CZ20012875A3 - Polymorphous crystalline forms of celecoxib - Google Patents

Abstract

The selective cyclooxygenase-2 inhibitory drug celecoxib is provided in amorphous form. Also provided is a celecoxib drug substance wherein the celecoxib is present, in at least a detectable amount, as amorphous celecoxib. Also provided is a celecoxib-crystallization inhibitor composite comprising particles of amorphous celecoxib or a celecoxib drug substance of the invention in intimate association with one or more crystallization inhibitors, for example polymers. Also provided is a pharmaceutical composition comprising such a celecoxib-crystallization inhibitor composite and one or more excipients. Also provided are processes for preparing amorphous celecoxib, a celecoxib drug substance of the invention, a celecoxib-crystallization inhibitor composite of the invention, and a pharmaceutical composition of the invention. Also provided is a method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated, comprising administering, for example orally, a composition of the invention in a therapeutically effective amount.

Description

Polymorphic crystalline forms of celecoxib

Technical field

The present invention relates to oral pharmaceutical compositions comprising a cyclooxygenase-2 inhibitor as an active ingredient, methods of preparing such compositions, methods of treating cyclooxygenase-2 mediated diseases comprising oral administration of such compositions to individuals, and the use of such compositions for the manufacture of medicaments.

The present invention relates to cyclooxygenase-2 inhibitory pharmaceutical agents, and more particularly to novel crystalline form I and crystalline form II of celecoxib, to processes for preparing such crystalline forms of celecoxib, to pharmaceutical compositions comprising such crystalline forms of celecoxib, and to methods of treating and / or preventing diseases and / cyclooxygenase-2 mediated disorders.

BACKGROUND OF THE INVENTION

Many compounds having a therapeutically and / or prophylactically selective cyclooxygenase-2 inhibitory effect have been described and have also been described as being useful for treating or preventing specific cyclooxygenase-2 mediated disorders or such diseases in general. Among such compounds there is a large number of substituted pyrazolylbenzenesulfonamides as described in U.S. Pat. No. 5,760,068 to Talley et al., Including, for example, 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -4-pyrazol-1-yl] benzenesulfonamide, also known as celecoxib, and 4- [ 5- (3-fluoro-4-methoxyphenyl) -3-difluoromethyl) -4-pyrazol-1-yl] benzenesulfonamide, also known as deracoxib. Celecoxib has the formula:

and deracoxib has the formula:

Other compounds known to have a therapeutically and / or prophylactically useful cyclooxygenase-2 inhibitory effect are the substituted isoxazolylbenzenesulfonamides described in U.S. Pat. Patent No.

No. 5,633,272 to Talley et al., Including, for example, a 4- [5- i -methyl-3-phenylisoxazol-4-yl] benzenesulfonamide compound, also referred to as valdecoxib, having the formula:

(lil)

Still other compounds known to have a therapeutically and / or prophylactically useful cyclooxygenase-2 inhibitory effect are substituted (methylsulfonyl) phenylfuranones as described in U.S. Pat. U.S. Patent No. 5,474,995 to Ducharme et al., Including, for example, the 3-phenyl-4- [4- (methylsulfonyl) phenyl] -5H-furan-2-one compound, also known as rofecoxib,

U.S. Pat. U.S. Patent No. 5,981,576 to Belley et al. Discloses another series of (methylsulfonyl) phenylfuranones reported to be effective as cyclooxygenase-2 inhibitors, including 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.

European Patent Application No. 0 863 134 discloses a compound

2- (3,5-difluorophenyl) -3- [4 (methylsulfonyl) phenyl] -2-cyclopenten-1-one as a useful cyclooxygenase-2 inhibitor.

International Application No. WO 99/55380 discloses, inter alia, a compound having the formula:

Many selective cyclooxygenase-2 inhibitors, including celecoxib, deracoxib, valdecoxib and rofecoxib, are hydrophobic and have poor water solubility. This causes practical problems in the preparation of such compounds for oral administration, especially when a rapid onset of therapeutic effect is desired or necessary.

By way of illustration, the preparation of celecoxib for effective oral administration to an individual has so far been complicated by the unique physical and chemical properties of celecoxib, particularly its poor solubility and factors associated with its crystalline structure, including cohesiveness, low bulk density and low compressibility. Celecoxib is unusually insoluble in aqueous media. Unformulated celecoxib is poorly soluble and dispersible for rapid absorption in the gastrointestinal tract following oral administration, for example in the form of capsules. Further, the unformulated celecoxib, which has a crystalline structure that tends to form long cohesive needles, typically fuses into a monolithic mass upon compression in a tablet press. Even when mixed with other substances, celecoxib crystals tend to separate from other substances and agglomerate together during mixing of the composition, resulting in an inhomogeneously mixed composition containing undesirable large aggregates of celecoxib. Therefore, it is difficult to prepare a pharmaceutical composition comprising celecoxib which has the desired homogeneity of the composition. Further, there are processing problems during the preparation of a pharmaceutical composition comprising celecoxib. For example, the low bulk density of celecoxib makes it difficult to process small amounts required during the preparation of pharmaceutical compositions. Therefore, there is a need to solve many of the problems associated with the preparation of suitable pharmaceutical compositions and dosage forms containing celecoxib, especially oral dosage units.

More generally, there is a need for oral compositions comprising low water solubility inhibitors of cyclooxygenase-2, such as celecoxib, having one or more of the following characteristics as compared to unformulated celecoxib or other celecoxib formulations:

(1) improved solubility;

(2) shorter disintegration time;

(3) shorter dissolution time;

(4) less tablet friability;

(5) higher tablet hardness;

(6 better wettability;

(7) better compressibility;

(8) better fluidity of liquid and particulate solid compositions;

(9) improved physical stability of the final composition;

(10) smaller size tablets or capsules;

(11) improved homogeneity of the mixture;

(12) better dose homogeneity;

(13) better control of weight variations during encapsulation and / or tabletting;

(14) higher granule density for wet granulated compositions;

(15) lower water demand for wet granulation;

(16) shorter wet granulation time; and (17) a shorter drying time for the wet granulated compositions.

Further, there is a great need for oral compositions containing low water solubility cyclooxygenase-2 inhibitory compounds, such as celecoxib, which would have a faster onset of therapeutic effect than the corresponding unformulated drugs or known formulations thereof. To the extent that rapid onset of therapeutic effect is related to pharmacokinetic parameters such as high maximum serum drug concentration (Cmax) and a short time from oral administration to such maximum serum concentration (Tmax), there is a need for oral compositions containing cyclooxygenase-2 inhibitory compounds. low water solubility such as celecoxib, which had a higher Cmax and / or shorter Tmax than the corresponding unformulated drugs or known formulations of these drugs.

As discussed below, treatment with selective cyclooxygenase-2 inhibitors, including celecoxib, is indicated or potentially indicated in various cyclooxygenase-2 mediated diseases and conditions. It would be advantageous to have compositions with pharmacokinetic properties corresponding to a rapid onset of therapeutic effect, especially for the treatment of acute diseases in which a faster relief of pain or other symptoms is desired or necessary.

Such compositions will represent a significant advance in the treatment of cyclooxygenase-2 mediated diseases and disorders.

Cyclooxygenase-2 inhibiting compounds, including celecoxib, having poor water solubility are most preferably formulated as solid particles. The individual or primary drug particles may be dispersed in a liquid medium, such as in suspensions, or aggregated to form secondary particles or granules, which may be filled into capsules, or which may be compressed or cast to give tablets.

Many processes are known and used in the art to prepare compositions having a primary particle size within a desired range, or having a desired average particle size, or having a particle size distribution characterized by a parameter such as D90, defined herein as a linear diameter measurement having such a value that 90% of the particle volume in the composition, in the longest particle size, is less than this diameter. In practice, it is preferable to use D90 by 90% by weight instead of volume.

To be consistent with previous publications, the terms microparticles and nanoparticles are defined herein as in U.S. Pat. No. 5,384,124, Courteille et al., and refers to particles having, respectively, a diameter of between 1 mm and 2000 mm, and a diameter of less than 1 mm (1000 nm). The preparation of microparticles and nanoparticles according to U.S. Pat. No. 5,384,124, is used to retard the dissolution of the active ingredients. However, U.S. Pat. U.S. Patent No. 5,145,684 to Liversidge et al. discloses nanoparticle compositions having an unexpectedly high bioavailability of drugs, particularly drugs having poor solubility in a liquid medium such as water. International Application No. WO 93/25190 discloses pharmacokinetic data from a rat study showing a higher absorption rate after administration of a nanoparticle (average particle size 240-300 nm) than after administration of a microparticle (particle size in the range of 20-30 mm) of a naproxen dispersion.

Many methods for preparing nanoparticulate preparations of therapeutic agents are known. Typically, these methods utilize mechanical means such as grinding or crushing to reduce the particle size to a nano size (less than 1 mm) or to precipitate the nano particles from solution. Illustrative processes are described in the following references: U.S. Pat. U.S. Patent No. 4,826,689 to Violanto & U.S. Patent No. 5,145,684 to Liversidge et al. U.S. Patent No. 5,298,262 to Na & Rajagopalan, U.S. Pat. U.S. Patent No. 5,302,401 to Liversidge et al. U.S. Patent No. 5,336,507 to Na & Rajagopalan, U.S. Pat. U.S. Patent No. 5,340,564 to Illig & Sarpotdar, U.S. Pat. U.S. Patent No. 5 / 346,702 to Na & Rajagopalan, U.S. Pat. U.S. Patent No. 5,352,459 to Hollister et al. No. 5,354,560 to Lovrecich, cited U.S. Pat. U.S. Patent No. 5,384,124 to Courteille et al. No. 5 / 429,824, June, U.S. Pat. U.S. Patent No. 5 / 510,118 to Bosch et al. U.S. Patent No. 5,518,738 to Eickhoff et al. U.S. Patent No. 5,503,723 to Ruddy & Eickhoff, U.S. Pat. U.S. Patent No. 5,534,270 to De Castro, U.S. Pat. U.S. Patent No. 5,536,508 to Canal et al. U.S. Patent No. 5,552,160 to Liversidge et al. U.S. Patent No. 5,560,931 to Eickhoff et al. U.S. Patent No. 5,560,932 to Bagchi et al. U.S. Patent No. 5 / 565,188 to Wong et al. U.S. Patent No. 5,569,448 to Wong et al. U.S. Patent No. 5,571,536 to Eickhoff et al. U.S. Pat.

5,573,783, Desieno & Stetsko, U.S. Pat. U.S. Patent No. 5,580,579 to Ruddy et al. U.S. Patent No. 5 / 585,108 to Ruddy et al. U.S. Pat.

5,587,143; Wong, U.S. Pat. U.S. Patent No. 5,591,456 to Franson & Snyder, U.S. Pat. U.S. Patent No. 5,662,883 to Bagchi et al. U.S. Patent No. 5 / 665,331 to Bagchi et al. U.S. Patent No. 5,718,919 to Ruddy & Roberts, U.S. Pat. No. 5 / 747,001 to Wiedmann et al., International Application No. WO 93/25190, International Application No. WO 96/24336, International Application No. 98/35666.

SUMMARY OF THE INVENTION

According to the present invention, a cyclooxygenase-2 inhibiting compound having poor water solubility such as celecoxib, deracoxib, valdecoxib or rofecoxib has a faster onset of therapeutic effect when, after oral administration of the composition comprising the compound, the compound exhibits pharmacokinetic properties leading to higher maximum serum concentration (Cmax). ) and / or less time after administration to maximum (Tmax). It is believed that higher Cmax and / or shorter Tmax are achieved by reducing the particle size of the compound-containing solids such that a significant proportion of the weight of the particles is less than 1 mm in diameter, in the longest particle size. Without wishing to be bound by theory, it is believed that higher C max and / or shorter T max are due to the faster dissolution that occurs when the particles are less than 1 mm.

Accordingly, the invention provides a pharmaceutical composition comprising one or more oral dosage units each containing a therapeutically effective amount of a low solubility selective cyclooxygenase-2 compound, wherein the compound is present in solid particles having a D 90 particle size of from about 0.01 to about about 200 mm, wherein a sufficient proportion of the particle weight is less than 1 mm to achieve a significantly higher C max and / or a significantly shorter T max compared to an otherwise similar composition in which substantially all particles are greater than 1 mm.

The invention also provides a pharmaceutical composition comprising one or more oral dosage units each containing a therapeutically effective amount of a compound having selectively inhibit cyclooxygenase-2 with low solubility, wherein the compound is present in solid particles having a D 90 particle size of from about 0.01 to about 200 mm and wherein about 25% to 100% by weight of the particles are less than 1 mm.

