Indian Patents. 204288:PROCESS FOR PREPARATION OF TEGASEROD MALEATE CRYSTALLINE POLYMORPHS

Title of Invention	PROCESS FOR PREPARATION OF TEGASEROD MALEATE CRYSTALLINE POLYMORPHS
Abstract	The present invention relates to a process for preparation of tegaserod maleate crystalline polymorphs, thus, for example, tegaserod free base is dissolved in acetone, maleic acid is added to the solution, the contents are stirred for 1 hour at 25°C and the separated solid is filtered to give tegaserod maleate form I.

Full Text	The present invention relates to novel crystalline forms of tegaserod maleate, to processes for their preparation and to pharmaceutical compositions containing them. BACKGROUND OF THE INVENTION EP Patent No. 0 442,378 describes, along with other compounds, the compound (1) or 2-[(5-Methoxy-1H-indol-3-yI)methylene]-N-pentylhydra2inecarboximidamide, which has the generic name tegaserod and forms maleic acid salt (tagaserod maleate). Tegaserod and related compounds are serotonin 5HT4-receptor partial agonist and useful in the treatment of irritable bowel syndrome and other utilities as described in EP Patent No. 0 442,378. Crystalline forms of tegaserod maleate have not been reported in the literature and also, the preparation of tegaserod maleate has not been described. So, there is a need for stable polymorphs of tegaserod maleate for better pharmaceutical preparations. It has now been discovered that tegaserod maleate can be prepared in four different crystalline forms. Thus the object of the present invention is to provide stable novel crystalline forms of tegaserod maleate, processes for preparing these forms and pharmaceutical compositions containing them. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a novel crystalline form of tegaserod maleate, designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.9, 6.4, 10.7, 16.1 and 26.8 degrees. Figure 1 shows typical Form I x-ray powder diffraction pattern. In accordance with the present invention, a process is provided for preparation of tegaserod maleate Form I. In this process, maleic acid is added to a solution of tegaserod free base in acetone and tegaserod maleate Form I is isolated from the mixture. Tegaserod maleate Form I may be isolated by usual techniques like cooling, partial removal of the solvent from the solution, adding an anti-solvent. In accordance with the present invention, an alternative process is provided for preparation of tegaserod maleate Form I. According to this process, tegaserod maleate is mixed with acetone and collecting tegaserod maleate Form I from the mixture by filtration. In this process any of the crystalline forms of tegaserod maleate may be used. In accordance with the present invention, there is provided a novel crystalline form of tegaserod maleate, designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 5.3, 6.4, 6.9, 7.8, 8.7, 10.2, 10.8, 15.5, 16.8, 17.0, 19.5, 21.2, 21.7, 22.7 and 25.2 degrees. Figure 2 shows typical Form II x-ray powder diffraction pattern. In accordance with the present invention, a process is provided for preparation of tegaserod maleate Form II. In this process, tegaserod maleate is dissolved in methanol and tegaserod maleate Form II is precipitated from the solution by adding acetonitrile. In this process any of the crystalline forms of tegaserod maleate may be used may be used to prepare the solution in methanol. In accordance with the present invention, there is provided a novel crystalline form of tegaserod maleate, designated as Form III, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 7.0, 7.9, 8.7, 10.2, 15.6, 15.9, 17.0, 19.5, 25.3 and 27.1 degrees. Figure 3 shows typical Form III x-ray powder diffraction pattern. In accordance with the present invention, a process is provided for preparation of tegaserod maleate Form III. In this process, maleic acid is added to a solution of tegaserod free base in methanol and the contents are maintained for about 30 minutes at about 20°C to 25°C and then the crystals are collected by filtration. In accordance with the present invention, another process is provided for preparation of tegaserod maleate Form III. According to this process, tegaserod maleate is dissolved in methanol and the solution is maintained for about 30 minutes at about 20°C to 25°C and then tegaserod maleate Form III crystals are collected by filtration. In accordance with the present invention, there is provided a novel crystalline form of tegaserod maleate, designated as Form IV, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 6.9, 8.0, 10.3, 16.5, 19.6, 20.4, 20.9, 22.0, 23.2, 25.4, 28.0 and 28.7 degrees. Figure 4 shows typical Form IV x-ray powder diffraction pattern. In accordance with the present invention, a process is provided for preparation of tegaserod maleate Form IV. In this process, maleic acid is added to a solution of tegaserod free base in methanol and tegaserod maleate Form IV is precipitated by adding methylene dichloride or isopropyl alcohol. Tegaserod free base used in the above processes may be obtained by the procedures described in EP Patent No. 0 442,378. In accordance with the present invention, there