Indian Patents. 202897:A PROCESS FOR PREPARATION OF VALDECOXIB CRYSTALLINE POLYMORPHS

Title of Invention	A PROCESS FOR PREPARATION OF VALDECOXIB CRYSTALLINE POLYMORPHS
Abstract	The present invention relates to novel crystalline forms of valdecoxib, to processes for their preparation and to pharmaceutical compositions containing them.

Full Text	The present invention relates to novel crystalline forms of valdecoxib, to processes for their preparation and to phannaceutical compositions containing them. BACKGROUND OF THE INVENTION Valdecoxib of formula (1): or 4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide is a highly selective and potent cyclooxygenase-2 inhibitor in human whole blood and useful for the treatment of arthritis and pain. The therapeutic uses of valdecoxib are disclosed in WO 9625405. Two crystalline forms of valdecoxib, form A and fond B, are mentioned in WO 9806708. We have discovered three stable novel crystalline forms of valdecoxib and these forms are found to be suitable for pharmaceutical preparations. The object of the present invention is to provide stable novel crystalline forms of valdecoxib, 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 valdecoxib, designated as form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 9.7, 13.1, 14.0, 14.5, 17.0, 17.1, 17.7, 19.4, 20.9, 21.3, 21.8, 24.1, 25.4, 26.3 and 29.1 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 valdecoxib form I. In this process, valdecoxib is dissolved in dimethyl fonnamide or N,N-dimethyl acetamide and valdecoxib form \ is isolated from the solution. Valdecoxib in any crystalline form may be used. If valdecoxib form I is used in the process, its serves as a method of purification of valdecoxib form 1. A mixture of dimethyl formamide and N,N"dimethyl acetamide; or dimethyl formamide or N,N-dimethyl acetamide mixed with any other solvent may be used. Valdecoxib form I can be isolated by the techniques like cooling, partial removal of the solvent or combination thereof. Crystallization may be initiated with the aid of seed crystals. Preferably, valdecoxib is mixed with dimethyl formamide or N,N-dimethyl acetamide and heated to about 50°C to reflux temperature. The solution so formed is preferably maintained at 25*^0 to • 30°C for 3 to 5 hours and the valdecoxib form I crystals formed are separated by filtration or centrifugation. In accordance with the present invention, there is provided a novel crystalline form of valdecoxib, designated as form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 12.2, 15.4, 15.9, 19.9, 20.6, 22.0, 23.0, 23.6, 23.9, 24.5, 25.1, 28.6 and 31.3 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 valdecoxib form II. In this process, valdecoxib is dissolved in acetonitrile and isolated valdecoxib form II from the solution. Valdecoxib in any crystalline form may be used. Preferably valdecoxib is dissolved in acetonitrile at about 40°C to 45°C and valdecoxib form II is separated at about 25°C - 30°C. The valdecoxib form II may be collected by filtration or centrifugation. In accordance with the present invention, there is provided a novel crystalline form of valdecoxib, designated as form III, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 11.6, 12.2, 12.9, 13.3, 15.4, 15.7, 16.7, 17.0, 17.4, 18.1, 19.7, 20.6, 21.9, 22.4, 23.1, 23.4, 23.8, 24.4, 25.3, 25.7, 26,1, 28.5 and 29.7 degrees. Figure 3 shows typical fonri III x-ray powder diffraction pattern. In accordance with the present invention, a process is provided for preparation of valdecoxib form III. In this process, valdecoxib is dissolved in an ester solvent and isolated valdecoxib four III from the solution. Preferably the solution is cooled to 5°C to 30°C to get the crystals of valdecoxib form III. The valdecoxib form III may be collected by filtration or centrifugation. Valdecoxib in any crystalline form may be used in the process. The suitable ester solvent is selected from n-butyl acetate, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate. A combination of the ester solvents may also be used. In accordance with the present invention, there is provided a pharmaceutical composition comprising form I of valdecoxib and a pharmaceutically acceptable carrier or diluent. In accordance with the present invention, . there is provided a pharmaceutical composition comprising form II of valdecoxib and a pharmaceutically acceptable cannier or diluent. In accordance with the present invention, there is provided a pharmaceutical composition comprising form III of valdecoxib and a pharmaceutically acceptable cannier or diluent. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction spectrum of valdecoxib form I. Figure 2 is a x-ray powder diffraction spectrum of valdecoxib form II. Figure 3 is a x-ray powder diffraction spectrum of valdecoxib form III. x-Ray powder diffraction spectrum was measured on a Sidemen’s D5000 x-ray powder diffract meter having a copper-Ka radiation. The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope of spirit of the invention. Example 1 Valdecoxib (10 gm, obtained by the process described in example 1 of WO 9625405) is dissolved in dimethyl formamide (50 ml), heated to 50°C and the solution obtained is cooled to 25°C and maintained at 25°C to 30°C for 3 hours. The separated crystals are filtered to give 9 gm of valdecoxib form I. Example 2 Valdecoxib (10 gm) is dissolved in acetonitrile (125 ml), heated to 40°C and the solution obtained is cooled to 25°C and maintained at 25°C to 30°C for 6 hours. The separated crystals are filtered to give 9.5 gm of valdecoxib form II. Example 3 Example 1 is repeated using valdecoxib form II for valdecoxib to give valdecoxib form I. Example 4 Example 2 is repeated using valdecoxib form I for valdecoxib to give valdecoxib form II. Example 5 Valdecoxib (10 gm) is mixed with n-butyl acetate (100 ml), heated to 80°C. The solution so formed is cooled to 25°C and maintained at about 25°C for 5 hours. The separated crystals are filtered to give 8.5 gm of valdecoxib form III. Example 6 Example 5 is repeated using valdecoxib form II for valdecoxib to give valdecoxib form Dill. We claim: 1. A process for the preparation of the valdecoxib crystalline polymorph, form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 9.7, 13.1, 14.0, 14.5. 17.0, 17.1, 17.7; 19.4. 20.9, 21.3, 21.8, 24.1, 25.4, 26.3 and 29.1 degrees as shown in figure 1; fame II, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 12.2, 15.4, 15.9, 19.9, 20.6, 22.0, 23.0, 23.6, 23.9, 24.5, 25.1, 28.6 and 31.3 degrees as shown in figure 2; and form III, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 11.6, 12.2, 12.9. 13.3, 15.4, 15.7, 16.7, 17.0, 17.4, 18.1. 19.7. 20.6. 21.9, 22.4, 23.1, 23.4, 23.8, 24.4, 25.3, 25.7, 26.1, 28.5 and 29.7 degrees as shown in figure 3; as herein described comprising the steps of: a) dissolving valdecoxib in a solvent selected either from dimethylformamide and N,N-dimethylacetamide at 50°C to reflux temperature or from acetonitrile at 40 - 45°C or from an ester solvent such as n-butyl acetate, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl fonnat and methyl format; and b) isolating the valdecoxib crystalline form I at 25 - 30°C or valdecoxib crystalline form II at 25 - 30°C or valdecoxib crystalline form III at 25 -30°C by a conventional method. 2. The process as claimed in claim 1, wherein the separated crystals formed in step-(b) are collected by filtration or centrifugation. 3. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving valdecoxib in dimethylformamide or N,N-dimethylacetamide at 50°C to reflux temperature; and b) isolating the valdecoxib crystalline form I from the solution obtained in step-(a) at 25 - 30°C by a conventional method. 4. The process as claimed in claim 3, wherein the separated crystals formed in step-(b) are collected by filtration or centrifugation. 5. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving valdecoxib in acetonitrile at 40 - 45°C; and b) isolating the valdecoxib crystalline form II from the solution obtained in step-(a) at 25 - 30°C by a conventional method. 6. The process as claimed in claim 5, wherein the separated crystals formed in step-(b) are collected by filtration or centrifugation. 7. The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving valdecoxib in an ester solvent; and b) isolating the desired crystalline polymorph form III of valdecoxib from the solution obtained in step-(a) by a conventional method. 8. The process as claimed in claim 7, wherein the ester solvent is selected from n-butyl acetate, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate. 9. The process as claimed in claim 8, wherein the ester solvent is n-butyl acetate. 10. The process as claimed in claim 7, wherein the separated crystals formed in step-(b) are collected by filtration or centrifugation. 11. The process as claimed in claim 1, wherein the solvent used in step-(a) is in the ratio of at least about 4 parts of the solvent to 1 part of the said valdecoxib by weight. 12. The process as claimed in claim 11, wherein the solvent is in the ratio of at least about 8 parts of the solvent to 1 part of the said valdecoxib by weight

