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Control of Crystallization and Crystal Growth of Drug by Cyclodextrin Complexation

环糊精络合控制药物的结晶和晶体生长

基本信息

批准号：
12672090
负责人：
HIRAYAMA Fumitoshi
金额：
$ 2.18万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672090/
关键词：
Cyclodextrin Tolbutamide Chlorpropamide Amorphous complex Polymorphism Crystallization Crystal growth Crystal engineering

项目摘要

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

众所周知，口服降糖剂如甲苯丁胺和氯丙胺在水中的溶解度较低，它们的溶解度在多态转变时会发生显著变化。本研究考察了非晶态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.甲苯丁酰胺与HP-环糊精包结物的摩尔比为2：1(主体：客体)，其中空腔较小的HP-α-CyD包合药物的丁基部分，而空腔较大的HP-β-CyD包合药物的苯基部分。另一方面，氯丙胺与HP-β-CyD以1：1的摩尔比形成包合物，其中氯苯部分较好地包含在空腔中。采用喷雾干燥法制备了甲苯磺丁胺与HP-环糊精无定形包合物。在储存过程中，HP-α-Cyd络合物中的无定形甲苯丁酰胺结晶为…更稳定的形式(第一种形式)。相反，HP-β-Cyd复合体中的药物结晶为亚稳态形式(第二种形式)。HP-β-CyD基质中的第二晶型比较稳定，在较长时间内很难转化为第一晶型。采用喷雾干燥法制备了氯丙胺与HP-β-CyD的无定形包合物。即使在较高的压力下，该复合体也几乎不会发生多态转变。在高温、高湿条件下长期存放时，在HP-β-CyD基质中，无定形氯丙胺结晶为亚稳态(C型)，但没有进一步从C型转变为稳定型(A型)。Hp-Cyds的溶出速度明显快于A型和C型药物。结论：Hp-Cyds有利于将晶态药物转化为无定形药物，有利于控制药物的结晶、晶体生长和晶型转变。这一结果为环状化合物包合物在晶体工程中的应用提供了有用的信息。较少