is provided a pharmaceutical composition comprising crystalline form of tegaserod maleate and a pharmaceutical^ acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction pattern of tegaserod maleate Form I. Figure 2 is a x-ray powder diffraction pattern of tegaserod maleate Form II. Figure 3 is a x-ray powder diffraction pattern of tegaserod maleate Form III. Figure 4 is a x-ray powder diffraction pattern of tegaserod maleate Form IV. x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Ka radiation. The following examples further illustrate the invention. Example 1 Tegaserod free base (10 gm) is dissolved in acetone (100 ml). Maleic acid (4 gm) is added to the solution and the contents are maintained for 1 hour at 25°C. The separated solid is filtered to give 12.5 gm of tegaserod maleate Form I. Example 2 Tegaserod maleate Form II (5 gm) and acetone (70 ml) are mixed and refluxed for 1 hour and cooled to 25°C and filtered to give 4.8 gm of tegaserod maleate Form I. Example 3 Tegaserod maleate Form I (10 gm) is dissolved in methanol (100 ml). Acetonitrile (150 ml) is added to the solution and the contents are heated to reflux. The contents are then cooled to 25°C and maintained for 30 minutes. The separated crystals are collected by filtration to give 9 gm of tegaserod maleate Form II. Example 4 Tegaserod free base (10 gm) is dissolved in methanol (100 ml) and maleic acid (4 gm) is added to the solution. Then the contents are maintained for 30 minutes at 25°C. Then the separated solid is filtered to give 13 gm of tegaserod maleate Form III. Example 5 Tegaserod maleate (5 gm) is dissolved in methanol (50 ml) and the solution is maintained at 25°C for 30 minutes. The separated crystals are collected by filtration to give 4.8 gm of tegaserod maleate Form III. Example 6 Tegaserod free base (10 gm) is dissolved in methanol (50 ml), maleic acid (4 gm) is added and the contents are refluxed for 30 minutes and then the resulting solution is cooled to 25°C. Methylene dichloride (200 ml) is added and the contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 13 gm of tegaserod maleate Form IV. Example 7 Maleic acid (4 gm) is added to a solution of tegaserod free base (10 gm) in methanol (50 ml). The contents are maintained for 30 minutes at 25°C and isopropyl alcohol (150 ml) is mixed and contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 12.5 gm of tegaserod maleate Form IV. We claim: 1. A process for the preparation of tegaserod maleate crystalline polymorph(s), Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.9, 6.4, 10.7, 16.1 and 26.8 degrees as shown in figure 1; Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 28 at about 5.3, 6.4, 6.9, 7.8, 8.7, 10.2, 10.8, 15.5, 16.8, 17.0, 19.5, 21.2, 21.7, 22.7 and 25.2 degrees as shown in figure 2; Form III, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 7.0, 7.9, 8.7, 10.2, 15.6, 15.9, 17.0, 19.5, 25.3 and 27.1 degrees as shown in figure 3; and Form IV, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 6.9, 8.0, 10.3, 16.5, 19.6, 20.4, 20.9, 22.0, 23.2, 25.4, 28.0 and 28.7 degrees; as herein described comprising the steps of: a) either adding maleic acid to a solution of tegaserod free base in a suitable solvent or dissolving tegaserod maleate in a suitable solvent; and b) isolating tegaserod maleate crystalline polymorph (Form I and/or Form III) from the solution obtained in step (a) by filtration; or precipitating tegaserod maleate crystalline polymorph (Form II and/or Form IV) from the solution obtained in step (a) by adding an anti-solvent; wherein the solvent used in step (a) is selected from acetone and methanol; and the anti-solvent used in step (b) is selected from the group consisting of acetonitrile, methylene dichloride and isopropyl alcohol. 2. The process as claimed in claim 1, wherein the process comprising the steps of: a) adding maleic acid to a solution of tegaserod free base in acetone; and b) Isolating tegaserod maleate Form I from the solution obtained in step (a). 3. The process as claimed in claim 1, wherein the process comprises stirring tegaserod maleate and acetone at reflux and collecting tegaserod maleate Form I by filtration. 4. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving tegaserod maleate in methanol; and b) precipitating tegaserod maleate Form II from the solution obtained in step (a) by adding acetonitrile. 5. The process as claimed in claim 1, wherein the process comprising the steps of: a) adding maleic acid to a solution of tegaserod free base in methanol; and b) collecting the separated tegaserod maleate Form II by filtration. 6. The process as claimed in claim 1, wherein the, process comprising the steps of: a) dissolving tegaserod maleate in methanol; b) maintaining for 30 minutes at about 20°C to 25°C; and c) collecting the separated tegaserod maleate Form II by filtration. 7. The process as claimed in claim 1, wherein the process comprising the steps of: a) adding maleic acid to a solution of tegaserod free base in methanol; and b) precipitating tegaserod maleate Form IV from the solution obtained in step (a) by adding methylene dichloride or isopropyl alcohol.

