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 ΔpKa 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.
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, People's Republic of China.
Sai-Fei
SF
He
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, People's Republic of China.
Xian-Rui
XR
Zhang
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, People's Republic of China.
Shuo
S
Zhang
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, People's Republic of China.
Su
S
Guan
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, People's Republic of China.
Jing
J
Li
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, People's Republic of China. Electronic address: lishan@scut.edu.cn.
Shan
S
Li
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, People's Republic of China. Electronic address: lzhang@scut.edu.cn.
Lei
L
Zhang
D062365:Aminobenzoates / Q000737:chemistry; D000928:Antidepressive Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D018360:Crystallography, X-Ray; D004339:Drug Compounding; D004355:Drug Stability; D006358:Hot Temperature; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D010879:Piperazines / Q000737:chemistry*; D012492:Salts; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013440:Sulfides / Q000737:chemistry*; D013818:Thermogravimetry; D000078784:Vortioxetine
D062365:Aminobenzoates; D000928:Antidepressive Agents; D010879:Piperazines; D012492:Salts; D013440:Sulfides; D000078784:Vortioxetine
crystal structure; equilibrium solubility; intrinsic dissolution rate; liquid-assisted grinding; thermal stability; vortioxetine