Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
J Pharm Biomed Anal. 2021 Jun 5;200:114072. doi: 10.1016/j.jpba.2021.114072. Epub 2021 Apr 15.
Sugammadex sodium is the first selective relaxant binding agent (SRBA) indicated for reversal of neuromuscular blockade induced by rocuronium or vecuronium during surgery. The chemical synthesis of sugammadex involved the nucleophilic substitution reaction between 6-per-deoxy-6-per-halo-γ-cyclodextrin and 3-mercaptopropionic acid under basic conditions. During the manufacture of sugammadex sodium, an unknown process-related impurity was observed in pilot batches in the range of 0.21-1.9 % based upon HPLC analysis. The same impurity was also detected in commercial Bridion® samples at the levels of more than 0.1 %. Thus this unknown impurity was enriched from the mother liquor of reaction by preparative HPLC and characterized by LC-MS/QTOF, 1D-NMR (H, C, DEPTQ) and 2D-NMR (H-H COSY, TOCSY, HSQC, HMBC, NOESY) techniques. Based on spectroscopic analysis and the synthetic route of sugammadex sodium, this new impurity was identified as monocyanoethyl sugammadex (impurity-I). The prospects to the formation mechanism and control strategy of impurity-I were discussed in detail. Moreover, the toxicological properties of impurity-I were evaluated using ADMET Predictor® software.
舒更葡糖钠是第一种用于逆转手术中罗库溴铵或维库溴铵引起的神经肌肉阻滞的选择性松弛剂结合剂（SRBA）。舒更葡糖钠的化学合成涉及在碱性条件下，6-去氧-6-卤代-γ-环糊精与 3-巯基丙酸之间的亲核取代反应。在舒更葡糖钠的生产过程中，在中试批次中观察到一种未知的工艺相关杂质，基于 HPLC 分析，其范围在 0.21-1.9%之间。在商业 Bridion®样品中也检测到相同的杂质，其水平超过 0.1%。因此，该未知杂质通过制备型 HPLC 从反应母液中富集，并通过 LC-MS/QTOF、1D-NMR（H、C、DEPTQ）和 2D-NMR（H-H COSY、TOCSY、HSQC、HMBC、NOESY）技术进行了表征。基于光谱分析和舒更葡糖钠的合成路线，确定了这种新杂质为单氰乙基舒更葡糖（杂质-I）。详细讨论了杂质-I 的形成机制和控制策略的前景。此外，使用 ADMET Predictor®软件评估了杂质-I 的毒理学性质。
