Molecular Modeling and Chiral Separation of Benzodiazepines by Capillary Electrophoresis Using Highly Sulfated Cyclodextrins

María Gabriela Vargas Martinez, Guillermo Ramírez Galicia


A capillary electrophoretic method for the chiral separation of the 3-chiral-1,4-benzodiazepines was developed. Enantiomeric resolution of oxazepam, lorazepam, temazepam, and lormetazepam was achieved using sulfated cyclodextrins (CD's) as chiral selectors. A 3-levels, 4-factors fractional factorial (34-2) design was applied to test 3 different CD's: heptakis-6-sulfato--cyclodextrin (HSCD), heptakis-(2,3-diacetyl-6-sulfato)--cyclodextrin (HDASCD), and heptakis-(2,3-dimethyl-6-sulfato)--cyclodextrin (HDMSCD). The CD type, its concentration, the pH of the electrolyte, and % organic modifier were tested as the factors in the experimental design. The highest resolution values were obtained using a 20 mM borate buffer, pH 9.0 with the addition of 5 % HSCD and 15 % methanol as an organic modifier. At these separation conditions, the equilibrium constants of the benzodiazepine-HSCD complex formation were calculated. A theoretical study of the interaction benzodiazepine-HSCD complex using semiempirical calculations is postulated.


Chiral Separation; Benzodiazepines; Sulfated Cyclodextrins; Molecular Modeling

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Mattson, R.H. in Woodbury, D.M., Penry J.K. and Schmidt R.P. (Editors), Antiepilectic Drugs, Raven Press, New York, 1982, 497.

Möhler H. and Okada, T. Science, 1977, 198, 849-851.

Maksay, G., Tegyey Z. and Otvos, L. J. Pharm. Sci., 1978, 67, 1208-1210.

Salvadori, P., Bertucci, C., Domenici, E. and Giannaccini, G. J. Pharm. Biom. Anal., 1989, 7, 1735.

Lu X.L. and Yang, S.K. J. Chromatogr., 1990, 535, 229.

Lu X.L. and Yang, S.K. J. Chromatogr. A, 1994, 666, 249-257.

Lui J. and Stewart, J.T. Anal. Lett., 1997, 30, 1555-1566.

Cabrera, K. and Ludba, D. J. Chromatogr. A, 1994, 666, 433-438.

Fitos, I., Visy, J., Simonyi, M. and Hermansson, J. J. Chromatogr. A, 1995, 709, 265-273.

Masafumi, T. and Okuyama, T. J Chromatogr. B, 1996, 678, 331-337.

Boonkerd, S., Detaevernier, M.R., Michotte, Y. and Vindevogel, J. J. Chromatogr. A, 1995, 704, 238-241.

Bechet, I., Fillet, M., Hubert, P. and Crommen, J., Electrophoresis, 1994, 15, 1316-1321.

Schafroth, M., Thormann, W. and Allemann, D. Electrophoresis, 1994, 15, 72-78.

Catabay, A.P., Sawada, H., Jinno, K., Pesek, J.J. and Matyska, M.T., J. Cap. Elec., 1998, 005:1/2, 89.

Loyd, D.K., Li, S. and Ryan, P., J. Chromatogr. A, 1995, 694, 285.

Schoetz, G., Trapp, O. and Schurig, V. Anal. Chem, 2000, 72, 2758-2764.

Hou, J., Rizvi, S.A.A., Zheng J. and Shamsi, S.A. Electrophoresis, 2006, 27, 1263–1275.

Ward, T.J. Anal. Chem., 1994, 66, 632A-640A.

Terabe, S., Otsuka, K. and Nishi, H. J. Chromatogr., 1994, 666, 295-319.

Nishi, H. and Terabe, S. J. Chromatogr., 1995, 694, 245-276.

Sepaniak, M.J., Copper, C.L., Whitaker, K.W. and Anigbogu, V.C. Anal. Chem., 1995, 67, 2037-2041.

Nishi, H., Fukuyama, T. and Terabe, S. J. Chromatogr., 1991, 553, 503-516.

Tait, R.J., Thompson, D.O., Stella, V.J. and Stobaugh, J.F. Anal. Chem., 1994, 66, 4013-4018.

Stalcup, A.M. and Gahm, K.H. Anal. Chem., 1996, 68, 1360-1368.

Vincent, J.B., Sokolowski, A.D., Nguyen, T.V. and Vigh, G. Anal. Chem., 1997, 69, 4226-4233.

Vincent, J.B., Kirby, D.M., Nguyen, T.V. and Vigh, G. Anal. Chem., 1997, 69, 4419-4428.

Cai, H., Nguyen, T.V. and Vigh, G. Anal. Chem., 1998, 70, 580-589.

Wren S.A.C. and Rowe, R.C. J. Chromatogr. 1992, 603 235.

Vargas, M.G., Vander Heyden, Y., Maftouh M. and Massart, D.L. J. Chromatogr. A, 1999, 855, 681 –693.

Giddings, J.C. Sep. Purif. Sci., 1969, 4, 181-189.

ACD/Labs Software, Advanced Research in Chemistry, ARC laboratories B.V., Amsterdam, The Netherlands.

Bergholdt A.B. and Lehmann, S.V. Chirality, 1998, 10, 699-704.

Wren S.A.C. and Rowe, R. C. J. Chromatogr. 1992, 603, 235.

Wren, S.A.C. J. Chromatogr., 1993, 636, 57-62.

Kuhn, R., Frei, R. and Christen, M. Anal. Biochem., 1994, 218, 131-135

Tanaka, Y., Terabe, S. and Yanagawa, M. J. High Resolut. Chromatogr., 1996, 19, 421-33.

Rundlett, K.L and Armstrong, D.W. J. Chromatogr. A, 1996, 721, 173-186.

Connors, K.A. Binding constants – The Measurement of Molecular Complex Stability, John Wiley & Sons, New York, 1987.

Gratz S.R. and Stalcup, A. M. Anal. Chem., 1998, 70, 5166-5171.

Cambridge Crystal Structure Database.

Allinget, N.L. J. Am. Chem. Soc., 1977, 99, 8127.

PCModel for Windows, version 1.0, Serena Software.

Dewar, M.J.S., Zoebish, E.G., Healy, E.F. and Stewart, J.J.P. J. Am. Chem. Soc., 1985, 107, 3902.

Stewart, J.J.P. QCPE Program 455, Chemistry Department, Indiana University, 1989.



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