Highly pure pemetrexed Diacid and processes for the preparation thereof

Abstract

Provided are highly pure pemetrexed diacid and pharmaceutically acceptable salts thereof, and processes for their preparation.

1 . Pemetrexed diacid of the following formula 
       
         
           
           
               
               
           
         
       
       having a purity of at least about 99%. 
     
     
         2 . The pemetrexed diacid of  claim 1 , having a purity of at least about 99.7%. 
     
     
         3 . A process for preparing pemetrexed diacid having a purity of at least about 99% comprising: a) measuring the purity of the pemetrexed diacid in at least one batch of pemetrexed diacid; b) selecting a batch of pemetrexed diacid having a purity of at least about 98%; and c) preparing pemetrexed diacid having a purity of at least about 99% from the selected batch. 
     
     
         4 . The process of  claim 3 , wherein the measurement in step (a) is done by an HPLC method comprising:
 a) combining a pemetrexed diacid sample with a solution of NaH 2 PO 4  to obtain a solution;   b) injecting the solution into a 150×4.6 mm×3 μm Phenyl C18 or Octadecyl (C18) reversed phase silica gel column;   c) eluting the sample from the column using a mixture of an aqueous solution of trifluoroacetic acid and acetonitrile; and   d) measuring the pemetrexed diacid content in the sample with a UV detector.   
     
     
         5 . The process of  claim 3 , wherein the pemetrexed diacid having a purity of at least about 99% is prepared from the selected batch by a process comprising crystallizing pemetrexed diacid from a mixture comprising at least one solvent selected from the group consisting of amides, pyrrolidinones, and sulfoxides, at least one anti-solvent selected from the group consisting of alcohols, esters, ketones, water, halogenated hydrocarbons, aromatic hydrocarbons, and ethers, and optionally at least one co-solvent selected from the group consisting of nitriles; wherein the starting pemetrexed diacid has a purity of at least about 98%. 
     
     
         6 . The process of  claim 5 , wherein the solvent is selected from the group consisting of C 2-4  amides, C 4-6  pyrrolidinones, and C 2-4  sulfoxides. 
     
     
         7 . The process of  claim 6 , wherein the solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, N-methyl pyrrolidinone, and dimethylsulfoxide. 
     
     
         8 . The process of  claim 5 , wherein the anti-solvent is selected from the group consisting of C 1-4  alcohols, C 3-6  esters, C 3-6  ketones, C 1-3  halogenated hydrocarbons, C 6-9  aromatic hydrocarbons, and C 4-8  ethers. 
     
     
         9 . The process of  claim 8 , wherein the anti-solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, methyl acetate, isobutyl acetate, acetone, dichloromethane, toluene, and tetrahydrofuran. 
     
     
         10 . The process of  claim 5 , wherein the solvent is dimethylsulfoxide and the anti-solvent is ethanol. 
     
     
         11 . The process of  claim 5 , wherein the solvent is dimethylsulfoxide and the anti-solvent is a mixture of water and methanol. 
     
     
         12 . The process of  claim 5 , wherein the solvent is dimethylformamide and the anti-solvent is a mixture of water and methanol. 
     
     
         13 . The process of  claim 5 , wherein the co-solvent is a C 2-4  nitrile. 
     
     
         14 . The process of  claim 13 , wherein the co-solvent is acetonitrile. 
     
     
         15 . The process of  claim 5 , wherein the pemetrexed diacid having a purity of at least about 98%, the solvent, and optionally the co-solvent, are combined to form a combination, and the combination is heated to obtain a solution, prior to adding the anti-solvent. 
     
     
         16 . The process of  claim 15 , wherein the combination is heated to a temperature of about 25° C. to about 75° C. to obtain the solution. 
     
     
         17 . The process of  claim 15 , wherein the anti solvent is added to the solution at a temperature of about 30° C. to about 65° C. 
     
     
         18 . The process of  claim 17 , wherein the addition of the anti-solvent to the solution results in the formation of a suspension having a precipitate of pemetrexed diacid. 
     
     
         19 . The process of  claim 18 , wherein the suspension is maintained at a temperature of about 30° C. to about 65° C. 
     
     
         20 . The process of  claim 5 , further comprising recovering pemetrexed diacid that has a purity of at least about 99%. 
     
     
         21 . The process of  claim 20 , wherein the recovered pemetrexed diacid has a purity of at least about 99.7%. 
     
     
         22 . The process of  claim 5 , further comprising slurrying the crystallized pemetrexed diacid in the anti-solvent; and recovering the pemetrexed diacid from the slurry. 
     
     
         23 . The process of  claim 22 , wherein the pemetrexed diacid is slurried in the anti-solvent at a temperature of about 5° C. to about 65° C. 
     
     
         24 . The process of  claim 22 , wherein the anti-solvent is water, ethanol, methanol, or a mixture thereof. 
     
     
         25 . A process for preparing a pharmaceutically acceptable salt of pemetrexed diacid comprising preparing pemetrexed diacid having a purity of at least about 99% by the process of  claim 3 ; and converting the pemetrexed diacid to the pharmaceutically acceptable salt of pemetrexed diacid. 
     
     
         26 . The process of  claim 25 , wherein the pharmaceutically acceptable salt of pemetrexed diacid is pemetrexed disodium. 
     
     
         27 . The process of  claim 25 , wherein the pharmaceutically acceptable salt of pemetrexed diacid has a purity of at least about 99%. 
     
     
         28 . A process for preparing a formulated pharmaceutically acceptable salt of pemetrexed diacid comprising preparing pemetrexed diacid having a purity of at least about 99% by the process of  claim 3 ; and formulating the obtained pemetrexed diacid into a formulation comprising a pharmaceutically acceptable salt of pemetrexed diacid. 
     
     
         29 . The process of  claim 28 , wherein the formulated pharmaceutically acceptable salt of pemetrexed diacid is lyophilized pemetrexed disodium. 
     
     
         30 . The process of  claim 28 , wherein the pharmaceutically acceptable salt of pemetrexed diacid in the formulation has a purity of at least about 99%.