HUP0200580A2 - Polymorphic crystalline forms of celecoxib, process their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to crystal forms I and II of celecoxib of formula (I), their production, the pharmaceutical preparation containing them and the production of these preparations. HE

Description

P02 00580

Bottom

POLYMORPHIC CRYSTALLINE FORMS OF CELECOXIB, l L Mi

Λ2

FOOD COPY , .-.T- ;,.- ·:··· -UM

This application claims priority from U.S. Provisional Patent Application No. 60/169,856, filed December 9, 1999.

The invention relates to an orally administrable pharmaceutical composition comprising a cyclooxygenase-2 inhibitory agent as an active ingredient, to the preparation of such a composition, and to the treatment of cyclooxygenase-2 mediated disorders comprising administering the composition to an individual. The invention also relates to the use of the composition for the manufacture of a medicament.

Our invention relates to medicinal substances with cyclooxygenase-2 inhibitory activity, in particular to novel crystalline forms I and II of celecoxib, to the preparation of these crystalline forms of celecoxib, to pharmaceutical compositions containing such crystalline forms of celecoxib, and to methods for the treatment and/or prevention of cyclooxygenase-2 mediated conditions and/or disorders.

A number of compounds have been described as exhibiting selective cyclooxygenase-2 inhibitory activity suitable for therapeutic and/or prophylactic purposes, and have been described as being useful specifically for the treatment or prevention of cyclooxygenase-2-mediated disorders or such disorders in general. Many of these compounds are substituted

95463-9223-FO-wood

- 2 pyrazolylbenzenesulfonamide derivatives have been described by Talley et al. in U.S. Patent No. 5,760,068, such as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, also known as celecoxib, and 4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, also known as deracoxib. Celecoxib corresponds to formula (I) and deracoxib corresponds to formula (II).

Other compounds exhibiting selective cyclooxygenase-2 inhibitory activity and suitable for therapeutic and/or prophylactic purposes are isoxazolylbenzenesulfonamide derivatives, such as 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, also known as valdecoxib, and represented by formula (III), also disclosed by Talley et al. in U.S. Patent No. 5,633,272.

Further compounds with selective cyclooxygenase-2 inhibitory activity suitable for therapeutic and/or prophylactic purposes are described by Ducharme et al. in U.S. Patent No. 5,474,995, such as 3-phenyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one, also known as rofecoxib and represented by formula (IV).

In U.S. Patent No. 5,981,576, Belley et al. disclosed additional (methylsulfonyl)phenylfuranone derivatives and claimed that they were useful as cyclooxygenase-2 inhibitors. Examples include 3-(1-cyclopropylmethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one and 3-[1-cyclopropylethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one.

- 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one, described in European Patent Specification No. 3Α 0 863 134, was found to have cyclooxygenase-2 inhibitory activity.

International patent specification WO 99/55380 discloses, inter alia, the compound of formula (V), which is also claimed to be a cyclooxygenase-2 inhibitor.

Many cyclooxygenase-2 inhibitory compounds, including celecoxib, deracoxib, valdecoxib, and rofecoxib, are hydrophobic and have low water solubility. This poses a practical problem in formulating such compounds for oral administration, especially when rapid onset of therapeutic effect is required.

Formulation of an effective amount of celecoxib for oral administration has been difficult due to the inherent physical and chemical properties of celecoxib, particularly its low solubility, and factors related to its crystal structure, such as cohesiveness, low bulk density, and low volumetric flexibility. Celecoxib is unusually insoluble in aqueous media. Unformulated celecoxib does not readily dissolve or disperse, as would be required for rapid gastrointestinal absorption when administered orally, such as in capsule form. In addition, unformulated celecoxib, which has a crystal structure that tends to form long cohesive needles, typically coalesces into a monolithic mass when compressed in a tabletting die. Even when mixed with other materials, celecoxib crystals tend to separate from the other materials and agglomerate during the mixing of the formulation, which

- 4 results in a non-uniform mixture composition containing undesirable large aggregates of celecoxib. Therefore, it is difficult to produce a pharmaceutical composition containing celecoxib that is uniformly mixed in the desired manner. Handling problems also arise in the production of pharmaceutical compositions containing celecoxib. For example, the low bulk density of celecoxib makes it difficult to process the small amounts required for formulation of pharmaceutical compositions. Therefore, there are many problems to be solved in the production of suitable pharmaceutical compositions and dosage forms containing celecoxib, especially orally administrable dosage units.

There is generally a great need for orally administrable formulations containing poorly water-soluble cyclooxygenase-2 inhibitory agents, such as celecoxib. These formulations have one or more of the following properties over unformulated or other celecoxib-containing formulations:

(1) better solubility;

(2) shorter disintegration time;

(3) shorter dissolution time;

(4) decreasing tablet friability;

(5) increasing tablet strength;

(6) better wetting;

(7) better pressability;

(8) improved flow properties for liquid and granular solid formulations;

(9) improved physical stability of the final formulation;

(10) smaller tablet or capsule size;

(11) more uniform mixture;

(12) better dose consistency;

(13) better control of weight variation during encapsulation and/or tableting;

(14) higher granule density in wet granulated formulations;

(15) lower water requirement for wet granulation, (16) shorter wet granulation time; and (17) shorter drying time for wet granulated mixtures.

There is a special need for orally administrable pharmaceutical compositions containing a low water solubility cyclooxygenase-2 inhibitory substance, such as celecoxib, since these compositions can induce a therapeutic effect more rapidly than with the corresponding unformulated active substances or with known compositions containing these active substances. If the rapid onset of the therapeutic effect is associated with pharmacokinetic parameters such as a high maximum serum concentration (C _max ) of the active substance and a short time from oral administration to reaching the maximum serum concentration (T _max ), there is a special need for orally administrable pharmaceutical compositions containing a low water solubility cyclooxygenase-2 inhibitory substance, such as celecoxib, since these compositions can achieve higher C _max and/or shorter T _max values than with the corresponding unformulated active substances or with known compositions containing these active substances.

As shown below, celecoxib is stored

- Treatment with selective cyclooxygenase-2 inhibitors is recommended or applicable for a wide range of cyclooxygenase-2 mediated conditions and disorders. It would be advantageous to provide formulations that have pharmacokinetic properties that are coupled with a rapid onset of therapeutic effect, particularly in the treatment of acute disorders where rapid relief of pain or other symptoms is required.

Such compositions are more advantageously useful for the treatment of cyclooxygenase-2 mediated conditions and disorders.

Medicinal products containing cyclooxygenase-2 inhibitors with low water solubility, such as celecoxib, can be formulated in the form of solid particles in a conventional manner. The individual or primary active ingredient particles can be dispersed in a liquid medium, such as in suspension formulations, or aggregated to form secondary particles or granules, which can be encapsulated to form a capsule dosage form or compressed or molded to form a tablet dosage form.

There are many methods known in the literature for preparing pharmaceutical compositions having a primary particle size in a desired range or a specific mean particle size or particle size distribution, which can be characterized, for example, by the parameter D ₉₀ , the latter being defined as the length of the diameter of the particles at their greatest extent being less than this diameter for 90% by volume of the particles in the composition. Practical reasons

- 7 of it is generally appropriate to base the determination of the D ₉₀ value on 90% by weight and not by volume.

In accordance with previous publications, the terms microparticle and nanoparticle are defined (Courteille et al., U.S. Patent No. 5,384,124), and are therefore understood to refer to particles with a diameter of between 1 pm and 2000 pm or less than 1 pm (1000 nm), respectively. According to U.S. Patent No. 5,384,124, the production of microparticles and nanoparticles is primarily used to delay the dissolution of active particles. However, in U.S. Patent Application No. 5,145,684, Liversidge et al. have described formulations containing nanoparticles that provide unexpectedly high bioavailability of active agents, particularly in liquid media, such as those with low water solubility. International patent specification WO 93/25190 presents pharmacokinetic data from studies conducted in rats, based on which it can be concluded that, in the case of oral administration of naproxen dispersion, the absorption rate of nanoparticles (mean particle size between 240 nm and 300 nm) is clearly higher than that of microparticles (particle size between 20 mm and 30 mm).

There are several methods known for preparing formulations containing nanoparticles of therapeutic agents. These methods typically use mechanical means, such as milling or grinding, to obtain nanosized particles (less than 1 pm).

- To produce particles of size 8 or larger, the nano-sized particles are precipitated from solution. Such methods are disclosed in the following references: U.S. Patent No. 4,826,689 (Violanto and Fischer), U.S. Patent No. 5,145,684 (Liversidge et al.), U.S. Patent No. 5,298,262 (Na & Rajagopalan), U.S. Patent No. 5,302,401 (Liversidge et al.), U.S. Patent No. 5,336,507 (Na & Rajagopalan), U.S. Patent No. 5,340,564 (Iliig & Sarpotdar), U.S. Patent No. 5,346,702 (Na & Rajagopalan), U.S. Patent No. 5,352,459 (Hollister et al.), 5,354 U.S. Patent No. 560 (Lovrecich), the aforementioned U.S. Patent No. 5,384,124 (Courteille et al.), U.S. Patent No. 5,429,824 (June), U.S. Patent No. 5,510,118 (Bosch et al.), U.S. Patent No. 5,518,738 (Eickhoff et al.), U.S. Patent No. 5,503,723 (Ruddy & Eickhoff), U.S. Patent No. 5,534,270 (De Castro), U.S. Patent No. 5,536,508 (Canal et al.), U.S. Patent No. 5,552,160 (Liversidge et al.), US Patent No. 5,560,931

- U.S. Patent No. 9 (Eickhoff et al.), U.S. Patent No. 5,560,932 (Bagchi et al.), U.S. Patent No. 5,565,188 (Wong et al.), U.S. Patent No. 5,569,448 (Wong et al.), U.S. Patent No. 5,571,536 (Eickhoff et al.), U.S. Patent No. 5,573,783 (Desieno & Stetsko), U.S. Patent No. 5,580,579 (Ruddy et al.), U.S. Patent No. 5,585,108 (Ruddy et al.), U.S. Patent No. 5,587,143 (Wong et al.) et al.), U.S. Patent No. 5,591,456 (Franson & Snyder), U.S. Patent No. 5,662,883 (Bagchi et al.), U.S. Patent No. 5,665,331 (Bagchi et al.), U.S. Patent No. 5,718,919 (Ruddy & Roberts), U.S. Patent No. 5,747,001 (Wiedmann et al.), International Publication Nos. WO 93/25190, WO 96/24336, and 98/35666.

In accordance with the above, the solution according to our invention ensures the rapid onset of the therapeutic effect of selective cyclooxygenase-2 inhibitory compounds with poor water solubility, such as celecoxib, deracoxib, valdecoxib or rofecoxib, in the pharmaceutical preparation containing the compound.

- 10. When administered orally, the compound exhibits pharmacokinetic properties that result in a higher maximum serum concentration (C _max ) and/or a shorter time to reach this maximum concentration (T _max ) after administration. Thus, by reducing the size of the solid particles containing the compound, higher C _max and/or shorter T _max values can be achieved, where a significant portion of the particles have a diameter of less than 1 pm, measured at their longest dimension. Without wishing to be bound by theory, it is believed that the higher C _max and/or shorter T _max values are the result of faster dissolution of compounds with particle sizes smaller than 1 pm.

Thus, the present invention provides a pharmaceutical composition comprising one or more orally administrable dosage units each containing a pharmaceutically effective amount of a low water-soluble, selective cyclooxygenase-2 inhibitory compound, which compound is present in the form of solid particles having a _D90 particle size of between about 0.01 pm and about 200 pm, wherein a defined weight fraction of the particles is less than 1 pm. This provides a substantially higher _Cmax and/or a substantially lower _Tmax compared to an otherwise similar composition in which substantially all of the particles are greater than 1 pm.

Our invention also encompasses a pharmaceutical composition comprising one or more orally administrable dosage units, each of which contains a therapeutically effective amount of a selective cyclooxygenase-2 inhibitor of low water solubility.

- 11 contains an active compound, wherein the compound is present in the form of solid particles with a D ₉₀ particle size of between about 0.01 pm and about 200 pm and wherein between about 25% by weight and 100% by weight of the particles are less than 1 pm.

The dosage units containing the composition may be in the form of discrete solid products such as tablets, pills, hard and soft capsules, lozenges, sachets or lozenges. In one embodiment, the composition may be in the form of a substantially homogeneous, free-flowing mass such as particulate or granular solids or liquid suspensions from which a single dosage unit can be measurably withdrawn.

The invention also provides a method of treating a medical condition or disorder for which treatment with a cyclooxygenase-2 inhibitor is indicated, comprising administering one or more dosage units of the composition of the invention orally once or twice daily. This method is particularly useful for treating medical conditions or disorders involving acute pain.

