CA2379005A1 - Low hygroscopic aripiprazole drug substance and processes for the preparation thereof - Google Patents

Low hygroscopic aripiprazole drug substance and processes for the preparation thereof Download PDF

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Publication number
CA2379005A1
CA2379005A1 CA 2379005 CA2379005A CA2379005A1 CA 2379005 A1 CA2379005 A1 CA 2379005A1 CA 2379005 CA2379005 CA 2379005 CA 2379005 A CA2379005 A CA 2379005A CA 2379005 A1 CA2379005 A1 CA 2379005A1
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Prior art keywords
aripiprazole
hydrate
anhydride crystals
aripiprazole anhydride
crystals
Prior art date
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Abandoned
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CA 2379005
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French (fr)
Inventor
Yoshihiro Nishioka
Tsutomu Fujimura
Takuji Bando
Noriyuki Kobayashi
Makoto Ishigami
Youichi Taniguchi
Tsuyoshi Yabuuchi
Satoshi Aoki
Junichi Kawasaki
Kiyoshi Fujimoto
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Priority to ARP020103511A priority Critical patent/AR033485A1/en
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Priority to MYPI20023512A priority patent/MY138669A/en
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Priority to CN201710019464.0A priority patent/CN106692151A/en
Priority to CN201610811822.7A priority patent/CN106420627A/en
Priority to EP08000359A priority patent/EP1927356B1/en
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Priority to DK08000359.3T priority patent/DK1927356T3/en
Priority to SI200230337T priority patent/SI1330249T1/en
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Priority to CN201410466919.XA priority patent/CN104306337A/en
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Priority to PT80003585T priority patent/PT1925308T/en
Priority to CN2009101474907A priority patent/CN101574347B/en
Priority to SI200230905T priority patent/SI1927355T1/en
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Priority to CA002688860A priority patent/CA2688860A1/en
Priority to PT02782507T priority patent/PT1330249E/en
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Priority to CN2008101254090A priority patent/CN101434573B/en
Priority to CN201410053920.XA priority patent/CN103751119A/en
Priority to DK08000357.7T priority patent/DK1927355T3/en
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Priority to EP02782507A priority patent/EP1330249B1/en
Priority to AT08000359T priority patent/ATE465737T1/en
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Priority to PT08000360T priority patent/PT1927357E/en
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Priority to EP08000358.5A priority patent/EP1925308B1/en
Priority to DK02782507T priority patent/DK1330249T3/en
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Priority to CN2009101474911A priority patent/CN101574348B/en
Priority to EP08000360A priority patent/EP1927357B1/en
Priority to CN2009101474926A priority patent/CN101579343B/en
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Priority to AT08000357T priority patent/ATE465736T1/en
Priority to EP08000357A priority patent/EP1927355B1/en
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Priority to NO20030247A priority patent/NO328134B1/en
Publication of CA2379005A1 publication Critical patent/CA2379005A1/en
Priority to HK15103616.1A priority patent/HK1203059A1/en
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Priority to HK16111449.6A priority patent/HK1223043A1/en
Priority to JP2004156130A priority patent/JP3750023B2/en
Priority to JP2005341187A priority patent/JP4614870B2/en
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Priority to US15/149,522 priority patent/US20160251315A1/en
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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.

Description

a CA 02379005 2002-03-27 Cross Reference to Related Priority Application The present application claims priority from Japanese patent application number JP-2001-290645 filed September 25, 2001.
DETAILED DESCRIPTION OF THE INVENTION
Field of the Invention The present invention relates to an improved form of aripiprazole having reduced hygroscopicity and processes for the preparation of this improved form.
Background of the Invention Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2(1H)-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia (U: S.
4,734,416 and U.S. 5,006,528). Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others.
Onset of schizophrenia typically.occurs between the age of 16 and 25 and affects 1 in 100 individuals worldwide. It is more prevalent than Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and _ outcome. Moreover, early therapeutic intervention can avert costly hospitalization.
According to Example 1 of Japanese Unexamined Patent Publication No. 191256/1990, aripiprazole anhydride crystals are manufactured for example by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with 1-(2,3-diehlorophenylpiperadine and recrystalli,zing the resulting raw aripiprazole anhydride with ethanol.
Also, acCOrding to the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (October 6-8, 1996), aripiprazole anhydride crystals are manufactured by heating aripiprazole hydrate at 80°C. However, the aripiprazole anhydride crystals obtained by the aforementioned methods have the disadvantage of being significantly hygroscopic.
The hygroscopicity of these crystals makes them difficult to handle since costly and burdensome measures must betaken in order ensure they are not exposed to moisture during process and formulation.
Exposed to moisture, the anhydrous form can take on water and convert to a hydrous form. This presents several disadvantages: First, the hydrous forms of aripiprazole have the disadvantage of being less bioavailable and less dissoluble than the anhydrous forms of aripiprazole. Second, the variation in the amount of hydrous versus anhydrous aripiprazole drug substance from batch to batch could fail to meet specifications set by drug regulatory agencies. Third, the milling may Cause the drug substance, Conventional Anhydride, to adhere to manufacturing equipment which c may further result in processing delay, increased operator involvement, increased cost, increased maintenance and lower production yield. Fourth, in addition to problems caused by introduction of moisture during the processing of these hygroscopic anhydrides, the potential for absorbance of moisture during storage and handling would adversely affect the dissolu.bility of aripiprazole drug substance: Thus shelf-life of the product could be significantly decreased and/or packaging costs could be significantly increased. It would be highly desirable to discover a form of aripiprazole that possessed low hygroscopici:ty thereby facilitating pharmaceutical processing and formulation operations required for producing dosage units of an aripiprazole medicinal product having improved shelf-life, suitable dissolubility and suitable bioavailability.
SITMMARY OF THE INVENTION
Thus according to the present invention is provided a form of aripiprazole having reduced hygroscopicity and which is more amenable to pharmaceutical processing and formulation. The inventors of the present invention have discovered that this reduced-hygroscopic form of Aripiprazole is a crystalline substance defined herein as Anhydride B. A
particular process for the preparation of this anhydrous crystalline substance has also been t _ 4 _ discovered and comprises yet another aspect of the present invention: Particularly, it was discovered as part of the present invention that in order to produce Anhydride B having the desired pharmaceutical properties and utilizing the most efficient process, Hydrate A, as defined herein, would have to serve as the intermediate. It was also discovered that a particular sequence of processing had to be implemented in order to form Hydrate A. It was discovered that the preparation of Hydrate A required milling what is defined herein as Conventional Hydrate. Then,' Hydra a A can be transformed into Anhydride B through suitable heating as defined herein. Surprisingly, if the Conventional Hydrate is first heated and then milled, serious agglomeration sets in rendering the processing commercially unsuitable.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a thermogravimetric/differential thermogram of the Aripiprazole Hydrate~A obtained in Example 1.
Figure 2 shows the 1H-NMR spectrum (DMSO-d6, TMS) of the Aripiprazole Hydrate A obtained in Example f.
Figure 3 is a powder x-ray diffraction diagram of the Aripiprazole Hydrate IA obtained in Example 1.
Figure 4 shows the 1H-NMR spectrum (DMSO-ds, _ 5 _ TMS) of the Aripiprazole Anhydride Crystals B obtained in Example 2.
Figure 5 is a powder x-ray diffraction diagram of the Aripiprazole Anhydride Crystals B
obtained in Example 2.
Figure 6 is a thermogravimetric/differential thermogram of the aripiprazole hydrate obtained in Reference Example 3.
Figure 7 is a powder x-ray diffraction diagram of the aripiprazole hydrate obtained in Reference Example 3:
DETAILED DESCRIPTION OF THE INVENTION
According to first embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a powder x-ray diffraction spectrum which is substantially the same as the powder x-ray diffraction spectrum shown in Figure 3.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripi.prazole wherein said Hydrate has powder x-ray diffraction characteristic peaks at 28 = 12.6°, 15.4°, 17.3°, 18:0°, 18.6°, 22.5° and 24.8°.
According to another embodiment of the first aspect of the present invention is provided 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.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has an 1H-NMR
spectrum which is substantially the same as the 1H-NMR
spectrum (DMSO-d6, TMS) shown in Figure 2.
According to another embodiment of the first aspect of the present invention is provided Hydrate A of aripiprazole wherein. said Hydrate has an 1H-NMR spectrum (DMSO-d6, TMS) having characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2:48-2.56 ppm (m, 4H + DMSO), 2.78 ppm (t, J = 7.4 Hz, 2H) , 2. 97 pprn (brt, J = 4. 6 Hz, 4H) , 3.92 ppm (t, J
- 6.3 Hz, 2H), 6.43 ppm (d, J = 2.4 Hz, 1H), 6.49 ppm (dd, J = 8 . 4 Hz, J = 2 . 4 Hz, 1H) , 7 » 04 ppm (d, J = 8 .1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H) .
According to another embodiment of the: first aspect of the present invention is provided Hydra. a 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 in Figure 1.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean r CA 02379005 2002-03-27 particle size of 50 ~m or less.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean particle size of 40 um or less.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean particle size of 35 um or less.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean particle size of 30 um or less.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean particle size of 25 pm. or less.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean particle size of 20 ~.m. or less.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean particle size range of 40 to 10 um.
According to another embodiment of the first aspect of the present invention is provided Hydrate A
of aripiprazole wherein aid Hydrate has a mean _ g _ particle size range of 36 to 14 um.
According to a second aspect of the present invention is provided a process for the preparation of Hydrate A wherein said process comprises the steps of milling Conventional Hydrate.
According to a first embodiment of the second aspect of the present invention is provided a process for the preparation of Hydrate A comprising the steps of milling Conventional Hydrate wherein said milling is performed by a milling machine:
According to another embodiment of the second aspect of the present invention is provided a process for the preparation of Hydrate A comprising the steps of milling Conventional. Hydrate wherein said milling machine is an atomizer, pin mill, jet mill or ball mill.
According to another embodiment of the second aspect of the present invention is provided a process for the preparation of Hydrate A comprising the tees of milling Conventional Hydrate wherein said milling machine is an atomizer According to another embodiment of the second aspect of the present invention is provided a process for the preparation of Hydrate A comprising the steps of milling Conventional Hydrate wherein said milling machine is 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.

