药物结晶中的经典与非经典结晶路径

晶体的结晶路径分为经典结晶路径和非经典结晶路径。经典结晶路径往往涉及一些简单的化学结构,晶体的成核、生长是通过单体的依次添加实现的,经过长期研究,目前研究人员已对其有了较为深刻的理解并形成了一套相对完善的理论体系;但对于非经典的结晶路径,由于涉及复杂中间态粒子的形成和多步结晶过程,尚未获得全面、统一的理论支持。在药物结晶领域,有机分子构象自由度的引入增加了体系的复杂性,分子间弱的相互作用使得固态药物分子存在多晶型现象。由于药物的理化性质及生物利用度与其晶型息息相关,同时,药物结晶过程中出现的一些复杂中间态粒子往往会改变最终得到的药物晶型,因此迫切需要加强对药物晶体成核和生长路径的研究,以期发展能实现对药物晶体成核和生长过程主动控制的方法。本文简要综述了目前药物在溶液或熔体中结晶的经典与非经典结晶路径,包括奥斯特瓦尔德阶段定律、独立成核、交叉成核。从溶液化学的角度看,分子在浓溶液中会通过自组装形成结构合成子,成核与溶液中的生长单元、结构合成子密切相关。从分子水平上探索溶液中有关分子运动的信息、分析各体系下晶核与结构合成子之间的关系是区分两种结晶路径的关键所在,非经典结晶在药物结晶领域是机遇也是挑战。

Classical and Non-Classical Crystallization Pathways in Pharmaceutical Crystallization

The crystallization pathways of crystals can be classical and non-classical. The classical crystallization pathways usually involve some simple chemical species, where the nucleation and growth are realized by adding monomers successively. After decades of research, the classical crystallization pathways have been fully understood and formed a relatively perfect theory. Recent studies have found that some materials, such as calcium carbonate (CaCO₃), crystallize in the non-classical pathway. Non-classical crystallization pathways have aroused extensive interest in academia. However, the non-classical crystallization pathways have not been fully and uniformly explained. They involve the multistep mechanisms and the formation of complex intermediate particles, which range from multi-ion complexes to aggregation of oriented and nearly oriented metastable nanocrystals. In the field of pharmaceutical crystallization, the introduction of the conformational degrees of freedom in organic molecular systems increases the complexity. Polymorphism of solid drugs exists due to the weak interactions between drug molecules. The physicochemical properties and bioavailability of drugs are closely related to their crystal forms. Meanwhile, the complex intermediate species appearing during crystallization affect the form of solid drugs. It’s thus in urgent need to strengthen the study about nucleation and growth pathways of crystalline drugs. Methods should be developed to provide absolute control over crystal nucleation and growth. This paper summarizes the classical and non-classical crystallization of drugs in solution and in melt, including the Ostwald’s law of stages, independent nucleation and cross nucleation. From the perspective of solution chemistry, molecules existing in concentrated solution may self-assemble, via hydrogen-bonds and aromatic stacking, or be solvated to form the structural synthons. Nucleation is closely related to the growth units and structural synthons in solution. In order to distinguish the two crystallization pathways, it is critical to find the information about molecular motion at the molecular level and the relationship between nuclei and structural synthons in each system. Non-classical crystallization implies both opportunities and challenges for pharmaceutical crystallization research.