Abstract:
The present invention relates to Aripiprazole, a useful agent for antipsychotic. The present invention also provides new acid addition salts of Aripiprazole and process for the preparation of polymorphs and solvates of Aripiprazole using Aripiprazole acid salts, their interconversion and the process for preparation of Aripiprazole acid salts.

Description:
[0001]    The present invention relates to a process for the preparation of polymorphs, solvates of Aripiprazole using Aripiprazole acid salts, their interconversion and the process for preparation of Aripiprazole acid salts 
       BACKGROUND OF THE INVENTION 
       [0002]    U.S. Pat. No. 4,734,416 and U.S. Pat. No. 5,006,528 discloses the Aripiprazole, 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydro-2(1H)-quinolinone or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro carbostyril, is a typical antipsychotic agent useful for the treatment of Schizophrenia, having the formula as given below. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0003]    U.S. Pat. No. 5,006,528 discloses preparation of Aripiprazole and its pharmaceutically acceptable acid-addition salts. The process for the preparation of acid salts involves reaction of Aripiprazole with a pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like; organic acids such as oxalic acid, maleic acid, fumaric acid, maleic acid, tartaric acid, citric acid, benzoic acid and the like as per Scheme-1. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    The product Aripiprazole obtained by the above process has melting point of 139.0°±139.5° C. 
         [0004]    The process involves purification of the intermediate, 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (III) by silica gel column chromatography to remove impurities formed during the reaction. The process further involves two recrystallizations of Aripiprazole from ethanol to obtain the pure Aripiprazole though compromising on yields by increasing the operational cost of the product. 
         [0005]    PCT publication WO 03/026659 discloses low hygroscopic forms of Aripiprazole and the process for their preparation from the Aripiprazole hydrate Form ‘A’. It further states that the anhydrous Aripiprazole made by the Japanese patent publication No. 191256/1990, yields the Aripiprazole, which is significantly hygroscopic. As per PCT publication WO 03/026659 anhydrous crystals of Aripiprazole exist as type-I crystals and type-II crystals. Further discloses that the type-I crystals are prepared by recrsytallization from ethanol solution of Aripiprazole or by heating Aripiprazole hydrate at 80° C. and type-II crystals by heating type-I crystals at 130 to 140° C. for 15 hrs. 
         [0006]    PCT application Publication WO 03/026659 discloses process for the Aripiprazole polymorphic form-B by heating the Aripiprazole hydrate ‘A’ at 90-125° C. for about 3-50 hrs. The process for Polymorphic Form-C is by heating the Aripiprazole anhydrous to a temperature of 140-150° C. The process for Form-D is recrystallization from toluene; process for Form-E is heating with acetonitrile or by recrystallization from acetonitrile and the process for Form-F is by heating the suspension of anhydrous Aripiprazole in acetone. The polymorphic Form-G is by heating to 170° C. for at least 2 weeks in a sealed tube, which is a glassy mass. 
         [0007]    PCT publication WO 03/026659 further discloses the characterization data X-ray diffraction pattern; IR absorption and DSC of Form B, Form C, Form-D, Form-E, Form-F and Form-G. It further reported the melting point of Aripiprazole anhydrous Form B as 139.7° C. 
         [0008]    A drawback of the disclosed process is that it produces a mixture of polymorphic forms. 
       SUMMARY OF THE INVENTION 
       [0009]    The main object of the present invention is to provide process for the preparation of pure polymorphs of Aripiprazole. 
         [0010]    Another object of the present invention is to provide process for the preparation of Aripiprazole solvates. 
         [0011]    Yet another object of the present invention is to provide process for preparation of polymorphs of Aripiprazole using acid salts. 
         [0012]    Another object of the present invention is to provide process for the preparation of Aripiprazole solvates using acid salts. 
         [0013]    Another object of the present invention is to provide process for the preparation of Aripiprazole form-B. 
         [0014]    Another object of the invention is to provide process for the preparation of Aripiprazole form-I. 
         [0015]    Another object of the invention is to provide process for the preparation of Aripiprazole form-D. 
         [0016]    Another object of the invention is to provide process for the preparation of Aripiprazole form-A. 
         [0017]    Yet another object of the invention is to provide process for the preparation of Aripiprazole methanol solvate for its use in the preparation of polymorphs of Aripiprazole. 
         [0018]    Yet another object of the invention is to provide finger printing of Aripiprazole form-I Yet another object of the invention is to provide finger printing of Aripiprazole acid salts. 
         [0019]    Yet another object of the invention is to provide finger printing of the Novel Aripiprazole solvates. 
         [0020]    Thus according to the present invention Aripiprazole acid salts on treatment with base in mixture of water-organic ester solvent, followed by separation and concentration of the organic layer, then maintaining the organic layer at high temperature, cooling, followed by isolation and drying gives Aripiprazole form-B. 
         [0021]    Aripiprazole acid salts on neutralization with base in mixture of water-water immiscible organic solvent followed by separation and concentration of the organic layer, then adding acetic acid and raising the temperature, followed by addition of ante-solvent, cooling, isolation and drying gives Aripiprazole acetic acid solvate. 
         [0022]    Aripiprazole acid salts on neutralization with base in mixture of water and water immiscible organic solvent followed by separation and concentration of the solvent, then dissolution in organic polar solvent and raising the temperature, followed by addition of ante-solvent, cooling or optionally direct crystallization from organic polar solvent, isolation and drying gives Aripiprazole form-I. 
         [0023]    Aripiprazole acid salts on neutralization with base in mixture of water-water immiscible organic-solvent followed by separation and concentration of the organic layer, then addition of alcohol followed by crystallization gives the Aripiprazole alcohol solvates. 
         [0024]    Another embodiment of the present invention is process for preparation of Aripiprazole acid salts. Reaction of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (III) with 1-(2,3-dichlorophenyl)piperazine (IV) in organic polar solvent in presence of sodium iodide and triethylamine, followed by removal of solvent, dissolution of residue in mixture of water-water immiscible solvent, separation and concentration of the organic layer followed by treatment with acid results in Aripiprazole acid salts. 
         [0025]    Alternatively Aripiprazole acid salts are prepared by reaction of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (III) with 1-(2,3-dichlorophenyl)piperazine (IV) in presence of sodium iodide and triethylamine in short chain alcohol followed by cooling results in crude Aripiprazole, which on dissolution in water immiscible solvent, treatment with acid, crystallization results in Aripiprazole acid salts. 
         [0026]    7-(4-bromobutoxy)-3,4-dihydrocarbostyril (III) is prepared by the reaction of 7-Hydroxy-3,4-dihydrocarbostyril (I) with 1,4-dibromobutane (II) in presence of alkali hydroxide, phase transfer catalyst in alcohol, followed by removal of insolubles, distillation of solvent, excess. 1,4-dibromobutane, isolation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (III) by addition of alcohol, cooling the resultant mass followed by isolation and washing with hydrocarbon. (Scheme-2) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0027]    By isolating Aripiprazole as Aripiprazole acid salts minimum of 98% purity is achieved as compared to reported processes, which yield purity of 80-85%. 
         [0028]    Yet another embodiment of the present invention is preparation of polymorphs of Aripiprazole using Aripiprazole methanol solvate. Aripiprazole methanol solvate on dissolution in organic solvent, addition of acetic acid, raising the temperature, addition of ante-solvent, cooling, followed by isolation and drying gives the Aripiprazole acetic acid solvate. 
