U.S. patent application number 12/407078 was filed with the patent office on 2009-09-17 for novel crystalline forms of lamotrigine.
This patent application is currently assigned to HETERO DRUGS LIMITED. Invention is credited to Reddy Dasari Muralidhara, Reddy Bandi Parthasaradhi, Reddy Rapolu Raji, Reddy Kura Rathnakar, Reddy Kesireddy Subash Chander.
Application Number | 20090233932 12/407078 |
Document ID | / |
Family ID | 33017813 |
Filed Date | 2009-09-17 |
United States Patent
Application |
20090233932 |
Kind Code |
A1 |
Parthasaradhi; Reddy Bandi ;
et al. |
September 17, 2009 |
NOVEL CRYSTALLINE FORMS OF LAMOTRIGINE
Abstract
The present invention relates to novel crystalline forms of
lamotrigine, to processes for their preparation and pharmaceutical
compositions containing them.
Inventors: |
Parthasaradhi; Reddy Bandi;
(Hyderabad, IN) ; Rathnakar; Reddy Kura;
(Hyderabad, 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: |
33017813 |
Appl. No.: |
12/407078 |
Filed: |
March 19, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10508099 |
Sep 15, 2004 |
7521553 |
|
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PCT/IN03/00057 |
Mar 17, 2003 |
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12407078 |
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Current U.S.
Class: |
514/242 |
Current CPC
Class: |
A61K 31/53 20130101;
C07D 253/075 20130101 |
Class at
Publication: |
514/242 |
International
Class: |
A61K 31/53 20060101
A61K031/53 |
Claims
1-13. (canceled)
14. A pharmaceutical composition comprising a crystalline form of
lamotrigine and a pharmaceutically acceptable carrier, wherein the
crystalline form of lamotrigine is Form I lamotrigine.
15. A pharmaceutical composition comprising a crystalline form of
lamotrigine and a pharmaceutically acceptable carrier, wherein the
crystalline form of lamotrigine is Form II lamotrigine.
16. A pharmaceutical composition comprising a crystalline form of
lamotrigine and a pharmaceutically acceptable carrier, wherein the
crystalline form of lamotrigine is Form III lamotrigine.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel crystalline forms of
lamotrigine, to processes for their preparation and pharmaceutical
compositions containing them.
BACKGROUND OF THE INVENTION
Lamotrigine of formula (I)
##STR00001##
[0002] or 6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine is an
anti-epileptic drug and its therapeutic uses are disclosed in U.S.
Pat. No. 4,602,017.
[0003] Different synthetic methods of lamotrigine are described in
WO 01/049669, U.S. Pat. No. 6,111,101, U.S. Pat. No. 6,333,198,
U.S. Pat. No. 5,912,345, EP 800521, U.S. Pat. No. 4,602,017.
[0004] Various polymorphic forms are disclosed in WO 02/068398.
[0005] We have discovered three novel crystalline forms of
lamotrigine. The novel forms have been found to be stable over the
time and does not automatically convert into other crystalline
forms of lamotrigine.
[0006] The novel forms of lamotrigine are, thus, suitable for
pharmaceutical preparations.
[0007] Thus the object of the present invention is to provide
stable novel crystalline forms of lamotrigine, to provide a
processes for preparation of the novel crystalline forms and to
provide a pharmaceutical compositions comprising these novel
crystalline forms.
SUMMARY OF THE INVENTION
[0008] According to one aspect of the present invention, there is
provided a novel crystalline Form I of lamotrigine characterized by
an x-ray powder diffraction pattern having peaks expressed as
2.theta. at about 12.5, 13.9, 16.7, 18.0, 22.3, 23.6, 26.8, 27.9,
28.5, 28.9, 29.4, 31.7, 40.2, 42.3 degrees. FIG. 1 shows typical
Form I x-ray powder diffraction pattern.
