A Four-Layer Numerical Model for Transdermal Drug Delivery: Parameter Optimization and Experimental Validation Using a Franz Diffusion Cell

<b>Background/Objectives:</b> A mechanistic understanding of transdermal drug delivery relies on accurately capturing the layered structure and barrier function of the skin. This study presents a four-layer numerical model that explicitly includes the donor compartment, stratum corneum (SC), viable skin (RS), and receptor compartment. <b>Methods:</b> The model is based on Fickian diffusion and incorporates interfacial partitioning and mass transfer resistance. It is implemented using the finite element method in MATLAB and calibrated through nonlinear least-squares optimization against experimental data from Franz diffusion cell studies using porcine skin. Validation was performed using receptor concentration profiles over time and final drug content in the SC and RS layers, assessed via tape stripping and residual skin analysis. <b>Results:</b> The model provided excellent agreement with experimental data. For diclofenac, the optimized partition coefficient at the SC-RS interface was close to unity, indicating minimal interfacial discontinuity and that a simplified three-layer model may be sufficient for this compound. <b>Conclusions:</b> The proposed four-layer framework provides a physiologically informed and generalizable platform for simulating transdermal drug delivery. It enables spatial resolution, mechanistic interpretation, and flexible adaptation to other drugs and formulations, particularly those with significant interfacial effects or limited lipophilicity.