Note: Descriptions are shown in the official language in which they were submitted.
a CA 02379005 2002-03-27
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Cross Reference to Related Priority Application
The present application claims priority from
Japanese patent application number JP-2001-290645 filed
September 25, 2001.
DETAILED DESCRIPTION OF THE INVENTION
Field of the Invention
The present invention relates to an improved
form of aripiprazole having reduced hygroscopicity and
processes for the preparation of this improved form.
Background of the Invention
Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-
piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-
[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-
dihydro-2(1H)-quinolinone, is an atypical antipsychotic
agent useful for the treatment of schizophrenia (U: S.
4,734,416 and U.S. 5,006,528). Schizophrenia is a
common type of psychosis characterized by delusions,
hallucinations and extensive withdrawal from others.
Onset of schizophrenia typically.occurs between the age
of 16 and 25 and affects 1 in 100 individuals
worldwide. It is more prevalent than Alzheimer's
disease, multiple sclerosis, insulin-dependent diabetes
and muscular dystrophy. Early diagnosis and treatment
can lead to significantly improved recovery and _
outcome. Moreover, early therapeutic intervention can
avert costly hospitalization.
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According to Example 1 of Japanese Unexamined
Patent Publication No. 191256/1990, aripiprazole
anhydride crystals are manufactured for example by
reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with
1-(2,3-diehlorophenylpiperadine and recrystalli,zing the
resulting raw aripiprazole anhydride with ethanol.
Also, acCOrding to the Proceedings of the 4th Japanese-
Korean Symposium on Separation Technology (October 6-8,
1996), aripiprazole anhydride crystals are manufactured
by heating aripiprazole hydrate at 80°C. However, the
aripiprazole anhydride crystals obtained by the
aforementioned methods have the disadvantage of being
significantly hygroscopic.
The hygroscopicity of these crystals makes
them difficult to handle since costly and burdensome
measures must betaken in order ensure they are not
exposed to moisture during process and formulation.
Exposed to moisture, the anhydrous form can take on
water and convert to a hydrous form. This presents
several disadvantages: First, the hydrous forms of
aripiprazole have the disadvantage of being less
bioavailable and less dissoluble than the anhydrous
forms of aripiprazole. Second, the variation in the
amount of hydrous versus anhydrous aripiprazole drug
substance from batch to batch could fail to meet
specifications set by drug regulatory agencies. Third,
the milling may Cause the drug substance, Conventional
Anhydride, to adhere to manufacturing equipment which
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may further result in processing delay, increased
operator involvement, increased cost, increased
maintenance and lower production yield. Fourth, in
addition to problems caused by introduction of moisture
during the processing of these hygroscopic anhydrides,
the potential for absorbance of moisture during storage
and handling would adversely affect the dissolu.bility
of aripiprazole drug substance: Thus shelf-life of the
product could be significantly decreased and/or
packaging costs could be significantly increased. It
would be highly desirable to discover a form of
aripiprazole that possessed low hygroscopici:ty thereby
facilitating pharmaceutical processing and formulation
operations required for producing dosage units of an
aripiprazole medicinal product having improved shelf-
life, suitable dissolubility and suitable
bioavailability.
SITMMARY OF THE INVENTION
Thus according to the present invention is
provided a form of aripiprazole having reduced
hygroscopicity and which is more amenable to
pharmaceutical processing and formulation. The
inventors of the present invention have discovered that
this reduced-hygroscopic form of Aripiprazole is a
crystalline substance defined herein as Anhydride B. A
particular process for the preparation of this
anhydrous crystalline substance has also been
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discovered and comprises yet another aspect of the
present invention: Particularly, it was discovered as
part of the present invention that in order to produce
Anhydride B having the desired pharmaceutical
properties and utilizing the most efficient process,
Hydrate A, as defined herein, would have to serve as
the intermediate. It was also discovered that a
particular sequence of processing had to be implemented
in order to form Hydrate A. It was discovered that the
preparation of Hydrate A required milling what is
defined herein as Conventional Hydrate. Then,' Hydra a
A can be transformed into Anhydride B through suitable
heating as defined herein. Surprisingly, if the
Conventional Hydrate is first heated and then milled,
serious agglomeration sets in rendering the processing
commercially unsuitable.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a thermogravimetric/differential
thermogram of the Aripiprazole Hydrate~A obtained in
Example 1.
Figure 2 shows the 1H-NMR spectrum (DMSO-d6,
TMS) of the Aripiprazole Hydrate A obtained in Example
f.
Figure 3 is a powder x-ray diffraction
diagram of the Aripiprazole Hydrate IA obtained in
Example 1.
Figure 4 shows the 1H-NMR spectrum (DMSO-ds,
4
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TMS) of the Aripiprazole Anhydride Crystals B obtained
in Example 2.
Figure 5 is a powder x-ray diffraction
diagram of the Aripiprazole Anhydride Crystals B
obtained in Example 2.
Figure 6 is a thermogravimetric/differential
thermogram of the aripiprazole hydrate obtained in
Reference Example 3.
Figure 7 is a powder x-ray diffraction
diagram of the aripiprazole hydrate obtained in
Reference Example 3:
DETAILED DESCRIPTION OF THE INVENTION
According to first embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a powder x-ray
diffraction spectrum which is substantially the same as
the powder x-ray diffraction spectrum shown in Figure
3.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripi.prazole wherein said Hydrate has powder x-ray
diffraction characteristic peaks at 28 = 12.6°, 15.4°,
17.3°, 18:0°, 18.6°, 22.5° and 24.8°.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has particular
infrared absorption bands at 2951, 2822, 1692, 1577,
CA 02379005 2002-03-27
1447, 1378, 1187, 963 and 784 cm 1 on the IR (KBr)
spectrum.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has an 1H-NMR
spectrum which is substantially the same as the 1H-NMR
spectrum (DMSO-d6, TMS) shown in Figure 2.
According to another embodiment of the first aspect of
the present invention is provided Hydrate A of
aripiprazole wherein. said Hydrate has an 1H-NMR spectrum
(DMSO-d6, TMS) having characteristic peaks at 1.55-1.63
ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m,
4H), 2:48-2.56 ppm (m, 4H + DMSO), 2.78 ppm (t, J = 7.4
Hz, 2H) , 2. 97 pprn (brt, J = 4. 6 Hz, 4H) , 3.92 ppm (t, J
- 6.3 Hz, 2H), 6.43 ppm (d, J = 2.4 Hz, 1H), 6.49 ppm
(dd, J = 8 . 4 Hz, J = 2 . 4 Hz, 1H) , 7 » 04 ppm (d, J = 8 .1
Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H)
and 10.00 ppm (s, 1H) .
According to another embodiment of the: first
aspect of the present invention is provided Hydra. a A
of aripiprazole wherein said Hydrate has an endothermic
curve which is substantially the same as the
thermogravimetric/differential thermal analysis
(heating rate 5°C/min) endothermic curve shown in
Figure 1.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean
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particle size of 50 ~m or less.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean
particle size of 40 um or less.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean
particle size of 35 um or less.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean
particle size of 30 um or less.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean
particle size of 25 pm. or less.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean
particle size of 20 ~.m. or less.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein said Hydrate has a mean
particle size range of 40 to 10 um.
