Understanding drug diffusion and permeation in transdermal patches: A kinetic perspective

Transdermal drug delivery (TDD) offers a non-invasive method for systemic medication, bypassing first-pass metabolism and allowing controlled release. Transdermal patches (TPs) are among the most common TDD systems, with performance influenced by drug properties, skin physiology, polymer matrices, adhesives, permeation enhancers, and patch design. Different TP architectures including reservoir, matrix, adhesive-dispersion, and micro-reservoir systems, have unique release and permeation features. The stratum corneum remains the main barrier to drug transport, significantly affecting transdermal flux, lag time, and bioavailability. This review systematically examines the mathematical, kinetic, and dermatokinetic models used to describe drug release, skin permeation, and systemic absorption from TPs. Classical models, including zero-order, first-order, Higuchi, Korsmeyer-Peppas, Peppas-Sahlin, Weibull, Gompertz, Hixson-Crowell, Baker-Lonsdale, and Hopfenberg, are critically analyzed for their mechanistic basis and relevance. It distinguishes intrinsic drug release from skin permeation processes and highlights advances in reaction-diffusion modeling, physiologically based pharmacokinetic (PBPK) modeling, and in vitro-in vivo correlation (IVIVC). Emerging computational techniques like molecular docking, molecular dynamics, artificial intelligence, and machine learning are also explored to optimize transdermal formulation design and predict drug transport behaviors.