WO2006051340A1

WO2006051340A1 - Novel form of celecoxib

Info

Publication number: WO2006051340A1
Application number: PCT/HR2005/000041
Authority: WO
Inventors: Ernest Mestrovic; Michaela Horvat; Ana Kwokal; Maja Devcic; Darko Filic; Aleksandar Danilovski; Biserka Cetina-Cizmek; Tina Mundorfer
Original assignee: Pliva - Istrazivanje I Razvoj D.O.O.
Priority date: 2004-07-22
Filing date: 2005-07-21
Publication date: 2006-05-18
Also published as: EP1768961A1; CA2574326A1

Abstract

The invention describes a novel solid state form of a pharmacologically active benzenesulfonamide derivative. Also described is a process for the preparation of the novel form and pharmaceutical compositions containing it for use in the treatment or prevention of painful inflammatory conditions.

Description

NOVEL FORM OF A BENZENESULFONAMIDE DERIVATIVE

FIELD OF THE INVENTION

The invention concerns a novel, solid state form of a pharmacologically active benzenesulfonamide derivative, a process for its preparation and pharmaceutical compositions containing it.

BACKGROUND TO THE INVENTION

A number of benzenesulfonamide derivatives such as 4-[5-(4-Methylphenyl)-3- trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (also known as celecoxib) are known for therapeutic and prophylactic use based at least in part on their activity as selective inhibitors 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.

The preparation and use as COX-2 inhibitors of benzenesulfonamide derivatives such as celecoxib is described in US Patent 5466823. The production of celecoxib is also described in US Patent 5910597. In addition the difficulty of formulating celecoxib and reference to its tendency to form long cohesive needles is described in US patent application publication no. US 2004/0087640 and PCT International patent application WO 01/42222. These applications also disclose three crystalline polymorphic forms designated as Form I, Il and III of celecoxib, two of which Forms I and Il respectively are said to have better physical properties for pharmaceutical purposes than Form III.

The crystal structure of a form of celecoxib has been described by R.V. Dev ef a/., in Acta Crystallogr. Sec C. C55 (1999) 9900161 [Cambridge Structural Database Code DIBBUL ] characterized by triclinic space group P- 1 and having crystallographic parameters a = 10.136(5)A, b = 16.778(6)A c = 5.066(6) A, a = 97.62(7)° β = 100.65(6)°, γ= 95.95(4). From consideration of the crystal parameters and the X-ray powder diffraction patters, this crystal form corresponds to the celecoxib form designated as Form III in US patent application publication number US 2004/087640 and PCT International publication no. WO 01/42222.

An amorphous solid state form of celecoxib has also been described in PCT International publication no. WO 01/41536.

One important solid state biopharmaceutical property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The solid state form of a compound may also affect its behavior on compaction and its storage stability. Important related solid state physical properties include the solid state stability, filterability, compressibility and flowability of the milled powder sample.

Normal manufacturing processes for celecoxib result in the production of the thermodynamically most stable crystalline form III. This crystalline form III has particular solid state properties which make it difficult to process and formulate for therapeutic or prophylactic administration. These unique properties include low intrinsic solubility and special factors associated with the crystal structure of Form III such as low bulk density, a tendency to agglomerate, and low compressibility. Form III is very poorly soluble in aqueous media and special approaches are required to ensure satisfactory absorption of celecoxib from the gastrointestinal tract following oral administration. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution in aqueous media is also a major consideration when formulating syrups, elixirs and other liquid medicaments for oral administration.

As a result of its crystal morphology, Form III celecoxib also tends to form elongate needles which may fuse into a monolithic mass during compression in a tableting die. This process can also occur when Form III celecoxib is mixed with other substances, leading to the separation and agglomeration of celecoxib crystals during the preparation of pharmaceutical compositions resulting in an unevenly blended composition containing undesirably large aggregates of celecoxib. Consequently, it is difficult to prepare a pharmaceutical composition with the required consistent and uniform blend of active ingredient and excipients. In addition, the low bulk density of form Nil celecoxib makes it difficult to process the small quantities required during formulation of the pharmaceutical compositions.

