手性固定相法分离手性药物对映体及其分离机制研究
|
摘要
本文研究了应用大环抗生素类手性固定相(Chimbiotic V，T和R)分离马布特罗、班布特罗、克伦特罗、克伦普罗、福莫特罗和特布他林六种β_2-受体激动剂对映体；应用Pirkle型手性固定相(Pirkle-1J和α-Burke-2)分离马布特罗、班布特罗、克伦特罗、克伦普罗和福莫特罗五种β_2-受体激动剂对映体；应用冠醚类手性固定相(Crownether-NH和N-CH_3)分离马布特罗、班布特罗、克伦特罗、克伦普罗和福莫特罗五种β_2-受体激动剂及普萘洛尔、阿替洛尔、醋丁酰洛尔、吲哚洛尔、烯丙洛尔、烯丙氧洛尔六种β-受体阻断剂对映体；一种新的Pirkle型手性固定相的合成及应用，并对分离机制分别进行了深入的探讨。
1．大环抗生素类手性固定相分离β_2-受体激动剂对映体
本文应用大环抗生素类手性固定相Chirobiotic V，T和R对六种β_2-受体激动剂对映体进行了分离，考察了洗脱模式、流动相组成和温度等因素对分离的影响，对分离结果进行了比较研究，并对其分离机制进行了探讨。六种β_2-受体激动剂对映体在Chirobiotic R手性固定相上均不能实现分离。在Chirobiotic V和T手性固定相上，分离β_2-受体激动剂对映体的最佳模式均为新极性有机相模式，最佳色谱条件为：甲醇-冰醋酸-三乙胺(100∶0.01∶0.01，v／v／v)。在此条件下，六种β_3-受体激动剂对映体均可得到较好的分离，并可实现多种β_2-受体激动剂对映体的同时分离。考察了此模式下β_2-受体激动剂对映体的热力学参数变化，证明了β_2-受体激动剂对映体与两种手性固定相之间的相互作用是焓控过程。β_2-受体激动剂与固定相之间的离子相互作用是实现对映体分离的最主要分离机制。
2．Pirkle型手性固定相分离β_2-受体激动剂对映体
本文应用Pirkle型手性固定相，Pirkle-1J和α-Burke-2，对马布特罗、班布特罗、克伦特罗、克伦普罗和福莫特罗五种β_2-受体激动剂药物对映体进行了分离，考察了流动
The enantiomeric resolution of sixβ_2-agonists including bambuterol, clenbuterol, clenproperol, fumoterol, mabuterol and terbutaline was studied on three macrocyclic antibiotic chiral stationary phases (CSPs): Chirobiotic V, T and R. The enantiomeric resolution of fiveβ_2-agonists including bambuterol, clenbuterol, clenproperol, fumoterol and mabuterol mentioned above was studied on two Pikle-type CSPs: Pirkle-1J andα-Burke-2. The enantiomeric resolution of fiveβ_2-agonists mentioned above except terbutaline and sixβ-blockers including propranolol, atenolol, acebutolol, pindolol, alprenolol and oxprenolol was investigated on Crown ether-NH and N-CH_3 CSPs. A new Pirkle-type CSP was prepared and applied to resolve a number of N-(3,5-dinitrobenzoyl)-α-amino amides and N-acyl-1-aryl-l-aminoalkanes and found to be effective. The chiral recognition mechanism for different enantioresolution was proposed. 1、Enantioresolution ofβ_2-agonists on macrocyclic antibiotic CSPsThe enantiomeric resolution of sixβ_2-agonists was studied on three macrocyclic antibiotic chiral stationary phases (CSPs): Chirobiotic V, T and R. Factors affecting the enantioresolution, such as the separation mode, composition of mobile phase and column temperature were investigated. No enantioresolution was achieved for the sixβ_2-agonists on Chirobiotic R CSP. On Chirobiotic V and T CSPs, the polar organic mode (POM) was proved to be the best, with methanol-acetic acid-triethylamine (100:0.01:0.01, v/v/v) as the mobile phase, the enantiorners of all the sixβ_2-agonists were successfully separated, and the simultaneous enantioseparation ofβ_2-agonist mixture was achieved. The thermodynamic parameters ofβ_2-agonists in this mode were investigated, the enantioselectivity was proved to be enthalpocally controlled. The chiral recognition mechanism was discussed, ionic interaction between the CSPs andβ2-agonists was confirmed to be the dramatic interaction responsible for the chiral discrimination.
2. Enantioresolution ofβ_2-agonists on Pirkle-type CSPs
The enantiomeric resolution of fiveβ_2-agonists was studied on two Pikle-type CSPs: Pirkle-1J and or-Burke-2. Factors affecting the enantioresolution, such as the type and concentration of the salts additives, the content of the organic solvents and temperature were investigated. Under the optimized chromatographic condition, enantiomers of fiveβ_2-agonists were successfully separated on or-Burke-2 CSE while only twoβ_2-agonist enantiomers were resolved on Pirkle-1J CSE The thermodynamic parameters ofβ_2-agonists on two CSPs were investigated, the enantioselectivity was proved to be enthalpocally controlled. The chiral recognition mechanism was discussed,π-πinteraction and hydrogen binding between the CSPs andβ_2-agonists were confirmed to be the interactions responsible for the chiral discrimination.
3、Enantioresolution ofβ_2-agonists andβ-blockers on crown ether CSPs
The enantiomeric resolution of fiveβ_2-agonists and sixβ-blockers was investigated on Crown ether-NH and N-CH_3 CSPs. By varying the mobile phase composition and temperature, the enantiomers of all analytess were successfully separated on Crown ether-NH CSP, while only enantiomers ofβ-blockers were partly resolved on Crown ether-N-CH_3 CSP, the enantioresolution ofβ_2-agonists was not achieved on it. The thermodynamic parameters ofβ_2-agonists andβ-blockers on the CSPs were investigated, the enantioselectivity was proved to be entropically controlled. The chiral recognition mechanism was discussed, hydrogen binding, ionic interaction and inclusion interaction between the CSPs and the analytes were confirmed to be the interactions responsible for the chiral discrimination.
