Crystal Structures, X-Ray Photoelectron Spectroscopy, Thermodynamic Stabilities, and Improved Solubilities of 2-Hydrochloride Salts of Vortioxetine

Two vortioxetine (VOT) salts with hydrochloride (VOT-HCl and VOT-0.5HCl) were prepared and structurally characterized. VOT-HCl features 1-dimensional P/M helical chains through N-H···Cl hydrogen bond interactions, whereas VOT-0.5HCl possesses a 1-dimensional zigzag structure in which 2 VOT molecules share a single proton through N···H+···N interactions. VOT-HCl converts into the monohydrate VOT-HCl·H2O after dissolution in water, whereas VOT-0.5HCl remains stable. The N 1s X-ray photoelectron spectroscopy analysis shows a characteristic binding energy peak at approximately 398.0 eV for VOT. The shift to high energy occurs at 400.3 eV for VOT-HCl and VOT-HBr, and at 399.7 eV for VOT-0.5HCl, which supports the salt formation by the degree of proton transfer and is confirmed by single-crystal X-ray analyses. The apparent equilibrium solubilities of VOT in water are significantly improved to 2.90 mg/mL (approximately a 32.0-fold increase over that of the free base) for VOT-HCl and to 0.59 mg/mL (approximately a 5.7-fold increase over that of the free base) for VOT-0.5HCl at 25°C.