Dosage units containing the preparation may be in the form of discrete solid products such as tablets, pills, soft or solid capsules, lozenges, medicated candies or powder sachets; or it may be in the form of a substantially homogeneous liquid mass such as particulate or granules! a solid material or a liquid suspension from which individual doses can be metered.

The invention also provides a method for treating a disease or condition in an individual wherein treatment with a cyclooxygenase-2 inhibitor is indicated, which comprises administering one or more dosage units of the composition of the present invention once or twice a day. Such a method is particularly advantageous when the disease or condition is accompanied by acute pain.

The present invention also provides a new solid form of celecoxib, Form I celecoxib. The present invention also provides another new solid form of celecoxib, Form II celecoxib. Each of these new solid forms includes solvated crystalline forms, unsolvated and non-hydrated crystalline forms. These novel forms of celecoxib described in the present invention have one or more of the above-mentioned advantageous chemical and / or physical properties over other solid forms described herein or in the literature.

In another embodiment, the invention provides a novel crystalline form of celecoxib. For example, one embodiment of the present invention provides Form I of a crystalline form of celecoxib, preferably a crystalline form having an X-ray powder with peaks at 5.5, 5.7, 7.2 and 16.6 degrees 2-theta.

In another embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of Form I of the crystalline form of celecoxib and at least one pharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, the invention provides a method of treating or preventing a cyclooxygenase-2 mediated disease or condition in an individual comprising administering a therapeutically effective amount of Form I celecoxib.

In another embodiment, the invention provides a process for preparing celecoxib Form I comprising crystallizing celecoxib from a mixture comprising celecoxib and a solvent, wherein the crystallization is performed at a temperature above the enantiotropic transition temperature of Form I celecoxib to obtain Form I celecoxib.

In another embodiment, the invention provides a method of preparing a crystalline form of celecoxib comprising heating the celecoxib solvate to obtain Form I celecoxib.

In another embodiment, the invention provides a process for preparing celecoxib Form I comprising milling or crushing celecoxib Form III to form celecoxib Form I.

In yet another embodiment, the invention provides a process for preparing celecoxib Form I comprising milling or grinding a celecoxib solvate to obtain celecoxib Form I.

In another embodiment, the invention provides a process for preparing celecoxib Form I comprising melting celecoxib Form II and cooling the melt to obtain celecoxib Form I.

In another embodiment, the invention provides a process for preparing celecoxib Form I comprising melting celecoxib Form III and cooling the melt to form celecoxib Form I.

In another embodiment, the invention provides a process for preparing Form I celecoxib comprising evaporating the solvent from a solution of celecoxib to obtain Form I celecoxib.

In another embodiment, the invention provides a new crystalline form

celecoxib. For example, one embodiment of the present invention provides Form II of a crystalline form of celecoxib, preferably a crystalline form having an X-ray powder diffraction pattern with peaks at 10.3, 13.8 or 17.7 degrees 2-theta.

In another embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline form II of celecoxib and at least one pharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, the invention provides a method of treating or preventing a cyclooxygenase-2 mediated disease or condition in an individual comprising administering a therapeutically effective amount of Form II celecoxib.

In another embodiment, the invention provides a process for preparing celecoxib Form II comprising crystallizing celecoxib from a mixture comprising celecoxib and a solvent, wherein the crystallization is performed at a temperature above the enantiotropic transition temperature of Form II celecoxib to yield Form II celecoxib.

In another embodiment, the invention provides a process for preparing a crystalline form of celecoxib comprising heating a solvate of celecoxib to obtain Form II celecoxib.

In another embodiment, the invention provides a process for preparing celecoxib Form II comprising milling or crushing celecoxib Form III to form celecoxib Form II.

In yet another embodiment, the invention provides a process for preparing celecoxib Form II comprising milling or crushing a celecoxib solvate to form celecoxib Form II.

4 · 4

In another embodiment, the invention provides a process for preparing Form II celecoxib comprising melting Form I celecoxib and cooling the melt to form Form II celecoxib.

In another embodiment, the invention provides a process for preparing celecoxib Form II comprising melting celecoxib Form III and cooling the melt to form celecoxib Form II.

In another embodiment, the invention provides a solid form of celecoxib comprising Form I celecoxib and Form II celecoxib.

In another embodiment, the invention provides a solid form of celecoxib comprising Form I celecoxib and Form III celecoxib.

In another embodiment, the invention provides a solid form of celecoxib comprising Form II celecoxib and Form III celecoxib.

In another embodiment, the invention provides a solid form of celecoxib comprising Form I celecoxib, Form II celecoxib, and Form II celecoxib.

Other features of the present invention will be apparent from the following description.

Description of the figures in the attached drawings

Giant. 1 shows a comparison of experimental PXRD results for celecoxib Form I (Figure 1a), a mixture of celecoxib Form II and celecoxib Form III (Figure 1b), and Celecoxib Form III (Figure 1c).

Giant. 2 shows an IR spectrum comparison for Form I celecoxib, a mixture of Form II celecoxib and Form III celecoxib, and Form III celecoxib.

•

Giant. 3 shows a comparison of DCS thermograms scanned at 0.5 [deg.] C./min for individual forms of celecoxib with overlaying (endotherms down).

Description of preferred embodiments

The terms cyclooxygenase-2 selective inhibitor or cyclooxygenase-2 selective inhibitor refer to compounds that inhibit cyclooxygenase-2 to a therapeutically useful extent and that inhibit cyclooxygenase-1 significantly less than conventional non-steroidal anti-inflammatory drugs (NSAIDs).

The terms poorly water soluble or poor water solubility used in connection with a cyclooxygenase-2 inhibitor refer to a water solubility at 25 ° C of less than about 10 g / l, preferably less than about 1 g / l.

The term oral administration refers to any method of administering a therapeutic agent or composition to an individual in which the agent or composition is placed in the mouth of an individual, whether or not the agent or composition is swallowed. Therefore, the term oral administration includes buccal and sublingual as well as esophageal administration. Absorption of the agent may occur in any part of the gastrointestinal tract including mouth, esophagus, stomach, duodenum, ileum and colon.

The term "orally administrable" means suitable for oral administration.

An individual to whom a therapeutic agent may be administered, or. . The means may be a human of any gender and age, but also a non-human animal, in particular a pet, such as a cat, dog or horse.

Dosage unit refers to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent, in this case a selective cyclooxygenase-2 inhibitor, that is suitable for a single oral administration to achieve a therapeutic effect. Typically, a single dosage unit, or a plurality of smaller units (up to 4), provides a sufficient amount of agent to achieve the desired effect.

The term present in solid particles, as used for compounds that selectively inhibit cyclooxygenase-2, refers to compositions in which the solid particles consist essentially of the compound only, and compositions in which the solid particles comprise the compound in admixture with one or more other ingredients. These additional ingredients may be one or more additional therapeutic agents other than a selective cyclooxygenase-2 inhibitor and / or one or more additional pharmaceutically acceptable ingredients.

The term additive as used herein refers to any substance that is not itself a therapeutic agent and which is used as a carrier or vehicle for administration of the therapeutic agent to an individual or added to a pharmaceutical composition to improve its processing or storage or to facilitate preparation of dosage units. such as capsules or tablets suitable for oral administration. Additives include, for example, diluents, disintegrants, binders, adhesives, wetting agents, glidants, lubricants, flavoring agents or odor control agents, dyes and substances 9 · · ···· * 9 * added ** to enhance the appearance of the composition.

The term substantially homogeneous as used for a pharmaceutical composition comprising several components means that the components are mixed so that the individual components are not present as separate layers and do not form concentration gradients in the composition.

The term purity refers to the chemical purity of celecoxib according to conventional HPLC assays.

The term phase purity refers to the solid phase purity of celecoxib for individual crystalline or amorphous forms of celecoxib as determined by infrared spectroscopy as described herein.

The term enantiotropic transition temperature refers to the temperature at which a thermodynamically stable polymorphic compound changes from one form to another. For example, for two polymorphic forms, Form A and Form B, Form A may be stable below the enantiotropic transition temperature, while Form B may be stable above the enantiotropic transition temperature.

The novel pharmaceutical compositions of the present invention comprise one or more orally administrable dosage units. Each dosage unit comprises a selective cyclooxygenase-2 inhibitor, for example celecoxib, in a therapeutically effective amount, which is preferably an amount from about 10 mg to about 1000 mg.

It will be appreciated that a therapeutically effective amount of a selective cyclooxygenase-2 inhibitor for an individual depends upon, inter alia, the body weight of the individual. When the Inhibitor is an Inhibitor Cyclooxygenase-2 celecoxib and the subject is a child or small animal (e.g. a dog), it is likely that a dose of celecoxib relatively low in the range of 10 mg to about 1000 mg will be sufficient to achieve serum concentrations appropriate to therapeutic efficacy. When the subject is an adult human or larger animal (e.g., a horse), achieving such serum celecoxib concentrations will require administration of a dosage unit containing a relatively high amount of celecoxib.

Typical dosage units in the composition comprise about 10, 20, 25, 37.5, 50, 75, 1000, 125, 150, 175, 200, 250, 300, 350 or 400 mg of a cyclooxygenase-2 inhibitor, for example celecoxib. For an adult human, the therapeutically effective amount of celecoxib per dosage unit in the composition is usually about 50 mg to about 400 mg. Particularly preferred amounts of celecoxib per dosage unit are about 100 mg to about 200 mg, for example about 100 mg or about 200 mg.

The compositions of the present invention comprise a selective cyclooxygenase-2 inhibitor, for example celecoxib, alone or in admixture with one or more excipients, in nanoparticulate form, i.e. in the form of solid particles less than 1 mm in diameter in the longest particle size.

The effect of particle size reduction from microparticles (greater than 1 mm) on nanoparticles on pharmacokinetic properties is generally unpredictable for any drug or class of drugs. According to the present invention, the selective cyclooxygenase-2 selective nanoparticle compositions with low water solubility have higher C max and / or shorter T max than the microparticle compositions. Therefore, in one embodiment of the invention, the percent weight of nanoparticle particles is sufficient to achieve a significantly higher C max and / or a significantly shorter T max compared to a comparable formulation in

wherein substantially all particles are greater than 1 mm. Preferably, the composition of this embodiment comprises a sufficient percentage of nanoparticle weight to achieve a significantly shorter Tmax, and more preferably comprises a sufficient percentage of nanoparticle weight to achieve both a significantly higher C _max and a significantly shorter T _max compared to a comparable composition.

When administered orally to a fasted adult 100 mg dose, T _{max has} less than about 90 minutes, preferably less than about 60 minutes, and more preferably less than about 45 minutes, and a C max of at least about 100 ng / ml _, preferably at least about 200 ng / ml. ml. Typically, the composition of the present invention allows serum concentrations of selective cyclooxygenase-2 inhibitors to be at least about 50 ng / ml within 30 minutes of oral administration; preferred compositions allow such concentrations to be reached within 15 minutes. It is believed that a rapid increase in serum concentrations is associated with a rapid onset of therapeutic effect achieved by the compositions of the present invention.

In another embodiment of the invention, the selective cyclooxygenase-2 inhibitor, for example celecoxib, is present in solid particles having a D 90 particle size of from about 0.01 to about 200 mm, wherein about 25% to 100% by weight of the particles are nanoparticles. When the percentage of nanoparticle weight is relatively low, for example about 25% to about 50%, preferably the D 90 is a particle size of about 0.01 to about 100 mm, more preferably about 0.01 to about 75 mm, more preferably about 0.01 to about 40 mm. mm, and most preferably about 0.01 to about 25 mm. The particle size may vary continuously within the nanoparticle and microparticle ranges, or the device may have a bimodal or multimodal particle size distribution, with one set of particles having a D90 particle size less than 1 mm and another set of particles having a D90 particle size significantly greater than 1 mm. In general, it is preferred that at least about 50% by weight, more preferably at least 75% by weight of the particles are nanoparticles. In one embodiment, substantially all of the particles are less than 1 mm, i.e., the percentage by weight of nanoparticles is 100% or nearly 100%.

The primary particles, prepared for example by grinding or crushing, or by precipitation from solution, may agglomerate to form secondary particles. The term particle size as used herein refers to the longest dimension of the primary particles, unless the context implies otherwise.

