Design and synthesis of alverine-based ionic liquids to improve drug water solubility

Abstract

Alverine [3-phenyl-N-(3-phenylpropyl)-N-ethylpropan-1-amine] is a widely known smooth muscle relaxant used to relieve cramps or spasms of the stomach and intestines. As a free base, alverine is a liquid practically insoluble in water while its commercialized form, alverine citrate, is a white solid that can form different crystalline forms. With the aim of increasing alverine water solubility while avoiding polymorphs, in this work, the design, total synthesis, and characterization of a series of new ionic liquids incorporating alverine as the cation were carried out. The selection of the most suitable anions for the active pharmaceutical ingredient-based ionic liquids (API-ILs) was performed calculating the ionic liquid solubility in water by using a priori the COSMO-RS computational tool. The computational analysis of the intermolecular interactions between water and the API-ILs allowed understanding the water solubility of these systems. All the new salts were found to be ionic liquids and their water solubility was shown to be significantly increased compared with the free drug alverine. The highest value was obtained for alverinium tosylate, with a value of 38.10 mg mL⁻¹, 39 937-fold higher than that of alverine. Compared to the commercialized drug alverine citrate, a slight increase in water-solubility was observed in all cases.