Accordingly, given the intrinsic beneficial pharmacological properties of celecoxib, there is a continuing need to provide alternative approaches to solve or avoid the problems associated with use of Form III celecoxib. In principle the Forms I and Il of celecoxib referred to above should provide such an alternative approach. However we have found that it is not possible to produce either of the Forms I and Il of celecoxib in a pure and reproducible manner suitable for operation on a commercial scale using the procedures exemplified in US patent application publication no. US 2004/0087640 and the equivalent PCT International patent application WO 01/42222. The celecoxib forms produced by those procedures are impure and contain both amorphous celecoxib and the thermodynamically stable Form IMI and are unstable and convert to mixtures containing increasing amounts of celecoxib Form III .

We have now discovered (and this a basis for our invention) that special steps need to be taken in order to produce a new discrete crystalline polymorphic form of celecoxib similar to known Form I but which is substantially free of amorphous form and which is stable and does not readily convert to Form III celecoxib. We designate this new form hereinafter as celecoxib Form N. By virtue of its stability and different physical properties to the thermodynamically more stable Form III, celecoxib Form N has advantages over Form III in respect of handling, formulation and/or administration of the celecoxib active ingredient as a pharmaceutical. Unlike the previously obtained celecoxib Form I, the Form N is surprisingly stable and does not readily transform to the thermodynamically more stable Form III celecoxib except under extreme conditions. As a result, it is especially suitable for processing and formulation for therapeutic or prophylactic use. In addition as stated earlier, it has improved properties in relation to celecoxib Form III, such as a higher intrinsic dissolution rate of about 11 μg/min. cm² compared with 8 μg/min. cm² for Form III.

SUMMARY OF THE INVENTION

The present invention provides a novel solid-state crystalline form of celecoxib substantially free of the amorphous form of celecoxib which is designated as celecoxib Form N, This crystalline form may be characterised, for example, by its X- ray powder diffraction (XRPD) pattern, infra-red or Raman spectra, differential scanning calorimetry (DSC) thermogram, and thermogravimetric analysis (TGA).

The present invention also includes a process for the manufacture of celecoxib Form N and pharmaceutical formulations containing celecoxib Form N.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a representative XRPD pattern of celecoxib Form N. Figure 2 is a representative near IR spectrum of celecoxib Form N.

Figure 3 is a representative Raman spectrum of celecoxib Form N.

Figure 4 is a comparison of a representative XRPD pattern of celecoxib Form N with the same sample after one week at 50 ⁰C and 80% relative humidity.

Figure 5 is a representative DVS isotherm plot of celecoxib Form N. Figure 6 is a comparison of a representative XRPD pattern of an 80:20 w/w mixture of celecoxib Form N and amorphous celecoxib with a scanned XRPD pattern for celecoxib Form I published as Figure 1a in European patent 1150960, US patent application publication US 2004/0087640 and the equivalent PCT International patent application WO 01/42222. Figure 7 is a representative XRPD pattern of celecoxib Form N plotted on the same

2Θ scale as Figure 6 above.

Figure 8 shows representative XRPD patterns of an 80:20 mixture by weight of celecoxib Form N and amorphous celecoxib plotted in A as d spacings at different times maintained at ambient temperature and relative humidity (RH) of 25 ⁰C and 60%. The presence of peaks characteristic of celecoxib Form III is indicated with arrows. Figure 9 shows the XRPD patterns of figure 8 on a larger scale. The presence of peaks characteristic of celecoxib Form III is again indicated with arrows.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention there is provided celecoxib Form N, that is a celecoxib polymorph having the following characteristic X-ray powder diffraction (XRPD) peaks (designated as d values) at about: 16.0+0.2 A, 15.3±0.2 A, 12.3+0.2 A, and 10.6+0.2 A and which is substantially amorphous free.

