Water-soluble Beta-cyclodextrin Inclusion Reaction To Extract The Drug Enantiomers

Chirality and chiral technology play an important role in the field of chemical research, nowadays. The availability of enantiopure compounds is of primary importance in the pharmaceutical and fine chemical industry. Chiral solvent extraction is considered as a very promising technology for the production of enantiopure compounds because it possesses a wide range of applications, can be operated continuously and economically and can be scaled up to an industrial scale easily. The development of chiral solvent extraction requires efficient chiral extractants. Hydrophilicβ-cyclodextrin (β-CD) are a kind of very promising chiral extractant for the separation of hydrophobic drug enantiomers because of their good chiral recognition ability and hydrophility.This thesis deals with the enantioselective extraction of some hydrophobic drug enantiomers to an aqueous phase of hydrophilicβ-CD solution. The influence of process variables on extraction efficiency was investigated experimentally. The extraction mechanism was investigated and a reactive extraction model was established. The model was validated by comparison of the model predictions with the experimental results. Extraction performances were evaluated using distribution ratio, enantioselectivity, enantiomeric excess and performance factor and the extraction systems were optimized by modeling and experiment.In Chapter 2, the theory of chiral solvent extraction was studied. Consideringβ-CD derivatives are highly hydrophilic and the hydrophobic drug enantiomers can distribute over the organic and aqueous phases, homogeneous aqueous phase reaction mechanism is applied. An inclusion reactive extraction model was established involving equilibrium of physical distribution, dissociation and inclusion complexation between enantiomers andβ-CD extractant. Some pharmacological studies have reported the distribution of ionic species between organic and aqueous phases, the model in this thesis therefore contains the physical distribution coefficient of ionic enantiomers, which is different from the models that have been reported. In Chapters 3-6, chiral solvent extraction of four drug enantiomers was investigated. The effects of process variables such as types of organic solvents andβ-CD derivatives, concentration of selector, pH and temperature, on extraction efficiency were investigated and important parameters of the model were determined experimentally. The most suitable extraction system for each drug enantiomers was obtained by experiment. Reactive extraction model was applied for each drug enantiomers. The models were then validated by comparison of the model predictions with the experimental results. Multivariate function models were then established based on the validated models. Modeling and optimization based on the multivariate function models were carried out to obtained the optimal extraction conditions and coefficients. Results show thatβ-CD derivatives can recognize all the drug enantiomers studied. For typical drug enantiomers,β-CD derivatives with different chemical structures preferentially recognize the same enantiomer but with different recognition abilities. Organic solvents type, concentration of extractant, pH and temperature strongly influence the extraction efficiency, but the pattern of their influence is different on different enantiomers. Application of the reactive extraction model need to be adjusted to each specific system and all the four systems are modeled successfully after the adjustment, which indicate the theory investigation of this thesis can be generally applied. Addition of the ionic physical distribution greatly improve the accuracy of the model predictions. The optimum conditions and coefficients of the four enantiomers were srparately obtained. The presented data indicates that the model is a powerful tool for modeling chiral solvent extraction system and can provide information for the engineering calculation and design.