CN101037419A - Crystalline parecoxib sodium - Google Patents

Abstract

Parecoxib sodium is provided in a crystalline form that is substantially anhydrous and substantially nonsolvated. Various such anhydrous, nonsolvated crystal forms have been identified, including Forms A, B and E as described herein. Also provided is a parecoxib sodium drug substance wherein at least about 90% of the parecoxib sodium is in one or more anhydrous, nonsolvated crystal forms. Such a drug substance is a storage-stable intermediate that can be further processed, for example by dissolution or slurrying in an aqueous medium together with one or more parenterally acceptable excipients, followed by lyophilization of the resulting solution or slurry to provide a reconstitutable injectable composition suitable for therapeutic use.

Description

Crystalline parecoxib sodium

The present invention is to be March 12, application number in 2003 the dividing an application for the Chinese patent application of " crystalline parecoxib sodium " that be 03806088.4 (PCT/US2003/007484), denomination of invention the applying date.

Technical field

The present invention relates to the parecoxib sodium crystal forms, relate to the pharmaceutical composition that comprises such crystalline form and use such composition to treat the method for cyclooxygenase-2 (COX-2) mediation illness.

Background technology

Nonsteroidal anti-inflammatory drug (NSAIDs) is widely used in treatment inflammation and slight illness, for example in sacroiliitis and headache.Such medicine is effectively, but their life-time service is subjected to comprising the gastrointestinal side-effect of maldigestion and abdominal pain and stomach in severe case or duodenum perforation and/or hemorrhage restriction.Render a service and very big improved stomach and intestine security situation by the treatment in conjunction with traditional NSAIDs, the exploitation of selective COX-2-2 suppressive drug has thoroughly changed inflammation and treatment of pain.

Believe that the inhibition to cyclo-oxygenase (COX) is main mechanism at least, wherein, by the prostaglandin(PG) synthetic being suppressed NSAIDs performance their characteristic anti-inflammatory, analgesic and analgesic effect.Conventional NSAIDs such as ketorolac, diclofenac, Naproxen Base and salt thereof can suppress the relevant or induction type COX-2 hypotype of inflammation of constructive expression's COX-1 and cyclo-oxygenase under therapeutic dose.COX-1 can produce the essential prostaglandin(PG) of normal cell function, seemingly uses the reason of some relevant harmful side effect with conventional NSAIDs.Contrast, selectivity suppresses COX-2 and do not have substantive inhibition will cause anti-inflammatory to COX-1, and is analgesic, and analgesia and other useful effect make such harmful side effect minimize or eliminate simultaneously.Therefore selective COX-2-2 inhibition medicine is represented the main progress in this area.Formulation that can various Orally-administrables is prepared these medicines.

For a variety of medicines, under particular condition, with respect to oral delivery many benefits are arranged through parenteral administrations such as subcutaneous, intramuscular and intravenous injections.For example, compare with oral administration, the parenteral admin of medicine can reach the effective serum-concentration of treatment of medicine usually in the shorter time.Especially true for the intravenous injection that medicine is directly inserted in the blood flow.Because eliminated owing to losing in metabolism, the gi tract to the combination of food and other reason, parenteral admin also makes can easier prediction drug serum concentration.Because similar, parenteral admin allows to reduce dosage usually.Preferred medicament delivery method when parenteral admin generally is emergency treatment also can be used for treating individuality uncooperative, senseless or the receiving port medication treatment of can not or being unwilling.

Less relatively NSAIDs is commercially available with injectable forms.Non-selective NSAIDs is effective anodyne as the ketorolac tromethamine salt that can be used for parenteral and use, but the side effect that has usually with this non-selective NSAIDs.These side effects comprise ulcer of upper digestive tract and hemorrhage, particularly in old individuality; The renal function that reduces, it may cause fluid retention and hypertensive increasing the weight of; With the inhibition of platelet function, it may bring out hemorrhage increase in the individuality, for example at intra-operative.Such side effect has seriously limited the use of non-selective NSAIDs as parenteral formulation.

At people's such as Talley U.S. patent No.5, disclosed parecoxib is the class water-soluble prodrug that selective COX-2-2 suppresses medicine in 932,598.After individual administration, parecoxib changes into water-fast substantially selective COX-2-2 fast and suppresses the medicine valdecoxib.Be exposed to water, when for example dissolving in water, parecoxib also changes into valdecoxib.Suppress medicine with most of selective COX-2s-2 such as celecoxib is compared with valdecoxib, the higher water solubility of parecoxib, particularly parecoxib salt such as sodium salt causes people to hanker after developing parecoxib using for parenteral.Parecoxib self with following structural formula (I) show to the vitro inhibition activity of COX-1 and COX-2 a little less than, and valdecoxib (II) has very strong anti-COX-2 to suppress active, but the weak inhibitor of COX-1 just.

Parecoxib sodium has following structural formula (III).

U.S. patent No.5 cited above, 932,598 disclose parecoxib sodium in embodiment 18.Can be by the process of describing in embodiment 13 and 14, that adopts suitable sulphonamide and acid anhydrides substitutes to synthesize parecoxib.

Need the parecoxib stable crystalline form that is suitable as active pharmaceutical ingredient (API), also be called as " medicine " at this, it can further process the pharmaceutical composition that is used for the treatment of purposes with preparation.

Except that disclosing fusing point is 271.5-272.7 ℃, the crystalline texture of parecoxib sodium is at U.S. patent No.5 cited above, characterizes in 932,598.Yet wherein the method for Miao Shuing relates to the step from alcohol crystal, hereinafter the step of the generation alcohol solvent compound shown in.Because up to the present all crystal forms of differentiating all shows similar fusing point, after changing mutually, also be so in some cases, so fusing point is not the indication of solid-state form.

For commercial medicine is provided, because a variety of causes comprises that this anhydrous non-solvent form trends towards showing enhanced physical stability, so anhydrous non-solvent crystalline form generally is better than solvate and hydrate.

Therefore need anhydrous, the non-solvent crystalline form of parecoxib sodium in this area especially, particularly need to have the crystalline form of agent of low hygroscopicity.

Summary of the invention

The invention provides the parecoxib sodium of crystallized form, it is substantially anhydrous, and solvation not substantially.Various so anhydrous and non-solvent crystalline forms have now been differentiated.

In the first embodiment, provide form A.This crystalline form of parecoxib sodium is anhydrous and non-solventization, and its feature is to have at least two powder x ray diffraction (PXRD) patterns that are selected from 2 following θ values at least: 5.6,9.6,11.0 and 14.5 degree.

The equipment and the set(ting)value that depend on use are mentioned all of 2 θ values at this all being interpreted as approximation, normal measuring error can be arranged, for example ± 0.2 the error of degree 2 θ.

In second embodiment, provide form B.This crystalline form of parecoxib sodium is anhydrous and non-solventization, and its feature is to have at least two PXRD patterns that are selected from 2 following θ values at least: 4.2,8.3,12.4,16.7,17.5,20.8 and 24.7 degree.

In the 3rd embodiment, provide form E.This crystalline form of parecoxib is anhydrous and non-solventization, and its feature is to have at least two PXRD patterns that are selected from 2 following θ values at least: 8.8,11.3,15.6,22.4,23.5 and 26.4 degree.

The parecoxib sodium medicine also is provided, and wherein at least about 90%, preferably at least about 95%, more preferably all basically parecoxib sodiums are one or more above-mentioned anhydrous, non-solvent crystalline forms.Such medicine is the intermediate of shelf-stable, this intermediate can further be processed, for example by dissolving or slurryization with the acceptable vehicle of one or more parenteral in water-bearing media, solution that freeze-drying subsequently obtained or slurry are to provide the reconfigurable Injectable composition that is applicable to therepic use.

