Title page for 972203011


[Back to Results | New Search]

Student Number 972203011
Author Chi-yu Su(蘇紀禹)
Author's Email Address 972203011@cc.ncu.edu.tw
Statistics This thesis had been viewed 891 times. Download 1115 times.
Department Chemistry
Year 2009
Semester 2
Degree Master
Type of Document Master's Thesis
Language zh-TW.Big5 Chinese
Title A novel method for separating ketoprofen and ibuprofen by α1-acid glycoprotein chiral column
with HPLC-APCI-MS/MS
Date of Defense 2010-06-22
Page Count 103
Keyword
  • AGP chiral column
  • HPLC-APCI-MS/MS
  • NSAIDs
  • Abstract Currently, pharmaceuticals are supplied and used in abundance, their residues become major targets in environmental. More than 25% of pharma- ceuticals are market as either recemates or the mixture of diastereoisomers. Although non-steroidal anti-inflammatory drugs(NSAIDs) has been studied for over 20 years, the subsequent environmental occurrence, fate, and effects of these residues are not well understood, especially the effects of chiral residues in our environment. Chiral residues should be concerned because of their different biological and/or toxicological effects from one another. Two widely used NSAIDs, Ibuprofen and ketoprofen, were used as the model chiral compounds in our study. A method of chiral liquid chromatography-tandem mass spectro- metry(LC-MS/MS) was developed to determine the ibuprofen and ketoprofen enantiomers in various water samples. A chiral α1-acid glycoprotein (AGP) column was used to separate two enantiomers. The retention and the enantio- selectivity of the analytes can easily be regulated by addition of tertiary amine N, N-dimethyloctylamine (DMOA) to the mobile phase as a charge modifier. Moreover, various ionization techniques including electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) and atmospheric photoionization (APPI) interfaced with chiral liquid chromatographic methods were evaluated with their ionization efficiencies, matrix effects and limitations. Water samples were extracted by HLB-solid-phase extraction. The limit of quantitation (LOQ) was 100 ng/L for ketoprofen enantiomers in 100 mL of water sample. The spiked recoveries of enantiomers ranged 50-100% while RSD was less than 8% (n=3). However, enantiomers were not detected in five selected water samples. Although DMOA can be added to improve the retention and enantioselectivity, of solute, it may bring seriously matrix effect to affect ionization efficience and detection limitation.
    Table of Content 第一章 前言------------------------------------------------------------------ 1
    1-1-0 研究緣起------------------------------------------------------------ 1
    1-2-0 研究目標------------------------------------------------------------ 4
    第二章 文獻回顧------------------------------------------------------------ 6
      2-1 藥物殘留------------------------------------------------------------- 6
    2-1-1 藥物殘留在環境中的作用與機制-------------------------- 6
    2-1-2非類固醇鎮痛解熱劑------------------------------------------ 8
    2-1-3 相關研究文獻-------------------------------------------------- 9
    2-20 對掌異構物之分離----------------------------------------------- 14
    2-2-1對掌異構物之簡介-------------------------------------------- 14   2-2-2 掌異構物分離之重要性-------------------------------------- 16
    2-2-3 掌異構物分離技術之原理----------------------------------- 17
    2-2-4 α1-AGP掌性分離管柱簡介--------------------------------- 21
    2-3 胺類添加劑介紹--------------------------------------------------- 25
    2-4- 液相層析質譜儀-------------------------------------------------- 28
    2-4-1電噴灑游離法-------------------------------------------------- 29
    2-4-2大氣壓力化學游離法----------------------------------------- 30
    2-4-3大氣壓力光游離法-------------------------------------------- 31
    2-5 固相萃取法-------------------------------------------------------- 34
    第三章 實驗方法----------------------------------------------------------- 38
    3-1 實驗藥品與儀器設備----------------------------------------------------- 38
    3-1-1實驗藥品-------------------------------------------------------- 38
    3-1-2 儀器設備------------------------------------------------------- 39
    3-20 實驗步驟---------------------------------------------------------- 40
    3-2-1 標準品的製備------------------------------------------------- 40
    3-2-2 HPLC動相溶液的製備--------------------------------------- 41
    3-2-3 標準品的測定-------------------------------------------------- 41
    3-2-4 液相層析質譜儀參數設定---------------------------------- 41
    3-2-5固相萃取步驟-------------------------------------------------- 43
    3-3 水樣採集----------------------------------------------------------- 44
    第四章 討論與結果-------------------------------------------------------- 45
    4-10 對掌異構物之分離最佳化------------------------------------ 45
    4-20 不同遊離源在正負模式下之分析結果---------------------- 53
    4-30 不同遊離源最佳化參數設定---------------------------------- 56
    4-3-1-不同流速對APCI游離源之影響------------------------ 58
    4-3-2-不同摻雜劑以及添加流速對APPI游離源之影響------ 61
    4-3-3-不同參數對ESI游離源之影響----------------------------- 62
    4-40 檢量線------------------------------------------------------------- 69
    4-5 固相萃取-------------------------------------------------------- 72
    4-6 真實水樣之分析結果-------------------------------------------- 73
    第五章 結論----------------------------------------------------------------- 77
    參考文獻------------------------------------------------------------------------------- 79
    Reference 王碧蓮,利用液相層析串聯質譜技術檢測水環境中藥物殘留物之方法開發與應用,碩士論文,國立中央大學化學研究所,民國94年
    林宛靜,快速分析水環境中醫療藥品殘留物之研究與探討,碩士論文,國立中央大學化學研究所,民國92年。
    高雅慧,以ATC分類探討全民健康保險 藥品之利用與分配,國立成功大學醫學院 臨床藥學研究所,民國89年。
    Abushoffa, A. M.; Fillet, M.; Hubert, P.; Crommen, J., Prediction of selectivity for enantiomeric separations of uncharged compounds by capillary electrophoresis involving dual cyclodextrin systems, J. Chromatogr. A, 2002, 948, 321-329.
