Pharmaceutical paroxetine-based organic salts of carboxylic acids with optimized properties: the identification and characterization of potential novel API solid forms

Abstract

Paroxetine hydrochloride, PRX HCl, is an important and widely prescribed antidepressant drug for anxiety and depression treatment. Since hydrochloride salts can cause problems in their manufacture, we have designed organic salts with oxalic, fumaric, maleic and L-tartaric acids based on the NH₂⁺⋯COO⁻ synthon. All the salts were obtained from an innovative anion exchange method: selective crystallization from a mixture of PRX HCl and an acid in a certain ratio. The crystal structures of paroxetine (PRX) salts with dicarboxylic acids were determined by the single-crystal X-ray diffraction (SCXRD) method and were also analysed by thermogravimetric analysis, differential scanning calorimetry and FT-IR spectroscopy. Except for FUM and MAL acids, all the carboxylic acids form hydrate salts. Oxalate and tartrate salts are formed through the complete protonation of the anion and exhibit a 1 : 2 stoichiometry. All structures have a Z′ > 1 and different conformations are found for the PRX molecules. In general, the ionic units in the salts extend into chains that pack cohesively, via CH⋯O and CH⋯π interactions, into layers. The oxalate salt forms a channel structure where H₂O molecules are hosted. On the other hand, the presence of water molecules in the tartrate salt allows the packing of ionic layers. The organic salts are thermally more stable than the commercial PRX form, m.p. > 143 °C. They exhibit lower solubility compared to the hydrochloride form. The scientific contributions of this study show the diversity of the PRX solid forms and identify candidates for use in new antidepressant API solid formulations.