A virtual factory for topical formulations based on molecular modeling and drug-polymer interaction studies

Topical drug delivery offers a cost-effective and non-invasive alternative to systemic drug administration but faces challenges due to the skin's barrier properties and the complex rheology of semisolid formulations. This necessitates a deeper understanding of the interplay between formulation components and their impact on drug release and therapeutic efficacy. Emulsifying two-component polymer system, supplied as ready-to-use liquid dispersions of oil and surfactant, is increasingly used to simplify manufacturing processes. However, their interaction with active pharmaceutical ingredients (APIs) can unpredictably alter formulation properties. This study investigates how the model APIs (bupivacaine, lidocaine, and atenolol) influence key formulation properties, such as rheology, drug release, and manufacturing efficiency. A systematic, dose-dependent reduction in viscosity was observed with increasing API concentration, an effect attributed to the disruption of the polymer network via electrostatic interactions. This effect remained consistent across different amine classes and was successfully fitted using an exponential function. While formulation pH did not significantly affect viscosity, lower pH values accelerated drug release, highlighting the interplay between gel microstructure, drug-polymer interactions, and release kinetics within this polymer system. Molecular modeling revealed preferential localization of ionized APIs at the polymer-oil interface, while unionized APIs adsorbed onto the oil surface. Detachment force simulations further quantified these interactions. Ex-vivo skin permeation studies confirmed the influence of viscosity on drug permeation, with lower viscosity gels exhibiting faster permeation rates. Finally, in a novel molecule-to-manufacturing approach, these multi-scale insights were integrated into a "Virtual Factory" model. This model successfully predicted the impact of API concentration on manufacturing parameters, offering a valuable tool to optimize equipment selection, process parameters, and energy consumption. This work provides a comprehensive framework for the rational design of topical systems, connecting molecular interactions to final manufacturing outcomes.