Full Text

The present invention relates to novel crystalline forms of tegaserod maleate, to processes for their preparation and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION EP Patent No. 0 442,378 describes, along with other compounds, the compound
(1)

or 2-[(5-Methoxy-1H-indol-3-yI)methylene]-N-pentylhydra2inecarboximidamide, which has the generic name tegaserod and forms maleic acid salt (tagaserod maleate). Tegaserod and related compounds are serotonin 5HT4-receptor partial agonist and useful in the treatment of irritable bowel syndrome and other utilities as described in EP Patent No. 0 442,378.
Crystalline forms of tegaserod maleate have not been reported in the literature and also, the preparation of tegaserod maleate has not been described. So, there is a need for stable polymorphs of tegaserod maleate for better pharmaceutical preparations.
It has now been discovered that tegaserod maleate can be prepared in four different crystalline forms.
Thus the object of the present invention is to provide stable novel crystalline forms of tegaserod maleate, processes for preparing these forms and pharmaceutical compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a novel crystalline form of tegaserod maleate, designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.9,

6.4, 10.7, 16.1 and 26.8 degrees. Figure 1 shows typical Form I x-ray powder diffraction pattern.
In accordance with the present invention, a process is provided for preparation of tegaserod maleate Form I. In this process, maleic acid is added to a solution of tegaserod free base in acetone and tegaserod maleate Form I is isolated from the mixture. Tegaserod maleate Form I may be isolated by usual techniques like cooling, partial removal of the solvent from the solution, adding an anti-solvent.
In accordance with the present invention, an alternative process is provided for preparation of tegaserod maleate Form I. According to this process, tegaserod maleate is mixed with acetone and collecting tegaserod maleate Form I from the mixture by filtration. In this process any of the crystalline forms of tegaserod maleate may be used.
In accordance with the present invention, there is provided a novel crystalline form of tegaserod maleate, designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 5.3, 6.4, 6.9, 7.8, 8.7, 10.2, 10.8, 15.5, 16.8, 17.0, 19.5, 21.2, 21.7, 22.7 and 25.2 degrees. Figure 2 shows typical Form II x-ray powder diffraction pattern.
In accordance with the present invention, a process is provided for preparation of tegaserod maleate Form II. In this process, tegaserod maleate is dissolved in methanol and tegaserod maleate Form II is precipitated from the solution by adding acetonitrile. In this process any of the crystalline forms of tegaserod maleate may be used may be used to prepare the solution in methanol.
In accordance with the present invention, there is provided a novel crystalline form of tegaserod maleate, designated as Form III, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 7.0, 7.9, 8.7, 10.2, 15.6, 15.9, 17.0, 19.5, 25.3 and 27.1 degrees. Figure 3 shows typical Form III x-ray powder diffraction pattern.
In accordance with the present invention, a process is provided for preparation of tegaserod maleate Form III. In this process, maleic acid is added to a solution of tegaserod free base in methanol and the contents are maintained for about 30 minutes at about 20°C to 25°C and then the crystals are collected by filtration.