For the nanoparticulate component of the composition of the present invention, the average particle size is preferably about 0.1 to about 0.8 mm (about 100 to about 800 nm), more preferably about 0.15 to about 0.6 mm (about 150 to about 600 nm) and more preferably about 0.2 to about 0.4 mm (about 200 to about 400 nm). The selective cyclooxygenase-2 inhibitor, for example celecoxib, may be in crystalline or amorphous form in the nanoparticles. Methods for preparing nanoparticles that include grinding or crushing typically provide the drug in crystalline form, while processes involving precipitation from solution usually provide the drug in amorphous form.

The compositions of the present invention comprise a selective cyclooxygenase-2 inhibitor of poor water solubility, for example celecoxib, optionally in admixture with one or more excipients selected from the group consisting of diluents, disintegrants, binders, wetting agents and glidants. In one embodiment, the nanoparticles comprising a selective cyclooxygenase-2 inhibitor have an adsorbed surface modifying agent on their surface. In another embodiment, the selective cyclooxygenase-2 inhibitor nanoparticles are contained within a matrix.

polymer. Preferably, the at least one additive is a water-soluble diluent or wetting agent. Such water-soluble diluents or wetting agents aid in dispersing or dissolving the cyclooxygenase-2 inhibitor upon ingestion of the composition of the present invention. Preferably both a water-soluble diluent and a wetting agent are included.

The composition of the present invention may be a substantially homogeneous liquid mass, such as a particulate or granular solid material or liquid, or may be in the form of discrete products such as tablets or capsules each containing a single dosage unit.

In a composition that is a substantially homogeneous liquid mass, the dosage unit may be metered in with a suitable volume measuring means such as a spoon or a cup. Suitable liquid materials are, for example, powders and granules. Alternatively, the liquid mass may be a suspension in which the cyclooxygenase-2 solids inhibitor is dispersed in a liquid phase, preferably an aqueous phase. At least a portion of the solid phase is in the form of nanoparticles. For the preparation of such a suspension, it is preferred to use a wetting agent such as polysorbate 80 and other similar agents. The suspension may be prepared by dispersing the nanoparticulate or partially nanoparticulate cyclooxygenase-2 inhibitor in the liquid phase; alternatively, the cyclooxygenase-2 inhibitor, for example celecoxib, may be precipitated from solution in a solvent such as an alcohol, preferably ethanol. The aqueous phase preferably comprises an edible vehicle such as water, syrup or fruit juice, for example apple juice.

The compositions of the present invention are useful for treating and preventing various cyclooxygenase-2 mediated diseases. The compositions of the present invention are useful, for example, for treating inflammation in an individual, as an analgesic, for example, in the treatment of headache and pain, and as an antipyretic in the treatment of fever. For example, such compositions are useful for the treatment of arthritis, including, for example, rheumatoid arthritis, spondyloarthropathies, gout arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. Such compositions are also useful in the treatment of asthma, bronchitis, menstrual cramps, preterm labor, tendinitis, bursitis, allergic neuritis, apoptosis including HIV-induced apoptosis, lumbago, liver diseases including hepatitis, skin diseases such as psoriasis, eczema, acne, UV burns. , burns and dermatitis, and postoperative inflammation, including inflammations following ophthalmic surgical procedures such as cataract or refractive disorders. The compositions of the present invention are also useful for the treatment of gastrointestinal disorders such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compositions of the present invention are useful for treating inflammation in diseases such as migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodkgin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular connection diseases such as myasthenia gravis, white matter disease nerve such as multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, wound swelling, including brain edema, myocardial ischemia and the like. The compositions of the present invention are also useful for treating ocular diseases such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia, and acute tissue injury to the eye. The compositions of the present invention are also useful for the treatment of pulmonary inflammations, such as those associated with viral infections and cystic fibrosis, and for the treatment of bone resorption, such as osteoporosis-associated resorption. The compositions of the present invention are also useful for treating certain diseases of the central nervous system, such as cortical dementias, including Alzheimer's disease, neurodegenerative diseases and central nervous system damage due to stroke, ischemia and trauma. The term treatment as used herein refers to partial or total inhibition of dementia, including Alzheimer's dementia, ischemic dementia, pre-senile dementia, alcohol dementia, and senile dementia.

The compositions of the present invention are mainly useful as anti-inflammatory agents, for example for the treatment of arthritis, and have the additional advantage of having fewer unwanted side effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs).

The compositions of the present invention are also useful for treating allergic rhinitis, respiratory insufficiency syndrome, endotoxin shock syndrome, and liver disease. The compositions of the present invention are also useful for treating pain, including post-operative pain, toothache, muscle pain, and tumor pain.

The compositions of the present invention are also useful for treating and preventing inflammation-related cardiovascular diseases in an individual. Such compositions are useful for treating and preventing vascular disease, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina pectoris including unstable angina pectoris, inflammation in the coronary, inflammation in the coronary including Chlamydial inflammation, viral inflammation and inflammation associated with surgical procedures such as vascular grafts including coronary bypasses, revascularization procedures including angioplasty, stent insertion, and · · · ··· Endarterectomy, or other invasive procedures on arteries, veins, and capillaries. · · · · · · · · · · · Such compositions are also useful for the treatment of angiogenesis-related diseases. The compositions of the present invention may be administered to an individual in need of angiogenesis inhibition. Such compositions are useful for the treatment of neoplasias, including metastasis; ophthalmic diseases such as corneal graft rejection, ocular neovascularization, retinal neovascularization including post-surgical or infection neovascularization, diabetic retinopathy, macular degeneration, retrolent fibroplasia, and neovascular glaucoma; ulcer diseases such as stomach ulcers; pathological but benign diseases such as hemangiomas, including pediatric hemangiomas, angiofibroma nasopharynx, and avascular bone necrosis; and diseases of the female reproductive system such as endometriosis.

The compositions of the present invention are also useful for treating or preventing benign and malignant tumors / neoplasias including carcinomas such as colorectal carcinoma, brain tumors, epithelial cell neoplasms (epithelial carcinomas) such as basalioma, adenocarcinomas, gastrointestinal tumors such as lip, oral cavity, esophagus, small intestine and stomach, large intestine, liver, bladder cancer, pancreas, ovaries, cervix, lung, breast and skin such as squamous and basocellular carcinomas, prostate cancer, kidney cancer and other epithelial cancer. Neoplasias for which the compositions of the present invention are particularly suitable are gastrointestinal tumors, Barrett's esophagus, liver cancer, bladder cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer, and skin cancers such as spinalioma and basalioma . The compositions of the present invention are also useful for treating fibrosis after irradiation. The compositions of the present invention may be used to treat individuals with adenoma polyps, including individuals with familial adenomatous polyposis (FAP). Further, such compositions may be used to prevent polyps from forming in individuals at risk of FAP.

The compositions of the present invention also have anti-inflammatory, antipyretic and analgesic properties similar to or better than conventional non-steroidal anti-inflammatory drugs. The compositions of the present invention also inhibit hormone-induced uterine contractions and have potential anti-tumor effects, and have less ability to induce some side effects of conventional NSAIDs. In particular, the compositions of the present invention have reduced gastrointestinal toxicity and less irritable to the gastrointestinal tract, including less risk of gastrointestinal ulcers and bleeding, have less renal side effects such as decreased renal function leading to fluid retention and exacerbation of hypertension, less inhibit bleeding including less inhibition of thrombocyte function , and appear to have less ability to induce asthma attacks in aspirin-sensitive asthmatics compared to conventional NSAIDs.

The compositions of the present invention are useful for alleviating pain, fever and inflammation in diseases such as rheumatoid fever, flu-related symptoms or other viral infections, common colds, lumbar and cervical spine pain, dysmenorrhea, headache, toothache, sprains and muscle strain , myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns and injuries following surgery and dental procedures. It is further believed that the compositions of the present invention are effective in inhibiting neoplastic cell transformation and metastasis of tumors and are therefore useful in the treatment of tumors such as colon cancer. The compositions of the present invention are also useful for the treatment and / or prevention of cyclooxygenase-mediated proliferative diseases that may occur in diabetic retinopathy and tumor angiogenesis.

The compositions of the present invention inhibit prostanoid-induced smooth muscle contractions by inhibiting the synthesis of contractile prostanoids and therefore can be used to treat dysmenorrhea, preterm labor, asthma and eosinophile-related diseases. They can also be used to treat Alzheimer's disease, to reduce bone loss in postmenopausal women (ie, to treat osteoporosis), and to treat glaucoma.

Due to the higher inhibitory activity for cyclooxygenase-2 (COX-2) and / or specific inhibition of cyclooxygenase-2 compared to cyclooxygenase-1 (COX-1), the compositions of the present invention are useful as an alternative to conventional NSAIDs, especially when they are common NSAIDs contraindicated, such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, or anamnesis of recurrent gastrointestinal lesions; gastrointestinal bleeding; coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding conditions; kidney disease; or in patients prior to surgery or in patients taking anticoagulants. For a brief description of the potential use of cyclooxygenase-2 inhibitors, see John Vane, Nature, Vol. 367, pp. 215-216; and in Drug News and Perspectives, Volume 7, pp. 501-512, 1994.

A preferred use of the pharmaceutical compositions of the present invention is their use in the treatment of rheumatoid arthritis and osteoarthritis, in the treatment of pain in general (especially pain following oral surgery, general surgery, orthopedic surgery and acute outbreaks of osteoarthritis), Alzheimer's disease and colon cancer.

Due to the rapid onset of therapeutic effect, the compositions of the present invention are more advantageous than conventional compositions containing a cyclooxygenase-2 inhibitor in the treatment of acute conditions mediated by cyclooxygenase-2, particularly for the treatment of pain.

The compositions of the present invention may be used in combination with opiates or other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (ie, non-addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers. Preferred combinations are compositions of the present invention together with compounds selected from the group consisting of morphine, meperidine, codeine, pentazotocin, buprenorphine, butorphanol, desocin, meptazinol, hydrocodone, oxycodone, methadone, DuP-747, Dynorphin A, Enadolin, RP-60180, HN -11608, E-2078, ICI-204448, acetaminophen (paracetamol), propoxyphene, nalbuphine, E-4018, filenadol, mirfentanil, amitryiptyline, DuP-631, GP-531, acadesine, AKI-1, AKI-2, GP- 1683, GP-3269, 4030W921, tramadol racemate and isolated (+) and (-) enantiomers, AXC-3742, SNX-111, ADL2-1294, CT-3, and CP99994.

A dosage unit containing an amount of a cyclooxygesy-2 inhibitor, for example celecoxib, may be selected to suit the desired frequency of administration to achieve the desired daily dose. The daily dose and frequency of administration, and thus the choice of a suitable dosage unit, depends on many factors, including the individual's age, weight, sex and health, and the nature and

the severity of the disease or disorder and therefore may vary.

In the case of celecoxib in the compositions of the present invention, the once-daily or twice-daily administration regimen exhibits better efficacy than other administration regimens for delivering the desired daily dose. Therefore, once a day or twice a day, administration of a composition of the present invention is preferred to achieve a therapeutically or prophylactically effective inhibition of cyclooxygenase-2.

For the treatment of rheumatoid arthritis, the compositions of the present invention may be used to administer a daily dose of celecoxib of about 50 mg to about 1000 mg, more preferably about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg, and most preferably about 175 mg to about 400 mg, for example about 200 mg. The dose may be administered once a day, twice a day, three times a day, or more frequently. For example, the dose may be a dose of 200 mg bid. When the composition of the present invention is administered, a suitable daily dose of celecoxib is about 0.67 to about 13.3 mg / kg body weight, more preferably about 1.33 to about 8.0 mg / kg body weight, more preferably about 2.00 to about about 6.67 mg / kg body weight, and more preferably about 2.33 to about 5.33 mg / kg body weight, for example, about 2.67 mg / kg body weight. The daily dose may be administered in one or four doses per day, preferably it is administered in one or two doses per day. Administration of the composition of the present invention at a dose of 100 mg twice daily is preferred for most patients, but for some patients it may be preferable to administer one 200 mg dosage unit or two 100 mg dosage units twice daily.

For the treatment of osteoarthritis, the compositions of the present invention may be used to administer a daily dose of celecoxib of about 50 mg to about 1000 mg, preferably about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg, and most preferably about 175 mg to about 400 mg. mg, for example about 200 mg. When the composition of the present invention is administered, a suitable daily dose of celecoxib is about 0.67 to about 13.3 mg / kg body weight, more preferably about 1.33 to about 8.0 mg / kg body weight, more preferably about 2.00 to about about 6.67 mg / kg body weight, and more preferably about 2.33 to about 5.33 mg / kg body weight, for example, about 2.67 mg / kg body weight. The daily dose may be administered in one or four doses per day, preferably in one or two doses per day. Administration of the composition of the present invention at a dose of 100 mg twice daily is preferred for most patients, but for some patients it may be preferable to administer one 200 mg dosage unit or two 100 mg dosage units twice daily.

