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研究生： 李弘霖
Hung-Lin Lee
論文名稱： Novel Crystallization Processes for Preparing Various Crystal Forms of Active Pharmaceutical Ingredients
指導教授： 李度
Tu Lee
口試委員:
學位類別： 博士
Doctor
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： 2018
畢業學年度： 106
語文別： 英文
論文頁數： 246
中文關鍵詞： 結晶 、製藥工程 、多形晶體 、共晶體 、鹽類
外文關鍵詞： Crystallization, Pharmaceutical Engineering, Polymorph, Co-crystal, Salt
相關次數： 點閱：17  下載：0 
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    • 本論文介紹了台灣製藥業的概況，由於生產和管理上的方便，準確的劑量控制以及穩定性高，使藥錠成為最常用的劑型。
    結晶是化學工程及製藥工程中關鍵的單元操作，用於生產高結晶性及高純度的產物，並確保晶體的質量和後續製程的性質。另一方面，結晶亦是重要的分離和純化製程，可將化學合成中所衍生的中間產物及副產物分離。在製藥工業中，結晶操作是活性藥物成分（API）製造的最後一步，更是最關鍵的一步，能夠控制結晶體的性質，多晶型和尺寸分佈。
    在本論文中，研究包含從溶劑到無溶劑的結晶製程，以及從批次處理到連續式結晶製程，藉由這些新穎結晶手法來製備API不同的晶型，如：多晶型（第三章），共晶（第四章）和鹽類（第五章）等。
    第三章，在500毫升的批式結晶槽中透過反應的耦合，成功地製備出40克乙醯胺酚的介穩態晶體。其工作原理除了溫度冷卻外，藉由其耦合反應使乙醯胺酚的溶解度曲線大幅地降低。
    第四章，開發三種共晶的新策略，直接從化學合成到溫度冷卻來組裝四種的藥物共晶通過。基於液體輔助研磨，開發了直接共晶組裝的篩選方法，並建立了從化學合成到溫度冷卻的三成份相圖。
    第五章，研究用連續式且無溶劑添加的雙螺桿熔融擠出機來製備氟哌啶醇與馬來酸的鹽類藥物的可行性，接著，探討操作溫度和螺桿構型對鹽類形成的影響，並發現此二參數為重要參數。由溶液結晶，液體輔助研磨和熱輔助研磨所製備的鹽類，與通過熔融擠出機所製得的鹽類進行比較，此無溶劑雙螺桿熔融擠出法可應用於連續式製造並易於製程放大。

    An overview on (Taiwan’s) pharmaceutical industry was presented. Making tablets of drug has become the most commonly used dosage form due to the ease of manufacturing and administration, accurate dosing, and stability (long shelf life).
    Crystallization is one of the oldest unit operations in a chemical engineering sense, which is an important separation and purification process employed for producing highly crystalline products, isolating from intermediates and byproducts in the synthesis, achieving a high degree of purity, and determining crystal quality and handling characteristics. In the pharmaceutical industry, crystallization operation often serves as the crucial final step of active pharmaceutical ingredient (API) manufacturing, and enables the control of crystal habit, polymorph and size distribution, which have profound effects on the downstream behaviors.
    In this dissertation, the novel crystallization processes for preparing various crystal forms of APIs including polymorph (Chapter 3), co-crystal (Chapter 4), and salt (Chapter 5) from solvent-based to solvent-free processes and from batch to continuous processes.
    More than 40 g of Form II acetaminophen crystals were made successfully in a 500 mL batch reactor by coupling the acetylation of p-aminophenol with neutralization of acetic acid before the crystallization of Form II crystals in an aqueous solution. The novel working principle involves a sudden drop in the solubility curves of acetaminophen from the acetic acid-water environment to the acetate-water system in addition to temperature cooling but without agitation.
    Four pharmaceutical co-crystals were assembled directly via chemical synthesis by cooling under three new strategies. The screening method for direct co-crystal assembly by a chemical reaction was developed based on liquid-assisted grinding. The ternary phase diagram involving a chemical reaction and co-crystallization was established for 2:1 co-crystal of benzoic acid-sodium benzoate.
    The potential for preparing pharmaceutical salt between haloperidol and maleic acid by a novel solvent-free method using twin-screw melt extruder was investigated. The pH-solubility relationship between haloperidol and maleic acid in aqueous medium was first determined, which demonstrated that 1:1 salt formation was feasible. The effects of operating temperature and screw configuration on salt formation were also investigated, and identified as key processing parameters. Salts were also prepared by solution crystallization, liquid-assisted grinding and heat-assisted grinding, and compared with those obtained by melt extrusion. This solvent-free twin-screw melt extrusion method for the preparation of pharmaceutical salt is amenable to continuous manufacturing and easy to scale up.

