FIELD OF THE INVENTION The present invention relates to novel process for obtaining Form A of valdecoxib with desired particle size characteristics directly by precipitation from solution and to pharmaceutical formulations containing polymorphic Form A as an active ingredient and at least one pharmaceutically acceptable carrier, adjuvant or diluent.

BACKGROUND OF THE INVENTION Valdecoxib known as 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide has the following formula.

Valdecoxib is marketed as Bextra, which is prescribed as oral tablets having a dosage of 10mg and 20mg for the treatment of inflammation. Valdecoxib exists in various crystalline forms.

U.S. Patent 6,441 ,014 discloses two crystalline forms of valdecoxib, designated Form A and Form B, and processes for their preparation, which is incorporated herein by reference. Both forms are characterized by melting point, X-Ray Powder Diffraction ("XRPD") pattern, IR spectrum in KBr and DSC thermogram. The Form B crystals are characterized in these patents by an XRPD pattern with peaks at 12.2, 15.4, 17.1 , 19.8 and 23.8. Form A crystals are reported to lack these peaks. Further, Form B crystals are reported to have an IR spectrum with characteristic absorptions at about 1170, 925, 844, and 729 cm-1. These absorptions are reported to be missing in the spectrum of Form A crystals.

US Patent Application 20020013357, which is enclosed herein as reference, discloses that Valdecoxib has extremely low solubility in water, and hence it has to be preferably micronized to less than 75 microns for usage in once-daily pharmaceutical formulations. It is reported that Form A crystals are thermally unstable and susceptible to change upon milling, especially since common techniques of particle size reduction such as jet milling being associated with heat generation would lead to polymorphic inter-conversion, thus making it undesirable for usage in commercial pharmaceutical preparations. Therefore alternate techniques for preparation of Form A wherein heat and compression forces are avoided, whilst still providing required particle size characteristics, are desirable.

One of the common crystallization techniques adapted wherein heat and compression forces are minimized by precipitation from solution. However, precipitation from solution is not related to obtaining the desired polymorph. Also, US Pat. No. 6,558,435 also generally refers to precipitation of a product from solution with low particle size by employing impinging fluid jet streams. However, this patent makes no reference to obtaining polymorphs, and also the large forces carried by the jet streams may not result in obtaining Form A of valdecoxib.

SUMMARY OF THE INVENTION

The present invention provides for a reactive crystallization procedure for obtaining Form A of valdecoxib of fine particle size characteristics. Specifically in the present invention the term fine particle size means a distribution of particle sizes wherein the D90 of the product isolated after filtration is less than 100 microns. The invention also provides a pharmaceutical formulation, such as a tablet, comprising Form A of valdecoxib as an active ingredient, associated with one or more pharmaceutically acceptable adjuvants, carriers or diluents.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is an XRPD pattern for valdecoxib Form A. Figure 2 is an FTIR spectrum of valdecoxib Form A.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a method of obtaining Form A of valdecoxib of fine particle size by precipitation techniques. In preparing Form A of valdecoxib of fine particle size according to the invention, the precipitation is performed by acidification of aqueous alkali salt of valdecoxib, or alkaline earth metal salt solution of valdecoxib. The valdecoxib used in this invention can be prepared by any process known per se, including in the manner set forth in U.S. Pat. No. 5,859,257 and U.S. Pat. No. 6,441 ,014.

In a preferred embodiment of the present invention Form A of valdecoxib is obtained by acidification of sodium salt of valdecoxib. The sodium salt solution of valdecoxib can be prepared by dissolving the valdecoxib in sodium hydroxide. The concentrations of the hydroxide used for the dissolution is around 1 to 10% and most preferred concentration is between 2 to 5%. The hydroxide is used in a proportion from 2 to 10 mole equivalent per mole equivalent of valdecoxib. The dissolution can be effected at a temperature between 20 to 8O0C and the most preferred temperature is between 50 to 700C. Before acidification, the solution preferably has a pH of above about 9 and preferably above about 11.

The precipitation can be carried out using an acid. The preferred acids are the mineral acids and most preferred acids are hydrochloric acid and sulfuric acid. After acidification the pH is preferably below 5, most preferably from about 1 to about 3. The acidification can be carried out at a temperature between 20 to 8O0C and preferably between 50 to 700C. The acidification can be performed by either adding alkali metal salt solution in to the acid or by adding the acid in to the alkali metal salt solution.

