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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許祐誠(Yu-Cheng Hsu) 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

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)

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摘要(中)

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。

摘要(英)

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.

關鍵字(中)

★ 共晶

關鍵字(英)

★ Co-crystal

論文目次

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
1.1 Brief Introduction of Micromixing, Mesomixing, and Macromixing 1
1.2 Brief Introduction of Co-crystals 4
1.3 Brief Introduction of HBz, NaBz, and 1:1 and 2:1 Co-crytals of HBz-NaBz 5
1.4 Conceptual Framework 9
1.5 References 11
Chapter 2 Experimental Materials and Methods 14
2.1 Materials 14
2.1.1 Chemicals 14
2.1.2 Solvent 14
2.2 Experimental Procedures 14
2.2.1 The Study of Synthesizing Co-crystals of Benzoic Acid-Sodium Benzoate (HBz-NaBz) 14
2.2.2 The Study of Different Scales of Mixing Effect to Co-crystals of HBz-NaBz in the U-tube 21
2.2.3 Wet Sieve Analysis Method 24
2.2.4 Solubility Test 25
2.2.5 Study of Sampling Locations and Speed of Turbine on Crystal Breakage 27
2.3 Analytical Measurements 29
2.3.1 Fourier Transform Infrared (FT-IR) Spectroscopy 29
2.3.2 Differential Scanning Calorimeter (DSC) 29
2.3.3 Thermal Gravimetric Analysis (TGA) 29
2.3.4 Powder X-ray Diffraction (PXRD) 30
2.3.5 Optical Microscopy (OM) 30
2.4 References 31
Chapter 3 Pharmaceutical Co-crystals 32
3.1 Results and Discussion 32
3.1.1 Use Tests 32
3.1.2 Different Molar Ratios of NaBz to HCl 40
3.1.3 Different Experiment Time of NaBz to HCl 45
3.1.4 Different Concentrations of NaBz to HCl 51
3.1.5 Different Scales of Mixing Effect to the Co-crystals of HBz-NaBz 55
3.1.6 Study of Sampling Locations and Speed of Turbine on Crystal Breakage 84
3.2 References 89
Chapter 4 Conclusions and Future Works 91
4.1 Conclusions 91
4.2 Future Works 93
4.3 References 95

參考文獻

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Chapter 2
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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.
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指導教授

李度(Tu Lee)

審核日期

2017-7-28

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