         [0029]    Aripiprazole methanol solvate, Aripiprazole acetic acid solvate can be converted into other crystalline forms of Aripiprazole such as Aripiprazole Form-A, Form-B, Form-D, Aripiprazole Type-I crystals and Type-II crystals by appropriate methods as per Scheme-3. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0030]    Aripiprazole acid salts used for the preparation of polymorphs of Aripiprazole in the present invention are Aripiprazole p-toluene sulfonate, benzenesulfonate, citrate, salicylate, hydrobromide and the solvates used for the preparation of Aripiprazole polymorphs are the acetic acid solvate and methanol solvate. These Aripiprazole methanol solvate, Aripiprazole acetic acid solvate, Aripiprazole form-I are to novel compounds and have characterized by chemical, IR, NMR, Mass spectral analysis and XRD. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0031]      FIG. 1X-ray  diffraction pattern of the Aripiprazole form-B 
           [0032]      FIG. 2  FTIR spectrum of the Aripiprazole form-B 
           [0033]      FIG. 3  DSC of the Aripiprazole of form-B 
           [0034]      FIG. 4  X-ray diffraction pattern of the Aripiprazole form-I 
           [0035]      FIG. 5  FTIR spectrum of the Aripiprazole form-I 
           [0036]      FIG. 6  DSC of the Aripiprazole of form-I 
           [0037]      FIG. 7  XRD of the Aripiprazole methanol solvate 
           [0038]      FIG. 8  FTIR of the Aripiprazole methanol solvate 
           [0039]      FIG. 9  TGA of the Aripiprazole methanol solvate 
           [0040]      FIG. 10  XRD of the Aripiprazole acetic acid solvate 
           [0041]      FIG. 11  FTIR of the Aripiprazole acetic acid solvate 
           [0042]      FIG. 12  TGA of the Aripiprazole acetic acid solvate 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0043]    Thus according to the present invention Aripiprazole acid salt on basification (base is selectively alkali hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, organic bases such as triethylamine, dimethylamine, methylamine, diisopropyl ethyl amine, diisopropylamine, dibutylamine, more preferably triethylamine, dimethylamine) at about 50° C. to about 90° C. in a mixture of water and organic ester solvent, (the organic solvent selected from ethyl acetate, isopropyl acetate), separating the solvent layers, washing the organic layer with water, concentrating the organic layer to reduce the water content to below 0.5%, raising the temperature to about 65° C.-90° C., maintaining at the temperature at about 65° C. to 90° C. for about 10 min to 8 hrs, cooling to about 15° C. to about 40° C., mixing for about 30 min-6 hrs, isolating and further drying at temperature of about 40° C.-90° C. gives the Aripiprazole Form-B. 
         [0044]    In another embodiment of the present invention Aripiprazole form-I is prepared from Aripiprazole acid salt by basification of Aripiprazole acid salt with base (base selectively alkali hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, barium carbonate, bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonia, organic bases selected from triethylamine, dimethylamine, methylamine, more preferably triethylamine, dimethylamine) in a mixture of water and water immiscible organic solvent, preferably methylene dichloride for about 10 min to 2 hrs, separating the layers, washing the organic layer with water, removal of the solvent from the organic layer, dissolution of residue in organic polar solvent such as DMF,DMA if required by heating 30° C.-65° C., cooling to low temperature about −15° C. to 20° C. isolating or optionally adding ante solvent (ante solvent selectively ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethers such as diethyl ether, diisopropyl ether, methyl tert butyl ether, hydrocarbons such as cyclohexane, n-hexane, n-heptane, and esters such as ethyl acetate, isopropyl acetate), at temperature of about 35° C. to followed by cooling to low temperature such as about −5° C. to about 35° C., preferably 5° C. to about 20° C., isolating and drying at temperature of about 35° C. to about 65° C. gives the Aripiprazole form-I. 
         [0045]    In another embodiment of the present invention Aripiprazole acetic acid solvate is prepared from Aripiprazole acid salt by basification of Aripiprazole acid salt with base (base selectively alkali hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, barium carbonate, bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonia, organic bases selected from triethylamine, dimethylamine, methylamine, more preferably triethylamine, dimethylamine) at about 50° C.-90° C. in a mixture of water-water immiscible organic solvent selected from ethyl acetate, isopropyl acetate, chloroform, toluene, n-butanol for about 10 min-2 hrs, separating the layers, washing the organic layer with water, concentrating the organic layer, adding acetic acid at about 25° C.-75° C., raising the temperature of the reaction mixture to about 65° C.-90° C., adding ante-solvent which is a hydrocarbon or ether; (hydrocarbon such as cyclohexane, n-hexane, n-heptane, methyl cyclohexane, and ether such as methyl tert butyl ether), maintaining the temperature of 65° C. to 90° C. for about 10 min to 8 hrs, cooling to about 35° C.-75° C., seeding with Aripiprazole acetic acid solvate, followed by further cooling to about 15° C.-40° C., mixing for about 30 min—6 hrs, isolating and drying at temperature of about 40° C.-90° C. gives the Aripiprazole acetic acid solvate. 
         [0046]    In another embodiment of the invention Aripiprazole methanol solvate is prepared from Aripiprazole acid salt by basification of Aripiprazole acid salt with base (base selectively alkali hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, barium carbonate, bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonia, organic bases such as triethylamine, dimethylamine, methylamine, more preferably triethylamine, dimethylamine) at about 50° C.-about 90° C. in a mixture of water-water immiscible organic solvent such as ethyl acetate, isopropyl acetate for about 10 min to 2 hrs, separating the layers, washing the organic layer with water, concentrating the organic layer, adding 3 to 6 volumes methanol at about 50° C.-90° C. over about 15 min followed by maintaining the temperature at about 50° C.-90° C. for about 15 min-4 hrs, cooling to about 40° C.-10° C., to give the Aripiprazole methanol solvate. Aripiprazole methanol solvate can be dried and the dry material or the wet cake as such can used for the preparation of various polymorphs; of Aripiprazole. The molar ratio of Aripiprazole: methanol is 1:1, in the Aripiprazole methanol solvate. 
         [0047]    In another embodiment of the present invention Aripiprazole methanol solvate and Aripiprazole acetic acid solvate suspensions in selected organic solvents when heated to about 450-90° C., maintaining the temperature at about 45° C.-90° C. for about 30 min to 6 hrs, cooling to about 15° C.-35° C., followed by isolation and drying at temperature of about 50° C.-about 90° C. results in polymorphs of Aripiprazole such as Aripiprazole form-B, form-D, form-A, type-I crystals and form-I. 
         [0048]    Solvents such as ethyl acetate, isopropyl acetate in the above process results in Aripiprazole Form-B; solvent such as acetonitrile, THF/n-heptane, ethyl acetate/n-heptane result in Form-D; solvent such as aq. Ethanol and water results in Aripiprazole Form-A and solvent such as ethanol results in Aripiprazole type-I crystals; solvent such as DMF, DMA results Aripiprazole form-I. 
         [0049]    In another embodiment of the invention Aripiprazole acetic acid solvate is prepared from Aripiprazole methanol solvate by dissolution of Aripiprazole methanol solvate in organic ester solvent, selected from methyl acetate, isopropyl acetate, adding acetic acid at temperature of 45° C. to 75° C., raising the temperature to 60° C.-90° C., followed by slow addition of ante-solvent selected from hydrocarbon of C 5  to C 7  such as cyclohexane, n-hexane, n-heptane, methyl cyclohexane, or aliphatic ether selected from diisopropyl ether, methyl tertbutyl ether, maintenance at temperature of about 60° C. to about 90° C. for about 10 min to 8 hrs, cooling to about 55° C. to 65° C., seeding with Aripiprazole acetic acid solvate followed by cooling to about 15° C. to 40° C., mixing for about 30 min to 6 hrs, followed by isolation and drying at temperature of about 40° C. to about 90° C. gives the Aripiprazole acetic acid solvate. 
         [0050]    In another embodiment of the invention the Aripiprazole methanol solvate is prepared from Aripiprazole acetic acid solvate by raising the temperature of a suspension of Aripiprazole acetic acid solvate in methanol to about 40° C. to 70° C., then maintaining for the temperature for about 30 min to 6 hrs, cooling to about 10° C. to 35° C., isolating and drying at about 30° C. to about 60° C. for about 1 hr to about 18 hrs to give Aripiprazole methanol solvate. 
