关键词: 药物结晶, 多晶型, 经典结晶路径, 非经典结晶路径, 晶体成核和生长, 分子运动

Abstract: 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.

Key words: pharmaceutical crystallization, polymorphism, classical crystallization pathway, non-classical crystallization pathway, crystal nucleation and growth, molecular motion