_ 9 _ According to various embodiments of a third aspect of the present invention is provided Hydrate A
defined according to one or more of the embodiments described herein wherein said Hydrate is made by a prowess as described herein.
According to a fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity.
According to a first embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said low hygroscopicity is a moisture content of 0.50 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.
According to a first embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said low hygroscopicity is a moisture content of 0.4% 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. According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said low hygroscopicity is a moisture content of 0:25 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~.

According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said low hygroscopicity is a moisture content of 0.15% 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%.
According to another embodiment of the four h aspect of the present invention is provided aripiprazole drug Substance of low hygroscopicity wherein said low hygroseopiCity is a moisture content of 0.100 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%.
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said low hygroscopicity is a moisture content of 0.05% 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%.
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said low hygroseopicity is a moisture content of 0.04 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%.

According to another embodiment of the fourth aspect of the present, invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance is Aripiprazole Anhydride Crystals B as defined herein.
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance has a powder x-ray diffraction spectrum which is substantially the same as the powder x-ray diffraction spectrum shown, in ,Figure 5.
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance has a powder x-ray diffraction spectrum having characteristic peaks at 29 =
11.0°, 16.6°, 19.3°, 20.3° and 22.1°.
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance has particular infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 7'79 cm.-1 on the IR (KBr) spectrum.
According to another embodiment of the, fourth aspect of the present invention is provided arip:i-prazole drug substance of low hygroscopicity wherein said drug substance has an 1H-NMR spectrum which is substantially the same as the 1H-NMR spectrum (DMSO-d6, TMS) shown in Figure 4.
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance has an 1H-NMR spectrum (DM50-ds, TMS) having characteristic peaks at 1.55-1.63 ppm (m; 2H), 1.68-1.78 ppm (m, 2H); 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H + DMSO), 2.78 ppm (t, J = 7.4 Hz, 2H) , 2 . 97 ppm (brt, J = 4 . 6 Hz, 4H) , 3. 92 ppm (t, J
- 6.3 Hz, 2H), 6.43 ppm (d, J = 2.4 Hz, 1H), 6.49 ppm (dd, J = 8.4 Hz, J = 2.4 Hz, 1H); 7.04 ppm (d, J = 8.1 Hz, lHj, 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H) .
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance exhibits an endothermic peak near about 141.5°C in thermogravimetric/
differential thermal analysis (heating rate 5°Clmin).
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance exhibits an endothermic peak near about 140.7°C in differential scanning calorimetry (heating rate 5°C/min).
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance is Aripiprazole Anhydride Crystals B and will not substantially convert to a hydrous form of aripiprazole when properly stored even for an extended period. For instance, said Aripiprazole Anhydride Crystals B can be stored under a relative humidity (RH) of 60 o and at a temperature of 25°C, even for a period not less than 1 year.
According to another embodiment of the fourth aspect: of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance is Aripiprazole Anhydride Crystals B and will not substantially convert to a hydrous form of aripiprazole when properly s ored even for an extended period. For instance, said Aripiprazole Anhydride Crystals B_can be stored under a relative humidity (RH) of 60 o and at a temperature of 25°C, even for a period not less than 4 years:
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein'said drug substance is Aripiprazole Anhydride Crystals B and will not substantially convert to a hydrous farm of aripiprazole when properly stored even for a period not less than 0.5 year under a relative humidity (RH) of 75 % and at a temperature of 40°C.
According to another embodiment of the fourth aspect of the present invention is provided _ 14 _ aripiprazole drug substance of low hygroscopicity wherein said drug substance has a mean size of 5pum or less when small particle size is required for the formulation such as Tablet and other solid dose formulations including for example flashmelt formulations.
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance has a mean size of 40um or less if small particle size is. required for the formulation such as Tablet and other solid dose formulations including for example flashmelt formulations.
According to another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity wherein said drug substance has a mean size of 30~:m or less if small particle size is required for formulation such as Tablet and other solid dose formulations including for example flashmelt formulations.
According to a fifth aspect of the present invention is provided a process for the preparation of Aripiprazole Anhydride Crystals B.
According to a first embodiment of the fifth aspect of the present invention is provided a process for the preparation of Ari:piprazole Anhydride Crystals B wherein said process comprises heating Aripiprazole Hydrate A.
According to a first embodiment of the fifth aspect of the present invention is provided 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.
According to another embodiment of the fifth aspect of the present invention is provided a process for the preparation of Aripiprazole Anhydride Crystals B wherein said process. comprises heating Aripiprazola Hydrate A at 100°C for about 18 hours.
According to another embodiment of the fifth aspect of the present invention is provided 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.
According to another embodiment of the fifth aspect of the present invention is provided 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.
According to another embodiment of the fifth aspect of the present invention is provided a process for the preparation of Aripiprazole Anhydride Crystals B wherein said process comprises heating Aripiprazole Hydrate A. for about l8 hours at 100°C followed by additional heating for about 3 hours at 120°C.
According to a sixth aspect of the present invention is provided Aripiprazole Anhydride Crystals B
defined according to one or more of the embodiments described herein: and made by a process as provided herein.
According to a seventh aspect of the,present invention is provided Aripiprazole Anhydride Crystals B
formulated with one or more pharmaceutically acceptable carriers.
Other embodiments of the present invention may comprise suitable combinations of two or more of the embodiments and/or aspects disclosed herein.
Yet other embodiments and aspects of the invention will be apparent according to the description provided below.
Yet another aspect of the present invention comprised discovering that when aripiprazole hydrate (Conventional Hydrate as defined herein) is milled, it converts to an aripiprazole hydrate (Hydrate A as defined herein) with a different powder x-ray diffraction spectrum by different peak intensities.
Moreover, it was found that Hydrate A loses the' harp dehydration endothermic peak of 123.5°C which characterizes unmilled Conventional Hydrate in thermogravimetricldifferential thermal analysis. Thus, the Conventional Hydrate is transformed into Hydrate A
after milling Conventional Hydrate and exhibits a gradual dehydration endothermic peak between about 60°C
and 120°C with a weak peak at about 71°C.