4. Preparation and application of a new Pirkle-type ehiral stationary phase
A new high-performance liquid chromatographic Pirkle-type chiral stationary, phase was prepared starting from R-(+)-1,1'-binaphthyl-2,2'-diamine. The CSP thus prepared was successfully applied to resolve a number of N-(3,5-dinitrobenzoyl)-α-amino amides and N-acyl-1-aryl-1-amino alkanes and found to be effective. The chiral recognition mechanism was proposed to beπ-πinteraction and simultaneously hydrogen bonding interactions between the CSP and the analytes.
1．大环抗生素类手性固定相分离β_2-受体激动剂对映体
本文应用大环抗生素类手性固定相Chirobiotic V，T和R对六种β_2-受体激动剂对映体进行了分离，考察了洗脱模式、流动相组成和温度等因素对分离的影响，对分离结果进行了比较研究，并对其分离机制进行了探讨。六种β_2-受体激动剂对映体在Chirobiotic R手性固定相上均不能实现分离。在Chirobiotic V和T手性固定相上，分离β_2-受体激动剂对映体的最佳模式均为新极性有机相模式，最佳色谱条件为：甲醇-冰醋酸-三乙胺(100∶0.01∶0.01，v／v／v)。在此条件下，六种β_3-受体激动剂对映体均可得到较好的分离，并可实现多种β_2-受体激动剂对映体的同时分离。考察了此模式下β_2-受体激动剂对映体的热力学参数变化，证明了β_2-受体激动剂对映体与两种手性固定相之间的相互作用是焓控过程。β_2-受体激动剂与固定相之间的离子相互作用是实现对映体分离的最主要分离机制。
2．Pirkle型手性固定相分离β_2-受体激动剂对映体
本文应用Pirkle型手性固定相，Pirkle-1J和α-Burke-2，对马布特罗、班布特罗、克伦特罗、克伦普罗和福莫特罗五种β_2-受体激动剂药物对映体进行了分离，考察了流动
The enantiomeric resolution of sixβ_2-agonists including bambuterol, clenbuterol, clenproperol, fumoterol, mabuterol and terbutaline was studied on three macrocyclic antibiotic chiral stationary phases (CSPs): Chirobiotic V, T and R. The enantiomeric resolution of fiveβ_2-agonists including bambuterol, clenbuterol, clenproperol, fumoterol and mabuterol mentioned above was studied on two Pikle-type CSPs: Pirkle-1J andα-Burke-2. The enantiomeric resolution of fiveβ_2-agonists mentioned above except terbutaline and sixβ-blockers including propranolol, atenolol, acebutolol, pindolol, alprenolol and oxprenolol was investigated on Crown ether-NH and N-CH_3 CSPs. A new Pirkle-type CSP was prepared and applied to resolve a number of N-(3,5-dinitrobenzoyl)-α-amino amides and N-acyl-1-aryl-l-aminoalkanes and found to be effective. The chiral recognition mechanism for different enantioresolution was proposed. 1、Enantioresolution ofβ_2-agonists on macrocyclic antibiotic CSPsThe enantiomeric resolution of sixβ_2-agonists was studied on three macrocyclic antibiotic chiral stationary phases (CSPs): Chirobiotic V, T and R. Factors affecting the enantioresolution, such as the separation mode, composition of mobile phase and column temperature were investigated. No enantioresolution was achieved for the sixβ_2-agonists on Chirobiotic R CSP. On Chirobiotic V and T CSPs, the polar organic mode (POM) was proved to be the best, with methanol-acetic acid-triethylamine (100:0.01:0.01, v/v/v) as the mobile phase, the enantiorners of all the sixβ_2-agonists were successfully separated, and the simultaneous enantioseparation ofβ_2-agonist mixture was achieved. The thermodynamic parameters ofβ_2-agonists in this mode were investigated, the enantioselectivity was proved to be enthalpocally controlled. The chiral recognition mechanism was discussed, ionic interaction between the CSPs andβ2-agonists was confirmed to be the dramatic interaction responsible for the chiral discrimination.
2. Enantioresolution ofβ_2-agonists on Pirkle-type CSPs
The enantiomeric resolution of fiveβ_2-agonists was studied on two Pikle-type CSPs: Pirkle-1J and or-Burke-2. Factors affecting the enantioresolution, such as the type and concentration of the salts additives, the content of the organic solvents and temperature were investigated. Under the optimized chromatographic condition, enantiomers of fiveβ_2-agonists were successfully separated on or-Burke-2 CSE while only twoβ_2-agonist enantiomers were resolved on Pirkle-1J CSE The thermodynamic parameters ofβ_2-agonists on two CSPs were investigated, the enantioselectivity was proved to be enthalpocally controlled. The chiral recognition mechanism was discussed,π-πinteraction and hydrogen binding between the CSPs andβ_2-agonists were confirmed to be the interactions responsible for the chiral discrimination.
3、Enantioresolution ofβ_2-agonists andβ-blockers on crown ether CSPs
The enantiomeric resolution of fiveβ_2-agonists and sixβ-blockers was investigated on Crown ether-NH and N-CH_3 CSPs. By varying the mobile phase composition and temperature, the enantiomers of all analytess were successfully separated on Crown ether-NH CSP, while only enantiomers ofβ-blockers were partly resolved on Crown ether-N-CH_3 CSP, the enantioresolution ofβ_2-agonists was not achieved on it. The thermodynamic parameters ofβ_2-agonists andβ-blockers on the CSPs were investigated, the enantioselectivity was proved to be entropically controlled. The chiral recognition mechanism was discussed, hydrogen binding, ionic interaction and inclusion interaction between the CSPs and the analytes were confirmed to be the interactions responsible for the chiral discrimination.
4. Preparation and application of a new Pirkle-type ehiral stationary phase
A new high-performance liquid chromatographic Pirkle-type chiral stationary, phase was prepared starting from R-(+)-1,1'-binaphthyl-2,2'-diamine. The CSP thus prepared was successfully applied to resolve a number of N-(3,5-dinitrobenzoyl)-α-amino amides and N-acyl-1-aryl-1-amino alkanes and found to be effective. The chiral recognition mechanism was proposed to beπ-πinteraction and simultaneously hydrogen bonding interactions between the CSP and the analytes.
引文
1 Nerurkar SG, Digbe SV, Wiliams RL. Bioequivalence of racemic drugs. J Clin Pharmacol, 1992, 32(10): 935.
2 Blaschke G, Kraft HP, Fickentscher K, Kohler F. Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers. Arzneimittelforschung. 1979, 29(10): 1640.
