Investigations on the Solubility of Vortioxetine Based on X-ray Structural Data and Crystal Contacts

Investigation on the solid-state pharmaceutical chemistry has been known as an intriguing strategy to not only modify the physicochemical properties of drugs but also expand the solid form landscape. Vortioxetine (VOT) is an effective but poorly soluble antidepressant. To improve the solubility of vortioxetine and expand possible solid forms, in this paper, four novel solid forms of vortioxetine with dihydroxybenzoic acids (VOT-23BA, VOT-24BA-TOL, VOT-25BA, and VOT-26BA, 23BA = 2,3-dihydroxybenzoic acid, 24BA = 2,4-dihydroxybenzoic acid, 25BA = 2,5-dihydroxybenzoic acid, 26BA = 2,6-dihydroxybenzoic acid, and TOL = toluene) were synthesized first by a solvent evaporation method and then characterized by single-crystal X-ray diffraction (SCXRD), thermal, and XRD techniques. VOT-24BA-TOL, VOT-25BA, and VOT-26BA, showed similar [2+2] tetrameric R-4(4) (12) hydrogen bonds by acid-piperazine heterosynthon. In the VOT-23BA-H2O salt, the VOT cation and 23BA anion interacted through protonated piperazine-hydroxyl N-H center dot center dot center dot O hydrogen bonds, not protonated piperazine-deprotonated carboxylic acid N-H center dot center dot center dot O hydrogen bonds. Solubility studies were carried out in purified water and it was found that the VOT-23BA-H2O, VOT-25BA, and VOT-26BA salts exhibited an increase in water compared to pure VOT. The solubility of the stabilized salt formations followed the order of VOT-25BA > VOT-26BA > VOT-23BA-H2O in purified water.