Yet another aspect of the invention comprised discovering that when heated to a specific temperature of 90-125 for 3-50hr, this novel aripiprazole hydrate dehydrates gradually avoiding the aggregation phenomenon thought to,be caused in conventional aripiprazole hydrate by rapid dehydration, and that aripiprazole anhydride crystals obtained by heating of the novel aripiprazole hydrate to a specific temperature are aripiprazole anhydride crystals with the desired properties.
Ch~,,racterization of I~ydrate A
Particles of "Hydrate A" as used herein have the physicochemical properties given in (1)-(5) below:
(1) It has an endothermic curve which is substantially the same as the thermogravimetric/
differential thermal analysis (heating rate 5°C/min) endothermic curve shown in figure 1. Specifically, it is characterized by the appearance of a small peak at about 71°C and a gradual endothermic peak around 60°C
to 120°C.
(2) It has an 1H-NMR spectrum which is substantially the same as the 1H-NMR spectrum (DMSO-d6, TMS) shown in Figure 2. Specifically, it has characteristic peaks at 1:55-1:63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2:46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H + DMSO), 2.78 ppm (t; J = 7.4 Hz, 2H), 2.97 ppm (brt, J = 4.6 Hz, 4H), 3.92 ppm (t, J = 6.3 Hz, 2H), 6.43 ppm (d, J = 2.4 Hz, 1H), 6.49 ppm (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10:00 ppm (s, 1H) .
(3) It has a powder x-ray diffraction spectrum which is substantially the same as the powder x-ray diffraction spectrum shown in Figure 3.
Specifically, it has characteristic peaks at 29 = 12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and 24.8°.
(4) It has clear infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm1 on the IR (KBr) spectrum.
(5) It has a mean particle size of 50 um or less.
Pr~~~ss for M~ract~~;~a uydrate A
Hydrate A is manufactured by milling Conventional Hydrate. Conventional milling methods can be used to mill. Conventional Hydrate. Far example, Conventional Hydrate can be milled in a milling machine. A widely used milling machine can be used, such as an atomizer, pin mill, jet mill or ball mill.
Of these, the atomizer is preferred.
Regarding the specific milling conditions when using an atomizer, a rotational speed of 5000-15000 rpm could be used for the main axis, for example, with a feed rotation of l0-30 rpm and a screen hole size of 1-5 mm.

