WHO Drug Information Vol. 24, No. 4, 2010

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Consultation DocumentsWHO Drug Information Vol. 24, No. 4, 2010The mobile phases for gradient elution consist of a mixture of Mobile phase A andMobile phase B, using the following conditions:Mobile phase A:Mobile phase B:90 volumes of a 0.05% solution of trifluoroacetic acid R and10 volumes of methanol R.10 volumes of a 0.05% solution of trifluoroacetic acid R and90 volumes of methanol R.Time Mobile phase A Mobile phase B Comments(min) (% v/v) (% v/v)0–16 60 to 50 40 to 50 Linear gradient16–23 50 to 35 50 to 65 Linear gradient23–28 35 to 30 65 to 70 Linear gradient28–29 30 to 20 70 to 80 Linear gradient29–31 20 80 Isocratic31–32 20 to 60 80 to 40 Return to initialcomposition32–40 60 40 Re-equilibrationPrepare the following solutions in the dissolution solvent, a mixture of equal volumesof acetonitrile R and water RFor solution (1) weigh and powder 20 tablets. Transfer a quantity of the powderedtablets containing about 25 mg of Efavirenz, accurately weighed, into about 20 mlof the dissolution solvent, sonicate for 5 minutes, allow to cool to room temperatureand dilute to 25.0 ml with the same solvent. Filter a portion of this solution through a0.45-µm filter, discarding the first few ml of the filtrate. Dilute 1.0 ml of the resultingsolution to 100.0 ml with the dissolution solvent. For solution (2) dissolve 25 mg ofefavirenz RS in the dissolution solvent and dilute to 25.0 ml with the same solvent.Dilute 1.0 ml of the resulting solution to 100.0 ml with the dissolution solvent. Forsolution (3) dissolve about 5 mg of efavirenz RS in 5 ml of a solution prepared asfollows: dissolve 1 mg of efavirenz impurity B RS in the dissolution solvent and diluteto 10 ml with the same solvent. Dilute 1 ml of the resulting solution to 25 ml with thedissolution solvent.Operate with a flow rate of 1.5 ml per minute. As a detector use an ultraviolet spectrophotometerset at a wavelength of about 250 nm.Maintain the column temperature at 40 °C.Inject separately 35 µl each of solutions (1), (2) and (3). In the chromatogram obtainedwith solution (3), the peak due to impurity B is eluted at a relative retention of about0.9 with reference to efavirenz (retention time about 20 minutes). The assay is notvalid unless the resolution factor between the peaks due to impurity B and efavirenz isat least 3.Measure the areas of the peak responses obtained in the chromatograms from solutions(1) and (2), and calculate the content of efavirenz (C 14H 9ClF 3NO 2) in the tablets.322
WHO Drug Information Vol. 24, No. 4, 2010Consultation Documents[Note from Secretariat: retention times and resolution factor to be confirmed.]B. Weigh and powder 20 tablets. Transfer a quantity of the powdered tablets containingabout 25 mg of Efavirenz, accurately weighed, to a 50-ml volumetric flask. Addabout 25 ml of methanol R, sonicate for about 5 minutes, allow to cool to room temperatureand make up to volume using the same solvent. Filter a portion of thissolution through a 0.45-µm filter, discarding the first few ml of the filtrate. Dilute 1.0 mlof this solution to 50.0 ml with methanol R. Measure the absorbance (1.6) of a 1-cmlayer of this solution at the maximum at about 247 nm. Calculate the content ofefavirenz (C 14H 9ClF 3NO 2) in the tablets using an absorptivity value of 55.01%(A = 550).1 cmImpurities. The impurities limited by the requirements of this monograph includethose listed in the monograph for Efavirenz.Efavirenz, emtricitabine and tenofovir tabletsDraft proposal for The International Pharmacopoeia (September2010). Please address any comments to Quality Assurance andSafety: Medicines, World Health Organization, 1211 Geneva 27,Switzerland. Fax +41227914730 or e-mail to mendyc@who.int.A subscriber mailing list is now available to speed up consultation.For more information please contact bonnyw@who.int.Category. Antiretroviral (Non-nucleoside/Nucleoside/Nucleotide Reverse TranscriptaseInhibitors).Storage. Efavirenz, emtricitabine and tenofovir tablets should be kept in a tightlyclosed container.Additional information. Strength in the current WHO Model List of Essential Medicines:600 mg Efavirenz, 200 mg Emtricitabine and 300 mg Tenofovir disoproxilfumarate.Comply with the monograph for “Tablets”.REQUIREMENTSDefinition. Efavirenz, emtricitabine and tenofovir tablets contain Efavirenz, Emtricitabineand Tenofovir disoproxil fumarate. They contain not less than 90.0% and not morethan 110.0% of the amount of efavirenz (C 14H 9ClF 3NO 2), emtricitabine (C 8H 10FN 3O 3S)and tenofovir disoproxil fumarate (C 19H 30N 5O 10P,C 4H 4O 4) stated on the label.Manufacture. The manufacturing process and the product packaging are designedand controlled so as to minimize the moisture content of the tablets. They ensure that,if tested, the tablets would comply with a water content limit of not more than 60 mg/gwhen determined as described under 2.8 Determination of water by the Karl Fischermethod, Method A, using about 0.5 g of the powdered tablets.323
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WHO Drug Information Vol. 24, No. 4, 2010

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