Hydrophobic Terpene-Based Eutectic Solvents: Stability, Selectivity, Cytotoxicity, and Sustainable Extraction

Abstract Hydrophobic eutectic solvents (ESs) based on terpenes were systematically investigated to establish structure–property–stability–toxicity relationships across fifteen binary systems (limonene, menthol, thymol, linalool, carvone, camphor, and borneol). ESs span viscosities of 1.5–47.9 mPa·s and densities of 856–973 kg·m–3 at 20 °C. Water-contact experiments reveal two stability regimes: limonene-containing systems exhibit exceptional water resistance (<250 ppm uptake), while phenolic/rigid alcohol donors undergo extensive hydration (>1000 ppm) with component partitioning. FTIR and GC–MS confirm hydrogen-bond reorganization rather than chemical degradation upon aqueous exposure. In vitro cytotoxicity on MDA-MB-231 and H1299 cells reveals a wide activity spectrum: limonene:menthol and linalool:menthol show high cytotoxicity (IC50 < 0.004%), while limonene:carvone—selected as the optimal extraction solvent—shows significantly lower toxicity (IC50 = 0.7999%). Using limonene:carvone for extraction of phenolic compounds from Pinus sylvestris buds, efficiency correlates with solute log P (Spearman's ρ = 0.82, p = 0.007) and specific molecular interactions, achieving 31% higher total phenolic recovery vs water alone. This integrated framework enables design of terpene-based ES with predictable stability, performance, and safety for sustainable separations.