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

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Consultation DocumentsWHO Drug Information Vol. 24, No. 4, 2010B. Carry out test B.1. or, where UV detection is not available, test B.2.B.1 Carry out the test as described under 1.14.1 Thin-layer chromatography, usingsilica gel R6 as the coating substance and a mixture of 50 volumes of heptane R, 30volumes of glacial acetic acid R and 20 volumes of dichloromethane R as the mobilephase. Apply separately to the plate 5 µl of each of the following two solutions inethanol R. For solution (A) disperse a quantity of powdered tablets to obtain a concentrationof 10 mg of Tenofovir disoproxil fumarate per ml, filter and use the filtrate. Forsolution (B) use 2 mg of fumaric acid R per ml. Develop the plate in an unsaturatedtank over a path of 10 cm. After removing the plate from the chromatographic chamber,allow it to dry exhaustively in air or in a current of air. Examine the chromatogramin ultraviolet light (254 nm).One of the spots obtained with solution A corresponds in position, appearance andintensity with that obtained with solution B.B.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using theconditions described above under test B.1 but using silica gel R5 as the coatingsubstance. Spray lightly with a 16 g/l solution of potassium permanganate R andexamine the chromatogram in daylight.One of the spots obtained with solution A corresponds in position, appearance andintensity with that obtained with solution B.C. See the test described under Assay. The retention times of the principal peaks inthe chromatogram obtained with the test solution are similar to those due to emtricitabine,tenofovir disoproxil and to fumarate in the chromatogram obtained with thereference solution.DissolutionCarry out the test as described under 5.5 Dissolution test for solid oral dosage forms,using as the dissolution medium, 900 ml of hydrochloric acid (~0.4 g/l) TS, and rotatingthe paddle at 50 revolutions per minute. At 45 minutes withdraw a sample of 10 mlof the medium and filter. Allow the filtered sample to cool to room temperature anddilute if necessary [solution (1)]. Prepare solution (2) using 0.22 mg of emtricitabineRS and 0.33 mg of tenofovir disoproxil fumarate RS per ml of dissolution medium.Determine the content of emtricitabine (C 8H 10FN 3O 3S) and tenofovir disoproxil fumarate(C 19H 30N 5O 10P,C 4H 4O 4) as described under Assay using solution (1) and solution(2).For each of the six tablets tested, calculate the total amount of emtricitabine(C 8H 10FN 3O 3S) and tenofovir disoproxil fumarate (C 19H 30N 5O 10P,C 4H 4O 4) in the mediumfrom the results obtained. For both substances, the amount in solution for each tabletis not less than 80% of the amount stated on the label. If the amount obtained for oneof the six tablets is less than 80%, repeat the test using a further six tablets; theaverage amount for all 12 tablets tested is not less than 75% and no tablet containsless than 60%.Tenofovir monoester. Carry out the test as described under 1.14.4 High-performanceliquid chromatography, using the conditions given under Assay.332
WHO Drug Information Vol. 24, No. 4, 2010Consultation DocumentsAfter preparation, keep the solutions at about 6 °C, or use an injector with cooling.Prepare the following solutions using a mixture of 20 volumes of acetonitrile R and 80volumes of water R as a diluent. For solution (1) weigh and powder 20 tablets. Dispersea quantity of the powder containing about 100 mg of Tenofovir disoproxil fumarate,accurately weighed, in 100 ml of the diluent and filter. For solution (2) dilute asuitable volume of solution (1) to obtain a concentration of 5 µg of Tenofovir disoproxilfumarate per ml. For solution (3) heat carefully 1 mg of tenofovir disoproxil fumarateRS per ml of water R in a boiling water-bath for 20 minutes.Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometerset at a wavelength of 280 nm.Maintain the column temperature at 35 °C.Inject 20 µl of solution (3). The peak due to tenofovir monoester elutes at a relativeretention of about 0.9 with reference to tenofovir disoproxil (retention time about 18minutes).Inject separately 20 µl each of solutions (1) and (2). The test is not valid unless in thechromatogram obtained with solution (1), three principal peaks are shown.In the chromatogram obtained with solution (1), the area of any peak due to tenofovirmonoester, is not greater than seven times the area of the principal peak obtained withsolution (2) (3.5%).AssayCarry out the test as described under 1.14.4 High-performance liquid chromatography,using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated particlesof silica gel the surface of which has been modified with chemically bondedoctadecylsilyl groups (5 µm). (Hypersil BDS column.)The 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:5 volumes of potassium dihydrogen phosphate (27.2 g/l) TSand 95 volumes of water R.70 volumes of acetonitrile R, 5 volumes of potassium dihydrogenphosphate (27.2 g/l) TS and 25 volumes of water R.Time Mobile phase A Mobile phase B Comments(min) (% v/v) (% v/v)0–9 93 7 Isocratic9–15 93 to 0 7 to 100 Linear gradient15–19 0 100 Isocratic19–19.1 0 to 93 100 to 7 Return to initialcomposition19.1–30 93 7 Re-equilibration333
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WHO Drug Information Vol. 24, No. 4, 2010

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