US2004176450A1PendingUtilityA1

Formoterol tartrate polymorph

Assignee: SEPRACOR INCPriority: Nov 9, 2001Filed: Mar 23, 2004Published: Sep 9, 2004
Est. expiryNov 9, 2021(expired)· nominal 20-yr term from priority
A61P 9/00A61P 9/08A61P 11/08C07C 231/24C07B 2200/13C07C 233/25A61K 31/205
60
PatentIndex Score
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Cited by
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Claims

Abstract

A method of preparation of a highly pure salt of R,R-formoterol L-tartrate is disclosed. The process provides the most thermodynamically stable polymorph by recrystallization of a novel polymorph.

Claims

exact text as granted — not AI-modified
1 . A crystalline solid consisting of greater than 99.5% by weight of (R,R)-formoterol L-tartrate and less than 0.5% by weight of chemical impurities other than formoterol L-tartrate; said chemical impurities including less than 0.2% by weight (based on total crystalline solid) of a compound of formula 7  
       
         
           
           
               
               
           
         
       
       said (R,R)-formoterol L-tartrate being at least 95% in the polymorphic form of a thermodynamically stable third polymorph (a) having peaks at the diffraction degrees with the intensity shown below in an x-ray powder diffraction pattern:  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                   peak number 
                   2-Theta 
                   Intensity 
                 
                     
                 
                     
                 
                 
                 
                 
               
                   1 
                   8.8 
                   33.1 
                 
                   2 
                   9.3 
                   33.4 
                 
                   3 
                   12.1 
                   58.1 
                 
                   4 
                   12.4 
                   60.6 
                 
                   5 
                   14.2 
                   30.9 
                 
                   6 
                   15.2 
                   87.4 
                 
                   7 
                   15.5 
                   82.8 
                 
                   8 
                   16.8 
                   69.8 
                 
                   9 
                   18.9 
                   39.6 
                 
                   10 
                   19.7 
                   41.1 
                 
                   11 
                   20.8 
                   40.6 
                 
                   12 
                   22.5 
                   38.8 
                 
                   13 
                   23.0 
                   59.9 
                 
                   14 
                   23.7 
                   100.0 
                 
                   15 
                   25.6 
                   55.9 
                 
                   16 
                   26.8 
                   37.2 
                 
                   17 
                   28.6 
                   25.6 
                 
                   18 
                   30.9 
                   37.2 
                 
                   19 
                   36.1 
                   28.0 
                 
                   20 
                   38.1 
                   25.0 
                 
                   21 
                   39.1 
                   22.7 
                 
                   22 
                   41.5 
                   21.3 
                 
                   23 
                   43.3 
                   20.9 
                 
                     
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 . A method for for preventing bronchoconstriction or inducing bronchodilation in a mammal comprising administering to said mammal a therapeutically effective amount of the solid R,R-formoterol L-(+)-tartrate of  claim 1 .  
     
     
         3 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the solid R,R-formoterol L-(+)-tartrate of  claim 1 .  
     
     
         4 . An aerosol pharmaceutical composition according to  claim 3 .  
     
     
         5 . An oral pharmaceutical composition according to  claim 3 .  
     
     
         6 . An oral pharmaceutical composition according to  claim 5  in the form of a tablet, capsule or syrup.  
     
     
         7 . A dry powder pharmaceutical composition for inhalation according to  claim 4 .  
     
     
         8 . A crystalline solid consisting of greater than 99.5% by weight of (R,R)-formoterol L-tartrate and less than 0.5% by weight of chemical impurities other than formoterol L-tartrate; said chemical impurities including less than 0.1% by weight (based on total crystalline solid) of a compound of formula 8  
       
         
           
           
               
               
           
         
       
       said (R,R)-formoterol L-tartrate being at least 95% in the polymorphic form of a thermodynamically stable third polymorph (A) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                   peak number 
                   2-Theta 
                   Intensity 
                 
                     
                 
                     
                 
                 
                 
                 
               
                   1 
                   8.8 
                   33.1 
                 
                   2 
                   9.3 
                   33.4 
                 
                   3 
                   12.1 
                   58.1 
                 
                   4 
                   12.4 
                   60.6 
                 
                   5 
                   14.2 
                   30.9 
                 
                   6 
                   15.2 
                   87.4 
                 
                   7 
                   15.5 
                   82.8 
                 
                   8 
                   16.8 
                   69.8 
                 
                   9 
                   18.9 
                   39.6 
                 
                   10 
                   19.7 
                   41.1 
                 
                   11 
                   20.8 
                   40.6 
                 
                   12 
                   22.5 
                   38.8 
                 
                   13 
                   23.0 
                   59.9 
                 
                   14 
                   23.7 
                   100.0 
                 
                   15 
                   25.6 
                   55.9 
                 
                   16 
                   26.8 
                   37.2 
                 
                   17 
                   28.6 
                   25.6 
                 
                   18 
                   30.9 
                   37.2 
                 
                   19 
                   36.1 
                   28.0 
                 
                   20 
                   38.1 
                   25.0 
                 
                   21 
                   39.1 
                   22.7 
                 
                   22 
                   41.5 
                   21.3 
                 
                   23 
                   43.3 
                   20.9 
                 
                     
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         9 . A crystalline solid according to  claim 8 , consisting of greater than 99.5% by weight of (R,R)-formoterol L-tartrate and less than 0.5% by weight of chemical impurities other than formoterol L-tartrate; said chemical impurities including 0.05% by weight (based on total crystalline solid) or less of a compound of formula 8.  
     
     
         10 . A method for preventing bronchoconstriction or inducing bronchodilation in a mammal comprising administering to said mammal a therapeutically effective amount of the solid R,R-formoterol L-(+)-tartrate of  claim 8 .  
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the solid R,R-formoterol L-(+)-tartrate of  claim 8 .  
     
     
         12 . An aerosol pharmaceutical composition according to  claim 10 .  
     
     
         13 . An oral pharmaceutical composition according to  claim 10 .  
     
     
         14 . An oral pharmaceutical composition according to  claim 12  in the form of a tablet, capsule or syrup.  
     
     
         15 . A dry powder pharmaceutical composition for inhalation according to  claim 10.

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