Title of Invention

PROCESS FOR PREPARATION OF PARECOXIB SODIUM CRYSTALLINE POLYMORPHS

Abstract The present invention provides processes for preparation of parecoxib sodium crystalline polymorphs.Thus, for example,parecoxib is dissolveed in acetonitrile,sodium hydroxide is added to the solution ,the content are stirred for 2 hours 30 minutes at 25oc to 27oc, cooled to Ooc and the separated crystatals are collected by filtration to give parecoxib sodium polymorph form 11.
Full Text

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

or N-[4-(5-Methyl-3-phenylisoxazol-4-yl)phenylsulfonyl]propionamide sodium salt is a highly selective and potent cyclooxygenase-2 inhibitor in human whole blood and useful in the treatment of arthritis and pain. The other therapeutic utilities of parecoxib and related compounds were disclosed in WO 9738986.
Crystalline forms of parecoxib sodium have not been reported in the literature. So, there is a need for stable polymorphs of parecoxib sodium for better pharmaceutical preparations.
We have discovered six stable novel crystalline forms of parecoxib sodium.
The object of the present invention is to provide stable novel crystalline forms of parecoxib sodium, 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 parecoxib sodium (hereinafter referred to as parecoxib sodium form I), which is characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.7, 8.3, 10.4, 17.4, 21.0 and 23.2 degrees. Figure 1 shows typical form I x-ray powder diffraction pattern.

In accordance with the present invention, there is provided a novel crystalline form of parecoxib sodium (hereinafter referred to as parecoxib sodium form II), which is characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.4, 6.8, 7.9, 10.6, 16.2, 17.1, 19.5, 20.4 and 22.4 degrees. Figure 2 shows typical form II x-ray powder diffraction pattern.
In accordance with the present invention, there is provided a novel crystalline form of parecoxib sodium (hereinafter referred to as parecoxib sodium form III), which is characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 5.3, 5.9, 6.6, 7.8, 8.3, 10.7, 11.9, 12.2, 16.1, 19.5, 20.0, 21.6, 23.4 and 30.1 degrees. Figure 3 shows typical form III x-ray powder diffraction pattern.
In accordance with the present invention, there is provided a novel crystalline form of parecoxib sodium (hereinafter referred to as parecoxib sodium form IV), which is characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.2, 7.9, 12.1, 17.3, 17.9, 22.5, 23.4 and 27.1 degrees. Figure 4 shows typical form IV x-ray powder diffraction pattern.
In accordance with the present invention, there is provided a novel crystalline form of parecoxib sodium (hereinafter referred to as parecoxib sodium form V), which is characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 6.5, 7.7, 9.3, 10.6, 13.2, 15.5, 15.9, 17.4, 17.8, 20.2, 21.7, 22.1, 22.8, 23.4 and 24.3 degrees. Figure 5 shows typical form V x-ray powder diffraction pattern.
In accordance with the present invention, there is provided a novel crystalline form of parecoxib sodium (hereinafter referred to as parecoxib sodium form VI), which is characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.4, 7.9, 9.5, 11.9, 18.1, 18.6, 20.9, 30.2 and 32.1 degrees. Figure 6 shows typical form IV x-ray powder diffraction pattern.
In accordance with the present invention, there is provided processes for the preparation the novel forms I - VI of parecoxib sodium.
A process is provided for preparing parecoxib sodium form I from either parecoxib or parecoxib sodium. In this process either parecoxib sodium in any

crystalline form or parecoxib and an sodium metal carrier are mixed with an alcohol solvent and then parecoxib sodium form I is isolated from the mixture.
Suitable alcohol solvents are methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol; and a mixture thereof. Preferred alcohol solvents are ethanol, methanol and isopropyl alcohol. Other solvents may also be mixed with the alcohol solvent as long as parecoxib form I can be isolated from the mixture.
A process is provided for preparing parecoxib sodium form II from either parecoxib or parecoxib sodium. In this process either parecoxib sodium in any crystalline form or parecoxib and an sodium metal carrier are mixed with acetonitrile and then parecoxib sodium form II is isolated from the mixture.
A process is provided for preparing parecoxib sodium form III from either parecoxib or parecoxib sodium. In this process either parecoxib sodium in any crystalline form or parecoxib and an sodium metal carrier are mixed with tetrahydrofuran and then parecoxib sodium form III is isolated from the mixture.
A process is provided for preparing parecoxib sodium form IV from either parecoxib or parecoxib sodium. In this process either parecoxib sodium in any crystalline form or parecoxib and an sodium metal carrier are mixed with an ether solvent and then parecoxib sodium form IV is isolated from the mixture.
Suitable ether solvents are diethyl ether, diisopropyl ether, methyl tert-butyl ether; and a mixture thereof.
A process is provided for preparing parecoxib sodium form V from either parecoxib or parecoxib sodium. In this process either parecoxib sodium in any crystalline form or parecoxib and an sodium metal carrier are mixed with an ester solvent and then parecoxib sodium form V is isolated from the mixture.
Suitable ester solvents are ethyl acetate (which is prererred), methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, methyl formate; and a mixture thereof.
A process is provided for preparing parecoxib sodium form VI from either parecoxib or parecoxib sodium. In this process either parecoxib sodium in any crystalline form or parecoxib and an sodium metal carrier are mixed with a ketone solvent and then parecoxib sodium form VI is isolated from the mixture.

