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研究生：	陳峙瑋 Chih-Wei Chen
論文名稱：	Reaction Crystallization Kinetics of Dimethyl Fumarate by Anti-Solvent Addition
指導教授：	李度 Tu Lee
口試委員:
學位類別：	碩士 Master
系所名稱：	工學院 - 化學工程與材料工程學系 Department of Chemical & Materials Engineering
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	98
中文關鍵詞：	富馬酸二甲酯、反應動力學、反溶劑結晶
外文關鍵詞：	Dimethyl fumarate, Reaction kinetics, Anti-solvent crystallization
相關次數：	點閱：13 下載：0
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此篇研究的主要目的在於結合反應與結晶的觀點，對於富馬酸二甲酯的合成與反結晶製程進行討論。首先，關於反應部分，利用富馬酸與甲醇進行酯化反應，並選擇以硫酸作為均相的酸性催化劑進而得到富馬酸二甲酯。然而，即使催化劑的添加能促使反應的進行，但過量的催化劑會導致副反應的產生進而影響產物的純度，因此，本反應過程中的催化劑濃度，參考文獻訂於富馬酸與硫酸的莫耳比等於4。而動力學研究是透過改變起始反應濃度及不同的反應溫度求得反應速率式與速率常數。此外，大多數的化學反應皆為放熱反應，在本研究中，透過理論計算去估計反應焓對於不同放大規模、熱力學系統及冷卻設備的效能需求進行討論。再者，有關結晶部分，比較冷卻結晶與反溶劑添加的結晶方法之差異，其中，反應後直接冷卻結晶的產物顆粒大小相較於透過反溶劑添的結晶方法大。另外，由於酸性催化劑的使用，中和步驟與否亦是重要的課題，我們發現在反溶劑添加的同時，有中和反應的產物之溶解度測試較沒有中和的產物緩慢。因此，我們推論在此系統中，顆粒大小分布並非為決定溶解度測試的關鍵因素，透過單晶X光繞射儀(SXD)的分析結果，結晶平面的官能基可能是造成親疏水性的重要因素。另外，利用MSMPR模型的顆粒平衡計算成核速率和晶體生長速率，透過濕篩法求得晶體尺寸分布。最後，從光學顯微鏡(OM)、示差掃描量熱儀(DSC)、傅立葉轉換紅外線光譜儀(FT-IR)、粉末X射線繞射儀(PXRD)和單晶X光繞射儀的檢測結果分別確認富馬酸二甲酯的晶貌、熔點及結構。

The aim of this thesis was about the kinetic studies for the formation of dimethyl fumarate and the crystallization of dimethyl fumarate by anti-solvent addition. The esterification of fumaric acid with methanol was in the presence of a homogeneous sulfuric acid catalyst. The catalyst concentration used in this reaction was the molar ratio of fumaric acid to sulfuric acid of 4. The reaction rate expressions and the enthalpy of reaction were estimated from experimental data and theoretical calculations. Dimethyl fumarate crystals produced by anti-solvent addition with and without neutralization were compared with the control patent method by cooling. The dimethyl fumarate generated from cooling had the largest crystal sizes and the one prepared from anti-solvent addition had relatively small crystal sizes. However, dimethyl fumarate crystals produced from anti-solvent crystallization with simultaneous neutralization exhibited a different dissolution profile from the one from anti-solvent addition without simultaneous neutralization. In addition, nucleation rate and crystal growth rate were investigated through the MSMPR formalism for the population balance by using wet sieving method for crystal size distribution. Finally, the solid-state characterizations for all sample solids by OM, FT-IR, DSC, PXRD and SXD were carried out for ensuring the chemical identity and polymorphism of dimethyl fumarate.

摘要    i
Abstract    ii
Acknowledgement    iii
List of Figures    vii
List of Tables    xi
List of Schemes    xii
Chapter 1    Introduction    1
1    The Development of Drug Synthesis in Pharmaceutical Industry    1
2    Crystallization Process in Pharmaceutical Industry    3
3    Reactive Crystallization    5
4    Conceptual Framework    6
5    References    8
Chapter 2    Experimental Materials and Methods    10
1    Materials    10
1.1    Chemicals    10
1.2    Solvents    11
2    Experimental Procedures    12
2.1    Kinetics Studies for the Synthesis of Dimethyl Fumarate    12
2.2    Analytical Titration Method    14
2.3    Solubility Curves Measurement    15
2.4    Anti-Solvent Addition Method    16
2.5    Wet Sieve Analysis Method    17
2.6    Dissolution Test    18
3    Analytical Measurements    19
3.1    Thermocouple    19
3.2    pH-indicator Strips    19
3.3    Ultraviolet and Visible Spectrophotometer (UV/Vis)    19
3.4    Optical Microscopy (OM)    20
3.5    Fourier Transform Infrared (FT-IR) Spectroscopy    20
3.6    Differential Scanning Calorimetry (DSC)    20
3.7    Powder X-Ray Diffraction (PXRD)    21
3.8    Single Crystal X-ray Diffraction (SXD)    21
4    References    22
Chapter 3    Reaction  Crystallization  Kinetics  of   Dimethyl  Fumarate  by  Anti-Solvent  Addition    23
1    Introduction    23
2    Results and Discussion    28
2.1    Efficacies of Various Catalysts    28
2.2    The Mechanism for Esterification    30
2.3    Kinetic Studies    32
2.4    Enthalpy of Reaction    40
2.5    Solubility Curves    45
2.6    Mixed Suspension Mixed Product Removal (MSMPR)    51
2.7    Dissolution Test    58
2.8    Overall Mass Balance    61
2.9    Solid-State Characterizations    63
3    Conclusions    71
4    References    72
Chapter 4    Conclusions and Future Works    77
1    Conclusions    77
2    Future Works    79
3    References    80
                                

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Chapter 4
1 Rönnback, R.; Salmi, T.; Vuori, A.; Haario, H.; Lehtonen, J; Sundqvist, A.; Tirronen, E. Development of a kinetic model for the esterification of acetic acid with methanol in the presence of a homogeneous acid catalyst. Chem. Eng. Sci. 1997, 52 (19), 3369-3381.
2 Yadav, G. D.; Thathagar, M. B. Esterification of maleic acid with ethanol over cation-exchange resin catalysts. React. Funct. Polym. 2002, 52 (2), 99-110.
3 Lindenberg, C.; Krättli, M.; Cornel, J.; Mazzotti, M. Design and optimization of a combined cooling/antisolvent crystallization process. Cryst. Growth Des. 2009, 9 (2), 1124-1136.
4 Chung, S.H.; David L. Ma, D. L.; Braatz, R.D. Optimal seeding in batch crystallization. Can. J. Chem. Eng. 1999, 77 (3), 590-596.
5 Polster, C. S.; Cole,K. P.; Burcham, C.L.; Campbell, B. M.; Frederick, A. L.; Hansen, M. M.; Harding, M.; Heller, M. R.; Miller, M. T.; Phillips, J. L.; Pollock, P. M.; Zaborenko, N. Pilot-scale continuous production of LY2886721: amide formation and reactive crystallization. Org. Process Res. Dev. 2014, 18 (11), 1295-1309.
6 Lee, T.; Chen, H. R.; Lin, H. Y.; Lee, H. L. Continuous co-crystallization as a separation technology: the study of 1:2 co-crystals of phenazine-vanillin. Cryst. Growth Des. 2012, 12 (12), 5897-5907.

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