Action and use
Potassium channel opener; vasodilator.
DEFINITION
Nicorandil Tablets contain Nicorandil.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of nicorandil, C8H9N3O4
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
Solvent A: 20 volumes of methanol and 80 volumes of dichloromethane.
(1) Dissolve a quantity of the powdered tablets containing 10 mg of Nicorandil in solvent A and mix with the aid of ultrasound. Add sufficient solvent A to produce a solution containing 0.1% w/v of Nicorandil and filter.
(2) 0.1% w/v of nicorandil BPCRS in methanol.
(3) 0.1% w/v each of nicorandil BPCRS and nicotinamide BPCRS in methanol.
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254 (Merck silica gel 60 F254 plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 10 μL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air and examine under ultraviolet light (254 nm).
MOBILE PHASE
1 volume of methanol, 4 volumes of dichloromethane and 5 volumes of ethyl acetate.
SYSTEM SUITABILITY
The test is not valid unless the chromatogram obtained with solution (3) shows two clearly separated spots.
CONFIRMATION
The principal spot in the chromatogram obtained with solution (1) corresponds in position and size to that in the chromatogram obtained with solution (2).
B. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the principal peak in the chromatogram obtained with solution (2).
TESTS
Dissolution
Comply with the dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 1, rotating the basket at 50 revolutions per minute.
(b) Use 900 mL of 0.1M hydrochloric acid, at a temperature of 37°, as the medium.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) After 30 minutes, withdraw a sample of the medium and filter (a 0.45-μm PTFE filter is suitable). Use the filtrate, diluted with dissolution medium if necessary, to give a solution expected to contain 0.0011% w/v of Nicorandil.
(2) 0.0011% w/v of nicorandil BPCRS in 0.1M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 μm) (YMC pack ODS AQ is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 40 μL of each solution.
MOBILE PHASE
Add 1.5 volumes of trifluoroacetic acid to 965 volumes of water. Separately mix 2 volumes of triethylamine, 10 volumes of tetrahydrofuran and 25 volumes of methanol. Mix the 2 solutions together.
When the chromatograms are recorded under the prescribed conditions the retention time of nicorandil is about 11 minutes.
DETERMINATION OF CONTENT
Calculate the total content of nicorandil, C8H9N3O4, in the medium from the chromatograms obtained and using the declared content of C8H9N3O4 in nicorandil BPCRS.
LIMITS
The amount of nicorandil released is not less than 80% (Q) of the stated amount.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions, prepared immediately before use.
Solution A: 7 volumes of methanol and 93 volumes of water.
(1) To a quantity of the powdered tablets containing 0.1 g of Nicorandil, add 4 mL of water and 28 mL of methanol and shake. Add sufficient water to produce 100 mL and filter (a 0.45-μm membrane filter is suitable).
(2) Dilute 1 volume of solution (1) to 100 volumes with solution A.
(3) 0.0004% w/v of nicorandil impurity standard BPCRS in solution A.
(4) Heat approximately 40 mg of nicorandil BPCRS for 2 hours at 70°. Allow to cool and dissolve a quantity of the material in sufficient solution A to produce a 0.8% w/v solution (generation of impurities 2, D, 4, 5 and 6).
(5) Dilute 1 volume of solution (2) to 5 volumes with solution A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 μm) (YMC pack ODS AQ is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 10 μL of each solution.
MOBILE PHASE
Mobile phase A: Add 1.5 volumes of trifluoroacetic acid to 965 volumes of water. Separately mix 2 volumes of triethylamine, 10 volumes of tetrahydrofuran and 25 volumes of methanol. Mix the 2 solutions together.
Mobile phase B: methanol.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-45 | 100 | 0 | isocratic |
| 45-80 | 100→75 | 0→25 | linear gradient |
| 80-82 | 75→100 | 25→0 | linear gradient |
| 82-92 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to nicorandil (retention time about 14 minutes) are: impurity 1, about 0.27; impurity B (nicorandil amide), about 0.31; impurity 2, about 0.36; impurity D (2-(3-pyridyl) 2-oxazoline), about 0.5; impurity 3, about 0.7; impurity 4, about 1.1; impurity 5, about 1.3 and impurity 6, about 1.6.
SYSTEM SUITABILITY
The test is not valid unless:
in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity 1 (nicotinic acid) and impurity B (nicorandil amide) is at least 1.5;
in the chromatogram obtained with solution (4), the peak-to-valley ratio is at least 4.5, where Hp is the height above the baseline of the peak due to impurity 4 and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to nicorandil.
LIMITS
Identify any peak in the chromatogram obtained with solution (1) due to impurity 4 using the chromatogram obtained with solution (4). Multiply the area of any peak corresponding to impurity 4 by a correction factor of 1.4.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity D is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1%);
the area of any peak corresponding to impurity 4 is not greater than half the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);
the area of any secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (5) (0.2%);
the sum of the areas of any other secondary peaks is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (2%).
Disregard any peak with an area less than half the area of the principal peak in the chromatogram obtained with solution (5) (0.1%).
ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions
prepared immediately before use.
Solution A: 7 volumes of methanol and 93 volumes of water.
(1) To a quantity of the powdered tablets containing 0.1 g of Nicorandil, add 4 mL of water and 28 mL of methanol and shake. Add sufficient water to produce 100 mL and filter (a 0.45-μm PTFE filter is suitable). Dilute 1 volume to 20 volumes with water.
(2) 0.005% w/v of nicorandil BPCRS in solution A.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used.
DETERMINATION OF CONTENT
Calculate the content of C8H9N3O4 in the tablets using the declared content of C8H9N3O4 in nicorandil BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include impurities A, B and D listed under Nicorandil and:
1. pyridine-3-carboxylic acid (nicotinic acid)
2. 2-aminoethyl pyridine-3-carboxylate nitrate (nicorandil nitrate)
3. methyl pyridine-3-carboxylate (methyl nicotinate)
4. N-[2-({N-[2-(nitro-oxy)ethyl]pyridin-3-carboximidoyl}oxy)ethyl]pyridine-3-carboxamide (nicorandil dimer)
5. N-{2-[{N-[2-({N-[2-(nitro-oxy)ethyl]pyridin-3-carboximidoyl}oxy)ethyl]pyridin-3-carboximidoyl}oxy]ethyl}pyridine-3-
carboxamide (nicorandil trimer)
6. N-{2-[(N-{2-[{N-[2-({N-[2-(nitro-oxy)ethyl]pyridin-3-carboximidoyl}oxy)ethyl]pyridin-3-carboximidoyl}oxy]ethyl}pyridin-3-
carboximidoyl)oxy]ethyl}pyridine-3-carboxamide (nicorandil tetramer)
