(Ph. Eur. monograph 1393)
C17H12Br2O3 424.1 3562-84-3
Action and use
Uricosuric; treatment of hyperuricaemia.
DEFINITION
(3,5-Dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone.
Content
98.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Practically insoluble in water, freely soluble in acetone and in methylene chloride, sparingly soluble in ethanol (96 per cent).
mp
About 152 °C.
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Comparison: benzbromarone CRS.
B. By means of a copper wire, previously ignited, introduce a small amount of the substance to be examined into the non-luminous part of a flame. The colour of the flame becomes green.
TESTS
Appearance of solution
The solution is clear (2.2.1) and not more intensely coloured than reference solution Y5 (2.2.2, Method II).
Dissolve 1.25 g in dimethylformamide R and dilute to 25 mL with the same solvent.
Acidity or alkalinity
Shake 0.5 g with 10 mL of carbon dioxide-free water R for 1 min and filter. To 2.0 mL of the filtrate add 0.1 mL of methyl red solution R and 0.1 mL of 0.01 M hydrochloric acid. The solution is red. Add 0.3 mL of 0.01 M sodium hydroxide. The solution is yellow.
Related substances
Liquid chromatography (2.2.29).
Test solution: Dissolve 0.125 g of the substance to be examined in 30 mL of methanol R and dilute to 50.0 mL with the mobile phase.
Reference solution (a): 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.
Reference solution (b): Dissolve 10 mg of benzarone CRS (impurity C) in the mobile phase and dilute to 20 mL with the mobile phase. To 5 mL of this solution add 1 mL of the test solution and dilute to 100 mL with the mobile phase.
Column:
— size: l = 0.25 m, Ø = 4.6 mm;
— stationary phase: octadecylsilyl silica gel for chromatography R (5 μm).
Mobile phase: glacial acetic acid R, acetonitrile R, water R, methanol R (5:25:300:990 V/V/V/V).
Flow rate: 1.5 mL/min.
Detection: Spectrophotometer at 231 nm.
Injection: 20 μL.
Run time: 2.5 times the retention time of benzbromarone.
Relative retention: With reference to benzbromarone: impurity A = about 0.6; impurity B = about 2.
System suitability: Reference solution (b):
— resolution: minimum 10.0 between the peaks due to impurity C (1 peak) and benzbromarone (2 peak).
Limits:
— impurity A: not more than 4 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.4 per cent);
— impurity B: not more than 10 times the area of the principal peak in the chromatogram obtained with reference solution (a) (1.0 per cent);
— unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent);
— sum of impurities other than A and B: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);
— disregard limit: 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.02 per cent).
Halides expressed as chlorides (2.4.4)
Maximum 400 ppm.
Shake 1.25 g with a mixture of 5 mL of dilute nitric acid R and 15 mL of water R. Filter. Rinse the filter with water R and dilute the filtrate to 25 mL with the same solvent. Dilute 2.5 mL of this solution to 15 mL with water R.
Iron (2.4.9)
Maximum 125 ppm.
Moisten the residue obtained in the test for sulfated ash with 2 mL of hydrochloric acid R and evaporate to dryness on a water-bath. Add 0.05 mL of hydrochloric acid R and 10 mL of water R, heat to boiling and maintain boiling for 1 min. Allow to cool. Rinse the crucible with water R, collect the rinsings and dilute to 25 mL with water R. Dilute 2 mL of this solution to 10 mL with water R.
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in vacuo at 50 °C for 4 h.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.300 g in 60 mL of methanol R. Stir until completely dissolved and add 10 mL of water R. Titrate with 0.1 M sodium hydroxide, determining the end-point potentiometrically (2.2.20).
1 mL of 0.1 M sodium hydroxide is equivalent to 42.41 mg of C17H12Br2O3.
STORAGE
Protected from light.
IMPURITIES
Specified impurities: A, B.
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) C.
A. (3-bromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone,
B. (6-bromo-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone,
C. (2-ethylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (benzarone).
