關於量產路徑之初步鹽類篩選程序:以外消旋布洛芬之兩個不同鹽類為例

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王業文(Yeh-Wen Wang) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

關於量產路徑之初步鹽類篩選程序:以外消旋布洛芬之兩個不同鹽類為例
(Initial Salt Screening Procedures for the Manufacturing Route: Case Example of Two Different Salt Forms of Racemic (R,S)-(±)-Ibuprofen)

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摘要(中)

在藥物市場中，大約有50%的藥物都是外消旋性混合物。因此，在藥物的研發上，對掌性質變的越來越重要了。在本論文中，右旋布洛芬((S)-(＋)-Ibuprofen)和外消旋布洛芬(racemic (R,S)-(±)-Ibuprofen)分別在「初步溶劑篩選」及「初步鹽類篩選」程序中被選為模式藥物。在初步溶劑篩選中，我們可以獲得在製藥業中相當重要的四個性質：溶解度、晶貌、結晶度及多形體性質。這個方法以簡單、經濟的方式，獲得一系列可用在量產情況的工程數據。另外，在這個方法中所建立的「多形體表」代表了材料特性，也同時提供了每個可能發現活性藥物多形體的機會。多形體表也和Hansen parameter互相結合來預測活性藥物在未知溶劑中的溶解度。
在初步鹽類篩選程序中，外消旋布洛芬被用來和七種製藥業中常用的鹼做酸鹼中和反應，藉此篩選出關於外消旋布洛芬可能的鹽類。在這套方法中只考慮兩種結晶方法：降溫和反溶劑法以配合量產方面的需求。此外，大量的水被用來做主要的溶劑以避免因弱酸或弱鹼的解離常數(pKa)在非水溶液中偏移，導致酸鹼之間的鹼離常數差(ΔpKa)小於二，以至於錯失掉形成鹽類的機會。外消旋布洛芬在這個方法中被篩選出兩鹽類：外消旋布洛芬鈉鹽二水合物及外消旋布洛芬三羥甲基氨基甲烷鹽。其中，後者在本研究中為新發現的鹽類。我們也利用FTIR來辨別它們的特徵官能基。OM、DSC及TGA分析可獲得其晶貌及熱性質。由PXRD及SXD可決定其晶體結構及分子結構。這兩種鹽類也在pH值-溶解度測試、吸濕性測試及溶解速率測試中被互相比較。由吸濕性測試可以知道外消旋布洛芬三羥甲基氨基甲烷鹽具有低吸濕性，在儲藏方面可能具有良好的穩定性。由溶解速率測試可得知外消旋布洛芬三羥甲基氨基甲烷鹽可能可以作為長效藥來使用。

摘要(英)

In the pharmaceutical market, approximately 50% are racemics (mixture of enantiomers); therefore, chirality becomes more and more important in drug discovery and development. In this thesis (S)-(＋)-Ibuprofen and racemic (R,S)-(±)-Ibuprofen were used as active pharmaceutical ingredients (APIs) in “initial solvent screening” and “initial salt screening” procedures respectively. In initial solvent screening, the four important properties in pharmaceutical industry such as solubility, crystal habit, crystallinity, and polymorphism of (S)-(＋)-Ibuprofen could be obtained. This approach was an easy, economical, and close to scale-up condition approach for obtaining a serious of engineering data. The “form space” constructed in this method was a material characteristic that can provide the API every opportunity to discover a new polymorph, and it could be combined with Hansen model to form a solubility sphere to predict the API solubility property in an unknown solvent.
In initial salt screening procedure, racemic (R,S)-(±)-Ibuprofen was reacted with seven bases used commonly in pharmaceutical industry to find possible salt. In this procedure only two crystallization pathways such as temperature cooling and the addition of anti-solvent were to be considered to a close-to scale-up conditions. Besides, water was used as a main solvent to avoid missing any opportunities for salt formation. Two salts: racemic (R,S)-(±)-Ibuprofen sodium dihydrate and racemic (R,S)-(±)-Ibuprofen tris(hydroxymethyl)aminomethane were produced by the method of initial salt screening. Their functional groups were identified by FTIR, and the crystal habit and thermal properties were determined by OM and DSC, TGA, respectively. Their crystal structures were determined by PXRD and SXD. They were also compared in their pH-solubility profiles, moisture sorption studies, and dissolution rate tests. Under these tests, racemic (R,S)-(±)-Ibuprofen tris(hydroxymethyl)aminomethane was considered to be stable during storage and could become a sustain-released drug.

