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 . Hydrate A of aripiprazole wherein said Hydrate has a powder x-ray diffraction spectrum which is substantially the same as the following powder x-ray diffraction spectrum shown in FIG. 3.  
     
     
         2 . Hydrate A of aripiprazole wherein said Hydrate has powder x-ray diffraction characteristic peaks at 2θ=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and 24.8°.  
     
     
         3 . Hydrate A of aripiprazole wherein said Hydrate has particular infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm −1  on the IR (KBr) spectrum.  
     
     
         4 . Hydrate A of aripiprazole wherein said Hydrate has an endothermic curve which is substantially the same as the thermogravimetric/differential thermal analysis (heating rate 5° C./min) endothermic curve shown below shown in FIG. 1.  
     
     
         5 . Hydrate A of aripiprazole wherein said Hydrate has a mean particle size of 50 μm or less.  
     
     
         6 . Hydrate A of aripiprazole wherein said Hydrate has a mean particle size range of 36 to 14 μm.  
     
     
         7 . Hydrate A of aripiprazole wherein said Hydrate has 
 a powder x-ray diffraction spectrum which is substantially the same as the following powder x-ray diffraction spectrum shown in FIG. 3;    particular infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm −1  on the IR (KBr) spectrum;    an endothermic curve which is substantially the same as the thermogravimetric/differential thermal analysis (heating rate 5° C./min) endothermic curve shown below shown in FIG. 1; and    a mean particle size of 50 μm or less.    
     
     
         8 . A process for the preparation of Hydrate A wherein said process comprises milling Conventional Hydrate to a mean particle size of 50 μm or less.  
     
     
         9 . A process according to  claim 8 , wherein said milling is performed by an atomizer using a rotational speed of 5000-15000 rpm for the main axis, a feed rotation of 10-30 rpm and a screen hole size of 1-5 mm.  
     
     
         10 . The Hydrate A according to  claim 8  made by a process comprising milling Conventional Hydrate to a mean particle size of 50 μm or less.  
     
     
         11 . The Hydrate A according to  claim 8  made by a process comprising milling Conventional Hydrate to a mean particle size of 50 μm or less wherein said milling is performed by an atomizer using a rotational speed of 5000-15000 rpm for the main axis, a feed rotation of 10-30 rpm and a screen hole size of 1-5 mm.  
     
     
         12 . Aripiprazole drug substance of low hygroscopicity wherein said low hygroscopicity is a moisture content of 0.40% or less after placing said drug substance for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100%.  
     
     
         13 . Aripiprazole Anhydride Crystals B having low hygroscopicity wherein said low hygroscopicity is a moisture content of 0.40% or less after placing said drug substance for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100%.  
     
     
         14 . Aripiprazole drug substance of low hygroscopicity wherein said low hygroscopicity is a moisture content of 0.10% or less after placing said drug substance for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100%.  
     
     
         15 . Aripiprazole Anhydride Crystals B having low hygroscopicity wherein said low hygroscopicity is a moisture content of 0.10% or less after placing said drug substance for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100%.  
     
     
         16 . Aripiprazole Anhydride Crystals B having a powder x-ray diffraction spectrum which is substantially the same as the following powder x-ray diffraction spectrum shown in FIG. 5.  
     
     
         17 . Aripiprazole Anhydride Crystals B having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.  
     
     
         18 . Aripiprazole Anhydride Crystals B having a particular infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm −1  on the IR (KBr) spectrum.  
     
     
         19 . Aripiprazole Anhydride Crystals B exhibiting an endothermic peak near about 141.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min).  
     
     
         20 . Aripiprazole Anhydride Crystals B exhibiting an endothermic peak near about 140.7° C. in differential scanning calorimetry (heating rate 5° C./min).  
     
     
         21 . Aripiprazole Anhydride Crystals B wherein said Crystals will not substantially convert to a hydrous form of aripiprazole when properly stored under a relative humidity (RH) of 60% and at a temperature of 25° C., even for an extended period being not less than 4 years.  
     
     
         22 . Aripiprazole Anhydride Crystal B wherein said crystals has a mean particle size of 50 μm or less.  
     
     
         23 . Aripiprazole Anhydride Crystal B wherein said crystals has a mean particle size of 30 μm or less.  
     
     
         24 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in claims  16  and  18  to  22 .  
     
     
         25 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in  claims 17  to  22 .  
     
     
         26 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in claims  13 ,  16 ,  18  to  20  and  22 .  
     
