FiioglB w mailoEd at 

conc.ntations of 3.12, t2.5 and 50 rgml, r, SuppFsiv. .ff*l of compoud ?14 (lcs = 

4-l+0.5 |r8nl') E obs.d d T+U polifcutioa sinih.ly ?19 lhoerd cxaldt Tall 

suppcaire activi9 dd it! ICs is 7.149 tgEL'' stich is duch grsLr the fi. plE l drug- 

Compourd ?27 showd e int€medi.t &iivity, It exlibitcd ilhibitory aclivity (98,7 %) with 

& lco l?.0 rgnl-j. Pqid 8l@ to lhc obriincd @ll3 (rlble 1.45 & fig@ 3.1lo) l*lt d 

ihai the @npounds 714, 719 ed 727 d.hibitcd mtic4q &dvity ed.ould b. preved l.ad 

@pourds in th.rqeudc snd and tu th studiB, 

T. .1rJ3 

ftrmihs dtuhhe nd ifi ttntfuttBd d.ttudh.t aW nM. uoaa fur hen intu@ nodllatks 

ithibitoty popetw 

r28l.r0 5741.4 169t2.1 9t.3 

t390_0 10580.7 t9306,5 

t2.5 

121 )8788.9 2546E,9 21469.6 15.6 22.2 

251t5.6 2431t_0 225t4_0 l6.t t1.7 25_4 

215r9.0 24U3.7 2$tz.n 22,1 t1.6 12.5 

727 r8J60.8 26244,2 93.9 15.9 

122 tao95.7 29551.0 -33_4 -11.0 2.1 

17266_l u!t20.6 2.s33.8 1.2 

297i.1 26967,6 lJ96r,9 4.0 9.6 23.1 

7tl 22285.2 25624.2 -24.5 t6l 7..1 

1t2 14503.' ,0285.6 2132t.0 -23.5 I5.3 1.2 

713 252t5.6 253L0 235t4,0 I5.9 I3.7 26.0 

22562.1 J41t7.8 17105.5 26.4 

I778.3 

SD 

155

.50 u, / i[ a r2s l{/ irl o3.12|,grnr 

i$ ^€ +\ O ,{9 rt nO nro nO n. no 

ntc lrr): So64d.drur.id tt &.tratE E{ rhL bL.d &.l|di u@ 

#4tffibry rlFdr 

t56

CONCLUSTON 

CaniziE is s@!d gder.rion Hr cAior d&sonisq us.d in thc leried of .wbq of 

audgic disordd &d ce b€ saf€ly coldninisrored with nubd of dngs ed supplddk. 

Fd {iruSiDg ald dtug-hel,l inter&tion snldi6 of etiriziE, i,ilially !s HII,C ncthods 

for lhe &temiMtion in dw D.i.riak, dosa. fodularions ed in tu 9@ .LveloFd, 

'nre mthods sw validai.d @rding to ICH 8!id.li6 ed pha@opoeial p.meleB 

dd 1l* foud to b€ eGitiv., 6pid, Eliabl., in€xrmiv., 6y !o follow and wjdety 

Thes sinullaneous nedods ll@ thcn appli.d for th. i, vr.o inle@tion snr(|i$ of Hr 

Eepror dlagodn (cimetdine, 6no0dift dd tuiddirc), slati$ (arorvstati!. b$v'st ti4 

rerdslain and simv.sr.rin)j quilolon€ eriber€riat agotl 0do0oei4 ofloecio, 

ciprcfloeit! emeia spdfloein ed @.flo&i!), cilcim chtuel bl@keB (dilrid, 

vdpuil, e odipine), non ilbitlrl erj-innallmbry druss (ris{@f.@ &i4 dictof@ 

$dim flurbiprcfcn, ibuprofd, m.fodh eid ed metoxim), etiDaldials 

(tyrioethdir. aad cholooqui@), &rildldllj. ddss (cujfffi'a phoyt@l[ift ed 

mont€luk !0, elhalosporin, (cetoisone, cephsldin arxt erohxin€) and drugs lsed ih non 

iisth d.poddr digbete mclitls (e.tfodia gtib€trctMi.le dd gliqujdoe) ,!d .sgial 

md tree Derals. These inrencion sludi6 werc ne.rioned on HpLC m

i o lne @F sh&te of eririziE with d ain !o i6pft dtijnfldturory 4rivitid of 

cetirizine, since ceihizine hs bm foud in nuber of c66 to pos*s sti-inllm@rory 

edvftid. on rh. b6is of sleao@ic acbriqc (w, Fr,t& |HNMR {d ns 

spebospy), n wa! stablbh€d thar c.ririzin fm.d @npl.x6 fouoMns nud@phittic 

sub6tiMd E tic 3l @tbxtli goup, 

All dE dsivativd wft foud to pos6s si8lifi@l mtiiondrDrory activity ed also 

shosrd €xelLd .llcls on D.mpl|g* AI lb. @Epou& wft fobd io be nEt noc 

pote Ure @tirizjne. Howq N

REFERENCES

l0 

ll 

t2 

l3 

I5 

l6 

REFERDNCES 

John CE, Histanin€ tupra, Conpphe8ive Me.licinal Ch.nistrr, Menhd of 

Mdwcll M&mille Peryuon Publishiry corponlion, !. 368 -370 (1990). 

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272 Sold Uniwia. su hiv.s! M ll|rgy b, rb€ Swporr crc|4 tor Su Sffnive 

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176

300 

301 

302 

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314 hnp//ww.yo@thmaii€1bdt..oE|/lll.Ey-@u€iicam€tab.hrn 

315 hftp:r\rw.&t gainstdleryy.codraa/l l2+act-6slinsr-aUeryy-hoD.page.hlrnl 

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t11

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148. 

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Ardysis, 37, 655{61- 

320 fini a, Glruri !! F&io G, Alv@-Fulnas J &d Eolgado ltlA (2001) Diclof@ 

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321 PeEdke A lvfih.shMi M, Tyasi AIq Chauh& B ed Kad@ SS (2003) Pcp@lion 

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CalciM Sili€lq Ch@i.liation &d Tablei Fomulalion, AAPS 

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J Phdr4 2O), lGl4, 

324 c.wilin Mv lrd PogFbrr?t AV (2001) Sy h€sis, cbE!.1€iizalion, dd rytlultion 

b+yclodext in ilcluion conpl.x, 

of th. l6al initalt a.lion of d ibuptof€n - 

Ph.m@lnical chdjsfy Johd, 35(?), 395-396 

325 Florcy K (1985) &alr'lrcal PrcfiL Drug Subsrdce 17, Acadmic Pc$ London 

326 Sh{if NA, xu Sx ald Ymi JM, En.d.siine A (1994) Pore , Hish Amnity 

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S@nd M.sosq snrdies, J. O.ul. PheMl., l0 (4),65H64. 

327 ToMa Y, Kubo H, H@e]fhi & I\r@rr T rnd Futuok! M (2001) Eflois of 

luplata( rosih& zItD C.pslLfl/ oD rh. prodlcrid of@tiv. oxyg.n by @utophils 

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328 Laetr A-K Fu.srli !, DiCEnl@ ,\ Ad.tls lil, Ludh.rg J, Ed.nis C, 

Govoni M, Monopoli A, Sab A" D| an S-E. dd lol@ G C (200n A tw clN of 

nitdc otderlding d6ivaliv6 of dnizirc; ph@losicd prcfil. in ve'ilr dd 

.iMy s@rh mwle pEpontioB, , & J Ph!d&ol., r5r(l), 35-44. 

329 Timothy Al, Mich.Ie AY, Msk PA, L)tu B. xiong C, Philippc C, Jo$ph BE, 

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178

330 Baltaba UA, MaklMov Ac, ZdkiFv UB, Bab.ev ID !d Shututl@ K (2002) 

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allergic ois! A.ia Phmeologica Sinic4 26, t 492-t 496. 

