Preparation Of β-cyclodextrin Functionalized Monoliths For The Application On Enantioseparation Of Chiral Drugs

Chiral is widespread phenomenon of nature. With the development of life science and pharmaceutical industry, the demand of the enantioseparation for pure single enantiomer is dramatically increasing. Since enantiomers present identical chemical and physical properties, it remains a great challenge to effectively resolve them to enantiomerically pure forms. Cyclodextrins(CD) has good chiral recognition ability for optical isomers. Until now, various kinds of CD or its derivatives functionalized stationary phase are widely exploited in the chiral resolution of racemic compounds. In the recent decades, owing to their advantages of high permeability, fast mass transfer and easy preparation, β-CD functionalized monoliths have aroused increasing interest in the field of chiral separations. In this present study, in order to improve the chiral separating ability of β-CD functionalized monoliths, a series of novel β-CD functionalized organic polymer capillary monolithic columns were designed and prepared. Then the effects of several parameters on the column efficiency and enantioseparation ability were systematically investigated, which could provide important information for preparing satisfactory β-CD functionalized organic polymer based monolithic column.Chapter 1. The research background of this thesis, including chirality of drugs, the properties of CD based stationary phases and the development of monoliths, were comprehensively introduced. In particular, the development of β-CD functionalized monoliths was reviewed. On this basis, the significances and innovations of this study were put forward.Chapter 2. In order to investigate the effect of the linking spacer on the enantioseparation ability of β-CD functionalized polymeric monoliths, three β-CD-functionalized organic polymeric monoliths with different spacer lengths were prepared by using three amino-β-CDs, i.e. mono-6-amino-6-deoxy-β-CD(NH2-β-CD), mono-6-ethylenediamine-6-deoxy-β-CD(EDA-β-CD), mono-6-hexamethylenediamine-6-deoxy-β-CD(HDA-β-CD), as starting materials. These amine-β-CDs reacted with glycidyl methacrylate(GMA) to produce functional monomers which were then “one-pot” copolymerized with ethylene dimethacrylate(EDMA). The enantioseparation ability of the three monoliths(poly(GMA-NH2-β-CD-co-EDMA), poly(GMA-EDA-β-CD-co-EDMA), and poly(GMA-HDA-β-CD-co-EDMA) was evaluated using 14 chiral acidic compounds under optimum chromatographic conditions. The results indicate that the enantioselectivity of β-CD monolithic columns would be decreased with increasing the length of spacer tethering β-CD to the polymeric support.Chapter 3. Three common-used crosslinkers, i.e. 1,4-bis(acryloyl)piperazine(PDA), N, N’-methylenebisacrylamide(MBA) and EDMA, were one-pot copolymerized with glycidyl methacrylate-mono-6-amino-6-deoxy-β-CD(GMA-NH2-β-CD), which reacted between glycidyl methacrylate and NH2-β-CD as functional monomers, respectively. The optimized three monolithic columns, including two novel columns poly(GMA-NH2-β-CD-co-PDA) and poly(GMA-NH2-β-CD-co-MBA), as well as a previously reported column poly(GMA-NH2-β-CD-co-EDMA) were systematically compared with the physicochemical properties and enantioseparation ability. Enantioseparation ability and column efficiency of chiral compounds were evaluated of each column. It was found that the β-CD functionalized monolith with MBA crosslinker exhibited best chiral separation performance than that with PDA and EDMA crosslinker.Chapter 4. Two poly(GMA-NH2-β-CD-co-MBA) monolithic columns have been prepared using hydrosoluble initiator 2,2-azobis(2-methylpropionamidine) dihydrochloride(AIBA) and hydrophobic initiator 2,2’-azobis(2-methylpropionitrile)(AIBN), respectively, in order to investigate the effect of initiator on the enantioseparation ability of β-CD-functionalized monolithic column. Scanning electron microscopy(SEM), elemental analysis, and micro-HPLC were carried out to characterize the physicochemical properties and enantioseparation performance of the monolithic column initiated by AIBA. Furthermore, the column efficiency, retention mechanism and enantioseparation ability of these two columns were compared. The result demonstrated that although the more hydrophilic initiator AIBA could speed up the free radical reaction, no significant influence on the enantioseparation ability of β-CD-functionalized monolithic column was observed. AIBN is more suitable for preparing the β-CD polymer organic monolithic column.Chapter 5. In order to investigate the effect of preparation approach on the enantioseparation ability of β-CD functionalized monoliths, the enantioselectivity of the poly(GMA-EDA-β-CD-co-EDMA) monolithic column prepared via the “two-step” approach was compared to that of the poly(GMA-EDA-β-CD-co-EDMA) monolithic column prepared via one-pot method. A series of mandelic acid derivatives and profens were used as analytes. The monolithic columns prepared by one-pot method showed higher column efficiency and enantioselectivity than that prepared by two-step method.Chapter 6. The conclusions and the prospects of β-CD-functionalized monoliths were described.