WO2011055233A2

WO2011055233A2 - Improved process for preparing celecoxib polymorph

Info

Publication number: WO2011055233A2
Application number: PCT/IB2010/003308
Authority: WO
Inventors: Kishore Charugundla; Venkateswara Rao; Neela Praveen Kumar; Nitin Sharadchandra Pradhan
Original assignee: Actavis Group Ptc Ehf
Priority date: 2009-11-03
Filing date: 2010-11-02
Publication date: 2011-05-12
Also published as: WO2011055233A3

Abstract

Provided herein is an improved process for preparing highly pure celecoxib polymorphic form III characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.32, 10.68, 10.97, 13.0, 14.82, 16.07, 17.91, 19.64, 21.49, 22.17, 22.43, 23.44, 25.37, 26.96 and 29.56 ± 0.2 degrees.

Description

IMPROVED PROCESS FOR PREPARING CELECOXIB POLYMORPH

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority to Indian provisional application No. 2654/CHE/2009, filed on November 3, 2009, which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

[0001] The present disclosure relates to a process for the preparation of polymorphic form of celecoxib. More particularly, the present disclosure relates to a process for the preparation of celecoxib polymorphic Form III.

BACKGROUND

[0002] Celecoxib, a diaryl-substituted pyrazole chemically named 4-[5-(4- methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide, is represented by the following structural formula:

[0003] Celecoxib is known for therapeutic and prophylactic use based on its activity as a selective inhibitor of the cyclooxygenase-2 (COX-2) enzyme. This enzyme is involved in the in vivo synthesis of prostaglandins, which are mediators of various painful inflammatory conditions. Benzenesulfonamide derivatives such as celecoxib are used as the active pharmaceutical agents in pharmaceutical compositions for the treatment and/or prevention of disorders or diseases of animals (including humans) mediated at least in part by the cyclooxygenase-2 prostaglandin synthesis enzyme.

[0004] The preparation and use as COX-2 inhibitors of benzenesulfonamide derivatives such as celecoxib is described in US Patent No. 5,466,823. Processes for the preparation of celecoxib are also described in U.S. Patent Nos. 5,760,068 and 5,910,597.

[0005] As per the process exemplified in the U.S. Patent No. 5,760,068 (hereinafter referred to as the Ό68 patent), celecoxib is prepared by the reaction of l-(4-methylphenyl)- 4,4,4-trifluorobutane-l,3-dione with 4-sulphonamidophenyl hydrazine hydrochloride in absolute ethanol at reflux temperature under argon for 24 hours. The resulting mass is cooled to room temperature, followed by filtering and concentrating the reaction mixture to afford an orange solid, which is then recrystallized from a solvent system containing methylene chloride/hexane to produce the product as a pale yellow solid (melting point: 157° - 159°C).

[0006] The recrystallization process for preparing celecoxib described in the '608 patent suffers from disadvantages since the recrystallization process requires large volumes of solvents (more than 20 volumes each of methylene chloride and hexane solvents per gram of celecoxib), which is not commercially and environmentally, advisable for scale up operations. Moreover, the use of methylene chloride is hazardous to the environment and human health. The use of n-hexane is not advisable because it causes an ignition and fire risk due to its electrostatic charge accumulation property.

[0007] PCT Publication No. WO 01/42222 (hereinafter referred to as the '222 application) discloses three polymorphic forms (Form I, Form II and Form III) of celecoxib, pharmaceutical compositions, and methods of use thereof. The crystalline forms are characterized by powder X-ray diffraction (P-XRD), differential scanning calorimetry (DSC) and Infrared (IR) spectroscopy. The '222 application further teaches that the crystalline Form III of celecoxib is more thermodynamically stable than Form I and Form II. The '222 application also teaches that crystalline Form III of celecoxib is produced by crystallization of celecoxib from a solvent comprising isopropanol and water, for example, as described in U.S. Patent No. 5,910,597.

[0008] According to the '222 application, the polymorphic Form I is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta at about 5.5, 5.7, 7.2 and 16.6 degrees; a melting point of about 162.5°C to about 163°C; a differential scanning calorimetry (DSC) endotherm maximum at about 163.3°C; and an Infra Red (IR) spectrum with peaks at about 3256 and 3356 cm^-1. The polymorphic Form II is characterized by an X- ray powder diffraction pattern having peaks expressed as 2-theta at about 10.3, 13.8 and 17.7 degrees, a melting point of about 161°C to about 162°C; a differential scanning calorimetry (DSC) endotherm maximum at about 162°C. The polymorphic Form III is characterized by a melting point of about 160.8°C.

