Natural deep eutectic solvents as active systems rather than inert solvents

Natural deep eutectic solvents (NADES) have emerged as promising alternatives to conventional pharmaceutical solvents and excipients. This review critically evaluates whether NADES can be accurately described as inert media within existing drug delivery paradigms. Current pharmaceutical frameworks assume linearity, additivity, and functional independence, yet growing experimental and computational evidence demonstrates that NADES exhibit non-ideal, supramolecular behavior governed by cooperative hydrogen bonding, dynamic microheterogeneity, and composition-dependent interactions. Apparent solubility enhancement in NADES has been experimentally shown to arise from kinetically stabilized supersaturation rather than equilibrium solubility, as time-dependent crystallization studies demonstrate delayed nucleation and prolonged metastable states rather than a shift in thermodynamic equilibrium, challenging equilibrium-based solubility models. Furthermore, small compositional variations, particularly in water content, produce disproportionate changes in physicochemical behavior, undermining reproducibility and predictability. Observed biological effects are frequently confounded by intrinsic component activity and lack clear differentiation between controlled modulation and nonspecific toxicity. To address these limitations, the “Active System Hypothesis” is proposed, positioning NADES as supramolecular systems that regulate local physicochemical environments. This work highlights the need for integrated, mechanism-driven frameworks that link composition, structure, and biological response. Ultimately, redefining NADES as complex, multicomponent systems is essential for developing predictive models, ensuring reproducibility, and enabling their rational translation into pharmaceutical applications.