臺灣博碩士論文加值系統

本研究方向是以抗憂鬱藥Paroxetine之關鍵性中間體Sesamol(3,4-Methylenedioxyphenol)為主題，其探討目的有二：一是要將Sesamol之不純物鑑定出，作為應用此特用化學品者，能更深入了解其不純物可能產生之物理、化學性質及降低生產成本。另一是利用氣相層析儀(Gas Chromatography)與高效能液相層析儀(High-Performance Liquid Chromatography) 進行分析上的比較，以了解分析方法間的差異與不純物之含量限制，來作為藥廠製程反應控制之選擇。其樣品來源是取自工業級Sesamol(台灣興農公司之產品)。首先是利用氣相層析質譜儀(Gas Chromatography / Mass Spectrometry)進行分析，且藉由質譜圖庫之資料做比對，進行主成份與不純物組成的初步鑑定，結果發現除了主成份外，還有4個不純物(Ⅰ、Ⅱ、Ⅲ、Ⅳ)。其中有2個不純物(Ⅱ、Ⅲ)無法從質譜圖庫之資料比對出為何物。因此，藉由高效能液相層析儀(High-Performance Liquid Chromatography)找一較合適分離條件，再利用製備型液相層析儀(Preparative Liquid Chromatography)分離收集其各不純物，藉由核磁共振光譜儀(Nuclear Magnetic Resonance Spectroscopy)鑑別出化學結構。再利用化學合成方法純化工業級Sesamol(台灣興農公司之產品)作為當標準品用與將其不純物(Ⅱ、Ⅲ)合成出，而不純物(Ⅰ、Ⅳ)分別取自試藥級TCI及中國大陸產品。用NMR、FTIR、GC/MS、HPLC等分析儀器去鑑定比對之。最後再以氣相層析儀(Gas Chromatography)與高效能液相層析儀(High-Performance Liquid Chromatography) 進行分析上的探討。

其4個不純物，分別為1,3-Benzodioxole(分子式：C7H6O2)、1,3-Benzodioxole-formate ester(分子式：C8H6O4)、Sesamol acetate(分子式：C9H8O4)、1,3-Benzodioxole-5-carboxaldehyde(分子式：C8H6O3)。而其主成份與不純物在GC與HPLC分析上之情形，其線性相關係數( r )分別大於0.980及0.999以上，以HPLC所得結果之精密度較佳。其不純物之偵測極限(LOD)，依GC的結果；除了，1,3-Benzodioxole-formate ester為0.240ng外，其餘介於5~7×10-3ng，而HPLC值介於6~23×10-2ng。另其不純物之定量極限(LOQ)，GC的結果為1.8~80.1×10-2ng，而HPLC的結果為21~75×10-2ng。總結；因1,3-Benzodioxole-formate ester揮發性較不完整，極性大且易殘留在管柱上，而CV%值大。所以，較不適合用GC作定量分析上之偵測，其偵測值僅供參考，但亦可偵測出4個不純物。因此，以HPLC作為Sesamol(3,4-Methylenedioxyphenol)在藥廠製程反應控制與不純物含量測定較為適當。

This research is focused on the study of Sesamol, which is the main chemical intermediate used in the manufacture of the antidepressant drug called Paroxetine. The main objectives of this study are: 1) The identification of Sesamol’s impurities, including their physical and chemical properties. That information would be helpful for the drug manufacturer to reduce the production cost. 2) Comparison of the impurities analysis results using two different analysis methods (Gas chromatography and High Performance Liquid Chromatography) and select the one which can be more suitable for the monitoring of the In-Process chemical reaction control. The source of the Sesamol sample was the industrial grade reagent made by Sinon company (Taiwan). The procedure of this research starts with the GC-MS analysis of the Sesamol sample. Based on the GC-MS analysis, the main ingredient, along with the four detectable impurities were shown on the mass spectra (I, II, III, IV). However, the mass spectra library failed to identify the two names (II, III) out of the four impurities. To find out the names of those two chemicals, we synthesized the impurity (II, III) and purified the Sinon company‘s sesamol for standard. Then, the remaining two impurities (I, IV) were bought from TCI Co. and other companies from PROC. To separate the impurities from each other, HPLC and PLC (Preparative Liquid Chromatography) were applied to find out the best separation condition for the impurities and collect them one by one (collected by PLC). Once the purified impurities were obtained, the exact chemical structures of each impurity were determined by using a combination of NMR, FTIR, GC-MS and HPLC. Finally, all the Sesamol’s impurities were analyzed using both GC and HPLC for analytical comparison.