The mean particle size of the Arlpiprazole Hydrate A obtained by milling should normally be 50 um or less, preferably 30 um or less. Mean particle size can be ascertained by the particle size measurement method described hereinafter.
r' B
"Aripiprazole Anhydride Crystals B" of the present invention as used herein have the physicochemical properties given in (6)-(12) below.
14 (6) They have an lH-NMR spectrum which is substantially the same as the 1H-NMR spectrum (DMSO-ds, TMS) shown in Figure 4. Specifically, they have characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2:48-2:56 ppm (m, 4H + DMSO); 2.78 ppm (t, J = 7.4 Hz, 2H), 2:97 ppm (brt, J = 4.6 Hz, 4H), 3.92 ppm (t, J = 6.3 Hz, 2H), 6.43 ppm (d, J = 2.4 Hz, 1H), 6.49 ppm (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm (d, J = 8.1 Hz, 1H), 7.11 7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H) .
(7) They have a powder x-ray diffraction spectrum which is substantially the same as the powder x-ray diffraction spectrum shown in Figure 5.
Specifically, they have characteristic peaks at 28 =
11.0°, 16:6°, 19.3°, 20:3° and 22.1°.
(8) They have clear infrared absorption bands at 2945, 2812, 1678, 1627; 1448, 137?; 1173, 960 and 779 cm-1 on the IR (KBr) spectrum.
(9) They exhibit an endothermic peak near about 141.5°C in thermogravimetric/differential thermal analysis (heating rate 5°C/min).
(10) They exhibit an endothermic peak near about 140.7°C in differential scanning calorimetry (heating rate 5°C/min).
(11) Aripiprazole Anhydride Crystals B of the present invention have low hygroscopicity: For example, Aripiprazole Anhydride Crystals B of the present invention maintain a water content of 0.40 or less after 24 hours inside a dessicator set at a temperature of 60°C and a humidity of 100. Well-known methods of measuring water content can be used as long as they are methods commonly used for measuring the water content of crystals. For example, a method such as the Karl Fischer method can be used.
(12) When the small particle size is required for the formulation such as tablet and other solid dose formulations including for example flashmelt formulations, the mean particle size is preferably 50 um or less:
Process fo_r Manufacti~rina~~dride B
In case of the formulation for which small particle size (less than 50 Vim) is required; the milling is necessary for the preparation. However, when a large amount of Conventional Aripiprazole Anhydride or Anhydride Crystals B having large particle size is milled, the milled substances adhere with each other :in the milling machine. Accordingly, there is a disadvantage that it is difficult to industrially prepare Aripiprazole Anhydride Crystals B having small particle size.
Under the circumstances, the inventors of the present invention have found that Conventional hydrate can be easily milled, and Aripiprazole Anhydride B
having, small particle size can be obtained in high yield with good-operability by heating the milled' hydrate A thus obtained.
The Aripiprazole Anhydride Crystals B,of the present invention are prepared for example by heating the aforementioned Aripiprazole Hydrate A at 90-125°C:
The heating time is generally about 3-50 hours,'but cannot'be stated unconditionally since it differs depending on heating temperature. The heating time and heating temperature are inversely related, so that for example the heating time will be longer the lower the heating temperature, and shorter the higher the'heating temperature. Specifically,, if the heating temperature of Aripiprazole Hydrate A is 100°C, the heating time should normally be 18 hours or more or preferably about 24 hours. If the heating temperature of Aripiprazole Hydrate A is 120°C, on the other hand, the heating time can be about 3 hours. The Aripiprazole Anhydride Crystals B of the present.invention can be prepared with certainty by heating Aripiprazole Hydrate A for about l8 hours at 100°C, and then heating it for about 3 hours at 120°C: The Aripiprazole .Anhydride Crystals B
of the present invention can also be obtained if the heating time is extended still further; but this may not be economical.
when small particle size is not required for the formulation, e.g.; when drug substance is being manufactured for injectable or oral solution formulations, Aripiprazole Anhydride Crystal B can be also obtained the following process.
The inventors also discovered that it is possible to obtain aripiprazole anhydride crystals by heating conventional aripiprazole hydrate or conventional aripiprazole anhydride crystals to a specific temperature but this process does not yield Anhydride B crystalline substance suitable for commercial use in the formulation of solid oral dose formulations.
Furthermore, the Aripiprazole Anhydride Crystals B of the present invention are prepared for example by heating conventional aripiprazole anhydride crystals at 90-125°C. The heating time is generally about 3-50 hours, but cannot be stated unconditionally since it differs depending on heating temperature. The heating time and heating temperature are inversely related, so that for example the heating time will be longer the lower the heating temperature, and shorter ~ CA 02379005 2002-03-27 _ 23 _ the higher the heating temperature. Specifically, if the heating temperature of the aripiprazole anhydride crystals is 100°C, the heating ime can be about 4 hours, and if the heating temperature is 120°C the heating time can be about 3 hours.
The aripiprazole anhydride crystals which are the raw material for preparing the Aripiprazole Anhydride Crystals B of the present invention are prepared for example by'Method a or b below.
" "~ s P a A a Cr~rstals Conventional Aripiprazole Anhydride crystals are prepared by well-known methods, as described in Example 1 of Japanese Unexamined Patent Publication No.
191256/1990.
A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 g of sodium iodide with 600 ml of acetonitrile was refluxed for 30 minutes. To this suspension was added 40 g of 1-(2,3-dichlorophenyl)piperazine and 33 m1 of triethylamine and the whole mixture was further refTuxed for 3 hours.
After the solvent was removed by evaporation, the residue thus obtained was dissolved in chloroform, washed with water then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue thus obtained was recrystaTlized from ethanol twice; to yield '57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril.
Colorless flake crystals Melting point: 139:0-139.5°C
" h "~ r r v n Anhydride The Method b is described in the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (October 6-8, 1995).
Furthermore, the Aripiprazole Anhydride Crystals B of the present invention are prepared for example by heating conventional aripiprazole hydrate at 90-125°G. The heating time is generally about 3-50 hours, but cannot be stated unconditionally since it differs depending on heating temperature. The heating time and heating temperature are inversely related, so that for example the heating time will be longer he lower the heating temperature; and shorter the higher the heating temperature. Specifically, if the heating temperature of the aripiprazole hydrate is 100°C, the heating time can be about 24 hours, while if the heating temperature is, 120°C, the heating time can be about 3 hours.
The aripiprazole hydrate which is the raw material for preparing the Aripiprazole Anhydride Crystals B of the present invention is prepared for example by Method c below.

CA 02379005 2002-03-27 .

.., f r l v 1, Aripiprazole hydrate is easily obtained by dissolving the aripiprazole anhydride crystals obtained by Method a above in a hydrous solvent, and heating and then cooling the resulting solution. Using this method, aripiprazole hydrato is precipitated as crystals in the hydrous solvent.
An organic solvent containing water is usually used as the hydrous solvent. The organic solvent should be one which is miscible with water, such as for example an alcohol such as methanol', ethanol, propanol or isopropanol, a ketone such as acetone, an ether such as tetrahydrofuran, dimethylformamide; or a mixture thereof, with ethanol being particularly desirable. The.amount of water in the hydrous solvent can be 10-25% by volume of the solvent, or preferably close to 20% by volume.
A medicinal composition of the present invention will contain Aripiprazole Anhydride Crystals B in a pharmaceutically acceptable carrier or combination of carriers:
Carriers which are pharmaceutically acceptable include diluents and excipients generally used in pharmaceuticals, such as fillers, extenders, binders, moisturizers; disintegrators, surfactants, and lubricants.

The medicinal composition of the present invention may be formulated as an ordinary medicinal preparation, for example in the form of tablets, flashmelt tablets, pills, powder, liquid, suspension, emulsion, granules; capsules, suppositories or'as an injection (liquid, suspension, etc. ) .
When a tablet formulation is used, awide variety of carriers that are known in the field can be used. Examples include lactose, saccharose, sodium chloride, glucose, urea, starch; calcium carbonate, kaolin, crystal cellulose, silic acid and other, excipients; water, ethanol, propanol, simple syrup, glucose liquid, starch liquid, gelatin solution;
carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrolidone and other binders; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethyl.ene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch,:
lactose and other disin egrators; saccharose, stearin, cacao butter, hydrogenated oil and other disintegration inhibitors; quaternary ammonium salt, sodium lauryl sulfate and other absorption promoters; glycerine, starch and other moisture retainers; starch, lactose, kaolin, bentonite, colloidal silk acid and other adsorbents; and refined talc, stearate; boric acid powder , polyethylene glycol and other lubricants and the like. Tablets can also be formulated if necessary as tablets with ordinary coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric coa ed tablets and film coated tablets, as well as double tablets and multilayered tablets.
When a pill formulation is used, a wide variety of carriers that are known in the field can, be used. ,Examples include glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc and other excipients; gum arabic powder, traganth powder, gelatin, ethanol and other binders: and laminaran; agar and other disintegrators and the like.
When a suppository formulation is used, a wide variety of carriers that are known in the field can be used. Examples include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin semi-synthetic glyceride and the like.
Capsules are prepared according to ordinary methods' by mixing aripiprazole anhydride crystals with the various carriers described above and packing them , in hard gelatin Capsules, soft capsules and the'like.
Tn addition, colorants, preservatives, perfumes, flavorings, sweeteners and the like as'well as other drugs may be included in the medicinal composition.
The amount of Aripiprazole Anhydride Crys als B that should be included in the medicinal composition of the present invention can be selected from a wide range suitable for the indication sought to be treated.

