罗米地辛结晶工艺的优化

Process Optimization for Romidepsin Crystallization

本试验使用混合溶剂对罗米地辛进行结晶,分别对罗米地辛添加量、结晶温度及混合溶剂比例进行优化。结果显示,低温环境对罗米地辛纯度影响较大,建议温度控制在25℃。使用丙酮与甲醇作为罗米地辛结晶的混合溶剂,能够有效提升罗米地辛纯度,由结晶前的96.5%提高至98.81%,罗米地辛的收率为83.07%;而使用乙醇与甲醇作为混合溶剂,在保证罗米地辛HPLC纯度的同时能有效提升收率至86.59%。所制备的罗米地辛为L晶型,罗米地辛晶核在乙醇与甲醇混合溶剂中形成速度较快,并且晶体颗粒较大。本研究为罗米地辛的动态结晶控制提供一个优化方向;首次对罗米地辛结晶前后杂质进行分析,观察到结晶后杂质Rl、R2、R3含量显著降低;首次对混合溶剂在罗米地辛结晶过程中的工艺参数进行研究与优化,使用乙醇与甲醇进行结晶,可大幅提高罗米地辛收率。同时,本研究所提供的罗米地辛结晶工艺不需要任何专业仪器设备即可实现。

In this study, the mixed solvent was used to crystallize romidepsin. The ratio of romidepsin, crystallization temperature and mixed solvent were optimized. The results showed that temperature had a great influence on the purity of romidepsin, which should be controlled at 25 ℃. When acetone and methanol were used as the mixed solvent for romidepsin crystallization, the HPLC purity of romidepsin were effectively improved, from 96.5 % before crystallization to 98.81%, with the yield of 83.07%. The mixed solvent of ethanol and methanol could help to enhance the yield of romidepsin effectively, and the final yield could reach 86.59%. In our work, romidepsin was tbrm L. The formation of romidepsin crystal nucleus in ethanol and methanol mixed solvent was faster, and the final crystalline particles were larger. This study provided an optimized direction for dynamic crystallization control of romidepsin. The impurities of romidepsin before and after crystallization were analyzed for the first time, and impurities R1, R2, R3 were significantly reduced after crystallization. The process parameters of the mixed solvent in the crystallization of romidepsin were studied and optimized for the first time as well. As ethanol and methanol were chosen for the crystallization of romidepsin, the yield was greatly impoved. Meanwhile, the crystallization process established in our work could be achieved without any professional equipment.