Interfacial architecture and stability of pharmaceutical nanoemulsions: From molecular organization to predictive design frameworks.

Pharmaceutical nanoemulsions are thermodynamically metastable colloidal dispersions whose physical integrity during storage depends on the continuous suppression of flocculation, coalescence, Ostwald ripening, creaming, and phase separation. These destabilization pathways are governed by interfacial phenomena whose molecular-level determinants remain incompletely understood. This review provides a point-to-point mechanistic perspective that connects molecular organization at curved oil-water interfaces to macroscopic stability behavior and predictive formulation design, organized around four themes. First, we examine the interfacial thermodynamic and kinetic foundations, Gibbs-Marangoni restoration, dynamic adsorption-desorption equilibration, molecular packing at nanoscale curvature, and interfacial rheology under shear and dilatational deformation, which determine the mechanical and electrostatic resistance of the stabilizing film. Second, we analyze colloidal interactions beyond the classical DLVO framework, with particular emphasis on hydration, structural, hydrophobic, Asakura-Oosawa depletion, undulation, and bridging forces that dominate droplet behavior at nanometric separations, complementing the Lifshitz-Slyozov-Wagner molecular-transport description of Ostwald ripening. Third, we critically evaluate formulation-driven interfacial modulation: surfactant architecture and concentration, oil-phase composition, ionic environment, excipient selection, and uniquely, the active pharmaceutical ingredient itself as an interfacial participant whose lipophilicity, ionization state, and amphiphilic balance reshape the film it is meant to be carried by. Fourth, we consolidate emerging predictive approaches, interaction-energy profiling, machine-learning-assisted stability modeling, and Stability-by-Design frameworks, as actionable tools for forecasting long-term physical integrity and guiding rational nanoemulsion development. By integrating molecular-level mechanistic understanding with colloidal-scale interaction theory and data-driven prediction, this review establishes a foundation for the design of physically robust pharmaceutical nanoemulsions with predictable shelf-life performance and engineered interfacial architecture.