The ideal duo for salt formation: vinpocetine and tosylic acid

Abstract

Two novel soluble salts of vinpocetine were prepared through simple and highly sustainable mechanochemical methods. Specifically, water-assisted grinding led to the formation of a crystalline, anhydrous, equimolar salt with p-toluenesulfonic acid, whereas neat grinding produced its amorphous counterpart. The structure of the crystalline salt was elucidated using single-crystal X-ray diffraction, while the ionic nature of the amorphous salt was confirmed by X-ray photoelectron spectroscopy. The large ΔpK_a between p-toluenesulfonic acid and vinpocetine promotes the formation of a stable salt, with strong ionic interactions between the protonated tertiary amine of vinpocetine and the tosylate anion (as also attested by amorphous salt glass transition of about 81 °C). Both salts significantly enhance the saturation solubility of vinpocetine at 37 °C in phosphate buffer, achieving thermodynamic equilibrium in half the time compared to the pure crystalline drug. These findings highlight new opportunities for the development of vinpocetine, a compound with well-documented effects on cerebral circulation, whose broader application has so far been limited by its extremely low aqueous solubility.