在不同尺度下的混合對苯甲酸－苯甲酸鈉共晶體所形成的化學劑量與粒徑分佈之效應

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研究生：	許祐誠 Yu-Cheng Hsu
論文名稱：	在不同尺度下的混合對苯甲酸－苯甲酸鈉共晶體所形成的化學劑量與粒徑分佈之效應 The Effects of Macro-, Meso-, and Micro-Mixing on the Stoichiometry and Particle Size Distribution of Benzoic Acid-Sodium Benzoate Co-crystals
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：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	120
中文關鍵詞：	共晶
外文關鍵詞：	Co-crystal
相關次數：	點閱：9 下載：0
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共晶是改善藥物溶解度的方法之一，近幾年發展尤為快速，但少有研究探討混合對共晶製程的影響，因此此篇研究的主要目的是利用U-tube探討不同尺度的混合效應對苯甲酸(benzoic acid)－苯甲酸鈉(sodium benzoate)共晶的化學計量比和粒徑分佈的影響進行討論。根據文獻， 1：1苯甲酸－苯甲酸鈉共晶用甲醇溶劑研磨法合成、Form A 2:1苯甲酸－苯甲酸鈉共晶用乙醇－水(4:1 v/v)溶劑研磨法或在乙醇溶劑中蒸發合成、Form B 2:1苯甲酸－苯甲酸鈉共晶用在甲醇溶劑中蒸發合成，然而，我們則是使用純水當溶劑進行反應直接得到共晶，鹽酸與苯甲酸鈉進行化學反應形成苯甲酸，苯甲酸再與溶劑中的苯甲酸鈉共結晶而得到苯甲酸－苯甲酸鈉共晶，得到的晶體透過熱重分析儀(TGA)、粉末繞X射線繞射儀(PXRD)等儀器檢測。我們還研究了不同的莫耳比、停留時間和濃度來尋找理想的操作條件。在本研究中，我們僅得到1:1和Form A 2:1苯甲酸－苯甲酸鈉共晶，並未合成出Form B 2:1苯甲酸－苯甲酸鈉共晶。我們已知1:1和Form B 2:1苯甲酸－苯甲酸鈉共晶是熱力學不穩定的相，Form A 2:1苯甲酸－苯甲酸鈉共晶是熱力學最穩定的相。在U-tube實驗中，我們觀察到在進料點的苯甲酸局部濃度會直接影響在半小時內結晶的組成。因此，透過不同的攪拌速率和鹽酸的進料速率等不同的混合效應來控制進料點的苯甲酸局部濃度來合成不同組成的產物。然而，根據Ostwald’s Rule of Stages，U-tube實驗所產生的結晶在經過4小時後都會轉化成1:1和2:1苯甲酸－苯甲酸鈉共晶混合物。根據Ostwald’s ripening，4小時後收穫的產物過篩後所繪製的粒徑分佈圖都有著相似的大小分佈。這項研究有助於共晶製程和產物知識的了解以及品質控制。

Co-crystal is regarded as an approach to promote the solubility of drugs and is developed rapidly in recent years. The aim of this thesis was to discuss the effects of macro-, meso-, and micro-mixing on the stoichiometry and particle size distribution of benzoic acid-sodium benzoate (HBz-NaBz) co-crystals. According to the literature, 1:1 co-crystals of HBz-NaBz was synthesized by the grinding method in methanol. The 2:1 co-crystals of HBz-NaBz of Form A was synthesized by grinding method in ethanol-water (4:1 v/v) or evaporating in ethanol, and the 2:1 co-crystals of HBz-NaBz of Form B was synthesized by evaporating in methanol. However, in this study, we used only the pure water as a solvent to obtain the co-crystals. The aqueous solution of hydrochloric acid and sodium benzoate were reacted to form benzoic acid, and benzoic acid was co-crystallized with sodium benzoate in the aqueous solution to give the co-crystals of HBz-NaBz. The stoichiometric ratios and crystal structure of the solids were characterized by thermal gravimetric analysis (TGA) and powder X-ray diffraction (PXRD). Different molar ratios of HCl and NaBz, experiment times, and concentrations were screened for the optimal operating condition. In this thesis, only 1: 1 co-crystals of HBz-NaBz and Form A of 2:1 co-crystals of HBz-NaBz were obtained. Form B of 2:1 co-crystals of HBz-NaBz was not detected. 1: 1 co-crystals of HBz-NaBz and Form B of 2:1 co-crystals of HBz-NaBz were unstable forms, and Form A of 2:1 co-crystals of HBz-NaBz was the thermodynamically stable form. In the U-tube experiments, the local concentration of benzoic acid at the feed point would influence the composition of the solids harvested at t = 0.5 h. Therefore, the local concentration of benzoic acid at the feed point was influenced by the stirring rates of the turbine and propeller and the feed rate of HCl(aq) to create the different effects of macro-, meso-, and micro-mixing to produce the different compositions of solids. However, according to Ostwald's Rule of Stages, the solids were transformed to a mixture of 1:1 and 2:1 co-crystals of HBz-NaBz at t = 4 h. According to Ostwald's ripening, all the harvested samples were given more or less the same particle size distribution (PSD) at t = 4 h. This study relates process understanding and product knowledge to the quality control of co-crystals: the stoichiometric ratio and the PSD.

Table of Contents
摘要    i
Abstract    ii
Acknowledgement    iv
List of Figures    viii
List of Tables    xxi
List of Schemes    xxii
Chapter 1    Introduction    1
1    Brief Introduction of Micromixing, Mesomixing, and Macromixing    1
2    Brief Introduction of Co-crystals    4
3    Brief Introduction of HBz, NaBz, and 1:1 and 2:1 Co-crytals of HBz-NaBz    5
4    Conceptual Framework    9
5    References    11
Chapter 2    Experimental Materials and Methods    14
1    Materials    14
1.1    Chemicals    14
1.2    Solvent    14
2    Experimental Procedures    14
2.1    The Study of Synthesizing Co-crystals of Benzoic Acid-Sodium Benzoate (HBz-NaBz)    14
2.2    The Study of Different Scales of Mixing Effect to Co-crystals of HBz-NaBz in the U-tube    21
2.3    Wet Sieve Analysis Method    24
2.4    Solubility Test    25
2.5  Study of Sampling Locations and Speed of Turbine on Crystal Breakage    27
3    Analytical Measurements    29
3.1    Fourier Transform Infrared (FT-IR) Spectroscopy    29
3.2    Differential Scanning Calorimeter (DSC)    29
3.3    Thermal Gravimetric Analysis (TGA)    29
3.4    Powder X-ray Diffraction (PXRD)    30
3.5    Optical Microscopy (OM)    30
4    References    31
Chapter 3    Pharmaceutical Co-crystals    32
1    Results and Discussion    32
1.1    Use Tests    32
1.2    Different Molar Ratios of NaBz to HCl    40
1.3    Different Experiment Time of NaBz to HCl    45
1.4    Different Concentrations of NaBz to HCl    51
1.5    Different Scales of Mixing Effect to the Co-crystals of HBz-NaBz    55
1.6    Study of Sampling Locations and Speed of Turbine on Crystal Breakage    84
2    References    89
Chapter 4    Conclusions and Future Works    91
1    Conclusions    91
2    Future Works    93
3    References    95


                                

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Brittain, H. G. Vibrational Spectroscopic Studies of Cocrystals and Salts. 3. Cocrystal Products Formed by Benzenecarboxylic Acids and Their Sodium Salts. Cryst. Growth Des. 2010, 10 (4), 1990-2003.
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Butterhof, C.; Bärwinkel, K.; Senker, J.; Breu, J. Polymorphism in Co-crystals: A Metastable Form of the Ionic Co-crystal 2 HBz-1 NaBz Crystallised by Flash Evaporation. CrystEngComm 2012, 14 (11), 6744-6749.
Lee, H. L.; Lee, T. Direct Co-crystal Assembly from Synthesis to Cocrystallization. CrystEngComm 2015, 17 (47), 9002-9006.

