OA11831A - Polymorphic crystalline forms of celecoxib. - Google Patents

Polymorphic crystalline forms of celecoxib. Download PDF

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Publication number
OA11831A
OA11831A OA1200100210A OA1200100210A OA11831A OA 11831 A OA11831 A OA 11831A OA 1200100210 A OA1200100210 A OA 1200100210A OA 1200100210 A OA1200100210 A OA 1200100210A OA 11831 A OA11831 A OA 11831A
Authority
OA
OAPI
Prior art keywords
celecoxib
température
crystalline form
milling
solvatéis
Prior art date
Application number
OA1200100210A
Inventor
Leonard J Ferro
Patricia J Miyake
Original Assignee
Pharmacia Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Pharmacia Corp filed Critical Pharmacia Corp
Publication of OA11831A publication Critical patent/OA11831A/en

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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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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

118 3 1
POLYMORPHIC CRYSTALLINE FORMS OF CELECOXIB
Cross Reference to Related Applications
This Patent Application daims priority to Ü.S.Provisional Patent Application Ser. No. 60/169,856,filed December 9, 1999.
FIELD OF THE INVENTION
The présent invention relates to orallydeliverable pharmaceutical compositions containing acyclooxygenase-2 inhibitory drug as an activeingrédient, to processes for preparing such compositions, to methods of treatment of cyclooxygenase-2 mediated disorders comprising orallyadministering such compositions to a subject, and tothe use of such compositions in the manufacture ofmédicaments.
This invention is in the field of cyclooxygenase-2 inhibitory pharmaceutical agents and specificallyrelates to the novel Form I and Form II crystallineforms of celecoxib, methods of preparing thesecrystalline forms of celecoxib, pharmaceuticalcompositions comprising these crystalline forms ofcelecoxib, and methods for the treatment and/orprophylaxie of cyclooxygenase-2-mediated conditionsand/or disorders, including conditions and disorders.
BACKGROUND OF THE INVENTION
Numerous compounds hâve been reported havingtherapeutically and/or prophylactically useful sélectivecyclooxygenase-2 inhibitory effect, and hâve beendisclosed as having utility in treatment or préventionof spécifie cyclooxygenase-2 mediated disorders or ofsuch disorders in general. Among such compounds are alarge number of substituted pyrazolyl / 118 3 1 -2- benzenesulfonamides as reported in U. S. Patent No.5,760,068 to Talley et al., including for example thecompound 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-l-yl]benzenesulfonamide, also referred to herein 5 as celecoxib, and the compound 4-[5-(3-fluor'o-4-methoxyphenyl) -3-dif luoromethyl) -lH-pyrazol-1-yl]benzenesulfonamide, also referred to herein asderacoxib. Celecoxib has the structure:
10 and deracoxib has the structure:
Other compounds reported to hâve therapeuticallyand/or prophylactically useful sélective cyclooxygenase-2 inhibitory effect are substituted isoxazolyl 15 benzenesulfonamides as reported in U.S. Patent No. 5,633,272 to Talley et al., including for example thecompound 4-[5-methyl-3-phenylisoxazol-4- yl]benzenesulfonamide, also referred to herein asvaldecoxib, which has the structure: -3- 118 3 1
Still other compounds reported to hâvetherapeutically and/or prophylactically useful sélectivecyclooxygenase-2 inhibitory effect are substituted 5 (methylsulfonyl)phenyl furanones as reported in U.S.Patent No. 5,474,995 to Ducharme et al., including forexample the compound 3-phenyl-4-[4- (methylsulfonyl)phenyl]-5H-furan-2-one, also referred toherein as rofecoxib, which has the structure:
discloses a further sériés of (methylsulfonyl)phenylfuranones said to be useful as cyclooxygenase-2inhibitors, including 3-(1-cyclopropylmethoxy)-5,5- 15 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 disclosesthe compound 2-(3,5-difluorophenyl)-3-[4- 20 (methylsulfonyl)phenyl]-2-cyclopenten-l-one said to beuseful as a cyclooxygenase-2 inhibitor. 118 3 1 -4-
International Publication No. WO 99/55380discloses, inter alla, a compound having the structure:
said to be useful as a cyclooxygenase-2 inhibitor.
Many sélective cyclooxygenase-2 inhibitorycompounds, including celecoxib, deracoxib, valdecoxiband rofecoxib, are hydrophobie and hâve low solubilityin water. This has presented practical difficulties informulating such compounds for oral administration,particularly where early onset of therapeutic effect isdesired or required.
Illustratively, the formulation of celecoxib foreffective oral administration to a subject has hithertobeen complicated by the unique physical and Chemicalproperties of celecoxib, particularly its low solubilityand factors associated with its crystal structure,including cohesiveness, low bulk density and lowcompressibility. Celecoxib is unusually insoluble inaqueous media. Unformulated celecoxib is not readilydissolved and dispersed for rapid absorption in thegastrointestinal tract when administered orally, forexample in capsule form. In addition, unformulatedcelecoxib, which has a crystal morphology that tends toform long cohesive needles, typically fuses into amonolithic mass upon compression in a tableting die.
Even when blended with other substances, the celecoxibcrystals tend to separate from the other substances andagglomerate together during mixing of the composition 1183 1 -5- resulting in a non-uniformly blended compositioncontaining undesirably large aggregates of celecoxib.Therefore, it is difficult to préparé a pharmaceuticalcomposition containing celecoxib that has the desiredblend uniformity. Further, handling problems areencountered durin'g the préparation of pharmaceuticalcompositions comprising celecoxib. For example, the lowbulk density of celecoxib makes it difficult to processthe small quantifies required during formulation of thepharmaceutical compositions. Accordingly, a need existsfor solutions to numerous problems associated withpréparation of suitable pharmaceutical compositions anddosage forms comprising celecoxib, particularly orallydeliverable dose units.
More generally, a need exists for orallydeliverable formulations of cyclooxygenase-2 inhibitorydrugs of low water solubility including celecoxib, suchformulations possessing one or more of the followingcharacteristics relative to unformulated celecoxib orother celecoxib compositions: (1) improved solubility; (2) shorter disintegration time; (3) shorter dissolution time; (4) decreased tablet friability; (5) increased tablet hardness; (6) improved wettability; (7) improved compressibility; (8) improved flow properties of liquid andparticulate solid compositions; (9) improved physical stability of the finishedcomposition; (10) reduced tablet or capsule size; (11) improved blend uniformity; (12) improved dose uniformity; 118 3 1 3 -6- (13) improved control of weight variation duringencapsulation and/or tableting; (14) increased granule density for wet granulatedcompositions; (15) Reduced water requirement for wet granulation; (16) Reduced wet granulation time; and (17) Reduced drying time for wet granulatedmixtures.
Further, there exists an especial need for orallydeliverable formulations of cyclooxygenase-2 inhibitorydrugs of low water solubility including celecoxib, suchformulations providing more rapid onset of therapeuticeffect than the corresponding unformulated drugs orknown formulations of these drugs. To the extent thatrapid onset of therapeutic effect is related topharmacokinetic parameters such as a high maximum bloodsérum concentration of the drug (Cmax) and a short timefrom oral administration to reach such maximum bloodsérum concentration (Τ,^) , there is an especial need fororally deliverable formulations of cyclooxygenase-2inhibitory drugs of low water solubility includingcelecoxib, such formulations providing a greater C^axand/or an earlier Τ^χ than the corresponding unformulated drugs or known formulations of these drugs.
As is indicated herein below, treatment withsélective cyclooxygenase-2 inhibitors includingcelecoxib is indicated or potentially indicated in avery wide array of cyclooxygenase-2 mediated conditionsand disorders. It would be of benefit to provideformulations exhibiting pharmacokinetics consistent withrapid onset of therapeutic effect especially fortreatment of acute disorders where early relief frompain or other symptoms is desired or required. -7- 118 3 1
Such formulations would represent a significantadvance in the treatment of cyclooxygenase-2 mediatedconditions and disorders.
Cyclooxygenase-2 inhibitory drugs includingcelecoxib that are of low solubility in water are mostconveniently formulated in solid particulate form. Theindividual or primary particles of the drug candispersed in a liquid medium, as in a suspensionformulation, or can be aggregated to form secondaryparticles or granules that can be encapsulated toprovide a capsule dosage form, or compressed or moldedto provide a tablet dosage form.
Numerous processes are known and used in the artfor preparing drug formulations having primary particlesizes in a desired range, or having a desired meanparticle size, or having a particle size distributioncharacterized by a parameter such as Dgo, which isdefined herein as a linear measure of diameter having avalue such that 90% by volume of particles in theformulation, in the longest dimension of the particles,are smaller than that diameter. For practical purposesa détermination of D90 based on 90% by weight ratherthan by volume is generally suitable.
For consistency with prior publications, the terms"microparticle" and "nanoparticle" are defined herein asin U.S. Patent No. 5,384,124 to Courteille et al., torefer to particles having respectively a diameter ofbetween 1 mm and 2000 mm, and a diameter of less than 1mm (1000 nm) . The préparation of microparticles andnanoparticles, according to U.S. Patent No. 5,384,124,"is principally used to retard dissolution of activeprinciples". However, U.S. Patent No. 5,145,684 toLiversidge et al. discloses nanoparticulate compositionssaid to provide "unexpectedly high bioavailability" ofdrugs, particularly drugs having low solubility in a -8- 118 3 1 liguid medium such as water. International PublicationNo. WO 93/25190 provides pharmacokinetic data from a ratstudy indicating a higher apparent rate of absorptionfrom oral administration of a nanoparticulate (averageparticle size 240-300 nm) than from oral administrationof a microparticulate (particle size range 20-30 mm)dispersion of naproxen.
Numerous processes for préparation ofnanoparticulate compositions of therapeutic agents areknown. Typically these processes use mechanical means,such as milling or grinding, to reduce particle size toa nano (less than 1 mm) range, or precipitate nano-sizedparticles from solution. Illustrative processes aredisclosed in the following individual references: U.S.Patent No. 4,826,689 to Violanto & Fischer, above-citedU.S. Patent No. 5,145,684 to Liversidge et al., U. S.Patent No. 5,298,262 to Na & Rajagopalan, U.S. PatentNo. 5,302,401 to Liversidge et al., U.S. Patent No. 5.336.507 to Na & Rajagopalan, U.S. Patent No. 5,340,564to Illig & Sarpotdar, U.S. Patent No. 5,346,702 to Na &Rajagopalan, U.S. Patent No. 5,352,459 to Hollister etal., U.S. Patent No. 5,354,560 to Lovrecich, above-citedU.S. Patent No. 5,384,124 to Courteille et al., U.S.Patent No. 5j429,824 to June, U.S. Patent No. 5,510,118to Bosch et al., U.S. Patent No. 5,518,738 to Eickhoffet al., U.S. Patent No. 5,503,723 to Ruddy & Eickhoff, U.S. Patent No. 5,534,270 to De Castro, U.S. Patent No. 5.536.508 to Canal et al., U.S. Patent No. 5,552,160 toLiversidge et al., U.S. Patent No. 5,560,931 to Eickhoffet 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 toEickhoff et al., U.S. Patent No. 5,573,783 to Desieno &Stetsko, U.S. Patent No. 5,580,579 to Ruddy et al., U.S. 118 3 1 -9-
Patent No. 5,585,108 to Ruddy et al., U.S. Patent No.5,587,143 to Wong, U.S. Patent No. 5,591,456 to Franson& Snyder, U.S. Patent No. 5,662,883 to Bagchi et al., U.S. Patent No. 5,665,331 to Bagchi et al., U.S. PatentNo. 5,718,919 to Ruddy & Roberts, U.S. Patent No.5,747,001 to Wiedmann et al., International PublicationNo. WO 93/25190, International Publication No. WO96/24336, International Publication No. 98/35666.
SÜMMARY OF THE INVENTION
According to the présent invention, a poorly watersoluble sélective cyclooxygenase-2 inhibitory compoundsuch as celecoxib, deracoxib, valdecoxib or rofecoxibprovides more rapid onset of tberapeutic effect if, uponoral administration of a composition comprising thecompound, the compound exhibits pharmacokineticproperties leading to a greater maximum blood sérumconcentration (CmaX) and/or a shorter time following theadministration to reach that maximum (Tmax) . It iscontemplated that a greater Cmax and/or a shorter Traax areobtained by réduction of size of solid particlescomprising the compound such that a substantial portionby weight of the particles are smaller than 1 mm indiameter, in the longest dimension of the particles.Without being bound by theory, it is believed that thegreater Cmax and/or the shorter Tmax resuit from fasterdissolution of the compound when particle size isreduced to less than 1 mm.
Accordingly, there is now provided a pharmaceuticalcomposition comprising one or more orally deliverabledose units, each comprising a sélective cyclooxygenase-2inhibitory compound of low water solubility in atherapeutically effective amount, wherein the .compoundis présent in solid particles having a D9q particle size 1183 1 -10- of about 0.01 to about 200 mm, a sufficient portion byweight of the particles being smaller than 1 mm toprovide a substantially higher Cmax and/or asubstantially shorter Tmax by comparison with anotherwise similar composition wherein substantially ailof the particles are larger than 1 mm.
There is also provided a pharmaceutical compositioncomprising one or more orally deliverable dose units,each comprising a sélective cyclooxygenase-2 inhibitorycompound of low water solubility in a therapeuticallyeffective amount, wherein the compound is présent insolid particles having a D90 particle size of about 0.01to about 200 mm, and wherein about 25% to 100% by weightof the particles are smaller than 1 mm.
The dose units comprising the composition can be inthe form of discrète solid articles such as tablets,pills, hard or soft capsules, lozenges, sachets orpastilles; alternatively the composition can be in theform of a substantially homogeneous flowable mass, suchas a particulate or granular solid or a liquidsuspension, from which single dose units are measurablyremovable.
Also provided is a method of treating a medicalcondition or disorder in a subject where treatment witha cyclooxygenase-2 inhibitor is indicated, comprisingorally administering one or more dose units of acomposition of the invention once or twice a day. Sucha method is particularly useful where the medicalcondition or disorder is accompanied by acute pain.