A kind of method for the treatment of the illness that COX-2 mediated in the individuality further is provided, and this method comprises the pharmaceutical composition for the treatment of significant quantity to individuality, and said composition comprises such parecoxib sodium medicine and at least a pharmaceutical excipient.

The such using method of parecoxib sodium medicine in the medicament preparation of treatment COX-2 mediation illness further is provided.

Description of drawings

Fig. 1 shows the PXRD pattern according to the parecoxib na form A of embodiment 4.

Fig. 2 shows fourier transform infrared (FTIR) spectrum according to the parecoxib na form A of embodiment 5.

Fig. 3 shows dsc (DSC) thermogram according to the parecoxib na form A of embodiment 6.

Fig. 4 shows the moisture absorption curve of form A under 25 ℃ according to embodiment 7.

Fig. 5 shows the PXRD pattern according to the parecoxib na form B of embodiment 4.

Fig. 6 shows the FTIR spectrum according to the parecoxib na form B of embodiment 5.

Fig. 7 shows the DSC thermogram according to the parecoxib na form B of embodiment 6.

Fig. 8 shows the moisture absorption curve of form B under 25 ℃ according to embodiment 7.

Fig. 9 shows the PXRD pattern according to the parecoxib na form E of embodiment 4.

Figure 10 shows the FTIR spectrum according to the parecoxib na form E of embodiment 5.

Figure 11 shows the DSC thermogram according to the parecoxib na form E of embodiment 6.

Figure 12 shows the moisture absorption curve of form E under 25 ℃ according to embodiment 7.

Detailed Description Of The Invention

Have been found that parecoxib sodium exists with unexpected multiple anhydrous, non-solvent crystalline form. Because improved the commercial viability of important novel treatment, the discovery of these crystalline forms and evaluation have consisted of the main progress of this area, wherein every kind of crystalline form preparation, purifying, storage and preparation aspect of being presented at parecoxib sodium has advantage.

Many hydrates and solvate have also been observed. These materials tend to unstable, gradually releasing water or solvent, and change into other solid-state form. Might be designated as form A at this, distinctive some the 2 θ value of the PXRD pattern of B or E also may reside in hydrate or the solvate. Yet, the anhydrous non-solvent crystalline form of novelty of the present invention can be easily by under the certain condition they PXRD pattern stability and make a distinction with such hydrate or solvate, wherein hydrate and solvate are because of releasing water from lattice or solvent less stable.

Form A

Novel anhydrous, the non-solvent crystalline form of the first shows to have at least two PXRD patterns that are selected from 2 following θ values: 5.6,9.6,11.0 and 14.5 degree are described as form A at this. Variable earthing or extra, the feature of form A can be the PXRD patterns that has basically such as 2 listed θ values of table 1 among this paper embodiment 5. Variable earthing or extra, the feature of form A can be the PXRD patterns that has substantially as shown in Figure 1.

Variable earthing or extraly, the feature of form A can be FTIR spectrum substantially as shown in Figure 2.

Variable earthing or extraly, the feature of form A can be DSC thermogram substantially as shown in Figure 3.

In a preferred embodiment of the invention, provide the parecoxib sodium medicine, wherein at least about 90%, more preferably at least about 95%, still more preferably basically all parecoxib sodium exist with form A. Such medicine can be at least about 1g, preferably at least about 10g, more preferably at least about 100g, the commercial size that most preferably is used for parecoxib sodium at least about the amount of 1kg is stored and is further processed in the prescription parecoxib sodium medicine manufacturing that is applicable to treat administration.

Form B

Second kind of novel anhydrous, non-solvent crystalline form shows to have at least two PXRD patterns that are selected from 2 following θ values: 4.2,8.3,12.4,16.7,17.5,20.8 and 24.7 degree are described as form B at this.Variable earthing or extraly, the feature of form B can be the PXRD patterns with basic 2 θ values shown in table 2 among this paper embodiment 5.Variable earthing or extraly, the feature of form B can be the PXRD pattern that has substantially as shown in Figure 5.

Variable earthing or extraly, the feature of form B can be the FTIR spectrum that has substantially as shown in Figure 6.

Variable earthing or extraly, the feature of form B can be the DSC thermogram that has substantially as shown in Figure 7.

In another preferred embodiment of the present invention, the parecoxib sodium medicine is provided, wherein at least about 90%, more preferably at least about 95%, still more preferably all basically parecoxib sodiums exist with form B.

Form E

The third novel anhydrous, non-solvent crystalline form shows to have at least two PXRD patterns that are selected from 2 following θ values: 8.8,11.3,15.6,22.4,23.5 and 26.4 spend, and are described as form E at this.Variable earthing or extraly, the feature of form E can be the PXRD patterns with basic 2 θ values shown in table 3 among this paper embodiment 5.Variable earthing or extraly, the feature of form E can be a PXRD pattern substantially as shown in Figure 9.

Variable earthing or extraly, the feature of form E can be a FTIR spectrum substantially as shown in figure 10.

Variable earthing or extraly, the feature of form E can be a DSC thermogram substantially as shown in figure 11.

In another preferred embodiment of the present invention, the parecoxib sodium medicine is provided, wherein at least about 90%, more preferably at least about 95%, still more preferably all basically parecoxib sodiums exist with form E.

The preparation of parecoxib sodium

The parecoxib sodium that can be used for above-mentioned any anhydrous, non-solvent crystalline form or any parecoxib sodium medicament preparation can comprise self known method by prepared by any suitable process.In a kind of such method, synthetic five chemical steps that begin from commercially available starting material that relate to of parecoxib sodium (III) are as shown in following scheme 1.

Scheme 1

In first step, in reaction vessel, add 210kg deoxybenzoin (IV), 711 liters of ethanol and 77 liter of 80% acetic acid aqueous solution.Perhaps, can use glacial acetic acid (63 liters) and water (16.5 liters).With mixture heating up to 70 ℃, and add 71 liter of 50% moisture azanol and 55 premium on currency.Mixture was remained under 70 ℃ 1 hour at least.The inspection of carrying out in the technology is not more than 0.5% with the amount that guarantees unreacted deoxybenzoin (IV).

With mixture cooling and remain on 45 ℃, add entry (266 liters) simultaneously with crystallized product.If do not cause crystallization, then can in mixture, put into crystal seed.The temperature of mixture was remained under 45 ℃ 1 hour at least, slowly add entry (816 liters) then to finish the precipitation of product.Mixture is cooled to 20 ℃ and remained under 20 ℃ at least 1 hour.

Product is separated, adopt mixture (ethanol is 1: 2 to the ratio of water, at least 420 liters) washing of second alcohol and water, adopt water (at least 168 liters) washing then.Product in 55 ℃ of following vacuum-dryings at the most, is not more than 0.5% up to residual water, obtains 1 with the typical yield of 223kg (106wt%), 2-diphenylethane ketone, oxime (1,2-diphenylethanone, oxime) (V).

In second step, in reaction vessel, add 1,2-diphenylethane ketone, oxime (V) are (93kg) and tetrahydrofuran (THF) (THF, 620 liters).Cooling solution adds hexyllithium (248kg), maintains the temperature at 10 ℃ or lower simultaneously.With minimum washed with heptane transfer line, and will clean thing and join in the reaction mixture.

After the hexyllithium adding is finished, reaction mixture is cooled to-15 ℃ or following, add ethyl acetate (237 liters).By following mode quenching reaction mixture: it is joined in the solution of sodium-chlor (41kg) in water (474 liters) maintain the temperature at 15 ℃ or lower simultaneously.Adopt ethyl acetate (118 liters) wash reaction vessels and transfer line.