According to another embodiment of the first
aspect of the present invention is provided Hydrate A
of aripiprazole wherein aid Hydrate has a mean
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particle size range of 36 to 14 um.
According to a second aspect of the present
invention is provided a process for the preparation of
Hydrate A wherein said process comprises the steps of
milling Conventional Hydrate.
According to a first embodiment of the second
aspect of the present invention is provided a process
for the preparation of Hydrate A comprising the steps
of milling Conventional Hydrate wherein said milling is
performed by a milling machine:
According to another embodiment of the second
aspect of the present invention is provided a process
for the preparation of Hydrate A comprising the steps
of milling Conventional. Hydrate wherein said milling
machine is an atomizer, pin mill, jet mill or ball
mill.
According to another embodiment of the second
aspect of the present invention is provided a process
for the preparation of Hydrate A comprising the tees
of milling Conventional Hydrate wherein said milling
machine is an atomizer
According to another embodiment of the second
aspect of the present invention is provided a process
for the preparation of Hydrate A comprising the steps
of milling Conventional Hydrate wherein said milling
machine is an atomizer using a rotational speed of
5000-15000 rpm for the main axis, a feed rotation of
10-30 rpm and a screen hole size of 1-5 mm.
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According to various embodiments of a third
aspect of the present invention is provided Hydrate A
defined according to one or more of the embodiments
described herein wherein said Hydrate is made by a
prowess as described herein.
According to a fourth aspect of the present
invention is provided aripiprazole drug substance of
low hygroscopicity.
According to a first embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said low hygroscopicity is a moisture content
of 0.50 or less after placing said drug substance for
24 hours in a dessicator maintained at a temperature of
60°C and a humidity level of 100.
According to a first embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said low hygroscopicity is a moisture content
of 0.4% or less after placing said drug substance for
24 hours in a dessicator maintained at a temperature of
60°C and a humidity level of 100. According to another
embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of
low hygroscopicity wherein said low hygroscopicity is a
moisture content of 0:25 or less after placing 'said
drug substance for 24 hours in a dessicator maintained
at a temperature of 60°C and a humidity level of;100~.
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According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said low hygroscopicity is a moisture content
of 0.15% or less after placing said drug substance for
24 hours in a dessicator maintained at a temperature of
60°C and a humidity level of 100%.
According to another embodiment of the four h
aspect of the present invention is provided
aripiprazole drug Substance of low hygroscopicity
wherein said low hygroseopiCity is a moisture content
of 0.100 or less after placing said drug substance for
24 hours in a dessicator maintained at a temperature of
60°C and a humidity level of 100%.
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said low hygroscopicity is a moisture content
of 0.05% or less after placing said drug substance for
24 hours in a dessicator maintained at a temperature of
60°C and a humidity level of 100%.
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said low hygroseopicity is a moisture content
of 0.04 or less after placing said drug substance for
24 hours in a dessicator maintained at a temperature of
60°C and a humidity level of 100%.
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According to another embodiment of the fourth
aspect of the present, invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance is Aripiprazole Anhydride
Crystals B as defined herein.
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance has a powder x-ray
diffraction spectrum which is substantially the same as
the powder x-ray diffraction spectrum shown, in ,Figure
5.
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance has a powder x-ray
diffraction spectrum having characteristic peaks at 29 =
11.0°, 16.6°, 19.3°, 20.3° and 22.1°.
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance has particular infrared
absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,
1173, 960 and 7'79 cm.-1 on the IR (KBr) spectrum.
According to another embodiment of the, fourth
aspect of the present invention is provided
arip:i-prazole drug substance of low hygroscopicity
wherein said drug substance has an 1H-NMR spectrum which
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is substantially the same as the 1H-NMR spectrum (DMSO-
d6, TMS) shown in Figure 4.
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance has an 1H-NMR spectrum
(DM50-ds, TMS) having characteristic peaks at 1.55-1.63
ppm (m; 2H), 1.68-1.78 ppm (m, 2H); 2.35-2.46 ppm (m,
4H), 2.48-2.56 ppm (m, 4H + DMSO), 2.78 ppm (t, J = 7.4
Hz, 2H) , 2 . 97 ppm (brt, J = 4 . 6 Hz, 4H) , 3. 92 ppm (t, J
- 6.3 Hz, 2H), 6.43 ppm (d, J = 2.4 Hz, 1H), 6.49 ppm
(dd, J = 8.4 Hz, J = 2.4 Hz, 1H); 7.04 ppm (d, J = 8.1
Hz, lHj, 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H)
and 10.00 ppm (s, 1H) .
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance exhibits an endothermic
peak near about 141.5°C in thermogravimetric/
differential thermal analysis (heating rate 5°Clmin).
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance exhibits an endothermic
peak near about 140.7°C in differential scanning
calorimetry (heating rate 5°C/min).
According to another embodiment of the fourth
aspect of the present invention is provided
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aripiprazole drug substance of low hygroscopicity
wherein said drug substance is Aripiprazole Anhydride
Crystals B and will not substantially convert to a
hydrous form of aripiprazole when properly stored even
for an extended period. For instance, said
Aripiprazole Anhydride Crystals B can be stored under a
relative humidity (RH) of 60 o and at a temperature of
25°C, even for a period not less than 1 year.
According to another embodiment of the fourth
aspect: of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance is Aripiprazole Anhydride
Crystals B and will not substantially convert to a
hydrous form of aripiprazole when properly s ored even
for an extended period. For instance, said
Aripiprazole Anhydride Crystals B_can be stored under a
relative humidity (RH) of 60 o and at a temperature of
25°C, even for a period not less than 4 years:
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein'said drug substance is Aripiprazole Anhydride
Crystals B and will not substantially convert to a
hydrous farm of aripiprazole when properly stored even
for a period not less than 0.5 year under a relative
humidity (RH) of 75 % and at a temperature of 40°C.
According to another embodiment of the fourth
aspect of the present invention is provided
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aripiprazole drug substance of low hygroscopicity
wherein said drug substance has a mean size of 5pum or
less when small particle size is required for the
formulation such as Tablet and other solid dose
formulations including for example flashmelt
formulations.
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance has a mean size of 40um or
less if small particle size is. required for the
formulation such as Tablet and other solid dose
formulations including for example flashmelt
formulations.
According to another embodiment of the fourth
aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity
wherein said drug substance has a mean size of 30~:m or
less if small particle size is required for formulation
such as Tablet and other solid dose formulations
including for example flashmelt formulations.
According to a fifth aspect of the present
invention is provided a process for the preparation of
Aripiprazole Anhydride Crystals B.
According to a first embodiment of the fifth
aspect of the present invention is provided a process
for the preparation of Ari:piprazole Anhydride Crystals
B wherein said process comprises heating Aripiprazole
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Hydrate A.
