Process for making amlodipine maleate

Abstract

A process for making amlodipine maleate comprises reacting amlodipine or an acid addition salt thereof with maleic acid under an acidic environment to form an amlodipine maleate product. The process allows for the formation of amlodipine maleate substantially free from amlodipine aspartate.

We claim:  
     
         1 . A process, which comprises reacting amlodipine or an acid addition salt thereof with maleic acid under an acidic environment to form an amlodipine maleate product.  
     
     
         2 . The process according to  claim 1 , which comprises: 
 adding said amlodipine or salt thereof to an equivalent or molar excessive amount of maleic acid.    
     
     
         3 . The process according to  claim 1 , wherein said amlodipine maleate product contains less than 1 wt % amlodipine aspartate, based on the amount of amlodipine maleate.  
     
     
         4 . The process according to  claim 3 , wherein said amlodipine maleate product contains less than 0.2 wt % amlodipine aspartate, based on the amount of amlodipine maleate.  
     
     
         5 . A process for the manufacture of an amlodipine maleate salt substantially free of amlodipine aspartate, which comprises the steps of: 
 a) adding, continuously or portionwise, a source of amlodipine into a solution or suspension of maleic acid to form a solution, wherein the relative molar amount of maleic acid to amlodipine being added is at least 1.01:1; and    b) separating amlodipine maleate in a solid form from the solution.    
     
     
         6 . The process according to  claim 5 , wherein the relative molar amount of maleic acid to amlodipine being added is at least about 1.05:1.  
     
     
         7 . The process according to  claim 5 , wherein the source of amlodipine is selected from the group consisting of raw amlodipine obtained after the synthesis of amlodipine; purified amlodipine free base; and an acid addition salt of amlodipine other than the maleate.  
     
     
         8 . The process according to  claim 7 , wherein said source of amlodipine is in a solid state form or dissolved in a solvent.  
     
     
         9 . A process for the manufacture of an amlodipine maleate salt substantially free of amlodipine aspartate, which comprises the steps of: 
 a) contacting, continuously or portionwise, a source of amlodipine with a solution or suspension of maleic acid under pH control to form a solution whereby the pH of the solution does not exceed 6.5; and    b) separating amlodipine maleate in a solid form from the solution.    
     
     
         10 . The process according to  claim 9 , wherein the source of amlodipine is selected from the group consisting of raw amlodipine obtained after the synthesis of amlodipine; purified amlodipine free base; and an acid addition salt of amlodipine other than the maleate.  
     
     
         11 . The process according to  claim 10 , wherein said source of amlodipine is in a solid state form or dissolved in a solvent.  
     
     
         12 . The process according to  claim 10 , wherein said source of amlodipine is an acid addition salt of amlodipine other than the maleate salt, in a solid state or dissolved or suspended in a suitable solvent.  
     
     
         13 . The process according to  claim 9 , wherein said amlodipine source is added to said maleic acid solution or suspension.  
     
     
         14 . A process of purification, which comprises crystallizing or precipitating amlodipine maleate from a solution thereof wherein said solution comprises an excess of maleic acid.  
     
     
         15 . The process according to  claim 14 , which further comprises converting said amlodipine maleate to another acid addition salt.  
     
     
         16 . The process according to  claim 15 , wherein said amlodipine maleate is converted to amlodipine benzene sulfonate acid or amlodipine hydrochloride.  
     
     
         17 . The process according to  claim 16 , wherein said conversion comprises treating said amlodipine maleate with base to form amlodipine free base and treating said amlodipine free base with benzene sulfonic acid or hydrochloric acid.  
     
     
         18 . Amlodipine maleate produced according to the process of  claim 1 .  
     
     
         19 . Amlodipine maleate produced according to the process of  claim 2 .  
     
     
         20 . Amlodipine maleate produced according to the process of  claim 3 .  
     
     
         21 . Amlodipine maleate produced according to the process of  claim 4 .  
     
     
         22 . Amlodipine maleate substantially free from amlodipine aspartate.  
     
     
         23 . Amlodipine maleate according to  claim 22 , wherein the amount of amlodipine aspartate is less than 0.2 wt %.  
     
     
         24 . A pharmaceutical composition for treating or preventing hypertension, angina, or heart failure, that comprises an effective amount of amlodipine maleate substantially free from amlodipine aspartate and a pharmaceutically acceptable excipient.  
     
     
         25 . The pharmaceutical composition according to  claim 24 , wherein said composition is in a unit dose form containing 1 to 20 mg of said amlodipine maleate and the amount of amlodipine aspartate is less than 0.2 wt %.  
     
     
         26 . A method for treating hypertension, angina, or heart failure, which comprises administering an effective amount of amlodipine maleate substantially free from amlodipine aspartate.