For the treatment of Alzheimer's disease, the compositions of the present invention can be used to administer a daily dose of celecoxib of about 50 mg to about 1000 mg, about 100 mg to about 800 mg, more preferably about 150 mg to about 600 mg, and most preferably about 175 mg to about 400 mg. mg, for example about 400 mg. When the composition of the present invention is administered, a suitable daily dose of celecoxib is about 0.67 to about 13.3 mg / kg body weight, more preferably about 1.33 to about 10.67 mg / kg body weight, more preferably about 2.00 to about about 8.0 mg / kg body weight, and more preferably about 2.33 to about 5.33 mg / kg body weight, for example, about 5.33 mg / kg body weight. The daily dose may be administered in one or four doses per day, preferably in one or two doses per day. Administration of the composition of the present invention in one 200 mg dosage unit or in two 100 mg dosage units twice daily is suitable for most patients.

For the treatment of tumors, the compositions of the present invention may be used to administer a daily dose of celecoxib of about 50 mg to about 1000 mg, about 100 mg to about 800 mg, more preferably about 150 mg to about 600 mg, and most preferably about 175 mg to about 400 mg e.g. about 400 mg. When the composition of the present invention is administered, a suitable daily dose of celecoxib is about 0.67 to about 13.3 mg / kg body weight, more preferably about 1.33 to about 10.67 mg / kg body weight, more preferably about 2.00 to about about 8.0 mg / kg body weight, and more preferably about 2.33 to about 5.33 mg / kg body weight, for example, about 5.33 mg / kg body weight. The daily dose may be administered in one or four doses per day, preferably in one or two doses per day. Administration of the composition of the present invention in a single 200 mg dosage unit or in two 100 mg dosage units twice daily is suitable for most patients.

For the treatment of pain, the compositions of the present invention may be used to administer a daily dose of celecoxib of about 50 mg to about 1000 mg, more preferably about 100 mg to about 600 mg, more preferably about 150 mg to about 500 mg, and most preferably about 175 mg to about 400 mg. mg, for example about 200 mg. When the composition of the present invention is administered, a suitable daily dose of celecoxib is about 0.67 to about 13.3 mg / kg body weight, more preferably about 1.33 to about 8.0 mg / kg body weight, more preferably about 2.00 to about about 6.67 mg / kg body weight, and more preferably about 2.33 to about 5.33 mg / kg body weight, for example, about 2.67 mg / kg body weight. The daily dose may be administered in one or four doses per day, preferably in one or two doses per day. When administering the composition of the present invention, it is preferable to administer one 50 mg dosage unit four times

daily, one 100 mg or two 50 mg dosage units twice daily or one 200 mg dosage unit, two 100 mg dosage units or four 50 mg dosage units once daily.

Generally, the composition of the present invention is administered in dosages and at a frequency sufficient to achieve an average serum celecoxib concentration in the subject of at least 100 ng / mL for a period of about 24 hours after administration.

Although the amount of celecoxib in the compositions described herein is preferably in the range indicated above, the compositions may also be used to administer celecoxib outside this range. For other selective cyclooxygenase-2 inhibitors, suitable dosages may be selected according to the patent literature cited above.

Nanoparticles comprising or consisting essentially of a compound having selectively inhibit cyclooxygenase-2 with poor water solubility, such as celecoxib, deracoxib, valdecoxib or rofecoxib, can be prepared by any method previously used for the preparation of poorly water-soluble drugs in the form of nanoparticles. Suitable methods, without limitation, are illustratively described for such other drugs in the above-mentioned U.S. Pat. Nos. 4826689, 5145684, 5298262, 5302401, 5336507,

5340564,

5518738,

5565188,

5346702,

5503723,

5569448,

5352459,

5534270,

5571536,

5354560,

5536508,

5573783,

5384124,

5552160,

5580579,

5429824,

5560931,

5585108,

5510118,

5560932,

5587143,

5591456,

5662883,

5665331,

5718919 and 5747001, and in the above

International Application Nos. WO 93/25190, WO 96/24336 and 98/35666, the contents of which are incorporated herein by reference. One of ordinary skill in the art will readily adapt the disclosed methods for preparing a selectively poor water-soluble cyclooxygenase-2 inhibitor, such as celecoxib, deracoxib, valdecoxib, or forecoxib, in the form of nanoparticles.

The ingredients used in the composition of the present invention may be solid or liquid. Preferably, the composition comprises about 1% to about 95%, more preferably 10% to about 90%, more preferably about 25% to about 85%, and more preferably about 30% to about 80%, by weight of a selective cyclooxygenase-2 inhibitor, for example celecoxib. Compositions of the present invention containing ingredients may be prepared by any known pharmaceutical technique comprising admixing the ingredients with a drug or therapeutic agent, except that in this case the drug or therapeutic agent, namely a selective cyclooxygenase-2 inhibitor, is at least partially preformed, together with one or more additives, in the form of nanoparticles, as described above.

The compositions of the present invention contain the required amount of cyclooxygenase-2 inhibitor, for example celecoxib, per dosage unit and may be, for example, in the form of a tablet, pill, hard or soft capsule, lozenge, wafer, powder, granules, suspension, elixir, liquid or any other form. suitable for oral administration. Such a composition is preferably made in the form of discrete dosage units, each containing a predetermined amount of a cyclooxygenase-2 inhibitor, such as tablets or capsules. These oral dosage forms may further comprise, for example, buffering agents. Tablets, pills and the like may further be prepared with or without a coating.

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

• · * · <

• · ·

Liquid dosage forms for oral administration include pharmaceutically acceptable suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also contain, for example, wetting agents, emulsifying and suspending agents, and sweetening, flavoring and odor modifying agents.

As mentioned above, the composition of the present invention containing the ingredients may be prepared by any suitable pharmaceutical method, which comprises carrying out mixing of the cyclooxygenase-2 inhibitor, at least in part in the form of nanoparticles, and the ingredients. Generally, such compositions are prepared by homogeneously and thoroughly mixing partially or wholly nanoparticulate cyclooxygenase-2 inhibitor (hereinafter sometimes referred to as a nanoparticulate compound) with a liquid or finely divided diluent, or both, and then, if necessary or desired, encapsulating or shaping. product. For example, a tablet may be prepared by compression or molding of the powder or granules of the nanoparticulate compound, together with one or more excipients. Compressed tablets may be prepared by compressing a free-flowing composition, such as a powder or granules, containing the nanoparticulate compound, optionally in admixture with one or more binders, glidants, inert diluents, wetting agents and / or dispersing agents, on a suitable machine. Molded tablets may be prepared by molding, on a suitable machine, nanoparticulate compounds moistened with an inert liquid diluent.

As mentioned above, the compositions of the present invention comprise a selective cyclooxygenase-2 inhibitor, for example celecoxib, in whole or in part in the form of nanoparticles, in a therapeutically or prophylactically effective amount per dosage unit, in combination with one or more pharmaceutically acceptable excipients suitable for oral administration. The compositions of the present invention preferably comprise the nanoparticulate compound in the desired amount in admixture with one or more excipients selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, adhesives, wetting agents, glidants and anti-adherent agents. Further, the nanoparticles themselves may optionally contain one or more polymers as a matrix and / or surface modifying agents as described in several of the above references. More preferably, such compositions are tableted or encapsulated for convenient administration in the form of immediate release tablets or capsules.

By appropriately selecting and combining additives, compositions having superior properties in efficacy, bioavailability, clearance, stability, compatibility of celecoxib and carriers, safety, dissolution profile, disintegration profile and / or other pharmacokinetic, chemical and / or physical properties can be prepared. The additives are preferably water-soluble and have wetting properties suitable to overcome poor water-solubility and hydrophobicity of the cyclooxygenase-2 inhibitor. When formulated as a tablet, the combination of selected ingredients allows the preparation of tablets having, inter alia, improved dissolution and disintegration profiles, hardness, less friability and / or crush resistance.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable diluents as additives.

Suitable diluents include, alone or in combination, lactose

USP; lactose USP, anhydrous; lactose USP, spray dried; starch

USP; directly compressible starch; mannitol USP; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; dibasic phosphate calcium atý nan az vápen vápen atý atý atý vápen vápen vápen atý atý atý atý atý atý atý atý atý atý atý atý atý atý atý atý atý atý atý atý NF dihydrate; sucrose-based diluents; regular sugar; calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate NF granular trihydrate NF; NF dextrates (e.g., Emdex); Celutab; dextrose (eg, Cerelose); inositol; hydrolysed cereal extracts such as Maltrons and Mor-Rex; amylose; Rexcel; powdered cellulose (eg, Elcema); calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; etc. Such diluents, if present, comprise in total about 5% to about 99%, preferably about 10% to about 85%; and most preferably about 20% to about 80% of the total weight of the composition. The diluents selected preferably have suitable flowability and, when preparing tablets, compressibility.

Preferred diluents are lactose and microcrystalline cellulose, alone or in combination. Both diluents are chemically compatible with celecoxib. The use of extragranular microcrystalline cellulose (i.e., microcrystalline cellulose added to the wet granular composition after the drying step) can be used to improve hardness (tablets) and / or disintegration time. Lactose, especially lactose monohydrate, is preferred. When using lactose, formulations having a suitable release rate of cyclooxygenase-2 inhibitors, stability, flowability prior to compression and / or drying properties are usually prepared at relatively low diluent costs. It is also a high density substrate, which aids in thickening during granulation (when wet granulation is used) and thus improves the flowability of the composition.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable disintegrants, particularly tablet compositions. Suitable disintegrants include, separately or in combination, for example, starches; sodium starch glycolate; clay (such as Veegum

HV); celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose); alginates; pregelatinized corn starches (such as National 1551 and National 1550); crospovidone USP NF; and gums (such as Arabic gum, guar gum, breadfruit gum, Karaya, pectin, and tragacanth). The disintegrants may be added at any suitable stage of the formulation, preferably they are added before granulation or during the lubrication stage before compression. Such disintegrants, if present, comprise a total of about 0.2% to about 30%, preferably about 0.2% to about 10%, most preferably about 0.2% to about 5% of the total weight of the composition.

Sodium croscarmellose is a preferred disintegrant of the tablet or capsule and, if present, constitutes about 0.2% to about 10%, more preferably about 0.2% to about 6%, even more preferably about 0.2% to about 5% of the total the weight of the composition. Croscarmellose sodium improves the intragranular disintegration of the compositions of the present invention.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable binders or adhesives as ingredients, in particular tablet compositions. Such binders and adhesives cause sufficient cohesiveness of the tableted powder and allow processing such as size determination, addition of glidants, compression and packaging, but also allow disintegration of the tablet and composition upon ingestion. Suitable binders and adhesives include, alone or in combination, acacia, tragacanth; sucrose; gelatine; glucose; starch; celluloses 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; hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose

(Klucel); ethylcellulose (Ethocel); pregelatinized starch (such as National 1511 and Starch 1500). Such binders and / or adhesives, if present, comprise in total about 0.5% to about 25%, more preferably about 0.75% to about 15%, and more preferably about 1% to about 10% of the total weight of the composition.

Polyvinylpyrrolidone is a preferred binder to improve the cohesiveness of the powder mixture of the cyclooxygenase-2 inhibitor and other granulating ingredients. Polyvinylpyrrolidone, if present, constitutes about 0.5% to about 10%, more preferably about 0.5% to about 7%, and more preferably about 0.5% to about 5% of the total weight of the composition. Polyvinylpyrrolidone with a viscosity of up to about 20 cPs may be used, although viscosities of about 6 cPs or less, especially about 3 cPS or less, are more preferred. Polyvinylpyrrolidone improves the cohesiveness of the powder mixture and facilitates the necessary binding to form granules during wet granulation.

The cyclooxygenase-2 inhibitory compounds used in the present invention, in particular celecoxib, are highly insoluble in aqueous solution. Therefore, the compositions of the present invention optionally, but preferably contain, as additives, one or more pharmaceutically acceptable wetting agents. Such wetting agents are used to maintain the cyclooxygenase-2 inhibitor in close association with water as a condition for improving the relative bioavailability of the composition. Suitable wetting agents include, alone or in combination, oleic acid; glyceryl monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate; polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan monolaurate; sodium oleate; and sodium lauryl sulfate. Wetting agents which are anionic surfactants are preferred. Such wetting agents, if present, comprise in total about 0.25% to about 15%, preferably about 0.4%.