According to a first embodiment of the fifth
aspect of the present invention is provided a process
for the preparation of Aripiprazole Anhydride Crystals
B wherein said process comprises heating Aripiprazole
Hydrate A at 90-125°C for about 3-50 hours.
According to another embodiment of the fifth
aspect of the present invention is provided a process
for the preparation of Aripiprazole Anhydride Crystals
B wherein said process. comprises heating Aripiprazola
Hydrate A at 100°C for about 18 hours.
According to another embodiment of the fifth
aspect of the present invention is provided a process
for the preparation of Aripiprazole Anhydride Crystals
B wherein said process comprises heating Aripiprazole
Hydrate A at 100°C for about 24 hours.
According to another embodiment of the fifth
aspect of the present invention is provided a process
for the preparation of Aripiprazole Anhydride Crystals
B wherein said process comprises heating Aripiprazole
Hydrate A at 120°C for about 3 hours.
According to another embodiment of the fifth
aspect of the present invention is provided a process
for the preparation of Aripiprazole Anhydride Crystals
B wherein said process comprises heating Aripiprazole
Hydrate A. for about l8 hours at 100°C followed by
additional heating for about 3 hours at 120°C.
According to a sixth aspect of the present
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invention is provided Aripiprazole Anhydride Crystals B
defined according to one or more of the embodiments
described herein: and made by a process as provided
herein.
According to a seventh aspect of the,present
invention is provided Aripiprazole Anhydride Crystals B
formulated with one or more pharmaceutically acceptable
carriers.
Other embodiments of the present invention
may comprise suitable combinations of two or more of
the embodiments and/or aspects disclosed herein.
Yet other embodiments and aspects of the
invention will be apparent according to the description
provided below.
Yet another aspect of the present invention
comprised discovering that when aripiprazole hydrate
(Conventional Hydrate as defined herein) is milled, it
converts to an aripiprazole hydrate (Hydrate A as
defined herein) with a different powder x-ray
diffraction spectrum by different peak intensities.
Moreover, it was found that Hydrate A loses the' harp
dehydration endothermic peak of 123.5°C which
characterizes unmilled Conventional Hydrate in
thermogravimetricldifferential thermal analysis. Thus,
the Conventional Hydrate is transformed into Hydrate A
after milling Conventional Hydrate and exhibits a
gradual dehydration endothermic peak between about 60°C
and 120°C with a weak peak at about 71°C.
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Yet another aspect of the invention comprised
discovering that when heated to a specific temperature
of 90-125 for 3-50hr, this novel aripiprazole hydrate
dehydrates gradually avoiding the aggregation
phenomenon thought to,be caused in conventional
aripiprazole hydrate by rapid dehydration, and that
aripiprazole anhydride crystals obtained by heating of
the novel aripiprazole hydrate to a specific
temperature are aripiprazole anhydride crystals with
the desired properties.
Ch~,,racterization of I~ydrate A
Particles of "Hydrate A" as used herein have
the physicochemical properties given in (1)-(5) below:
(1) It has an endothermic curve which is
substantially the same as the thermogravimetric/
differential thermal analysis (heating rate 5°C/min)
endothermic curve shown in figure 1. Specifically, it
is characterized by the appearance of a small peak at
about 71°C and a gradual endothermic peak around 60°C
to 120°C.
(2) It has an 1H-NMR spectrum which is
substantially the same as the 1H-NMR spectrum (DMSO-d6,
TMS) shown in Figure 2. Specifically, it has
characteristic peaks at 1:55-1:63 ppm (m, 2H), 1.68-
1.78 ppm (m, 2H), 2.35-2:46 ppm (m, 4H), 2.48-2.56 ppm
(m, 4H + DMSO), 2.78 ppm (t; J = 7.4 Hz, 2H), 2.97 ppm
(brt, J = 4.6 Hz, 4H), 3.92 ppm (t, J = 6.3 Hz, 2H),
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6.43 ppm (d, J = 2.4 Hz, 1H), 6.49 ppm (dd, J = 8.4 Hz,
J = 2.4 Hz, 1H), 7.04 ppm (d, J = 8.1 Hz, 1H), 7.11-
7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10:00 ppm
(s, 1H) .
(3) It has a powder x-ray diffraction
spectrum which is substantially the same as the powder
x-ray diffraction spectrum shown in Figure 3.
Specifically, it has characteristic peaks at 29 = 12.6°,
15.4°, 17.3°, 18.0°, 18.6°, 22.5° and
24.8°.
(4) It has clear infrared absorption bands at
2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784
cm1 on the IR (KBr) spectrum.
(5) It has a mean particle size of 50 um or
less.
Pr~~~ss for M~ract~~;~a uydrate A
Hydrate A is manufactured by milling
Conventional Hydrate. Conventional milling methods can
be used to mill. Conventional Hydrate. Far example,
Conventional Hydrate can be milled in a milling
machine. A widely used milling machine can be used,
such as an atomizer, pin mill, jet mill or ball mill.
Of these, the atomizer is preferred.
Regarding the specific milling conditions
when using an atomizer, a rotational speed of 5000-
15000 rpm could be used for the main axis, for example,
with a feed rotation of l0-30 rpm and a screen hole
size of 1-5 mm.
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The mean particle size of the Arlpiprazole
Hydrate A obtained by milling should normally be 50 um
or less, preferably 30 um or less. Mean particle size
can be ascertained by the particle size measurement
method described hereinafter.
r' B
"Aripiprazole Anhydride Crystals B" of the
present invention as used herein have the
physicochemical properties given in (6)-(12) below.
14 (6) They have an lH-NMR spectrum which is
substantially the same as the 1H-NMR spectrum (DMSO-ds,
TMS) shown in Figure 4. Specifically, they have
characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-
1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2:48-2:56 ppm
(m, 4H + DMSO); 2.78 ppm (t, J = 7.4 Hz, 2H), 2:97 ppm
(brt, J = 4.6 Hz, 4H), 3.92 ppm (t, J = 6.3 Hz, 2H),
6.43 ppm (d, J = 2.4 Hz, 1H), 6.49 ppm (dd, J = 8.4 Hz,
J = 2.4 Hz, 1H), 7.04 ppm (d, J = 8.1 Hz, 1H), 7.11
7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm
(s, 1H) .
(7) They have a powder x-ray diffraction
spectrum which is substantially the same as the powder
x-ray diffraction spectrum shown in Figure 5.
Specifically, they have characteristic peaks at 28 =
11.0°, 16:6°, 19.3°, 20:3° and 22.1°.
(8) They have clear infrared absorption bands
at 2945, 2812, 1678, 1627; 1448, 137?; 1173, 960 and
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779 cm-1 on the IR (KBr) spectrum.
(9) They exhibit an endothermic peak near
about 141.5°C in thermogravimetric/differential thermal
analysis (heating rate 5°C/min).
(10) They exhibit an endothermic peak near
about 140.7°C in differential scanning calorimetry
(heating rate 5°C/min).