- 28 _ Generally, the Aripiprazole Anhydride Crystals B should be pre ent in about 1-,70o by weight or particularly about 1-30~ by weight based on the medicinal composition.
The method of administration of the medicinal composition of the present invention may be adjusted to suit, for example, the formulation of the drug product, the age, gender and other conditions (including the severity thereof) of the patient. In the case of tablets, pills, liquids, suspensions, emulsions, granules and capsules, for example, administration is oral. In the Case of an injection, it is administered intravenously either by itself or mixed with an ordinary replenishes such as glucose or amino acids, or may also be administered by itself intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as necessary. In the ease of a suppository, administration is intrarectal.
The dosage of the medicinal composition of the present invention is selected depending on the usage, the age, gender,and other conditions of the patient, the severity of the condition and so forth, but ordinarily the amount of aripiprazole anhydride crystals can be about 0:1-10 mg per 1 kg of body weight per day. The preparation which is the unit of administration should contain in the range of about 1-100 mg of Aripiprazole Anhydride Crystals B, more particularly 1-30 mg per unit dose.

, CA 02379005 2002-03-27 The medicinal composition of the present invention is extremely stable, with substantially no' decrea a in solubility even when stored for long periods of time.
The medicinal composition of the present invention is effective in the prevention and treatment of central nervous system disorders such as schizophrenia and may also be effective in the treatment of intractable (drug-resistant, chronic) schizophrenia with cognitive impairment and intractable (drug-resistant, chronic) schizophrenia without cognitive impairment, anxiety including mild anxiety, mania including bipolar disorder acute mania and acute mania, bipolar disorder, depression including bipolar disorder depression., autism, Down's syndrome, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, panic, obsessive compulsive disorder (OCD), sleep disorders, sexual dysfunction, alcohol'and drug dependency, vomiting, motion sickness, obesity; miparticlee headache and cognitive impairment.
Anal~,tica'~,I~etY~Q~I.~
( 1 ) The 1H-NMR spectrum was measured iri DMSO-d6 using TMS as the standard.
(2) Powder x-ray Diffraction Using a Rigaku Denki RAD-2n diffraction meter, the powder x-ray diffraction pattern was ~ CA 02379005 2002-03-27 - 30 _ measured at room temperature using a Cu Ka filled tube (35 kV 2OmA) as the x-'ray source with a wide-angle goniometer, a 1° scattering slit, an 0:15 mm light-intereepting slit, a graphite secondary monochromator and a scintillation counter. Data collection was done in 2B continuous scan mode at a scan speed of 5°/minute in scan steps of 0.02° in the range of 3° to 40;°.
(3) The IR spectrum was measured by the KBr method:
(4) ThermogravimetriclDifferential Thermal Analysis Thermogravimetric/differential thermal analysis was performed using a Seiko SSC 5200 control°
unit and. a TG/DTA 220 simultaneous differential thermal/thermogravimetric measurement unit. 5-1:0 mg samples were placed in open aluminum pans and heated from 20°C to 200°C in a dry nitrogen. atmosphere at a heating rate of 5°C/minute. a-alumina was used as the standard substance.
(5) Differential Scanning Calorimetry Thermogravimetric/differenti.al thermal analysis was performed using a Seiko 5SC 5200 control unit and a DSC 220C differential scanning calorimeter.
5-10 mg samples were placed in crimped aluminum pans and heated from 20°C to 200°C in a dry nitrogen atmosphere at a heating rate of 5°C/minute. a-alumina was used as the standard substance.
(6) Particle Size Measurement 0.1 g of the particles to be measured were suspended in a 20 ml n-hexane 5alution of 0.5 g soy lecithin, and particle size was measured using a size distribution meter (Microtrack HRA, Microtrack Co.).
('7) Hygroscopicity Test Method One g of the sample was accurately weighed in a weighing bottle (diameter 5 cm), covered with kimwipes and left to rest in a 60°C/100~ RH environment (water/dessicator). 24 hours later, the weighing bottle was removed, transferred to an environment of a room temperature and about 30o RH (magnesium chloride hexahydrate saturated water solution/dessicator) and left to rest for 24 hours and the water content of the sample was measured by the Karl Fischer method.
The present invention is explained in more detail below using reference examples, examples, sample preparations and formulation examples.
Re Qr~~~~.~Xam l~l 19.4 g of 7-(4-chlorobutoxy)-3,4-24 dihydrocarbostyril and 16.2 g of 1-(2,3-dichlorophenyl) piperadine.l hydrochloride were added to 8.39 g of potassium carbonate dis-solved in 140 ml ofwater, and circulated for 3 hours under agitation. After reaction the mixture was cooled and the precipitated crystals filtered out. These crystals were dissolved in 350 m1 of ethyl' acetate, and about 210 ml of water/ethyl acetate;azeotrope removed under reflux. The remaining' _ 32 _ solution was cooled, and the precipitated crystals filtered out. The resulting crystals were dried for l4 hours at 60°C to produce 20.4 g (74.2%) of raw, aripiprazole.
30 g of the raw aripiprazole obtained: above was recrystallized from. 450 ml of ethanol according to the methods described in Japanese Unexamined Patent Publication No. 19125611990; and the resulting crystals dried for 40 hours at 80°C to obtain aripiprazole anhydride crystals. The yield was 29.4 g (98.0o).
The melting point (mp) of these aripiprazole anhydride crystals was 140°C, matching the melting point of the aripiprazole anhydride crystals described in Japanese Unexamined Patent Publication No.
192256/1990.
When these crystals were left for 24 hours in a dessicator set at humidity 100, temperature 60°C, hey exhibited hygroscopicity of 3.28$ (see Table 1 below) .
Reference Example 2 6930 g of the intermediate raw aripiprazole obtained in Reference Example 1 was heat dissolved in 138 liters of hydrous ethanol (water content 20~) according to the method presented at the 4th Japa,nese-Korean Symposium on Separation Technology, gradually (2-3 hours) cooled to room temperature, and then chilled to near 0°C. The precipitated crystals were ,.

