The extraction and purification of high-value phytosterol compounds from plant-derived feedstocks remains an important challenge in the fields of nutraceuticals, functional foods, and pharmaceutical applications. Conventional solvent-based extraction methods often rely on volatile, toxic, petroleum-derived solvents that raise sustainability concerns. Conventional solvent-based extraction methods often rely on volatile, toxic, petroleum-derived solvents such as n-hexane, ethanol, petroleum ether, or dichloromethane, which are considered volatile organic compounds (VOCs) and raise sustainability concerns. Natural Deep Eutectic Solvents (NADES) have emerged as alternative and promising green solvents for the selective recovery of phytosterols. In this work, we employ COSMO-RS (COnductor-like Screening MOdel for Real Solvents) modelling to systematically design and screen a large library of NADES formulations, with natural compounds as components, for the efficient extraction from vegetable sources of 19 typically occurring phytosterols. The COSMO-RS methodology allows the simulation of each NADES property, including their melting point and composition. It also calculates the activity coefficients with the phytosterols that will be used to rule out unsuitable combinations and evaluates toxicological parameters to assess their safety. After conducting nearly 2000 solubility tests, NADES demonstrated 1.5 to 5 times higher extractive capacity than common solvents for all phytosterols, with significantly lower volatilities. Finally, the use of NADES, especially the carvacrol-menthol mixture, significantly improves the extraction of phytosterols compared to conventional solvents, offering a more efficient, safe, and sustainable alternative, capable of dissolving a wide range of phytosterols.