(11) Aripiprazole Anhydride Crystals B of the
present invention have low hygroscopicity: For
example, Aripiprazole Anhydride Crystals B of the
present invention maintain a water content of 0.40 or
less after 24 hours inside a dessicator set at a
temperature of 60°C and a humidity of 100. Well-known
methods of measuring water content can be used as long
as they are methods commonly used for measuring the
water content of crystals. For example, a method such
as the Karl Fischer method can be used.
(12) When the small particle size is required
for the formulation such as tablet and other solid dose
formulations including for example flashmelt
formulations, the mean particle size is preferably 50
um or less:
Process fo_r Manufacti~rina~~dride B
In case of the formulation for which small
particle size (less than 50 Vim) is required; the
milling is necessary for the preparation. However,
when a large amount of Conventional Aripiprazole
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Anhydride or Anhydride Crystals B having large particle
size is milled, the milled substances adhere with each
other :in the milling machine. Accordingly, there is a
disadvantage that it is difficult to industrially
prepare Aripiprazole Anhydride Crystals B having small
particle size.
Under the circumstances, the inventors of the
present invention have found that Conventional hydrate
can be easily milled, and Aripiprazole Anhydride B
having, small particle size can be obtained in high
yield with good-operability by heating the milled'
hydrate A thus obtained.
The Aripiprazole Anhydride Crystals B,of the
present invention are prepared for example by heating
the aforementioned Aripiprazole Hydrate A at 90-125°C:
The heating time is generally about 3-50 hours,'but
cannot'be stated unconditionally since it differs
depending on heating temperature. The heating time and
heating temperature are inversely related, so that for
example the heating time will be longer the lower the
heating temperature, and shorter the higher the'heating
temperature. Specifically,, if the heating temperature
of Aripiprazole Hydrate A is 100°C, the heating time
should normally be 18 hours or more or preferably about
24 hours. If the heating temperature of Aripiprazole
Hydrate A is 120°C, on the other hand, the heating time
can be about 3 hours. The Aripiprazole Anhydride
Crystals B of the present.invention can be prepared
CA 02379005 2002-03-27
- 22 -
with certainty by heating Aripiprazole Hydrate A for
about l8 hours at 100°C, and then heating it for about
3 hours at 120°C: The Aripiprazole .Anhydride Crystals B
of the present invention can also be obtained if the
heating time is extended still further; but this may
not be economical.
when small particle size is not required for
the formulation, e.g.; when drug substance is being
manufactured for injectable or oral solution
formulations, Aripiprazole Anhydride Crystal B can be
also obtained the following process.
The inventors also discovered that it is
possible to obtain aripiprazole anhydride crystals by
heating conventional aripiprazole hydrate or
conventional aripiprazole anhydride crystals to a
specific temperature but this process does not yield
Anhydride B crystalline substance suitable for
commercial use in the formulation of solid oral dose
formulations.
Furthermore, the Aripiprazole Anhydride
Crystals B of the present invention are prepared for
example by heating conventional aripiprazole anhydride
crystals at 90-125°C. The heating time is generally
about 3-50 hours, but cannot be stated unconditionally
since it differs depending on heating temperature. The
heating time and heating temperature are inversely
related, so that for example the heating time will be
longer the lower the heating temperature, and shorter
~ CA 02379005 2002-03-27
_ 23 _
the higher the heating temperature. Specifically, if
the heating temperature of the aripiprazole anhydride
crystals is 100°C, the heating ime can be about 4
hours, and if the heating temperature is 120°C the
heating time can be about 3 hours.
The aripiprazole anhydride crystals which are
the raw material for preparing the Aripiprazole
Anhydride Crystals B of the present invention are
prepared for example by'Method a or b below.
" "~ s P a A a
Cr~rstals
Conventional Aripiprazole Anhydride crystals
are prepared by well-known methods, as described in
Example 1 of Japanese Unexamined Patent Publication No.
191256/1990.
A suspension of 47 g of 7-(4-bromobutoxy)-
3,4-dihydrocarbostyril, 35 g of sodium iodide with 600
ml of acetonitrile was refluxed for 30 minutes. To
this suspension was added 40 g of 1-(2,3-
dichlorophenyl)piperazine and 33 m1 of triethylamine
and the whole mixture was further refTuxed for 3 hours.
After the solvent was removed by evaporation, the
residue thus obtained was dissolved in chloroform,
washed with water then dried with anhydrous magnesium
sulfate. The solvent was removed by evaporation, and
the residue thus obtained was recrystaTlized from
ethanol twice; to yield '57.1 g of 7-{4-[4-(2,3-
CA 02379005 2002-03-27
dichlorophenyl)-1-piperazinyl]butoxy}-3,4-
dihydrocarbostyril.
Colorless flake crystals
Melting point: 139:0-139.5°C
" h "~ r r v n
Anhydride
The Method b is described in the Proceedings
of the 4th Japanese-Korean Symposium on Separation
Technology (October 6-8, 1995).
Furthermore, the Aripiprazole Anhydride
Crystals B of the present invention are prepared for
example by heating conventional aripiprazole hydrate at
90-125°G. The heating time is generally about 3-50
hours, but cannot be stated unconditionally since it
differs depending on heating temperature. The heating
time and heating temperature are inversely related, so
that for example the heating time will be longer he
lower the heating temperature; and shorter the higher
the heating temperature. Specifically, if the heating
temperature of the aripiprazole hydrate is 100°C, the
heating time can be about 24 hours, while if the
heating temperature is, 120°C, the heating time can be
about 3 hours.
The aripiprazole hydrate which is the raw
material for preparing the Aripiprazole Anhydride
Crystals B of the present invention is prepared for
example by Method c below.
CA 02379005 2002-03-27 .
- 25 -
.., f r l v 1,
Aripiprazole hydrate is easily obtained by
dissolving the aripiprazole anhydride crystals obtained
by Method a above in a hydrous solvent, and heating and
then cooling the resulting solution. Using this
method, aripiprazole hydrato is precipitated as
crystals in the hydrous solvent.
An organic solvent containing water is
usually used as the hydrous solvent. The organic
solvent should be one which is miscible with water,
such as for example an alcohol such as methanol',
ethanol, propanol or isopropanol, a ketone such as
acetone, an ether such as tetrahydrofuran,
dimethylformamide; or a mixture thereof, with ethanol
being particularly desirable. The.amount of water in
the hydrous solvent can be 10-25% by volume of the
solvent, or preferably close to 20% by volume.
A medicinal composition of the present
invention will contain Aripiprazole Anhydride Crystals
B in a pharmaceutically acceptable carrier or
combination of carriers:
Carriers which are pharmaceutically
acceptable include diluents and excipients generally
used in pharmaceuticals, such as fillers, extenders,
binders, moisturizers; disintegrators, surfactants, and
lubricants.
CA 02379005 2002-03-27
- 26 -
The medicinal composition of the present
invention may be formulated as an ordinary medicinal
preparation, for example in the form of tablets,
flashmelt tablets, pills, powder, liquid, suspension,
emulsion, granules; capsules, suppositories or'as an
injection (liquid, suspension, etc. ) .
