Control of site-specific deprotonation through mechanochemical interconversion of two ionic cocrystal forms of resveratrol

Abstract

In drug development, multicomponent pharmaceutical materials have become useful tools for improving the properties and efficacy of a drug. In addition to the active drug, inclusion of a second component in the solid can provide stabilization or increase solubility of the pharmaceutical. Resveratrol, an antioxidant with many potential pharmacological effects, is limited by low aqueous solubility. Cocrystallization with 4-aminopyridine, an FDA approved medication used in the treatment of multiple sclerosis, was utilized and two ionic cocrystal phases were obtained. The two phases differ by stoichiometry, water inclusion, and proton transfer site on resveratrol. Reversible interconversion between both phases was achieved mechanochemically, a rare occurrence among multicomponent solids. This system demonstrates the first ionic crystalline forms of resveratrol, significantly enhanced solubility, and a rare example of a cocrystal system exhibiting different deprotonation sites at molecular locations with identical functional groups. The presence of anionic resveratrol in the solid could enhance its antioxidant efficacy compared to neutral resveratrol or other antioxidants. Furthermore, resveratrol has been previously reported to improve clinical markers in a mice model of multiple sclerosis, indicating this combination could offer a unique dual-therapeutic treatment.