In terms of solubilization effect, it was found that phase solubility of RDV increased significantly from intrinsic 1.7 mmol/L at 25 oC to 60 mmol/L at 37 oC in pH = 1.5 solution with increase of SBE-β-CD concentration from 0 to 185 mM. The solubilization could reach equilibrium in as quick as 3 h incubation time. Thermodynamically, the solubilization of RDV in SBE-β-CD is a spontaneous clathration process with negative Gibbs free energy ΔG driving the process toward more stable complexation with increased entropy ΔS. Accurate pKa calculations helped decide the appropriate protonation states at different pH conditions. Specific conformations at corresponding pH conditions were used in the subsequent calculations to correlate with drug loading pH dependence and stabilization of the drug solubility supersaturation.
The computational explorations (quantum mechanics (QM), molecular docking and molecular dynamics (MD) calculations) conformed to the experimentally determined phase solubilization and well elucidated the mechanism of macroscopic clathration between RDV and SBE-β-CD from the perspective of microscopic molecular calculations.