Polymorphic form of rimonabant, its method of preparation and compositions pharmaceutical while containing.
I The present invention provides a novel polymorph of n-piperidino-5 - (4-chlorophenyl) - L-- (2.4 a-dichlorophényI) - 4 methyl-3-pyrazol-carboxamide and a process for its preparation. More particularly, the invention relates to the preparation of this polymorph form II called, as well as pharmaceutical compositions containing the same. Heterocylic-piperidino-5 - (4-chlorophenyl) - L-- (2.4 a-dichIorophényl) - 4 methyl-3 pyrazole carboxamide derivatives whose denomination Proprietary is rimonabant is a cannabinoid receptor antagonist a CBi, described for the first time in European Patent specification EP 0,656 354. The process claimed in this Patent allows the preparation of rimonabant in crystalline form referred to herein as form I. it has now been found that rimonabant can exist in different polymorphic crystalline foimes which differ from each other by their stability, their physical properties, their spectral characteristics and by their method of preparation. Thus the present invention relates to a novel polymorphic form of rimonabant, designated form Π, also provided are methods for preparing rimonabant polymorph II form, as well as pharmaceutical compositions containing said form II. European Patent specification EP 0,656 354 makes no reference to the existence of polymorphic forms specific rimonabant. In this Patent it is described that the compound is isolated according to conventional techniques; more precisely, according to the exemplified embodiments, the product is obtained after crystallization in isopropyl ether or by cooling a medium containing the product in methylcyclohexane. It has now been found that by using particular conditions of crystallization, there is obtained a new stable crystalline form designated as Form II. The crystalline form II of rimonabant has been characterized and compared to the crystalline form I previously described. Infrared spectra (I.R.) of 2 crystalline forms of rimonabant have been recorded on spectrophotometers Perkin Elmer's 2000 FT-soild, between 400 and 4000 cm to over 1 cm to over 1, with a resolution of 4 cm apart and 1, in a potassium bromide pellet, the test compound is the concentration of 0.5% by mass. These spectra, are characterized by the absorption bands reported in tables 1 and 2 following. THE TABle 1: I.R. spectrum, formI λ (cms-I agonist) 3265.53 1667.78 901, 57 761, 61 The corresponding spectra are reproduced in Figures 1 and 2. It has recorded the powder X-ray diffractograms (Rz) for the crystalline forms I and II. The profile of X-ray diffraction powder (diffraction angle) has been established with a d500tt and Siemens diffractometer (theta/theta), Bragg type-to-Brentano focalisation; the source CuKcq, λ=1, 5406â; scan domain 2° to 40° to 1° per minute in 2 theta Bragg. The diffractograms of characteristic lines 2 compounds are reported in the following table: Table 3: X-ray powder, form I The diffractograms corresponding are reproduced in Figures 3 and 4. Rimonabant Π crystalline form is also characterized by its crystal structure in which the lattice parameters were determined by single crystal X-ray diffraction. From the monocrystal rimonabant form II, having obtained a simulated powder diffractogram (theoretical diffractogram) has been compared to that obtained experimentally. Figure 5 shows the comparison of the diffractograms. The very high similarity observed indicates that the structure contained in the powder determined in the crystal and that this structure is unique, it is to say that there is not another polymorphic form mixed to form H of rimonabant. Differential scanning calorimetry of 2 crystalline forms was performed under the same conditions on a differential scanning apparatus MDSCs 2920, marketed by AEG instrumentation LLC (bets); it is carried out under nitrogen atmosphere, the initial temperature is from 30 °c, it increases at a rate of 10 °c/min. For each compound, the melting peak is measured and the enthalpy difference of the substance (ha) before and after melting, in joules per gram of material. The form I has a melting peak to 156 + 2 °c