以一般化結晶技術篩選藥物多晶型的研究

Screening Polymorphic Forms of Drug Substances by Using Generalized Crystallization Techniques

梁峻銘(Chun Ming Liang)

指導教授 ： 魏正琪

國立臺北科技大學/工程學院/化學工程研究所/碩士(2007年)

https://doi.org/10.6841/NTUT.2007.00373

摘要

本研究的目的是利用一般化結晶技術篩選出藥物的多晶型。文中採用Chlorpropamide為模式藥物以及三種不同的結晶方法，包括冷卻結晶、鹽析結晶與熔融結晶以尋找各種多晶型。冷卻結晶是以不同極性與官能基的13種溶劑在不同冷卻速率下進行再結晶程序。鹽析結晶則採用水及正庚烷作為反溶劑，並以其他有機溶液作為良溶劑。熔融結晶是將高溫液態的模式藥物以不同降溫速率冷卻使其再結晶。文中進一步採用XRD、DSC、FTIR和TGA等儀器鑑識各種多晶型晶體的特性。此外，我們利用X-射線結晶量測原理對於少數混合晶型加以分析及鑑定。相對穩定性實驗則採用乙酸乙酯作為溶劑，觀察不同多晶型在長時間平衡下的晶型變化，藉以獲得最穩定的晶型。本研究證實此一般化的篩選方法將可出現各種可能的多晶型結晶，藉此提升製藥工業的製程技術以及藥物品質。

關鍵字

多晶型 ； Chlorpropamide ； 冷卻結晶 ； 鹽析結晶 ； 熔融結晶 ； 相對穩定性實驗

並列摘要

The purpose of this study is to screen polymorphic forms of drug substances through the use of generalized crystallization techniques. Chlorpropamide was used as a model drug and three different crystallization methods including cooling crystallization, salting out crystallization, and melting crystallization were used to search for various polymorphs. In cooling crystallization, thirteen solvents with different polarity and functional groups were chosen for the recrystallization process under different cooling rates. In salting out crystallization, water and heptane were used as anti-solvents while the other organic solvents were used as good solvents. In melting crystallization, the model drug at high-temperature liquid state was cooled at different rates and was solidified. Furthermore, XRD, DSC, FTIR, and TGA were used to characterize the polymorphic form of each crystal. In addition, X-ray crystallography was used to identify the polymorphic forms mixed in a few crystals. A relative stability study was carried out using ethyl acetate as a solvent to observe the transition of different polymorphic forms under a long period of equilibrium, from which the most stable form was obtained. The study showed that various possible polymorphic forms may appear through this generalized screening method, allowing manufacturing processes in pharmaceutical industry to enhance the quality of drug products.

並列關鍵字

Polymorphism ； Chlorpropamide ； Cooling Crystallization ； Salting Out Crystallization ； Melting crystallization ； Relative stability study.

參考文獻

[1] Sudo, S., Sato, K. and Harano, Y., “Growth and solvent-mediated phase transition of cimetidine polymorphic forms A and B”, Journal of Chemical Engineering of Japan, vol. 24, pp. 628-632(1991).

[2] Li, R., Mayer, P. T., Trivedi, J. S. and Fort, J. J., “Polymorphism and crystallization behavior of Abbott-79175, a second-generation 5-lipoxygenase inhibitor”, J. Pharm. Sci., vol. 85, no 7, pp. 773-780(1996).

[3] Wurster, D. E. and Taylor, P. W., “Dissoultion rate”, J. Pharm. Sci., vol. 54, pp. 169-175(1965).

[4] Chikaraishi, Y., Otsuka, M. and Mastuda, Y., “Dissolution phenomenon of the piretanide amorphous from involving phase change”, Chem. Pharm. Bull., vol. 44, no. 11, pp. 2111-2115(1996).

[5] Gennaro, A. R., Remington's Pharmaceutical Sciences, Ch. 35, 17th ed., Mack Publishing Co.(1985).