Deep Eutectic Solvents in Pharmaceutical Drug Delivery: Structure–Property Relationships, Mechanistic and Computational Insights, and Translational Challenges

Abstract

Volatile organic solvents remain central to pharmaceutical extraction and formulation despite well-documented toxicity, flammability, and regulatory limits on residual-solvent content. Deep eutectic solvents (DESs)   liquid systems formed when a hydrogen-bond acceptor (HBA) and a hydrogen-bond donor (HBD) combine to produce a eutectic mixture with a melting point far below that of either parent component have emerged as tunable, low-cost, and often biodegradable alternatives with growing relevance to drug delivery. This review synthesises current knowledge on DES classification (Types I–V), natural, therapeutic and hydrophobic subclasses, structural hydrogen-bonding chemistry, and the six principal preparation routes (hot-melt extrusion, conventional heating, vacuum evaporation, grinding, freeze-drying, and ultrasound-/microwave-assisted synthesis). Fourteen representative DES systems are examined in terms of structure–property relationships, and the density, viscosity, polarity, and surface-tension behaviours of DESs are related to their hydrogen-bonding architecture. The review evaluates DES integration into polymeric drug carriers (hydrogels, nanoparticles, electrospun fibres, films, and scaffolds), oral bioavailability enhancement for Biopharmaceutics Classification System (BCS) Class II/IV drugs, and self-assembled DES-based nanomicelles for transdermal delivery. Mechanistic contributions membrane fluidisation, polymer plasticisation, supersaturation maintenance, mucoadhesion, and nanocarrier stabilisation   are discussed alongside computational approaches (molecular dynamics, density functional theory, and COSMO-RS) that rationalise these effects. DES- and THEDES-based platforms offer a compositionally flexible, often GRAS-compatible strategy for solubility and permeability enhancement, but translation is constrained by unpredictable DES–polymer interactions, regulatory ambiguity around eutectic mixtures as novel excipients, and a scarcity of in vivo pharmacokinetic and long-term toxicological data. Closing these gaps through standardised characterisation, computational screening, and harmonised regulatory frameworks will be essential for clinical translation.