Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage

Abstract

The present invention relates to the novel vortioxetine salts, solvates and crystalline forms thereof, specifically, vortioxetine hemihydrobromide and a crystalline form thereof, and isopropanol solvate of vortioxetine hydrobromide and a crystalline form thereof. Compared to the known vortioxetine hydrobromide, the vortioxetine salts, solvates and crystalline forms of the present invention have improved features in stability, hygroscopicity and purity. The present invention also relates to preparation methods of the vortioxetine salts, solvates and crystalline forms, pharmaceutical compositions thereof and their uses in the manufacture of antidepressant drugs.

1 . Vortioxetine hemihydrobromide represented by formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         2 . A preparation method of the vortioxetine hemihydrobromide according to  claim 1 , which comprises the following procedures: respectively preparing solutions of vortioxetine and hydrobromic acid in solvents, wherein the molar ratio of vortioxetine to hydrobromic acid is 10:1-2:1; mixing the two solutions to produce a suspension and stirring, then removing the solvents by rotary evaporation to obtain the vortioxetine hemihydrobromide; wherein the solvents are selected from the group consisting of alcohols, esters, ketones and mixtures thereof. 
     
     
         3 . A crystalline form of the vortioxetine hemihydrobromide according to  claim 1 , which is characterized in that, measured with Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form of vortioxetine hemihydrobromide, expressed as 2θ angles, has the following characteristic peaks: 4.3±0.2°, 14.9±0.2°, 17.8±0.2°, 18.9±0.2°, 19.4±0.2° and 22.8±0.2°. 
     
     
         4 . The crystalline form of vortioxetine hemihydrobromide according to  claim 3 , which is characterized in that, measured with Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form of vortioxetine hemihydrobromide, expressed as 2θ angles, has the following characteristic peaks: 4.3±0.2°, 14.9±0.2°, 17.1±0.2°, 17.8±0.2°, 18.9±0.2°, 19.4±0.2°, 22.0±0.2°, 22.4±0.2°, 22.8±0.2°, 24.4±0.2°, 25.4±0.2° and 29.7±0.2°. 
     
     
         5 . The crystalline form of vortioxetine hemihydrobromide according to  claim 4 , which is characterized in that, the X-ray powder diffraction pattern of the crystalline form of vortioxetine hemihydrobromide, expressed as 2θ angles, has the following characteristic peaks with the following relative intensities: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Diffraction angle 
                   Relative intensity 
                 
                     
                   2θ 
                   % 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                    4.3 ± 0.2° 
                   25.6 
                 
                     
                   14.9 ± 0.2° 
                   23.3 
                 
                     
                   16.8 ± 0.2° 
                   11.2 
                 
                     
                   17.1 ± 0.2° 
                   17.6 
                 
                     
                   17.8 ± 0.2° 
                   100.0 
                 
                     
                   18.9 ± 0.2° 
                   22.5 
                 
                     
                   19.4 ± 0.2° 
                   49.5 
                 
                     
                   22.0 ± 0.2° 
                   24.5 
                 
                     
                   22.4 ± 0.2° 
                   16.7 
                 
                     
                   22.8 ± 0.2° 
                   31.8 
                 
                     
                   24.4 ± 0.2° 
                   17.7 
                 
                     
                   25.4 ± 0.2° 
                   15.6 
                 
                     
                   25.9 ± 0.2° 
                   10.1 
                 
                     
                   27.8 ± 0.2° 
                   11.8 
                 
                     
                   28.6 ± 0.2° 
                   11.1 
                 
                     
                   29.0 ± 0.2° 
                   10.3 
                 
                     
                   29.7 ± 0.2° 
                   24.0 
                 
                     
                   31.3 ± 0.2° 
                   12.9 
                 
                     
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         6 . The crystalline form of vortioxetine hemihydrobromide according to  claim 3 , which is characterized in that, the Fourier infrared spectrum of the crystalline form of vortioxetine hemihydrobromide has characteristic peaks at the wave numbers of 3171, 2952, 2916, 2828, 2808, 2733, 1580, 1474, 1439, 1146, 1053, 924, 861 and 735 cm −1 . 
     
     
         7 . A preparation method of the crystalline form of vortioxetine hemihydrobromide according to  claim 3 , which comprises the following procedures: respectively preparing solution systems of vortioxetine and hydrobromic acid in solvents, wherein the solvents are selected from the group consisting of C 1 -C 4  alcohols, C 4 -C 5  esters, C 3 -C 4  ketones and mixtures thereof, the molar ratio of vortioxetine to hydrobromic acid in the two solution systems is 10:1-2:1; mixing the two solution systems to produce a suspension and stirring to crystallize for 1-48 hours at a crystallization temperature of −10-50° C., then removing the solvents to obtain the crystalline form of vortioxetine hemihydrobromide. 
     
     
         8 . The preparation method of the crystalline form of vortioxetine hemihydrobromide according to  claim 7 , which is characterized in that, the solvents are selected from the group consisting of ethanol, isopropanol, ethyl acetate and acetone, the molar ratio of vortioxetine to hydrobromic acid is 4:1-2:1, the crystallization temperature is room temperature, and the duration of crystallization is 2-4 hours. 
     
     
         9 . The preparation method of the crystalline form of vortioxetine hemihydrobromide according to  claim 7 , which is characterized in that, the concentration of vortioxetine in the solvent is 0.1-1 times of its solubility in the solvent at the crystallization temperature. 
     
     
         10 . The preparation method of the crystalline form of vortioxetine hemihydrobromide according to  claim 9 , which is characterized in that, the concentration of vortioxetine in the solvent is 0.5-1 times of its solubility in the solvent at the crystallization temperature. 
     
     
         11 . The preparation method of the crystalline form of vortioxetine hemihydrobromide according to  claim 7 , which is characterized in that, the concentration of hydrobromic acid in the solvent is 0.5-1 times of its solubility in the solvent at the crystallization temperature. 
     
     
         12 . A pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of the vortioxetine hemihydrobromide according to  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , which is characterized in that, the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, capsules, granules, pulvis, pills, powder, lozenges, syrups and suspensions by oral administration, and aqueous solutions, non-aqueous solutions and emulsions for injection by parenteral administration. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , which is characterized in that, the pharmaceutical composition is selected from the group consisting of tablets, capsules and suspensions by oral administration. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , which is characterized in that, the tablets or the capsules by oral administration are prepared by wet granulation processes. 
     
     
         16 . (canceled) 
     
     
         17 . A method of treating and/or preventing the diseases selected from the group consisting of affective disorders, major depression, routine anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, depressions associated with cognitive deficits, Alzheimer's disease and anxiety disorder, depression with residual symptoms, chronic pain, eating disorders, alcoholism, nicotine or carbohydrate addiction, drug abuse, alcohol and drug abuse, which comprises administering to a patient in need a therapeutically and/or preventively effective amount of the vortioxetine hemihydrobromide according to  claim 1 . 
     
     
         18 . A pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of the crystalline form of vortioxetine hemihydrobromide according to  claim 3  and at least one pharmaceutically acceptable excipient. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , which is characterized in that, the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, capsules, granules, pulvis, pills, powder, lozenges, syrups and suspensions by oral administration, and aqueous solutions, non-aqueous solutions and emulsions for injection by parenteral administration. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , which is characterized in that, the pharmaceutical composition is selected from the group consisting of tablets, capsules and suspensions by oral administration. 
     
     
         21 . The pharmaceutical composition according to  claim 20 , which is characterized in that, the tablets or the capsules by oral administration are prepared by wet granulation processes.