Mechanistic Insights into Membrane- and Release-Controlled Drug Permeation from Ketoprofen-Lidocaine Eutectic Fluids

Eutectic fluids (EFs) are liquid pharmaceutical systems formed through intermolecular interactions between their components. This study aims to clarify the mechanistic basis of membrane- and release-controlled drug permeation from the ketoprofen-lidocaine (KP-LD) EFs by characterizing their physicochemical properties and molecular interactions.

Two types of liquid EFs were prepared by mixing and heating KP with LD. The prepared EFs were characterized using thermodynamic, rheological, and NMR-based analyses to obtain parameters related to phase behavior, viscosity, molecular dynamics, and molecular diffusion. Silicone membrane permeation behavior was evaluated to elucidate how these physicochemical properties influence membrane‑controlled and release‑controlled drug permeation.

Differential scanning calorimetry indicated the absence of detectable crystallinity, and the mixtures appeared to form a homogeneous liquid phase. Rheological analysis revealed a Newtonian flow behavior, and the viscosity of EF_A (KP:LD = 1:1) was markedly lower than that of EF_B (KP:LD = 2:1). Permeation studies showed KP permeation was membrane-controlled, whereas LD permeation was release-controlled within the EFs, allowing for the calculation of its diffusion coefficient. Analyses of ¹H-¹H NOESY and DOSY suggested close spatial proximity and weak intermolecular interactions, indicating cooperative molecular dynamics between KP and LD.

EFs examined in this study can accommodate a high drug content and function as reservoirs of active pharmaceutical ingredients. In particular, EF_A exhibited unique physicochemical and permeation properties that are not observed in aqueous solutions or conventional formulations, suggesting its potential as a novel EF system for transdermal drug delivery.