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. 2025 Jun 5;13(23):8556-8566.
doi: 10.1021/acssuschemeng.5c00269. eCollection 2025 Jun 16.

Eco-Friendly Solvents for Bioactives: Solubilization of Hydroxycinnamic Acids in Glycerol-Derived Ethers

Sara Gracia-Barberán  1   2 , María Lanau  2 , Alejandro Leal-Duaso  1   2 , Pilar López Ram de Viu  1   2 , Ana M Mainar  3 , José A Mayoral  1   2 , Elísabet Pires  1   2
Affiliations

Eco-Friendly Solvents for Bioactives: Solubilization of Hydroxycinnamic Acids in Glycerol-Derived Ethers

Sara Gracia-Barberán et al. ACS Sustain Chem Eng. .

Abstract

Hydroxycinnamic acids, such as coumaric, ferulic, and caffeic acids, stand out for their pharmacological and cosmetic applications due to their bioactive properties. However, their low solubility in water and conventional solvents can be considered a drawback for their effective utilization. This study investigates the solubility of these acids in renewable glycerol-derived ethers, which exhibit good ecotoxicological profiles and tunable physicochemical properties. Experimental solubility data revealed that monoethers and diethers with shorter alkyl chains significantly enhance the solubility of the studied hydroxycinnamic acids. The findings were further corroborated by COSMO-RS modeling, highlighting the importance of both hydrogen-bond donor capacity and polarity-polarizability in solubility enhancement. Hydrotropic effects of glycerol ethers in water were also experimentally demonstrated, indicating their potential in pharmaceutical and industrial formulations. These results underscore the efficacy of glycerol-derived solvents as sustainable alternatives for solubilizing hydroxycinnamic acids, paving the way for greener and more efficient applications.

Keywords: caffeic; coumaric; ferulic; glycerol ethers; green solvents; hydroxycinnamic acid; solubility.

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Figures

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Chemical structures of hydroxycinnamic acids and glycerol-derived ethers used in this work.
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Solubility (mg mL–1) of coumaric, caffeic, and ferulic acids in glycerol-derived monoethers, EG, and PG.
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Solubility (mg mL–‑1) of coumaric, caffeic, and ferulic acids in glycerol-derived monoethers vs log P (a), α (b), π* (c), and β (d) solvent parameters.
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Solubility (mg mL–1) of coumaric, caffeic, and ferulic acids in glycerol-derived diethers.
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Solubility (mg mL–1) of coumaric, caffeic, and ferulic acids in glycerol-derived diethers vs log P (a), α (b), π* (c), and (d) β solvent parameters.
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Comparison of solubility (mg mL–1) of coumaric, caffeic, and ferulic acids in several methyl ethers.
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σ-Profile for the glycerol derived solvents (a) and hydroxycinnamic acids (b) used in this study (the vertical dashed lines indicate the threshold for hydrogen bond interaction energy and the COSMO-RS cavities of the most stable conformer).
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Comparison of the COSMO-RS solubility predictions and experimental data. (a) Relative screening method and (b) SLE method.
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Effect of glycerol ether (100, 101, and 400) molar fraction on the solubility of (a) coumaric, (b) ferulic, and (c) caffeic acids in aqueous solutions.
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Comparison of the hydrotropic effect on ferulic acid solubilization in glycerol-derived ethers and biobased solvents.
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