[0009] However, it has been observed by the present inventors that the celecoxib obtained after crystallization from isopropanol and water is fluffier resulting in low bulk density and poor flow properties. Moreover, it has also been observed that the particles of the crystalline form III of celecoxib obtained by the aforementioned crystallization processes are static or cohesive thereby increasing the difficulties of formulation scientists.

[0010] PCT Publication No. WO 01/42221 discloses an amorphous form of celecoxib, and processes for preparing amorphous celecoxib using crystallization inhibitors. Amorphous celecoxib exhibits an apparent glass transition at 111.4°C (onset).

[0011] EP Patent No. 1167355 (hereinafter referred to as the '355 patent) discloses a crystalline form, designated as Form I, of celecoxib, processes for the preparation, and pharmaceutical compositions thereof. The crystalline form is characterized by powder X-ray diffraction (P-XRD) and scanning electron microscopy (SEM). According to the '355 patent, the crystalline Form I is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta at about 14.8, 16.05, 17.875, 19.615, 21.455, 22.080, 22.385, 23.425, 25.33 and 29.355 degrees. The crystalline Form I is further characterized by an X-ray powder diffraction pattern having additional peaks expressed as 2-theta at about 10.67, 10.97, 12.985, 13.855, 18.340, 18.685, 20.425, 20.67, 23.185, 24.51, 24.93, 25.73, 26.915, 27.63, 28.185, 29.955, 30.375, 31.405, 34.915, 35.585, 37.895, 44.070 and 45.250 degrees. The '355 patent teaches that the crystalline Form I has improved properties over prior art crystal form which is used for formulating celecoxib as disclosed in International Application No. WO 95/15316. The '355 patent teaches that the prior art crystal form (designated as Form II) has several disadvantages, caused by its crystal structure, since it has low bulk density and a crystal morphology that tends to form long cohesive needles.

[0012] According to the '355 patent, the celecoxib crystalline Form I is prepared by dissolving celecoxib in a solvent system comprising at least one amide solvent selected from the group consisting of N,N-dimethylformamide, Ν,Ν-dimethylacetamide, and mixtures thereof; and isolating the crystals of Form I by adding a non-solvent, especially water, to the solution.

[0013] The process for the preparation of the celecoxib crystalline Form I described in the '355 patent also suffers from drawbacks since the use of amide solvents in the purification/crystallization of celecoxib leads to the formation of solvates (for example, the formation of solvates of celecoxib with amide solvents such as dimethylacetamide and dimethylformamide can be found in the preparative examples of the WO 01/42222). It is well known that the removal of these residual amide solvents from the celecoxib crystalline form is very difficult and requires high temperatures.

[0014] Formation of solvates of celecoxib with amide solvents such as dimethylacetamide and dimethylformamide is also described in PCT Publication No. WO2005/014546. Moreover, celecoxib obtained by the crystallization process using amide solvents described in the '355 patent does not have satisfactory purity for pharmaceutical use.

[0015] The solvated forms of celexicob are not acceptable from regulatory point of view since they include substantial amounts of organic solvents, and thus are not acceptable for clinical use. It is well known that impurities and residual solvents in celecoxib or any active pharmaceutical ingredient (API) are undesirable and might be harmful. Purity standards are set by regulatory authorities with the intention of ensuring that an API is as free of impurities and residual solvents as possible, and, thus, are as safe as possible for clinical use. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurities and/or residual solvents are present in the lowest possible levels.

[0016] PCT Publication No. WO 06/051340 (hereinafter referred to as the '340 application) discloses a crystalline Form N of celecoxib characterized by a powder X-ray diffraction (P-XRD) pattern having peaks (designated as d-values) at about 16.0, 15.3, 12.3, 10.6 ± 0.2 A. According to the '340 application, the crystalline Form N of celecoxib is prepared by suspending celecoxib Form III in a hydrocarbon solvent selected from the group consisting of n-tetradecane, and n-decane, heating the suspension at high temperatures (about 165°C) while stirring, stirring the resulting emulsion at the same high temperature, followed by cooling to 145°C. The resulting mass is then reheated to about 165°C, followed by cooling to about 110°C, filtering the separated crystals, and drying at 100°C under the vacuo for 12 hours to produce celecoxib Form N.

[0017] The crystallization process for preparing celecoxib described in the '340 application also suffers from disadvantages since the processes involve tedious and cumbersome procedures such as the use of high boiling point solvents, large amounts of solvents (about 20 volumes of high boiling point solvents per gram of celecoxib), high temperatures (about 165°C), high drying temperatures (about 100°C), and prolonged periods of drying at a high temperature, resulting in formation of unwanted impurities, thereby making the process industrially unfeasible.

