U.S. patent application number 15/149522 was filed with the patent office on 2016-09-01 for low hygroscopic aripiprazole drug substance and proce3sses for the preparation thereof.
This patent application is currently assigned to OTSUKA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is OTSUKA PHARMACEUTICALS CO., LTD.. Invention is credited to Kaoru Abe, Satoshi Aoki, Takuji Bando, Kiyoshi Fujimoto, Tsutomu Fujimura, Makoto Ishigami, Junichi Kawasaki, Noriyuki Kobayashi, Tomonori Nakagawa, Yoshihiro Nishioka, Yoshihiro Ooi, Koichi Shinhama, Masanori Takahashi, Youichi Taniguchi, Kenji Tomikawa, Michiaki Tominaga, Naoto Utsumi, Tsuyoshi Yabuuchi, Shohei Yamada.
Application Number | 20160251315 15/149522 |
Document ID | / |
Family ID | 27171631 |
Filed Date | 2016-09-01 |
United States Patent
Application |
20160251315 |
Kind Code |
A1 |
Bando; Takuji ; et
al. |
September 1, 2016 |
LOW HYGROSCOPIC ARIPIPRAZOLE DRUG SUBSTANCE AND PROCE3SSES 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 anhydrous aripiprazole
crystals is stored for an extended period.
Inventors: |
Bando; Takuji; (Tokushima,
JP) ; Aoki; Satoshi; (Tokushima, JP) ;
Kawasaki; Junichi; (Tokushima, JP) ; Ishigami;
Makoto; (Tokushima, JP) ; Taniguchi; Youichi;
(Tokushima, JP) ; Yabuuchi; Tsuyoshi; (Tokushima,
JP) ; Fujimoto; Kiyoshi; (Tokushima, JP) ;
Nishioka; Yoshihiro; (Tokushima, JP) ; Kobayashi;
Noriyuki; (Tokushima, JP) ; Fujimura; Tsutomu;
(Tokushima, JP) ; Takahashi; Masanori; (Tokushima,
JP) ; Abe; Kaoru; (Tokushima, JP) ; Nakagawa;
Tomonori; (Tokushima, JP) ; Shinhama; Koichi;
(Tokushima, JP) ; Utsumi; Naoto; (Tokushima,
JP) ; Tominaga; Michiaki; (Tokushima, JP) ;
Ooi; Yoshihiro; (Tokushima, JP) ; Yamada; Shohei;
(Tokushima, JP) ; Tomikawa; Kenji; (Tokushima,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA PHARMACEUTICALS CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
OTSUKA PHARMACEUTICAL CO.,
LTD.
|
Family ID: |
27171631 |
Appl. No.: |
15/149522 |
Filed: |
May 9, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14049777 |
Oct 9, 2013 |
9359302 |
|
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15149522 |
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13350117 |
Jan 13, 2012 |
8580796 |
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14049777 |
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10333244 |
Jun 16, 2003 |
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PCT/JP02/09858 |
Sep 25, 2002 |
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13350117 |
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Current U.S.
Class: |
544/363 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 25/04 20180101; A61P 3/04 20180101; C07D 215/227 20130101;
A61P 1/08 20180101; A61P 25/30 20180101; A61P 25/20 20180101; C07B
2200/13 20130101; A61P 25/00 20180101; A61P 25/16 20180101; A61P
25/28 20180101; Y10T 428/2982 20150115; A61P 15/00 20180101; A61P
15/10 20180101; A61P 25/32 20180101; C07D 215/22 20130101; A61P
25/24 20180101; A61P 25/06 20180101; A61P 25/18 20180101 |
International
Class: |
C07D 215/227 20060101
C07D215/227 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 25, 2001 |
JP |
JP 2001-290645 |
Nov 14, 2001 |
JP |
JP 2001-348276 |
Mar 27, 2002 |
CA |
CA 2379005 |
Claims
1-48. (canceled)
49. A process for preparing Anhydrous Aripiprazole Crystals B
having low hygroscopicity, wherein said process comprises heating
Hydrate A of aripiprazole, wherein said low hygroscopicity is
defined as a moisture content of 0.40% or less when the Anhydrous
Aripiprazole Crystals B are placed for 24 hours in a dessicator
maintained at a temperature of 60.degree. C. and a humidity level
of 100%.
50. The process according to claim 49, wherein said process
comprises heating Hydrate A of aripiprazole at 90-125.degree. C.
for about 3-50 hours.
51. The process according to claim 49, wherein said process
comprises heating Hydrate A of aripiprazole at 100.degree. C. for
about 18 hours.
52. The process according to claim 49, wherein said process
comprises heating Hydrate A of aripiprazole at 100.degree. C. for
about 24 hours.
53. The process according to claim 49, wherein said process
comprises heating Hydrate A of aripiprazole at 120'C for about 3
hours.
54. The process according to claim 49, wherein said process
comprises heating Hydrate A of aripiprazole for about 18 hours at
100.degree. C. followed by additional heating for about 3 hours at
120.degree. C.
55. A process for preparing Anhydrous Aripiprazole Crystals B
having low hygroscopicity, wherein said process comprises heating
Hydrate A of aripiprazole, wherein said low hygroscopicity is
defined as a moisture content of 0.10% or less when the Anhydrous
Aripiprazole Crystals B are placed for 24 hours in a dessicator
maintained at a temperature of 60.degree. C. and a humidity level
of 100%.
56. The process according to claim 55, wherein said process
comprises heating Hydrate A of aripiprazole at 90-125.degree. C.
for about 3-50 hours.
57. The process according to claim 55, wherein said process
comprises heating Hydrate A of aripiprazole at 100.degree. C. for
about 18 hours.
58. The process according to claim 55, wherein said process
comprises heating Hydrate A of aripiprazole at 100.degree. C. for
about 24 hours.
59. The process according to claim 55, wherein said process
comprises heating Hydrate A of aripiprazole at 120.degree. C. for
about 3 hours.
60. The process according to claim 55, wherein said process
comprises heating Hydrate A of aripiprazole for about 18 hours at
100.degree. C. followed by additional heating for about 3 hours at
120.degree. C.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/350,117, filed Jan. 13, 2012, which is a
continuation of U.S. patent application Ser. No. 10/333,244, which
is a .sctn.371 of International Application No. PCT/JP02/09858,
filed Sep. 25, 2002, which claims priority of Japanese Patent
Application Nos. JP 2001-290645, filed Sep. 25, 2001, and JP
2001-348276, filed Nov. 14, 2001, and of Canadian Patent
Application No. CA 2379005, filed Mar. 27, 2002, the contents of
all of which are incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to an improved form of
aripiprazole having reduced hygroscopicity and processes for the
preparation of this improved form.
[0004] 2. Background of the Invention
[0005] 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)-qui-
nolinone, is an atypical antipsychotic agent useful for the
treatment of schizophrenia (U.S. Pat. No. 4,734,416 and U.S. Pat.
No. 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.
[0006] According to Example 1 of Japanese Unexamined Patent
Publication No. 191256/1990, anhydrous aripiprazole crystals are
manufactured for example by reacting
7-(4-bromobutoxy)-3,4-dihydrocarbostyril with
1-(2,3-dichlorophenylpiperadine and recrystallizing the resulting
raw anhydrous aripiprazole with ethanol. Also, according to the
Proceedings of the 4th Japanese-Korean Symposium on Separation
Technology (Oct. 6-8, 1996), anhydrous aripiprazole crystals are
manufactured by heating aripiprazole hydrate at 80.degree. C.
However, the anhydrous aripiprazole crystals obtained by the
aforementioned methods have the disadvantage of being significantly
hygroscopic.
[0007] The hygroscopicity of these crystals makes them difficult to
handle since costly and burdensome measures must be taken 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 Anhydrous Aripiprazole, to adhere to
manufacturing equipment which 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 crystals, the potential for absorbance of
moisture during storage and handling would adversely affect the
dissolubility 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 hygroscopicity
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.
[0008] Also, Proceedings of the 4th Japanese-Korean Symposium on
Separation Technology (Oct. 6-8, 1996) state that, anhydrous
aripiprazole crystals exist as type-I crystals and type-II
crystals; the type-I crystals of anhydrous aripiprazole can be
prepared by recrystallizing from an ethanol solution of
aripiprazole, or by heating aripiprazole hydrate at 80.degree. C.;
and the type-II crystals of anhydrous aripiprazole can be prepared
by heating the type-I crystals of anhydrous aripiprazole at 130 to
140.degree. C. for 15 hours.
[0009] By the aforementioned methods, anhydrous aripiprazole
type-II crystals having high purity can not be easily prepared in
an industrial scale with good repeatability.
SUMMARY OF THE INVENTION
[0010] 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 Anhydrous Aripiprazole Crystals B. A particular
process for the preparation of this anhydrous crystalline substance
has also been 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 Anhydrous Aripiprazole
Crystals 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, Hydrate A can be transformed into Anhydrous
Aripiprazole Crystals 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.
[0011] An object of the present invention is to provide novel
anhydrous aripiprazole crystals.
[0012] Moreover, another object of the present invention is to
provide anhydrous aripiprazole crystals which neither easily
convert into hydrates nor substantially decrease the original
solubility, even when a pharmaceutical composition comprising
anhydrous aripiprazole is stored for a long period of time.
[0013] Further object of the present invention is to provide
preparation methods, in order to obtain anhydrous aripiprazole
crystals having high purity in an industrial scale with good
repeatability.
[0014] The present inventors have conducted research works aimed to
attain the aforementioned objects. In the course of the research,
they have found that the desired anhydrous aripiprazole crystals
can be obtained when a well-known anhydrous aripiprazole is heated
at the specific temperature. Further, the present inventors have
found that the desired anhydrous aripiprazole crystals can be
obtained from recrystallization of a well-known anhydrous
aripiprazole by using the specific solvents. Moreover, the present
inventors found that the desired anhydrous aripiprazole crystals
can be obtained by suspending a well-known anhydrous aripiprazole
in the specific solvent, and heating thus obtained suspension.
[0015] The present invention thus completed on the basis of these
findings and knowledge.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a thermogravimetric/differential thermogram of the
Aripiprazole Hydrate A obtained in Example 1.
[0017] FIG. 2 shows the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the Aripiprazole Hydrate A obtained in Example 1.
[0018] FIG. 3 is a powder x-ray diffraction diagram of the
Aripiprazole Hydrate A obtained in Example 1.
[0019] FIG. 4 shows the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the Anhydrous Aripiprazole Crystals B obtained in Example 2.
[0020] FIG. 5 is a powder x-ray diffraction diagram of the
Anhydrous Aripiprazole Crystals B obtained in Example 2.
[0021] FIG. 6 is a thermogravimetric/differential thermogram of the
aripiprazole hydrate obtained in Reference Example 3.
[0022] FIG. 7 is a powder x-ray diffraction diagram of the
aripiprazole hydrate obtained in Reference Example 3.
[0023] FIG. 8 shows thermogravimetric/differential thermal analysis
endothermic curve of the type C crystals of anhydrous aripiprazole
obtained in Example 11.
[0024] FIG. 9 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the type C crystals of anhydrous aripiprazole obtained in Example
11.
[0025] FIG. 10 shows a powder X-ray diffraction spectrum of the
type C crystals of anhydrous aripiprazole obtained in Example
11.
[0026] FIG. 11 shows an IR spectrum of the type C crystals of
anhydrous aripiprazole obtained in Example 11.
[0027] FIG. 12 shows a solid .sup.13C-NMR spectrum of the type C
crystals of anhydrous aripiprazole obtained in Example 11.
[0028] FIG. 13 shows a thermogravimetric/differential thermal
analysis endothermic curve of the type D crystals of anhydrous
aripiprazole obtained in Example 12 or Example 13.
[0029] FIG. 14 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the type D crystals of anhydrous aripiprazole obtained in Example
12 or Example 13.
[0030] FIG. 15 shows a powder X-ray diffraction spectrum of the
type D crystals of anhydrous aripiprazole obtained in Example 12 or
Example 13.
[0031] FIG. 16 shows an IR spectrum of the type D crystals of
anhydrous aripiprazole obtained in Example 12 or Example 13.
[0032] FIG. 17 shows a solid .sup.13C-NMR spectrum of the type D
crystals of anhydrous aripiprazole obtained in Example 12 or
Example 13.
[0033] FIG. 18 shows a thermogravimetric/differential thermal
analysis endothermic curve of the type E crystals of anhydrous
aripiprazole obtained in Example 14.
[0034] FIG. 19 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the type E crystals of anhydrous aripiprazole obtained in Example
14.
[0035] FIG. 20 shows a powder X-ray diffraction spectrum of the
type E crystals of anhydrous aripiprazole obtained in Example
14.
[0036] FIG. 21 shows an IR spectrum of the type E crystals of
anhydrous aripiprazole obtained in Example 14.
[0037] FIG. 22 shows a thermogravimetric/differential thermal
analysis endothermic curve of the type F crystals of anhydrous
aripiprazole obtained in Example 15.
[0038] FIG. 23 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the type F crystals of anhydrous aripiprazole obtained in Example
15.
[0039] FIG. 24 shows a powder X-ray diffraction spectrum of the
type F crystals of anhydrous aripiprazole obtained in Example
15.
[0040] FIG. 25 shows an IR spectrum of the type F crystals of
anhydrous aripiprazole obtained in Example 15.
[0041] FIG. 26 shows thermogravimetric/differential thermal
analysis endothermic curve of the type G crystals of anhydrous
aripiprazole obtained in Example 16-b).
[0042] FIG. 27 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the type G crystals of anhydrous aripiprazole obtained in Example
16-b).
[0043] FIG. 28 shows a powder X-ray diffraction spectrum of the
type G crystals of anhydrous aripiprazole obtained in Example
16-b).
[0044] FIG. 29 shows an IR spectrum of the type G crystals of
anhydrous aripiprazole obtained in Example 16-b).
[0045] FIG. 30 shows a thermogravimetric/differential thermal
analysis endothermic curve of the glass form of anhydrous
aripiprazole obtained in Example 16-a).
