(Ph. Eur. monograph 2332)
C8H9N3O4 211.2 65141-46-0
Action and use
Potassium channel opener.
Preparation
Nicorandil Tablets
DEFINITION
2-[(Pyridin-3-ylcarbonyl)amino]ethyl nitrate.
Content
99.0 per cent to 101.0 per cent (anhydrous substance).
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Sparingly soluble in water, freely soluble in anhydrous ethanol, practically insoluble in heptane.
IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Comparison: nicorandil CRS.
TESTS
pH (2.2.3)
5.5 to 7.0.
Dissolve: 0.25 g in carbon dioxide-free water R and dilute to 25 mL with the same solvent.
Related substances
Liquid chromatography (2.2.29). Prepare the solutions immediately before use.
Test solution: Dissolve 50 mg of the substance to be examined in the mobile phase and dilute to 25.0 mL with the mobile phase.
Reference solution (a): Dissolve 2 mg of nicorandil impurity A CRS in the mobile phase using sonication and dilute to 25.0 mL with the mobile phase. Dilute 1.0 mL of the solution to 20.0 mL with the test solution.
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 = 0.25 m, Ø = 4.6 mm;
— stationary phase: end-capped octadecylsilyl silica gel for chromatography compatible with 100 per cent aqueous mobile phases R (5 μm).
Mobile phase: trifluoroacetic acid R, triethylamine R, tetrahydrofuran R, water R (3:5:10:982 V/V/V/V).
Flow rate: 1.0 mL/min.
Detection: Spectrophotometer at 254 nm.
Injection: 10 μL.
Run time: 1.5 times the retention time of nicorandil.
Identification of impurities: Use the chromatogram obtained with reference solution (a) to identify the peak due to impurity A.
Relative retention: With reference to nicorandil (retention time = about 19 min): impurity A = about 0.9.
System suitability: Reference solution (a):
— resolution: minimum 2.5 between the peaks due to impurity A and nicorandil.
Calculation of percentage contents:
— for each impurity, use the concentration of nicorandil in reference solution (b).
Limits:
— unspecified impurities: for each impurity, maximum 0.10 per cent;
— total: maximum 0.2 per cent;
— reporting threshold: 0.05 per cent.
Sulfates (2.4.13)
Maximum 100 ppm.
Dissolve 5.000 g in 30 mL of ethanol (50 per cent V/V) R, add 1 mL of dilute hydrochloric acid R and dilute to 50.0 mL with distilled water R.
Water (2.5.32)
Maximum 0.5 per cent.
Dissolve 0.300 g in a suitable solvent and dilute to 1.0 mL with the same solvent. Inject 0.400 mL of the solution through the septum.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.150 g in 50 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 21.12 mg of C8H9N3O4.
STORAGE
At a temperature of 2 °C to 8 °C.
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) A, B, C, D.
A. 2-[(pyridin-4-ylcarbonyl)amino]ethyl nitrate,
B. N-(2-hydroxyethyl)pyridine-3-carboxamide,
C. 2-aminoethyl pyridine-3-carboxylate,
D. 3-(4,5-dihydro-1,3-oxazol-2-yl)pyridine.
