瑞戈非尼结晶工艺研究

Crystallization Process Study of Regorafenib

关键词:  瑞戈非尼  基因毒性杂质  择优取向  悬浮转晶试验  养晶时间

Key words:  regorafenib  genotoxic impurities  preferred orientation  suspension test  ripening time

摘要:

目的 优化瑞戈非尼结晶工艺,以控制基毒杂质含量。 方法 测定粗品在不同溶剂中的溶解度以及不同溶剂中基毒杂质的增长情况,确定溶剂体系和结晶方式；采用悬浮转晶试验确定目标晶型的结晶工艺条件；采用研磨的方式研究择优取向；采用考察养晶过程中的液相浓度变化和固相形貌变化来控制养晶时间。 结果 瑞戈非尼晶型的实际测试XRPD与单晶模拟XRPD衍射峰2θ值一致,相对峰强度存在差异,结晶工艺相关的水合物晶型未检出,基毒杂质未检出。结论 瑞戈非尼晶型结构可以通过XRPD衍射峰2θ值确证,衍射峰相对强度的差异来源于择优取向。优化后的结晶工艺产品中基毒杂质含量低、晶型纯度高、工艺参数易于控制,适宜工业化生产。

Abstract:

OBJECTIVE The genotoxic impurity 2 in regorafenib was controled by optimizing its crystallization process. METHODS The solvent system and crystallization mode were determined by measuring the solubility and the increase of the genotoxic impurity of crude in different solvents; the crystallization conditions were determined by suspension tests; the preferred orientation was studied by the use of grinding; the ripening time during crystallization was controlled by considering the changes of liquid concentration and solid morphology. RESULTS The measured XRPD patterns of regorafenib agreed with the single crystal simulated XRPD in peak 2θ values, but there were differences in the relative peak intensities, not only the hydrate which related to the process but also the genotoxic impurity were not detected in regorafenib API. CONCLUSION The crystalline structures of regorafenib can be characterized by the XRPD diffraction peak 2θ value, and the difference in the relative intensity of the diffraction peaks is due to the preferred orientation. The optimized crystallization process is suitable for industrial production because it has the advantages of low genotoxic impurity, high crystal purity and the parameters of the crystallization process were easy to control.