The présent invention also embodies a novel solidState form of celecoxib, Form I celecoxib. The présentinvention further embodies another solid State form ofcelecoxib, Form II celecoxib. Each of these novelsolid state forms includes solvated crystalline forms,non-solvated and non-hydrated crystalline forms. 118 3 1 -11-
These novel forms of celecoxib described in theprésent application possess one or more of the above-described advantageous Chemical and/or physicalproperties relative to the other solid State formsdescribed herein or otherwise disclosed in theliterature.
Another embodiment of the présent inventioncomprises a novel crystalline form of celecoxib. Forexample, one embodiment of the présent inventionincludes a Form I crystalline form of celecoxib,preferably a crystalline form having an X-ray powderdiffraction pattern with peaks at 5.5, 5.7, 7.2, and16.6 degrees two thêta.
In another embodiment, the présent inventionprovides a pharmaceutical composition comprising atherapeutically-effective amount of the Form Icrystalline form of celecoxib and at least onepharmaceutically-acceptable carrier, adjuvant ordiluent.
In another embodiment, the présent inventionprovides a method of treating or preventing acyclooxygenase-2-mediated condition or disorder in asubject, wherein the method comprises administering tothe subject a therapeutically effective amount of FormI celecoxib.
In yet another embodiment, the présent inventionprovides a method of preparing Form I celecoxibcomprising crystallizing celecoxib from a mixturecomprising celecoxib and a solvent, wherein thecrystallization is performed at a température abovethe enantiotropic transition température of Form Icelecoxib thereby producing Form I celecoxib.
In still another embodiment, the présentinvention provides a method of preparing a crystalline -12- 118 3 1 form of celecoxib wherein the method comprises heatinga solvaté of celecoxib thereby producing Form Icelecoxib.
In another embodiment, the présent inventionprovides a method of producing Form I celecoxibwherein the method comprises milling or grinding FormIII celecoxib thereby producing Form I celecoxib.
In yet another embodiment, the présent inventionprovides a method of producing Form I celecoxibwherein the method comprises milling or grinding acelecoxib solvaté thereby producing Form I celecoxib.
In another embodiment, the présent inventionprovides a method of producing Form I celecoxibwherein the method comprises melting Form II celecoxiband cooling the melt thereby producing Form Icelecoxib.
In another embodiment, the présent inventionprovides a method of producing Form I celecoxibwherein the method comprises melting Form IIIcelecoxib and cooling the melt thereby producing FormI celecoxib.
In another embodiment, the présent inventionprovides a method of producing Form I celecoxibwherein the method comprises evaporating solvent froma celecoxib solution thereby producing Form Icelecoxib.
Another embodiment of the présent inventioncomprises a novel crystalline form of celecoxib. Forexample, one embodiment of the présent inventionincludes a Form II crystalline form of celecoxib,preferably a crystalline form having an X-ray powderdiffraction pattern with a peak at about 10.3, 13.8 or17.7 degrees two thêta.
Another embodiment of the présent inventionprovides a pharmaceutical composition comprising a 113 3 1 -13- therapeutically-effective amount of the crystallineform of at least one pharmaceutically-acceptablecarrier, adjuvant or diluent.
Another embodiment of the présent inventionprovides a method of treating or preventing acyclooxygenase-2-mediated condition or disorder in asubject, the method comprising administering to thesubject a therapeutically-effective amount of Form IIcelecoxib.
Yet another embodiment of the présent inventionprovides a method of preparing Form II celecoxibcomprising crystallizing celecoxib from a mixturecomprising celecoxib and a solvent, wherein thecrystallization is performed at a température abovethe enantiotropic transition température of Form IIcelecoxib thereby producing Form II celecoxib.
Yet another embodiment of the présent inventionprovides a method of preparing a crystalline form ofcelecoxib wherein the method comprises heating asolvaté of celecoxib thereby producing Form IIcelecoxib.
Another embodiment of the présent inventionprovides a method of producing Form II celecoxibwherein the method comprises milling or grinding FormIII celecoxib thereby producing Form II celecoxib.
Another embodiment of the présent inventionprovides a method of producing Form II celecoxibwherein the method comprises milling or grinding acelecoxib solvaté thereby producing Form II celecoxib.
Still another embodiment of the présent inventionprovides a method of producing Form II celecoxibwherein the method comprises melting Form I celecoxib andcooling the melt thereby producing Form II celecoxib. 1183 1 -14-
Yet another embodiment of the présent inventionprovides a method of producing Form II celecoxibwherein the method comprises melting Form III celecoxib andcooling the melt thereby producing Form II celecoxib.
Another embodiment of the présent inventionprovides a solid form of celecoxib comprising Form Icelecoxib and Form II celecoxib.
Another embodiment of the présent inventionprovides a solid form of celecoxib comprising Form Icelecoxib and Form III celecoxib.
Another embodiment of the présent inventionprovides a solid form of celecoxib comprising FormII celecoxib and Form III celecoxib.
Another embodiment of the présent inventionprovides a solid form of celecoxib comprising Form Icelecoxib, Form II celecoxib, and Form III celecoxib.
Other features of this invention will be in partapparent and in part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts a comparison of experimental PXRDpatterns between Form I celecoxib (Figure la), amixture of Form II celecoxcib and Form III celecoxib(Figure lb) , and Form III celecoxib (Figure le) .
Fig. 2 depicts a comparison between the IRspectra of Form I celecoxib, a mixture of Form IIcelecoxcib and Form III celecoxib, and Form IIIcelecoxib.
Fig. 3 depicts a comparison of DSC thermogramsscanned at 0.5°C/minute for individual celecoxib Formswith overlay (endotherms down).
DESCRIPTION OF THE PREFERRED EMBODIMENTS -15- 118 3 1
The term "sélective cyclooxygenase-2 inhibitor" or"sélective cyclooxygenase-2 inhibitory compound" hereinmeans a compound that inhibits cyclooxygenase-2 to atherapeutically useful degree while causing markedlyless inhibition of cyclooxygenase-l than conventionalnonsteroidal anti-inflammatory drugs (NSAIDs).
The term "poorly water soluble" or "of low watersolubility" with respect to a sélective cyclooxygenase-2inhibitor herein means having a solubility in distilledwater at 25°C lower than about 10 g/1, preferably lowerthan about 1 g/1.
The term "oral administration" herein includes anyform of delivery of a therapeutic agent or a compositionthereof to a subject wherein the agent or composition isplaced in the mouth of the subject, whether or not theagent or composition is swallowed. Thus "oral administration" includes buccal and sublingual as wellas esophageal administration. Absorption of the agentcan occur in any part or parts of the gastrointestinaltract including the mouth, esophagus, stomach, duodénum,ileum and colon.
The term "orally deliverable" herein means suitablefor oral administration. A "subject" herein to which a therapeutic agent orcomposition thereof can be administered includes a humanpatient of either sex and of any âge, and also includesany nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or horse.
The term "dose unit" herein means a portion of apharmaceutical composition that contains an amount of atherapeutic agent, in the présent case a sélectivecyclooxygenase-2 inhibitor, suitable for a single oraladministration to provide a therapeutic effect.
Typically one dose unit, or a small plurality (up to 118 3 1 -16- about 4) of dose units, provides a sufficient amount ofthe agent to resuit in the desired effect.
The term "présent in solid particles" as applied toa sélective cyclooxygenase-2 inhibitory compound hereinencompasses compositions wherein the solid particlesconsist essentially of the compound and compositionswhere the solid particles comprise the compound inintimate mixture with one or more other ingrédients.
These other ingrédients can include one or moretherapeutic agents other than the sélective cyclooxygenase-2 inhibitory compound and/or one or morepharmaceutically acceptable excipients.
The term "excipient" herein means any substance,not itself a therapeutic agent, used as a carrier orvehicle for delivery of a therapeutic agent to a subjector added to a pharmaceutical composition to improve itshandling or storage properties or to permit orfacilitate formation of a dose unit of the compositioninto a discrète article such as a capsule or tabletsuitable for oral administration. Excipients caninclude, by way of illustration and not limitation,diluents, disintégrants, binding agents, adhesives,wetting agents, lubricants, glidants, substances addedto mask or counteract a disagreeable taste or odor,flavors, dyes, fragrances, and substances added toimprove appearance of the composition.
The term "substantially homogeneous" with referenceto a pharmaceutical composition that comprises severalcomponents means that the components are sufficientlymixed such that individual components are not présent asdiscrète layers and do not form concentration gradientswithin the composition.
The term "purity" means the Chemical purity ofcelecoxib according to conventional HPLC assay.
The term "phase purity" means the solid state -17- 118 3 1 purity of celecoxib with regard to a particular crystalline or amorphous form of the celecoxib asdetermined by the infrared spectroscopy analyticalmethods described herein.
The term "enantiotropic transition température "means the température at which a thermodynamicallystable polymorph changes from one form to another. Forexample, for two polymorphs, Form A and Form B, belowthe enantiotropic transition température, Form A may'bethe thermodynamically stable form, but above thistempérature Form B may be the thermodynamically stableform.
Novel pharmaceutical compositions according to theprésent invention comprise one or more orallydeliverable dose units. Each dose unit comprises asélective cyclooxygenase-2 inhibitor, illustrativelycelecoxib, in a therapeutically effective amount that ispreferably about 10 mg to about 1000 mg.
It will be understood that a therapeuticallyeffective amount of a sélective cyclooxygenase-2inhibitor for a subject is dépendent inter alia on thebody weight of the subject. Where the cyclooxygenase-2inhibitor is celecoxib and the subject is a child or asmall animal (e.g. , a dog) , for example, an amount ofcelecoxib relatively low in the preferred range of about10 mg to about 1000 mg is likely to provide blood sérumconcentrations consistent with therapeuticeffectiveness. Where the subject is an adult human or alarge animal (e.g., a horse), achievement of such bloodsérum concentrations of celecoxib are likely to requiredose units containing a relatively greater amount ofcelecoxib.
Typical dose units in a composition of theinvention contain about 10, 20, 25, 37.5, 50, 75, 100,125, 150, 175, 200, 250, 300, 350 or 400 mg of the 118 3 1 4 cyclooxygenase-2 inhibitor, illustratively celecoxib.
For an adult human, a therapeutically effective amountof celecoxib per dose unit in a composition of theprésent invention is typically about 50 mg to about 400mg. Especially preferred amounts of celecoxib per doseunit are about 100 mg to about 200 mg, for example about100 mg or about 200 mg.
Compositions of the présent invention contain asélective cyclooxygenase-2 inhibitor, illustrativelycelecoxib, alone or in intimate mixture .with one or moreexcipients, in nanoparticulate form, i.e., in the formof solid particles of diameter less than 1 mm in thelongest dimension of the particles.
The effects on pharmacokinetic properties ofreducing particle size from the microparticle range(greater than 1 mm diameter) to the nanoparticle rangeis generally unpredictable for any particular drug orclass of drugs. Àccording to the présent invention, forsélective cyclooxygenase-2 inhibitors of low watersolubility, nanoparticulate compositions exhibit higherCmax and/or shorter Tmax than microparticulatecompositions. In one embodiment of the invention,therefore, the percentage by weight of the particlesthat are nanoparticles is sufficient to provide asubstantially higher Cmax and/or a substantially shorterImax by comparison with a comparative composition whereinsubstantially ail of the particles are larger than 1 mm.Preferabiy a composition of this embodiment has asufficient percentage by weight of nanoparticles toprovide a substantially shorter Trasx, and more preferabiya sufficient percentage by weight of nanoparticles toprovide both a substantially higher Cmax and asubstantially shorter Τπ,3Χ, than the comparativecomposition. -19- 118 3 1
When administered orally to a fasting adult human,a 100 mg dose unit preferably exhibits a Tmax of les sthan about 90 minutes, more preferably less than about60 minutes and preferably less than about 45 minutes,and a Cmax of at least about 100 ng/ml, more preferablyat least about 200 ng/ml. Typically a composition ofthe invention provides a blood sérum concentration ofthe sélective cyclooxygenase-2 inhibitor of at leastabout 50 ng/ml within 3 0 minutes of oral administration;preferred compositions achieve such a concentration inas little as 15 minutes. This early rise in blood sérumconcentration is believed to be associated with therapid onset of therapeutic effect achieved bycompositions of the présent invention.
In another embodiment of the invention, thesélective cyclooxygenase-2 inhibitor, illustrativelycelecoxib, is présent in solid particles having a Dgoparticle size of about 0.01 to about 200 mm, whereinabout 25% to 100% by weight of the particles arenanoparticles. Where the percentage by weight ofnanoparticles is relatively low, for example about 25%to about 50%, preferably the Dgo particle size is about0.01 to about 100 mm, more preferably about 0.01 toabout 75 mm, still more preferably about 0.01 to about40 mm, and even more preferably about 0.01 to about 25mm. Particle size can vary continuously across thenanoparticulate and microparticulate range, or thecomposition can hâve a bimodal or multimodal particlesize distribution, with one set of particles having aDoq particle size less than 1 mm and another set cfparticles having a Dgo particle size substantiallygreater than 1 mm. It is generally preferred that atleast about 50% by weight, and especially preferred thatat least about 75% by weight, of the particles arenanoparticles. In one embodiment substantially ail of 118 3 1 -20- the partiales are smaller than 1 mm, i.e., the percentage by weight of nanoparticles is 100% or closeto 100%.
Primary particles, generated for example bymilling or grinding, or by précipitation from solution,can agglomerate to form secondary aggregate particles.
The term "particle size" as used herein refers to size,in the longest dimension, of primary particles, unlessthe context demands otherwise.
Considering only the nanoparticulate component of acomposition of the invention, average particle size ispreferably about 0.1 to about 0.8 mm (about 100 to about800 nm), more preferably about 0.15 to about 0.6 mm(about 150 to about 600 nm), and preferably about 0.2 toabout 0.4 mm (about 200 to about 400 nm). The sélectivecyclooxygenase-2 inhibitor, illustratively celecoxib,can be in crystalline or amorphous form in thenanoparticles. Processes for preparing nanoparticlesthat involve milling or grinding typically provide the 'drug in crystalline form, whereas processes that involveprécipitation from solution typically provide the drugin amorphous form.
Compositions of the invention comprise a sélectivecyclooxygenase-2 inhibitor of low water solubility, forexample celecoxib, optionally together with one or moreexcipients selected from diluents, disintegrants,binding agents, wetting agents and lubricants. In oneembodiment, nanoparticles comprising the sélectivecyclooxygenase-2 inhibitor hâve a surface-modifyingagent adsorbed on the surface thereof. In anctherembodiment, nanoparticles of the sélective cyclocxygenase-2 inhibitor are contained in a matrixformed by a polymer. Preferably at least one of theexcipients is a water-soluble diluent or wetting agent.Such a water-soluble diluent or wetting agent assists in 118 3 1 -21- the dispersion and dissolution of the cyclooxygenase-2inhibitor when a composition of the invention isingested. Preferably both a water-soluble diluent and awetting agent are présent. A composition of the invention can be asubstantially homogeneous flowable mass such as aparticulate or granular solid or a liquid, or it can bein the form of discrète articles such as capsules ortablets each comprising a single dose unit.
In a composition that is a substantiallyhomogeneous flowable mass, single dose units aremeasurably removable using a suitable volumétriemeasuring device such as a spoon or cup. Suitableflowable masses include, but are not liraited to, powdersand granules. Altematively, the flowable mass can be asuspension having the cyclooxygenase-2 inhibitor in asolid particulate phase dispersed in a liquid phase,preferably an aqueous phase. At least a portion of theparticulate phase is nanoparticulate. In preparing sucha suspension, use of a wetting agent such as polysorbate80 or the like is likely to be bénéficiai. A suspensioncan be prepared by dispersing nanoparticulate orpartially nanoparticulate cyclooxygenase-2 inhibitor inthe liquid phase; altematively the cyclooxygenase-2inhibitor, illustratively celecoxib, can be precipitatedfrom solution in a solvent such as an alcohol,preferably éthanol. The aqueous phase preferablycomprises a palatable vehicle such as water, syrup orfruit juice, for example apple juice.
Compositions of the présent invention are useful intreatment and prévention of a very wide range ofdisorders mediated by cyclooxygenase-2. Presentlycontemplated compositions are useful for, but notliraited to, the treatment of inflammation in a subject,as an analgésie for example in the treatment of pain and 113 3 1 -22- headaches, and as an antipyretic in the treatment offever. For example, such compositions are useful totreat arthritic disorders, including but not limited torheumatoid arthritis, spondyloarthropathies, goutyarthritis, osteoarthritis, systemic lupus erythematosusand juvénile arthritis. Such compositions are alsouseful in the treatment of asthma, bronchitis, menstrualcramps, preterm labor, tendonitis, bursitis, allergieneuritis, cytomégalovirus infectivity, apoptosisincluding HIV-induced apoptosis, lumbago, liver diseaseincluding hepatitis, skin-related conditions such aspsoriasis, eczema, acné, UV damage, burns anddermatitis, and post-operative inflammation includingthat following ophthalmic surgery such as cataractsurgery or refractive surgery. Contemplatedcompositions are useful to treat gastrointestinalconditions such as inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome andulcerative colitis. Contemplated compositions areuseful in treating inflammation in such diseases asmigraine headaches, periarteritis nodosa, thyroiditis,aplastic anémia, Hodgkin's disease, sclerodoma,rheumatic fever, type I diabètes, neuromuscular junctiondisease including myasthenia gravis, white matterdisease including multiple sclerosis, sarcoidosis,nephrotic syndrome, Behcet's syndrome, polymyositis,gingivitis, nephritis, hypersensitivity, swellingoccurring after injury including brain edema, myocardial ischemia, and the like. Contemplated compositions areuseful in the treatment of ophthalmic diseases, such asretinitis, conjunctivitis, rétinopathies, uveitis,ocular photophobia, and of acute injury to the systissue, Contemplated compositions are useful in thetreatment of pulmonary inflammation, such as thatassociated with viral infections and cystic fibrosis, -23- 118 3 1 and in bone résorption such as that associated withosteoporosis. Contemplated compositions are useful forthe treatment of certain central nervous Systemdisorders, such as cortical dementias includingAlzheimer's disease, neurodegeneration, and centralnervous system damage resulting from stroke, ischemiaand trauma. The term "treatment" in the présent contextincludes partial or total inhibition of dementias,including Alzheimer's disease, vascular dementia,multi-infarct dementia, pre-senile dementia, alcoholicdementia, and senile dementia.
Compositions of the invention are especially usefulas anti-inflammatory agents, such as for the treatmentof arthrit-is, with the additional benefit of havingsignificantly less harmful side effects than compositions of conventional nonsteroidal anti- inflammatory drugs (NSAIDs) .
Contemplated compositions are useful in thetreatment of allergie rhinitis, respiratory distresssyndrome, endotoxin shock syndrome, and liver disease.Contemplated compositions are useful in the treatment ofpain, including but not limited to postoperative pain,dental pain, muscular pain, and pain resulting fromcancer.
Contemplated compositions are useful for, but notlimited to, treating and preventing inf lammation-relatedcardiovascular disorders in a subject. Such compositions are useful for treatment and prévention ofvascular diseases, coronary artery disease, aneurysm,vascular rejaction, artérioscléroses, athérosclérosesincluding cardiac transplant athéroscléroses, myocardialënfarction, embolism, stroke, thrombosés includingvenous thromboses, angina including unstable angina,coronary plaque inflammation, bacterial-inducedinflammation including Chlamydia-induced inflammation, 1183 1 -24- viral induced inflammation, and inflammation associatedwith surgical procedures such as vascular graftingincluding coronary artery bypass surgery, revascularisation procedures including angioplasty,stent placement, endarterectomy, or other invasiveprocedures involving arteries, veins and capillaries.
Such compositions are useful for, but not limited to,the treatment of angiogenesis-related disorders in asubject. Compositions of the invention can beadministered to a subject in need of angiogenesisinhibition. Such compositions are useful for thetreatment of neoplasia, including metastasis;ophthalmological conditions such as corneal graftrejection, oculàr neovascularization, retinalneovascularization including neovascularizationfollowing injury or infection, diabetic retinopathy,macular degeneration, retrolental fibroplasia andneovascular glaucoma; ulcerative diseases such asgastric ulcer; pathological, but non-malignant,conditions such as hemangiomas, including infantilehemangiomas, angiofibroma of the nasopharynx andavascular necrosis of bone; and disorders of the femalereproductive System such as endometriosis.
Contemplated compositions are useful for theprévention or treatment of benign and malignanttumors/neoplasia including cancer, such as colorectalcancer, brain cancer, bone cancer, épithélialcell-derived neoplasia (épithélial carcinoma) such asbasal cell carcinoma, adenocarcinoma, gastrointestinalcancer such as lip cancer, mouth cancer, esophagealcancer, small bowel cancer and stomach cancer, coloncancer, liver cancer, bladder cancer, pancréas cancer,ovary cancer, cervical cancer, lung cancer, breastcancer and skin cancer, such as sguamous cell and basalcell cancers, prostate cancer, rénal cell carcinoma, and 1183 1 -25- other known cancers that effect épithélial cells throughout the body. Neoplasias for which compositionsof the invention are contemplated to be particuiarlyuseful are gastrointestinal cancer, Barrett's esophagus,liver cancer, bladder cancer, pancréas cancer, ovarycancer, prostate cancer, cervical cancer, lung cancer,breast cancer and skin cancer, such as squamous cell andbasal cell cancers. Compositions of the invention canalso be used to treat the fibrosis which occurs withradiation therapy. Such compositions can be used totreat subjects having adenomatous polyps, includingthose with familial adenomatous polyposis (FAP).Additionally, such compositions can be used to preventpolyps from forming in patients at risk of FAP.
Compositions of the présent invention possess anti-inf lammatory, antipyretic and analgésie propertiessimilar or superior to those of compositions ofconventional nonsteroidal anti-inflammatory drugs.Contemplated compositions also inhibit hormone-induceduterine contractions and hâve potentiel anti-cancereffects, but with a diminished ability to induce soins ofthe mechanism-based side effects of conventional NSAIDs.In particular, compositions of the invention hâvereduced potential for gastrointestinal toxicity andgastrointestinal irritation including uppergastrointestinal ulcération and bleeding, reducedpotential for rénal side effects such as réduction inrénal function leading to fluid rétention andexacerbation of hypertension, reduced effect on bleedingtimes including inhibition of platelet function, andpossibly a lessened ability to induce asthma attacks inaspirin-sensitive asthmatic subjects, by comparison withcompositions of conventional NSAIDs.
Contemplated compositions are useful for the reliefof pain, fever and inflammation of a variety of -26- 118 3 1 conditions including rheumatic fever, symptoms associated with influenza or other viral infections,coimrton cold, low back and neck pain, dysmenorrhea,headache, toothache, sprains and strains, myositis,neuralgia, synovitis, arthritis, including rheumatoidarthritis, degenerative joint diseases (osteoarthritis),goût and ankylosing spondylitis, bursitis, burns, andinjuries following surgical and dental procedures. Inaddition, contemplated compositions inhibit cellularneoplastic transformations and metastatic tumor growthand hence can be used in the treatment of cancer, suchas cancer of the colon. Contemplated compositions arealso of use in the treatment and/or prévention ofcyclooxygenase mediated proliférative disorders such asmay occur in diabetic retinopathy and tumorangiogenesis.
Contemplated compositions inhibit prostanoid-induced smooth muscle contraction by preventing thesynthesis of contractile prostanoids and hence can be ofuse in the treatment of dysmenorrhea, prématuré labor,asthma and eosinophil-related disorders. They also canbe of use in the treatment of Alzheimer's disease, fordecreasing bone loss particularly in postmenopausalwomen (i.e., treatment of osteoporosis) , and fortreatment of glaucoma.
By virtue of their high cyclooxygenase-2 (COX-2)inhibitory activity and/or their specificity forinhibition of cyclooxygenase-2 over cyclooxygenase-1(COX-1), compositions of the invention are useful as analternative to conventional NSAIDs, particularly wheresuch NSAIDs are contraindicated, for example in patientswith peptic ulcers, gastritis, régional enteritis,ulcerative colitis, diverticulitis or with a récurrenthistory of gastrointestinal lésions; gastrointestinalbleeding, coagulation disorders including anémia such as 118 3 1 -27- hypoprothrombinemia, hemophilia or other bleedingproblems; kidney disease; or in patients prior tosurgery or patients taking anticoagulants. A briefdescription of the potential utility of cyclooxygenase-2inhibitors is given in an article by John Vane, Nature,Vol. 367, pp. 215-216, 1994, and in an article in DrugNews and Perspectives, Vol. 7, pp. 501-512, .1994.
Preferred uses for the pharmaceutical compositionsof the présent invention are for the treatment ofrheumatoid arthritis and osteoarthritis, for painmanagement generally (particularly post-oral surgerypain, post-general surgery pain, post-orthopedic surgerypain, and acute flares of osteoarthritis), the treatmentof Alzheimer's disease, and colon cancerchemoprevention.
By virtue of the rapid onset of therapeutic effectexhibited by compositions of the invention, these ·compositions hâve particular advantages over priorformulations of cyclooxygenase-2 inhibitory compoundsfor treatment of acute cyclooxygenase-2 mediateddisorders, especially for the relief of pain.
The présent compositions can be used in combinationthérapies with opioids and other analgésies, includingnarcotic analgésies, Mu receptor antagonists, Kappareceptor antagonists, non-narcotic (i.e. non-addictive)analgésies, monamine uptake inhibitors, adenosineregulating agents, cannabinoid dérivatives, Substance Pantagonists, neurokinin-1 receptor antagonists andsodium, channel blockers, among others. Preferredcombination thérapies comprise use of a composition, ofthe invention with compounds selected from morphine,meperidine, codeine, pentazocine, buprénorphine,butorphanol, dezocine, meptazinol, hydrocodone,oxycodone, methadone, DuP-747, Dynorphine A, Enadoline,RP-60180, HN-11608, E-2078, ICI-204448, acetaminophen -28- 118 3 1 (paracétamol), propoxyphene, nalbuphine, E-4018, filenaâol, mirfentanil, amitriptyiine, DuP-631, GP-531,acadesine, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92,tramadol racemate and isolated (+) and (-) enantiomers,AXC-3742, SNX-111, ADL2-1294, CT-3, and CP-99994. A dose unit containing a particular amount of acyclooxygenase-2 inhibitor, for example celecoxib, canbe selected to accommodate any desired frequency ofadministration used to achieve a desired daily dosage.
The daily dosage and frequency of administration, andtherefore the sélection of appropriate dose unit,dépends on a variety of factors, including the âge,weight, sex and medical condition of the subject, andthe nature and severity of the condition or disorder,and thus may vary widely.
In the case of celecoxib, a once-a-day or twice-a-day administration regimen to provide the required· dailydosage of celecoxib exhibits improved efficacy relativeto other administration regimens, for compositions of ·the présent invention. Accordingly, once-a-day ortwice-a-day oral administration of a composition of theinvention is preferred for providing therapeutically orprophylactically effective inhibition of cyclooxygenase-2 mediated disorders.
For the treatment of rheumatoid arthritis,compositions of the'invention can be used to provide adaily dosage of celecoxib of about 50 mg to about 1000mg, preferably about 100 mg to about 600 mg, morepreferably about 150 mg to about 500 mg, and still morepreferably about 175 to about 400, for example about 200mg. The dosage can be once a day, twice a day, threetimes a day, or more. For example, the dosage can be200 mg bid. A daily dose of celecoxib of about 0.67 toabout 13.3 mg/kg body weight, preferably about 1.33 toabout 8.00 mg/kg body weight, more preferably about 2.00 113 3 1 -29- to about 6.67 mg/kg body weight, and still morspreferably about 2.33 to about 5.33 mg/kg body weight,for example about 2.67 mg/kg body weight, is generallyappropriate when administered in a composition of the 5 invention. The daily dose can be administered in one tofour doses per day, preferably one or two doses per day.Administration of a composition of the invention at therate of one 100 mg dose unit twice a day is preferredfor most patients, but sonie patients may benefit from 10 administration of one 200 mg dose unit or two 100 mgdose units twice a day.
