U.S. patent application number 11/870090 was filed with the patent office on 2008-04-10 for novel crystalline forms of aripiprazole.
This patent application is currently assigned to HETERO DRUGS LIMITED. Invention is credited to Dasari Muralidhara Reddy, Bandi Parthasaradhi Reddy, Rapolu Raji Reddy, Kura Rathnakar Reddy, Kesireddy Subash Chander Reddy.
Application Number | 20080086005 11/870090 |
Document ID | / |
Family ID | 33017818 |
Filed Date | 2008-04-10 |
United States Patent
Application |
20080086005 |
Kind Code |
A1 |
Parthasaradhi Reddy; Bandi ;
et al. |
April 10, 2008 |
NOVEL CRYSTALLINE FORMS OF ARIPIPRAZOLE
Abstract
The present invention provides novel crystalline forms of
aripiprazole and aripiprazole hydrochloride, processes for their
preparation and pharmaceutical compositions containing them.
Inventors: |
Parthasaradhi Reddy; Bandi;
(Hyderabad, IN) ; Rathnakar Reddy; Kura;
(Hederabad, IN) ; Raji Reddy; Rapolu; (Hyderabad,
IN) ; Muralidhara 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: |
33017818 |
Appl. No.: |
11/870090 |
Filed: |
October 10, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10508498 |
Sep 21, 2004 |
|
|
|
PCT/IN03/00064 |
Mar 21, 2003 |
|
|
|
11870090 |
Oct 10, 2007 |
|
|
|
Current U.S.
Class: |
544/363 |
Current CPC
Class: |
C07D 215/22 20130101;
C07D 215/227 20130101; C07B 2200/13 20130101 |
Class at
Publication: |
544/363 |
International
Class: |
C07D 401/00 20060101
C07D401/00 |
Claims
1-13. (canceled)
14. A crystalline Form B of aripiprazole hydrochloride
characterized by an x-ray powder diffraction pattern having peaks
expressed as 2.theta. at about 9.3, 14.8, 16.4, 17.4, 18.7, 19.7,
21.4, 21.9, 23.8, 25.1, 25.9, 29.7 degrees.
15. A crystalline aripiprazole hydrochloride, characterized by an
x-ray powder diffraction pattern as in FIG. 4.
16. A process for preparation of Form B of aripiprazole
hydrochloride of claim 14, comprising the steps of: a) dissolving
aripiprazole in a ketonic solvent; b) adding hydrochloric acid; c)
maintaining for about 1 hour to 4 hours at about 15.degree. C. to
25.degree. C.; and d) filtering the solid separated; wherein the
ketonic solvent is selected from the group consisting of acetone,
methyl isobutyl ketone and methyl ethyl ketone.
17. A process according to claim 16, wherein the ketone is
acetone.
18. A process according to claim 16, wherein the ketone is methyl
isobutyl ketone.
19-30. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention provides novel crystalline forms of
aripiprazole and aripiprazole hydrochloride, processes for their
preparation and pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
[0002] Aripiprazole of Formula (I): ##STR1## or
7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quin-
olinone and its salts are useful for treating schizophrenia and
their therapeutic uses were disclosed in U.S. Pat. No.
5,006,528.
[0003] Processes for the preparation of aripiprazole and its salts
were described in U.S. Pat. No. 5,006,528. These processes do not
produce well defined, reproducible crystalline forms.
[0004] Thus there is a need for stable and reproducible crystalline
forms of aripiprazole and its salts.
[0005] We have discovered two novel crystalline forms of
aripiprazole and four novel crystalline forms of aripiprazole
hydrochloride. The novel forms have been found to be stable over
the time and reproducible and so, suitable for pharmaceutical
preparations.
[0006] Thus, the object of the present invention is to provide
stable novel crystalline forms of aripiprazole, processes for
preparation of the novel crystalline forms and pharmaceutical
compositions containing these novel crystalline forms.
[0007] Another object of the present invention is to provide stable
novel crystalline forms of aripiprazole hydrochloride, processes
for preparation of the novel crystalline forms and pharmaceutical
compositions containing these novel crystalline forms.
