近年來藥物市場的供應和使用量節節高升，且市售藥物中超過25%是以消旋或是結構異構物的型態來販售，因此環境藥物殘留的檢測越來越受矚目。雖然這些非類固醇鎮痛解熱劑(non-steroidal anti- inflammatory drugs，簡稱NSAIDs)的作用機制已經有20幾年的研究歷史了，但尚未明白殘留於環境中是否在未來對環境將造成什麼不可預期的影響。特別是具有掌性特性的藥物，因為不同掌性異構物對生物體的生物活性與毒性皆有所不同，因此研究環境中對掌藥物的含量與比例越來越受大家關注。本研究挑選兩個常用且含有掌性特性的非類固醇陣痛解熱劑－凱妥普洛芬和異布洛芬來當作目標待測物。分離管柱選擇α1-酸性醣蛋白掌性分離管柱(α1-acid glycoprotein chiral column，簡稱AGP掌性分離管柱)，搭配液相層析串聯質譜儀開發出可檢測環境不同水樣中掌性異構物比例的分析方法。在動相溶液中添加三級胺的電荷修飾劑－DMOA(N, N-dimethyloctylamine)可大幅改善掌性異構物之分離效果但會造成某程度上的基質干擾。比較三種不同遊離介面(ESI, APCI和APPI)的游離效果、基質干擾程度及偵測極限，來選擇最佳遊離介面。真實樣品則利用HLB固相萃取法萃取環境水樣中的待測物。本實驗的凱妥普洛芬之偵測極限(LOD)為100 ng/L，而添加之水樣掌性異構物回收率為50-100%，相對標準偏差皆在8以內，然而五個真實水樣中皆未偵測到凱妥普洛芬異構物的存在。雖然添加DMOA可以大幅改善待測物的滯留時間以及管柱掌性選擇性，但也會產生嚴重的基質干擾影響游離源的游離效果以及質譜偵測極限。

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.

 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.