Mechanistic Study Of Solubilizing Small-molecule Compounds By Cyclodextrins

Cyclodextrins are natural cyclic oligosaccharides,which can be directly used as solubilizers for drugs because of its non-toxic and degradable properties.Cyclodextrins have structural characteristics "hydrophobic inner cavity and hydrophilic outer parts",which makes it oftenly adopted as solubilizers for insoluble drugs.Plant pigments belong to one kind of well-known natural compounds.Normally,plant pigments have anti-cancer,antibacterial,antiviral and anti-oxidant properties,which makes them widely used in clinical practice as medicine,dyes and health food.Because plant pigments are generally insoluble in water,poorly dispersed in aqueous solutions,bioavailability of direct oral administration is very low.So it is an important issue to explore methods for increasing solubility of plant pigments.Compared with all avaiable methods,cyclodextrin encapsulation solubilization with high solubility and stability is the most applicapable and widely used method.In this dissertation,five kinds of cyclodextrins including 2,6-dimethyl-?-cyclodextrin(DM-?-CD),6 glucosyl-?-cyclodextrin(6Glu-?-CD),2-hydroxypropyl-?-cyclodextrin(2HP-?-CD),?-cyclodextrin(?-CD)and ?-cyclodextrin(?-CD)are used as solubilizers.Five plant pigments including luteolin(Lut),nobiletin(Nob),myricetin(Myr),kaempferol(Kae),curcumin(Cur),and 5-methyl-7-methoxy isoflavone(5MIF),a drug intermediate,are adopted as insoluble targets.UV-Vis spectroscopy was first used to confirm that all the five cyclodextrins had certain solubilizing effect on the above five plant pigments,Among all cyclodextrins,DM-?-CD has the best solubilizing effect on luteolin,nobiletin and 5-methyl-7-methoxy isoflavone,where as 2HP-?-CD has the most obvious solubilizing effect on myricetin,kaempferol and curcumin.According to the classification of Higuchi and Connors' theory,it can be seen that cyclodextrin contributes to solubility by forming a 1:1 host-guest complexes with these natural plant pigment compounds.Infrared spectroscopy,X-ray powder diffraction,and thermogravimetric analysis were used to verify the formation of complexes between cyclodextrins and natural plant pigment compounds.This work uses PM6-D3H4,PM6-DH+,and PM7 force fields to perform thermodynamic calculation and analysis of the binding energy of formed complexes.The results show that the formation of the above-mentioned host-guest complexes are spontaneous processes with free energy less than zero,small molecule compounds actively enter the cavities of cyclodextrins.In this study,it can be determined that the stable 1:1 type complex can be formed during the solubilization process of cyclodextrins to luteolin,nobiletin,myricetin,kaempferol,curcumin and 5-methyl-7-methoxy isoflavone.