Separate each layer, organic phase is adopted the solution washing of sodium bicarbonate (28.4kg) in water (474 liters).Organic phase is adopted toluene (355 liters) dilution, and under atmospheric pressure distillating mixture is up to the quality of approximately removing about 2/3rds.Hot solution is adopted heptane (1,300 liter) dilution, be cooled to 5 ℃, and remained under 5 ℃ at least 1 hour.Sedimentary product is separated, and adopt mixture (heptane is 1: 1 to the toluene ratio, at least 110 liters) washing of heptane and toluene.

With product under vacuum at the most 50 ℃ down dry, be not more than 0.5% up to weight loss on drying (LOD), obtain 4,5-dihydro-5-methyl-3, the different  azoles of 4-phenylbenzene-5-alcohol (VI), output is 72kg (77wt%) usually.

In third step, in reaction vessel, add 4,5-dihydro-5-methyl-3, the different  azoles of 4-phenylbenzene-5-alcohol (VI) are (152kg) and trifluoroacetic acid (TFA, 116 liters).Cooling mixture adds chlorsulfonic acid (705kg), keeps the temperature of reaction mixture to be lower than 25 ℃ simultaneously.

After adding is finished, mixture slowly is heated to 60 ℃, and remained under 60 ℃ at least 1 hour.With reaction mixture cooling, and by following mode quenching: it is joined in the mixture of water (456 liters) and toluene (570 liters), and this mixture remains on below 25 ℃ during this adding.Adopt the mixture wash reaction vessels and the transfer line of water (152 liters) and toluene (61 liters).Separate each layer, and organic phase is adopted water (220 liters) washing.

Adopt aqueous ammonium hydroxide (190 liters) to handle organic phase,, and remained under 35 ℃ at least 30 minutes mixture heating up to 35 ℃.Carry out checking in the technology that the pH to guarantee water is not less than 9.

Add Virahol (729 liters), mixture was remained under 35 ℃ 1 hour at least.Mixture is cooled to 20 ℃, remained under 20 ℃ at least 1 hour.Sedimentary product is separated, and adopted Virahol (304 liters) washing, adopt water (at least 101 liters) washing then.

Crude product is dissolved in hot methanol (709 liters).Solution is filtered to remove degranulation, adopt the dilution of other methyl alcohol (355 liters) and water (274 liters).With mixture heating up to 70 ℃ with dissolved solids, then slowly cooling to cause the crystallization of product.If when reaching 45 ℃, do not begin crystallization, then can put into crystal seed to mixture.In case the generation crystallization is down stirred mixture 1 hour at 50 ℃ at least, slowly is cooled to 5-10 ℃ then, and remained under this temperature at least 1 hour.Product is separated, adopt mixture (methyl alcohol is 3: 1 to the ratio of water, at least 95 liters) washing of first alcohol and water.Perhaps, can use above-mentioned identical process from the mixture recrystallize of ethanol (1,300 liter) and water (68 liters) and purified product.

Product dry under 100 ℃ temperature at the most under the vacuum, is not more than 0.5% up to the amount of residual solvent that is recorded by LOD or gas-chromatography, obtains 4-(the 5-methyl-different  azoles of 3-phenyl-4-base) benzsulfamide (VII), output is 103kg (62wt%) usually.

In the 4th step, in reaction vessel, add 4-(the 5-methyl-different  azoles of 3-phenyl-4-base) benzsulfamide (VII) (21kg) and propionic anhydride (86kg).The suspension that obtains is warmed up to 50 ℃, and adds sulfuric acid (21ml).Reaction mixture is warmed up to 80 ℃, kept at least 30 minutes.

Mixture slowly is cooled to 50 ℃ to cause the crystallization of product.After causing crystallization, mixture was remained under 50 ℃ 30 minutes at least.If fail to cause crystallization down, then can in mixture, put into crystal seed at 50 ℃.Mixture slowly is cooled to 0 ℃, remains under 0 ℃ at least 1 hour to finish crystallization.

Product is separated; adopt methyl tertiary butyl ether (80 liters) washing; in strainer top drying; check that in technology indication LOD is not more than 5%; obtain n-[[4-(the 5-methyl-different  azoles of 3-phenyl-4-base) phenyl for wet cake] alkylsulfonyl] propionic acid amide (VIII), it is directly carried into the 5th step does not have further purifying or drying.

In the 5th step, the wet cake that will obtain in the 4th step is dissolved in dehydrated alcohol (counting 12.6kg/kg (VIII) with dry weight) under 45 ℃, and filtering mixt is to remove particulate.

In independent reaction vessel, prepare the appearance liquid of sodium hydroxide (approximately 5wt%) in dehydrated alcohol, determine the volumetric molar concentration of solution by titration.The sodium hydroxide solution of calculated amount is joined by pot strainer in the ethanolic soln of (VIII), mixture is remained under 45 ℃, put into crystal seed to cause crystallization.

Put into after the crystal seed, mixture is warmed up to 50 ℃, kept at least 30 minutes, be cooled to 0 ℃ then to finish crystallization.Mixture was stirred 30 minutes down at 0 ℃ at least, and separated product also adopts cold dehydrated alcohol (88kg at least) washing.

At last, with product under vacuum at the most 135 ℃ down dry, obtain parecoxib sodium (III), normal yield is 17.2kg (82wt%).

Should understand above technology description and just be used for illustrative purposes.The variation of above technology comprises the variation of processing condition and scale, can easily be carried out by those skilled in the art and does not deviate from the present invention.

Parecoxib na form A, the preparation of B and E

Astoundingly, have been found that during the 5th step of above-mentioned technology that the slight variation of drying conditions can be produced multiple anhydrous, solvation and hydration crystalline form.Typically, the parecoxib sodium of at least a portion production is the alcohol solvent compound form.Can produce parecoxib sodium alcohol solvent compound with different chemical metering, promptly higher and lower alcohol solvent compound, they are directly related with drying efficiency.

Yet no matter the crystalline form of the parecoxib sodium that obtains in the 5th step how, if during drying or afterwards temperature is increased to about 210 ℃, parecoxib sodium will change into form A.When cooling, parecoxib sodium remains form A.

Therefore, first kind of preparation method of form A parecoxib sodium is provided, the parecoxib sodium crystal forms that this method comprises the steps: to heat except that form A arrives from about 210 ℃ of fusing points to parecoxib sodium, be enough to transform parecoxib sodium heat-up time and become form A, the form A parecoxib sodium that cooling obtains is to envrionment temperature.

Further find, by under environmental stress about 3 hours of about 150 ℃ of following heated mixt, the form A of parecoxib sodium and the mixture of alcohol solvent compound can be changed into pure substantially form A.

Therefore, second kind of preparation method of form A parecoxib sodium is provided, this method comprises the steps: under the situation that form A parecoxib sodium exists, the alcohol solvent compound of heating parecoxib sodium arrives from about 150 ℃ of temperature to the parecoxib sodium fusing point, be enough to transform alcohol solvent compound heat-up time and become form A, and the form A parecoxib sodium that cooling obtains is to envrionment temperature.

Further find when when moisture is heated to about 125 ℃-Yue 130 ℃ in the presence of not, the amorphous form of parecoxib sodium will change into form A, and the amorphous form of this parecoxib sodium can be dissolved in the water by any solid-state form with parecoxib sodium, freeze-drying subsequently prepares.

