Industrial & Engineering Chemistry Research, Vol.55, No.5, 1413-1418, 2016
Secondary Nucleation Behavior and the Mechanism in Antisolvent Crystallization of Thiazole Derivative Polymorphs
Antisolvent crystallization of a thiazole derivative, 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (BPT), was performed, and the secondary nucleation behavior and the mechanism were examined. At 313 K, the D form crystallized almost exclusively even though the A form was seeded at an initial concentration (C-0) of 0.040 mol/L. The shortening of the induction period by seeding indicates that secondary nucleation occurs and that the mechanism is not microattrition. We propose that cluster A is formed in the adsorption layer on the crystal surface of seeds, and under these conditions the conformation of molecules in the adsorption layer easily converts to the more stable D form (cluster D). Cluster D will be liberated from the adsorption layer to produce the nuclei of the D form. On the other hand, at 0.024 mol/L (313 K), the amount of polymorph A increased with addition time (T-s) and amount of seeds (S-w), and the pure crystals of A form could be obtained at large T-s and S-w. The effect of S-w arises from the increase in the active surface area of the seeds. As for the difference in secondary nucleation behavior at different C-0, we propose that it is caused by the difference in thickness of the adsorption layer, which increases with solute concentration, and in the conversion rate. In a thin layer (0.024 mol/L), the interaction between molecules in the adsorption layer and the crystal surface may be strong and the molecular conformation may be the same as for the A form (cluster A). This causes the secondary nucleation of the A form. However, as the solute concentration increases (0.040 mol/L), the thickness of the adsorption layer increases and the interaction between the molecules and the crystal surface weakens. Therefore, the molecular conformation in the adsorption layer or cluster near the bulk solution may be similar to the D form. Consequently, the conversion rate to D form may be large, resulting in the production of cluster D and nuclei D. The effect of T-s is consistent with this mechanism. This effect may arise from water addition decreasing the solute concentration and the decrease in the adsorption layer thickness with T-s. This may increase the production of cluster A and nuclei A. At 333 K and high C-0 and W, it was difficult to distinguish the secondary nucleation and primary nucleation over a short time. However, after crystallization, the amount of A form and the solution-mediated transformation rate from BH to A form increased with S-w, indicating that seeding increased the amount of A form.