Insights into the Classical and Nonclassical Crystallization Pathways in Pharmaceutical Science

The crystallization pathways of crystals can be classical or nonclassical. The classical crystallization pathways usually involve simple chemical species, which are added successively as monomers during nucleation and crystal growth. After decades of research, classical crystallization pathways have been fully understood and formed into a relatively perfect theory. However, nonclassical crystallization pathways have not been fully and consistently explained. These pathways involve multistep mechanisms and the formation of complex intermediate particles, which range from multi-ion complexes to the aggregation of oriented and nearly oriented metastable nanocrystals. In the field of pharmaceutical crystallization, polymorphism of solid drugs exists due to the weak intermolecular interactions between drug molecules. The physicochemical properties and bioavailability of drugs are closely related to their crystal forms. It is thus urgent to strengthen the study of nucleation and growth pathways of drug crystals. Methods should be developed to provide absolute control over crystal nucleation and growth. This chapter summarizes the progress of classical and nonclassical crystallization of drugs in solution and in melt. From the perspective of solution chemistry, molecules existing in a concentrated solution may self-assemble via hydrogen bonds and aromatic stacking or be solvated to form structural synthons. Nucleation is closely related to the growth units and the structural synthons in solution. To distinguish between the two crystallization pathways, it is critical to find information about particle motion at the molecular level and the relationship between nuclei and structural synthons in each system. Nonclassical crystallization presents both opportunities and challenges for pharmaceutical crystallization research.