Improved Kaempferol Solubility via Heptakis-O-(2-hydroxypropyl)-β-cyclodextrin Complexation: A Combined Spectroscopic and Theoretical Study

Four cyclodextrins (CDs) including heptakis-O-(2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), heptakis-O-(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD) were evaluated for their ability to enhance the aqueous solubility of kaempferol (Kae). Phase solubility studies indicated that these four CDs can form 1:1 type complexes with Kae and that HP-β-CD demonstrated the most significant solubilizing effect on Kae. Among the CDs tested, HP-β-CD demonstrated the most significant solubilizing effect on Kae. With an HP-β-CD concentration of 5.00 × 10^-3 mol·L^-1, the concentration of Kae reached 4.56 × 10^-5 mol·L^-1, which is 12.7 times greater than its solubility in water. Characterization of the HP-β-CD/Kae complex was performed using empirical methods. Molecular docking indicated that the A and C rings of Kae fit into the hydrophobic cavity of HP-β-CD, while the B ring remained at the rim. Six hydrogen bonds were found between HP-β-CD and the -OH groups of Kae. The negative complexation energy (Δ<i>E</i>) suggests the complex formation was exergonic. A 30-ns molecular dynamics simulation revealed no significant structural changes, with average root-mean-square deviation RMSD values of 2.230 Å for HP-β-CD and 0.786 Å for Kae, indicating high stability of the complex.