When a tablet formulation is used, awide
variety of carriers that are known in the field can be
used. Examples include lactose, saccharose, sodium
chloride, glucose, urea, starch; calcium carbonate,
kaolin, crystal cellulose, silic acid and other,
excipients; water, ethanol, propanol, simple syrup,
glucose liquid, starch liquid, gelatin solution;
carboxymethyl cellulose, shellac, methyl cellulose,
potassium phosphate, polyvinyl pyrolidone and other
binders; dried starch, sodium alginate, agar powder,
laminaran powder, sodium bicarbonate, calcium
carbonate, polyoxyethyl.ene sorbitan fatty acid esters,
sodium lauryl sulfate, monoglyceride stearate, starch,:
lactose and other disin egrators; saccharose, stearin,
cacao butter, hydrogenated oil and other disintegration
inhibitors; quaternary ammonium salt, sodium lauryl
sulfate and other absorption promoters; glycerine,
starch and other moisture retainers; starch, lactose,
kaolin, bentonite, colloidal silk acid and other
adsorbents; and refined talc, stearate; boric acid
powder , polyethylene glycol and other lubricants and
the like. Tablets can also be formulated if necessary
CA 02379005 2002-03-27
as tablets with ordinary coatings, such as sugar-coated
tablets, gelatin-coated tablets, enteric coa ed tablets
and film coated tablets, as well as double tablets and
multilayered tablets.
When a pill formulation is used, a wide
variety of carriers that are known in the field can, be
used. ,Examples include glucose, lactose, starch, cacao
butter, hardened vegetable oil, kaolin, talc and other
excipients; gum arabic powder, traganth powder,
gelatin, ethanol and other binders: and laminaran; agar
and other disintegrators and the like.
When a suppository formulation is used, a
wide variety of carriers that are known in the field
can be used. Examples include polyethylene glycol,
cacao butter, higher alcohol, esters of higher alcohol,
gelatin semi-synthetic glyceride and the like.
Capsules are prepared according to ordinary
methods' by mixing aripiprazole anhydride crystals with
the various carriers described above and packing them ,
in hard gelatin Capsules, soft capsules and the'like.
Tn addition, colorants, preservatives,
perfumes, flavorings, sweeteners and the like as'well
as other drugs may be included in the medicinal
composition.
The amount of Aripiprazole Anhydride Crys als
B that should be included in the medicinal composition
of the present invention can be selected from a wide
range suitable for the indication sought to be treated.
CA 02379005 2002-03-27
- 28 _
Generally, the Aripiprazole Anhydride Crystals B should
be pre ent in about 1-,70o by weight or particularly
about 1-30~ by weight based on the medicinal
composition.
The method of administration of the medicinal
composition of the present invention may be adjusted to
suit, for example, the formulation of the drug product,
the age, gender and other conditions (including the
severity thereof) of the patient. In the case of
tablets, pills, liquids, suspensions, emulsions,
granules and capsules, for example, administration is
oral. In the Case of an injection, it is administered
intravenously either by itself or mixed with an
ordinary replenishes such as glucose or amino acids, or
may also be administered by itself intramuscularly,
intracutaneously, subcutaneously or intraperitoneally,
as necessary. In the ease of a suppository,
administration is intrarectal.
The dosage of the medicinal composition of
the present invention is selected depending on the
usage, the age, gender,and other conditions of the
patient, the severity of the condition and so forth,
but ordinarily the amount of aripiprazole anhydride
crystals can be about 0:1-10 mg per 1 kg of body weight
per day. The preparation which is the unit of
administration should contain in the range of about 1-
100 mg of Aripiprazole Anhydride Crystals B, more
particularly 1-30 mg per unit dose.
, CA 02379005 2002-03-27
- 29 -
The medicinal composition of the present
invention is extremely stable, with substantially no'
decrea a in solubility even when stored for long
periods of time.
The medicinal composition of the present
invention is effective in the prevention and treatment
of central nervous system disorders such as
schizophrenia and may also be effective in the
treatment of intractable (drug-resistant, chronic)
schizophrenia with cognitive impairment and intractable
(drug-resistant, chronic) schizophrenia without
cognitive impairment, anxiety including mild anxiety,
mania including bipolar disorder acute mania and acute
mania, bipolar disorder, depression including bipolar
disorder depression., autism, Down's syndrome, attention
deficit hyperactivity disorder (ADHD), Alzheimer's
disease, Parkinson's disease and other
neurodegenerative diseases, panic, obsessive compulsive
disorder (OCD), sleep disorders, sexual dysfunction,
alcohol'and drug dependency, vomiting, motion sickness,
obesity; miparticlee headache and cognitive impairment.
Anal~,tica'~,I~etY~Q~I.~
( 1 ) The 1H-NMR spectrum was measured iri DMSO-
d6 using TMS as the standard.
(2) Powder x-ray Diffraction
Using a Rigaku Denki RAD-2n diffraction
meter, the powder x-ray diffraction pattern was
~ CA 02379005 2002-03-27
- 30 _
measured at room temperature using a Cu Ka filled tube
(35 kV 2OmA) as the x-'ray source with a wide-angle
goniometer, a 1° scattering slit, an 0:15 mm light-
intereepting slit, a graphite secondary monochromator
and a scintillation counter. Data collection was done
in 2B continuous scan mode at a scan speed of 5°/minute
in scan steps of 0.02° in the range of 3° to 40;°.
(3) The IR spectrum was measured by the KBr
method:
(4) ThermogravimetriclDifferential Thermal
Analysis
Thermogravimetric/differential thermal
analysis was performed using a Seiko SSC 5200 control°
unit and. a TG/DTA 220 simultaneous differential
thermal/thermogravimetric measurement unit. 5-1:0 mg
samples were placed in open aluminum pans and heated
from 20°C to 200°C in a dry nitrogen. atmosphere at a
heating rate of 5°C/minute. a-alumina was used as the
standard substance.
(5) Differential Scanning Calorimetry
Thermogravimetric/differenti.al thermal
analysis was performed using a Seiko 5SC 5200 control
unit and a DSC 220C differential scanning calorimeter.
5-10 mg samples were placed in crimped aluminum pans
and heated from 20°C to 200°C in a dry nitrogen
atmosphere at a heating rate of 5°C/minute. a-alumina
was used as the standard substance.
(6) Particle Size Measurement
CA 02379005 2002-03-27
- 31 -
0.1 g of the particles to be measured were
suspended in a 20 ml n-hexane 5alution of 0.5 g soy
lecithin, and particle size was measured using a size
distribution meter (Microtrack HRA, Microtrack Co.).
('7) Hygroscopicity Test Method
One g of the sample was accurately weighed in
a weighing bottle (diameter 5 cm), covered with
kimwipes and left to rest in a 60°C/100~ RH environment
(water/dessicator). 24 hours later, the weighing
bottle was removed, transferred to an environment of a
room temperature and about 30o RH (magnesium chloride
hexahydrate saturated water solution/dessicator) and
left to rest for 24 hours and the water content of the
sample was measured by the Karl Fischer method.