In this specification, the term "substantially amorphous free" denotes a polymorphic form of celecoxib that contains less than about 5% by weight of an amorphous form oi celecoxib and, particularly, less than about 2.5% by weight and, preferably, less than about 1 % of an amorphous form of celecoxib. As a practical definition, for example samples of celecoxib Form N which are substantially amorphous free show no significant content of celecoxib Form III by XRPD analysis after being stored at 25°C and 60% relative humidity for prolonged periods of at least 2 months. This is based on the fact that amorphous celecoxib decomposes readily to the thermodynamically stable celecoxib Form III which unlike the amorphous form has distinctive XRPD peaks.

Celecoxib Form N of the present invention also has the following additional characteristic XRPD peaks (designated as d values): 8.0 ±0.2 A, 6.5 ±0.1 A , 5.4 +0.1 A. An illustrative XRPD pattern for celecoxib Form N according to the invention is shown in Figure 1 , measured using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer. An illustrative near infrared (NIR) spectrum for celecoxib Form N according to the invention is shown in Figure 2, measured using a Bruker NIR Multi Purpose Analyser (MPA) with He-Ne laser as a light source. The spectra were obtained using a reflection fibre-optical solid probe, with the probe tip in close contact with the samples. The measurements were carried out in triplicate over the range 4000 cm^"1 - 12000 cm^"1, with a resolution of 8 cm^"1. The spectra were averaged over 32 scans.

An illustrative Raman spectrum for celecoxib Form N according to the present invention is shown in Figure 3. Celecoxib Form N has characteristic Raman absorption peaks at 3152, and 3140 cm^"1 with additional characteristic Raman absorption peaks at 620, 1200, 970, 800, 498, and 245 cm^"1. Fourier transform (FT) Raman spectra were obtained using a Bruker Equinox 55 spectrophotometer with a Bruker FT-Raman module 106/S. Radiation of 1064 nm from an Nd: YAG laser was used for excitation. The resolution was set at 4 cm^"1 with the laser power at the sample set at 50 mW.

It will be understood that when characteristic peaks are referred to although these are definitive for the celecoxib Form N, the numerical values quoted, for example of XRPD peaks and spectroscopic absortpion, may be subject to some experimental variation when the measurements are repeated with different measuring equipment.

It is known that the amorphous forms of many active substances often suffer from significant problems with solid state stability, for example at above ambient temperature and under conditions of high humidity. Thus, they may readily transform into other crystalline forms of that substance or into various mixtures of crystalline and amorphous phases of that substance. However, as mentioned above, the celecoxib Form N of the present invention is stable, as evidenced by the lack of any phase transformation into any other crystalline or amorphous form of celecoxib when stored for one week under non-ambient stress condition of 50 ⁰C and 80% relative humidity (RH). A non-ambient XRPD experiment was performed using CuKαi radiation on a powder sample of celecoxib Form N using a PANalytical X'Pert PRO powder diffractometer. The sample was held one week at 50 ⁰C and 80 % RH in an Anton Pa temperature humidity chamber (THC). The temperature of the sample was controlled using a Temperature Control Unit 100 (TCU 100), and the RH Generator Software RH 200 from VTI Corporation controlled the relative humidity. After one week under these conditions, no change was observed in the X-Ray powder pattern. This is shown in Figure 4. No further change was seen after a further 3 weeks under these conditions.

Celecoxib Form N of the present invention is also non-hygroscopic as is demonstrated in Figure 5 which shows an illustrative Dynamic Vapour Sorption (DVS isotherm plot for celecoxib Form N. In conducting the DVS isotherm measurements, a representative sample of celecoxib Form N was analyzed using a DVS-1 gravimetric sorption analyzer (Surface Measurement System, U.K.). Measurements were preformed at 25°C on a sample size of approximately 20 mg. The uptake and loss of vapor was gravimetrically measured using Cahn D200 recording ultra- microbalance. In sorption and desorption experiments, the relative humidity was increased in 10 steps from 0-90% relative humidity. It can be seen from Figure 5 shows that celecoxib Form N adsorbed only 0.023% water.

