Non-Covalent PEG Systems Incorporating Quercetin and Silibinin: A Comparative Evaluation of Polymer–Flavonoid Interactions and Physicochemical Characteristics

Flavonoids are widely known for their significant biological activities; however, their poor aqueous solubility limits their practical applications. Recently, non-covalent loading methods using FDA-approved poly(ethylene glycol) (PEG) have been increasingly explored as simpler and more cost-effective alternatives to covalent conjugation strategies. In our previous work, the feasibility of non-covalent PEG–flavonoid systems was demonstrated as a promising approach to address these limitations. In the present study, non-covalent PEG systems having two structurally distinct flavonoids, quercetin and silibinin, were comparatively investigated to evaluate the combined effect of polymer molecular weight and flavonoid structure on physicochemical behavior. The prepared products were analyzed by UV–Vis spectroscopy for flavonoid content determination, along with FTIR spectroscopy to elucidate molecular interactions between PEG and flavonoids, thermogravimetric analysis (TGA), and particle size measurements. Despite the same loading conditions (1:20, w/w), post-washing behavior suggested a dependence on both flavonoid structure and PEG molecular weight. Silibinin-loaded PEG-2k systems exhibited higher flavonoid retention, smaller particle sizes, and improved thermal stability compared to PEG-5k counterparts suggesting relatively stronger non-covalent interactions within shorter PEG chains. In contrast, quercetin-loaded systems displayed similar flavonoid contents and thermal behavior across different PEG molecular weights, suggesting a lower sensitivity to polymer chain length. Overall, these findings demonstrate that non-covalent PEG–flavonoid systems are governed not only by nominal loading ratios but also by molecular structure and polymer architecture, providing a practical framework for the design of PEG-based carriers for poorly water-soluble bioactive compounds.