In accordance with the present invention, another process is provided for preparation of tegaserod maleate Form III. According to this process, tegaserod maleate is dissolved in methanol and the solution is maintained for about 30 minutes at about 20°C to 25°C and then tegaserod maleate Form III crystals are collected by filtration.
In accordance with the present invention, there is provided a novel crystalline form of tegaserod maleate, designated as Form IV, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 6.9, 8.0, 10.3, 16.5, 19.6, 20.4, 20.9, 22.0, 23.2, 25.4, 28.0 and 28.7 degrees. Figure 4 shows typical Form IV x-ray powder diffraction pattern.
In accordance with the present invention, a process is provided for preparation of tegaserod maleate Form IV. In this process, maleic acid is added to a solution of tegaserod free base in methanol and tegaserod maleate Form IV is precipitated by adding methylene dichloride or isopropyl alcohol.
Tegaserod free base used in the above processes may be obtained by the procedures described in EP Patent No. 0 442,378.
In accordance with the present invention, there is provided a pharmaceutical composition comprising crystalline form of tegaserod maleate and a pharmaceutical^ acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction pattern of tegaserod maleate Form I. Figure 2 is a x-ray powder diffraction pattern of tegaserod maleate Form II. Figure 3 is a x-ray powder diffraction pattern of tegaserod maleate Form III. Figure 4 is a x-ray powder diffraction pattern of tegaserod maleate Form IV. x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Ka radiation.
The following examples further illustrate the invention.
Example 1
Tegaserod free base (10 gm) is dissolved in acetone (100 ml). Maleic acid (4 gm) is added to the solution and the contents are maintained for 1 hour at 25°C. The separated solid is filtered to give 12.5 gm of tegaserod maleate Form I.

Example 2 Tegaserod maleate Form II (5 gm) and acetone (70 ml) are mixed and refluxed for 1 hour and cooled to 25°C and filtered to give 4.8 gm of tegaserod maleate Form I.
Example 3 Tegaserod maleate Form I (10 gm) is dissolved in methanol (100 ml). Acetonitrile (150 ml) is added to the solution and the contents are heated to reflux. The contents are then cooled to 25°C and maintained for 30 minutes. The separated crystals are collected by filtration to give 9 gm of tegaserod maleate Form II.
Example 4 Tegaserod free base (10 gm) is dissolved in methanol (100 ml) and maleic acid (4 gm) is added to the solution. Then the contents are maintained for 30 minutes at 25°C. Then the separated solid is filtered to give 13 gm of tegaserod maleate Form III.
Example 5 Tegaserod maleate (5 gm) is dissolved in methanol (50 ml) and the solution is maintained at 25°C for 30 minutes. The separated crystals are collected by filtration to give 4.8 gm of tegaserod maleate Form III.
Example 6 Tegaserod free base (10 gm) is dissolved in methanol (50 ml), maleic acid (4 gm) is added and the contents are refluxed for 30 minutes and then the resulting solution is cooled to 25°C. Methylene dichloride (200 ml) is added and the contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 13 gm of tegaserod maleate Form IV.
Example 7 Maleic acid (4 gm) is added to a solution of tegaserod free base (10 gm) in methanol (50 ml). The contents are maintained for 30 minutes at 25°C and isopropyl alcohol (150 ml) is mixed and contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 12.5 gm of tegaserod maleate Form IV.

