Amorphous ziprasidone hydrochloride (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1, 3-dihydro-2H-indol-2-one hydrochloride) and processes to produce the same

Abstract

The present invention relates to a new and useful amorphous form of ziprasidone hydrochloride (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride) and preparations thereof.

1 . A process for the preparation of substantially amorphous ziprasidone hydrochloride comprising the steps of: 
 (i) suspending ziprasidone free base in a low-polarity organic solvent or mixture of solvents;    (ii) adding hydrogen chloride to the suspension;    (iii) recovering the amorphous ziprasidone hydrochloride.    
   
   
       2 . A process for the preparation of substantially amorphous ziprasidone hydrochloride comprising the steps of: 
 (i) mixing ziprasidone free base with a suitable low-polarity organic solvent to prepare a suspension;    (ii) bubbling anhydrous hydrogen chloride gas;    (iii) stirring the reaction mixture for a sufficient amount of time to obtain ziprasidone hydrochloride;    (iv) recovering the substantially amorphous ziprasidone hydrochloride and drying the product to suitable residual solvent levels; and    (v) optionally stirring the solid with a suitable organic solvent, filtering and drying.    
   
   
       3 . A process for the preparation of substantially amorphous ziprasidone hydrochloride comprising the steps of: 
 (i) mixing ziprasidone free base with a suitable low-polarity organic solvent to prepare a suspension;    (ii) pressurizing a suitable pressure vessel with hydrogen chloride;    (iii) stirring the reaction mixture for a sufficient amount of time to obtain ziprasidone hydrochloride formation;    (iv) isolating the substantially amorphous ziprasidone hydrochloride and drying to obtain suitable residual solvent levels; and    (v) if required, stirring the solid with a suitable organic solvent, filtering and drying.    
   
   
       4 . A process for the preparation of substantially amorphous ziprasidone hydrochloride comprising the steps of: 
 (i) mixing ziprasidone free base with a suitable low-polarity organic solvent to prepare a suspension;    (ii) adding a solution of hydrogen chloride in a suitable organic solvent,    (iii) stirring the reaction mixture for a sufficient amount of time to obtain ziprasidone hydrochloride formation;    (iv) isolating the substantially amorphous ziprasidone hydrochloride and drying to obtain suitable residual solvent levels; and    (v) if required, stirring the solid with a suitable organic solvent, filtering and drying.    
   
   
       5 . The process of claims  1 ,  2 ,  3  or  4 , wherein the organic solvent for step i is a low-polarity organic solvent.  
   
   
       6 . The process of  claim 5 , wherein the low-polarity organic solvent is a C 5  to C 12  substituted or unsubstituted cyclic and acyclic hydrocarbon.  
   
   
       7 . The process of  claim 6  wherein the low-polarity organic solvent is selected from hexanes, heptanes, cyclohexanes and mixtures thereof.  
   
   
       8 . The process of  claim 5 , wherein the low-polarity organic solvent is a C 1  to C 3  chlorinated hydrocarbon solvent such as dichloromethane or chloroform.  
   
   
       9 . The process of  claim 8  wherein the low-polarity organic solvent is selected from dichloromethane, chloroform and mixtures thereof.  
   
   
       10 . The process of  claim 1 ,  2 ,  3  or  4 , wherein the low-polarity organic solvent is dichloromethane.  
   
   
       11 . The process of  claim 1 ,  2 ,  3  or  4 , wherein the low-polarity organic solvent is heptanes.  
   
   
       12 . A substantially amorphous form of ziprasidone hydrochloride compound.  
   
   
       13 . The compound of  claim 12  having a PXRD diffractogram as depicted in  FIG. 1 .  
   
   
       14 . The compound of  claim 12  having an IR spectum as depicted in  FIG. 2 .  
   
   
       15 . The compound of  claim 12  having a DSC thermogram as depicted in  FIG. 3 .  
   
   
       16 . The compound of  claim 12  having a PXRD diffractogram as depicted in  FIG. 1 , an IR spectum as depicted in  FIG. 2 , and a DSC thermogram as depicted in  FIG. 3 .  
   
   
       17 . The process according to  claim 5  wherein the amount of the organic solvent of step (i) comprises about 5-100 volumes of such low-polarity organic solvent or mixture of solvents and the temperature at which step (i) is carried out is between about −10° C. to about 40° C.  
   
   
       18 . The process according to  claim 6  wherein the amount of the organic solvent of step (i) comprises about 5-100 volumes of such low-polarity organic solvent or mixture of solvents and the temperature at which step (i) is carried out is between about −10° C. to about 40° C.  
   
   
       19 . The process according to  claim 7  wherein the amount of the organic solvent of step (i) comprises about 5-100 volumes of such low-polarity organic solvent or mixture of solvents and the temperature at which step (i) is carried out is between about −10° C. to about 40° C.  
   
   
       20 . The process according to  claim 8  wherein the amount of the organic solvent of step (i) comprises about 5-100 volumes of such low-polarity organic solvent or mixture of solvents and the temperature at which step (i) is carried out is between about −10° C. to about 40° C.  
   
   
       21 . The process according to  claim 9  wherein the amount of the organic solvent of step (i) comprises about 5-100 volumes of such low-polarity organic solvent or mixture of solvents and the temperature at which step (i) is carried out is between about −10° C. to about 40° C.  
   
   
       22 . The process according to  claim 10  wherein the amount of the organic solvent of step (i) comprises about 5-100 volumes of such low-polarity organic solvent or mixture of solvents and the temperature at which step (i) is carried out is between about −10° C. to about 40° C.  
   
   
       23 . The process according to  claim 11  wherein the amount of the organic solvent of step (i) comprises about 5-100 volumes of such low-polarity organic solvent or mixture of solvents and the temperature at which step (i) is carried out is between about −10° C. to about 40° C.