Method of resolving amlodipine racemate

Abstract

The invention relates to methods of resolving racemic amlodipine into enantiomerically enriched compositions by precipitation with tartaric acid in the presence of a non-aqueous solvent, such as N,N′-dimethylacetamide. The molar ratio of tartaric acid:amlodipine is preferably less than 0.25:1.0 or greater than 0.75:1.0.

1 . A composition comprising crystalline S-(−)-amlodipine D-hemitartrate dimethylacetamide monosolvate, wherein at least 80% of the amlodipine in the composition is S-(−)-amlodipine.  
     
     
         2 . The composition of  claim 1 , wherein at least 90% of the amlodipine in the composition is S-(−)-amlodipine.  
     
     
         3 . The composition of  claim 1 , wherein at least 97% of the amlodipine in the composition is S-(−)-amlodipine.  
     
     
         4 . A composition comprising crystalline R-(+)-amlodipine L-hemitartrate dimethylacetamide monosolvate, wherein at least 80% of the amlodipine in the composition is R-(+)-amlodipine.  
     
     
         5 . The composition of  claim 4 , wherein at least 90% of the amlodipine in the composition is R-(+)-amlodipine.  
     
     
         6 . The composition of  claim 4 , wherein at least 97% of the amlodipine in the composition is R-(+)-amlodipine.  
     
     
         7 . A composition consisting essentially of a solvate of an addition salt of amlodipine with a chiral acid enriched to at least 90% of one enantiomer of the chiral acid, wherein the composition is a free-flowing solid.  
     
     
         8 . The composition of  claim 7 , wherein the addition salt is amlodipine hemitartrate.  
     
     
         9 . The composition of  claim 7 , wherein the solvate is a dimethylacetamide solvate.  
     
     
         10 . The composition of  claim 7 , wherein the solvate of an addition salt of amlodipine is amlodipine hemitartrate dimethylacetamide monosolvate.  
     
     
         11 . The composition of  claim 7 , wherein the free-flowing solid is a powder or granular solid.  
     
     
         12 . The composition of  claim 7 , wherein at least 80% of the amlodipine in the composition is S-(+)-amlodipine.  
     
     
         13 . A solid medicament tablet comprising crystalline amlodipine or a granular salt or hydrate thereof, and one or more pharmaceutically acceptable carriers, wherein at least 80% of the amlodipine in the composition is S-(+)-amlodipine.  
     
     
         14 . A method for purifying amlodipine free base from an addition salt of amlodipine with a chiral acid enriched to at least 90% of one enantiomer of the chiral acid, comprising: 
 a. suspending the addition salt in a liquid consisting essentially of one or more non-chlorinated, substantially water-immiscible organic solvents;    b. contacting the liquid with a basic aqueous solution to extract the tartrate ions into the aqueous solution; and    c. precipitating amlodipine free base from the organic solvent by at least partial removal of the liquid and addition of a non-polar organic solvent.    
     
     
         15 . The method of  claim 14 , wherein the one or more non-chlorinated, substantially water-immiscible organic solvents are selected from methyl tert-butyl ether, ethyl acetate, isopropyl acetate, or any combination thereof.