title: Degradation kinetics study of cabozantinib by a novel stability-indicating LC method and identification of its major degradation products by LC/TOF-MS and LC-MS/MS.
abstract: The chemical stability of cabozantinib (CBZ) was investigated using a novel stability-indicating LC method. Forced degradation of CBZ was carried out under acidic, basic, thermal, oxidative and photolytic stress conditions. Hydrolysis and oxidation were the primary pathways for this compound and three major unknown degradation products were characterized by LC/TOF-MS and LC-MS/MS. The major oxidative degradation product was isolated by preparative LC and identified by UV, HRMS and NMR techniques to be N-{4-[(N-oxide-6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide. The developed method was validated as per ICH guidelines and then successfully applied to investigate the degradation kinetics of CBZ. Degradation of CBZ followed first-order kinetics under all experimental conditions. A V-shaped pH-rate profile over the pH range 2-10 was observed with maximum stability at pH 6. The effect of temperature on the rate of CBZ degradation was characterized using the Arrhenius equation. The activation energy for hydrolysis was 57.31kJmol(-1) in alkaline solution.
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Wu
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Xu
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Feng
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai 200040, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutics of Traditional Chinese Medicine, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: ivy366300@hotmail.com.
authors.forename: Junying
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000813:Anilides / Q000737:chemistry*; D002853:Chromatography, Liquid / Q000379:methods; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D010084:Oxidation-Reduction; D010782:Photolysis; D011725:Pyridines / Q000737:chemistry*; D053719:Tandem Mass Spectrometry / Q000379:methods; D013696:Temperature
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib
keywords: Cabozantinib; Degradation; LC/TOF-MS; LC–MS/MS; Stability-indicating LC