The search for environmentally benign solvents has become a central task in natural product research, as conventional organic solvents remain problematic for both safety and sustainability. Hydrotropes (HTs) are emerging as an attractive alternative because they can significantly increase the aqueous solubility of poorly soluble compounds. This study explored the use of aqueous HT solutions for alkaloid recovery, exemplified by the case of Coptis chinensis. Initial screening highlighted sodium salicylate (SS) as a particularly effective solvent, affording higher yields of coptisine, palmatine, berberine, and total alkaloids than conventional or other green solvents. Through response surface methodology, the optimum conditions were identified (46.4% SS, liquid–solid ratio 26.7 mL/g, 21.8 min, 60 °C), under which the yields of coptisine, palmatine, berberine, and total alkaloids reached 1.85%, 1.39%, 8.97%, and 15.57%, respectively. Mechanistic analyses, combining electrostatic potential mapping, interaction region indicator plots, and molecular dynamics simulations, revealed that the strong performance of SS stems from cooperative anion–Cδ+ electrostatic interactions together with dispersion forces and weak hydrogen bonding. The extraction followed a second-order kinetic model (Ea = 26.14 kJ/mol), suggesting contributions from both dissolution and diffusion. Importantly, alkaloids were efficiently recovered with macroporous resins (best with HPD-400), and both SS and the resins could be reused for at least five cycles with negligible efficiency loss. Sustainability was further quantitatively assessed using the AGREEprep metric. Taken together, these findings establish aqueous SS as a practical, reusable, and environmentally responsible solvent system for sustainable alkaloid extraction, with mechanistic validation demonstrated for berberine.
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