Emerging green organic solvents for reversed-phase liquid chromatography: Sustainable alternatives to traditional mobile phases

Reversed-phase liquid chromatography (RPLC) is the most widely used analytical technique for pharmaceutical, environmental, and bioanalytical determinations, yet its dependence on toxic and fossil-derived solvents such as acetonitrile and methanol presents environmental and safety concerns. This review critically evaluates viable green organic solvent substitutes for RPLC, with particular emphasis on the similarity of their solvation properties to those of traditional solvents. Chromatographic performance, physicochemical properties, and sustainability aspects are also reviewed and compared. Green RPLC solvents were compiled and analyzed using parameters such as elution strength, viscosity, polarity, UV cut-off, retention behavior, and solvatochromic and solubility parameters. This review critically evaluates viable green organic solvent substitutes for RPLC, with particular emphasis on the similarity of their solvation properties to those of traditional solvents. Chromatographic performance, physicochemical properties, and sustainability aspects are also reviewed and compared. Green RPLC solvents were compiled and analyzed using parameters such as elution strength, viscosity, polarity, UV cut-off, retention behavior, and solvatochromic and solubility parameters. Solvents were categorized as alcohols (ethanol and isopropanol), alkanones (acetone and Cyrene), esters (ethyl lactate, ethyl acetate, and methyl acetate), carbonates (dimethyl carbonate and propylene carbonate), and polyols (glycerol). Greenness was quantified through the GSK and CHEM21 Solvent Sustainability Guides. Results show that several bio-based and low-toxicity solvents provide chromatographic selectivity and efficiency comparable to acetonitrile and methanol while reducing environmental hazard scores. The similarity of the compiled green solvents to the traditional ones was assessed by the Snyder–Carr–Rutan solvatochromic triangle, Principal Component Analysis (PCA) and d -distance metric of their main solvation properties. Overall, this review confirms that multiple renewable solvents can feasibly replace conventional organic modifiers in RPLC without compromising analytical performance, supporting the transition toward sustainable and low-impact chromatographic science aligned with Green Analytical Chemistry principles.