Process for making amlodipine, derivatives thereof, and precursors therefor

Abstract

Impurities associated with the commercial production of amlodipine are identified along with methods of assaying the same.

1 . A process, which comprises the steps of: 
 (a) assaying a sample from a batch of phthalimidoamlodipine for at least one phthalimidoamlodipine impurity selected from the group consisting of compounds 2b-2f:                          (b) determining whether said at least one phthalimidoamlodipine impurity is contained in said sample below a predetermined limit, and, if below said predetermined limit;    (c) subjecting said phthalimidoamlodipine batch to deprotection to form a batch of amlodipine.    
   
   
       2 . The process according to  claim 1 , which further comprises crystallizing said batch of phthalimidoamlodipine prior to said assaying step.  
   
   
       3 . The process according to  claim 2 , which further comprises converting said batch of amlodipine to a pharmaceutically acceptable salt of amlodipine; and combining said pharmaceutically acceptable salt of amlodipine with at least one pharmaceutically acceptable excipient to form pharmaceutical unit dosage forms containing an effective amount of said amlodipine salt.  
   
   
       4 . The process according to  claim 3 , which further comprises assaying a sample of at least one of said batch amlodipine, said amlodipine salt, or said pharmaceutical unit dosage form, for an amlodipine impurity selected from the group consisting of (1b)-(1f):  
     
       
         
         
             
             
         
       
     
   
   
       5 . The process according to  claim 1 , wherein said phthalimidoamlodipine impurity is 2b or 2c.  
   
   
       6 . A process for making a pharmaceutical active ingredient, which comprises: 
 forming in an alcohol solvent a batch of phthalimidoamlodipine;    deprotecting said phthalimidoamlodipine to form a batch of amlodipine;    converting said batch of amlodipine to a salt thereof;    assaying a sample from said batch of amlodipine or its salt to determine the amount of at least one of compounds (1b)-(1f):                          and if said determined amount of said at least one compound of formula (1b)-(1f) is below 0.5 wt %, then releasing said amlodipine batch or salt thereof.    
   
   
       7 . The process according to  claim 6 , wherein said assaying determines the amount of compound of formula (1b), (1c) or both.  
   
   
       8 . The process according to  claim 7 , wherein the amount of said compound of formula (1b), (1c), or both are each less than 0.2 wt % before said batch of amlodipine or its salt is released.  
   
   
       9 . The process according to  claim 6 , wherein said alcohol solvent is ethanol or isopropanol.  
   
   
       10 . A process which comprises: 
 subjecting at least one of the following compounds (1b)-(1f):                          in sufficiently pure state to HPLC analysis under a set of conditions to obtain a reference standard analytical result;    subjecting a sample from a batch of amlodipine or a salt thereof to HPLC analysis under said set of conditions to obtain a sample analytical result;    determining the amount of said compound in said sample of amlodipine or salt thereof by comparing said reference standard analytical result to said sample analytical result; and    releasing said batch of amlodipine or its salt if said amount of said compound is 0.2 wt. % or less.    
   
   
       11 . The process according to  claim 10 , wherein said compound is a compound of formula (1b) or (1c).  
   
   
       12 . The process according to  claim 10 , wherein said comparison is performed by an automated process.  
   
   
       13 . The process according to  claim 10 , wherein said determination of the amount of said compound involves the Response factor for said compound obtained as said reference standard analytical result.