New Vortioxetine Salts: Design?Prepartion?Characterization And Properties

Vortioxetine(namely 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine,abbreviated as VOT)is a new chemical class of bis-aryl-sulfanyl amine psychotropics for the treatment of major depressive disorder(MDD)as the serotonin reuptake inhibitor with an activity on serotonin receptor 1A(5-HT1A)and the serotonin receptor 3(5-HT3)in adults.Confirmed by related clinic research,the effect in the treatment of depression by VOT is remarkable and the possibility of recurrence is reduced after the cure.So the drug has a good research prospect.However,the solubility of VOT in water is poor(0.1 mg/mL).So the salification of VOT is very significant to modify the pharmaceutical properties in the pharmaceutical industry,such as solubility,stability etc.The purpose of research is to discover the new form of VOT salt,which can be used in the formulation in future.In this paper,the research content mainly includes the following aspects:(1)VOT features basic nature because of the presence of secondary amine group(pKa of N1 8.85).So VOT is very easy to form a pharmaceutically acceptable salt with different acid.And according to the ?pKa rule,organic acids and inorganic acids were selected mainly to investigate the salt formation in this paper.The VOT salts with organic acids have been prepared by the quick and green method: liquid-assisted grinding(LAG),while salts with inorganic acids have been prepared by solution crystallization.Most of crystals suitable for X-ray diffraction have been obtained through the slow evaporation of the corresponding solution.Nine new VOT salts have been successfully prepared and characterized by single crystal X-ray diffraction(SXRD).The reasults indicate that the proton is transferred from the guest molecule to piperazidine N1 atom of vortioxetine,which mean the formation of salts.(2)The salts were confirmed by powder X-ray diffraction(PXRD),nuclear magnetic resonance spectroscopy(NMR),differential scanning calorimetry(DSC),thermogravimetric analysis(TGA)and infrared analysis(IR).The PXRD patterns of new salts exhibit readily distinguishable differences compared with VOT.The experimental PXRD patterns for the crystal samples are symmetric and sharp,and exhibit good agreement with the calculated PXRD patterns from the single crystal data of VOT salts,which indicates that the prepared salts are of good crystalline purity.In the FT-IR spectra of VOT free base and new salts,there are obvious distinctions in the N–H stretching vibration frequencies(as a characteristic peak).Characterized by TG-DSC analysis,there are one hydrone in vortioxetine hydrochloride hydrate.(3)As organic acids,different substituent or different location of substituent on the benzoic acid and benzene acetic acid series were selected mainly to investigate the salt formation in this paper.Characterized by SXRD,guest molecules of different substituent or different location of substituent could have significantly effects on hydrogen bonding interaction after salification.(4)Actually,equilibrium solubility is often to be measured in the actual environment to represent solubility.An excess amount of the salt was added in double-distilled water,and the resulting suspension was shaken for 24 h at 25 °C.After equilibration,the suspension was filtered through syringe filter and the concentration of the salt was quantified by HPLC with the predetermined calibration curve.The results of the equilibrium solubility experiments show that new salts feature improved solubility than free VOT base,especially for salts with inorganic acids and p-aminobenzoic acid.