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Practical synthetic approach to related substances of Rivaroxaban; an anticoagulant drug substance

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Author Affiliations

  • 1Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik-422 202, Maharashtra, India and Organic Chemistry Research Center, Department of Chemistry, K. T.H.M College, Nashik-422 002, Maharashtra, India
  • 2Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik-422 202, Maharashtra, India
  • 3Organic Chemistry Research Center, Department of Chemistry, K. T.H.M College, Nashik-422 002, Maharashtra, India
  • 4Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik-422 202, Maharashtra, India

Res.J.chem.sci., Volume 7, Issue (5), Pages 38-45, May,18 (2017)

Abstract

During the process development of an anticoagulant drug, Rivaroxaban (1), three related substances were detected by a gradient high performance liquid chromatography (HPLC) method. Liquid chromatography mass spectrometry (LC-MS) was performed to identify the molecular mass of these impurities. A detailed study was undertaken to characterize these impurities. Based on the spectral data (1H NMR, 13C NMR and MS), these impurities were characterized as 2-[(2S)-2,3-dihydroxypropyl]-1H-indene-1,3(2H)-dione (impurity-1), [2-({4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin -3-yl]phenyl}amino) ethoxy]acetic acid (impurity-2) and 5-chloro-N-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl]amino}propyl] thiophene-2-carboxamide (impurity-3). A practical and efficient approach for the synthesis of these impurities with good yields and purities by HPLC is described in this report. The structures of the synthesized impurities (imputiy-1, impurity-2 and impurity-3) were further confirmed by co-injecting these impurities with the standard Rivaroxaban sample containing all the three impurities. The retention times of synthesized impurities matches (co-eluted) with the retention times of the impurities present in the standard sample.

References

  1. Susanne R., Alexander S., Jens P., Thomas L., Josef P., Karl-Heinz S., Peter R. and Elisabeth P. (2005)., Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor., J. Med. Chem. 48(19), 5900-5908.
  2. Alexander S., Thomas L., Jens P., Susanne R., Elisabeth P., Karl-Heinz S. and Joseph P. (2005)., Substituted Oxazolidinones and Their Use in the Field of Blood Coagulation., US patent 7,576,111.
  3. Drug index (2017). http://www.rxlist.com/xarelto-drug.htm Last reviewed 17th April 2017, undefined, undefined
  4. Highlights of prescribing information of XARELTO, Rivaroxaban, Extended-Release tablets. http://www.accessdata.fda.gov/drugsatfdadocs/label/2011/202439s001lbl.pdf. 2011, undefined, undefined
  5. Gizawy Samia M., Bebawy Loris I., Abdelmageed Osama H., Omar Mahmoud A., Deryea Sayed M., Abdel-Megied Ahmed M. (2013)., High Performance Liquid Chromatography, TLC Densitometry, First derivative and First-derivative ratio spectrophotometry for de-termination of Rivaroxaban and its alkaline Degradates in Bulk Powder and its Tablets., J. Chromatography Separat Techniq, 36(10), 1323-1339.
  6. Rajan N. and Basha A.K. (2014)., A Stability-Indicating Ultra-Performance Liquid Chromatographic Method for Estimation of Related Substances and Degradants in Rivaroxaban Active Pharmaceutical Ingredient., Journal of Pharmacy Research, 8(11), 1719-1725.
  7. ICH harmonized tripartite guideline (2006)., Impurities in New Drug Substances., Q3A (R2), current step, 4.
  8. Mali A.C., Deshmukh D.G., Joshi D.R., Lad H.D., Patel P.L., Medhane V.J. and Mathad V.T. (2015)., Facile approach for the synthesis of rivaroxaban using alternate synthon: reaction, crystallization and isolation in single pot to achieve desired yield, quality and crystal form., Sustain Chem Process, 3(1), 11.