     
         27 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in claims  15 ,  16 ,  18  to  20  and  22 .  
     
     
         28 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in claims  13 ,  17  to  20  and  22 .  
     
     
         29 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in claims  15 ,  17  to  20  and  22 .  
     
     
         30 . A process for the preparation of Aripiprazole Anhydride Crystals B wherein said process comprises heating Aripiprazole Hydrate A.  
     
     
         31 . A process for the preparation of Aripiprazole Anhydride Crystals B wherein said process comprises heating Aripiprazole Hydrate A at 90-125° C. for about 3-50 hours.  
     
     
         32 . A process for the preparation of Aripiprazole Anhydride Crystals B wherein said process comprises heating Aripiprazole Hydrate A at 100° C. for about 18 hours.  
     
     
         33 . A process for the preparation of Aripiprazole Anhydride Crystals B wherein said process comprises heating Aripiprazole Hydrate A at 100° C. for about 24 hours.  
     
     
         34 . A process for the preparation of Aripiprazole Anhydride Crystals B wherein said process comprises heating Aripiprazole Hydrate A at 120° C. for about 3 hours.  
     
     
         35 . A process for the preparation of Aripiprazole Anhydride Crystals B wherein said process comprises heating Aripiprazole Hydrate A for about 18 hours at 100° C. followed by additional heating for about 3 hours at 120° C.  
     
     
         36 . The Aripiprazole Anhydride Crystals B according to any one of claims  24 - 29  made by a process comprising heating Aripiprazole Hydrate A for about 18 hours at 100° C. followed by additional heating for about 3 hours at 120° C.  
     
     
         37 . The Aripiprazole Anhydride Crystals B according to any one of claims  24 - 29  formulated with one or more pharmaceutically acceptable carriers.  
     
     
         38 . The Aripiprazole Anhydride Crystals B according to any one of claims  24 - 29  formulated with one or more pharmaceutically acceptable carriers to form a solid oral tablet.  
     
     
         39 . The Aripiprazole Anhydride Crystals B according to any one of claims  24 - 29  formulated with one or more pharmaceutically acceptable carriers to form an oral flashmelt tablet.  
     
     
         40 . A process for the pharmaceutical solid oral preparation comprising Aripiprazole Anhydride Crystals B defined in  claim 26  and one or more pharmaceutically acceptable carriers, wherein said process comprises heating Aripiprazole Hydrate A defined in  claim 7 .  
     
     
         41 . A process for the pharmaceutical solid oral preparation comprising Aripiprazole Anhydride Crystals B defined in  claim 26  and one or more pharmaceutically acceptable carriers, wherein said process comprises heating Aripiprazole Hydrate A defined in  claim 7  at 90-125° C. for about 3-50 hours.  
     
     
         42 . A process for the pharmaceutical solid oral preparation comprising Aripiprazole Anhydride Crystals B defined in  claim 27  and one or more pharmaceutically acceptable carriers, wherein said process comprises heating Aripiprazole Hydrate A defined in  claim 7 .  
     
     
         43 . A process for the pharmaceutical solid oral preparation comprising Aripiprazole Anhydride Crystals B defined in  claim 27  and one or more pharmaceutically acceptable carriers, wherein said process comprises heating Aripiprazole Hydrate A defined in  claim 7  at 90-125° C. for about 3-50 hours.  
     
     
         44 . A process for the pharmaceutical solid oral preparation comprising Aripiprazole Anhydride Crystals B defined in  claim 28  and one or more pharmaceutically acceptable carriers, wherein said process comprises heating Aripiprazole Hydrate A defined in  claim 7 .  
     
     
         45 . A process for the pharmaceutical solid oral preparation comprising Aripiprazole Anhydride Crystals B defined in  claim 28  and one or more pharmaceutically acceptable carriers, wherein said process comprises heating Aripiprazole Hydrate A defined in  claim 7  at 90-125° C. for about 3-50 hours.  
     
     
         46 . A process for the pharmaceutical solid oral preparation comprising Aripiprazole Anhydride Crystals B defined in  claim 29  and one or more pharmaceutically acceptable carriers, wherein said process comprises heating Aripiprazole Hydrate A defined in  claim 7 .  
     
     
         47 . A process for the pharmaceutical solid oral preparation comprising Aripiprazole Anhydride Crystals B defined in  claim 29  and one or more pharmaceutically acceptable carriers, wherein said process comprises heating Aripiprazole Hydrate A defined in  claim 7  at 90-125° C. for about 3-50 hours.  
     
