Crystal Growth & Design, 6 (5), 1181 -1185, 2006.
Selective Crystallization of the Metastable Form IV Polymorph of Tolbutamide in the Presence of 2,6-Di-O-methyl-β-cyclodextrin in Aqueous Solution
Yoh Sonoda, Fumitoshi Hirayama, Hidetoshi Arima, Yoshihiro Yamaguchi, Wolfram Saenger, and Kaneto Uekama
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.