[0009] According to another aspect of the present invention, there
is provided a novel crystalline Form II of lamotrigine
characterized by an x-ray powder diffraction pattern having peaks
expressed as 2.theta. at about 8.9, 11.2, 12.3, 13.2, 13.9, 17.0,
17.4, 18.0, 18.2, 18.7, 19.8, 21.4, 22.1, 22.7, 25.1, 25.4, 25.7,
26.4, 26.8, 27.1, 27.5, 28.3, 28.8, 29.2, 30.1, 30.9, 31.4, 32.9,
35.3, 35.7, 36.5 degrees. FIG. 2 shows typical Form II x-ray powder
diffraction pattern.
[0010] According to another aspect of the present invention, there
is provided a novel crystalline Form III of lamotrigine
characterized by an x-ray powder diffraction pattern having peaks
expressed as 2.theta. at about 9.9, 12.0, 13.3, 16.1, 17.0, 18.1,
18.7, 19.5, 24.4, 26.0, 26.3, 27-6, 28.1, 37.1 degrees. FIG. 3
shows typical Form III x-ray powder diffraction pattern.
[0011] According to another aspect of the present invention there
is provided a process for preparation of Form I lamotrigine
comprising the steps of:
a) dissolving lamotrigine in an ester; b) maintaining at 15.degree.
C. to 30.degree. C. for about 30 minutes to 2 hours; c) filtering
Form I lamotrigine.
[0012] The ester is selected from the group consisting of ethyl
acetate, methyl acetate, ethyl formate, isopropyl acetate.
[0013] According to another aspect of the present invention there
is provided a process for preparation of Form II lamotrigine
comprising the steps of:
a) dissolving lamotrigine in dioxane; b) maintaining at about
15.degree. C. to about 30.degree. C. for about 1 hour to 3 hours;
c) filtering Form II lamotrigine.
[0014] According to another aspect of the present invention there
is provided a process for preparation of Form III lamotrigine
comprising the steps of: [0015] a) mixing lamotrigine, isopropyl
acetate, chloroform and dimethyl formamide at about 60.degree. C.
to about 70.degree. C.; [0016] b) filtering the Form III
lamotrigine at about 20.degree. C. to about 30.degree. C.
Lamotrigine prepared by any of the known methods can be used in the
above processes. Lamotrigine solvate or hydrate may also be used in
the above processes.
[0017] According to another aspect of the present invention there
is provided a pharmaceutical composition comprising Form I or Form
II or Form III lamotrigine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a x-ray powder diffraction pattern of Form I
lamotrigine.
[0019] FIG. 2 is a x-ray powder diffraction pattern of Form II
lamotrigine.
[0020] FIG. 3 is a x-ray powder diffraction pattern of Form III
lamotrigine.
[0021] x-Ray powder diffraction spectrum was measured on a Siemens
diffractometer.
DETAILED DESCRIPTION OF THE INVENTION
[0022] According to one aspect of the present invention, there is
provided a novel crystalline Form I of lamotrigine characterized by
an x-ray powder diffraction pattern having peaks expressed as
2.theta. at about 12.5, 13.9, 16.7, 18.0, 22.3, 23.6, 26.8, 27.9,
28.5, 28.9, 29.4, 31.7, 40.2, 42.3 degrees. FIG. 1 shows typical
Form I x-ray powder diffraction pattern.
[0023] According to another aspect of the present invention, there
is provided a process for preparation of Form I lamotrigine. Thus
lamotrigine is dissolved in an ester. The ester is selected from
the group consisting of ethyl acetate, methyl acetate, ethyl
formate, isopropyl acetate. The Form I lamotrigine is maintained at
about 15.degree. C. to about 30.degree. C., preferably at about
20.degree. C. to about 25.degree. C., for about 30 minutes to about
2 hours and filtered. Lamotrigine prepared by any of the known
methods can be used in the process. Lamotrigine solvate or hydrate
may also be used.