The present invention also includes a novel solid state form of celecoxib, Form I celecoxib. The present invention also includes another solid state form of celecoxib, Form II celecoxib. Each of these novel solid state forms includes solvated crystal forms, unsolvated crystal forms, and unhydrated crystal forms. The novel forms of celecoxib described in this application are those having one or more of the above-described

- They exhibit the aforementioned advantageous chemical and/or physical properties compared to other solid state forms described herein or known in the literature.

Another embodiment of the invention relates to a novel crystalline form of celecoxib. For example, one embodiment of the invention relates to a crystalline form I of celecoxib, the X-ray powder diffraction spectrum of which preferably includes peaks occurring at the following 2-theta values: 5.5°, 5.7°, 7.2° and 16.6°.

Another embodiment of our invention relates to pharmaceutical compositions comprising a pharmaceutically effective amount of crystalline Form I of celecoxib together with at least one pharmaceutically acceptable carrier, excipient or diluent.

Another embodiment of our invention relates to a method for treating or preventing cyclooxygenase-2 mediated conditions or disorders comprising administering to a subject a therapeutically effective amount of celecoxib Form I.

Another embodiment of our invention relates to the preparation of celecoxib Form I, which involves crystallizing celecoxib from a solvent mixture, wherein the crystallization is carried out at a temperature above the enantiotropic transformation temperature of celecoxib Form I, thereby producing celecoxib Form I.

In another embodiment of our invention, celecoxib is prepared in crystalline form by heating a solvate of celecoxib to produce celecoxib.

- 13I form.

In another embodiment of our invention, celecoxib Form I is prepared by grinding or comminuting celecoxib Form III to obtain celecoxib Form I.

In another embodiment of our invention, Form I of celecoxib is prepared by grinding or milling a celecoxib solvate to obtain Form I celecoxib.

In another embodiment of our invention, Form I of celecoxib is prepared by melting Form II of celecoxib and cooling the melt to obtain Form I of celecoxib.

In another embodiment of our invention, Form I celecoxib is prepared by melting Form III celecoxib and cooling the melt to obtain Form I celecoxib.

In another embodiment of our invention, celecoxib Form I is prepared by evaporating the solvent from a solution of celecoxib to obtain celecoxib Form I.

Further embodiments of the invention relate to novel crystalline forms of celecoxib. For example, one embodiment of the invention relates to crystalline form II of celecoxib, the X-ray powder diffraction spectrum of which comprises peaks occurring at approximately the following 2-theta values: 10.3°, 13.8°, and 17.7°.

A further embodiment of our invention relates to a pharmaceutical composition which is pharmaceutically

- Contains a 14% amount of crystalline form and at least one pharmaceutically acceptable carrier, additive and/or diluent.

Another embodiment of our invention relates to a method for treating or preventing cyclooxygenase-2 mediated conditions or disorders comprising administering to an individual a therapeutically effective amount of celecoxib Form II.

A further embodiment of our invention relates to the preparation of celecoxib Form II by crystallizing celecoxib from a solvent mixture, wherein the crystallization is carried out at a temperature above the enantiotropic transformation temperature of celecoxib Form II, thereby obtaining celecoxib Form II.

A further embodiment of the present invention relates to the preparation of celecoxib in crystalline form by heating a celecoxib solvate to produce celecoxib Form II.

A further embodiment of our invention relates to the preparation of celecoxib Form II, wherein celecoxib Form III is ground or ground to produce celecoxib Form II.

A further embodiment of our invention relates to the preparation of celecoxib in Form II, which comprises grinding or milling a celecoxib solvate to produce celecoxib Form II.

A further embodiment of our invention relates to the preparation of celecoxib form II, which process

- In step 15, celecoxib Form I is melted and the melt is cooled to produce celecoxib Form II.

A further embodiment of our invention relates to the preparation of celecoxib Form II, which comprises melting celecoxib Form III and cooling the melt to produce celecoxib Form II.

A further embodiment of our invention relates to a solid form of celecoxib comprising celecoxib Form I and celecoxib Form II.

A further embodiment of our invention relates to a solid form of celecoxib comprising celecoxib Form I and celecoxib Form III.

A further embodiment of our invention relates to a solid form of celecoxib comprising celecoxib Form II and celecoxib Form III.

A further embodiment of our invention relates to a solid form of celecoxib comprising celecoxib Form I, celecoxib Form II and celecoxib Form III.

Other features of our invention are described in detail below.

Of the accompanying figures, Figure 1 shows the experimental PXRD spectra of celecoxib Form I (spectrum 1a), a mixture of celecoxib Form II and celecoxib Form III (spectrum 1b), and celecoxib Form III (spectrum 1c);

Figure 2 shows the infrared (IR) spectra of celecoxib Form I, a mixture of celecoxib Form II and celecoxib Form III, and celecoxib Form III;

- 16 - ·>

· it · · · ·< · ··’ Figure 3 shows the DSC thermograms of each celecoxib form scanned at a rate of 0.5 °C/min, as well as their superimposed plot (endotherms pointing downwards).

The terms selective cyclooxygenase-2 inhibitor and selective cyclooxygenase-2 inhibitory compound are intended to mean a compound that inhibits the activity of cyclooxygenase-2 to a therapeutically adequate extent, while inhibiting the activity of cyclooxygenase-1 to a significantly lesser extent than conventional non-steroidal anti-inflammatory drugs (NSAIDs).

The terms "sparingly water-soluble" and "low water solubility" in relation to the selective cyclooxygenase-2 inhibitors described herein are understood to mean that their water solubility in distilled water at 25°C is less than about 10 g/L, preferably less than about 1 g/L.

The term oral administration or oral administration refers to any form of administration of a therapeutic agent or composition containing the same to a given individual, wherein the agent or composition is placed in the mouth of the individual, whether or not the individual swallows the agent or composition. Thus, the term oral administration includes buccal, sublingual, and esophageal routes of administration. Absorption of the agent may occur in any part or parts of the gastrointestinal tract, including the mouth, esophagus, stomach, jejunum, ileum, and colon.

The term "orally administrable" or "orally administrable" refers to devices suitable for oral administration.

- 17The term individual in connection with the administration of a therapeutic agent or preparation is understood to mean a human patient of any sex or age, as well as any other living being, especially a domestic animal or an animal living alongside humans, such as a cat, dog or horse.

The term "unit dosage" refers to a single dose of a pharmaceutical composition suitable for oral administration, which is sufficient to produce a therapeutic effect of a therapeutic agent, in this case a selective cyclooxygenase-2 inhibitor. Typically, the amount of material required to produce the desired effect is contained in one dosage unit or a small number (up to about 4) of dosage units.

The term "present in solid particulate form" is used to refer to compositions containing a compound having selective cyclooxygenase-2 inhibitory activity, the solid particles of which comprise essentially the compound, and compositions wherein the solid particles comprise the compound in intimate admixture with one or more other ingredients. These additional ingredients may be one or more therapeutic agents other than the compound having selective cyclooxygenase-2 inhibitory activity and/or one or more pharmaceutically acceptable additives.

The term excipient refers to any agent, not active in itself, which is used as a carrier or vehicle for the delivery of the therapeutic agent of the invention or as a substance which improves the handling and storage properties of the pharmaceutical composition or facilitates the administration of a dose of the composition as a separate product.

- 18for example, the preparation of a tablet or capsule suitable for oral administration. The ingredients may include, for example, diluents, disintegrants, binders, adhesives, wetting agents, glidants, lubricants, substances added to mask or counteract an intolerable taste or odor, flavorings, colorings, perfuming substances, and substances added to improve the appearance of the composition.

In the case of a pharmaceutical preparation containing several components, the term substantially homogeneous means that the components are properly mixed, so that the individual components are not present in the form of separate parts and no concentration gradient is formed in the preparation.

The term purity refers to the chemical purity of celecoxib as determined by HPLC assay in a conventional manner.

The term phase purity refers to the purity of solid state celecoxib with respect to a specific crystal or amorphous form of celecoxib, as determined by the infrared spectroscopy analytical method described herein.

The term enantiotropic transition temperature refers to the temperature at which a thermodynamically stable polymorph transforms from one form to another. For example, for two polymorphs, Form A and Form B, below the enantiotropic transition temperature, Form A is the thermodynamically stable form, and above this temperature, Form B is the thermodynamically stable form.

The novel pharmaceutical compositions of our invention comprise one or more orally administrable dosage units,

- 19wherein each dosage unit contains a therapeutically effective amount of a selective cyclooxygenase-2 inhibitor, such as celecoxib, preferably between about 10 mg and about 1000 mg.

Of course, the therapeutically effective amount of a selective cyclooxygenase-2 inhibitor for a given individual will depend, among other things, on the individual's body weight. When celecoxib is used as the cyclooxygenase-2 inhibitor and the individual is a child or a small animal (e.g., a dog), the amount of celecoxib is relatively small, i.e., the preferred range is from about 10 mg to about 1000 mg, which is expected to provide a serum concentration adequate for therapeutic effect. When the individual is an adult or a large animal (e.g., a horse), a dose containing relatively large amounts of celecoxib is likely to be required to achieve an adequate serum concentration of celecoxib.

A dosage unit of the composition of the present invention typically contains about 10 mg, 20 mg, 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of a cyclooxygenase-2 inhibitor, such as celecoxib. The composition of the present invention for adults typically contains a therapeutically effective amount of celecoxib per dosage unit, typically from about 50 mg to about 400 mg. The amount of celecoxib per dosage unit is particularly preferably from about 100 mg to about 200 mg, such as from about 100 mg or about 200 mg.

- 20- ♦.> . ^: .Λ. <>·

The compositions of our invention comprise the cyclooxygenase-2 inhibitor, e.g. celecoxib, alone or in intimate admixture with one or more additives, in the form of nanoparticles, i.e. solid particles with a diameter of less than 1 pm in the longest dimension of the particle.

The effect of reducing the particle size from the microparticle range (diameter greater than 1 pm) to the nanoparticle range on the pharmacokinetic properties of a given drug or class of drugs is generally unpredictable. Our invention is based on the recognition that formulations containing nanoparticles of a selective cyclooxygenase-2 inhibitor with low water solubility exhibit higher C _max and/or lower T _max values than formulations containing the corresponding microparticles. In one embodiment of our invention, a specified weight percent of nanoparticle-sized particles provides a significantly higher C _max and/or a significantly shorter T _max value compared to a comparative formulation in which substantially all of the particles are larger than 1 pm. The composition of this embodiment preferably comprises a weight percent amount of nanoparticles that provides a substantially shorter T _max , and more preferably comprises a weight percent amount of nanoparticles that provides both a substantially higher C _max and a substantially lower T _max , compared to the comparative composition.

For a fasted adult, a dose of 100 mg

- Oral administration of 21 units preferably results in a T _max of less than about 90 minutes, more preferably less than about 60 minutes, and preferably less than about 45 minutes, and a C _max of at least about 100 ng/ml, more preferably at _least about 200 ng/ml. Oral administration of the composition of the present invention typically provides a serum concentration of at least about 50 ng/ml of selective cyclooxygenase-2 inhibitor within 30 minutes, and with preferred compositions this concentration is achieved in as little as 15 minutes. Based on this early rise in serum concentration, it is believed that the therapeutic effect of the composition of the present invention is rapid.

In another embodiment of the invention, the selective cyclooxygenase-2 inhibitor, e.g., celecoxib, is used in solid particles with a D ₉₀ particle size of between about 0.01 pm and about 200 pm, wherein between about 25% and 100% of the particles are nanoparticles. When the weight percent of the nanoparticles is relatively small, e.g., between about 25% and about 50%, the D ₉₀ particle size is preferably between about 0.01 pm and about 100 pm, more preferably between about 0.01 pm and about 75 pm, even more preferably between about 0.01 pm and about 40 pm, and even more preferably between about 0.01 pm and about 25 pm. The particle size may vary continuously in the nanoparticle and microparticle range or the composition may exhibit a bimodal or multimodal particle distribution, where a portion of the particles have a D ₉₀ particle size of less than 1 pm and the

- Another portion of the particles 22 have a particle size D ₉₀ of substantially greater than 1 pm. It is generally preferred that at least about 50% by weight of the particles, and particularly preferred that at least about 75% by weight of the particles are nanoparticle sized. In one embodiment, substantially all of the particles, i.e., 100% or nearly 100% by weight of the nanoparticles, are smaller than 1 pm.

Primary particles, which are produced by grinding or crushing or, for example, by precipitation from solution, may agglomerate to form secondary aggregate particles. The term particle size is understood to mean the size of the primary particles in their longest dimension, unless otherwise indicated in the context.

The composition of the present invention, with respect to the nanoparticle component alone, preferably has a mean particle size of about 0.1 pm to about 0.8 pm (i.e., about 100 nm to about 800 nm), more preferably about 0.15 pm to about 0.6 pm (i.e., about 150 nm to about 600 nm), and even more preferably about 0.2 pm to about 0.4 pm (i.e., about 200 nm to about 400 nm). The selective cyclooxygenase-2 inhibitor, such as celecoxib, in the nanoparticles may be in crystalline or amorphous form. A nanoparticle preparation process involving milling or comminution typically produces the active ingredient in a crystalline form, whereas a solution precipitation process typically produces the active ingredient in an amorphous form.

