Study On Enantioselective Extraction Of Chiral Drugs And Mechianism Of Inclusion Interaction With β-cyclodextrin Derivatives

In this paper, enantioselective extraction of clorprenaline (CPE) and2-chloromandelic acid (CMA) enantiomers with β-cyclodextrin derivatives as selector were investigated. The influence of the type of organic solvent and P-cyclodextrin derivatives, concentration of selector, pH and temperature on extraction efficiency was investigated. In order to obtain the best conditions, distribution ratio, enantioselectivity, enantiomeric excess, performance factor were introduced to optimize extraction condition. The contents were summarized as follows:(1) With the use of physical partition coefficient, dissociation constant, complexation equilibrium constants and considering the chemical properties of different systems (acid and alkaline), different models were developed. In consideration of ionic enantiomers maybe distribute in the organic phase, physical distribution coefficients for ionic enantiomers were introducd into the model.(2) The physical distribution coefficient for ionic CPE in the organic phase was introduced to develop the model. This system used the alkaline model. The physical distribution coefficients for molecular and ionic CPE (0.3and8.93) were determined by experiment. The results showed that the experimental data were agreement with the model predictions. R-clorprenaline was preferentiallly recognized by all β-cyclodextrin derivatives. Comprehensive consideration of experiment and model, the extraction conditions were optimized and the best extraction conditions were:pH of6.0, SBE-β-CD concentration of0.04mol/L, and temperature of5℃, providing the enantioselectivity (a) of1.25, the fraction of R-CPE (φr) in aqueous phase of0.71and performance factor (pf) of0.025.(3) Enantioselective extraction of CMA used the model for the acid system without considering physical distribution coefficients for ionic CMA enantiomers in the organic phase. Results showed that all P-cyclodextrin derivatives preferentiallly recognize S-CMA and the experimental data agree with the model predictions perfectly. Combining the experiment and the model data, the best extraction conditions were: pH of2.5, HP-β-CD concentration of0.05mol/L, and temperature of5℃, providing the enantioselectivity of1.29and the performance factor (pf) of0.011.Inclusion interaction between hydroxypropyl-β-cyclodextrin and CMA was also investigated by ultraviolet (UV) absorption specetrophotometer, HNMR spectrum, thermo-ravimetric/differential thermal analyzer (TG/DTA) and molecular modeling. The experimental results showed that the stoichiometry between the hydroxypropyl-β-cyclodextrin and CMA was1:1. Compared pure CMA, ultraviolet (UV) absorption specetrophotometer of the the inclusion complexs moved to long wave direction. Through the method of Benesi-Hildebrand’s, inclusion stability constants KR and Ks were determined as24L/mol and39L/mol. The result of thermo-gravimetric/differential thermal analyzer (TG/DTA) informed that inclusion complex formation between hydroxypropyl-β-cyclodextrin and CMA greatly enhanced the stability of CMA in solid state. Molecular modeling confirmed that the main molecular force between hydroxypropyl-β-cyclodextrin and CMA was the hydrogen bonding interaction.