3 Veloo RA, Koomen GJ. Pharmacology study of propranolol and synthesis of enantiomerically pure (S)-(-)-propranolol from sorbitol. Tetrahedron: Asym, 1993, 4: 2401.
4 Ohta T, Takaya H, Kitamura M, et al. Asymmetric hydrogenation of unsaturated carboxylic acids catalyzed by BINAP-Ruthenium (Ⅱ) complex. J. Org. Chem, 1987, 52: 3174.
5 徐铮奎．世界手性药物发展新动向．中国制药信息，1999，15(9)：29．
6 Wilson H, Camp DE. Chiral drugs: the FDA perspective on manufacturing and control. J Pharm Biomed Anal, 1993, 11(11/12): 1167.
7 丁慈．手性药物的开发与前景．药学进展，1996，20(3)：147．
8 王普善．加速手性技术的开发，迎接世界制药工业的手性挑战．中国医药情报，1998，4(1)：9．
9 曾苏，李艳，王似菊．手性新药的开发及临床药物动力学因素．中国医药工业杂志，1996，27(9)：430．
10 何煦昌．手性药物的发展．中国医药工业杂志，1997，28(11)：519．
11 Piffeici G, Rerucca E. The cost benefit ratio of enantiomeric drugs. Eur J Drag Metab Pharmacokinet, 1995, 20(1): 15.
12 Nation RI. Chirality in new drug development. Clinical pharmacokinetic considerations. Clin Pharmacokinet, 1994, 27(4): 249.
13 曾苏，章立，王似菊等．人体中氧氟沙星的立体选择性代谢．中国药理学和毒理学杂志，1995，9(2)：87．
14 钟大放．手性药物的对映体选择性分析．李发美主编，医药高效液相色谱技术．人民卫生出版社．1999：76．
15 曾苏．高效液相色谱手性试剂衍生化法及其应用．色谱，1994，12(6)：406．
16 彭清涛，胡文祥，谭生键．药物对映体HPLC分离测定研究新进展．药学学报，1998，33(10)：793．
17 曾苏．高效液相色谱手性流动相添加剂法分离药物对映体．色谱，1995，13(1)：21．
18 吕湘林，杨宪桂．光学异构体的手性HPLC拆分法及其药学应用研究的进展(续)．药学学报，1988，23(1)：67．
19 Allenmark S. Optical resolution by on immobilized bovine serum albumin. J. Liq. Chromatogr. 1986, 9: 425.
20 Kirkland K. M., Mdombs D. A. Comparison of a new ovomacoid and a second-generation α-acid glycoprotein-based chiral column for the direct HPLC resolution of drug enantiomers. J. Chromatogr. 1991, 545: 43.
21 Hesse C, Hagel R. Inclusion chromatography and a new retention mechanism for benzene derivatives. Chromatographia. 1976, 9: 62.
22 Shibata T, Sei -T, Nishimara H. Hysteretic effect of the coating solvent on chiral recognition by cellulosederivative. Chromatographia. 1987, 24: 552.
23 Ichida A, Shibata T, Okamoto l, et al. Resoluton of enantiomers by HPLC on cellulose derivatives. Chromatographia. 1984, 19: 280.
24 Shibata T, Okamoto I, Ishii K. Chromatographic optical resolution on polysaccharides and their derivatives. J. Liq. Chromatogr. 1986, 9: 313.
25 Rumback K. H., Kastner F, Mannschreck A. Microcrystalline tribenzoyllulose: a HPLC sorbent for the separation of enantiomers. J. Chromatogr. 1986, 351: 346.
26 Fugimura K, Ueda T, Anodo T. Retention behavior of some aromatic compounds on chemically bonded cyclodextrin silica stationary phase in liquid chromatography. Anal. Chem. 1983, 55: 446.
27 Armstong D. W., Xiufeng Y, Han S. M., et al. Direct LC separation of racemates with an α-cyclodextrin bonded phase. Anal. Chem. 1987, 59: 2594.
28 Ward J. T., Arnstrong D. W. Improved cyclodextrin chiral phases: a comparison and review. J. Liq. Chromatogr. 1986, 9: 407.
29 Armstong D. W., Demond W, Czech B. P. Separation of metallocene enantiomers by liquid chromatography: chiral recognition via cyclodextrin bonded phases. Anal. Chem. 1985, 57: 481.
30 Armstrong D. W., Han Y. I., Han S. M. LC resolution of enantiomers containing single aromatic rings with β-cyclodextrin-bonded phases. Anal. Chem. Acta. 1988, 208: 275.
31 Chirobiotic Handbook. Advanced Separation Technologies. Whippany, USA. 1996.
32 Pirkle WH, Murray PG, Yang Q. Chiral recognition of N-acyl-1-(2-fluorenyl)-1-aminoalkanes by π-acidic chiral stationary phases: a mechanis view. J. Liq. Chromatogr., 1994,17:1665.
33 Pirkle WH, Finn JM. Chiral high-pressure liquid chromatographic stationary phase. 3. General resolution of arylalkylcarbinols. J. Org. Chem., 1981,46:2935.
34 Pirkle WH, Pochapsky TC. A new, easily accessible reciprocal chiral stationary phase for the chromatographic separation of enantiomers. J. Am. Chem. Soc, 1986,108:352.
35 Pirkle WH, Welch CJ. Chromatographic separation of the enantiomers of acylated amines on chiral stationary phases. J. Org. Chem., 1984,49:138.
36 Pirkle WH, Welch CJ, Hyun MH. A chiral recognition model for the chromatographic resolution of N-acrylated 1-aryl-1-aminoalkanes. J. Org. Chem., 1983,48:5022.
37 Pirkle WH, Hyun MH, Bank B. A rational approach to design of highly-effective chiral stationary phases. J. Chromatogr., 1984,316:585.
38 Wainer IW, Doyle TD, Breder CD. The application of HPLC chiral stationary phases to pharmaceutical analysis: The resolution of some tropic acid derivatives. J. Liq. Chromatogr., 1984,7:731.
39 Pikle WH, Welch CJ, Hyun MH. Concerning the role of face-to-edge π-π interactions in chiral recognition. J. Chromatogr., 1992,607:126.