- 23 The compositions of the present invention comprise a selective cyclooxygenase-2 inhibitor with low water solubility, such as celecoxib, optionally together with one or more additives, namely diluents, disintegrants, binders, wetting agents and lubricants. In one embodiment, the nanoparticles comprising the selective cyclooxygenase-2 inhibitor comprise a surface modifying agent absorbed on their surface. In another embodiment, the selective cyclooxygenase-2 inhibitor nanoparticles are present in a matrix formed from a polymer. At least one of the additives is preferably a water-soluble diluent or wetting agent. When the composition of the present invention is administered, this water-soluble diluent or wetting agent promotes the dispersion and dissolution of the cyclooxygenase-2 inhibitor. Preferably, both a water-soluble diluent and a wetting agent are present.

The composition of the present invention may be in the form of a substantially homogeneous free-flowing mass, such as a particulate or granulated solid or liquid, or in the form of discrete products such as caplets or tablets, each containing a single dosage unit.

A single dosage unit can be measurably withdrawn from the substantially homogeneous free-flowing mass formulation using a suitable volumetric device, such as a spoon or cap. Suitable free-flowing masses include, but are not limited to, powders and granules. In one embodiment, the free-flowing mass is, for example, a suspension containing the cyclooxygenase-2 inhibitor.

- 24 in a liquid phase, preferably in a solid particle phase dispersed in an aqueous phase. At least a portion of the particle phase comprises nanoparticles. In preparing such a suspension, it is advantageous to use a wetting agent, such as polysorbate 80 or the like. The suspension may be prepared by dispersing the nanoparticle-sized or partially nanoparticle-sized cyclooxygenase-2 inhibitor in a liquid phase. In one embodiment, the cyclooxygenase-2 inhibitor, such as celecoxib, may be prepared by precipitation from a solution, wherein the solvent is, for example, an alcohol, preferably ethanol. The aqueous phase preferably comprises an edible carrier, such as water, fruit syrup or fruit juice, such as apple juice.

The compositions of the present invention are useful for the treatment and prevention of a very wide range of cyclooxygenase-2 mediated disorders. The compositions of the present invention are useful for the treatment of inflammation, for example as analgesics, for example for the treatment of pain and headache, and as antipyretics for the treatment of fever, but the invention is not limited thereto. For example, these compositions are useful for the treatment of arthritic disorders, such as rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, but the invention is not limited thereto. The compositions are also useful for the treatment of: asthma, bronchitis, menstrual cramps, premature labor pains, tendonitis, urethritis, allergic neuritis, cytomegalovirus

- 25 infections, apoptosis, including HIV-induced apoptosis, lumbago, liver disease, including hepatitis, skin conditions such as psoriasis, eczema, acne, UV damage, burns and dermatitis, and post-operative inflammation, including inflammation following ophthalmic surgery such as cataract surgery or refractive surgery. The proposed compositions are suitable for treating gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The proposed compositions are also useful for treating inflammation in diseases such as migraine headache, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, neuromuscular junction disorders including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, post-traumatic swelling including cerebral edema, myocardial ischemia, and the like. The proposed compositions are also useful for treating ophthalmic diseases such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia, and acute ocular tissue injury. The proposed compositions are also useful for treating pneumonia, such as pneumonia associated with viral infection or cystic fibrosis, and bone resorption, such as resorption associated with osteoporosis. The proposed compositions are also useful for treating certain central nervous system disorders, such as cortical dementia, including Alzheimer's disease.

- 26diseases, neurodegeneration, and central nervous system damage resulting from stroke, ischemia, and trauma are also suitable for treatment. The term treatment in this application means the partial or complete inhibition of dementia, such as Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, and senile dementia.

The compositions of our invention are particularly useful as anti-inflammatory agents, for example for the treatment of arthritis, with the additional advantage that their side effects are significantly less harmful than those of conventional non-steroidal anti-inflammatory agent (NSAID) compositions.

The proposed compositions are also useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and liver disease. The compositions can be used to treat pain, including, but not limited to, postoperative pain, dental pain, muscle pain, and pain resulting from cancer.

The proposed compositions are also useful for treating and preventing cardiovascular disorders associated with inflammation in an individual, but the invention is not limited thereto. The compositions are useful for treating vascular diseases, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including heart transplant arteriosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina including unstable angina, coronary thromboembolism, bacterial inflammation,

- 27 including Chlamydia-induced inflammation, viral-induced inflammation, and inflammation associated with surgical procedures such as vascular grafting, including coronary artery bypass grafting, revascularization procedures including angioplasty, stent placement, endarterectomy, or other procedures involving arteries, veins, and capillaries. These compositions are useful in treating disorders associated with angiogenesis in an individual, but are not limited thereto. The compositions of the present invention may be administered to an individual in need of inhibition of angiogenesis. These compositions include neoplasia, including metastasis; ophthalmic conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization, including neovascularization following injury or infection, diabetic retinopathy, macular degeneration, posterior lenticular fibroplasia, and neovascular glaucoma; ulcerative diseases such as gastric ulcers; pathological but non-malignant conditions such as hemangiomas, including childhood hemangiomas, nasopharyngeal angiofibroma and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis.

The proposed compositions are suitable for the treatment of benign and malignant tumors/neoplasia, including cancer such as colorectal cancer, brain tumor, bone cancer, neoplasia arising from epithelial cells (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, oral cancer, esophageal cancer, small

- 28intestinal and gastric cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma and other known types of cancer that affect epithelial cells in the body. The compositions of our invention are particularly suitable for the treatment of neoplasias, such as gastrointestinal cancer, Barrett's esophagus, liver cancer, lip cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer, skin cancer, such as squamous cell and basal cell cancers. The compositions of our invention can also be used to treat fibrosis occurring in radiotherapy. These compositions are also suitable for the treatment of individuals suffering from laryngeal polyps, such as hereditary laryngeal polyps (FAP). In addition, the preparations are also suitable for preventing polyps from forming in patients at risk of FAP.

The compositions of the present invention exhibit superior anti-inflammatory, antipyretic and analgesic effects to those of similar or conventional non-steroidal anti-inflammatory agents. The proposed compositions also inhibit hormone-induced uterine contractions and have potential anticancer effects, but are less likely to induce certain mechanism-based side effects of conventional NSAIDs. In particular, the compositions of the present invention exhibit less gastrointestinal toxicity and gastrointestinal irritation, including upper gastrointestinal ulceration and bleeding, and less renal side effects, such as renal dysfunction leading to fluid retention and high blood pressure.

- 29 worsening of blood pressure, its effect on bleeding time is also less, including inhibition of platelet function, and the occurrence of asthma attacks in aspirin-sensitive asthmatics, compared to conventional NSAID-containing preparations.

The proposed compositions are useful for the relief of pain, fever and inflammation in conditions such as rheumatic fever, symptoms associated with influenza or other viral infections, the common cold, lower back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns and injuries following surgical or dental procedures. In addition, the proposed compositions inhibit neoplastic transformation of cells and tumor growth in metastasis, and accordingly can be used in the treatment of cancer, such as colon cancer. The proposed compositions can also be used for the treatment and/or prevention of cyclooxygenase-mediated proliferative disorders, such as diabetic retinopathy, and can also occur in tumor angiogenesis.

The proposed compositions inhibit prostanoid-induced smooth muscle contraction by inhibiting the synthesis of prostanoids that trigger contraction, and are therefore useful in the treatment of dysmenorrhea, premature labor pain, asthma, and eosinophil-related disorders. In addition, they are useful in the treatment of Alzheimer's disease and, in particular, menopause.

- They are suitable for reducing bone loss (i.e. treating osteoporosis) and treating glaucoma in women over 30.

Due to their significant cyclooxygenase-2 (COX-2) inhibitory activity and/or their specific cyclooxygenase-2 inhibitory activity against cyclooxygenase-1 (COX-1), the compositions of the present invention may be used as an alternative to conventional NSAIDs, particularly in cases where NSAIDs are contraindicated, such as in peptic ulcer, gastritis, regional enteritis, ulcerative colitis, diverticulitis or recurrent gastrointestinal injury, in patients with coagulation disorders (including anemia such as hypoprothrombinemia), hemophilia or other bleeding problems, or in patients undergoing surgery or taking anticoagulants. The potential use of cyclooxygenase-2 inhibitors has been described by John Vane [Nature, 367, 215-216 (1994) and Drug News and Perspectives, 7, 501-512 (1994)].

The pharmaceutical compositions of our invention are preferably suitable for the treatment of rheumatoid arthritis and osteoarthritis, for the relief of pain in general (especially pain after oral surgery, pain after general surgery, pain after orthopedic surgery and acute skin rashes in osteoarthritis), for the treatment of Alzheimer's disease and for the chemoprevention of colon cancer.

Due to the rapid onset of therapeutic effect of the compositions of our invention, these compositions are particularly

- 31 are particularly useful for the treatment of acute cyclooxygenase-2-mediated disorders, especially for the relief of pain, compared to preparations containing previously known cyclooxygenase-2 inhibitory compounds.

The present compositions may also be used in combination therapy with opioids and other analgesics, such as narcotic analgesics, M1 receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e., non-additive) analgesics, monamine uptake inhibitors, adenosine modulators, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists, and sodium channel blockers, and the like. In combination therapies, the compositions of our invention can be preferably used together with the following compounds: morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone, DuP-747, Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078, ICI-204448, acetaminophen (paracetamol), propoxyphene, nalbuphine, E-4018, filenadol, morfentanil, amitriptyline, DuP-631, GP-531, acadesine, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate and its isolated (+) and (-) enantiomers, AXC-3742, SNX-111, ADL2-1294, CT-3 and CP-99994.

A dosage unit containing a defined amount of a cyclooxygenase-2 inhibitor, such as celecoxib, may be selected for any frequency of administration necessary to achieve the desired daily dose. The daily dose and frequency of administration, and thus the selection of the appropriate dosage unit, are dependent on the

- It depends on 32 factors, including the age, weight, sex and medical condition of the individual, as well as the nature and severity of the condition or disorder, and can therefore be varied over a wide range.

In the case of celecoxib, a once or twice daily dosing regimen to provide the desired daily dose is more effective than other dosing regimens with the compositions of the present invention. Accordingly, the composition of the present invention is preferably administered orally once or twice daily for the treatment or prevention of cyclooxygenase-2 mediated disorders.

In the treatment of rheumatoid arthritis, the compositions of the invention are used to provide a daily dose of celecoxib of between about 50 mg and about 1000 mg, preferably between about 100 mg and about 600 mg, more preferably between about 150 mg and about 500 mg, and even more preferably between about 175 mg and about 400 mg, for example about 200 mg. The dose may be administered once daily, twice daily, three times daily or more. For example, the dose may comprise 200 mg of active ingredient. The daily dose of celecoxib is between about 0.67 mg/g and about 13.3 mg/kg, preferably between about 1.33 mg/kg and about 8.00 mg/kg, more preferably between about 2.00 mg/kg and about 6.67 mg/kg, more preferably between about 2.33 mg/kg and about 5.33 mg/kg, and it is generally appropriate to administer the compositions of the invention at a dose of, for example, about 100 mg/kg to about 1000 mg/kg per body weight.

- 332.67 mg/kg daily dose of celecoxib. The daily dose may be administered in one to four doses per day, more preferably one or two doses per day. For most patients, the compositions of the present invention are preferably administered as a 100 mg dosage unit twice daily, however, some patients may benefit from administration of a 200 mg dosage unit once or 100 mg dosage unit twice daily.

In the treatment of osteoarthritis, the compositions of the present invention may be used to provide a daily dose of celecoxib of between about 50 mg and about 1000 mg, preferably between about 100 mg and about 600 mg, more preferably between about 150 mg and about 500 mg, even more preferably between about 175 mg and about 400 mg, e.g. about 200 mg. When administering the compositions of the present invention, a daily dose of celecoxib of between about 0.67 mg/kg and about 13.3 mg/kg, preferably between about 1.33 mg/kg and about 8.00 mg/kg, more preferably between about 2.00 mg/kg and about 6.67 mg/kg, and even more preferably between about 2.33 mg/kg and about 5.33 mg/kg, e.g. about 2.67 mg/kg, based on body weight, is generally appropriate. The daily dose may be administered in between one and four doses per day, more preferably one or two doses per day. The composition of the invention is preferably administered in a dosage unit of 100 mg twice daily or in a dosage unit of 200 mg once daily or in two dosage units of 100 mg once daily.

