Stable pemetrexed arginine salt and compositions comprising it

Abstract

The present invention relates to arginine salt of pemetrexed of formula (1), particularly to a stable solid form thereof, and to pharmaceutical compositions comprising such salt.

1 . Arginine salt of pemetrexed of formula (1) 
       
         
           
           
               
               
           
         
       
     
     
         2 . The salt according to  claim 1  having the formula (2) 
       
         
           
           
               
               
           
         
       
     
     
         3 . The salt according to  claim 1  in solid form. 
     
     
         4 . The salt according to  claim 3 , in amorphous form. 
     
     
         5 . A pharmaceutical composition comprising the arginine salt of pemetrexed according to  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         6 . The composition according to  claim 5 , which is a solid composition. 
     
     
         7 . The composition according to  claim 6  comprising the arginine salt of pemetrexed in an amorphous form. 
     
     
         8 . The composition according to  claim 1 , which is a lyophilized powder useful for reconstitution into an infusion solution by an infusion liquid. 
     
     
         9 . The composition according to  claim 1 , wherein the excipient include one or more of diluents or bulking agents including one or more sugars such as dextrose, sucrose, mannose, lactose, trehalose and the like, one or more sugar alcohols such as mannitol, xylitol and the like; antibacterial preservatives, including one or more of thiomersal, benzalkonium chloride, benzethonium chloride, chlorobutanol; antioxidants including ascorbic acid, glutathione, L-cysteine, lipoic acid and the like; pH-adjustors such as hydrochloric acid; buffers including one or more of acetate, citrate, tartrate, phosphate, benzoate, and bicarbonate buffers; chelating agents such as disodium edetate; tonicity contributors including one or more of sodium chloride, potassium chloride, dextrose, mannitol, and lactose. 
     
     
         10 . The composition according to  claim 8 , wherein the excipient is mannitol. 
     
     
         11 . A process for making arginine salt of pemetrexed comprising combining pemetrexed diacid of formula (1) with L-arginine in a solution and removing the solvent. 
     
     
         12 . The process according to  claim 11 , wherein the removal of the solvent is carried out by evaporation or lyophilization. 
     
     
         13 . A process for making a pharmaceutical composition, comprising a step of combining arginine salt of pemetrexed with at least one pharmaceutically acceptable excipient. 
     
     
         14 . The process according to  claim 13 , wherein the pharmaceutical composition is a solid composition. 
     
     
         15 . The process according to  claim 13 , wherein the step of combining comprises providing arginine salt of pemetrexed, contacting it with excipient(s) in a solvent and removing the solvent. 
     
     
         16 . The process according to  claim 15 , wherein the step of providing the arginine salt of pemetrexed comprises mixing pemetrexed diacid with arginine in a solvent.