| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
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
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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
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