Methods for the purification of levofloxacin

Abstract

Levofloxacin has been purified by dissolving levofloxacin in a polar solvent at an elevated temperature and crystallizing purified levofloxacin. Preferably, an antioxidant is added to increase the purity.

1 . A process for preparing levofloxacin having a purity of about 99% or greater, comprising: 
 dissolving levofloxacin in a polar solvent at an elevated temperature; and    crystallizing purified levofloxacin.    
     
     
         2 . The process of  claim 1 , wherein the purity of the purified levofloxacin is about 99.5% by weight or greater.  
     
     
         3 . The process of  claim 1 , wherein the elevated temperature ranges from about 80° C. to about 110° C.  
     
     
         4 . The process of  claim 1 , wherein the elevated temperature is the reflux temperature of the solution.  
     
     
         5 . The process of  claim 1 , wherein the polar solvent is selected from the group consisting of dimethyl sulfoxide, methyl ethyl ketone, acetonitrile, butanol, mixtures thereof, and aqueous mixtures thereof.  
     
     
         6 . The process of  claim 1 , wherein the solvent is acetonitrile.  
     
     
         7 . The process of  claim 1 , wherein the solvent is a mixture of acetonitrile and water, wherein the amount of water in the solvent is about 10% or less.  
     
     
         8 . The process of  claim 1 , wherein the amount of desmethyl levofloxacin in the purified levofloxacin is at least one-third less than the amount in the initial levofloxacin.  
     
     
         9 . The process of  claim 1 , further comprising adding an antioxidant prior to the crystallizing step.  
     
     
         10 . The process of  claim 9 , wherein the antioxidant is selected from the group consisting of ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic palmitate, butylated hydroxyanisole, butylated hydroxytoluene, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, tocopherols, and pharmaceutically acceptable salts and mixtures thereof.  
     
     
         11 . The process of  claim 9 , wherein the antioxidant is sodium metabisulfite.  
     
     
         12 . The process of  claim 9 , wherein the antioxidant is ascorbic acid.  
     
     
         13 . The process of  claim 9 , wherein the amount of N-oxide levofloxacin in the purified levofloxacin is at least one-third less than the amount in the initial levofloxacin.  
     
     
         14 . The process of  claim 9 , wherein the amount of N-oxide levofloxacin in the purified levofloxacin is about 0.1% or less.  
     
     
         15 . The process of  claim 9 , wherein the purity of the purified levofloxacin is about 99.5% by weight or greater.  
     
     
         16 . The process of  claim 9 , further comprising a step of determining whether the initial levofloxacin contains an amount of N-oxide levofloxacin that is detectable by HPLC.  
     
     
         17 . The process of  claim 9 , wherein the solvent is acetonitrile and wherein the purified levofloxacin is substantially pure levofloxacin hemihydrate.  
     
     
         18 . The process of  claim 1 , and wherein the purified levofloxacin is substantially pure levofloxacin hemihydrate.  
     
     
         19 . A process for preparing levofloxacin hemihydrate having a purity of about 99% or greater, comprising: 
 dissolving levofloxacin in a polar solvent at an elevated temperature; and    crystallizing levofloxacin hemihydrate.    
     
     
         20 . The process of  claim 19 , wherein the elevated temperature ranges from about 80° C. to about 110° C.  
     
     
         21 . The process of  claim 19 , wherein the elevated temperature is the reflux temperature of the solution.  
     
     
         22 . The process of  claim 19 , wherein the solvent is selected from the group consisting of acetonitrile, dimethyl sulfoxide:H 2 O, methyl ethyl ketone, butanol, and mixtures thereof.  
     
     
         23 . The process of  claim 19 , wherein the solvent is dimethyl sulfoxide:H 2 O in a ratio of about 1:5.  
     
     
         24 . The process of  claim 19 , wherein the solvent is methyl ethyl ketone.  
     
     
         25 . The process of  claim 19 , wherein the solvent is n-butanol.  
     
     
         26 . The process of  claim 19 , wherein the solvent is acetonitrile.  
     
     
         27 . The product of the process of  claim 1 .  
     
     
         28 . The product of the process of  claim 9 .  
     
     
         29 . The product of the process of  claim 19 .  
     
     
         30 . A process for preparing levofloxacin having a purity of about 99% or greater, comprising: 
 dissolving levofloxacin in a polar solvent; adding an antioxidant; and    crystallizing purified levofloxacin, wherein the adding step occurs before or after the dissolving step and before the crystallizing step.    
     
     
         31 . The process of  claim 9 , wherein the antioxidant ranges from about 0.2% to about 5% by weight levofloxacin.  
     
     
         32 . The process of  claim 9 , wherein the antioxidant is added to the levofloxacin before the dissolving step.  
     
     
         33 . The process of  claim 1 , further comprising adding an antioxidant during the crystallization step.  
     
     
         34 . A process for preparing levofloxacin having a purity of about 99% or greater comprising converting (S)-(−)-9,10-Difluoro-3-Methyl-7-oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de][1,4]Benzoxazine-6-Carboxylic Acid to levofloxacin at an elevated temperature in the presence of an antioxidant.  
     
     
         35 . The process of  claim 34 , wherein the purity of the levofloxacin is about 99.5% by weight or greater.  
     
     
         36 . The process of  claim 34 , wherein the amount of N-oxide levofloxacin in the levofloxacin is about 0.1% or less.  
     
     
         37 . The process of  claim 20 , wherein the elevated temperature is greater than 80° C. and less than about 110° C.  
     
     
         38 . The process of claim of  claim 21 , wherein the solvent is selected from the group consisting of acetonitrile, acetonitrile:H 2 O, dimethyl sulfoxide:H 2 O, methyl ethyl ketone, butanol, butanol:H 2 O, and mixtures thereof.  
     
     
         39 . The process of  claim 19 , wherein the solvent is selected from the group consisting of acetonitrile, acetonitrile:H 2 O, dimethyl sulfoxide:H 2 O, methyl ethyl ketone, butanol, butanol:H 2 O, and mixtures thereof.  
     
     
         40 . The process of  claim 39 , wherein the solvent consists essentially of butanol:H 2 O in a ratio of about 9:1 or acetonitrile:H 2 O in a ratio of about 99:1.  
     
     
         41 . The process of  claim 40 , wherein the solvent consists essentially of acetonitrile:H 2 O in a ratio of about 99:1.  
     
     
         42 . The process of  claim 19 , further comprising adding an antioxidant prior to the crystallizing step.  
     
     
         43 . The process of  claim 19 , wherein the amount of N-oxide levofloxacin in the purified levofloxacin is about 0.1% or less.  
     
     
         44 . The process of  claim 19 , wherein the purity of the purified levofloxacin is about 99.5% by weight or greater.  
     
     
         45 . The process of  claim 19 , wherein the levofloxacin hemihydrate is prepared with a yield of about 80% or greater.  
     
     
         46 . The process of  claim 40 , wherein the levofloxacin hemihydrate is prepared with a yield of about 80% or greater.  
     
     
         47 - 68 . (canceled)