Therefore, the third preparation method of form A parecoxib sodium is provided, this method comprises the steps: under the non-existent substantially situation of moisture, heating amorphous or freeze dried parecoxib sodium arrives from about 125 ℃ of temperature to the parecoxib sodium fusing point, be enough to transform amorphous or freeze dried parecoxib sodium heat-up time and become form A, and the form A parecoxib sodium that cooling obtains is to envrionment temperature.

A kind of preparation contain method at least about the parecoxib sodium medicine of 90% form A comprise the steps: (a) from recrystallisation solvent (as ethanol) the crystalline parecoxib sodium crystalline parecoxib sodium that with the crystallized form of producing parecoxib sodium and (b) heating obtains under about 110 ℃-Yue 230 ℃ temperature to produce required parecoxib sodium medicine.

Be higher than under the situation of about 60%RH in relative humidity (RH) level, form A changes into the crystalline hydrate form in time.For example, after form A is exposed to about 7 days of the about 3-of about 75%RH, with the conversion fully that takes place to hydrate.Have been found that when dry such hydrate at ambient temperature, for example by efficient drying agent such as P ₂O ₅When dry, solid-state form does not change into form A, becomes form B on the contrary.

Therefore, provide the preparation method of form B parecoxib sodium, this method comprises the steps: to utilize the crystalline hydrate form of siccative dry parecoxib sodium under the temperature that is lower than generation form A, generation form B parecoxib sodium.

Form E parecoxib sodium can be prepared by following mode: the alcohol solvent compound of recrystallize parecoxib sodium from heptane, and with production form E crystal.

Parecoxib na form A, the performance of B and E

Respectively at Fig. 4, shown form A at ambient temperature, the moisture sorption isotherms of B and E in 8 and 12.Form A absorbs less than 1% moisture under less than about 60%RH, but more trends towards absorbing water even deliquescence during greater than about 60%RH.Form B and E be not as the easy moisture absorption of form A, show in addition under up to about 80%RH the tendency of absorption water still very little.

Can mediate the more agent of low hygroscopicity of comparing form B and E with form A by relatively hot mechanical stability with reference to these solid-state forms.Shown in energy/hygrogram of Figure 17, the energy of form A is higher than form B and E, and the latter two are similar each other.Though be not limited to particular theory, infer it is because form B and C have represented lower energy state, i.e. thermodynamics stable status more, thereby form B and E are not as form A moisture absorption.

The present invention found unexpectedly can be relatively easily on commercial size other solid-state form from parecoxib sodium prepare form A, for example by heating and cooling prepared form A, this provides main commercial benefit for form A.In case after the preparation, form A shows the stability of high level, thereby has the hydrate of being better than and solvate (for example it is believed that by U cited above.S. benefit patent No.5, the alcohol solvent compound that the technology that proposes in 932,598 obtains).The various hydrates and the solvate that exist with the different chemical metering cause product easily to change, and this is overcome in the present invention.More under the situation of agent of low hygroscopicity, form B and form E are better than form A at needs.

The auspicious person of handkerchief former times na form A, the practicality of B and E

As discussed previously, be particularly suitable for as medicine or API by parecoxib sodium new crystalline form provided by the invention, they can be stored up to downstream processing and preparing pharmaceutical composition.As needs, these forms can self, introduce solid formulation with one or more pharmaceutical excipients, as are used for the tablet or the capsule of oral administration, perhaps are used for the gel or the paster agent of topical.As necessary, can be before formulation preparation, by grinding or grind or other physical measure reducing the granularity of these crystallized forms or makes it to become more even.

Perhaps, can in preparation of drug combination, new crystalline form be changed into noncrystalline form, for example dissolve or amorphous form.For example, new crystalline form can be regarded stable process intermediates as.

In one embodiment of the invention, provide a kind of preparation to can be used for the method for the pharmaceutical composition of COX-2 mediation treatment for diseases, this method comprises the steps: dissolving parecoxib sodium medicine in water-bearing media, be form A wherein at least about 90% parecoxib sodium, one or more forms among B and the E, and at least a pharmaceutical excipient, to form solution.

Such solution can be the instant Injectable composition.Perhaps, can carry out further step of freeze drying so that the solid particulate that comprises amorphous parecoxib sodium pharmaceutical composition to be provided to such solution.Can be by the such composition of following mode reconstruct: add the acceptable aqueous diluent of parenteral to form the Injectable solution of parecoxib sodium.Term " solution " is interpreted as and comprises slurry and real solution when being applied to want freeze dried material.

According to the present embodiment, preferably before pharmaceutical composition preparation, wait to be dissolved in the medicine of water-bearing media at least about 90%, be form A or form B or form E more preferably at least about 95%.Most preferably such medicine is substantial phase respective pure form A, form B or form E.

The methods of treatment of using

Medicine of the present invention in the time of in changing into or be incorporated into aforesaid pharmaceutical composition, can be used for treating or prevents a variety of illnesss by the COX-2 mediation, and this illness includes but not limited to be characterized as the illness of inflammation, pain and/or heating.The special useful as anti-inflammatory agents of such composition, as be used for arthritic treatment, and and lacking the preferential COX-2 of selection but not the optionally conventional NSAIDs composition of COX-1 is compared, the present composition has extra benefit in addition, be that harmful side effect is significantly littler, especially true when being administered systemically.Therefore, at the conventional NSAIDs of forbidding, for example suffering from peptide ulceration, gastritis, regional ileitis, ulcerative colitis, diverticulitis or gastrointestinal damage recurrence medical history; Gastrointestinal hemorrhage, coagulation disorders comprise anaemia such as Hypoprothrombinemia, hemophilia or other bleeding problems; Among the patient of kidney disease, or among the patient of patient before operation or absorption anti-coagulant, composition of the present invention can be used as the surrogate of conventional NSAIDs especially.

Composition of the present invention can be used for treating various arhritis conditions, includes but not limited to rheumatoid arthritis, spondyloarthropathy, urarthritis, osteoarthritis, systemic lupus erythematous and juvenile arthritis.

The uviolizing that such composition can be used for treating asthma, bronchitis, menstrual cramps, preterm labor (preterm labor), tendonitis, bursitis, allergic neuritis, cytomegalovirus infectivity, programmatic small cell death (comprising HIV inductive apoptosis), pain in the back, the hepatopathy that comprises hepatitis, skin related conditions such as psoriasis, eczema, acne, burn, dermatitis and comprising sunburn is operated and post-operation inflammatory.

Such composition can be used for treating the stomach and intestine patient's condition such as inflammatory enteritis, regional enteritis, gastritis, irritable bowel syndrome and ulcerative colitis.

Such composition can be used for treating the inflammation in the following disease: migraine, polyarteritis nodosa, thyroiditis, aplastic anemia, Hokdkin disease, scleroderma (sclerodoma), rheumatic fever, type i diabetes, the myoneural junction disease that comprises myasthenia gravis, the white matter disease that comprises multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet, polymyositis, oulitis, ephritis, allergy, comprise swelling after the damage of cerebral edema, myocardial ischemia etc.

Such composition can be used for treating ophthalmic, as the retinitis, conjunctivitis, retinopathy, uveitis, eyes photophobia with to the acute injury of ocular tissue.

Such composition can be used for treating lung inflammation, as lung inflammation relevant and cystic fibrosis with virus infection, and bone resorption (as the bone resorption relevant with osteoporosis).

Such composition can be used for treating some central nervous system disorders, as comprises the cortex dementia, nerve degeneration of Alzheimer's and from the central nervous system injury of apoplexy, local asphyxia and wound.Term in the present context " treatment " comprises dull-witted partially or completely inhibition, and this dementia comprises Alzheimer's, vascular dementia, Dementia with Multiple Brain Infarction, presenile dementia, excessive drinking dementia (alcoholic dementia) and senile dementia.

Such composition can be used for treating rhinallergosis, respiratory distress syndrome, endotoxin shock syndrome and hepatopathy.

Such composition can be used for treating pain, the pain that includes but not limited to postoperative pain, toothache, myalgia and cause because of cancer.For example, such composition can be used for alleviating pain, heating and the inflammation in the multiple patient's condition: comprise rheumatic fever, influenza and comprise other virus infection, back of the body bottom and neck pain, dysmenorrhoea, headache, toothache, sprain and strain, myositis, neurodynia, synovitis, the sacroiliitis that comprises rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burn and surgery and the dental procedure wound afterwards of common cold.

Such composition can be used for treating the cardiovascular disorder relevant with preventing inflammation, comprises vascular disease, coronary artery disease, aneurysma, the vascular rejection, arteriosclerosis, the atherosclerosis that comprises the cardiac transplantation atherosclerosis, myocardial infarction, embolism, apoplexy, the thrombosis that comprises venous thrombosis, the stenocardia that comprises unstable angina, coronary pluques shape inflammation, comprise that chlamydozoan induces the cell induction inflammation of inflammation, the virus induction inflammation, with with operation technique such as the relevant inflammation of vascular transplantation (comprising coronary artery bypass surgery), the revascularization that comprises angioplasty becomes operation, support is placed, endarterectomy, or relate to artery, vein and other invasive operation capillaceous.

Such composition can be used for treating individual medium vessels relevant illness takes place, and for example is used to suppress tumor vessel and takes place.Such composition can be used for treating the tumorigenesis that comprises transfer, the ophthalmology patient's condition such as corneal graft rejection, the eyes neovascularization, be included in damage or infect neovascularization afterwards in interior retina neovascularization, diabetic retinopathy, macular degeneration, Terry's sign disease and neovascular glaucoma, ulcer disease such as stomach ulcer, pathologic but nonmalignant patient's condition are as comprising the vascular tumor of juvenile form capillary hemangioma, nasopharyngeal fibrohemangioma and ANB, and female reproductive system illness such as endometriosis.

Such composition can be used for treating disease precancer, as actinic keratosis.

Such composition is used for the prevention of following illness, treatment and inhibition: optimum and malignant tumour and the tumorigenesis that comprises tumorigenesis in the metastasis, for example colorectal carcinoma, the cancer of the brain, osteocarcinoma, epithelial cell deutero-tumorigenesis (epithelial cancer) is as rodent cancer, gland cancer, gastrointestinal cancer such as lip cancer, oral carcinoma, the esophageal carcinoma, carcinoma of small intestine, cancer of the stomach, colorectal carcinoma, liver cancer, bladder cancer, the pancreas cancer, ovarian cancer, cervical cancer, lung cancer, mammary cancer, skin carcinoma such as squamous cell carcinoma and rodent cancer, prostate cancer, renal cell carcinoma, with epithelial other known cancer in the whole health of influence.Estimate that the useful especially tumorigenesis of the present composition is gastrointestinal cancer, Ba Leiteshi oesophagus, liver cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, prostate cancer, cervical cancer, lung cancer, mammary cancer and skin carcinoma.Such composition also can be used for treating the fibrosis that adopts radiotherapy to take place.Such composition also can be used for treating the individuality with adenomatous polyp, comprises have familial adenomatous polyposis those individualities of (FAP).In addition, such composition can be used for preventing to form polyp in the patient that FAP danger is arranged.

More particularly, composition can be used for following treatment of conditions, prevention and inhibition: acra color spot sample melanoma, actinic keratosis, gland cancer, cystadenocarcinoma, adenoma, sarcoadenoma, adenosquamous carcinoma, astrocytic tumor, bartholin gland carcinoma, rodent cancer, mammary cancer, bronchial gland carcinoma, capillary hemangioma, carcinoid, sarcocarcinoma, cavernous hemangioma, cholangiocarcinoma, chondrosarcoma, papilloma choroideum or cancer knurl, clear cell carcinoma, T-cell lymphoma,cutaneous (mycosis fungoides), cystadenoma, dysplastic nevus, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymoma, EA, Ewing sarcoma, plumage stratiform sarcoma, focal nodular hyperplasia, gastrinoma, gonioma, glioblastoma, glucagonoma of pancreas, hemangioblastoma, hemangioendothelioma, vascular tumor, adenoma of liver, the adenoma of liver disease, hepatocellular carcinoma, insulinoma, last intracutaneous tumorigenesis, squamous cell tumorigenesis between epithelium, the invasive squamous cell carcinoma, Kaposi sarcoma, large cell carcinoma, leiomyosarcoma, pernicious lentigo sample melanoma, malignant melanoma, pernicious mesothelium tumour, medulloblastoma, medulloepithelioma, melanoma, meningioma, mesothelioma, mucoepidermoid carcinoma, neuroblastoma, neuro epithelium gland cancer, NM, oat-cell carcinoma, oligodendroglioma, osteosarcoma, papillary serous adenocarcinoma, pinealoma, pituitary tumor, plasmoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdosarcoma, sarcoma, serous carcinoma, small cell carcinoma, the soft tissue cancer, the Somatostatin secreting tumor, the squama cancer, squamous cell carcinoma, following carcinoma mesothelial, show the shallow type melanoma that spreads, undifferentiated carcinoma, the uveal tract melanoma, verrucous carcinoma, the vasoactive intestinal polypeptide knurl, WD cancer and Wei Ermusishi tumour.

Such composition suppresses prostanoid inductive smooth muscle contraction by suppressing synthesizing of shrinkability prostanoid, therefore can be used for treating the relevant illness of dysmenorrhoea, premature labor, asthma and eosinocyte.They also can be used for reducing bone loss, the particularly loss of the bone in the postmenopausal women (promptly treating osteoporosis), and are used for the treatment of glaucoma.

The preferable use of the present composition is to be used for the treatment of rheumatoid arthritis and osteoarthritis, generally be used for pain management (particularly behind the operation on oral cavity after pain, the common surgical procedures after pain, the plastic surgery operations the acute solar flare of pain and osteoarthritis), be used for prevention and treatment headache and migraine, be used for the treatment of degenerative brain disorder and be used for the prevention of colorectal carcinoma chemistry.

Any administration be can pass through, parenteral, oral, rectum, lung, nasal cavity, ear and local approach comprised.Topical application is from form A, the parecoxib composition of sodium of one or more preparations among B and the E is particularly useful for treating any kind skin disorder with inflammatory component, can be pernicious, non-pernicious or premalignant, this illness comprises that scar forms and ketoboidies disease, also comprise burn and the sun burn, for example tan severely, corrugate etc.Such composition can be used for treating the inflammation that causes because of various skin injuries, including, but not limited to cause by virus disease those, this virus disease comprises herpes infection (as herpes labialis, genital herpes), zoster and varicella.Can adopt such combination treatment to other infringement of skin or damage comprise hyper-proliferative activity, psoriasis, eczema, acne, dermatitis in bedsore, the epidermis, scratch where it itches, boss and acne erythematosa.Such composition also can promote the agglutination after the operation technique, and this operation technique comprises that the beauty treatment operation is as chemical peel, laser therapy, dermabrasion, beauty and shaping art, the operation of eye face etc.

Except that being used for the human treatment, composition of the present invention also can be used for companion animals, external animal, farm-animals etc., particularly comprises the mammiferous veterinary treatment of rodents.More particularly, composition of the present invention can be used for the veterinary treatment of the illness that COX-2 mediated in horse, dog and the cat.

This composition can be used for the combination therapy with following material:opioid and other anodyne comprise anodyne, monoamine absorption inhibitor, adenosine conditioning agent, cannabinoid derivatives, P substance antagonist, antagonists of neurokinine-1 receptor and the sodium channel inhibitor etc. of narcotic analgesic, Mu receptor antagonist, k-receptor antagonist, non-narcotic (promptly can not be addicted). preferred therapeutic alliance comprises uses composition of the present invention and one or more to be selected from following compound: Aceclofenac; Acemetacin; ε-acetylamino caproic acid; Paracetamol; Acetaminosalol; Antifebrin; Acetylsalicylsalicylic acid; SAM; Alclofenac; Alfentanil; Allylprodine; Alminoprofen; Aloxiprin; Alphaprodine; Two (acetylsalicylic acid) aluminium; The fragrant acid of ammonia; Ammonia chlorobenzene  piperazine; 3-amino-4-hydroxybutyric acid; 2-AMINO-4-PICOLINE; Aminopropylon; Aminopyrine; Amixetrine; Ammonium salicylate; Ampiroxicam; Amtolmetin Guacil; Anileridine; Antipyrine; Salazon; Antrafenine; Apazone; Aspirin; Balsalazide; Bendazac; Benorylate (benorylate); Benzene  Lip river is fragrant; Benzpiperilone; Benzydamine; Benzylmorphine; Jamaicin; Bermoprofen; Bezitramide; α-bisabol; The fragrant acid of bromine; Antisepsin; The 5 bromosalicylic acid acetic acid esters; Bromosaligenin; Bucetin; The bucloxic acid; Bucolome; Bufexamac; Bumadizone; Buprenorphine; Butacetin; Butibufen; Butorphanol; Tylcalsin; Carbamazepine; Carbiphene; Carprofen; Carsalam; Anesin; Chlorthenoxazine; Choline Salicylate; Quinophan; Cinmetacin; Ciramadol; Clidanac; Clometacin; Clonitazene; Clonixin; Clopirac; Cloves; Codeine; Codeine methyl bromide; Codeine phosphate; Codeine sulfate; Cropropamide; Crotetamide; Desomorphine; Dexoxadrol; Dextromoramide; Dezocine; Diampromide; Diclofenac; Difenamizole; Difenpiramide; Diflunisal; Dihydrocodeine; Dihydrocodeinone enol acetate; Dihydromorphine; Dihydroxyaluminum acetylsalicylate; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Dipyrocetyl; Analgin; Ditazole; Bend  former times health; Emorfazone; Enfenamic acid; Epirizole; Eptazocine; Etanercept; Etersalate; Ethenzamide; Ethoheptazine; Diamino ethoxy diazobenzene; Ethylmethylthiambutene; Dionin; Etodolac; Etofenamate; Etonitazene; Eugenol; Felbinac; Fenbufen; Fenclozic acid; Fendosal; Fenoprofen; Fentanyl; Fentiazac; Fepradinol; Feprazone; Floctafenine; Flufenamic acid; Flunoxaprofen; Fluoresone; Flupirtine; Fluproquazone; Flurbiprofen; Fosfosal; Gentianic acid; Glafenine; Glucametacin; Glycol salicylate; Guaiazulene; Hydrocodone; Hydromorphone; Hydroxypethidine; Ibufenac; Brufen; Ibuproxam; Imidazole salicylate; Indomethacin; Indoprofen; Infliximab; Interleukin 10; Isofezolac; Isoladol; Isomethadone; Isonixin; Isoxepac; Isoxicam; Ketobemidone; Ketoprofen; Ketorolac; P-Lactylphenetidine (p-lactophenetide); Lefetamine; Levorphanol; Lexipafant; Lofentanil; Lonazolac; Lornoxicam; Loxoprofen; Lysine acetylsalicylate; Magnesium acetylsalicylate; Meclofenamic acid (meclofenamic acid); Mefenamic acid; Meloxicam; Pethidine; Meptazinol; 5-aminosalicylic acid; Metazocine; Methadone; Levomepromazine; Metiazinic acid; Methopholine; Metopon; Mofebutazone; Mofezolac; Morazone; Morphine; Morphine hydrochloride; Morphine sulfate; Morophine salicylate; Myrophine; Nabumetone; Nalbuphine; 1-Naphthyl Salicylate; Naproxen; Narceine; Fenazoxine; Nicomorphine; Nifenazone; Niflumic Acid; Aulin; 5 '-nitro-2 '-propoxyl group antifebrin; Norlevorphanol; Normethadone; Normorphine; Norpipanone; Olsalazine; Opium; Oxaceprol; Oxametacin; The  promazine; Oxycodone; Oxymorphone; Oxyphenbutazone; Narsco; Paranyline; Parsalmide; Pentazocine; Perisoxal; Phenacetin; Phenadoxone; Phenazocine; Phenazopyridine hydrochloride; Phenocoll; Phenoperidine; Phenopyrazone; Acetylphenyl salicylate; Phenylbutazone; Phenyl salicytate; Fenyramidol; Piketoprofen; Piminodine; Pipebuzone; Piperylone; Pirazolac; Pirinitramide; Piroxicam; The pyrroles is fragrant; Pranoprofen; Proglumetacin; The Pu Luokang piperazine; Trimeperidine (promedol); Propacetamol; Propiram; Dextropropoxyphene; Propyphenazone; Proquazone; Protizinic acid; Ramifenazone; Remifentanil (remifentanil); Rimazolium Metilsulfate; Salacetamide; Salicin; Salicylamide; The adjacent acetic acid of salicylamide; Salicyloyl sulfuric acid; Salsalate; Salverine; Simetride; Sodium salicylate; Sufentanil; SASP; Sulindac; Superoxide dismutase; Suprofen; Suxibuzone; Talniflumate; Tenidap; Tenoxicam; Terofenamate; Tet; Thiazoline and phenylbutazone (thiazolinobutazone); Tiaprofenic Acid; Tiaramide; Tilidine; Tinoridine; Tolfenamic Acid; Tolmetin; C16H25NO2; Tropesin; Viminol; Xenbucine; Ximoprofen; Zaltoprofen; Ziconotide and Zuo Mei acid (referring to.The Merck Index, the 13rd edition (2001), Therapeutic Category andBiological Activity Index, wherein topic head is " pain killer ", the enumerating of " anti-inflammatory agent " and " febrifugee ").

Particularly preferred combination therapy comprises uses composition of the present invention and opioid compounds, and more particularly wherein opioid compounds is morphine monomethyl ether, Pethidine, morphine or derivatives thereof.

To can prepare separately with the compound of present composition Combined Preparation, and by any suitable way administration, comprise that oral, per rectum, parenteral or topical are to skin or other position.Perhaps, can therewith be mixed with the coating tablet composition with the compound of present composition Combined Preparation.

In embodiments of the invention, when particularly wherein the patient's condition of COX-2 mediation is headache or migraine, in conjoint therapy with this composition with following material administration: regulation of blood vessels agent, the xanthine derivative that preferably has the regulation of blood vessels effect, more preferably alkyl-yellow purine compound.

No matter whether alkyl-yellow purine is the regulation of blood vessels agent, and no matter whether the treatment of conjoint therapy is renderd a service to a certain extent owing to the regulation of blood vessels effect, and wherein the alkyl-yellow purine compound all is included in the embodiments of the present invention scope with combination therapy at the composition co-administered that this provides.Term herein " alkyl-yellow purine " comprises and contains one or more C _1-4Alkyl, the pharmacologically acceptable salt of the substituent xanthine derivative of preferable methyl and such xanthine derivative.Especially preferably dimethyl xanthine and trimethyl xanthine comprise caffeine, Theobromine and theophylline.Most preferably the alkyl-yellow purine compound is a caffeine.

Regulation of blood vessels agent in the combination therapy or alkyl-yellow purine component can adopt any suitable formulation, by any suitable way administration, comprise that oral, per rectum, parenteral or topical are to skin or other position.Optionally, can be formulated in regulation of blood vessels agent or alkyl-yellow purine and this composition single in the skin formulation jointly.Therefore transdermal composition of the present invention optionally comprise valdecoxib or its prodrug or its salt and regulation of blood vessels agent or alkyl-yellow purine (as caffeine) both, its total amount and relative quantity be treatment effectively.

Embodiment

The detailed description that following embodiment comprises has illustrated the present invention, but limits its scope never in any form.Unless otherwise indicated, all percentages.The parecoxib sodium raw materials that uses among each following embodiment is according to above scheme 1 preparation.

Embodiment 1: the preparation of form A

Parecoxib na form A is by each preparation in the following method.

1. the aqueous solution of freeze-drying parecoxib sodium.The amorphous parecoxib sodium that obtains is not being had to put into the DSC dish in the presence of the moisture, with 10 ℃/minute speed raising temperature.The crystallization of parecoxib sodium takes place down at about 125-130 ℃, is a heat release activity.Crystal is confirmed as form A by one or more modes in following PXRD, FTIR, DSC and the moisture absorption.

2. the parecoxib na form A of total amount 10g and the mixture of alcohol solvent compound were being put into baking oven 3 hours under 150 ℃ under environmental stress.The solid that obtains is cooled off in the drying bottle that comprises the Drierite siccative, by following PXRD, FTIR, one or more modes in DSC and the moisture absorption are confirmed as form A.

3. find to change into form A at about 210 ℃ of following form E parecoxib sodiums, observing this solid state transformation by DSC is a kind of broad band heat absorption activity.By following PXRD, FTIR, one or more modes in DSC and the moisture absorption are confirmed as form A.

By the PXRD that is shown in respectively among Fig. 1-4, FTIR, DSC and moisture absorption data are accredited as form A.

Embodiment 2: the preparation of form B

Parecoxib na form B prepares by every kind in the following method.

1. parecoxib na form A is exposed to several days crystallized forms of about 75%RH with the production hydration.Pass through the crystallized form of dry this hydration of siccative then.The solid that obtains is by following PXRD, FTIR, and one or more modes in DSC and the moisture absorption are confirmed as form B.

2. the alcohol solvent compound for preparing parecoxib sodium by following mode: by on hot plate, being heated to boiling under the situation of magnetic agitation having, recrystallize 11.5g parecoxib sodium in 100ml ethanol, subsequently by environment cools to room temperature.In addition, about 1g form B crystal seed is joined in the 450ml heptane.Collect freshly prepd alcohol solvent compound by vacuum filtration, and be transferred to immediately in the heptane suspension that comprises form B crystal seed.Under violent magnetic agitation with the suspension reflux that obtains 4 hours.Collect crystal by vacuum filtration, under 40 ℃, descend dried overnight in chamber vacuum (house vacuum), by following PXRD, FTIR, one or more modes in DSC and the moisture absorption are confirmed as form B.

Form B is characterised in that PXRD, FTIR, DSC and the moisture absorption data that show respectively in Fig. 5-8.

Embodiment 3: the preparation of form E

Parecoxib na form E is prepared as follows.To transfer in the 450ml heptane by the parecoxib sodium alcohol solvent compound crystalline form of embodiment 2 methods 2 preparations, not put into crystal seed.Adopt violent magnetic agitation with the suspension reflux that obtains 4 hours.Collect crystal by vacuum filtration, under 40 ℃ under the vacuum of chamber dried overnight, by following PXRD, FTIR, one or more modes in DSC and the moisture absorption are confirmed as form E.

Form E is characterised in that respectively at the PXRD shown in Fig. 9-12, FTIR, DSC and moisture absorption data.

Embodiment 4:PXRD

Adopt Siemens D5000 or Inel Multipurpose diffractometer to use Cu-K α radiation under 30kV voltage and 30mA electric current, to collect powder x ray diffraction (powder x-raydiffraction, PXRD) data.Inel is equipped with the position sensing detector, can be used for obtaining simultaneously all diffraction datas.Contrast silicon and mica reference standard thing and direct beam calibration diffractometer.Carry out the kapillary observed value in the 1mm sealing glass kapillary in being installed in the capillary pipe furnace on the goniometer head.For the kapillary observed value, contrast silicon and direct beam calibration diffractometer.

Parecoxib na form A, the diffraction pattern of B and E is shown in Fig. 1 respectively, and 5 and 9, the diffraction peak of every kind of form is listed in table 1 respectively, in 2 and 3.

The PXRD peak of table 1: form A

D-spacing ()	Angle 2 θ (± 0.2)	Intensity (%)
			15.7	5.6	100.0
9.3	9.6	10.3
			8.0	11.0	12.7
6.1	14.5	6.0
			5.4	16.5	6.5
4.0	22.0	1.3
			3.7	24.0	3.7
3.5	25.3	2.5

The PXRD peak of table 2: form B

D-spacing ()	Angle 2 θ (± 0.2)	Intensity (%)
			20.9	4.2	74.3
10.6	8.3	81.1
			7.2	12.3	39.3
7.2	12.4	22.7
			6.9	12.8	100.0
6.8	13.0	8.0
			6.0	14.8	1.0
5.4	16.4	22.0
			5.3	16.7	14.6
5.2	16.1	9.7
			5.1	17.5	32.4
4.7	18.7	0.9
			4.4	20.1	8.6
4.3	20.6	3.0
			4.3	20.8	8.1
3.9	22.7	4.0
			3.9	22.9	2.6
3.7	23.8	21.4
			3.7	24.2	23.4
3.6	24.7	74.9

The PXRD peak of table 3: form E

D-spacing ()	Angle 2 θ (± 0.2)	Intensity (%)
			10.0	8.8	26.2
7.9	11.3	12.7
			6.9	12.8	100.0
5.8	15.3	5.4
			5.7	15.6	22.4

The PXRD peak of table 3: form E

D-spacing ()	Angle 2 θ (± 0.2)	Intensity (%)
			5.1	17.4	45.0
4.7	18.7	25.7
			4.5	19.9	4.1
4.2	21.1	3.8
			4.1	21.5	3.2
4.0	22.4	40.8
			3.9	22.7	25.5
3.8	23.5	11.5
			3.7	24.2	0.9
3.6	25.0	5.8
			3.5	25.7	9.6
3.4	25.9	3.9
			3.4	26.4	35.2
3.3	26.8	7.4
			3.2	27.8	2.6

Embodiment 5:FTIR spectrum

Fourier transform is infrared, and (Fourier-transform infrared, FTIR) spectrum adopts Nicolet Nexus 670 FT-IR beam split photometry degree records.Use NicoletSMARTDuraSamplIR attenuated total reflectance attenuated total refraction (ATR) annex scanning samples.With 4cm ^-1Resolving power from 4000 to 400cm ^-1Average totally 64 scanning samples.

Parecoxib na form A, B and E from 4000 to 500cm ^-1FTIR spectrum be shown in Fig. 2 respectively, 6 and 10.

