Crystal and process for producing the same

Abstract

A process for producing crystals of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimdazole-7-carboxylic acid (compound (I)), characterized by dissolving or suspending the compound (I) or a salt thereof in a solvent comprising an aprotic polar solvent and crystallizing it. By the process, the contaminants which are contained in the compound (I) or its salt and are difficult to remove, such as tin compounds, analogues of the compound (I), and a residual organic solvent, can be easily removed. Crystals of the compound (I) can be efficiently and easily mass-produced in high yield on an industrial scale.

1 . A process for producing a crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, which comprises dissolving or suspending 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof in a solvent containing an aprotic polar solvent, followed by mixing the solution or suspension with water and/or an organic solvent to crystallize.  
     
     
         2 . The process according to  claim 1 , wherein 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof is dissolved or suspended in a solvent containing an aprotic polar solvent, followed by mixing the solution or suspension with an organic solvent to crystallize.  
     
     
         3 . The process according to  claim 1 , wherein 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof is dissolved or suspended in a solvent containing an aprotic polar solvent, followed by mixing the solution or suspension with water and an organic solvent solvent to crystallize.  
     
     
         4 . The process according to  claim 1 , wherein the organic solvent is the solvent described in a class 2 or 3 of guideline of International Conference on Harmonisation of Pharmaceutical for Human USE (ICH).  
     
     
         5 . The process according to  claim 4 , wherein the solvent described in a class 2 or 3 of ICH guideline is one or more kinds of organic solvents selected from ketones, acetic acid esters, alcohols, ethers and hydrocarbons.  
     
     
         6 . The process according to  claim 4 , wherein the solvent described in a class 2 or 3 of ICH guideline is one or more kinds of organic solvents selected from acetone, ethyl acetate, methanol, ethanol, propanol, tert-butyl methyl ether, hexane and heptane.  
     
     
         7 . The process according to  claim 1 , wherein the organic solvent is composed of two or more kinds of organic solvents.  
     
     
         8 . The process according to  claim 1 , wherein the mixing with an organic solvent includes steps of (1) mixing with one or more kinds of organic solvents (B1) selected from acetone, ethyl acetate, methanol, ethanol and propanol and, thereafter, (2) mixing with an organic solvent (B2) selected from heptane, hexane and tert-butyl methyl ether.  
     
     
         9 . The process according to  claim 1 , wherein the amount of the organic solvent is 1 to 10-fold (volume) of the aprotic polar solvent.  
     
     
         10 . The process according to  claim 1 , wherein the amount of water is 0.1 to 3-fold (volume) of the aprotic polar solvent.  
     
     
         11 . The process according to  claim 1 , wherein the mixing volume ratio of water and an organic solvent is 1:50 to 5:1.  
     
     
         12 . A process for producing a crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, which comprises reacting methyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate or a salt thereof with a compound represented by the formula (R) 3SnN3 (wherein R represents alkyl having a carbon number of 4 to 18), and subjecting the resulting methyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate or a salt thereof to hydrolysis, followed by dissolving or suspending the resulting 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof in a solvent containing an aprotic polar solvent to crystallize.  
     
     
         13 . A crystal of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid obtained by reacting methyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate or a salt thereof with a compound represented by the formula (R)3SnN3 (wherein R represents alkyl having a carbon number of 4 to 18), and subjecting the resulting methyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate or a salt thereof tohydrolysis, followed by dissolving or suspending the resulting 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or a salt thereof in a solvent containing an aprotic polar solvent to crystallize.  
     
     
         14 . The crystal according to  claim 13 , which contains 5000 ppm or less of tetrahydrofuran.  
     
     
         15 . The crystal according to  claim 13 , wherein a content of a tin compound is 10 ppm or less.  
     
     
         16 . The crystal according to  claim 13 , wherein the content of analogues of 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid is 1% or less.  
     
     
         17 . The crystal according to  claim 13 , wherein the content of all residual organic solvents is 5000 ppm or less, and the amount of residual dichloromethane is less than 50 ppm.  
     
     
         18 . A pharmaceutical composition comprising the crystal according to  claim 13  and a pharmaceutically acceptable carrier, excipient or diluent.