Suitable ketone solvents are acetone (which is preferred), diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl propyl ketone; and a mixture thereof.
Through out this specification, sodium metal carriers are sodium ethyl hexanoate, sodium hydroxide, and the like.
The mixing step of the processes of the present invention may be accomplished by, for example, slurrying or stirring. Isolation can be accomplished by, for example, filtration or centrifugation of the reaction mixture.
In accordance with the present invention, there is provided a pharmaceutical composition comprising parecoxib sodium form I and a pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising parecoxib sodium form II and a pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising parecoxib sodium form III and a pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising parecoxib sodium form IV and a pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising parecoxib sodium form V and a pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising parecoxib sodium form VI and a pharmaceutically acceptable carrier or diluent.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a x-ray powder diffraction spectrum of parecoxib sodium form I. Figure 2 is a x-ray powder diffraction spectrum of parecoxib sodium form II. Figure 3 is a x-ray powder diffraction spectrum of parecoxib sodium form III. Figure 4 is a x-ray powder diffraction spectrum of parecoxib sodium form IV. Figure 5 is a x-ray powder diffraction spectrum of parecoxib sodium form V. Figure 6 is a x-ray powder diffraction spectrum of parecoxib sodium form VI.

x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Kot radiation.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Example 1 Parecoxib (5.0 gm) is dissolved in ethanol (25 ml) and then sodium hydroxide (0.5 gm) is added. The contents are maintained for 2 hours at 25°C to 30°C, cooled to 0°C and the separated crystals are collected by filtration to give 4.5 gm of parecoxib sodium form I.
Example 2 Parecoxib (5.0 gm) is dissolved in acetonitrile (25 ml) and then sodium hydroxide (0.5 gm) is added. The contents are maintained for 2 hours 30 minutes at 25°C to 27°C, cooled to 0°C and the separated crystals are collected by filtration to give 4.0 gm of parecoxib sodium form II.
Example 3 Parecoxib sodium form II (10 gm) is mixed with isopropyl alcohol (50 ml), the contents are maintained for 2 hours at 25°C to 30°C, cooled to 0°C and solid is collected by filtration to give parecoxib sodium form I in quantitative yield.
Example 4 Parecoxib (5.0 gm) is dissolved in tetrahydrofuran (30 ml) and then sodium hydroxide (0.5 gm) is added. The contents are maintained for 1 hours 30 minutes at 20°C to 25°C, cooled to 0°C and the separated crystals are collected by filtration to give 3.0 gm of parecoxib sodium form III.
Example 5 Parecoxib sodium form I (10 gm) is mixed with tetrahydrofuran (60 ml), the contents are stirred for 3 hours at 25°C to 30°C, cooled to 0°C and solid is collected by filtration to give 9.5 gm of parecoxib sodium form III.
Example 6 Parecoxib (5.0 gm), methyl tert-butyl ether (25 ml) and sodium hydroxide (0.5 gm) are mixed. The contents are maintained for 3 hours at 28°C to 30°C, cooled to 20°C and the separated crystals are collected by filtration to give 4.5 gm of parecoxib sodium form IV.

Example 7 Parecoxib (5.0 gm) is dissolved in ethyl acetate (30 ml) and then sodium hydroxide (0.5 gm) is added. The contents are maintained for 18 hours at 28°C to 30°C. The separated crystals are collected by filtration to give 4.0 gm of parecoxib sodium form V.
Example 8 Parecoxib sodium form II (5 gm) is mixed with ethyl acetate (25 ml), the contents are maintained for 2 hours at 25°C to 30°C, cooled to 0°C and solid is collected by filtration to give 4.8 gm of parecoxib sodium form V.
Example 9 Parecoxib (5.0 gm) is dissolved in acetone (25 ml) and then sodium hydroxide (0.5 gm) is added. The contents are maintained for 2 hours at 57°C to 60°C, cooled to 25°C and the separated crystals are collected by filtration to give 4.0 gm of parecoxib sodium form VI.



