Methods of preparing aripiprazole crystalline forms

Abstract

The invention encompasses aripiprazole crystalline forms, methods of preparing the same, and pharmaceutical compositions having aripiprazole crystalline forms.

1 . A method of preparing Form II by slurrying crystalline Compound 2 in acetone until Form II is formed. 
     
     
         2 . The method of  claim 1 , wherein crystalline Compound 2 is slurried in acetone for about one to about 24 hours. 
     
     
         3 . The method of  claim 1 , wherein crystalline Compound 2 is slurried in acetone for about three to about 24 hours. 
     
     
         4 . The method of  claim 1 , wherein crystalline Compound 2 is slurried in acetone for about five hours. 
     
     
         5 . The method of  claim 1 , wherein Form II has an average size of about 300 microns or less. 
     
     
         6 . The method of  claim 1  further comprising drying the Form II at about 50° C. 
     
     
         7 . A method of preparing at least one of crystalline Compound 1, crystalline Compound 2, Form D, Form I, Form II, Form VI, Form VIII, Form X, Form XI, or Form XII comprising:
 dissolving aripiprazole in a solvent to form a mixture, heating the mixture to between about 40° C. and about 132° C.;   cooling the mixture until at least one of aripiprazole crystalline compound 1, crystalline compound 2, crystalline Form I, II, VI, VIII, X, XI, or XII precipitates; and   collecting the aripiprazole.   
     
     
         8 . The method of  claim 7 , wherein aripiprazole is dissolved in a solvent comprising at least one of C 3-6  ketones, C 1-6  nitrites, C 1-4  alcohols, C 1-6  halogenated alkanes, C 1-6  amines, C 2-6  amides, C 2-6  esters, C 2-6  ethers, C 1-6  sulfoxides, or C 4-10  aromatics. 
     
     
         9 . The method of  claim 8 , wherein aripiprazole is dissolved in a solvent comprising at least one of acetone, acetonitrile, trichloroacetonitrile, methanol, ethanol, n-propanol, isobutanol, propylene glycol, methylethylketone, tetrahydrofuran, DMF, piperidine, pyridine, xylene, toluene, cyclohexanamide, diethylamine, hexylamine, dimethylsulfoxide, ethyl acetate, butyl acetate, dichloromethane, dibromomethane, chloroform, 1-bromopropane, 1,4-dioxane, 1,2-diaminoethane, 1,4-dibromobutane, isopropanol, 1-butanol, 2-dimethylaminoethanol, cyclopropylmethylketone, or isobutlymethylketone. 
     
     
         10 . A method of preparing crystalline Compound 2, comprising: dissolving aripiprazole in a solvent to form a mixture, heating the mixture to about 40° C. to about 132° C., cooling the mixture until crystalline compound 2 precipitates, and collecting the precipitated crystalline compound 2. 
     
     
         11 . The method of  claim 10 , wherein aripiprazole is dissolved in a solvent comprising at least one of C 3-6  ketones, C 1-6  nitriles, C 1-4  alcohols, C 1 -6 halogenated alkanes, C 1-6  amines, C 2 -6 amides, C 2-6  esters, C 2-6  ethers, C 1-6  sulfoxides, and C 4-10  aromatics. 
     
     
         12 . The method of  claim 11 , wherein aripiprazole is dissolved in a solvent comprising at least one of chloroform, tetrahydrofuran, diethylamine, acetone, acetonitrile, piperidine, butylacetate, or DMF. 
     
     
         13 . The method of  claim 7  or  10 , wherein the mixture of aripiprazole and solvent is heated to the lower of about the boiling point of the solvent or aripiprazole's melting point. 
     
     
         14 . The method of  claim 7  or  10 , wherein the cooling step is carried out at a temperature of about 4° C. 
     
     
         15 . The method of  claim 14 , wherein the cooling step is carried out for about 15 hours. 
     
     
         16 . The method of  claim 7  or  10  further comprising drying the aripiprazole precipitate. 
     
     
         17 . A method of preparing at least one of aripiprazole crystalline compound 1, crystalline compound 2, crystalline form D, II, XII or XIX, comprising: dissolving aripiprazole in a solvent to form a mixture, heating the mixture to the solvent's boiling point until aripiprazole dissolves, cooling the mixture, adding a co-solvent to the mixture of aripiprazole and solvent until at least one of aripiprazole crystalline compound 1, crystalline compound 2, crystalline Form D, II, XII, or XIX precipitates, and collecting the aripiprazole. 
     
     
         18 . The method of  claim 17 , wherein the solvent used is at least one of the group comprising C 2-6  esters, C 2-6  ethers, methylethylketones, or C 1-6  halogenated alkanes. 
     
     
         19 . The method of  claim 18 , wherein the solvent used is at least one of ethyl acetate, methylethylketone, chloroform, or tetrahydrofuran. 
     
     
         20 . The method of  claim 17 , wherein the co-solvent is at least one of water, C 1-4  alcohol, ether, or acetone. 
     
     
         21 . The method of  claim 20 , wherein the co-solvent is at least one of water, methanol, ethanol, acetone, ether, or 2-propanol. 
     
     
         22 . A method of preparing aripiprazole crystalline form II comprising: providing aripiprazole crystalline compound 1; and drying the aripiprazole to obtain aripiprazole crystalline form II. 
     
     
         23 . The method of  claim 22 , wherein the drying step is performed at a temperature of about 35° C. 
     
     
         24 . The method of  claim 22 , wherein the drying step is performed at a pressure of less than about 100 mm Hg