For the treatment of Alzheimer's disease, the compositions of our invention contain between about 50 mg and about 1000 mg of

- A daily dose of celecoxib of between 34mg, preferably between about 100mg and about 800mg, more preferably between about 150mg and about 600mg, even more preferably between about 175mg and about 400mg, e.g. about 400mg is administered. When administering the compositions of the invention, a daily dose of between about 0.67mg/kg and about 13.3mg/kg, preferably between about 1.33mg/kg and about 10.67mg/kg, more preferably between about 2.00mg/kg and about 8.00mg/kg, and even more preferably between about 2.33mg/kg and about 5.33mg/kg, e.g. about 5.33mg/kg, based on body weight, is generally suitable. The daily dose is administered in between one and four doses per day, preferably one or two doses per day. The composition of our invention is preferably administered to most patients in a dosage unit of 200 mg twice daily or in a dosage unit of 100 mg twice daily.

In the treatment of cancer, the compositions of the present invention can be used to provide a daily dose of celecoxib of between about 50 mg and about 1000 mg, preferably between about 100 mg and about 800 mg, more preferably between about 150 mg and about 600 mg, and even more preferably between about 175 mg and about 400 mg, for example about 400 mg. The composition of the present invention is generally administered at a dose of between 0.67 mg/kg and about 13.3 mg/kg, preferably between about 1.33 mg/kg and about 10.67 mg/kg, more preferably between about 2.00 mg/kg and about 8.00 mg/kg, even more preferably between about 2.33 mg/kg and about 5.33 mg/kg, based on body weight.

- 35 mg/kg daily, for example about 5.33 mg/kg daily is suitable. The daily dose is administered in one to four doses per day, preferably two doses per day. The composition of the invention is preferably administered to most patients in two 200 mg dosage units or two 100 mg dosage units per day.

For pain relief, the compositions of the present invention comprise a daily dose of celecoxib of between about 50 mg and about 1000 mg, preferably between about 100 mg and about 600 mg, more preferably between about 150 mg and about 500 mg, even more preferably between about 175 mg and about 400 mg, e.g. about 200 mg. The composition of the present invention will generally be administered at a daily dose of celecoxib of between about 0.67 mg/kg and about 13.3 mg/kg, preferably between about 1.33 mg/kg and about 8.00 mg/kg, more preferably between about 2.00 mg/kg and about 6.67 mg/kg, even more preferably between about 2.33 mg/kg and about 5.33 mg/kg, e.g. about 2.67 mg/kg, based on body weight. The daily dose may be administered in one to four doses per day. The composition of the invention is preferably administered as a 50 mg dosage unit four times daily, a 100 mg dosage unit or two 50 mg dosage units twice daily, or a 200 mg dosage unit, two 100 mg dosage units or four 50 mg dosage units once daily.

The composition of the present invention is generally administered to achieve a mean serum celecoxib concentration of at least about 100 ng/ml, preferably about 24 hours after administration.

- 36administered in the required dose and frequency.

Although the amount of celecoxib in the compositions of the present invention is preferably within the range defined herein, compositions capable of administering amounts of celecoxib outside these dosage ranges may be used. For other selective cyclooxygenase-2 inhibitors, the appropriate dosage may be selected in light of the above-mentioned patent documents.

Nanoparticles containing or consisting of selective cyclooxygenase-2 inhibitory compounds with substantially low water solubility, such as celecoxib, deracoxib, valdecoxib or rofecoxib, can be prepared according to methods previously used for the preparation of other poorly water-soluble active ingredients in nanoparticle form. Such methods are disclosed, for example, in the following patents, however-

invention not for us limit in these booked: 4,826,689.5 145,684, 5,298,262, 5 302 401, 5,336,507, 5,340,564.5 346,702, 5,352,459, 5,354,560, 5,384,124, 5,429,824.5 510 118, 5,518,738, 5,503,723, 5,534,270, 5,536,508.5 552,160, 5,560,931, 5,560,932, 5 565 1 88, 5,569,448.5 571,536, 5,573,783, 5 580 579, 5 585 1 08, 5,587,143, 5,591,456, 5 662,883.5 665,331.5 718 919 and American United States No. 5,747,001 state patent

descriptions and the above-cited WO 93/25190, WO 96/24336 and WO

International Publication No. 98/35666, all of which are incorporated herein by reference. One skilled in the art can readily utilize a poorly water-soluble selective cyclooxygenase-2 inhibitor, such as celecoxib, deracoxib,

- 37the processes described therein for preparing valdecoxib or rofecoxib in nanoparticle form.

The excipients used in the compositions of the present invention may be in solid or liquid form or both. The composition preferably comprises from about 1% to about 95% by weight, preferably from about 10% to about 90% by weight, more preferably from about 25% to about 85% by weight, even more preferably from about 30% to about 80% by weight of a selective cyclooxygenase-2 inhibitor, such as celecoxib. The compositions of the present invention comprising excipients may be prepared by methods well known in the art of pharmacy, in which the excipients are mixed with an active ingredient or medicinal substance, except that in this case the active ingredient or medicinal substance, namely the selective cyclooxygenase-2 inhibitor, is at least partially prepared in the form of nanoparticles as described above, optionally mixed with one or more excipients.

The composition of the present invention comprises a desired amount of a cyclooxygenase-2 inhibitor, such as celecoxib, per dosage unit and may be in the form of, for example, a tablet, pill, hard or soft capsule, lozenge, wafer, sachet, distributable powder, granulate, suspension, elixir, liquid or any other form suitable for oral administration. These compositions are preferably prepared in the form of discrete dosage units containing a predetermined amount of the cyclooxygenase-2 inhibitor, such as tablets and

- 38 capsules. These oral dosage forms may also contain, for example, buffers. Tablets, pills and the like may also be produced with or without a coating.

Compositions of the invention suitable for buccal or sublingual administration may include, for example, lozenges containing the cyclooxygenase-2 inhibitor in a flavored base, such as sucrose, and acacia or tragacanth, or lozenges containing the cyclooxygenase-2 inhibitor in an inert base, such as gelatin, and glycerin or sucrose and acacia.

Oral liquid dosage forms include, for example, pharmaceutically acceptable suspensions, syrups or elixirs containing inert diluents such as water, which are conventionally used in the art. The compositions may also contain, for example, wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfuming agents.

As described above, the additive-containing compositions of the present invention can be prepared by any method commonly used in the pharmaceutical arts, which includes the step of mixing the cyclooxygenase-2 inhibitor compound in at least partially nanoparticulate form and the additive(s). The compositions are generally prepared by mixing the cyclooxygenase-2 inhibitor compound in partially or completely nanoparticulate form (hereinafter also referred to as the compound nanoparticle) with a liquid or finely divided diluent or

- 39both are thoroughly and uniformly mixed, and then the product is encapsulated or molded, if desired or necessary. For example, a tablet is prepared by compressing or bulking a powder or granule of the compound nanoparticles with one or more binders. Compressed tablets can be prepared by compressing a powder or granule containing the compound nanoparticles, optionally mixed with one or more binders, lubricants, inert diluents, wetting agents and/or dispersants, in a suitable apparatus. Bulk tablets can be prepared by bulking the compound nanoparticles with an inert liquid diluent in a suitable apparatus.

As mentioned above, the compositions of the present invention comprise, per dosage unit, a therapeutically or prophylactically effective amount of a selective cyclooxygenase-2 inhibitor compound, such as celecoxib, in partially or completely nanoparticulate form, in combination with one or more pharmaceutically acceptable excipients suitable for oral administration. The compositions of the present invention comprise the desired amount of nanoparticles of the compound in admixture with one or more excipients, namely a pharmaceutically acceptable diluent, disintegrant, binder, adhesive, wetting agent, lubricant and/or anti-adherent agent. In addition, optionally, the nanoparticles themselves comprise one or more matrix polymers and/or surface modifying agents as described in the above-mentioned references. More preferably, these compositions are tableted or encapsulated in the form of immediate release capsules or tablets in a conventional manner.

By appropriate selection and combination of excipients, formulations can be prepared which exhibit, among other things, improved properties, efficacy, bioavailability, elimination time, stability, compatibility between celecoxib and excipients, safety, dissolution profile, disintegration profile and/or other pharmacokinetic, chemical and/or physical properties. The excipients are preferably water-soluble or water-dispersible and their wetting properties compensate for the low water solubility and hydrophobicity of the cyclooxygenase-2 inhibitor. When the formulation is formulated as a tablet, the combination of selected excipients produces tablets which, among other properties, have a suitable dissolution and disintegration profile, strength, breaking strength and/or friability.

The compositions of the present invention optionally contain one or more pharmaceutically acceptable diluents as additives. Suitable diluents, alone or in combination, include, for example, lactose USP; anhydrous lactose USP; spray-dried lactose USP; starch USP; directly compressible starch; confectioners' sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; granulated calcium-1-lactate dihydrate NF; dextrate NF (e.g. Emdex); Celutab; dextrose (e.g. Cerelose); inositol; hydrolyzed solid cereal products such as Maltrons and Mor-41 Rex; amylose; Rexcel; powdered cellulose (e.g. Elcema); calcium carbonate; glycine; bentonite; polyvinylpyrrolidone and the like. These diluents, if present, comprise a total of about 5% to about 99% by weight of the composition, preferably about 10% to about 85% by weight, and more preferably about 20% to about 80% by weight. The diluent or diluents are selected to provide, preferably, suitable free-flow properties and, in the case of tablets, compressibility.

Preferred diluents, alone or in combination, are lactose and microcrystalline cellulose. Both diluents are chemically compatible with celecoxib. Microcrystalline cellulose outside the granulate (i.e., microcrystalline cellulose added to the wet granulated formulation during the drying step) may be used to increase strength (in the case of tablets) and/or disintegration time. Lactose, especially lactose monohydrate, is particularly preferred. Lactose typically provides formulations that provide adequate cyclooxygenase-2 inhibitor release rates, stability, pre-compression free-flow properties, and/or drying properties at relatively low diluent costs. It also provides a high-density substrate that aids in densification during granulation (where wet granulation is used), thereby improving the free-flow properties of the blend.

- 42 The compositions of the invention optionally contain one or more pharmaceutically acceptable disintegrants as additives, especially tablet formulations. Suitable disintegrants, alone or in combination, include starches; sodium starch glycolate; clays (e.g. Veegum HV); celluloses (e.g. purified cellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose); alginates; pregelatinized corn starch (e.g. National 1551 and National 1550); crospovidone USP NF; and gums (e.g. agar, guar, locust bean, karaya, pectin or tragacanth). The disintegrants may be added at any suitable stage during the preparation of the compositions, in particular before granulation or before compression in the lubrication stage. Such disintegrants, if present, comprise from about 0.2% to about 30% by weight of the total weight of the composition, preferably from about 0.2% to about 10% by weight, and more preferably from about 0.2% to about 5% by weight.

A preferred disintegrant for tablet or capsule disintegration is croscarmellose sodium, which, when present, preferably constitutes an amount of between about 0.2% and about 10% by weight of the total weight of the composition, more preferably between about 0.2% and about 6% by weight, and even more preferably between about 0.2% and about 5% by weight. Croscarmellose sodium provides the compositions of our invention with outstanding intragranular disintegration capacity.

The compositions of the invention optionally contain one or more pharmaceutically acceptable binders or adhesives as additives, particularly in the case of tablet formulations. These binders and adhesives preferably promote adequate cohesion of the tableted powder, which allows the use of normal processing operations such as sizing, lubrication, compression and packaging, and also promote the disintegration of the tablet and the absorption of the composition during digestion. Suitable binders and adhesives, alone or in combination, include, but are not limited to, acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose (e.g. Tylose); alginic acid and alginic acid salts; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropyl methylcellulose (HPMC); hydroxypropyl cellulose (Klucel); ethyl cellulose (Ethocel); pregelatinized starch (e.g. National 1511 and Starch 1500). Such binders and/or adhesives, if present, comprise a total of about 0.5% to about 25% by weight of the total weight of the composition, preferably about 0.75% to about 15% by weight, and more preferably about 1% to about 10% by weight.

Polyvinylpyrrolidone is preferably used as a binder to provide cohesive properties to the powder mixture of cyclooxygenase-2 inhibitor and other granulation additives.

- 44ra. Polyvinylpyrrolidone, if present, comprises from about 0.5% to about 10% by weight of the total weight of the composition, more preferably from about 0.5% to about 7% by weight, and even more preferably from about 0.5% to about 5% by weight. Polyvinylpyrrolidone having a viscosity of up to about 20 cPs can be used, but preferably a viscosity of about 6 cPs or less, and more preferably about 3 cPs or less, is used. Polyvinylpyrrolidone provides cohesive properties to the powder mixture and the necessary bonding to form granules during wet granulation.

The cyclooxygenase-2 inhibitor compounds used in the present invention, particularly celecoxib, are highly insoluble in aqueous solution. Accordingly, the compositions of the present invention optionally but preferably also contain one or more pharmaceutically acceptable wetting agents as additives. These wetting agents are preferably selected to maintain the cyclooxygenase-2 inhibitor in close association with water. It is believed that this improves the relative bioavailability of the composition. Suitable wetting agents, alone or in combination, include oleic acid; glyceryl monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate; polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan monolaurate, sodium oleate and sodium lauryl sulfate. Preferred wetting agents are anionic surfactants. These wetting agents, when present, are completely

- They constitute a total amount of between about 0.25% and about 15% by weight, preferably between about 0.4% and about 10% by weight, and more preferably between about 0.5% and about 5% by weight, of the weight of the composition.

