Development of Sustainable Reaction and Separation Processes for Amantadine and Amantadine Hydrochloride

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题名:	Development of Sustainable Reaction and Separation Processes for Amantadine and Amantadine Hydrochloride
作者:	曾梓涵;Tseng, Zi-Han
贡献者:	化學工程與材料工程學系
关键词:	金剛烷胺;金剛烷胺鹽酸鹽;分離過程;永續的;Amantadine;Amantadine Hydrochloride;Separation Process;Sustainable
日期:	2022-07-26
上传时间:	2022-10-04 10:58:27 (UTC+8)
出版者:	國立中央大學
摘要:	隨著全球人口的快速增長，高齡化和能源危機的議題，逐漸引起人們的關注。在本研究中，我們將節能減廢的概念應用於製程改進。在文獻中，合成金剛烷胺鹽酸鹽的原始方法包括三個步驟：（1）1-乙酰氨基金剛烷水解合成金剛烷胺，（2）蒸氣蒸餾方式分離得到金剛烷胺，和（3）形成鹽酸鹽。在這項研究中，我們設計和開發了一種製造金剛烷胺鹽酸鹽的強化製程。首先，將1-乙酰氨基金剛烷水解合成金剛烷胺的反應時間從24小時縮短到16小時。接著，利用金剛烷胺和副產物醋酸鈉在水中溶解度的差異，成功分離出金剛烷胺，取代了能源密集型蒸餾步驟。省去繁瑣且耗能的分離操作（即蒸汽蒸餾、萃取和溶劑去除），成功改進了合成金剛烷胺的製程，並計算得到較低數值的 E factor，為3.9。這意味著強化的製程更貼近永續發展，減少製造過程產生的浪費。在結晶步驟中加水分離出金剛烷胺時，觀察到當金剛烷胺上的伯胺與大氣二氧化碳反應時，產生金剛烷胺碳酸鹽(AC)。在過濾、沖洗濾餅和乾燥步驟研究金剛烷胺碳酸鹽的形成。在氮氣環境下乾燥金剛烷胺的濾餅可以有效防止金剛烷胺轉化為金剛烷胺碳酸鹽。為了提高金剛烷胺在水溶液中的生物利用度，分別以漿料反應結晶及反溶劑結晶製備金剛烷胺鹽酸鹽。由於漿料反應結晶法具較低的 E factor (3.4)，選擇其作為成鹽步驟的手法。金剛烷胺鹽酸鹽整體製程的 E factor為7.7，遠低於原始方法的數值21.5。並且在0.5公升玻璃攪拌槽中進行了製程放大，總產率高達82.9%，本研究具有在製程中縮短反應時間、節約能源和減少廢物產生等特點。;The rapid growth of the global population, aging and energy crisis have gradually captured the people’s attention. The concept of energy saving and waste reduction had been applied to process enhancement in the present study. In the literature, the original production of amantadine HCl included three steps: (1) hydrolysis of 1-acetamidoadamantane to synthesize amantadine, (2) steam distillation, and (3) salt formation. In this study, an intensified process of making amantadine HCl had been designed and developed. Firstly, the reaction time for the synthesis of amantadine by hydrolyzing 1-acetamidoadamantane was shortened from 24 to 16 h. The energy-intensive distillation step had been replaced by the direct separation of amantadine from sodium acetate, based on the difference in their solubilities in water. The intensified process for the synthesis of amantadine had been developed to get rid of a series of tedious and energy-intensive separation operations (i.e. steam distillation, extraction, and solvent removal). A much smaller E factor of 3.9 had been obtained, meaning that the intensified process was more sustainable with minimized waste generation. After the water addition in the crystallization step, it was observed that amantadine carbonate (AC) is produced when the primary amine of amantadine reacted with the atmospheric CO2. The formation of AC was investigated upon filtration, cake rinsing, and drying. Amantadine wet cake was dried under a nitrogen atmosphere to prevent the conversion of amantadine to AC. To increase the bioavailability of amantadine in an aqueous solution, it was further prepared as a HCl salt by slurry reactive crystallization and antisolvent crystallization, respectively. The slurry reactive crystallization was selected by achieving a lower E factor of 3.4. The overall E-factor became 7.7, much lower than the original method of 21.5. This intensified process has been scaled up in a 0.5 L-stirred tank, which showed an improved overall yield of 82.9%, and provided some significant features, such as the shortening of reaction time, saving of energy, and waste minimization.
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