Low hygroscopic aripiprazole drug substance and processes for the preparation thereof

Abstract

The present invention provides low hygroscopic forms of aripiprazole and processes for the preparation thereof which will not convert to a hydrate or lose their original solubility even when a medicinal preparation containing the aripiprazole anhydride crystals is stored for an extended period.

1 - 93 . (canceled)  
   
   
       94 . Anhydrous Aripiprazole Crystals E having a powder x-ray diffraction spectrum shown in  FIG. 20 .  
   
   
       95 . Anhydrous Aripiprazole Crystals E having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5° and 24.0°.  
   
   
       96 . Anhydrous Aripiprazole Crystals E having a particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969 and 774 cm −1  on the IR (Kbr) spectrum.  
   
   
       97 . Anhydrous Aripiprazole Crystals E exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min).  
   
   
       98 - 113 . (canceled)  
   
   
       114 . A process for preparing Anhydrous Aripiprazole Crystals E having a powder x-ray diffraction spectrum shown in  FIG. 20 ; 
 having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min) or    Anhydrous Aripiprazole Crystals E    having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5°, and 24.0°;    having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min), characterized by heating and dissolving aripiprazole anhydride crystals in acetonitrile, then cooling it.    
   
   
       115 - 122 . (canceled)  
   
   
       123 . A process for the preparation of granules, characterized by wet granulating Anhydrous Aripiprazole Crystals E having a powder x-ray diffraction spectrum shown in  FIG. 20 ; 
 having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min), drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.    
   
   
       124 . A process for the preparation of granules, characterized by wet granulating Anhydrous Aripiprazole Crystals E having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5°, and 24.0°; 
 having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min), drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.    
   
   
       125 - 132 . (canceled)  
   
   
       133 . A process for a pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising Anhydrous Aripiprazole Crystals E having a powder x-ray diffraction spectrum shown in  FIG. 20 ; 
 having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min) and one or more pharmaceutically acceptable carriers at 70 to 100° C.    
   
   
       134 . A process for a pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising Anhydrous Aripiprazole Crystals E having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5°, and 24.0°; 
 having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min) and one or more pharmaceutically acceptable carriers at 70 to 100° C.    
   
   
       135 - 147 . (canceled)  
   
   
       148 . A pharmaceutical solid oral preparation comprising Anhydrous Aripiprazole Crystals E having a Powder x-ray diffraction spectrum shown in  FIG. 20 ; 
 having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min) and one or more pharmaceutically acceptable carriers, wherein said pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.    
   
   
       149 . A pharmaceutical solid oral preparation comprising Anhydrous Aripiprazole Crystals E having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5°, and 24.0°; 
 having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min) and one or more pharmaceutically acceptable carriers, wherein said pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.    
   
   
       150 - 157 . (canceled)  
   
   
       158 . Anhydrous Aripiprazole Crystals E 
 having a powder x-ray diffraction spectrum shown in  FIG. 20 ;    having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min).    
   
   
       159 . Anhydrous Aripiprazole Crystals E 
 having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5°, and 24.0°;    having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min).    
   
   
       160 . A pharmaceutical composition comprising 
 anhydrous aripiprazole crystals E    having a powder x-ray diffraction spectrum shown in  FIG. 20 ;    having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min);    together with a pharmaceutically acceptable carrier.    
   
   
       161 . A pharmaceutical composition comprising 
 anhydrous aripiprazole crystals E    having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=8.0°, 13.7°, 14.6°, 17.6°, 22.5°, and 24.0°;    having particular infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm −1  on the IR (KBr) spectrum; and    exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min);    together with a pharmaceutically acceptable carrier.