Miconazole Nitrate

(Ph. Eur. monograph 0513)

C ₁₈ H ₁₄ Cl ₄ N ₂ O,HNO ₃     479.1      22832-87-7

Antifungal azole.

Miconazole Cream

Miconazole and Hydrocortisone Cream

Miconazole and Hydrocortisone Acetate Cream

Miconazole and Hydrocortisone Ointment

Ph Eur

1-[(2RS)-2-[(2,4-Dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole nitrate.

99.0 per cent to 101.0 per cent (dried substance).

White or almost white powder.

Very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol (96 per cent).

First identification   A, B.

Second identification   A, C, D.

A. Melting point (2.2.14): 178 °C to 184 °C.

B. Infrared absorption spectrophotometry (2.2.24).

Comparison   miconazole nitrate CRS.

C. Thin-layer chromatography (2.2.27).

Test solution  Dissolve 30 mg of the substance to be examined in the mobile phase and dilute to 5 mL with the mobile phase.

Reference solution (a)  Dissolve 30 mg of miconazole nitrate CRS in the mobile phase and dilute to 5 mL with the mobile phase.

Reference solution (b)  Dissolve 30 mg of miconazole nitrate CRS and 30 mg of econazole nitrate CRS in the mobile phase, then dilute to 5 mL with the mobile phase.

Plate  TLC octadecylsilyl silica gel plate R.

Mobile phase  ammonium acetate solution R, dioxan R, methanol R (20:40:40 V/V/V).

Application  5 µL.

Development  Over 3/4 of the plate.

Drying  In a current of warm air for 15 min.

Detection  Expose to iodine vapour until the spots appear and examine in daylight.

System suitability  Reference solution (b):

• — the chromatogram shows 2 clearly separated spots.

Results  The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with reference solution (a).

D. It gives the reaction of nitrates (2.3.1).

Dissolve 0.1 g in methanol R and dilute to 10 mL with the same solvent.

Solution S is clear (2.2.1) and not more intensely coloured than reference solution Y₇ (2.2.2, Method II).

-0.10° to + 0.10°, determined on solution S.

Liquid chromatography (2.2.29).

Test solution  Dissolve 0.100 g of the substance to be examined in the mobile phase and dilute to 10.0 mL with the mobile phase.

Reference solution (a)  Dissolve 2.5 mg of miconazole nitrate CRS and 2.5 mg of econazole nitrate CRS in the mobile phase, then dilute to 100.0 mL with the mobile phase.

Reference solution (b)  Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 5.0 mL of this solution to 20.0 mL with the mobile phase.

• — size: l = 0.10 m, Ø = 4.6 mm;

• — stationary phase: octadecylsilyl silica gel for chromatography R (3 µm).

Mobile phase  Dissolve 6.0 g of ammonium acetate R in a mixture of 300 mL of acetonitrile R, 320 mL of methanol R and 380 mL of water R.

Flow rate  2 mL/min.

Detection  Spectrophotometer at 235 nm.

Injection  10 µL.

Run time  1.2 times the retention time of miconazole.

Relative retention  With reference to miconazole (retention time = about 20 min): impurity A = about 0.1; impurity E = about 0.3; impurity C = about 0.4; econazole = about 0.5; impurity B = about 0.6; impurity D = about 0.75; impurity F = about 0.85; impurity G = about 0.9.

System suitability  Reference solution (a):

• — resolution: minimum 10 between the peaks due to econazole and miconazole.

• — impurities A, B, C, D, E, F, G: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.25 per cent);

• — unspecified impurities: for each impurity, not more than 0.4 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);

• — total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (0.5 per cent);

• — disregard limit: 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent); disregard any peak due to the nitrate ion.

Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 2 h.

Maximum 0.1 per cent, determined on 1.0 g.

Dissolve 0.350 g in 75 mL of anhydrous acetic acid R, with slight heating if necessary. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20). Carry out a blank titration.

1 mL of 0.1 M perchloric acid is equivalent to 47.91 mg of C₁₈H₁₅Cl₄N₃O₄.

Protected from light.

Specified impurities   A, B, C, D, E, F, G.

Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): H, I.

A. (1RS)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol,

B. 1-[(2RS)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole,

C. (2RS)-2-[(2,4-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethanamine,

D. 1-[(2RS)-2-[(2,6-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole,

E. 2-[1-[(2RS)-2-[(2,4-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazol-3-io]-2-methylpropanoate,

F. 1-[(2RS)-2-[(3,4-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole,

G. 1-[(2RS)-2-[(2,5-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole,

H. 1-[(2RS)-2-benzyloxy-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole,

I. 1-[(2RS)-2-[(2-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole.

Ph Eur