40 Cram D. Multiheteromacrocyclic compounds bound to a styrenedivinylbenzene mixed polymer, useful for enantiomer separation. CA, 1978, 88:50938.
41 Polettini A. Bioanalysis of pVagonists by hyphenated chromatographic and mass spectrometric techniques. J.Chromatogr. B. 1996,687:27.
42 Clarkson P.M.; Thompson H.J. Drugs and sport. Research findings and limitations. Sports Med. 1997, 24:366.
43 Salpeter S.R.; Ormiston T.M.; Salpeter E.E.; Poole P.J.; Cates CJ. Cardioselective beta-agonists for chronic obstructive pulmonary disease: a meta-analysis. Respir Med. 2003, 97, 1094.
44 Anan'eva I.A.; Shapovalova E.N.; Shpigun O.A.; Armstrong D.W. Separation of β-agonists on chiral stationary phases based on the teicoplanin macrocyclic antibiotic. J. Anal. Chem. 2003, 58:663.
45 Murai T.; Maejima T; Sanai K.; Osada E. Pharmacological studies of mabuterol, a new selective beta-2-stimulant. I: Bronchodilating effect. Arzneimittelforschung. 1984,34(11 A): 1633.
46 Aboul-Enein H.Y.; Serginese V. Optimized enantioselective separation of clenbuterol on macrocyclic antibiotic teicoplanin chiral stationary phase. J Liq. Chromatogr. Rel. Technol. 1999,22:2177.
47 Aboul-Enein H.Y.; Ali L. Chiral resolution of clenbuterol, cimaterol, and mabuterol on Chirobiotic V, T, and TAG columns. J. Sep. Sci. 2002,25:851.
48 Desiderio C; Aturki Z.; Fanali S. Use of vancomycin silica stationary phase in packed capillary electrochromatography: I. Enantiomer separation of basic compounds. Electrophoresis 2001,22:535.
49 Fanali S.; Catarcini P., Quaglia M.G Use of vancomycin silica stationary phase in packed capillary electrochromatography: III. Enantiomeric separation of basic compounds with the polar organic mobile phase. Electrophoresis 2002,23:477.
50 Chang S.C.; Chen G.L. III. Chen S.; Chang C.D.; Armstrong D.W. Evaluation of a new polar-organic high-performance liquid chromatographic mobile phase for cyclodextrin-bonded chiral stationary phases. Trends Anal Chem 1993,12:144.
51 Sellergren B., Shea K.J. Origin of peak asymmetry and the effect of temperature on solute retention in enantiomer separations on imprinted chiral stationary phases. J. Chromatogr. A. 1995, 690:29.
52 Brien T.O., Crocker L., Thompson R., Thompson K., Toma P.H., Conlon D.A., Feibush B., Moeder C, Bicker G, Grinberg N. Mechanistic aspects of chiral discrimination on modified cellulose. Anal. Chem. 1997,69:1999.
53 Aboul-Enein H.Y., Ali L. Macrocyclic antibiotic as effective chiral selectors for enantiomeric resolution by liquid chromatography and capillary electrophoresis. Chromatographia 2000,52:679.
54 Ward T.J.; Farris (?) A.B. Chiral separations using the macrocyclic antiobiotics: a review. J. Chromatogr. A. 2001,906:73.
55 Gasper M.P.; Berthod A.; Nair U.B.; Armstrong D.W. Comparison and modeling study of vancomycin, ristocetin A, and teicoplanin for CE enantioseparations. Anal. Chem. 1996,68:2501.
56 Pirkle WH., Pochapsky TC. Considerations of chiral recognition relevant to the liquid chromatographic separation of enantiomers. Chem. Rev. 1989, 89:347.
57 Welch CJ. Evolution of chiral stationary phase design in the Pikle laboratories. J. Chromatogr. A. 1994, 666:3.
58 Hyun MH, Cho YJ, Baik IK. Liquid chromatographic resolution of N-protected α-amino acids as their anilide and 3,5-dimethylanilide derivatives. Bull. Kor. Chem. Soc. 2002, 23:1291.
59 Hyun MH, Lee GS, Han SC, Cho YJ. Liquid chromatographic resolution of N-acyl-α-amino acids as their anilide derivatives on a chiral stationary phase based on (S)-leucine. Chirality. 2002, 14:503.
60 Pirkle. W.H.; Burke III J.A. Chiral stationary phase designed for β-blockers. J Chraomagtogr. 1991, 557:173.
61 Lee W. Investigation of chiral recognition of conformationally rigid chiral stationary phases. Ph.D. Dissertation, Unversity of Illinois, Urbana; 1994.
62 Chilmonczyk Z.; Ksycinska H.; Aboul-Enein H.Y.; Lee W.J. Enatiomeric separation of some clinically used racemic drugs on Pirkle-1J chiral stationary phase. J. Liq. Chrom & Rel. Technol. 2001,24:2505.
63 Machida Y, Nishi H, Nakamura K, Nakai H, Sato T. Enantiomer separation of amino compounds by a novel chiral stationary phase derived from crown ether. J.Chromatohr.A 1998, 805:85.
64 Hyun MH, Jin JS, Lee W. Liquid chromatographic resolution of racemic amino acids and their derivatives on a new chiral stationary phase based on crown ether. J.Chromatogr.A 1998, 822:155.
65 Hyun MH, Cho YJ, Jin JS. Liquid chromatographic direct resolution of P-amino acids on a chiral crown ether stationary phase. J. Sep.Sci. 2002, 25(10/11):648.
66 Hyun MH, Jin JS, Koo HJ, Lee W. Liquid chromatographic resolution of racemic amines and amino alcohols on a chiral stationary phase derived from crown ether. J. Chromatogr. A 1999, 837:75.
67 Hyun MH, Han SC, Jin JS, Lee W. Separation of the stereoisomers of racemic fluoroquinolone antibacterial agents on a crown-ether-based chiral HPLC stationary phase. Chromatographia. 2000, 52:473.
68 Hyun MH, Han S.C, Cho YJ, Jin JS, Lee W. Liquid chromatographic resolution of gemifloxacin mesylate on a chiral stationary phase derived from crown ether. Biomed. Chromatogr. 2002,16:356.
69 . 刘宣. 小剂量普萘洛尔治疗扩张型心肌病心力衰竭疗效观察.新疆医学,2000,30(1):47.
70 Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W. Influence of beta blockers on melatonin release. Eur. J. Clin. Pharmacol. 1999, 55:111.
71 Santoro MIRM, Cho HS, Kedor-Hackmann ERM. Enantiomeric separation and quantitative determination of propranolol in tablets by chiral high-performance liquid chromatography. Drug Develop. Ind. Pharm. 2001, 27:693.
72 Chilmonczyk Z, Ksycinska H, Aboul-Enein HY, Lee W. Enantiomeric separation of some clinical used racemic drugs on Pikle-1J chiral stationary phase. J. Liq. Chromatogr. Rel. Technol. 2001,24:2505.
73 Cass QB, Tiritan ME, Calafatti SA, Matlin SA. Enantioseparation on amylase tris-(3,5-dimethoxyphenyl carbamate): application to commercial pharmaceutical chiral drugs. J. Liq. Chromatogr. Rel. Technol. 1999, 22:3091.
74 Desiderio C, Aturki Z, Fanali S. Use of vancomycin silica stationary phase in packed capillary electrochromatography I . Enantiomer separation of basic compounds. Electrophoresis, 2001.22:535.
75 Fanali S, Catarcini P, Quaglia MG. Use of vancomycin silica stationary phase in packed capillary electrochromatography HI. Enantiomeric separation of basic compounds with the polar organic mobile phase. Electrophoresis, 2002, 23:477.
76 Aboul-Enein HY, Ali I. Chiral resolution of clenbuterol, cimaterol, and mabuterol on Chirobiotic V, T, and TAG columns. J. Sep. Sci. 2002,25(13):851.
77 Dyas AM. J. Pharm. The chiral chromatographic separation of β-adrenoceptor blocking drugs. Biomed. Anal. 1992, 10:383.
78 Hilhorst MJ, Somsen GW, De Jong GJ. Capillary electrochromatography of basic compounds using octadecyl-silica stationary phases with an amine-containing mobile phase. J. Chromatogra. A. 2000, 872:315.
79 Reta M, Carr PW. Comparative study of divalent metals and amines as silanol-blocking agents in reversed-phase liquid chromatography. J. Chromatogr. A. 2000,855:121.
80 Hill DW. Evaluation of alkyl bonded silica and solvent phase modifiers for the efficient elution of basic drugs on HPLC. J. Liq. Chromatogr. 1990,13:3147.
81 Myk HO, Erhard KF, Chen TK. Pre-treatment of chiral a-AGP column with triethylamine significantly improves the detection sensitivity of an enantiomeric leukotriene antagonist. J. Liq. Chromatogr. 1994, 17:761.
82 Jin JS, Stalcup AM, Hyun MH. Impact of triethylamine as a mobile phase additive on the resolution of racemic amino acids on an (+)-18-crown-6-tetracarboxylic acid-derived chiral stationary phase. J. Chromatogr. A. 2001, 933:83.
83 Hyun MH. Characterization of liquid chromatographic chiral separation on chiral crown ether stationary phase. J. Sep. Sci. 2003,26:242.
84 Pirkle WH, Welch C.J. An investigation into the role of solvation in a well characterized chiral recognition system. J. Liq. Chromatogr. 1991, 14:2027.
85 Pirkle WH, Murray PG. An instance of temperature-dependent elution order of enantiomers from a chiral brush-type HPLC-column. J. High Resol. Chromatogr. 1993, 16:285.
86 Stringham RW, Blackwell J.A. "Entropically driven" chiral separations in supercritical fluid chromatography. Confirmation of islelution temperature and reversal of elution order. Anal. Chem. 1996,68:2179.
87 Stringham RW, Blackwell J.A. Factors that control successful entropically driven chiral separations in SFC and HPLC. Anal. Chem. 1997, 69:1414.
88 Schurig V. Practice and theory of enantioselective complexation gas chromatography. J. Chromatogr. A. 2002,965:315.
89 Cirilli R, Ferretti R, Gallinella B, Torre FL. A new application of stopped-flow chiral HPLC: inversion of enantiomer elution order. J. Chromatogr. A. 2004, 1061:27.
90 Fulde K, Frahm AW. Temperature-induced inversion of elution order in the enantioseparation of sotalol on a cellobiohydrolase I-based stationary phase. J. Chromatogr. A. 1999, 858:33.
91 Okamoto M. Reversal of elution order during the chiral separation in high performance liquid chromatography. J. Pharm. Biom. Anal. 2002,27:401.
92 Persson BA, Andersson S. Unusual effects of separation conditions on chiral separations. J. Chromatogr. A. 2001,906:195.
93 Pirkle WH. Unusual effect of temperature on the retention of enantiomers on a chiral column. J. Chromatogr. 1991,558:1.
94 Kuhn R, Steinmetz C, Bereuter T, Haas P. Enantiomeric separations using a chiral crown ether. J. Chromatogr. A 1994,666:367.
95 Lin JM, Hobo T. Combined chiral crown ether and β-cyclodextrin for the separation of o-, m-, p-fluoro-D,L-phenylalanine by capillary gel electrophoresis. Chromatographia 1996,42:559.
96 Shinbo T, Yamaguchi T, Nishimura K, Sugiura M. Chromatographic separation of racemic amino acids by use of chirai crown ether-coated reversed-phase packings. J. Chromatogr. 1987, 405: 145.
97 Hyun MH, Pirkle WH. Preparation and evaluation of a chiral stationary phase bearing both π-acidic and-basic sites. J. Chromatogr., 1957, 393: 357.
98 Vercauteren A, Van der Weken G, Vankeirsbiick T, AbouI-Enein HY, Baeyens WR. Enantiomeric separation of diuretics on a novil Pikle-type chiral stationary phase. Biomed. Chromatogr. 2002, 16(7): 437.
99 WelCh CJ, Perrin SR. Improved chiral stationary phase for β-blocker enantioseparafions. J. Chromatogr., 1995, 690: 218.
100 M. H. Hyun, C. S. Min, Y. J. Cho. Examples of liquid chromatographic resolution of π-acidic racemates on a π-acidic chiral stationary phase. J. High Resol. Chromatogr. 1995, 18, 63.
2 Blaschke G, Kraft HP, Fickentscher K, Kohler F. Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers. Arzneimittelforschung. 1979, 29(10): 1640.
3 Veloo RA, Koomen GJ. Pharmacology study of propranolol and synthesis of enantiomerically pure (S)-(-)-propranolol from sorbitol. Tetrahedron: Asym, 1993, 4: 2401.
4 Ohta T, Takaya H, Kitamura M, et al. Asymmetric hydrogenation of unsaturated carboxylic acids catalyzed by BINAP-Ruthenium (Ⅱ) complex. J. Org. Chem, 1987, 52: 3174.
5 徐铮奎．世界手性药物发展新动向．中国制药信息，1999，15(9)：29．
6 Wilson H, Camp DE. Chiral drugs: the FDA perspective on manufacturing and control. J Pharm Biomed Anal, 1993, 11(11/12): 1167.
7 丁慈．手性药物的开发与前景．药学进展，1996，20(3)：147．
8 王普善．加速手性技术的开发，迎接世界制药工业的手性挑战．中国医药情报，1998，4(1)：9．
9 曾苏，李艳，王似菊．手性新药的开发及临床药物动力学因素．中国医药工业杂志，1996，27(9)：430．
10 何煦昌．手性药物的发展．中国医药工业杂志，1997，28(11)：519．
11 Piffeici G, Rerucca E. The cost benefit ratio of enantiomeric drugs. Eur J Drag Metab Pharmacokinet, 1995, 20(1): 15.
12 Nation RI. Chirality in new drug development. Clinical pharmacokinetic considerations. Clin Pharmacokinet, 1994, 27(4): 249.
13 曾苏，章立，王似菊等．人体中氧氟沙星的立体选择性代谢．中国药理学和毒理学杂志，1995，9(2)：87．
14 钟大放．手性药物的对映体选择性分析．李发美主编，医药高效液相色谱技术．人民卫生出版社．1999：76．
15 曾苏．高效液相色谱手性试剂衍生化法及其应用．色谱，1994，12(6)：406．
16 彭清涛，胡文祥，谭生键．药物对映体HPLC分离测定研究新进展．药学学报，1998，33(10)：793．
17 曾苏．高效液相色谱手性流动相添加剂法分离药物对映体．色谱，1995，13(1)：21．
18 吕湘林，杨宪桂．光学异构体的手性HPLC拆分法及其药学应用研究的进展(续)．药学学报，1988，23(1)：67．
19 Allenmark S. Optical resolution by on immobilized bovine serum albumin. J. Liq. Chromatogr. 1986, 9: 425.
20 Kirkland K. M., Mdombs D. A. Comparison of a new ovomacoid and a second-generation α-acid glycoprotein-based chiral column for the direct HPLC resolution of drug enantiomers. J. Chromatogr. 1991, 545: 43.
21 Hesse C, Hagel R. Inclusion chromatography and a new retention mechanism for benzene derivatives. Chromatographia. 1976, 9: 62.
22 Shibata T, Sei -T, Nishimara H. Hysteretic effect of the coating solvent on chiral recognition by cellulosederivative. Chromatographia. 1987, 24: 552.
23 Ichida A, Shibata T, Okamoto l, et al. Resoluton of enantiomers by HPLC on cellulose derivatives. Chromatographia. 1984, 19: 280.
24 Shibata T, Okamoto I, Ishii K. Chromatographic optical resolution on polysaccharides and their derivatives. J. Liq. Chromatogr. 1986, 9: 313.
25 Rumback K. H., Kastner F, Mannschreck A. Microcrystalline tribenzoyllulose: a HPLC sorbent for the separation of enantiomers. J. Chromatogr. 1986, 351: 346.
26 Fugimura K, Ueda T, Anodo T. Retention behavior of some aromatic compounds on chemically bonded cyclodextrin silica stationary phase in liquid chromatography. Anal. Chem. 1983, 55: 446.
27 Armstong D. W., Xiufeng Y, Han S. M., et al. Direct LC separation of racemates with an α-cyclodextrin bonded phase. Anal. Chem. 1987, 59: 2594.
28 Ward J. T., Arnstrong D. W. Improved cyclodextrin chiral phases: a comparison and review. J. Liq. Chromatogr. 1986, 9: 407.
29 Armstong D. W., Demond W, Czech B. P. Separation of metallocene enantiomers by liquid chromatography: chiral recognition via cyclodextrin bonded phases. Anal. Chem. 1985, 57: 481.
30 Armstrong D. W., Han Y. I., Han S. M. LC resolution of enantiomers containing single aromatic rings with β-cyclodextrin-bonded phases. Anal. Chem. Acta. 1988, 208: 275.
31 Chirobiotic Handbook. Advanced Separation Technologies. Whippany, USA. 1996.
32 Pirkle WH, Murray PG, Yang Q. Chiral recognition of N-acyl-1-(2-fluorenyl)-1-aminoalkanes by π-acidic chiral stationary phases: a mechanis view. J. Liq. Chromatogr., 1994,17:1665.
33 Pirkle WH, Finn JM. Chiral high-pressure liquid chromatographic stationary phase. 3. General resolution of arylalkylcarbinols. J. Org. Chem., 1981,46:2935.
34 Pirkle WH, Pochapsky TC. A new, easily accessible reciprocal chiral stationary phase for the chromatographic separation of enantiomers. J. Am. Chem. Soc, 1986,108:352.
35 Pirkle WH, Welch CJ. Chromatographic separation of the enantiomers of acylated amines on chiral stationary phases. J. Org. Chem., 1984,49:138.
36 Pirkle WH, Welch CJ, Hyun MH. A chiral recognition model for the chromatographic resolution of N-acrylated 1-aryl-1-aminoalkanes. J. Org. Chem., 1983,48:5022.
37 Pirkle WH, Hyun MH, Bank B. A rational approach to design of highly-effective chiral stationary phases. J. Chromatogr., 1984,316:585.
38 Wainer IW, Doyle TD, Breder CD. The application of HPLC chiral stationary phases to pharmaceutical analysis: The resolution of some tropic acid derivatives. J. Liq. Chromatogr., 1984,7:731.
39 Pikle WH, Welch CJ, Hyun MH. Concerning the role of face-to-edge π-π interactions in chiral recognition. J. Chromatogr., 1992,607:126.