[0046] FIG. 31 shows a powder X-ray diffraction spectrum of the
glassy state of anhydrous aripiprazole obtained in Example
16-a).
DETAILED DESCRIPTION OF THE INVENTION
[0047] 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 FIG. 3.
[0048] According to another embodiment of the first aspect of the
present invention is provided Hydrate A of aripiprazole wherein
said Hydrate has powder x-ray diffraction characteristic peaks at
2.theta.=12.6.degree., 15.4.degree., 17.3.degree., 18.0.degree.,
18.6.degree., 22.5.degree. and 24.8.degree..
[0049] 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.sup.-1 on the IR
(KBr) spectrum.
[0050] According to another embodiment of the first aspect of the
present invention is provided Hydrate A of aripiprazole wherein
said Hydrate has an .sup.1H-NMR spectrum which is substantially the
same as the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG.
2.
[0051] According to another embodiment of the first aspect of the
present invention is provided Hydrate A of aripiprazole wherein
said Hydrate has an .sup.1H-NMR spectrum (DMSO-d.sub.6, 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, 1H), 7.11-7.17 ppm (m, 1H),
7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).
[0052] According to another embodiment of the first aspect of the
present invention is provided 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.degree. C./min) endothermic curve shown in FIG.
1.
[0053] 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 50 .mu.m or less.
[0054] 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 .mu.m or less.
[0055] 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 .mu.m or less.
[0056] 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 .mu.m or less.
[0057] 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 .mu.m or less.
[0058] 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 .mu.m or less.
[0059] 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 .mu.m.
[0060] 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 36 to 14 .mu.m.
[0061] 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.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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 process as described herein.
[0067] According to a fourth aspect of the present invention is
provided aripiprazole drug substance of low hygroscopicity.
[0068] 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 0.5% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
[0069] 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.degree. C.
and a humidity level of 100%.
[0070] 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.degree. C.
and a humidity level of 100%.
[0071] 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.degree. C.
and a humidity level of 100%.
[0072] 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 0.10% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
[0073] 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.degree. C.
and a humidity level of 100%.
[0074] 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 0.04% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
[0075] 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 Anhydrous
Aripiprazole Crystals B as defined herein.
[0076] 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 FIG. 5.
[0077] 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
2.theta.=11.0.degree., 16.6.degree., 19.3.degree., 20.3.degree. and
22.1.degree..
[0078] 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 779 cm.sup.-1 on the IR (KBr) spectrum.
[0079] 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 .sup.1H-NMR
spectrum which is substantially the same as the .sup.1H-NMR
spectrum (DMSO-d.sub.6, TMS) shown in FIG. 4.
[0080] 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 .sup.1H-NMR
spectrum (DMSO-d.sub.6, 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, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and
10.00 ppm (s, 1H).
[0081] 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.degree. C. in thermogravimetric/differential
thermal analysis (heating rate 5.degree. C./min).
[0082] 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.degree. C. in differential scanning
calorimetry (heating rate 5.degree. C./min).
[0083] 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 Anhydrous
Aripiprazole Crystals B and will not substantially convert to a
hydrous form of aripiprazole when properly stored even for an
extended period. For instance, said Anhydrous Aripiprazole Crystals
B can be stored under a relative humidity (RH) of 60% and at a
temperature of 25.degree. C., even for a period not less than 1
year.
[0084] 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 Anhydrous
Aripiprazole Crystals B and will not substantially convert to a
hydrous form of aripiprazole when properly stored even for an
extended period. For instance, said Anhydrous Aripiprazole Crystals
B can be stored under a relative humidity (RH) of 60% and at a
temperature of 25.degree. C., even for a period not less than 4
years.
[0085] 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 Anhydrous
Aripiprazole Crystals B and will not substantially convert to a
hydrous form 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.degree. C.
[0086] 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 50
.mu.m or less when small particle size is required for the
formulation such as Tablet and other solid dose formulations
including for example flashmelt formulations.
[0087] 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 40
.mu.m or less if small particle size is required for the
formulation such as Tablet and other solid dose formulations
including for example flashmelt formulations.
[0088] 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
.mu.m or less if small particle size is required for formulation
such as Tablet and other solid dose formulations including for
example flashmelt formulations.
[0089] According to a fifth aspect of the present invention is
provided a process for the preparation of Anhydrous Aripiprazole
Crystals B.
[0090] According to a first embodiment of the fifth aspect of the
present invention is provided a process for the preparation of
Anhydrous Aripiprazole Crystals B wherein said process comprises
heating Aripiprazole Hydrate A.
[0091] According to a first embodiment of the fifth aspect of the
present invention is provided a process for the preparation of
Anhydrous Aripiprazole Crystals B wherein said process comprises
heating Aripiprazole Hydrate A at 90-125.degree. C. for about 3-50
hours.
[0092] According to another embodiment of the fifth aspect of the
present invention is provided a process for the preparation of
Anhydrous Aripiprazole Crystals B wherein said process comprises
heating Aripiprazole Hydrate A at 100.degree. C. for about 18
hours.
[0093] According to another embodiment of the fifth aspect of the
present invention is provided a process for the preparation of
Anhydrous Aripiprazole Crystals B wherein said process comprises
heating Aripiprazole Hydrate A at 100.degree. C. for about 24
hours.
[0094] According to another embodiment of the fifth aspect of the
present invention is provided a process for the preparation of
Anhydrous Aripiprazole Crystals B wherein said process comprises
heating Aripiprazole Hydrate A at 120.degree. C. for about 3
hours.
[0095] According to another embodiment of the fifth aspect of the
present invention is provided a process for the preparation of
Anhydrous Aripiprazole Crystals B wherein said process comprises
heating Aripiprazole Hydrate A for about 18 hours at 100.degree. C.
followed by additional heating for about 3 hours at 120.degree.
C.
[0096] According to a sixth aspect of the present invention is
provided Anhydrous Aripiprazole Crystals B defined according to one
or more of the embodiments described herein and made by a process
as provided herein.
[0097] According to a seventh aspect of the present invention is
provided Anhydrous Aripiprazole Crystals B formulated with one or
more pharmaceutically acceptable carriers.
[0098] Other embodiments of the present invention may comprise
suitable combinations of two or more of the embodiments and/or
aspects disclosed herein.
[0099] Yet other embodiments and aspects of the invention will be
apparent according to the description provided below.
[0100] 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 sharp dehydration endothermic
peak of 123.5.degree. C. which characterizes unmilled Conventional
Hydrate in thermogravimetric/differential 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.degree. C. and 120.degree. C.
with a weak peak at about 71.degree. C.
[0101] Yet another aspect of the invention comprised discovering
that when heated to a specific temperature of 90-125.degree. C. for
3-50 hr, this novel aripiprazole hydrate dehydrates gradually
avoiding the aggregation phenomenon thought to be caused in
conventional aripiprazole hydrate by rapid dehydration, and that
anhydrous aripiprazole crystals obtained by heating of the novel
aripiprazole hydrate to a specific temperature are anhydrous
aripiprazole crystals with the desired properties.
Characterization of Hydrate A
[0102] Particles of "Hydrate A" as used herein have the
physicochemical properties given in (1)-(5) below:
[0103] (1) It has an endothermic curve which is substantially the
same as the thermogravimetric/differential thermal analysis
(heating rate 5.degree. C./min) endothermic curve shown in FIG. 1.
Specifically, it is characterized by the appearance of a small peak
at about 71.degree. C. and a gradual endothermic peak around
60.degree. C. to 120.degree. C.
[0104] (2) It has an .sup.1H-NMR spectrum which is substantially
the same as the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 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).
[0105] (3) It has a powder x-ray diffraction spectrum which is
substantially the same as the powder x-ray diffraction spectrum
shown in FIG. 3. Specifically, it has characteristic peaks at
2.theta.=12.6.degree., 15.4.degree., 17.3.degree., 18.0.degree.,
18.6.degree., 22.5.degree. and 24.8.degree..
[0106] (4) It has clear infrared absorption bands at 2951, 2822,
1692, 1577, 1447, 1378, 1187, 963 and 784 cm.sup.-1 on the IR (KBr)
spectrum.
[0107] (5) It has a mean particle size of 50 .mu.m or less.
Process for Manufacturing Hydrate A
[0108] Hydrate A is manufactured by milling Conventional Hydrate.
Conventional milling methods can be used to mill Conventional
Hydrate. For 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.
[0109] 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 10-30 rpm and a
screen hole size of 1-5 mm.
[0110] The mean particle size of the Aripiprazole Hydrate A
obtained by milling should normally be 50 .mu.m or less, preferably
30 .mu.m or less. Mean particle size can be ascertained by the
particle size measurement method described hereinafter.
Characterization of Anhydrous Aripiprazole Crystals B
[0111] "Anhydrous Aripiprazole Crystals B" of the present invention
as used herein have the physicochemical properties given in
(6)-(12) below.
[0112] (6) They have an .sup.1H-NMR spectrum which is substantially
the same as the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 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).
[0113] (7) They have a powder x-ray diffraction spectrum which is
substantially the same as the powder x-ray diffraction spectrum
shown in FIG. 5.
[0114] Specifically, they have characteristic peaks at
2.theta.=11.0.degree., 16.6.degree., 19.3.degree., 20.3.degree. and
22.1.degree..
[0115] (8) They have clear infrared absorption bands at 2945, 2812,
1678, 1627, 1448, 1377, 1173, 960 and 779 cm.sup.-1 on the IR (KBr)
spectrum.
[0116] (9) They exhibit an endothermic peak near about
141.5.degree. C. in thermogravimetric/differential thermal analysis
(heating rate 5.degree. C./min).
[0117] (10) They exhibit an endothermic peak near about
140.7.degree. C. in differential scanning calorimetry (heating rate
5.degree. C./min).
[0118] (11) Anhydrous Aripiprazole Crystals B of the present
invention have low hygroscopicity. For example, Anhydrous
Aripiprazole Crystals B of the present invention maintain a water
content of 0.4% or less after 24 hours inside a dessicator set at a
temperature of 60.degree. 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.
[0119] (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 .mu.m or less.
Process for Manufacturing Anhydrous Aripiprazole Crystals B
[0120] In case of the formulation for which small particle size
(less than 50 .mu.m) is required, the milling is necessary for the
preparation. However, when a large amount of Conventional Anhydrous
Aripiprazole or Anhydrous Aripiprazole 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 Anhydrous Aripiprazole
Crystals B having small particle size.
[0121] Under the circumstances, the inventors of the present
invention have found that Conventional hydrate can be easily
milled, and Anhydrous Aripiprazole Crystals B having small particle
size can be obtained in high yield with good-operability by heating
the milled hydrate A thus obtained.
[0122] The Anhydrous Aripiprazole Crystals B of the present
invention are prepared for example by heating the aforementioned
Aripiprazole Hydrate A at 90-125.degree. 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.degree.
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.degree. C., on the other hand, the
heating time can be about 3 hours. The Anhydrous Aripiprazole
Crystals B of the present invention can be prepared with certainty
by heating Aripiprazole Hydrate A for about 18 hours at 100.degree.
C., and then heating it for about 3 hours at 120.degree. C. The
Anhydrous Aripiprazole Crystals B of the present invention can also
be obtained if the heating time is extended still further, but this
may not be economical.
[0123] When small particle size is not required for the
formulation, e.g., when drug substance is being manufactured for
injectable or oral solution formulations, Anhydrous Aripiprazole
Crystal B can be also obtained the following process.
[0124] The inventors also discovered that it is possible to obtain
anhydrous aripiprazole crystals by heating conventional
aripiprazole hydrate or conventional anhydrous aripiprazole
crystals to a specific temperature but this process does not yield
Anhydrous Aripiprazole Crystal B crystalline substance suitable for
commercial use in the formulation of solid oral dose
formulations.
[0125] Furthermore, the Anhydrous Aripiprazole Crystals B of the
present invention are prepared for example by heating conventional
anhydrous aripiprazole crystals at 90-125.degree. 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.
[0126] Specifically, if the heating temperature of the anhydrous
aripiprazole crystals is 100.degree. C., the heating time can be
about 4 hours, and if the heating temperature is 120.degree. C. the
heating time can be about 3 hours.
[0127] In addition to Aripiprazole Hydrate A and Anhydrous
Aripiprazole Crystals B mentioned above, the present invention
provides Anhydrous Aripiprazole Crystals C to G as follows.
[0128] 1. The present invention relates to anhydrous aripiprazole
crystals (hereinafter referred to as "type C crystals of anhydrous
aripiprazole") having the following physicochemical properties (1)
to (5):
[0129] (1) an endothermic curve which is substantially identical to
the thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 8;
[0130] (2) an .sup.1H-NMR spectrum which is substantially identical
to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG.
9;
[0131] (3) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 10;
[0132] (4) an IR spectrum which is substantially identical to the
IR (KBr) shown in FIG. 11; and
[0133] (5) a solid .sup.13C-NMR spectrum which is substantially
identical to the solid .sup.13C-NMR spectrum shown in FIG. 12.
[0134] 2. The present invention relates to anhydrous aripiprazole
crystals (hereinafter referred to as "type D crystals of anhydrous
aripiprazole") having the following physicochemical properties (6)
to (10):
[0135] (6) an endothermic curve which is substantially identical to
the thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 13;
[0136] (7) an .sup.1H-NMR spectrum which is substantially identical
to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG.
14;
[0137] (8) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 15;
[0138] (9) an IR spectrum which is substantially identical to the
IR (KBr) shown in FIG. 16; and
[0139] (10) a solid .sup.13C-NMR spectrum which is substantially
identical to the .sup.13C-NMR spectrum shown in FIG. 17.