Embodiment 6:DSC

Adopt Mettler-Toledo DSC821 to collect dsc (differentialscanning calorimetry, DSC) data.Adopt indium and zinc reference standard thing base measuring temperature and enthalpy.The sealing or pin hole 40 μ l aluminium dishes in from 25 ℃ to 300 ℃ analytic sample.Heating rate is 10 ℃/minute, and nitrogen purging speed is 50ml/ minute.

Parecoxib na form A, the DSC thermogram of B and E is shown in Fig. 3 respectively, and 7 and 11.

Form A is presented at single fusion heat absorption (the Δ H of about 273.1 ℃ of beginnings _t=23.8kJ/ mole).Form B is presented at heat absorption (the Δ H of about 195.9 ℃ of beginnings _t=20.71kJ/ mole), representative is in the rapid fusion heat absorption of 273.7 ℃ form A to the transformation of form A subsequently.Form E is presented at wide heat absorption (the Δ H of about 206.6 ℃ of beginnings _t=18.35kJ/ mole), representative is in the rapid fusion heat absorption of 273.2 ℃ form A to the transformation of form A subsequently.By hot stage microscopy (hot-stage microscopy) solid confirmed before fusion form B and E to changing into of form A solid-transformation.

According to the transition heat rule, believe that form B is relevant with form A change with E, means at transition temperature T _tAbout exist in the stability relation between each form and change.Form A is measured the T of form B and E by using the congruent melting data pin _t

At reference compound (RC) and parecoxib sodium A, form eutectic mixture between every kind of form of B and E.Use the melting heat data to derive the free energy difference between each crystalline form (formula I) under eutectic temperature subsequently:

x _Ej(G _j-G _i) _Tei=Δ H _Mej(T _Ei-T _Ej)/T _e-Δ C _Pij[T _Ei-T _Ej-T _EiLn (T _Ei/ T _Ej)]+T _Ei{ X _EjLn (X _Ej/ X _Ei)+(1-X _Ej) ln[(1-X _Ej)/(1-X _Ei)] (formula I)

X wherein _EjAnd x _EiIt is respectively the mole fraction of crystalline form j and i in the eutectic mixture; (G _j-G _i) be at T _EiFree energy difference between following crystalline form i and the j; Δ H _MejWith Δ H _MeiIt is respectively the congruent melting enthalpy of crystalline form j and i; T _EiAnd T _EjIt is respectively the eutectic temperature of crystalline form i and j; Δ C _PijIt is thermal capacitance variation through eutectic; With R be ideal gas constant.

In table 4, provide form A, the congruent melting data of the reference compound of B and E and selection.

Table 4: form A, the congruent melting data of B and E

	Form A	Form B	Form B
				Fusing point, ℃	274-276	Change mutually	Change mutually
RC is a Phenacetin
				x e	0.25	0.25	0.25
T e, ℃ (on average)	118.2	124.7	124.7
				ΔH me, the kJ/ mole	24.64	25.99	27.08
RC is N-benzanilide (benzanilide)
				x e	0.17	0.18	0.18
T e, ℃ (on average)	155.6	156.6	156.2
				ΔH me, the kJ/ mole	28.32	31.95	31.42
RC is salophen (salophen)
				x e	0.42	0.42	0.42
T e, ℃ (on average)	171.7	170.1	170.1
				ΔH me, the kJ/ mole	25.82	36.83	34.62

The congruent melting data validation change relation between form A and B or E.In table 5, provide other thermodynamical coordinate derived from Δ G-T (Δ S) and Δ G/T-1/T (Δ H) figure.In table 5, also provide the form E/ form A and the form B/ form A paired Δ H that measure from the solution calorimetry to be used for contrast.

Table 5: thermodynamical coordinate

Form/transformation	Δ H (kJ/ mole)	Δ S (the J/ mole/K)	Tt(℃)
				LT=form B, HT=form A	16.63(15.34 *)	38.1	163.3
LT=form E, HT=form A	17.15(17.94 *)	39.2	163.9

The LT=low temperature form

The HT=high temperature form

^*Δ H from the solution dsc data

The energy of discovery form B and E is quite approaching, and the energy of the form of discovery A is higher than form B and E.(form B, the 1.46 ± 0.01g/cm of being associated with crystalline form real density data that put in order of stability by helium colorimeter measurement ³Form E, 1.42 ± 0.01g/cm ³Form A, 1.34 ± 0.01g/cm3.)

By definition, the free energy difference under transition temperature between crystalline form is zero.Calculate the transition temperature that in above table 5, provides according to formula II:

Tt=Δ H/ Δ S (formula II)

The similar transition temperature of form E/ form A and form B/ form A counterpart is less relevant with the capacity volume variance between form E and the B.The similar free energy of form E and B makes and can difficultly determine which kind of form is more thermodynamically stable at ambient temperature.For example, solution heat and congruent melting data suggest form E are more stable, and according to transition energy, DSC data declaration form B is more stable form.

Embodiment 7: moisture absorption

Under 25 ℃, use Surface Measurement SystemsDynamic Vapor Water Sorption analyser to collect the moisture absorption data from 0% to 80%RH.Balance window dm/dT be 0.0003 or maximum time be 120 minutes.

Shown that in Fig. 4 parecoxib na form A is at 25 ℃ moisture absorption curve.Form A absorbs the moisture less than 1% in the 0-60%RH scope, but deliquescence during greater than 60%RH.

The moisture absorption curve that in Fig. 8 and 12, has shown parecoxib na form B and E respectively.Discovery form B and E absorb the moisture less than 1% not as form A moisture absorption in the whole 0-80%RH scope of test.

Claims (13)

1. the parecoxib sodium of crystallized form, its substantially anhydrous and solvation not substantially, it is form E, feature is at least has at least two powder x ray diffraction patterns that are selected from 2 following θ values: 8.8,11.3,15.6,22.4,23.5 and 26.4 ± 0.2 degree.

2. the parecoxib sodium of claim 1, it is form E, the powder x ray diffraction pattern shown in feature is at least substantially as shown in Figure 9.

3. the parecoxib sodium of claim 1, it is form E, feature is at least fourier transform infrared spectroscopy substantially as shown in figure 10.

4. the parecoxib sodium of claim 1, it is form E, feature is at least dsc thermogram substantially as shown in figure 11.

5. parecoxib sodium medicine, the parecoxib sodium of described anhydrous, the non-solvent crystallized form E of the claim 1 comprising at least 90%.

6. the medicine of claim 5, wherein at least 95% parecoxib sodium is anhydrous, the non-solvent crystallized form E of claim 1.

7. the medicine of claim 5, wherein all basically parecoxib sodiums are anhydrous, the non-solvent crystallized form E of claim 1.

8. method for preparing the parecoxib sodium medicine that contains at least 90% the described crystallized form E of claim 1, this method comprises the steps: that the alcohol solvent compound of recrystallize parecoxib sodium from heptane is to produce the crystallized form E of parecoxib sodium.

9. method for preparing the pharmaceutical composition of the illness that can be used for treating the COX-2 mediation, this method comprises the steps: the parecoxib sodium medicine and at least a pharmaceutical excipient of dissolving claim 5 in water-bearing media, to form solution.

10. the method for claim 9 comprises the steps: further that wherein this solution of freeze-drying is to provide the solid particulate that comprises amorphous parecoxib sodium composition.

11. a pharmaceutical composition is comprising the parecoxib sodium medicine and at least a pharmaceutical excipient of the claim 5 for the treatment of significant quantity.

12. the composition of claim 11 is used for the treatment of purposes in the medicine of illness of the mediation of COX-2 in the individuality in preparation.

13. the parecoxib sodium medicine of claim 5 is used for the treatment of purposes in the medicine of illness of the COX-2 mediation in the individuality in preparation.

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