Crystal Structures of Tetramorphic Forms of Donepezil and Energy/Temperature Phase Diagram via Direct Heat Capacity Measurements

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• 作者：Yeojin Park ; Jangmi Lee ; Sun Hye Lee ; Hoo Gyun Choi ; Chen Mao ; Sung Kwon Kang ; Sang-Eun Choi ; Eun Hee Lee
• 刊名：Crystal Growth & Design
• 出版年：2013
• 出版时间：December 4, 2013
• 年：2013
• 卷：13
• 期：12
• 页码：5450-5458
• 全文大小：572K
• 年卷期：v.13,no.12(December 4, 2013)
• ISSN：1528-7505

文摘

Donepezil is used for the palliative treatment of mild to moderate dementia of the Alzheimer鈥檚 disease. Donepezil crystallized as four solvent-free polymorphs including forms I, II, C, and F which differ in molecular conformations and packing. Conformational difference comes from the torsion of the 2, 3-dihydroinden-1-one moiety and methyl-benzyl ring with respect to piperidyl ring. Similar melting temperatures and heats of fusion were observed for four solvent-free polymorphic forms and made polymorph selection by solvent crystallization method poor. The relative thermodynamic stability relationships of each polymorph with respect to the amorphous form were determined using direct heat capacity (C_p) measurement and then used to evaluate the relative thermodynamic stability between polymorphs. Form F was the stable form over the temperature ranges we studied. Other than form F, form C was the stable form among three polymorphic forms including I, II, and C, below 53 掳C, and is enantiotropically related to both forms I and II. Form II is the stable form above 53 掳C and monotropically related to form I. The thermodynamic relationships between polymorphs were further confirmed by measuring the solubility over temperatures ranging from 35 to 60 掳C in ethanol. Slurry conversion in ethanol, isopropyl alcohol, and cyclohexane was conducted to provide a guideline to obtain pure and desired polymorphic forms. The establishment of the thermodynamic relationships among four polymorphic forms greatly facilitated polymorph selections of donepezil.