Journal: Journal of Clinical Medicine Research DOI: 10.32629/jcmr.v7i3.5445
Abstract
Rivaroxaban is a direct factor Xa inhibitor whose expanding generic manufacture requires robust, selective, and environmentally improved synthetic routes. Conventional batch routes to rivaroxaban frequently depend on prolonged heating, high-boiling polar solvents, discrete intermediate isolation, and late-stage acid chloride chemistry, which increase process mass intensity and create opportunities for process-related and degradation impurities. In this study, a green continuous-flow route was developed from commercially accessible aryl-morpholinone and chiral oxazolidinone intermediates using ethanol, 2-methyltetrahydrofuran, dimethyl carbonate, and an acid-activated coupling strategy to minimize hazardous reagent inventory and suppress impurity formation. The optimized telescoped sequence gave rivaroxaban in 86.7% isolated yield and 99.74% HPLC purity at 14.6 g h−1 productivity, while reducing total related substances from 0.84% in the batch reference process to 0.18%. Process mass intensity decreased from 134 to 49 kg kg−1 API, and the calculated E-factor decreased from 102 to 38. A stability-indicating impurity-profiling method combining RP-HPLC, chiral HPLC, and LC-MS was used to track eight critical impurities, including hydroxy-open-chain intermediates, bis-alkylated adducts, dehalogenated thiophene amide, R-rivaroxaban, oxidative N-oxide, and nitrosamine drug substance-related impurity candidates. The results indicate that continuous-flow control of residence time, temperature, and reagent stoichiometry can simultaneously improve yield, sustainability, and impurity control for rivaroxaban manufacture.
Keywords
rivaroxaban, continuous flow, green synthesis, impurity profiling, HPLC, process mass intensity, nitrosamine drug substance-related impurity
Full Text
PDF - Viewed/Downloaded: 0 TimesReferences
[1] Hyer A, Gregory D, Kay K, et al. Continuous manufacturing of active pharmaceutical ingredients: current trends and perspectives[J]. Advanced Synthesis & Catalysis, 2024, 366(3): 357-389.
[2] Nolan L J, King S J, Wharry S, et al. A pharma perspective on sustainability advantages through adoption of continuous flow[J]. Current Opinion in Green and Sustainable Chemistry, 2024, 46: 100886.
[3] Sanoja-Lopez K A, Nope E, Luque R. Sustainable optimization of pharmaceutical synthesis: applications and benefits of continuous flow chemistry[J]. Green Chemistry Letters and Reviews, 2025, 18(1): 2549732.
[4] Alfano A I, García-Lacuna J, Griffiths O M, et al. Continuous flow synthesis enabling reaction discovery[J]. Chemical Science, 2024, 15(13): 4618-4630.
[5] Boyall S L, Clarke H, Dixon T, et al. Automated optimization of a multistep, multiphase continuous flow process for pharmaceutical synthesis[J]. ACS Sustainable Chemistry & Engineering, 2024, 12(41): 15125-15133.
[6] Yin L, Yu L, Guo Y, et al. Green analytical chemistry metrics for evaluating the greenness of analytical procedures[J]. Journal of Pharmaceutical Analysis, 2024, 14(11): 101013.
[7] Mehta M, Mehta D, Mashru R. Recent application of green analytical chemistry: eco-friendly approaches for pharmaceutical analysis[J]. Future Journal of Pharmaceutical Sciences, 2024, 10(1): 83.
[8] Rao W, Li L, Zhang C, et al. Development and validation of a stability-indicating RP-HPLC method for the determination of fifteen impurities in rivaroxaban[J]. Journal of pharmaceutical and biomedical analysis, 2023, 228: 115325.
[9] dos Santos N O, Wingert N R, Steppe M. Quality by design approach for enantiomeric evaluation by RP-HPLC method of Rivaroxaban and its chiral impurity[J]. Microchemical Journal, 2023, 192: 108911.
[10] Nakov N, Anastasova L, Gjorgievska M Z, et al. Green RP-HPLC methods for assay and related substances in rivaroxaban tablets[J]. Acta Chromatographica, 2024, 36(4): 371-382.
[11] Li P, Zhang F M, Zhou P, et al. Detection of trace genotoxic impurities in rivaroxaban by HPLC-MS/MS[J]. Chinese Journal of Pharmaceutical Analysis, 2024, 44(1): 101-108.
[12] Epuru M R, Saroja J, Pilli V V N K, et al. Detection, isolation, characterization, analytical method development with validation and in-silico analysis of new impurity in rivaroxaban[J]. Future Journal of Pharmaceutical Sciences, 2025, 11: 20.
[13] Kim M, Jung S, Lee J. Development and validation of a liquid chromatography–triple quadrupole tandem mass spectrometry-based method for the simultaneous determination of five nitrosamine drug substance-related impurities in rivaroxaban[J]. Chromatographia, 2026, 89(2): 183-195.
[14] Jahangir M, Awan A, Azhar A. Development of a validated RP-HPLC method for rivaroxaban quantification in pharmaceutical formulation and human blood plasma[J]. Pakistan Journal of Pharmaceutical Sciences, 2023, 36(5): 1507-1514.