filtered out, producing about 7200 g of aripiprazole hydrate (wet state).
The we -state aripiprazole hydrate crystals obtained above were dried for 30 hours at 80°C to obtain 6480 g (93.50 of conventional aripiprazole anhydride crystals. The melting point (mp) of these crystals was 139:5°C. These crystals were confirmed by the Karl Fischer method o be anhydrous, with a moisture value of 0.030.
When left for 24 hours in a dessicator set at humidity 1000, temperature 60°C, these crystals exhibited hygroscopicity of 1.780 (see Table 1 below).
Refere~~~e Example 33 820 g of the 'intermediate wet-state aripiprazole hydrate obtained in Reference Example 2 was dried for 2 hours at 50°C to obtain 780 g of aripiprazole hydrate crystals. These crystals had a moisture value of 3.820 according to the Karl Fischer method: As shown in Figure 6, thermogravimetric/:
differential thermal analysis revealed endothermic peaks at 75.0, 123.5 and'140.5°C. Because dehydration began near 70°C, there was no clear melting point (mp).
As shown in Figure 7, the powder x-ray diffraction spectrum of aripiprazole hydrate obtained by this method exhibited characteristic peaks at 28 =
12.6°, 15:1°, 17.4°, 18.2°, 18.7°~
24.8° arid 27.5°, The powder x-ray diffraction spectrum of this aripiprazole hydrate was identical to the powder x-ray diffraction spectrum of aripiprazole hydrate presented at the 4th Joint Japanese-Korean Symposium on Isolation Technology.
example 1 500.3 g of the aripiprazole hydrate crystals obtained in Reference Example 3 were milled using a sample. mill (small atomizer). The main axis rotation rate was set to 12,000 rpm and the feed rotation rate to 17 rpm; and a 1.O mm herringbone screen was used.
Milling was completed in 3 minutes, resulting in 474.6 g (94.9%) of Aripiprazole Hydrate A powder.
The Aripip.razole Hydrate A (powder) obtained in this way had a mean particle size of 20-25 um. The melting point (mp) was'undetermined because dehydration was observed beginning near 7f°C.
The Aripiprazole Hydrata A (powder) obtained above exhibited an 1H-NMR (DMSO-d6, TMS) spectrum which was sub tantially the same as the lH-NMR spectrum shown in Figure 2. Specifically, it had characteristic peak at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2:35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H + DMSO), 2.78 ppm (t, J = 7.4 Hz, 2H); 2.97 ppm (brt, J = 4.6 Hz, 4H) , 3. 92 ppm (t, J = 6. 3 Hz, 2H) , 6. 43 ppm (d, J = 2 . 4 Hz, 1H) , 6.49 ppm (dd, J = 8 . 4 Hz, J = 2 . 4 Hz, 1H) , 7.04 ppm (d, J = 8.1 Hz; 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H) .

_ 35 _ The Aripiprazole Hydrate A (powder) obtained above had a powder x-ray diffraction spectrum which was substantially tha same!as the powder x-ray diffraction spectrum shown in Figure 3. Specifically, it had characteristic peaks at 26 = 12.6°, 15.4°, 17.3°, 18.0°, 18.6°,,22.5° and 24.8° This pattern is different from the powder x-ray spectrum of unmilled aripiprazole hydrate shown in Figure 7.
The Aripiprazole Hydrate A (powder) obtained above had infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm-1 on the IR
(KBr) spectrum.
As shown in Figure T, the Aripiprazole Hydrate A (powder) obtained above had a weak peak at 71.3°C in thermogravimetric/differential thermal analysis and a broad endothermic peak (wefight loss observed corresponding to one water molecule) between 60-120°C--clearly different from the endothermic curve of unmilled aripiprazole hydrate (see Figure 6).
example 2 450 g of the .A;ripiprazole Hydrate A. (powder) obtained in Example l was dried for 24 hours at 100°C
using a hot air dryer to produce 427 g (yield 98.70: of Aripiprazole Anhydride Crystals B.
These Aripiprazole Anhydride Crystals B! had a.
melting point (mp) of 139.7°C.
The Aripiprazole Anhydride Crystals B

obtained above had an'1H-NMR spectrum (DMSO-d6, TMS) which was substantially the same as the 1H-NMR spectrum shown in Figure 4. Specifically, they had characteristic peak at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2',.56 ppm (m, 4H + DMSO~, 2.78 ppm (t, J = 7.4 Hz, 2H), 2.97 ppm (brt, J _ 4 . 6 Hz, 4H) , 3. 92 ppm (t, J = 6. 3 Hz, 2H) , 6.43 ppm (d, J = 2:4 Hz, 1H), 6.49 ppm (dd, J = 8.4 Hz, J = 2.41Hz, 1H), 7.04 ppm (d, J = 8,1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7:28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H) .
The Aripiprazole Anhydride Crystals B' obtained above had a powder y-ray diffraction spectrum which was substantially the same as the powder x-ray diffraction spectrum shown in Figure 5. Specifically, they had characteristic peaks at 26 = 11.0°, 16.6°, 19:3°, 20.3° and 22.1°.
The Aripiprazole Anhydride Crystals B
obtained above had remarkable infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cml on the IR (KBr) spectrum.
The Aripiprazole Anhydride Crystals B
obtained above exhibited an. endothermic peak near about 141.5°C in thermogravimetricldifferential thermal' analysis:
The Aripiprazole Anhydride Crystals B
obtained above exhibited an endothermic peak near about 140.7°C in differential scanning calorimetry.

Even when the Aripiprazole Anhydride Crystals B obtained above were left for 24 hours in a dessicator set at humidity 1000, temperature 60°C, they did not exhibit hygroscopicity exceeding 0.4~ (See Table 1 below) .
Exam 1p a 3 44.29 kg of the Aripiprazole Hydrate A
(powder) obtained in Example 1 was dry heated for 18 hours in a 100°C hot air dryer and then heated for 3 hours at 120°C to produce 42.46 kg (yield 99.3x) of Aripiprazole Anhydride Crystals B.
The physicochemical properties of the resulting Aripiprazole Anhydride Crystals B were the same as the physicochemical properties of the Aripiprazole Anhydride Crystals B obtained in Example 2.
'The Aripiprazole Anhydride Crystals B
obtained in this way dil not exhibit hygroscopicity of more than 0.4o even when left for 24 hours in a dessicator set at humidity 100%, temperature 60°C (see Table 1 below).
40.67 kg of the Aripiprazole Hydrate A
(powder) obtained in Example 1 was dry heated for 18 hours in a 100°C hot air dryer and then heated for 3 hours at 120°C to produce 38.95 kg (yield 99.60) of _ 3g -Aripiprazole Anhydride Crystals B.
The physicochemical properties of the resulting Aripiprazole Anhydride Crystals B were the same as the physicochemical properties of the Aripiprazole Anhydride Crystals B obtained in Example 2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhib it hygroscopicity of more than 0.4% even when left for 24 hours in a dessicator set at humidity 100%, temperature 60°C (see Table 1 below).
Examples 5-10 are useful for injectable or oral solution formulations but not solid dose formulations since they were made by heating Conventional Anhydride or Conventional Hydrate instead of Hydrate A.
Example 5 The hygroscopic aripiprazole anhydride crystals obtained in Reference Example 1 were heated for 50 hours at 100°C using the same methods as in Example 2. The physicochemical properties of the resulti',ng Aripiprazole Anhydride Crystals B were the same as the physicochemical properties of the Aripiprazole Anhydride Crystals B obtained in Example 2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of _ 3g _ more than 0.4% even when left for 24 hours in a dessicator set at humidity 100%, temperature 60°C (see Table 1 below).
Example 6 The hygroscopic aripiprazole anhydride crystals obtained in Reference Example 1 were heated for 3 hours at 120°C using the same methods as in Example 2. The physicochemical properties of the resulting Aripiprazole Anhydride Crystals B were the same as, the physicochemical properties of the Aripiprazole Anhydride Crystals B obtained in Example 2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of more than 0.4% even when left for 24 hours in a dessica or set at humidity 100%, temperature 60°C (see Table 1 below).
Example 7 The hygroscopic aripiprazole anhydride crystals obtained in Reference Example 2 were heated for 50 hours at 100°C using the same methods as in Example 2. The physicochemical properties of the resulting Aripiprazole Anhydride Crystals B were the same as,the physicochemical properties of the Aripiprazole Anhydride Crystals B obtained in Example 2.