% To about 10%, and preferably about 0.5% to about 5% of the total weight of the composition.

Sodium lauryl sulfate is a preferred wetting agent. Sodium lauryl sulfate, if present, constitutes about 0.25% to about 7%, more preferably about 0.4% to about 6%, and more preferably about 0.5% to about 5% of the total weight of the composition.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable lubricating and / or glidants as an additive. Suitable lubricating and / or glidants include, alone or in combination, glyceryl behapat (Compritol 888); stearates (magnesium, calcium and sodium); 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 (eg, Carbowax 4000 and Carbowax 6000); sodium oleate; sodium lauryl sulfate and magnesium lauryl sulfate. Such glidants, when present, preferably comprise from about 0.1% to about 10%, more preferably from about 0.2% to about 8%, and more preferably from about 0.25% to about 5% of the total weight of the composition.

Magnesium stearate is the preferred glidant used and serves, for example, to reduce friction between the equipment and the granulated mixture during compression of tablet compositions.

Other ingredients (such as anti-adhesion agents, colorants, flavoring agents, sweeteners and preservatives) are known in the pharmaceutical art and can be used in the compositions of the present invention. Iron oxide may be added to the composition to achieve a yellow color.

In one embodiment of the present invention, the composition is in the form of a tablet or capsule that is a dosage unit and comprises a partially or totally nanoparticulate selective cyclooxygenase-2 inhibitor, for example celecoxib, in the required amount, together with a binder. Such a composition preferably comprises one or more ingredients selected from the group consisting of pharmaceutically acceptable diluents, disintegrants, binders, wetting agents and glidants. More preferably, the composition comprises one or more ingredients selected from the group consisting of lactose, sodium lauryl sulfate, polyvinylpyrrolidone, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Even more preferably, the composition comprises lactose monohydrate and croscarmellose sodium. Even more preferably, the composition further comprises one or more carriers such as sodium lauryl sulfate, magnesium stearate and microcrystalline cellulose.

Although the dosage unit in capsule or tablet form of the present invention may be prepared, for example, by direct encapsulation or direct compression, preferably wet granulation is performed prior to encapsulation or compression. Wet granulation, among other things, thickens the milled material, which improves flowability, improves compression characteristics, and facilitates measurement or weighing of the encapsulation or tableting composition. The size of the secondary granules formed in the granulation (i.e., the granule size) is not critical and is only important in terms of whether it is suitable for easy handling and processing and for tablets - whether it allows the formation of a directly compressible mixture that forms pharmaceutically acceptable tablets.

The desired bulk density of the granules is usually about 0.3 g / ml to about 1.0 g / ml.

The ingredients for the capsules and tablets of the present invention are preferably selected such that the disintegration time of the tablet or capsule is less than about 30 minutes, preferably less than about 25 minutes, more preferably less than about 20 minutes, and still more. preferably less than about 15 minutes.

To prepare tablet compositions, the complete mixture in an amount sufficient to produce a uniform batch is tabletted to a conventional range on a tabletting machine at normal compression pressure (for example, by applying a force of about 1 kN to about 50 kN in a typical tablet press). Any tablet hardness suitable for handling, processing, storage and ingestion may be used. For a 100 mg tablet, the hardness is preferably at least 4 kP, more preferably at least about 5 kP and even more preferably at least about 6 kP. For a 200 mg tablet, the hardness is preferably at least 7 kP, more preferably at least about 9 kP, and even more preferably at least about 11 kP. However, the mixture should not be compressed enough to make it difficult to achieve hydration upon exposure to the gastric fluid.

For tablet compositions, the tabletability is preferably less than about 1.0%, more preferably less than 0.8%, and even more preferably less than about 0.5% in standard tests.

The present invention is also directed to a therapeutic method for treating a disease or disorder wherein treatment with a cyclooxygenase-2 inhibitor, which comprises oral administration of one or more dosage units of the composition of the present invention to an individual in need of such treatment, is indicated. The dosage regimen for preventing, ameliorating or alleviating the disease preferably corresponds to a once-daily or twice-daily treatment as described above, but may be modified according to many factors. These factors include the type, age, weight, sex, dietary habits and general health of the individual, and the nature and severity of the disease. Therefore, the dosage regimen used may be significantly different from the preferred dosage regimen set forth above.

Initial treatment of a disease or disorder in which treatment with a cyclooxygenase-2 inhibitor is indicated may be initiated with the doses indicated above. Treatment usually continues as needed for several weeks to months or years until the disease is controlled or eliminated. Individuals treated with the composition of the present invention may be routinely monitored by any method known in the art to determine the efficacy of therapy. Continuous analysis of such data allows modification of the treatment regimen during such therapy to always deliver the optimal dose of the cyclooxygenase-2 inhibitor, and thus the duration of treatment can also be determined. In this way, the treatment regimen / dosage may be rationally modified during therapy to administer the lowest amount of cyclooxygenase-2 inhibitor exhibiting satisfactory efficacy, and so that administration of the composition continues only to the form necessary for the successful treatment of the disease or condition.

The present invention is also directed to methods for preparing compositions comprising a poorly water-soluble selective cyclooxygenase-2 inhibitor, for example celecoxib, partially or completely in the nanoparticulate form of the present invention. More specifically, the invention relates to methods of preparing discrete dosage unit formulations such as tablets or capsules, wherein each tablet or capsule contains an amount of cyclooxygenase-2 inhibitor sufficient to achieve a rapid onset of therapeutic effect as described above, and preferably for the duration of the therapeutic. effect for about 12 to 24 hours. Each tablet or capsule preferably contains about 50 mg to about 200 mg, for example about 50 mg to about 100 mg, or about 200 mg of a cyclooxygenase-2 inhibitor, for example,

celecoxib. Wet granulation, dry granulation, direct compression or encapsulation may be used to prepare the tablets or capsules of the present invention.

Wet granulation is a preferred method for preparing the pharmaceutical compositions of the present invention. In the wet granulation process, any portion of the cyclooxygenase-2 inhibitor that is not in nanoparticulate form (if desired with one or more carriers) is first ground or micronized to a desired particle size greater than 1 mm. Although various conventional grinders or crushers may be used, impact grinding, such as tip grinding, achieves a better homogeneity of the composition compared to other types of grinding. Cooling the milled material, for example with liquid nitrogen, may be necessary during grinding to prevent the cyclooxygenase-2 inhibitor from heating to undesired temperatures. The D90 particle size is preferably reduced to less than about 25 mm during this milling step.

The milled or micronized cyclooxygenase-2 inhibitor, if any, is then mixed with the desired amount of cyclooxygenase-2 inhibitor in nanoparticulate form, prepared by any of the processes known in the art as described above, to yield a cyclooxygenase-2 inhibitor partially or wholly. in the form of nanoparticles (nanoparticulate compounds). Simultaneously or thereafter, the nanoparticulate compound is mixed, for example, in a high shear mixer / granulator, a planetary mixer, a double jacket mixer or a sigma mixer, with one or more ingredients, including ingredients that have been milled together with celecoxib or present in nanoparticles. to obtain a dry powder mixture. Usually, the nanoparticulate compound is mixed at this stage with one or more diluents, disintegrants and / or binders, and optionally one or more wetting agents, but alternatively,

all or part of the ingredients may be added at a later stage. For example, in tablet formulations containing croscarmellose sodium as a disintegrant, it has been found that adding a proportion of croscarmellose sodium during mixing (to obtain intragranular croscarmellose sodium) and adding the remainder after the drying step described below (to obtain extragranular croscarmellose sodium tablets) can improve tablets . In this situation, preferably about 60% to about 75% of croscarmellose sodium is added intragranularly and about 25% to about 40% of croscarmellose sodium is added extragranularly. Similarly, it has been found for tablet formulations that the addition of microcrystalline cellulose after the drying step (to obtain extargranular microcrystalline cellulose) can improve the compressibility of the granules and the hardness of the tablet prepared from the granules.

The mixing step in the process of the present invention preferably comprises mixing the nanoparticulate compound, lactose, polyvinylpyrrolidone and croscarmellose sodium. It has been found that a mixing time of as little as three minutes can result in a dry powder mixture having a sufficiently homogeneous distribution of the cyclooxygenase inhibitor.

2.

Thereafter, water, preferably purified water, is added to the dry powder mixture, and the mixture is blended for an additional time to obtain a wet granular mixture. Preferably, a wetting agent is used and this agent is preferably first added to water and mixed for at least 15 minutes, more preferably 20 minutes, before adding water to the dry powder mixture. Water may be added to the mixture at once, sequentially over a period of time, or in several portions over a period of time. The water is preferably added gradually over a period of time. Alternatively, the wetting agent may be added to the dry powder mixture and then water may be added to the resulting mixture. Further mixing after the addition of water is advantageous to ensure a homogeneous distribution of water in the mixture.

• · · ·

The wet granulated mixture is then preferably wet milled, for example on a sieve mill, to eliminate large agglomerates of material that are formed as a by-product of wet granulation. If not removed, these agglomerates could prolong subsequent fluid bed drying and could increase the variability in moisture control.

The wet granulated or wet milled mixture is then dried, for example, in an oven or fluid bed dryer, preferably a fluid bed dryer, to obtain dry granules. If desired, the wet granulated mixture may be extruded or spheronized prior to drying. During drying conditions such as air inlet temperature and drying time are adjusted to give the dry granules the desired degree of moisture. It may be desirable to combine two or more granulations for this drying step and subsequent processing.

The size of the granules is then reduced to the extent necessary to prepare them for compression or encapsulation. Conventional particle size reduction equipment such as oscillators or impact mills (such as a Fitz mill) may be used.

A slight decrease in granule size is observed as the mixing time increases with mixtures containing small amounts of water. It is believed that when the water concentration is too low to fully activate the binder used, the cohesive forces between the primary particles in the granules are insufficient to withstand the shear forces generated by the mixing sheets and thus reduce the size of the granules instead of their growth. Conversely, when the amount of water is increased sufficiently to fully activate the binder, the cohesive forces between the primary particles overcome the shear forces generated by the mixing sheets and thus increase the granule size during mixing as the mixing time increases and / or the water concentration increases. The size of the sieve in the grinder has a greater influence on the size of the granules than the range of movements and / or grinding speed.

The dry granules are then placed in a suitable mixer, such as a double-shell mixer, and optionally a glidant (such as magnesium stearate) and any other carrier (such as extragranular microcrystalline cellulose and / or extragranular croscarmellose sodium in some tablet compositions) are added. to obtain a final blend. When the diluents comprise microcrystalline cellulose, it has been found that adding a proportion of microcrystalline cellulose during this step significantly increases the compressibility of the granules and the hardness of the tablets. However, increasing the amount of magnesium stearate above about 1% to about 2% reduces the hardness of the tablets and increases the friability and dissolution time.

The final blend is then filled into capsules (or compressed into tablets of desired weight and hardness using a suitable tool to prepare tablets). Conventional capsule compression and filling techniques known in the art may be used. Suitable results are obtained for capsules using a bed height ranging from about 20 mm to about 60 mm, a compaction from about 0 mm to about 5 mm, and speeds from about 60000 capsules per hour to about 130000 capsules per hour. The formation of aggregates can be minimized or eliminated by using the lowest degree of compaction at which the weight of the capsule can be controlled. Conventional coating techniques known to those skilled in the art may be used in the manufacture of coated capsules.

This combination of operations results in granules having a uniform content of cyclooxygenase-2 inhibitor, such as celecoxib, in a dosage unit that disintegrates readily, having sufficient fluidity to easily control weight during capsule filling or tableting, and having • ·

sufficient bulk density to allow the batch to be processed in the selected equipment and the unit doses corresponding to specific capsules or tablets.

The present invention also relates to the use of the composition of the present invention in the preparation of medicaments useful for the treatment and / or prophylaxis of cyclooxygenase-2 mediated diseases, particularly those diseases and disorders in which a rapid onset of therapeutic effect is desired or necessary.

The present invention also relates to a novel solid form of celecoxib, Form I celecoxib. The present invention also relates to another new solid form of celecoxib, Form II celecoxib. Each of these new solid forms includes solvated crystalline forms, unsolvated and non-hydrated crystalline forms. These novel forms of celecoxib described in the present invention have one or more of the above-mentioned advantageous chemical and / or physical properties over other solid forms described herein or in the literature.

In one embodiment of the invention, the solid form is Form I celecoxib. Without limiting the present invention, it is believed that Form I celecoxib has a higher solubility and a higher dissolution rate than Form III because Form III is more thermodynamically stable and has less free energy than Form I. A higher dissolution rate is preferred because the higher rate dissolution of the drug usually increases its bioavailability.

