Incorporation of Molecular Complexation into Novel Etodolac Hydrogels: A Strategy for Dramatic Enhancement of Drug Release

Driven by advances in gel research, pharmaceutical small-molecule hydrogels are gaining significant attention as drug delivery systems. This study explored the viability of designing small-molecule hydrogels as a solubilization approach, using the poorly water-soluble etodolac (ETO) as a model compound. The novel ETO hydrogels were yielded by simple mixing of ETO with biocompatible small-molecule ligands in minimal deionized water. These hydrogels displayed characteristic three-dimensional network structures with pronounced viscoelastic properties. Through comprehensive characterization and molecular simulation analyses, it was demonstrated that hydrogel formation was dependent on three crucial factors: favorable miscibility between ETO and ligands, a dynamic equilibrium between dissolution and aggregation, as well as self-assembly processes fueled by intermolecular interactions in the aqueous phase. Remarkably, the solubility of ETO within these hydrogels exceeded that of pure ETO by over 16-fold. Furthermore, the novel ETO hydrogels demonstrated enhanced release kinetics and supersaturation maintenance capacity, achieving rapid peak concentrations followed by sustained supersaturated release owing to amorphization and molecular complexation. These beneficial characteristics arose from the inherent high-energy state of the hydrogels, as well as the complexation interaction between ETO and the ligand throughout the release process. Overall, this study validated the rational design of small-molecule hydrogel systems as an effective formulation approach to overcome the poor aqueous solubility of challenging ingredients.