    Ahrer, W.; Scherwenk, E.; Buchberger, W., Determination of drug residues in water by the combination of liquid chromatography or capillary electrophoresis with electrochromatography or capillary electrophoresis with electrospray mass spectrometry, J. Chromatogr. A, 2001, 910, 69-78.
    Ali, I.; Gupta, V. K.; Aboul-Enein, H. Y., Chiral resolution of some environmental pollutants by capillary electrophoresis, Electrophoresis, 2003, 24, 1360-1374.
    Andersson, M.; Hultin, U. -K.; Sokolowski A., Effects of Amine Additives on the Resolution of Antipsychotic and Antidepressant Drugs on a Cyanoalkyl HPLC Column, Chromatographia, 1998, 48, 770-776.
    Blanco, M.; Gonz?lez, J. M.; Torras, E., Enantiomeric purity determination of ketoprofen by capillary electrophoresis: development and validation of the method, Anal. Bioanal. Chem., 2003, 375, 157-163.
    Bonato, P. S.; Del Lama, M. P. F. M.; Carvalho, R., Enantioselective determination of ibuprofen in plasma by high-performance liquid chromatography-electrospray mass spectrometry, J. Chromatogr. B, 2003, 796, 413-420.
    Boyd, G. R.; Reemtsma, H.; Grimm, D. A.; Mitra, S., Pharmaceuticals and personal care products(PPCPs) in surface and treated waters of Louisiana, USA and Ontario, Canada, The Science of the Total Environmental, 2003, 311, 135-149.
    Cole, R.B., Electrospray Ionization Mass Spectrometry, John Wiley & Sons, Ltd., 1997.
    Chiral Application Handbook A Comprehensive Guide on Chiral HPLC Separations, Chromtech. http://www.chromtech.net.au/08/pdf08/ct_chiral-handbook_1-40A.pdf
    Davies, N. M., Methods of analysis of chiral non-steroidal anti-inflammatory drugs, J. chromatogr. B, 1997, 691, 229-261.
    Dey, J.; Mohanty, A.; Roy, S.; Khatua, D., Cationic vesicles as chiral selector for enantioseparations of nonsteroidal antiinflammatory drugs by micellar electrokinetic chromatography, J. Chromatogr. A, 2004, 1048, 127-132.
    Eichhold, T. H.; Bailey, R. E.; Tanguay, S. L.; Hoke, S. H., Determination of (R)- and (S )-ketoprofen in human plasma by liquid chromatography/ tandem mass spectrometry following automated solid-phase extraction in the 96-well format, J. Mass Spectrom., 2000, 35, 504-511.
    Fanali, S.; Aturki, Z., Use of cyclodextrins in capillary electrophoresis for the chiral resolution of some 2-arylpropionic acid non-steroidal anti-inflammatory drugs, J. Chromatogr. A, 1995, 694, 297-305.
    Farr?, M.; Ferrer, I.; Ginebreda, A.; Figueras, M.; Olivella, L., Determination of drugs in surface water and wastewater samples by liquid chromatography–mass spectrometry: methods and preliminary results including toxicity studies with Vibrio fischeri, J. Chromatogr. A, 2001, 938, 187-197.
    Farr? M.; Petrovic M.; Barcel? D., Recently developed GC/MS and LC/MS methods for determining NSAIDs in water samples, Anal. Bioanal. Chem., 2007, 387, 1203–1214.
