Rajput Niraj, Soni Fatema, Sahu Amit Kumar, Jadav Tarang, Sharma Satyasheel, Sengupta Pinaki
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India.
Department of Natural Products, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India.
J Pharm Biomed Anal. 2022 Jun 5;215:114753. doi: 10.1016/j.jpba.2022.114753. Epub 2022 Apr 5.
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 (H) 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.
比美替尼（BMT）最近已获美国食品药品监督管理局（USFDA）批准用于治疗黑色素瘤。广泛的文献检索显示，尚无任何科学报告报道过BMT的降解动力学。迄今为止，尚无用于在其杂质存在下定量BMT的稳定性指示分析方法（SIAM）。此外，关于BMT的降解产物（DPs）及其降解途径的信息尚不清楚。在本研究中，我们开发了一种用于BMT的SIAM，并使用液相色谱-四极杆-飞行时间串联质谱（LC-Q-TOF-MS/MS）对其主要DPs进行了表征。该SIAM根据国际人用药品注册技术协调会（ICH）指南进行了验证，随后用于研究BMT的降解动力学。结果发现该方法可用于分离BMT及其在不同应激条件下形成的所有DPs。已鉴定并表征了三种新的DPs。通过核磁共振氢谱（1H NMR）对H1（酸水解DP）和O1（氧化降解产物）进行了分离和表征。使用ProTox-II毒性预测软件对DPs进行了计算机模拟毒性评估。降解动力学研究获得的数据表明，在酸性水解和氧化应激条件下，BMT的降解遵循一级动力学。通过本研究建立的降解动力学机制和降解途径知识，可有助于改善药物的稳定性，并提出更合适的储存条件。我们鉴定和表征的降解杂质在经过必要的鉴定后，可用于设定药物的质量控制验收标准。该定量分析方法可用于制药行业和研究实验室中BMT的常规质量控制和稳定性研究分析。
