Identification and characterization of synthetic impurity in Ticagrelor drug substance

Abstract

Three process impurities ranging from 0.43 to 1.42% in Ticagrelor were detected by a simple gradient reverse-phase high-performance liquid chromatography (HPLC). LC–MS was performed to identify the mass of the impurities. These impurities in the Ticagrelor crude sample have been isolated by using a column. Based on the spectral data (NMR, IR, and MS), the structures of these impurities were characterized as TIC-1: (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol,TIC-2:2-(((3aR,4S,6R,6aS)-6-((5-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol,TIC-3: (1S,2S,3R,5S)-3-((3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The structure was elucidated by various techniques MS, 1D NMR (1H, 13C, and DEPT), 2D NMR(HSQC, HMBC and 15N HSQC, HMBC) and IR confirmed the proposed chemical structures of impurities.Identification, isolation, structural characterization, and prospects of the formation of these impurities were first reported in this paper.