In situ phase transition to a hydrated ionic liquid-like state: a new application strategy for enhancing topical delivery of potassium 4-methoxysalicylate

Hyperpigmented lesions and uneven skin tone are cosmetic concerns caused by excessive melanin deposition. Potassium 4-methoxysalicylate (4MSK) is a widely used active agent for inhibiting melanogenesis; however, its efficacy is constrained by poor skin penetration due to its ionic, highly hydrophilic nature and crystallization on the skin. Ionic liquids (ILs) can suppress crystallization and enhance skin penetration, yet their practical application is limited by high viscosity, poor spreadability, and concerns regarding skin tolerability. Here, we developed an in situ strategy for IL-like amorphous phase formation that overcomes these barriers by decoupling formulation processability from delivery performance. This approach utilizes aqueous mixtures of acidic and basic precursors that undergo counterion exchange as water evaporates, generating an IL phase directly on the skin. Screening of 4-methoxysalicylic acid (4MS) with amino acids identified arginine (Arg) as an effective counterion, yielding a stable IL, [Arg][4MS], with glass transition behavior and reduced crystallinity. Importantly, a formulation-relevant precursor pair-4MSK and arginine hydrochloride-undergoes the same molecular conversion during drying, reproducing the IL-like state without pre-synthesized ILs. This phase transition markedly enhanced skin penetration, increasing human skin permeation to 237% of control and enabling deeper penetration into viable epidermal layers. In a reconstructed human epidermis model, treatment reduced melanin content by 33% without compromising tissue viability. These findings establish in situ IL formation as a viable strategy to combine formulation compatibility with high-performance skin penetration of hydrophilic actives.