臺灣博碩士論文加值系統

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。

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.

中文摘要i
英文摘要ii
誌謝iv
目錄v
表目錄vii
圖目錄viii
第一章 序論1
第二章 晶體成長概論3
2.1 液-固結晶作用3
2.2 晶核的形成4
2.2.1 初級成核4
2.2.2 次級成核5
2.3 晶體生長學說5
第三章 結晶技術7
3.1 溶液結晶7
3.1.1 溶解度與過飽和度對於結晶之關係7
3.1.1.1 冷卻結晶9
3.1.1.2 鹽析結晶9
3.2 熔融結晶10
3.3 蒸發結晶11
3.4 反應結晶11
3.5 其他結晶方法12
第四章 藥物多晶型之相關文獻14
4.1 藥物CPM多晶型的製備14
4.2 壓力對藥物晶型的影響17
4.3 儲存環境對於藥物晶型的影響19
第五章 實驗方法27
5.1 實驗藥品與儀器27
5.1.1 實驗藥品27
5.1.1.1 模式藥物27
5.1.1.2 溶劑種類27
5.1.2 實驗儀器28
5.2 實驗規劃30
5.3 溶劑選擇依據31
5.4 冷卻結晶實驗33
5.4.1 冷卻結晶過量法34
5.5 鹽析結晶實驗36
5.6 熔融結晶實驗37
5.7 相對穩定性實驗38
5.8 分析藥物晶體的儀器原理38
5.8.1 X光粉末繞射分析38
5.8.2 示差熱分析39
5.8.3 熱重減損分析40
5.8.4 紅外線光譜分析41
5.8.5 掃描式電子顯微鏡分析41
第六章 結果與討論42
6.1 冷卻結晶42
6.1.1 快速冷卻結晶對藥物晶體影響之探討42
6.1.2 慢速冷卻結晶對藥物晶體影響之探討58
6.1.3 急驟冷卻結晶對藥物晶體影響之探討72
6.2 鹽析結晶86
6.2.1 以Water為反溶劑之鹽析結晶對藥物晶體的影響86
6.2.2 以Heptane為反溶劑之鹽析結晶對藥物晶體的影響96
6.3 熔融結晶110
6.4 模式藥物CPM晶型之鑑定分析113
6.4.1 TGA鑑定分析113
6.4.2 SEM晶型分析116
6.4.3 FTIR鑑定分析119
6.5 混合晶型之鑑定分析120
6.6 相對穩定性實驗123
第七章 結論129
參考文獻133

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