Selective crystallization of the metastable form IV polymorph of tolbutamide in the presence of 2,6-di-O-methyl-beta-cyclodextrin in aqueous solution

摘要

It is of great importance in the pharmaceutical fields to discover, produce, and isolate crystalline polymorphs of a given solid drug and to control their polymorphic transformations. In this paper, we report that a cyclic oligosaccharide derivative. 2,6-di-O-methyl-beta-cyclodextrin, is useful for detection and isolation of Ostwald's intermediate metastable polymorphs occurring during an early stage of crystallization. The metastable Form IV of a hyperglycemic agent, tolbutamide, exclusively crystallized from an aqueous solution of 2,6-di-O-methyl--cyclodextrin, whereas the stable Form I crystallized in the absence of the cyclodextrin. The selective crystallization of the metastable Form IV was attributable to an inhibition of the solution-mediated transformation of the metastable form to the stable form by the complexation with 2,6-di-O-methyl-beta-cyclodextrin.