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

• It is the first report on the analytical method and stability study of cabozantinib.
• A stability-indicating LC method of cabozantinib was developed and validated.
• Three unknown degradants were identified by LC/TOF-MS and LC–MS/MS.
• The major oxidative degradant was isolated and confirmed to be a new compound.
• Degradation kinetics of cabozantinib under different conditions was investigated.

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 57.31 kJ mol−1 in alkaline solution.

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