         [0051]    Yet another embodiment of the invention is a process for preparation of Aripiprazole acid salts from 7-Hydroxy-3,4-dihydrocarbostyril. Reaction of 7-Hydroxy-3,4-dihydrocarbostyril (I) with 1,4-dibromobutane (II) is carried out in presence of alkali hydroxide such as sodium hydroxide, potassium hydroxide, phase transfer reagent such as quaternary ammonium salts, preferably tetra butyl ammonium bromide, triethyl benzyl ammonium bromide, in alcohol, (preferable alcohol is isopropyl alcohol, methanol, ethanol, butanol and more preferably isopropyl alcohol) at about 45° C., to 90° C. for about 3 hrs to 8 hrs, removing the insolubles if any, removing the solvent along with excess 1,4-dibromobutane below 125° C., cooling, adding alcohol, mixing at about 10° C.-40° C. preferably at about 15° C. to 30° C. for about 30 min to 8 hrs, isolating the acid salt, washing with hydrocarbon such as n-hexane, n-heptane, cyclohexane, methyl cyclohexane, toluene and drying at temperature of about 35° C. to 75° C., preferably at about 40° C. to 50° C. to give 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (III). 
         [0052]    Reaction of 7-(41-bromobutoxy)-3,4-dihydrocarbostyril (III) with 1-(2,3-dichlorophenyl)piperazine (IV) is carried out as follows. 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (III) is added to sodium iodide in a short chain alcohol such as methanol, ethanol, isopropanol, butanol, n-propanol, mixed for about 30 min, and triethylamine and 1-(2,3-dichlorophenyl)piperazine are added and the temperature is maintained at about 50° C. to 75° C. for about 12 hrs to 18 hrs followed by cooling to 15° C. to 40° C. to give crude Aripiprazole. The crude Aripiprazole is dissolved in a water immiscible solvent selected from methylene chloride, ethylene dichloride, chloroform, ethyl acetate, isopropyl acetate more preferably in methylene chloride stirred at about 20° C.-50° C. for about 10 min-2 hrs followed by slow addition of acid to the reaction mass at about 10° C. to 30° C. over 15 min to 2 hrs then mixed at about 10° C.-30° C. for about 1 hr to 8 hrs. The product is isolated and dried at about 35° C. to 75° C. to give Aripiprazole acid salt. The acid used may be an organic acid or inorganic acid. The organic acid is selected from citric acid, p-toluene sulfonic acid, benzene sulfonic acid and salicylic acid; inorganic acid is hydrobromic acid. 
         [0053]    The acids may be added as neat solid or in form of solution by dissolving in suitable solvent selected from ethyl acetate, acetone and isopropyl acetate. 
         [0054]    Alternately the Aripiprazole acid salts may be prepared from the reaction mass directly without isolating the crude Aripiprazole. 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (III) is added to sodium iodide in an organic polar solvent, such as acetonitrile, THF, mixing for about 10 min to 1 hr at reflux temperature, cooling the reaction mass -20° C. to about 40° C., followed by addition of 1-(2,3-dichlorophenyl)piperazine (IV) and triethylamine, maintaining the reaction mass at about 60° C. to about 80° C. for about 2 hrs to about 6 hrs, followed by removal of solvent under vacuum at temperature below 60° C. The residue is dissolved in mixture of water and water immiscible solvent such as methylene chloride, ethylene dichloride, chloroform, ethyl acetate, isopropyl acetate followed by the separation of layers. The organic layer is washed with water and concentrated followed by slow addition of acid to the reaction mass at about 10° C. to about 30° C. over 15 min to about 2 hrs followed by mixing at about 10° C. to about 30° C. for about 1 hr to about 8 hrs. The precipitated product is isolated and dried at about 35° C. to about 75° C. to give the Aripiprazole acid salt. 
         [0055]    The Aripiprazole acid salts prepared are Aripiprazole p-toluene sulfonate monohydrate, Aripiprazole benzene sulfonate, Aripiprazole salicylate, Aripiprazole citrate, and Aripiprazole hydro bromide. The advantage of converting the crude Aripiprazole into Aripiprazole acid—addition salt is removal of bis impurity, (V) 7-(4-[1-(7-oxy-3,4-dihydrocarbostyril)]butoxy)-3,4-dihydro-2(1H)-quinolinone, formed during the reaction of 7-Hydroxy-3,4-dihydro carbostyril (I) with 1,4-dibromobutane (II), resulting in Aripiprazole of 98% purity. It may be noted that the methods of prior art give purity of 80-85%. 
         [0056]    Purification of Aripiprazole acid salt is carried out by mixing the Aripiprazole acid salt with methanol at temperature of about 25° C. to about 50° C. for about 15 min-4 hrs followed by cooling and maintaining temperature of about 10° C.-30° C. for about 30 min-6 hrs. 
         [0057]    The invention is now illustrated with non-limiting examples. 
       Example-I 
     Preparation of Aripiprazole Form-B from Aripiprazole p-toluene Sulfonate 
       [0058]    Aripiprazole p-toluene sulfonate salt (100 g) is suspended in a mixture of ethyl acetate (2000 ml), water (400 ml) and the temperature is raised to 70° C.-75° C. Triethylamine (25.7 g) is slowly added over 20 min and the temperature is maintained at 70° C.-75° C. for about 30 min. The reaction mass is allowed to settle, the layers are separated and aq. layer is extracted with ethyl acetate (300 ml) at 0.70° C.-75° C. The organic layers are combined and washed with water (2×400 ml) at 70° C.-75° C. The organic layer is concentrated to 900 ml by distillation of ethyl acetate (m/c of the mass is below 0.5%). The reaction mass is maintained at reflux temperature for 15 min. The reaction mass is cooled to 25° C. and maintained at 25° C.-30° C. for 60 min. The solid is filtered, washed the wet cake with ethyl acetate (50 ml) and dried at 40° C.-45° C. till constant weight. 
         [0059]    The dry wt of the Aripiprazole form-B is 58.0 g (Yield: 68.8%). 
         [0060]    The product is identical with the reported Aripiprazole Form-B by its FTIR, DSC and X-ray diffraction values. 
         [0061]    Similarly Aripiprazole form-B can be prepared by using other Aripiprazole acid-addition salts such as benzene sulfonate, citrate, salicylate, hydro bromide and using the solvents such as ethyl acetate, isopropyl acetate. 
       Example-II 
     Preparation of Aripiprazole Form-B from Aripiprazole p-toluene Sulfonate 
       [0062]    Aripiprazole p-toluene sulfonate salt (60 g) is suspended in a mixture of n-butanol (600 ml), water (240 ml) and sodium hydroxide solution (4 g in 10 ml of water) is added. The temperature of the reaction mass is raised to 70° C.-75° C. and maintained at that temperature for about 15 min. Reaction mass is allowed to settle, and the layers are separated, and the aqueous layer is extracted with n-butanol (300 ml). Organic layer is combined, washed with water (240 ml) at 70° C.-75° C. and n-butanol is distilled off under vacuum at temperature below 70° C. till volume of reaction mass is 160 ml. The reaction mass is cooled to 25° C. and maintained at 20° C.-25° C. for 60 min. The solid is filtered, and the wet cake is washed with n-butanol (30 ml) and dried at 40° C.-45° C. till constant weight. 
         [0063]    The dry wt of the Aripiprazole form-B is 28.8 g (Yield: 68.3%). 
       Example-III 
     Preparation of Aripiprazole Form-I from Aripiprazole p-toluene Sulfonate 
       [0064]    Aripiprazole p-toluene sulfonate salt (100 g) is suspended in a mixture of methylene dichloride (900 ml), water (400 ml). Triethylamine (25.7 g) is added slowly over 20 min and maintained at 25° C.-35° C. for about 30 min., allowed to settle, and the layers are separated and the aqueous layer is extracted with methylene dichloride (400 ml) at 0.25° C.-30° C. The organic layers are combined, washed with water (2×400 ml) and dried over anhydrous sodium sulphate (20 g). The solvent is removed by distillation of methylene dichloride followed by vacuum. DMF (70 ml) is added and distilled off to get the residue under vacuum at temperature below 45° C. DMF (140 ml) is added to the residue, the temperature is raised to 50° C. to get clear solution and acetone (280 ml) is slowly added at 50-55° C. over 30 min. The total mass is gradually cooled to 35° C. and further cooled to 10° C. The temperature is maintained at 5° C. to 10° C. for 60 min. The solid is filtered, washed with acetone (50 ml) and the wet cake is slurry washed with acetone (140 ml). Dried the wet cake at 40° C.-45° C. to constant weight. 
         [0065]    The dry wt of the Aripiprazole form-I is 55 g (Yield: 78.3%). 
         [0066]    The XRD shows peaks at 5.4, 10.0, 10.75, 11.6, 12.6, 15.7, 16.3, 18.5, 19.8, 20.4, 21.8, 22.2, 23.3, 24.5, 26.0, 27.1, 28.8, 32.6 and 33.6±0.2° 2 theta 
         [0067]    DSC shows an endotherm at 118.47° C. and 148.47° C. 
         [0068]    IR shows the absorptions at 3193, 2939, 2830, 2804, 1680, 1628, 1593, 1579, 1520, 1479, 1449, 1375, 1270, 1192, 1169, 965, 949, 869, 780, 712, 672 and 588±2 cm −1    
         [0069]    Aripiprazole form-I can be prepared by using other Aripiprazole acid salts, various solvents, and ante-solvents by following the similar procedure as in example-III and the results are given in the table-1 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 (Aripiprazole form-I) 
               