[0008] Since the novel crystalline forms of aripiprazole
hydrochloride are obtained with high purity, preparation of
aripiprazole via the crystalline forms of aripiprazole
hydrochloride serves as a means of producing pure aripiprazole.
SUMMARY OF THE INVENTION
[0009] According to one aspect of the present invention, there is
provided a novel crystalline form of aripiprazole, designated as
Form I, characterized by an x-ray powder diffraction pattern having
peaks expressed as 2.theta. at about 8.7, 11.6, 16.3, 17.7, 18.6,
20.3, 23.4, 24.9 degrees. FIG. 1 shows typical Form I x-ray powder
diffraction pattern.
[0010] According to another aspect of the present invention there
is provided a process for preparation of the Form I of aripiprazole
comprising the steps of:
a) dissolving aripiprazole in a suitable solvent;
b) refluxing for about 30 minutes to 1 hour;
c) cooling slowly to about 15.degree. C. to 25.degree. C.;
d) maintaining for about 2 hour to 4 hours at about 15.degree. C.
to 25.degree. C.; and
e) filtering the solid separated.
[0011] The suitable solvent is selected from the group consisting
of acetone, ethyl acetate, methanol or ethanol.
[0012] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole, designated as
Form II, characterized by an x-ray powder diffraction pattern
having peaks expressed as 2.theta. at about 12.7, 15.1, 17.5, 18.2,
18.8, 19.5, 20.6, 21.2, 22.6, 23.3, 24.2, 24.9, 27.6, 30.0, 31.6,
35.8 degrees. FIG. 2 shows typical Form II x-ray powder diffraction
pattern.
[0013] According to another aspect of the present invention there
is provided a process for preparation of the Form II of
aripiprazole, which comprises dissolving aripiprazole in
tetrahydrofuran and vacuum drying at about 25.degree. C. or spray
drying.
[0014] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole hydrochloride,
designated as Form A, characterized by an x-ray powder diffraction
pattern having peaks expressed as 2.theta. at about 6.2, 8.5, 11.5,
15.2, 15.5, 16.8, 17.2, 18.3, 18.9, 19.6, 20.6, 21.3, 23.4, 24.1,
24.7, 25.9, 27.5, 28.3, 28.9, 32.8 degrees. FIG. 3 shows typical
Form A x-ray powder diffraction pattern.
[0015] According to another aspect of the present invention there
is provided a process for preparation of the Form A of aripiprazole
hydrochloride comprising the steps of:
a) dissolving aripiprazole in methanol or isopropyl alcohol;
b) adding hydrochloric acid;
c) maintaining for about 1 hour to 3 hours at about 15.degree. C.
to 25.degree. C.;
d) filtering the solid separated.
[0016] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole hydrochloride,
designated as Form B, characterized by an x-ray powder diffraction
pattern having peaks expressed as 2.theta. at about 9.3, 14.8,
16.4, 17.4, 18.7, 19.7, 21.4, 21.9, 23.8, 25.1, 25.9, 29.7 degrees.
FIG. 4 shows typical Form B x-ray powder diffraction pattern.
[0017] According to another aspect of the present invention there
is provided a process for preparation of the Form B of aripiprazole
hydrochloride comprising the steps of:
a) dissolving aripiprazole in a ketonic solvent;
b) adding hydrochloric acid;
c) maintaining for about 1 hour to 4 hours at about 15.degree. C.
to 25.degree. C.;
d) filtering the solid separated.
The ketonic solvent is selected from the group consisting of
acetone, methyl isobutyl ketone and methyl ethyl ketone.
[0018] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole hydrochloride,
designated as Form C, characterized by an x-ray powder diffraction
pattern having peaks expressed as 2.theta. at about 3.3, 10.3,
14.2, 14.6, 15.1, 16.4, 16.6, 19.4, 20.3, 20.8, 24.5, 24.9, 25.5,
26.4, 26.7, 28.5, 29.3, 30.1 degrees. FIG. 5 shows typical Form C
x-ray powder diffraction pattern.
[0019] According to another aspect of the present invention there
is provided a process for preparation of the Form C of aripiprazole
hydrochloride comprising the steps of:
a) dissolving aripiprazole in an ester solvent;
b) adding hydrochloric acid;
c) maintaining for about 1 hour to 4 hours at about 15.degree. C.
to 25.degree. C.;
d) filtering the separated solid.
The ester solvent is selected from the group consisting of ethyl
acetate, methyl acetate, ethyl formate and tert-butyl acetate.
[0020] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole hydrochloride,
designated as Form D, characterized by an x-ray powder diffraction
pattern having peaks expressed as 2.theta. at about 9.0, 14.7,
16.4, 17.4, 19.0, 19.3, 19.8, 21.4, 23.4, 24.7, 25.4 degrees. FIG.
6 shows typical Form D x-ray powder diffraction pattern.
[0021] According to another aspect of the present invention there
is provided a process for preparation of the Form D of aripiprazole
hydrochloride comprising the steps of:
a) dissolving aripiprazole in tetrahydrofuran;
b) adding hydrochloric acid;
c) maintaining for about 2 hour to 4 hours at about 15.degree. C.
to 25.degree. C.;
d) filtering the solid separated.
[0022] According to another aspect of the present invention there
is provided a pharmaceutical composition comprising crystalline
Form I or Form II of aripiprazole.
[0023] According to another aspect of the present invention there
is provided a pharmaceutical composition comprising novel
crystalline form of aripiprazole hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 is a x-ray powder diffraction pattern of crystalline
Form I of aripiprazole.
[0025] FIG. 2 is a x-ray powder diffraction pattern of crystalline
Form II of aripiprazole.
[0026] FIG. 3 is a x-ray powder diffraction pattern of crystalline
Form A of aripiprazole hydrochloride.
[0027] FIG. 4 is a x-ray powder diffraction pattern of crystalline
Form B of aripiprazole hydrochloride.
[0028] FIG. 5 is a x-ray powder diffraction pattern of crystalline
Form C of aripiprazole hydrochloride.
[0029] FIG. 6 is a x-ray powder diffraction pattern of crystalline
Form D of aripiprazole hydrochloride.
[0030] x-Ray powder diffraction spectrum was measured on a Siemens
diffractometer.
DETAILED DESCRIPTION OF THE INVENTION
[0031] According to one aspect of the present invention, there is
provided a novel crystalline form of aripiprazole, designated as
Form I, characterized by an x-ray powder diffraction pattern having
peaks expressed as 2.theta. at about 8.7, 11.6, 16.3, 17.7, 18.6,
20.3, 23.4, 24.9 degrees. FIG. 1 shows typical Form I x-ray powder
diffraction pattern.
[0032] According to another aspect of the present invention, there
is provided a process for preparation of the Form I of
aripiprazole. Thus aripiprazole is dissolved in a suitable solvent.
The suitable solvent is selected from the group consisting of
acetone, ethyl acetate, methanol and ethanol. Aripiprazole obtained
by a known method or crystalline Form II of aripiprazole obtained
by the process described below may be used. The solution is
refluxed for about 30 minutes to 1 hour. The solution is then
cooled slowly to about 15.degree. C. to 25.degree. C. in about 1
hour and maintained for about 2 hour to 4 hours at the same
temperature. The separated crystals are filtered and dried to give
Form I of aripiprazole.
[0033] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole, designated as
Form II, characterized by an x-ray powder diffraction pattern
having peaks expressed as 2.theta. at about 12.7, 15.1, 17.5, 18.2,
18.8, 19.5, 20.6, 21.2, 22.6, 23.3, 24.2, 24.9, 27.6, 30.0, 31.6,
35.8 degrees. FIG. 2 shows typical Form II x-ray powder diffraction
pattern.
[0034] According to another aspect of the present invention there
is provided a process for preparation of the Form II of
aripiprazole, which comprises dissolving aripiprazole in
tetrahydrofuran and vacuum drying at about 25.degree. C. or spray
drying.
[0035] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole hydrochloride,
designated as Form A, characterized by an x-ray powder diffraction
pattern having peaks expressed as 2.theta. at about 6.2, 8.5, 11.5,
15.2, 15.5, 16.8, 17.2, 18.3, 18.9, 19.6, 20.6, 21.3, 23.4, 24.1,
24.7, 25.9, 27.5, 28.3, 28.9, 32.8 degrees. FIG. 3 shows typical
Form A x-ray powder diffraction pattern.
[0036] According to another aspect of the present invention there
is provided a process for preparation of the Form A of aripiprazole
hydrochloride. Thus aripiprazole is dissolved in ethanol or
isopropyl alcohol. If necessary, the solvent may be heated to
effect dissolution of aripiprazole. Hydrochloric acid is added to
the solution. Hydrochloric acid may be added as an aqueous solution
or as a solution in any other solvent; or hydrochloric acid gas may
be passed through the solution of aripiprazole. Then the contents
are maintained for about 1 hour to 3 hours at about 15.degree. C.
to 25.degree. C. and the separated crystals are filtered and dried
to yield Form A of aripiprazole hydrochloride.
[0037] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole hydrochloride,
designated as Form B, characterized by an x-ray powder diffraction
pattern having peaks expressed as 2.theta. at about 9.3, 14.8,
16.4, 17.4, 18.7, 19.7, 21.4, 21.9, 23.8, 25.1, 25.9, 29.7 degrees.
FIG. 4 shows typical Form B x-ray powder diffraction pattern.
[0038] According to another aspect of the present invention there
is provided a process for preparation of the Form B of aripiprazole
hydrochloride. Thus aripiprazole is dissolved in a ketonic solvent.
If necessary, the solvent may be heated to dissolve aripiprazole.
The ketonic solvent is acetone or methyl isobutyl ketone or methyl
ethyl ketone; or mixture thereof. Hydrochloric acid is added to the
solution. Hydrochloric acid may be added as an aqueous solution or
as a solution in any other solvent; or hydrochloric acid gas may be
passed through the solution of aripiprazole. Then the contents are
maintained for about 1 hour to 4 hours at about 15.degree. C. to
25.degree. C. and the separated crystals are filtered and dried to
yield Form B of aripiprazole hydrochloride.
[0039] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole hydrochloride,
designated as Form C, characterized by an x-ray powder diffraction
pattern having peaks expressed as 2.theta. at about 3.3, 10.3,
14.2, 14.6, 15.1, 16.4, 16.6, 19.4, 20.3, 20.8, 24.5, 24.9, 25.5,
26.4, 26.7, 28.5, 29.3, 30.1 degrees. FIG. 5 shows typical Form C
x-ray powder diffraction pattern.
[0040] According to another aspect of the present invention there
is provided a process for preparation of the Form C of aripiprazole
hydrochloride. Thus aripiprazole is dissolved in an ester solvent.
If necessary, the solvent may be heated to effect dissolution of
aripiprazole. The ester solvent is selected from the group
consisting of ethyl acetate, methyl acetate, ethyl formate and
tert-butyl acetate. Hydrochloric acid is added to the solution.
Hydrochloric acid may be added as an aqueous solution or as a
solution in any other solvent; or hydrochloric acid gas may be
passed through the solution of aripiprazole. Then the contents are
maintained for about 1 hour to 4 hours at about 15.degree. C. to
25.degree. C. and the separated solid is filtered and dried to
obtain Form C of aripiprazole hydrochloride.
[0041] According to another aspect of the present invention, there
is provided a novel crystalline form of aripiprazole hydrochloride,
designated as Form D, characterized by an x-ray powder diffraction
pattern having peaks expressed as 2.theta. at about 9.0, 14.7,
16.4, 17.4, 19.0, 19.3, 19.8, 21.4, 23.4, 24.7, 25.4 degrees. FIG.
6 shows typical Form D x-ray powder diffraction pattern.
[0042] According to another aspect of the present invention there
is provided a process for preparation of the Form D of aripiprazole
hydrochloride. Thus aripiprazole is dissolved in tetrahydrofuran.
Hydrochloric acid is added to the solution. Hydrochloric acid may
be added as an aqueous solution or as a solution in any other
solvent; or hydrochloric acid gas may be passed through the
solution of aripiprazole. Then the contents are maintained for 2
hour to 4 hours at about 15.degree. C. to 25.degree. C. and the
separated crystals are filtered and dried to produce Form D of
aripiprazole hydrochloride.
