In addition, the knowledge of the binding constants values is very useful to calculate one of the most important parameters for separation: the optimal CD concentration [39 - 40]. In this way, it will be possible to evaluate the performance of our experimental design to predict the best condition for the separation of the benzodiazepine enantiomers. It is well known from the literature  that the mobility depends on the viscosity of the medium, the ionic strength, and the temperature.
The mobilities of the drug-CD complex were calculated and corrected for the changes in viscosity and EOF. The EOF was determined using methanol as the neutral marker which was simultaneously detected at nm. In this work it was assumed that solute interactions with the wall-bound are negligible, only complexation occurs, and no correction in the ionic strength was done. A linear Newtonian behavior of the CD solution viscosity, as a function of its concentration, was observed slope 0. Binding constants were determined by CE using the relationship between the CD concentration and the electrophoretic mobility of the analyte.
The relationship used in this work Eq. The advantage of this equation is that it is not necessary to know the value of the maximum mobility of the drug-CD complex which, many times, was observed to be overestimated at high CD concentration . Good fitting of the experimental data was obtained which confirms the complex assumption.
Since K's values are very small, it was necessary to use, experimentally, the highest CD concentration 5. On the other hand, theoretically, the optimal CD concentration can be calculated according to the relationship proposed by Wren et al. Using Eq. It can be observed, that in most of the cases except for temazepam , the calculated optimal CD concentration is experimentally limited by the Joule heat that can be generated by the high current at CD concentration greater than Therefore, for practical use, it is impossible to utilize those optimal concentrations to perform the benzodiazepines chiral separation.
It should be mentioned that the equilibrium free ligand concentration [CD free ] was approximately the same as the total ligand concentration [CD total ].
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In addition, the mobility is influenced by the absorption of the charged chiral selector on the capillary wall as was reported before by Gratz et al . Because they observed that it is a dynamical process, no corrections for absorption were incorporated to the equilibrium constants calculated in this work. The conformational analysis of the benzodiazepines was performed by the inversion of the C3 chiral carbon , as well as the rotation barrier of the bond in the position C5.
After minimization of the molecular energy for all structures, 3 stable conformations for oxazepam and temazepam were found, as well as 6 stable conformations for lorazepam and lormetazepam. Only the most stable conformers of the benzodiazepines were used to perform the subsequent calculations. Two molecular models were proposed to be computed Fig.
First, an inclusion complex where the benzodiazepine interacts with the cyclodextrin cavity, the second one, an external compound interaction with the smallest rim of the CD close to the sulfate groups.
Each molecular model was constructed using the more abundant conformations Table 5. A mathematical model was built using the calculated formation energies for the proposed complexes and the Boltzmann distribution low Eq. The results obtained, applying the mathematical model, are summarized in Table 6.
Enantiomeric Separation of Sibutramine by Capillary Zone Electrophoresis
The energy calculation predicted the elution order of each enantiomer correctly. The results of the molecular modeling lead to the conclusion that the exclusion complexes are more stable than the inclusion complexes. However, the inclusion complex model reproduces, in a satisfactory way, the tendency of the observed experimental results. Therefore, it is probable that the first elute should be the S enantiomers. According to these molecular modeling calculations and the molecular structures of the benzodiazepines Fig.
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It is also probable that the hydroxyl group, attached to the chiral carbon C3 , must have a kind of interaction i. Host-guest interaction with CD was found to be useful for the separation of the enantiomers of the 3-chiral-1,4-benzodiazepines. The use of highly sulfated cyclodextrins as chiral agents provided a net mobility to the formed diasteromers drug-CD complexes which allows us to obtain separation. The fractional factorial design of 3 levels was an efficient scheme for the selection of good experimental conditions to obtain high resolutions between 3.
Knowledge of binding constants can provide a better understanding of the separation mechanism and, consequently, can help in predicting migration behavior and designing optimization strategies. Molecular modeling studies allow us to conclude that the exclusion complexes are more stable than the inclusion complexes. However, the latter ones reproduce, in a satisfactory way, the tendency of the experimental results observed.
The models obtained, through means of these kinds of calculations, can provide us with a good approach on how the analyte can interact with the CD in solution. Therefore, it is likely that the first eluted peak is the S enantiomer, which is extremely useful when the standards of the pure enantiomers are not available. Levy, R. In Antiepileptic drugs ; Woodbury, D. Maksay, G. Salvadori, P. Lu, X. A , , Lui, J. Cabrera, K. Fitos, I.
Masafumi, T. B , , Boonkerd, S. Bechet, I. Schafroth, M. Catabay, A.
Lloyd, D. Schoetz, G. Hou, J. Ward, T. Terabe, S. Nishi, H. Sepaniak, M. Tait, R. Stalcup, A. Vincent, J. Cai, H. Wren, S. Vargas, M. Giddings, J. Dejaegher, B. Scriba, G. Massart, D. Elsevier, Amsterdam, , , Miller, J. Blanco, M. Carison, R. Bergholdt, A. Kuhn, R. Tanaka, Y. High Resolut. Rundlett, K. Connors, K. Gratz S. The Cambridge Structural Database. Groom, C. DOI: Allinget, N. PCModel for Windows, version 1. Dewar, M.
Separation of Enantiomers by Capillary Electrophoresis Using Cyclodextrins
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