From molecular clusters to phase separation: A unified framework for predicting aqueous miscibility

Miscibility in water-rich mixtures—ranging from homogeneous molecular solutions to mesoscale heterogeneity, emulsions, and macroscopic phase separation—governs biological, geological, environmental, and industrial processes. This review presents a unified framework linking molecular interactions, solvent restructuring, mesoscale organization, and thermodynamic nonideality to predict aqueous miscibility and demixing behavior. We describe how preferential solvation and competitive hydrogen bonding drive the emergence of correlated concentration fluctuations prior to macroscopic phase separation. In particular, additives can promote solvent–water demixing either by competing for water through solvent-like hydrogen-bonding motifs or by preferentially interacting with the solvent through water-like motifs. Small-angle neutron and X-ray scattering (SANS/USANS/SAXS/USAXS) reveal the growth of mesoscale heterogeneity through changes in low- scattering intensity, correlation length, fractal character, and dispersity, providing early structural signatures of immiscibility. Complementary Fourier-transform infrared spectroscopy (FTIR) resolves the redistribution of water hydrogen-bonding populations through deconvolution of the OH stretching region, while sigma profiles and activity coefficients derived from the COnductor-like Screening MOdel for Realistic Solvation (COSMO-RS), complemented by atomistic simulations, quantify the underlying interaction strengths and thermodynamic driving forces. Together, these complementary experimental and theoretical approaches establish a coherent multiscale framework for predicting, interpreting, and tuning miscibility and phase behavior in complex aqueous fluids.