臺灣博碩士論文加值系統

製藥工業中， 製藥工業中， 65% 以上的新候選藥 物其 水溶性 極低，可 通過 將一 活性藥物成分（ 活性藥物成分（ API） 與一共形成體結合共晶（ 形成體結合共晶（ 形成體結合共晶（ 形成體結合共晶（ Co-crystal），藉此提升 ），藉此提升 ），藉此提升 高端產物 高端產物 的純化 效果以及藥物的 效果以及藥物的 效果以及藥物的 生 物相容性 來克服 此問題。 問題。 在我的研究當中，苯甲酸作為活性藥物成分與鈉共 在我的研究當中，苯甲酸作為活性藥物成分與鈉共 在我的研究當中，苯甲酸作為活性藥物成分與鈉共 形成體通過反應結晶的方式在積比 4：1的乙醇 －水溶液中產生共晶：將含有 溶液中產生共晶：將含有 溶液中產生共晶：將含有 17.22克 （0.141 莫耳）的苯甲酸溶液Ａ在 50毫升的乙醇水溶液加入 含有 1.89克（0.047莫耳 ） 的氫氧化鈉 溶液Ｂ 在 6毫升的乙醇水溶液 。接著， 接著， 將溶液Ａ與Ｂ混合後所形成的一 澄清飽和溶液 從室溫冷卻至 16度，直到晶體 開始形成 ，即溶液變得渾濁，表明該 系統 的成核引發 時間 （τ）結束 ，進而 可用於 推算出 一些 重要結晶成 核與長的動力 學和熱學參數 ，例如：界面能 （γ）、 Gibbs能障（ΔGcr）、 成核速率 （J）、 成核的臨界尺寸 （rc） 及相對生長速率 （RG），針對此系統不同初始過飽和比（ ），針對此系統不同初始過飽和比（ ），針對此系統不同初始過飽和比（ ），針對此系統不同初始過飽和比（ S0）： 1.66、1.54、1.48與 1.43來 計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸 計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸 計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸 計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸 計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸 計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸 計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸 計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸 納、苯甲酸其 2:1以及 1:1的共結晶分別以 1.5的重量百分比添加至上述所提之溶液 A，重複量測其結晶的 ，重複量測其結晶的 動力學和熱參數 。此 系統的 成核引發 時間為 3到 40分鐘， 分鐘， 隨 著較高的初始過飽和比，可得到 著較高的初始過飽和比，可得到 著較高的初始過飽和比，可得到 較短的成核引發 短的成核引發 時間。 時間。 此外，在分子模板的影響下可 此外，在分子模板的影響下可 此外，在分子模板的影響下可 此外，在分子模板的影響下可 此外，在分子模板的影響下可 此外，在分子模板的影響下可 在更短的 時間內來引發共晶系統成核過程，提供較低在更短的 時間內來引發共晶系統成核過程，提供較低在更短的 時間內來引發共晶系統成核過程，提供較低Gibbs能障和成 障和成 核的臨界尺寸 ， 以及較高的 成核速率 和相對生長速率。 相對生長速率。 不同條件下所形成的產物經由 不同條件下所形成的產物經由 PXRD、FTIR、DSC和 TGA的鑑定，證實 的鑑定，證實 的鑑定，證實 為苯甲酸 －苯甲酸鈉的 2:1共晶 。最後，這些 。最後，這些 。最後，這些 。最後，這些 研究 結果 說明不論是 從動力學或是熱的角度， 苯甲酸 －苯甲酸鈉的 2:1共晶的形成是可行

More than 65% of new drug candidates in pharmaceutical industry are poorly aqueous soluble drug. Co-crystallization technique can be used to overcome this problem through enhancing the high-end product purification and bioavailability of the drug by combining the API (Active Pharmaceutical Ingredient) with the co-former agent. In this work, co-crystallization of benzoic acid as the API with sodium benzoate as the co-former in co-solvent of 4:1 v/v of ethanol-water was generated by reaction crystallization method. A clear saturated solution was prepared by diluting Solution A containing 17.22 g (0.141 mol) of benzoic acid (HBz) in 50 mL of 4:1 v/v ethanol – water co-solvent and Solution B containing 1.89 g (0.047 mol) of sodium hydroxide (NaOH) in 6 mL of 2:1 v/v ethanol – water co-solvent. The solution then was cooled from room temperature to 16oC until the crystals were generated and the solution became turbid, indicating that the system had reached the end of the induction time, τ, of crystallization which can be used to determine some fundamental kinetic and thermodynamic parameters of nucleation and crystal growth, such as: the interfacial energy, γ, the Gibbs energetic barrier, ΔGcr, the nucleation rate, J, the critical size of stable nuclei, rc, and the relative growth rate, RG. All of these parameters were evaluated with different initial supersaturation ratio of the system, S0, which were: 1.66, 1.54, 1.48, and 1.43. To study the effect of templating in co-crystal system, about 1.5 wt % template of: sodium benzoate, 2:1 co-crystal of benzoic acid-sodium benzoate, and 1:1 co-crystal of benzoic acid-sodium benzoate were
iii
introduced for each system with different S0. In general, the induction times for all systems ranged from 3 to 40 minutes, where the higher S0 value gave the faster τ value. Moreover, introducing a template in the system gave a faster induction time, τ. ΔGcr and rc decreased, while J and RG increased on a faster induction time, indicating that co-crystallization thermodynamic and kinetic were directly related to the initial concentration of the drug. The final product of the solid crystals for each system was verified as 2:1 co-crystal of benzoic acid – sodium benzoate by PXRD, FTIR, DSC, and TGA. Finally, these results showed that co-crystallization of API, benzoic acid, with its co-former, sodium benzoate, was feasible, both kinetically and thermodynamically.

Table of Contents
摘要 i
Abstract ii
Acknowledgement iv
List of Figures viii
List of Tables xvi
List of Schemes xviii
Chapter 1 Introduction 1
11 Drug-Related Issues 1
12 Brief Introduction of Co-crystal 2
13 Brief Introduction of Benzoic Acid and Sodium Benzoate 4
14 Templating Crystallization 9
15 Synthesis of 2:1 Co-crystal of Benzoic Acid–Sodium Benzoate by Reaction Crystallization through Cooling Method 11
16 Conceptual Framework 16
17 References 18

Chapter 2 Experimental Materials and Methods 23
21 Materials 23
211 Chemicals 23
212 Solvents 24
22 Experimental Procedures 25
221 Solubility Measurement of the Basic Materials 25
222 Synthesis of 2:1 Co-crystal of Benzoic Acid – Sodium Benzoate by Reaction Crystallization 27
223 Co-crystallization of 2:1 Co-crystal of Benzoic Acid – Sodium Benzoate by Cooling Method 29
224 Templating Experiment 32
225 Stability Test 36
23 Analytical Measurements 37
231 Optical Microscopy (OM) 37
232 Fourier Transform Infrared (FTIR) Spectroscopy 38
233 Differential Scanning Calorimetry (DSC) 39
234 Thermal Gravimetric Analysis (TGA) 41
235 Powder X-ray Diffraction (PXRD) 42
236 Ultraviolet and Visible Spectrometer (UV-Vis) 43
24 References 44

Chapter 3 Results and Discussion 45
31 Crystallization Behavior of 2:1 Co-crystal of Benzoic Acid-Sodium Benzoate and the Templating Effect 47
311 Concentration Calibration 47
312 Induction Time Profile of Initial Supersaturation Ratio, So 48
313 Supersaturation and Nucleation Mechanism 50
314 Crystal Growth Mechanism 69
32 Characteristic Study of 2:1 Co-crystal of Benzoic Acid-Sodium Benzoate and the Effect of Templating 87
321 Crystallization Characteristic of Pure 2:1 Co-Crystal of Benzoic Acid - Sodium Benzoate 87
322 The Effect of Templating in Crystallization Characteristic of 2:1 Co-Crystal of Benzoic Acid - Sodium Benzoate 96
33 References 102
Chapter 4 Conclusions and Future Works 105
41 Conclusions 105
42 Future Works 107
43 References 108

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