We claim:
1. A process for the preparation of tegaserod maleate crystalline polymorph(s),
Form I, characterized by an x-ray powder diffraction pattern having peaks
expressed as 29 at about 5.3, 5.9, 6.4, 10.7, 16.1 and 26.8 degrees as
shown in figure 1; Form II, characterized by an x-ray powder diffraction
pattern having peaks expressed as 28 at about 5.3, 6.4, 6.9, 7.8, 8.7, 10.2,
10.8, 15.5, 16.8, 17.0, 19.5, 21.2, 21.7, 22.7 and 25.2 degrees as shown in
figure 2; Form III, characterized by an x-ray powder diffraction pattern having
peaks expressed as 29 at about 7.0, 7.9, 8.7, 10.2, 15.6, 15.9, 17.0, 19.5,
25.3 and 27.1 degrees as shown in figure 3; and Form IV, characterized by
an x-ray powder diffraction pattern having peaks expressed as 26 at about
6.9, 8.0, 10.3, 16.5, 19.6, 20.4, 20.9, 22.0, 23.2, 25.4, 28.0 and 28.7
degrees; as herein described comprising the steps of:
a) either adding maleic acid to a solution of tegaserod free base in a suitable solvent or dissolving tegaserod maleate in a suitable solvent; and
b) isolating tegaserod maleate crystalline polymorph (Form I and/or Form III) from the solution obtained in step (a) by filtration; or precipitating tegaserod maleate crystalline polymorph (Form II and/or Form IV) from the solution obtained in step (a) by adding an anti-solvent;
wherein the solvent used in step (a) is selected from acetone and methanol; and the anti-solvent used in step (b) is selected from the group consisting of acetonitrile, methylene dichloride and isopropyl alcohol.
2. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) adding maleic acid to a solution of tegaserod free base in acetone; and
b) Isolating tegaserod maleate Form I from the solution obtained in step (a).

3. The process as claimed in claim 1, wherein the process comprises stirring tegaserod maleate and acetone at reflux and collecting tegaserod maleate Form I by filtration.
4. The process as claimed in claim 1, wherein the process comprising the steps of:
a) dissolving tegaserod maleate in methanol; and

b) precipitating tegaserod maleate Form II from the solution obtained in step (a) by adding acetonitrile.
5. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) adding maleic acid to a solution of tegaserod free base in methanol; and
b) collecting the separated tegaserod maleate Form II by filtration.
6. The process as claimed in claim 1, wherein the, process comprising the steps
of:
a) dissolving tegaserod maleate in methanol;
b) maintaining for 30 minutes at about 20°C to 25°C; and
c) collecting the separated tegaserod maleate Form II by filtration.
7. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) adding maleic acid to a solution of tegaserod free base in methanol; and
b) precipitating tegaserod maleate Form IV from the solution obtained in step (a) by adding methylene dichloride or isopropyl alcohol.

Documents:

777-chenp-2003-abstract.pdf

777-chenp-2003-claims duplicate.pdf

777-chenp-2003-claims original.pdf

777-chenp-2003-correspondnece-others.pdf

777-chenp-2003-correspondnece-po.pdf

777-chenp-2003-description(complete) duplicate.pdf

777-chenp-2003-description(complete) original.pdf

777-chenp-2003-drawings.pdf

777-chenp-2003-form 1.pdf

777-chenp-2003-form 19.pdf

777-chenp-2003-form 3.pdf

777-chenp-2003-form 5.pdf

777-chenp-2003-pct.pdf

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Patent Number

204288

Indian Patent Application Number

777/CHENP/2003

PG Journal Number

26/2007

Publication Date

29-Jun-2007

Grant Date

13-Feb-2007

Date of Filing

21-May-2003

Name of Patentee

M/S. HETERO DRUGS LIMITED

Applicant Address

Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018, Andhrapradesh

Inventors:

#	Inventor's Name	Inventor's Address
1	PARTHASARADHI, Reddy, Bandi	Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018,
2	RATHNAKAR, Reddy, Kura	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018, Andhrapradesh
3	RAJI, Reddy, Rapolu	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018, Andhrapradesh
4	MURALIDHARA, Reddy, Dasari	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018, Andhrapradesh
5	Srinivas, Reddy, Itiyala	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018, Andhrapradesh

PCT International Classification Number

A61K31/404

PCT International Application Number

PCT/IN03/00076

PCT International Filing date

2003-03-25

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA