Hydrolytic Degradation Study of Rivaroxaban: Degradant Products Identification by LC-MS Isolation by Prep-HPLC and Characterization by HRMS, NMR and FT-IR

Abstract

Present work illustrates the stress degradation behaviour of rivaroxaban under hydrolytic, oxidative, thermal and photolytic conditions as per ICH guidelines. Under thermal and photolytic conditions drug had a fair stability where as in other stress conditions degradation products were observed. Initial identification of the degradation products was performed by hyphenated mass spectrometry coupled to ultra-performance liquid chromatography (UPLC-MS) and mass directed auto purification (MDAP) was used for isolation. Various 1D and 2D nuclear magnetic resonance (NMR) were performed to characterize the degradation products which were assisted by FT-IR and HRMS data. Two novel degradant products were observed in hydrolytic conditions, isolated and characterized by spectroscopic techniques as (R)-2-(2-((4-((3-(5-chlorothiophene-2-carboxamido)-2-hydroxypropyl)amino)phenyl)- amino)ethoxy)acetic acid (DP-2) (m.w. of 427.90 g/mol and m.f. C18H22N3O5SCl), and 5-chlorothiophene-2-carboxylic acid (DP-3) (m.w. 161.95 g/mol and m.f. C5H3O2SCl). Additionally, two more degradation products were observed in basic and acidic conditions, viz. (R)-5-chloro-N-(2- hydroxy-3-((4-(3-oxomorpholino)-phenyl)amino)propyl)thiophene-2-carboxamide (DP-1) (m.w. 409.09 g/mol and m.f. C18H20N3O4SCl) and (S)-2-(2-((4-(5-((5-chlorothio-phene-2- carboxamido)methyl)-2-oxooxazolidin-3-yl)phenyl)amino)ethoxy)acetic acid (DP-4) (m.w. 453.08g /mol and m.f. C19H20N3O6SCl) are already reported.