Crystalline ziprasidone HCI and processes for preparation thereof

Abstract

Provided is crystalline ziprasidone HCl and processes for preparation thereof.

1 . A process for preparing color-improved crystalline ziprasidone HCl form A, comprising: 
 a) combining ziprasidone base with a mixture of acetic acid or formic acid in ethanol, methanol, water or mixtures thereof to obtain a solution;    b) cooling the solution to about −5° C. to about 15° C.;    c) adding active carbon, tonsil, alumina, silica gel, cellite, or mixtures thereof to the solution;    d) adding aqueous HCl to the solution to precipitate ziprasidone HCl form A; and    e) recovering the ziprasidone HCl form A.    
   
   
       2 . A process for reducing the level of residual solvents in ziprasidone HCl form A, comprising drying the ziprasidone HCl at a temperature of about 50° C. to about 110° C. at a pressure of about 0.1 mmHg to about 20 mmHg to obtain ziprasidone HCl having 500 ppm to 2000 ppm of residual solvents.  
   
   
       3 . The process of  claim 2 , wherein the drying takes place at a temperature of 60° C. to 100° C.  
   
   
       4 . A process for increasing the water content of ziprasidone HCl form A, comprising exposing the dried ziprasidone HCl under water vapor at a relative humidity of about 40% to about 100% at a temperature of about 20° C. to 60° C., to obtain ziprasidone HCl having a water content of about 5% to about 6%.  
   
   
       5 . A process for increasing the water content of ziprasidone HCl form A, comprising humidifying the dried ziprasidone HCl in a humid air fluidized bed drier equipped with a water spraying system, wherein the temperature of the inlet water is at least 50° C., to obtain ziprasidone HCl having a water content of about 5% to about 6%.  
   
   
       6 . A process for increasing the water content of ziprasidone HCl form A, comprising increasing the water content of the dried ziprasidone HCl by wet granulation to obtain ziprasidone HCl having a water content of about 5% to about 6% or about 10% to about 12% or about 18% to about 20%.  
   
   
       7 . A process for preparing ziprasidone HCl hemihydrate, comprising: 
 a) dissolving crystalline ziprasidone base in an organic solvent to form a solution;    b) adding aqueous HCl to the solution at a temperature of about 40° C. to about 80° C.; and    c) recovering ziprasidone HCl hemihydrate.    
   
   
       8 . The process of  claim 7 , wherein the organic solvent is tetrahydrofuran.  
   
   
       9 . The process of  claim 7 , wherein the organic solvent is dimethylacetamide.  
   
   
       10 . The process of  claim 7 , wherein the organic solvent is ethanol.  
   
   
       11 . A process for preparing ziprasidone HCl hemihydrate, comprising: 
 a) adding crystalline ziprasidone base to an organic solvent to form a slurry;    b) adding an HCl solution to the slurry at a temperature of about 40° C. to about 80° C.; and    c) recovering ziprasidone HCl hemihydrate.    
   
   
       12 . The process of  claim 11 , wherein the organic solvent is a C 2  to C 4  alcohol.  
   
   
       13 . The process of  claim 11 , wherein the organic solvent is methanol and the recovery step comprises drying the ziprasidone HCl in an air-over.  
   
   
       14 . A process for preparing ziprasidone HCl anhydrous, comprising: 
 a) adding crystalline ziprasidone base to methanol to form a slurry;    b) adding an HCl solution to the slurry at a temperature of about 40° C. to about 80° C.; and    c) recovering ziprasidone HCl anhydrous.    
   
   
       15 . A process for preparing ziprasidone HCl anhydrous, comprising: 
 a) adding crystalline ziprasidone base to ethanol to form a slurry;    b) adding HCl gas to the slurry at a temperature of about 40° C. to about 80° C.; and    c) recovering ziprasidone HCl anhydrous.    
   
   
       16 . A process for reducing color impurities in crystalline ziprasidone HCl form A with 500 ppm to 2000 ppm of residual solvents and about 5% to about 6% water content, comprising: 
 a) dissolving ziprasidone base in a mixture of acetic acid or formic acid in ethanol, methanol, other alkanols, water or mixtures thereof;    b) cooling the solution to about −5° C. to about 15° C.;    c) adding active carbon, tonsil, alumina, silica gel, or cellite, or mixtures thereof to the solution;    d) adding aqueous HCl to the solution; and    e) recovering ziprasidone HCl form A.    f) drying the ziprasidone HCl at a temperature of about 50° C. to about 110° C. at a pressure of about 0.1 mmHg to about 20 mmHg; and    g) exposing the dried ziprasidone HCl under water vapor at a relative humidity of about 40% to about 100% at a temperature of about 20° C. to 60° C.    
   
   
       17 . The ziprasidone HCl prepared by the process of  claim 1 .  
   
   
       18 . Crystalline ziprasidone HCl form A having 500 ppm to 2000 ppm residual solvents.  
   
   
       19 . Crystalline ziprasidone HCl form A having a water content of about 5% to about 6%.  
   
   
       20 . Crystalline ziprasidone HCl form A having a water content of about 10% to about 12%.  
   
   
       21 . Crystalline ziprasidone HCl form A having a water content of about 18% to about 20%.