332 v@a M. T.ipaihi M, Sq€B AK.nd Shdld K ( 1994) Anriinilamaiory .diviry of 

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313 Dolgld GD, Gmrse DM, Jo*ph.lP,Io& ES, willim O ed Rich.rd RH (1990) 2- 

Subslituted-l-mphd@ls d Pol.iit 5.Lipoxyg.nse Inlibirob wir\ Topical 

Amiir1ls@alory A.iivity, Jomal of M.dicinil Chemisty. 33 ( l), 36G370. 

134 leng L, xa Y, C@i. Oq Hwes D od Wlson CB (1995) InvolMot of r*tive 

oxyge! iri.mediales in cyclooxyg@.2 dprcsion ind@d by interl€ulir- 1, rnor 

Mbsis fa.loF, od lipopolysMhdide, J- Clii- lnv.s1., 95, 1669- 1675. 

135 Mon H, AEi T,llirra K, khiiH, Eodo N, Mrtilo K 6d Fukuda K, (2000) Etrects of 

Gfomylpt ril! a hdine oxila$ inlibiior ad ! supercnde smg6 @ 

pnnucijor of nitic onde h Rr{\v 264,7 n1!@ph!96, BiehiD. Biophrs. Acia, 1474, 

91-99. 

336 lulagmi Y, Ydo S, Hori. S, Tsliya S. Ikcgmi I, S.tinc T, Y@oto Y, 

Fljimdi H, Trt Doto K ard w!|rE!. K (195) Ar.ls6ic, rewDl ct+ ct!fuI, 

blctins rnd tu@tt 6us.l. Eh@r erivitie of nidlglnie, d in

In vlt.o studie. ol tte interac on betweeD c€tl.Line 

rnd H, .€ceptor rnalgoDisl! u!|ry s?et ophotonetry 

od rcvcE€d-phise blst-p€fo@ liquid 

N.lnr Sllr.o. M. ss.d AryF ntm Sbrmbd 

MEDEMI 

CHEIIEIR/ 

RE5EAAq 

alioi H, Mepbr snbsoni$ is us.d tu rh! 

..f d.r dil.'g, ombi'rd Hi .d H, 

lErpy !.dry \ nYE rff6r\e rh.n Mlld' .rr6trd, qr} H, tr H:. 

.xrbgn rhjs lyagdic .nd n6 d b..n fMd i. 6ildi6. Mmoq. 

d@iE in vib $rdi6 [rE inBr]sred $. afIecb rh, rh. '[ cddnjnjdid of 

H. Rprd sbsons hr.. o d. ph.|mor'd+ !d phm'Eynln,fl of 

'h. h H' kprs Dugoird3 

|proeh b invdir& rr'. in@dm of eriri.n. wirh cmhmty H, 

Er@ absdjrB (i.?.. cinddk otrrdirc. md fmjd'tr.) in 'dhinb@,td libulaj4 body 

tui! ir d'naar pH r.Eb ad r r?.C lns cEMJ.phe tush pen(M 

rqDid chrcDrotBphy ,Rt .HPL., ud rtkUokr rLM \!o tu Rp. 

HPICm$odsr.o"! 

'rcdMmEr. 

or nEs dtoss. The mobil. phrr. .oD!{.d ot jndhaol wdn (BO 20) pumpc,l .r r 

flo*nrof I munin Tn ctuomrosM *N nmirocd n 230 m rr. a,rlB 

iq dE uv $edopr6h.ry .nd Rl Hn-c.Ldy id,qr.d rhd rll ,v.iLbiftv 

of eridti. w6 uDfield by smd@ou rdmi njM of lr, ed H2 @otd 

M63on'4. llae rs dr& d k sf.tr ldm,DrkGd *,rh 

'n * m rr. 

HPLC Uv rhmDbbnd^ 

-

cdi;rrcdihyddhroid. (Ps)-2-12-l4l(4rhlomph.nvl) ph.nvl manvl)l piF+ 

,Fltll.rErl Mn. 

2mr ||! ditun rd Lpodxhrv b.ht ior dd lrn ddrlv disl. bo b 

Err mnb'u.d dibilz n. x 5 oppo*d rt.r i i ibis rt. DN^ bindins 

'dvny ol NF-bppr B (Hryrh dd ssiimdo. r99), *hich pr.vs r pilor.l sk 

in ID;rDrcsiotr or innrmdq ctbr]ns, .h.rokji4 dhesion mLculs. rnd 

iDrmaory nedn,or (vn:g and S&h. 2m2) 

Fs mr 6re d1.ryrc diffi ({ti.rl ind frs unkM. d.lfultr|ljs). 

'nd 6rfid Lf sh.m rh! cl,xrDbr ,miDtub or u H, lEptd &ugdd 

.n;H)eDr.,rbsoni', 

husdirr o' d H. rlrgonLr 

'o'e 

oh.6&d rhd @bin d p'funr with H' td fi: uagsnb ca!.d ! l@b 

i.ribidd of nituim-inn4.d 6d b|€r4t ds did H' mb3dno tu 

(!'t6 .t ,4, l96i Hrvs .r ,l , 1936i S&hd .r ,/ , l93a Tivld d al. 2mt ft 

rr'll* rhrt ,.orhd iorHr8, pdrr{ty is 6poi6ibL rtr th. asidurl nad 

hlckrgc, $e!$dDg sotu d.gre ol iia@ion b.t*..tr dE Hr dd 8r trii8bd 

mrh*r6 lltordh 3,r, )(rx)) 

.ffctrw d*tion ol ohdElv trEftd 

i,glbh.r'cr*idllh.cmbiDiiotrofH'sdH,uLgofu*{Hohb.,l.,d'' 

cbM..hv CPrr) dtho& b( brD E od.d for d.ldm'n'U diti:j* 

drft ;' r.. !0oti G.*t' a c/.. 2m7: surhr / c/ . !m$ .id Hr Et@r 

-'i-,*,.rrt,u . "t. zsr€. e'h'ru.''l !'rrr 'n b!rr' dds. trmns@ 

'd;'*"** 

H"**'. . ror 3 rrrd6 dlM rioi orrhe dn& 

h ".h"d borlr EriE sd d6is. fmulrrior. ha b..i dudnd b d:b 

l. 0EEfrc b..s. rhd . ftthd tor a{indlng s6' &u5 h Mr 

m!li||.do.g!fffiuldfl\!dh 'lFnnr 

'pi* HPLC HI'l-Ct llus tdiik d 

'RP 

6.rb dosonisb G'hcidii., rsitjdid. md fmoridin.) in difrer' smeb 

- 

r^\--'-\-^\--'o.

ody .nvircmenb li rddirion. I uv 

fudr* strppd ro rh. rcsuth or u 'n rro {udy .xminjns @ririzie iihnon 

*jrh H, 'E4q ub3onbb. 

S.Ed p'lbrm @ lalvd i rh. sinutboN d.6idid of u. 

e9o!tr(rl inBdld.d. TrF ftn *'s rb. !t crio of &![rdd o.dniG 6 

dlug3 a w[ a d. i'knd !r.&rd fim 

hum lff w n miitnun inblf4nc, fM rmm endog.rdr @r|Funr Ttu 

*oid probLm wcs rh. .hoie ot prcp.r .hrcnrbgnphi. loidtrion. ro obbir 

&pdtion ot me dE @mporma fon rh..idosdNs onrouidr. 

Th. hrir sMin. ..!ririn. dihydehbndc @yn{ t0 m0 dd rb. r,, e.por 

aqoEr om.ridjn. (uk.rd 4m n9. hmdidine tHits 20 nl!), miridii. 