[0018] PCT Publication No. WO 05/089511 discloses a hydrate of celecoxib sodium salt characterized by a powder X-ray diffraction (P-XRD) pattern having peaks at 3.05, 8.91 and 10.77 degrees 2-theta.

[0019] PCT Publication No. WO 2006079923A1 discloses a crystalline Form IV of celecoxib characterized by a powder X-ray diffraction (P-XRD) pattern having peaks at about 4.46, 13.13, 18.29, 20.21, 21.83 and 26.24 degrees 2-theta. [0020] Based on the aforementioned drawbacks, the prior art crystallization processes may be unsuitable for the preparation of celecoxib, especially in crystalline Form III, in commercial scale operations.

[0021] Solvent medium, volume of the solvents and mode of isolation play very important roles in obtaining one polymorphic form over another.

[0022] Hence, there is a strong technical and commercial need to develop an improved crystallization process for the preparation of celecoxib, especially in thermodynamically most stable crystalline Form III of celecoxib, having enhanced bulk, flow properties, and compression characteristics in the preparation of tablets and capsules.

SUMMARY

[0023] Extensive research and experimentation was carried out by the present inventors to produce celecoxib in thermodynamically most stable crystalline Form III with high purity, which is free from other polymorphs and undesired solvated forms, and has enhanced bulk density, flow properties, and compression characteristics. As a result, the present inventors have arrived at the industrially advantageous, commercially viable and environmentally friendly crystallization process disclosed herein to produce the thermodynamically most stable crystalline Form III of celecoxib with higher yields and purity (more than 99.8% pure, and specifically more than 99.9% pure, as measure by HPLC), that is free from possibility of formation of the impurities and residual solvents.

[0024] In one aspect, provided herein is an improved, commercially viable, consistently reproducible and environmentally friendly process for the preparation of substantially pure celecoxib polymorphic Form III, which is free of other polymorphs and solvating agents such as water and organic solvents. The method comprises dissolving a form of celecoxib in low volumes of a ketone solvent, specifically acetone, to form a solution, combining the solution with water, and then recovering substantially pure celecoxib polymorphic Form III.

[0025] Advantageously, the crystallization process described herein avoids the use of expensive and cumbersome procedures and solvents, the use of hazardous and high boiling point solvents, the use of more than one organic solvent, the use of solvents which have electrostatic charge accumulation properties, the use of the solvents which cause the formation of unwanted solvates, the use of large amounts of solvents, high crystallization and drying temperatures, prolonged drying time periods, and formation of solvated forms and impurities. [0026] By "substantially pure" is meant having purity greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.9% measured by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is a characteristic powder X-ray diffraction (XRD) pattern of celecoxib polymorphic Form III.

[0028] Figure 2 is a characteristic infra-red (IR) spectrum of celecoxib polymorphic Form III.

DETAILED DESCRIPTION

[0029] According to one aspect, there is provided a process for the preparation of celecoxib polymorphic Form III, comprising:

a) providing a solution of celecoxib in a ketone solvent;

b) heating the solution at a temperature of above about 40°C to produce a hot solution;

c) combining the hot solution with water to form a slurry; and

d) recovering the celecoxib polymorphic Form III from the slurry.

[0030] In one embodiment, the polymorphic Form III of celecoxib is characterized by one or more of the following properties:

i) a powder X-ray diffraction pattern substantially in accordance with Figure 1 ;

ii) a powder X-ray diffraction pattern having peaks at about 5.32, 10.68, 10.97, 13.0, 14.82, 16.07, 17.91, 19.64, 21.49, 22.17, 22.43, 23.44, 25.37, 26.96 and 29.56 ± 0.2 degrees; iii) an Infra red (IR) spectrum substantially in accordance with Figure 2; and

iv) an Infra red (IR) spectrum having absorption bands at about 3340, 3233, 3099, 1582, 1562, 1498, 1474, 1446, 1403, 1374, 1347, 1275, 1229, 1163, 1134, 1102, 1093, 981, 906, 846, 792, 761 and 742 ± 2 cm^"1.

[0031] The process can produce polymorphic Form III of celecoxib in substantially pure form.