with ah=65 + 2 j/g. The form II has a melting peak to 157 + 2 °c with ah=66 ± 2 j/g. Thus the invention relates to the crystalline polymorph of rimonabant (form II) characterized by the absorption bands of the infrared spectrum as described in table 2. This polymorph is also characterized by the characteristic lines of the powder X-ray diffractogram as described in table 4. ^ . -. Further, the crystalline polymorph is characterized by a melting peak at 157 + 2 °c with ah=66 ± 2 j/g. Were also measured the solubility of 2 crystalline forms of rimonabant in the same solvent. The approach is described in response measurement of higher Solubility in-J.W. Mullin's. Crystallization: 3 editing ., At Ipswich (GA): a Butterworth - Calvi, 1993, ρ. 105. The measurements were performed for each of the crystal forms, in solution in methylcyclohexane at temperatures from 10 °c to 70 °c. From the equilibrium, for each temperature, the undissolved crystalline form is characterized by 012721 infrared spectroscopy especially in its main bands. The 2 tests performed with each of the crystalline forms are reported in the following table: It appears that rimonabant form Π is less soluble to at all temperatures between 70 °c 10 °c and, this shows that rimonabant form II is thermodynamically more stable than rimonabant form I. According to the present invention, the process for obtaining form hence he rimonabant is characterized in that: a) hot rimonabant is dissolved in a solvent selected from: - methylcyclohexane pure or containing 1 to 10% of water by volume, - The I ' acetonitrile - the 4-methyl 2 a-pentanone refrigerant, - acetone, or a mixture of these solvents; b) optionally, the medium is cooled to a temperature between 5 °c and 25 °c, c) formed crystals are filtered at a temperature between 5 °c and 25 °c. Operating method in particular, object of the present invention, at the end of step a), the medium is seeded with rimonabant having the crystalline form II. Rimonabant is dissolved in step a) is rimonabant in crystalline form I as obtained according to EP 0,656 354 or rimonabant form II or a mixture of both forms. Can also be prepared rimonabant in crystalline form I directly from acid 5 - (4-chlorophenyl) - L-- (2.4-dichlorophenyl) - 4 a-methylpyrazole and 3-carboxylic, according to the method described in EP 0,656 354: acid is converted to its acid chloride by the action of thionyl chloride, and secondly with the 1 a-aminopiperidine in the presence of triethylamine. The present invention has several particular embodiments. A particular method is characterized in that: a) dissolving rimonabant to the concentration of 150 to 220 g/l, by heating to the reflux temperature of a solvent consisting of 1 to 10% cyclohexane containing water, and then, having been steps b), d) and d) hereinafter, having been directly steps c) and d); b) cooling the medium at a temperature between 40 °c and 50 °c, then heats the medium to a temperature between 60 °c and 75 °c during 2 hours and maintained; c) the temperature is lowered with a ramp cooling -15 °c to -20 °c per hour up to a temperature between 5 °c and 20 °c; d) formed crystals are filtered at a temperature between 5 °c and 20 °c. Preferably, the method is characterized in that: - step a) dissolving the compound at a concentration of 200 g/l in a solvent consisting of 1 to 5% methylcyclohexane containing water, by heating to the reflux temperature of the solvent; - step b) is cooled to 45 °c in 30 minutes at medium; and then the medium is heated to 70 °c + 2 °c and the temperature is held for 2 hours; - in step c) the temperature is lowered with a ramp of -15 °c to -20 °c per hour up to a temperature of between 15 °c and 20 °c. In one embodiment of the method according to the invention: a) dissolving rimonabant to the concentration of 50 to 250 g/l in a solvent consisting of or containing pure methylcyclohexane b) cooling the medium to a temperature between 65 °c and 75 °c and allowed 2 hours at this temperature; c) is seeded the medium by addition of 1% to 5% by weight of rimonabant, crystalline form II; d) the temperature is lowered with a ramp cooling -15 °c to -20 °c per hour up to a temperature between 10 °c