    Fillet, M.; Chankvetadze, B.; Crommen, J.; Blaschke, G., Designed combination of chiral selectors for adjustment of enantioseparation selectivity in capillary electrophoresis, Electrophoresis, 1999, 20, 2691-2697.
    Garrison, A. W., Probing the Enantioselectivity of CHIRAL pesticides, Environ. Sci. Technol., 2006, 40, 16-23.
    Gibson, R.; Becerril-Bravo, E.; Silva-Castro, V.; Jim?nez, B., Determination of acidic pharmaceuticals and potential endocrine disrupting compounds in wastewaters and spring waters by selective elution and analysis by gas chromatography-mass spectrometry, J. Chromatogr. A, 2007, 1169, 31-39.
    Gl?wka, F.; Karazniewicz, M., Enantioselective CE method for pharmacokinetic studies on ibuprofen and its chiral metabolites with reference to genetic polymorphism, Electrophoresis, 2007, 28, 2726-2737.
    Heo, S. K.; Cho, J.; Cheon, J. W.; Choi, M. K.; Im, D. S.; Kim, J. J.; Choi, Y. G.; Jeon, D. Y.; Chung, S. J.; Shim, C. K.; Kim, D. D., Pharmacokinetics and pharmacodynamics of ketoprofen plasters, Biopharm. Drug Dispos., 2008, 29, 37-44.
    Hermansson, J.; Eriksson, M., Direct liquid chromatographic resolution of acidic drugs using a chiral α1-acid glycoprotein column (Enantiopac), J. Liq. Chromatogr., 1986, 9, 621-639.
    Hernando, M. D.; Heath, E.; Petrovic, M.; Barcel?, D., Trace-level determination of pharmaceutical residues by LC-MS/MS in natural and treated waters. A pilot-survey study, Anal. Bioanal. Chem., 2006, 385, 985-991.
    H?hnerfuss, H.; Shah, M.R., Enantioselective chromatography-A powerful tool for the discrimination of biotic and abiotic transformation processes of chiral environmental pollutants, J. chromatogr. A, 2009, 1216, 481-502.
    Hynninen, V. V.; Olkkola, K. T.; Leino K.; Lundgren, S.; Neuvonen, P. J.; Rane, A.; Valtonen, M.; Vyyryl?inen, H.; Laine K., Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S-(+)- and R-(-)-Ibuprofen, Antimicrob. Agents. Chemother., 2006, 50, 1967-1972.
    Jabor, V. A. P.; Lanchote, V. L.; Bonato, P. S., Enantioselective analysis of ibuprofen in human plasma by anionic cyclodextrin-modified electrokinetic chromatography, Electrophoresis, 2002, 23, 3041-3047.
    Kasprzyk-Hordem, B.; Dinsdale, R. M.; Guwy, A. J., The effect of signal suppression and mobile phase composition on the simultaneous analysis of multiple classes of acidic/neutral pharmaceuticals and personal care products in surface water by solid-phase extraction and ultra performance liquid chromatography-negative electrospray tandem mass spectrometry, Talanta, 2008, 74, 1299-1312.
    Kosjek, T.; Heath, E.; Krbavčič, A., Determination of non-steroidal anti-inflammatory drug (NSAIDs) residues in water samples, Environment International, 2005, 31, 679-685.
    K?mmerer, K., Pharmaceuticals in the Environment, Source, Fate, Effects and Risks, 2001, Springer-Verlag, Berlin.
    Leli?vre, F.; Gareil, P., Chiral separations of underivatized arylpropionic acids by capillary zone electrophoresis with various Cyclodextrins Acidity and inclusion constant determinations, J. Chromatogr. A, 1996, 735, 311-320.
    Li, C.; Benet, L. Z.; Grillo, M. P., Enantioselective covalent binding of 2-phenylpropionic acid to protein in vitro in rat hepatocytes, Chem. Res. Toxicol., 2002, 15, 1480-1487.
    Lin, X.; Zhu, C.; Hao, A., Evaluation of newly synthesized derivative of cyclodextrin for the capillary electrophoretic separation, J. Chromatogr. A, 2004, 1059, 181-189.
    L?ffler, D.; Ternes, T. A., Determination of acidic pharmaceuticals, antibiotics and ivermectin in river sediment using liquid chromatography-tandem mass spectrometry, J. Chromatogr. A, 2003, 1021, 133-144.
    Lovlin, R.; Vakily, M.; Jamali, F., Rapid, sensitive and direct chiral high-performance liquid chromatographic method for ketoprofen enantiomers, J. Chromatogr. B, 1996, 679, 196-198.
