title: Four process-related potential new impurities in ticagrelor: Identification, isolation, characterization using HPLC, LC/ESI-MS(n), NMR and their synthesis.
abstract: Five process-related impurities were detected in the range of 0.08-0.22% in ticagrelor laboratory batches by HPLC and LC-MS methods. These impurities were named as TIC Imp-I, -II, -III, -IV and -V. Four of these impurities, TIC Imp-I to -IV were unknown and have not been reported previously. Based on LC-ESI/MS(n) study, the chemical structures of new impurities were presumed as (1S,2S,3S,5S)-3-(2-hydroxyethoxy)-5-(7-amino-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)cyclopentane-1,2-diol (TIC Imp-I), (1S,2S,3S,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylsulfinyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (TIC Imp-II), (1S,2R,3S,4S)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (TIC Imp-III) and (3S,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (TIC Imp-IV). The unknown impurities were isolated from enriched crude sample by column chromatography and preparative HPLC. The complete spectral analysis, MS, 1D NMR ((1)H, (13)C and DEPT), 2D NMR (HSQC and HMBC) and IR confirmed the proposed chemical structures of impurities. Identification, isolation, structural characterization, prospects for the formation of impurities and their synthesis were first reported in this paper.
authors.affiliation: Microlabs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Microlabs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India.
authors.forename: Subba Rao
authors.initials: SR
authors.lastname: Devineni
authors.affiliation: Microlabs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India.
authors.forename: Prasad Reddy
authors.initials: PR
authors.lastname: Gajjala
authors.affiliation: Microlabs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India.
authors.forename: Dharmendra Kumar
authors.initials: DK
authors.lastname: Gupta
authors.affiliation: Microlabs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India.
authors.forename: Sandesh
authors.initials: S
authors.lastname: Bhat
authors.affiliation: Microlabs Ltd., Analytical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Microlabs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India.
authors.forename: Shailendra Kumar
authors.initials: SK
authors.lastname: Dubey
authors.affiliation: Microlabs Ltd., Chemical Research Department, API R&D Centre, Bommasandra-Jigani Link Road, KIADB INDL Area, Bommasandra, Bangalore 560105, Karnataka, India. Electronic address: pramodkumar@microlabs.in.
authors.forename: Pramod
authors.initials: P
authors.lastname: Kumar
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D004340:Drug Contamination; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D053719:Tandem Mass Spectrometry / Q000379:methods*; D000077486:Ticagrelor
chemical_list: D000077486:Ticagrelor; D000241:Adenosine
keywords: Identification; Impurities; Isolation; LC–ESI/MS; NMR; Ticagrelor