Effect of Temperature on Antisolvent Crystallization and Transformation Behaviors of Thiazole-Derivative Polymorphs

Abstract

Crystallization of the thiazole-derivative (BPT) was performed by adding water, which is an antisolvent for the solute, to methanol solutions of BPT. BPT has three polymorphs (A, B, C) and two solvates (BH(hydrate) and D(methanolate)). The effect of temperature on the polymorphic crystallization and transformation behavior was investigated in relation to the effect of the addition rate of water and the initial concentration. In the crystallization at temperatures between 333 and 313 K, the stable C form did not crystallize. At 333 K, the metastable A and BH forms crystallized competitively. At low initial concentration and slow addition rate, the A form crystallized preferentially, though at a high initial concentration and high addition rate BH tended to crystallize. It was presumed that the nucleation process of the unsolvated A form is not controlled by the dissociation equilibrium of the BH and D forms but is controlled by the kinetic process. This nucleation behavior of polymorphs at 333 K is very different from that at 323 K, which was reported previously, i.e., at low initial concentration BH crystallized, and at higher concentration the D form crystallized with BH. Furthermore, after crystallization at 333 K transformation from the BH form to the A form was observed, and it was found that the transformation rate decreases with the addition rate and the initial concentration. Such tendency is similar to that observed at 323 K. Conversely, at 313 K, the D form tended to crystallize preferentially. At low concentration the BH form also appeared with the D form, and it transformed to the D form. With a decrease of the temperature to 313 K, the D form becomes much more stable than the A and BH forms. This may accelerate preferential crystallization of the D form at 313 K.