[0043] The novel crystalline forms of aripiprazole hydrochloride
obtained by the processes described above are very pure. So,
aripiprazole with high purity can be obtained by basifying a
solution of aripiprazole hydrochloride crystalline form and
isolating aripiprazole from the solution by usual processes known
in the art.
[0044] According to another aspect of the present invention there
is provided a pharmaceutical composition comprising Form I or Form
II of aripiprazole and a pharmaceutically acceptable carrier.
[0045] According to another aspect of the present invention there
is provided a pharmaceutical composition comprising crystalline
form of aripiprazole hydrochloride and a pharmaceutically
acceptable carrier. The crystalline form may be Form A, Form B,
Form C or Form D.
[0046] The forms of aripiprazole or aripiprazole hydrochloride may
be formulated in a form suitable for oral administration or
injection. The examples of pharmaceutical compositions are tablets,
capsules, powders, suspensions, emulsions, injections and the
like.
[0047] The following examples will serve to further illustrate the
invention.
EXAMPLE 1
[0048] Aripiprazole (2 gm) (obtained by a process described in U.S.
Pat. No. 5,006,528) is dissolved in acetone (42 ml) and refluxed
for 30 minutes. The solution is slowly cooled to 25.degree. C. in 1
hour and maintained at 25.degree. C. for 3 hours. The separated
crystals are filtered and dried to give 1 gm of Form I of
aripiprazole.
EXAMPLE 2
[0049] Aripiprazole (2 gm) (obtained by a process described in U.S.
Pat. No. 5,006,528) is dissolved in tetrahydrofuran and the solvent
is removed by vacuum drying at 25.degree. C. for 6 hours to give
Form II of aripiprazole in quantitative yield.
EXAMPLE 3
[0050] Aripiprazole (2 gm) (obtained by a process described in U.S.
Pat. No. 5,006,528) is dissolved in tetrahydrofuran and the solvent
is removed by spray drying at 25.degree. C. for 6 hours to give
Form II of aripiprazole in quantitative yield.
EXAMPLE 4
[0051] Aripiprazole (2 gm) (obtained by a process described in U.S.
Pat. No. 5,006,528) is dissolved in methanol (12 ml) and conc.
hydrochloric acid (1 ml) is added to the solution. The contents are
maintained for 2 hours at 25.degree. C. and the separated solid is
filtered to give 2 gm of Form A of aripiprazole hydrochloride.
EXAMPLE 5
[0052] Aripiprazole (2 gm) (obtained by a process described in U.S.
Pat. No. 5,006,528) is dissolved in acetone (12 ml) and conc.
hydrochloric acid (1 ml) is added to the solution. The contents are
maintained for 3 hours at 25.degree. C. and the separated solid is
filtered to give 1.9 gm of Form B of aripiprazole
hydrochloride.
EXAMPLE 6
[0053] Aripiprazole (2 gm) (obtained by a process described in U.S.
Pat. No. 5,006,528) is dissolved in ethyl acetate (12 ml). 10% W/V
HCl in ethyl acetate (4 ml) is added to the solution. The solution
is maintained at 25.degree. C. for 2 hours and the separated
crystals are collected by filtration to give 2 gm of Form C of
aripiprazole hydrochloride.
EXAMPLE 7
[0054] Aripiprazole (2 gm) (obtained by a process described in U.S.
Pat. No. 5,006,528) is dissolved in tetrahydrofuran (12 ml) and
conc. hydrochloric acid (1 ml) is added to the solution. The
contents are maintained for 3 hours at 25.degree. C. and the
separated solid is collected by filtration to give 2 gm of Form D
of aripiprazole hydrochloride.
EXAMPLE 8
[0055] Example 1 is repeated using Form II of aripiprazole instead
of aripiprazole to give Form I of aripiprazole.
EXAMPLE 9
[0056] Example 2 is repeated using Form I of aripiprazole instead
of aripiprazole to give Form II of aripiprazole.
EXAMPLE 10
[0057] Example 5 is repeated using Form I of aripiprazole instead
of aripiprazole to give Form B of aripiprazole hydrochloride.
EXAMPLE 11
[0058] Example 7 is repeated using Form II of aripiprazole instead
of aripiprazole to give Form D of aripiprazole hydrochloride.
* * * * *