In silico prediction of the formation, solubilization, and stabilization of a cyclodextrin-based ternary complex of ivermectin using long-timescale molecular dynamics simulations

Ivermectin (IVM) is one of the currently available drugs for controlling Haemonchus contortus , but its poor aqueous solubility severely limits its potential for mass prophylaxis via drinking-water administration. In this study, the cyclodextrin-based ternary supramolecular system—composed of IVM, sulfobutylether-β-cyclodextrin (SBE-β-CD), and sodium dodecyl sulfate (SDS)—was constructed to enhance its solubility and stability. This ternary inclusion complex increased IVM solubility by ~3506-fold, with an entrapment efficiency of 44.69 ± 0.64 % and a drug loading of 43.60 ± 1.67 %, while maintaining a mean particle diameter of 20.20 ± 0.39 nm (polydispersity index [PDI] = 0.17 ± 0.06). Long-timescale molecular dynamics (MD) simulations revealed that the ternary supramolecular system self-assembled into stable nanoparticles within 200 ns. The negative binding free energy (ΔG bind ) values among all three components indicated that the self-assembly process of the ternary inclusion system was thermodynamically spontaneous. Hydrogen bond analysis further identified SBE-β-CD as the core of the ternary complex, with SDS acting as a molecular bridge; together, these two components enhanced the stability and solubility of the nanoparticles. In conclusion, long-timescale MD simulations elucidated self-assembly, stabilization, and solubilization mechanisms of the cyclodextrin-based ternary complex, offering a strategy to enhance the solubility and stability of macrolide drugs.