以結晶技術系統化篩選藥物的多晶型研究

Systematic Screening of Drug Substances for Polymorphs Using Crystallization Techniques

陳重守(Chong-Shou Chen)

指導教授 ： 魏正琪

國立臺北科技大學/工程學院/化學工程所/碩士(2006年)

摘要

本研究的目的在建立一套系統化的方法，藉由結晶技術篩選藥物的多晶型結晶。文中採用Tolbutamide（TBM）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。冷卻結晶採用純水及12種不同官能基與極性的有機溶劑在三種不同冷卻模式下進行系統化篩選。鹽析結晶則採用水及正庚烷作為反溶劑，並採用其它有機溶液作為良溶劑。熔融結晶是以不同冷卻速率在示差熱分析儀中觀察其熔融體的變化。文中採用XRD 、DSC 、FTIR 和TGA 等儀器鑑識各多晶型的特性。此外，以相對穩定性實驗採用丙酮、乙醇及乙酸乙酯作為溶劑，藉以確認最穩定晶型。本研究證實經此系統化的篩選方法確實將可出現各種多晶型結晶，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 ； Tolbutamide ； 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 research is to establish a systematic methodology to screen polymorphic forms of drug substances through the use of crystallization techniques. In this study, tolbutamide was used as a model drug and three different approaches of crystallization methods including cooling crystallization, salting out crystallization, and melting crystallization were used to search for various polymorphs. In cooling crystallization, water and twelve organic solvents of different functional groups and polarity were chosen for systematic screening with three cooling modes. 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 melt observed with a differential scanning calorimeter was cooled at different rates. XRD, DSC and FTIR and TGA were employed to characterize the polymorphic forms. In addition, a relative stability study was carried out using acetone, ethanol and ethyl acetate as solvents to identify the most stable form. It is validated in this study that various polymorphic forms appear with this systematic screening methodology through which the manufacturing processes and the quality of drug products are enhanced in the pharmaceutical industry.

並列關鍵字

Polymorphism ； Tolbutamide ； Cooling Crystallization ； Salting Out Crystallization ； Melting crystallization ； Relative stability experiment

參考文獻

1. Mersmann, A., Crystallization Technology Handbook, Second Edition, Marcel-Dekker, 2001.

4. Kenya, K., Fumitoshi, H. and Kaneto U., ”Characterization of tolbutamide polymorphs（Burger’s forms II IV）and polymorphic transition behavior”, J. Pharm. Sci., vol. 88, pp. 385-391 (1999).

5. Olives, A. I., Martin, M. A., Castillo, B. del and Barba C., ”Influence of the presence of trace amounts of metals on the polymorphism of tolbutamide”, J. Pharm. Biomedical Analysis, vol. 14, pp. 1069-1076 (1996).

6. Yuji, C., Akimitsu, S., Tsuyoshi, T., Makoto, O. and Yoshihisa, M., “Preparation of piretanide polymorphs and their physicochemical properties and dissolution behaviors”, Chem. Pharm. Bull., vol. 42(5), pp. 1123-1128 (1994).

8. Mullin, J. W., Crystallization, Fourth Edition, Butterworth-Heinemann, Oxford, 2001.