Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Eur J Pharm Sci. 2010 Feb 19;39(4):248-55. doi: 10.1016/j.ejps.2009.12.008. Epub 2009 Dec 29.
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.
研究了环糊精对氯丙酰脲结晶以及药物在水溶液中多晶型转变机制的影响。在 2-羟丁基-β-环糊精存在下，氯丙酰脲仅结晶为亚稳定的 II 型和 III 型多晶型物，而在 4°C 下不存在β-环糊精时则结晶为稳定的 A 型。结晶为亚稳定的 II 型或 III 型多晶型物取决于所使用的 2-羟丁基-β-环糊精浓度，即在较低浓度（0.5mM）下结晶为 III 型，而在较高浓度（5mM）下结晶为 II 型。在中间浓度（2mM）下，最初沉淀出最不稳定的 II 型晶体，但它会转化为 III 型晶体。在较高温度下，III 型晶体转化为稳定的 A 型晶体。在水溶液中，氯丙酰脲通过亚稳定的 II 型和 III 型连续结晶为稳定的 A 型晶体，符合“奥斯特瓦尔德阶段规则”。2-羟丁基-β-环糊精在较高浓度下抑制 II 型向 III 型的转变，在较低浓度下抑制 III 型向 A 型的转变。结果表明，2-羟丁基-β-环糊精可根据奥斯特瓦尔德规则用于选择性制备结晶过程中出现的亚稳定氯丙酰脲多晶型物。
