MXPA99001526A - Crytalline form of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide - Google Patents

Abstract

A stable crystalline form of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide is described. This crystal structure, designated Form B, is more stable, has favorable handling properties and is characterized by its melting point, x-ray and other physical characterizations.

Description

CRYSTALLINE FORM OF 4- [5-METHYL-3-PHENYLISOXAZOL-4- ILL BENCENSULFONAMIDE FIELD OF THE INVENTION This invention is in the field of anti-inflammatory pharmaceutical agents and specifically refers to a crystalline form of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide, the methods of preparing the crystalline form, the pharmaceutical compositions and methods to treat disorders associated with cyclooxygenase-2 (COX-2), including inflammation.

BACKGROUND OF THE INVENTION Prostaglandins play a major role in the processes of inflammation and the inhibition of prostaglandin production, especially the production of PGG2, PGH2, and PGE2, have been a common goal of the discoveries of anti-inflammatory drugs. However, common non-steroidal anti-inflammatory drugs (NSAIDs), which are active in the reduction of prostaglandin-induced pain and the inflammation associated with inflammatory processes are also active in the effect on other processes regulated by prostaglandin not associated with the processes of inflammation. In this way, the use of high doses of most common NSAIDs can produce severe side effects, including life-threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long-term therapy is involved. It has been found that the above NSAIDs prevent the production of prostaglandins by inhibiting enzymes in the human metabolic pathway of arachidonic acid / prostaglandin, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named cyclooxygenase-2 (COX-2) or "prostaglandin G / H synthetase II") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects related to the inhibition of cyclooxygenase-1 (COX-1). In the patent of E.U.A. No. 5,633,272, Talley et al., And in International Application O96 / 25405, a group of substituted isoxazoles is described. The compounds are described to be used for the treatment of inflammation and disorders associated with inflammation. 4- [5-Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide demonstrates potential as a selective inhibitor of COX-2 over COX-1. With all compounds and pharmaceutical compositions, the physical and chemical stability of a pharmaceutical compound is important in the commercial development of that active substance. Such stability includes stability to environmental conditions, especially to humidity and under storage conditions. The high stability to different storage conditions is necessary to anticipate the different possible storage conditions during the shelf life of the commercial product. A stable drug avoids the use of special storage conditions as well as frequent replacement by inventory. A drug must also be stable during manufacturing processes which often require grinding of the drug to obtain active material with uniform particle size and surface area. Unstable materials often undergo polymorphic changes. Therefore, any modification of an active substance that improves its stability profile provides a significant benefit over less stable substances. It has been found that 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide can be prepared in different crystalline forms. A previous material (form "A") is unstable after mechanical milling and is also thermally unstable. A recently determined crystalline form ("B" form) is described which is more stable and has improved physical properties.

BRIEF DESCRIPTION OF THE DRAWINGS The figure 1 shows a differential scanning calorimetry (DSC) profile of Form A of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide. Figure 2 shows a differential scanning calorimetry (DSC) profile of Form B of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide. Figure 3a shows an infrared spectrum of form B of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide. Figure 3b shows an infrared spectrum of Form A of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide. Figure 4 shows a ray diffraction pattern X of Form A of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide. Figure 5 shows an X-ray diffraction pattern of Form B of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide.

DETAILED DESCRIPTION OF THE INVENTION It has been discovered that 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide can be prepared in a crystalline form termed "form B". Form B can be characterized by the following methods. FUSION The melting points were determined in an apparatus for Thomas Hoover melting point or in a Mettier FP900 Thermosistem melting point apparatus. The melting intervals were determined by differential scanning calorimetry in a Differential Scanning Calorimeter of TA Instruments (model 2100 controller, model 912 dual calorimeter). The sample (1 to 2 mg) was placed in an unsealed aluminum tray and heated to 10 ° C / minute. Form A showed a melting onset at 160.2 ° C with an exotherm embedded at 170.9 ° C due to rearrangement of the crystal (see Figure 1). Form B showed a melting onset at 170.9 ° C (peak at 172.5 ° C). An example of the DSC profile of Form B is shown in Figure 2.

INFRARED SPECTROSCOPY The infrared spectra were obtained with a Nicolet DRIFT Magna System 550 spectrophotometer (diffuse infrared reflectance with Fourier transforms).

A Spectra-Tech collector system and a 3 mm sample cup were used. The samples (2%) were analyzed in KBr and swept from 400 to 4000 cm-1. An example of an infrared absorption spectrum of Form B is shown in Figure 3a, and that of Form A is shown in Figure 3b. The Y axis represents the reflectance corrected in Kubella-Munk units. The infrared spectrum of form B is characterized by absorptions at approximately 3377, 1170, 1151, 925, 844, 745, 729, and 534 cm "1 which are different from those observed in the spectrum for form A. The spectrum for form A the infrared is characterized in part by an absorption at approximately 723 cm "1 which is different from that observed in the spectrum of form B. The crystals of the form B of the present invention preferably show an infrared spectrum substantially equal to that shown in Figure 3a.

DIFFACTION OF X-RAYS OF POWDER The analysis was developed with a Siemens D5000 powder diffractometer. The materials obtained were measured for 2U values from 2 to 50, with steps of 0.020 and step periods of 2 seconds. Table 1 sets the significant parameters of the main peaks in terms of the values of 2U and the intensities for the form B. An example of the X-ray diffraction pattern for the form A is shown in figure 4. An example of the pattern X-ray diffraction for form B is shown in figure 5. The significant differences between form A and form B are evident at 12,221, 15,447, 17,081, 19,798 and 23,861.

TABLE I PICO ÁNGULO- 2 í ESPACIAMIENTO PICO I / IMAX NO. (DEGREES) D Cps (%) 1 12,221 7.2361 502.38 63.29 2 13.693"6.4617 38.03 4.79 3 14,227 6.2203 51.46 6.48 4 15,447 5.7314 599.94 75.58 15.801 5.6039 793.79 100.00 6 16,678 5.3110 239.95 30.23 7 17,081 5,168 331.31 41,74 8 18,165 4.8796 270.21 34.04 9 19,066 4.6510 73.16 9.22 19,400 4.5717 200.13 25.21 11 19.798 4.4807 789.23 99.43 12 20,578 4.3126 209.43 26.38 13 22,008 4.0354 691.33 87.09 14 22,540 3.9414 71.87 9.05 22.975 3.8678 137.23 17.29 16 23,580 3.7699 394.27 49.67 17 23,861 3.7261 602.27 75.87 18 24,553 3.6226 397.23 50.04 TABLE I (CONTINUED) 19 25.206 3.5302 192.44 24.24 25,560 3.4822 77.74 9.79 21 25.940 3.4320 31.47 3.96 22 26.200 3.3985 20.87 2.63 23 27.295 3.2646 151.54 19.09 24 28,595 3,191 207.74 26.17 29.124 3.0636 161.44 20.34 26 29.656 3.0099 73.94 9.32 Form B can be. prepared by recrystallization of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide from an appropriate solvent. To prepare form B, 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide is dissolved in a volume of solvent and cooled until the crystals are formed. Preferably, the compound is added to a solvent at a temperature of at least about 25 ° C. More preferably, the temperature of the solvent is between 30 ° C and the boiling point of the solvent. An even more preferred temperature is in the range of about 65-75 ° C. Alternatively, the hot solvent may be added to the compound and the composition may be cooled until the crystals are formed. Preferably, the solvent is at a temperature of at least 25 ° C. More preferably, the temperature of the solvent is at a temperature in the range of 50-80 ° C. Even more preferred, the temperature is in a range near 65-75 ° C. Preferably, the compound is mixed with an amount of solvent of about three times the weight of the compound. More preferably, the ratio of the solvent to compound is about 7 to 10 times. Preferably, the solution is slowly cooled to precipitate form B. More preferably, the solution is cooled at a slower rate of 0.5 ° C / minute. Even more preferably, the solution is cooled at a rate of about 0.3 ° C / minute or slower. A suitable solvent is a solvent or mixture of solvents which dissolves the compound and any impurity at an elevated temperature, but upon cooling, preferentially precipitates form B. A suitable solvent is selected from alcohol, methylterbutyl ether, methyl ethyl ketone and a combination of solvents selected from alcohol, methyl butyl ether, acetonitrile, water, acetone, tetrahydrofuran and methyl ethyl ketone. An alcohol or aqueous alcohol is preferred. A more preferred solvent is selected from methanol, aqueous methanol, ethanol, aqueous ethanol, isopropyl alcohol and aqueous isopropyl alcohol. Even more preferred is aqueous methanol, methanol, 3A ethanol, aqueous ethanol and a mixture of isopropanol / methanol. Alternatively, the compound is dissolved in a solvent and a co-solvent is added to aid in the crystallization of the desired form. The crystals of form B thus formed are separated from the solvent by means such as filtration or centrifugation. Preferably, the crystals are dried, and more preferably at a temperature in the range of about 30 ° C to 100 ° C. Even more preferably, the crystals are dried under vacuum. Alternatively, form B can be prepared by heating form A to a temperature sufficient to convert it to form B. Preferably, form A is heated to a temperature in the range of 50 ° C to about 140 ° C.

PREPARATION The following examples contain detailed descriptions of the preparation methods of Form B. These detailed descriptions fall within the field, and serve to exemplify the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the field of the invention. All parts are by weight and temperatures are in degrees centigrade unless otherwise indicated. 4- [5-Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide was prepared by the following method where ethanol 3A is an aqueous ethanol (5% water) denatured with methanol: EXAMPLE 1 Step 1. Preparation of oxime d-deoxybenzoin Sodium acetate trihydrate (152.5 g, 1.12 mol, 1.1 eq) was added to deoxybenzoin (200 g, 1.02 mol) and dissolved with ethanol (3A, 0.8 1) and water ( 0.24 1) in a 5 liter flask with mechanical stirrer, reflux condenser and thermometer. The solution was stirred and heated to 70 + 1 ° C. Water (0.1 l) was added to the hydroxylamine hydrochloride (78.0 g, 1.12 mol, 1.1 eq.) In a separate 500 ml flask with stirring. The hydroxylamine hydrochloride solution was transferred to the deoxybenzoin solution, while the reaction mixture was maintained at the temperature of 70 ° C. The mixture was heated to boiling (about 84 ° C) and maintained at this temperature for 40 minutes. The mixture was cooled to 40 ° C in two hours and water (10.5 1) was added to the reaction mixture. The reaction mixture was cooled to 20 ° C with stirring, over a period of one hour. The crystals formed from the pure oxime which were separated by filtration (Buchner funnel, Whatman No.l filter paper) using the vacuum line, were washed with a mixture of 50 ml of 3A ethanol and 100 ml of water, and with a 1 liter of water. The solid was dried under vacuum for 2 hours, and at 55 ° C under the vacuum line for 12 hours to provide the oxime of pure deoxybenzoin (213.2 g, 99%).

Step 2_. Preparation of 5-hydroxy-5-methyl-3,4-diphenylisoxazoline. The deoxybenzoin oxime (step 1) was dissolved in anhydrous THF (565 ml) under nitrogen atmosphere. The solution was cooled to -20 ° C. The solution was treated with lithium diisopropylamide (2 M, 800 ml, 1.60 mol) while allowing the reaction temperature to warm to 10-15 ° C. The reaction mixture was cooled between -10 ° C and -20 ° C and anhydrous ethyl acetate (218 ml) was added to the solution, while allowing the reaction temperature to rise to a maximum of 25 ° C and kept like this for 30 minutes at 25 ° C. The reaction mixture was cooled to 0 C. To a quench flask was added water and cooled to 0-5 ° C. The pre-cooled reaction mixture was transferred from the reaction flask to the quench flask while maintaining the temperature of the quench mixture below 25 ° C. The extinguishing mixture was cooled to 0-5 ° C. Hydrochloric acid (12 M) was added to the mixture, keeping the temperature below 25 ° C during the addition, controlling the rate of addition and stirring until all the solids dissolved (approximately 5 minutes). The pH of the stirred mixture was measured and was between pH = 3-4. The layers were separated and the organic layer was removed. Heptane organic layer was added with stirring. The organic layer was distilled until the bath temperature reached 90-91 ° C, the solution was cooled to 5 ° C and filtered. The solid was washed with 2 portions of 300 ml of ethyl acetate / heptane (20/80), and cooled to 5 ° C. The solid product was dried in the funnel for several hours, then dried at room temperature under vacuum with nitrogen flow throughout the weekend to provide the isoxazoline (108.75g, 57.7%).

