U.S. patent application number 11/869961 was filed with the patent office on 2008-07-31 for aripiprazole crystalline forms.
This patent application is currently assigned to HETERO DRUGS LIMITED. Invention is credited to Dasari Murallidhara Reddy, Bandi Parthasaradhi Reddy, Rapolu Raji Reddy, Kura Rathnakar Reddy, Kesireddy Subash Chander Reddy.
Application Number | 20080182988 11/869961 |
Document ID | / |
Family ID | 34090464 |
Filed Date | 2008-07-31 |
United States Patent
Application |
20080182988 |
Kind Code |
A1 |
Parthasaradhi Reddy; Bandi ;
et al. |
July 31, 2008 |
ARIPIPRAZOLE CRYSTALLINE FORMS
Abstract
The present invention provides novel crystalline forms of
aripiprazole and processes for their preparation.
Inventors: |
Parthasaradhi Reddy; Bandi;
(Hyderabad, IN) ; Rathnakar Reddy; Kura;
(Hyderabad, IN) ; Raji Reddy; Rapolu; (Hyderabad,
IN) ; Murallidhara Reddy; Dasari; (Hyderabad, IN)
; Subash Chander Reddy; Kesireddy; (Hyderabad,
IN) |
Correspondence
Address: |
CAESAR, RIVISE, BERNSTEIN,;COHEN & POKOTILOW, LTD.
11TH FLOOR, SEVEN PENN CENTER, 1635 MARKET STREET
PHILADELPHIA
PA
19103-2212
US
|
Assignee: |
HETERO DRUGS LIMITED
Hyderabad
IN
|
Family ID: |
34090464 |
Appl. No.: |
11/869961 |
Filed: |
October 10, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10518214 |
Dec 16, 2004 |
|
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11869961 |
|
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Current U.S.
Class: |
544/363 |
Current CPC
Class: |
C07D 215/227
20130101 |
Class at
Publication: |
544/363 |
International
Class: |
C07D 401/12 20060101
C07D401/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 25, 2003 |
IN |
PCT/IN03/00251 |
Claims
1-5. (canceled)
6. A crystalline aripiprazole methanolate form IV, characterized by
an x-ray powder diffraction spectrum having peaks expressed as 20
at about 9.8, 11.0, 11.8, 12.1, 12.6, 13.6, 17.4, 18.8, 20.1, 23.3,
24.6, 25.0, 25.9, 27.2, 28.4, 29.3, 30.1 and 31.5 degrees.
7. A crystalline aripiprazole methanolate form IV as defined in
claim 6, further characterized by an x-ray powder diffraction
spectrum as in FIG. 2.
8. (canceled)
9. A process according to claim 8, wherein the product obtained is
aripiprazole methanolate.
10-18. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention provides novel crystalline forms of
aripiprazole and processes for their preparation.
BACKGROUND OF THE INVENTION
[0002] Aripiprazole of formula (I):
##STR00001##
[0003] or
7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2-
(1H)-quinolinone and its salts are useful for treating
schizophrenia and their therapeutic uses were disclosed in U.S.
Pat. No. 5,006,528.
[0004] Processes for the preparation of aripiprazole and its salts
were described in U.S. Pat. No. 5,006,528. Various crystalline
forms of aripiprazole and its hydrates were disclosed in WO
03/026659, Japanese Unexamined Patent Publication No. 191256/1990
and 4.sup.th Japanese-Korean Symposium on Separation Technology
(Oct. 6-8, 1996).
[0005] We have discovered a novel crystalline form of aripiprazole,
aripiprazole methanolate and aripiprazole ethylene dichloride
solvate. The novel crystalline form of aripiprazole is non
hygroscopic, do not have the tendency to convert to other forms and
suitable for pharmaceutical preparations.
[0006] The methanolate and ethylene dichloride solvate are
non-hygroscopic, obtainable in pure form and can be converted to
crystalline forms of aripiprazole and aripiprazole hydrates.
