Rational Selection of Bio-Ionic Liquids for Zeaxanthin Solubilization: Computational Prediction to Biocompatibility Assessment

Zeaxanthin, a potent antioxidant, is recognized for its benefits in promoting skin health, enhancing cognitive function, preventing cancer, supporting cardiovascular health, and mitigating age-related macular degeneration. However, its poor aqueous solubility and preferential dissolution in organic solvents raise concerns about toxicity and environmental compatibility, posing significant challenges for formulating zeaxanthin with suitable solvents or excipients for safe and effective use. Biocompatible ionic liquids (bio-ILs), derived from renewable natural sources such as plants, animals, and microorganisms, have emerged as promising environmentally friendly alternatives to conventional solvents, offering biodegradability and low toxicity, making them suitable for pharmaceutical and cosmetic applications. Nevertheless, the vast chemical diversity of bio-ILs necessitates a rational selection strategy to identify optimal candidates for zeaxanthin solubilization. In this study, a computational screening approach using the Conductor-like Screening Model for Real Solvents (COSMO-RS) was employed to evaluate the solubility of zeaxanthin in 825 bio-ILs. Seven choline-based bio-ILs were shortlisted based on predicted solubility, alkyl-chain diversity, and functional group characteristics. These bio-ILs were synthesized and structurally validated via 1 H NMR and FT-IR spectroscopy. COSMO-RS calculations were employed to predict zeaxanthin solubility in bio-ILs using both electroneutral cation–anion (C+A) and coordinated cation–anion (CA) approaches. The predictive models were validated by direct comparison with experimentally measured solubilities of the seven bio-ILs, with the CA approach showing superior agreement (R 2 = 0.543). Biocompatibility was assessed using the Hs27 fibroblast cell line via the MTT assay, while biodegradability and antimicrobial properties were evaluated according to OECD 301D and CLSI M02-A13 protocols, respectively. Among the tested bio-ILs, choline cation paired with glycine and hexanoate anions exhibited superior zeaxanthin solubility, minimal cytotoxicity, and high biodegradability. These findings highlight the potential of bio-ILs as safe, environmentally compatible excipients for zeaxanthin, paving the way for their use in topical and transdermal therapeutic systems.