Form I celecoxib is a crystalline form of celecoxib having an X-ray powder with peaks at 5.5, 5.7, 7.2 and 16.6 degrees 2theta. Form I of celecoxib has an X-ray powder pattern that is the same as the X-ray pattern shown in the upper curve of Figure 1a. Celecoxib Form I has a melting point of about 162.5 ° C to about 163 ° C, preferably about 162.8 ° C. Form I of celecoxib has a maximum endotherm at differential scanning calorimetry at approximately

163.3 ° C at a scan rate of 0.5 ° C / minute as shown in FIG.

3. Form I of celecoxib is characterized by the IR spectrum shown in Figure 2, with a peak between about 3250 and 3260 cm ^-1 , and another between 3350 and 3360 cm ^-1 , preferably peaks at about 3256 cm ^-1 and 3356 cm ^-1 , respectively. The solid form of the present invention has 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, more preferably at least about 50% celecoxib Form I, more preferably at least about 75 % of Form I celecoxib, more preferably at least about 90% of Form I celecoxib, and more preferably is substantially phase pure Form I celecoxib.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a celecoxib solid form and at least one pharmaceutically acceptable carrier, excipient or diluent, wherein the celecoxib solid form comprises at least 2% celecoxib Form I, and preferably at least 10% celecoxib Form I, more preferably at least 50% celecoxib Form I and even more preferably at least 98% celecoxib Form I. In one embodiment, the solid form of celecoxib is primarily Form I celecoxib.

In yet another embodiment, the present invention provides a method for treating or preventing a cyclooxygenase-2 mediated disease in a subject, wherein the subject is administered a therapeutically effective amount of Form I of celecoxib. Preferably, the cyclooxygenase-2 mediated disease treated is pain, inflammation, arthritis, tumor growth, metastasis, or familial adenomatous polyposis.

• ·

· ♦ · · · · · · ** ** ** ** ** ** ** ** **

Yet another embodiment of the invention is a process for the preparation of celecoxib Form I which comprises crystallizing Form I celecoxib from a mixture of celecoxib and a solvent, wherein the crystallization is performed at a temperature above the enantiotropic transition temperature of Form I celecoxib. Prior to crystallization of Form I celecoxib, seed crystals of Form I celecoxib must be added to the solvent resulting in the production of Form I celecoxib having a phase purity of at least about 5% by weight, more preferably a phase purity of at least about 10% by weight. % by weight, more preferably with a phase purity of at least about 50% by weight, and even more preferably with a phase purity of at least about 90% by weight.

Yet another embodiment of the invention is a process for preparing a crystalline form of celecoxib which comprises heating a celecoxib solvate to obtain Form I celecoxib. The solvate may be heated, for example, at a temperature of about 50 ° C to about 160 ° C, more preferably about 60 ° C to about 150 ° C, more preferably about 70 ° C to about 140 ° C, even more preferably about 80 ° C to about 160 ° C. 130 ° C, more preferably about 85 ° C to about 120, more preferably at a temperature of about 90 ° C to about 110 ° C, and more preferably at a temperature of about 100 ° C. The heating may be carried out for any suitable period of time, for example for more than 1 minute, preferably more than about 5 minutes, preferably longer than about 60 minutes, more preferably about 2 hours, and most preferably about 4 hours or more. Further, the method can be carried out at any pressure, preferably at a pressure below atmospheric pressure. The solvate used in the process of the present invention comprises celecoxib and a solvent. The solvent may be, for example, an amide solvent. Suitable amide solvents are 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 any mixture of these solvents.

······ · · · · · · · · · · · · · · · · · · · · · ··· ··· ·· ···

A preferred solvent is 1,1,3,3-tetramethylurea. Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone. Yet another preferred solvent is 1-methyl-2-pyrrolidinone. Yet another preferred solvent is N, N-dimethylformamide. Yet another preferred solvent is N, N-dimethylacetamide.

The solvate may be prepared by a process comprising mixing celecoxib with an amide 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 1,1,3,3-tetramethylurea, or any mixture of these solvents. A preferred solvent is 1,1,3,3-tetramethylurea. Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone. Yet another preferred solvent is 1-methyl-2-pyrrolidinone. Yet another preferred solvent is N, N-dimethylformamide. Yet another preferred solvent is N, N-dimethylacetamide.

The present invention also relates to a process for preparing celecoxib Form I which comprises grinding or crushing celecoxib Form III. Suitable grinding is, for example, wet grinding or ball grinding. Suitable crushing is, for example, crushing or shaking.

The present invention also relates to a process for preparing celecoxib Form I, which comprises grinding or crushing a celecoxib solvate. Suitable grinding is, for example, wet grinding or ball grinding. Suitable crushing is, for example, crushing or shaking.

In another embodiment, the invention provides a process for preparing celecoxib Form I comprising melting celecoxib Form II and cooling the melt to form celecoxib Form I.

In another embodiment, the invention provides a process for preparing celecoxib Form I comprising melting celecoxib Form III and cooling the melt to form celecoxib Form I.

In another embodiment, the invention provides a process for preparing celecoxib Form I comprising evaporating the solvent from a celecoxib solution. The solvent may be, for example, an ether or a hydrocarbon, or a mixture of an ether and a hydrocarbon. Preferably, the solvent comprises ethyl acetate and heptane, preferably in a ratio of 15:85. The process may be carried out at any pressure, preferably at a pressure below atmospheric pressure. The process may be carried out at various temperatures, preferably at a temperature of about 35 ° C.

In another embodiment, the solid form is Form II celecoxib. Without limiting the present invention, it is believed that Form II celecoxib has a higher solubility and faster dissolution rate than Form III because Form III is more thermodynamically stable and has less free energy than Form II. A higher dissolution rate is advantageous because a higher dissolution rate of the drug usually increases its bioavailability.

Form II celecoxib is a crystalline form of celecoxib having an X-ray powder with peaks at 10.3, 13.8, 17.7 degrees 2-theta. The mixture of Form I and Form II has the peaks shown in the upper curve of Fig. Ib. Form II of celecoxib has a melting point of about 161 ° C to about 162 ° C, preferably about 161.5 ° C. Form II celecoxib has a maximum endotherm at differential scanning calorimetry at about 162.0 ° C when scanned at 0.5 ° C / minute. Form II celecoxib is believed to have better solubility and greater dissolution rate than form III celecoxib. The solid form of the present invention has a phase purity of at least about 5% celecoxib Form II, preferably at least about 10% celecoxib Form II, more preferably at least about 25% form Celecoxib II, more preferably at least about 50% celecoxib form II, more preferably at least about 75% celecoxib form II, more preferably at least about 90% celecoxib form II, and more preferably is substantially phase-pure celecoxib form II.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a celecoxib solid form and at least one pharmaceutically acceptable carrier, excipient or diluent, wherein the celecoxib solid form comprises at least 2% celecoxib Form II, and preferably at least 10% celecoxib Form II, more preferably at least 50% of Form II celecoxib and even more preferably at least 98% of Form II celecoxib. In one embodiment, the solid form of celecoxib is primarily Form II celecoxib.

In yet another embodiment, the present invention provides a method for treating or preventing a cyclooxygenase-2 mediated disease in an individual comprising administering to the individual a therapeutically effective amount of Form II celecoxib. Preferably, the cyclooxygenase-2 mediated disease treated is pain, inflammation, arthritis, tumor growth, metastasis, or familial adenomatous polyposis.

Yet another embodiment of the invention is a process for preparing celecoxib Form II comprising crystallizing celecoxib Form II from a mixture of celecoxib and a solvent, wherein the crystallization is performed at a temperature above the enantiotropic transition temperature of celecoxib Form II. Before crystallization of Form II celecoxib, seed crystals of Form II celecoxib must be added to the solvent resulting in the production of Form II celecoxib having a phase purity of at least about 5% by weight, preferably with a phase purity of at least about 10% by weight, and even more preferably with phase purity. at least about 25% by weight.

• 9 • 9 • 9

Yet another embodiment of the invention is a process for preparing a crystalline form of celecoxib which comprises heating a celecoxib solvate to obtain celecoxib Form II. The solvate may be heated at a temperature of about 50 ° C to about 160 ° C, more preferably 60 ° C to about 145 ° C, even more preferably about 70 ° C

140 ° C, more preferably about 80 ° C to about 140 ° C, more preferably 90 ° C to about 140 ° C ° C ° C ° C ° C.

for example, about to about about about about about about

100 ALIGN!

110

120

125

130 up to az up to

140

140

140

135 at a suitable time than about better still at &lt; 0 &gt; C and even better at &lt; 0 &gt; C, even better at &lt; 0 &gt; C, even better at &lt; 0 &gt; minutes, still approximately approximately approximately approximately

For example, the heating may be for more than 5 minutes, preferably longer than preferably about 2 hours, and most preferably about 4 hours or more. Further, the method can be carried out at any pressure, preferably at a pressure below atmospheric pressure. The solvate used in the process of the present invention comprises celecoxib and a solvent. The solvent may be, for example, an amide solvent. Suitable amide solvents are N, we control thylformamide, 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 any mixture of these solvents. A preferred solvent is -pyrimidinone. Yet another pyrrolidinone. Yet another dimethylformamide. Yet another preferred solvent is N, N-dimethylacetamide.

1.1.3.3- tetramethylurea. Others

1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) the preferred solvent is 1-methyl-2 the preferred solvent is N, NV of another embodiment of the present invention wherein the form is ································

II of celecoxib prepared by heating the celecoxib solvate to form celecoxib form II, the solvate is prepared by a method comprising mixing celecoxib with an amide solvent selected from the group consisting of N, N-dimethylformamide, Ν, Ν-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3- dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone, and 1,1,3,3-tetramethylurea, or any mixture of these solvents. A preferred solvent is 1,1,3,3-tetramethylurea. Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone. Yet another preferred solvent is 1-methyl-2-pyrrolidinone. Yet another preferred solvent is N, N-dimethylformamide. Yet another preferred solvent is Ν, Ν-dimethylacetamide.

Another embodiment of the present invention is a solid form of celecoxib consisting of Form I celecoxib and Form II celecoxib.

Yet another embodiment of the present invention is a solid form of celecoxib consisting of Form I celecoxib and Form III celecoxib.

Yet another embodiment of the present invention is a solid form of celecoxib consisting of Form II celecoxib and Form III celecoxib.

Yet another embodiment of the present invention is a solid form of celecoxib consisting of Form I celecoxib, Form II celecoxib and Form III celecoxib.

The present invention also relates to a process for preparing celecoxib Form II which comprises grinding or crushing Celecoxib Form III. Suitable grinding is, for example, wet grinding or ball grinding. Suitable crushing is, for example, crushing or shaking.

The present invention also relates to a process for preparing celecoxib Form II which comprises grinding or crushing a celecoxib solvate.

Suitable grinding is, for example, wet grinding or ball grinding. Suitable crushing is, for example, crushing or shaking.

In another embodiment, the invention provides a process for preparing Form II celecoxib comprising melting Form I celecoxib and cooling the melt to form Form II celecoxib.

In another embodiment, the invention provides a process for preparing celecoxib Form II comprising melting celecoxib Form III and cooling the melt to form celecoxib Form II.

Celecoxib Form III is prepared by crystallizing celecoxib from a solvent comprising isopropanol and water (see, eg, US 5910597).

Form III celecoxib has a complex transition melting according to differential scanning calorimetry. When scanned at 0.5 ° C / minute, the melting of celecoxib Form III is observed at approximately

160.8 ° C and then recrystallization to form II of celecoxib followed by melting of form II at about 162.0 ° C. Form III of celecoxib is a thermodynamically stable form of celecoxib.

Characterization of polymorphic crystalline forms of celecoxib

X-ray powder diffraction (PXRD), infrared absorption spectroscopy (IR) and differential scanning calorimetry (DSC) as well as Raman spectroscopy were used to characterize forms I and II.

X-ray powder diffraction (PXRD)

Various crystalline forms of celecoxib can be analyzed on either the Siemens D5000 Powder Diffractometer or the Inel Multipurpose Diffractometer. For the Siemens D5000 Powder Diffractometer, raw data can be measured for 2-theta values from 2 ° to 50 °, with 0.02 ° steps and a 2 second step period. For the Inel Multipurpose Diffractometer, samples are placed in an aluminum sample holder and raw data is measured for all theta values simultaneously.

