Controlling Factors and Mechanism of Polymorphic Crystallization

The mechanism and controlling factors of polymorphic crystallization were investigated using amino acids and a thiazole derivative (BPT) (pharmaceutical). The controlling factors depend on the system and crystallization method. In the cooling crystallization of amino acids, supersaturation hardly influenced the crystallization behavior of either l-glutamic acid or l-histidine polymorphs. On the other hand, the effects of temperature and polymorphous seeds were remarkable in the polymorphic crystallization of l-glutamic acid, whereas no effect appeared in the crystallization of l-histidine polymorphs. Such a difference between the amino acids may be due to the conformational difference and/or the exchange rate between the conformers (or embryos) corresponding to each polymorph. The controlling factor in antisolvent crystallization of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5- thiazolecarboxylic acid (BPT) was also examined in water−methanol mixture solvents. The thermodynamic stability of each polymorph and the transformation behavior between the polymorphs appeared to be affected by the methanol composition. The transformation behavior, comprised of two steps, was explained by the chemical potential difference between the stable and metastable form, and the preferable nucleation and growth of the other metastable forms, due to the specific solute−solvent interaction. In the crystallization of BPT by addition of water, it is clear that the initial concentration and the water addition rate are controlling factors, and the crystallization zone of the polymorphs was shown with respect to these factors. It was also found that the transformation occurs after the crystallization and the rate depends on the initial concentration of BPT and the addition rate of the antisolvent. From these results, the controlling factors of polymorphic crystallization were grouped and shown on the scheme.