關鍵字(中)

★ 結晶度
★ 晶貌
★ 溶解度
★ 三羥甲基氨基甲烷
★ 多形體表
★ 鹽類篩選
★ 多形體
★ 溶劑篩選
★ 布洛芬

關鍵字(英)

★ solvent screening
★ ibuprofen
★ salt screening
★ tris(hydroxymethyl)aminomethane
★ polymorph
★ crystal habit
★ from space
★ solubility
★ crystallinity

論文目次

摘要......................................................i
Abstract................................................iii
Acknowledgement...........................................v
List of Tables...........................................ix
List of Figures...........................................x
Chapter 1 Executive Summary...............................1
1.1 Introduction..........................................1
1.2 Brief Introduction of Chiral Compound.................3
1.3 Conceptual Framework..................................4
References................................................7
Chapter 2 Analytical Instruments..........................9
2.1 Introduction..........................................9
2.2 Thermal Analysis.....................................12
2.2.1 Differential Scanning Calorimetry (DSC)............12
2.2.2 Thermal Gravimetric Analysis (TGA).................14
2.3 Spectroscopic Analysis...............................16
2.3.1 Powder X-ray Diffraction (PXRD)....................16
2.3.2 Single Crystal X-ray Diffraction (SXD).............18
2.3.3 Fourier Transform Infrared Spectroscope (FTIR).....20
2.4 Microscopic analysis.................................21
2.4.1 Optical Microscope (OM)............................21
2.5 Conclusions..........................................23
Reference ................................................24
Chapter 3 Solubility, Crystal Habit, Crystallinity, and Polymorphism of (S)-(＋)-Ibuprofen－by Initial Solvent Screening ................................................27
3.1 Introduction.........................................27
3.1.1 Solubility.........................................28
3.1.2 Crystal Habit......................................30
3.1.3 Crystallinity......................................30
3.1.4 Polymorphism .......................................31
3.1.5 Hansen Parameters..................................33
3.1.6 (S)-(＋)-Ibuprofen.................................34
3.2 Materials............................................34
3.3 Experimental Section.................................38
3.3.1 Solvent Screening Process..........................38
3.3.2 Analytical Measurements............................39
3.4 Results and Discussions..............................40
3.4.1 Solubility Studies.................................40
3.4.2 Crystal habit Study................................47
3.4.3 Crystallinity Study................................51
3.4.4 Polymorphism Study.................................53
3.4.5 Hansen Parameters study............................55
3.5 Conclusions..........................................59
References...............................................60
Chapter 4 Initial Salt Screening Procedures for the Manufacturing Route: Case Example of Racemic (R,S)-(±)-Ibuprofen ................................................64
4.1 Introduction.........................................64
4.1.1 Drug Candidate and Its Form........................64
4.1.2 The Aim of Salt Formation..........................67
4.1.3 Review of Salt Selection/Formation.................68
4.1.4 Racemic (R,S)-(±)-Ibuprofen........................71
4.2 Materials............................................72
4.3 Experimental Section.................................76
4.3.1 Salt Formation Procedures..........................76
4.3.2 pH-Solubility Studies..............................79
4.3.3 Moisture Absorption Studies........................79
4.3.4 Dissolution Test...................................79
4.3.5 Analytical Instruments.............................81
4.4 Results and Discussions..............................84
4.4.1 Screening Results..................................84
4.4.2 FTIR study.........................................87
4.4.3 OM, DSC, TGA, and PXRD Study.......................89
4.4.4 pH-Solubility Study................................94
4.4.5 Moisture Absorption Study..........................98
4.4.6 Dissolution Test...................................99
4.4.7 Single-Crystal X-ray Diffraction (SXD)............100
4.5 Conclusions.........................................103
References..............................................105
Chapter 5 Conclusions and Future Work...................111

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指導教授

李度(Tu Lee)

審核日期

2008-7-4

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