(Ph. Eur. monograph 2932)
C19H18ClN3O5S 435.9 366789-02-8
Action and use
Factor Xa inhibitor; anticoagulant
Preparation
Rivaroxaban Tablets
DEFINITION
5-Chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide.
Content
98.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance
White or yellowish powder.
Solubility
Practically insoluble in water, freely soluble in dimethyl sulfoxide, practically insoluble in anhydrous ethanol and in heptane.
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Comparison: rivaroxaban CRS.
B. Enantiomeric purity (see Tests).
TESTS
Enantiomeric purity
Liquid chromatography (2.2.29).
Test solution: Dissolve 20 mg of the substance to be examined in 25 mL of acetonitrile R and dilute to 50 mL with anhydrous ethanol R.
Reference solution (a): Dissolve 1 mg of rivaroxaban impurity A CRS in 5 mL of acetonitrile R and dilute to 10 mL with anhydrous ethanol R.
Reference solution (b): Dissolve 20 mg of the substance to be examined in 25 mL of acetonitrile R, add 1 mL of reference solution (a) and dilute to 50 mL with anhydrous ethanol R.
Column:
— size: l = 0.25 m, Ø = 2.0 mm;
— stationary phase: cellulose derivative of silica gel for chiral separation R (10 μm);
— temperature: 50 °C.
Mobile phase: anhydrous ethanol R, heptane R (30:70 V/V).
Flow rate: 0.2 mL/min.
Detection: Spectrophotometer at 250 nm.
Injection: 3.0 μL of the test solution and reference solution (b).
Run time: 1.5 times the retention time of rivaroxaban.
Relative retention: With reference to rivaroxaban (retention time = about 17 min): impurity A = about 0.9.
System suitability: Reference solution (b):
— resolution: minimum 1.5 between the peaks due to impurity A and rivaroxaban.
Limit:
— impurity A: maximum 0.5 per cent; calculate the ratio of the area of the peak due to impurity A to the sum of the areas of the peaks due to rivaroxaban and impurity A.
Related substances
Liquid chromatography (2.2.29).
Solution A: Dissolve 1.36 g of potassium dihydrogen phosphate R in water for chromatography R, add 200 μL of phosphoric acid R and dilute to 1000 mL with water for chromatography R.
Solvent mixture acetonitrile R, solution A (40:60 V/V).
Test solution: Dissolve 25.0 mg of the substance to be examined in the solvent mixture and dilute to 50.0 mL with the solvent mixture.
Reference solution (a): Dissolve 25.0 mg of rivaroxaban CRS in the solvent mixture and dilute to 50.0 mL with the solvent mixture.
Reference solution (b): Dilute 1.0 mL of the test solution to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.
Reference solution (c): Dissolve 2.5 mg of rivaroxaban for system suitability CRS (containing impurity G) in the solvent mixture and dilute to 5 mL with the solvent mixture.
Column:
— size: l = 0.15 m, Ø = 3.0 mm;
— stationary phase: end-capped extra-dense bonded octadecylsilyl silica gel for chromatography R (3.5 μm);
— temperature: 60 °C.
Mobile phase:
— mobile phase A: mix 5 volumes of methanol R and 95 volumes of a 1.0 g/L solution of sodium hexanesulfonate R in solution A;
— mobile phase B: acetonitrile R;
| Time (min) |
Mobile phase A (per cent V/V) |
Mobile phase B (per cent V/V) |
| 0 – 2 | 98 | 2 |
| 2 – 8 | 98 → 84 | 2 → 16 |
| 8 – 25 | 84 → 64 | 16 → 36 |
| 25 – 37 | 64 → 20 | 36 → 80 |
Flow rate: 1.0 mL/min.
Detection: Spectrophotometer at 250 nm.
Injection: 3 μL of the test solution and reference solutions (b) and (c).
Identification of impurities: Use the chromatogram supplied with rivaroxaban for system suitability CRS and the chromatogram obtained with reference solution (c) to identify the peak due to impurity G.
Relative retention: With reference to rivaroxaban (retention time = about 16 min): impurity G = about 0.9.
System suitability: Reference solution (c):
— resolution: minimum 7.0 between the peaks due to impurity G and rivaroxaban.
Calculation of percentage contents:
— for each impurity, use the concentration of rivaroxaban in reference solution (b).
Limits:
— unspecified impurities: for each impurity, maximum 0.10 per cent;
— total: maximum 0.3 per cent;
— reporting threshold: 0.05 per cent.
Water (2.5.32)
Maximum 0.5 per cent, determined on 0.150 g using the evaporation technique at 150 °C.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 2.0 g.
ASSAY
Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.
Injection: Test solution and reference solution (a).
Calculate the percentage content of C19H18ClN3O5S taking into account the assigned content of rivaroxaban CRS.
IMPURITIES
Specified impurities A.
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, D, E, F, G, H, I, J.
A. 5-chloro-N-[[(5R)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide,
B. N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]acetamide,
D. N,N′-bis[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]urea,
E. N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide,
F. 5-chlorothiophene-2-carboxylic acid,
G. 2-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]-2H-isoindole-1,3-dione,
H. 4,5-dichloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide,
I. [2-[1 ,9 -dichloro-2,5 ,8-trioxo-3,7-diaza-5(3,5)-1,3-oxazolidina-1,9(2)-dithiophena-4(1,4)-benzenanonaphan-3- yl]ethoxy]acetic acid,
J. 5-chloro-N-[4-[(5S)-5-[(5-chlorothiophene-2-carboxamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl]-N-[2-[2-oxo-2-[[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]amino]ethoxy]ethyl]thiophene-2-carboxamide.
