Formation and stabilization mechanism of Ginsenoside Rg3 inclusion complexes based on molecular simulation

The formation of inclusion complexes between Ginsenoside Rg3 and cyclodextrins represents a promising strategy to enhance the solubility of G-Rg3. Nevertheless, the molecular mechanisms underlying the interaction between G-Rg3 and cyclodextrins have yet to be fully elucidated. In this study, we employed a combination of molecular simulation and experimental methodologies to identify the most effective solubilizing carriers among G-Rg3, β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), and 2,6-dimethyl-β-cyclodextrin (DM-β-CD). The inclusion complexes formed with HP-β-CD demonstrates superior stability and water solubility compared to those formed with β-CD and DM-β-CD. The preparation process for the inclusion complexes of G-Rg3 and HP-β-CD was optimized through an orthogonal testing approach. The optimal conditions were determined to be a mass ratio of G-Rg3 to HP-β-CD of 1:125, an inclusion time of 2 h, and an inclusion temperature of 30 °C. The formation of the inclusion complexes was confirmed using DSC, Fourier Transform Infrared FTIR, and XRD techniques. In vitro solubility tests indicated that the solubility of the G-Rg3 inclusion complexes was 2.9 times greater than that of G-Rg3. Molecular dynamics (MD) simulations provided insights into the mechanisms that stabilize the inclusion complexes and enhance their water solubility. The primary interaction force between G-Rg3 and HP-β-CD was identified as the van der Waals force.