For the treatment of osteoarthritis, compositionsof the invention can be used to provide a daily dosageof celecoxib of about 50 mg to about 1000 mg, preferably 15 about 100 mg to about 600 mg, more preferably about 150mg to about 500 mg, and still more preferably about 175to about 400, for example about 200 mg. A daily dose ofcelecoxib of about 0.67. to about 13.3 mg/kg body weight,preferably about 1,33 to about 8.00 mg/kg body weight, 20 more preferably about 2.00 to about 6.67 mg/kg bodyweight, and still more preferably about 2.33 to about5.33 mg/kg body weight, for example about 2.67 mg/kgbody weight, is generally appropriate when administeredin a composition of the invention. The daily dose can 25 be administered in one to four doses per day, preferablyone or two doses per day. Administration of acomposition of the invention at the rate of one 100 mgdose unit twice a day or of one 2 00 mg dose unit or two100 mg dose units once a day is preferred. 30 For the treatment of Alzheimer's disease, compositions of the invention can be used to provide adaily dosage of celecoxib of about 50 mg to about 1000mg, preferably about 100 mg to about 800 mg, morepreferably about 150 mg to about 600 mg, and still more 35 preferably about 175 to about 400, for example about 400 -30- 118 3 1 mg. A daily dose of about 0.67 to about 13.3 mg/kg bodyweight, preferably about 1.33 to about 10.67 mg/kg bodyweight, more preferably about 2.00 to about 8.00 mg/kgbody weight, and still more preferably about 2.33 toabout 5.33 mg/kg body weight, for example about 5.33mg/kg body weight, is generally appropriate whenadministered in a composition of the invention. Thedaily dose can be administered in one to four doses perday, preferably one or two doses per day.
Administration of a composition of the invention at therate of one 200 mg dose unit or two 100 mg dose unitstwice a day is preferred for most patients.
For the treatment of cancer, compositions of theinvention can be used to provide a daily dosage ofcelecoxib of about 50 mg to about 1000 mg, preferablyabout 100 mg to about 800 mg, more preferably about 150mg to about 600 mg, and still more preferably about 175to about 400, for example about 400 mg. A daily doseofabout 0.67 to about 13.3 mg/kg body weight, preferablyabout 1.33 to about 10.67 mg/kg body weight, morepreferably about 2.00 to about 8.00 mg/kg body weight,and still more preferably about 2.33 to about 5.33 mg/kgbody weight, for example about 5.33 mg/kg body weight,is generally appropriate when administered in acomposition of the invention. The daily dose can beadministered in one to four doses per day, preferablytwo doses per day. Administration of a composition ofthe invention at the rate of one 200 mg dose unit or two100 mg dose units twice a day is preferred for mostpSClSïiuS <.
For pain management, compositions of the inventioncan be used to provide a daily dosage of celecoxib ofabout 50 mg to about 1000 mg, preferably about 100 mg toabout 600 mg, more preferably about 150 mg to about 500mg, and still more preferably about 175 to about 400, -31- 118 3 1 for example about 200 mg. A daily dose of celecoxib ofabout 0.67 to about 13.3 mg/kg body weight, preferablyabout 1.33 to about 8.00 mg/kg body weight, morepreferably about 2.00 to about 6.67 mg/kg body weight,and still more preferably about 2.33 to about 5.33 mg/kgbody weight, for example about 2.67 mg/kg body weight,is generally appropriate when administered in acomposition of the invention. The daily dose can beadministered in one to four doses per day.
Administration of a composition of the invention at therate of one 50 mg dose unit four times a day, one 100 mgdose unit or two 50 mg dose units twice a day or one 200mg dose unit, two 100 mg dose units or four 50 mg doseunits once a day is preferred.
In general, a composition of the invention ispreferably administered at a dose and freguency suitableto provide an average blood sérum concentration ofcelecoxib of at least about 100 ng/ml in a subject overa period of about 24 hours after administration.
While the amount of celecoxib in compositions ofthe invention preferably is in a range disclosed herein,the compositions also may be useful for the administration of an amount of celecoxib falling outsidethe disclosed dosage ranges. For other sélectivecyclooxygenase-2 inhibitors, appropriate doses can beselected by reference to the patent literature citedhereinabove.
Nanoparticles comprising or consisting essentiallyof a sélective cyclooxygenase-2 inhibitory compound oflow water solubility, such as celecoxib, deracoxib,valdecoxib or rofecoxib, can be prepared according toany process previously applied to the préparation ofother poorly water-soluble drugs in nanoparticulateform. Suitable processes, without restriction, areillustratively disclosed for such other drugs in above 1183 1 cited U.S.5,302,401,5,354,560,5,503,723,5,560,932,5,580,579,
Patent Nos. 4,826,689, 5,145,684, 5,298,262,5,336,507, 5,340,564, 5,346,702, 5,352,459,5,384,124, 5,429,824, 5,510,118, 5,518,738,5,534,270, 5,536,508, 5,552,160, 5,560,931,5,565,188, 5,569,448, 5,571,536, 5,573,783,5,585,108, 5,587,143, 5,591,456, 5,662,883, 5,665,331, 5,718,919 and 5,747,001, and above-citedInternational Publication Nos. WO 93/25190, WO 96/24336and WO 98/35666, the pertinent disclosure of ail ofwhich is hereby incorporated by reference. One ofordinary skill in the art will readily adapt theprocesses therein described to the préparation of apoorly water-soluble sélective cyclooxygenase-2inhibitor, for example celecoxib, deracoxib, valdecoxibor rofecoxib, in nanoparticulate form.
Any excipients employed in a composition of theinvention can be solids or liquids or both. Thecomposition preferably contains about 1% to about 95%,preferably about 10% to about 90%, more preferably about25% to about 85%, and still more preferably about 30% toabout 80%, by weight of the sélective cyclooxygenase-2inhibitor, illustratively celecoxib. Compositions ofthe invention containing excipients can be prepared byany of the well known techniques of pharmacy thatcomprise admixing the excipients with a drug ortherapeutic agent, except that in the présent case thedrug or therapeutic agent, namely a sélectivecyclooxygenase-2 inhibitor, is at least partially pre-prepared, optionally together with one or moreexcipients, in nanoparticulate form as indicated above. A composition of the invention contains a desiredamount of a cyclooxygenase-2 inhibitor, illustrativelycelecoxib, per dose unit and can be in the form of, forexample, a tablet, a pill, a hard or soft capsule, alozenge, a cachet, a dispensable powder, granules, a -33- 118 3 1 suspension, an élixir, a liquid, or any other formreasonably adapted for oral administration. Such acomposition is preferably made in the form of discrètedose units each containing a predetermined amount of thecyclooxygenase-2 inhibitor, such as tablets or capsules.These oral dosage forms may further comprise, forexample, buffering agents. Tablets, pills and the likeadditionally can be prepared with or without coatings.
Compositions of the invention suitable for buccalor sublingual administration include, for example,lozenges comprising the cyclooxygenase-2 inhibitor in aflavored base, such as sucrose, and acacia ortragacanth, and pastilles comprising the cyclooxygenase-2 inhibitor in an inert base such as gelatin andglycerin or sucrose and acacia.
Liquid dosage forms for oral administration includepharmaceutically acceptable suspensions, syrups, andélixirs containing inert diluents commonly used in theart, such as water. Such compositions may alsocomprise, for example, wetting agents, emulsifying andsuspending agents, and sweetening, flavoring, andperfuming agents.
As indicated above, excipient-containingcompositions of the invention can be prepared by anysuitable method of pharmacy, which includes the step ofbringing into association the cyclooxygenase-2inhibitor, at least partially in nanoparticulate form,and the excipient(s). In general, such compositions areprepared by uniformly and intimately admixing thepartially or wholly nanoparticulate cyclooxygenase-2inhibitory compound (hereinafter sometimes referred toas the "nanoparticulate compound") with a liquid orfinely divided diluent, or both, and then, if necessaryor desired, encapsulating or shaping the product. Forexample, a tablet can be prepared by compressing or 113 3 1 -34- molding a powder or granules of the nanoparticulatecompound, together with one or more excipients.
Compressed tablets. can be prepared by compressing, in asuitable machine, a free-flowing composition, such as apowder or granules, comprising the nanoparticulatecompound optionally mixed with one or more bindingagent(s), lubricant(s}, inert diluent(s), wettingagent(s) and/or dispersing agent(s). Molded tablets canbe made by molding, in a suitable machine, thenanoparticulate compound moistened with an inert liquiddiluent.
As noted above, compositions of the présentinvention comprise a partially or wholly nanoparticulatesélective cyclooxygenase-2 inhibitory compound, illustratively celecoxib, in a therapeutically orprophylactically effective amount per dose unit incombination with one or more pharmaceutically acceptableexcipients appropriate for oral administration.Compositions of the présent invention preferablycomprise the nanoparticulate compound in a desiredamount admixed with one or more excipients selected fromthe group consisting of pharmaceutically acceptablediluents, disintegrants, binding agents, adhesives,wetting agents, lubricants, and anti-adherent agents.
In addition, the nanoparticles themselves can optionallycontain one or more matrix polymers and/or surfacemodifying agents as disclosed in several of the above-cited references. More preferably, such compositionsare tableted or encapsulated for convenientadministration in the form of immédiate release capsulesor tablets.
Through appropriate sélection and combination ofexcipients, compositions can be provided exhibitingimproved performance with respect to, among otherproperties, efficacy, bioavailability, clearance time. -35- 118 3 1 stability, compatibility of celecoxib and carriermaterials, safety, dissolution profile, disintegrationprofile and/or other pharmacokinetic, Chemical and/orphysical properties. The excipients preferably arewater-soluble or water dispersible and hâve wettingproperties to offset the low aqueous solubility andhydrophobieity of the cyclooxygenase-2 inhibitor. Wherethe composition is formulated as a tablet, thecombination of excipients selected provides tablets thatcan exhibit improvement, among other properties, indissolution and disintegration profiles, hardness,crushing strength, and/or friability.
Compositions of the invention optionally compriseone or more pharmaceutically acceptable diluents asexcipients. Suitable diluents include, eitherindividually or in combination, lactose USP; lactoseUSP, anhydrous; lactose USP, spray dried; starch USP;directly compressible starch; mannitol USP; sorbitol;dextrose monohydrate; microcrystalline cellulose NF;dibasic calcium phosphate dihydrate NF; sucrose-baseddiluents; confectioner's sugar; monobasic calciumsulfate monohydrate; calcium sulfate dihydrate NF;calcium lactate trihydrate granular NF; dextrates, NF(e.g., Emdex); Celutab; dextrose (e.g., Cerelose);inositol; hydrolyzed cereal solids such as the Maltronsand Mor-Rex; amylose; Rexcel; powdered cellulose (e.g.,Elcema); calcium carbonate; glycine; bentonite;polyvinylpyrrolidone; and the like. Such diluents, ifprésent, constitute in total about 5% to about 99%,preferably about 10% to about 85%, and more preferablyabout 20% to about 80%, of the total weight of thecomposition. The diluent or diluents selectedpreferably exhibit suitable flow properties and, wheretablets are desired, compressibility. -36- 1183 1
Lactose and microcrystalline cellulose, eitherindividually or in combination, are preferred diluents.Both diluents are chemically compatible with celecoxib.
The use of extragranular microcrystalline cellulose(that is, microcrystalline cellulose added to a wetgranulated composition after the drying step) can beused to improve hardness. (for tablets) and/or disintegration time. Lactose, especially lactose monohydrate, is particularly preferred. Lactose typicallv provides compositions having suitable releaserates of the cyclooxygenase-2 inhibitor, stabilitv, pre-compression flowability, and/or drying properties at arelatively low diluent cost. It provides a high densitysubstrate that aids densification during granulation(where wet granulation is employed) and thereforeimproves blend flow properties.
Compositions of the invention optionally compriseone or more pharmaceutically acceptable disintegrants asexcipients, particularly for tablet formulations.
Suitable disintegrants include, either individually orin combination, starches; sodium starch glycolate; clays(such as Veegum HV); celluloses (such as purifiedcellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose);alginates; pregelatinized corn starches (such asNational 1551 and National 1550); crospovidone USP NF;and gums (such as agar, guar, locust bean, Karaya,pectin, and tragacanth). Disintegrants may be added atanv suitable step during the préparation of thecomposition, particularly prior to granulation or duringthe lubrication step prior to compression. Suchdisintegrants, if présent, constitute in total about0.2% to about 30%, preferably about 0.2% to about 10%,and more preferably about 0.2% to about 5%, of the totalweight of the composition. 1183 1 -37-
Croscarmellose sodium is a preferred désintégrantfor tablet or capsule disintegration, and, if présent,preferably constitutes about 0.2% to about 10%, morepreferably about 0.2% to about 6%, and still morepreferably about 0.2% to about 5%, of the total weightof the composition. Croscarmellose sodium conferssuperior intragranular disintegration capabilities tocompositions of the présent invention.
Compositions of the invention optionally compriseone or more pharmaceutically acceptable binding agentsor adhesives as excipients, particularly for tabletformulations. Such binding agents and adhesivespreferably impart sufficient cohésion to the powderbeing tableted to allow for normal processing operationssuch as sizing, lubrication, compression and packaging,but still allow the tablet to disintegrate and thecomposition to be absorbed upon ingestion. Suitablebinding agents and adhesives include, either individually or in combination, acacia; tragacanth;sucrose; gelatin; glucose; starch; cellulose materialssuch as, but not limited to, methylcellulose and sodiumcarboxymethylcellulose (e.g., Tylose); alginic acid andsalts of alginic acid; magnésium aluminum silicate;polyethylene glycol; guar gum; polysaccharide acids;bentonites; polyvinylpyrrolidone; polymethacrylates;hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (Klucel) ; ethylcellulose(Ethocel); pregelatinized starch (such as National 1511and Starch 1500). Such binding agents and/or adhesives,if présent, constitute in total about 0.5% to about 25%,preferably about 0.75% to about 15%, and more preferablyabout 1% to about 10%, of the total weight of thecomposition.
Polyvinylpyrrolidone is a preferred binding agentused to impart cohesive properties to a powder blend of 418 3 1 -38- the cyclooxygenase-2 inhibitor and other excipients forgranulation. Polyvinylpyrrolidone, if présent,preferably constitutes about 0.5% to about 10%, morepreferably about 0.5% to about 7%, and still morepreferably about 0.5% to about 5% of the total weight ofthe composition. Polyvinylpyrrolidone viscosities up toabout 20 cPs may be used although viscosities of about 6cPs or lower are preferred, particularly about 3 cPs orlower. Polyvinylpyrrolidone provides cohesiveness tothe powder blend and facilitâtes the necessary bindingto form granules during wet granulation.
The cyclooxygenase-2 inhibitory compounds used inthe présent invention, in particular celecoxib, arelargely insoluble in aqueous solution. Accordingly,compositions of the invention optionally but preferablycomprise one or more pharmaceutically acceptable wettingagents as excipients. Such wetting agents arepreferably selected to maintain the cyclooxygenase-2inhibitor in close association with water, a conditionthat is believed to improve the relative bioavailabilityof the composition. Suitable wetting agents include,either individually or in combination, oleic acid;glyceryl monostearate; sorbitan monooleate; sorbitanmonolaurate; triethanolamine oleate; polyoxyethylenesorbitan monooleate; polyoxyethylene sorbitanmonolaurate; sodium oleate; and sodium lauryl sulfate.Wetting agents that are anionic surfactants arepreferred. Such wetting agents, if présent, constitutein total about 0.25% to about 15%, preferably about 0.4%to about 10%, and more preferably about 0.5% to about5%, of the total weight of the composition.
Sodium lauryl sulfate is a preferred wetting agent.Sodium lauryl sulfate, if présent, constitutes about0.25% to about 7%, more preferably about 0.4% to about
η 8 3 J -39- 6%, and still more preferably about 0.5 to about 5% ofthe total weight of the composition.
Compositions of the invention optionally compriseone or more pharmaceutically acceptable lubricantsand/or glidants as excipients. Suitable lubricantsand/or glidants include, either individually or incombination, glyceryl behapate (Compritol 888);stéarates (magnésium, calcium, and sodium); stearicacid; hydrogenated vegetable oils (e.cr. , Sterotex);talc; waxes; Stearowet; boric acid; sodium benzoate;sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g., Carbowax 4000 andCarbowax 6000); sodium oleate; sodium lauryl sulfate;and magnésium lauryl sulfate. Such lubricants, ifprésent, constitute in total about 0.1% to about 10%,preferably about 0.2% to about 8%, and more preferablyabout 0.25% to about 5%, of the total weight of thecomposition.
Magnésium stéarate is a preferred lubricant used,for example, to reduce friction between the equipmentand granulated mixture during compression of tabletformulations.
Other excipients (such as anti-adherent agents,colorants, flavors, sweeteners and préservâtives) areknown in the pharmaceutical art and can be included incompositions of the invention. For example, iron oxidecan be added to the composition to provide a yellowcolor.
In one embodiment of the présent invention, thecomposition is in the form of unit dose capsules ortablets and comprises a' partially or whollynanoparticulate sélective cyclooxygenase-2 inhibitor,illustratively celecoxib, in a desired amount togetherwith a binding agent. Such a composition preferably -40- 1 i 8 3 1 further comprises one or more excipients selected fromthe group consisting of pharmaceutically acceptablediluents, désintégrants, binding agents, wetting agentsand lubricants. More preferably, the compositioncomprises one or more excipients selected from the groupconsisting of lactose, sodium iauryl sulfate,polyvinylpyrrolidone, croscarmellose sodium, magnésiumstéarate and microcrystalline cellulose. Still morepreferably, the composition comprises lactosemonohydrate and croscarmellose sodium. Even morepreferably, the composition further comprises one ormore of the carrier materials sodium Iauryl sulfate,magnésium stéarate and microcrystalline cellulose.
Although unit dose capsule and tablet compositionsof the invention can be prepared, for example, by directencapsulation or direct compression, they preferably arewet granulated prior to encapsulation or compression.
Wet granulation, among other effects, densifies milledcompositions resulting in improved flow properties,improved compression characteristics and easier meteringor weight dispensing of the compositions for encapsulation or tableting. The secondary particle sizeresulting from granulation (i.e., granule size) is notnarrowly critical, it being important only that theaverage granule size preferably is such as to allow forconvenient handling and Processing and, for tablets, topermit the formation of a directly compressible mixturethat forms pharmaceutically acceptable tablets.
The desired tap and bulk densities of the granulesare normally about 0.3 g/ml to about 1.0 g/ml.
Excipients for capsule and tablet compositions ofthe invention preferably are selected to provide adisintegration time of less than about 30 minutes,preferably about 25 minutes or less, more preferably 118 3 1 -41- about 20 minutes or less, and still more preferablyabout 15 minutes or less.
For tablet formulations, the complété mixture in anamount sufficient to make a uniform batch of tablets issubjected to tableting in a conventional productionscale tableting machine at normal compression pressure(for example, applying a force of about 1 kN to about 50kN in a typical tableting die). Any tablet hardnessconvenient with respect to handling, manufacture,storage and ingestion may be employed. For 100 mgtablets, hardness is preferably at least 4 kP, morepreferably at least about 5 kP, and still more preferably at least about 6 kP. For 200 mg tablets,hardness is preferably at least 7 kP, more preferably atleast about 9 kP, and still more preferably at leastabout 11 kP. The mixture, however, is not to becompressed to such a degree that there is subséquent .difficulty in achieving hydration when exposed togastric fluid.
For tablet formulations, tablet friabilitypreferably is less than about 1.0%, more preferably lessthan 0.8%, and still more preferably less than about0.5% in a standard test.
The présent invention also is directed to atherapeutic method of treating a condition or disorderwhere treatment with a cyclooxygenase-2 inhibitor isindicated, the method comprising oral administration ofone or more dose units of a composition of the inventionto a subject in need thereof. The dosage regimen toprevent, give relief from, or ameliorate' the conditionor disorder preferably corresponds to the once-a-day ortwice-a-day treatments discussed above, but can bemodified in accordance with a variety of factors. Theseinclude the type, âge, weight, sex, diet, and medicalcondition of the subject and the nature and severity of 113 3 1 -42- the disorder. Thus, the dosage regimen actually employed can vary widely and can therefore deviate fromthe preferred dosage regimens set forth above.
Initial treatment of a subject suffering from acondition or disorder where treatment with acyclooxygenase-2 inhibitor is indicated can begin withthe dosages indicated above. Treatment is generallycontinued as necessary over a period of several weeks toseveral months or years until the condition or disorderhas been controlled or eliminated. Subjects undergoingtreatment with a composition of the invention can beroutinely monitored by any of the methods well known inthe art to détermine the effectiveness of therapy.Continuons analysis of such data permits modification ofthe treatment regimen during therapy so that optimallyeffective amounts of the cyclooxygenase-2 inhibitor areadministered at any point in time, and so that theduration of treatment can be determined as well. Inthis way, the treatment regimen/dosing schedule can berationally modified over the course of therapy so thatthe lowest amount of the cyclooxygenase-2 inhibitorexhibiting satisfactory effectiveness is administered,and so that administration is continued only so long asis necessary to successfully treat the condition ordisorder.
The présent invention also is directed to methodsfor the préparation of compositions comprising a poorlywater soluble sélective cyclooxygenase-2 inhibitor,illustratively celecoxib, partially or wholly innanoparticulate form in accordance with the invention.
More particularly, the invention is directed to methodsfor preparing such compositions in the form of discrèteunit dose tablets or capsules, such that each tablet orcapsule contains an amount of the cyclooxygenase-2inhibitor sufficient to provide rapid onset of 118 3 1 -43- therapeutic effect as described hereinabove, and preferably a continuing therapeutic effect for about 12to 24 hours. Each tablet or capsule preferably containsabout 50 mg to about 200 mg, for example about 50 mg,about 100 mg or about 200 mg, of the cyclooxygenase-2inhibitor, illustratively celecoxib. According to theprésent invention, wet granulation, dry granulation ordirect compression or encapsulation methods can beemployed to préparé tablet or capsule compositions ofthe invention.
Wet granulation is a preferred method of preparingpharmaceutical compositions of the présent invention.
Xn the wet granulation process, any portion of thecyclooxygenase-2 inhibitor that is not to be included innanoparticulate form (if desired, together with one ormore carrier materials) is initially milled ormicronized to a desired range of particle sizes greaterthan 1 mm. Although various conventional mills orgrinders can be used, impact milling such as pin millingof the drug provides improved blend uniformity to thefinal composition relative to other types of milling.
Cooling of the material being milled, for example, usingliquid nitrogen, may be necessary during milling toavoid heating the cyclooxygenase-2 inhibitor toundesirable températures. The D9o particle size duringthis milling step is preferably reduced to less thanabout 25 mm.
The milled or micronized cyclooxygenase-2inhibitor, if any, is then blended with the desiredamount of the cyclooxygenase-2 inhibitor innanoparticulate form, prepared by any process known inthe art as indicated hereinabove to provide a partiallyor wholly nanoparticulate cyclooxygenase-2 inhibitorycompound ("the nanoparticulate compound").
Simultaneously or thereafter, the nanoparticulate -44- 118 3 1 compound is blended, for example in a high shear mixer/granulator, planetary mixer, twin-shell blender orsigma mixer, with one or more excipients, includingexcipients that hâve been milled together with thecelecoxib or are présent in the nanoparticles, to form adry powder mixture. Typically, the nanoparticulatecompound is blended with one or more diluent(s),disintegrant(s) and/or binding agent(s) and, optionally,one or more wetting agent(s) in this step, butalternatively ail or a portion of one or more of theexcipients can be added in a later step. For example,in tablet formulations where croscarmellose sodium isemployed as a disintegrant, it has been discovered thataddition of a portion of the croscarmellose sodiumduring the blending step (providing intragranularcroscarmellose sodium) and addition of the remainingportion after the drying step discussed below (providingextragranular croscarmellose sodium) can improvedisintegration of the tablets produced. In thissituation, preferably about 60% to about 75% of thecroscarmellose sodium is added intragranularly and about25% to about 40% of the croscarmellose sodium is addedextragranularly. Similarly, for tablet formulations ithas been discovered that addition of microcrystallinecellulose after the drying step below (extragranularmicrocrystalline cellulose) can improve compressibilityof the granules and hardness of the tablets preparedfrom the granules.
This blending step of the process preferablycomprises blending of nanoparticulate compound, lactose,polyvinylpyrrolidone and croscarmellose sodium. It hasbeen discovered that blending times as short as threeminutes can provide a dry powder mixture having asufficiently uniform distribution of the cyclooxygenase-2 inhibitor. <119 3 1 -45-
Water, preferably purified water, is then added tothe dry powder mixture and the mixture is blended for anadditional period of time, to form a wet granulatedmixture. Preferably a wetting agent is used, and thisis preferably first added to the water and mixed for atleast 15 minutes, preferably at least 20 minutes, priorto adding the water to the dry powder mixture. Thewater can be added to the mixture at once, graduallyover a period of time, or in several portions over aperiod of time. The water preferably is added graduallyover a period of time. Alternatively, the wetting agentcan be added to the dry powder mixture and water thencan be added to the resulting mixture. An additional ·period of mixing after the water addition is complété ispreferred to ensure the uniform distribution of thewater in the mixture.
The wet granulated mixture preferably is then wetmilled, for example with a screening mill, to eliminatelarge agglomérations of material that form as a by-product of the wet granulation operation. If notremoved, these agglomérations would prolong thesubséquent fluidized bed drying operation and increasethe variation with respect to moisture control.
The wet granulated or wet milled mixture is thendried, for example, in an oven or a fluidized bed dryer,preferably a fluidized bed drier, to form dry granules.If desired, the wet granulated mixture can be extrudedor spheronized prior to drying. For the drying process,conditions such as inlet air température and drying timeare adjusted to achieve the desired moisture content forthe dry granules. It may be désirable to combine two ormore granulation sections for this drying step andsubséquent Processing steps.
To the extent necessary, the dry granules are thenreduced in size in préparation for compression or 118 3 1 -46- encapsulation. Conventional particle size réductioneguipment such as oscillators or impact mills (such asFitz mills) can be employed. A slight decrease in granule size has been observedas mixing time increases for mixtures containing lowerwater amounts. It is hypothesized that where the waterconcentration is too low to fully activate the bindingagent employed, the cohesive forces between the primaryparticles within the granules are insufficient tosurvive the shearing forces generated by the mixingblades and granule size attrition rather than growthoccurs. Conversely, increasing the amount of water tofully activate the binding agent allows cohesive forcesbetween the primary particles to survive the shearingforces generated by the mixing blades and granule growthrather than attrition occurs with increased mixing timeand/or water addition rate. Variation of the screensize of the wet mill tends to hâve a greater impact onthe granule size than variation of the feed rate and/ormill speed.
The dry granules are then placed in a suitableblender, such as a twin-shell blender, and optionally alubricant (such as magnésium stéarate) and any additional carrier materials are added (such as extragranular microcrystalline cellulose and/or extragranular croscarmellose sodium in certain tabletformulations) to form a final blended mixture. Wherethe diluents include microcrystalline cellulose, theaddition of a portion of the microcrystalline celluloseduring this step has been found to materially increasegranule compressibility and tablet hardness. However,increasing the amount of magnésium stéarate above about1% to about 2% tends to decrease tablet hardness andincrease friability and dissolution time. -47-
This final blended mixture is then encapsulated(or, if tablets are to be prepared, compressed intotablets of the desired weight and hardness usingappropriately sized tooling). Conventional compressionand encapsulation techniques known to those of ordinaryskill in the art can be employed. Suitable results areobtained for capsules by employing bed heights rangingfrom about 20 mm to about 60 mm, compaction settingsranging from about 0 to about 5 mm, and speeds fromabout 60,000 capsules per hour to about 130,000 capsulesper hour. Slug formation can be minimized or eliminatedby using the lowest compaction setting at which capsuleweight control can be maintained. Where coated tabletsare desired, conventional coating techniques known tothose of ordinary skill in the art can be employed.
This combination of unit operations producesgranules that are uniform in cyclooxygenase-2 inhibitor,illustratively celecoxib, content at the unit doselevel, that readily disintegrate, that flow withsufficient ease so that weight variation can be reliablycontrolled during capsule filling or tableting, and thatare dense enough in bulk so that the batch can beprocessed in the selected equipment and individual dosesfit into the specified capsules or tablet dies.
The présent invention also is directed to use ofcompositions of the invention in préparation ofmédicaments useful in the treatment and/or prophylaxisof cyclooxygenase-2 mediated conditions and disorders,in particular such conditions and disorders whererapid onset of therapeutic effect is desired orrequired.
The présent invention also embodies a novel solidState form of celecoxib, Form I celecoxib. The présentinvention further embodies another solid State form ofcelecoxib, Form II celecoxib. Each of these novel -48- 118 3 1 solid State forms includ.es solvated crystalline forms,non-solvated and non-hydrated crystalline forms.
These novel forms of celecoxib described in theprésent application possess one or more of the above- 5 descrihed advantageous Chemical and/or physical properties relative to the other solid state formsdescribed herein or otherwise disclosed in theliterature.
In one embodiment of the invention, the solid 10 state form comprises Form I celecoxib. Without limiting the invention, it is believed that Form Icelecoxib has higher solubility and a more rapid rateof dissolution than Form III, because Form III is morethermodynamically stable than Form I and because Form 15 III has a lower free energy than Form I. A rapid rateof dissolution is useful because increasing the rateof dissolution of a drug typically increases itsbioavailability.
Form I celecoxib is a crystalline form of 20 celecoxib having an X-ray powder diffraction patternwith peaks at about 5.5, 5.7, 7.2, and 16.6 degreestwo thêta. Form I celecoxib has an X-ray powderdiffraction pattern substantially as shown in the toptrace in Figure la. Form I celecoxib has a melting 25 point of about 162.5°C to about 163°C, preferablyabout 162.8°C. Form I celecoxib has a differentialscanning calorimetry endotherm maximum at about163.3°C when scanned at 0.5°C/min as Figure 3. Form Icelecoxib is characterized by the IR spectrum shown in 30 Figure 2, with a peak between about 3250 and 3260 cm'1,and another between 3350 and 3360 cm"1, preferably thepeaks are at about 3256 cm"1 and 3356 cm'1,
respectively. The solid form of the présent inventionhas a phase purity of at least about 5% Form I
35 celecoxib, preferably at least about 10% Form I 118 3 1 1 -49- celecoxib, more preferably at least about 25% Form Icelecoxib, still more preferably at least about 50%Form I celecoxib, yet more preferably at least about75% Form I celecoxib, more preferably still at leastabout 90%, and still more preferably having asubstantially phase pure form of Form I celecoxib.
In another embodiment of the invention, apharmaceutical composition is provided which comprisesa therapeutically-effective amount of a solid form ofcelecoxib and at least one pharmaceutically-acceptablecarrier, adjuvant or diluent, wherein the solid formof celecoxib comprises at least 2% Form I celecoxib,and preferably 10% Form I celecoxib, or more preferably 50% Form I celecoxib, and still morepreferably 98% Form I celecoxib. In one preferredembodiment, the solid form of celecoxib ispredominantly Form I celecoxib.
In yet another embodiment of the présentinvention, a method is described of treating orpreventing a cyclooxygenase-2-mediated condition ordisorder in a subject, the method comprisingadministering to a subject a therapeutically-ef f ectiveamount of Form I celecoxib. Preferably thecyclooxygenase-2-mediated condition or disorder to betreated or prevented is pain, inflammation, arthritis,tumor growth, metastasis, or familial adenomatouspolyposis.
Still another embodiment of the invention is amethod of preparing Form I celecoxib wherein themethod comprises crystallizing Form I celecoxib from amixture of celecoxib and a solvent, wherein thecrystallization is performed at a température abovethe enantiotropic transition température of Form Icelecoxib. Prior to the crystallization of Form Icelecoxib, the solvent may be seeded with a seed 119 3 1 -50- crystal of Form I celecoxib, resulting in the production of Form I celecoxib with at least about 5weight percent phase purity, preferably at least about10 weight percent phase purity, more preferably atleast about 25 weight percent phase purity, morepreferably at least about 50 weight percent phasepurity, and still more preferably at least about 90weight percent phase purity.
The présent invention is also directed to thepréparation of a crystalline form of celecoxib whereinthe method comprises heating a solvaté of celecoxibthereby producing Form I celecoxib. The solvaté canbe heated for example, to a température of about 50°Cto about 160°C, preferably to a température of about60°C to about 150°C, more preferably to a températureof about 70°C to about 140°C, still more preferably toa température of about 80°C to about 130°C, yet morepreferably to a température of about 85°C to about120°C, more preferably still to a température of about90°C to about 110°C, and more preferably to a
température of about 100°C. The heating can beperformed over any convenient period of time, forexample for more than about 1 minute, preferably formore than about 5 minutes, more preferably for morethan about 60 minutes, still more preferably for about2 hours and more preferably still for about 4 hours orlonger. Furthermore, this method may be performed atany pressure, preferably below atmospheric pressure.The solvaté used in the présent invention comprisescelecoxib and a solvent. For example, the solvent canbe an amide solvent. Useful amide solvents includeN,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 118 3 1 -51- preferred solvent is 1,1,3,3-tetramethylurea. Anotherpreferred solvent is l,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Still another preferred solventis l-methyl-2-pyrrolidinone. Still another preferredsolvent is N,N-dimethylformamide. Still anotherpreferred solvent is N,N-dimethylacetamide.
The solvaté can be prepared by a processcomprising mixing celecoxib with an amide solventselected front the group consisting of N,N-dimethylf ormamide, N,N-dimethylacetamide, l-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and 1,1,3,3-tetramethylurea, or anymixture 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.
Still another preferred solvent is l-methyl-2-pyrrolidinone. Still another preferred solvent is N,N-dimethylformamide. Still another preferred solventis N,N-dimethylacetamide.
The présent invention is also directed to amethod of producing Form I celecoxib wherein themethod comprises milling or grinding Form IIIcelecoxib. A useful milling step can include forexample, wet milling or bail milling. A usefulgrinding step can include for example, grinding orshaking.
The présent invention is also directed to amethod of producing Form I celecoxib wherein themethod comprises milling or grinding a celecoxibsolvaté. A useful milling step can include forexample, wet milling or bail milling. A usefulgrinding step can include for example, grinding orshaking.
Another embodiment of the présent invention is amethod of producing Form I celecoxib wherein the -52-
method comprises melting Form II celecoxib and coolingthe melt thereby producing Form I celecoxib.
Another embodiment of the présent invention is amethod of producing Form I celecoxib wherein themethod comprises melting Form III celecoxib andcooling the melt thereby producing Form I celecoxib.
The présent invention is also directed to amethod of producing Form I celecoxib wherein themethod comprises evaporating solvent from a celecoxibsolution. For example the solvent can be an ether ora hydrocarbon, or a mixture of an ether and ahydrocarbon. Preferably the solvent comprises ethylacetate and heptane, preferably at a ratio of 15:85.The présent method can be performed at any pressure,preferably below atmospheric pressure. The method canbe performed over a wide range of températures,preferably at about 35°C.
In another embodiment of the invention, the solidState form comprises Form II celecoxib. Withoutlimiting the invention, it is believed that Form IIcelecoxib has higher solubility and a more rapid rateof dissolution than Form III, because Form III is morethermodynamically stable than Form II and because FormIII has a lower free energy than Form II. A rapidrate of dissolution is useful because increasing therate of dissolution of a drug typically increases itsbioavailability.
Form II celecoxib has an X-ray powder diffractionpattern with a peaks at about 10.3, 13.8, 17.7 degreestwo thêta. A mixture of Form I and Form II has thepeaks as shown in the top trace in Figure lb. Form IIcelecoxib has a melting point of about 161°C to about162°C, preferably about 161.5°C. Form II celecoxibhas a differential scanning calorimetry endothermmaximum at about 162.0°C when scanned at 0.5°C/min. -53- 118 3 1
Form II celecoxib is expected to hâve higher solubility and more rapid dissolution than Form IIIcelecoxib. The solid form of the présent invention hasa phase purity of at least about 5% Form II celecoxib,preferably at least about 10% Form II celecoxib, morepreferably at least about 25% Form II celecoxib, stillmore preferably at least about 50% Form II celecoxib,yet more preferably at least about 75% Form IIcelecoxib, yet still more preferably at least about90%, and still more preferably having a substantiallyphase pure form of Form II celecoxib.
In another embodiment of the invention, apharmaceutical composition is provided which comprisesa therapeutically-effective amount of a solid form ofcelecoxib and at least one pharmaceutically-acceptablecarrier, adjuvant or diluent, wherein the solid formof celecoxib comprises at least 2% Form II celecoxib,and preferably 10% Form II celecoxib, or more preferably 50% Form II celecoxib, still more preferably 98% Form II celecoxib. In one preferredembodiment, the solid form of celecoxib ispredominantly Form II celecoxib.
In yet another embodiment of the présentinvention, a method is described of treating orpreventing a cyclooxygenase-2-mediated condition ordisorder in a subject, the method comprisingadministering to a subject a therapeutically-effectiveamount of Form II celecoxib. Preferably thecyclooxygenase-2-mediated condition or disorder to betreated or prevented is pain, inflammation, arthritis,tumor growth, metastasis, or familial adenomatouspolyposis.
Still another embodiment of the invention is amethod of preparing Form II celecoxib from a mixturecomprising celecoxib and a solvent wherein the 11 8 -54- crystallization is performed at a température abovethe enantiotropic transition température of Form IIcelecoxib thereby producing Form II celecoxib. Priorto the crystallization of Form II celecoxib, thesolvent may be seeded with a seed crystal of Form IIcelecoxib, resulting in the production of Form IIcelecoxib with at least about 5% weight percent phasepurity, preferably at least about 10% weight percentphase purity, and more preferably at least about 25%weight percent phase purity.
The présent invention is also directed to thepréparation of a crystalline form of celecoxib whereinthe method involves heating a solvaté of celecoxibthereby producing Form II celecoxib. The solvaté canbe heated for example, to a température of about 50°Cto about 160°C, preferably to a température of about6Q°C to about 145°C, more preferably to a températureof about 70°C to about 140°C, still more preferably toa température of about 80°C to about 140°C, yet morepreferably to a température of about 90°C to about140°C, yet more preferably to a température of about100°C to about 14Û°C, more preferably to a températureof about 110°C to about 14Q°C, more preferably still toa température of about 12 0°C to about 140°C, morepreferably to a température of about 125°C to about135°C, and more preferably still to a température ofabout 130°C. The heating can be performed over anyconvenient period of time, for example for more thanabout 1 minute, preferably for more than about 5minutes, preferably for more than about 60 minutes,still more preferably for about 2 hours and preferablyfor about 4 hours or longer. Furthermore, this methodmay be performed at any pressure, preferably belowatmospheric pressure. The solvaté used in the présentinvention comprises celecoxib and a solvent. For 118 3 1 -55- example, the solvent can be an amide solvent. Usefulamide solvents include Ν,Ν-dimethylformamide, N,N-dimethylacetamide, l-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and 1,1,3,3-tetramethylurea, or any mixture of thesesolvents. A preferred solvent is 1,1,3,3- tetramethylurea. Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Stillanother preferred solvent is l-methyl-2-pyrrolidinone.Still another preferred solvent is Ν,Ν- dimethylformamide. Still another preferred solvent isN,N-dimethylacetamide.
In another embodiment of the présent invention,wherein Form II celecoxib is prepared by heating asolvaté of celecoxib to produce Form II celecoxib, thesolvaté is prepared by a process comprising mixingcelecoxib with an amide solvent selected from a groupconsisting of Ν,Ν-dimethylformamide, N,N- dimethylacetamide, l-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 ( 1H) -pyrimidinone, and 1,1,3,3-tetramethylurea, or any mixture of thesesolvents, preferably 1,1,3,3-tetramethylurea, morepreferably 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H) -pyrimidinone, still more preferably l-methyl-2-pyrrolidinone, yet more preferably Ν,Ν- dimethylformamide, and preferably, N,N- dimethylacetamide.
Another embodiment of the présent invention is asolid form of celecoxib comprised of Form I celecoxiband Form II celecoxib.
Still another embodiment of the présent inventionis a solid form of celecoxib comprising Form Icelecoxib and Form III celecoxib. 113 3 1 -56-
Yet another embodiment of the présent inventionis a solid form of celecoxib comprising Form IIcelecoxib and Form III celecoxib.
Still yet another embodiment of the présentinvention is a solid form of celecoxib comprising FormI celecoxib, Form II celecoxib and Form III celecoxib.
The présent invention is also directed to amethod of producing Form II celecoxib wherein themethod comprises milling or grinding Form IIIcelecoxib. A useful milling step can include forexample, wet milling or bail milling. A usefulgrinding step can include for example, grinding orshaking.
The présent invention is also directed to amethod of producing Form I celecoxib wherein themethod comprises milling or grinding a celecoxibsolvaté. A useful milling step can include forexample, wet milling or bail milling. A usefulgrinding step can include for example, grinding orshaking.
Another embodiment of the présent invention is amethod of producing Form II celecoxib wherein themethod comprises melting Form I celecoxib and coolingthe melt thereby producing Form II celecoxib.
Another embodiment of the présent invention is amethod of producing Form II celecoxib wherein themethod comprises melting Form III celecoxib andcooling the melt thereby producing Form II celecoxib.
Form III celecoxib is produced bycrystallization of celecoxib from a solvent comprisingisopropanol and water (see for example U.S. 5,910,597) .
Form III celecoxib has a complex differential -57- 118 3 1 scanning calorimetry melting transition. When scannedat û.5°C/min, the melting of Form III celecoxib isobserved at about 160.8°C followed by recrystallizationto Form II celecoxib and subséquent melting of Form IIat about 162.0°C. Form III celecoxib is thethermodynamically stable form of celecoxib.
Characterization o£ Polymorphie Crystalline Forma of
Celecoxib X-Ray Powder Diffraction (PXRD) , InfraredAbsorption Spectroscopy (IR), and Differential ScanningCalorimetry (DSC), as well as Raman Spectroscopy were used to characterize Forms I and Forms II. X-Ray Powder Diffraction (PXRD)
The various crystalline forms of celecoxib can beanalyzed with either a Siemens D5000 PowderDiffractometer or an Inel Multipurpose Diffractometer.For the Siemens D5000 Powder Diffractometer, the rawdata can be measured for 2-theta values from 2° to 50°,with steps of 0.02° and step periods of two seconds.
For the Inel Multipurpose Diffractometer, samples wereplaced in an aluminum sample holder and raw data wascollected for 30 minutes at ail two thêta valuessimultaneously.
As illustrated in Figure 1, the three forms wereeasily distinguishable by PXRD. Using a Cu x-ray source(1.54 nm), the characteristic diffractions were observedat 2-theta values of about 5.5°, 5.7°, 7.2° and 16.6° forForm I celecoxib and about 10.3°, 13.8° and 17.7° forForm II celecoxib.
