Ibandronate sodium propylene glycol solvate and processes for the preparation thereof

Abstract

A novel form of Ibandronate sodium which is particularly suitable for pharmaceutical applications, and a process for preparing said novel form.

1 . The preparation of Ibandronic acid and its sodium salt comprising reacting 3-(N-methylpentylamino)propanoic acid, or it's hydrochloride salt, phosphorous acid and phosphorous trichloride in the presence of polyethylene glycol. 
     
     
         2 . The preparation of Ibandronic acid and its sodium salt according to  claim 1  wherein the polyethylene glycol has an average molecular weight of about 400. 
     
     
         3 . The preparation of Ibandronic acid and its sodium salt according to  claim 1  or  2  wherein the phosphorylation reaction is performed at about 45° C. to about 70° C. 
     
     
         4 . The preparation of Ibandronic acid and its sodium salt according to  claim 1  or  2  wherein the phosphorylation reaction is performed at about 55° C. to about 60° C. 
     
     
         5 . The preparation of Ibandronic acid and its sodium salt according to  claim 3  or  4  wherein the phosphorylation reaction is performed in about 0.8 to about 2 volumes of polyethylene glycol. 
     
     
         6 . The preparation of Ibandronic acid and its sodium salt according to  claim 3  or  4  wherein the phosphorylation reaction is performed using about 0.8 to about 2.0 equivalents of phosphorous acid and phosphorous trichloride relative to the amount of 3-(N-methyl-N-pentylamino)propanoic acid substrate. 
     
     
         7 . The preparation of Ibandronic acid and its sodium salt according to  claim 3  or  4  wherein the phosphorylation reaction is performed using about 1.0 to about 1.6 equivalents of phosphorous acid and phosphorous trichloride relative to the amount of 3-(N-methyl-N-pentylamino)propanoic acid substrate. 
     
     
         8 . The preparation of Ibandronic acid and its sodium salt according to  claims 1 ,  2  or  3  wherein the phosphorylation reaction is performed in the presence of a co-solvent. 
     
     
         9 . The preparation of Ibandronic acid and its sodium salt according to  claim 8  wherein the phosphorylation reaction is performed in the presence of toluene as a co-solvent. 
     
     
         10 . The preparation of Ibandronic acid and its sodium salt according to  claim 9  wherein the phosphorylation reaction is performed in a toluene co-solvent where the amount of toluene is about 2 to about 4 volumes, relative to the weight of the 3-(N-methyl-N-pentylamino)propanoic acid substrate. 
     
     
         11 . The preparation of Ibandronate sodium according to  claims 1 ,  2  or  8  wherein the Ibandronate sodium is further converted to Ibandronate sodium propylene glycolate.