Control of Crystallization and Crystal Growth of Drug by Cyclodextrin Complexation

已知口服降血糖剂如甲苯磺丁脲和氯磺丙脲在水中具有低溶解度，并且它们的溶解度在多晶型转变时显著变化。研究了无定形2-羟丙基-环糊精（HP-α-CyD和HP-β-CyD）对药物结晶和晶体生长的影响。主要研究结果如下：1.甲苯磺丁脲与HP-CyD形成的包合物的主体：客体摩尔比为2：1，其中具有小空腔的HP-α-CyD优选包含药物的丁基部分，而具有大空腔的HP-β-CyD优选包含苯基部分。另一方面，氯磺丙脲与HP-β-CyD以1：1的摩尔比形成包合物，其中氯苯部分优选包含在空腔中。采用喷雾干燥法制备了甲苯磺丁脲与HP-CyDs的无定形包合物。储存时，HP-α-CyD复合物中的无定形甲苯磺丁脲结晶， ...更多信息 稳定形式（I型）。相反，HP-β-CyD复合物中的药物结晶为亚稳态形式（II型）。HP-β-CyD基质中的晶型II稳定，并且在较长的储存时间内几乎不转化为晶型I晶体。采用喷雾干燥法制备了氯磺丙脲与HP-β-CyD的无定形包合物。该配合物在高压下几乎不发生多晶型转变。在高温高湿条件下长期储存时，复合物中的无定形氯磺丙脲结晶为亚稳态（C型），但在HP-β-CyD基质中C型没有进一步转变为稳定型（A型）。复合物的溶出速率比A型和C型的溶出速率快得多。总之，HP-CyDs可用于将结晶药物转化为无定形复合物，并用于控制结晶、晶体生长和多晶型转变。本研究结果可为CyDs包结配合物在晶体工程中的应用提供有用的信息。少

Oral hypoglycemic agents such as tolbutamide and chlorpropamide are known to have low solubility in water, and their solubility significantly changes upon polymorphic transitions. In the study, the effects of amorphous 2-hydoxypropyl-cyclodextrins (HP-α-CyD and HP-β-CyD) on the crystallization and crystal growth of these drugs were investigated. The results obtained are summarized as follows :1. Tolbutamide formed the inclusion complexes with HP-CyDs in a molar ratio of 2 : 1 (host : guest), where HP-α-CyD with a small cavity included preferably the butyl moiety of the drug, whereas HP-β-CyD with a large cavity included the phenyl moiety. On the other hand, chlorpropamide formed the inclusion complex with HP-β-CyD in a molar ratio of 1 : 1, where the chlorbenzene moiety was preferably included in the cavity.2. The amorphous inclusion complexes of tolbutamide with HP-CyDs were prepared by the spray-drying method. On storage, amorphous tolbutamide in the HP-α-CyD complex crystallized to … More the stable form (Form I). In contrast, the drug in the HP-β-CyD complex crystallized to a metastable form (Form II). Form II in the HP-β-CyD matrix was stable arid hardly converted to Form I crystals for longer storage.3. The amorphous inclusion complex of chlorpropamide with HP-β-CyD was prepared by the spray-drying method. The complex was hardly subject to polymorphic transition even-under higher pressure. On long storage under high temperature and humidity, the amorphous chlorpropamide in the complex crystallized to a metastable form (Form C), but there was no further transition of Form C to the stable form (Form A) in the HP-β-CyD matrix. The dissolution rate of the complex was much faster than those of Form A and Form C.In conclusion, HP-CyDs were useful for converting crystalline drug to amorphous complexes and for controlling the crystallization, crystal growth and polymorphic transition. The present results may provide useful information for application of the inclusion complexation of CyDs to crystal engineering. Less