The present invention is explained in more
detail below using reference examples, examples, sample
preparations and formulation examples.
Re Qr~~~~.~Xam l~l
19.4 g of 7-(4-chlorobutoxy)-3,4-
24 dihydrocarbostyril and 16.2 g of 1-(2,3-dichlorophenyl)
piperadine.l hydrochloride were added to 8.39 g of
potassium carbonate dis-solved in 140 ml ofwater, and
circulated for 3 hours under agitation. After reaction
the mixture was cooled and the precipitated crystals
filtered out. These crystals were dissolved in 350 m1
of ethyl' acetate, and about 210 ml of water/ethyl
acetate;azeotrope removed under reflux. The remaining'
CA 02379005 2002-03-27
_ 32 _
solution was cooled, and the precipitated crystals
filtered out. The resulting crystals were dried for l4
hours at 60°C to produce 20.4 g (74.2%) of raw,
aripiprazole.
30 g of the raw aripiprazole obtained: above
was recrystallized from. 450 ml of ethanol according to
the methods described in Japanese Unexamined Patent
Publication No. 19125611990; and the resulting crystals
dried for 40 hours at 80°C to obtain aripiprazole
anhydride crystals. The yield was 29.4 g (98.0o).
The melting point (mp) of these aripiprazole
anhydride crystals was 140°C, matching the melting
point of the aripiprazole anhydride crystals described
in Japanese Unexamined Patent Publication No.
192256/1990.
When these crystals were left for 24 hours in
a dessicator set at humidity 100, temperature 60°C,
hey exhibited hygroscopicity of 3.28$ (see Table 1
below) .
Reference Example 2
6930 g of the intermediate raw aripiprazole
obtained in Reference Example 1 was heat dissolved in
138 liters of hydrous ethanol (water content 20~)
according to the method presented at the 4th Japa,nese-
Korean Symposium on Separation Technology, gradually
(2-3 hours) cooled to room temperature, and then
chilled to near 0°C. The precipitated crystals were
CA 02379005 2002-03-27
,.
- 33 -
filtered out, producing about 7200 g of aripiprazole
hydrate (wet state).
The we -state aripiprazole hydrate crystals
obtained above were dried for 30 hours at 80°C to
obtain 6480 g (93.50 of conventional aripiprazole
anhydride crystals. The melting point (mp) of these
crystals was 139:5°C. These crystals were confirmed by
the Karl Fischer method o be anhydrous, with a
moisture value of 0.030.
When left for 24 hours in a dessicator set at
humidity 1000, temperature 60°C, these crystals
exhibited hygroscopicity of 1.780 (see Table 1 below).
Refere~~~e Example 33
820 g of the 'intermediate wet-state
aripiprazole hydrate obtained in Reference Example 2
was dried for 2 hours at 50°C to obtain 780 g of
aripiprazole hydrate crystals. These crystals had a
moisture value of 3.820 according to the Karl Fischer
method: As shown in Figure 6, thermogravimetric/:
differential thermal analysis revealed endothermic
peaks at 75.0, 123.5 and'140.5°C. Because dehydration
began near 70°C, there was no clear melting point (mp).
As shown in Figure 7, the powder x-ray
diffraction spectrum of aripiprazole hydrate obtained
by this method exhibited characteristic peaks at 28 =
12.6°, 15:1°, 17.4°, 18.2°, 18.7°~
24.8° arid 27.5°,
The powder x-ray diffraction spectrum of this
aripiprazole hydrate was identical to the powder x-ray
diffraction spectrum of aripiprazole hydrate presented
at the 4th Joint Japanese-Korean Symposium on Isolation
Technology.
example 1
500.3 g of the aripiprazole hydrate crystals
obtained in Reference Example 3 were milled using a
sample. mill (small atomizer). The main axis rotation
rate was set to 12,000 rpm and the feed rotation rate
to 17 rpm; and a 1.O mm herringbone screen was used.
Milling was completed in 3 minutes, resulting in 474.6
g (94.9%) of Aripiprazole Hydrate A powder.
The Aripip.razole Hydrate A (powder) obtained
in this way had a mean particle size of 20-25 um. The
melting point (mp) was'undetermined because dehydration
was observed beginning near 7f°C.
The Aripiprazole Hydrata A (powder) obtained
above exhibited an 1H-NMR (DMSO-d6, TMS) spectrum which
was sub tantially the same as the lH-NMR spectrum shown
in Figure 2. Specifically, it had characteristic peak
at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2:35-
2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H + DMSO), 2.78
ppm (t, J = 7.4 Hz, 2H); 2.97 ppm (brt, J = 4.6 Hz,
4H) , 3. 92 ppm (t, J = 6. 3 Hz, 2H) , 6. 43 ppm (d, J = 2 . 4
Hz, 1H) , 6.49 ppm (dd, J = 8 . 4 Hz, J = 2 . 4 Hz, 1H) ,
7.04 ppm (d, J = 8.1 Hz; 1H), 7.11-7.17 ppm (m, 1H),
7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H) .
CA 02379005 2002-03-27
_ 35 _
The Aripiprazole Hydrate A (powder) obtained
above had a powder x-ray diffraction spectrum which was
substantially tha same!as the powder x-ray diffraction
spectrum shown in Figure 3. Specifically, it had
characteristic peaks at 26 = 12.6°, 15.4°, 17.3°,
18.0°,
18.6°,,22.5° and 24.8° This pattern is different from
the powder x-ray spectrum of unmilled aripiprazole
hydrate shown in Figure 7.
The Aripiprazole Hydrate A (powder) obtained
above had infrared absorption bands at 2951, 2822,
1692, 1577, 1447, 1378, 1187, 963 and 784 cm-1 on the IR
(KBr) spectrum.
As shown in Figure T, the Aripiprazole
Hydrate A (powder) obtained above had a weak peak at
71.3°C in thermogravimetric/differential thermal
analysis and a broad endothermic peak (wefight loss
observed corresponding to one water molecule) between
60-120°C--clearly different from the endothermic curve
of unmilled aripiprazole hydrate (see Figure 6).
example 2
450 g of the .A;ripiprazole Hydrate A. (powder)
obtained in Example l was dried for 24 hours at 100°C
using a hot air dryer to produce 427 g (yield 98.70: of
Aripiprazole Anhydride Crystals B.
These Aripiprazole Anhydride Crystals B! had a.
melting point (mp) of 139.7°C.
The Aripiprazole Anhydride Crystals B
CA 02379005 2002-03-27
36 -
obtained above had an'1H-NMR spectrum (DMSO-d6, TMS)
which was substantially the same as the 1H-NMR spectrum
shown in Figure 4. Specifically, they had
characteristic peak at 1.55-1.63 ppm (m, 2H), 1.68-
1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2',.56 ppm
(m, 4H + DMSO~, 2.78 ppm (t, J = 7.4 Hz, 2H), 2.97 ppm
(brt, J _ 4 . 6 Hz, 4H) , 3. 92 ppm (t, J = 6. 3 Hz, 2H) ,
6.43 ppm (d, J = 2:4 Hz, 1H), 6.49 ppm (dd, J = 8.4 Hz,
J = 2.41Hz, 1H), 7.04 ppm (d, J = 8,1 Hz, 1H), 7.11-
7.17 ppm (m, 1H), 7:28-7.32 ppm (m, 2H) and 10.00 ppm
(s, 1H) .