40 Cram D. Multiheteromacrocyclic compounds bound to a styrenedivinylbenzene mixed polymer, useful for enantiomer separation. CA, 1978, 88:50938.
41 Polettini A. Bioanalysis of pVagonists by hyphenated chromatographic and mass spectrometric techniques. J.Chromatogr. B. 1996,687:27.
42 Clarkson P.M.; Thompson H.J. Drugs and sport. Research findings and limitations. Sports Med. 1997, 24:366.
43 Salpeter S.R.; Ormiston T.M.; Salpeter E.E.; Poole P.J.; Cates CJ. Cardioselective beta-agonists for chronic obstructive pulmonary disease: a meta-analysis. Respir Med. 2003, 97, 1094.
44 Anan'eva I.A.; Shapovalova E.N.; Shpigun O.A.; Armstrong D.W. Separation of β-agonists on chiral stationary phases based on the teicoplanin macrocyclic antibiotic. J. Anal. Chem. 2003, 58:663.
45 Murai T.; Maejima T; Sanai K.; Osada E. Pharmacological studies of mabuterol, a new selective beta-2-stimulant. I: Bronchodilating effect. Arzneimittelforschung. 1984,34(11 A): 1633.
46 Aboul-Enein H.Y.; Serginese V. Optimized enantioselective separation of clenbuterol on macrocyclic antibiotic teicoplanin chiral stationary phase. J Liq. Chromatogr. Rel. Technol. 1999,22:2177.
47 Aboul-Enein H.Y.; Ali L. Chiral resolution of clenbuterol, cimaterol, and mabuterol on Chirobiotic V, T, and TAG columns. J. Sep. Sci. 2002,25:851.
48 Desiderio C; Aturki Z.; Fanali S. Use of vancomycin silica stationary phase in packed capillary electrochromatography: I. Enantiomer separation of basic compounds. Electrophoresis 2001,22:535.
49 Fanali S.; Catarcini P., Quaglia M.G Use of vancomycin silica stationary phase in packed capillary electrochromatography: III. Enantiomeric separation of basic compounds with the polar organic mobile phase. Electrophoresis 2002,23:477.
50 Chang S.C.; Chen G.L. III. Chen S.; Chang C.D.; Armstrong D.W. Evaluation of a new polar-organic high-performance liquid chromatographic mobile phase for cyclodextrin-bonded chiral stationary phases. Trends Anal Chem 1993,12:144.
51 Sellergren B., Shea K.J. Origin of peak asymmetry and the effect of temperature on solute retention in enantiomer separations on imprinted chiral stationary phases. J. Chromatogr. A. 1995, 690:29.
52 Brien T.O., Crocker L., Thompson R., Thompson K., Toma P.H., Conlon D.A., Feibush B., Moeder C, Bicker G, Grinberg N. Mechanistic aspects of chiral discrimination on modified cellulose. Anal. Chem. 1997,69:1999.
53 Aboul-Enein H.Y., Ali L. Macrocyclic antibiotic as effective chiral selectors for enantiomeric resolution by liquid chromatography and capillary electrophoresis. Chromatographia 2000,52:679.
54 Ward T.J.; Farris (?) A.B. Chiral separations using the macrocyclic antiobiotics: a review. J. Chromatogr. A. 2001,906:73.
55 Gasper M.P.; Berthod A.; Nair U.B.; Armstrong D.W. Comparison and modeling study of vancomycin, ristocetin A, and teicoplanin for CE enantioseparations. Anal. Chem. 1996,68:2501.
56 Pirkle WH., Pochapsky TC. Considerations of chiral recognition relevant to the liquid chromatographic separation of enantiomers. Chem. Rev. 1989, 89:347.
57 Welch CJ. Evolution of chiral stationary phase design in the Pikle laboratories. J. Chromatogr. A. 1994, 666:3.
58 Hyun MH, Cho YJ, Baik IK. Liquid chromatographic resolution of N-protected α-amino acids as their anilide and 3,5-dimethylanilide derivatives. Bull. Kor. Chem. Soc. 2002, 23:1291.
59 Hyun MH, Lee GS, Han SC, Cho YJ. Liquid chromatographic resolution of N-acyl-α-amino acids as their anilide derivatives on a chiral stationary phase based on (S)-leucine. Chirality. 2002, 14:503.
60 Pirkle. W.H.; Burke III J.A. Chiral stationary phase designed for β-blockers. J Chraomagtogr. 1991, 557:173.
61 Lee W. Investigation of chiral recognition of conformationally rigid chiral stationary phases. Ph.D. Dissertation, Unversity of Illinois, Urbana; 1994.
62 Chilmonczyk Z.; Ksycinska H.; Aboul-Enein H.Y.; Lee W.J. Enatiomeric separation of some clinically used racemic drugs on Pirkle-1J chiral stationary phase. J. Liq. Chrom & Rel. Technol. 2001,24:2505.
63 Machida Y, Nishi H, Nakamura K, Nakai H, Sato T. Enantiomer separation of amino compounds by a novel chiral stationary phase derived from crown ether. J.Chromatohr.A 1998, 805:85.
64 Hyun MH, Jin JS, Lee W. Liquid chromatographic resolution of racemic amino acids and their derivatives on a new chiral stationary phase based on crown ether. J.Chromatogr.A 1998, 822:155.
65 Hyun MH, Cho YJ, Jin JS. Liquid chromatographic direct resolution of P-amino acids on a chiral crown ether stationary phase. J. Sep.Sci. 2002, 25(10/11):648.
66 Hyun MH, Jin JS, Koo HJ, Lee W. Liquid chromatographic resolution of racemic amines and amino alcohols on a chiral stationary phase derived from crown ether. J. Chromatogr. A 1999, 837:75.
67 Hyun MH, Han SC, Jin JS, Lee W. Separation of the stereoisomers of racemic fluoroquinolone antibacterial agents on a crown-ether-based chiral HPLC stationary phase. Chromatographia. 2000, 52:473.
68 Hyun MH, Han S.C, Cho YJ, Jin JS, Lee W. Liquid chromatographic resolution of gemifloxacin mesylate on a chiral stationary phase derived from crown ether. Biomed. Chromatogr. 2002,16:356.