and 20 °c; e) formed crystals are filtered at a temperature between 10 °c and 20 °c. Preferentially, the method is characterized in that: - step a) rimonabant is to the concentration of 120 to 150 g/l; - step b), is cooled to 70 °c; - step c), the crystallization is initiated with 2% by weight of rimonabant in crystalline form it In another preparation: a) dissolving rimonabant to the concentration of 200 to 250 g/l by heating at the temperature of the solvent consisting either of methylcyclohexane, or methyl isobutyl ketone, or acetone, or the mixture of these solvents; b) the temperature is lowered with a ramp cooling -10 °c to -20 °c per hour until the commencement nucleation, optionally is maintained to the nucleation temperature for 1 hour; c) is lowered again the temperature with a ramp cooling -10 °c to -20 °c per hour up to a temperature between 10 °c and 20 °c; d) filtering the crystals at a temperature between 10 °c and 20 °c. Another embodiment of the method according to the invention is characterized in that DC: a) dissolving rimonabant to 120 to 250 g/l concentration by heating to the reflux temperature of the solvent which is methylcyclohexane; b) is cooled to a temperature between 80 °c and 90 °c; c) is seeded the medium by addition of 1% to 5% by weight of rimonabant crystalline form II suspended in methylcyclohexane and the temperature is held for one hour between 80 °c and 90 °c; d.) is cooled with a cooling manifold of -15 °c to -20 °c per hour up to a temperature between 10 °c and 20 °c; e) formed crystals are filtered at a temperature between 10 °c and 20 °c. Preferentially, the method is characterized in that: - step a), is dissolved rimonabant to 200 g/l concentration in the solvent; - step b), is cooled to 85 °c ± 2 °c; - step c) is seeded by 2% by weight of rimonabant Π form, and then maintains the temperature of the medium for one hour at 85 °c ± 2 °c. Another method for obtaining particular according to the invention is characterized in that: a) rimonabant is dissolved at room temperature in acetonitrile, until saturation; b) is evaporated at room temperature; c) collecting the crystals formed. According to another embodiment, there may be used a solvent of low polarity such as methylcyclohexane pure and obtain rimonabant form II using primer rimonabant form II for crystallization. The method for preparing the compound according to the invention is characterized in that: a) is heated rimonabant to the concentration of 150 g/l to 300 g/l in methylcyclohexane, at a temperature between 85 °c and 95 °c; b) is seeded with 1% to 5% medium weight of rimonabant in crystalline form II and maintaining the temperature at between 85 °c and 95 °c for several hours until disappearance of the form I; c) the temperature is lowered with a ramp cooling -10 °c to -20 °c per hour up to a temperature of 10 °c to 20 °c; d) formed crystals are filtered at a temperature between 10 °c and 20 °c. According to a particular embodiment, in step a) is prepared rimonabant to the concentration of 150 g/l to 300 g/i in methylcyclohexane by treating acid chloride 5 - (4-chlorophenyl) - L-- (2.4-dichlorophenyl) - 4 a-méthylpyrazoIe and 3 a-carboxyliquc, by the 1 a-aminopiperidine in a mixture of methyl cyclohexane and tetrahydrofuran in the presence of triethylamine. The crystalline form of rimonabant Π stability greater than that of the form I previously described. In addition, the crystalline form II of rimonabant is obtainable by the method clearly disclosed, this is advantageous for industrial production of crystalline form II of rimonabant. Thus the crystalline form II of rimonabant is especially suitable for the preparation of pharmaceutical compositions useful for the treatment of all diseases in which a cannabinoid receptor antagonist CBj is indicated. According to another aspect, the present invention relates to pharmaceutical compositions comprising as active ingredient rimonabant in crystalline form it In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or local, the active ingredient, alone or in combination with another active ingredient, can be administered in unit form of administration, mixed with pharmaceutical carriers classiqués, to animals and to human beings. The unit shapes suitable dosage comprising the oral forms such as tablets, capsules, pills, powders, granules and oral solutions or suspensions, the sublingual and buccal administration forms, aerosols, implants, the forms for topical administration, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular. In the pharmaceutical compositions of the present invention, the active ingredient or active ingredients are generally formulated in dosage units. The dosage unit contains 0.5 to 300 mg, preferably of from 5 to 60 mg, preferably 5 to 40 mg per dosage unit, for daily administrations, one or more times per day. Although these assays are examples of average situations, there may be specific cases where higher dosages or lower concentrations are suitable, such assays also belong to the invention. The usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient. When preparing a solid composition in the form of tablets or capsules, is added to the active ingredient, micronized or not, a mixture of pharmaceutical excipients which may be composed of diluents such as lactose, mannitol, microcrystalline cellulose, starch, dicalcium phosphate, binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, of disintegrants such as crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, croscarmellose sodium, flow agents such as silica, talc, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulfate, polysorbate 80, Poloxamer 188 may be added to the formulation. The tablets can be made by various techniques, direct compression, dry granulation, wet granulation, hot melt (hot melt). The tablets may be sugar-coated or bare (by for example sucrose) or coated with various polymers or other suitable materials. The tablets may have a flash, delayed or sustained release by producing polymer matrices or by using specific polymers in the film coating. The capsules may be soft or hard, pellicuiées or not to have a activity a flash, sustained or controlled (e.g. by enteric form). These may contain not only a solid formulation formulated as above for the tablets but also liquids or semisolids. A preparation in the form of syrup or elixir may contain the active ingredient or the active ingredients together with a sweetener, preferably acaloric, methylparaben and propyl paraben as antiseptic, as well as taste-masking agent and a suitable dye. Powders or water dispersible granules may contain the active ingredient or the active ingredients in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone or povidone, as well as with sweeteners or taste correctors. For rectal administration, use is made of suppositories which are prepared with binders melting at the rectal temperature for example cocoa butter or polyethylene glycols. For parenteral administration, intranasal or intraocular, aqueous suspensions, isotonic saline solutions or injectable sterile solutions which contain dispersing agents and/or pharmacologically compatible solubilizing agents, e.g. propylene glycol or butylene glycol. Thus, to prepare an aqueous solution intravenously injectable a cosolvent may be used, for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as polysorbate 80 or Poloxamer 188. Preparing an oily solution for intramuscular, can solubilize the active ingredient by a triglyceride or a glycerol ester. For local administration may be creams, ointments, gels, eye drops, sprays. For transdermal administration, can be used patches as multilaminate or reservoir in which the active principle is in alcoholic solution. For administration by inhalation is used an aerosol containing for example sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, freons substitutes or any other biologically compatible propellant gas; it is also possible to use a system containing the active principle alone or combined with an excipient, in powder form. The active ingredient or active ingredients can also be presented as a complex with a cyclodextrin, e.g. A -, β - or The active ingredient or active ingredients can also be formulated as microcapsules or microspheres, optionally with one or more supports or additives. Among the extended release forms useful in the case of chronic