In a preferred mode the acid is added in to the alkali metal salt solution. The acid is added in to alkali metal salt solution through dip pipe. Acidification results in precipitation of Form A of valdecoxib with desired particle size characteristics, which can be recovered by techniques well known in the art, such as filtration. The wet product is preferably dried at 40 - 8O0C under vacuum. The product obtained on analysis by IR, XRPD and DSC showed that it is form A of Valdecoxib. The product obtained in a typical experiment showed a practical size D90 less than 100 micron.

Thus, the fine particle size attained with the novel process provides a method for preparation of high surface area end product crystals, thereby eliminating the need for subsequent high intensity milling to meet bioavailability requirements. By removing the need for milling, the novel processes avoids associated problems of polymorphic inter-conversion which also removes other associated problems of noise and dusting, cuts yield loss, and saves the time and extra expense incurred during milling. It also removes an extra opportunity for personnel contact with a highly potent pharmaceutical agent.

The Form A prepared by this invention is also tested for its storage stability with respect to inter conversion of the polymorphs. The product stored at a temperature of about 40°C and a relative humidity of about 75% for at least about 3 months showed no substantial change in the polymorphic form confirmed by IR, XRPD and DSC analysis. Thus, the present invention refers to a pharmaceutically acceptable composition comprising a therapeutically effective amount of Form A of valdecoxib obtained by the process of present invention. It may be administered as an anti-inflammatory agent as described in the above- mentioned US Patent No. 5,633,272 or US Patent No. 6,441 ,014. Administration to a human subject may be alone or, preferably, in combination with pharmaceutically acceptable carriers, adjuvants, or diluents in a pharmaceutical composition, in accordance with standard pharmaceutical practice. The effective dosage for valdecoxib depends on the intended route of administration, and other factors such as age and weight of the subject, as generally known.

The present invention will now be described in more detail by way of examples, which should not be construed as limiting the invention thereto. Further, it may be appreciated by one skilled in the art that particle size of the product obtained by precipitation can be controlled by varying the agitation speed, temperature and concentration of solutions.

EXAMPLES Example 1 : Preparation of fine-particle size valdecoxib Form A

Valdecoxib (250 g, 0.795 mole) is added in to aqueous sodium hydroxide (5000 ml, 5% w/v, 6.25 moles) at 500C and stirred. The content is heated to 6O0C to get a clear solution. The pH of the solution after dissolution is 11.6. To the alkaline solution is added aqueous hydrochloric acid (1280 ml, 5 N, 6.4 moles) through dip pipe. During the acidification the product precipitates from the solution of pH 1.5. The precipitated product is filtered immediately and the product is then washed with water (6500 ml). The product obtained is dried at 70 to 75°C under reduced pressure till the water content in the product is less then 0.3% w/w to yield the product (235 g). The product conforms to form A of Valdecoxib by IR, DSC and powder X- ray diffraction. Sample analysis indicated the D90 particle size less than 72 microns

Example 2: Preparation of fine-particle size valdecoxib Form A

Valdecoxib (25 g, 0.0796 mole) is added in to aqueous potassium hydroxide (500 ml, 7% w/v, 0.625 moles) at 500C and stirred. The content is heated to 600C to get a clear solution. The pH of the solution after dissolution is 12.1. To the alkaline solution is added aqueous hydrochloric acid (140 ml, 0.682 mole) through dip pipe. During the acidification the product precipitates from the solution at pH 1.5. The precipitated product is filtered immediately and the product is then washed with water (650 ml). The product obtained is dried at 70 to 75°C under reduced pressure till the water content in the product is less then 0.3% w/w to yield the product (22 g). The product conforms to form A of Valdecoxib by IR, DSC and powder X- ray diffraction. Sample analysis indicated the D90 particle size less than 85 microns

Example 3: Preparation of fine-particle size valdecoxib Form A

Valdecoxib (25 g, 0.0796 mole) is added to aqueous potassium hydroxide (500 ml, 7% w/v, 0.625 moles) at 50°C and stirred. The content is heated to 6O0C to get a clear solution. The pH of the solution after dissolution is 12.1. To the alkaline solution is added aqueous sulfuric acid (48.5ml, 0.6265mole) through dip pipe. During the acidification the product precipitates from the solution at pH 1.5. The precipitated product is filtered immediately and the product is then washed with water (650 ml). The product obtained is dried at 70 to 750C under reduced pressure till the water content in the product is less then 0.3% w/w to yield the product (22.5 g).

The product conforms to form A of Valdecoxib by IR, DSC and powder X- ray diffraction. Sample analysis indicated the D90 particle size less than 92 microns.