Effects of cyclodextrins on crystallization of chlorpropamide and the polymorphic transition mechanism of the drug in aqueous solution were investigated. In the presence of 2-hydroxybutyl-beta-cyclodextrin, chlorpropamide was exclusively crystallized to metastable Form II and III polymorphs, whereas it was crystallized to stable Form A in the absence of the beta-cyclodextrin at 4 degrees C. The crystallization to metastable Form II or III polymorph was dependent upon 2-hydroxybutyl-beta-cyclodextrin concentrations employed, i.e. crystallization to Form III at a lower concentration (0.5 mM), whereas to Form II in a higher concentration (5 mM). At an intermediate concentration (2 mM), the least stable Form II crystal was initially precipitated, but it was transformed to Form III crystal. At higher temperature, Form III crystal was converted to stable Form A crystal. In aqueous solution, chlorpropamide crystallized to stable Form A crystal consecutively through metastable Forms II and III, according to "Ostwald's Rule of Stages". 2-Hydroxybutyl-beta-cyclodextrin inhibits the transition of Form II to Form III at higher concentrations and that of Form III to Form A at lower concentrations. The results suggest that 2-hydroxybutyl-beta-cyclodextrin is useful for selective preparation of metastable chlorpropamide polymorphs occurring during crystallization according to the Ostwald's rule.
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