             
          
           
               
                   
                   
                 Organic 
                   
                   
               
               
                   
                   
                 polar 
               
               
                 S. No. 
                 Aripiprazole acid salt 
                 solvent 
                 Ante-solvent 
                 Yield 
               
               
                   
               
             
          
           
               
                 1 
                 p-Toluene sulfonate 
                 DMF 
                 — 
                 40.0% 
               
               
                 2 
                 p-Toluene sulfonate 
                 DMF 
                 Acetone 
                 78.3% 
               
               
                 3 
                 p-Toluene sulfonate 
                 DMF 
                 Cyclohexane 
                 42.8% 
               
               
                 4 
                 p-Toluene sulfonate 
                 DMF 
                 Ethyl acetate 
                 46.2% 
               
               
                 5 
                 p-Toluene sulfonate 
                 DMF 
                 n-Hexane 
                 40.8% 
               
               
                 6 
                 p-Toluene sulfonate 
                 DMF 
                 Methyl tert butyl 
                 54.3% 
               
               
                   
                   
                   
                 ether 
               
               
                 7 
                 p-Toluene sulfonate 
                 DMF 
                 n-Heptane 
                 45.7% 
               
               
                 8 
                 p-Toluene sulfonate 
                 DMF 
                 Di isopropyl ether 
                 51.6% 
               
               
                 9 
                 p-Toluene sulfonate 
                 DMA 
                 Methyl tert butyl 
                 48.5% 
               
               
                   
                   
                   
                 ether 
               
               
                 10 
                 Benzene sulfonate 
                 DMF 
                 Acetone 
                 68.4% 
               
               
                 11 
                 Citrate 
                 DMF 
                 Cyclohexane 
                 77.2% 
               
               
                 12 
                 Salicylate 
                 DMF 
                 n-Heptane 
                 56.2% 
               
               
                 13 
                 Hydro bromide 
                 DMF 
                 Cyclohexane 
                 81.3% 
               
               
                   
               
             
          
         
       
     
       Example-IV 
     Preparation of Aripiprazole Acetic Acid Solvate from Aripiprazole p-toluene Sulfonate 
       [0070]    Aripiprazole p-toluene sulfonate salt (100 g) is suspended in a mixture of isopropyl acetate (2000 ml), water (400 ml) and raised the temperature to 70° C.-75° C. Triethylamine (25.7 g) is added slowly over 20 min and maintained at 70° C.-75° C. for about 30 min., allowed to settle, and the layers are separated and the aqueous layer is extracted with isopropyl acetate (300 ml) at 70° C.-75° C. The organic layers are combined and washed with water (2×400 ml) at 70° C.-75° C. The reaction mass is concentrated to 900 ml by distillation of isopropyl acetate (m/c of the reaction mass becomes below 0.5%). Acetic acid (25 ml) is added, the temperature is raised to reflux (83° C. to 86° C.) and cyclohexane (900 ml) is slowly added at reflux temperature over 30 min. The reaction mass is maintained at reflux temperature (75° C. to 78° C.) for about 1 hr, then cooled to 63° C., seeded with Aripiprazole acetic acid solvate (500 mg) and further cooled to 35° C. The temperature is maintained at 25° C. to 35° C. for 30 min. The solid is filtered, washed with cyclohexane (50 ml) and dried at 40° C.-50° C. to constant weight. 
         [0071]    The dry wt of the Aripiprazole acetic acid solvate is 51 g (Yield: 72.65%). 
         [0072]    The XRD shows peaks at 10.1, 17.4, 18.0, 19.7, 23.3, 24.2, 27.8°±0.2° 2 theta 
         [0073]    DSC shows an endotherm at 125.7° C. 
         [0074]    IR shows the absorptions at 2947, 2901, 1674, 1521, 1381, 1274, 1172, 1048, 856, 781 cm −1 . 
         [0075]    Aripiprazole acetic acid solvate can be prepared by using other Aripiprazole acid salts, various solvents, and ante-solvents by following the similar procedure as in example-IV and the results are given in the table-2 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 (Aripiprazole acetic acid solvate) 
               
             
          
           
               
                 S. No 
                 Aripiprazole acid salt 
                 Organic solvent 
                 Ante-solvent 
                 Yield 
               
               
                   
               
             
          
           
               
                 1 
                 p-Toluene sulfonate 
                 Isopropyl 
                 n-Heptane 
                 72.65% 
               
               
                 2 
                 p-Toluene sulfonate 
                 Ethyl acetate 
                 Cyclohexane 
                 76.9% 
               
               
                 3 
                 p-Toluene sulfonate 
                 Toluene 
                 Cyclohexane 
                 54.8% 
               
               
                 4 
                 p-Toluene sulfonate 
                 Chloroform 
                 Cyclohexane 
                 68.4% 
               
               
                 5 
                 p-Toluene sulfonate 
                 Isopropyl 
                 n-Hexane 
                 83.6% 
               
               
                 6 
                 p-Toluene sulfonate 
                 Isopropyl 
                 Methyl tert 
                 77.1% 
               
               
                 7 
                 p-Toluene sulfonate 
                 Ethyl acetate 
                 n-Heptane 
                 81.5% 
               
               
                 8 
                 p-Toluene sulfonate 
                 Ethyl acetate 
                 n-Hexane 
                 77.2% 
               
               
                 9 
                 p-Toluene sulfonate 
                 Ethyl acetate 
                 Methyl tert 
                 75.7% 
               
               
                 10 
                 Benzene sulfonate 
                 Isopropyl 
                 Cyclohexane 
                 70.34% 
               
               
                 11 
                 Citrate 
                 Isopropyl 
                 Cyclohexane 
                 81.4% 
               
               
                 12 
                 Salicylate 
                 Isopropyl 
                 Cyclohexane 
                 49.1% 
               
               
                 13 
                 Hydro bromide 
                 Isopropyl 
                 Cyclohexane 
                 85.0% 
               
               
                   
               
             
          
         
       
     
       Example-V 
     Preparation of Aripiprazole Form-A from Aripiprazole p-toluene Sulfonate 
       [0076]    Suspend Aripiprazole p-toluene sulfonate salt (60 g) in a mixture of n-butanol (600 ml), water (240 ml) and add sodium hydroxide solution (4 g in 10 ml of water). Raise the temperature of the mass to 70° C.-75° C. and maintain at that temperature for about 15 min. Allow to settle, separate the layers, extract the aqueous layer with n-butanol (300 ml). Combine organic layers, wash with water (240 ml) at 70° C.-75° C. Cool the reaction mass to 10° C. and maintain at 10° C.-12° C. for 60 min. Filter the solid, wash the wet cake with n-butanol (30 ml) and dry at 40° C.-45° C. till constant weight. 
         [0077]    The dry wt of the Aripiprazole Form-A is 21 g (Yield: 49.9%). 
         [0078]    The product is identical with the reported Aripiprazole Form-A by its FTIR, DSC and X-ray diffraction values. 
         [0079]    Similarly Aripiprazole Form-A can be prepared by using other Aripiprazole acid salts, ethyl acetate, isopropyl acetate instead of n-Butanol, without distillation of solvent, by direct cooling following the similar procedure as in example-XV. 
       Example-VI 
     Preparation of Aripiprazole Form-D from Aripiprazole p-toluene Sulfonate 
       [0080]    Aripiprazole p-toluene sulfonate salt (60 g) is suspended in a mixture of n-butanol (600 ml), water (240 ml) and sodium hydroxide solution (4 g in 10 ml of water) is added. The temperature of the mass is raised to 70° C.-75° C. and maintained at that temperature for about 15 min. It is allowed to settle, the layers are separated, the aqueous layer is extracted with n-butanol (300 ml). The organic layer is combined, washed with water (240 ml) at 70° C.-75° C. and n-butanol is distilled off at temperature 75° C.-80° C. under vacuum till the reaction mass volume becomes 200 ml. Slowly cyclohexane (200 ml) is added at temperature 80° C. over 30 min and is maintained at 75° C.-80° C. for 1 hr. The reaction mass is cooled to 30° C. and maintained at 25° C.-30° C. for 30 min. The solid is filtered and the wet cake is washed with cyclohexane (50 ml) and dried at 40° C.-45° C. till constant weight. 
         [0081]    The dry wt of the Aripiprazole Form-D is 23.4 g (Yield: 55.6%). 
         [0082]    The product is identical with the reported Aripiprazole Form-D by its FTIR, DSC and X-ray diffraction values. 
         [0083]    Similarly Aripiprazole Form-D can be prepared by using other Aripiprazole acid salts, using the solvents such as methyl ethyl ketone, THF and cyclohexane, n-hexane, n-heptane as ante-solvent without distillation of first solvent, addition of ante-solvent and cooling. 
       Example-VII 
     Preparation of Aripiprazole Methanol Solvate from Aripiprazole p-toluene Sulfonate 
       [0084]    Aripiprazole p-toluene sulfonate salt (50 g) is suspended in a mixture of isopropyl acetate (1000 ml), water (200 ml) and sodium hydroxide solution (10 g in 10 ml of water) is added. The temperature of the reaction mass is raised to 70° C.-75° C. and maintained for about 30 min. The pH of the reaction mass is adjusted to 11.0 with sodium hydroxide solution. The layers are allowed to settle. The layers are separated and the aqueous layer is extracted with isopropyl acetate (150 ml) at 70° C.-75° C. The organic layers are washed with water (2×200 ml) at 70° C.-75° C. The reaction mass is concentrated to 400 ml by distilling off isopropyl acetate. Methanol (200 ml) is added, and the temperature is raised to reflux and maintained at reflux for about 30 min. The reaction mass is cooled to 35° C., the solid is filtered, washed with methanol (100 ml) and suck dried. 
         [0085]    The wt of the Aripiprazole methanol solvate is 36 g (Yield: 95.4%). 
         [0086]    HPLC purity: 99.39%, Methanol content: 6.57% 
         [0087]    Elemental analysis: C, 59.88%, H, 6.60%, N, 8.62% and calculated values for C 21 H 31 Cl 2 N 3 O 3 . C, 59.95%, H, 6.45%, N, 8.74% 
         [0088]    IR Spectrum (KBr, cm −1 ): 3196, 3108, 2948, 2819, 1675, 1628, 1595, 1578, 1522, 1449, 1378, 1335, 1274, 1243, 1197, 1173, 1140, 1127, 1040, 997, 960, 859, 830, 809, 784, 748, 713 and 532. 
         [0089]      1 H NMR (300 MHz, CDCl 3 , ppm): 1.65-1.85 (m, 4H), 2.49 (t, 2H), 2.51 (t, 2H), 2.59-2.64 (m, 4H), 2.89 (t, 2H), 3.08 (m, 4H), 3.49 (s, 3H), 3.97 (t, 2H), 6.32 (d, 1H), 6.51-6.54 (dd, 1H), 6.94-6.97 (m, 1H), 7.05 (d, 1H), 7.11-7.17 (m, 2H), 8.04 (s, 1H). 
         [0090]      13 C NMR (300 MHz, DMSO-d 6 , ppm): 23.19, 24.38, 27.14, 30.90, 50.17, 51.08, 53.12, 58.07, 67.7, 102.2, 108.7, 115.5, 118.5, 124.39, 127.31, 127.34, 128.4, 133.8, 138.1, 151.1, 158.5 and 172.41. 
         [0091]    Mass Spectrum (M+): 448.2, 285.1, 218.1, 176.0, and 164.1. 
         [0092]    The XRD shows the peaks at 9.4, 10.7, 11.4, 11.8, 12.3, 13.3, 17.3, 18.4, 19.8, 23.3, 24.3, 25.6, 26.8, 28.0, 28.9, 31.2°±0.2 2 theta values 
         [0093]    DSC shows endotherm (peaks) at 113, 139° C. 
         [0094]    Aripiprazole methanol solvate can be prepared similarly by using other Aripiprazole acid salts and solvents by following the similar procedure as in example-IV and the results are given in the table-3 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 (Aripiprazole methanol solvate) 
               
             
          
           
               
                 S. No 
                 Aripiprazole acid salt 
                 Organic solvent 
                 Second solvent 
                 Yield 
               
               
                   
               
               
                 1 
                 Benzene sulfonate 
                 Isopropyl 
                 Methanol 
                 92.3% 
               
               
                 2 
                 Citrate 
                 Isopropyl 
                 Methanol 
                 90.7% 
               
               
                 3 
                 Salicylate 
                 Isopropyl 
                 Methanol 
                 94.1% 
               
               
                 4 
                 Hydro bromide 
                 Isopropyl 
                 Methanol 
                 89.7% 
               
               
                   
               
             
          
         
       
     
       Example-VII 
     Preparation of Aripiprazole Acetic Acid Solvate from Aripiprazole Methanol Solvate 
       [0095]    Aripiprazole methanol solvate (50 g) is suspended in isopropyl acetate (600 ml) and acetic acid (7 ml) is added. The temperature is raised to reflux and cyclohexane (600 ml) is slowly added at reflux temperature over 20 min. The mass is maintained at reflux temperature for about 1 hr, cooled to 60° C. and seeded with Aripiprazole acetic acid solvate (200 mg). The reaction mass is cooled to 30° C. and maintained at 25° C.-30° C. for 30 min. Filter, wash the wet cake with cyclohexane (50 ml) and dry at 40° C.-50° C. till constant weight. 
         [0096]    The dry wt of Aripiprazole acetic acid solvate is 42 g (Yield 90.0%) 
         [0097]    The product is identical with Aripiprazole acetic acid solvate by its IR, DSC and X-ray diffraction pattern. 
       Example-IX 
     Preparation of Aripiprazole Type-I Crystals from Aripiprazole Methanol Solvate 
       [0098]    Aripiprazole methanol solvate (50 g) is suspended in ethanol (600 ml), the temperature of the reaction mass is raised to reflux and maintained at reflux for about 2 hrs. The reaction mass is cooled to 30° C., filtered, washed the wet cake with ethanol (50 ml) and dried at 45° C.-50° C. till constant weight. 
         [0099]    The dry weight of Aripiprazole Type-I crystals is 43 g (78.5%) 
         [0100]    Similarly Aripiprazole Type-I crystals can be prepared by treating the Aripiprazole acetic acid solvate with ethanol. 
       Example-X 
     Preparation of Aripiprazole Form-B from Aripiprazole Methanol Solvate 
       [0101]    Aripiprazole methanol solvate (50 g) is suspended in Isopropyl acetate (600 ml), the temperature is raised to reflux and maintained at reflux temperature for about 2 hrs. The reaction mass is cooled, filtered, the wet cake is washed with isopropyl acetate (50 ml) and dried at 50° C.-60° C. till becomes constant weight. 
         [0102]    The dry wt of Aripiprazole Form-B is 40 g (Yield 85.7%) 
         [0103]    Similarly Aripiprazole Form-B can be prepared by treating the Aripiprazole methanol solvate or Aripiprazole acetic acid solvate with isopropyl acetate, ethyl acetate or by directly drying the Aripiprazole methanol solvate at 80° C. for about 12 hrs. 
       Example-XI 
     Preparation of Aripiprazole Form-D from Aripiprazole Methanol Solvate 
       [0104]    Aripiprazole methanol solvate (50 g) is suspended in acetonitrile (600 ml), the temperature is raised to reflux and maintained at reflux for about 2 hrs. The reaction mass is cooled to 25° C., the solid is filtered, the wet cake is washed with acetonitrile (50 ml) and dried at 55° C.-60° C. till becomes constant weight. 
         [0105]    The dry weight of Aripiprazole Form-D is 43.0 g (Yield 91.4%) 
         [0106]    Similarly Aripiprazole Form-D can be prepared by treating the Aripiprazole methanol solvate or Aripiprazole acetic acid solvate with acetonitrile, THF/n-Heptane, ethyl acetate/n-heptane. 
       Example-XII 
     Preparation of Aripiprazole Form-A from Aripiprazole Methanol Solvate 
       [0107]    Aripiprazole methanol solvate (50 g) is suspended in 30% aqueous ethanol (600 ml), and the temperature is raised to reflux and maintained at reflux for about 2 hrs. The reaction mass is cooled to 25° C., the solid is filtered, the wet cake is washed with aqueous ethanol (50 ml) and dried at 55° C.-60° C. till becomes constant weight. 
         [0108]    The dry weight of Aripiprazole Form-A is 38.0 g (Yield 77.8%) 
         [0109]    Similarly Aripiprazole Form-A can be prepared by treating the Aripiprazole methanol solvate or Aripiprazole acetic acid solvate with aqueous ethanol, water. 
       Example-XIII 
     Preparation of Aripiprazole p-toluenesulfonate 
     Step-1: 
       [0110]    Sodium hydroxide (29.5 g, 0.737 mole) is added to a suspension of 7-Hydroxy carbostyril (100 g, 0.613 mole) in isopropyl alcohol (1850 ml) and mixed at 25° C. to 30° C. for about 30 min. Tetra butyl ammonium bromide is added (5 g, 0.015 mole) followed by 1,4-Dibromo butane (530 g, 2.45 mole), raised to reflux and maintained at reflux temperature 80° C.-85° C. for 3 hrs. The insolubles are filtered in hot condition, and isopropyl alcohol is distilled off from the filtrate under vacuum at temperature up to 110° C.-115° C. The reaction mass is cooled and isopropyl alcohol (300 ml) is added to the reaction mass, maintained at 30° C.-35° C. for 1 hr. The mass is further cooled and maintained at 20° C.-22° C. for 2 hrs, filtered, washed with isopropyl alcohol (50 ml) to give the wet cake of about 250 g. The wet cake (250 g) is suspended in n-hexane (300 ml), raised the temperature to reflux and maintained for about 60 min. The reaction mass is cooled to a temperature of 25° C.-35° C. and maintained for 1 hr. The mass is filtered; washed and dried the wet cake at 40° C. to 50° C. till becomes constant weight. 
         [0111]    The dry weight of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril is 135 g (Yield: 73.8%). 
       Step-2: 
       [0112]    Sodium iodide (63.7 g, 0.424 mole) is suspended in acetonitrile (1275 ml), mixed for about 10 min and 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (100 g, 0.335 mole) is added. The temperature is raised to reflux maintained for 30 min and cooled to 35° C. 1-(2,3-dichloro phenyl)piperazine (81.5 g, 0.352 mole) is added followed by triethylamine (51.5 g, 0.51 mole) at 25° C.-35° C. to the reaction mass. The temperature of the reaction mass is raised to reflux and maintained at reflux temperature 3 hrs. Acetonitrile is distilled off at temperature below 45° C. under reduced pressure; the residual mass is cooled to 35° C. Methylene chloride (1000 ml), water (500 ml) are added, and the total mass is mixed for 15 min, allowed to settle, the layers are separated and the aqueous layer is extracted with methylene chloride (500 ml). The combined organic layer is washed with water (500 ml) and dried the organic layer over anhydrous sodium sulphate (15 g). Methylene chloride is distilled out initially at atmospheric pressure finally under vacuum. Further methylene chloride (1000 ml) is added and mixed for 15 min to get a clear solution. p-toluene sulfonic acid solution in ethyl acetate (56 g, in 400 ml) is added to the clear solution at a temperature of 25° C.-35° C. over 60 min and maintained at 25° C.-35° C. for 2 hrs. The solid is filtered, the wet cake is washed with ethyl acetate (50 ml) and dried at 40° C.-50° C. till becomes constant weight. The dried material is suspended in methanol (650 ml), the temperature of the mass is raise to 40° C.-45° C. and maintained at that temperature for 30 min. The mass is cooled to 25° C.-35° C. and maintained for 60 min. Filtered, washed the wet cake with methanol (65 ml) and dried at 40° C.-50° C. till becomes constant weight. 