Full Text

The present invention relates to novel crystalline forms of valdecoxib, to processes for their preparation and to phannaceutical compositions containing them.
BACKGROUND OF THE INVENTION Valdecoxib of formula (1):

or 4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide is a highly selective and potent cyclooxygenase-2 inhibitor in human whole blood and useful for the treatment of arthritis and pain. The therapeutic uses of valdecoxib are disclosed in WO 9625405.
Two crystalline forms of valdecoxib, form A and fond B, are mentioned in WO 9806708.
We have discovered three stable novel crystalline forms of valdecoxib and these forms are found to be suitable for pharmaceutical preparations.
The object of the present invention is to provide stable novel crystalline forms of valdecoxib, 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 valdecoxib, designated as form I, characterized by an x-ray

powder diffraction pattern having peaks expressed as 20 at about 9.7, 13.1, 14.0, 14.5, 17.0, 17.1, 17.7, 19.4, 20.9, 21.3, 21.8, 24.1, 25.4, 26.3 and 29.1 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 valdecoxib form I. In this process, valdecoxib is dissolved in dimethyl fonnamide or N,N-dimethyl acetamide and valdecoxib form \ is isolated from the solution. Valdecoxib in any crystalline form may be used. If valdecoxib form I is used in the process, its serves as a method of purification of valdecoxib form 1. A mixture of dimethyl formamide and N,N"dimethyl acetamide; or dimethyl formamide or N,N-dimethyl acetamide mixed with any other solvent may be used. Valdecoxib form I can be isolated by the techniques like cooling, partial removal of the solvent or combination thereof. Crystallization may be initiated with the aid of seed crystals. Preferably, valdecoxib is mixed with dimethyl formamide or N,N-dimethyl acetamide and heated to about 50°C to reflux temperature. The solution so formed is preferably maintained at 25*^0 to • 30°C for 3 to 5 hours and the valdecoxib form I crystals formed are separated by filtration or centrifugation.
In accordance with the present invention, there is provided a novel crystalline form of valdecoxib, designated as form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 12.2, 15.4, 15.9, 19.9, 20.6, 22.0, 23.0, 23.6, 23.9, 24.5, 25.1, 28.6 and 31.3 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 valdecoxib form II. In this process, valdecoxib is dissolved in acetonitrile and isolated valdecoxib form II from the solution. Valdecoxib in any crystalline form may be used. Preferably valdecoxib is dissolved in acetonitrile at about 40°C to 45°C and valdecoxib form II is separated at about 25°C - 30°C. The valdecoxib form II may be collected by filtration or centrifugation.
In accordance with the present invention, there is provided a novel crystalline form of valdecoxib, designated as form III, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 11.6, 12.2, 12.9, 13.3, 15.4, 15.7, 16.7, 17.0, 17.4, 18.1, 19.7, 20.6, 21.9, 22.4, 23.1, 23.4, 23.8, 24.4, 25.3, 25.7, 26,1, 28.5 and 29.7 degrees. Figure 3 shows typical fonri III x-ray powder diffraction pattern.

In accordance with the present invention, a process is provided for preparation of valdecoxib form III. In this process, valdecoxib is dissolved in an ester solvent and isolated valdecoxib four III from the solution. Preferably the solution is cooled to 5°C to 30°C to get the crystals of valdecoxib form III. The valdecoxib form III may be collected by filtration or centrifugation. Valdecoxib in any crystalline form may be used in the process. The suitable ester solvent is selected from n-butyl acetate, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate. A combination of the ester solvents may also be used.
In accordance with the present invention, there is provided a pharmaceutical composition comprising form I of valdecoxib and a pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, . there is provided a pharmaceutical composition comprising form II of valdecoxib and a pharmaceutically acceptable cannier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising form III of valdecoxib and a pharmaceutically acceptable cannier or diluent.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction spectrum of valdecoxib form I. Figure 2 is a x-ray powder diffraction spectrum of valdecoxib form II. Figure 3 is a x-ray powder diffraction spectrum of valdecoxib form III. x-Ray powder diffraction spectrum was measured on a Sidemen’s D5000 x-ray powder diffract meter having a copper-Ka radiation.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope of spirit of the invention.
Example 1 Valdecoxib (10 gm, obtained by the process described in example 1 of WO 9625405) is dissolved in dimethyl formamide (50 ml), heated to 50°C and

the solution obtained is cooled to 25°C and maintained at 25°C to 30°C for 3 hours. The separated crystals are filtered to give 9 gm of valdecoxib form I.
Example 2 Valdecoxib (10 gm) is dissolved in acetonitrile (125 ml), heated to 40°C and the solution obtained is cooled to 25°C and maintained at 25°C to 30°C for 6 hours. The separated crystals are filtered to give 9.5 gm of valdecoxib form II.
Example 3 Example 1 is repeated using valdecoxib form II for valdecoxib to give valdecoxib form I.
Example 4 Example 2 is repeated using valdecoxib form I for valdecoxib to give valdecoxib form II.
Example 5 Valdecoxib (10 gm) is mixed with n-butyl acetate (100 ml), heated to 80°C. The solution so formed is cooled to 25°C and maintained at about 25°C for 5 hours. The separated crystals are filtered to give 8.5 gm of valdecoxib form III.
Example 6 Example 5 is repeated using valdecoxib form II for valdecoxib to give valdecoxib form Dill.