    摘　要 i ABSTRACT iii ACKNOWLEDGEMENT v MY PUBLICATION LIST viii TABLE OF CONTENTS xii LIST OF FIGURES xvii LIST OF TABLES xxv LIST OF SCHEMES xxvi CHAPTER 1 AN OVERVIEW ON PHARMACEUTICAL INDUSTRY 1 1.1 Pharmaceuticals 1 1.2 Drug Discovery to Marketing 2 1.3 The Role of Patent in Pharmaceutical Industry 7 1.4 Pharmaceuticals versus Biopharmaceuticals 12 1.5 The Pharmaceutical Industry in Taiwan 16 1.5.1 Western Medicine 21 1.5.2 Active Pharmaceutical Ingredient (API) 23 1.5.3 Biopharmaceutical (Biologic) 25 1.5.4 Traditional Chinese Medicine (TCM) 27 CITED REFERENCES 35 CHAPTER 2 PHARMACEUTICAL CRYSTALLIZATION AND VARIOUS SOLID FORMS 42 2.1 What Is Crystallization? 42 2.2 Unit Operations in Pharmaceutical Industry 61 2.3 Batch versus Continuous Processing 69 2.4 Solid Forms of Active Pharmaceutical Ingredient (API) 72 CITED REFERENCES 76 CHAPTER 3 LARGE-SCALE CRYSTALLIZATION OF A PURE METASTABLE POLYMORPH BY REACTION COUPLING 85 3.1 Introduction 85 3.2 Experimental Section 89 3.2.1 Large-scale Crystallization with Reaction Coupling 89 3.2.2 Solubility Values Measurement 89 3.2.3 Solution Complex Effect by Higuchi’s Plot 90 3.2.4 Polymorphic Transformation Test 90 3.2.5 Dissolution Rate Test 91 3.2.6 Stability Test 91 3.3 Results and Discussion 92 3.4 Conclusions 107 CITED REFERENCES 108 CHAPTER 4 DIRECT CO-CRYSTAL ASSEMBLY FROM SYNTHESIS TO CO-CRYSTALLIZATION 113 4.1 Introduction 113 4.2 Experimental Section 116 4.2.1 Liquid-Assisted Grinding for Direct Co-crystal Assembly 116 4.2.2 Solvent Selection for Cooling Co-crystallization 116 4.2.3 Cooling Co-crystallization 119 4.2.4 Direct Assembly from Chemical Synthesis to Co-crystallization 119 4.2.4.1 1:1 Co-crystal of Acetaminophen-Theophylline 119 4.2.4.2 2:1 Co-crystal of Acetaminophen-Naphthalene 120 4.2.4.3 1:1 Co-crystal of Acetaminophen-Theophylline with the Presence of 3-Acetamidophenol 120 4.2.4.4 1:1 Co-crystal of Aspirin-Carbamazepine 120 4.2.4.5 1:2 Co-crystal of Sodium Benzoate-Benzoic Acid 120 4.2.4.6 1:1 Co-crystal of Acetaminophen-Caffeine 121 4.2.5 Establishment of Ternary Phase Diagram (TPD) 121 4.3 Results and Discussion 122 4.4 Conclusions 140 CITED REFERENCES 141 CHAPTER 5 CONTINUOUS PREPARATION OF 1:1 HALOPERIDOL-MALEIC ACID SALT BY NOVEL SOLVENT-FREE METHOD USING TWIN SCREW MELT EXTRUDER 147 5.1 Introduction 147 5.2 Experimental Section 153 5.2.1 pH-Solubility Profile 153 5.2.2 Salt Preparation via Solution Crystallization 154 5.2.3 Salt Screening via Neat Grinding, Liquid-Assisted Grinding, and Heat-Assisted Grinding 154 5.2.4 Single Crystal Growth 155 5.2.5 Continuous Salt Preparation via Twin Screw Extrusion (TSE) 155 5.2.6 Characterization of Physicochemical Properties of Salts 157 5.2.6.1 Optical Microscopy 157 5.2.6.2 Differential Scanning Calorimetry (DSC) 157 5.2.6.3 Powder X-ray Diffraction (PXRD) 158 5.2.6.4 Thermogravimetric Analysis (TGA) 158 5.2.6.5 Solution Proton Nuclear Magnetic Resonance (1H-NMR) 158 5.2.6.6 Transmission Fourier-Transform Infrared (FTIR) Spectroscopy 159 5.2.6.7 Single Crystal X-ray Diffraction (SXD) 159 5.2.7 Moisture Study and Stability Analysis 159 5.2.8 Investigation of Eutectic Behavior 160 5.3 Results and Discussion 162 5.3.1 Feasibility of Salt Formation by pH-Solubility Relationship 162 5.3.2 Salt Formation by Solution Crystallization 168 5.3.3 Salt Formation by Grinding 172 5.3.4 Salt Formation by Twin Screw Extrusion (TSE) 174 5.3.5 Confirmation of Salt Formation 181 5.3.6 Moisture Sorption 195 5.3.7 Eutectic Formation 196 5.3.8 Possible Mechanism of Salt Formation 197 5.4 Conclusions 201 CITED REFERENCES 203 CHAPTER 6 CONCLUDING REMARKS & FUTRUE WORKS 212 CITED REFERENCES 217

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    Chapter 6
    Singh, S.; Parikh, T.; Sandhu, H. K.; Shah, N. H.; Malick, A. W.; Singhal, D.; Serajuddin, A. T. M. Supersolubilization and Amorphization of a Model Basic Drug, Haloperidol, by Interaction with Weak Acids. Pharm. Res. 2013, 30 (6), 1561-1573.
    Parikh, T.; Sandhu, H. K.; Talele, T. T.; Serajuddin, A. T. M. Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying. Pharm. Res. 2016, 33 (6), 1456-1471
    Mukaida, M.; Sugano, K.; Terada, K. Stability Order of Caffeine Co-crystals Determined by Co-crystal Former Exchange Reaction and Its Application for the Validation of in Silico Models. Chem. Pharm. Bull. 2015, 63 (1), 18-24.

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