Impact of Drug Hydrophilicity on Transdermal Delivery by Nanoemulsions

<b>Background/Objectives:</b> Nanoemulsions (NEs) are a promising platform for transdermal drug delivery (TDD); however, how the polarity of the active pharmaceutical ingredient (API) influences NE structure-performance relationships remains insufficiently understood. This study aimed to systematically compare the transdermal delivery behavior of a hydrophilic API, salbutamol hemisulphate (log <i>P</i> ≈ 0.1), and a lipophilic API, ibuprofen (log <i>P</i> ≈ 3.3), incorporated into compositionally matched nanoemulsion systems. <b>Methods:</b> Kolliphor EL-based NEs were prepared using identical excipients, with systematic variation of oil, surfactant, and water ratios. Thirty-six formulations were produced for each API. Physical stability, droplet size, and viscosity were characterized, and in vitro skin permeation studies were conducted using excised mouse skin. Flux and cumulative permeation were quantified, and statistical analyses were performed to identify key compositional drivers of permeation. <b>Results:</b> Ibuprofen-containing NEs exhibited superior physical stability compared to salbutamol formulations, likely due to interfacial interactions that imparted surfactant-like behavior. Both APIs formed nanoscale droplets, with salbutamol formulations ranging from 16 to 507 nm and ibuprofen formulations spanning 12-563 nm, more frequently yielding sub-100 nm droplets. Viscosity values covered broad ranges (3-9532 mPa·s for salbutamol; 13.4-9759 mPa·s for ibuprofen), with salbutamol generating an extended high-viscosity domain at 50% (<i>w</i>/<i>w</i>) surfactant and ibuprofen showing a narrower viscosity maximum at 30-40% surfactant. Salbutamol NEs achieved high fluxes (up to 374 µg/cm²·h) and cumulative permeation of approximately 80% of the applied dose, whereas ibuprofen formulations showed markedly lower fluxes (maximum 32 µg/cm²·h) and cumulative permeation below 6%. High surfactant levels suppressed permeation for both APIs, but the dominant positive drivers differed: balanced oil-water ratios for salbutamol and hydration-dependent diffusional resistance for ibuprofen. <b>Conclusions:</b> These findings demonstrate that API polarity and interfacial portioning behavior decisively govern NE performance, providing a framework for rational tailoring of oil-surfactant-water ratios to maximize transdermal delivery efficiency.