69 . 刘宣. 小剂量普萘洛尔治疗扩张型心肌病心力衰竭疗效观察.新疆医学,2000,30(1):47.
70 Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W. Influence of beta blockers on melatonin release. Eur. J. Clin. Pharmacol. 1999, 55:111.
71 Santoro MIRM, Cho HS, Kedor-Hackmann ERM. Enantiomeric separation and quantitative determination of propranolol in tablets by chiral high-performance liquid chromatography. Drug Develop. Ind. Pharm. 2001, 27:693.
72 Chilmonczyk Z, Ksycinska H, Aboul-Enein HY, Lee W. Enantiomeric separation of some clinical used racemic drugs on Pikle-1J chiral stationary phase. J. Liq. Chromatogr. Rel. Technol. 2001,24:2505.
73 Cass QB, Tiritan ME, Calafatti SA, Matlin SA. Enantioseparation on amylase tris-(3,5-dimethoxyphenyl carbamate): application to commercial pharmaceutical chiral drugs. J. Liq. Chromatogr. Rel. Technol. 1999, 22:3091.
74 Desiderio C, Aturki Z, Fanali S. Use of vancomycin silica stationary phase in packed capillary electrochromatography I . Enantiomer separation of basic compounds. Electrophoresis, 2001.22:535.
75 Fanali S, Catarcini P, Quaglia MG. Use of vancomycin silica stationary phase in packed capillary electrochromatography HI. Enantiomeric separation of basic compounds with the polar organic mobile phase. Electrophoresis, 2002, 23:477.
76 Aboul-Enein HY, Ali I. Chiral resolution of clenbuterol, cimaterol, and mabuterol on Chirobiotic V, T, and TAG columns. J. Sep. Sci. 2002,25(13):851.
77 Dyas AM. J. Pharm. The chiral chromatographic separation of β-adrenoceptor blocking drugs. Biomed. Anal. 1992, 10:383.
78 Hilhorst MJ, Somsen GW, De Jong GJ. Capillary electrochromatography of basic compounds using octadecyl-silica stationary phases with an amine-containing mobile phase. J. Chromatogra. A. 2000, 872:315.
79 Reta M, Carr PW. Comparative study of divalent metals and amines as silanol-blocking agents in reversed-phase liquid chromatography. J. Chromatogr. A. 2000,855:121.
80 Hill DW. Evaluation of alkyl bonded silica and solvent phase modifiers for the efficient elution of basic drugs on HPLC. J. Liq. Chromatogr. 1990,13:3147.
81 Myk HO, Erhard KF, Chen TK. Pre-treatment of chiral a-AGP column with triethylamine significantly improves the detection sensitivity of an enantiomeric leukotriene antagonist. J. Liq. Chromatogr. 1994, 17:761.
82 Jin JS, Stalcup AM, Hyun MH. Impact of triethylamine as a mobile phase additive on the resolution of racemic amino acids on an (+)-18-crown-6-tetracarboxylic acid-derived chiral stationary phase. J. Chromatogr. A. 2001, 933:83.
83 Hyun MH. Characterization of liquid chromatographic chiral separation on chiral crown ether stationary phase. J. Sep. Sci. 2003,26:242.
84 Pirkle WH, Welch C.J. An investigation into the role of solvation in a well characterized chiral recognition system. J. Liq. Chromatogr. 1991, 14:2027.
85 Pirkle WH, Murray PG. An instance of temperature-dependent elution order of enantiomers from a chiral brush-type HPLC-column. J. High Resol. Chromatogr. 1993, 16:285.
86 Stringham RW, Blackwell J.A. "Entropically driven" chiral separations in supercritical fluid chromatography. Confirmation of islelution temperature and reversal of elution order. Anal. Chem. 1996,68:2179.
87 Stringham RW, Blackwell J.A. Factors that control successful entropically driven chiral separations in SFC and HPLC. Anal. Chem. 1997, 69:1414.
88 Schurig V. Practice and theory of enantioselective complexation gas chromatography. J. Chromatogr. A. 2002,965:315.
89 Cirilli R, Ferretti R, Gallinella B, Torre FL. A new application of stopped-flow chiral HPLC: inversion of enantiomer elution order. J. Chromatogr. A. 2004, 1061:27.
90 Fulde K, Frahm AW. Temperature-induced inversion of elution order in the enantioseparation of sotalol on a cellobiohydrolase I-based stationary phase. J. Chromatogr. A. 1999, 858:33.
91 Okamoto M. Reversal of elution order during the chiral separation in high performance liquid chromatography. J. Pharm. Biom. Anal. 2002,27:401.
92 Persson BA, Andersson S. Unusual effects of separation conditions on chiral separations. J. Chromatogr. A. 2001,906:195.
93 Pirkle WH. Unusual effect of temperature on the retention of enantiomers on a chiral column. J. Chromatogr. 1991,558:1.
94 Kuhn R, Steinmetz C, Bereuter T, Haas P. Enantiomeric separations using a chiral crown ether. J. Chromatogr. A 1994,666:367.
95 Lin JM, Hobo T. Combined chiral crown ether and β-cyclodextrin for the separation of o-, m-, p-fluoro-D,L-phenylalanine by capillary gel electrophoresis. Chromatographia 1996,42:559.
96 Shinbo T, Yamaguchi T, Nishimura K, Sugiura M. Chromatographic separation of racemic amino acids by use of chirai crown ether-coated reversed-phase packings. J. Chromatogr. 1987, 405: 145.
97 Hyun MH, Pirkle WH. Preparation and evaluation of a chiral stationary phase bearing both π-acidic and-basic sites. J. Chromatogr., 1957, 393: 357.
98 Vercauteren A, Van der Weken G, Vankeirsbiick T, AbouI-Enein HY, Baeyens WR. Enantiomeric separation of diuretics on a novil Pikle-type chiral stationary phase. Biomed. Chromatogr. 2002, 16(7): 437.
99 WelCh CJ, Perrin SR. Improved chiral stationary phase for β-blocker enantioseparafions. J. Chromatogr., 1995, 690: 218.
100 M. H. Hyun, C. S. Min, Y. J. Cho. Examples of liquid chromatographic resolution of π-acidic racemates on a π-acidic chiral stationary phase. J. High Resol. Chromatogr. 1995, 18, 63.