The Aripiprazole Anhydride Crystals B'
obtained above had a powder y-ray diffraction spectrum
which was substantially the same as the powder x-ray
diffraction spectrum shown in Figure 5. Specifically,
they had characteristic peaks at 26 = 11.0°, 16.6°,
19:3°, 20.3° and 22.1°.
The Aripiprazole Anhydride Crystals B
obtained above had remarkable infrared absorption bands
at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and
779 cml on the IR (KBr) spectrum.
The Aripiprazole Anhydride Crystals B
obtained above exhibited an. endothermic peak near about
141.5°C in thermogravimetricldifferential thermal'
analysis:
The Aripiprazole Anhydride Crystals B
obtained above exhibited an endothermic peak near about
140.7°C in differential scanning calorimetry.
CA 02379005 2002-03-27
Even when the Aripiprazole Anhydride Crystals
B obtained above were left for 24 hours in a dessicator
set at humidity 1000, temperature 60°C, they did not
exhibit hygroscopicity exceeding 0.4~ (See Table 1
below) .
Exam 1p a 3
44.29 kg of the Aripiprazole Hydrate A
(powder) obtained in Example 1 was dry heated for 18
hours in a 100°C hot air dryer and then heated for 3
hours at 120°C to produce 42.46 kg (yield 99.3x) of
Aripiprazole Anhydride Crystals B.
The physicochemical properties of the
resulting Aripiprazole Anhydride Crystals B were the
same as the physicochemical properties of the
Aripiprazole Anhydride Crystals B obtained in Example
2.
'The Aripiprazole Anhydride Crystals B
obtained in this way dil not exhibit hygroscopicity of
more than 0.4o even when left for 24 hours in a
dessicator set at humidity 100%, temperature 60°C (see
Table 1 below).
40.67 kg of the Aripiprazole Hydrate A
(powder) obtained in Example 1 was dry heated for 18
hours in a 100°C hot air dryer and then heated for 3
hours at 120°C to produce 38.95 kg (yield 99.60) of
CA 02379005 2002-03-27
_ 3g -
Aripiprazole Anhydride Crystals B.
The physicochemical properties of the
resulting Aripiprazole Anhydride Crystals B were the
same as the physicochemical properties of the
Aripiprazole Anhydride Crystals B obtained in Example
2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhib it hygroscopicity of
more than 0.4% even when left for 24 hours in a
dessicator set at humidity 100%, temperature 60°C (see
Table 1 below).
Examples 5-10 are useful for injectable or
oral solution formulations but not solid dose
formulations since they were made by heating
Conventional Anhydride or Conventional Hydrate instead
of Hydrate A.
Example 5
The hygroscopic aripiprazole anhydride
crystals obtained in Reference Example 1 were heated
for 50 hours at 100°C using the same methods as in
Example 2. The physicochemical properties of the
resulti',ng Aripiprazole Anhydride Crystals B were the
same as the physicochemical properties of the
Aripiprazole Anhydride Crystals B obtained in Example
2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of
CA 02379005 2002-03-27
_ 3g _
more than 0.4% even when left for 24 hours in a
dessicator set at humidity 100%, temperature 60°C (see
Table 1 below).
Example 6
The hygroscopic aripiprazole anhydride
crystals obtained in Reference Example 1 were heated
for 3 hours at 120°C using the same methods as in
Example 2. The physicochemical properties of the
resulting Aripiprazole Anhydride Crystals B were the
same as, the physicochemical properties of the
Aripiprazole Anhydride Crystals B obtained in Example
2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of
more than 0.4% even when left for 24 hours in a
dessica or set at humidity 100%, temperature 60°C (see
Table 1 below).
Example 7
The hygroscopic aripiprazole anhydride
crystals obtained in Reference Example 2 were heated
for 50 hours at 100°C using the same methods as in
Example 2. The physicochemical properties of the
resulting Aripiprazole Anhydride Crystals B were the
same as,the physicochemical properties of the
Aripiprazole Anhydride Crystals B obtained in Example
2.
CA 02379005 2002-03-27
a
- 40 -
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of
more than 0.4o even when left for 24 hours in a
dessicator set at humidity 1000, temperature 60°C (see
Table 1' below).
Example 8
The hygroscopic aripiprazole anhydride
crystals obtained in Reference Example 2 were heated
for 3 hours at 120°C using the same methods as in
Example 2. The physicochemical properties of the
resulting Aripiprazole Anhydride Crystals B were the
same as the physicochemical properties of the
Aripiprazole Anhydride Crystals B obtained in Example
2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of
more than 0.4o even when left for 24 hours in a
dessicator set at humidity 1000, temperature 60°C (see
Table 1 below).
Example 9
The aripiprazole hydrate crystals obtained in
Reference Example 3 were heated for 50 hours at 100°C
using the same methods as in Example 2. The
physicochemical properties of the resulting
Aripiprazole Anhydride Crystals B were the same'as the
physicochemical properties of the Aripiprazole
CA 02379005 2002-03-27
- 41 -
Anhydride Crystals B obtained in Example 2.
The Aripiprazole Anhydride Crystals B
obtained in this way did not exhibit hygroscopicity of
more than 0.4°s even when left for 24 hours in a
dessicator set at humidity 1000, temperature 60°C (see
Table l below).
Example 10
The aripiprazole hydrate crystals obtained in
Reference Example 3 were heated for 3 hours at 120°C
using the same methods as in Example 2. The
physicochemical properties of the resulting
Aripiprazole Anhydride Crystals B were the same'as the
physicochemical properties of the Aripiprazole
Anhydride' Crystals B obtained in Example 2.
The Aripiprazole Anhydride Crystals B-
obtained in this way exhibited hygroscopicity of no
more than 0.4o even when left for 24 hours in a
dessicator set at humidity 100%, temperature 60°C (see
Table 1 below).
CA 02379005 2002-03-27
- 42 _
Table 1
Sample Initial Moisture Moisture Content
Content ( o ) After 24 hrs ( ~
)
Reference Example 1 0.04 3.28
Reference Example 2 0.04 1.78
Example 2 0.04 0.04
Example 3 0.02 0.02
Example 4 0.02 0.02
Example 5 0.04 0.04
Example 6 0.04 0:04
Example 7 0.04 0.03
Example 8 0.04 0.03
Example 9 0.03 0.01
Example l0 0.05 0.05
Sample ,~reparatiorL 1
Aripiprazole anhydride crystals B 5 mg
Starch 132 mg;
Magnesium stearate 18 mg
Lactose 45 mg
Total 200 mg
Tablets containing the above ingredients in each tablet
were prepared by formulation methods known to one
skilled in the art of pharmaceutical formulation.