The names of the four Sesamol derived impurities are: 1,3-Benzodioxole (C7H6O2), 1,3-Benzodioxole-formate ester (C8H6O4), Sesamol acetate (C9H8O4), 1,3-Benzodioxole-5-carboxaldehyde (C8H6O3). Based on the GC analysis results of Sesamol and It’s impurities, it was understood that the linearity constant ( r ) was good (over 0.980) and the LOD plus LOQ were 5~7×10-3ng (except for 1,3-Benzodioxole-formate ester which has LOD of 0.240ng) and 1.8~80.1×10-2ng respectively. On the other hand, the analysis results from HPLC were even better with ( r ) value over 0.999 plus the LOD and LOQ values of 6~23×10-2ng and 21~75×10-2ng respectively. Conclusion: Due to the low volatility of 1,3-Benzodioxole-formate ester, high polarity which, tends to remain in GC’s column plus its high CV% value, it would be more suitable to use HPLC as the tool for drug manufacturer’s monitoring of the In-Process chemical reaction control. Even though the GC can detect all four impurities in Sesamol, It would be more preferable to measure the Sesamol using HPLC.

目錄
Page
第一章、緒論…………………………………………….………. 1

第二章、實驗方法與步驟
一、儀器設備………………………………………………….. 3
二、藥品……………………………………………………….. 5
三、實驗方法…………………………………………………. 6
四、實驗步驟
(一) 工業級Sesamol(台灣興農公司之產品)主成份初步鑑定
分析………………………………………………………. 12
(二)不純物的分離與鑑別…………………………………….. 14
(三)Sesamol標準品的取得與成份鑑定……………………… 21
(四)不純物的取得與成份鑑定……………………………….. 26
(五)Sesamol主成份與不純物定量分析………………………. 35

第三章、結果與討論
一、 儀器鑑定比對之結果………………………………….. 40
二、 不純物產生之機制…………………………………….. 45
三、 檢量線之製作………………………………………….. 46
四、 定量分析……………………………………………….. 56
五、 不純物偵測極限(LOD)及定量極限(LOQ)之結果…… 58
第四章、結論……………………………………………………... 59
第五章、參考文獻………………………………………... 60

參考文獻


1.李明濱：情緒與疾病。台大醫學院：金名圖書，1998；第九章。
2.李明濱：實用精神醫學。台大醫學院：金名圖書，1999；第二十二章。
3.T.F. Sun, P.Y. Lin, C.K. Wu, Chang Gung Med J 2001；24： 587-92.
4.P. Schloss, D.C. Williams, J Psychopharmacol 1998；12(2)：115-21.
5.中華藥典,第五版(2000)。
6.U.S.PHARMACOPEIA NATIONAL FORMULARY 24 (2000).
7.李文輝：胡麻。經濟植物集：豐年社，1998；p.72-77.
8.R.J. Alabaster, I.F. Cottrell, H. Marley, S.H.B. Wright, Synthesis 1988；December：950-952.
9.Beil., 19, 115；19, 4(5), 225.
10.Merk Index, 10, 7350；11, 7445.
11.O.L. Brady, J.Chem.Soc., 1931, 756.
12.R.D. Knudsen, et al.,, J.Org.Chem., 1975, 40, 2878.
13.X.J. Meng, J. LÜ, Y. Wang, J.Y. Yao, S.J. Wang, Chinese Journal of Pharmaceuticals 1998；29(2)：870.
14.C.B. Fuh, M.L. Wu, Analytica Chimica Acta 1999；395： 257-263.