Coordination-induced conformation diversity for pharmaceutical polymorph control

Abstract

Template-induced heteronucleation can dramatically influence crystal polymorphism. However, the existing screening techniques rarely consider targeting the crystalline form by molecular design. In this study, a new method for controlling polymorphism via the coordination-induced conformation diversity of the target compound was proposed using sulfathiazole (ST) as the model compound. Different complexes with diverse conformations of the ST ligand were synthesized by the coordination reaction between ST as the ligand and metal ions. The crystal structures of the complexes were confirmed by SXRD. These complexes were used to induce the crystallization of ST polymorphs. It was found that different metastable polymorphs of ST could be obtained using different complexes as templates. Conformational analysis showed that the conformational match between the specific ST ligand part in the complex and the corresponding ST form was the molecular mechanism of polymorph regulation by coordination-induced conformation diversity. The approach presented in this study provides a new tool for the screening of polymorphs.