         [0113]    The dry weight of Aripiprazole p-toluene sulfonate salt is 110.5 g (51.6%). 
         [0114]    Purity by HPLC is 98.6%, Water content: 2.86% 
         [0115]    Elemental analysis: C, 56.23%, H, 6.13%, N, 6.53%, S, 4.62% and calculated values for C 30 H 35 Cl 2 N 3 O 5 S.H 2 O C, 56.42%, H, 5.84%, N, 6.58%, S, 5.02% 
         [0116]    IR Spectrum (KBr, cm −1 ): 3488, 3208, 3130, 3069, 3026, 2954, 1661, 1621, 1595, 1520, 1474, 1448, 1395, 1373, 1333, 1312, 1264, 1224, 1189, 1170, 1117, 1092, 1057, 1031, 1009, 966, 950, 865, 836, 824, 817, 786, 764, 682, 565 and 547 
         [0117]      1 H NMR (300 MHz, CDCl 3 , ppm): 1.75-1.82 (m, 4H), 2.28 (s, 3H), 2.41 (t, 2H), 2.43 (t, 2H), 2.49-2.54 (m, 4H), 2.79 (t, 2H), 2.99-3.64 (t, 2H), 2.99-3.64 (m, 2H), 6.44 (d, 1H), 6.48-6.52 (dd, 1H), 6.48-6.52 (m, 2H), 7.05-7.12 (m, 1H), 7.05-7.12 (m, 2H), 7.20-7.26 (dd, 1H), 7.33-7.48 (m, 2H), 9.41 (s, OH), 10.02 (s, NH). 
         [0118]      13 C NMR (300 MHz, CDCl 3 , ppm): 20.32, 20.72, 23.97, 25.76, 30.72, 47.87, 51.31, 55.32, 66.64, 101.7, 107.49, 115.66, 119.86, 125.35, 125.46, 126.08, 128.07, 128.37, 128.60, 132.72, 137.74, 139.20, 145.4, 149.38, 157.67 and 170.26. 
         [0119]    Mass Spectrum (M+): 448 
       Example-XIV 
     Preparation of Aripiprazole p-toluenesulfonate (Alternate Procedure) 
     Step-1: 
       [0120]    The step-1 is carried out in the same way as given in example-XII. 
       Step-2: 
       [0121]    Sodium iodide (69.5 g, 0.463 mole) is suspended in methanol (1500 ml), mixed for about 10 min and 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (100 g, 0.335 mole) is charged into the mixture. The reaction mass is maintained at 25° C.-35° C. for 30 min and triethylamine (69 g, 0.68 mole) is added followed by 1-(2,3-dichloro phenyl)piperazine (90.0 g, 0.39 mole) at 25° C.-35° C. to the reaction mass. The temperature of the reaction mass is raised to reflux and maintained at reflux temperature for 15 hrs. The reaction mass is cooled to 25° C.-35° C. and maintained for 30 min. The solid is filtered, and the wet cake is washed with methanol (100 ml). The weight of the wet cake is 120 g. The wet cake is dissolved in methylene chloride (1000 ml) and p-toluene sulfonic acid solution in ethyl acetate (48 g, in 400 ml) is added at temperature of 20° C.-25° C. over 60 min and maintained at 20° C.-25° C. for 3 hrs. The solid is filtered, and the wet cake is washed with mixture of 1:1 methylene chloride, ethyl acetate (100 ml) and dried at 40° C.-50° C. till becomes constant weight. The dried material is suspended in methanol (650 ml), the temperature is raised to 40° C.-45° C. and maintained the mass at that temperature of for 30 min. The mass is cooled and maintained at 25° C.-35° C. for 60 min. The wet cake is filtered, washed with methanol (65 ml) and dried at 40° C.-45° C. till becomes constant weight. 
         [0122]    The dry weight of Aripiprazole p-toluene sulfonate-salt is 140 g (Yield 65.44%). 
         [0123]    Purity by HPLC is 0.99.1% 
       Example-XV 
     Preparation of Aripiprazole Benzene Sulfonate 
     Step-1: 
       [0124]    The step-1 is carried out in the same way as given in example-XII. 
       Step-2: 
       [0125]    Sodium iodide (69.5 g, 0.463 mole) is suspended in methanol (1500 ml), mixed for about 10 min and 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (100 g, 0.335 mole) is charged. The reaction mass temperature is raised to 25° C.-35° C. for 30 min and triethylamine (69 g, 0.68 mole) is added followed by 1-(2,3-dichloro phenyl)piperazine (90.0 g, 0.39 mole) at 25° C.-35° C. to the reaction mass. The temperature of the reaction mass is raised to reflux and maintained at reflux temperature for 15 hrs; The reaction mass is cooled to 25° C.-35° C. and maintained for 30 min. The solid is filtered, washed the wet cake with methanol (100 ml). The wet cake weight is 120 g. The wet cake is dissolved in methylene chloride (600 ml) and benzene sulfonic acid solution in ethyl acetate (44.6 g, in 400 ml) is added at a temperature of 20° C.-25° C. over 30 min and is maintained at 20° C.-25° C. for 30 min. The methylene chloride is distilled off under vacuum, ethyl acetate (600 ml) is added and maintained at 20° C.-22° C. for 45 min. The solid is filtered, and the wet cake is washed with ethyl acetate (100 ml) and dried at 40° C.-50° C. till becomes constant weight. The dried material is suspended in methanol (650 ml), the temperature of the mass is raised to 40° C.-45° C. and maintained for 30 min. The reaction mass is cooled to 25° C.-30° C. and maintained for 30 min. The wet cake is filtered and washed with methanol (65 ml) and dry at 40° C.-45° C. till becomes constant weight. 
         [0126]    The dry weight of Aripiprazole benzene sulfonate salt is 88.4 g (Yield 43.5%). 
         [0127]    Purity by HPLC is 98.4% 
         [0128]    Elemental analysis: C, 57.48%, H, 5.41%, N, 6.98% and calculated values for C 29 H 33 Cl 2 N 3 O 5 S. C: 57.42%, H, 5.48%, N, 6.93% 
         [0129]    IR Spectrum (KBr, cm −1 ): 3446, 3194, 2979, 2901, 2706, 2619, 1672, 1627, 1596, 1580, 1521, 1479, 144, 6, 1422, 1388, 1331, 1319, 1269, 1234, 1191, 1167, 1119, 1068, 1054, 1032, 1015, 996, 957, 943, 851, 807, 784, 767, 727, 713, 698, 613, 566 and 551. 
         [0130]      1 H NMR (300 MHz, DMSO-ds, ppm): 1.75-1.91 (m, 4H), 2.41 (t, 2H), 2.79 (t, 2H), 2.99-3.64 (m, 10H), 3.94 (t, 3H), 6.44 (d, 1H), 6.48-6.52 (dd, 1H), 7.06 (d, 1H), 7.20-7.41 (m, 6H), 7.58-7.63 (m, 2H), 9.42 (brs, 1H), 10.02 (s, 1H). 
         [0131]      13 C NMR (300 MHz, DMSO-d 6 , ppm): 20.82, 24.48, 26.26, 31.28, 48.38, 48.30, 51.80, 51.81, 55.81, 67.13, 102.26, 108.0, 116.16, 120.38, 125.86, 125.90, 125.95, 126.59, 128.1, 128.15, 128.88, 128.97, 129.13, 133.23, 139.71, 148.62, 149.88, 158.18 and 170.76. 
         [0132]    Mass Spectrum (M+): 448 
       Example-XVI 
     Preparation of Aripiprazole Salicylate 
     Step-1: 
       [0133]    The step-1 is carried out in the same way as given in example-XII. 
       Step-2: 
       [0134]    Sodium iodide (69.5 g, 0.463 mole) is suspended in methanol (1500 ml) and 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (100 g, 0.335 mole) is added. The reaction mass is maintained at 25° C.-35° C. for 30 min and triethylamine (69 g, 0.68 mole) is added followed by 1-(2,3-dichloro phenyl)piperazine (90.0 g, 0.39 mole) at 25° C.-35° C. to the reaction mass. The temperature of the reaction mass is raised to reflux and maintained at reflux temperature for 15 hrs. The reaction mass is cooled to 25° C.-35° C. and maintained for 30 min. The solid is cooled and filtered. The wet cake is washed with methanol (100 ml). The wet cake is dissolved in methylene chloride (600 ml) and salicylic acid solution in ethyl acetate (37.0 g, in 400 ml) is added at temperature of 20° C.-25° C. over 20 min and maintained at 20° C.-25° C. for 60 min. The solid is filtered, washed the wet cake with ethyl acetate (120 ml) and dried at 40° C.-50° C. till becomes constant weight. The dried material is suspended in methanol (600 ml), the mass is raise to a temperature of 40° C.-45° C. and maintained for 30 min. The mass is cooled to a temperature of 25° C.-30° C. and maintained for 30 min. The wet cake is filter, washed with methanol (60 ml) and dried at 40° C.-45° C. till becomes constant weight. 
         [0135]    The dry weight of Aripiprazole salicylate salt is 112.0 g (Yield 57.0%). 
         [0136]    Purity by HPLC is 0.98.24% 
         [0137]    Elemental analysis: C, 60.09%, H, 5.55%, N, 7.12% and calculated values for C 30 H 33 Cl 2 N 3 O 5 . C, 61.44%, H, 5.67%, N, 7.16% 
         [0138]    IR Spectrum (KBr, cm −1 ): 3436, 3203, 3059, 2953, 2879, 2839, 1675, 1626, 1593, 1577, 1520, 1486, 1453, 1423, 1381, 1291, 1276, 1260, 1193, 1173, 1137, 1087, 1044, 1025, 979, 960, 941, 859, 830, 810, 795, 764, 708, 667, 586 and 564. 
         [0139]      1 H NMR (300 MHz, DMSO-d 6 , ppm): 1.75 (s, 4H); 2.39 (t, 2H), 2.79 (t, 2H), 2.92-3.17 (m, 10H), 3.99 (t, 2H), 6.45 (d, 1H), 6.48-6.50 (dd, 1H), 6.71-6.78 (m, 2H), 7.04 (d, 1H), 7.15-7.36 (m, 4H), 7.71-7.75 (dd, 1H). 
         [0140]      13 C NMR (300 MHz, DMSO-d 6 , ppm): 20.86, 24.00, 26.10, 30.74, 48.70, 48.72, 51.40, 51.45, 55.74, 66.88, 101.74, 107.56, 115.56, 116.18, 117.34, 117.78, 119.65, 124.96, 126.07, 128.34, 128.51, 130.23; 132.71, 132.90, 139.17, 149.98, 157.74, 161.82, 170.26 and 172.62. 
         [0141]    Mass Spectrum (M+): 448 
       Example-XVII 
     Preparation of Aripiprazole Citrate 
       [0142]    Aripiprazole citrate salt can be prepared similarly by using the citric acid instead of salicylic acid by following the same procedure described as in example-XV 
         [0000]    The dry weight of Aripiprazole citrate salt is 115.7 g (Yield 53.9%) 
         [0143]    Purity by HPLC is 98.91% 
         [0000]    Elemental analysis: C, 53.80%, H, 5.37%, N, 6.35% and calculated values for C 29 H 35 Cl 2 N 3 O 9 . C, 54.38%, H, 5.51%, N, 6.56% 
         [0144]    IR Spectrum (KBr, cm −1 ): 3469, 3211, 3097, 3065, 2969, 2844, 2726, 2623, 1728, 1639, 1589, 1518, 1452, 1403, 1318, 1275, 1261, 1194, 1170, 1096, 1052, 1045, 1030, 1010, 958, 952, 931, 894, 864, 826, 785, 734, 712, 670, 640 and 566. 
         [0145]      1 H NMR (300 MHz, DMSO-d 6 , ppm): 1.72 (brs, 4H), 2.39-2.88 (m, 16H), 3.09 (brs, 2H), 3.93 (t, 2H), 6.44 (d, 1H), 6.48-6.51 (dd, 1H), 7.04 (d, 1H), 7.17 (t, 1H), 7.33 (d, 2H), 9.99 (s, 1H). 
         [0146]      13 C NMR (300 MHz, DMSO-d 6 , ppm): 21.49, 24.03, 26.27, 30.78, 43.35, 43.55, 43.57, 49.40, 49.42, 51.95, 51.97, 56.31, 67.02, 72.03, 101.78, 107.58, 115.58, 119.71, 124.82, 126.09, 128.41, 128.53, 132.71, 139.21, 150.37, 157.83, 170.33, 171.43, 171.45 and 175.90. 
         [0147]    Mass Spectrum (M+): 448 
       Example-XVIII 
     Preparation of Aripiprazole Hydro Bromide Salt 
     Step-1: 
       [0148]    The step-1 is to be carried out in the same way as given in example-XII. 
       Step-2: 
       [0149]    Sodium iodide (69.5 g, 0.463 mole) is suspended in methanol (1500 ml), mixed for about 10 min and charged 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (100 g, 0.335 mole): The reaction mass is maintained at 25° C.-35° C. for 30 min and triethylamine (69 g, 0.68 mole) is added followed by 1-(2,3-dichloro phenyl)piperazine (90.0 g, 0.39 mole) at 25° C.-35° C. The temperature of the reaction mass is raised to reflux and maintained at reflux temperature for 15 hrs. Then reaction mass is cooled to 25° C.-35° C. for 30 min. The solid is filtered and the wet cake is washed with methanol (100 ml). The wet cake is dissolved in methylene chloride (600 ml), and aqueous hydrobromic acid (48%, 30 ml) is added at a temperature of 20° C.-25° C. over 20 min and maintained at 20° C.-25° C. for 60 min. The solid is filtered and the wet cake is washed with methylene chloride (100 ml) and dried at 40° C.-50° C. till becomes constant weight. The dry material is suspended in methanol (750 ml), the temperature of the mass is raised to 40° C.-45° C. and maintained for 30 min. The mass is cooled to 25° C.-30° C. and maintained for 30 min. The wet cake filtered and washed with methanol (100 ml) and dry at 40° C.-45° C. till becomes-constant weight. 
         [0150]    The dry weight of Aripiprazole hydro bromide salt is 90.8 g (52.7%) 
         [0151]    Purity by HPLC is 98.18% 
         [0000]    Elemental analysis: C, 51.99%, H, 5.40%, N, 7.66% and calculated values for C 23 H 28 BrCl 2 N 3 O 2 . C, 52.19%, H, 5.33%, N, 7.94% 
         [0152]    IR Spectrum (KBr, cm −1 ): 3426, 3191, 3057, 2953, 2651, 2587, 1692, 1626, 1592, 1520, 1483, 1455, 1378, 1333, 1311, 1271′, 1196, 1171, 1133, 1033, 960, 866, 813, 771, 737, 707 and 569. 
         [0153]      1 H NMR (300 MHz, DMSO-d 6 , ppm): 1.75-1.85 (m, 4H), 2.41 (t, 2H), 2.79 (t, 2H), 3.03-3.65 (m, 10H), 3.95 (t, 2H), 6.44 (d, 1H), 6.49-6.52 (dd, 1H), 7.06 (d, 1H), 7.21-7.41 (m, 3H), 9.56 (brs, 1H), 10.02 (s, 1H). 
         [0154]      13 C NMR (300 MHz, DMSO-d 6 , ppm): 20.17, 23.96, 25.85, 30.71, 47.65, 47.67, 51.15, 51.16, 55.22, 66.68, 101.77, 107.48, 115.62, 119.79, 125.27, 126.02, 128.33, 128.60, 132.69, 139.16, 149.38, 157.64 and 170.21. 
         [0155]    Mass Spectrum (M+): 448 
       Example-XIX 
     Preparation of Aripiprazole Methanol Solvate from Aripiprazole Acetic Acid Solvate 
       [0156]    Aripiprazole acetic acid solvate (50 g) is suspended in methanol (600 ml), the temperature is raised to reflux and maintained at reflux temperature for about 2 hrs. The reaction mass is cooled, filtered, washed with methanol (50 ml) and dry at 40° C.-50° C. for 6 hrs. 
         [0157]    The dry wt of Aripiprazole methanol solvate is 46 g (Yield 84.9%) 
         [0158]    Its DSC, IR and XRD identified the product as Aripiprazole methanol solvate