[15] Silva-Brenes D V, Reyes-Vargas S K, Monbaliu J C M. Continuous flow intensification for the synthesis of high-purity warfarin[J]. Organic Process Research & Development, 2024, 28(5): 1704-1712.
[16] Kelly S M, Lebl R, Malig T C, et al. Synthesis of a highly functionalized quinazoline organozinc toward KRAS G12C inhibitor divarasib (GDC-6036), enabled through continuous flow chemistry[J]. Organic Process Research & Development, 2024, 28(5): 1546-1555.
[17] Murbach G, Akturk I, Nagy Z, et al. Process development and kinetic analysis in the green synthesis of lomustine[J]. Organic Process Research & Development, 2024, 28(5): 1910-1916.
[18] Cole K P, Jaworski J N, Kappe C O, et al. Flow chemistry and continuous processing: more mainstream than ever![J]. Organic Process Research & Development, 2024, 28(5): 1269-1271.
[2] Nolan L J, King S J, Wharry S, et al. A pharma perspective on sustainability advantages through adoption of continuous flow[J]. Current Opinion in Green and Sustainable Chemistry, 2024, 46: 100886.
[3] Sanoja-Lopez K A, Nope E, Luque R. Sustainable optimization of pharmaceutical synthesis: applications and benefits of continuous flow chemistry[J]. Green Chemistry Letters and Reviews, 2025, 18(1): 2549732.
[4] Alfano A I, García-Lacuna J, Griffiths O M, et al. Continuous flow synthesis enabling reaction discovery[J]. Chemical Science, 2024, 15(13): 4618-4630.
[5] Boyall S L, Clarke H, Dixon T, et al. Automated optimization of a multistep, multiphase continuous flow process for pharmaceutical synthesis[J]. ACS Sustainable Chemistry & Engineering, 2024, 12(41): 15125-15133.
[6] Yin L, Yu L, Guo Y, et al. Green analytical chemistry metrics for evaluating the greenness of analytical procedures[J]. Journal of Pharmaceutical Analysis, 2024, 14(11): 101013.
[7] Mehta M, Mehta D, Mashru R. Recent application of green analytical chemistry: eco-friendly approaches for pharmaceutical analysis[J]. Future Journal of Pharmaceutical Sciences, 2024, 10(1): 83.
[8] Rao W, Li L, Zhang C, et al. Development and validation of a stability-indicating RP-HPLC method for the determination of fifteen impurities in rivaroxaban[J]. Journal of pharmaceutical and biomedical analysis, 2023, 228: 115325.
[9] dos Santos N O, Wingert N R, Steppe M. Quality by design approach for enantiomeric evaluation by RP-HPLC method of Rivaroxaban and its chiral impurity[J]. Microchemical Journal, 2023, 192: 108911.
[10] Nakov N, Anastasova L, Gjorgievska M Z, et al. Green RP-HPLC methods for assay and related substances in rivaroxaban tablets[J]. Acta Chromatographica, 2024, 36(4): 371-382.
[11] Li P, Zhang F M, Zhou P, et al. Detection of trace genotoxic impurities in rivaroxaban by HPLC-MS/MS[J]. Chinese Journal of Pharmaceutical Analysis, 2024, 44(1): 101-108.
[12] Epuru M R, Saroja J, Pilli V V N K, et al. Detection, isolation, characterization, analytical method development with validation and in-silico analysis of new impurity in rivaroxaban[J]. Future Journal of Pharmaceutical Sciences, 2025, 11: 20.
[13] Kim M, Jung S, Lee J. Development and validation of a liquid chromatography–triple quadrupole tandem mass spectrometry-based method for the simultaneous determination of five nitrosamine drug substance-related impurities in rivaroxaban[J]. Chromatographia, 2026, 89(2): 183-195.
[14] Jahangir M, Awan A, Azhar A. Development of a validated RP-HPLC method for rivaroxaban quantification in pharmaceutical formulation and human blood plasma[J]. Pakistan Journal of Pharmaceutical Sciences, 2023, 36(5): 1507-1514.
[15] Silva-Brenes D V, Reyes-Vargas S K, Monbaliu J C M. Continuous flow intensification for the synthesis of high-purity warfarin[J]. Organic Process Research & Development, 2024, 28(5): 1704-1712.
[16] Kelly S M, Lebl R, Malig T C, et al. Synthesis of a highly functionalized quinazoline organozinc toward KRAS G12C inhibitor divarasib (GDC-6036), enabled through continuous flow chemistry[J]. Organic Process Research & Development, 2024, 28(5): 1546-1555.
[17] Murbach G, Akturk I, Nagy Z, et al. Process development and kinetic analysis in the green synthesis of lomustine[J]. Organic Process Research & Development, 2024, 28(5): 1910-1916.
[18] Cole K P, Jaworski J N, Kappe C O, et al. Flow chemistry and continuous processing: more mainstream than ever![J]. Organic Process Research & Development, 2024, 28(5): 1269-1271.
Copyright © 2026 Xiaoyu Liu, Feifan Cheng, Yan Miao, Kang Yang
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License