Hygroscopicity is defined in European Pharmacopoeia Technical Guide (1999, p. 86), based on the static method, after storage at 25 ⁰C for 24 hours at 80% relative humidity. As defined therein, slightly hygroscopic means that the increase in mass due to absorption of water by a compound is equal to or greater than 0.2 % m/m but less than 2 % m/m. Hygroscopic means that the increase in mass due to absorption of water by a compound is equal to or greater than 2% m/m but less than 15 % m/m Very hygroscopic means that the increase in mass due to absorption of water is equa to or greater than 15 % m/m. Deliquescent means that the compound absorbs sufficient water so as to form a liquid. Assessed against these definitions, the celecoxib Form N of the present invention is essentially non-hygroscopic. Celecoxib Form N can be prepared from any form of celecoxib, including amorphous and/or crystalline forms, and solvated and/or desolvated forms thereof. A typical process for preparing celecoxib Form N according to the invention comprises heating the celecoxib to a suitable temperature (i.e., a melting temperature) to form a melt, and then (ii) cooling the melt in a controlled manner. The starting celecoxib may, for example, be crystalline celecoxib Form III produced as described in US patent application publication no. 2004/0087640A starting from celecoxib produced by any known process, for example that described in example 1 of US Patent no. 5910597. During the cooling step, a phase transformation occurs, thereby producing celecoxib Form N. Although the process may be conducted in the absence of solvent, for large- scale operations it is preferably carried out in the presence of a suitable solvent or diluent. Suitable solvents of diluents include those which do not interact with the celecoxib to form solvates, complexes or the like and which have a boiling point greater than about 170, for example, hydrocarbons such as decane, tetradecane and tetrahydronaphthalene, of which n-decane is particularly preferred.

The cooling step can typically be carried out over a time period of from about 1 hour to about 10 hours, preferably from about 2 hours to about 5 hours, and more preferably over a period of about 3 hours.

The temperature at which the process is carried out is typically in the range of from about 160 ⁰C to about 170 ⁰C, for example from about 162 ⁰C to about 165 ⁰C, and preferably from about 162.5⁰C to about 163.5⁰C.

As mentioned above, the solid state purity of the resultant celecoxib Form N in respect of any other amorphic or polymorphic form of celecoxib is typically greater than about 95% by weight and, more particularly, is greater than about 97.5 % by weight.

According to a further aspect of the invention there is provided a pharmaceutical composition or other dosage form comprising celecoxib Form N together with one or more pharmaceutically acceptable excipients for use in the treatment or prevention of those diseases and medical conditions where treatment with a cyclooxygenase-2 (COX-2) inhibitor is desirable. In particular, celecoxib Form N or a pharmaceutical composition thereof according to the present invention can be employed in the treatment or prevention of diseases and medical conditions including, but not limited to, osteoarthritis, rheumatoid arthritis, familial adenomatous polyposis, and the relief of pain associated with inflammatory conditions.

Celecoxib Form N according to the invention may be used in the preparation of rapid, controlled, and sustained release pharmaceutical formulations, suitable for oral, rectal, parenteral, transdermal, buccal, nasal, sublingual, subcutaneous or intravenous administration. The formulations are preferably administered orally, for example in the form of rapid or controlled release tablets, microparticles, mini tablets, capsules and oral solutions or suspensions, or powders for the preparation thereof.

In addition to the celecoxib Form N, formulations of the present invention may optionally include various standard pharmaceutically acceptable excipients well known in the pharmaceutical art, such as binders, fillers, diluents, buffers, lubricants, glidants, disintegrants, perfumes, sweeteners, surfactants and coatings. Some excipients may serve multiple roles in the formulations, for example they may act as both binders and disintegrants.

Examples of suitable disintegrants include, but are not limited to, starch, pre- gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and cross-linked polyvinylpyrrolidone.

Examples of suitable binders include, but are not limited to, acacia, cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium- aluminum silicate, polyethylene glycol and bentonite.

Examples of suitable fillers and diluents include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium phosphate, calcium carbonate and calcium sulfate.

Examples of suitable lubricants useful in the formulations of the invention include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal silicon dioxide.

Examples of suitable perfumes include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits and combinations thereof.

Examples of suitable dyes include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.

Conventional pharmaceutically acceptable coatings may typically be used to facilitate swallowing, modify the release properties, improve the appearance, and/or mask the taste of formulations according to the invention. Examples of such coatings include, but are not limited to hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate-methacrylate copolymers.

Examples of suitable sweeteners include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.

Examples of suitable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide. Examples of suitable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.

The celecoxib Form N according to the invention is also suitable for inclusion in conventional formulations intended for administration by intravenous or intraperitonea means. Dispersions can also be prepared in a liquid carrier or intermediate, such as glycerin, liquid polyethylene glycols, triacetin oils, and mixtures thereof. To improve storage stability, such preparations may also contain a preservative to prevent the growth of microorganisms.

The celecoxib Form N according to the invention may also be used for the preparation of conventional formulations adapted for local or topical administration. Such formulations typically contain other pharmaceutically acceptable excipients, such as polymers, oils, liquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants and perfumes well known in the art.

In addition to the celecoxib Form N active ingredient, compositions of the invention may also contain one or more other pharmaceutical active ingredients well known in the art for use in the treatment or prevention of diseases and medical conditions including, but not limited to, osteoarthritis, rheumatoid arthritis, familial adenomatous polyposis, and for the relief of pain associated with inflammatory conditions. For example an opiate or non-opiate analgesic may be also be present in a composition of the invention.

Compositions of the invention will typically contain about 100-700 mg of celecoxib Form N per unit pharmaceutical composition (for example per tablet), and preferably about 150-450 mg.

Although celecoxib Form N differs in some properties such as intrinsic solubility from celecoxib Form III, it will generally be administered in doses similar to those described in the art for the commercially available celecoxib preparations. Such doses will necessarily be varied with the mode of administration, treatment conditions, age and status of the patient or animal receiving treatment. Typical doses for use in osteoarthritis are, for example, about 100 to about 200 mg, for rheumatoid arthritis, for example, about 200 to about 400 mg, for acute pain, for example, up to about 400 mg and for familial adenomatous polyposis, for example, up to about 800 mg.

The invention will now be illustrated by the following non-limiting examples 1-9 in which Examples 1-6 describe the production of celecoxib Form N and Examples 7-9 illustrate its stability at above ambient temperature and elevated relative humidity. Further example 10 illustrates the comparable instability under a variety of conditions of an artificial mixture of celecoxib Form N containing 20% by weight of the amorphous form of celecoxib. Example 11 describes attempts at repeating the preparation of celecoxib Form I described in US patent publication US 2004/0087640 and equivalent patent applications. Example 12 describes the intrinsic dissolution rates of celecoxib Form N and Example 3 describes the preparation of tablet formulations of celecoxib Form N.

EXAMPLES

Example 1

Celecoxib Form III (2.5g) was suspended in 50 ml of n-tetradecane and then heated to about 165 ⁰C while stirring. The emulsion obtained was stirred at the same temperature for about 15 min and then cooled to about 145 °C. It was then reheated to about 165 °C and then cooled to about 110 ⁰C. The resultant suspension was separated by filtration and the crystals obtained were dried at 100 ⁰C under the vacuo for 12 hours to yield celecoxib Form N.

Example 2

Celecoxib Form III (5.0 g) was suspended in 50 ml of n-decane and heated to about 165 ⁰C while stirring. Obtained emulsion was cooled to about 145 ⁰C , heated again to about 165 ⁰C and finally cooled to about 110 ⁰C. Suspension was filetered and obtained crystals were dried at 100 ⁰C under the vacuo for 12 hours to yield celecoxib Form N. Example 3

Celecoxib Form III (250 mg) was suspended in 30 ml of n-decane and heated to about 120 °C. The suspension was stirred at the same temperature for 3 hours. Undissolved celecoxib was removed by filtration and the filtrate was heated to about 130 ⁰C and then cooled to 110 ⁰C while stirring. The solution was then seeded with about 2.5 mg of celecoxib Form N and cooled to room temperature resulting in the isolation of 40 mg of celecoxib Form N.