[0140] 3. The present invention relates to anhydrous aripiprazole
crystals (hereinafter referred to as "type E crystals of anhydrous
aripiprazole") having the following physicochemical properties (11)
to (14):
[0141] (11) an endothermic curve which is substantially identical
to the thermogravimetric/differential thermal analysis (heating
rate: 5.degree. C./min.) endothermic curve shown in FIG. 18;
[0142] (12) an .sup.1H-NMR spectrum which is substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 19;
[0143] (13) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 20; and
[0144] (14) an IR spectrum which is substantially identical to the
IR (KBr) shown in FIG. 21.
[0145] 4. The present invention relates to anhydrous aripiprazole
crystals (hereinafter referred to as "type F crystals of anhydrous
aripiprazole") having the following physicochemical properties (15)
to (18):
[0146] (15) an endothermic curve which is substantially identical
to the thermogravimetric/differential thermal analysis (heating
rate: 5.degree. C./min.) endothermic curve shown in FIG. 22;
[0147] (16) an .sup.1H-NMR spectrum which is substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 23;
[0148] (17) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 24; and
[0149] (18) an IR spectrum which is substantially identical to the
IR (KBr) shown in FIG. 25.
[0150] 5. The present invention relates a process for preparing
anhydrous aripiprazole crystals stated in the aforementioned item
1, characterized by heating anhydrous aripiprazole crystals at a
temperature being higher than 140.degree. C. and lower than
150.degree. C.
[0151] 6. The present invention relates a process for preparing
anhydrous aripiprazole crystals stated in the aforementioned item
2, characterized by recrystallizing from toluene.
[0152] 7. The present invention relates to a process for preparing
anhydrous aripiprazole crystals stated in the aforementioned item
3, characterized by heating and dissolving anhydrous aripiprazole
crystals in acetonitrile, and cooling it.
[0153] 8. The present invention relates to a process for preparing
anhydrous aripiprazole crystals stated in the aforementioned item
4, characterized by heating a suspension of anhydrous aripiprazole
crystals in acetone.
[0154] 9. The present invention relates to a pharmaceutical
composition containing at least one anhydrous aripiprazole crystals
selected from the group consisting of the anhydrous aripiprazole
crystals stated in the aforementioned item 1, the anhydrous
aripiprazole crystals stated in the aforementioned item 2, the
anhydrous aripiprazole crystals stated in the aforementioned item
3, the anhydrous aripiprazole crystals stated in the aforementioned
item 4, and the anhydrous aripiprazole crystals stated in the
after-mentioned item 10, together with pharmaceutically acceptable
carriers.
[0155] 10. The present invention relates to anhydrous aripiprazole
crystals (hereinafter referred to as "type G crystals of anhydrous
aripiprazole") having the following physicochemical properties (19)
to (22):
[0156] (19) an endothermic curve which is substantially identical
to the thermogravimetric/differential thermal analysis (heating
rate; 5.degree. C./min.) endothermic curve shown FIG. 26.
[0157] (20) an .sup.1H-NMR spectrum which is substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 27.
[0158] (21) a power X-ray diffraction spectrum which is
substantially identical to the power X-ray diffraction spectrum
shown in FIG. 28; and
[0159] (22) an IR spectrum which is substantially identical to the
IR (Kbr) shown in FIG. 29.
[0160] 11. The present invention relates to a process for preparing
anhydrous aripiprazole crystals stated in the aforementioned item
10, characterized by putting glassy state of Anhydrous Aripiprazole
in a sealed vessel and keeping it at room temperature for at least
2 weeks.
[0161] 12. The present invention relates to a process for the
preparation of granules, characterized by wet granulating
conventional Anhydrous Aripiprazole Crystals or Anhydrous
Aripiprazole Crystals B, C, D, E, F or G, drying the obtained
granules at 70 to 100.degree. C. and sizing it, then drying the
sized granules at 70 to 100.degree. C. again.
[0162] 13. The present invention relates to a process for the
pharmaceutical solid oral preparation, characterized by drying a
pharmaceutical solid oral preparation comprising conventional
Anhydrous Aripiprazole Crystals or Anhydrous Aripiprazole Crystals
B, C, D, E, F or G, and one or more pharmaceutically acceptable
carriers at 70 to 100.degree. C.
[0163] 14. The present invention relates to a pharmaceutical solid
oral preparation comprising Anhydrous Aripiprazole Crystals B, C,
D, E, F or G 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.
[0164] 15. The present invention relates to 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.
[0165] 16. The present invention relates to a pharmaceutical solid
oral preparation obtained by wet granulating conventional Anhydrous
Aripiprazole Crystals, drying the obtained granules at 70 to
100.degree. C. and sizing it, then drying the sized granules at 70
to 100.degree. C. again, and the 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.
[0166] 17. The present invention relates to a pharmaceutical solid
oral preparation obtained by drying a pharmaceutical solid oral
preparation comprising conventional Anhydrous Aripiprazole Crystals
and one or more pharmaceutically acceptable carriers at 70 to
100.degree. C., and the 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.
[0167] 18. The present invention relates to a process for the
preparation of granules, characterized by wet granulating
conventional Aripiprazole Hydrate Crystals, drying the obtained
granules at 70 to 100.degree. C. and sizing it, then drying the
sized granules at 70 to 100.degree. C. again.
[0168] 19. The present invention relates to 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.degree. C.
[0169] 20. The present invention relates to a pharmaceutical solid
oral preparation obtained by wet granulating conventional
Aripiprazole Hydrate Crystals, drying the obtained granules at 70
to 100.degree. C. and sizing it, then drying the sized granules at
70 to 100.degree. C. again, and the 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.
[0170] 21. The present invention relates to a pharmaceutical solid
oral preparation obtained by drying a pharmaceutical solid oral
preparation comprising conventional Aripiprazole Hydrate Crystals
and one or more pharmaceutically acceptable carriers at 70 to
100.degree. C., and the 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.
[0171] The Type C to F crystals of anhydrous aripiprazole of the
present invention correspond to the Type-III to VI crystals of
anhydrous aripiprazole disclosed in JP-2001-348276.
Type C Crystals of Anhydrous Aripiprazole
[0172] Type C crystals of anhydrous aripiprazole of the present
invention have the following physicochemical properties (1) to
(5):
[0173] (1) an endothermic curve which is substantially identical to
the thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 8, more
particularly, it has an endothermic peak around 150.2.degree.
C.;
[0174] (2) an .sup.1H-NMR spectrum which is substantially identical
to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 9.
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);
[0175] (3) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 10. Specifically, it has characteristic peaks at
2.theta.=12.6.degree., 13.7.degree., 15.4.degree., 18.1.degree.,
19.0.degree., 20.6.degree., 23.5.degree. and 26.4.degree.;
[0176] (4) an IR spectrum which is substantially identical to the
IR (KBr) spectrum shown in FIG. 11. Specifically, it has clear
infrared absorption bands at 2939, 2804, 1680, 1375 and 780
cm.sup.-1; and
[0177] (5) a solid .sup.13C-NMR spectrum which is substantially
identical to the solid .sup.13C-NMR spectrum shown in FIG. 12,
specifically, it has characteristic peaks at 32.8 ppm, 60.8 ppm,
74.9 ppm, 104.9 ppm, 152.2 ppm, 159.9 ppm and 175.2 ppm.
Preparation Method of Type C Crystals of Anhydrous Aripiprazole
[0178] Type C crystals of anhydrous aripiprazole of the present
invention is prepared, for example by heating an anhydrous
aripiprazole at a temperature of higher than 140.degree. C. and
lower than 150.degree. C.
[0179] Anhydrous aripiprazole used as the raw material may be
conventional anhydrous aripiprazole crystals, for example, type-I
crystals of anhydrous aripiprazole, type-II crystals of anhydrous
aripiprazole crystals and the like, and these anhydrous
aripiprazoles may be either purified products or crude materials.
Alternatively, type B crystals of anhydrous aripiprazole, type D
crystals of anhydrous aripiprazole, type E crystals of anhydrous
aripiprazole, type F crystals of anhydrous aripiprazole, or type G
crystals of anhydrous aripiprazole being prepared in the present
invention can be used as the raw material of anhydrous
aripiprazole. These anhydrous aripiprazoles can be used singly or
in combination of at least 2 kinds thereof.
[0180] Heating temperature is generally higher than 140.degree. C.
and lower than 150.degree. C., preferably at 142-148.degree. C.,
and heating time is generally for 15 minutes to 3 hours, preferably
for 30 minutes to 1 hour.
[0181] When, an anhydrous aripiprazole is heated at the
above-mentioned temperature, then type C crystals of anhydrous
aripiprazole are formed.
[0182] Thus obtained type C crystals of anhydrous aripiprazole can
be isolated and purified by well-known methods. For example, after
heating the anhydrous aripiprazole at the above-mentioned
temperature, and by cooling to a room temperature, then type C
crystals of anhydrous aripiprazole, having 100% of purity can be
obtained.
Type D Crystals of Anhydrous Aripiprazole
[0183] Type D crystals of anhydrous aripiprazole of the present
invention have the following physicochemical properties (6) to
(10):
[0184] (6) an endothermic curve which is substantially identical to
the thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 13; more
particularly, it has an endothermic peak around 136.8.degree. C.
and 141.6.degree. C.;
[0185] (7) an .sup.1H-NMR spectrum which is substantially identical
to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 14.
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);
[0186] (8) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 15. Specifically, it has characteristic peaks at
2.theta.=8.7.degree., 11.6.degree., 16.3.degree., 17.7.degree.,
18.6.degree., 20.3.degree., 23.4.degree. and 25.0.degree.;
[0187] (9) an IR spectrum which is substantially identical to the
IR (KBr) spectrum shown in FIG. 16. Specifically, it has clear
infrared absorption bands at 2946, 1681, 1375, 1273, 1175 and 862
cm.sup.-1; and
[0188] (10) a solid .sup.13C-NMR spectrum which is substantially
identical to the solid .sup.13C-NMR spectrum shown in FIG. 17,
specifically, it has 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.
Preparation Method of Type D Crystals of Anhydrous Aripiprazole
[0189] Type D crystals of anhydrous aripiprazole of the present
invention is prepared, for example, by recrystallization of
anhydrous aripiprazole from toluene. Specifically, an anhydrous
aripiprazole is added to toluene, further heated and dissolved,
then thus obtained solution is cooled. By such procedures, type D
crystals of anhydrous aripiprazole of the present invention is
separated out as crystals in toluene.
[0190] Anhydrous aripiprazole to be used as the raw materials may
be conventional anhydrous aripiprazole, for example type-I crystals
of anhydrous aripiprazole, type-II crystals of anhydrous
aripiprazole and the like, and these anhydrous aripiprazoles may be
either purified products or crude materials. Alternatively, type B
crystals of anhydrous aripiprazole, type C crystals of anhydrous
aripiprazole, type E crystals of anhydrous aripiprazole, type F
crystals of anhydrous aripiprazole, or type G crystals of anhydrous
aripiprazole being prepared in the present invention can be used as
the raw material for anhydrous aripiprazoles. These anhydrous
aripiprazoles can be used singly or in combination of at least 2
kinds thereof.
[0191] When the solution obtained by heating and dissolving is
cooled, type D crystals of anhydrous aripiprazole may be added as a
seed crystal to said solution. Further, the seed crystal may be
formed by cooling gradually said solution being obtained by heating
and dissolving. In the presence of the seed crystal, type D
crystals of anhydrous aripiprazole may be separated out.
[0192] Thus separated out type D crystals of anhydrous aripiprazole
can be isolated and purified in accordance with well-known methods.
By such procedures, type D crystals of anhydrous aripiprazole,
having the purity of 100% can be obtained.
Type E Crystals of Anhydrous Aripiprazole
[0193] Type E crystals of anhydrous aripiprazole of the present
invention have the following physicochemical properties (11) to
(14):
[0194] (11) an endothermic curve which is substantially identical
to the thermogravimetric/differential thermal analysis (heating
rate: 5.degree. C./min.) endothermic curve shown in FIG. 18,
specifically, it has an endothermic peak around 146.5.degree.
C.;
[0195] (12) an .sup.1H-NMR spectrum which is substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 19. 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);
[0196] (13) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 20. Specifically, it has characteristic peaks at
2.theta.=8.0.degree., 13.7.degree., 14.6.degree., 17.6.degree.,
22.5.degree. and 24.0.degree.; and
[0197] (14) an IR spectrum which is substantially identical to the
IR (KBr) spectrum shown in FIG. 21. Specifically, it has clear
infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969 and
774 cm.sup.-1.
Preparation Method of Type E Crystals of Anhydrous Aripiprazole
[0198] Type E crystals of anhydrous aripiprazole of the present
invention is prepared, for example by recrystallization of the
anhydrous aripiprazole from acetonitrile. Specifically, by adding a
well-known anhydrous aripiprazole to acetonitrile, heating and
dissolving, then the solution thus obtained may be cooled. In
accordance with such procedures, type E crystals of anhydrous
aripiprazole of the present invention are separated out in the
acetonitrile.
[0199] When a conventional anhydrous aripiprazole is added to
acetonitrile, type-I crystals of anhydrous aripiprazole, type-II
crystals of anhydrous aripiprazole and type D crystals of anhydrous
aripiprazole are separated out, other than type E crystals of
anhydrous aripiprazole. Plate crystals being separated out from the
acetonitrile solution at 70.degree. C. are type-I crystals, type-II
crystals and type D crystals, while type E crystals are
precipitated out as needle crystals. When the acetonitrile solution
after separated out of these crystals is heated again (for example,
heated at over 75.degree. C.), the plate crystals (type-I crystals,
type-II crystals and type D crystals) are quickly dissolved, on the
contrary, the needle form crystals (type E crystals) do not
dissolved. Additionally, when the acetonitrile solution is cooled
again, then needle form crystals (type E crystals) are further
separated out around the needle form crystals (type E crystals)
previously precipitated as the seed crystals. Thus, type E crystals
of anhydrous aripiprazole can be precipitated in the acetonitrile
solution.
[0200] Anhydrous aripiprazoles used as the raw materials may be
conventional anhydrous aripiprazoles, for example any one of type-I
crystals of anhydrous aripiprazole and type-II crystals of
anhydrous aripiprazole and the like, and these anhydrous
aripiprazoles may be either purified products or crude materials.