     
         48 . Aripiprazole Anhydride Crystals B wherein said Crystals will not substantially convert to a hydrous form of aripiprazole when properly stored under a relative humidity (RH) of 60% and at a temperature of 25° C., even for an extended period being not less than 1 year.  
     
     
         49 . Aripiprazole Anhydride Crystals B wherein said Crystals will not substantially convert to a hydrous form of aripiprazole when properly stored under a relative humidity (RH) of 75% and at a temperature of 40° C., even for an extended period being not less than 0.5 year.  
     
     
         50 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in claims  16 ,  18  to  20 ,  22  and  48 .  
     
     
         51 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in  claims 17  to  20 ,  22  and  48 .  
     
     
         52 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in claims  16 ,  18  to  20 ,  22  and  49 .  
     
     
         53 . Aripiprazole Anhydride Crystals B having all physicochemical properties defined in  claims 17  to  20 ,  22  and  49 .  
     
     
         54 . The Aripiprazole Anhydride Crystals B according to any one of claims  50 - 53  formulated with one or more pharmaceutically acceptable carriers.  
     
     
         55 . The Aripiprazole Anhydride Crystals B according to any one of claims  50 - 53  formulated with one or more pharmaceutically acceptable carriers to form a solid oral tablet.  
     
     
         56 . The Aripiprazole Anhydride Crystals B according to any one of claims  50 - 53  formulated with one or more pharmaceutically acceptable carriers to form an oral flashmelt tablet.  
     
     
         57 . The use of aripiprazole anhydride crystals B for the treatment of central system disorder.  
     
     
         58 . The use of aripiprazole anhydride crystals B for the treatment of schizophrenia.  
     
     
         59 . The use of aripiprazole anhydride crystals B for the treatment of bipolar disorder.  
     
     
         60 . The use of aripiprazole anhydride crystals B for the treatment of intractable (drug-resistent, chronic) schizophrenia with cognitive impairment or intractable (drug-resistant, chronic) schizophrenia without cognitive impairment.  
     
     
         61 . The use of aripiprazole anhydride crystals B for the treatment of autism, Down's syndrome or attention deficit hyperactivity disorder (ADHD).  
     
     
         62 . The use of aripiprazole anhydride crystals B for the treatment of Alzheimer's disease, Parkinson's disease or other neurodegenerative diseases.  
     
     
         63 . The use of aripiprazole anhydride crystals B for the treatment of panic, obsessive compulsive disorder (OCD), sleep disorders, sexual dysfunction, alcohol and drug dependency, vomiting, motion sickness, obesity, miparticlee headache or cognitive impairment.  
     
     
         64 . The use of aripiprazole anhydride crystals B for the treatment of anxiety, depression or mania.  
     
     
         65 . The use of aripiprazole anhydride crystals B to prepare a medicament to treat or prevent schizophrenia and the symptoms associated with schizophrenia.  
     
     
         66 . A drug for treating schizophrenia or symptoms associated with schizophrenia, which comprises aripiprazole anhydride crystals B in an amount effective to treat schizophrenia or the symptoms thereof, in admixture with a pharmaceutically acceptable diluent.  
     
     
         67 . The drug as claimed in  claim 66 , which is contained in a commercial package carrying instructions that the drug should be used for treating schizophrenia, or symptoms thereof.  
     
     
         68 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals B defined in  claim 26 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         69 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals B defined in  claim 27 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         70 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals B defined in  claim 28 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         71 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals B defined in  claim 29 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         72 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals B defined in  claim 26  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         73 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals B defined in  claim 27  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         74 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals B defined in  claim 28  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         75 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals B defined in  claim 29  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         76 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals B defined in  claim 26  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.  
     
     
         77 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals B defined in  claim 27  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.  
     
     
         78 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals B defined in  claim 28  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.  
     
     
         79 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals B defined in  claim 29  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.  
     
     
         80 . Aripiprazole Anhydride Crystals C having a powder X-ray diffraction spectrum shown in FIG. 10.  
     
     
         81 . Aripiprazole Anhydride Crystals C having a powder X-ray diffraction spectrum having characteristics peaks at 2θ=12.6°, 13.7°, 15.4°, 18.1°, 19.0°, 20.6°, 23.5° and 26.4°.  
     
     
         82 . Aripiprazole Anhydride crystals C having a particular infrared absorption bands at 2939, 2804, 1680, 1375 and 780 cm −1  on the IR (Kbr) spectrum.  
     
     
         83 . Aripiprazole Anhydride crystals C exhibitng an endothermic peak near about 150.2° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min).  
     
     
         84 . Aripiprazole Anhydride crystals C having a solid  13 C-NMR spectrum having characteristic peaks at 32.8 ppm, 60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2 ppm and 175.2 ppm.  
     
     
         85 . Aripiprazole Anhydride crystals C having all physicochemical properties defined in claims  80 ,  82  to  84 .  
     
     
         86 . Aripiprazole Anhydride crystals C having all physicochemical properties defined in  claims 81  to  84 .  
     
     
         87 . Aripiprazole Anhydride crystals D having a powder x-ray diffraction spectrum shown in FIG. 15.  
     
     
         88 . Aripiprazole Anhydride crystals D having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=8.7°, 11.6°, 16.3°, 17.7°, 18.6°, 20.3°, 23.4° and 25.0°.  
     
     
         89 . Aripiprazole Anhydride crystals D having a particular infrared absorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm −1  on the IR (Kbr) spectrum.  
     
     
         90 . Aripiprazole Anhydride crystals D exhibiting an endothermic peak near about 136.8° C. and 141.6° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min).  
     
     
         91 . Aripiprazole Anhydride crystals D having a solid  13 C-NMR spectrum having characteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.4 ppm, and 174.1 ppm.  
     
     
         92 . Aripiprazole Anhydride crystals D having all physicochemical properties defined in claims  87 ,  89  to  91 .  
     
     
         93 . Aripiprazole Anhydride crystals D having all physicochemical properties defined in  claims 88  to  91 .  
     
     
         94 . Aripiprazole Anhydride crystals E having a powder x-ray diffraction spectrum shown in FIG. 20.  
     
     
         95 . Aripiprazole Anhydride 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 . Aripiprazole Anhydride 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 . Aripiprazole Anhydride crystals E exhibiting an endothermic peak near about 146.5° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min).  
     
     
         98 . Aripiprazole Anhydride crystals E having all physicochemical properties defined in claims  94 ,  96  to  97 .  
     
     
         99 . Aripiprazole Anhydride crystals E having all physicochemical properties defined in  claims 95  to  97 .  
     
     
         100 . Aripiprazole Anhydride crystals F having a powder x-ray diffraction spectrum shown in FIG. 24.  
     
     
         101 . Aripiprazole Anhydride crystals F having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=11.3°, 13.3°, 15.4°, 22.8°, 25.2° and 26.9°.  
     
     
         102 . Aripiprazole Anhydride crystals F having a particular infrared absorption bands at 2940, 2815, 1679, 1383, 1273, 1177, 1035, 963 and 790 cm −1  on the IR (Kbr) spectrum.  
     
     
         103 . Aripiprazole Anhydride crystals F exhibiting an endothermic peak near about 137.5° C. and 149.8° C. in thermogravimetric/differential thermal analysis (hating rate 5° C./min).  
     
     
         104 . Aripiprazole Anhydride crystals F having all physicochemical properties defined in claims  100 ,  102  to  103 .  
     
     
         105 . Aripiprazole Anhydride crystals F having all physicochemical properties defined in  claims 101  to  103 .  
     
     
         106 . Aripiprazole Anhydride crystals G having a powder x-ray diffraction spectrum shown in FIG. 28.  
     
     
         107 . Aripiprazole Anhydride crystals G having a powder x-ray diffraction spectrum having characteristic peaks at 2θ=10.1°, 12.8°, 15.2°, 17.0°, 17.5°, 19.1°, 20.1°, 21.2°, 22.4°, 23.3°, 24.5° and 25.8°.  
     
     
         108 . Aripiprazole Anhydride crystals G having a particular infrared absorption bands at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787 cm −1  on the IR (Kbr) spectrum.  
     
     
         109 . Aripiprazole Anhydride crystals G exhibiting an endothermic peak near about 141.0° C. and an exothermic peak around 122.7° C. in thermogravimetric/differential thermal analysis (heating rate 5° C./min).  
     
     
         110 . Aripiprazole Anhydride crystals G having all physicochemical properties defined in claims  106 ,  108  to  109 .  
     
     
         111 . Aripiprazole Anhydride crystals G having all physicochemical properties defined in  claims 107  to  109 .  
     
     
         112 . A process for preparing aripiprazole anhydride crystals C according to  claim 85  or  86 , characterized by heating aripiprazole anhydride crystals at a temperature higher than 140° C. and lower than 150° C.  
     