Example 4

Celecoxib Form III (2.5g) was suspended in 50 ml of r?-decane and heated to about 168 ⁰C while stirring. The emulsion obtained was stirred at 165-168 ⁰C for 15 minutes and then slowly cooled to about 144 °C. A seed of 0.025 g of celecoxib Form N was added and stirring was continued at about 143 ⁰C for 35 minutes. The resultant suspension was cooled to 25 ⁰C and stirred for an additional 1 hour. The precipitate was removed by filtration and dried at 100 ⁰C in vacuo for 2 hours to yield 2.44 g of celecoxib Form N.

Example 5

Celecoxib Form III (80.0 g) was suspended in 3600 ml of /i-decane and heated to about 168 ⁰C while stirring. The emulsion obtained was stirred at the same temperature for 40 minutes and cooled to about 149 °C. Seed crystals of celecoxib Form N (1.8g) were added and stirring was continued at about 148-150 ⁰C for 20 min. The resultant suspension was cooled to 25 ⁰C and stirred for 15 minutes. The precipitated material was separated by filtration and dried at 100 ⁰C in vacuo for 18 hours yielding 167.6 g of celecoxib Form N.

Example 6 (a) Celecoxib Form III (4.0g) having an approximate particle size of 30 μm was homogenously distributed on a Petri dish having a diameter 9 cm. The dish was put in an oven, heated from room temperature to 163 ⁰C and held at 163⁰C for 1 hour. The heating was stopped and the celecoxib was allowed to cool in the oven for 3 hours. During the cooling period the oven was not opened. A compact film of celecoxib Form N crystallized at the Petri dish surface.

(b) Celecoxib Form III (4.Og) was homogenously distributed on a Petri dish having a diameter 3 cm. The dish was put in an oven, heated from room temperature to 163⁰C and held at 163 ⁰C for 1 hour. The heating was stopped and the celecoxib was allowed to cool in the oven for 3 hours. During the cooling period the oven was not opened. A compact film of celecoxib Form N crystallized at the Petri dish surface.

Figure 1 shows an X-ray powder diffraction (XRPD) pattern for a representative sample of celecoxib Form N obtained by one of Examples 1-6 measured using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer. The pattern has characteristic peak position (expressed in d values) at 16.0±0.2A, 15.3±0.2A, 12.3±0.2A and 10.6±0.2A, and further characteristic peaks at 8.0±0.2A, 6.5 ±0.1 A , and 5.4 ±0.1 A.

Figure 2 shows an illustrative near infrared (NIR) spectrum for a representative sample of celecoxib Form N obtained by one of Examples 1-6 , measured using a Bruker NIR Multi Purpose Analyser (MPA) with He-Ne laser as a light source. The spectra were obtained using a reflection fibre-optical solid probe, with the probe tip in close contact with the samples. The measurements were carried out in triplicate over the range 4000 cm^"1 - 12000 cm^'1, with a resolution of 8 cm^"1. The spectra were averaged over 32 scans.

