Interfacial Molecular Interactions as Determinants of Nanostructural Preservation in Ibuprofen-Loaded Nanoemulsions and Nanoemulsion Gels

<b>Background/Objectives</b>: Nanoemulsions (NEs) are highly promising drug delivery systems that can be made user-friendlier by thickening to nanoemulsion gels (NEGs). However, in order to be regulatory accepted, such a transformation requires systematic understanding of the underlying interactions and stabilization mechanisms, especially when the incorporated active pharmaceutical ingredient may infiltrate the stabilizer layer. <b>Methods</b>: NEs with/without ibuprofen were submitted through direct vs. indirect gelation using three different gelling agents (carbomer 980, xanthan gum, or polyacrylate crosspolymer-6). Multi-technique characterization was employed to demonstrate nanoparticle preservation within the gel networks, a point often neglected when studying nanogels. <b>Results</b>: The nanoemulsion with the most favorable properties (55.07 ± 0.82 nm, PDI 0.075 ± 0.022) was successfully transformed into nanoemulgels with all three gelling agents, both by an indirect and direct approach. The combination of Fourier-transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) revealed complex interactions and electron paramagnetic resonance spectroscopy (EPR)-discerned localization of the small-molecule model drug within the surfactants/co-solvents' microenvironment, while atomic force microscopy (AFM) successfully visualized nanodroplets, with or without the presence of aggregates originating from the applied gelling agent. <b>Conclusions</b>: A series of complementary techniques confirmed the preservation of nanodroplets after transformation while highlighting the potential of novel polyacrylate crosspolymer-6 to produce robust gel network while effectively increasing zeta potential from -11.07 to -30.5 mV and allowing for satisfactory ibuprofen release from nanoparticles.