[0032] The term "substantially pure celecoxib polymorphic Form III" refers to the celecoxib polymorphic Form III having purity greater than about 99%, specifically greater than about 99.8%, and more specifically greater than about 99.9% (measured by HPLC). For example, the purity of celecoxib polymorphic Form III obtained by the process disclosed herein can be about 99%> to about 99.95%), or about 99.8%> to about 99.99%), as measured by HPLC. [0033] In one embodiment, disclosed herein is an efficient, convenient, commercially viable and consistently reproducible process for the preparation of celecoxib polymorphic Form III, the polymorphic Form III obtained by this process is substantially free from other solid state forms, such as crystalline, amorphous and solvate forms, of celecoxib detectable by the spectral methods typically used.

[0034] The specific solvent system and particular temperature and maintenance conditions disclosed herein for isolating the polymorphic Form III of celecoxib allows the product to be easily isolated and purified, thereby producing the polymorphic Form III with high yield and high purity. Moreover, the polymorphic Form III of celecoxib obtained by the crystallization process disclosed herein has enhanced bulk density and good flow properties, and is less electrostatically charged and is particularly suitable for bulk preparation and handling.

[0035] The term "polymorphic Form III substantially free from other solid state forms" refers to the polymorphic Form III of celecoxib containing less than about 5% of other solid state forms of celecoxib, specifically less than 1% of other solid state forms of celecoxib, and still more specifically is essentially free of other solid state forms of celecoxib. "Essentially free of other solid state forms of celecoxib" means that no other solid state forms of celecoxib can be detected within the limits of a powder X-ray diffractometer. "Other solid state forms of celexicob" means forms other than Form III of celexicob, including amorphous celexicob.

[0036] Exemplary ketone solvents used in step-(a) include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof. The term solvent also includes mixtures of solvents. A most specific ketone solvent is acetone.

[0037] In one embodiment, the amount of ketone solvent employed in the step-(a) is less than about 10 volumes, specifically about 4 volumes to about 6 volumes, and more specifically about 5 volumes, per gram of celecoxib.

[0038] Step-(a) of providing a solution of celecoxib includes dissolving a known form of celecoxib (including crude celecoxib, amorphous or crystalline forms) in the ketone solvent, or obtaining an existing solution from a previous processing step.

[0039] In another embodiment, the celecoxib is dissolved in the solvent at a temperature of below about the reflux temperature of ketone solvent used, specifically at about 20°C to about 40°C, and more specifically at about 25°C to about 35°C. [0040] In one embodiment, the heating in step-(b) is carried out at a temperature of about 40°C to about 65°C for at least 5 minutes and specifically at a temperature of about 45°C to about 55°C for about 10 minutes to about 2 hours to form the hot solution.

[0041] The solution obtained in step-(a) or step-(b) is optionally subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 15 minutes, specifically at a temperature of about 40°C to about 55°C for at least 30 minutes; and filtering the resulting mixture through hyflo to obtain a filtrate containing celecoxib by removing charcoal or silica gel. Specifically, finely powdered carbon is an active carbon. A specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

[0042] Combining of the hot solution with water in step-(c) is done in a suitable order, for example, the hot solution is added to the water, or alternatively, the water is added to the hot solution. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at a temperature of above about 40°C for at least 10 minutes, and more specifically at about 45°C to about 55°C under stirring for about 15 minutes to about 1 hour. After completion of addition process, the resulting mass is cooled and stirred at a temperature of below about 35°C for at least 15 minutes and specifically at a temperature of about 0°C to about 30°C for about 30 minutes to about 20 hours to form the slurry containing celecoxib.

[0043] The recovering in step-(d) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof. In one embodiment, celecoxib polymorphic Form III can be recovered by filtration employing a filtration media of, for example, a silica gel or celite.

[0044] The substantially pure celecoxib polymorphic Form III obtained by above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.

[0045] In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 70°C. The drying can be carried out for any desired time period that achieves the desired result, such as about 1 to 10 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.

[0046] The purity of the celecoxib polymorphic Form III obtained by the process disclosed herein is of greater than about 99.%, specifically greater than about 99.8%>, and more specifically greater than about 99.9% as measured by HPLC.

[0047] Celecoxib as used herein as starting material can be obtained by processes described in the prior art, for example by the process described in the U.S. Patent No. 5,466,823.

INSTRUMENTAL DETAILS:

X-Ray Powder Diffraction (P-XRD):

[0048] The X-Ray powder diffraction was measured by an X-ray powder diffractometer equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 40kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 1976, Corundum standard. The sample was analyzed using the following instrument parameters: measuring range= 3-45° 2-theta; step width = 0.01579°; and measuring time per step = 0.11 second.

Infra-Red Spectroscopy (FT-IR):

FT-IR spectroscopy was carried out with a Perkin Elmer Spectrum 100 series spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 to 650 cm^"1.

