(Ph. Eur. monograph 1018)
C18H14Cl4N2O 416.1 27523-40-6
Action and use
Antifungal.
DEFINITION
1-[(2RS)-2-(2,4-Dichlorophenyl)-2-[(2,6-dichlorophenyl)methoxy]ethyl]-1H-imidazole.
Content
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white powder.
Solubility
Practically insoluble in water, very soluble in methanol, freely soluble in ethanol (96 per cent).
IDENTIFICATION
A. Melting point (2.2.14): 111 °C to 115 °C.
B. Infrared absorption spectrophotometry (2.2.24).
Comparison: isoconazole CRS.
TESTS
Solution S
Dissolve 0.20 g in methanol R and dilute to 20.0 mL with the same solvent.
Appearance of solution
Solution S is clear (2.2.1) and not more intensely coloured than reference solution Y6 (2.2.2, Method II).
Optical rotation (2.2.7)
-0.10° to + 0.10°, determined on solution S.
Related substances
Liquid chromatography (2.2.29).
Test solution: Dissolve 0.100 g of the substance to be examined in 3.2 mL of methanol R. Add 3.0 mL of acetonitrile R and dilute to 10.0 mL with a 15.78 g/L solution of ammonium acetate R.
Reference solution (a): Dissolve 2.5 mg of isoconazole CRS and 2.5 mg of miconazole nitrate CRS (impurity D) in the mobile phase, then dilute to 100 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 1.0 mL of this solution to 10.0 mL with the mobile phase.
Column:
— size: l = 0.10 m, Ø = 4.6 mm;
— stationary phase: end-capped 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 for chromatography R, 320 mL of methanol R1 and 380 mL of water for chromatography R.
Flow rate: 2 mL/min.
Detection: Spectrophotometer at 235 nm.
Injection: 10 μL.
Run time: Twice the retention time of isoconazole.
Identification of impurities: Use the chromatogram obtained with reference solution (a) to identify the peak due to impurity D.
Relative retention: With reference to isoconazole (retention time = about 14 min): impurity D = about 1.4.
System suitability: Reference solution (a):
— resolution: minimum 5.0 between the peaks due to isoconazole and impurity D.
Calculation of percentage contents:
— for each impurity, use the concentration of isoconazole in reference solution (b).
Limits:
— unspecified impurities: for each impurity, maximum 0.10 per cent;
— total: maximum 0.5 per cent;
— reporting threshold: 0.05 per cent.
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 2 h.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.300 g in 50 mL of a mixture of 1 volume of anhydrous acetic acid R and 7 volumes of methyl ethyl ketone R.
Using 0.2 mL of naphtholbenzein solution R as indicator, titrate with 0.1 M perchloric acid until the colour changes from orange-yellow to green.
1 mL of 0.1 M perchloric acid is equivalent to 41.61 mg of C18H14Cl4N2O.
STORAGE
Protected from light.
IMPURITIES
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) B, C, D.
B. (1RS)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol,
C. (2RS)-2-(2,4-dichlorophenyl)-2-[(2,6-dichlorophenyl)methoxy]ethan-1-amine,
D. 1-[(2RS)-2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole (miconazole).