Alternatively, type B crystals of anhydrous aripiprazole, type C
crystals of anhydrous aripiprazole, type D crystals of anhydrous
aripiprazole, type F crystals of anhydrous aripiprazole, or type G
crystals of anhydrous aripiprazole can be used as the raw materials
for anhydrous aripiprazoles. These anhydrous aripiprazoles can be
used singly or in combination of at least 2 kinds thereof.
[0201] When the acetonitrile solution obtained by heating (heating
and dissolving) is cooled, the type E crystals of aripiprazole may
be added as a seed crystal to said solution. Further, the seed
crystal may be formed by cooling gradually said acetonitrile
solution which was obtained by heating.
[0202] Thus separated out type E crystals of anhydrous aripiprazole
can be isolated and purified in accordance with well-known methods.
By such procedures, type E crystals of anhydrous aripiprazole,
having the purity of 100% can be obtained.
Type F Crystals of Anhydrous Aripiprazole
[0203] Type F crystals of anhydrous aripiprazole of the present
invention have the following physicochemical properties (15) to
(18):
[0204] (15) an endothermic curve which is substantially identical
to the thermogravimetric/differential thermal analysis (heating
rate: 5.degree. C./min.) endothermic curve shown in FIG. 22,
specifically, it has an endothermic peaks around 137.5.degree. C.
and 149.8.degree. C.;
[0205] (16) an .sup.1H-NMR spectrum which is substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 23. 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);
[0206] (17) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 24. Specifically, it has characteristic peaks at
2.theta.=11.3.degree., 13.3.degree., 15.4.degree., 22.8.degree.,
25.2.degree. and 26.9.degree., and
[0207] (18) Having an IR spectrum which is substantially identical
to the IR (KBr) spectrum shown in FIG. 25. Specifically, it has
clear infrared absorption bands at 2940, 2815, 1679, 1383, 1273,
1177, 1035, 963 and 790 cm.sup.-1.
Preparation Method of Type F Crystals of Anhydrous Aripiprazole
[0208] Type F crystals of anhydrous aripiprazole of the present
invention is prepared, for example by suspending an anhydrous
aripiprazole in acetone, and thus obtained acetone suspension is
heated.
[0209] Anhydrous aripiprazoles used as the raw materials may be
conventional anhydrous aripiprazole, for example any one of type-I
crystals of anhydrous aripiprazole and type-II crystals of
anhydrous aripiprazole and the like, and these anhydrous
aripiprazoles may be either purified products or crude materials.
Alternatively, type B crystals of anhydrous aripiprazole, type C
crystals of anhydrous aripiprazole, type D crystals of anhydrous
aripiprazole, type E crystals of anhydrous aripiprazole, or type G
crystals of anhydrous aripiprazole prepared in the present
invention can be used as the raw materials for anhydrous
aripiprazoles. These anhydrous aripiprazoles can be used singly or
in combination of at least 2 kinds thereof.
[0210] Heating temperature of the acetone suspension may be
generally about the boiling point of acetone, and heating time is
generally 5 to 10 hours. When the acetone suspension is heated
about the boiling point of acetone, then type F crystals of
anhydrous aripiprazole is formed, the crystals are isolated by
filtration with heating. Isolation of the crystals may be carried
out in accordance with well-known methods. By such procedures, type
F crystals of anhydrous aripiprazole, having the purity of 100% can
be obtained.
Type G Crystals of Anhydrous Aripiprazole
[0211] Type G crystals of anhydrous aripiprazole of the present
invention have the following physicochemical properties (19) to
(22):
[0212] (19) an endothermic curve which is substantially identical
to the thermogravimetric/differential thermal analysis (heating
rate: 5.degree. C./min.) endothermic curve shown in FIG. 26, more
particularly, it has an endothermic peak around 141.0.degree. C.
and an exothermic peak around 122.7.degree. C.;
[0213] (20) an .sup.1H-NMR spectrum which is substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 27. 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), 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);
[0214] (21) a powder X-ray diffraction spectrum which is
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 28. Specifically, it has characteristic peaks at
2.theta.=10.1.degree., 12.8.degree., 15.2.degree., 17.0.degree.,
17.5.degree., 19.1.degree., 20.1.degree., 21.2.degree.,
22.4.degree., 23.3.degree., 24.5.degree. and 25.8.degree.; and
[0215] (22) an IR spectrum which is substantially identical to the
IR (KBr) spectrum shown in FIG. 29. Specifically, it has clear
infrared absorption bands at 2942, 2813, 1670, 1625, 1377, 1195,
962 and 787 cm.sup.-1.
Preparation Method of Type G Crystals of Anhydrous Aripiprazole
[0216] Type G crystals of anhydrous aripiprazole of the present
invention can be prepared, for example by putting glassy state of
anhydrous aripiprazole in a sealed vessel and leaving to stand it
at room temperature for at least two weeks, preferably two weeks to
six months. Further, glassy state of anhydrous aripiprazole as
starting material can be obtained by heating and melting anhydrous
aripiprazole at around 170.degree. C., then cooling it to room
temperature.
[0217] Anhydrous aripiprazole used as the raw material may be
well-known anhydrous aripiprazole crystals, for example, any one of
type-I crystals of anhydrous aripiprazole and type-II crystals of
anhydrous aripiprazole and the like, and these anhydrous
aripiprazoles may be either purified products or crude materials.
Alternatively, type B crystals of anhydrous aripiprazole, type C
crystals of anhydrous aripiprazole, type D crystals of anhydrous
aripiprazole, type E crystals of anhydrous aripiprazole, or type F
crystals of anhydrous aripiprazole being prepared in the present
invention can be used as the raw material of anhydrous
aripiprazoles. These anhydrous aripiprazoles can be used singly or
in combination of at least 2 kinds thereof.
[0218] Thus obtained type G crystals of anhydrous aripiprazole can
be isolated and purified by well-known methods. For example, glassy
state of anhydrous aripiprazole leave to stand according to the
above-mentioned method, then type G crystals of anhydrous
aripiprazole, having 100% of purity can be obtained.
[0219] Type C crystals of anhydrous aripiprazole, type D crystals
of anhydrous aripiprazole, type E crystals of anhydrous
aripiprazole, type F crystals of anhydrous aripiprazole and type G
crystals of anhydrous aripiprazole of the present invention neither
easily convert into hydrates thereof, nor substantially decrease
the original solubility, even when they are stored for a long
period of time.
[0220] In accordance with the present invention, methods for
preparing anhydrous aripiprazole crystals having high purity, which
can apply in an industrial scale with a good repeatability is
provided.
[0221] In accordance with the present invention, pharmaceutical
compositions comprising anhydrous aripiprazole crystals are
provided, of which the solubility does not decrease, and of which
the stability can keep excellent, even if they are stored for long
time.
[0222] The anhydrous aripiprazole crystals which are the raw
material for preparing the Anhydrous Aripiprazole Crystals B to G
of the present invention are prepared for example by Method a or b
below.
"Method a": Process for Preparing Crude Aripiprazole Crystals
[0223] Conventional Anhydrous Aripiprazole crystals are prepared by
well-known methods, as described in Example 1 of Japanese
Unexamined Patent Publication No. 191256/1990.
[0224] 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 ml of triethylamine and the whole mixture was further refluxed
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
recrystallized from ethanol twice, to yield 57.1 g of
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril-
.
[0225] Colorless flake crystals
[0226] Melting point: 139.0-139.5.degree. C.
"Method b": Process for Preparing Conventional Anhydrous
Aripiprazole
[0227] The Method b is described in the Proceedings of the 4th
Japanese-Korean Symposium on Separation Technology (Oct. 6-8,
1996).
[0228] Furthermore, the Anhydrous Aripiprazole Crystals B of the
present invention are prepared for example by heating conventional
aripiprazole hydrate at 90-125.degree. 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 the aripiprazole hydrate is 100.degree.
C., the heating time can be about 24 hours, while if the heating
temperature is 120.degree. C., the heating time can be about 3
hours.
[0229] The aripiprazole hydrate which is the raw material for
preparing the Anhydrous Aripiprazole Crystals B of the present
invention is prepared for example by Method c below.
"Method c": Process for Preparing Conventional Hydrate
[0230] Aripiprazole hydrate is easily obtained by dissolving the
anhydrous aripiprazole crystals obtained by Method a above in a
hydrous solvent, and heating and then cooling the resulting
solution. Using this method, aripiprazole hydrate is precipitated
as crystals in the hydrous solvent.
[0231] 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.
Medicinal Composition
[0232] A medicinal composition of the present invention will
contain Anhydrous Aripiprazole Crystals B, C, D, E, F and G in a
pharmaceutically acceptable carrier or combination of carriers.
[0233] Carriers which are pharmaceutically acceptable include
diluents and excipients generally used in pharmaceuticals, such as
fillers, extenders, binders, moisturizers, disintegrators,
surfactants, and lubricants.
[0234] 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.).
[0235] When a tablet formulation is used, a wide variety of
carriers that are known in the field can be used. Examples include
lactose, saccharose, sodium chloride, glucose, xylitol, mannitol,
erythritol, sorbitol, 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, polyoxyethylene sorbitan fatty acid
esters, sodium lauryl sulfate, monoglyceride stearate, starch,
lactose and other disintegrators; 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 silic 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 coated tablets and film coated tablets, as well as
double tablets and multilayered tablets.
[0236] 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.
[0237] 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.
[0238] Capsules are prepared according to ordinary methods by
mixing anhydrous aripiprazole crystals with the various carriers
described above and packing them in hard gelatin capsules, soft
capsules, hydroxypropylmethyl cellulose capsules (HPMC capsules)
and the like.
[0239] In addition, colorants, preservatives, perfumes, flavorings,
sweeteners and the like as well as other drugs may be included in
the medicinal composition.
[0240] In case of forming the pharmaceutical solid oral preparation
in the form of granules, it can be prepared by wet granulating a
mixed powder of granulating ingredients comprising, anhydrous
aripiprazole crystals (conventional anhydrous aripiprazole crystals
or anhydrous aripiprazole crystals selected from the group
consisting of anhydrous aripiprazole type B, C, D, E, F and G
crystals) and various carriers which are heretofore well-known in
this field, such as excipients, disintegrators, disintegration
inhibitors, humectants, absorption accelerators, adsorbents,
lubricants, colorants and the like (for the examples of these
agents, those of previously mentioned can be referred to) by adding
a liquid (generally, water or an aqueous solution containing
binding agents). As for the wet granulation, there are various
methods are included, for example, fluidized bed granulation,
kneading granulation, extruding granulation, rotating granulation
and the like can be mentioned. Among these methods, in case of
conducting the fluidized bed granulation, the granulating
ingredients containing various carriers are mixed with inlet air,
then upon continued fluidizing the granulating ingredients and the
liquid is sprayed to conduct granulation. In case of conducting the
kneading granulation, the granulating ingredients containing
various carriers are mixed by agitation, then upon continued
agitating the granulating ingredients, granulation is conducted by
adding the liquid. After the granulation, if necessary, the
obtained granules are sized to make them to the desired size by use
of a suitable sieve or a mill having suitable screen size. The
granules thus obtained by such a method are dried again in addition
to usual drying being conducted when preparing the granules. As for
the drying methods, various methods can be applied, for example,
methods by use of a fluidized bed dryer, a fan dryer, a vacuum
dryer and the like can be mentioned. Generally, drying methods can
be conducted under conventional conditions, for example, in case of
using the fluidized bed dryer, drying procedure is conducted with
an air flow of 0.5 m.sup.3/min to 50 m.sup.3/min, an inlet air
temperature at 70 to 100.degree. C. for 10 min to 1 hour. After
dried, the granules are subjected to size, then further dried. In
case of using the fluidized bed dryer or fan dryer or the like, the
drying procedure is conducted under the conditions with an air flow
of 0.5 m.sup.3/min to 50 m.sup.3/min, an inlet air temperature at
70 to 100.degree. C. for 1 to 6 hours. In case of using the vacuum
dryer, the drying procedure is conducted under the conditions of
reduced pressure of about at 0-10 torr of degree of vacuum at 70 to
100.degree. C. of jacket temperature for 1 to 6 hour.
[0241] The thus prepared granules may be used as they are for the
pharmaceutical solid oral preparations, or if necessary, they may
be shaped in the form of tablets. Further, the dried granules dried
by usual manner are shaped in the form of tablets, then they may be
dried again.
[0242] The thus prepared pharmaceutical solid oral preparation
comprising anhydrous aripiprazole crystals hardly changes to
hydrates even if they are stored for a long period of time,
therefore the pharmaceutical solid oral preparation, of which
dissolution rate does not hardly lowered (dissolution rate to
maintain maximum drug concentration (Cmax): 60% or higher
dissolution rate obtained after 30 minutes at pH 4.5, 70% or higher
dissolution rate obtained after 60 minutes at pH 4.5, or 55% or
higher dissolution rate obtained after 60 minutes at pH 5.0) can be
provided.
[0243] Another pharmaceutical solid oral preparation can be
provided by granulating a conventional aripiprazole hydrate
crystals by a method similar to that of mentioned above, and dried
by usual manner under similar conditions, then dried again.
Alternatively, the dried granules dried by usual manner are shaped
to tablets form, then they are dried again, then pharmaceutical
solid oral preparations of which dissolution rate does not lowered
(dissolution rate to maintain maximum drug concentration (Cmax):
60% or higher dissolution rate obtained after 30 minutes at pH 4.5,
70% or higher dissolution rate obtained after 60 minutes at pH 4.5
or 55% or higher dissolution rate obtained after 60 minutes at pH
5.0) can be provided. These facts can be understood that, the
conventional anhydrous aripiprazole crystals or the aripiprazole
hydrate crystals contained in the pharmaceutical solid oral
preparation are changed to "B type crystals" of anhydrous
aripiprazole by drying twice.