We claim:
1. A process for the preparation of the parecoxib sodium crystalline polymorph(s), form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 5.4, 6.8, 7.9, 10.6, 16.2, 17.1, 19.5, 20.4 and 22.4 degrees as shown in figure 2; form III, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.9, 6.6, 7.8, 8.3, 10.7, 11.9, 12.2, 16.1, 19.5, 20.0, 21.6, 23.4 and 30.1 degrees as shown in figure 3; form IV, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 5.2, 7.9, 12.1, 17.3, 17.9, 22.5, 23.4 and 27.1 degrees as shown in figure 4; form V, characterized by an x-ray powder diffraction pattern having peaks expressed -as 26 at about 6.5, 7.7, 9.3, 10.6, 13.2, 15.5, 15.9, 17.4, 17.8, 20.2, 21.7, 22.1, 22.8, 23.4 and 24.3 degrees as shown in figure 5; form VI, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 5.4, 7.9, 9.5, 11.9, 18.1, 18.6, 20.9, 30.2 and 32.1 degrees as shown in figure 6; as herein described comprising the steps of:
a) mixing together i) either 1) parecoxib sodium or 2) parecoxib and a sodium metal carrier such as sodium hydroxide, and ii) a specific organic solvent selected from the group consisting of acetonitrile, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate, acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; and
b) isolating i) parecoxib sodium crystalline polymorph form II from the reaction mass obtained in step (a) when acetonitrile is used as the solvent; ii) parecoxib sodium crystalline polymorph form III from the reaction mass obtained in step (a) when tetrahydrofuran is used as the solvent; iii) parecoxib sodium crystalline polymorph form IV from the reaction mass obtained in step (a) when diethyl ether, diisopropyl ether, methyl tert-butyl ether are used as the solvents; iv) parecoxib sodium crystalline polymorph form V from the reaction mass obtained in step (a) when ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate are used as the solvents; v) parecoxib sodium crystalline polymorph form V from the reaction mass obtained in

step (a) when acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone are used as the solvents.
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) mixing together i) either 1) parecoxib sodium or 2) parecoxib and a sodium metal carrier such as sodium hydroxide, and ii) acetonitrile;
b) maintaining the reaction mixture obtained in step (a) for 2 hours 30 minutes at 25 - 27°C; and
c) isolating parecoxib sodium crystalline form II from the reaction mass obtained in step (b) at 0 - 5°C.
4. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) mixing together i) either 1) parecoxib sodium or 2) parecoxib and a sodium metal carrier such as sodium hydroxide, and ii) tetrahydrofuran;
b) maintaining the reaction mixture obtained in step (a) for 1 hour 30 minutes at 20 - 25°C; and
c) isolating parecoxib sodium crystalline form III from the reaction mass obtained in step (b) at 0 - 5°C.
5. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) mixing together i) either 1) parecoxib sodium or 2) parecoxib and a sodium metal carrier such as sodium hydroxide, and ii) a solvent selected from the group consisting of diethyl ether, diisopropyl ether and methyl tert-butyl ether;
b) maintaining the reaction mixture obtained in step (a) for 3 hours at 25 -30°C; and
c) isolating parecoxib sodium crystalline form IV from the reaction mass obtained in step (b) at 15 - 20°C.

6. The process as claimed in claim 5, wherein the solvent is methyl tert-butyl ether.
7. The process as claimed in claim 1, wherein the process comprising the steps of:

a) mixing together i) either 1) parecoxib sodium or 2) parecoxib and a
sodium metal carrier such as sodium hydroxide, and ii) a solvent
selected from the group consisting of ethyl acetate, methyl acetate,
isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate;
b) maintaining the reaction mixture obtained in step (a) for 2 hours to 18
hours at 25 - 30°C; and
c) isolating parecoxib sodium crystalline form V from the reaction mass
obtained in step (b) at 0 - 5°C.
8. The process as claimed in claim 7, wherein the solvent is ethyl acetate.
9. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) mixing together i) either 1) parecoxib sodium or 2) parecoxib and a
sodium metal carrier such as sodium hydroxide, and ii) a solvent
selected from the group consisting of acetone, diethyl ketone, methyl
ethyl ketone, methyl isobutyl ketone and methyl propyl ketone;
b) maintaining the reaction mixture obtained in step (a) for 2 hours at 55 -
60°C; and
c) isolating parecoxib sodium crystalline form VI from the reaction mass
obtained in step (b) at 20 - 25°C.
10. The process as claimed in claim 9, wherein the solvent is acetone.


Documents:

826-chenp-2003-abstract.pdf

826-chenp-2003-claims duplicate.pdf

826-chenp-2003-claims original.pdf

826-chenp-2003-correspondnece-others.pdf

826-chenp-2003-correspondnece-po.pdf

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

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

826-chenp-2003-drawings.pdf

826-chenp-2003-form 1.pdf

826-chenp-2003-form 3.pdf

826-chenp-2003-form 4.pdf

826-chenp-2003-form 5.pdf


Patent Number 206272
Indian Patent Application Number 826/CHENP/2003
PG Journal Number 26/2007
Publication Date 29-Jun-2007
Grant Date 23-Apr-2007
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 SUBASH CHANDHANDER REDDY,KESIREDDY Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
3 RATHNAKAR, Reddy, Kura Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
4 RAJI REDDY,RAPOLU Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
5 MURALIDHARA REDDY Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
PCT International Classification Number C07D 261/08
PCT International Application Number PCT/IN2003/000140
PCT International Filing date 2003-04-04
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA