Selective Crystallization of the Metastable Form IV Polymorph of Tolbutamide in the Presence of 2,6-Di-O-methyl-β-cyclodextrin in Aqueous Solution

Abstract

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-β-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-β-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-β-cyclodextrin.