We claim:
1. A process for the preparation of the valdecoxib crystalline polymorph, form I,
characterized by an x-ray powder diffraction pattern having peaks expressed
as 26 at about 9.7, 13.1, 14.0, 14.5. 17.0, 17.1, 17.7; 19.4. 20.9, 21.3, 21.8,
24.1, 25.4, 26.3 and 29.1 degrees as shown in figure 1; fame II,
characterized by an x-ray powder diffraction pattern having peaks expressed
as 29 at about 12.2, 15.4, 15.9, 19.9, 20.6, 22.0, 23.0, 23.6, 23.9, 24.5, 25.1,
28.6 and 31.3 degrees as shown in figure 2; and form III, characterized by
an x-ray powder diffraction pattern having peaks expressed as 29 at about
11.6, 12.2, 12.9. 13.3, 15.4, 15.7, 16.7, 17.0, 17.4, 18.1. 19.7. 20.6. 21.9,
22.4, 23.1, 23.4, 23.8, 24.4, 25.3, 25.7, 26.1, 28.5 and 29.7 degrees as
shown in figure 3; as herein described comprising the steps of:
a) dissolving valdecoxib in a solvent selected either from dimethylformamide and N,N-dimethylacetamide at 50°C to reflux temperature or from acetonitrile at 40 - 45°C or from an ester solvent such as n-butyl acetate, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl fonnat and methyl format; and
b) isolating the valdecoxib crystalline form I at 25 - 30°C or valdecoxib crystalline form II at 25 - 30°C or valdecoxib crystalline form III at 25 -30°C by a conventional method.

2. The process as claimed in claim 1, wherein the separated crystals formed in step-(b) are collected by filtration or centrifugation.
3. The process as claimed in claim 1, wherein the process comprising the steps of:

a) dissolving valdecoxib in dimethylformamide or N,N-dimethylacetamide at 50°C to reflux temperature; and
b) isolating the valdecoxib crystalline form I from the solution obtained in step-(a) at 25 - 30°C by a conventional method.

4. The process as claimed in claim 3, wherein the separated crystals formed in step-(b) are collected by filtration or centrifugation.
5. The process as claimed in claim 1, wherein the process comprising the steps of:
a) dissolving valdecoxib in acetonitrile at 40 - 45°C; and

b) isolating the valdecoxib crystalline form II from the solution obtained in step-(a) at 25 - 30°C by a conventional method.
6. The process as claimed in claim 5, wherein the separated crystals formed in
step-(b) are collected by filtration or centrifugation.
7. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) dissolving valdecoxib in an ester solvent; and
b) isolating the desired crystalline polymorph form III of valdecoxib from the
solution obtained in step-(a) by a conventional method.
8. The process as claimed in claim 7, wherein the ester solvent is selected from
n-butyl acetate, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl
acetate, ethyl formate and methyl formate.
9. The process as claimed in claim 8, wherein the ester solvent is n-butyl
acetate.
10. The process as claimed in claim 7, wherein the separated crystals formed in
step-(b) are collected by filtration or centrifugation.
11. The process as claimed in claim 1, wherein the solvent used in step-(a) is in
the ratio of at least about 4 parts of the solvent to 1 part of the said
valdecoxib by weight.
12. The process as claimed in claim 11, wherein the solvent is in the ratio of at
least about 8 parts of the solvent to 1 part of the said valdecoxib by weight

Documents:

827-chenp-2003-abstract.pdf

827-chenp-2003-claims filed.pdf

827-chenp-2003-claims granted.pdf

827-chenp-2003-correspondnece-others.pdf

827-chenp-2003-correspondnece-po.pdf

827-chenp-2003-description(complete) filed.pdf

827-chenp-2003-description(complete) granted.pdf

827-chenp-2003-drawings.pdf

827-chenp-2003-form 1.pdf

827-chenp-2003-form 3.pdf

827-chenp-2003-form 4.pdf

827-chenp-2003-form 5.pdf

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Patent Number

202897

Indian Patent Application Number

827/CHENP/2003

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

30-Oct-2006

Date of Filing

28-May-2003

Name of Patentee

M/S. HETERO DRUGS LIMITED

Applicant Address

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

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,
3	RAJI, Reddy, Rapolu	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018
4	MURALIDHARA, Reddy, Dasari	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
5	SUBASH CHANDER, Reddy, Kesireddy	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018
6	PARTHASARADHI, Reddy, Bandi	Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018
7	RATHNAKAR, Reddy, Kura	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
8	RAJI, Reddy, Rapolu	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018
9	MURALIDHARA, Reddy, Dasari	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
10	SUBASH CHANDER, Reddy, Kesireddy	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018
11	PARTHASARADHI, Reddy, Bandi	Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018
12	RATHNAKAR, Reddy, Kura	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
13	RAJI, Reddy, Rapolu	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018
14	MURALIDHARA, Reddy, Dasari	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
15	SUBASH CHANDER, Reddy, Kesireddy	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018

PCT International Classification Number

C07D261/08

PCT International Application Number

PCT/IN2003/000139

PCT International Filing date

2003-04-04

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA