EP1846377A2 - Form iv crystalline celecoxib - Google Patents

Abstract

A novel crystalline form of celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)­1H-pyrazol-1-yl] benzenesulfonamide), methods for its preparation, and pharmaceutical compositions comprising the same are described.

Description

FORM IV CRYSTALLINE CELECOXIB

TECHNICAL FIELD

This invention is in the field of pharmaceutical agents active as cyclooxygenase-2 inhibitors, and more particularly concerns the cyclooxygenase-2 inhibitor 4-[5-(4- methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl] benzenesulfonamide ("celecoxib"). Specifically, the invention relates to a novel crystalline form of celecoxib.

BACKGROUND OF THE INVENTION The use of non-steroidal anti-inflammatory drugs (NSAIDs) in treating pain and the swelling associated with inflammation may produce severe side effects, including life-threatening ulcers. The discovery of an inducible enzyme associated with inflammation ("prostaglandin G/H synthase H" or "cyclooxygenase-2 (COX-2)") provides a viable target of inhibition that more effectively reduces inflammation and produces fewer and less drastic side effects.

Compounds that selectively inhibit COX-2 have been described. For example, substituted pyrazolyl benzenesulfonamides as described in U.S. Patent No. 5,466,823, incorporated herein by reference, include, for example, celecoxib:

U.S. Patent No. 5,892,053, incorporated herein by reference, describes processes for preparing celecoxib.

International Patent Publication WO 00/04021 , incorporated herein by reference, illustrates a solvated crystal form of celecoxib and a synthesis therefore.

There are currently four known solid forms of celecoxib, known as Form I, Form II, Form III, and amorphous celecoxib.

Form I and Form Il celecoxib are described in International Patent Publication WO 01/42222, incorporated herein by reference. Form I celecoxib is a crystalline form of celecoxib having an X-ray powder diffraction ("PXRD") pattern with peaks at about 5.5, 5.7, 7.2 and 16.6 degrees 2Θ, and a differential scanning calorimetry ("DSC") maximum at about 163.3°C when scanned at 0.5°C/minute. Form Il celecoxib is a crystalline form of celecoxib having a PXRD pattern with peaks at about 10.3, 13.8 and 17.7 degrees 2Θ, and a DSC maximum at about 162.O⁰C when scanned at 0.5°C/minute.

International Patent Publication WO 01/42221, incorporated herein by reference, describes amorphous celecoxib and processes for preparing amorphous celecoxib using crystallization inhibitors. Amorphous celecoxib exhibits an apparent glass transition at 111.4⁰C (onset).

U.S. Patent No. 6,391 ,906 purports to describe another solid state form of celecoxib referred to therein as Form I.

The formulation of celecoxib for oral administration has hitherto been complicated by unique physical and chemical properties of celecoxib, particularly its low solubility and factors associates with its crystal structure, including cohesiveness, low bulk density and low compressibility. Celecoxib is unusually insoluble in aqueous media. Unformulated celecoxib is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract after oral administration, for example in capsule form. In addition, unformulated celecoxib, which has a crystal morphology that tends to form long cohesive needles, typically fuses into a monolithic mass upon compression in a tableting die. Even when blended with other substances, the celecoxib crystals tend to separate from the other substances and agglomerate together during mixing of the composition resulting in a non-uniformly blended composition containing undesirably large aggregates of celecoxib. Therefore, it is difficult to prepare a pharmaceutical composition comprising celecoxib that has the desired blend uniformity.

Suspensions are a preferred form for many pharmaceutical dosages where rapid onset is desirable. In a suspension, the viscosity and sedimentation rate are important factors when addressing consumer preferences. If the viscosity is too high, the suspension will not pour easily and accurate dosing is hard to achieve due to excessive hold-up in the dosing cup or spoon. The sedimentation rate is important because if the particles in the suspension settle too quickly and form cakes in the bottom of the bottle, it is much harder for the consumer to resuspend the particles by vigorous shaking. Celecoxib has a relatively high dose requirement. With respect to such high dose/low solubility drugs, the size of the capsule or volume of solution required to provide a therapeutic dose becomes a limiting factor. For example, a drug that has a solubility of 10 mg/mL in a given solvent and a therapeutic dose of 400 mg/day would require ingestion of at least 40 ml_ of solution. Such a volume can be inconvenient or unacceptable for consumption in imbibable form; this volume also presents particular problems where an encapsulated dosage form is desired because capsules that contain more than about 1.0 mL to about 1.5 mL of liquid are generally considered to be too large for comfortable swallowing. Thus, where a solution is administered in capsule form, multiple capsules would need to be ingested in order to provide the required dose. Celecoxib, as a COX-2 selective inhibitor, can be administered where use of a

COX-2 selective inhibitor is desired, such as in the treatment or prevention of COX-2 mediated disorders, such as inflammatory disorders (including, for example, arthritis), disorders associated with pain, and disorders associated with fever.

In the treatment of acute pain, for example in headache or migraine, crystal forms of celecoxib having enhanced bioavailability would be useful to provide fast pain relief. A celecoxib form having greater solubility in aqueous media would be useful in providing for new formulations with superior properties. These superior properties include, but are not limited to, one or more of the following: (1) improved bioavailability; (2 ) improved solubility; (3) decreased disintegration times for solid dosage formulations; (4) decreased dissolution times for solid dosage formulations; and (5) improved dissolution profiles for solid dosage formulations.

As with all compounds, the chemical and physical properties, including without limitation, thermodynamic and pharmacokinetic properties, of a celecoxib formulation are important to therapeutic applicability and commercial development. Unfortunately, many useful drugs have low solubility in water and, therefore, are difficult to formulate at convenient concentrations as solutions in an aqueous vehicle. Even when a suitable solvent is found as a vehicle for such a drug, there is often a tendency, particularly for a drug of low water solubility, such as celecoxib, to precipitate out of solution and/or recrystallize when the drug comes in contact with water, for example in the aqueous environment of the gastrointestinal tract. Such precipitation and/or re-crystallization can offset or reduce the benefit of a rapid onset of therapeutic effect sought by formulating the drug as a solution. Moreover, such precipitation or re-crystallization may raise regulatory objections during the new drug approval process.