A preferred humectant is sodium lauryl sulfate. Sodium lauryl sulfate, when present, is present in an amount of from about 0.25% to about 7% by weight of the total weight of the composition, more preferably from about 0.4% to about 6% by weight, and even more preferably from about 0.5% to about 5% by weight.

The compositions of the present invention optionally contain one or more pharmaceutically acceptable lubricants and/or glidants as additives. Suitable lubricants and/or glidants, alone or in combination, include glyceryl behapate (Compritol 888); stearates (magnesium, calcium and sodium stearate); stearic acid; hydrogenated vegetable oils (e.g. Sterotex); talc; waxes; Stearowet; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g. Carbowax 4000 and Carbowax 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, comprise a total of between about 0.1% and about 10% by weight of the total weight of the composition, preferably between about 0.2% and about 8% by weight, and more preferably between about 0.25% and about 5% by weight.

- 46 Magnesium stearate is preferably used as a lubricant, for example during compression of the tablet formulation, to reduce adhesive friction between the equipment and the granulated mixture.

Other additives (e.g. anti-caking agents, colouring agents, flavouring agents, sweeteners and preservatives) are known to the pharmacist and may be used in the compositions of the invention. For example, iron oxide may be added to provide a yellow colour to the composition.

One embodiment of the invention is a unit dosage form of a capsule or tablet containing a desired amount of a selective cyclooxygenase-2 inhibitor, such as celecoxib, in partially or completely nanoparticulate form, together with a binder. Such a formulation preferably also contains one or more excipients, namely pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and lubricants. More preferably, the formulation contains one or more of the following excipients: lactose, sodium lauryl sulfate, polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Even more preferably, the formulation contains lactose monohydrate and/or croscarmellose sodium. More preferably, the composition also comprises one or more excipients, namely sodium lauryl sulfate, magnesium stearate and/or microcrystalline cellulose. Although the dosage unit of the capsule and tablet compositions of the present invention can be formed, for example, by direct encapsulation

- 47 or can be prepared by direct compression, preferably by wet granulation before encapsulation or compression. Wet granulation, among other things, can densify the milled composition, resulting in improved free-flow properties, improved compression characteristics, and easier weight measurement of the composition during encapsulation or tableting. The secondary particle size (i.e. granule size) resulting from granulation is not very critical, it is only important that the average granule size allows for conventional handling and processing of the tablets and the production of a directly compressible mixture from which pharmaceutically acceptable tablets are made.

The desired tapped density and bulk density of the granules are normally between about 0.3 g/ml and about 1.0 g/ml.

The additives in the capsule and tablet formulations of our invention are preferably selected to provide a disintegration time of less than 30 minutes, preferably about 25 minutes or less, more preferably about 20 minutes or less, and even more preferably about 15 minutes or less.

For tablet formulations, the total mixture required to produce a uniform batch of tablets is tableted in a conventionally sized tabletting machine at normal compression pressure (e.g., typically from about 1 kN to about 50 kN of force is applied to the tabletting die). Tablets of any strength suitable for handling, manufacturing, storage, and digestion can be produced.

- 48 can be produced. For 100 mg tablets, the strength is preferably at least 4 kP, more preferably at least about 5 kP, and even more preferably at least about 6 kP. For 200 mg tablets, the strength is preferably at least 7 kP, more preferably at least 9 kP, and even more preferably at least about 11 kP. However, the mixture is not compressed to an extent that would cause difficulty in subsequent hydration upon contact with gastric juice.

For tablet formulations, tablet friability is preferably less than about 1.0%, more preferably less than 0.8%, and even more preferably less than about 0.5% according to standard tests.

The invention also includes a method of treating conditions and disorders in which treatment with a cyclooxygenase-2 inhibitor is indicated, comprising administering one or more dosage units of the composition of the invention orally to a patient in need of such treatment. The dosage regimen for preventing, alleviating or reducing the condition or disorder preferably comprises the once-daily or twice-daily regimen as described above, but this may be modified by a number of factors. These include, for example, the type of individual, age, weight, sex, diet and medical condition, and the nature and severity of the disorder. Accordingly, the dosage regimen actually employed may vary widely and may therefore differ from the preferred dosage regimens given above.

- 49Treatment of an individual suffering from a condition or disorder for which a cyclooxygenase-2 inhibitor is indicated may be initiated at the dosages indicated above. Treatment is generally continued for a period of time sufficient to control or eliminate the condition or disorder, for example, for several weeks, several months, or several years. An individual undergoing treatment with a composition of the present invention may be examined by any conventional method known in the art to determine the efficacy of the therapy. Continuous analysis of these data allows modification of the treatment regimen during the course of therapy, whereby the optimally effective amount of cyclooxygenase-2 inhibitor may be administered at any time, and the duration of treatment may also be determined. In this manner, the treatment regimen or dosage regimen may be reasonably modified during the course of therapy, whereby the smallest amount of cyclooxygenase-2 inhibitor required for satisfactory efficacy is administered, and administration is continued for the period necessary to successfully treat the condition or disorder.

Our invention also extends to a method for preparing compositions of our invention comprising a poorly water-soluble selective cyclooxygenase-2 inhibitor, such as celecoxib, which comprises a partially or wholly nanoparticle. More particularly, our invention also extends to the preparation of such compositions in the form of discrete tablet or capsule unit dosage forms, each tablet or capsule containing an amount of cyclooxygenase-2 inhibitor sufficient to achieve the above-described rapid onset of therapeutic effect and to maintain therapeutic efficacy.

- 50% is required for a period of about 12 hours to about 24 hours. Each tablet or capsule preferably contains from about 50 mg to about 200 mg, for example about 50 mg, about 100 mg or about 200 mg of a cyclooxygenase-2 inhibitor, such as celecoxib. In the embodiment of the present invention, the tablet or capsule formulations of the present invention may be prepared by wet granulation, dry granulation or direct compression or encapsulation.

The pharmaceutical compositions of the present invention are preferably prepared by a wet granulation process. In the wet granulation process, the portion of the cyclooxygenase-2 inhibitor that is not in nanoparticulate form is first ground or micronized (optionally with one or more carriers) to the desired particle size range of greater than 1 pm. Although a variety of conventional milling or grinding equipment may be used, a more uniform mixture of the final composition is obtained by impact milling of the active ingredient, such as in a pin mill, compared to other types of milling processes. For example, liquid nitrogen may be used to cool the milled material during milling to avoid heating the cyclooxygenase-2 inhibitor to undesirable temperatures. During this milling step, the D ₉₀ particle size is preferably reduced to less than about 25 pm.

Then, the ground or micronized cyclooxygenase-2 inhibitor, if used, is added in the desired amount.

- 51 • · · · I ·· ··· • · · · · · · · · · · «*· mixed with a cyclooxygenase-2 inhibitor in nanoparticulate form, which can be prepared by any of the above-mentioned literature processes, to prepare a cyclooxygenase-2 inhibitor compound in partial or complete nanoparticulate form (compound nanoparticle). Simultaneously or subsequently, the compound nanoparticle is mixed with one or more additives, for example, additives that are co-milled with the celecoxib or are present in the nanoparticles to prepare a dry powder blend, for example, in a high shear mixer/granulator, planetary mill, twin roller mixer or sigma mixer. In this step, the compound nanoparticles are typically mixed with one or more diluents, disintegrants and/or binders and optionally one or more wetting agents, although in one embodiment all or part of the additives may be added in this step. It has been found that in tablet formulations where croscarmellose sodium, for example, is used as a disintegrant, the disintegration properties of the tablets produced can be improved by adding a portion of the croscarmellose sodium in the mixing step (intragranular croscarmellose sodium) and the remainder after the drying step as described above (extragranular croscarmellose sodium). In this case, preferably between about 60% and about 75% of the croscarmellose sodium is added intragranularly and between about 25% and about 40% of the croscarmellose sodium is added extragranularly. We have also found that in the preparation of tablet formulations, the addition of microcrystalline cellulose before the drying step (extragranular microcrystalline cellulose) can improve the compressibility of the granules and the strength of the tablets produced from the granules.

In the mixing step of the process, the compound nanoparticles are preferably mixed with lactose, p ο I i v i n i I p i rro I i d ο η n a I and croscarmellose sodium. We have found that in just three minutes of mixing time, a dry powder mixture can be produced in which the cyclooxygenase-2 inhibitor is distributed sufficiently uniformly.

Water, preferably purified water, is then added to the dry powder mixture and the mixture is further mixed to form a wet granulated mixture. Preferably, a wetting agent is also used and preferably this is first added to the water and then mixed for at least 15 minutes, preferably at least 20 minutes, before adding the water to the dry powder mixture. The water is added to the mixture all at once, gradually over a defined period of time or in several portions. The water is preferably added gradually over a defined period of time. In one embodiment, the wetting agent is added to the dry powder mixture and the water is added to the resulting mixture. After the total amount of water has been added, the mixture is preferably further mixed to ensure uniform incorporation of the water.

The wet granulated mixture is then wet milled, for example in a screen mill, to remove large agglomerates of material which are by-products of the wet granulation process. If these agglomerates are not removed, they will extend the duration of the subsequent fluidized bed drying process and produce products with varying moisture contents.

The wet granulated or wet milled mixture is then dried, for example in an oven or in a fluidized bed dryer, preferably in a fluidized bed dryer, to form dry granules. If desired, the wet granulate mixture is extruded or spheronized before drying. In the drying process, the conditions, such as the inlet air temperature and the drying time, are adjusted to achieve the desired moisture content of the dry granules. It may be advantageous to combine two or more granulation stages in this drying step and in the subsequent processing step.

The dry granules are then reduced in size to the desired size for compression or encapsulation. Conventional particle size reduction equipment may be, for example, an oscillator or a pin mill (e.g., a Fitz mill).

It was observed that for mixtures containing a smaller amount of water, the granule size decreases slightly with increasing grinding time. It can be assumed that when the water concentration is too low, the cohesive forces between the primary particles in the granule are not sufficient to fully activate the binder used, against the shear forces created by the mixing paddles, and the granule size decreases rather than increases. On the contrary, by increasing the amount of water added to fully activate the binder, the cohesive forces between the primary particles become strong enough to withstand the shear forces created by the mixing paddles, and the granule size increases rather than decreases with increasing mixing time and/or water addition rate. Changing the screen size of the wet mill has a greater effect on the granule size than changing the addition rate and/or the grinding speed.

The dry granules are then placed in a suitable mixer, such as a twin-roll mixer, and optionally a lubricant (e.g., magnesium stearate) and any additional excipients (e.g., extragranular microcrystalline cellulose and/or extragranular croscarmellose sodium in certain tablet formulations) are added to form the final blend. When the diluent comprises microcrystalline cellulose and a portion of the microcrystalline cellulose is added during this step, it has been found that the compressibility of the granules and the strength of the tablet are significantly increased. However, increasing the amount of magnesium stearate to between about 1% and about 2% decreases the strength of the tablet and increases its friability and dissolution time.

The final blend is then encapsulated (if tablets are being prepared, compressed into tablets of the desired weight and strength using a suitably sized tool). Conventional compression and encapsulation techniques known to those skilled in the art can be used. For capsules, suitable results are obtained with a bed height of between about 20 mm and about 60 mm, a compression setting of between about 0 and about 5 mm, and a compression ratio of about 60,000.

- Using a production rate of between 55 capsules/hour and about 130,000 capsules/hour. By using the lowest compression setting at which the capsule weight can still be controlled, waste generation can be minimized or eliminated. When coated tablets are required, conventional coating processes known to those skilled in the art can be used.

This combination of processing units can produce granules whose unit dose content of cyclooxygenase-2 inhibitor, e.g. celecoxib, is uniform, disintegrates rapidly, has a sufficiently free-flowing property, whereby the weight change during capsule filling or tableting can be reliably controlled, and forms a sufficiently dense mass, whereby the batch can be processed in the selected equipment and the doses can be adjusted according to the given capsule or tablet tool.

Our invention extends to the use of the compositions of our invention for the preparation of pharmaceutical compositions suitable for the treatment and/or prevention of cyclooxygenase-2 mediated conditions and disorders, particularly conditions and disorders where a rapid onset of therapeutic effect is desired or required.

Our invention includes a novel solid form of celecoxib, celecoxib form I. Our invention also includes another solid form of celecoxib, celecoxib form II. Each of these novel solid forms is, for example, a solvated crystalline form, an unsolvated or non-hydrated crystalline form. The celecoxib described in our present application

- These new forms exhibit one or more of the above-described advantageous chemical and/or physical properties compared to other solid state forms described herein and elsewhere in the literature.

In one embodiment of the invention, the solid state form is celecoxib Form I. Without limiting the invention, it is believed that Form I of celecoxib has a greater solubility and dissolution rate than Form III because Form III is thermodynamically more stable than Form I, and because Form III has a lower free energy than Form I. A rapid dissolution rate is useful because as the dissolution rate of an active ingredient increases, its bioavailability typically increases.

Celecoxib Form I is a crystalline form with X-ray powder diffraction peaks occurring at approximately 5.5° 5 7° 7 2° and 16.6° 2-theta. The X-ray powder diffraction pattern of celecoxib Form I corresponds substantially to the 1a spectrum shown in Figure 1. The melting point of celecoxib Form I is between about 162.5°C and about 163°C, preferably about 162.8°C. The differential scanning calorimetry endothermic curve of celecoxib Form I, scanned at a rate of 0.5°C/min, exhibits a maximum at about 163.3°C, as shown in Figure 3. The infrared spectrum of celecoxib Form I is shown in Figure 2, where peaks appear between 3250 ^cm'1 and 3260 ^cm'1 , with additional peaks between 3350 cm'' and 3360 ^cm'1 . The peaks preferably appear between about 3256 ^cm'1 and 3356 cm ^' '. Our invention

- The solid forms of claim 57 have a phase purity of at least about 5% celecoxib Form I, preferably at least about 10% celecoxib Form I, more preferably at least about 25% celecoxib Form I, even more preferably at least about 50% celecoxib Form I, even more preferably at least about 75% celecoxib Form I, even more preferably at least about 90%, and even more preferably substantially phase pure celecoxib Form I.

Another embodiment of our invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of celecoxib in solid form and at least one pharmaceutically acceptable carrier, excipient or diluent, wherein the solid form of celecoxib comprises at least 2% celecoxib Form I, and preferably 10% celecoxib Form I, more preferably 50% celecoxib Form I, and even more preferably 98% celecoxib Form I. In a preferred embodiment of our invention, the solid form of celecoxib is predominantly Form I celecoxib.

Another embodiment of our invention is a method for treating or preventing a cyclooxygenase-2 mediated condition or disorder comprising administering to a subject a therapeutically effective amount of celecoxib Form I. The cyclooxygenase-2 mediated condition or disorder to be treated or prevented is preferably pain, inflammation, arthritis, tumor growth, metastasis, or hereditary adenomatous polyposis.

- 58 Another embodiment of our invention is the preparation of Form I of celecoxib, which process comprises crystallizing Form I celecoxib from a mixture of celecoxib and a solvent, which crystallization process is carried out at a temperature above the enantiotropic transformation temperature of Form I celecoxib. Prior to crystallization of Form I of celecoxib, the solvent is seeded with a seed crystal of Form I celecoxib, resulting in the formation of Form I celecoxib with at least about 5% by weight phase purity, preferably at least about 10% by weight phase purity, more preferably at least about 25% by weight phase purity, more preferably at least about 50% by weight phase purity, and even more preferably at least about 90% by weight phase purity.

Our invention relates to the preparation of a crystalline form of celecoxib, which process comprises heating a solvate of celecoxib to form celecoxib Form I. The solvate is heated, for example, to a temperature of about 50°C to 160°C, preferably to a temperature of about 60°C to about 150°C, more preferably to a temperature of about 70°C to about 140°C, even more preferably to a temperature of about 80°C to about 130°C, even more preferably to a temperature of about 85°C to about 120°C, even more preferably to a temperature of about 90°C to about 110°C, and more preferably to a temperature of about 100°C. The heating is carried out for a suitable period of time, for example, for more than about 1 minute, preferably for more than about 5 minutes, even more preferably for more than about

- 59 within 60 minutes, more preferably about 2 hours, and even more preferably about 4 hours or more. Furthermore, the process can be carried out at any pressure, preferably subatmospheric. The solvate used in the present invention comprises celecoxib and a solvent. The quenching agent can be, for example, an amide solvent. Suitable amide solvents include N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1,1,3,3-tetramethylurea or a mixture of any of these solvents. The solvent used is preferably 1,1,3,3-tetramethylurea. Also a preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Also a preferred solvent is 1-methyl-2-pyrrolidinone. Another preferred solvent is N,N-dimethylformamide. Also a preferred solvent is N,N-dimethylacetamide.

The solvate can be prepared by mixing celecoxib with an amide solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1,1,3,3-tetramethylurea or a mixture of any of these solvents. The solvent is preferably 1,1,3,3-tetramethylurea. Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro2(1H)-pyrimidinone. Another preferred solvent is 1-methyl-2-pyrrolidinone. More preferably, the solvent is N,N-dimethylformamide. Also preferred is N,N-dimethylacetamide.

Our invention also extends to the preparation of celecoxib Form I, which process comprises grinding celecoxib Form III.

- 60 - < ,:, z, -% or grinding. In the grinding step, for example, wet grinding or ball milling is used. In the grinding step, for example, grinding or shaking is used.

Our invention also includes a process for preparing celecoxib Form I, which comprises milling or comminuting a celecoxib solvate. The milling step may be performed, for example, by wet milling or ball milling. The milling step may be performed, for example, by comminuting or shaking.

Another embodiment of our invention relates to the preparation of celecoxib Form I, in which celecoxib Form II is melted and celecoxib Form I is prepared by cooling the melt.

Another embodiment of our invention relates to the preparation of celecoxib Form I by melting celecoxib Form III and cooling the melt to produce celecoxib Form I.

Our invention also includes a method for preparing celecoxib Form I by removing the solvent from a solution of celecoxib. The solvent may be, for example, an ether or a hydrocarbon, or a mixture of ether and hydrocarbon. The solvent is preferably ethyl acetate and heptane, preferably mixed in a ratio of 15:85. Our invention can be carried out at any pressure, but preferably at a pressure less than atmospheric pressure. The process can be carried out over a wide temperature range, preferably at about 35 °C.

Another embodiment of our invention is a solid state formulation comprising Form II celecoxib.

- 61 • « ·» 4Wt

Without limiting the invention, it is believed that Form II of celecoxib has a greater solubility and dissolution rate than Form III because Form III is thermodynamically more stable than Form II and because the free energy of Form III is lower than that of Form II. A rapid dissolution rate is useful because as the dissolution rate of an active ingredient increases, its bioavailability typically increases.

The X-ray powder diffraction pattern of celecoxib Form II shows peaks at 10.3°, 13.8°, 17.7° 2-theta. The peaks of the mixture of Form I and Form II are shown in the upper part of Figure 1, spectrum 1b. The melting point of Form II celecoxib is between about 161°C and about 162°C, preferably about 161.5°C. The endothermic peak of Form II celecoxib, determined by differential scanning calorimetry, has a maximum at about 162.0°C at a scan rate of 0.5°C/min. Form II celecoxib is expected to have higher solubility and to dissolve more rapidly than Form III celecoxib. The solid form of the present invention has a phase purity of at least about 5%, preferably at least about 10%, more preferably at least about 25%, even more preferably at least about 50%, even more preferably at least about 75%, even more preferably at least about 90%, and even more preferably the Form II celecoxib is in a substantially phase pure form.

Another embodiment of our invention is a pharmaceutical composition comprising a solid form of celecoxib.

- a pharmaceutically effective amount of Form 62 and at least one pharmaceutically acceptable carrier, excipient or diluent, wherein the solid form of celecoxib comprises at least 2% Form II celecoxib and preferably 10% Form II celecoxib or more preferably 50% Form II celecoxib, even more preferably 98% Form II celecoxib. In a preferred embodiment, the solid form of celecoxib is predominantly Form II celecoxib.

Another embodiment of the invention is a method for treating or preventing a condition or disorder mediated by cyclooxygenase-2, comprising administering to a subject a therapeutically effective amount of celecoxib Form II. Preferably, the cyclooxygenase-2 mediated condition or disorder to be treated or prevented is pain, inflammation, arthritis, tumor growth, metastasis, or hereditary adenoma polyposis.

A further embodiment of the invention is a process for preparing celecoxib Form II from a mixture containing a solvent, wherein the celecoxib Form II is crystallized at a temperature above its enantiotropic transformation temperature to produce celecoxib Form II. Prior to crystallization of celecoxib Form II, the solvent is seeded with a seed crystal of celecoxib Form II, thereby producing celecoxib Form II with at least about 5% by weight phase purity, preferably at least about 10% by weight phase purity, and more preferably at least about 25% by weight phase purity.

- 63Our invention also extends to the preparation of a crystalline form of celecoxib, which process comprises heating a celecoxib solvate to produce Form II of celecoxib. The solvate is heated, for example, to a temperature of about 50°C to about 160°C, preferably to a temperature of about 60°C to about 145°C, more preferably to a temperature of about 70°C to about 140°C, even more preferably to a temperature of about 80°C to about 140°C, even more preferably to a temperature of about 90°C to about 140°C, even more preferably to a temperature of about 100°C to about 140°C, even more preferably to a temperature of about 110°C to about 140°C, even more preferably to a temperature of about 120°C to about 140°C, even more preferably to a temperature of about 125°C to about 135°C, and even more preferably to a temperature of about 130°C. Heating may be carried out for any conventional period of time, for example, greater than about 1 minute, preferably greater than about 5 minutes, more preferably greater than about 60 minutes, more preferably greater than about 2 hours, and most preferably greater than about 4 hours or longer. In addition, this process may be carried out at any pressure, most preferably subatmospheric. The solvate used in the present invention comprises celecoxib and a solvent. The solvent is, for example, an amide solvent. Suitable amide solvents include N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and 1,1,3,3- 64···· * | ·· ···· • · ♦ ·’ ····

-tetramethylurea or a mixture of any of these solvents. The solvent is preferably 1,1,3,3-tetramethylurea. Also a preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. A more preferred solvent is 1-methyl-2-pyrrolidinone. An even more preferred solvent is N,N-dimethylformamide. An even more preferred solvent is N,N-dimethylacetamide.

According to another embodiment of our invention, during the preparation of celecoxib Form II, the celecoxib solvate is heated, which solvate is prepared by mixing celecoxib with an amide type solvent, namely N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1,1,3,3-tetramethylurea or a mixture of any of these solvents, preferably 1,1,3,3-tetramethylurea, more preferably 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone, even more preferably 1 -methyl-2-pyrrolidinone, even more preferably Ν,Ν-dimethylformamide and most preferably N,N-dimethylacetamide.

A further embodiment of our invention is a solid form of celecoxib comprising celecoxib Form I and celecoxib Form II.

A more preferred embodiment of our invention is a solid form of celecoxib comprising celecoxib Form I and celecoxib Form III.

A further preferred embodiment of our invention is a solid form of celecoxib comprising Form II and Form III celecoxib.

- 65 A further embodiment of our invention is a solid form of celecoxib comprising celecoxib Form I, celecoxib Form II and celecoxib Form III.

Our invention also includes a process for preparing celecoxib Form II, which comprises grinding or comminuting celecoxib Form III. A suitable grinding step is, for example, wet grinding or ball milling. A suitable grinding step is, for example, grinding or shaking.

Our invention also includes a process for preparing celecoxib Form I, which comprises grinding or milling a celecoxib solvate. The grinding step may, for example, be performed by milling or ball milling. A suitable grinding step may, for example, be performed by grinding or shaking.

Another preferred embodiment of our invention is a process for preparing Form II celecoxib, wherein Form I celecoxib is melted and the melt is cooled to produce Form II celecoxib.

Another embodiment of our invention relates to a process for preparing Form II celecoxib, wherein Form III celecoxib is melted and the melt is cooled to produce Form II celecoxib.

Form III of celecoxib is prepared by crystallization of celecoxib from a solvent containing isopropanol and water, as described, for example, in U.S. Patent No. 5,910,597.

Differential scanning calorimetry melting transformation of celecoxib form III shows a complex picture. When

Scanning at a rate of 0.5 °C/min, celecoxib Form III melts at approximately 160.8 °C, then crystallizes to celecoxib Form II, and finally Form II melts at approximately 162.0 °C. The thermodynamically stable form of celecoxib is Form III celecoxib.

Characterization of polymorphic crystal forms of celecoxib

Powder X-ray diffraction (PXRD), infrared absorption spectroscopy (IR), differential scanning calorimetry (DSC), and Raman spectroscopy are used to characterize Form I and Form II.

Powder X-ray diffraction (PXRD)

The different crystal forms of celecoxib are analyzed using a Siemens D5000 powder diffractometer or an Inéi Multipurpose diffractometer. When using the Siemens D5000 powder diffractometer, the raw data is determined between 2° and 50° 2-theta values in 0.02° increments and with a step time of two seconds. When using the Inéi Multipurpose diffractometer, the samples are placed in an aluminum sample holder and the raw data is collected simultaneously for 30 minutes for all 2-theta values.

Figure 1 shows that the three forms are easily distinguished by PXRD. Using a copper X-ray source (1.54 nm), characteristic diffractions are observed at approximately 5.5°, 5.7°, 7.2°, and 16.6° 2-theta values for celecoxib Form I and approximately 10.3°, 13.8°, and 17.7° for celecoxib Form II.

- 67 Melting/decomposition temperature

The melting and/or decomposition temperatures of the unsolvated celecoxib crystal forms were determined using a TA Instruments 2920 differential scanning calorimeter. Each sample (1-2 mg) was placed in a sealed or unsealed aluminum holder and heated at a rate of 0.5 °C/min. The melting/decomposition ranges were determined from the extrapolated location of the maximum of the melting/decomposition endotherm.

Three polymorphic forms of celecoxib are identified. Polymorphic form I of celecoxib melts at about 162.8°C, form II of celecoxib melts at about 161.5°C, and form II of celecoxib melts at about 160.8°C. During melting of form III of celecoxib, it is observed to partially recrystallize to form II of celecoxib or form I of celecoxib.

Three polymorphic forms and N,N-dimethylacetamide (DMA) and N,N-dimethylformamide (DMF) solvates are identified. The physical properties and distinguishing features of the new polymorphs are shown in Table 1.

Table 1

Form I Melting point (°C) ΔΗ (J/g) Distinguished transformations* IR Raman PXRD (2 theta) I 162.8 72 3256 cm' ¹ 3356 cm' ¹ NA 5.5°, 5.7°, 7.2° and 16.6° II** 161.5 <84 none 712 cm' ¹ 10.3°, 13.8° and 17.7° J 160.8 91 — —

- 68 We do not observe any transformations typical of other forms.

** Pure Form II celecoxib sample was not prepared.

Differential scanning calorimetry (DSC)

DSC is used to characterize the polymorphic form of celecoxib. Form I of celecoxib is the highest melting polymorph, melting at 162.8 °C and having an endothermic peak maximum at 163.3 °C. Form II of celecoxib melts at 161.5 °C and having an endothermic peak maximum at 162.0 °C. A complex transformation is observed for Form III of celecoxib. The complexity of this transformation, which is only observed at slow scan rates, involves melting of Form III of celecoxib, followed by recrystallization to Form II of celecoxib, followed by melting of Form II of celecoxib. Considering only the endothermic transformations, Form III of celecoxib melts at 160.8 °C and has an endothermic peak maximum at 161.5 °C. A small amount of Form I of celecoxib is detected in Form III of celecoxib by DSC.

Infrared absorption spectroscopy

Celecoxib Form I can be distinguished from celecoxib Form II and celecoxib Form III by IR, as shown in Figure 2.

Without further investigation, it is believed that, based on the above description, a person skilled in the art can fully utilize the solution according to our invention. Therefore, the following preferred specific embodiments are presented for illustrative purposes only and we do not intend to limit our invention to the remaining parts of the description.

Examples

The following examples describe in detail the preparation of celecoxib crystals of Form I and Form II according to our invention. These details are within the scope of our invention and are intended to illustrate our invention through them. The details are provided for illustrative purposes only and are not intended to limit the scope of our invention to the contents contained therein. All amounts are in parts by weight and temperatures are in °C unless otherwise indicated. The starting material celecoxib used in each of the following examples was prepared as described in U.S. Patent No. 5,910,597.

Production examples

Example 1

Preparation of the Ν,Ν-dimethylacetamide (DMA) solvate of celecoxib (celecoxib-DMA ratio 1:1)

Procedure A: In a round bottom flask, 4.84 g of celecoxib and approximately 125 mL of N,N-dimethylacetamide were mixed. The solvent was removed under reduced pressure and crystallization was initiated at 60 °C. The dry solid was collected on a filter. This procedure produced 5 g of a 1:1 solvate. TGA at 10 °C/min

- 70··*’. .: .··.:··· * · « · · · ** ·

Method B: In a 1 L beaker, 38.2 g of celecoxib and approximately 1000 ml of N,N-dimethylacetamide are weighed and mixed. The resulting solution is transferred to a 2 L beaker. Approximately 400 ml of water is added to initiate crystallization. The crystals are isolated by filtration. The wet yield is 5.44 g. Additional crystals are formed by adding water to the filtrate. TGA at a rate of 10 °C/min indicates decomposition at approximately 100 °C and a maximum at approximately 150 °C. The total weight loss is 1 8 % solvent.

Example 2

Preparation of the dimethylformamide solvate of celecoxib (celecoxib-dimethylformamide ratio 1:1)

In a crystallizing dish, approximately 1 g of celecoxib is dissolved in 50 ml of dimethylformamide. The crystallizing dish is covered with aluminum foil, in which small holes are cut, then placed under a hood and evaporated to dryness. This procedure yields approximately 1.02 g of product. TGA at 10 °C/min shows two mass losses during decomposition, one starting at approximately 75 °C and a second with a maximum at approximately 156 °C. The total mass loss is 13.4%.

- 71 EXAMPLES

Example 1

General procedures for the preparation of celecoxib Form I

Process A: Preparation of celecoxib Form I by heating celecoxib solvate

The celecoxib solvate was heated in an open container in an oven at the lowest temperature at which desolvation was observed. Briefly, 0.3 g of celecoxib dimethylacetamide solvate was heated in an oven at about 100°C for about 48 hours. PXRD analysis of the resulting sample showed characteristic reflections corresponding to celecoxib Form I and reflections of celecoxib-DMA; TGA analysis showed a 9.6% weight loss at about 147°C, indicating about 50% conversion to Form I.

Process B: Preparation of celecoxib Form I by evaporation

A high purity sample of celecoxib was crystallized from ethyl acetate-heptane by evaporation. 16.03 g of celecoxib was purified by preparative liquid chromatography on a 150 mm column (50.8 mm id) containing 40-63 mcm silica gel using 15/85 ethyl acetate/heptane. Fractions between 270 ml and 900 ml were collected and pooled. The solvent was removed under vacuum at approximately 35 °C to initiate crystallization and evaporated to dryness. This procedure yielded 8.6 g of celecoxib Form I. The crystals were TGA-identified as

- 72 do not contain any solvent and their PXRD pattern corresponds to form I, as shown in the spectrum 1a shown in Figure 1.

Process C: Preparation of celecoxib Form I by melting

Briefly, celecoxib is placed in an open container and melted, then allowed to cool. In more detail, a beaker containing celecoxib is heated to 170°C on a hot plate and the celecoxib is allowed to melt completely. The molten celecoxib is then poured into a watch glass and allowed to cool. DSC scanning at a rate of 0.5°C/min indicates a melting of Form I at approximately 163°C. Melting of Form III and recrystallization of Form II and melting of Form II are also observed.

Example 2

General procedures for the preparation of celecoxib form II

A. Preparation of celecoxib form II by heating celecoxib solvate

1. Application of dimethylacetamide solvate

Briefly, an open container containing celecoxib dimethylacetamide solvate is heated in an oven at a temperature close to the peak temperature of the observed desolvation. In detail, 0.3 g of celecoxib dimethylacetamide is heated in an oven at about 130 °C for about 48 hours. The PXRD pattern of the resulting sample shows

- 73Celecoxib form II and celecoxib form III reflections are visible; DSC analysis at 0.5 °C/min shows a single melting endotherm at 161.4 °C with a maximum at 161.9 °C, TGA analysis shows no weight loss below 200 C. The X-ray powder diffraction pattern of the mixture is shown in the spectrum 1b in Figure 1.

2. Application of dimethylformamide solvate

Briefly, the celecoxib dimethylformamide solvate is heated in an open container in an oven at a temperature close to the peak temperature of observed desolvation. More specifically, about 0.2 g of celecoxib dimethylformamide is heated in an oven overnight at about 130 °C. The resulting sample shows characteristic reflections of celecoxib Form II and reflections of celecoxib Form III; DSC at a rate of 0.5 °C/min shows a melting endotherm starting at 161.5 °C and peaking at 161.8 °C, and a small endotherm with a peak at about 163.8 °C (Form I); TGA shows no weight loss below 200 °C.

B. Preparation of celecoxib form II from celecoxib form III by mechanical conversion

Briefly, celecoxib Form III is milled in a planetary mill. In more detail, celecoxib Form III is milled using a “wiggle-bug” at maximum intensity for 30 seconds. The resulting solid

- 74A mixture of form III and form II, which is examined by X-ray powder diffraction.

C. Preparation of celecoxib form II by melting

Celecoxib is melted in a test tube at 170 °C in an oil bath. A Teflon spatula is dipped into the molten celecoxib, the spatula is removed, scraped and the dried solid is collected. The dried solid is a mixture of Form II and Form III according to X-ray powder diffraction. DSC at 10 °C/min also shows the presence of Form I.

Claims (175)

- 75Patent claims 1. Celecoxib crystal form I. 2. The crystalline form of claim 1, having an X-ray powder diffraction spectrum with peaks at approximately the following 2-theta values: 5.5°, 5.7°, 7.2° and 16.6°. 3. The crystal form of claim 1, having an X-ray powder diffraction spectrum substantially corresponding to the spectrum 1a of Figure 1. The crystalline form of claim 1, having a melting range of about 160°C to about 164°C. 5. The crystalline form of claim 1, having a melting range of about 162°C to about 163°C. 6. The crystalline form of claim 5, having a melting point of about 162.8°C. 7. The crystalline form of claim 5, having an endothermic peak between about 160.0°C and about 164.0°C as determined by differential scanning calorimetry. 8. The crystalline form of claim 5, having an endothermic peak at about 163.3°C. 9. The crystalline form of claim 8, having a further melting range of about 160°C to about 164°C. 10. The crystalline form of claim 9, having a melting point of about 162.8°C. 11. The crystalline form of claim 1, having an infrared spectrum having a peak between about 3250 cm ^-1 and about 3260 cm ^-1 . 12. The crystalline form of claim 11, having an infrared spectrum showing a peak at about 3256 cm ^-1 . 13. The crystalline form of claim 1, having an infrared spectrum having a peak between about 3350 cm ^-1 and about 3360 cm ^-1 . 14. The crystalline form of claim 13, wherein the infrared spectrum exhibits a peak at approximately 3356 cm- ¹ . 15. The crystalline form of claim 1, having infrared peaks at about 3256 cm ^-1 and about 3356 cm ^-1 and a melting point of about 162.8°C. 16. The crystalline form of claim 1, having a phase purity of at least about 5% for Form I celecoxib. 17. The crystalline form of claim 1, having a phase purity of at least about 10% for Form I celecoxib. 18. The crystalline form of claim 1, wherein the phase purity of Form I celecoxib is at least about 25%. 19. The crystalline form of claim 1, wherein the phase purity of Form I celecoxib is at least about 50%. 20. The crystalline form of claim 1, wherein the phase purity of Form I celecoxib is at least about 75%. 21. The crystalline form of claim 1, wherein the phase purity of Form I celecoxib is at least about 90%. 22. The crystalline form of claim 1, which is substantially a phase-pure form of Form I celecoxib. 23. A pharmaceutical composition comprising a pharmaceutically effective amount of a crystalline form according to any one of claims 2-22 and at least one pharmaceutically acceptable carrier, excipient and/or diluent. 24. The composition of claim 23, wherein the celecoxib comprises at least 2% Form I celecoxib. 25. The composition of claim 23, wherein the celecoxib comprises at least 10% Form I celecoxib. 26. The composition of claim 23, wherein the celecoxib comprises at least 50% Form I celecoxib. 27. The composition of claim 23, wherein the celecoxib comprises at least 98% Form I celecoxib. 28. The composition of claim 23, wherein the celecoxib is predominantly Form I celecoxib. 29. A method for treating or preventing a cyclooxygenase-2 mediated condition in an individual, comprising administering to the individual a pharmaceutical form of celecoxib Form I. - We administer an effective amount of 78. 30. The method of claim 29, wherein the condition or disorder is pain. 31. The method of claim 29, wherein the condition or disorder is inflammation. 32. The method of claim 29, wherein the condition or disorder is arthritis. 33. The method of claim 29, wherein the condition or disorder is tumor growth. 34. The method of claim 29, wherein the condition or disorder is metastasis. 35. The method of claim 29, wherein the condition or disorder is hereditary adenomatous polyposis. 36. A process for preparing celecoxib Form I, comprising crystallizing celecoxib from a mixture containing celecoxib and a solvent, said crystallization being carried out at a temperature above the enantiotropic transformation temperature of celecoxib Form I, thereby producing celecoxib Form I. 37. The process of claim 36, wherein the solvent is seeded with a seed crystal of celecoxib Form I prior to crystallization. 38. The process of claim 36, wherein at least about 5% by weight of Form I celecoxib is produced. 39. The process of claim 36, wherein at least about 10% by weight of Form I celecoxib is produced. 40. The process of claim 36, wherein celecoxib Form I is produced at least about 50% by weight of phase purity. 41. The process of claim 36, wherein celecoxib Form I is produced with a phase purity of at least about 90% by weight. 42. The process of claim 36, wherein at least about 25% by weight of Form I celecoxib is produced. 43. A process for preparing a crystalline form of celecoxib, comprising heating a solvate of celecoxib to produce Form I celecoxib. 44. The process of claim 43, wherein the solvate is heated to a temperature of between about 50°C and about 160°C. 45. The method of claim 43, wherein the solvate is heated to a temperature of between about 60°C and about 150°C. 46. The process of claim 43, wherein the solvate is heated to a temperature of between about 70°C and about 140°C. 47. The process of claim 43, wherein the solvate is heated to a temperature of between about 80°C and about 130°C. 48. The process of claim 43, wherein the solvate is heated at a temperature of about 85°C and about - Heat to a temperature between 80 and 120 °C. 49. The process of claim 43, wherein the solvate is heated to a temperature of between about 90°C and about 110°C. 50. The process of claim 43, wherein the solvate is heated to about 100°C. 51. The method of claim 43, wherein the solvate is heated for a period of time greater than about 1 minute. 52. The method of claim 43, wherein the solvate is heated for a period of time greater than about 5 minutes. 53. The method of claim 43, wherein the solvate is heated for a period of time greater than about 60 minutes. 54. The process of claim 43, wherein the solvate is heated for a period of time greater than about 2 hours. 55. The process of claim 43, wherein the solvate is heated for about 4 hours or longer. 56. The method according to any one of claims 43-55, characterized in that the heating is carried out at a pressure less than atmospheric. 57. The method of claim 56, wherein the solvate is a solvate comprising celecoxib and an amide type solvent. 58. The process according to claim 57, wherein the amide type solvent is N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or 1,1,3,3-tetramethylurea. 59. The process according to claim 58, characterized in that the amide type solvent used is N,N-dimethylformamide. 60. The process according to claim 58, characterized in that the amide type solvent used is N,N-dimethylacetamide. 61. The process according to claim 58, characterized in that 1-methyl-2-pyrrolidinone is used as the amide type solvent. 62. The process according to claim 58, characterized in that the amide type solvent used is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. 63. The process according to claim 58, characterized in that the amide type solvent used is 1,1,3,3-tetramethylurea. 64. The process of claim 58, wherein the celecoxib solvate is prepared by mixing celecoxib with an amide type solvent selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and/or 1,1,3,3-tetramethylurea. 65. The process according to claim 64, characterized in that N,N-dimethylformamide is used as the solvent. 66. The process of claim 64, wherein the solvent used is N,N-dimethylacetamide. 67. The process of claim 64, wherein the solvent used is 1-methyl-2-pyrrolidinone. 68. The process according to claim 64, characterized in that the solvent used is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. 69. The process according to claim 64, characterized in that 1,1,3,3-tetramethylurea is used as the solvent. 70. A process for preparing celecoxib Form I, comprising grinding or comminuting celecoxib Form III to produce celecoxib Form I. 71. The method of claim 70, wherein celecoxib Form III is ground. 72. The method according to claim 71, characterized in that the grinding is carried out using a wet grinding process. 73. The method according to claim 71, characterized in that ball milling is used as the milling. 74. The method of claim 70, wherein celecoxib Form III is ground. 75. The method according to claim 74, characterized in that the comminution is carried out by shaking. 76. A process for preparing celecoxib Form I, comprising grinding or comminuting a celecoxib solvate to produce celecoxib Form I. 77. The method of claim 76, wherein celecoxib solvate is milled. 78. The method according to claim 77, characterized in that the grinding is carried out using a wet grinding process. 79. The method according to claim 77, characterized in that ball milling is used as the milling. 80. The method of claim 76, wherein celecoxib solvate is crushed. 81. The method according to claim 80, characterized in that the comminution is carried out by shaking. 82. A process for preparing celecoxib Form I, comprising melting celecoxib Form II and cooling the melt to produce celecoxib Form I. 83. A process for preparing celecoxib Form I, comprising melting celecoxib Form III and cooling the melt to produce celecoxib Form I. 84. A process for preparing celecoxib Form I, characterized in that the solvent is evaporated from a solution of celecoxib, thereby preparing celecoxib Form I. 85. The process according to claim 84, characterized in that the solvent used is an ether or a hydrocarbon. 86. The process of claim 84, wherein a solvent comprising an ether and a hydrocarbon is used. 87. The method of claim 86, wherein j e I I e - 84m e z v e that a solvent containing ethyl acetate and heptane is used. 88. The process of claim 76, wherein the ethyl acetate and heptane are used in a ratio of about 15:85. 89. The method of claim 84, wherein the evaporation is carried out at atmospheric pressure. 90. The process of claim 84, wherein the evaporation is carried out at a temperature of about 35°C. 91. Crystal form II of celecoxib. 92. The crystalline form of claim 91, having an X-ray powder diffraction spectrum showing peaks at approximately the following 2-theta values: 10.3°, 13.8° and 17.7°. 93. The crystal form of claim 91, having an X-ray powder diffraction spectrum substantially corresponding to the spectrum 1a of Figure 1. 94. The crystalline form of claim 91, having a melting range of about 159°C to about 164°C. 95. The crystalline form of claim 91, having a melting range of about 161°C to about 163°C. 96. The crystalline form of claim 95, having a melting point of about 161.5°C. 97. The crystal form of claim 95, wherein the endoplasmic reticulum is determined by differential scanning calorimetry. 85 J. .::. The atherm peak occurs between about 160.0 °C and about 164.0 °C. 98. The crystalline form of claim 95, having a differential scanning calorimetry endothermic peak at about 162.0°C. 99. The crystalline form of claim 98, having a further melting range of from about 160°C to about 163°C. 100. The crystalline form of claim 99, having a melting point of about 161.5°C. 101. The crystalline form of claim 91, wherein the phase purity of Form II celecoxib is at least about 5%. 102. The crystalline form of claim 91, wherein the phase purity of celecoxib Form II is at least about 10%. 103. The crystalline form of claim 91, wherein the phase purity of Form II celecoxib is at least about 25%. 104. The crystalline form of claim 91, wherein the phase purity of celecoxib Form II is at least about 50%. 105. The crystalline form of claim 91, wherein the phase purity of Form II celecoxib is at least about 75%. 106. The crystalline form of claim 91, wherein the phase purity of Form II celecoxib is at least about 90%. 107. The crystalline form of claim 91, which is substantially a phase-pure form of Form II celecoxib. 108. A pharmaceutical composition comprising a pharmaceutically effective amount of a crystalline form according to any one of claims 91-107 and at least one pharmaceutically acceptable carrier, excipient and/or diluent. 109. The composition of claim 108, wherein the celecoxib comprises at least 2% Form II celecoxib. 110. The composition of claim 108, wherein the celecoxib comprises at least 10% Form II celecoxib. 111. The composition of claim 108, wherein the celecoxib comprises at least 50% Form II celecoxib. 112. The composition of claim 108, wherein the celecoxib comprises at least 98% Form II celecoxib. 113. The composition of claim 108, wherein the celecoxib is predominantly Form II celecoxib. 114. A method for treating or preventing a cyclooxygenase-2 mediated condition in an individual, comprising administering to the individual a therapeutically effective amount of celecoxib Form II. 115. The method of claim 114, wherein the condition or disorder is pain. 116. The method of claim 114, wherein the condition or disorder is inflammation. 117. The method of claim 114, wherein the condition or disorder is arthritis. 118. The method of claim 114, wherein j e I I e- - 87m e z v e that the condition or disorder is a tumorous growth. 119. The method of claim 114, wherein the condition or disorder is metastatic. 120. The method of claim 114, wherein the condition or disorder is hereditary adenomatous polyposis. 121. A process for preparing Form II celecoxib, comprising crystallizing celecoxib from a mixture containing celecoxib and a solvent, said crystallization being carried out at a temperature above the enantiotropic transformation temperature of Form II celecoxib, thereby producing Form II celecoxib. 122. The process of claim 121, wherein the solvent is seeded with a seed crystal of celecoxib Form II prior to crystallization. 123. The process of claim 121, wherein at least about 5% by weight of celecoxib is phase pure Form II. 124. The process of claim 121, wherein at least about 10% by weight of celecoxib is phase pure Form II. 125. The process of claim 121, wherein at least about 25% by weight of celecoxib Form II is produced. 126. The process of claim 36, wherein at least about 50% by weight of celecoxib Form II is produced. 127. The process of claim 36, wherein celecoxib Form II is produced with a phase purity of at least about 90% by weight. 128. A process for preparing a crystalline form of celecoxib, comprising heating a solvate of celecoxib to produce Form II celecoxib. 129. The method of claim 128, wherein the solvate is heated to a temperature of between about 50°C and about 160°C. 130. The method of claim 128, wherein the solvate is heated to a temperature of between about 60°C and about 145°C. 131. The method of claim 128, wherein the solvate is heated to a temperature of between about 70°C and about 140°C. 132. The method of claim 128, wherein the solvate is heated to a temperature of between about 80°C and about 140°C. 133. The method of claim 128, wherein the solvate is heated to a temperature of between about 90°C and about 140°C. 134. The method of claim 128, wherein the solvate is heated to a temperature of between about 100°C and about 140°C. 135. The method of claim 128, wherein the solvate is heated to a temperature of between about 110°C and about 140°C. 136. The method of claim 128, wherein the solvate is heated to a temperature of about 120°C to about 140°C. 137. The method of claim 128, wherein the solvate is heated to a temperature of between about 125°C and about 135°C. 138. The process of claim 128, wherein the solvate is heated to a temperature of about 130°C. 139. The method of claim 128, wherein the solvate is heated for a period of time greater than about 1 minute. 140. The method of claim 128, wherein the solvate is heated for a period of time greater than about 5 minutes. 141. The method of claim 128, wherein the solvate is heated for a period of time greater than about 60 minutes. 142. The method of claim 128, wherein the solvate is heated for a period of time greater than about 2 hours. 143. The method of claim 128, wherein the solvate is heated for about 4 hours or longer. 144. The method of any one of claims 128-143, wherein the heating is carried out at subatmospheric pressure. 145. The method of claim 128, wherein the solvate is a solvate comprising celecoxib and an amide type solvent. 146. The process according to claim 145, characterized in that the amide type solvent used is N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or 1,1,3,3-tetramethylurea. 147. The process according to claim 146, characterized in that the amide type solvent used is N,N-dimethylformamide. 148. The process of claim 146, wherein the amide type solvent is N,N-dimethylacetamide. 149. The process of claim 136, wherein the amide solvent is 1-methyl-2-pyrrolidinone. 150. The process of claim 146, wherein the amide type solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. 151. The process of claim 146, wherein the amide type solvent is 1,1,3,3-tetramethylurea. 152. The process of claim 145, wherein the celecoxib solvate is prepared by reacting celecoxib with an amide type solvent, namely N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. - Mix with 91 and/or 1,1,3,3-tetramethylurea. 153. The process of claim 152, wherein the solvent used is N,N-dimethylformamide. 154. The process of claim 152, wherein the solvent used is N,N-dimethylacetamide. 155. The process according to claim 152, characterized in that 1-methyl-2-pyrrolidinone is used as the solvent. 156. The process of claim 152, wherein the solvent used is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. 157. The process of claim 152, wherein the solvent used is 1,1,3,3-tetramethylurea. 158. A solid form of celecoxib comprising celecoxib Form I and celecoxib Form II. 159. 158. A solid form of celecoxib comprising celecoxib Form I and celecoxib Form III. 160. 158. A solid form of celecoxib comprising celecoxib Form II and celecoxib Form III. 161. A solid form of celecoxib comprising celecoxib Form I, celecoxib Form II, and celecoxib Form III. 162. A process for preparing Form II celecoxib, comprising grinding or comminuting Form III celecoxib to produce Form II celecoxib. 163. The method of claim 162, wherein celecoxib Form III is obtained. 164. The method according to claim 163, characterized in that the grinding is performed using a wet grinding process. 165. The method according to claim 163, characterized in that the grinding is ball milling. 166. The method of claim 162, wherein celecoxib Form III is ground. 167. The method of claim 166, wherein the comminution is performed by shaking. 168. A process for preparing Form II celecoxib, comprising grinding or comminuting a celecoxib solvate to produce Form II celecoxib. 169. The method of claim 168, wherein celecoxib solvate is milled. 170. The method of claim 169, wherein the grinding is performed using a wet grinding process. 171. The method according to claim 169, characterized in that the grinding is ball milling. 172. The method of claim 168, wherein celecoxib solvate is crushed. 173. The method of claim 172, wherein the comminution is performed by shaking. 174. A process for preparing celecoxib Form I, comprising melting celecoxib Form II and cooling the melt to produce celecoxib Form I. 175. A process for preparing Form II celecoxib, comprising melting Form III celecoxib and cooling the melt to produce Form II celecoxib. Instead of the notifier, the authorized person DANUBE Patent and Trademark Office Ltd. Dr. Flóra Fehérvári, patent attorney