As shown in Figure 1, three forms were easily distinguished by PXRD. Using a Cu X-ray source (1.54 nm), characteristic diffractions were observed at 2-theta values of about 5.5 °, 5.7 °, 7.2 ° and 16.6 ° for Form I celecoxib and about 10.3. °, 13.8 ° and 17.7 ° for celecoxib form II.

Melting / decomposition temperature

Melting and / or decomposition temperatures of unsolvated crystalline forms of celecoxib were determined using a TA Instruments 2920 differential scanning calorimeter. Each sample (1-2 mg) was placed in a closed or non-closed aluminum pan and heated at 0.5 ° C / minute. The melting / decomposition range was defined from the extrapolated reaching the melting / decomposition endotherm.

Three polymorphic forms of celecoxib have been identified. Celecoxib polymorph Form I melted at about 162.8 ° C; Form II celecoxib melted at about 161.5 ° C; and celecoxib Form III melted at about 160.8 ° C. Upon melting, it was observed that Form III of celecoxib partially recrystallized to form II of celecoxib or to form I of celecoxib.

Three polymorphic forms and solvates of N, N55 dimethylacetamide (DMA) and N, N-dimethylformamide (DMF) were identified. The physical properties and distinguishing characteristics of the new polymorphic forms are shown in Table 1.

Table 1

Form Melting point (° C) Δη (J / g) Distinguishing transition IR Raman PXRD (2 Theta) AND 162.8 72 3256 cm ^-1 3356 cm ^-1 ON 2.5 °, 5.7 °, 7.2 ^U 16 6 ° II ** 161.5 <84 none 712 cm ^-1 10.3 ^U , 13.8 °, 17.7 ° ^C III 160.8 91 - - -

* characteristic transitions not observed for other forms ** pure samples of Form II celecoxib were not prepared

Differential Scanning Calorimetry (DSC)

DSC was used to characterize polymorphic forms of celecoxib. Form I celecoxib has the highest melting point of the polymorphic form at 162.8 ° C with a maximum endotherm at 163.3 ° C. Form II celecoxib melts at 161.5 ° C and has a maximum endotherm at 162.0 ° C. A complex transition is observed for celecoxib form III. The complexity of this transition, which is only observed at a slow scan rate, is the melting of celecoxib Form III, followed by recrystallization of celecoxib Form II and subsequent melting of Celecoxib Form II. When only the first endothermic transition is considered, celecoxib Form III melts at

160.8 ° C and has a maximum endotherm at 161.5 ° C. DSC detects low concentrations of celecoxib Form I in celecoxib Form III.

Infrared absorption spectroscopy

Μ · «

IR distinguishes Form I celecoxib from Form II celecoxib and form

III of celecoxib (see Figure 2).

Without further modification, it is believed that one skilled in the art will be able to utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, merely illustrative and in no way limit the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The following examples provide a detailed description of the processes for preparing crystalline Form I and Form II of celecoxib described in the present invention. These detailed descriptions are within the scope of the invention and serve as examples of embodiments thereof. Therefore, these detailed descriptions are illustrative only and do not limit the scope of the present invention. All proportions are by weight and temperatures are in ° C unless otherwise indicated. The starting material (celecoxib) used in each of the following examples was prepared according to the method of US 5910597.

Preparation examples

Example 1: Preparation of celecoxib DMA solvate (celecoxib: DMA ratio = 1: 1)

Method A: In a round-bottomed flask, 4.84 g of celecoxib was mixed with approximately 125 ml of DMA. The solvent was removed under reduced pressure and at 60 ° C to induce crystallization. The dry solid material is obtained on a filter. 5 g of a 1: 1 solvate are thus obtained. As determined by TGA at 10 ° C / min, degradation begins at about 100 ° C with a maximum at about 148 ° C, and the total weight loss is 17%.

Method B: Place 38.2 g of celecoxib in approximately 1000 ml of DMA in a 1 L beaker and mix. The solution obtained is transferred to a 2 L beaker. Approximately 400 mL of water was added causing crystallization. The crystals were isolated by filtration. The wet yield is

5.44 g. Further crystal formation is induced by adding water to the crystals. As determined by TGA at 10 ° C / minute, decomposition begins at about 100 ° C with a maximum at about 150 ° C, and the total weight loss is 18% solvent.

Example 2: Preparation of a celecoxib DMF solvate (celecoxib: DMF ratio = 1: 1)

In the crystallization disk, approximately 1 g of celecoxib is dissolved in 50 ml of DMF. The crystallization disk, covered with aluminum foil and perforated by small holes, is placed in a fume cupboard and allowed to evaporate to dryness. In this way, about 1.02 g is obtained. TGA at 10 ° C / minute shows two weight loss during decomposition starting at about 75 ° C and continuing with a second maximum at about 156 ° C. Total weight loss is 13.4%.

Processing examples

Example 1: General Methods for the Preparation of Celecoxib Form I

A. Preparation of celecoxib Form I by heating a celecoxib solvate

The open celecoxib solvate reservoir is heated in an oven at the lowest temperature at which desolvation is observed. Briefly, 0.3 g of celecoxib-DMA is heated in an oven at about 100 ° C for about 48 hours. The PXRD of the sample obtained exhibits reflections characteristic of Form I of celecoxib, as well as of:.

celecoxib-DMA; TGA shows a 9.6% weight loss most significantly at about 147 ° C, indicating about 50% conversion to Form I.

B. Preparation of Celecoxib Form I by Evaporation

A high purity celecoxib sample is crystallized from ethyl acetate-heptane solvent by evaporation. Celecoxib (16.03 g) was purified by preparative liquid chromatography using 15/85 (v / v) ethyl acetate / heptane and a 150 mm column (50.8 mm id) containing 40-63 mm silica gel. Fractions eluting between 270 ml and 900 ml are collected and combined. The solvent was removed at about 35 ° C under vacuum to induce crystallization and evaporated to dryness. 8.6 g of celecoxib Form I are obtained. The crystals do not contain a solvent as determined by TGA, and Form I has the PXRD X-ray pattern shown in Fig. 1a.

C. Melting of Celecoxib Form I

Generally, celecoxib is placed in an open container and melted and then allowed to cool. More specifically, the beaker containing celecoxib is heated to a temperature of 170 ° C and the celecoxib is allowed to melt completely. The molten celecoxib is then poured onto glass and allowed to cool. According to DSC, with a scan at 0.5 ° C / minute, melting of Form I was observed at approximately 163 ° C. Melting of Form III and recrystallization to Form II, and melting of Form II are also observed.

Example 2: General Methods for the Preparation of Celecoxib Form II

A. Preparation of celecoxib Form II by heating a celecoxib solvate

1. Use of the DMA solvate

Generally, an open reservoir of celecoxib DMA solvate is heated in an oven at near peak temperature at which desolvation is observed. Briefly, 0.3 g of celecoxib-DMA is heated in an oven at about 130 ° C for about 48 hours. The PXRD of the obtained sample shows reflections characteristic of Form II of celecoxib as well as reflections characteristic of Form III; DSC at 0.5 ° C / min shows one melting endotherm with formation at 161.4 ° C and peak at 161.9 ° C; TGA shows no weight loss up to 200 ° C. The PXRD pattern of the mixture is shown in Figure 1b.

2. Use of a DMF solvate

Generally, an open container of celecoxib DMF solvate is heated in an oven at near peak temperature at which desolvation is observed. Briefly, approximately 0.2 g of celecoxib-DMA is heated in an oven at approximately 130 ° C overnight. The PXRD of the obtained sample shows reflections characteristic of Form II of celecoxib as well as reflections characteristic of Form III; DSC at 0.5 ° C / min shows one melting endotherm with formation at 161.5 ° C and peak at

161.8 ° C and a mild endothermic transition with a maximum at about 163.8 ° C (Form I); TGA shows no weight loss up to 200 ° C.

B. Preparation of Celecoxib Form II from Celecoxib Form III by Mechanical Conversion

Generally, Form III of celecoxib is ground in a ball mill.

Briefly, using wiggle-bug, celecoxib Form III is ground at maximum intensity for 30 seconds. The solid material obtained is a mixture of Form III and Form II as determined by X-ray powder diffraction.

• ·

C. Melting of Celecoxib Form II

Celecoxib is melted in a test tube at 170 ° C in an oil bath. The Teflon spoon is immersed in molten celecoxib, removed, scraped and the dry solid material removed from the spoon. The solid material obtained is a mixture of Form III and Form II as determined by X-ray powder diffraction. DSC at 10 ° C / minute also indicates the presence of Form I.

Claims (173)