[0024] According to another aspect of the present invention, there
is provided a novel crystalline Form II lamotrigine characterized
by an x-ray powder diffraction pattern having peaks expressed as
2.theta. at about 8.9, 11.2, 12.3, 13.2, 13.9, 17.0, 17.4, 18.0,
18.2, 18.7, 19.8, 21.4, 22.1, 22.7, 25.1, 25.4, 25.7, 26.4, 26.8,
27.1, 27.5, 28.3, 28.8, 29.2, 30.1, 30.9, 31.4, 32.9, 35.3, 35.7,
36.5 degrees. FIG. 2 shows typical Form II x-ray powder diffraction
pattern.
[0025] According to another aspect of the present invention there
is provided a process for preparation of Form II lamotrigine. Thus
lamotrigine is dissolved in dioxane and maintained at about
15.degree. C. to about 30.degree. C. for about 1 hour to 3 hours.
The separated Form II lamotrigine is filtered. Lamotrigine prepared
by any of the known methods can be used in the process. Lamotrigine
solvate or hydrate may also be used.
[0026] According to another aspect of the present invention, there
is provided a novel crystalline Form III of lamotrigine
characterized by an x-ray powder diffraction pattern having peaks
expressed as 2.theta. at about 9.9, 12.0, 13.3, 16.1, 17.0, 18.1,
18.7, 19.5, 24.4, 26.0, 26.3, 27.6, 28.1, 37.1 degrees. FIG. 3
shows typical Form III x-ray powder diffraction pattern.
[0027] According to another aspect of the present invention there
is provided a process for preparation of Form III lamotrigine. Thus
lamotrigine isopropyl acetate, chloroform and dimethyl formamide
are mixed and heated to about 60.degree. C. to about 70.degree. C.
The contents are maintained for about 30 minutes and cooled to
about 20.degree. C. to about 30.degree. C. The Form III lamotrigine
is filtered. Lamotrigine prepared by any of the known methods can
be used in the process. Lamotrigine solvate or hydrate may also be
used.
[0028] According to another aspect of the present invention there
is provided a pharmaceutical composition comprising Form I or Form
II or Form III lamotrigine. The forms of lamotrigine may be
formulated in a form suitable for oral administration or
injection.
[0029] The following examples are given for the purpose of
illustrating the present invention and should not be considered as
limitations on the scope or spirit of the invention.
Example 1
[0030] Lamotrigine (10 gm) (obtained by the process described in
example 1 of U.S. Pat. No. 4,602,017) is mixed with ethyl acetate
(100 ml) and maintained at about 70.degree. C. for 30 minutes. Then
the contents are cooled to about 20.degree. C. The solid is
separated by filtration to give 9.0 gm of Form I lamotrigine.
Example 2
[0031] Lamotrigine (10 gm) (obtained by the process described in
example 1 of U.S. Pat. No. 4,602,017) is added to dioxane (100 ml),
maintained at 50.degree. C. to 55.degree. C. for 30 minutes, cooled
to 25.degree. C. and maintained at this temperature for 2 hours.
The solid is separated by filtration to give 8.5 gm of Form II
lamotrigine.
Example 3
[0032] Lamotrigine (10 gm) (obtained by the process described in
example 1 of U.S. Pat. No. 4,602,017) is added to isopropyl acetate
(150 ml) and the contents are heated to about 65.degree. C.
Chloroform (50 ml) and dimethyl formamide (48 ml) are added at this
temperature and stirred for 30 minutes. The contents are cooled to
25.degree. C. and filtered to give 9.5 gm of Form III
lamotrigine.
Example 4
[0033] Example 1 is repeated using Form II lamotrigine instead of
lamotrigine to give Form I lamotrigine.
Example 5
[0034] Example 1 is repeated using Form III lamotrigine instead of
lamotrigine to give Form I lamotrigine.
Example 6
[0035] Example 2 is repeated using Form III lamotrigine instead of
lamotrigine to give Form II lamotrigine.
Example 7
[0036] Example 2 is repeated using Form I lamotrigine instead of
lamotrigine to give Form II lamotrigine.
Example 8
[0037] Example 3 is repeated using Form II lamotrigine instead of
lamotrigine to give Form III lamotrigine.
Example 9
[0038] Example 3 is repeated using Form I lamotrigine instead of
lamotrigine to give Form III lamotrigine.
* * * * *