Naturally Derived Versus Synthetic Salicylic Acid: Physicochemical Properties, Transdermal Permeation and Macrophage...

Salicylic acid is widely used in dermatological and cosmetic formulations, yet the influence of its production route on solid-state structure and biological behaviour remains underexplored. This study compares a naturally derived salicylic acid (NSA), obtained from wintergreen oil through green chemistry, with a synthetic form (SSA) produced via the Kolbe-Schmitt reaction, integrating physicochemical characterization with antioxidant and immunomodulatory profiling. Crystal morphology, crystallinity (XRD, FTIR), melting point, solubility, dissolution and Franz-cell skin permeation were determined, alongside intrinsic radical scavenging (DPPH), intracellular reactive oxygen species (DCFH-DA), cytoprotection (MTT), CD9⁺ extracellular-vesicle (EV) release and cytokine transcription in RAW 264.7 macrophages. SSA formed uniform, needle-like crystals of higher crystallinity, comparable equilibrium solubility (2.239 vs. 2.115 mg/mL; not significant) and faster dissolution, whereas the less-ordered NSA showed a numerically higher steady-state flux (39.94 ± 16.43 µg cm^-2 h^-1) and a shorter lag time (2.47 ± 1.71 h). SSA was the stronger radical scavenger (DPPH 20.7% vs. 8.7%) and reduced intracellular ROS more effectively, while NSA afforded greater cytoprotection. Both forms were associated with a lower CD9⁺ EV concentration in the conditioned medium following LPS stimulation, with SSA consistently more active across radical scavenging, ROS and vesicle endpoints. These findings show that the synthesis route, through its effect on solid-state properties, influences the physical performance, while the biological behaviour is discussed separately from the anti-inflammatory behaviour of salicylic acid, informing the rational selection of natural versus synthetic material for topical applications.