Degradation kinetics and characterization of major degradants of binimetinib employing liquid chromatography-high resolution mass spectrometry

Abstract

Binimetinib (BMT) has recently been approved by the USFDA for the treatment of melanomas. An extensive literature search revealed that degradation kinetics of BMT is not reported in any scientific report. Till date, no stability indicating analytical method (SIAM) is available for quantification of BMT in presence of its impurities. Moreover, information on degradation products (DPs) of BMT and the degradation pathway is not known. In this study, we have developed a SIAM for BMT and characterized its major DPs using LC-Q-TOF-MS/MS. The SIAM was validated according to the ICH guideline and subsequently used to study the degradation kinetics of BMT. The method was found to be useful for separating BMT and all its DPs formed during different stress conditions. Three new DPs have been identified and characterized. H1 (acid hydrolytic DP) and O1 (oxidative degradation product) were isolated and characterized by NMR (1H) spectroscopy. An in silico toxicity evaluation of the DPs was performed using ProTox-II toxicity prediction software. Data obtained from the degradation kinetic study revealed that BMT degradation follows first-order kinetics under acidic hydrolysis and oxidative stress conditions. The degradation kinetics mechanism and knowledge on the pathway of degradation established through this study can be useful to improve the stability profile of the drug and to propose a more appropriate storage condition. The degradation impurities we have identified and characterized can be useful in setting the quality control acceptance criteria of the drug after their required qualification. The quantitative assay method can be used for routine quality control and stability study analysis of BMT in pharmaceutical industries and research laboratories.