An Investigation Into Vortioxetine Salts: Crystal Structure, Thermal Stability, and Solubilization

Three 1:1 salts containing vortioxetine (VOT), an orally antidepressant drug, and 3 aryl monoacids have been designed and successfully prepared by liquid-assisted grinding based on the ΔpK a rule. The C-O bond lengths (∼1.25 Å) in the COOH groups show that the proton transfer has occurred from aryl monoacid to piperazine N1 atom of vortioxetine in the crystal structures. Three salts feature cyclic [2 + 2] structural units through R 4 4 (12) N–H···O hydrogen bonding interactions which result in the remarkable thermal stabilities, and VOT– p -aminobenzoic acid shows 2-dimensional framework by linking cyclic [2 + 2] units through additional hydrogen bonding interactions. The equilibrium solubility of VOT in VOT– p -aminobenzoic acid salt can be largely improved up to 0.50 mg/mL (about 450% above the free base) at 25°C in water, which also accelerates the intrinsic dissolution rate.