Crystalline pyrazoles

Abstract

The present invention relates to crystal forms of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide and methods for preparation, interconversion, and isolation of such crystals.

1 .- 52 . (canceled) 
   
   
       53 . A process for converting a crystal form, Form II, of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide into a crystal form, Form I, of said compound, having a powder X-ray diffraction pattern comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 14.0, 18.9, 21.3, 21.9, and 25.7 obtained using CuKα 1  X-ray (wavelength=1.5406 Angstroms) comprising:
 (a) mixing a suspension of Form II of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide in a suitable solvent at a temperature from 0° C. to 60° C.;   (b) stirring the suspension at a temperature from 0° C. to 60° C. for 24 to 72 hours.   
   
   
       54 . The process of  claim 53  wherein the solvent is chosen from the group consisting of water, methanol, ethanol, isopropanol, acetone, acetonitrile, methylene chloride, toluene, and tetrahydrofuran, and mixtures thereof. 
   
   
       55 . A process for converting a crystal form, Form II, of 4-[5-(4-fluorophenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide into a crystal form, Form I, of said compound, having a powder X-ray diffraction pattern comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 14.0, 18.9, 21.3, 21.9, and 25.7 obtained using CuKα 1  X-ray (wavelength=1.5406 Angstroms) comprising:
 (a) dissolving said Form II in a water miscible solvent in which the solubility of Form II is greater than 2 mg/mL at a temperature from 10° C. to 60° C.;   (b) precipitating the compound by the addition of water;   (c) stirring the suspension of step ii) for 2 to 72 hours at a temperature from 15° C. to 45° C.   
   
   
       56 . The process of  claim 55  in which the solvent is selected from the group consisting of ethanol, acetone, acetonitrile, tetrahydrofuran, dioxane, and dimethylformamide. 
   
   
       57 . A pharmaceutical composition which comprises the crystal form, Form I, of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide having a powder X-ray diffraction pattern comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 14.0, 18.9, 21.3, 21.9, and 25.7 obtained using CuKα 1  X-ray (wavelength=1.5406 Angstroms) and a pharmaceutically acceptable carrier or excipient. 
   
   
       58 . The pharmaceutical composition of  claim 57  in which the pharmaceutically acceptable carrier or excipient is starch or lactose. 
   
   
       59 . A method of treating an arthritis in an animal by administering a therapeutically effective amount of the crystal form, Form I, of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide having a powder X-ray diffraction pattern comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 14.0, 18.9, 21.3, 21.9, and 25.7 obtained using CuKα 1  X-ray (wavelength=1.5406 Angstroms) to the animal. 
   
   
       60 . The me hod of  claim 59  wherein said animal is selected from the group consisting of cattle, sheep, goats, horses, pigs, birds, cats, dogs, and humans. 
   
   
       61 . The use of the composition of  claim 57  in the manufacture of a medicament for the prevention or treatment of an inflammatory condition in an animal. 
   
   
       62 . A process for making the crystal form, Form I, of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide having a powder X-ray diffraction pattern comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 14.0, 18.9, 21.3, 21.9, and 25.7 obtained using CuKα 1  X-ray (wavelength=1.5406 Angstroms), comprising the steps of:
 (a) mixing 1.0 to 1.6 moles of alkyl trifluoroacetate per mole of 4-fluoroacetophenone, 1.0 to 1.5 moles of a metal alkoxide per mole of 4-fluoroacetophenone, and a known quantity of 4-fluoroacetophenone to make a mixture;   (b) combining the mixture from step (a) with a combination of 415 to 1,245 ml of water per mole of 4-fluoroacetophenone, 1.1 to 2.0 moles of concentrated hydrochloric acid per mole of 4-fluoroacetophenone, 0.8 to 1.2 moles of 4-sulfonamidophenylhydrazine hydrochloride per mole of 4-fluoroacetophenone, and an amount of a suitable solvent so that the total amount of the solvent in the mixture is from 550 to 1,660 ml per mole of 4-fluoroacetophenone;   (c) adding to the mixture a seeding amount of crystals of Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide based on 4-fluoroacetophenone.   
   
   
       63 . The process of  claim 62 , further comprising adding in step (a), up to 1,380 ml of a suitable solvent per mole of 4-fluoroacetophenone to the mixture. 
   
   
       64 . The process of  claim 63 , wherein the solvent is 2-propanol. 
   
   
       65 . The process of  claim 62 , wherein the metal alkoxide is chosen from the group consisting of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tertiary butoxide, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tertiary butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tertiary butoxide, and mixtures thereof. 
   
   
       66 . The process of  claim 65  wherein the metal alkoxide is sodium methoxide. 
   
   
       67 . The process of  claim 62 , further comprising a step following step (a) comprising heating the mixture at a temperature above ambient temperature up to reflux temperature until the reaction is complete. 
   
   
       68 . The process of  claim 67 , further comprising a step following the heating step comprising cooling the mixture to −5° C. to 30° C. 
   
   
       69 . The process of  claim 62 , wherein step (b) comprises adding the mixture to the combination of water, hydrochloric acid, and 4-sulfonamidophenylhydrazine hydrochloride. 
   
   
       70 . The process of  claim 62 , wherein the solvent of step (b) is an alcohol. 
   
   
       71 . The process of  claim 70 , wherein the alcohol is 2-propanol. 
   
