158 © Pharmeuropa 30.

04 | October 2018

Reference: PA/PH/Exp. P4/T (16) 19 ANP

XXXX:2932

RIVAROXABAN

Rivaroxabanum

C19H18ClN3O5S Mr 435.9
[366789-02-8]

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.

It shows polymorphism (5.9).

IDENTIFICATION

A. Infrared absorption spectrophotometry (2.2.24).

Comparison : rivaroxaban CRS.

If the spectra obtained in the solid state show differences, dissolve the substance to be
examined and the reference substance separately in warm glacial acetic acid R (about 40 °C),
evaporate to dryness in a water-bath and record new spectra using the residues.

B. Enantiomeric purity (see Tests).

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TESTS
Enantiomeric purity. Liquid chromatography (2.2.29).

The following chromatogram is shown for information but will not be published in the European
Pharmacopoeia.

1. impurity A 2. rivaroxaban

Figure 2932.-1. – Chromatogram for the test for enantiomeric purity of rivaroxaban : reference
solution (b)
Test solution. Dissolve 20.0 mg of the substance to be examined in 25 mL of acetonitrile R and
dilute to 50.0 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)(58) ;
– 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.

(58) VDS Optilab Chiral OD column is suitable. A Chiralcel OD-H 150 × 2.1 mm 5 µm column with a flow rate of
0.13 mL/min was also found suitable.

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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)(59) ;
– 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(60) Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-2 98 2
2-8 98 - 84 2 - 16
8 - 25 84 - 64 16 - 36
25 - 37(61) 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)(62).
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.

(59) ZORBAX Eclipse XDB C18 is suitable.

(60) D0 (dwell volume used for development of the method) = 0.92 mL.
(61) A long re-equilibration time is necessary to obtain stable retention times. The following conditions with mobile phase A
as component A and mobile phase B as component B have been found suitable : 37-40 min : A 20 % → 98 %, B 80 % →
2 % ; 40-50 min : A 98 %, B 2 % ; flow rate : 1.0 mL/min.
(62) To curtail carry-over, rinse the injector with a mixture of methanol R and water for chromatography R (5:95 V/V) and
inject 2 blanks before each series of injections.

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The following chromatogram is shown for information but will not be published in the European
Pharmacopoeia.

1. impurity B 4. impurity G 7. impurity H

2. impurity D 5. rivaroxaban 8. impurity I
3. impurity E 6. system peak 9. impurity J

Figure 2932.-2. – Chromatogram for the test for related substances of rivaroxaban : test solution
spiked with impurities B, D, E, G, H, I and J

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(63).
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.

(63) Hydranal Coulomat AG-Oven is suitable as reagent.

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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. 1,3-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]-1H-isoindole-
1,3(2H)-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,

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I. [2-[[(5-chlorothiophen-2-yl)carbonyl][4-[(5S)-5-[[[(5-chlorothiophen-2-yl)carbonyl]ami-
no]methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl]amino]ethoxy]acetic acid,

J. 5-chloro-N-[4-[(5S)-5-[[[(5-chlorothiophen-2-yl)carbonyl]amino]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.

PA/PH/Exp. P4/T (16) 19 ANP