Ici 8 3 1 -58-
Melting/Décomposition Température
The températures of melting and/or décomposition of 5 non-solvated celecoxib crystalline forma wers determinedusing a TA Instruments 2920 differential scanningcalorimeter. Each sample (1-2 mg) was placed in eithera sealed or unsealed aluminum pan and heated at0.5°C/minute. Melting/decomposition ranges were defined iO from the extrapolated onset to the maximum of themelting/decomposition endotherm.
Three polymorphie forms of celecoxib hâve beenidentified. Polymorphie Form I celecoxib melted atabout 162.8 °C; Form II celecoxib melted at about 161.5 15 °C; and Form III celecoxib melted at about 160.8 °C. On melting, Form III celecoxib has been observed topartially recrystallize to Form II celecoxib or Form Icelecoxib.
Three polymorphie forms and solvatés of 20 N,N-dimethylacetamide (DMA) and Ν,Ν-dimethylformamide(DMF) were identified. The physical properties anddistinguishing characteristics of the novel polymorphsare shown in Table 1. 25 Table 1.
Form MeltingPoint <°C) ΔΗ (J/g) Distinguishing Transitions* IR Raman PXRD (2 thêta) I 162.8 72 3 256 cm’1 3356 cm"1 NA 5.5°, 5.7°, 7.2°and 16.6° II** 161.5 <84 none 712 cm*1 10.3°, 13.8° and17.7° III 160.8 91 — — — * Characteristic transitions not observed for other forms. ** Pure samples of Form II celecoxib hâve not been produced. 1183 1 -59-
Differential Scanning Calorimetry (DSC) DSC is used to characterize the polymorphie forms of celecoxib. Form I celecoxib is the highest meltingpolymorph at 162.8 °C with an endotherm maximum at 163.3°C. Form II celecoxib melts at 161.5 °C and has anendotherm maximum at 162.0 °C. A complex transition isobserved for Form III celecoxib. The complexity of thistransition, which is only observed at slow scan rates,represents melting of Form III celecoxib, followed byrecrystallization to Form II celecoxib and subséquentmelting of Form II celecoxib. Considering only theinitial endothermie transition, Form III celecoxib meltsat 160.8 °C and has an endotherm maximum at 161.5 °C. DSC detects low levels of Form I celecoxib in Form IIIcelecoxib.
Infrared Absorption Spectroscopy IR distinguished Form I celecoxib from Form IIcelecoxib and Form III celecoxib, (see Figure 2) .
Without further élaboration, it is believed thatone skilled in the art can, using the precedingdescription, utilize the présent invention to itsfullest extent. The following preferred spécifieembodiments are, therefore, to be construed as merelyillustrative, and not limitative of the remainder ofthe disclosure in any way whatsoever.
Examples
The following examples contain detaileddescriptions of the methods of préparation ofcrystalline Form I and Form II celecoxib described inthis application. These detailed descriptions fallwithin the scope, and serve to exemplify the invention. 113 3 1 -60-
These detailed descriptions are presented for illustrative purposes only and are not intended as arestriction on the scope of the invention. Ail partsare by weight and températures are in degrees Centigradeunless otherwise indicated. The celecoxib startingmaterial used in each of the followirig examples wasprepared in accordance with U.S. 5910597.
Préparative Examplea:
Example 1: Préparation of a DMA Solvaté of Celecoxib (aratio of 1:1 celecoxib-DMA)
Method A. In a round bottom flask, 4.84 g ofcelecoxib were combined with approximately 125 mL ofDMA. The solvent was removed at reduced pressure and at60 °C to induce crystallization. The dry solids werecollected on a filter. This process produced 5g of 1:1solvaté. As determined by TGA at 10 °C/min, décomposition began at about 100 °C with a maximum atabout 148 °C, and a total weight loss of 17%.
Method B. In a 1 L beaker, 38.2 g of celecoxib wasplaced in approximately 1000 mL of DMA with stirring.
The resulting solution was transferred to a 2 L beaker.Approximately 400 mL of water was added to causecrystallization. The crystals were isolated byfiltration. The wet yield was 5.44 g. Additionalcrystal crops were generated by the addition of water tothe filtrate. TGA at 10 °C/min showed décompositionbeginning at about 100 °C with maximum at about 150 °C,and with a total weight loss of 18% solvent. -61- 118 3 1
Example 2: Préparation of a DMF Solvaté of Celecoxib (aratio of 1:1 celecoxib-DMF)
In a crystallizing dish, about 1 g of celecoxib wasdissolved in 50 mL of DMF. The crystallizing dish,covered with aluminum foil, which was perforated withsmall holes, was placed in a hood and allowed toevaporate to dryness. This process produced about 1.02g. TGA at 10 °C/min showed two weight losses duringdécomposition which began at about 75 °C and continuedwith a second maximum at about 156 °C. Total weightloss was 13.4%.
Working Examples:
Example 1: General Methods for Preparing Celecoxib.Form I A. Préparation of Celecoxib Form Z by Heating a
Celecoxib Solvaté:
An open container of a celecoxib solvaté was heatedin an oven at the lowest température at whichdesolvation was observed. Briefly, 0.3 g of celecoxib-DMA was heated in an oven at about 100°C for about 48hours. The PXRD of the resulting sample showedcharacteristic reflections due to celecoxib Form Icelecoxib as well as reflections of celecoxib-DMA; TGAshowed a 9.6% weight loss centered at about 147 °C,indicating about 50% conversion to Form I. B. Préparation of Celecoxib Form I by Evaporation: A high purity sample of celecoxib was crystallizedfrom ethyl acetate-heptane solvent by évaporation. -62-
Celecoxib 16.03 g) was purified by préparative liquidchromatography using 15/85 (v/v)ethyl acetate/heptaneand a 150 mm column (50.8 mm id) of 40-63 mon silicagel. The fractions eluded between 270 mL and 900 mLwere collected and combined. The solvent was removed atabout 35 °C under vacuum to induce crystallization andevaporated to dryness. This process produced 8.6gcelecoxib Form I. Crystallizes were free of solvent, asdetermined by TGA, and had the Form I PXRD pattern shownin Figure la. C. Préparation of Celecoxib Form I by Melting:
In general, celecoxib was placed in an open containerand was melted and then allowed to cool. In more'detail, a beaker containing celecoxib was heated on ahot plate to 170°C and the celecoxib was allowed tofully melt. Molten celecoxib was then poured on to awatch glass and allowed to cool. By DSC, scanned at0.5°C/min, the melt of Form I was observed at about163°C. The melt of Form III, and the recrystallizationto Form II, and the melt of Form II, were also observed.
Example 2: General Methods for Preparing CelecoxibForm II A. Préparation of Celecoxib Form II by Heating aCelecoxib Solvatés 1. Use of a DMA solvaté.
In general, an open container of a celecoxib-DMAsolvaté was heated in an oven near the peak températureat which desolvation was observed. Briefly, in an ovenat about 13 0 °C, 0.3 g of celecoxib-DMA was heated forapproximately 48 hours. The PXRD of the resulting 118 3 1 -63- sample showed characteristic reflections due to celecoxib Form II as well as reflections of celecoxibForm III; DSC at 0.5 °C/min showed a single meltingendotherm with onset at 161.4 °C and maximum at161.9 °C; TGA showed no weight loss below 200 °C. Thepowder x-ray diffraction pattern of the mixture wasshown in Figure lb. 2. Use of a DMF solvaté.
In general, an open container of a celecoxib-DMFsolvaté was heated in an oven near the peak températureat which desolvation was observed. Briefly, in an ovenat about 13 0 °C, approximately 0.2 g of celecoxib-DMFwas heated overnight. The PXRD of the resulting sampleshowed characteristic reflections due to celecoxibForm II as well as reflections of celecoxib Form III; DSC at 0.5 °C/min showed a one melting endotherm withonset at 161.5 °C and maximum at 161.8 °C and a smallendothermie transition with maximum at about 163.8 °C(Form I); TGA showed no weight loss below 200 °C. B. Préparation of Celecoxib Form II from Celecoxib FormIII, by Mechanical Conversion.
In general, celecoxib Form III was ground in a bailmill. Briefly, using a wiggle-bug, celecoxib Form IIIwas ground at a maximum intensity for 3 0 seconds. Theresulting solids were a mixture of Form III and Form IIwas determined by powder x-ray diffraction. C. Préparation of Celecoxib Form II by Melting
Celecoxib was melted in a test tube at 170 °C usingan oil bath. A Teflon spatula was dipped into themolten celecoxib, the spatula was removed, scraped, and -64- 1T8 3 1 the dried solids from the spatula were collected. Thedried solids were a mixture of Form II and Form III asdetermined by powder x-ray. DSC at 10°C/min also showedthe presence of Form I. 5

Claims (173)

  1. -65- 118 3 1 WHAT XS CLAIMED XS:
    1. A Form I crystalline form of celecoxib.
  2. 2. The crystalline form of Claim 1 having an X-ray powder diffraction pattern with peaks at about5.5, 5.7, 7.2, or 16.6 degrees two thêta.
  3. 3. The crystalline form of Claim 1 having an X-ray powder diffraction pattern substantially as shown.in the top trace in Figure la.
  4. 4. The crystalline form of Claim 1 having amelting range from about 160°C to about 164°C.
  5. 5. The crystalline form of Claim 1 having amelting range from about 162°C to about 163°C.
  6. 6. The crystalline form of Claim 5 having amelting point of about 162.8°C.
  7. 7. The crystalline form of Claim 5 having adifferential scanning calorimetry endotherm maximumfrom about 160.0°C to about 164.0°C.
  8. 8. The crystalline form of Claim 5 having anendotherm maximum at about 163.3°C.
  9. 9. The crystalline form of Claim 8 further havinga melting range from about 160°C to about 164°C.
  10. 10. The crystalline form of Claim 9 having amelting point of about 162.8°C. 118 3 1 -66-
  11. 11. The crystalline form of Claim 1 having anInfrared Spectrum which has a peak at about 3250 toabout 32 60 cm'1.
  12. 12. The crystalline form of Claim 11 having anInfrared Spectrum which has a peak at about 3256 cm*1.
  13. 13. The crystalline form of Claim 1 having anInfrared Spectrum which has a peak at about 3350 toabout 33 60 cm'1.
  14. 14. The crystalline form of Claim 13 having anInfrared Spectrum which has a peak at about 3356 cm'1.
  15. 15. The crystalline form of Claim 1 having anInfrared Spectrum which has peaks at about 3256 cm'1and about 3356 cm'1, and having a melting point ofabout 162.8°C.
  16. 16. The crystalline form of Claim 1 having aphase purity of at least about 5% Form I celecoxib.
  17. 17. The crystalline form of Claim 1 having aphase purity of at least about 10% Form I celecoxib.
  18. 18. The crystalline form of Claim 1 having aphase purity of at least about 25% Form I celecoxib.
  19. 19. The crystalline form of Claim 1 having aphase purity of at least about 50% Form I celecoxib.
  20. 20. The crystalline form of Claim 1 having aphase purity of at least about 75% Form I celecoxib. 118 3 1 -67-
  21. 21. The crystalline form of Claim 1 having a phasepurity of at least about 90% Form I celecoxib.
  22. 22. The crystalline form of Claim 1 having asubstantially phase pure form of Form I celecoxib.
  23. 23. A pharmaceutical composition comprising atherapeutically-effective amount of the crystallineform of any oneof Claims 2 to22 and atleastonepharmaceutically-acceptable carrier, adjuvant ordiluent.
  24. 24. The composition of Claim 23 wherein thecelecoxib comprises at least 2% Form I celecoxib.
  25. 25. The composition of Claim 23 wherein thecelecoxib comprises at least 10% Form I celecoxib.
  26. 26. The composition of Claim 23 wherein thecelecoxib comprises at least 50% Form I celecoxib.
  27. 27. The composition of Claim 23 wherein thecelecoxib comprises at least 98% Form I celecoxib.
  28. 28. The composition of Claim 23 wherein thecelecoxib is predominantly Form I celecoxib.
  29. 29. Use of Form I celecoxib, in the manufacture of a médicament for thetreatment or prévention of a cyclooxygenase-2-mediated condition or disorder in asubject.
  30. 30. Use according to Claim 29 wherein the condition or disorder is pain. -68- tel 8 3 1 31. · Use according to Claim 29 wherein the condition or disorder isinflammation.
  31. 32. Use according to Claim 29 wherein the condition or disorder isarthritis.
  32. 33. Use according to Claim 29 wherein the condition or disorder is tumor growth.
  33. 34. Use according to Claim 29 wherein the condition or disorder ismetastasis.
  34. 35. Use according to Claim 29 wherein the condition or disorder is familialadenomatous polyposis.
  35. 36. A method of preparing Form I celecoxibcomprising crystallizing celecoxib from a mixturecomprising celecoxib and a solvent, wherein thecrystalli'zation is performed at a température abovethe enantiotropic transition température of Form Icelecoxib thereby producing Form I celecoxib.
  36. 37. The method of Claim 36 further comprisingseeding the solvent with a seed crystal of Form Icelecoxib prior to the crystallization.
  37. 38. The method of Claim 36 wherein the Form Icelecoxib thereby produced has at least about 5 weightpercent phase purity.
  38. 39. The method of Claim 36 wherein the Form Icelecoxib thereby produced has at least about 10weight percent phase purity. -69- 14*8 3 1
  39. 40. The method of Claim 36 wherein the Form Icelecoxib thereby produced has at least about 50weight percent phase purity.
  40. 41. The method of Claim 36 wherein the Form Icelecoxib thereby produced has at least about 90weight percent phase purity.
  41. 42. The method of Claim 36 wherein the Form Icelecoxib thereby produced has at least about 25weight percent phase purity.
  42. 43. A method of preparing a crystalline form ofcelecoxib wherein the method comprises heating asolvaté of celecoxib thereby producing Form Icelecoxib.
  43. 44. The method of Claim 43 in which the solvatéis heated to a température of about 50°C to about160°C.
  44. 45. The method of Claim 43 in which the solvatéis heated to a température of about 60°C to about150°C.
  45. 46. The method of Claim 43 in which the solvatéis heated to a température of about 70°C to about140°C.