[0244] The amount of Anhydrous Aripiprazole Crystals B, C, D, E, F
and G 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. Generally, the Anhydrous
Aripiprazole Crystals B should be present in about 1-70% by weight
or particularly about 1-30% by weight based on the medicinal
composition.
[0245] 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 replenisher such as glucose or amino acids,
or may also be administered by itself intramuscularly,
intracutaneously, subcutaneously or intraperitoneally, as
necessary. In the case of a suppository, administration is
intrarectal.
[0246] 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 anhydrous aripiprazole
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 Anhydrous Aripiprazole Crystals
B, more particularly 1-30 mg per unit dose.
[0247] The medicinal composition of the present invention is
extremely stable, with substantially no decrease in solubility even
when stored for long periods of time.
[0248] 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.
Analytical Methods
[0249] (1) The .sup.1H-NMR spectrum was measured in DMSO-d.sub.6
using TMS as the standard.
[0250] (2) Powder X-ray Diffraction
[0251] Using a Rigaku Denki RAD-2B diffraction meter, the powder
x-ray diffraction pattern was measured at room temperature using a
Cu K.alpha. filled tube (35 kV 20 mA) as the x-ray source with a
wide-angle goniometer, a 1.degree. scattering slit, an 0.15 mm
light-intercepting slit, a graphite secondary monochromator and a
scintillation counter. Data collection was done in 2.theta.
continuous scan mode at a scan speed of 5.degree./minute in scan
steps of 0.02.degree. in the range of 3.degree. to 40.degree..
[0252] (3) The IR spectrum was measured by the KBr method.
[0253] (4) Thermogravimetric/Differential Thermal Analysis
[0254] Thermogravimetric/differential thermal analysis was
performed using a Seiko SSC 5200 control unit and a TG/DTA 220
simultaneous differential thermal/thermogravimetric measurement
unit. 5-10 mg samples were placed in open aluminum pans and heated
from 20.degree. C. to 200.degree. C. in a dry nitrogen atmosphere
at a heating rate of 5.degree. C./minute. .alpha.-alumina was used
as the standard substance.
[0255] (5) Differential Scanning Calorimetry
[0256] Thermogravimetric/differential thermal analysis was
performed using a Seiko SSC 5200 control unit and a DSC 220C
differential scanning calorimeter. 5-10 mg samples were placed in
crimped aluminum pans and heated from 20.degree. C. to 200.degree.
C. in a dry nitrogen atmosphere at a heating rate of 5.degree.
C./minute. .alpha.-alumina was used as the standard substance.
[0257] (6) Particle Size Measurement
[0258] 0.1 g of the particles to be measured were suspended in a 20
ml n-hexane solution of 0.5 g soy lecithin, and particle size was
measured using a size distribution meter (Microtrack HRA,
Microtrack Co.).
[0259] (7) Hygroscopicity Test Method
[0260] 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.degree. C./100% RH environment (water/dessicator). 24 hours
later, the weighing bottle was removed, transferred to an
environment of a room temperature and about 30% 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.
[0261] (8) Solid .sup.13C-NMR Spectrometry
[0262] Solid .sup.13C-NMR spectrum was measured under the
conditions as follows.
[0263] Measuring apparatus: CMX-360 Solid State NMR Spectrometer
(manufactured by Chemagnetic Inc.)
[0264] Computer: SPARC Station 2 (manufactured by SUN Microsystem,
Inc.)
[0265] OS, Software: Solalis 1.1.1 Rev. B (Registered trademark:
UNIX), Spinsight Ver. 2.5
[0266] Name of measured pulse: TOSS method (TOSS is a program name
of the apparatus) among CP/MAS method.
[0267] Width of measured puls: 90.degree. puls was used under the
condition of CP.
[0268] Measuring sample tube: Test tube made of zirconia, having
the outside diameter of 7.5 mm, and inside capacity of 0.8 ml
[0269] Revolution: 4250 Hz (Revolution per second Contact time: 1
msec.
[0270] Waiting time: 20 sec.
[0271] Integrated times: 512 times
[0272] Measuring temperature: About 25.degree. C. temperature of
outside of test tube)
[0273] External standard: Methyl group (.delta. 17.3) of
hexamethylbenzene was used as the external standard.
[0274] The present invention is explained in more detail below
using reference examples, examples, sample preparations and
formulation examples.
Reference Example 1
[0275] 19.4 g of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril and 16.2
g of 1-(2,3-dichlorophenyl) piperadine 1 hydrochloride were added
to 8.39 g of potassium carbonate dissolved in 140 ml of water, 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 ml of ethyl acetate, and about 210
ml of water/ethyl acetate azeotrope removed under reflux. The
remaining solution was cooled, and the precipitated crystals
filtered out. The resulting crystals were dried for 14 hours at
60.degree. C. to produce 20.4 g (74.2%) of raw aripiprazole.
[0276] 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.
191256/1990, and the resulting crystals dried for 40 hours at
80.degree. C. to obtain anhydrous aripiprazole crystals. The yield
was 29.4 g (98.0%).
[0277] The melting point (mp) of these anhydrous aripiprazole
crystals was 140.degree. C., matching the melting point of the
anhydrous aripiprazole crystals described in Japanese Unexamined
Patent Publication No. 191256/1990.
[0278] When these crystals were left for 24 hours in a dessicator
set at humidity 100%, temperature 60.degree. C., they exhibited
hygroscopicity of 3.28% (see Table 1 below).
Reference Example 2
[0279] 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 Japanese-Korean Symposium on Separation Technology,
gradually (2-3 hours) cooled to room temperature, and then chilled
to near 0.degree. C. The precipitated crystals were filtered out,
producing about 7200 g of aripiprazole hydrate (wet state).
[0280] The wet-state aripiprazole hydrate crystals obtained above
were dried for 30 hours at 80.degree. C. to obtain 6480 g (93.5%)
of conventional anhydrous aripiprazole crystals. The melting point
(mp) of these crystals was 139.5.degree. C. These crystals were
confirmed by the Karl Fischer method to be anhydrous, with a
moisture value of 0.03%.
[0281] When left for 24 hours in a dessicator set at humidity 100%,
temperature 60.degree. C., these crystals exhibited hygroscopicity
of 1.78% (see Table 1 below).
Reference Example 3
[0282] 820 g of the intermediate wet-state aripiprazole hydrate
obtained in Reference Example 2 was dried for 2 hours at 50.degree.
C. to obtain 780 g of aripiprazole hydrate crystals. These crystals
had a moisture value of 3.82% according to the Karl Fischer method.
As shown in FIG. 6, thermogravimetric/differential thermal analysis
revealed endothermic peaks at 75.0, 123.5 and 140.5.degree. C.
Because dehydration began near 70.degree. C., there was no clear
melting point (mp).
[0283] As shown in FIG. 7, the powder x-ray diffraction spectrum of
aripiprazole hydrate obtained by this method exhibited
characteristic peaks at 2.theta.=12.6.degree., 15.1.degree.,
17.4.degree., 18.2.degree., 18.7.degree., 24.8.degree. and
27.5.degree..
[0284] 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.
Reference Example 4
[0285] Preparation of 15 mg tablets containing type I crystals of
anhydrous aripiprazole obtained in Reference Example 2.
[0286] Type-I crystals of anhydrous aripiprazole (525 g), lactose
(1,995 g), corn starch (350 g) and crystalline cellulose (350 g)
were charged in a fluidized bed granulating dryer (Flow coater
FLO-5, manufactured by FREUND INDUSTRIAL CO., LTD.), and these
granulating ingredients were mixed by fluidizing for about 3
minutes with an inlet air temperature at 70.degree. C. and air flow
rate of 3 m.sup.3/min. Further, the granulating ingredients were
upon continued fluidizing under the same condition and sprayed
about 1,400 g of the aqueous solution to obtained wet granules. The
wet granules were dried under inlet air at temperature at
80.degree. C., for about 15 minutes. The obtained dried granules
contained 4.3% of water. (Yield: 99%). The dried granules were
subjected to sizing by passing to a sieve of 710 .mu.m.
[0287] About 1% by weight of magnesium stearate was added to the
sized granules and mixed, then the granules were supplied to a
tablet machine (Rotary single tablet press 12HUK: manufactured by
KIKUSUI SEISAKUSHO CO., LTD.), there were obtained tablets, each
having 95 mg of weight.
[0288] Water content of the tablets was measured according to
volumetric titration method (Karl-Fischer method) described in
water content measuring method in Japanese Pharmacopoea or the
electrical quantity titration method.
Water Content Measuring Method:
[0289] Sample (0.1 to 0.5 g) (in case of a tablet, 1 tablet was
used) was weighed precisely, and the water content was measured by
use of a water content measuring equipment.
[0290] Volumetric Titration:
[0291] Automated water content measuring equipment [0292] Model:
KF-06 (manufacture by MITSUBISHI CHEMICAL CORP.)
[0293] Electrical Quantity Titration Method:
[0294] Automated micro-water content measuring equipment [0295]
Model: AQ-7F (manufactured by HIRANUMA SANGYO CO., LTD.) [0296]
Automated water vaporization equipment Model: [0297] LE-20S
(manufactured by HIRANUMA SANGYO CO., LTD.) [0298] Heating
temperature: 165.+-.10.degree. C. [0299] Nitrogen gas flow rate:
about 150 ml/min.
Reference Example 5
[0300] Preparation of 15 mg tablets containing type B crystals of
anhydrous aripiprazole
[0301] Type B crystals of anhydrous aripiprazole (4,500 g), lactose
(17,100 g), corn starch (3,000 g) and crystalline cellulose (3,000
g) were charged in a fluidized bed granulating dryer
(NEW-MARUMERIZER Model: NQ-500, manufactured by FUJI PAUDAL CO.,
LTD.), and these granulating ingredients were mixed by fluidizing
for about 3 minutes with an inlet air temperature at 70.degree. C.,
air flow rate of 10 to 15 m.sup.3/min. Further, the granulating
ingredients were upon continued fluidizing under the same
condition, and sprayed about 12,000 g of 5% aqueous solution of
hydroxypropyl cellulose to obtained wet granules. The wet granules
were dried under inlet air at temperature at 85.degree. C., for
about 28 minutes. The thus obtained dried granules contained 3.8%
of water (measured by the method according to Reference Example 4).
(Yield: 96%). The dried granules were subjected to sizing by
passing to a sieve of 850 .mu.m.
[0302] About 1% by weight of magnesium stearate was added to the
sized granules and mixed, then the granules were supplied to a
tablet machine (Rotary single tablet press 12HUK: manufactured by
KIKUSUI SEISAKUSHO CO., LTD.), there were obtained tablets, each
having 95 mg of weight.
Example 1
[0303] 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 1.0 mm herringbone screen
was used. Milling was completed in 3 minutes, resulting in 474.6 g
(94.9%) of Aripiprazole Hydrate A powder.
[0304] The Aripiprazole Hydrate A (powder) obtained in this way had
a mean particle size of 20-25 .mu.m. The melting point (mp) was
undetermined because dehydration was observed beginning near
70.degree. C.
[0305] The Aripiprazole Hydrate A (powder) obtained above exhibited
an .sup.1H-NMR (DMSO-d.sub.6, TMS) spectrum which was substantially
the same as the .sup.1H-NMR spectrum shown in FIG. 2. Specifically,
it had 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).
[0306] The Aripiprazole Hydrate A (powder) obtained above had a
powder x-ray diffraction spectrum which was substantially the same
as the powder x-ray diffraction spectrum shown in FIG. 3.
Specifically, it had characteristic peaks at 2.theta.=12.6.degree.,
15.4.degree., 17.3.degree., 18.0.degree., 18.6.degree.,
22.5.degree. and 24.8.degree.. This pattern is different from the
powder x-ray spectrum of unmilled aripiprazole hydrate shown in
FIG. 7.
[0307] The Aripiprazole Hydrate A (powder) obtained above had
infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378,
1187, 963 and 784 cm.sup.-1 on the IR (KBr) spectrum.
[0308] As shown in FIG. 1, the Aripiprazole Hydrate A (powder)
obtained above had a weak peak at 71.3.degree. C. in
thermogravimetric/differential thermal analysis and a broad
endothermic peak (weight loss observed corresponding to one water
molecule) between 60-120.degree. C.--clearly different from the
endothermic curve of unmilled aripiprazole hydrate (see FIG.
6).
Example 2
[0309] 450 g of the Aripiprazole Hydrate A (powder) obtained in
Example 1 was dried for 24 hours at 100.degree. C. using a hot air
dryer to produce 427 g (yield 98.7%) of Anhydrous Aripiprazole
Crystals B.
[0310] These Anhydrous Aripiprazole Crystals B had a melting point
(mp) of 139.7.degree. C.
[0311] The Anhydrous Aripiprazole Crystals B obtained above had an
.sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was substantially
the same as the .sup.1H-NMR spectrum shown in FIG. 4. Specifically,
they had 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).
[0312] The Anhydrous Aripiprazole Crystals B obtained above had a
powder x-ray diffraction spectrum which was substantially the same
as the powder x-ray diffraction spectrum shown in FIG. 5.
Specifically, they had characteristic peaks at
2.theta.=11.0.degree., 16.6.degree., 19.3.degree., 20.3.degree. and
22.1.degree..
[0313] The Anhydrous Aripiprazole Crystals B obtained above had
remarkable infrared absorption bands at 2945, 2812, 1678, 1627,
1448, 1377, 1173, 960 and 779 cm.sup.-1 on the IR (KBr)
spectrum.
[0314] The Anhydrous Aripiprazole Crystals B obtained above
exhibited an endothermic peak near about 141.5.degree. C. in
thermogravimetric/differential thermal analysis.
[0315] The Anhydrous Aripiprazole Crystals B obtained above
exhibited an endothermic peak near about 140.7.degree. C. in
differential scanning calorimetry.
[0316] Even when the Anhydrous Aripiprazole Crystals B obtained
above were left for 24 hours in a dessicator set at humidity 100%,
temperature 60.degree. C., they did not exhibit hygroscopicity
exceeding 0.4% (See Table 1 below).