     
         113 . A process for preparing aripiprazole anhydride crystals D according to  claim 92  or  93 , characterized by recrystallizing it from toluene.  
     
     
         114 . A process for preparing aripiprazole anhydride crystals E according to  claim 98  or  99 , characterized by heating and dissolving aripiprazole anhydride crystals in acetonitrile, then cooling it.  
     
     
         115 . A process for preparing aripiprazole anhydride crystals F according to  claim 104  or  105 , characterized by heating a suspension of aripiprazole anhydride in acetone.  
     
     
         116 . A process for preparing aripiprazole anhydride crystals G according to  claim 110  or  111 , characterized by leaving to stand aripiprazole anhydride glassy state in a sealed vessel at room temperature for at least 2 weeks.  
     
     
         117 . A pharmaceutical composition comprising at least one aripiprazole anhydride crystals selected from the group consisting of the aripiprazole anhydride crystals C according to  claim 85 , the aripiprazole anhydride crystals D according to  claim 92 , the aripiprazole anhydride crystals E according to  claim 98 , the aripiprazole anhydride crystals F according to  claim 104  and the aripiprazole anhydride crystals G according to  claim 110 , together with pharmaceutically acceptable carriers.  
     
     
         118 . A pharmaceutical composition comprising at least one aripiprazole anhydride crystals selected from the aripiprazole anhydride crystals C according to  claim 86 , the aripiprazole anhydride crystals D according to  claim 93 , the aripiprazole anhydride crystals E according to  claim 99 , the aripiprazole anhydride crystals F according to  claim 105 , and the aripiprazole anhydride crystals G according to  claim 111 , together with pharmaceutically acceptable carriers.  
     
     
         119 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals C defined in  claim 85 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         120 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals C defined in  claim 86 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         121 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals D defined in  claim 92 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         122 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals D defined in  claim 93 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         123 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals E defined in  claim 98 , 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 the Aripiprazole Anhydride Crystals E defined in  claim 99 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         125 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals F defined in  claim 104 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         126 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals F defined in  claim 105 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         127 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals G defined in  claim 110 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         128 . A process for the preparation of granules, characterized by wet granulating the Aripiprazole Anhydride Crystals G defined in  claim 111 , drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         129 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals C defined in  claim 85  and one or more pharmaceutically acceptable carriers at 70 to 100°C.  
     
     
         130 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals C defined in  claim 86  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         131 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals D defined in  claim 92  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         132 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals D defined in  claim 93  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         133 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals E defined in  claim 98  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         134 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals E defined in  claim 99  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         135 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals F defined in  claim 104  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         136 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals F defined in  claim 105  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         137 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals G defined in  claim 110  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         138 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals G defined in  claim 111  and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         139 . A process for the preparation of granules, characterized by wet granulating conventional Aripiprazole Anhydride Crystals, drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         140 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising conventional Aripiprazole Anhydride Crystals and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         141 . A pharmaceutical solid oral preparation having 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.  
     
     
         142 . The pharmaceutical solid oral preparation prepared by the process of  claim 139 , 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.  
     
     
         143 . The pharmaceutical solid oral preparation prepared by the process of  claim 140 , wherein said pharmaceutical solid oral preparation having 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.  
     
     
         144 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals C defined in  claim 85  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.  
     
     
         145 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals C defined in  claim 86  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.  
     
     
         146 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals D defined in  claim 92  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.  
     
     
         147 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals D defined in  claim 93  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.  
     
     
         148 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals E defined in  claim 98  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 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals E defined in  claim 99  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 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals F defined in  claim 104  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.  
     
     
         151 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals F defined in  claim 105  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.  
     
     
         152 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals G defined in  claim 110  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.  
     
     
         153 . The pharmaceutical solid oral preparation comprising the Aripiprazole Anhydride Crystals G defined in  claim 111  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.  
     
     
         154 . A process for the preparation of granules, characterized by wet granulating conventional Aripiprazole Hydrate Crystals, drying the obtained granules at 70 to 100° C. and sizing it, then drying the sized granules at 70 to 100° C. again.  
     
     
         155 . A process for the pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising conventional Aripiprazole Hydrate Crystals and one or more pharmaceutically acceptable carriers at 70 to 100° C.  
     
     
         156 . The pharmaceutical solid oral preparation prepared by the process of  claim 154 , 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.  
     
     
         157 . The pharmaceutical solid oral preparation prepared by the process of  claim 155 , 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.