Abstract:

Chirality is a ubiquitous property in nature and organisms. More than half of the active pharmaceutical ingredients contain at least one chiral center. Because of the stereoselectivity of chiral molecules, the chiral enantiomers often exhibit higher activity with lower side effects than racemates. The precise manufacturing of chiral enantiomer is, therefore, of great significance. At present, chiral resolution of racemate is one of the most efficient and convenient way to harvest enantiomer, whereas chiral resolution by crystallization is of key importance and widely applied technology to obtain pure enantiomer. Here, the recent progress on chiral resolution of pharmaceuticals by crystallization is summarized. Firstly, the history and development of chiral resolution by crystallization is briefly introduced. The enantiomeric resolution approaches based on classical resolution methods(diastereomeric salt resolution and preferential crystallization) and some recent developed novel chiral resolution methods including preferential enrichment and Viedma ripening, as well as their process intensification, are reviewed in detail. Then, other racemate separation methods such as chromatography and membrane separation are also briefly reviewed. Finally, the future study and development on pharmaceutical chiral resolution by crystallization are discussed and prospected.

Key words: chiral resolution, crystallization, purification, separation, preferential crystallization, preferential enrichment, Viedma ripening

摘要：

手性是自然界和生物体中广泛存在的一种性质，约半数以上的药物活性成分含有手性中心，受手性分子的空间立体选择性影响，手性对映体药物往往较其外消旋体表现出更高的活性、更低的副作用，因而，精准制备手性单一对映体药物具有非常重要的研究意义。目前，手性外消旋体拆分是制备单一对映体的最高效、便捷的途径，而结晶拆分是实现手性单一对映体分离最为重要且广泛应用的技术。综述了近年来手性药物结晶拆分的研究进展，梳理了结晶拆分研究的发展历程，重点介绍了基于经典拆分方法（非对映体成盐拆分和优先结晶）和近年来发展的基于优先富集和Viedma熟化的对映体拆分新技术以及结晶拆分的强化方法，并简述了色谱、膜分离等其他手性外消旋体分离方法。最后，对手性药物的结晶拆分方法进行了总结和展望。

关键词: 手性拆分, 结晶, 纯化, 分离, 优先结晶, 优先富集, Viedma熟化