Example 3
[0317] 44.29 kg of the Aripiprazole Hydrate A (powder) obtained in
Example 1 was dry heated for 18 hours in a 100.degree. C. hot air
dryer and then heated for 3 hours at 120.degree. C. to produce
42.46 kg (yield 99.3%) of Anhydrous Aripiprazole Crystals B.
[0318] The physicochemical properties of the resulting Anhydrous
Aripiprazole Crystals B were the same as the physicochemical
properties of the Anhydrous Aripiprazole Crystals B obtained in
Example 2.
[0319] The Anhydrous Aripiprazole Crystals B obtained in this way
did not exhibit hygroscopicity of more than 0.4% even when left for
24 hours in a dessicator set at humidity 100%, temperature
60.degree. C. (see Table 1 below).
Example 4
[0320] 40.67 kg of the Aripiprazole Hydrate A (powder) obtained in
Example 1 was dry heated for 18 hours in a 100.degree. C. hot air
dryer and then heated for 3 hours at 120.degree. C. to produce
38.95 kg (yield 99.6%) of Anhydrous Aripiprazole Crystals B.
[0321] The physicochemical properties of the resulting Anhydrous
Aripiprazole Crystals B were the same as the physicochemical
properties of the Anhydrous Aripiprazole Crystals B obtained in
Example 2.
[0322] The Anhydrous Aripiprazole Crystals B obtained in this way
did not exhibit hygroscopicity of more than 0.4% even when left for
24 hours in a dessicator set at humidity 100%, temperature
60.degree. C. (see Table 1 below).
[0323] Examples 5-10 are useful for injectable or oral solution
formulations but not solid dose formulations since they were made
by heating Conventional Anhydrous Aripiprazole or Conventional
Hydrate instead of Hydrate A.
Example 5
[0324] The hygroscopic anhydrous aripiprazole crystals obtained in
Reference Example 1 were heated for 50 hours at 100.degree. C.
using the same methods as in Example 2. The physicochemical
properties of the resulting Anhydrous Aripiprazole Crystals B were
the same as the physicochemical properties of the Anhydrous
Aripiprazole Crystals B obtained in Example 2.
[0325] The Anhydrous Aripiprazole Crystals B obtained in this way
did not exhibit hygroscopicity of more than 0.4% even when left for
24 hours in a dessicator set at humidity 100%, temperature
60.degree. C. (see Table 1 below).
Example 6
[0326] The hygroscopic anhydrous aripiprazole crystals obtained in
Reference Example 1 were heated for 3 hours at 120.degree. C. using
the same methods as in Example 2 The physicochemical properties of
the resulting Anhydrous Aripiprazole Crystals B were the same as
the physicochemical properties of the Anhydrous Aripiprazole
Crystals B obtained in Example 2.
[0327] The Anhydrous Aripiprazole Crystals B obtained in this way
did not exhibit hygroscopicity of more than 0.4% even when left for
24 hours in a dessicator set at humidity 100%, temperature
60.degree. C. (see Table 1 below).
Example 7
[0328] The hygroscopic anhydrous aripiprazole crystals obtained in
Reference Example 2 were heated for 50 hours at 100.degree. C.
using the same methods as in Example 2. The physicochemical
properties of the resulting Anhydrous Aripiprazole Crystals B were
the same as the physicochemical properties of the Anhydrous
Aripiprazole Crystals B obtained in Example 2.
[0329] The Anhydrous Aripiprazole Crystals B obtained in this way
did not exhibit hygroscopicity of more than 0.4% even when left for
24 hours in a dessicator set at humidity 100%, temperature
60.degree. C. (see Table 1 below).
Example 8
[0330] The hygroscopic anhydrous aripiprazole crystals obtained in
Reference Example 2 were heated for 3 hours at 120.degree. C. using
the same methods as in Example 2 The physicochemical properties of
the resulting Anhydrous Aripiprazole Crystals B were the same as
the physicochemical properties of the Anhydrous Aripiprazole
Crystals B obtained in Example 2.
[0331] The Anhydrous Aripiprazole Crystals B obtained in this way
did not exhibit hygroscopicity of more than 0.4% even when left for
24 hours in a dessicator set at humidity 100%, temperature
60.degree. C. (see Table 1 below).
Example 9
[0332] The aripiprazole hydrate crystals obtained in Reference
Example 3 were heated for 50 hours at 100.degree. C. using the same
methods as in Example 2. The physicochemical properties of the
resulting Anhydrous Aripiprazole Crystals B were the same as the
physicochemical properties of the Anhydrous Aripiprazole Crystals B
obtained in Example 2.
[0333] The Anhydrous Aripiprazole Crystals B obtained in this way
did not exhibit hygroscopicity of more than 0.4% even when left for
24 hours in a dessicator set at humidity 100%, temperature
60.degree. C. (see Table 1 below).
Example 10
[0334] The aripiprazole hydrate crystals obtained in Reference
Example 3 were heated for 3 hours at 120.degree. C. using the same
methods as in Example 2. The physicochemical properties of the
resulting Anhydrous Aripiprazole Crystals B were the same as the
physicochemical properties of the Anhydrous Aripiprazole Crystals B
obtained in Example 2.
[0335] The Anhydrous Aripiprazole Crystals B obtained in this way
exhibited hygroscopicity of no more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Example 11
Preparation of Type C Crystals of Anhydrous Aripiprazole
[0336] 100 Milligrams of type-I crystals of anhydrous aripiprazole
obtained in Reference Example 2 were heated about 145.degree. C.
(.+-.3.degree. C.). In this occasion, there was observed the
phenomena that the crystals were once melted, then again
crystallized. After that, 100 mg (yield: 100%) of Type C crystals
of anhydrous aripiprazole were obtained. The melting point of the
crystals was 150.degree. C. The crystals were colorless prism
form.
[0337] The type C crystals of anhydrous aripiprazole obtained above
had an endothermic curve which was substantially identical to the
endothermic curve of thermogravimetric/differential thermal
analysis (heating rate: 5.degree. C./minute) shown in FIG. 8.
Specifically, it showed the endothermic curve around 150.2.degree.
C.
[0338] The type C crystals of anhydrous aripiprazole thus obtained
exhibited an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 9.
Specifically, it had the 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).
[0339] The type C crystals of anhydrous aripiprazole obtained above
had a powder X-ray diffraction spectrum which was substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
10. Specifically, it had the characteristic peaks at
2.theta.=12.6.degree., 13.7.degree., 15.4.degree., 18.1.degree.,
19.0.degree., 20.6.degree., 23.5.degree. and 26.4.degree..
[0340] The type C crystals of anhydrous aripiprazole obtained above
had an IR spectrum which was substantially identical to the IR
(KBr) spectrum shown in FIG. 11. Specifically, it had the
characteristic infrared absorption bands at 2939, 2804, 1680, 1375
and 780 cm.sup.-1.
[0341] The type C crystals of anhydrous aripiprazole obtained above
exhibited a solid .sup.13C-NMR spectrum, which was substantially
identical to the solid .sup.13C-NMR spectrum shown in FIG. 12.
Specifically, it had the characteristic peaks at 32.8 ppm, 60.8
ppm, 74.9 ppm, 104.9 ppm, 152.2 ppm, 159.9 ppm and 175.2 ppm.
[0342] According to the above-mentioned data on endothermic curve
of thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) and powder X-ray diffraction spectrum, the
formation of the type C crystals of anhydrous aripiprazole was
confirmed.
[0343] When the type C crystals of anhydrous aripiprazole crystals
obtained above were left for 24 hours in a dessicator where the
conditions were set at humidity 100%, and temperature 60.degree.
C., then the crystals did not exhibit hygroscopicity higher than
0.4% (see, Table 1 below).
Example 12
Preparation of Type D Crystals of Anhydrous Aripiprazole
[0344] The type-I crystals of anhydrous aripiprazole obtained in
Reference Example 2 were added in 200 ml of toluene, and dissolved
by heating at 74.degree. C. After confirmed that it was dissolved
completely, the toluene solution was cooled to 7.degree. C., and
the precipitated crystals were collected by filtration. The
crystals were subjected to air-drying as they were so as to obtain
17.9 g (yield: 89.5%) of type D crystals of anhydrous
aripiprazole.
[0345] The type D crystals of anhydrous aripiprazole obtained above
had an endothermic curve substantially identical to the endothermic
curve of thermogravimetric/differential thermal analysis (heating
rate: 5.degree. C./minute) shown in FIG. 13. Specifically, it had
the endothermic peaks at about 136.8.degree. C. and about
141.6.degree..
[0346] The type D crystals of anhydrous aripiprazole obtained above
exhibited .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 14. Specifically, they had the 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).
[0347] The type D crystals of anhydrous aripiprazole obtained above
had a powder X-ray diffraction spectrum which was substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
15. Specifically, it had the characteristic peaks at
2.theta.=8.7.degree., 11.6.degree., 16.3.degree., 17.7.degree.,
18.6.degree., 20.3.degree., 23.4.degree. and 25.0.degree..
[0348] The type D crystals of anhydrous aripiprazole obtained above
had an IR spectrum which was substantially identical to the IR
(KBr) spectrum shown in FIG. 16. Specifically, it had the
characteristic infrared absorption bands at 2946, 1681, 1375, 1273,
1175 and 862 cm.sup.-1.
[0349] The type D crystals of anhydrous aripiprazole obtained above
exhibited a solid .sup.13C-NMR spectrum which was substantially
identical to the solid .sup.13C-NMR spectrum shown in FIG. 17.
Specifically, it had the characteristic peaks at 32.1 ppm, 62.2
ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.5 ppm and 174.1 ppm.
[0350] According to the above-mentioned data on the endothermic
curve of thermogravimetric/differential thermal analysis (heating
rate: 5.degree. C./minute) and powder X-ray diffraction spectrum,
the formation of type D crystals of anhydrous aripiprazole was
confirmed.
[0351] When the type D crystals of anhydrous aripiprazole crystals
obtained above were left for 24 hours in a dessicator where the
conditions were set at humidity 100%, and temperature 60.degree.
C., the crystals did not have hygroscopicity higher than 0.4% (see,
Table 1 below).
Example 13
Preparation of Type D Crystals of Anhydrous Aripiprazole
[0352] 1,200 Grams of the type-I crystals of anhydrous aripiprazole
obtained in Reference Example 2 were dissolved in 18 liters of
toluene, with heating. This toluene solution was cooled to
40.degree. C., and 36 g of type-D crystals of anhydrous
aripiprazole obtained in Example 12 were added as seed crystals,
then the solution was cooled to 10.degree. C. and allowed to stand
as it is. The precipitated crystals were collected by filtration,
dried at 60.degree. C. for 18 hours to obtain 1,073 g (yield:
86.8%) of type D crystals of anhydrous aripiprazole (purity: 100%).
The crystals were colorless plate form.
[0353] The type D crystals of anhydrous aripiprazole had an
endothermic curve substantially identical to the endothermic curve
of thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) shown in FIG. 13. Specifically, it had the
endothermic peaks around about 136.8.degree. C. and about
141.6.degree..
[0354] The type D crystals of anhydrous aripiprazole obtained above
exhibited an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 14. Specifically, it had the 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).
[0355] The type D crystals of anhydrous aripiprazole obtained above
had a powder X-ray diffraction spectrum which was substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
15. Specifically, it had the characteristic peaks at
2.theta.=8.7.degree., 11.6.degree., 16.3.degree., 17.7.degree.,
18.6.degree., 20.3.degree., 23.4.degree. and 25.0.degree..
[0356] The type D crystals of anhydrous aripiprazole obtained above
had an IR spectrum which was substantially identical to the IR
(KBr) spectrum shown in FIG. 16. Specifically, it had
characteristic infrared absorption bands at 2946, 1681, 1375, 1273,
1175 and 862 cm.sup.-1.
[0357] The type D crystals of anhydrous aripiprazole obtained above
had a solid .sup.13C-NMR spectrum which was substantially identical
to the solid .sup.13C-NMR spectrum shown in FIG. 17. Specifically,
it had the characteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm,
104.1 ppm, 152.4 ppm, 158.5 ppm and 174.1 ppm.
[0358] According to the above-mentioned data on the endothermic
curve of thermogravimetric/differential thermal analysis (heating
rate: 5.degree. C./minute) and powder X-ray diffraction spectrum,
the formation of type D crystals of anhydrous aripiprazole was
confirmed.
[0359] When the type D crystals of anhydrous aripiprazole crystals
obtained above were left for 24 hours in a dessicator where the
conditions were set at humidity 100%, and temperature 60.degree.
C., the crystals did not exhibit hygroscopicity higher than 0.4%
(see, Table 1 below).
Example 14
Preparation of Type E Crystals of Anhydrous Aripiprazole
[0360] 40 Grams of type-I crystals of anhydrous aripiprazole
obtained in Reference Example 2 was dissolved in 1000 ml of
acetonitrile with heating at 80.degree. C. This acetonitrile
solution was cooled to about 70.degree. C. by taking for about 10
minutes, and was kept at this temperature for about 30 minutes to
precipitate the seed crystals. Next, the temperature of said
solution was slowly risen to 75.degree. C., and the crystals were
grown up by keeping this temperature for 1 hour. Then, the solution
was cooled to 10.degree. C. by taking about 4 hours, and the
precipitated crystals were collected by filtration. Thus obtained
crystals were subjected to air-drying overnight, there were
obtained 37.28 g (yield: 93.2%) of type E crystals of anhydrous
aripiprazole (purity: 100%). The melting point of these crystals
was 145.degree. C., and the crystals were colorless needle
form.
[0361] The type E crystals of anhydrous aripiprazole had an
endothermic curve substantially identical to the endothermic curve
of thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) shown in FIG. 18. Specifically, it had
endothermic peak at about 146.5.degree..
[0362] The type E crystals of anhydrous aripiprazole obtained above
exhibited an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 19. Specifically, it had the 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).
