Rivaroxaban

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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C₁₉H₁₈ClN₃O₅S 435.88 

2-Thiophenecarboxamide, 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-5-oxazolidinyl]methyl]-; 

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide CAS RN®: 366789-02-8; UNII:  9NDF7JZ4M3. 

1 DEFINITION 

Rivaroxaban contains NLT 98.0% and NMT 102.0% of rivaroxaban (C₁₉H₁₈ClN₃O₅S), calculated on the anhydrous basis.

2 IDENTIFICATION 

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K 

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

3 ASSAY 

Procedure 

Solution A: Dissolve 1.36 g of potassium dihydrogenphosphate, 1 g of sodium hexane sulfonate, and 200 µL of phosphoric acid in water. Dilute with water to 1 L. 

Solution B: Dissolve 1.36 g of potassium dihydrogenphosphate and 200 µL of phosphoric acid in water. Dilute with water to 1 L. Diluent: Acetonitrile and Solution B (40:60) 

Solution C: Methanol and Solution A (5:95) 

Solution D: Acetonitrile 

Mobile phase: See Table 1. NLT 7 min of column equilibration with the initial mobile phase conditions is recommended between injections. Table 1 

Standard solution: 0.5 mg/mL of USP Rivaroxaban RS in Diluent 

Sample solution: 0.5 mg/mL of Rivaroxaban in Diluent 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 250 nm 

Column: 3.0-mm × 15-cm; 3.5-µm packing L1 

Column temperature: 60° 

Flow rate: 1 mL/min 

Injection volume: 3 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 2.0 

Relative standard deviation: NMT 0.73% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of rivaroxaban (C₁₉H₁₈ClN₃O₅S) in the portion of Rivaroxaban taken: 

Acceptance criteria: 98.0%–102.0% on the anhydrous basis 

4 IMPURITIES 

Residue on Ignition 〈281〉: NMT 0.1% 

Organic Impurities 

Diluent, Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay. 

System suitability solution: 0.5 mg/mL of USP Rivaroxaban RS and 0.5 µg/mL each of USP Rivaroxaban Related Compound B RS, USP Rivaroxaban Related Compound D RS, USP Rivaroxaban Related Compound G RS, and USP Rivaroxaban Related Compound J RS in Diluent Standard solution: 0.5 µg/mL of USP Rivaroxaban RS in Diluent 

Sensitivity solution: 0.25 µg/mL of USP Rivaroxaban RS in Diluent from the Standard solution 

System suitability 

Samples: System suitability solution, Standard solution, and Sensitivity solution 

Suitability requirements 

Resolution: NLT 8.0 between rivaroxaban related compound G and rivaroxaban, System suitability solution 

Relative standard deviation: NMT 5.0%, Standard solution 

Signal-to-noise ratio: NLT 10, Sensitivity solution 

Analysis 

Samples: Sample solution and Standard solution 

Calculate the percentage of each individual impurity in the portion of Rivaroxaban taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of each individual impurity from the Sample solution

r_S = peak response of rivaroxaban from the Standard solution 

C_S = concentration of USP rivaroxaban RS in the Standard solution (mg/mL)  

C_U = concentration of rivaroxaban in the Sample solution (mg/mL)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%. 

Table 2 

^aThis impurity is included for establishing the Resolution requirement in System suitability. It is controlled as an unspecified impurity.Enantiomeric Purity 

Mobile phase: Acetonitrile 

System suitability solution: 0.5 mg/mL of USP Rivaroxaban RS and 0.015 mg/mL of USP Rivaroxaban R-Enantiomer RS in acetonitrile Sensitivity solution: 0.25 μg/mL of USP Rivaroxaban R-Enantiomer RS in acetonitrile 

Standard solution: 0.5 μg/mL of USP Rivaroxaban RS in acetonitrile 

Sample solution: 0.5 mg/mL of Rivaroxaban in acetonitrile 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 254 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L119 

Temperatures 

Autosampler: 12° 

Column: 30° 

Flow rate: 0.7 mL/min 

Injection volume: 20 µL 

Run time: NLT 2.5 times the retention time of rivaroxaban 

System suitability 

Samples: System suitability solution, Sensitivity solution, and Standard solution 

[Note—The relative retention times for the rivaroxaban R-enantiomer and rivaroxaban are about 0.8 and 1.0, respectively.] Suitability requirements 

Resolution: NLT 1.5 between the rivaroxaban R-enantiomer and rivaroxaban, System suitability solution Relative standard deviation: NMT 5.0%, Standard solution 

Signal-to-noise ratio: NLT 10, Sensitivity solution 

Analysis 

Sample: Sample solution 

Calculate the percentage of enantiomeric excess in the portion of Rivaroxaban taken: 

Result = (r₁ − r₂ )/(r + r₂ ) × 100 

r₁ = peak response of rivaroxaban from the Sample solution  

r₂ = peak response of the rivaroxaban R-enantiomer from the Sample solution 

Acceptance criteria: NLT 99.0% 

5 SPECIFIC TESTS 

Water Determination 〈921〉, Method I, Method Ic: NMT 1.0% 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight, light-resistant containers at controlled room temperature. Keep away from heat and moisture. 

USP Reference Standards 〈11〉 

USP Rivaroxaban RS 

USP Rivaroxaban R-Enantiomer RS 

(R)-5-Chloro-N-({2-oxo-3-[4-(3-oxomorpholino)phenyl]oxazolidin-5-yl}methyl)thiophene-2-carboxamide. 

C₁₉H₁₈ClN₃O₅S 435.88 

USP Rivaroxaban Related Compound B RS 

(S)-N-({2-Oxo-3-[4-(3-oxomorpholino)phenyl]oxazolidin-5-yl}methyl)acetamide. 

C₁₆H₁₉N₂O₅ 333.34 

USP Rivaroxaban Related Compound D RS 

1,3-Bis({(S)-2-oxo-3-[4-(3-oxomorpholino)phenyl]oxazolidin-5-yl}methyl)urea. 

C₂₉H₃₂N₆O₉ 608.61 

USP Rivaroxaban Related Compound G RS 

(S)-2-({2-Oxo-3-[4-(3-oxomorpholino)phenyl]oxazolidin-5-yl}methyl)isoindoline-1,3-dione. 

C₂₂H₁₉N₃O₆ 421.41 

USP Rivaroxaban Related Compound J RS 

5-Chloro-N-(4-{(S)-5-[(5-chlorothiophene-2-carboxamido)methyl]-2-oxooxazolidin-3-yl}phenyl)-N-(2-{2-oxo-2-[({(S)-2-oxo-3-[4-(3- oxomorpholino)phenyl]oxazolidin-5-yl}methyl)amino]ethoxy}ethyl)thiophene-2-carboxamide. 

C₃₈H₃₆Cl₂N₆O₁₀S2 871.76