臺灣博碩士論文加值系統

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。

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.

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 緒論...................................................................................................................1
第二章 晶體成長的基本規律.......................................................................................3
2.1 晶體的形成方式…….….............................................................................3
2.1.1 物質狀態和結晶作用..........................................................................3
2.1.2 液-固結晶作用....................................................................................4
2.1.3 固-固相結晶作用................................................................................6
2.2 晶核的形成...................................................................................................7
2.2.1 晶核的相變趨動力..............................................................................7
2.2.2 均勻成核作用..……….……...............................................................7
2.3 晶體的成長....................................................................................................9
2.3.1 晶體生長的型態..…….…...................................................................9
2.3.2 晶體生長學說………………………………………………………10
第三章 結晶技術…….................................................................................................12
3.1 溶液結晶….................................................................................................12
3.1.1 冷卻結晶………………………………………………...………12
3.1.2 鹽析或溶析結晶………………………..………………….………13
3.1.3 蒸發結晶………………………………………………………...14
3.1.4 反應結晶.......................................................................................14
3.2 熔融結晶……….……………………………………………………….15
3.3 其它結晶方法..…………………………..…………………………….….16
第四章 開發藥物多晶型相關技術回顧.....................................................................17
4.1 多晶型的製備..…………………………..…………………………….….17
4.2 添加物對多晶型的影響............................................................................20
4.3 不同溶劑對多晶型及水合物的影響..........................................................23
第五章 實驗方法.........................................................................................................30
5.1 實驗藥品與儀器......................................................................30
5.1.1 實驗藥品…......................................................................................30
5.1.2 實驗儀器.........................................................................................31
5.2 實驗規劃.....................................................................................................33
5.3 溶劑的選擇..................................................................................................34
5.4 冷卻結晶實驗..............................................................................................36
5.5 鹽析結晶實驗…..........................................................................................38
5.6 熔融結晶實驗..............................................................................................39
5.7 相對穩定性實驗..........................................................................................40
5.8 藥物晶體分析..............................................................................................41
5.8.1 X光粉末繞射分析.............................................................................41
5.8.2 示差熱分析.......................................................................................42
5.8.3 熱重減損分析...................................................................................43
5.8.4 紅外線光譜分析...............................................................................43
第六章 結果與討論....................................................................................................44
6.1 冷卻結晶對藥物晶體之影響......................................................................44
6.1.1 快速冷卻結晶對藥物晶體之影響……….......................................45
6.1.2 慢速冷卻結晶對藥物晶體之影響...................................................63
6.1.3 驟冷結晶對藥物晶體之影響….......................................................80
6.1.4 TGA鑑定分析…………..................................................................100
6.1.5 FTIR鑑定分析………….................................................................104
6.2 鹽析結晶對藥物晶體之影響……............................................................105
6.2.1 以純水為反溶劑之鹽析結晶對藥物晶體之影響.........................106
6.2.2 鹽析結晶在不同平衡時間的晶型轉變.........................................120
6.2.3 以正庚烷為反溶劑之鹽析結晶對藥物晶體之影響….................126
6.3 熔融結晶對藥物晶體之影響....................................................................141
6.4 相對穩定性實驗........................................................................................143
6.4.1 丙酮為溶劑條件下藥物晶型穩定性之探討.................................143
6.4.2 乙醇為溶劑條件下藥物晶型穩定性之探討.................................148
6.4.3 乙酸乙酯為溶劑條件下藥物晶型穩定性之探討.........................153
第七章 結論...............................................................................................................158
參考文獻.......................................................................................................................162

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