Comparative Study On Preparation Strategy Of β-cyclodextrin Functionalized Polymeric Monoliths And Their Application

Over 50% of pharmaceutical ingredients are chiral.They have identical physicochemical properties,whereas their pharmacological activities and metabolism are often significantly different in biological conditions.Therefore,enantioseparations are urgency and various chiral stationary phases are developed as effective tools for enantioseparations.As a typical chiral stationary phase,cyclodextrin(CD)functionalized monolithic column has attracted increasing attention due to its combination of the specific chiral recognition ability of CDs and the flexibility of monolithic materials,such as high permeability and easy modification.Most researches of CD functionalized monolithic column are focused on the development of novel preparation approaches aimed to simplify process and improve efficiency.On the other hand,some researches are focused on the derivatization of CDs aimed to improve chiral recognition of CDs and satisfy more analytical applications.However,so far the effect of preparation strategies(i.e.two-step,single-step and one-pot strategy)on the enantioseparation performance of CD functionalized monoliths has not been studied comprehensively under comparable conditions.So in this thesis,the effect of the preparation strategy on the enantioseparation performance of β-CD functionalized monoliths and preparation of novel derived β-CD functionalized monoliths were investigated.A series of β-CD functionalized organic polymeric monolithic columns were prepared through two-step,single-step and one-pot approaches.Physicochemical characterization and the comparative enantioresolutions on the columns were carried out to have a systematic evaluation.As a result,this study could provide scientific evidences for preparing satisfactory β-CD and derivatives functionalized organic polymer monolithic column or other chiral monoliths.Chapter 1.In the researches of pharmaceutical analysis,the importance and scientific background of enantioseparation as well as the developed enantioseparation technology based on CDs have been introduced.Based on β-CD functionalized monoliths,the recent advance of chromatographic matrix,preparation strategy and derivatizations for applications have been particularly summarized in a review.The factors that affect β-CD functionalized monoliths were included in discussion.Accordingly,the conception and originality of this study were put forward.Chapter 2.In order to evaluate the effect of the preparation strategy on the β-CD functionalized monoliths,β-CD functionalized monoliths(poly(GMA-EDA-β-CD-co-EDMA))were prepared through two-step,one-step and one-pot approaches.In the two-step approach,the first step is the preparation of poly(GMA-co-EDMA)monolith with proper pore structure and the second step is the modification with EDA-β-CD on column;For the one-step approach,a polymerizable monomer GMA-EDA-β-CD is copolymerization with EDMA directly to obtain a monolith;In the one-pot approach,monomers GMA and EDA-β-CD with porogens are pre-reacted and EDMA and AIBN are added to the reaction pot to obtain a monolith,which comprises both the synthesis of a polymerizable CD monomer and the copolymerization in one-pot.Physicochemical characterization of the columns,such as determining morphology,β-CD density,permeability and chromatographic efficiency,was carried out and compared.For the enantioseparation ability of each column prepared by different strategy,22 chiral compounds including mandelic acid derivatives,nonsteroidal anti-inflammatory drugs,N-derivatized amino acids,and herbicides were tested comparatively under optimum chromatographic conditions.The column prepared through one-pot approach exhibited higher enantioresolution for most chiral compounds with the good controllability and simple preparation.However,the enantioresolution obtained on the column prepared through one-step approach was quite unsatisfactory.Chapter 3.In order to further investigate the unsatisfactory results of column prepared through one-step strategy,the effect of linking spacers and crosslinkers on column prepared through one-step strategy was studied.Three β-CD functionalized monoliths with different linking spacers were prepared by the one-step copolymerization of EDMA and polymerizable β-CD monomers,i.e.GMA-EDA-β-CD,MAC-EDA-β-CD and PMA-β-CD.After the enantioseparation test for 2-chloro-mandelic acid,better resolution was obtained on poly(GMA-EDA-β-CD-co-EDMA)and poly(MAC-EDA-β-CD-co-EDMA)columns,which had similar linking spacers.For further improvement,GMA-EDA-β-CD and MAC-EDA-β-CD were selected to the crosslinker study of one-step approach.Four β-CD functionalized monoliths with different crosslinkers were prepared by the one-step copolymerization of N,N’-methylenebisacrylamide(MBA)or EDMA and β-CD monomers(GMA-EDA-β-CD and MAC-EDA-β-CD).It was found that a significant improvement of enantioresolution was obtained using MBA instead of EDMA as crosslinker in the one-step preparation.Chapter 4.In order to investigate the preparation via one-step approach for novel β-CD derivative functionalized monoliths,two columns were prepared by the copolymerization of EDMA and two β-CD derivatives(mono-6-methacrylate-per-2,3,6-tris((p-chloro)phenylcarbamoyl)-β-CD and mono-6-propargylmethacrylate-2-O-imidazole-β-CD)via one-step approach for chiral separation and enzyme reaction.After the optimization of preparation conditions,a series of physicochemical characterizations were conducted by scanning electron microscopy(SEM),infrared spectroscopy(IR)and elemental analysis.The assay of enzymatic activity for the enzyme mimics monolith and a test of enantioseparation ability for the chiral monolith were used to investigate the application of β-CD derivative functionalized monoliths.The results indicated that β-CD derivative functionalized monoliths were prepared via one-step approach successfully.Chapter 5.The conclusion of the study on preparation strategies of β-CD functionalized monoliths and the outlook for further studies were presented.