Role of saturation dynamics in driving skin permeation from topical gel formulations

The thermodynamic activity of an active pharmaceutical ingredient (API) is a key driver of permeation performance in topical formulations. This study investigated how solvent composition and evaporation impact the degree of saturation (DS) and skin permeation of three representative APIs: diclofenac sodium, metronidazole, and lidocaine. Model hydroxyethyl cellulose gels containing 1%, 10%, or 20% w/w Polyethylene Glycol (PEG-200) were prepared and characterized for solubility, pH, viscosity, and drying behavior. The solubility of all APIs increased with increasing PEG-200 concentration, whereas the DS varied correspondingly at a given drug load. Polystyrene substrate drying studies demonstrated that higher PEG-200 levels slowed solvent loss. The in situ drying studies on human cadaver skin using Franz cells enabled dynamic tracking of PEG-200 content and API saturation. Diclofenac sodium and lidocaine gels formulated with 1% PEG-200 showed progressively increasing DS over time and correspondingly higher permeation fluxes in in vitro permeation studies. In contrast, metronidazole gels showed little discrimination in DS and flux across PEG-200 concentrations, consistent with their hydrophilic nature and distinct solubility dynamics. The cumulative absorption confirmed a strong concordance between DS and permeation for diclofenac sodium and lidocaine, but not for metronidazole. Overall, the findings highlight that thermodynamic activity, modulated by solvent evaporation and shifts in solubility, governs the performance of topical formulations. These results underscore the value of monitoring DS profiles as predictive markers of drug delivery efficiency in topical product design.