[0363] The type E crystals of anhydrous aripiprazole obtained above
had a powder X-ray diffraction spectrum which was substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
20. Specifically, it had the characteristic peaks at
2.theta.=8.0.degree., 13.7.degree., 14.6.degree., 17.6.degree.,
22.5.degree. and 24.0.degree..
[0364] The type E crystals of anhydrous aripiprazole obtained above
had an IR spectrum which was substantially identical to the IR
(KBr) spectrum shown in FIG. 21. Specifically, it had the
characteristic infrared absorption bands at 2943, 2817, 1686, 1377,
1202, 969 and 774 cm.sup.-1.
[0365] According to the data on the endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) and powder X-ray diffraction spectrum, the
formation of type E crystals of anhydrous aripiprazole was
confirmed.
[0366] When the type E crystals of anhydrous aripiprazole obtained
above were left for 24 hours in a dessicator where the conditions
were set at humidity 100%, and temperature 60.degree. C., the
crystals did not exhibit hygroscopicity higher than 0.4% (see,
Table 1 below).
Example 15
Preparation of Type F Crystals of Anhydrous Aripiprazole
[0367] 140 Grams of type-I crystals of anhydrous aripiprazole
obtained in Reference Example 2 were suspended in 980 ml of acetone
and continued to reflux for 7.5 hours with stirring. Next, the
suspension was filtered in hot condition, and crystals separated
out were subjected to air-drying for 16 hours at room temperature,
there was obtained 86.19 g (yield: 61.6%) of type F crystals of
anhydrous aripiprazole (purity: 100%). The crystals were colorless
prism form.
[0368] The type F crystals of anhydrous aripiprazole had an
endothermic curve substantially identical to the endothermic curve
of thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) shown in FIG. 22. Specifically, it had the
exothermic peaks at about 137.5.degree. C. and about 149.8.degree.
C.
[0369] The type F crystals of anhydrous aripiprazole obtained above
exhibited an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 23. Specifically, it had the 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).
[0370] The type F crystals of anhydrous aripiprazole obtained above
had a powder X-ray diffraction spectrum which was substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
24. Specifically, it had the characteristic peaks at
2.theta.=11.3.degree., 13.3.degree., 15.4.degree., 22.8.degree.,
25.2.degree. and 26.9.degree..
[0371] The type F crystals of anhydrous aripiprazole obtained above
had an IR spectrum which was substantially identical to the IR
(KBr) spectrum shown in FIG. 25. Specifically, it had the
characteristic infrared absorption bands at 2940, 2815, 1679, 1383,
1273, 1177, 1035, 963 and 790 cm.sup.-1
[0372] According to the data on endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) and powder X-ray diffraction spectrum, the
formation of type F crystals of anhydrous aripiprazole was
confirmed.
[0373] When the type F crystals of anhydrous aripiprazole crystals
obtained above were left for 24 hours in a dessicator where the
conditions were set at humidity 100%, and temperature 60.degree.
C., the crystals did not exhibit hygroscopicity higher than 0.4%
(see, Table 1 below).
TABLE-US-00001 TABLE 1 Initial Moisture Moisture Content Sample
Content (%) 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
10 0.05 0.05 Example 11 0.03 0.03 Example 12 0.04 0.03 Example 13
0.04 0.03 Example 14 0.06 0.09 Example 15 0.04 0.04
Example 16
[0374] a) Type I crystals of anhydrous aripiprazole (10 g) obtained
in Reference Example 2 was charged in a stainless steel round tray
(diameter: 80 mm), and heated to about 170.degree. C. so as to
melted completely. When this melted liquid was cooled, then it
solidified clarity with pale brawn in color, the solid was peeled
off from the stainless steel round tray, there was obtained 9.8 g
(yield: 98%) of glassy state of anhydrous aripiprazole. The
obtained glassy state product was characterized by having no
significant peak observed in a powder X-ray determination. (cf.
FIG. 31).
[0375] According to the thermogravimetric/differential thermal
analysis (heating rate: 5.degree. C./minute), as shown in FIG. 30,
an exothermic peak of type B crystals of anhydrous aripiprazole was
observed at around 86.5.degree. C. While, an endothermic peak of
type B crystals of anhydrous aripiprazole owing to melting was
observed at around 140.1.degree. C.
b) When the glassy state of anhydrous aripiprazole obtained in
Example 16-a) were charged in a sealed vessel and left to stand at
room temperature for about 6 months, then type G crystals of
anhydrous aripiprazole having white in color was obtained by
changing the color from pale brown (25 g, yield: 100%). Melting
point: 138 to 139.degree. C.
[0376] The type G crystals of anhydrous aripiprazole had an
endothermic curve which was substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 26, more
particularly, it has an endothermic peak around 141.0.degree. C.
and an exothermic peak around 122.7.degree. C.
[0377] The type G crystals of anhydrous aripiprazole obtained as
above exhibited an .sup.1H-NMR spectrum which was substantially
identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 27. 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).
[0378] The type G crystals of anhydrous aripiprazole obtained as
above had a powder X-ray diffraction spectrum which was
substantially identical to the powder X-ray diffraction spectrum
shown in FIG. 28. Specifically, it has characteristic peak at
2.theta.=10.1.degree., 12.8.degree., 15.2.degree., 17.0.degree.,
17.5.degree., 19.1.degree., 20.1.degree., 21.2.degree.,
22.4.degree., 23.3.degree., 24.5.degree. and 25.8.degree..
[0379] The type G crystals of anhydrous aripiprazole obtained above
had an IR spectrum which was substantially identical to the IR
(KBr) spectrum shown in FIG. 29. Specifically, it has clear
infrared absorption bands at 2942, 2813, 1670, 1625, 1377, 1195,
962 and 787 cm.sup.-1.
Example 17
a) Preparation of Granules of 30 mg Tablets Containing Type B
Crystals of Anhydrous Aripiprazole for Additional Drying
[0380] Type B crystals of anhydrous aripiprazole (1,500 g), lactose
(5,700 g), corn starch (1,000 g) and crystalline cellulose (1,000
g) were charged in a fluidized bed granulating dryer (Flow Coater
Model FLO-5M; manufactured by FROINT SANGYO KABUSHIKI KAISHA), and
these granulating ingredients were mixed by fluidizing for about 3
minutes with an inlet air temperature at 60.degree. C., air flow
rate of 3 to 4 m.sup.3/min. Further, the granulating ingredients
were continued fluidizing under the same condition, and sprayed
with about 4,000 g of 5% aqueous solution of hydroxypropyl
cellulose to obtain wet granules. The wet granules were dried under
an inlet air temperature at 85.degree. C., for about 20 minutes.
The obtained dried granules contained 3.8% of water (measured by
the method according to Reference Example 4).
b) The Dried Granules (4 kg) Obtained in Example 17-a) were Sized
by Use of a Mill (FIORE F-0: Manufactured by TOKUJU
CORPORATION).
[0381] The sized granules (3 kg) were charged in a fluidized bed
granulating dryer (Flow Coater Model FLO-5M; manufactured by FREUND
INDUSTRIAL CO., LTD.), and these granulating ingredients were dried
under an inlet air temperature at 85.degree. C., and air flow rate
of 2 m.sup.3/min for 2 hours. The obtained dried granules contained
3.6% of water (measured by the method according to Reference
Example 4).
[0382] About 1% by weight of magnesium stearate was added to the
sized granules and mixed, then the granules were supplied to a
tabletting machine (a Rotary single tablet press, Model VIRGO:
manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and there were
obtained tablets, each having 190 mg of weight.
c) The dried granules (3 kg) obtained in Example 17-a) were charged
in a vacuum dryer (vacuum granulating dryer model; VG-50:
manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and dried at
70.degree. C. of a jacket temperature, under a reduced pressure at
5 torr of degree of vacuum for 1 hour. The thus obtained dried
granules contained 3.1% of water (measured by the method according
to Reference Example 4). The dried granules were subjected to
sizing by passing to a sieve of 850 .mu.m.
[0383] About 1% by weight of magnesium stearate was added to the
sized granules and mixed, then the granules were supplied to a
tablet machine (Rotary single tablet press, Model VIRGO:
manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and there were
obtained tablets, each having 190 mg of weight.
Example 18
a) Preparation of 30 mg Tablets Containing Type B Crystals of
Anhydrous Aripiprazole
[0384] Anhydrous aripiprazole (type B crystals) (4,500 g), lactose
(17,100 g), corn starch (3,000 g) and crystalline cellulose (3,000
g) were charged in a fluidized bed granulating dryer
(NEW-MARUMERIZER Model: NQ-500, manufactured by FUJI PAUDAL CO.,
LTD.), and these granulating ingredients were mixed by fluidizing
for about 3 minutes with an inlet air temperature at 70.degree. C.,
air flow rate of 10-15 m.sup.3/min. Further, the granulating
ingredients were continued fluidizing under the same condition, and
were sprayed with about 12,000 g of 5% aqueous solution of
hydroxypropyl cellulose to obtain wet granules. The wet granules
were dried under inlet air at temperature of 85.degree. C., for
about 30 minutes. The obtained dried granules contained 3.6% of
water (measured by the method according to Reference Example 4).
(Yield: 96%). The dried granules were sized by passing to a mill
(FIOLE F-0: manufactured by TOKUJU CORPORATION).
[0385] About 1% by weight of magnesium stearate was added to the
sized granules and mixed, then the granules were supplied to a
tablet machine (a Rotary single tablet press, VIRGO: manufactured
by KIKUSUI SEISAKUSHO CO., LTD.), and there were obtained tablets,
each having 190 mg of weight.
b) The tablets (5 kg) obtained in Example 18-a) were charged in a
fan dryer (AQUA COATER AQC-48T, manufactured by FREUND INDUSTRIAL
CO., LTD.), and dried under inlet air at temperature of 90.degree.
C., air flow rate of 2 m.sup.3/min for 6 hours. The obtained dried
granules contained 3.3% of water (measured by the method according
to Reference Example 4). c) The dried tablets (3 kg) obtained in
Example 18-a) were charged in a vacuum dryer (vacuum granulating
dryer, VG-50: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and
dried at 80.degree. C. of a jacket temperature, under reduced
pressure of 5 torr of degree of vacuum for 4 hours. The obtained
dried tablets contained 2.7% of water (measured by the method
according to Reference Example 4).
Example 19
[0386] a) By the procedures similar to those of Example 18-a),
there were obtained tablets (containing type I crystals of
anhydrous aripiprazole obtained in Reference Example 2), each
having 190 mg of weight, b) The tablets were dried by the
procedures similar to those of Example 18-b), except that air inlet
temperature was 100.degree. C. and dried for 1 hour. c) The tablets
were dried by the procedures similar to those of Example 18-b),
except that inlet air temperature was 100.degree. C. and dried for
3 hours.
Example 20
[0387] By the procedures similar to those of Example 18-a), there
were obtained tablets, each having 190 mg of weight, containing
type C crystals of anhydrous aripiprazole.
Example 21
[0388] By the procedures similar to those of Example 18-a), there
were obtained tablets, each having 190 mg of weight, containing
type D crystals of anhydrous aripiprazole.
Example 22
[0389] a) Aripiprazole hydrate crystals (156 g) obtained in
Reference Example 3, lactose (570 g), corn starch (100 g) and
crystalline cellulose (100 g) were charged in a fluidized bed
granulating dryer (NEW-MARUMERIZER, NQ-160: manufactured by FUJI
POWDAL CO., LTD.), and these granulating ingredients were mixed
under fluidizing for about 3 minutes with an inlet air temperature
at 60.degree. C., air flow rate of 1.0 to 1.5 m.sup.3/min, and
rotating disc with rotary speed of 400 rpm. Further, the
granulating ingredients were continued fluidizing under the same
condition, and sprayed about 500 g of 4% aqueous solution of
hydroxypropyl cellulose to obtain wet granules. The inlet air
temperature was elevated up to 85.degree. C., and dried until the
temperature of the product was reached to 46.degree. C. The
obtained dried granules were sized by passing to a sieve of 850
.mu.m. The dried granules contained 4.37% of water (measured by the
method according to Reference Example 4). b) The dried granules
(200 g) obtained in Example 22-a) were charged in a fluidized bed
dryer (multiplex, MP-01: manufactured by POWREX CORPORATION), and
dried at 85.degree. C. of inlet air temperature, air flow rate of
0.5 m.sup.3/min for 2 hours. The dried granules contained 3.50% of
water (measured by the method according to Reference Example 4). c)
The dried granules (100 g) obtained in Example 22-a) were charged
in a vacuum dryer (vacuum granulating dryer LCV-232: manufactured
by TABAI CO., LTD.), and dried 80.degree. C. of tray temperature,
about 760 mmHg of degree of vacuum for 2 hours. The dried granules
were further dried similarly for 6 hours. The dried granules
contained 3.17% of water (the product being dried for 2 hours:
measured by the method according to Reference Example 4). The
further dried granules contained 2.88% of water (the product being
dried for 6 hours: measured by the method according to Reference
Example 4). d) About 1% by weight of magnesium stearate was added
to the sized granules being obtained in Example 22-b) and mixed,
then the mixed granules were supplied to a tablet machine (Single
type Tablet machine No. 2B: manufactured by KIKUSUI SEISAKUSHO CO.,
LTD.), and tabletted with punch, there were obtained tablets, each
having 191 mg of weight. e) About 1% by weight of magnesium
stearate was added to the sized granules being obtained in Example
22-c) and mixed, then the mixed granules were supplied to a tablet
machine (Single type Tablet machine No. 2B: manufactured by KIKUSUI
SEISAKUSHO CO., LTD.), and tabletted with punch, there were
obtained tablets, each having 191 mg of weight.
Dissolution Test
[0390] Each tablets of the pharmaceutical solid oral preparations
obtained previously was kept, respectively under the open at
25.degree. C./60% RH for 6 months, and at 40.degree. C./75% RH for
1 week, then their dissolution rates were measured by the following
methods. The dissolution rates obtained from 60 minutes after the
exposure are shown in Tables 2 and 3. The dissolution rates after
60 minutes, using the tablets kept under the open at 40.degree.
