Unveiling the structure-function relationship of natural deep eutectic solvents in enhancing the solubility, stability, and antioxidant activity of baicalein

Baicalein (Bai), a flavonoid with multiple pharmacological effects, suffers from poor solubility and low stability, limiting its therapeutic application. To overcome these limitations, biocompatible solvents with high solvation capacity present a simple and efficient strategy. In this work, three natural deep eutectic solvents (NADES) were prepared from choline chloride (ChCl) and structurally comparable organic acids: levulinic acid (LevA), lactic acid (LacA), and malic acid (MalA). These NADES exhibited good biocompatibility and were mixed with water to improve the solubility and stability of Bai. The solubility enhancement of Bai in these solvents followed the order: ChCl-LevA > ChCl-LacA > ChCl-MalA > water. Thermodynamic analysis revealed an entropy-driven dissolution process. To delve deeper into the dissolution mechanism, density measurements, FTIR spectroscopy, and molecular dynamics simulations were conducted to elucidate solvent-solvent and solute-solvent interactions. Additionally, the storage stability, photostability, and pH stability of Bai in NADES were also investigated. The results indicated that the differences in intermolecular interactions caused by different NADES exerted varying effects on the stability of Bai. The DPPH free radical scavenging assay was used to investigate the synergistic or antagonistic antioxidant effects between Bai and NADES, with the data analyzed by response surface methodology. These results are expected to provide a theoretical basis for the development of NADES-based solubilizers or drug carriers in pharmaceutical and food science.