Step 3. Preparation of 4- [(5-methyl-3-phenyl) -4-isoxazolyl] -benzenesulfonamide. The 5-hydroxy-5-methyl-3,4-diphenylisoxazoline (step 2) (142 g, 0.56 mol) was dissolved in dichloromethane (568 ml) in a 3 liter round bottom flask equipped with a heating mantle, stirrer mechanical, cold water condenser, J-KEM temperature controller and a thermocouple, forming a suspension. The suspension was stirred and cooled to <; 10 ° C. Chlorosulphonic acid (335 ml, 586 g, 5.04 mol) was added to the suspension, keeping the temperature of the flask below 20 ° C by controlling the addition. The mixture was heated to reflux (about 40 ° C), maintained so for 5 hours, then cooled to 0-5 ° C. The cooled reaction solution was slowly transferred to a 3-liter three-necked round bottom flask (with mechanical stirrer and thermocouple) containing water (1000 ml) previously cooled to 0-5 ° C, using vigorous stirring and maintaining the temperature of the flask. bathroom below 10 ° C. The mixture was stirred for an additional 5 minutes. The layers were separated. In a separate 3-liter flask (with mechanical stirrer, external ice / salt bath, and thermocouple), 28% ammonium hydroxide was cooled (700 ml) at 0-5 ° C. The methylene chloride solution was transferred to the stirred ammonium hydroxide solution, keeping the temperature below 10 ° C. The mixture was stirred at room temperature for 60 minutes. The resulting suspension was filtered and the solid was washed with water (200 ml) and dried to give 4- [(5-methyl-3-phenyl) -4-isoxazolyl] benzenesulfonamide as a white solid (94.3 g, 53. 5%) .

Step 4; Recrystallization of 4- [(5-methyl-3-phenyl) -4-isoxazolyl] benzenesulfonamide The 4- [(5-methyl-3-phenyl) -4-isoxazolyl] benzenesulfonamide from step 3 was dissolved in 300 mL of methyl ethyl ketone boiling (2-butanone) and diluted with 10% aqueous isopropyl alcohol (300 mL, (270 mL of anhydrous isopropyl alcohol and 30 mL of water)). The material was cooled to room temperature, where the crystals formed. The crystals were separated by filtration and dried in a vacuum drying oven (10 mm Hg, 100 ° C) to obtain the pure B form (112.95 g, 65%): mp 172-173 ° C.

EXAMPLE 2 The 5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (Example 1 step 3) (3 g) was combined with 82% ethanol 3A / 20% water (9 mL) and heated until the solids dissolved. The flask was cooled in a bath of running water and maintained for 1 hour to form a precipitate. The solid was filtered and washed with 3A ethanol. The material was heated to dryness under reduced pressure (50-60 ° C, 20 in Hg). The formed material was identified as form B.

EXAMPLE 3 The 5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (Example 1 step 3) (10 g) was combined with 3A ethanol (100 mL) and heated until the solids dissolved (about 70 ° C). The flask was cooled to 20-25 ° C in 1.5 hours and kept so for 30 minutes to form a precipitate. The solid was filtered (Whatman filter paper # 1) and washed with water. The material was heated to dryness under vacuum (90 ° C, 50-100 mm Hg). The material formed was identified as form B.

EXAMPLE 4 -Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (Example 1, step 3) (9.8 g), methanol (73.5 mL) and water (24.5 mL) were combined and heated to 65-70 ° C. The solution remained so for about 10 minutes and was filtered while hot to remove any particulate matter. The solution was slowly cooled to 50 ° C (about 0.3 ° C / min) and maintained at 50 ° C for 1 hour (crystallization begins during the resting period). The solution was subsequently cooled to 5 ° C (about 0.3 ° C / min) and maintained at 5 ° C for 1 hour. The product was separated by filtration and washed with 10 mL of a cold mixture of methanol / water (75/25). The product was dried at 95-100 ° C for 4 hours to yield 8.55 g of Form B.

EXAMPLE 5 A mixture of methanol / isopropanol (80/20, 120 mL) was added to the 5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (Example 1 step 3) (25 g) and heated to about 68 ° C. The solution was kept so for 15 minutes and filtered with a glass filtration funnel, while hot, to remove any particulate matter. The solution was slowly cooled to 5 ° C over a period of 3.3 hours (about 0.3 ° C / min) and maintained at 5 ° C for 2 hours. The product was separated by filtration and washed with 10 mL of cold mixture of methanol / isopropanol (80/20). The product was dried at 95-100 ° C for 3 hours to yield 11 g of Form B.

COMPARATIVE EXAMPLE 6 -Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (Example 1, step 3) (10 g) was combined with 20 mL of water: methanol (25:75) mixture, and heated until the solids dissolved. The flask containing the solution was placed on ice and the mixture was rapidly cooled to < 10 ° C with no crystallization observed upon cooling. A few crystals were observed forming at the bottom of the flask, and soon the crystallization became rapid. Letting it stay for about 10 minutes. The solid was filtered and washed with 75% aqueous methanol. The material was heated to dryness under reduced pressure with nitrogen bleeding (50-60 ° C)., 20 in Hg). The formed material was identified as form A. The present invention also includes a method of treating or preventing a disorder associated with cyclooxygenase-2 such as inflammation in a subject, the method includes treating the subject having or being susceptible to such inflammation or disorder with a therapeutically effective amount of the crystalline B-form of 4- [5-methyl-3-phenylisoxasol-4-yl] benzenesulfonamide. Form B of 4- [5-methyl-3-phenylisoxasol-4-yl] benzenesulfonamide could be useful for, but not limited to, the treatment of inflammation in a subject, and for the treatment of other disorders mediated by cyclooxygenase-2, such as, an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, form B could be useful for treating arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. Form B could be useful in the treatment of asthma, bronchitis, menstrual cramps, labor, tendinitis, bursitis, liver diseases including hepatitis, skin-related conditions such as psoriasis, eczema, burns and dermatitis, and of post-operative inflammation including that of ophthalmic intervention such as cataract operation and corneal operation. Form B could also be useful to treat gastrointestinal conditions such as inflammatory bowel diseases, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. Form B could be useful for the treatment or prevention of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, uterus and skin. Form B could be useful in treating glaucoma, angiogenesis and retinopathies. Form B could be useful in the treatment of inflammations in diseases such as vascular diseases including atherosclerosis, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, Type I diabetes, neuromuscular diseases that »include severe amiastenia, white matter disease which include multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet syndrome, polyomyositis, gingivitis, nephritis, hypersensitivity, inflammation that occurs after damage , myocardial ischemia and the like. Form B could also be useful in the treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia, and acute damage to ocular tissue. Form B could also be useful in the treatment of pulmonary inflammations, such as those associated with viral infections and cystic fibrosis. Form B could also be useful for the treatment of certain disorders of the central nervous system, such as cortical dementias including Alzheimer's disease, and damage to the central nervous system resulting from cardiac arrest, ischemia, seizures and trauma. Form B is useful as an anti-inflammatory agent, as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. Form B could also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome, osteoporosis and to inhibit bone resorption. Form B may also be useful in the treatment of pain, but is not limited to postoperative pain, dental pain, muscle and pain resulting from cancer. Form B could be useful for the prevention of cardiovascular diseases, such as atherosclerosis, liver diseases and dementias, such as Alzheimer's disease. In addition to being useful for human treatment, this form is also useful for veterinary treatment of pet animals, exotic animals and farm animals, including mammals, rodents and the like. The most preferred animals include horses, dogs and cats. The present B form can also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatories, such as together with steroids, NSAIDs, inhibitors of 5-lipoxygenase LTB4 receptor antagonists and inhibitors of the hydrolase of LTA4. Suitable inhibitors of the hydrolase of LTA4 include RP-64966, the benzyl ester of (S, S) -3-amino-4- (4-benzyloxyphenyl) -2-hydroxybutyric acid (Scripps Res. Inst.), N- ( 2 (R) - (cyclohexylmethyl) -3- (hydroxycarbamoyl) propionyl) -L-alanine (Searle), 7- (4- (4-ureidobenzyl) phenyl) heptanoic acid (Rhone-Poulenc Rorer), and the lithium salt of 3- (3- (lE, 3E-tetradecadienyl) -2-oxiranyl) benzoic acid (Searle). Suitable LTB4 receptor antagonists include, among others, ebselen, linazolast, ontazolast, Bayer Bay-x-1005, Ciba Geygi composite CGS-25019C, Leo Denmark ETH-615 compound, Merck MAFP compound, Terumo TMK-688 compound, Tanabe T compound -0757, compounds Lilly LY-213024, LY-210073, LY223982, LY233469, and LY255283, LY-293111, 264086 and 292728, compounds ONO ONO-LB457, ONO-4057, and ONO-LB-448, compound Shionogi S-2474 , calcitrol, Lilly compounds Searle compounds SC-53228, SC-41930, SC-50605 and SC-51146, Warner Lambert BPC 15 compounds, compound. Smithkline Beecham SB-209247 and composite SK & F SKF-104493. Preferably, LTB4 receptor antagonists are selected from calcitrol, ebselen, Bayer Bay-x-1005, Ciba Geigy CGS-25019C compound, Leo Denmark ETH-615 compound, Lilly compound LY-293111, Ono ONO-4057 compound, and Terumo TMK-688 compound. Suitable 5-OR inhibitors include, inter alia, Abbott A-76745, 78773 and ABT761, Bayer Bay-X-1005, Citomed CMI-392 compounds. Eisai E-3040, Scotia Pharmaceutica EF-40, Fujirebio F-1322, Merckle ML-3000, Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, flobufen, linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton, pranlukast , tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast. The present form can also be used in combination therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (ie non-addictive) analgesics, inhibitors of monoamine consumption, regulatory agents of adenosine, cannabinoid derivatives, Substance P antagonist, neurokinin-1 receptor antagonists and sodium channel blockers, among others. Further combinations with compounds selected from morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocin, meptazinol, hydrocodone, oxycodone, methadone, Tramadol [(+) enantiomer], Dup 747, Dinorphin A, Enadoline, RP may be preferred. -60180, HN-11608, E-2078, ICI-204448, acetaminophen (paracetamol), propoxyphene, nalbuphine, E-4018, filnadol, mirfentanil, amitriptyline, DuP631, Tramdol [(-) enantiomer], GP-531, acadesin, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92, tramadol (racemate), Dinorphin A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI-204448, CT-3, CP- 99,994, and CP-99, 994. The present invention includes a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form B of 4- [5-methyl-3-phenylisoxazol-4-yl] benzensulfonamide in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent. Further included within this invention is a class of pharmaceutical compositions comprising the crystalline form B in association with one or more pharmaceutically acceptable non-toxic carriers, and / or diluents and / or adjuvants, (collectively referred to hereinbelow as carrier materials) and, if desired, other active ingredients. Form B of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the intended treatment. The active form B and the compositions can, for example, be administered orally, intravenously, intraperitoneally, subcutaneously, intramuscularly or topically. For oral administration, the pharmaceutical composition should be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient can also be administered by injection as a composition wherein, for example, saline solution, dextrose solution or water can be used as the appropriate carrier. The amount of therapeutically active compound that is administered and the dosage regimen for the treatment of a disease condition with the compound and / or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the patient. subject, the severity of the disease, the route and frequency of administration, and the particular compound used, and therefore may vary widely. The pharmaceutical composition may contain active ingredients in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and more preferably between about 1 and 100 mg. A daily dose of about 0.01 to 100 mg / kg of body weight, preferably between about 0.5 and about 20 mg / kg of body weight and more preferably about 0.1 to 10 mg / kg of body weight, may be appropriate. The daily dose can be administered in 1 to 4 doses per day. In the case of psoriasis and other skin conditions it may be preferable to apply a topical preparation to the affected area 2 to 4 times per day. For inflammations of the eye or other external tissues, for example, mouth and skin, the formulations are preferably applied as a topical ointment or cream, such as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% p / p, preferably 0.2 to 20% w / w and more preferably 0.4 to 15% w / w. When formulated as an ointment, the active ingredients can be used with either a paraffinic ointment base or a water miscible base. Alternatively, the active ingredients can be formulated in an oil-in-water-based cream. If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyhydric alcohol such as propylene glycol, butan-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. of all of them. The topical formulation may desirably include a compound that increases the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. Form B can also be administered by a transdermal artifact, preferably topical administration will be completed using a patch either of the reservoir type and porous membrane or of a variety of solid matrix. In any case, the active agent is continuously released from the reservoir or microcapsules through a membrane towards the adhesive permeable to the active agent, which is in contact with the skin or mucosa of the container. If the active agent is absorbed through the skin, a predetermined and controlled flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent can also function as the membrane. The oil phase of the emulsions of this invention may be constituted with known ingredients in a known manner. While the phase may merely comprise an emulsifier, it may use a mixture of at least one emulsifier with a fat or with an oil or both. Preferably a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together the emulsifier or emulsifiers with or without the stabilizer or stabilizers form the so-called emulsifying wax, and the wax together with the oil and the fat form the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and stabilizers for emulsions suitable for use in the formulation of the present invention include Tween 60, Span 80, ketostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of oils or greases suitable for the formulation, is based on achieving the desired cosmetic properties, since the solubility of the active compound in most of the oils that are likely to be used in the formulation of the pharmaceutical emulsion, is very low. Therefore, the cream should preferably be of the non-greasy type, which does not tint and should be washable, with adequate consistency to prevent runoff from the tubes or other containers. Linear or branched chain mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate can be used, butyl stearate, 2-ethylhexyl palmitate, or a mixture of branched chain esters. These can be used alone or in combination, depending on the properties needed. Alternatively, high melting point lipids such as mild white paraffin and / or liquid paraffin or other mineral oil may be used. Formulations suitable for topical administration to the eyes also include ophthalmic drops, wherein the active ingredients are dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in said formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly close to 1.5% w / w. For therapeutic purposes, Form B is ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compound can be mixed with lactose, sucrose, powdered starch, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium salts and calcium of sulfuric and phosphoric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tabletted or encapsulated for proper administration. Such capsules or tablets may contain a controlled release formulation that could be provided in a dispersion of the active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous, isotonic and sterile injectable solutions or suspensions. These solutions and suspensions may be prepared with sterile powders or with granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The crystalline form B can also be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, safflower oil, benzyl alcohol, and / or various pH regulators. Other adjuvants and modes of administration are well and widely known in the pharmaceutical industry. All references mentioned are incorporated by reference as if they were written here. Although this invention has been described with respect to specific modalities, the details of these modalities should not be taken as limitations.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - A form of 4- [5-methyl-3-phenylisoxazol-4-yl] -benzenesulfonamide having a melting point of about 170 to 174 °.

2. A form according to claim 1, having a spectrum to the IR with the following peaks: 1170, 925, 844, and 729 cm "1.

3. A form according to claim 1 having a spectrum to the IR without a significant peak at 723 cm "1

4. - A form according to claim 1, having a powder X-ray diffraction pattern substantially as shown in figure

5. 5. - A pharmaceutical mixture comprising a therapeutically effective amount of the crystalline form B of the 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

6. The use of a crystalline form B of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide for the preparation of a medicament for the treatment or prevention of disorders associated with cyclooxygenase-2 in a subject .

7. The use according to claim 6 for use in the treatment of inflammation.

8. The use according to claim 6, for use in the treatment of arthritis.

9. The use according to claim 6, for use in the treatment of pain

10. The use according to claim 6, for use in the treatment of fever.

11. A method of preparing crystals, according to claim 1, which comprises recrystallizing 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide using an alcohol-based solvent system.

12. The process according to claim 11, further characterized in that the solvent system comprises one or more solvents selected from methanol, isopropanol, aqueous methanol and aqueous ethanol.

13. The method according to claim 11, characterized in that the crystals are recrystallized from a mixture of isopropanol and methanol.