- 學位論文
以脂解酶乳化反應併合油水分離膜進行鏡像異構藥物拆分純化之研究
Enzymatic enantioselective resolution of racemic ibuprofen through emulsion reaction and oil water membrane separation
摘要
在製藥工業中，生產高光學純度的藥物來提升藥效及避免鏡像異構物 帶來的副作用影響非常重要，將鏡像異構物進行分離純化的步驟稱為拆分。 i buprofen 為一種市面上常見的非類固醇消炎止痛藥 (N SA ID)ID)，在其鏡像異構 物中， ，( i buprofen 為藥效的主要提供者。在現有之拆分方法中，以生物酵 素法拆分鏡像異構物，具有高立體專一性、反應條件溫和與對環境友善等 優點。本研究中使用 Candida rugosa lipase 催化 rac i buprofen 進行不對稱酯 化，再利用 NaOH 水溶液處理未反應物，以油水分離膜回收酵素與分離產 物，來對 rac i buprofen 進行手性拆分。接著使用高效能液相層析儀 ( 來檢測產物中的成份及 p NPP 水解法檢測脂解酶殘留程度。結果顯示，在 i sooctane 溶液中，於 37°C 下、加入 C.rugosa lipase 與 5% 水相乳化反應 72 小時，並以 2M NaOH 水溶液與 PVDF 油水分離膜對產物純化與分離後，產 物之對映體過量百分數 (enantiomeric excess , 值可達 70%70%，且幾乎沒有酵 素殘留於產物中，同時，還能透過 PVDF 油水分離膜將反應後的脂解酶與 NaOH 水溶液進行回收再利用。本研究 利用簡便與成本較低的程序 ，達成鏡 像異構物的拆分純化，並具有良好的分離效率。
並列摘要
In the pharmaceutical industry, it is important to produce drugs with high optical purity to enhance the efficacy and avoid the side effects caused by enantiomers . The step s of purifying the enantiomers are defined as resolution . For example, i buprofen is a common NS A ID and, a mong its enantiomers , ( i buprofen is the one with the primary potency R esolution of enantiomers by enzyme has the advantages of high s tereoselectivity , mild reaction conditions and being environmental friendl y . In this study, Ca ndida rugosa l ipase was used to catalyze the asymmetric esterification of rac i buprofen, and then t he l eftovers reacted with NaOH solution. U sing the oil water separation membranes to separate the products and recover t he enzymes to perform chiral resolution of rac i buprofen A fter that HPLC was used to detect the components and p NPP hydrolysis was applied to detect the enzyme residues in the products. A t the optimal temperature at 37°C , emulsi on composed of i sooctane solution, C rugosa l ipase and 5% aqueous buffer w as reacted for 72 hours, followed by corresponding purif ication and separation The results showed that t he enantiomeric excess of the product can reach 70%, and there is almost no residual enzyme in the product Moreover , the enzyme and the NaOH solution after the reaction can be recovered and re cycled through the PVDF oil water membrane separation system In summary a simple and cost effective membrane process was designed for the resolution of enantiomers , a nd showed good separation efficiency possible for other valuable pharmaceutical products
參考文獻
延伸閱讀
- 張文銓（2017）。固定脂肪酶於幾丁聚醣／氧化石墨烯複合膜以製備滲透蒸發型酵素膜反應器〔碩士論文，中原大學〕。華藝線上圖書館。https://doi.org/10.6840/cycu201700706
- 陳瑞堂、吳美虹、簡玉菁（2011）。應用離子液體萃取分離芳香族／脂肪族混合系統之進展。化工，58(3)，3-14。https://doi.org/10.29803/CE.201106.0002
- 鄭玳育（2017）。利用脂肪酶催化合成或自中草藥分離新穎性唾液酸衍生物及其對脂多醣的結合力分析〔碩士論文，國立臺灣師範大學〕。華藝線上圖書館。https://doi.org/10.6345/NTNU202202810
- Zadeh, S. M. (2020). Identification and Evaluation of Key Enzymes in Biosynthesis of Nucleoside Antibiotic Caprazamycin [doctoral dissertation, National Tsing Hua University]. Airiti Library. https://www.airitilibrary.com/Article/Detail?DocID=U0016-2412202116174692
- Kuo, S. Y. (2022). Enzymatic transglycosylation of Saccharomyces cerevisiae EXG1 to synthesize laminarin-derived oligosaccharides [master's thesis, National Taiwan University]. Airiti Library. https://doi.org/10.6342/NTU202200331