Dependence of Polymorphic Transformation on Anti-Solvent Composition and Crystallization Behavior of Thiazole-Derivative Pharmaceutical.

Abstract

The transformation and crystallization behaviors of the polymorphs (A and C) and solvated crystals (BH (BPT·0.5H2O) and D (BPT·MeOH)) of the thiazole-derivative pharmaceutical (BPT) were investigated. The solubility of metastable form was measured with the vigorous stirring using a magnetic stirrer. It was found that at 323 K with the volume fraction of methanol (VMeOH) of 0.5, A and D forms dose not transform to the stable C form directly, but transform in two steps via the metastable BH form. The stability of A tended to decrease and the stability of D form increased with the decreased of temperature from 323 to 303 K. The A and D forms also transformed to the metastable BH form at 303 K and 313 K. This is because of the selective nucleation and growth of BH crystals due to the specific solute-solvent interaction in comparison with C crystals. The small free energy difference between BH and C forms also stabilizes BH form.It appeared that the C form is the stable form and A is the metastable form with the methanol composition (VMeOH) ranges of 0.5–0.8 at 323 K. At the methanol composition of 0.7 A, BH and D forms transformed to the stable form, C. With increase of methanol composition the stability of D form is increased and that of BH form decreased. Such tendency may be due to the dissociation of the solvated crystals.In the crystallization at 323 K by adding water as an anti-solvent to BPT solution of methanol and water mixture, it cleared that only the metastable forms of BH and D crystallize and the crystallization ratio of these polymorphs depends on the addition rate of water. Further more, it was found that BH transforms to A by solution-mediated mechanism after the crystallization.