[0007] Therefore, the solvates are useful as intermediates for
preparing pure aripiprazole or aripiprazole hydrates in any
crystalline form.
[0008] Thus, one object of the present invention is to provide
stable, non-hygroscopic crystalline form of aripiprazole, process
for preparing this form and pharmaceutical compositions containing
it.
[0009] Another object of the present invention is to provide
aripiprazole methanolate and aripiprazole ethylenedichloride
solvate and process for preparing the solvates; and use of these
solvates to prepare other forms of aripiprazole.
DESCRIPTION OF THE INVENTION
[0010] In accordance with the present invention, there is provided
a novel crystalline form of aripiprazole. The crystalline form is
designated as aripiprazole form III and typical form III x-ray
powder diffraction spectrum of aripiprazole form III is shown in
FIG. 1.
[0011] Aripiprazole form III is characterized by peaks in the
powder x-ray diffraction spectrum having 20 angle positions at
about 8.8, 11.2, 11.4, 11.9, 13.6, 14.4, 15.0, 15.9, 16.4, 17.8,
18.7, 20.4, 20.8, 21.4, 22.2, 23.5, 25.0, 25.9 and 26.5
degrees.
[0012] In accordance with the present invention, there is provided
a process for preparation of the aripiprazole form III comprising
the steps of: [0013] a) preparing a solution of aripiprazole in a
mixture of methyl tert-butyl ether, acetonitrile and
tetrahydrofuran; and [0014] b) isolating aripiprazole form III from
the solution.
[0015] Aripiprazole used in the process can be in any of the
crystalline forms. Aripiprazole solvate or hydrate form can also be
used in the process to produce aripiprazole form III.
[0016] The solution of aripiprazole is usually prepared at elevated
temperature, preferably at reflux temperature and then the solution
is cooled preferably to 0.degree. C. to 30.degree. C., more
preferably to 15.degree. C. to 30.degree. C. The precipitated form
III crystals are collected by filtration or centrifugation.
[0017] In accordance with the present invention, there is provided
aripiprazole methanolate. The content of methanol is between about
2 to 6% of the weight of aripiprazole methanolate. Aripiprazole
methanolate typically shows a crystalline form, which is designated
as aripiprazole methanolate form IV and typical form IV x-ray
powder diffraction spectrum of aripiprazole methanolate form IV is
shown in FIG. 2.
[0018] Aripiprazole methanolate form IV is characterized by peaks
in the powder x-ray diffraction spectrum having 20 angle positions
at about 9.8, 11.0, 11.8, 12.1, 12.6, 13.6, 17.4, 18.8, 20.1, 23.3,
24.6, 25.0, 25.9, 27.2, 28.4, 29.3, 30.1 and 31.5 degrees.
[0019] In accordance with the present invention, there is provided
a process for preparation of the aripiprazole methanolate form IV
comprising the steps of: [0020] a) preparing a solution of
aripiprazole in a mixture of methanol and tetrahydrofuran; and
[0021] b) isolating aripiprazole methanolate form IV from the
solution.
[0022] The solution of aripiprazole is usually prepared at elevated
temperature, preferably at reflux temperature and then the solution
is cooled preferably to 0.degree. C. to 30.degree. C. The
precipitated form IV crystals are collected by filtration or
centrifugation.
[0023] Aripiprazole methanolate can be used to prepare aripiprazole
forms by crystallizing from the appropriate solvent system. Thus,
for example aripiprazole form III can be prepared by preparing a
solution of aripiprazole methanolate in a mixture of methyl
tert-butyl ether, acetonitrile and tetrahydrofuran and isolating
aripiprazole form III from the solution.