a The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of more than 0.4o even when left for 24 hours in a dessicator set at humidity 1000, temperature 60°C (see Table 1' below).
Example 8 The hygroscopic aripiprazole anhydride crystals obtained in Reference Example 2 were heated for 3 hours at 120°C using the same methods as in Example 2. The physicochemical properties of the resulting Aripiprazole Anhydride Crystals B were the same as the physicochemical properties of the Aripiprazole Anhydride Crystals B obtained in Example 2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of more than 0.4o even when left for 24 hours in a dessicator set at humidity 1000, temperature 60°C (see Table 1 below).
Example 9 The aripiprazole hydrate crystals obtained in Reference Example 3 were heated for 50 hours at 100°C
using the same methods as in Example 2. The physicochemical properties of the resulting Aripiprazole Anhydride Crystals B were the same'as the physicochemical properties of the Aripiprazole Anhydride Crystals B obtained in Example 2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of more than 0.4°s even when left for 24 hours in a dessicator set at humidity 1000, temperature 60°C (see Table l below).
Example 10 The aripiprazole hydrate crystals obtained in Reference Example 3 were heated for 3 hours at 120°C
using the same methods as in Example 2. The physicochemical properties of the resulting Aripiprazole Anhydride Crystals B were the same'as the physicochemical properties of the Aripiprazole Anhydride' Crystals B obtained in Example 2.
The Aripiprazole Anhydride Crystals B-obtained in this way exhibited hygroscopicity of no more than 0.4o even when left for 24 hours in a dessicator set at humidity 100%, temperature 60°C (see Table 1 below).

- 42 _ Table 1 Sample Initial Moisture Moisture Content Content ( o ) After 24 hrs ( ~
) Reference Example 1 0.04 3.28 Reference Example 2 0.04 1.78 Example 2 0.04 0.04 Example 3 0.02 0.02 Example 4 0.02 0.02 Example 5 0.04 0.04 Example 6 0.04 0:04 Example 7 0.04 0.03 Example 8 0.04 0.03 Example 9 0.03 0.01 Example l0 0.05 0.05 Sample ,~reparatiorL 1 Aripiprazole anhydride crystals B 5 mg Starch 132 mg;
Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets containing the above ingredients in each tablet were prepared by formulation methods known to one skilled in the art of pharmaceutical formulation.

_ 43 _ Formulation Example The following examples used aripiprazole drug substance made by first milling or pulverizing the conventional hydrate of aripiprazole and then heating it to form the anhydrous form (anhydride B).
Formulation Examp~ 1 Flash-melt tablets were prepared as follows:
Intragranulation:
I~r ~r~d~ n ~ Percent w/w Ma--~'er table Xylitol (300) Xylisorb 26 52 Avicel~ PH 102 12 24 Calcium Silicate 43.35 86.7 Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 92.75 185.5 The ingredients except for the magnesium stearate were blended in a commercial V-blender in geometric proportions for 5 minutes each until all were added. The magnesium stearate was then added and the mixture blended for an additional three minutes. The blended formulation was compacted at a pressure of 30-35 kgF/cm2 in a commercial compactor equipped with an orifice such that the compacts therefrom are in the form of ribbons. The ribbons were passed through a 30 mesh (600 microns) screen to form stable granules of about 150 to 400 microns.
Ex ragranL~lation Inc~redi n Ma~per Incxredi ent ,.'_ Percent w/w table.t Intragranulation 92.75 185.5 Avicel~ PH 200 3 6 Crospovidone 4 8 Magnesium stearate 0.25 0.5 Total weight 100 200 The intragranulation was placed in the blender and the Avicel~ PH 200 and crospovidone added thereto and blended for five minutes. The magnesium stearate was then added and the mixture blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2:3 kP (3.5 SCU) and disintegrated in 10 seconds in 5 ml of water. The final blend formulation demonstrated excellent flow and was free of other problems such as chipping, capping and sticking. It has been found that utilizing Avicel~ PH 102 for the intragranulation and AvicelC~ PH 200 for the extragranulation ingredient enhanced the quality of the resultant tablets.
Fr~_rmulation Examx~le 2 Flash-melt tablets containing a combination of two grades of calcium silicate were prepared as follows:
Inc,~redient Percent w/w Via' per Xylitol (300) Xylisorb 26 52 Avicel~ PH 102 12 24 Calcium Silicate (crystalline, alpha 33.35 66.7 triclinic) Hubersnrb 600 NF
(amorphous calcium 10 20 silicate ) Crospovidone 3 6 Amorphous silica 2 4 Aspartame' 2 4 Wild cherry flavbr 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearato 0.25 0.5 Total weight 92.75 185.5 The ingredients except for the magnesium stearate were blended-in a commercial V-blender in ~ 02379005 2002-03-27 i geometric proportions for 5 minutes each until all were added. The magnesium stearate was added and the mixture blended for an additional three minutes: The blended formulation was compacted, and screened to form stable granules in accordance with the procedure of Formulation Example 1.
Ex aranulatio-n_ Ingredients --per Ingredient percent w/w e tabl Intragranulation 92.75 185.5 Avicel~ PH 200 3 6 Crospovidone 4 8 Magnesium stearate 0.25 0.5 Total weight 100 200 The intragranulation was placed in the blender and the Avicel~ PH 200 and crospovidone added thereto and blended for five minutes. The magnesium stearate was then added and the mixture blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2.0 kP (3.1 SCU) and disintegrated in 10 seconds in 5 ml of water.
Formul anon Exan~~le 3 Flash-melt tablets containing aripiprazole, an antischizophrenic drug, were prepared as follows:

T n t r,~.g r anu'~S2 t i on _ M~per ~,nc~redient Percent w/w table, Aripiprazole 15 30 Xylitol L300) Xylisorb 25 50 Avicel~ PH 102 6 12 Calcium Silicate 37 74 Crospoviclone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 94.4 188.8 The ingredients except for the magnesium stearate were blended in a commercial V-blender in geometric proportions for 5 minutes each until all were added. The magnesium stearate was added and the mixture blended for an additional three minutes. The blended formulation was: compacted, and screened to form stable granules in accordance with the procedure of Formulation Example 1.

