Novel Crystallization Processes for Preparing Various Crystal Forms of Active Pharmaceutical Ingredients

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題名:	Novel Crystallization Processes for Preparing Various Crystal Forms of Active Pharmaceutical Ingredients
作者:	李弘霖;Lee, Hung-Lin
貢獻者:	化學工程與材料工程學系
關鍵詞:	結晶;製藥工程;多形晶體;共晶體;鹽類;Crystallization;Pharmaceutical Engineering;Polymorph;Co-crystal;Salt
日期:	2018-01-30
上傳時間:	2018-04-13 10:48:33 (UTC+8)
出版者:	國立中央大學
摘要:	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.
顯示於類別:	[化學工程與材料工程研究所] 博碩士論文

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