Figure 3 shows an illustrative Raman spectrum for celecoxib Form N obtained by one of Examples 1-6, demonstrating characteristic Raman absorption peaks at 3152, and 3140 cm^"1 with additional characteristic Raman absorption peaks at 620, 1200, 970, 800, 498, and 245 cm^"1. Fourier transform (FT) Raman spectra were obtained using a Bruker Equinox 55 spectrophotometer with a Bruker FT-Raman module 106/S. Radiation of 1064 nm from an Nd: YAG laser was used for excitation. The resolution was set at 4 cm^"1 with the laser power at the sample set at 50 mW. Example 7

A non-ambient XRPD experiment was performed using CuKαi radiation on a small powder sample of celecoxib Form N obtained by one of Examples 1-6 using a PANalytical X'Pert PRO powder diffractometer. The sample was held for one week at 50 ⁰C and 80 % RH in an Anton Par temperature humidity chamber (THC). The temperature of the sample was controlled using a Temperature Control Unit 100 (TCU 100), and the RH Generator Software RH 200 from VTI Corporation controlled the relative humidity. After one week under these conditions, no change was observed in the X-Ray powder pattern of the celecoxib Form N sample. This can be seen from Figure 4 and demonstrates the stability of celecoxib Form N at above ambient temperature and under conditions of high relative humidity.

Example 8

A representative sample of celecoxib Form N obtained by one of Examples 1-6 was analyzed by Dynamic Vapour Sorption (DVS) methodology using a DVS-1 gravimetric sorption analyzer (obtained from Surface Measurement System, U.K.).

Measurements were performed at 25⁰C on a sample size of approximately 20 mg. The uptake and loss of vapor were gravimetrically measured using Cahn D200 recording ultra-microbalance. In sorption and desorption experiments, the relative humidity was increased in 10 steps from 0-90% relative humidity. It can be seen from the DVS isotherm plot in Figure 5 that celecoxib Form N adsorbed only 0.023% water indicating negligible hygroscopicity.

Example 9

Samples of celecoxib Form N prepared by one of Examples 1-6 were monitored for change in solid state composition in response to different environmental conditions using XRPD techniques. The samples were fitted with PET/AI/PET/LDPE bags to maintain the correct environmental conditions with the results shown in Table 1 below: Table 1

Conditions Length of storage Polymorph content

40 °C/75 % RH 0 Pure form N

1 week Pure form N

2 week Pure form N

4 week Pure form N

6 week Pure form N

8 week Pure form N

50 °C/80 % RH 0 Pure form N

1 week Pure form N

2 week Pure form N

4 week Pure form N

50 ⁰C 0 Pure form N

1 week Pure form N

2 week Pure form N

4 week Pure form N

25 °C/60 % RH 0 Pure form N

4 week Pure form N

8 week Pure form N

Example 10

(a) A mixture was prepared containing 80% by weight celecoxib Form N and 20% amorphous celecoxib. The XRPD pattern is shown in Figure 6 hereof together with a scanned image of the XRPD pattern stated to be celecoxib Form I from Figure 1a of US patent application 2004/ 0087640A, International application publication no. WO 01/42222 and also European patent 1150960. Figure 7 hereof shows the XRPD pattern of celecoxib Form N alone plotted on the same 2Θ scale.

(b) The stability of 80:20 (w/w) mixture of celecoxib Form N and amorphous celecoxib was investigated under ambient conditions that is at 25°C and 60% RH using XRPD techniques. The samples were put into open Petri dishes and results are shown in Table 2. Illustrative XRPD patterns are given in Figure 8 and 9 hereof which show increasing amounts of celecoxib Form III for the mixture stored under ambient conditions. Table 2

Storage conditions Length of Pure form N 80:20 (w/w) mixture storage

25°C/60% RH 0 (start) Pure form N Mixture

1 day Pure form N No change

2 days Pure form N Form III appeared

5 days Pure form N Form III increased over day 2

Example 11

The procedure described in working Example 1 of US patent application 2004/ 0087640 was repeated in an attempt to produce celecoxib Form I and the products were analysed by XRPD and NIR analysis. The following results were obtained:

Working Example 1 A was repeated six times starting with the dimethylacetamide (DMA) celecoxib solvate. In each case a mixture of material having the XRPD pattern for Form I and Form III was obtained. No reflections for the starting DMA celecoxib solvate were seen in the XRPD pattern.

Working Example 1 B was repeated twice as closely as possible but each time pure Form III celecoxib was obtained based on the XRPD pattern obtained.

