Abstract: OBJECTIVE To research solubility enhancement of luteolin(Lut) by 5 cyclodextrin and to investigate solubility enhancement mechanism of cyclodextrin on insoluble drugs. METHODS The technique of phase solubility was adopted to compare solubility enhancement effect of Lut by β-cyclodextrin(β-CD), γ-cyclodextrin, heptakis-(2-hydroxypropyl)-β- cyclodextrin, heptakis-(2,6-dimethyl)-β-cyclodextrin(DM-β-CD) and 6-glucosyl-β-cyclodextrin. Fourier transform infrared spectroscopy(FT-IR) and X-ray diffraction(XRD) were used to characterize the complex formed by DM-β-CD and Lut. Molecular docking and molecular dynamics simulation were applied to speculate the structure of complex. RESULTS The result of phase solubility experimentalindicated DM-β-CD had the maximum solubility enhancement effect to Lut among the above five cyclodextrins. When the concentration of DM-β-CD reached 2.5×10^-3 mol·L^-1, the solubility of Lut was 1.56×10^-4 mol·L^-1, which was 6.37 times higher than it in pure water. The structure of DM-β-CD/Lut complex was characterized by FT-IR and XRD. The results showed that there existed week intermolecular interaction between DM-β-CD and Lut in the complex. The result of molecular docking indicated the ring A and C of Lut were complexed in the hydrophobic cavity of DM-β-CD, and the ring B was located at the larger rim of the cyclodextrin. There were several hydrogen bonding interactions between the host and the guest. The result of molecular dynamics simulationshowedthestructure was stable in 5 ns and no large structural deformation was observed. The root mean square deviation changed of the host and the guest were 2.632 0 and 0.475 4 Å, respectively. CONCLUSION DM-β-CD can effectively enchance the aquous solubility of Lut and the enhancement mechamism is due to the formation non-covalent complex between DM-β-CD and Lut.