From Static Patches to Smart Ions: A Computational Perspective on Next-Generation Painless and Efficient Ionic Liquid-Driven Transdermal Drug Design-A Review

Abstract:

Ionic liquids (ILs) are multifunctional materials with tunable physicochemical properties, including adjustable polarity, high thermal stability, low volatility, and excellent solubilization capacity, which make them promising for transdermal drug delivery. ILs can act as conventional permeation enhancers, modulate stratum corneum lipids and proteins, and enhance drug solubility, biomolecular interactions, membrane permeation, and controlled drug delivery. Recent advances have improved understanding of the molecular mechanisms underlying IL-skin interactions and enabled the rational classification of ILs based on their mechanism of action, therapeutic applications, drug compatibility, toxicity profile, and biocompatibility. Computational approaches such as quantitative structure–activity relationship (QSAR) and quantitative structure–property relationship (QSPR) modeling, molecular dynamics simulations, artificial intelligence, and machine learning have further accelerated the rational design and optimization of IL-based formulations. The growing use of ILs in advanced pharmaceutical technologies is further illustrated by emerging applications such as active pharmaceutical ingredient ionic liquids (API-ILs), stabilization of nanoparticles, polymeric ionic liquids, ionogels, smart wearable devices, and responsive drug delivery systems. The molecular mechanisms, classification, computational design strategies, pharmaceutical applications, toxicity and biocompatibility, smart wearable drug delivery systems, regulatory challenges, and future perspectives of IL-based transdermal drug delivery are discussed, and their potential to enable safer, smarter, and clinically translatable therapeutic systems is highlighted.