[0024] In accordance with the present invention, there is provided
aripiprazole ethylenedichloride solvate. The content of
ethylenedichloride is between about 15 to 40% of the weight of
aripiprazole ethylenedichloride solvate. Aripiprazole
ethylenedichloride solvate typically shows a crystalline form,
which is designated as aripiprazole ethylenedichloride solvate form
V and the typical form V x-ray powder diffraction spectrum of
aripiprazole ethylenedichloride solvate form V is shown in FIG.
3.
[0025] Aripiprazole ethylenedichloride solvate form V is
characterized by peaks in the powder x-ray diffraction spectrum
having 20 angle positions at about 10.7, 17.6, 17.8, 20.6, 22.1,
23.4, 24.7 and 26.4 degrees.
[0026] In accordance with the present invention, there is provided
a process for preparation of the Aripiprazole ethylenedichloride
solvate form V comprising the steps of: [0027] a) preparing a
solution of aripiprazole in ethylenedichloride and [0028] b)
isolating aripiprazole ethylenedichloride solvate form V from the
solution.
[0029] The solution of aripiprazole is usually prepared at elevated
temperature, preferably at reflux temperature and then the solution
is cooled preferably to 0.degree. C. to 30.degree. C. The
precipitated form V crystals are collected by filtration or
centrifugation.
[0030] Aripiprazole ethylenedichloride solvate can be used to
prepare aripiprazole forms by crystallizing from the appropriate
solvent system. Thus, for example aripiprazole form III can be
prepared by preparing a solution of aripiprazole ethylenedichloride
in a mixture of methyl tert-butyl ether, acetonitrile and
tetrahydrofuran and isolating aripiprazole form III from the
solution.
[0031] In accordance with the present invention, there is provided
a pharmaceutical composition comprising aripiprazole form III and a
pharmaceutically acceptable carrier or diluent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 is a x-ray powder diffraction spectrum of
aripiprazole form III.
[0033] FIG. 2 is a x-ray powder diffraction spectrum of
aripiprazole methanolate form IV.
[0034] FIG. 3 is a x-ray powder diffraction spectrum of
aripiprazole ethylenedichloride solvate form V.
[0035] x-Ray powder diffraction spectrum was measured on a Bruker
axs D8 advance x-ray powder diffractometer having a copper-K.alpha.
radiation.
[0036] The invention will now be further described by the following
examples, which are illustrative rather than limiting.
EXAMPLE 1
[0037] Aripiprazole (3 gm) is mixed with methyl tert-butyl ether
(25 ml) and heated to reflux temperature. Then acetonitrile (45 ml)
and tetrahydrofuran (25 ml) are added to the mixture and heated to
about 55.degree. C. to form a clear solution. The solution is
slowly cooled to 25.degree. C., stirred for 1 hour at about
25.degree. C. and the precipitated crystals are collected by
filtration to give 2 gm of aripiprazole form III.
EXAMPLE 2
[0038] Aripiprazole (3 gm), obtained by a known method is mixed
with methanol (30 ml) and heated to reflux temperature. Then
tetrahydrofuran (25 ml) is added at the same temperature to form a
clear solution. The solution is slowly cooled to about 25.degree.
C., stirred for 1 hour at about 25.degree. C. and the separated
crystals are collected by filtration to give 2.9 gm of aripiprazole
methanolate form IV.
EXAMPLE 3
[0039] Example 1 is repeated using aripiprazole methanolate
obtained as in example 2 instead of aripiprazole to give
aripiprazole form III.
EXAMPLE 4
[0040] Aripiprazole (3 gm) is mixed with ethylenedichloride (30 ml)
and heated to 50.degree. C. to form a clear solution. The solution
is slowly cooled to 25.degree. C., stirred for 1 hour at about
25.degree. C. and the separated crystals are collected by
filtration to give 2.5 gm of aripiprazole ethylenedichloride
solvate form V.
EXAMPLE 5
[0041] Example 1 is repeated using aripiprazole ethylenedichloride
solvate obtained as in example 4 instead of aripiprazole to give
aripiprazole form III.
* * * * *