สารบัญ

Clotrimazole contains not less than 98.0 per centand not more than 102.0 per cent of C₂₂H₁₇ClN₂, calculatedon the dried basis.

Description White or pale yellow, crystalline powder.

Solubility Practically insoluble in water; soluble in chloroform and in ethanol; slightly soluble in ether.

Contra-indication It is contra-indicated in patients who are hypersensitive to imidazole derivatives.

Warning
          1. Clotrimazole is not for ophthalmic use and should be used with caution around the eyes.
          2. It may cause blistering, erythema, edema, pruritus, burning, stinging, peeling, urticaria, skin fissures, and general irritation of the skin.
          3. Mild burning, skin rash, itching, vulval irritation, lower abdominal cramps, bloating, slight cramping, vaginal soreness, dyspareunia, and slight urinary frequency may occasionally occur in patients receiving clotrimazole vaginal tablets.
          4. Risk-benefit should be considered if it is to be used in pregnant women, especially during the first trimester.

Precaution
          1. Clotrimazole should be discontinued upon the appearance of any symptoms suggesting sensitivity or irritation, and the appropriate treatment should be instituted.
          2. When this medication is used in the treatment of candidiasis, occlusive dressings should be avoided since they provide conditions which favour growth of yeast and release of its irritating endotoxin.
          3. Periodic determinations of liver function should be performed, particularly in patients with pre-existing hepatic impairment.

Additional information It is advisable to continue medicine for full time of treatment.

Packaging and storage Clotrimazole shall be kept in well-closed containers, protected from light.

Identification
          A. The infrared absorption spectrum is concordant with the spectrum obtained from Clotrimazole RS (Appendix 2.1) or with the reference spectrum of Clotrimazole.
          B. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using silica gel GF254 as the coating substance and a mixture of 1 volume of strong ammonia solution, 20 volumes of 1-propanol and 180 volumes of toluene as the mobile phase. Apply separately to the plate, 10 μl of each of the following solutions. For solution (A), dissolve 500 mg of the test substance in ethanol and dilute to 5 ml with the same solvent. For solution (B) dilute 1 ml of solution (A) to 10 ml with ethanol. Solution (C) contains 10 mg per ml of Clotrimazole RS in ethanol. 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 (B) is similar in position and size to that obtained from solution (C).
          C. Dissolve 10 mg in 3 ml of sulfuric acid: the solution is pale yellow. Add 10 mg of yellow mercury(II) oxide and 20 mg of sodium nitrite. Allow to stand with occasional shaking: an orange colour develops, becoming orange-brown.

Melting range 141º to 145º (Appendix 4.3).

Loss on drying Not more than 0.5 per cent w/w after drying at 105º for 2 hours (Appendix 4.15).

Sulfated ash Not more than 0.1 per cent w/w (Appendix 5.3).

Heavy metals Not more than 10 ppm (Method II, Appendix 5.2). Use 2.0 g; for the Standard preparation, use lead standard solution (1 ppm Pb).

(2-Chlorophenyl)diphenylmethanol Not more than 0.2 per cent. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using silica gel G as the coating substance and a mixture of 90 volumes of toluene, 10 volumes of 1-propanol and 0.5 volume of strong ammonia solution as the mobile phase.
          Reference solution (a) Dissolve 50 mg of Clotrimazole RS in ethanol and dilute to 5 ml with the same solvent.
          Reference solution (b) Dissolve 10 mg of (2- Chlorophenyl)diphenylmethanol RS in ethanol and dilute to 5 ml with the same solvent. Dilute 1 ml of the solution to 10 ml with ethanol.
          Test solution (a) Dissolve 500 mg of the test substance in ethanol and dilute to 5 ml with the same solvent.
          Test solution (b) Dilute 1 ml of Test solution (a) to 10 ml with ethanol.
          Apply separately to the plate 10 μl of each solution. After removal of the plate, allow it to dry in air. Spray with a 10 per cent v/v solution of sulfuric acid in ethanol and heat at 100º to 105º for 30 minutes. Any spot corresponding to (2-chlorophenyl)diphenylmethanol in the chromatogram obtained from Test solution (a) is not more intense than the spot in the chromatogram obtained from Reference solution (b).

Imidazole Not more than 0.2 per cent. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using silica gel G as the coating substance and a mixture of 90 volumes of toluene, 10 volumes of 1-propanol and 0.5 volume of strong ammonia solution as the mobile phase.
          Reference solution Dissolve 10 mg of Imidazole RS in ethanol and dilute to 10 ml with the same solvent. Dilute 1 ml of the solution to 10 ml with ethanol.

          Test solution Dissolve 500 mg of the test substance in ethanol and dilute to 10 ml with the same solvent.
          Apply separately to the plate 10 μl of each solution. After removal of the plate, allow it to dry in air. At the bottom of a chromatographic tank, place an evaporating dish containing a mixture of 1 volume of hydrochloric acid, 1 volume of water and 2 volumes of a 1.5 per cent w/v solution of potassium permanganate, close the tank and allow to stand for 15 minutes. Place the dried plate in the tank and close the tank. Leave the plate in contact with the chlorine vapour for 5 minutes. Withdraw the plate and place it in a current of cold air until the excess of chlorine is removed and an area of coating below points of application does not give a blue colour with a drop of potassium iodide and starch TS. Spray with potassium iodide and starch TS. Any spot corresponding to imidazole in the chromatogram obtained from Test solution is not more intense than the spot in the chromatogram obtained from Reference solution.
Assay Dissolve about 170 mg of Clotrimazole, accurately weighed, in 50 ml of anhydrous glacial acetic acid. Titrate with 0.1 M perchloric acid VS, using 0.5 ml of 1- naphtholbenzein TS as indicator or determining the endpoint potentiometrically (Appendix 6.1). Perform a blank determination, and make any necessary correction. Each ml of 0.1 M perchloric acid is equivalent to 34.48 mg of C₂₂H₁₇ClN₂.