    Maci?, A.; Borrull, F.; Calull, M.; Aguilar, C., Different sample stacking strategies to analyse some nonsteroidal anti-inflammatory drugs by micellar electrokinetic capillary chromatography in mineral waters, J. Chromatogr. A, 2006, 1117, 234-245.
    Magnusson, J.; Wan, H.; Blomberg, L. G., Illustration of a simple and versatile scheme for reversing enantiomeric elution order and facilitating enantiomeric impurity determination in capillary electrophoresis, Electrophoresis, 2002, 23, 3013-3019.
    Makino, K.; Itoh, Y.; Teshima, D.; Oishi, R., Determination of nonsteroidal anti-inflammatory drugs in human specimens by capillary zone electrophoresis and micellar electrokinetic chromatography, Electrophoresis, 2004, 25, 1488-1495.
    Matsunaga, H.; Haginaka, J.,Investigation of chiral recognition mechanism on chicken α1-acid glycoprotein using separation system, J. Chromatogr. A, 2006, 1106, 124-130.
    Miao, X. S.; Koenig, B. G.; Metcalfe, C. D., Analysis of acidic drugs in the effluents of sewage treatment plants using liquid chromatography-electrospray ionization tandem mass spectrometry., J. Chromatogr. A, 2002, 952, 139-147.
    Nakada, N.; Tanishima, T.; Shinohara, H.; Kiri, K.; Takada, T., Pharmaceutical chemicals and endocrine disrupters in municipal wastewater in Tokyo and their removal during activated sludge treatment, Water Res., 2006, 40, 3297-3303.
    ?llers, S.; Singer, H. P.; F?ssler, P.; M?ller, S. R., Simultaneous quantification of neutral and acidic pharmaceuticals and pesticides at the low-ng/ l level in surface and waste water, J. Chromatogr. A, 2001, 911, 225-234.
    Raffaelli, A.; Saba, A., Atmospheric Pressure Photoionization Mass Spectrometry., Mass Spec. Rev., 2003, 22, 318-331.
    Reddy, A.; Hashim, M.; Wang, Z.; Penn, L.; Stankovic, C. J.; Burdette, D.; Surendran, N.; Cai, H., A novel method for assessing inhibition of ibuprofen chiral inversion and its application in drug discovery, International Journal of Pharmaceutics, 2007,335, 63-69.
    Sadakane, Y.; Matsunaga, H.; Nakagomi, K.; Hatanaka, Y.; Haginaka J., Protein domain of chicken α1-acid glycoprotein is responsible for chiral recognition, Biochemical and Biophysical Research Communications, 2002, 295, 587-590.
    Sigma-Aldrich, http://www.sigmaaldrich.com/taiwan.html
    Tanaka, Y.; Kishimoto, Y.; Terabe, S., Separtion of acidic enantiomers by capillary electrophoresis-mass spectrometry employing a partial filling technique, J. Chromatogr. A, 1998, 802, 83-88.
    Ternes, T. A., Occurrence of drugs in German sewage treatment plants and rivers., Water Res., 1998, 32, 3245-3260.
    Vanderford, B. J.; Pearson, R. A.; Rexing, D. J.; Snyder, S. A., Analysis of endocrine disruptors, pharmaceuticals, and personal care products in water using liquid chromatography/tandem mass spectrometry, Anal. Chem., 2003, 75, 6265-6274.
    Vermeulen, B.; Remon, J.P., Validation of a high-performance liquid chromatographic method for the determination of ibuprofen enantiomers in plasma of broiler chickens, J. Chromatogr. B, 2000, 749, 243-251.
    Vollhardt, K. P. C.; Schore, N. E., Organic chemistry: structure and function, fourth edition, 2002, W. H. Freeman and Company.
    Yang, S.; Evenson, M. A., Simultaneous liquid chromatographic determination of antidepressant drugs in human plasma, Anal. Chem., 1983, 55, 994-998.
    Zohmann, A.; Hawel, R. ; Klein, G.; Kullich, W.; L?tsch, G., S(+)-ibuprofen (dexibuprofen)-excellent tolerance has not to be combined with poor clinical efficacy, Inflammopharmacology, 1998, 6, 75-79.
    Advisor
  • Wang-Hsien Ding(丁望賢)
  • Files
  • 972203011.pdf
  • approve in 2 years
    Date of Submission 2010-06-23

    [Back to Results | New Search]


    Browse | Search All Available ETDs

    If you have dissertation-related questions, please contact with the NCU library extension service section.
    Our service phone is (03)422-7151 Ext. 57407,E-mail is also welcomed.