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CLOTRIMAZOLE CREAM

Category Antifungal (topical).

          Clotrimazole Cream contains not less than 90.0 per cent and not more than 110.0 per cent of the labelled amount of C22H17ClN2.

Strength available 1 per cent w/w.

Dose Topical, to the affected area of the skin and surrounding areas, twice a day, morning and evening.

Contra-indication; Warning; Precaution; Additional information See under Clotrimazole, p. 81.

Packaging and storage Clotrimazole Cream shall be kept in tightly closed containers.

Identification
          A. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using silica gel GF254 as the coating substance and 200 ml of ether as the mobile phase. Place a beaker, containing 25 ml of strong ammonia solution, in the chromatographic chamber, cover the chamber, and allow to equilibrate for 2 hours. Apply separately to the plate, 20 μl of each of the following solutions. For solution (A), transfer a portion of the cream, containing 5 mg of clotrimazole, to a 50-ml centrifuge tube. Add 5 ml of chloroform, mix and centrifuge to obtain a clear chloroform phase. Solution (B) contains a 0.1 per cent w/v solution of Clotrimazole RS in chloroform. After removal of the plate, allow it to dry in air and examine under ultraviolet light (254 nm): the principal spot in the chromatogram obtained from solution (A) corresponds to that obtained from solution (B). Dissolve 3 g of bismuth oxynitrate and 30 g of potassium iodide in 10 ml of diluted hydrochloric acid (1 in 4), dilute with water to 100 ml, mix, and prepare a spraying reagent by diluting 10 ml of this solution and 5 ml of diluted hydrochloric acid (1 in 4) with water to 200 ml, and mixing. Spray the plate evenly with this spraying reagent: the principal spots from solutions (A) and (B) are orange.
          B. The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
(2-Chlorophenyl)diphenylmethanol Not more than 1.0 per cent. Carry out the test as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).
          Mobile phase and Chromatographic system Proceed as directed in the Assay.
          Diluting solution A mixture of 7 volumes of methanol and 3 volumes of 0.02 M phosphoric acid.
          Reference solution Dissolve an accurately weighed quantity of (2-Chlorophenyl)diphenylmethanol RS in Diluting solution to obtain a solution having a known concentration of about 2 μg per ml.
          Test solution (a) Extract a portion of the cream, containing 20 mg of clotrimazole by warming with 20 ml of methanol in a water-bath at 50º for 5 minutes, shaking occasionally. Remove from the water-bath, shake the mixture vigorously while cooling to room temperature, cool in ice for 15 minutes, centrifuge for 5 minutes and decant the supernatant liquid. Repeat the extraction with two further 20-ml quantities of methanol. To the combined methanol extracts add 10 ml of methanol and dilute to 100.0 ml with 0.02 M phosphoric acid. Cool in ice and filter.
          Test solution (b) Dilute volume of Test solution (a) to 50 volumes with Diluting solution.
          To determine the suitability of the chromatographic system, chromatograph Test solution (b), and record the peak responses as directed under Procedure: the column efficiency, determined from the clotrimazole peak, is not less than 1800 theoretical plates and the relative standard deviation for replicate injections is not more than 2.0.
          Procedure Separately inject equal volumes (about 20 μl) of Reference solution and Test solution (a) into the chromatograph, and record the chromatograms for Test solution (a) for 1.5 times the retention time of the principal peak. The area of any peak corresponding to (2- chlorophenyl)diphenylmethanol in the chromatogram obtained from Test solution (a) is not greater than the area of the peak in the chromatogram obtained from Reference solution.

Assay Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).


          Mobile phase Prepare a mixture of 30 volumes of 0.02 M phosphoric acid and 70 volumes of methanol, the pH of the mixture being adjusted to 7.5 with a 10 per cent v/v solution of triethylamine in methanol. Make adjustments if necessary.
          Standard preparation Dissolve about 20 mg of Clotrimazole RS, accurately weighed, in 70 ml of methanol, add sufficient 0.02 M phosphoric acid to produce 100.0 ml and dilute 10.0 ml of the resulting solution to 50.0 ml with a mixture of 70 volumes of methanol and 30 volumes of 0.02 M phosphoric acid.
          Assay preparation Extract an accurately weighed portion of Clotrimazole Cream, containing about 20 mg of clotrimazole, by warming with 20 ml of methanol in a water-bath at 50º for 5 minutes, shaking occasionally. Remove from the water-bath, shake the mixture vigorously while cooling to room temperature, cool in ice for 15 minutes, centrifuge for 5 minutes and decant the supernatant liquid. Repeat the extraction with two further 20-ml quantities of methanol. To the combined methanol extracts add 10 ml of methanol and dilute to 100.0 ml with 0.02 M phosphoric acid. Cool in ice and filter. Dilute 10.0 ml of the filtrate to 50.0 ml with a mixture of 70 volumes of methanol and 30 volumes of 0.02 M phosphoric acid.
          Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (20 cm × 4.6 mm) packed with octadecylsilane chemically bonded to porous silica or ceramic microparticles (5 μm), (b) Mobile phase at a flow rate of about 1.5 ml per minute, and (c) an ultraviolet photometer set at 215 nm.
          To determine the suitability of the chromatographic system, chromatograph Standard preparation, and record the peak responses as directed under Procedure: the relative standard deviation for replicate injections is not more than 2.0.
          Procedure Separately inject equal volumes (about 20 μl) of Standard preparation and Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks.
          Calculation Calculate the content of C22H17ClN2 in the portion of the Cream taken, using the declared content of C22H17ClN2 in Clotrimazole RS.

Other requirements Complies with the requirements described under “Topical Semi-solid Preparations (Appendix 1.16).

MONOGRAPHS • CLOTRIMAZOLE CREAM
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หมายเหตุ / Note : TP II 2011 PAGE 85 - 86