共结晶分离技术研究进展

doi:10.16085/j.issn.1000-6613.2019-0620

摘要/Abstract

摘要：

使用共结晶技术分离有机小分子，特别是一些不能成盐的、高纯度要求的原料药(API)的分离是晶体工程应用的前沿。其原理是通过分子间的识别作用形成共晶，改变目标分子的晶格能或溶解特性，从而实现分离。针对共结晶在分离中的应用，本文从共结晶分离的热力学原理出发，系统综述了共结晶在分离纯化非手性分子以及手性API及中间体中的实例。从分子结构、分子间的相互作用力、溶度积常数、溶剂体系等不同角度对分离实例进行分析。针对该技术现存的问题如共晶形成物的选择缺乏规律性，实际API纯化体系的复杂性，共晶形成物回收利用的可行性，指出建立系统的共晶形成物选择方法、深入地研究热力学行为是未来的主要研究方向。

关键词: 分离, 结晶, 药物, 选择性

Abstract:

The separation of small organic molecules by co-crystallization technology, especially the separation of some high-purity APIs that cannot be salted, is the frontier of crystal engineering applications. The principle is to form cocrystal by intermolecular recognition, and to change the lattice energy or solubility characteristics of the target molecule, thereby achieving separation. Aiming at the application of cocrystallization in separation, this paper systematically reviews the examples of co-crystallization in separation and purification of achiral molecules and chiral APIs and intermediates from the thermodynamic principle of cocrystal separation. Separation examples are analyzed from different perspectives such as molecular structure, intermolecular interaction force, solubility product constant, solvent system, etc. For the existing problems of this technology, such as the lack of regularity in the choice of cocrystal formation, the complexity of the actual API purification system, the feasibility of recycling eutectic formation, it is pointed out that establishing the cocrystal formation selection method of the system and in-depth study of thermodynamic behavior are the main research directions in the future.

Key words: separation, crystallization, pharmaceuticals, selectivity

中图分类号:

TQ463

蒋成君, 程桂林. 共结晶分离技术研究进展[J]. 化工进展, 2020, 39(1): 311-319.

Chengjun JIANG, Guilin CHENG. Progress in co-crystallization as a separation technology[J]. Chemical Industry and Engineering Progress, 2020, 39(1): 311-319.

图/表 24

图1 API/CF/溶剂系统三元相图

图2 芳香族卤键与氢键供体的竞争

图3 脂肪族族卤键与氢键供体的竞争

图4 肉桂酸/3-硝基苯甲酰胺结构式

图5 布洛芬/酮洛芬/4,4’-联吡啶结构式

图6 苯甲酰胺/苯甲酸/肉桂酰胺/肉桂酸结构式

图7 酶促合成阿莫西林路线

图8 阿莫西林/4-羟基苯甘氨酸结构式

图9 若干CF的结构式

图10 肉桂酰胺/苯甲酰胺/肉桂酸/苯甲酸结构式

图11 非诺贝特/非诺贝特酸结构式

图12 对硝基苯酚/邻氨基苯甲酸结构式

图13 大黄酸/精氨酸结构式

图14 香草醛/香草醇/吩嗪结构式

图15 氨基-对氯丁酸内酰胺/酒石酸结构式

图16 脱氢胆酸/芳基烷基亚砜结构式

图17 DL-精氨酸/富马酸结构式

图18 环己烷二甲醇/环己二胺结构式

图19 拉米夫定/(S)-BINOL结构式

图20 RS-吡喹酮/ L-苹果酸结构式

图21 布洛芬/左乙拉西坦结构式

图22 氧氟沙星/酒石酸衍生物结构式

图23 乙拉西坦/左乙拉西坦结构式

图24 酒石酸/苹果酸的选择性自组装

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