A novel crystalline form of celecoxib having enhanced bioavailability would provide more flexibility regarding the selection of excipients in pharmaceutical compositions. If such an improved crystalline form of celecoxib could be provided, a significant advance would be realized in treatment of COX-2 mediated conditions and disorders. SUMMARY OF THE INVENTION

There is now provided a crystalline form of celecoxib, referred to herein as Form IV crystalline celecoxib. Form IV crystalline celecoxib is characterized by at least one of: a powder x-ray diffraction pattern comprising at least one peak at about 4.46, 13.13, 18.29, 20.21 , 21.83, or 26.24 degrees 2Θ; a differential scanning calorimetry profile having an endotherm between about 144°C and 149°C; and an infrared spectrum with at least one peak at about 3342, 3295, or 3213 cm^'1. In a more preferred embodiment, Form IV crystalline celecoxib is characterized by at least one of: a powder x-ray diffraction pattern comprising peaks at about 4.46, 13.13, 18.29, 20.21 , 21.83, and 26.24 degrees 2Θ; a differential scanning calorimetry profile having an endotherm between about 144°C and 149°C; and an infrared spectrum with peaks at about 3342, 3295, and 3213 cm^"1.

There is still further provided a pharmaceutical composition comprising Form IV crystalline celecoxib and at least one pharmaceutically acceptable excipient. There is still further provided a process for preparing a composition comprising

Form IV celecoxib, the process comprising the steps of preparing a first solution by dissolving a water soluble polymer and a surfactant in an aqueous solvent to form a first solution; preparing a second solution by dissolving celecoxib in a liquid PEG; adding the second solution to the first solution to form a mixture, such that a Form IV crystalline celecoxib precipitate is created; and isolating the celecoxib precipitate from the mixture.

There is still further provided a process for preparing Form III celecoxib comprising heating Form IV crystalline celecoxib to a temperature from about 150⁰C to about 162⁰C.

There is still further provided a method of treating or preventing a COX-2- mediated condition or disorder in a subject comprising administration to the subject a pharmaceutical composition comprising Form IV crystalline celecoxib.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the pharmacokinetic profile of the Form IV suspension (Lot B) following oral dosing in dogs two months after its preparation (top); celecoxib suspension (middle); and the commercial capsule (bottom).

FIG. 2A shows the SEM photomicrograph of Form III celecoxib.

FlG. 2B shows the SEM photomicrograph of Lot B (Form IV) celecoxib.

FIG. 3 shows qualitative SEM-EDS elemental profiles (for Z>4) for Lot B. FIG. 4 shows DSC thermograms for (from top to bottom) Form III, Lot A, and Lot B celecoxib.

FIG. 5 shows a PXRD comparison of (from top to bottom) Lot B celecoxib, Form I celecoxib, Form Il celecoxib, and Form III celecoxib. FIG. 6 shows PXRD patterns (from top to bottom) of Form III celecoxib, Lot B celecoxib after the isopropanol slurry experiment of Example 11 , and Lot B celecoxib before the isopropanol slurry experiment.

FIG. 7 shows the IR spectra of (from top to bottom) Lot D, Lot B, and Form III celecoxib. FIG. 8 shows the IR spectra of (from top to bottom) Lot B celecoxib, HPMC, PVP,

Polysorbate 80, and PEG 400.

FIG. 9 shows the IR spectra of Form III celecoxib, Lot B celecoxib after heating at 145°C for 20 min, and Lot B without heating.

FIG. 10 shows Raman spectra of amorphous celecoxib, Lot B celecoxib, Lot D, and Form III celecoxib.

FIG. 11 shows Raman spectra of (from top to bottom) Form III celecoxib, a single lath-shaped Form III crystals recovered from Lot B, and Form IV crystals from Lot B. FIG. 12 shows a plot of the data obtained from the rotating disk dissolution for Form IV (top line) and Form III (bottom two lines) celecoxib.

DETAILED DESCRIPTION OF THE INVENTION In one way to make Form IV crystalline celecoxib, celecoxib (produced as described in U.S. Patent No. 5,466,823) is dissolved in a solvent to produce a celecoxib solution. The celecoxib solution is contacted with an aqueous solution to form a Controlled Precipitation Mixture. The phase purity of the celecoxib precipitates in the Controlled Precipitation Mixture is controlled by adjusting the proportions of the starting reagents and/or the manufacturing techniques as taught hereinbelow. In one embodiment of the present invention, Form IV crystalline celecoxib comprises substantially all of the celecoxib present in the Controlled Precipitation Mixture. In another embodiment of the present invention, Form III celecoxib comprises substantially all of the celecoxib present in the Controlled Precipitation Mixture. In another embodiment of the present invention, a blend of Form IV crystalline celecoxib and Form III celecoxib comprises substantially all of the celecoxib present in the Controlled Precipitation Mixture. An exemplary procedure for controlled precipitation of Form IV crystalline celecoxib is described in Example 1.

An exemplary celecoxib solution for controlled precipitation of Form IV crystalline celecoxib can comprises celecoxib, PEG and Polysorbate 80. In one embodiment, the celecoxib solution is made by slowly adding celecoxib with stirring to PEG or PEG and Polysorbate 80.

In one embodiment, the Controlled Precipitation Mixture is made as follows. Approximately PEG 400 having celecoxib in solution therein is added to an HPMC- containing aqueous solution optionally further comprising PVP. Such optional PVP can be, for example, prepared in a solution and then added to the aqueous solution, before, simultaneously, or after combination with the celecoxib solution. Following the addition of the HPMC (or HPMC + PVP) -containing aqueous solution to the celecoxib solution, Form IV crystalline celecoxib precipitates. In an optional embodiment, other agents can be added to one or more of the aqueous solution, the celecoxib solution, or the Controlled Precipitation Mixture. Exemplary agents are sucrose, citric acid, sodium citrate, and sodium benzoate.

The Controlled Precipitation Mixture can optionally be homogenized with an emulsifier for several minutes.

To isolate Form IV crystalline celecoxib particles from the precipitating suspension, the Controlled Precipitation Mixture is stored until the precipitation reaction has reached equilibrium. The precipitated Form IV crystalline celecoxib particles are separated, for example with a vacuum filtration apparatus. The Form IV crystalline celecoxib particles may be washed with water to remove water-soluble ingredients from the particles. The Form IV crystalline celecoxib particles may then be dried, for example under vacuum at room temperature for 24 hours before being placed in a dessicator until the particles are completely dried.

One solvent useful to form the aqueous solution in accordance with the present invention is polyethylene glycol (PEG). Any pharmaceutically acceptable liquid PEG can be used. In one embodiment of the present invention, the PEG has an average molecular weight of about 100 to about 800. In another embodiment, the PEG has an average molecular weight of about 200 to about 600. In another embodiment, the PEG has an average molecular weight of about 300 to about 500. Non-limiting examples of PEGs that can be used as a solvent in the aqueous solution of the present invention include PEG-200, PEG-350, PEG-400, PEG-540 and PEG-600. A presently preferred PEG has an average molecular weight of about 375 to about 450, for example PEG- 400.

In another embodiment, the aqueous solution of the present invention further comprises a polymer. Exemplary polymers are HPMC, PVP, and mixtures thereof, as described below.

In another embodiment of the present invention, the aqueous solution further comprises both HPMC and PVP. PVPs can comprise high viscosity PVPs, medium viscosity PVPs, or low viscosity PVPs. Examples of PYPs useful in accordance with the present invention include PVP K-17, PVP K-30 and PVP K-90. Without being bound by theory, it is believed that the interaction between HPMC and Polysorbate 80 may reduce the surfactant molecules available for solubilization of the drug. As shown in Table 2 hereinbelow, the solids separated from the suspension containing 5% HPMC and 1% of polysorbate 80 (Lot C and Lot D) had much higher levels of Form IV than those separated from the suspension containing lower concentration of HPMC and Polysorbate 80 (Lot E) or the suspension without the surfactant (Lot F), reflected by the DSC ratios. Since the dissolution rates of the samples containing high purity of Form IV were 2-3 times faster than those primarily containing Form III, the improved bioavailability of the precipitated suspension, prepared with appropriate levels of HPMC and Polysorbate 80, is likely due both to the presence of a novel solid form of celecoxib, Form IV and smaller particle size. The formation of Form IV celecoxib appears to be associated with the change of diffusivity of celecoxib molecules, surface tensions, and supersaturation that is induced by the presence of both HPMC and Polysorbate 80.

In another embodiment of the present invention, the aqueous solution further comprises a surfactant. Suspensions prepared in the absence of a surfactant have not been shown to produce a detectable amount of Form IV crystalline celecoxib. Surfactants can be, for example, sodium laurel sulfate, polyoxyethylene alkyl ether, polyoxyethylene stearate, Polysorbate 80, or combinations thereof. Without being bound by theory, it is believed that the presence of a surfactant, rather than the amount thereof, effects the precipitation of Form IV crystalline celecoxib.

Useful amounts of surfactant such as Polysorbate 80 are amounts of at least about 0.1% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about 0.25% to about 50% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about 0.3% to about 33% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about 0.25% to about 25% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about .3% to about 15% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about 0.35% to about 5% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about 0.4% to about 1.5% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about 0.45% to about 1% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about 0.5% to about 0.55% by weight of the suspension. In another embodiment, Polysorbate 80 is present in an amount of about 0.54% by weight of the suspension. Other surfactants mentioned herein, either substituted for Polysorbate 80 or used in conjunction with Polysorbate 80, may be used in amounts equivalent to the illustrative ranges of Polysorbate 80 detailed above. Optional additional components, including without limitation, excipients,. should be physically and chemically compatible with the other ingredients of the composition and should not be deleterious to the recipient. Importantly, some classes of excipients overlap each other. Compositions of the present invention can be adapted for administration by any suitable oral route by selection of appropriate solvent liquid components and a dosage of the drug effective for the treatment intended. Accordingly, components employed in the solvent can themselves be solids, liquids, or combinations thereof.

Exemplary compositions of the present invention include pharmaceutical dosage forms, intermediates for pharmaceutical dosage forms such as compositions useful for production of Form IV crystalline celecoxib.

Pharmaceutical compositions prepared in accordance with the present invention comprise Form IV crystalline celecoxib and at least one pharmaceutically acceptable excipient. Pharmaceutical dosage forms include liquid dosage forms and solid dosage forms. Liquid dosage forms can comprise inert diluents commonly used in the art, such as water. Liquid dosage forms can also comprise excipients, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. Liquid dosage forms of the present invention may be in the form of a concentrated solution that may or may not be encapsulated as a discrete article. If encapsulated, preferably a single such article or a small plurality, up to about 10, more preferably no more than about 4, of such articles is sufficient to provide the daily dose. Alternatively, liquid dosage forms can be in the form of a concentrated imbibable liquid.

Liquid dosage forms suitable for oral administration, have become an important method by which drugs are delivered to subjects, particularly where rapid onset of therapeutic effect is desired. As an alternative to directly imbibable liquid formulations of a drug, it is also known to encapsulate liquid formulations, for example in soft or hard gelatin capsules, to provide a discrete dosage form.

A drug administered in imbibable solution can be available for absorption higher in the alimentary tract, for example, in the mouth and esophagus, than one that becomes available for absorption only upon disintegration of the carrier formulation in the stomach or bowel.

An advantage of liquid dosage forms such as imbibable solutions and suspensions for many subjects is that these dosage forms are easy to swallow. A further advantage of imbibable liquid dosage forms is that metering of doses is continuously variable, providing considerably greater dose flexibility. The benefits of ease of swallowing and dose flexibility are particularly advantageous for infants, children and the elderly.

Alternatively, a composition of the present invention can be prepared in the form of discrete unit dose articles, for example, capsules having a wall that illustratively comprises gelatin and/or a cellulosic polymer such as HPMC, each capsule containing a liquid composition comprising a predetermined amount of drug in a solvent liquid. The liquid composition within the capsule is released by breakdown of the wall on contact with gastrointestinal fluid. The particular mechanism of capsule wall breakdown is not important and can include such mechanisms as erosion, degradation, dissolution, etc.

In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more excipients appropriate to the desired route of administration, for example lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, citric acid, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.

Pharmaceutical compositions of the invention can be prepared by any suitable method of pharmacy that includes the step of bringing into association the drug and at least one excipient.

In general, liquid dosage forms of the present invention are prepared by uniformly and intimately admixing celecoxib with a solvent liquid in such a way that at least a portion, preferably substantially all, of the celecoxib is dissolved or suspended in the solvent liquid; and then, if desired, encapsulating the resulting solution, suspension or solution/suspension, in hard or soft capsules.

In general, solid dosage forms of the present invention are prepared by isolating Form IV crystalline celecoxib particles and intimately admixing Form IV crystalline celecoxib particles with at least one excipient.

Those skilled in the art will recognize that the amount of Form IV crystalline celecoxib that can be combined with excipients to produce a dosage form will vary depending upon the mammalian host treated and the particular mode of administration. A particular dose unit can be selected to accommodate the desired frequency of administration used to achieve a specified daily dose. For example, a fixed dosage amount of 400 mg can be accommodated by administration of one 200 mg dose unit, or two 100 mg dose units, twice a day. The dosage amount may also be expressed as a ratio of the mass of the dosage form to the body weight of the subject, for example between about 1 mg/kg body mass to about 50 mg/kg body mass, or between about 5 mg/kg body mass to about 45 mg/kg body mass, or between about 10 mg/kg body mass to about 40 mg/kg body mass, or between about 15 mg/kg body mass to about 35 mg/kg body mass, or about 30 mg/kg body mass.

The amount of the composition that is administered and the dosage regimen for treating the condition or disorder will depend on a variety of factors, including the age, weight, sex and medical condition of the subject, the nature and severity of the condition or disorder, the route and frequency of administration, and the particular drug selected, and thus may vary widely. It is contemplated, however, that for most purposes a once-a- day or twice-a-day administration regimen provides the desired therapeutic efficacy.

In one embodiment of the present invention, the Form IV crystalline celecoxib is present in an amount of about 0.25% to about 90% of the total amount of all celecoxib present in the composition. In another embodiment of the present invention, the Form IV crystalline celecoxib is present in an amount of about 0.05 grams to about 2 grams, or about 0.1 grams to about 1.5 grams, or 0.15 grams to about 1 gram, or about 0.2 grams to about .5 grams, or about 0.3 grams.

For certain therapeutic applications, it is desirable to blend Form IV crystalline celecoxib with at least one other solid state form of celecoxib selected from the group consisting of Form I₁ Form II, Form III and amorphous celecoxib.

In one embodiment of the present invention, a composition comprises a blend of Form IV crystalline celecoxib and Form III celecoxib, where Form IV crystalline celecoxib is present in a detectable amount and the remainder of the celecoxib comprises Form III celecoxib. In another embodiment of the present invention, a composition comprises a blend of Form IV crystalline celecoxib and Form III celecoxib, where the percent of Form IV crystalline celecoxib in relation to the total amount of celecoxib present is about 25%, or about 50%, or about 75% or about 90%, and the remainder of the composition comprises Form III celecoxib. A composition of the invention may comprise Form IV crystalline celecoxib in combination with a second selective COX-2 inhibitory drug, for example valdecoxib, parecoxib, darecoxib, or rofecoxib.

The term "polyethylene glycol" is abbreviated herein to "PEG".

The term "HPMC as used herein means hydroxypropylmethylcellulose." The term "solvent" as used herein encompasses all of the components of the liquid medium in which a particular drug is dissolved or solubilized. Thus the "solvent" includes not only one or more solvents but optionally additional excipients such as co- solvents, surfactants, co surfactants, antioxidants, sweeteners, flavoring agents, colorants, etc. The term "polyvinylpyrrolidone" is abbreviated herein to "PVP"

The term "excipient" as used herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling, storage, disintegration, dispersion, dissolution, release or organoleptic properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule suitable for oral administration. Excipients can include, by way of illustration and not limitation, solvents, diluents, disintegrants, dispersants, binding agents, adhesives, wetting agents, lubricants, glidants, crystallization inhibitors, stabilizers, antioxidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, preservatives.

The term "AUC₍o-_t)" as used herein means the area under the plasma drug concentration time curve between times 0 and t. The term "C_max" herein means the highest drug concentration observed in plasma.

The term "t_max" or "T_maχ" as used herein means the time of maximum drug concentration.

The term "standard deviation" is abbreviated herein to "S. D." The term "onset rate" means the slope of the blood plasma concentration time curve from 0 to 0.5 hour.

The phrase "imbibable liquid" is used herein to refer to an unencapsulated substantially homogeneous flowable mass, such as a solution or solution/suspension, administered orally and swallowed in liquid form and from which single dose units are measurably removable.

The term "substantially homogeneous" with reference to a pharmaceutical composition that comprises a plurality of components means that the components are sufficiently mixed such that individual components are not present as discrete layers and do not form concentration gradients within the composition. The meaning of the term "celecoxib" (as distinguished from "Form IV crystalline celecoxib") as used in the examples below depends upon the context wherein such term is used. For example, where "celecoxib" is shown as a starting material, such celecoxib is not Form IV crystalline celecoxib but instead is celecoxib in the form made, for example, by the method taught in WO 95/15316 or WO 96/37476. The term "liquid dosage form" includes pharmaceutically acceptable emulsions, solutions, suspensions, solutions/suspensions, syrups, and elixirs. Liquid dosage forms of the present invention may or may not be encapsulated as a discrete article.

The term "solid dosage forms" includes capsules, tablets, pills, powders, and granules. The term "particle size" as used herein refers to particle size as measured by conventional particle size measuring techniques well known in the art, such as laser light scattering, sedimentation field flow fractionation, photon correlation spectroscopy or disk centrifugation. One nonlimiting example of a technique that can be used to measure particle size is a liquid dispersion technique employing a Sympatec Particle Size Analyzer.

The term "DSC" means differential scanning calorimetry.

The term "HPLC" means high pressure liquid chromatography. The term "IR" means infrared.

The term "msec" means millisecond.

The term "PXRD" means X-ray powder diffraction.

The term "TGA" means thermogravimetric analysis.

The compounds of the invention may be administered alone or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid- filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11(6), 981-986 (2001).

For tablet dosage forms, depending on dose, the drug may make up from 1 to 80 wt.% of the dosage form, more typically from 5 to 60 wt.% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 to 25 wt.%, preferably from 5 to 20 wt.% of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and Polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 to 5 wt.% of the tablet, and glidants may comprise from 0.2 to 1 wt.% of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 to 10 wt.%, preferably from 0.5 to 3 wt.% of the tablet.

Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 to about 90 wt.% binder, from about 0 to about 85 wt.% diluent, from about 2 to about 10 wt.% disintegrant, and from about 0.25 to about 10 wt.% lubricant.

Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980). Consumable oral films for human or veterinary use are typically pliable water- soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of Formula I₁ a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity- modifying agent and a solvent. Some components of the formulation may perform more than one function.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 wt.%, more typically in the range 30 to 80 wt.%.

Other possible ingredients include anti-oxidants, colorants, flavorings and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste- masking agents.

Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze- drying or vacuuming.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, ^■ pulsed-, controlled-, targeted- and programmed-release. Suitable modified release formulations for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al., Pharmaceutical Technology On-line. 25(2), 1 -14 (2001). The use of chewing gum to achieve controlled release is described in PCT Publication No. WO 00/35298.

The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of Formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, e.g., Finnin and Morgan, J Pharm Sci. 88(10), 955-958 (1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 μm). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 to 100 μl_. A typical formulation may comprise a compound of Formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and nonbiodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- or programmed-release.

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518, and WO 98/55148.

Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.

Such kits comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

Such kits are particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of about 50 to about 400 mg depending, of course, on the mode of administration. Typical dose units in a composition of the invention contain about 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg of the COX-2 inhibitor, illustratively celecoxib. For an adult human, a therapeutically effective amount of celecoxib per dose unit in a composition of the present invention is typically about 50 mg to about 400 mg. Especially preferred amounts of celecoxib per dose unit are about 100 mg to about 200 mg, for example about 100 mg or about 200 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

These dosages are based on an average human subject having a weight of about 60 to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

EXAMPLES

Example 1 : Preparation and isolation of Form IV celecoxib

Hydroxypropyl methylcellulose (HPMC .2910 USP 15; Dow Chemical) and polyvinylpyrollidone (PVP) were dispersed in water under agitation to generate homogenous solutions comprising approximately 15% HPMC and 20% PVP. These solutions were diluted with water as shown in Table 1 , below. To form the precipitates, a pre-made PEG-400 solution containing celecoxib powder (10% - 30%, micronized; manufactured at Pharmacia) and Polysorbate 80 was added into the polymeric solution under stirring. After the addition of the celecoxib mixture, the sucrose and other excipients were added to the already precipitated celecoxib suspension. PEG 400 NF, Polysorbate 80 NF Food Grade, Sodium Benzoate NF, Citric acid USP, andSodium Citrate USP were supplied by Brenntag Great Lakes. PVP K90 was purchased from ISP Technology, and Sucrose NF was from Indiana Sugars. Representative formulations are listed in Table 1. The suspensions were continuously stirred for another 10-30 min to dissolve the soluble excipients. Homogenization was applied for 3-5 min if necessary.

Table 1

The precipitated crystals were then separated from the suspension and washed by diluting the suspension with water. The diluted sample was filtered using a Millipore vacuum filtering apparatus and a 0.8 μm Millipore AA filters. The particles were then dried under vacuum at room temperature for 24 hours before being placed in a dessicator with anhydrous calcium sulfate for at least 72 hours to dry the crystals thoroughly. The integrity of the isolation process was confirmed by analyzing wet samples prior to filtration and comparing them to the filtered and dried solids after isolation by PXRD. These experiments showed that there was no change in the crystal form after the isolation process was completed.

Example 2: Solubility and Particle Size

The solubility of the aqueous phase of the suspensions prepared according to Example 1 was measured using centrifugation to separate the particles from the supernatant. A Beckman J2-21 centrifuge was used and the liquid supernatant was filtered and diluted with a 3:1 ratio of methanol and water before analysis. HPLC analysis on an Hewlett Packard 1090 HPLC was used to analyze the concentration of celecoxib in the supernatant. The celecoxib was detected at 254 nm using an isocratic method and pH 3.0 mobile phase.

Particle size measurement of these samples was done using single particle optical sensing (SPOS). Approximately 50 mg of suspension was weighed into a 1.5 mL centrifuge tube, followed by sufficient 2% PVP-K30 / 0.15% sodium lauryl sulfate diluent to bring the final drug concentration to 0.20%. The resulting suspension was vigorously agitated with a vortex mixing, and sonicated for 30 seconds with a probe sonicator by holding that part of the tube containing the suspension under the 5 mm probe tip both of which were immersed in water. The power level setting of the sonicator (Sonifier 350; Branson; Danbury, CT) was adjusted to "5" with a duty cycle of 40%. An additional vortexing step was carried out and the suspensions allowed to sit for 15 minutes before the vortex-sonicate-vortex process was repeated one time. A scattering-obscuration sensor (Model LE400-0.5; Particle Sizing Systems; Santa Barbara, CA) fitted with a stepper motor-controlled pump was used for size characterization. A stirred 300 mL beaker, placed in a laminar flow hood, was filled to overflowing and thereafter continuously flushed with 0.2 μm filtered MiIIi-Q water. After an appropriate interval, the flow was turned off and the water volume allowed to stabilize to a value between 270 and 280 mL. Water was pulled through the sensor at 60 mL/min for 1 minute and the total particle count was measured to be less than 50 with no particle being larger than 2 μm. A 9 μL aliquot of a 0.2% suspension was added to the stirred beaker, and after being allowed to disperse, another 60 mL was pulled through the sensor. As shown in Table 2, the average particle size of celecoxib in the precipitated suspension is about half of that in the control suspension. The solubility of celecoxib in water is 5-10 μg/ml while those in the suspensions were significantly increased in the presence of Polysorbate 80, PEG 400 and PVP. The solubility of celecoxib in the suspension without HPMC is about 600 μg/ml and it decreased when the HPMC concentration increased.

As shown in Table 2, the solids separated from the suspension containing 5% HPMC and 1% of Polysorbate 80 (Lot C and Lot D) had much higher levels of Form IV than those separated from the suspension containing lower concentration of HPMC and Polysorbate 80 (Lot E) or the suspension without the surfactant (Lot F), reflected by the DSC ratios.

Example 3: Dissolution

A fiber optic rotating disk dissolution apparatus (Eurostar Power Control Vise by IKA-Werke with a Model D1000 CE UV Light Source by Analytical Instrument Services Inc., Ocean Optics PC1000 UV/Vis spectrometer) was used for the testing. The pellets were prepared using a Carver Laboratory Press (Fred S Carver Hydraulic Equipment Inc.) with a sample surface area of 0.178 cm² and minimal porosity. Dissolution media was a 150 ml of 50% isopropyl alcohol aqueous solution. The rotating speed was 300 RPM and temperature was controlled at 25°C. The calibration was done by placing the probe in a 0.027 mg/ml of celecoxib solution in the media and measuring the absorbance at 260 nm. Approximately 20 mg of solid samples were placed in the pellet press apparatus, and pressed at over 35,000 psi to ensure a zero porosity compact, for 1 min. The pellet was then suspended in the media and spun at 300 RPM. About 200 data points were collected over the 20 min for plotting and calculation. FIG. 12 shows the results of the rotating disk dissolution experiments. Clearly,

Form IV of ceiecoxib is less stable than Form III, hence it dissolves at a much faster rate. The data indicates that Form IV is about 2-3 times more soluble than Form III.

Example 4: Scanning electron microscopy with energy dispersive X-rav spectrometry (SEM-EDS) A Philips XL30 ESEM with EDAX energy dispersive x-ray spectrometer, in high vacuum mode, using an Everhart-Thornley secondary electron detector collected the micrographs. Micrographs were generated at 1OkV with a spot size of 3.0 and O°tilt. EDS spectra were generated at 2OkV, spot of 4.0, and O°tilt. Samples were coated with gold/palladium using a Pelco SC-6 sputter coater.

Polarized light microscopical examinations of Lot B and Lot D precipitates revealed both to be apparently homogeneous, crystalline materials. Crystallinity was confirmed by the occurrence of birefringence in crossed polars; for Lot B, particles were often elongated with an extinction angle near 45°, while particles in lot D usually did not exhibit complete extinction, indicating aggregation/multiple crystal centers. No significant content of HPMC or other amorphous structures was evident, but both lots contained a small population of discrete lath or needle shaped crystals. Particle sizes in both lots were fairly small, generally <1 Oμm, which made determination of optical properties difficult. For Lot B, refractive indices were approximated at n_α~1.56, np~1.60, and n_γ~1.66. Particle morphologies were further examined using SEM, which revealed that the samples consisted largely of aggregated, stacked plates and laths. SEM photomicrographs of Lot B and the bulk celecoxib (Form III) are shown in FIGS. 2A and 2B. Qualitative SEM-EDS elemental profiles (for Z>4) for Lot B revealed carbon, oxygen, nitrogen, fluorine, and sulfur, as would be expected for celecoxib; no other elements were detected at stoichiometric levels, as shown in FIG. 3.

Example 5: Infrared spectroscopy (IR) and Hot-stage microscopy

Infrared spectra were collected using a Thermo Nicolet Nexus 670 FTIR spectrometer with a Continuum microscope accessory. Samples were flattened onto sodium chloride plates. Spectra collected at 4 cm^'1 spectral resolution, spectral range of 4000-650 cm^'1, using an MCT detector.

Infrared spectra of lots B and D were similar to each other, as shown in FlG. 7, and did not conform to a reference spectrum of Form III celecoxib. The reference spectrum of Form III shows peaks at 3342 and 3236 cm^"1, which are attributed to the symmetric and asymmetric stretch of the sulfonamide N-H₂ group. The precipitated celecoxib samples also exhibit these two peaks, indicating some Form III presence, but further show the appearance of peaks at 3295 and 3213 cm^"1 not found on the spectrum of Form III celecoxib (the latter peak is more evident after subtraction of Form III contribution from the precipitate spectra). There are also a number of peak shifts and peak ratio differences throughout the fingerprint region of the precipitate spectra relative to the Form III reference spectra, as is typical with polymorphic variation. These differences cannot be attributed to any of the other compounds present at the time of precipitation, as shown in FIG. 8. Although no reference spectra were available for celecoxib Forms I and II, the precipitated celecoxib samples did not conform to published Form I sulfonamide peak positions at 3256 and 3356 cm^"1. Celecoxib Form Il has only been created in mixtures with Form III, and published form ll/lll mixture spectra show the same sulfonamide N-H pattern as Form III, hence no peaks at 3295 and 3213 cm^"1. Thus, infrared spectra of Lots B and D are distinctive from the previously recognized celecoxib crystal forms. An infrared spectrum was also generated on a sample of Lot B that was held at 145°C for 20 minutes. Hot stage studies indicated that this temperature condition caused a transition to the higher melting form. The resulting spectrum was a close match to Form III celecoxib, as shown in FIG. 9. Thus, the transition observed in hot stage experiments is the creation of Form III celecoxib. Hot stage microscopy found thermal behavior that varied with conditions. Experiments are often run with the sample immersed in silicone oil to improve contrast and show de-solvation via the formation of gas bubbles. No out-gassing was observed up to 165°C for either Lot B or Lot D samples run in silicone oil. In silicone oil? both samples underwent a gradual transition to lath-shaped crystals starting at 90-100⁰C, with complete conversion by 145-150⁰C. The newly formed crystals melted at 160-162°, . similar to the known celecoxib forms. Viewing the stored video of the experiments in reverse revealed that small populations of the higher melting form were present at the onset in both lots, which were the observed lath/needle forms described in the polarized light microscope examinations. Hot stage experiments run in air again revealed the transition to laths melting around 160-162⁰C; at extended ramp times (50⁰C initial, 10°C/minute heating program). No differences compared to silicone oil experiments were observed. However, when rapidly heated to 138⁰C, followed by a 10°C/minute increase, most of the material did not transition but instead melted from 148-150⁰C; some (but not all) of the melt phase then recrystallized into laths, which melted at 160- 162⁰C. The conclusion from hot stage experiments is that the samples do not appear to be hydrates or solvates of celecoxib, the material melts at 148-150⁰C, and converts to a higher melting form as well as small amounts of the higher melting point form was present in both samples at the start of the analyses.

Example 6: Raman spectroscopy

Raman spectra were collected with a Thermo Nicolet Almega dispersive Raman microscope using a 532 nm laser at 20% power, a 25μm pinhole spectrograph aperture, and grating blaze of 672 lines/mm to provide spectral resolution of 6-10 cm^"1. Broad areas of the samples were analyzed using a 10x objective, and individual crystals were analyzed using a 100x objective.

Both samples Lot B and Lot D produced equivalent spectra that were not equivalent to Form III celecoxib. The precipitate spectra were somewhat similar to, but not an exact match to an amorphous celecoxib reference spectrum. Raman spectra are shown in FIG. 10. No reference samples or spectra of celecoxib Forms I and Il were available, but celecoxib Form Il is reported to have a distinctive peak at 712 cm^"1, which was not present in the precipitated samples. Furthermore, several single lath-shaped crystals in Lot B were evaluated using higher magnification (1 μm spatial resolution), which confirmed the presence of some Form III celecoxib crystals in the sample (FIG. 11).

Example 7: Differential scanning calorimetrv (DSC)

The test samples were prepared by weighing approximately 1 mg of the separated crystals into a pan and then sealing the. pan with a corresponding lid. The weight of the sample was recorded and entered into the data collection software for use in calculating the energy released per gram when melting occurs. The data was collected on a DSC 2920 Differential Scanning Calorimeter supplied by TA Instruments. The software used to collect and analyze the data was TA Instrument Control software for the data collection and TA Universal Analysis for data analysis. The experimental conditions included equilibrating the sample at 25°C and ramping by 10⁰C per minute to 180.0⁰C.

Differential scanning calorimetry results for the same two lots are shown in FIG. 4. The lots showed melt onsets at 148°C and 145°C respectively. The flat baseline suggested that no phase transitions or excess solvent content was present prior to initial melting. The melting of Form III (at about 160°C) was also observed in these samples. PXRD analysis suggested that Lot A contained about 30% Form III, while Lot B contained about 5% Form III. The difference is not evident in the DSC since Form III crystallizes from the Form IV melt. In an effort to compare formulations, a DSC ratio was calculated to determine the energy lost due to Form IV melting versus Form III. This ratio was simply the area of the lower melting peak to the total peak area of the scan. As this ratio was closer to one, the formulation was assumed to have more Form IV present than formulations with lower ratios. This ratio did show that there was more Form IV present in Lot A as compared to Lot B (see Table 2).

Table 2

Example 8: Power X-rav diffraction ( PXRD) Powder X-ray diffraction data was collected using a Scintag Advanced Diffraction

System operating under Scintag DMS/NT™ software. The system uses a peltier cooled solid state detector and a copper X-ray source maintained at 45 kV and 40 mA to provide CuKcrt emission at 1.5406 Λ. The beam aperture was controlled using tube divergence and anti-scatter slits of 2 and 4 mm, respectively, while the detector anti- scatter and receiving slits were set at 0.5 and 0.3 mm, respectively. Data was collected from 2° to 35° 2Θ using a scan step of 0.037point and a one second/point integration time. The samples were prepared using Scintag round; top-loading stainless steel sample cups (Part no. 1ZEO-20-0120-01), and were fitted with 12 mm diameter aluminum inserts to accommodate small sample volumes. FIG. 5 shows a comparison of Lot B precipitate to the three known crystal forms of celecoxib using PXRD method. The powder pattern of the precipitated material was not consistent with any of these known crystal forms. Form III celecoxib was present as about 5% of the sample. To show that the unidentified reflections in the powder pattern were not caused by some of the excipients, the PXRD patterns of sodium benzoate, sodium citrate, citric acid and sucrose were also collected. These results (not shown) demonstrated that the unique PXRD pattern was not consistent with any of the known excipients in the suspensions. This was not surprising considering the fact that the materials were analyzed to have very high potency.

Example 9: Bioavailability Study in Dogs Bioavailability of Form IV celecoxib was studied in 6 male beagle dogs in a nonrandomized crossover study. The target dose was 200 mg celecoxib for all formulations. Capsule formulations were dosed orally, and suspension formulations (Lot B, Example 1 , dosed two months after preparation) were administered by gastric intubation. A control suspension was prepared by dispersing the bulk drug powders in an aqueous dispersion containing xanthan gum, colloidal silicone dioxide, sucrose, polysorbate 80, sodium benzoate, citric acid and sodium citrate. Dosing of all formulations was followed by administration of a quantity of water sufficient to deliver 10 ml_ of water to the stomach by gastric intubation. A washout period of at least one week was allowed between treatments. Serial blood samples (~2 ml) were collected from individual animals at pre-dose, 0.25, 0.5, 0.75, 1 , 1.5, 2, 3, 5 and 8 h after dosing via jugular venipuncture using potassium EDTA as the anticoagulant. Plasma was collected after centrifugation of the samples and was extracted via acetonitrile precipitation directly in polypropylene LC vials by mixing 1-part plasma and 2-parts acetonitrile. The vials were centrifuged and supernatant was injected directly into an LC/MS/MS platform for analysis.

Quantitation of celecoxib in dog plasma was carried out by liquid chromatography with mass spectrometric detection following removal of proteins by acetonitrile precipitation. The typical quantitation range of the method was 10 to 10,000 ng/mL celecoxib.

Chromatography was performed using a Perkin-Elmer Series 200 chromatography system by injecting sample supernatant (10 mcL) onto a 2.1 x 100 mm, 5 μm, Waters Xterra® RP 18 column at a temperature of 5O⁰C and a flow rate of 0.5 ml/min with an initial mobile phase of aqueous 5 mM ammonium formate. A 1 -minute linear gradient (from the initial mobile phase to 5 mM ammonium formate in acetonitrile) was initiated at the time of sample injection followed by a 1.5-minute hold in acetonitrile w/ 5 mM ammonium formate. The column was subsequently re-equilibrated in the initial mobile phase for a 4-minutes. The total LC effluent was directed to waste for 3.5 minutes following sample injection and then introduced into a Sciex API 3000 triple quadrupole mass spectrometer for 2 minutes. Ionization was achieved using Atmospheric Pressure Chemical Ionization (APCI) in the negative ion mode. The analyte was monitored using a transition from m/z 380®316. Quantitation of celecoxib was achieved by calculating the peak area ratio of the analyte relative to an internal standard and comparing the ratio to a standard curve using quadratic regression analysis with 1/x weighting, where x is the concentration of the standard sample.

Plasma-time concentration profiles were analyzed using a 2-compartment pharmacokinetic model using WinNonLin Professional software (ver 3.1). The resulting pharmacokinetic profile and parameters are shown in FIG. 1 and Table 3. Surprisingly, the absorption of celecoxib from the precipitated suspension (Lot B, Example 1) was much faster than those from the commercial capsules and the control suspension prepared by dispersing the bulk drug powders in an aqueous solution (Control suspension). Although the values of T_maχ calculated from these three formulations were almost identical, the drug concentration in plasma at 0.5 hour from the precipitated suspension was 7.5 and 4.2 times higher than those from the capsules and the control suspension respectively, indicating a possible rapid onset of the precipitated suspension. The precipitated suspension also showed at least four-fold superior bioavailability to the other tested formulations.

Table 3

Example 10: lsopropanol slurry experiment

To verify the thermodynamic stability of Form IV₁ a 25°C slurry experiment was completed. A small sample was produced by slurrying approximately equal amounts of Form III celecoxib with Form IV at about 30 mg/mL in a saturated solution of celecoxib in isopropanol. After slurrying overnight, the powder pattern of the suspended particles is shown in FIG. 6. The slurry conversion study clearly showed that Form IV was metastable with respect to Form III and converted relatively rapidly to Form III of celecoxib at ambient temperature under these conditions.

The examples herein can be performed by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. In view of the above, it will be seen that the several objects of the invention are achieved. As various changes could be made in the above methods, combinations and compositions of the present invention without departing from the scope of the invention, it is intended that all matter contained in the above description be interpreted as illustrative and not in a limiting sense. All documents mentioned in this application are expressly incorporated by reference as if fully set forth at length.

When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

Claims

CLAIMSWhat is claimed is:

1. A crystalline form of celecoxib having an X-ray powder diffraction pattern comprising at least one peak selected from the group consisting of 4.46, 13.13, 18.29, 20.21 , 21.83, and 26.24 degrees 2Θ.

2. A crystalline form of celecoxib having a melting point in a range from about 144°C to about 149°C.

3. A crystalline form of celecoxib having an infrared absorption band profile comprising at least one absorption band at about 3342, 3295, and 3213 cm^"1.

4. A crystalline form of celecoxib having an infrared absorption band profile comprising at least one absorption band at about 3342, 3295, and 3213 cm^'1, and an

X-ray powder diffraction pattern comprising at least one peak at about 4.46, 13.13, 18.29, 20.21 , 21.83, and 26.24 degrees 2Θ.

5. A method for making the crystalline form of celecoxib of any one of claims 1-4, the method comprising: dissolving celecoxib in a solvent to produce a celecoxib solution; contacting said celecoxib solution with an aqueous solution to form a Controlled Precipitation Mixture; separating said crystalline form of celecoxib from the Controlled Precipitation Mixture.

6. The method of claim 5 wherein said solvent is a polyethylene glycol.

7. The method of claim 5 or claim 6 wherein the aqueous solution comprises a polymer selected from the group consisting of HPMC, PVP, and mixtures thereof.

8. A pharmaceutical composition comprising celecoxib and one or more pharmaceutically acceptable excipients, wherein a detectable amount of the celecoxib is present as the crystalline form of celecoxib set forth in any one of claims 1 , 2, 3, or 4.

9. The pharmaceutical composition of Claim 8 wherein at least about 50% of the celecoxib is present as the crystalline form of celecoxib set forth in any one of claims 1 , 2, 3, or 4.

10. The pharmaceutical composition of Claim 8 wherein at least about 90% of the celecoxib is present as the crystalline form of celecoxib set forth in any one of claims 1 ,

2, 3, or 4.

11. The pharmaceutical composition of Claim 8 wherein the celecoxib present in the composition is substantially the crystalline form of celecoxib set forth in any one of claims 1 , 2, 3, or 4.

12. The pharmaceutical composition of Claim 8 wherein the amount of celecoxib present in the composition is between about 0.1 mg to about 1000 mg.

13. The pharmaceutical composition of Claim 13 wherein the amount of celecoxib present in the composition is between about 0.1 mg to about 500 mg.

14. A method of treating or preventing a COX-2-mediated condition, the method comprising administering to a subject having or susceptible to such condition or disorder a therapeutically or prophylactically effective amount of the composition of Claim 8.