  46. 47. The method of Claim 43 in which the solvatéis heated to a température of about 80°C to about130°C. 1Ί 3 3 i -70-
  47. 48. The method of Claim 43 in which the solvatéis heated to a température of about 85°C to about120°C.
  48. 49. The method of Claim 43 in which the solvatéis heated to a température of about 90°C to about110°C.
  49. 50. The method of Claim 43 in which the solvatéis heated to a température of about 100°C.
  50. 51. The method of Claim 43 wherein the solvaté isheated for more than about 1 minute.
  51. 52. The method of Claim 43 wherein the solvaté isheated for more than about 5 minutes.
  52. 53. The method of Claim 43 wherein the solvaté isheated for more than about 60 minutes.
  53. 54. The method of Claim 43 wherein the solvaté isheated for more than about 2 hours.
  54. 55. The method of Claim 43 wherein the solvaté isheated for about 4 hours or longer.
  55. 56. The method of any one of Claims 43-55 whereinthe heating is performed below atmospheric pressure.
  56. 57. The method of Claim 56 wherein the solvaté ofcelecoxib comprises celecoxib and an amide solvent.
  57. 58. The method of Claim 57 wherein the amidesolvent is selected from the group consisting of N,N-dimethylf ormamide, N, N-dimethy lacet amide, l-methyl-2- 118 3 1 -71- pyrrolidinone, 1,3-dimethyl-3,4,5, 6-tetrahydro-2(1H)-pyrimidinone and 1,1,3,3-tetramethylurea.
  58. 59. The method of Claim 58, wherein the amidesolvent is Ν,Ν-dimethylformamide.
  59. 60. The method of Claim 58, wherein the amidesolvent is N,N-dimethylacetamide.
  60. 61. The method of Claim 58, wherein the amidesolvent is l-methyl-2-pyrrolidinone.
  61. 62. The method of Claim 58, wherein the amidesolvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
  62. 63. The method of Claim 58, wherein the amidesolvent is 1,1,3,3-tetramethylurea.
  63. 64. The method of Claim 58 wherein the solvaté ofcelecoxib is prepared by a process comprising mixingcelecoxib with an amide solvent selected from a groupconsisting of Ν,Ν-dimethylformamide, N,N- dimethylacetamide, l-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and1,1,3,3-tetramethylurea.
  64. 65. The method according to Claim 64 wherein theamide solvent is Ν,Ν-dimethylformamide.
  65. 66. The method according to Claim 64 wherein theamide solvent is, N,N-dimethylacetamide.
  66. 67. The method according to Claim 64 wherein theamide solvent is l-methyl-2-pyrrolidinone. 113 3 1 -72-
  67. 68. The method according to Claim 64 wherein theamide solvent is 1,3-dimethyl-3,4,5,6-tetrahydro- 2(1H)-pyrimidinone.
  68. 69. The method according to Claim 64 wherein theamide solvent is 1,1,3, 3-tetramethylurea.
  69. 70. A method of producing Form I celecoxibwherein the method comprises milling or grinding FormIII celecoxib thereby producing Form I celecoxib.
  70. 71. The method of Claim 70 comprising millingForm III celecoxib.
  71. 72. The method of Claim 71 wherein the milling iswet milling.
  72. 73. The method of Claim 71 wherein the milling isbail milling.
  73. 74. The method of Claim 70 comprising grindingForm III celecoxib.
  74. 75. The method of Claim 74 wherein the grindingis performed by shaking.
  75. 76. A method of producing Form I celecoxibwherein the method comprises milling or grinding acelecoxib solvaté thereby producing Form I celecoxib.
  76. 77. The method of Claim 76 comprising milling acelecoxib solvaté. -73- 118 3 1
  77. 78. The method of Claim 77 wherein the milling iswet milling.
  78. 79. The method of Claim 77 wherein the milling isbail milling.
  79. 80. The method of Claim 76 comprising grinding acelecoxib solvaté.
  80. 81. The method of Claim 80 wherein the grindingis performed by shaking.
  81. 82. A method of producing Form I celecoxibwherein the method comprises melting Form II celecoxiband cooling the melt thereby producing Form I celecoxib.
  82. 83. A method of producing Form I celecoxib•wherein the method comprises melting Form IIIcelecoxib and cooling the melt thereby producing FormI celecoxib.
  83. 84. A method of producing Form I celecoxibwherein the method comprises evaporating solvent froma celecoxib solution thereby producing Form Icelecoxib.
  84. 85. The method of Claim 84 wherein the solvent isselected from the group consisting of an ether and ahydrocarbon.
  85. 86. The method of Claim 84 wherein the solventcomprises an ether and a hydrocarbon. 11-3 3 1 -74-
  86. 87 . The method of Claim 86 wherein the solventcomprises ethyl acetate and heptane.
  87. 88. The method of Claim 87 wherein the ethylacetate and the heptane are at a ratio of about 15:85.
  88. 89. The method of Claim 84 wherein theévaporation is performed below atmospheric pressure.
  89. 90. The method of Claim 84 wherein theévaporation is performed at a température of about35°C.
  90. 91. A Form II crystalline form of celecoxib.
  91. 92 . The crystalline form of Claim 91 having an X-ray powder diffraction pattern with a peak at about10.3, 13.8 or 17.7 degrees two thêta.
  92. 93. The crystalline form of Claim 91 having an X-ray powder diffraction pattern substantially as shownin Figure la.
  93. 94. The crystallinemelting range from about
  94. 95. The crystallinemelting range from about
  95. 96. The crystallinemelting point of about 1 form of Claim 91 having a159°C to about 164°C. form of Claim 91 having a161°C to about 163°C. form of Claim 95 having a1.5°C.
  96. 97. The crystalline form of Claim 95 having adifferential scanning calorimetry endotherm maximumfrom about 160.0°C to about 164.0°C. Π 8 3 1 -75-
  97. 98. The crystalline form of Claim 95 having adifferential scanning calorimetry endotherm maximum atabout 162.0°C.
  98. 99. The crystalline form of Claim 98 furtherhaving a melting range from about 160°C to about163°Ç.
  99. 100. The crystalline form of Claim 99 having amelting point of about 161.5°C.
  100. 101. The crystalline form of Claim 91 having aphase purity of at least about 5% Form II celecoxib.
  101. 102. The crystalline form of Claim 91 having aphase purity of at least about 10% Form II celecoxib.
  102. 103. The crystalline form of Claim 91 having aphase purity of at least about 25% Form II celecoxib.
  103. 104. The crystalline form of Claim 91 having aphase purity of at least about 50% Form II celecoxib.
  104. 105. The crystalline form of Claim 91 having aphase purity of at least about 75% Form II celecoxib.
  105. 106. The crystalline form of Claim 91 having aphase purity of at least about 90% Form II celecoxib.
  106. 107. The crystalline form of Claim 91 having asubstantially phase pure form of Form II celecoxib.
  107. 108. A pharmaceutical composition comprising atherapeutically-effective amount of the crystalline -76- 11.8 3 1 form of any one of Claims 91 to 107 and at least onepharmaceutically-acceptable carrier, adjuvant ordiluent.
  108. 109. The composition of Claim 108 wherein thecelecoxib comprises at least 2% Form II celecoxib.
  109. 110. The composition of Claim 108 wherein thecelecoxib comprises at least 10% Form II.
  110. 111. . The composition of Claim 108 wherein thecelecoxib comprises at least 50% Form II.
  111. 112. The composition of Claim 108 wherein thecelecoxib comprises at least 98% Form II.
  112. 113. The composition of Claim 108 wherein thecelecoxib is predominantly Form II celecoxib.
  113. 114. Use of Form Π celecoxib, in the manufacture of a médicament fortreating or preventing a cyclooxygenase-2-mediated condition or disorder in a subject.
  114. 115. Use according to Claim 114 wherein the condition or disorder is pain.
  115. 116. Use according to Claim 114 wherein the condition or disorder isinflammation.
  116. 117. Use according to Claim 114 wherein the condition or disorder is arthritis. 1183 1 -77-
  117. 118. Use according to Claim 114 wherein the condition or disorder is tum growth. 199 Use according to Claim 114 wherein the condition or disordermetastasis.
  118. 120. Use according to Claim 114 wherein the condition or disorderfamilial adenomatous polyposis.
  119. 121. A method of preparing Form II celecoxibcomprising crystallizing celecoxib from a mixturecomprising celecoxib and a solvent, wherein thecrystallization is performed at a température abovethe enantiotropic transition température of Form IIcelecoxib thereby producing Form II celecoxib.
  120. 122. The method of Claim 121 further comprisingseeding the solvent with a seed crystal of Form II-celecoxib prior to the crystallization.
  121. 123. The method of Claim 121 wherein the Form IIcelecoxib thereby produced has at least about 5 weightpercent phase purity.
  122. 124. The method' of Claim 121 wherein the Form IIcelecoxib thereby produced has at least about 10weight percent phase purity.
  123. 125. The method of Claim 121 wherein the Form IIcelecoxib thereby produced has at least about 25weight percent phase purity. -78- 1**1 3 3 Ί
  124. 126. The method of Claim 36 wherein the Form IIcelecoxib thereby produced has at least about 50weight percent phase purity.
  125. 127. The method of Claim 36 wherein the Form IIcelecoxib thereby produced has at least about 90weight percent phase purity.
  126. 128. A method of preparing a crystalline form ofcelecoxib wherein the method comprises heating acelecoxib solvaté thereby producing Form II celecoxib.
  127. 129. The method of Claim 128 in which the solvatéis heated to a température from about 50°C to about160°C.
  128. 130. The method of Claim 128 in which the solvatéis heated to a température from about 60°C to about145°C.
  129. 131. The method of Claim 128 in which the solvatéis heated to a température from about 70°C to about140°C.
  130. 132. The method of Claim 128 in which the solvatéis heated to a température from about 80°C to about140°C.
  131. 133. The method of Claim 128 in which the solvatéis heated to a température from about 90°C to about140°C.
  132. 134. The method of Claim 128 in which the solvatéis heated to a température from about 100°C to about 140°C. -79- 118 3 1
  133. 135. The method of Claim 128 in which the solvatéis heated to a température from about 110°C to about140°C.
  134. 136. The method of Claim 128 in which the solvatéis heated to a température from about 120°C to about140°C.
  135. 137. The method of Claim 128 in which the solvatéis heated to a température from about 125°C to about135°C.
  136. 138. The method of Claim 128 in which the solvatéis heated to a température of about 130°C.
  137. 139. The method of Claim 128 wherein the solvatéis heated for more than about 1 minute.
  138. 140. The method of Claim 128 wherein the solvatéis heated for more than about 5 minutes.
  139. 141. The method of Claim 128 wherein the solvatéis heated for more than about 60 minutes.
  140. 142. The method of Claim 128 wherein the solvatéis heated for more than about 2 hours.
  141. 143. The method of Claim 128 wherein the solvatéis heated for about 4 hours or longer.
  142. 144. The method of any one of Claims 128-143wherein the heating is performed below atmosphericpressure. 118 3 1 -80-
  143. 145. The method of Claim 128 wherein thecelecoxib solvaté comprises celecoxib and an amidesolvent.
  144. 146. The method of Claim 145 wherein the amidesolvent is selected from the group consisting of Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, l-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and-1,1,3,3 -tetramethylurea.
  145. 147. The method of Claim 146, wherein the amidesolvent is Ν,Ν-dimethylformamide.
  146. 148. The method of Claim 146, wherein the amidesolvent is Ν,Ν-dimethylacetamide.
  147. 149. The method of Claim 146, wherein the amidesolvent is l-methyl-2-pyrrolidinone.
  148. 150. The method of Claim 146, wherein the amidesolvent is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H) -pyrimidinone.
  149. 151. The method of Claim 146, wherein the solventis 1,1,3,3-tetramethylurea.
  150. 152. The method of Claim 145 wherein thecelecoxib solvaté is prepared by a process comprisingmixing celecoxib with an amide solvent selected from agroup consisting of Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, l-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and1,1,3,3-tetramethylurea. -81- 118 3 1
  151. 153. The method according to Claim 152 whereinthe amide solvent is Ν,Ν-dimethylformamide.
  152. 154. The method according to Claim 152 whereinthe amide solvent is N,N-dimethylacetamide.
  153. 155 . The method according to Claim 152 whereinthe amide solvent is l-methyl-2-pyrrolidinone.
  154. 156. The method according to Claim 152 whereinthe amide solvent is, 1, 3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
  155. 157. The method according to Claim 152 whereinthe solvent is 1,1,3,3-tetramethylurea.
  156. 158. A solid form of celecoxib comprising FormI celecoxib and Form II celecoxib.
  157. 159. A solid form of celecoxib comprising Form I celecoxib and Form III celecoxib.
  158. 160. A solid form of celecoxib comprising Form II celecoxib and Form III celecoxib.
  159. 161. A solid form of celecoxib comprising FormI celecoxib, Form II celecoxib, and Form IIIcelecoxib.
  160. 162. A method of producing Form II celecoxibwherein the method comprises milling or grinding Form III celecoxib thereby producing Form II celecoxib.
  161. 163. The method of Claim 162 comprising millingForm III celecoxib. -82- 11 8 3 1
  162. 164. The method of Claim 163 wherein the millingis wet milling.
  163. 165. The method of Claim 163 wherein the millingis bail milling.
  164. 166. The method of Claim 162 comprising grindingForm III celecoxib.
  165. 167. The method of Claim 166 wherein grinding is-performed by shaking.
  166. 168. A method of producing Form II celecoxibwherein the method comprises milling or grinding acelecoxib solvaté thereby producing Form II celecoxib.
  167. 169. The method of Claim 168 comprising milling acelecoxib solvaté.
  168. 170. The method of Claim 169 wherein milling iswet milling.
  169. 171. The method of Claim 169 wherein milling isbail milling.
  170. 172. The method of Claim 168 comprising grindinga celecoxib solvaté.
  171. 173. The method of Claim 172 wherein the grindingis performed by shaking.
  172. 174. A method of producing Form II celecoxibwherein the method comprises melting Form I celecoxib 113 3 1 -83- and cooling the melt thereby producing Form IIcelecoxib.
  173. 175. A method of producing Form II celecoxib5 wherein the method comprises melting Form III celecoxib and cooling the melt thereby producing FormII celecoxib.
OA1200100210A 1999-12-08 2000-12-01 Polymorphic crystalline forms of celecoxib. OA11831A (en)

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