Potential degradation products of abemaciclib: Identification and structural characterization employing LC-Q/TOF-MS and NMR including mechanistic explanation

Abstract

Degradation products are the potential drug impurities that can be generated during transport and storage of pharmaceuticals. Before this study, degradation chemistry and potential degradation products of abemaciclib (ABM) were unknown. Moreover, no stability-indicating analytical method was available that can be used to analyse ABM in presence of its degradation products. In this study, stress testing on ABM was carried out under oxidative, thermal, photolytic (UV & visible), and hydrolytic (acid, alkaline, and neutral) degradation conditions. The study revealed that ABM is susceptible to photolytic, oxidative, and thermal stress leading to the formation of five degradation products (DPs). ABM and its degradation products were chromatographically separated employing a developed RP-HPLC-based stability-indicating analytical method. The method was transferred to an LC-Q-TOF system for further analysis. To elucidate the structure of degradation products, fragmentation pathway of ABM was initially established through high-resolution mass spectrometry (HRMS). Subsequently, mass fragmentation pathways of all the DPs have been established through HRMS and MSn based analysis. The major degradation product was isolated and fully characterized using atmospheric chemical ionization-mass spectrometry and nuclear magnetic resonance techniques. ABM showed extensive degradation under oxidative and photolytic systems. Therefore, special care may be sought during storage and transport of ABM or its formulations to avoid photolytic and oxidative stress exposure to the drug. Lastly, in silico toxicity of the characterized degradation products was assessed employing ProTox ІІ online web predictor freeware in which some of them were found to have the potential of hepatotoxicity, immunogenicity and mutagenicity.