Adhikari Sarju, Rustum Abu M
Boehringer Ingelheim Animal Health USA Inc. (BIAH), 631 US Route 1 South, North Brunswick, NJ 08902, USA.
Boehringer Ingelheim Animal Health USA Inc. (BIAH), 631 US Route 1 South, North Brunswick, NJ 08902, USA.
J Pharm Biomed Anal. 2022 May 30;214:114730. doi: 10.1016/j.jpba.2022.114730. Epub 2022 Mar 18.
Ivermectin (IVM) drug substance is a semi-synthetic macrocyclic lactone that exhibits a broad spectrum of activity and high potency towards endo- and ectoparasites. In this study, a comprehensive forced degradation study was carried out on IVM drug substance (under the conditions recommended in the ICH guidelines) to identify and characterize its major degradation products (DPs). IVM drug substance was subjected to acidic, alkaline, oxidation (HO and KCrO), thermal (solid and solution state), and photolytic (solid and solution state) stress degradations. Chromatographic separation of the drug substance and its DPs was achieved using a gradient elution on a HALO C18 column (150 × 4.6 mm, 2.7 µm). A total of five major DPs were observed for IVM drug substance under various stressed conditions. Additionally, ivermectin API lots exhibited instability when stored under room temperature and at 45% relative humidity for two years. These DPs were identified and characterized using liquid chromatography-high resolution mass spectrometry (LC-HRMS) and a comparison of their fragmentation profile with IVM HB using tandem mass spectrometry. Of these, HO induced oxidative degradation product (3,4-epoxide HB) was isolated using semi-preparative HPLC and its structure was elucidated comprehensively using LC-HRMS and nuclear magnetic resonance spectroscopy. The proposed structures of the DPs have been rationalized by appropriate degradation pathways of IVM HB. Comprehensive degradation profile of IVM drug substance should facilitate the understanding of the stability profile of IVM drug substance, setting the specification of DPs in finished products as well as aid in the design of generic formulation made with IVM.
伊维菌素原料药是一种半合成大环内酯类药物，对体内和体外寄生虫具有广谱活性和高效力。在本研究中，对伊维菌素原料药进行了全面的强制降解研究（在国际人用药品注册技术协调会指南推荐的条件下），以鉴定和表征其主要降解产物（DPs）。伊维菌素原料药经历了酸性、碱性、氧化（过氧化氢和重铬酸钾）、热（固态和溶液态）以及光解（固态和溶液态）应激降解。原料药及其降解产物通过在HALO C18柱（150×4.6 mm，2.7 µm）上进行梯度洗脱实现色谱分离。在各种应激条件下，共观察到伊维菌素原料药有五种主要降解产物。此外，伊维菌素原料药批次在室温及45%相对湿度下储存两年时表现出不稳定性。这些降解产物通过液相色谱 - 高分辨率质谱（LC - HRMS）进行鉴定和表征，并通过串联质谱将其碎片图谱与伊维菌素氢溴酸盐（IVM HB）进行比较。其中，过氧化氢诱导的氧化降解产物（3,4 - 环氧氢溴酸盐）通过半制备高效液相色谱分离得到，其结构通过LC - HRMS和核磁共振光谱进行了全面阐明。降解产物的推测结构已通过伊维菌素氢溴酸盐的适当降解途径进行了合理化解释。伊维菌素原料药的全面降解概况应有助于理解伊维菌素原料药的稳定性概况，设定成品中降解产物的规格，并有助于设计含伊维菌素的仿制药制剂。