C./75% RH for 2 weeks, are shown in Tables 4 and 5. The dissolution
rates after 60 minutes, using the tablets kept under the open
condition at 40.degree. C./75% RH for 1 week, are shown in Table
6.
Dissolution Test Equipment: USP
[0391] Model: NTR-6100 (manufactured by TOYAMA SANGYO CO., LTD.)
[0392] Model: DT-610 (manufactured by JASCO CORPORATION)
a) Method of Dissolution Test of the 15 mg Tablet
[0393] One tablet (containing 15 mg each of anhydrous aripiprazole
or hydrate) was tested by using 900 ml of acetic acid buffer
solution (pH 5.0) (Note: 1) as the test solution, and by rotating a
paddle at 100 rpm according to the method of USP (United States
Pharmacopoea) (Note: 2).
[0394] The test solutions obtained respectively from 10 minutes, 20
minutes, 30 minutes, 45 minutes and 60 minutes after the start of
test are named as T10, T20, T30, T45 and T60.
[0395] On the other hand, about 0.05 g of standard sample of
aripiprazole was weighed accurately, dissolved in ethanol (95%) so
as to make exactly 50 ml of ethanol solution. Twenty (20) ml of
this ethanol solution was taken accurately, and to prepared exactly
1000 ml of the standard solution by adding 0.01 mol/liter of
hydrochloric acid reagent solution (Note: 3).
[0396] The test solutions and the standard solution were subjected
to filtration, respectively by using a filter having micropores of
10 to 20 .mu.m in diameters, then each of the filtrates were
introduced to a spectrophotometer installed with flow cell (cell
length: 10 mm), and to measure the absorbance of wave length at 249
nm and absorbance of wave length at 325 nm and determined the
differences between absorbances to named as At10, At20, At30, At45,
At60 and As, respectively.
[0397] After the measurements, the test solutions of T10, T20, T30
and T45 were put back to the test vessels respectively. Further,
similar procedures were conducted to other 5 samples of the test
solutions.
Dissolution rate (%) relating to the indicated amount of
aripiprazole=Amount of the standard sample of aripiprazole
(mg).times.At.times.As.times.9/5.times.20/C
wherein, At: At10, At20, At30, At45 or At60
[0398] As: standard solution
[0399] C: Indicated amount of aripiprazole (mg) [0400] (Note:1)
Water was added to 1.97 g of acetic acid (100) and 9.15 g of sodium
acetate.trihydrate to make 1000 ml of solution (0.1 mol/1). [0401]
(Note:2) Paddle method [0402] (Note:3) Water was added to 100 ml of
0.1 mol/1 hydrochloric acid (Note:4) to make 1000 ml of solution.
[0403] (Note:4) Water was added to 0.9 ml of hydrochloric acid to
make 1000 ml of solution.
b) Method of Dissolution Test of the 30 mg Tablet
[0404] One tablet each of the pharmaceutical solid oral
preparations (containing 30 mg each of anhydrous aripiprazole or
hydrate) was tested by using 900 ml of acetic acid buffer solution
(pH 4.5) (Note: 5) as the test solution, and to conduct the test by
rotating a paddle at 75 rpm in accordance with the method of USP
(United States Pharmacopoea) (Note: 6).
[0405] The test solutions obtained respectively from 10 minutes, 20
minutes, 30 minutes 45 minutes and 60 minutes after the start of
test, were named as T10, T20, T30, T45 and T60.
[0406] On the other hand, about 0.05 g of the standard sample of
aripiprazole was weighed accurately, and dissolved in ethanol (95%)
so as to made exactly 50 ml of the ethanol solution. Twenty (20) ml
of the ethanol solution was taken accurately, and prepared exactly
1000 ml of the standard solution by adding 0.01 mol/liter of
hydrochloric acid reagent solution (Note: 7).
[0407] The test solutions and standard solution were subjected to
filtration, respectively by using a filter having micropores of 10
to 20 .mu.m in diameters, then each of the filtrates were
introduced to a spectrophotometer in which a flow cell (cell
length: 10 mm) was installed, and measured the absorbance of wave
length at 249 nm and absorbance of wave length at 325 nm, and the
difference between these absorbances were named as At10, At20,
At30, At45, At60 and As, respectively.
[0408] After the measurements, the test solutions of T10, T20, T30
and T45 were put back respectively to the test vessels. Further,
similar procedures were conducted to other 5 samples of the test
solutions.
Dissolution rate (%) relating to the indicated amount of
aripiprazole=Amount of the standard sample of aripiprazole
(mg).times.At.times.As.times.9/5.times.20/C
wherein, At: At10, At20, At30, At45 or At60
[0409] As: standard solution
[0410] C: Indicated amount of aripiprazole (mg) [0411] (Note:5)
Water was added to 1.91 g of acetic acid (100) and 2.99 g of sodium
acetate.trihydrate to made 1000 ml of solution (0.05 mol/1). [0412]
(Note:6) Paddle method [0413] (Note:7) Water is added to 100 ml of
0.1 mol/1 hydrochloric acid (Note:8) to made 1000 ml of solution.
[0414] (Note:8) Water was added to 0.9 ml of hydrochloric acid to
make 1000 ml of solution.
TABLE-US-00002 [0414] TABLE 2 Open at 25.degree. C./60% RH Open at
40.degree. C./75% RH After After Samples used Initial 6 months
Initial 1 week Tablet(15 mg) 83.4% 44.3% 83.4% 44.1% of Reference
Example 4 Tablet(15 mg) 90.1% 61.9% 90.1% 65.2% of Reference
Example 5
TABLE-US-00003 TABLE 3 Open at 25.degree. C./60% RH Open at
40.degree. C./75% RH After After Samples used Initial 6 months
Initial 1 week Tablet (30 mg) 96.7% 77.1% 96.7% 75.9% of Example
18-a) Tablet (30 mg) 96.5% 93.6% 95.0% 92.2% of Example 17-b)
Tablet(30 mg) 97.0% 96.3% 94.7% 94.8% of Example 17-c) Tablet (30
mg) 97.2% 95.3% 97.2% 97.8% of Reference Example 18-b) Tablet(30
mg) 97.8% 96.3% 97.8% 96.9% of Reference Example 18-c)
TABLE-US-00004 TABLE 4 Samples used Initial After 2 weeks Samples
used Tablet 89.8% 66.9% (30 mg) of Example 19-a) Tablet (30 mg) of
-- 79.8% Example 19-b) Tablet (30 mg) of -- 85.9% Example 19-c)
TABLE-US-00005 TABLE 5 Samples used Initial After 2 weeks Tablet
(30 of 94.8% 94.7% Example 18-a) Tablet (30 mg) of 93.7% 93.1%
Example 20 Tablet (30 mg) of 94.8% 90.9% Example 21
TABLE-US-00006 TABLE 6 Samples used Initial After 1 weeks Tablet
(30 mg) of 96.5% 84.5% Example 22-d) Tablet (30 mg) of 92.5% 74.4%
Example 22-e) (dreid for 2 hours) Tablet (30 mg) of 96.2% 83.4%
Example 22-e) (dreid for 6 hours)
[0415] (Note: Dissolution tests in Table 5 were conducted similarly
to the procedures in the above-mentioned "b) Method of dissolution
test of the 30 mg tablet" except that by using 900 ml of acetic
acid buffer solution (pH 4.0) as the test solution, and by rotating
a paddle at 50 rpm.
[0416] As can be seen clearly from the data shown in Table 2, in
comparison with the 15 mg tablet containing conventional anhydrous
aripiprazole crystals (Reference Example 4), the 15 mg tablet
containing type B crystals of anhydrous aripiprazole (Reference
Example 5) had the dissolution rate to maintain maximum drug
concentration (Cmax), at pH 5.0 after 60 minutes, even though such
tablet was kept under the open at 25.degree. C./60% RH for 6 months
and under the open at 40.degree. C./75% RH for 1 week.
[0417] As can be seen clearly from the data shown in Table 3, even
though 30 mg tablets (Examples 17-b) and 17-c)) prepared from twice
dried granules of type B crystals of anhydrous aripiprazole, and 30
mg tablets (Examples 18-b) and 18-c)) prepared from further dried
pharmaceutical solid oral preparation containing type B crystals of
anhydrous aripiprazole were subjected to keep under the open at
25.degree. C./60% RH for 6 months or 40.degree. C./75% RH for 1
week, the dissolution rates of these tablets obtained 60 minutes
after the test at pH 4.5 were not substantially lowered.
[0418] As can be seen clearly from the data shown in Table 4, when
30 mg tablets (Examples 19-a), 19-b) and 19-c)) containing
conventional anhydrous aripiprazole crystals were further dried and
subjected to keep under open at 40.degree. C./75% RH for 2 weeks,
then the dissolution rates of the tablets obtained 60 minutes after
the test at pH 4.5 were the dissolution rates to maintain maximum
drug concentration (Cmax).
[0419] As can be seen clearly from the data shown in Table 5, when
30 mg tablet (Example 18-a)) containing type B crystals of
anhydrous aripiprazole, 30 mg tablet (Example 20) containing type C
crystals of anhydrous aripiprazole and 30 mg tablet (Example 21)
containing type D crystals of anhydrous aripiprazole were subjected
to keep under open at 40.degree. C./75% RH for 2 weeks, then the
dissolution rates of the tablets obtained 60 minutes after the test
at pH 4.0 were not substantially lowered.
[0420] As can be seen clearly from the data shown in Table 6, when
30 mg tablets (Examples 22-d) and 22-e)) prepared from granules of
conventional aripiprazole hydrate being twice dried, and subjected
to keep under open at 40.degree. C./75% RH for 1 week, then the
dissolution rates of the tablets obtained 60 minutes after the test
at pH 4.5 were the dissolution rates to maintain maximum drug
concentration (Cmax).
TABLE-US-00007 Sample Preparation 1 Anhydrous aripiprazole crystals
B 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total
200 mg
[0421] Tablets containing the above ingredients in each tablet were
prepared by formulation methods known to one skilled in the art of
pharmaceutical formulation.
TABLE-US-00008 Sample Preparation 2 Type C crystals of anhydrous
aripiprazole 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 200 mg
[0422] In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
TABLE-US-00009 Sample Preparation 3 Type D crystals of anhydrous
aripiprazole 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 200 mg
[0423] In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
TABLE-US-00010 Sample Preparation 4 Type E crystals of anhydrous
aripiprazole 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 200 mg
[0424] In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
TABLE-US-00011 Sample Preparation 5 Type F crystals of anhydrous
aripiprazole 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 200 mg
[0425] In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
TABLE-US-00012 Sample Preparation 6 Type G crystals of anhydrous
aripiprazole 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60
mg Total 200 mg
[0426] In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
Formulation Example
[0427] 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
(anhydrous aripiprazole crystals B).
Formulation Example 1
[0428] Flash-melt tablets were prepared as follows:
Intragranulation:
TABLE-US-00013 [0429] Mg. per Ingredient Percent w/w tablet Xylitol
(300) Xylisorb 26 52 Avicel .RTM. 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
[0430] 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/cm.sup.2 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.
Extragranulation Ingredients:
TABLE-US-00014 [0431] Mg. per Ingredient Percent w/w tablet
Intragranulation 92.75 185.5 Avicel .RTM. PH 200 3 6 Crospovidone 4
8 Magnesium stearate 0.25 0.5 Total weight 100 200
[0432] The intragranulation was placed in the blender and the
Avicel.RTM. 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.RTM. PH 102 for the intragranulation and
Avicel.RTM. PH 200 for the extragranulation ingredient enhanced the
quality of the resultant tablets.
Formulation Example 2
[0433] Flash-melt tablets containing a combination of two grades of
calcium silicate were prepared as follows:
Intragranulation:
TABLE-US-00015 [0434] Mg. per Ingredient Percent w/w tablet Xylitol
(300) Xylisorb 26 52 Avicel .RTM. PH 102 12 24 Calcium Silicate
33.35 66.7 (crystalline, alpha triclinic) Hubersorb 600 NF 10 20
(amorphous calcium silicate) 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
[0435] 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:
TABLE-US-00016 [0436] Mg. per Ingredient Percent w/w tablet
Intragranulation 92.75 185.5 Avicel .RTM. PH 200 3 6 Crospovidone 4
8 Magnesium stearate 0.25 0.5 Total weight 100 200
[0437] The intragranulation was placed in the blender and the
Avicel.RTM. 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.
Formulation Example 3
[0438] Flash-melt tablets containing aripiprazole, an
antischizophrenic drug, were prepared as follows:
Intragranulation
TABLE-US-00017 [0439] Mg. per Ingredient Percent w/w tablet
Aripiprazole 15 30 Xylitol (300) Xylisorb 25 50 Avicel .RTM. PH 102
6 12 Calcium Silicate 37 74 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 94.4
188.8
[0440] 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:
TABLE-US-00018 [0441] Mg. per Ingredient Percent w/w tablet
Intragranulation 94.4 188.8 Avicel .RTM. PH 200 1.1 2.2
Crospovidone 4 8 Magnesium stearate 0.5 1 Total weight 100 200
[0442] The intragranulation was placed in the blender and the
Avicel.RTM. 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.
Formulation Example 4
[0443] Flash-melt tablets containing aripiprazole were prepared as
follows:
Intragranulation:
TABLE-US-00019 [0444] Mg. per Ingredient Percent w/w tablet
Aripiprazole 0.5 1 Xylitol (300) Xylisorb 27 54 Avicel .RTM. 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
[0445] 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:
TABLE-US-00020 [0446] Mg. per Ingredient Percent w/w tablet
Intragranulation 92.9 185.8 Avicel .RTM. PH 200 2.6 5.2
Crospovidone 4 8 Magnesium stearate 0.5 1 Total weight 100 200
[0447] The intragranulation was placed in the blender and the
Avicel.RTM. 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.
* * * * *