(N!lq 150 m!), rlld iftmil sbdr'd ptufylp.nben of rllm@dal Fn9 

*E oti|jn.r tmm vdio6 phr@ukd @mpcni6. Th. dnftt u.d rs of 

sPra 3rd. An dE nri.r usd e.d or olrrrid s'r& iEl'djn! hr&eNdic 

*id (E. Mnr). lorsium cNodq $di!n hydoxid., pdsium dihynmi.i 

dhoprt6ph&, ud dhoph$phori. eid (8, M.rk). Deio 4d w.b w6 ftshty 

Trrddic.r b!l|r. (M.nkr Tokno jABra, cotmhs, usA), ot tu(rr.nlr 

Tor.do rlP 220. cotumbus, usA), uv.viribte 160l snin&u ddbLjce 

NFhpnorom.tr, r4m rcchsute qumz !€ns. dcioriry (Sbd.c csw_30, 

Jr ' ,CFt t)F 20ot 2. Cmd!, rtr &d 

Ihsi'nrd'uHPLCr*m,i

uor fron I b 9, ud rd lk Fq dutb: cl .oluriB of o I inbr 

"-i *.4. wcrmc ."'d.d -r"u 

* i..ia r a,u"g r. "p.p"'E rNJtr o' ur oruuon m .n. ** butr' 

QffiaMa ol dtus| n 'tu@.aa 

To did. d*. dr3r. . Gri.d 6ii! th. winlbl. rpdEdlM *B 

ddieEd b d@c qmin6 o 

'h. m For rht Pnipos 3 h.rh@ric'l Eh d_ 

lhip *s ued rhi gay. $. .onentdrioi or rwo drug. smuraourv wFn 

mud d et rbsrprion malni 

*h.E b n d* ldh Lnsrh or lll. ..ll (r cd in ff .rp.ncits) 'd c n & 

cididiE, rd lmdidm in ln. Fs 

(D 

\1) 

r&oIting I dhtircdY difi*nr 

*lv.ldgrhs tridy ld lod dch o$d 

Ba.E rc6$ng ddivniv. tp..n is rhe mdt .olmd prdm ror 

ins sF.h i' birry mn@ (Ab&l .t .1" 

2m5), &. 6{ daivlM srhp*Mhc ndnod P5 qcli.d fd siml|@ 

didim of ov.ilrppins spc6 of eftizir. od dildlE h e p.ffi. ot 

oP'iiiand 4 h. aobb Ptu. 

To &Elo D n}.HPr-c mlnod. idrlly qxtuol qu r90 ro, E b.d fa 

ihuhu!ru dinrtd of @'n,ii. x h H, 'Epb sLgon'u 'crdn'jne 

miridjn. md fMidii.) lidividtrd dtus $lutions *d i!j4r.d inb $. oruhi 

.! a @htsdoi ol lLto !e/n -. sid borh rhe eluboi p4En dd e 6drtd 

h Phe .x 'hr Hr 'efls lotlM srtr 

* a"i.a -,' * *."i'oi rR i. :rnrl d m Fd*rd 

.fid % ob*i.d {irh E djudtr 

d.d f( d. quiF! pulpoe Fd rhii ft$trd:lrb 13020) vs ti.4 ad 

iidius shorcd rhr 4 rhis drio, rh. H 

Hotrv.r. r lunhd dec@e of mdh 

-

phft hrd no crfd oi $. H, s.rror 'rqoi;r bur onty incEcd e @dM 

rjtu oferirtirc Ti. pH.nd lbrrd rhr oprinjz.d.ddiooo e tuLd !h.n 

o. pH vdE 3 r.5. gldeing *ll-c.olv.d [d stu,p F.tc fd dt dius sly.d 

ri iddirion, $e w ry..h or indiri 

r03c of 200 ro 4o0 im dnd .onpr&d. Th. choie b R h. lobdri. poi .a ar 

227 nm ** .@id.Ed &$shcbry. prmhri.s rhe de@do of jl &r$ *o 

M.$hd:yad (30 20) 16 rh. !mpk$ mbit. phe fd nDid sd ,nu6ds 

4rirutim or ..riri!in. *irl H: H€prd dbsonisr pmpyl pmbcr pa @n b 

J nin. Tn. ffinm imt w robd o h. 

2.5 mii ro! dE Hi e.'td uras@rh !d 3 5 fh ror crinzii., *nh , €8 nE 

S.pu& t@r siuror d c zi( $d omudi. qer dipcd by d,stnlg 

lohg or eri dns ir rm d s04 4rdr Ddhmj o lhn |n. i!.1 

@nhrid wa loo lEn wdrms stukn rs $eE pEp.Fd sFd.ty bj 

d,ruu4 rmm ,rr $drd {rrnotu L obum Lo.dw;;bd@i rrr ud 

33.33 lrc/'br F6wv.. iiamrr drd M:d 

oNbr (i., 16.66 |3/nL) ii r[ rh. hdiig drnd.rd stlriois. rr. @ 

pc.dua wa Ep.!r.d for hmddin 

To!.!min. dr sb' oI bodr &uu tr o. romudod rL.m.ldra fuoddim, 

s. cor{.d rnd .{udor b ro oE of 

€riizr.d|o'm!ofH)Dtrgdtrb'wE*q!lBl',ndlh.€|utronlsd.!p 

b r(lo dL * h eoq 4hr crhoot Th. nrk,ns €rron w 6tkr!d.: ri. 

4ordinsly dirucd *ft rh. qme yi{m 6.d in nrd.td oturid ro oo,cn 

eruood. yid' rh. tin{l .on.enf&on A shpb and xbndrd ,olurjm rm 

nltdEd rbnlsb 0..r ! ,ilk, Fp.r b.rm qdum dd ,lE ry*m a pturo 

6rc .l,o ea lubF.d b df, $ nE pcdbrtry d 

*'p6 mM 

'n 

h drr5 *B {ni.d 

Phhr.mp s obbrmd.rcn hqtn ..,hmR^ re ! , ckd rd iod lrun. 

--

l ni[ rh.n annilused fdr 10 nii n 10,000 rth. TIE rlp.rmbr wt ilr.t d bv r 

tunh.n! fiha wirh r pft .iz. ot 0 45 |ls. Ad aliqbl ..lm rMplc t t fdi6'd 

Mh e.h drus b eh d. Llt turl .onaNdiotr 

-!ar( F h. r. J rt ol 6 h rmPl. i( 

I b r'rr [g/ml weE p,tpslr. dd l0 lt|- or 

r.rdid ws jij..red dd chrcmdosnph.d. Fon dr' lin.dnv and p.@n!!. of 

Eldir lbndtd .Lviarior (*RsD) ! 

To mR bund q'b pH 1.v.." ol I rnd | ! 0 | rovl olurion or poB'un 

ch|;d; "* etFd qrh qd'dtri1. a d 

iplap ab pH *6 araiEd Fof prcPlrdiotr or pH ?4 poedun dihvdbg.i 

onhophdphe (0.6 s), dMdium hvdrug.n onhophosph.b (6 4 g) rid !di!m 

cbls& ri 35 s sge d,"shd h rltu(i' d.rookd $M b Dr.d*. 1000 d - 

*i,i ,h. oH ;Ned i R!6s 

! a3 s or m'um 

dbe;Ldilelv.drr.0oomLorq& tr h rrE pH 

'di'!.d b o uD, r'qu'd 

Tr. i'lt.rurjd odls vse Fdon*d 

by pt'ariis 2ol}|g^nl tck $lutiotr or 

oh dtu! itr bufieG ot an dp{y sonrh pH ol l , tull sMeh pH or 4 t 

iieaind DH ol9.6d r blood pH of ? 4 Ndt.20 ftr or d$k cctnrne lorltd 

ws rftf.dld in r cooE.l fldh, did ro rhir es ad&d 20 o[ ot rd] cid$ddlF 

$tunoi Tnc @Dic,l f,a3t !s plsc.d h r "!rd br$ r r7r fd r h Th€ spia 

sF vi$d:nen.!.4 hrlt hor rid rn y7.d ulidg the Lw Yiribl. stdropho' 

orub ed gPLc ardr sir$I. diluriN\ rud b. made. Aboturc.s d p.4 

I{ *4 n orJ.d 2nd rmm un d 

TL !m Bi!.!dm wr E .:rd rd ouw Ht c.p6 tusdjlB 6 {.lL Ir' 

€n! lnE otritr d bv uin! bdn ft Ehiiqu @ 6nFr.d. !n cc|ui6 

@ d..s b.'.d oD tu lg16. T1F 

Uvrkibl. rp.rbphoromtr 

Caltb.ad Md .ohrbtb$ 

tu lhdiq .ndi6 ro difidr d..rinris or d ds 14 Fr.d u 

dirdr nir6 rd $dn!d ftE lhqprDi nsitr or@idtm Dd ciisi'liE 

ts o{xdld d 21r m dd !16 nn Fn f sdG rlE rb6ol'to |uind 

I

. {heu u! nm % ok ftd d pH ?.4 Dd 

Th.* dru$ *a carn.ros rms , 

*dudbi6|{ldnu$.qudti'i.toIliA!dnsjiasolutiotrofunloow' 

.d..ihron. Tn 'bsprio ryinun oI dniridii. ws rolnd 6 hc ar 225 nm, 

whioh oErhpFd rh. r&ihum or alid?inc (23 | ii) Th(dc, 'n* lppliaron 

of !eoid{edvlriE(Fis ?)'p.crophorm.ticnrlhod,rhediflditab$prton 

tuinr ror EfnziE !.d mitidin. wR eod.d d dffeE pH Lv.h. 

Irr qlihr.riq .N.s rrs wrc rolnd b b. tiB'r lnhh dr .tre.u!!m 

dl. ot 0 0r ro 0.1 n)mr/r- td dinri* .!d tuirdjn.. TtE prcdua * ldrd 

b e rhpr.. n!id. d'i r.rBbt. tn jt 'h. c*,. rh. crn. i.br or .$1e B 

,d'dbb.dllrcdEr2* 

R.pl.!.Iulivechrcndogramswe( 

P6tlb]ypl.Fdinlhesnp|?mf 

si$ii.! chriscs ji 4a undd rh! c$o rAU() or fu DD ljme of qE {qj ,n 

.bo' (iiotu nadrrd) ctdty idiclr.d rtE 

sDe'n i! ot oE n inod Gi!. r) 

t t@tt, tnrn ol d2k n2^ (roD\ a d ti,'tit o! 4btuddiil Qno) 

rs fiMity !Ndi6. d difrdr mirrur dEnmjms (13 31 16.66. t3-t3, lO, 

t66.3.13 Ig/nL)of@rdru!, ii p!.sR orrh. iikn n drd wE sy.n 

TrE [Miry of rh. trd]od *s o6c^qr *irhin rh. .iFd.n limcrrnom tu$i 

li 

t' 

: 

J 

@

i.!r.IFliEdMJennd'd,4 

JLD$ ftt ' 'om !$r' rop. 'ME PL ',ld 

.*r*"."-.rn "" "i *.*'.a 

or tu For ru tSlnn the om.ddion *se $'l. it agEsiotr $'h'i' LoD 

xd l-oQ @ lhom iD rabL l 

f|hmcsdsF6jubdrlhEdful 

'a-a.i ;**" " " *'irr' 'o :s .na z. *hr bv rdd'* rem 

q""itu or,r'. .,ry,. . ,n. a.e p..a 

nddd *! @urE ror rLl Lh. rbov 

Trx mftod Drxd 'r 6r ro .P.'rh 

or tu Fr! or rL Eplar mrdnft n r'^ 4 r{.on rnmtrd Th' rqrL ror 

i'rd.dnE pdi6m m showi ii Trbk r 

ftre.FhUftsftd'0is. Fopo$d ndhod. d.rtud. dsditotid i! pH 

vicr ot th. tubil. Phs$ !4 

lrE ohtbdbgraphc paEmetB 

E

*! lblnd b b. ?65 mdpg r rnd 4, vh.@ 234 nm w6 ahrd.d d pH 7 4,.d 

TlEe dogs wd *rimEd uiig !i Malr .bsorprivnhs 

*cr u8d ror catculains ln. qudiri.r of rh.r. drurs ii r pturioi or unuo*n 

!h ot ffiridin. was rotrd ro be !r 225 nn. 

rnich oh hpp.d numum of dh.m Uj I M rnRrm. rna lppjddon 

'nr ' ' 

of ri. @DdieJildr rFu. 2r {dhoohft h.ridt, tu drn.t@ !ryon 

dni rd €Iirizir ad tuiddiE w @d.d !r difiamr pH Lv.ls 

rE drt riu ffi ,tio rw fold b h. tiE[ *nnin Ihe crc.did 

nI3. of 0ol b ol rmt/L fa dniziE !n dnidiE. rh ,E i'r. rs foua 

b b. !hpL, npi4,!d Eridt |! ru d. c. rb. .cficid of ,arr|E w 

rdndbb.d@tnd295. 

R.ptrnbdr .hlmrbglm3 $.a 

polroLy p.ud r k spk T&,r E Boh.d IDm ft. prd, ,nJrE No 

ngnrnqd cbr4.r u 'E udq lh. .@. i AL c) tr leron M of rl! ders h 

ft. enEtu o abd.G oi pneytpobo rti@.t sbidd/.rdy ndsrd rr. 

l'e'f(i" of r]l m'5od c'! rr. 

edry. rrin otdaai,n tttDI .,n t .t ol q@neh (rro) 

Fo.liEiry sbdia rdx difidr oir@ @oHj* (3j.lt, 16.64 t3.jr, lO, 

t64 3 33 u/bt) of sn doC, ir !@ oa rh. iihl ,r.ndzd wc &ey.d. 

nr liMiy of dE dtod E orqv.n $&in rh. aFcr.d (:lrlllfuid d!.. 

rb.t k*e,!v:Fde'hd,dd,Br 

!ib..ir.l 

@

n.'tr'ddn.nq!t4-d.F 

ut rr!-orre@dma 

e'eq.! 

@hld&dr,ohtdFdd 

dr.lit 4 h. ulbility ld dtt"t ll. r8hd @.L?e 'nct'!' d 

@lud .odftkit *G .L&di.d Fd cd.!l!lm ol 'n' t|Ifu c@ D6 

or u eor, 

.dlrQe tlm i. T|l* I 

-.r.- 

u *mt- @ u'd It qdtio' sid€ r'OD 

I1E i'd.v Fitim.!d clrv of rt re ddud d |!F t'irtod 

'D.dod 

'J-.&.i i*-u-, *nv. lo. 25. !d 20 |JIh|- hv r'dl! hbn 

;;ddr or 6. &dvE o dE dot F.dd Ti. dli ra mv ji''td $a6' 

ddhod *u c@ f4.ll thl $oE Mh*d prlPc 

T1rdiodost drr6rdF{alhlir) .ddan$.dbv*RSDrdr*@ 

or d. Frr. or rir E L*rFUdur1004dcoeimd TbtuLrd 

'ncm.dLE @rm G ihoM h r|t& r' 

Fbr rh. .!hos*$ ddy or tb. 

v.lc or fi. nbb,rc de ** 

dE cbena.tnrruc Fnl|'6 

E 

mmd i.rhod. &llt & b.dtiorior i! pH 

;j.!. I o b. s lhd r& .E Y otririio ut 4 

e h uldrE *iot rh. ..rtiitlF! vrl*, a

:t0.1{ir pH ch&3. of .!or 3.JO (,H or ri. ,FriL ph&) hd m cdj@* 

unFd d dEni.rnpht Ff(me. 