Chapter 2
Butterhof, C.; Bärwinkel, K.; Senker, J.; Breu, J. Polymorphism in Co-crystals: A Metastable Form of the Ionic Co-crystal 2 HBz-1 NaBz Crystallised by Flash Evaporation. CrystEngComm 2012, 14 (11), 6744-6749.
Brittain, H. G. Vibrational Spectroscopic Studies of Cocrystals and Salts. 3. Cocrystal Products Formed by Benzenecarboxylic Acids and Their Sodium Salts. Cryst. Growth Des. 2010, 10 (4), 1990-2003.
Torbacke, M.; Rasmuson, Å. C. Influence of Different Scales of Mixing in Reaction Crystallization. Chem. Eng. Sci. 2001, 56 (7), 2459-2473.
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Chapter 3
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Butterhof, C.; Bärwinkel, K.; Senker, J.; Breu, J. Polymorphism in Co-crystals: A Metastable Form of the Ionic Co-crystal 2 HBz-1 NaBz Crystallised by Flash Evaporation. CrystEngComm 2012, 14 (11), 6744-6749.
Martin, T. W.; Gorelik, T. E.; Greim, D.; Butterhof, C.; Kolb, U.; Senker, J.; Breu, J.; Microphase Separation upon Crystallization of Small Amphiphilic Molecules: ‘Low’ Temperature Form II of Sodium Benzoate (E 211). CrystEngComm 2016, 18 (31), 5811-5817.
Deun, R. V.; Ramaekers, J.; Nockemann, P.; Hecke, K. V.; Meervelt, L. V.; Binnemans, K. Alkali-Metal Salts of Aromatic Carboxylic Acids: Liquid Crystals without Flexible Chains. Eur. J. Inorg. Chem. 2005, 2005 (3), 563-571.
Lide, D. R. CRC Handbook of Chemistry and Physics, 74th ed.; CRC Press: Boca Raton, FL, 1993; pp. 3-42.
Roberts, R. M.; Gibert, J. C. Modern Experimental Organic Chemistry, 4th ed.; Saunders College Publishing: Philadelphia: PA,1985; pp. 222-223.
Brittain, H. G. Vibrational Spectroscopic Studies of Cocrystals and Salts. 3. Cocrystal Products Formed by Benzenecarboxylic Acids and Their Sodium Salts. Cryst. Growth Des. 2010, 10 (4), 1990-2003.
Butterhof, C.; Milius, W.; Breu, J. Co-crystallisation of Benzoic Acid with Sodium Benzoate: the Significance of Stoichiometry. CrystEngComm 2012, 14 (11), 3945-3950.
Baldyga, J.; Bourne, J. R. Interactions between Mixing on Various Scales in Stirred Tank Reactors. Chem. Eng. Sci. 1992, 47 (8), 1839-1848.
Torbacke, M.; Rasmuson, Å. C. Influence of Different Scales of Mixing in Reaction Crystallization. Chem. Eng. Sci. 2001, 56 (7), 2459-2473.
Marcant, B.; David, R. Experimental Evidence for and Prediction of Micromixing Effects in Precipitation. AlChE J. 1991, 37 (11), 1698-1710.
Hsu, Y. C.; Lee, T. A Cross-Performance Relationship Between Carr’s Index and Dissolution Rate Constant: The Study of Acetaminophen Batches. Drug Dev. Ind. Pharm. 2007, 33 (11), 1273-1284.
Mullin J. W. Crystallization, 4th ed.; Butterworth-Heinemann: Oxford, OFE, 2001; pp. 320.

Chapter 4
Kulkarni, C.; Wood, C.; Gough, T.; Blagden, N.; Paradkar, A. Stoichiometric Control of Co-Crystal Formation by Solvent Free Continuous Co-Crystallization (SFCC). Cryst. Growth Des. 2015, 15 (12), 5648-5651.
Bag, P. P.; Patni, M.; Reddy, C. M. A Kinetically Controlled Crystallization Process for Identifying New Co-crystal Forms: Fast Evaporation of Solvent from Solutions to Dryness. CrystEngComm 2011, 13 (19), 5650-5652.
Alhalaweh, A.; Velaga, S. P. Formation of Cocrystals from Stoichiometric Solutions of Incongruently Saturating Systems by Spray Drying. Cryst. Growth Des. 2010, 10 (8), 3302-3305.
Chadwick, C.; Davey, R.; Sadiq, G.; Cross. W.; Pritchard, R. The Utility of a Ternary Phase Diagram in the Discovery of New Co-crystal Forms. CrystEngComm 2009, 11 (3), 412-414.

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