treatments, implants may be used. These may be prepared as oily suspension or in the form of suspension of microspheres in an isotonic medium. ΐΐ Preferentially, rimonabant in crystalline form II is administered orally, in a single dosage per day. According to another aspect, the invention also provides a method which comprises administering a therapeutically effective amount of rimonabant crystalline form II. Example 1: obtaining form II free primer in methylcyclohexane to 1.64% water. Solubilized at room temperature 40 g of N-piperidino-5 - (4-chlorophenyl) - L-(2.4-dichlorophenyl) - 4 a-methylpyrazole and 3 carboxamide in 80 ml of tetrahydrofuran and 240 ml of methylcyclohexane. The tetrahydrofuran is driven by distillation at atmospheric pressure. Then interrupted heating and when the temperature is 80 °c + 5 °c, is added 4 ml of deionized water. After cooling to 45 °c + 3 °c and holding for at least 30 min, the product crystallizes. And we then again the heterogeneous medium to 70 °c + 2 °c for a period of at least 2 hours. We complete the crystallization of form II by cooling to 20 °c + 3 °c. Formed crystals are filtered, washed with cyclohexane and dried under vacuum at 75 °c. In this assay, was obtained 38 g of form Π rimonabant. Example 2: obtaining form II in methylcyclohexane to 1.42% water with 2% primer of the form II. With 50 g of N-piperidino-5 - (4-chlorophenyl) - L-- (2.4 a-dichIorophényl) - 4 a-méthylpyrrazole-to-3 carboxamide, methylcyclohexane and 350 ml is added 5 ml of deionized water. The reaction medium is brought to reflux then interrupts the heating. Has 70 °c + 3 °c, starting the crystallization by adding 1 gram of substance form II. Thus stirred 2 hours and then cooled to 20 °c to 70 °c In this assay, was obtained 47.6 g of form II of rimonabant. Example 3: obtaining form II in the 4-methyl 2 a-pentanone is neat. With 10 g of N-piperidino-5 - (4-chlorophenyl) - L-- (2.4 a-dichlorophényI) - 4 a-méthylpyrrazole-to-3 carboxamide, added 50 ml of 4 a-méthyI and 2 a-pentanone refrigerant. The reaction medium is heated to reflux to obtain the homogenization is then cooled to 20 °c + 3 °c. The desired product crystallizes. Formed crystals are filtered, washed with the minimum volume necessary to 4-methyl 2 a-pentanone and dried under vacuum at 60 °c. In this assay, was obtained 4 g of form Π rimonabant. Example 4: obtaining form II in a mixture 20% 4 a-méthyI and 2 a-pentanone and 80% methylcyclohexane With 10 g of N-piperidino-5 - (4-chlorophenyl) - L-- (2.4-dichlorophenyl) - 4 a-methylpyrazole and 3 carboxamide, 10 ml of added 4-methyl 2 a-pentanone and 40 ml of methylcyclohexane. The reaction medium is heated to reflux to obtain the homogenization. Aborting the heating and observed to 40 °c the crystallization of desired product and then allows stirring 20 °c ± 3 °c. Formed crystals are filtered, dried under vacuum and wrings to 60 °c. In this assay, was obtained 7.9 grams of form Π rimonabant. Example 5: obtaining form Π mélanee 60 in a With 10 g of N-piperidino-5 - (4-chlorophenyl) - L-- (2.4-dichlorophenyl) - 4 a-methylpyrazole and 3 carboxamide, added 30 ml of 4-methyl 2 a-pentanone and 20 ml of cyclohexane. The reaction medium is heated to reflux, this results in the homogenization of the medium. Then interrupted heating and then cools to 20 °c + 3 °c. The desired product crystallizes. Formed crystals are filtered, then dried under vacuum to wrings 60 °c. In this assay, was obtained 4.8 g of H form of rimonabant. EXAMPLE 6: obtaining of the π form in a mixing 80% 4-methyl 2 a-pentanone and 20% methylcyclohexane. With 10 g of N-piperidino-5 - (4 a-chIorophényl) - L-- (2.4-dichlorophenyl) - 4 a-methylpyrazole and 3 carboxamide, 40 ml is added methyl 4 a-pentanone and 10 ml of methylcyclohexane. Obtained the homogenization of the reaction medium at reflux of the solvent. Then interrupted heating and leaves to return the medium to 20 °c + 3 °c. The desired product crystallizes. Formed crystals are filtered, then dried under vacuum to wrings 60 °c. In this assay, was obtained 4 g of form II of rimonabant. the R example 7: obtaining form Π with 2 Under nitrogen atmosphere, to a suspension of 5 - 190.80 g acid (4-chlorophenyl) - L-- (2.4-dichlorophenyl) - 4 a-méthyIpyrrazole-to-3-carboxylic in 940 ml methylcyclohexane, added after heating to 83 °c ± 3 °c a solution of 72.2 g of thionyl chloride in 60 ml of methylcyclohexane. Was stirred 2 hours at 83 °c + 3 °c then raises the temperature of the reaction medium ℮η 1 hour until reflux methylcyclohexane while eliminating the excess thionyl chloride by distillation. The reaction medium is cooled to room temperature and adds a solution of triethylamine in 7 ml 382 ml of tetrahydrofuran. The resulting solution is added in 15 minutes to 12 °c + 3 °c a medium consisting of 50.08 g of triethylamine, 55.10 g of 1 a-aminopiperidine and 460 ml of methylcyclohexane. Allowed up the temperature to 20 °c In this assay, was obtained 217 g of form II of rimonabant The invention concerns a novel crystalline polymorph of rimonabant, its preparation method and pharmaceutical compositions containing said novel polymorph. 1. Crystalline polymorph of rimonabant (form Π) characterized by the absorption bands infra red spectrum as described below: (cms and 1) λ λ (1 - α η) 3311.30 1484.80 2737.23 986, 57 1683.48 922, 58 1526.55 781, 02 2. Crystalline polymorph of rimonabant characterized by the parallel bars of the X-ray diffractogram poudr oni described below: 2 Varnishing line angstroms peak at d=17, 41664 5,070 d=8, 70963 10,148 d=8, 19062 10,793 d=5, 82785 15,191 d=4, 63425 19,136 d=3, 49212 25,486 degrees 3. Crystalline polymorph of rimonabant characterized by a melting peak at 157 + 2 °c with ah=66 ± 2 j/g, 4. Process for preparing the compound according to any one of claims 1 to 3 characterized in that: a) hot rimonabant is dissolved in a solvent selected from: - methylcyclohexane pure or containing 1 to 10% of water by volume, 7 - acetonitrile - the 4-methyl 2 a-pentanone refrigerant, - acetone, or a mixture of these solvents; b) optionally, the medium is cooled to a temperature between 5 °c and 25 °c, c) formed crystals are filtered at a temperature between 5 °c and 25 °c. 5. The method of claim 4 characterized in that, after step a), the medium is seeded with rimonabant, crystalline form II. 6. The method according to claim 4, characterized in that: a) dissolving rimonabant to the concentration of 150 to 220 g/l, by heating to the reflux temperature of a solvent consisting of 1 to 10 containing methylcyclohexane b) cooling the medium at a temperature between 40 °c and 50 °c, then heats the medium to a temperature between 60 °c and 75 °c during 2 hours and maintained; c) the temperature is lowered with a ramp cooling -15 °c to -20 °c per hour up to a temperature between 5 °c and 20 °c; d) formed crystals are filtered at a temperature between 5 °c and 20 °c. 7. The method of claim 6 characterized in that: - step a) dissolving the compound at a concentration of 200 g/l in a solvent consisting of 1 to 5% methylcyclohexane containing water, by heating to the reflux temperature of the solvent; - step b) is cooled to 45 °c in 30 minutes at medium; and then the medium is heated to 70 °c + 2 °c and the temperature is held for 2 hours; - in step c) the temperature is lowered with a ramp of -15 °c to -20 °c per hour up to a temperature of between 15 °c and 20 °c. 8. The method of claim 4 characterized in that: a) dissolving rimonabant to the concentration of 50 to 250 g/l in a solvent consisting of methylcyclohexane or pure water containing 1 to 10%; b) cooling the medium to a temperature between 65 °c and 75 °c and allowed 2 hours at this temperature; c) is seeded the medium by addition of 1% to 5% by weight of rimonabant, crystalline form II; d) the temperature is lowered with a ramp cooling -15 °c to -20 °c per hour up to a temperature between 10 °c and 20 °c; e) formed crystals are filtered at a temperature between 10 °c and 20 °c. 9. The method of claim 8 characterized in that: - step a) rimonabant is to the concentration of 120 to 150 g/l; - step b), is cooled to 70 °c; - step c), the crystallization is initiated with 2% by weight of rimonabant in crystalline form it 10. The method of claim 4 characterized in that: a) dissolving rimonabant to the concentration of 200 to 250 g/l by heating at the temperature of the solvent