I]'.d.Eop.dmllFd*cr!p|'.db 

'n 6.d In nhilrl, or$. rlab6 rn dE I oj 6e dngl u d: ltEE d 

Em dbiEd in T$k a sbor rh.l?jf,:ni|i|' ot $. mdod ta uEi&c 

appletqorftxmu/b.st{u 

bdx6 tu( rd H, bbr.u. s!rutu 

tdc lft o!6ay.d .tta k ohdr.d trm Hplf 

'rir 

nk rnLD|t,ty vjE 

d dirtft Dd I! bbrft n Fee of tr rdtd @ Ioud b b. tfir&, 

sb b .tulq ir Nrir$ihy du fd r|l d..E a F*E of jr 4h db.r n 

d dE b{ff.n sdj.4 . rh*. h Trbk 5 

tEr

wdEldaNPlh.iffu&!nd@ry 

Modv.., our m.dod wd rNid o b. wid'lv applic'bL ond Gplod*ible Fd 

df .!.!. nou.d l!ls\ is.thn w'h ..dvss um e* or oF !d d 

**.Dd *.t.u't"r . .*",.t 

'dnfttu s d'nv&E c'PlbiljrLv uF 

'n 

.r-'l.r a**,.o,uu$ old add bnrq@ Fdhaff 

6. ii!d; "'.-a*;n.. .df- t ubbite dd p'!cd!s rc tudB or 

"f "'rv$ 

*-* i'o r, *,.' -":-. -rr* -d b h eurp'( or d'lds 15' 

prlrudiql des. of rhe &u!.. 

iE ddH 'aP'n mu€onB! *d srffi 

i* u' ii**. . '* ;"ry". 6.rd B"* d or tb' su'r* $'ftd 

ri-,i,*,**.l *,i^. .g* i, wr orr'd.d ,rd dri 'v".{ir'c 'rd 

rcr", N".d"*. t.*"d b.*fi' rDn co'dntu'tun ofiMndir lirb 

sivsriic. ..tirizina and ldahdim i 

*s obercd (ch.i d ar . l99a) 

l" -"+. 'r,. --.^**,. 

q.*-.r *-;a *. *a'"-v 

-

Ae ,uppErsid, $us co.idiig rh. dioi.t tor r ad ot d.!. rarc4rc6 

.dniii3rEd coEomihrry ro sn. rri.ii! wirh .lnonic udicd, utulp,ur. ro 

@dn d wid f Hr aMgonhr ilorc Ir w6 .ondud.d rhn $d n no rcraEum 

uriomr. b, cocdnidknns..un.R *,rh !,m.ud m fq F. kdmn o";(&! 

sd da ure n.didimr my b. coodlntibkrd sf.ty wjrhour fd or m.djorid 

iildum rNirsu ? c/.. t999, Hc64. rhit syn.ryrj! .na, *s nor rNnd,n 

dr rh. dudis (Er.rL a a/.. ,95. cor 

I!.d q tn. 6d pd ol dE sdt. r {hurll@s ru-riPr_c rs d.v.loFd sd 

viidlr.d rc ur dd.tueq or drotr in rlr Fffi d Hr iaFa 

&4djrB ftopylpc,xn D w!reLc 

'id Ed mdy s r F*djE in rr,&G. Trr 

(hnfugnphictr'hod*av.ld!.{b'|lgsnslifutr'Itrny''|.dlqly' 

rF. *rdrE d q@ddiE. Tn mlhod ra fiq oj rd.'tc rrem 

.rcipi.ib. ft wa u&d b .vrlub $. p6ribl. in vjh idbrerions bqwai 

ehn* ,nd H, Ecpt6 ebgonkt 

h h sfd pd orrh.sudy, rh. uv,vilibt. lp@hnpic r..hijqu. w ued 

b 3rrd, d! inlfmioL Fo' tur rtr qlu. *E ldldaE nw \rluo *.8 

non, b.r*en ln. dnss, fd sds sc 

.onprd *d rl'e ot firl_c. Fbf rh. Erulr4 ir *s ctsnv .vjddr lnr rc 

hbla:ru M,i,!d in Dy of n. b{If*. rd m .hrns. ,n p*dus. ol 

Arrhd{ft nis @n djd d .bp. b ii6ia& d. j. vid n,di4 ri. 

ffi dlnod otd b. ea{u y b ttE sd, oj sDp|.s inojql! ir 

vi6 rbr6B Frcn "9t'.d d! Be3td.d,hd rr. syEBiloc.fld 

Fd@d b' fr.mbi.Jm 'hclumrody.,r of lh4 dr!33 lhodd b. rud,e! d lbr Iw or 

Atur .ll th. rcs'nb obrriR! by HPI-C odl.r hd b..i oaty*!, ir *a .oicrud.d 

rDwr | tosh p.Mn{s. or doErid. ed tr Ln{ !p ro I qde rus. ot 

i. of ,nkrucuon Eutb ohdd tom bod 

eh'qua. n vs orrud.d rhr no inhnon @uftd bdGi dinzjn. Dd u: 

lIE

vi4l.slocl?@'fud!@e@dd'd,(D''ih)'dyiteii|!bE' 

*nqiFfud&.rdb,r&+ft'dhr4bdf't.d 

-

J.cd.s(P'r.. yor Jq Nq.., !a 

Oltimirrion of Qrzrrir.riv. AnrlyrL of C.tari.hc i. Bulk Dngt Dofg. 

F.16ul.rjd rnd Hum.r s.ruD UsirsSp.c.rotn.ron.try 

NAJMA SULTAIiA. IMUHAMMAD SAEEO ATAYNE' AND IHINA S'{AMSHAO 

' R^,otch kilid. at phoncIlttcct s.i.rc6. Foah, ot t\moq. 

u, q:itt af Xdtutt Xd@hi-75)70 

. 

'DE otntu oIch,hrL-t, u,ie4ilt ofka.tuh| Kro.1t7t270, Patktan 

lc'6P|ti'd1i'Fi@'^'dEnni'dElqd&iEd!UjE*bft 

drq@Ptrfu.*ddled!diEnj'.dddqiB,6hqdiq] 

&hri d! d 6r dfid ndi6 &!nj* rdi6 EE F1fu e dE@r rie d 

cdn z i. dhydmhloride (Rs)-2-12-la-{(4. 

drrorooh*yl) pr'?n, i.thrl)l pir.di*l- 

)ildhorrrcdi. ,.id dihydnrhlnid. Ill, i! . 

!{oid ltisn'oi Hi 4..!b mbsotrist 'nd 0 &id 

ru i. Bridry rldorb.d 

hdr Food d.l.r! rh. rim. b pel rlsd 

rienraroi bd de3 ndr dftI6. rh. munr of 

Jf!! sbsod.d n k lishly bound b pl6ro pmkin 

.doiq i *{dcd Pl meiry in 

'h. 

, urir b,r n x/q o!,isnifrca' dGdtr,rl 

uin. mrhi { 

Mrny pro(durci m ddnib.d for 

+Jdbtrv. ddqniilloi or ftrnizirc in !ulk, 

rrc 5p4bfluori'.r-y I4l, 

\vR l5l fPrLc 16?l HPLC{3 ltl,potn'lon4t 

co*lpoDd.nce should b€ qddE$.d. 

llel .oloindry [e] nd dpill.ry .l.ci6rlor4n 

[20]. Tha. m.rhods d rin. conluniig,.rpctuivr 

rd inblE ddriE B of dsrnlc stv.its o rE 

hs e$ iva adh.mm dlly:ii of .didrjft hs 

rrK b..n *ldi.d by uv $.tu*op, [4, e, r0] hn 

nr !.$ n.rho4. iircrE ?iftd r dl'!. tustt 

spt. or th. us of inhrl shdrd. s. r idd 

ra f.h b d.vie sndr i i.dodi *[h[ .duld b. 

dd. ks rin. coL,ni'g *6iriv., pcig ad 

rc!d. H.nafo'rh, ii r€rdr wek . hdhdd ra 

d.vdop.d aid wrid,rd for rh.,otr$ otd&rjn! 

h bllk lc|g. ramutrid.r md ii *dh lor 

rr'.nr.!ric praos nsiis,n'ryri.rl idrun.d w. 