CA 02379005 2002-03-27
_ 43 _
Formulation Example
The following examples used aripiprazole drug
substance made by first milling or pulverizing the
conventional hydrate of aripiprazole and then heating
it to form the anhydrous form (anhydride B).
Formulation Examp~ 1
Flash-melt tablets were prepared as follows:
Intragranulation:
I~r ~r~d~ n ~ Percent w/w Ma--~'er
table
Xylitol (300) Xylisorb 26 52
Avicel~ PH 102 12 24
Calcium Silicate 43.35 86.7
Crospovidone 3 6
Amorphous silica 2 4
Aspartame 2 4
Wild cherry flavor 0.15 0.3
Tartaric acid 2 4
Acesulfame K 2 4
Magnesium stearate 0.25 0.5
Total weight 92.75 185.5
The ingredients except for the magnesium
stearate were blended in a commercial V-blender in
geometric proportions for 5 minutes each until all were
added. The magnesium stearate was then added and the
CA 02379005 2002-03-27
- 44 -
mixture blended for an additional three minutes. The
blended formulation was compacted at a pressure of 30-
35 kgF/cm2 in a commercial compactor equipped with an
orifice such that the compacts therefrom are in the
form of ribbons. The ribbons were passed through a 30
mesh (600 microns) screen to form stable granules of
about 150 to 400 microns.
Ex ragranL~lation Inc~redi n
Ma~per
Incxredi ent ,.'_ Percent w/w table.t
Intragranulation 92.75 185.5
Avicel~ PH 200 3 6
Crospovidone 4 8
Magnesium stearate 0.25 0.5
Total weight 100 200
The intragranulation was placed in the
blender and the Avicel~ PH 200 and crospovidone added
thereto and blended for five minutes. The magnesium
stearate was then added and the mixture blended for an
additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of
2:3 kP (3.5 SCU) and disintegrated in 10 seconds in 5
ml of water. The final blend formulation demonstrated
excellent flow and was free of other problems such as
chipping, capping and sticking. It has been found that
utilizing Avicel~ PH 102 for the intragranulation and
CA 02379005 2002-03-27
AvicelC~ PH 200 for the extragranulation ingredient
enhanced the quality of the resultant tablets.
Fr~_rmulation Examx~le 2
Flash-melt tablets containing a combination
of two grades of calcium silicate were prepared as
follows:
Inc,~redient Percent w/w Via' per
Xylitol (300) Xylisorb 26 52
Avicel~ PH 102 12 24
Calcium Silicate
(crystalline, alpha 33.35 66.7
triclinic)
Hubersnrb 600 NF
(amorphous calcium 10 20
silicate )
Crospovidone 3 6
Amorphous silica 2 4
Aspartame' 2 4
Wild cherry flavbr 0.15 0.3
Tartaric acid 2 4
Acesulfame K 2 4
Magnesium stearato 0.25 0.5
Total weight 92.75 185.5
The ingredients except for the magnesium
stearate were blended-in a commercial V-blender in
~ 02379005 2002-03-27
i
- 46 -
geometric proportions for 5 minutes each until all were
added. The magnesium stearate was added and the
mixture blended for an additional three minutes: The
blended formulation was compacted, and screened to form
stable granules in accordance with the procedure of
Formulation Example 1.
Ex aranulatio-n_ Ingredients
--per
Ingredient percent w/w e
tabl
Intragranulation 92.75 185.5
Avicel~ PH 200 3 6
Crospovidone 4 8
Magnesium stearate 0.25 0.5
Total weight 100 200
The intragranulation was placed in the
blender and the Avicel~ PH 200 and crospovidone added
thereto and blended for five minutes. The magnesium
stearate was then added and the mixture blended for an
additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of
2.0 kP (3.1 SCU) and disintegrated in 10 seconds in 5
ml of water.
Formul anon Exan~~le 3
Flash-melt tablets containing aripiprazole,
an antischizophrenic drug, were prepared as follows:
CA 02379005 2002-03-27
- 47 -
T n t r,~.g r anu'~S2 t i on
_ M~per
~,nc~redient Percent w/w table,
Aripiprazole 15 30
Xylitol L300) Xylisorb 25 50
Avicel~ PH 102 6 12
Calcium Silicate 37 74
Crospoviclone 3 6
Amorphous silica 2 4
Aspartame 2 4
Wild cherry flavor 0.15 0.3
Tartaric acid 2 4
Acesulfame K 2 4
Magnesium stearate 0.25 0.5
Total weight 94.4 188.8
The ingredients except for the magnesium
stearate were blended in a commercial V-blender in
geometric proportions for 5 minutes each until all were
added. The magnesium stearate was added and the
mixture blended for an additional three minutes. The
blended formulation was: compacted, and screened to form
stable granules in accordance with the procedure of
Formulation Example 1.
CA 02379005 2002-03-27
- 48 -
Fxt-rac~ranulation Ingredients
M~per
Ingrredient Percent w/w tablet
Intragranulation 94.4 1.88.8
Avicel~ PH 200 1.1 2.2
Crospovidone 4 8
Magnesium stearate 0.5 1
Total weight 100 200
The intragranulation was placed in the
blender and the AvicelC~ PH 200 and crospovidone added
thereto and blended for five minutes. The magnesium
stearate was then added and the mixture blended for an
additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of
2.O kP (3.1 SCU) and disintegrated in 10 seconds in 5
ml of water.
Formulation Example 4
Flash-melt tablets containing aripiprazole
were prepared as follows:
CA 02379005 2002-03-27
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Intraaranulation:
Mg. per
Ingredient Percent w/w tablet
Aripiprazole 0.5 1
Xylitol (300) Xylisorb 27 54
Avicel~ PH 102 ~ 12 24
Calcium Silicate 42 84
Crospovidone 3 6
Amorphous silica 2 4
Aspartame 2 4
Wild cherry flavor 0.15 0.3
Tartaric acid 2 4
Acesulfame K 2 4
Magnesium stearate 0.25 0.5
Total weight 92.9 185.8
The ingredients except for the magnesium
stearate were blended in a commercial V-blender in
geometric proportions for 5 minutes each until all were
added. The'magnesium stearate was added and the
mixture blended for an additional three minutes. The
blended formulation was compacted, and screened to form
stable granules in accordance with the procedure of
Formulation Example 1.
CA 02379005 2002-03-27
- 50 -
Extragranulation Ingredients:
M~-per
Ingredient Percent w/w tablet
Intragranulation 92.9 185.8
Avicel~ PH 200 2.6 5.2
Crospovidone 4 8
Magnesium stearate 0.5 1
Total weight 100 200
The intragranulation was placed in the
blender and the Avicel~ PH 200 and crospovidone added
thereto and blended for five minutes. The magnesium
stearate was then added and the'mixture blended for an
additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of
2.3 kP,(3.5 SCU) and disintegrated in 10 seconds in 5
ml of water.