[0049] The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of Celecoxib Polymorphic Form III [0050] Celecoxib (10 g) was dissolved in acetone (50 ml) and the solution was heated to 50°C. Water (50 ml) was added to the solution at 50°C over a period of 30 minutes. The separated product was cooled to 5°C and the slurry was stirred for 1 hour at 5°C and then filtered. The product obtained was washed with a mixture of acetone and water followed by drying at 60°C for 12 hours to give 8.6 g of celecoxib in polymorphic form III (Purity by HPLC: 99.92%).

Example 2

Preparation of Celecoxib polymorphic Form III

[0051] Celecoxib (10 g) was dissolved in acetone (50 ml) and the solution was heated to 50°C. Water (40 ml) was added to the solution at 50°C over a period of 30 minutes. The separated product was cooled to 0°C and the slurry was stirred for 1 hour at 0°C and then filtered. The product obtained was washed with a mixture of acetone and water followed by drying at 60°C for 12 hours to give 8.3 g of celecoxib in polymorphic form III (Purity by HPLC: 99.93%).

Example 3

Preparation of Celecoxib polymorphic Form III

[0052] Celecoxib (10 g) was dissolved in acetone (50 ml) and the solution was heated to 50°C. Water (50 ml) was added to the solution at 50°C over a period of 30 minutes. The separated product was cooled to 25°C and the slurry was stirred for 1 hour at 25°C and then filtered. The product obtained was washed with a mixture of acetone and water followed by drying at 60°C for 12 hours to give 8.0 g of celecoxib in polymorphic form III (Purity by HPLC: 99.8%).

Claims

We claim:

1. A process for the preparation of celecoxib polymorphic Form III, comprising:

a) providing a solution of celecoxib in a ketone solvent;

b) heating the solution at a temperature of above about 40°C to produce a hot solution; c) combining the hot solution with water to form a slurry; and

d) recovering the celecoxib polymorphic Form III from the slurry;

wherein the polymorphic Form III of celecoxib is characterized by one or more of the following properties:

ii) a powder X-ray diffraction pattern having peaks at about 5.32, 10.68, 10.97, 13.0, 14.82, 16.07, 17.91, 19.64, 21.49, 22.17, 22.43, 23.44, 25.37, 26.96 and 29.56 ± 0.2 degrees;

iii) an infra red (IR) spectrum substantially in accordance with Figure 2; and

2. The process of claim 1, wherein the ketone solvent used in step-(a) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert- butyl ketone, and mixtures thereof; and wherein the amount of ketone solvent employed in the step-(a) is less than about 10 volumes per gram of celecoxib.

3. The process of claim 2, wherein ketone solvent is acetone; and wherein the amount of ketone solvent employed is about 4 volumes to about 6 volumes per gram of celecoxib.

4. The process of claim 1, wherein the solution in step-(a) is provided by dissolving celecoxib in the ketone solvent at a temperature of below the reflux temperature of ketone solvent used; wherein the heating in step-(b) is carried out at a temperature of about 40°C to about 65°C for at least 5 minutes; and wherein the solution obtained in step-(a) or step- (b) is optionally subjected to carbon treatment or silica gel treatment.

5. The process of claim 4, wherein the dissolution in step-(a) is carried out at a temperature of about 20°C to about 40°C; and wherein the heating in step-(b) is carried out at a temperature of about 45°C to about 55°C for about 10 minutes to about 2 hours.

6. The process of claim 1, wherein the combining in step-(c) is accomplished by adding the hot solution to the water or by adding the water to the hot solution at a temperature of above about 40°C for at least 10 minutes; and wherein the reaction mass obtained after completion of the addition process in step-(c) is cooled and stirred at a temperature of below about 35°C for at least 15 minutes to produce the slurry.

7. The process of claim 6, wherein the addition in step-(c) is carried out at a temperature of about 45°C to about 55°C under stirring for about 15 minutes to about 1 hour; and wherein the reaction mass obtained after completion of the addition process in step-(c) is cooled at a temperature of about 0°C to about 30°C for about 30 minutes to about 20 hours.

8. The process of claim 1, wherein the recovering in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof; and wherein the substantially pure celecoxib polymorphic Form III obtained is further dried under vacuum or at atmospheric pressure, at a temperature of about 35°C to about 70°C.

9. The process of claim 1, wherein the celecoxib polymorphic Form III obtained has a purity of greater than about 99.8% as measured by HPLC.

10. The process of claim 9, wherein the celecoxib polymorphic Form III obtained has a purity of greater than about 99.9% as measured by HPLC.