*.d ftn ndiod ror .quiv!l.rc. nudilr oI di,T.i€d 

brlndr of cftirn. (lviihbh i Plk n$} Th. 

fr.rhod i. !ay, eiomhil mu k .qurly .ppli.rblr 

ro rh. burk drus, dos4. fomur'rions aid for hrro 

Simr n!frb6 ofrh. quDrirniE mdFb of 

diE rd d&s. flnd ids ii vriou. d.r.nn.tu 

or ulyri.rl *i.ics e cricd od !p!@ 

ph@h.ticdlr rhl pmpod n.rhod n3.ppli.d ro 

tudy rl..quivrr.ry ofdjtflEnr b6fd, ed b d 

rrr pH .lf!d. Trr n4hod q3 .ppli.d ro rh. miyljr 

of dtu8lpik.d ii $run as v.ll.

I 

56,|J'ciri's.c'.'|',vo|I.No'4.!04 

'Md of rh. pdvioG von oi $! 

ffioDhdomtrklD|).tshsb4iaradodl| 

,ro*i *, i"dd e P'' - *'"' 

zid m'h. ^ Uv/ \ribh (sion "h"d-'" i' b!fr'6 tpp"i{ n 

zrrin llels rhR lrdng'lr wd dsd or.B' 

id{tral nuds (F's l) n'it nd@ Noso 

'i;|6.od ur or li..ri EsnsLon totroFn 

obl,ind by Plon trg d. oi"nrdrion tn6 $$r 

bde in Ih. wllliis cunc.nranoi dBc 

Iis.l: Uv sr..6 ofd.€e dinzi*' 

t/hedlr 

' Suirabili(v ot fic n'thod E ch*kcd bv 

sal!2 cft.liisnrv rr tne t' conciudoi digc 

id rcbk-r rh.s dd, $u wE lPpr'd rc m'' 

dft3idn fun.ff rnd Euls obbbd e 8'vd h 

r;roa. Ttu rcFrB ddrY indi'lk tut 6' nm 

I'i;*'iJ::,j,:',lllitiT" ]5"*T,ffi ;tii 

twoc, and Pkson 

Ir on' to d4m* esdv 0r k 

-d[d !m*n oudrir,6 offtu nn.w$sprk6h 

6. dd; orcdu.r rollo*'ls usP m01 tbddr Dd 

** $;idd r",i.. Fdr'6r* h *"5"@si! 

d!nlthod"*ef4.vilhitrth.glddg.'In9 

mdhod D!*d rhl Hr ior E*Mbilid d d4'm$€ 

bv dmirqrir Reli*t otrn: l0o q d $Nrm 

;JiB & lcH sudd.d rh' drM'or EsB 

R.o!q or c.nizin. ii blflst or PH 

obbii.d 6oir rlr*e LrAr gd di! rn borh d rrr 

D4e,a.dndaL 'tul'dLrut 

n. d.kdion rimtr or (LoD) a ii( or 

ourriifianid (Loo) tor cnr'ii' wd ch(rrd ! 

,;" pH k*G ,. pr! r1 d'r prr ir r''''| hi 

(.tr,i;ft x pH I r.s rohd 'o b.0N /r/ '/ "'r 

oo!pst^tatpH1. LoO uruB w@ bund 'o E 

". i',i"-t n. roo *a too "L*' r' *'"' 

'tlrlIrr//x/'rnI 

d,r.-d ti."d, .r -,-i". ofdinzh!iom 

omn.rtr||y|€'6|.@q3.foru*cokd,ld 

4Bm'd rm 

lT$k.))6!lswd rortrd ro b. 'tr 

it'. t*ta a"m vo". "o P'o--eo 'r'' 

E$ d.n.d 'n (e of !H r 2 rnd 74 lnd sc 

i6u|s w.E foBdrdbc pH iid.p'nd'd'' :mr aI 

rrimuhLng bro.d pH) wE (kftd lor

Siimrda l60l dorble b!.n Uv-vh'brr 

Jp..hphdmra p.$dtitr8 a nx.n ,l[ sidtt r] 

nh) eirh qu@.dL ol rcnn p.rl' kiah Th. 

hi.d wirh shinda UVPC €6ioi 1.9 $nw. 

md! HP D*U.r 1200 p.iit'vausd to rc@tc rh. 

Sbct elotion of einte El|'* 

tud:rd (loo /s/ r/) *a pt p,r.d by dielYi.s l0 

ns df etidzii? in l00 nl olbutt 6 otpH 1.2 (Kcv 

T,bk{. Lii..r L'norrcFspi r.@sion rtrriont rffiro sd dd $.n $.1sati'icrl'.m!ku. 

sdktcrl 

'bk-4: EE bD 

r:ri!--!--.!s!e!lq4s 

d.6 

-f,---!93 

rnd pdLirn o{ th. Pmpo*d 

Th. .runn. dhyd'o.hlolid. ar.a(. 

{rd{d $' rindryprclidld by alicotu Pr]:n} 

curn (Prliihn) Kechi. 

ldifi'miis trepriryby ndrin!Poi .id lRspdn 

DrlTqor .ohht illlt rEihhl. hbh6 i. Av& 

d'fuiur l'homartulul5), c4izin. (rim Elo 

frrnme.u'i.llt, cM (Brtrdt Hodgson). Rgix 

ai cohai Ph'm&u:ca, Ptlilhl, Rm.x 

rHihoi). z.il'i (sridoz Noyinir), zynrt (ucBl 

HCU and 74 (PnorPhE) 

dilurioft w.ro nd. in rh. tu butTd n.diuns 

hN ig 9 2H6 I /€/ 'l .oi4irrior roigc Tis. 

dilurioBwrcsnn.d h d. uv/visibL. rc8ion lnd 

wd. rdnd ro siv. ! dhtiid p€ak { 13 l nn Th. 

.bsbrcd for rll rhB. elurions v.rc n.luEi . 

sriaially. MomEr. in o'n . ro find otr if tl'.E ir 

sy hyplehoni. or bdidhlmn $i( s nldid 

in @ of dnizii. rdffidlatimt, difi.Mr 

b.mdr orEbl6 @ dis|}.n in r00 ml mludn 

fl*kt ind volum. G mrdc up 'ith n.tdir 

buff.F. IrE $rl. * fiheEd rtuotro whrMm 

fihdp.p.i:dildioi!1923_2771 rg/nl)rcEn!d. 

i. ?5 ml volrndnc n.!k rollowins rh. lMr 

proeduE a ior rf.Ene ntnd,id studi.3 

oE slrdt of Plan. 6 d.prckiDt d b, 

dr. slu6. or doiitilc md filt.Ed rhbulh 

v|lrnmin fi lt'p.pd l0 nl of thk fi &En,obrioi 

ec rnBllrcd to 100 nl volun*c nlrk 0d 

volui. w6 hrdc up by phGphrt bult{ tH 74 

a'dh ftn @l eluioi, dilltions of etif,tE 

(1233{1.57 ,a/ rI) rE nid. tre Mr@

Y* ser r.cl..,f.*,r, v"r. ro uIr., 

ll@ wE .&i:d our for dch cmc.ihim: sc 

sffe.y .@hrio @fiici.d 6d dtcP' 

ErB *fr obrrind rot &t @rdd 

solrtidBlat ,aerrco o1 tsq 

A6@Y of rt. hd.d 6 .h..kd bY 

rErd'nr nr E lk k srds a.r uf diritn. n 

rh; dfi.Enr. *-"dio t*k s0tirll a?) 100 

(21.06) lnd 120 % (27 ?O) ud cal.uldthl rchrv! 

'6 slad d.vidiloi %RSC 

fta rcsux ol rh. $ove sodv i^dicd.3 rhr 

$ibbiliry ofrh. d$od b 4dtu e.;:itE in bulk 

dq s *.115 r dGrs. fmuldnd od in g'14 

ftE F.riod E noc r.rhbk thD d' uv 3pdF 

phosntric m.rhods rid ir .ncouEs* on. ro 'pprv 

lhk mnhod ror rcuLnc cirrYt3. 

I Evtoe.or Phdh@o.tia H.t M4dt! 

srilloncd otfie. 3-. .d., I, 342 (2000) 

t t. P. D.s.e1, Cli^ PtutuI th.t.5tatl 

M. B Mdv*liki dd J 

s.! &.m!pp3, J Pralr. Bioncd ,1ndt 25 

5 6. Emdd| G. C.4 O. Bolclu.d, B. va P 

croB.k, a P'!lid, T c. cmdi, A P.ft 

rl 

K X. PridF R. A. Ba@tu, T P A$dii r A 

Modi {d s K cnlrtzfiiv J Phun 

Pha6o.at., 13, tt0 lt96e) 

s. x. Mdd,ja ard 

ttu d. l^d ,2s,6ai l2$1) 

x xu.jui. G. Fr. L. zhrn. z w.ns. J sh. v 

Sn n ,ti H. s6s Zhanscto ritvon tto\q. 

Fr walily, M A Konry, Er CiidY sd M F 

B{j'i.J Phdt qk^.d tnd, t1,4)S ltqes) 

s O Cioi. s. H. Lc, u S (ons, E I Kimrd 

A. J.llnsk!, B sr.nirz. M z:Fc dd w 

MEiclt, Acto Pat Photh . s1, t7t lzadt)l 

M s. ,{n i., N. slltir rid F ^ jdd'qr'. 

P.r r Pho, s.i, ts,1 \loot). 

Phath simed 

^.ot 2t.139eaaa) 

w. Linsw.i F. Mtngx. aid z F!ig. )oo,r 

Y. chd3. Y Qin 

Yitz.n rMt. zahi. t9,1 t6 | t999) 

M T Ros*l and 

Chnnctost., 36a. 5aa (99 D 

sszrlp'Jl'U.P.H.|k,.mds.IRat. 

M zijr, w M6i.r. ^ 

R tu k t1 P ifuacapo. n. 2e 1, ( tee 3). 

uyrl !lkd:runf?|. M!^$... r .l L'q 

Crt ^tuE & Ret T..hDUtq ,10. u8t l2ntit

) 

\1 

pcio\ 

2nd International Symposium 

Cum Training Course on Molecular Medicine 

Drug Research (MMDR-2) 

Janurrr l2- 15,2009, Krrachi, Pakistan 

Abstract Book 

I)r. I'aniwrni Ccnlcr tor Molecular MediciDc and Drug llcsearch 

Intcrnalional Ccnter tbr Chcmical and lliological Scicnces 

Ulivcrsity of Krrachi. Karachi-752?0, Pakistan

Simultrnoous Dctermination of Cctirizine, Diltiazc nnd 

Anlodipinc Using Rosvast!(in $ In tcinal Strnderd in Dosrgc 

l.ormohtion ,nd lhman Scflin| by RP-HPLC 

I lina slnpslpdr, 14. S@d AnynC atrd N.jrtr slll!tu' 

't,b r, D@t*tu Eckdiitt, ud.Biry 4r,4hi xftN,752?a, Iolbb. iR.trqct td tu. ol 

Phdtdkaikd sdqat, D,Ntr.N {tr ,mtuid ckEhw f..'ltt 4rtu 44. 

udkhit otb6hi ks@^l, 75r74 Poltt@ 

PO-31 

ir bci &Erq.d sd uiida.d for ric dddniiflii or dkr.rn. ti 

[$uc ordrciln.rnii.r blcr.B (di *4 rnrodipii.) Grig @4prc k 

idnrosnd rc *tsnrlq hdhrn 'h'r 

t. dc, (6ttid rrnrdror l i wi 

diod ws roL nd b e .nicicir ud ks c 

dftJ!Jrogln'|*Da@'idF'djNdsp|6'I'..mhdlidlIE 

I re d@t,ryr@i @r4Mn4 n. r a

ADR, 

imLe 

Pror. K C Strghal 

SOCIE?Y OF pt{ARMACoVtctLANCE (lNDlA} 

Executlv€ Comhittee (2008.09) 

ChletEdti.r 

S.cr.trry - tni.m.dor||t R.hrrbn. 

r,r, PDe8€ 8bB 

organt hca.Jnt ry 

Oi S:nl!ru K Tdp.tft; 

1l! 

Yl \

P49 An RP-HPIC m.lhod tor tte slnullar.ous d.temlnauo. ol celi.Line ln 

pEsence ol qulnolon$ in bulk maletul, phamaceulidl lonnulations and human 

U!!:S!!!$3!, NaJm. sultana and M. saeld A'.yno 

Rese.rch Inslitule ot Plamaceuti*l Scienca, F cully of Pham.cy lt tab 9, 

0eparlmenl olChemiBlry UnlveFity ol Xaracht, Ka.achi.75270, Pakistan 

An acc"rale. sens lNe and easr Ine mlsum.T RP.FPLC reh;d to'rhe estmahol ol 

c€Inzine in lhe presence ot quinotones i.e cipofloxacin onofloncin, spamoxacin, 

norfiorecin, levolloxacin and olloxac n was devetoted and vatidated in active, dosage 

tomurations .nd in h! man seah Ceridn n. €tuled tom purcspher Srar, C 1 8 (5 nm. 250 

t 4 6 nm) column al room temperature us ng mob te phase of melhanot: scelon ldte: 

waier (50:20:30 vA/) at a fld .ale of lml ninurei $hite W deteclion l!?s periomed al 

?25 nm. The .elention lime of celiizine was tound Io be 4.00nin and that ot ouinotones 

wes 2 5rri The LOO and LOO vatues ro, @, ?r @e tound ro be OOI and O 0l 

mqnnLi. The method ,as va rdared tor accuracy, sensitiul, pecision, spe.jktry and 

ruggedness. Calibralion cuft€s were tound to be ltneff wilhin the Enge ? 5-50 mgmriL. 

, Mlh regressjon coeficient t2) O 999 The esrabtished H pLC method sas tou; to b€ 

Eo'd ac.urate a.d seled ve be(else or 'rs se-5nv(yat Rpbduc,bilt Moreo/er, rhe 

D.esenl rethod was found ro be etiecl,vF tor rhe,aDeulc olrooscs

.i-' 

P.10 Pnvsical ard chenidl cha'act€tizttion ol mli'namic tcld in difrerent_ 

t", , $eir stabititv studles u'lng novel RP tlPlc ' 

"nd 

',t1"-..1,"""i1*"s" 

ff"jltto*, .*"0 o.te' Hlnasham3had mtalir Asla Naz shari 

'Nishar 

iiiiiiEt-ii urza ". ana srruna raz st'at' 

1"",-"rw ne*atctr ldlitute ol Pharmtceuxcal scloncs I l'b I' 

o;prrinenl 

"ipr'"ma"v, olch€mistrt, univet3'tvol Krrachi haacht 75270 P'kisttn 

A n@l RP-HPLC melhod ,s lhe estimalion ol mfenamic acid in rd maleri'l difier€nl 

bhamaceutiel dosaoe lofms and in human serum io' rculircb analysls' lherapeulc 

irroos"s anO tor statit'ry sruO'es Ms deve'oped Presenl w* is elso a cllkclion or 

