Crystalline tiotropium bromide monohydrate, processes for the preparation thereof, and pharmaceutical compositions

Abstract

Crystalline monohydrate of (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0 2,4 ]nonane bromide (tiotropium bromide monohydrate), processes for the preparation thereof, pharmaceutical compositions thereof, and their use.

We claim:  
     
         1 . Crystalline tiotropium bromide monohydrate.  
     
     
         2 . Crystalline tiotropium bromide monohydrate according to  claim 1 , having an endothermic peak at 230° C.±5° C. occurring during thermal analysis using DSC at a heating rate of 10 K/min.  
     
     
         3 . Crystalline tiotropium bromide monohydrate according to  claim 1 , having an IR spectrum comprising bands at wave numbers 3570, 3410, 3105, 1730, 1260, 1035, and 720 cm −1 .  
     
     
         4 . Crystalline tiotropium bromide monohydrate according to  claim 2 , having an IR spectrum comprising bands at wave numbers 3570, 3410, 3105, 1730, 1260, 1035, and 720 cm −1 .  
     
     
         5 . Crystalline tiotropium bromide monohydrate according to  claim 1 , having a single monoclinic cell having the following dimensions: a=18.0774 Å, b=11.9711 Å, c=9.9321 Å, β=102.691°, and V=2096.96 Å 3 .  
     
     
         6 . Crystalline tiotropium bromide monohydrate according to  claim 2 , having a single monoclinic cell having the following dimensions: a=18.0774 Å, b=11.9711 Å, c=9.9321 Å, β=102.691°, and V=2096.96 Å 3 .  
     
     
         7 . Crystalline tiotropium bromide monohydrate according to  claim 3 , having a single monoclinic cell having the following dimensions: a=18.0774 Å, b=11.9711 Å, c=9.9321 Å, β=102.691°, and V=2096.96 Å 3 .  
     
     
         8 . Crystalline tiotropium bromide monohydrate according to  claim 4 , having a single monoclinic cell having the following dimensions: a=18.0774 Å, b=11.9711 Å, c=9.9321 Å, β=102.691°, and V=2096.96 Å 3 .  
     
     
         9 . A process for preparing crystalline tiotropium bromide monohydrate, the process comprising: 
 (a) dissolving tiotropium bromide in water to obtain a solution;    (b) heating the resulting solution;    (c) adding activated charcoal to the heated solution;    (d) removing the activated charcoal; and    (e) allowing the solution to slowly cool to obtain crystalline tiotropium bromide monohydrate.    
     
     
         10 . A process for preparing crystalline tiotropium bromide monohydrate, the process comprising: 
 (a) dissolving tiotropium bromide in water to obtain a solution;    (b) heating the resulting solution to more than 50° C.;    (c) adding activated charcoal to the heated solution;    (d) removing the activated charcoal; and    (e) allowing the solution to slowly cool to obtain crystalline tiotropium bromide monohydrate.    
     
     
         11 . The process according to  claim 10 , wherein 0.4 to 1.5 kg of water are used per mole of tiotropium bromide in step (a).  
     
     
         12 . The process according to  claim 11 , wherein 10 g to 50 g of activated charcoal per mole of tiotropium bromide is added in step (c).  
     
     
         13 . The process according to  claim 12 , wherein the activated charcoal added in step (c) is stirred for between 5 and 60 minutes before it is removed in step (d).  
     
     
         14 . The process according to  claim 13 , wherein step (d) is performed by filtration of the solution.  
     
     
         15 . The process according to  claim 14 , wherein the solution of step (e) is cooled to a temperature of 20° C.-25° C. at a cooling rate of 1 to 10° C. per 10 to 30 minutes.  
     
     
         16 . A pharmaceutical composition comprising an effective amount of crystalline tiotropium bromide monohydrate according  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         17 . A method for treatment of diseases in which the administration of an anticholinergic agent may have a therapeutic benefit, in a patient in need of such treatment, which method comprises administering the patient an effective amount of a compound according to  claim 1 .  
     
     
         18 . The method according to  claim 17 , wherein the disease is asthma or COPD.  
     
     
         19 . A process for preparing crystalline hydrates of tiotropium bromide, the process comprising: 
 (a) dissolving tiotropium bromide in water to obtain a solution;    (b) heating the resulting solution; and    (c) allowing the solution to slowly cool to obtain crystalline hydrates of tiotropium bromide.    
     
     
         20 . A process for preparing crystalline hydrates of tiotropium bromide, the process comprising: 
 (a) dissolving tiotropium bromide in water to obtain a solution;    (b) heating the solution of step (a);    (c) adding activated charcoal to the heated solution of step (b);    (d) removing the activated charcoal from the solution of step (c); and    (e) allowing the solution to slowly cool to obtain crystalline hydrates of tiotropium bromide.    
     
     
         21 . The process of  claim 20 , wherein the solution of step (a) is heated to more than 50° C.