Form I crystalline forms of celecoxib. The crystalline form of claim 1 having an X-ray powder diffraction pattern with peaks at about 5.5, 5.7, 7.2 or 16.6 degrees two theta. The crystalline form according to claim 1, characterized in that the X-ray powder diffraction pattern has substantially the same X-ray pattern shown in the upper curve of Fig. 1a. 4. The crystalline form of claim 1 having a melting point in the range of about 165 ° C to about 164 ° C. 5. The crystalline form of claim 1 having a melting point in the range of about 162 ° C to about 163 ° C. A crystalline form according to claim 5 having a melting point of 162.8 ° C. 7. The crystalline form of claim 5 having a differential scanning calorimetric endothermic peak from about 160.0 ° C to about 164.0 ° C. 8. The crystalline form of claim 5 having an endothermic peak at about 163.3 ° C. The crystalline form of claim 8, further having a melting point in the range of about 160 ° C to about 164 ° C. The crystalline form of claim 9 having a melting point of about 162.8 ° C. The crystalline form of claim 1 having an infrared spectrum with a peak at about 3250 to about 3260 cm ^-1 . The crystalline form of claim 11 having an infrared spectrum with a peak at about 3256 cm ^-1 . The crystalline form of claim 1 having an infrared spectrum with a peak at about 3350 to about 3360 cm ^-1 . 14. The crystalline form of claim 13 having an infrared spectrum with a peak at about 3356 cm @ ^-1 . The crystalline form of claim 1 having an infrared spectrum with 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 at least about 5% phase purity of celecoxib Form I. 17. The crystalline form of claim 1 having at least about 10% phase purity of Form I celecoxib. • • • • 18. The crystalline form of claim 1 having at least about 25% phase purity of celecoxib Form I. 19. The crystalline form of claim 1 having at least about 50% phase purity of Form I celecoxib. 20. The crystalline form of claim 1 having at least about 75% phase purity of Form I celecoxib. 21. The crystalline form of claim 1 having at least about 90% phase purity of Form I celecoxib. 22. The crystalline form of claim 1, wherein said crystalline form is substantially phase pure form I of celecoxib. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 2 to 22 and at least one pharmaceutically acceptable carrier, excipient or diluent. The composition of claim 23 wherein the celecoxib comprises at least 2% The composition of claim 23 wherein the celecoxib comprises at least 10 ' The composition of claim 23 wherein the celecoxib comprises at least 50 ^: indicating form I of celecoxib. with E t i m, indicating with E t i m, of Form I celecoxib. indicating with E t i m, of Form I celecoxib. • * · · • 9 · · The composition of claim 23, wherein the celecoxib comprises at least 98% celecoxib Form I. 28. The composition of claim 23, wherein the celecoxib is primarily Form I celecoxib. 29. A method of treating or preventing a cyclooxygenase-2 mediated disease or condition in a subject comprising administering to the subject a therapeutically effective amount of Form I of celecoxib. The method of claim 29, wherein the disease or disorder is pain 31. The method of claim 29, wherein the disease or disorder is inflammation. 32. The method of claim 29, wherein the disease or disorder is arthritis The method of claim 29, wherein the disease or disorder is a tumor. 34. The method of claim 29, wherein the disease or disorder is metastasis 35. The method of claim 29, wherein the disease or disorder is familial adenomatous polyposis. 36. A process for preparing celecoxib Form I, comprising crystallizing celecoxib from a mixture comprising celecoxib and a solvent, wherein the crystallization is performed at a temperature above 9 ° C of the enantiotropic transition temperature of Form I celecoxib, thereby forming Form I celecoxib. 37. The method of claim 36, further comprising adding seed crystals of Form I celecoxib to the solvent prior to crystallization. 38. The process of claim 36 wherein the celecoxib Form I thus prepared has a phase purity of at least 5% by weight. 39. The process of claim 36 wherein the celecoxib Form I thus prepared has a phase purity of at least 10% by weight. 40. The process of claim 36 wherein the celecoxib Form I thus prepared has a phase purity of at least 50% by weight. 41. The process of claim 36 wherein the celecoxib Form I thus prepared has a phase purity of at least 90% by weight. 42. The process of claim 36 wherein the celecoxib Form I thus prepared has a phase purity of at least 25% by weight. 43. A process for preparing a crystalline form of celecoxib comprising heating the solvate of celecoxib to obtain Form I celecoxib. 44. The method of claim 128, wherein the solvate is heated to a temperature of about 50 ° C to about 160 ° C. • · · · The method of claim 128, wherein the solvate is heated to a temperature of about 60 ° C to about 150 ° C. 46. The method of claim 128, wherein the solvate is heated to a temperature of about 70 ° C to about 140 ° C. 47. The method of claim 128, wherein the solvate is heated to a temperature of about 80 ° C to about 130 ° C. 48. The method of claim 128, wherein the solvate is heated to a temperature of about 85 ° C to about 120 ° C. 49. The method of claim 128, wherein the solvate is heated to a temperature of about 90 ° C to about 110 ° C. The process of claim 128, wherein the solvate is heated to a temperature of about 100 ° C. i se m that i se 51. The process of claim 128, wherein the solvate is heated for more than about 1 minute. m that The process of claim 128, wherein the solvate is heated for more than about 5 minutes. m that 53. The method of claim 128, wherein the solvate is heated for more than about 60 minutes. 54. The process of claim 128, wherein the solvate is heated for more than about 2 hours. i m that 55. The process of claim 128, wherein the solvate is heated for about 4 hours or more. m that 56. The method of any one of claims 43-55, wherein the heating is performed at a pressure below atmospheric pressure. 57. The method of claim 56, wherein the celecoxib solvate comprises celecoxib and the amide solvent. 58. The process of claim 57 wherein the amide solvent is 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 1,1,3,3-tetramethylurea. 59. The process of claim 146 wherein the amide solvent is N, N-dimethylformamide. m that 60. The process of claim 146 wherein the amide solvent is N, N-dimethylacetamide. m that 61. The process of claim 146 wherein the amide solvent is 1-methyl-2-pyrrolidinone. m that 62. The process of claim 146 wherein the amide solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone. 63. The process of claim 146 wherein the amide solvent is 1,1,3,3-tetramethylurea. 64. The method of claim 146, wherein the celecoxib solvate is prepared by a method comprising mixing celecoxib with an amide solvent selected from the group consisting of: 1-Methyl68 • · « Including N, N-dimethylformamide, N, N-dimethylacetamide, -2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H); -pyrimidinone and 1,1,3,3-tetramethylurea. 65. The process of claim 64 wherein the amide solvent is N, N-dimethylformamide. m that 66. The process of claim 64 wherein the amide solvent is N, N-dimethylacetamide. m that 67. The process of claim 64 wherein the amide solvent is 1-methyl-2-pyrrolidinone. m that m that 68. The process of claim 64 wherein the amide solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone. 69. The process of claim 64 wherein the amide solvent is 1,1,3,3-tetramethylurea. 70. A process for preparing celecoxib Form I, comprising milling or grinding a celecoxib Form I yield. forms III and celecoxib 71. The method of claim 70 comprising milling of Form III of celecoxib. m that 72. The method of claim 71 wherein the grinding is wet grinding. 73. The method of claim 71, wherein the milling is a ball mill. m that Μ · » 74. The method of claim 70, comprising crushing celecoxib Form III. 75. The method of claim 74 wherein the crushing is performed by shaking. 76. A process for preparing celecoxib Form I, comprising milling or grinding a celecoxib solvate to form celecoxib Form I. 77. The method of claim 76 comprising milling a celecoxib solvate. 78. The method of claim 77, wherein the grinding is wet grinding. m that 79. The method of claim 77 wherein the grinding is a ball mill grinding. 80. The method of claim m, comprising crushing the celecoxib solvate. The method of claim 80, characterized in that the shredding is carried out by shaking. 82. A process for the preparation of celecoxib Form I by: comprising melting the celecoxib Form II to form Celecoxib Form I. cooling 83. A process for preparing celecoxib Form I, comprising melting celecoxib Form III and cooling the melt to form celecoxib Form I. 84. A process for preparing celecoxib Form I, comprising evaporating the solvent from the celecoxib solution to obtain celecoxib Form I. 85. The process of claim 84 wherein the solvent is selected from the group consisting of ether and a hydrocarbon. 86. The method of claim solvent comprises ether and a hydrocarbon. m that 87. The process of claim 86 wherein the solvent comprises ethyl acetate and heptane. m that 88. The process of claim 87 wherein ethyl acetate and heptane are in a ratio of about 15:85. 89. The method of claim 84 in the evaporation is performed at a pressure y z n lower than atmospheric y z n and the evaporation is carried out at a temperature of about 35 90. The method of claim 84, wherein the temperature is t ° C. m, m, the pressure. that i m that 91. Form II crystalline forms of celecoxib. 92. The crystalline form of claim 91 having an X-ray powder diffraction pattern with peaks at about 10.3, 13.8, or 17.7 degrees two theta. 93. The crystalline form of claim 91, wherein the X-ray powder diffraction pattern is substantially the same as that shown in FIG. 1a. 94. The crystalline form of claim 91, wherein: Having a melting point in the range of about 159 ° C to about 164 ° C. 95. The crystalline form of claim 91 having a melting point in the range of about 161 ° C to about 163 ° C. 96. The crystalline form of claim 95 having a melting point of 161.5 ° C. 97. The crystalline form of claim 95 having a differential scanning calorimetric endothermic peak from about 160.0 ° C to about 164.0 ° C. 98. The crystalline form of claim 95 having an endothermic peak at about 162.0 ° C. 99. The crystalline form of claim 98, further having a melting point in the range of 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 having at least about 5% phase purity of celecoxib Form II. 102. The crystalline form of claim 91 having at least about 10% phase purity of celecoxib Form II. 103. The crystalline form of claim 91 wherein: · · * * * * * * II p The composition of claim 1, wherein at least about 25% has a phase purity of the form of celecoxib. 104. The crystalline form of claim 91 having at least about 50% phase purity of the form II celecoxib. 105. The crystalline form of claim 91 having at least about 75% phase purity of the form II celecoxib. 106. The crystalline form of claim 91 having at least about 90% phase purity of the form II celecoxib. 107. The crystalline form of claim 91, wherein said crystalline form is substantially phase pure form II of celecoxib. 108. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 91 to 107 and at least one pharmaceutically acceptable carrier, excipient or diluent. The composition of claim 108, wherein the celecoxib comprises at least 2% of Form II. 110. The composition of claim 108, wherein the celecoxib comprises at least 10% of the mold II. The composition of claim 108, wherein the celecoxib comprises at least 50% of the mold 112. The composition of claim 108 wherein the celecoxib comprises at least 98% Form II. 113. The composition of claim 108, wherein the celecoxib is primarily Form II celecoxib. 114. A method of treating or preventing a cyclooxygenase-2 mediated disease or condition in an individual comprising administering to the individual a therapeutically effective amount of Form II celecoxib. 115. The method of claim 114 wherein the disease or disorder is characterized by pain. m, 116. The method of claim 114 wherein the disease or disorder is inflammation. m, 117. The method of claim 114 wherein the disease or disorder is arthritis. m, 118. The method of claim 114, wherein the disease or disorder is a tumor. m, 119. The method of claim 114, wherein the disease or disorder m is metastasis. 120. The method of claim 114 wherein the disease or disorder is familial adenomatous polyposis. 121. A process for the preparation of celecoxib Form II, comprising crystallizing celecoxib from a mixture comprising celecoxib and a solvent, wherein the crystallization is performed at a temperature above the enantiotropic temperature. The transition of Form II celecoxib to form Form II celecoxib. 122. The method of claim 121 further comprising adding seed crystals of Form II celecoxib to the solvent prior to crystallization. 123. The process of claim 121 wherein the celecoxib Form II thus prepared has a phase purity of at least 5% by weight. 124. The process of claim 121, wherein the celecoxib Form II thus prepared has a phase purity of at least 10% by weight. 125. The process of claim 121 wherein the celecoxib Form II thus prepared has a phase purity of at least 25% by weight. 126. The process of claim 36 wherein the celecoxib Form II thus prepared has a phase purity of at least 50% by weight. 127. The process of claim 36 wherein the celecoxib Form II thus prepared has a phase purity of at least 90% by weight. 128. A process for preparing a crystalline form of celecoxib which comprises heating a celecoxib solvate to form celecoxib Form II. 129. The method of claim 128, wherein the solvate is heated to a temperature of about 50 ° C to about 160 ° C to about three ° C. 130. The method of claim 128, wherein the solvate is heated to a temperature of about 60 ° C. approximately 145 131. The method of claim 128, wherein the solvate is heated to a temperature of about 70 ° C. ° C until you are approximately 140 132. The process of claim 128, wherein the solvate is heated to a temperature of about 80 ° C. ° C until you are approximately 140 133. The method of claim 128, wherein the solvate is heated to a temperature of about 90 ° C. lei ° C until you are approximately m, 140 wherein the solvate is heated to a temperature of about 100 ° C. 134. The method of claim 128, wherein up to about 3 m is about 140%. 135. The method of claim 128, wherein the solvate is heated to a temperature of about 110 ° C. by about 140 136. The process of claim 128, wherein the solvate is heated to a temperature of about 120 ° C. up to about 140 137. The method of claim 128, wherein the solvate is heated to a temperature of about 125 ° C. up to about 135 138. The method 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 more than about 1 minute. 140. The method of claim 128, wherein the solvate is heated for more than about 5 minutes. 141. The method of claim 128, wherein the solvate is heated for more than about 60 minutes. 142. The method of claim 128, wherein the solvate is heated for more than about 2 hours. 143. The method of claim 128, wherein the solvate is heated for about 4 hours or more. 144. The method of any of claims 128-143, wherein the heating is performed at a pressure below atmospheric pressure. 145. The method of claim 128, wherein the celecoxib solvate comprises celecoxib and an amide solvent. 146. The process of claim 145 wherein the amide solvent is 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 1,1,3,3-tetramethylurea. 147. The process of claim 146 wherein the amide solvent is N, N-dimethylformamide. 148. The process of claim 146 wherein the amide solvent is N, N-dimethylacetamide. 149. The process of claim 146 wherein the amide solvent is 1-methyl-2-pyrrolidinone. m, m, 150. The method according to claim 146 wherein the amide solvent is characterized by m, 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone. 151. The process of claim 146 wherein the amide solvent is 1,1,3,3-tetramethylurea. 152. The method of claim 145 wherein the celecoxib solvate is prepared by a process comprising mixing celecoxib with an amide solvent selected from the group consisting of Ν, Ν-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. »» 153. The method of claim 152 wherein the amide solvent is Ν, Ν-dimethylformamide. m, 154. The process according to claim 152 wherein the amide solvent is characterized N, N-dimethylacetamide. m, 155. The method according to claim 152 wherein the solvent is 1-methyl-2-pyrrolidinone. m, 156. The process of claim 152 wherein the amide solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone. • · · · 157. The process of claim 152 wherein the amide solvent is 1,1,3,3-tetramethylurea. 158. A solid form of celecoxib which comprises Form I celecoxib form II celecoxib. 159. A solid form of celecoxib comprising Form I celecoxib form III of celecoxib. 160. A solid form of celecoxib comprising Form II celecoxib and Form III celecoxib. 161. A solid form of celecoxib comprising Form I celecoxib, Form II celecoxib, and Form III celecoxib. 162. A process for preparing celecoxib Form II, comprising grinding or crushing celecoxib Form III to form II celecoxib. 163. The method of claim 162 comprising grinding Form III of celecoxib. 164. The method of claim 163 wherein the grinding is wet grinding. 165. The method of claim 163 wherein the milling is a ball mill. 166. The process of claim 162 comprising crushing Form III of celecoxib. • * • · ··· 167. The method of claim 166 wherein the crushing is performed by shaking. 168. A process for preparing celecoxib Form II, comprising milling or grinding a celecoxib solvate to form celecoxib Form II. 169. Method according to claim 168 confesses C u j ✓ z 1 C 1 se t i m, that includes grinding solvate celecoxib. 170. Method according to claim 169 confesses C U j ici se t í m that grinding is wet grinding. 171. The method of claim 169 wherein the grinding is a ball mill grinding. 172. The method of claim 168 comprising crushing the celecoxib solvate. 173. The method of claim 172 wherein the crushing is performed by shaking. 174. A process for preparing celecoxib Form II, comprising melting celecoxib Form I and cooling the melt to form celecoxib Form II. 175. A process for preparing celecoxib Form II, comprising melting celecoxib Form III and cooling the melt to obtain celecoxib Form II.