!"i.r o"rr"-"4 - tr'" pr'yo""t ,nd oemical asper ls o're'enarrc acid The m€lhod 

;ewooed consl ur€s L_i oDs Io nf, (25 cm x 4 6mm)column sth mobilF Ph'se 

;;Br'rd"972s%6@ronit.e, I%a(eric.Ld ?b5%wale'el279ndelul'9oulat42 

minure Th€ 0164l method or HPLC ms also compadd wilh fte UV visible tsnnque 

end ir was oljserued thal HPLC melhod is more pGcise, sensitve and accuhle 

1 

{

Ilt 

3'7i-- 

L:; -_I 

i' 

a 

\l

PR-180 

SrEd. Syntl.|b of C.lirLln. .nrloeua 

shr gnrdbd,, N{if Sdbn', ldtn Xrr,r .ut nt, &-a AnF 

t 4.a qPLa*d Crd.a, F-l'.,AJr,6,, ud.,*{t tdL r.,*ti 

zDptut {cldbxt urlpds dt n tl, r.nlrL 

tdd...b.--ct /dd&c.r.nj-.{'- 

9.&6! lRs)-z{2j.{adrt dEyl)cE t rdiy't pfdbr4lcidrFce rd dirrdnd ijltu 

r.rr.Fd durr |Id.j.r6ordlrE: i.r b{r tl4!d Tr. ffi of itE,t inrvtr 

wdlmcd b, uj4 |,..ruo|*) !c[r{E,{.6dtelt NMR 

cl 

'Q*'--*'" 

C.ddn.. dllrd r..r |. rd. 

Cdnic, dod- 4dE a|*h-a!! II}mL

Intenational Clenistry Conference 

Recent Advances in Chemistry 

E-3 Novernbel., aocrT 

Lqhore - pqjdsfqn 

ABSTRACTS 

:GWg HEC csP 

{oMr,tNG;" "#i,:iffi.- *"i:Ylitj:.*

thtu$ro^t chnbl4 hrf,.zht!- Ruut )tiax! h crt|rj| 

I/irro ttrlersction Sludi6 ofCetirizirewith Hi Re"Ptor Atrtagorkls 

Nltrg SpeFoPhotomctry !id RP-HPLC 

N',mSulbn, M. Stad /dvneltnd ltiDr Sbrmthld 

i:l;;;i;;i ;;*;io'-d'v D'p'nn'dorPhrnderu'ci'm 

Phms. UtrN.i,ry of Knd'i 

rD.D, ;-' .rck."'ry. !'""i'v , 

q fi'rh o 

*:C.ridzinc, $cond sd.htio HI d.ptordttsonitt, rs usl fo' rhc rratnc or'llclgn 

i'dirodqs. In eh. of tlE dis4@ combincd lheEPv of III and Ir2 is lcNrallv norc 

fictrdiv. tlE ii the ro'@.r orHr and H2 alone ahhoush rhG svnctsrsric cIlecr b's tol 

qtien found i. all studi6 Motovct, dl.nsiw t vD stldier ha!' bd catried dur oi 

!: lhe efilcLs of coadminismtion ofrhe rD tu.ptor antasooist on lhe pnamacokincr:cs 

rtnd phEn&odynmics oflh. Hl tccp@r dilgonisG so i! 

i"liln@h w6 adopcd 1o sludy lhe incraclion or cctiriznrc witn comnonlt admrnisteft'l 

(hc p'csc'l l)a €r a r/r' 

'' 

| tl2re.plor antagonhls ie ciniridinc, tuiridinc sd f.nordirc in simul'rinB bodv 

i 'nu{s !r diflercnt pH .nd al 3?oc cing RP_HPLC and Uv sD€chpholometv An RP' 

Fi. HPLC ncrhod was aho dev.loped and v'lidded for rbe sinuhmsus dcrcminrtion or 

:l tnce dtuls.--r'hc nobil. phs.onsisred ofn lhlnol: w!r.r (80:20) punp€d ar, flo* 

r.t. ol lmlmirll tlt€ ctuomotostam verc monilcrcd al 210 nm Th. rc$'lb tom llv 

spd1tophobmclry and HPLC clc.rly i.dic.kd thal lh. availabilnv ol tclnizinc wa{ 

unnlfc&d bt sn.ulhncou adninislmion of H2 reeplor anlalonisl Uctrcc rc lwo 

drugs euld bc aar.ly adninislorcd wirb each olher ' 

'X.y vor.t: Cedrizinc, IJI Kcnbr anlrgonist, lI2 rcccp(or mr|gonirr' ci'nitidinc, 

tuifti.. dd [motidine, i.r.Fcrion sludics, UV spcctoPhobmclry and I II'LC 

D.paiad o/

,/ 

:l 

i{ 

AB,S RACTS 

7'I INTERIATIoNAL &I7,, NATIoNAL 

'|{r.€llco.e Tirougi Inrovirion" 

Februsry 2G28,2007 

Under 

Chemical 

the auspices 

of 

Society of Pakistan 

Orarnized Bv 

Depannant ofCh;mtutrv 

comrl Udversitv. 

Dem Isnall Xhrn (NwFijpikisran

t- 

tionrl o.udrt .rntafut,. Pa tnt, 

OP4IMIZ4TION OF QU NTITATIV!] ANALYSIS oT 

CEI'IRJZINE USING MULTIVARTATE SPECIR^L 

CALIBDITTONS IN BULK DRUG AND DOSAGE 

TORMUL TIONS 

N.jmnsuirano , M, Saed Aiay.e, and Hin! Shamshad' 

Itrrcmch lnslitute of Phameeuljcrt Scicnc.s, Fncllry ot ph nrcy, 

UilvcNity ol Kdrochi. K,rachi.7527O. prkhlan. 

Dcplnmcnt ofChcmlsrry, Univcail! ot Xtlch , Kuraohr.75270, prtrr|i0j 

A !implc muhvsare sp€crmt cahbr on Incrt,oJ t4r rne quJnrnr,,\( 

rnrlysj! ol ccuhz'nc wrs ,leyctopcJ ,t hJr bccn loDpaEJ wnh rh. 

llNicll ull'rvnt.r sp.dmphoromerric ftrhoJs tor rhe 6umalor ul 

@dnnm.Thc n.thod was d€vctop€! in butf.^ of sjmutarcd sasrncju,cc 

dd rinuh@d blood pH. Th. I'n* Egrssion cqurlon wJs uscd d ',vc 

dfl.rcnr wJv.i.n8rhs. To lrtidlc 'tns n.rhoJ. inJbnc,,t prtumere s 

luci 6 siccrrvr). 4-Jii!) MJ pr.rkiun ho\e beer e{rbhJco lrl 

djlfcrcnt br.nG of tobleb and have b.cD .yatoitcd datsricany ro r$e$ 

lh. eplic!rion of rhe nrrhod. This ncthod js rupid,c$y, rnexpensive dxl 

a powcdui t@l wnh very sinpie ndrhcmuricut ;onb ; ror sy(ems. Thc 

mrhod hos bem jourd ro hJ\e ,,t\.ntJ8c tor ,,mp,r.r.). j..ti,,r.). 

rnririvtry l0 56,-B), rrpndu! 'b'hry,n-lO, !nd rcdfu, tor E.r3 L\cL: \ 

rn .rcnrlc to rhe crisring ,nermnhnromrnc mcrtroJs ro, rtc rrrtr,. 

aialysis ot ti. drg ns ph@@dcat tomutarjons and for cknical 

dudi6. Euivalcrce uudie we4 dso pcrfomcd ror difaeEm btunds ol 

cdnizinc rvail$lc in Pnkishn

Clw@terizclon of tL*Mi. ,1cid in Di&tu',t Pho@dicd Dotuge Fw.d tn ...

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