Working Example 1C could not be repeated exactly as described as celecoxib did not melt at 170 ⁰C in an open container on a hotplate. However a portion of celecoxib could be melted in an oven at 170 ⁰C. The melt was then poured onto a watch-glass to cool to ambient temperature. This procedure was repeated 4 times. On each occasion amorphous celecoxib was obtained, followed after several days by crystals of celecoxib Form III based on the XRPD obtained. Example 12

The intrinsic dissolution rates (IDR) for celecoxib Form N and Form III were determined using the following standard procedure:

The sample substance (200mg) was first compressed using an infrared punch and die set (0.57 cm²) to 1 tons, 1 min, to ensure minimal porosity and improved compaction. The compressed sample disc obtained was fixed to the holder of the rotating disc dissolution apparatus. The disc was then rotated at 100 rpm in water (900 ml) pre-adjusted to pH 1.2 by addition of dilute hydrochloric acid and containing 0.5% by weight of sodium laurylsulphate at a temperature of 37 ⁰C. The amount of drug in solution was determined by UV spectrometry analysis at 254 nm at different time point from 5 min to 300 min where the plot of concentration against time is essentially linear.

The following results were obtained:

Example 13

Procedure : a mixture of microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose and crosscarmellose sodium is blended with celecoxib Form N, then granulated by fluid bed granulation with the addition of aqueous solution of surfactant. The granules are dried in the fluid-bed dryer, sized, and homogenized with the external phase. Tableting blend is then compressed into tablet cores that are subsequently coated with the aqueous suspension for film coating in a semi perforated or perforated coating pan. The amounts of the active ingredient and excipients for 100 and 200 mg dosage immediate release tablet formulations are shown below in Table 3 below:

Table 3: celecoxib Form N 100 and 200 mg tablets

water is not calculated as part of the formulation

Claims

What is claimed is: 1. A crystalline form of celecoxib substantially free of amorphous form and designated celecoxib Form N and having characteristic X-ray diffraction pattern peaks, expressed in d values, at abouti 6.0+0.2 A, 15.3±0.2 A, 12.3+0.2 A, and 10.6+0.2 A.

2. Celecoxib Form N as claimed in claim 1 having additional characteristic X- ray diffraction pattern peaks, expressed in d values, at about 8.0 ±0.2 A,

6.5 ±0.1 A , and 5.4 +0.1 A.

3. A crystalline form of celecoxib substantially free of amorphous form and designated celecoxib Form N having an X-ray diffraction pattern substantially as shown in Figure 1.

4. Celecoxib Form N as defined in claim 1 having characteristic Raman peaks at about 3152 cm^"1' 3140 cm^"1, 1620 cm^'1, 1200 cm^"1, 970 cm^"1, 800 cm^"1, 498 cm^"1, and 245 cm^"1.

5. Celecoxib Form N as claimed in claim 4 having a Raman spectrum substantially as shown in Figure 3.

6. Celecoxib Form N as claimed in any preceding claim which contains no more than about 5% by weight of an amorphous form of celecoxib.

7. A process for the preparation of celecoxib Form N as defined in claim 1 which comprises heating any solid form of celecoxib optionally in the presence of a suitable solvent or diluent to a melting temperature to form a melt, and then allowing the melt to cool under controlled conditions.

8. The process of claim 7 wherein the melting temperature is from about 160 ⁰C to about 170 ⁰C.

9. The process of claim 7 or 8 which is performed in the presence of a hydrocarbon diluent or solvent of boiling point above 170 ⁰C.

10. Celecoxib Form N obtainable by any one of processes 7-9.

11. A pharmaceutical composition comprising celecoxib Form N as claimed in any of claims 1-6 or 10 together with one or more pharmaceutically acceptable excipients.

12. A method of treating or preventing a specific cyclooxygenase-2 mediated disorder in a patient or animal in need of such treatment, which comprises administering to said patient or animal an effective amount of celecoxib Form N as defined in any of claims 1-6 or 10.

P564 14 JulO5