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Category Antifungal (topical).

      Miconazole Nitrate contains not less than 98.0 per cent and not more than 102.0 per cent of C₁₈H₁₄Cl₄N₂O.HNO₃, calculated on the dried basis.

Description White or almost white, crystalline or microcrystalline powder; odourless or almost odourless.

Solubility Very slightly soluble in water and in ether ; slightly soluble in chloroform  and in ethanol.

Contra-indication See under Clotrimazole , p. 83.

Warning

      1. It should not be used in children under 2 years of age.

      2. It should be used cautiously around the eyes.

      3. It may cause skin rash, blistering, burning, redness, or other signs of skin irritation.

      4. Risk-benefit should be considered if it is to be used in pregnancy, especially during the first trimester.

Precaution

      1. Miconazole nitrate should be discontinued upon the appearance of any symptoms suggesting sensitivity or irritation.

      2. When this medication is used in the treatment of candidiasis, occlusive dressing should be avoided since they provide conditions which favour growth of yeast and release of its irritating endotoxin.

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

Identification

      A. The infrared absorption spectrum is concordant with the spectrum obtained from Miconazole Nitrate RS (Appendix 2.1) or with the reference spectrum of Miconazole Nitrate.

      B. The ultraviolet absorption spectrum of a 0.04 per cent w/v solution in a mixture of 9 volumes of methanol  and 1 volume of 0.1 M hydrochloric acid , when observed between 230 and 350 nm, exhibits three maxima at 264 nm, 272 nm and 280 nm; the absorbances of a 1-cm layer at these wavelengths are about 0.40, 0.58 and 0.48, respectively (Appendix 2.2).

      C. Shake 10 mg with 5 ml of water  and cool in an ice-bath. Keeping the suspension cool throughout, add 8 drops of a 10 per cent w/v solution of potassium chloride , 2 drops of diphenylamine TS and dropwise, with shaking, 5 ml of sulfuric acid : an intense blue colour is produced.

Melting range 178º to 184º (Appendix 4.3).

Clarity of solution A 1.0 per cent w/v solution in methanol  is clear (Appendix 4.1).

Specific rotation –0.10º to +0.10º, determined in a 1.0 per cent w/v solution in methanol  (Appendix 4.8).

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 0.2 per cent w/w (Appendix 5.3).

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

      Mobile phase Prepare a solution of 6.0 g of ammonium acetate in a mixture of 300 ml of acetonitrile, 320 ml of methanol  and 380 ml of water. Make adjustments if necessary.

      Resolution solution Dissolve 2.5 mg of Miconazole Nitrate RS and 2.5 mg of Econazole Nitrate RS in Mobile phase  and dilute to 100.0 ml with the same solvent.

      Test solution (a) Dissolve 100 mg of the test substance in Mobile phase  and dilute to 10.0 ml with the same solvent.

      Test solution (b) Dilute 1.0 ml of Test solution (a)  to 100.0 ml with Mobile phase. Dilute 5.0 ml of this solution to 20.0 ml with the same solvent.

      Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (10 cm × 4.6 mm) packed with octadecylsilane chemically bonded to porous silica particles (3 μm), (b) Mobile phase  at a flow rate of about 2 ml per minute and (c) an ultraviolet photometer set at 235 nm.

      To determine the suitability of the chromatographic system, chromatograph Resolution solution, and record the peak responses as directed under Procedure: the resolution factor between the miconazole and econazole peaks is not less than 10. Chromatograph Test solution (b), and record the peak responses as directed under Procedure: the relative standard deviation for replicate injections is not more than 2.0 per cent.

      Procedure Separately inject equal volumes (about 10 μl) of Test solution (a) and Test solution (b) into the chromatograph, record the chromatograms and measure the responses for the major peaks. Continue the chromatography for 1.2 times the retention time of the principal peak. In the chromatogram obtained from Test solution (a), the area of any peak apart from the principal peak is not greater than the area of the principal peak in the chromatogram obtained from Test solution (b) (0.25 per cent); the sum of the areas of the peaks apart from the principal peak is not greater than twice the area of the principal peak in the chromatogram obtained from Test solution (b) (0.5 per cent). Disregard any peak due to the nitrate ion and any peak with an area less than 0.2 times the area of the principal peak in the chromatogram obtained from Test solution (b).

Assay Dissolve about 350 mg of Miconazole Nitrate, accurately weighed, in 50 ml of anhydrous glacial acetic acid. Titrate with 0.1 M perchloric acid VS, determining the end-point potentiometrically (Appendix 6.4). Perform a blank determination, and make any necessary correction. Each ml of 0.1 M perchloric acid is equivalent to 47.91 mg of C₁₈H₁₄C_l4N₂O.HNO₃.