Molecular Salts of the Antidepressant Venlafaxine: An Effective Route to Solubility Properties Modifications

The possibility of decreasing the solubility of the antidepressant drug venlafaxine hydrochloride by formation of molecular salts with organic acids accepted by the Pharmacopeia has been successfully investigated. Reacting venlafaxine with coumaric, ferulic, oxalic, salicylic, fumaric, and citric acids results in the protonation of the amino group and formation of the corresponding 1:1 molecular salts. All compounds have been characterized by a combination of solid state techniques, i.e., single crystal and powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy and solid-state NMR (1H MAS,13C and15N CPMAS,1H DQ MAS, two-dimensional (2D)13C-1H HETCOR, and 2D14N-1H J-HMQC) spectroscopy. Intrinsic dissolution tests were performed on the pure salts, and suitable candidates were selected for the preparation of solid formulations with excipients; dissolution profiles for the solid formulations were measured in water and sodium chloride solution, and compared with that of the commercial form of venlafaxine, showing that the coumarate salt might represent an improvement for extended release administrations.