   
       72 . The process of  claim 62 , further comprising a step following step (b) comprising heating the mixture at temperatures above ambient temperature up to reflux temperature until the reaction is complete. 
   
   
       73 . The process of  claim 72 , further comprising a step following the heating step comprising stabilizing the mixture at a temperature from ambient temperature to 70° C. 
   
   
       74 . The process of  claim 62 , wherein the seeding amount is from 0.0001% to 50% wt/wt. 
   
   
       75 . The process of  claim 74 , wherein the seeding amount is from 0.001% to 5% wt/wt. 
   
   
       76 . The process of  claim 74 , wherein the seeding amount is from 0.01% to 0.5% wt/wt. 
   
   
       77 . The process of  claim 62 , further comprising a step following step (c) comprising heating the mixture at a temperature from 40° C. to less than 70° C. for 1 to 10 hours. 
   
   
       78 . The process of  claim 77 , further comprising a step following the heating step comprising cooling the mixture to −5° C. to 30° C. 
   
   
       79 . The process of  claim 62 , further comprising a step following step (c) comprising filtering the mixture, and washing the Form I crystals with a suitable solvent or water, or a mixture thereof. 
   
   
       80 . The process of  claim 79 , wherein the solvent is an alcohol. 
   
   
       81 . The process of  claim 80 , wherein the alcohol is 2-propanol. 
   
   
       82 . The process of  claim 62 , further comprising a step following step (c) comprising collecting the Form I crystals and drying said crystals at a temperature of 15° C. to 80° C. 
   
   
       83 . A process for making the crystal form, Form I, of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide having a powder X-ray diffraction pattern comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 14.0, 18.9, 21,3, 21.9, and 25.7 obtained using CuKα 1  X-ray (wavelength=1.5406 Angstroms), comprising the steps of:
 (a) mixing 1.2 to 1.45 moles of alkyl trifluoroacetate per mole of 4-fluoroacetophenone, 1.1 to 1.35 moles of a metal alkoxide per mole of 4-fluoroacetophenone, and a known quantity of 4-fluoroacetophenone to make a mixture;   (b) combining the mixture from step (a) with a combination of 650 to 870 ml of water per mole of 4-fluoroacetophenone, 1.2 to 1.7 moles of concentrated hydrochloric acid per mole of 4-fluoroacetophenone, 0.9 to 1.1 moles of 4-sulfonamidophenylhydrazine hydrochloride per mole of 4-fluoroacetophenone, and an amount of a suitable solvent so that the total amount of the solvent in the mixture is from 600 to 1,000 ml per mole of 4-fluoroacetophenone;   (c) adding to the mixture a seeding amount of crystals of Form I of 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide based on 4-fluoroacetophenone.   
   
   
       84 . The process of  claim 83 , further comprising adding in step (a), up to 900 ml of a suitable solvent per mole of 4-fluoroacetophenone to the mixture. 
   
   
       85 . The process of  claim 84 , wherein the solvent is 2-propanol. 
   
   
       86 . The process of  claim 83 , wherein the metal alkoxide is chosen from the group consisting of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tertiary butoxide, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tertiary butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, and potassium tertiary butoxide, and mixtures thereof. 
   
   
       87 . The process of  claim 86 , wherein the metal alkoxide is sodium methoxide. 
   
   
       88 . The process of  claim 83 , further comprising a step following step (a) comprising heating the mixture at a temperature above ambient temperature up to reflux temperature until the reaction is complete. 
   
   
       89 . The process of  claim 88 , further comprising a step following the heating step comprising cooling the mixture to ambient temperature. 
   
   
       90 . The process of  claim 83 , wherein step (b) comprises adding the mixture to the combination of water, hydrochloric acid, and 4-sulfonamidophenylhydrazine hydrochloride. 
   
   
       91 . The process of  claim 83 , wherein the solvent of step (b) is an alcohol. 
   
   
       92 . The process of  claim 91 , wherein the alcohol is 2-propanol. 
   
   
       93 . The process of  claim 83 , further comprising a step following step (b) comprising heating the mixture at a temperature above ambient temperature up to reflux temperature until the reaction is complete. 
   
   
       94 . The process of  claim 93 , further comprising a step following the heating step comprising stabilizing the mixture at a temperature from 40° C. to 65° C. 
   
   
       95 . The process of  claim 83 , wherein the seeding amount is from 0.001% to 50% wt/wt. 
   
   
       96 . The process of  claim 95 , wherein the seeding amount is from 0.001% to 5% wt/wt. 
   
   
       97 . The process of  claim 95 , wherein the seeding amount is from 0.01% to 0.5% wt/wt. 
   
   
       98 . The process of  claim 83 , further comprising a step following step (c) comprising heating the mixture at a temperature from 50° C. to less than 70° C. for 3 to 8 hours. 
   
   
       99 . The process of  claim 98 , further comprising a step following the heating step of cooling the mixture to ambient temperature. 
   
   
       100 . The process of  claim 83 , further comprising a step following step (c) comprising filtering the mixture, and washing the Form I crystals with a suitable solvent or water, or a mixture thereof. 
   
   
       101 . The process of  claim 100 , wherein the solvent is an alcohol. 
   
   
       102 . The process of  claim 101 , wherein the alcohol is 2-propanol. 
   
   
       103 . The process of  claim 83 , further comprising a step following step (c) comprising collecting the Form I crystals and drying said crystals at a temperature of 30° C. to 65° C.