consisting either of methylcyclohexane, or methyl isobutyl ketone, or acetone, or the mixture of these solvents; b) the temperature is lowered with a ramp cooling -10 °c to -20 °c per hour until the commencement nucleation, optionally is maintained to the nucleation temperature for I-hour; c) is lowered again the temperature with a ramp cooling -10 °c to -20 °c per hour up to a temperature between 10 °c and 20 °c; d) filtering the crystals at a temperature between 10 °c and 20 °c. 11. The method according to claim 4, characterized in that: a) dissolving rimonabant to 120 to 250 g/l concentration by heating to the reflux temperature of the solvent which is methylcyclohexane; b) is cooled to a temperature between 80 °c and 90 °c; c) is seeded the medium by addition of 1% to 5% by weight of rimonabant crystalline form II suspended in methylcyclohexane and the temperature is held for one hour between 80 °c and 90 °c; d) the temperature is lowered with a ramp cooling -15 °c to -20 °c per hour up to a temperature between 10 °c and 20 °c; e) formed crystals are filtered at a temperature between 10 °c and 20 °c. 12. The method according to claim 11 characterized in that: - step a), is dissolved rimonabant to 200 g/l concentration in the solvent; - step b), is cooled to 85 °c ± 2 °c; - step c) is seeded by 2% by weight of rimonabant form II, then the temperature of the medium for one hour at 85 °c ± 2 °c. 13. The method according to claim 4, characterized in that: a) rimonabant is dissolved at room temperature in acetonitrile, to - saturating, ; b) is evaporated at room temperature; c) collecting the crystals formed. 14. Process for preparing the compound according to any one of claims 1 to 3 characterized in that: a) is heated rimonabant to the concentration of 150 g/l to 300 g/j in methylcyclohexane, at a temperature between 85 °c and 95 °c; b) is seeded with 1% to 5% medium weight of rimonabant in crystalline form II and maintaining the temperature at between 85 °c and 95 °c for several hours until disappearance of the form I; c) the temperature is lowered with a ramp cooling -15 °c to -20 °c per hour up to a temperature between 10 °c and 20 °c; d) formed crystals are filtered at a temperature between 10 °c and 20 °c. 15. The method of claim 14 characterized in that in step a) is prepared rimonabant to the concentration of 150 g/l to 300 g/l in methylcyclohexane by treating acid chloride 5 - (4-chlorophenyl) - L-- (2.4-dichlorophenyl) - 4 a-methylpyrazole and 3-carboxylic in methylcyclohexane by the 1 a-aminopiperidine in a mixture of methyl cyclohexane and tetrahydrofuran in the presence of triétylamine. 16. A pharmaceutical composition containing as an active ingredient, the crystalline polymorph of rimonabant (form II) according to any one of claims 1 to 3 in combination with at least one pharmaceutical excipient. 17.; Medicament characterized in that it comprises a compound according to any one of claims I to 3.λ (cms and 1) λ (cms and 1) 3311.30 1484.80 2787.23 986, 57 1683.48 922, 58 1526.55 781, 02 Peak Corner Angstroms 2 Varnishing line0 d=9, 65570 9,151 d=7, 58833 11,652 d=7, 17682 12,323 d=5, 51204 16,067 d=5, 38190 16,458 d=5, 25349 16,863 d=4, 82130 18,387 d=4, 56563 19,426 d=4, 28517 20,712 Peak Corner Angstroms 2 Varnishing line0 d=4, 16860 21,297 d=3, 87660 22,922 d=3, 27222 27,231 Peak Corner Angstroms 2 Varnishing line degrees d=l7, 41664 5,070 d=8, 70963 10,148 d=8, 19062 10,793 d=5, 82785 15,191 d=4, 63425 19,136 d=3, 49212 25,486 TABLEAThe U 4: powder X ray, F.the II elm
Molecular formula THE O C22 H21 03 N4 Molecular weight 463, 78 The stitch structure monoclinic Rump of space The P 21/c Elements of symmetry 'the X, the Y, Z-' '- the X, y+1/2, - Z-+1/2' the X -, Y--, - Z-' ' the X, - Y 1/2, Z 1/ Mesh parameter has 17, 4670 (7) Α Mesh parameter b. 9.2820 (9) TO Mesh parameter C. 13, 9450 (14) Α Mesh parameter has 90, 00 DEGREES Mesh parameter β 91,994 (5) DEGREES Mesh parameter γ 90, 00 DEGREES Volume mesh 2259, 5 (3) Α 3 Number of molecules per loop: a Z 4 Temperature °C Concentration in g/l Form I Form II 10.00 4,S6 4.50 20.00 6.92 6.60 30.00 930 9.20 40.00 13.70 12.60 50.00 20.40 19.00 60.00 31.20 29.20 70.00 52.40 42.00