Fxt-rac~ranulation Ingredients M~per Ingrredient Percent w/w tablet Intragranulation 94.4 1.88.8 Avicel~ PH 200 1.1 2.2 Crospovidone 4 8 Magnesium stearate 0.5 1 Total weight 100 200 The intragranulation was placed in the blender and the AvicelC~ PH 200 and crospovidone added thereto and blended for five minutes. The magnesium stearate was then added and the mixture blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2.O kP (3.1 SCU) and disintegrated in 10 seconds in 5 ml of water.
Formulation Example 4 Flash-melt tablets containing aripiprazole were prepared as follows:

Intraaranulation:
Mg. per Ingredient Percent w/w tablet Aripiprazole 0.5 1 Xylitol (300) Xylisorb 27 54 Avicel~ PH 102 ~ 12 24 Calcium Silicate 42 84 Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 92.9 185.8 The ingredients except for the magnesium stearate were blended in a commercial V-blender in geometric proportions for 5 minutes each until all were added. The'magnesium stearate was added and the mixture blended for an additional three minutes. The blended formulation was compacted, and screened to form stable granules in accordance with the procedure of Formulation Example 1.

Extragranulation Ingredients:
M~-per Ingredient Percent w/w tablet Intragranulation 92.9 185.8 Avicel~ PH 200 2.6 5.2 Crospovidone 4 8 Magnesium stearate 0.5 1 Total weight 100 200 The intragranulation was placed in the blender and the Avicel~ PH 200 and crospovidone added thereto and blended for five minutes. The magnesium stearate was then added and the'mixture blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2.3 kP,(3.5 SCU) and disintegrated in 10 seconds in 5 ml of water.

Claims (67)

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 Figure 3.
2. Hydrate A of aripiprazole wherein said Hydrate has powder x-ray diffraction characteristic peaks at 2.theta. = 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 Figure 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 Figure 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 analyses (heating rate 5°C/min) endothermic curve shown below shown in Figure 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 l0-30 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 hygroscopieity 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 Figure 5.
17. Aripiprazole Anhydride Crystals B having a powder x-ray diffraction spectrum having characteristic peaks at 2.theta. = 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 Aripiprazale 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 aripiprasole anhydride crystals B for the treatment of schisophrenia.
59. The use of aripsprazole anhydride crystals B for the treatment of bipolar disorder.
60. The use of aripiprasole anhydride crystals B for the treatment of intractable (drug-resistant, chronic) schizophrenia with cognitive impairment or intractable (drug-resistant, chronic) schizophrenia without cognitive impairment.
61. The use of aripiprazo1e 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, malparticlee 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 Lo prepare a medicament to treat or prevent achizophrenia and the symptoms associated with schizophrenia.
66. A drug for treating schisophrenia 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 80, which is contained in a commercial package carrying instructions that the drug should be used for treating schizophrenia, or symptoms thereof.
CA 2379005 2001-09-25 2002-03-27 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof Abandoned CA2379005A1 (en)

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ARP020103511A AR033485A1 (en) 2001-09-25 2002-09-18 MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME
PE2002000922A PE20030445A1 (en) 2001-09-25 2002-09-20 ARIPIPRAZOLE MEDICINAL SUBSTANCE OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME
MYPI20023512A MY138669A (en) 2001-09-25 2002-09-20 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
PE2008001435A PE20090124A1 (en) 2001-09-25 2002-09-20 PHARMACEUTICAL COMPOSITION INCLUDING LOW HYGROSCOPICITY ARIPIPRAZOLE CRYSTALS AND PROCEDURE FOR PREPARING THE SAME
TW098116881A TWI332839B (en) 2001-09-25 2002-09-23 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
TW091121771A TWI318572B (en) 2001-09-25 2002-09-23 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
ES08000357T ES2343219T3 (en) 2001-09-25 2002-09-25 ARIPIPRAZOL-BASED MEDICINAL PRODUCT (CRYSTAL F) THAT HAS REDUCED HYGROSCOPICITY AND ITS PREPARATION PROCEDURE.
CA2689051A CA2689051C (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
CN201710019464.0A CN106692151A (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for preparation thereof
CN201610811822.7A CN106420627A (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
EP08000359A EP1927356B1 (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole (crystal D) drug substance and processes for the preparation thereof
CN201610811281.8A CN106420640A (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
DK08000359.3T DK1927356T3 (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug (crystal D) and methods of preparation thereof
SI200230337T SI1330249T1 (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
BR0205391-8A BR0205391A (en) 2001-09-25 2002-09-25 Aripiprazole hydrate a, Process for the preparation of hydrate a, Low hygroscopicity aripiprazole drug substance, Aripiprazole b anhydrous crystals, Processes for the preparation of aripiprazole anhydride crystals b for the preparation of a solid oral pharmaceutical preparation, use of aripiprazole anhydride crystals, medicament for treating schizophrenia or symptoms associated with schizophrenia, process for preparing granules, pharmaceutical solid oral preparation, aripiprazole anhydride crystals c to g, process for preparing anhydrous crystals aripiprazole c to g, e, pharmaceutical composition.
ES02782507T ES2261750T3 (en) 2001-09-25 2002-09-25 PHARMACEUTICAL SUBSTANCE OF ARIPIPRAZOL THAT HAS A REDUCED HYGROSCOPICITY AND ASSOCIATED PREPARATION METHODS.
CN201410053617.XA CN103751118A (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
CN200610006215XA CN1817882B (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
SI200230903T SI1419776T2 (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
CNA2008101254118A CN101434575A (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
KR10-2004-7007990A KR100530731B1 (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
PL393601A PL219565B1 (en) 2001-09-25 2002-09-25 Anhydrous aripiprazole D crystals, method of their preparation, pharmaceutical composition and pharmaceutical solid oral preparation containing D crystals of anhydrous aripiprazole
HU0600141A HUP0600141A3 (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole-anhydrate process for its preparation, pharmaceutical compositions containing it and its use
KR10-2003-7000818A KR100490222B1 (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
CN201510333215.XA CN104945321A (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
SI200230904T SI1927356T1 (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole (crystal D) drug substance and processes for the preparation thereof
GEAP2002005101 GEP20053457B (en) 2001-09-25 2002-09-25 Low Hygroscopic Aripiprazole Drug Substance and Processes for Preparation Thereof
CN2008101254103A CN101434574B (en) 2001-09-25 2002-09-25 Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8039621B2 (en) 2006-10-24 2011-10-18 Cambrex Charles City, Inc. Process for preparing anhydrous Aripirazole type I

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8039621B2 (en) 2006-10-24 2011-10-18 Cambrex Charles City, Inc. Process for preparing anhydrous Aripirazole type I

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