Preparation of levofloxacin and forms thereof

Abstract

Levofloxacin was prepared by reacting (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with N-methyl piperazine in a polar solvent or in a neat mixture to form levofloxacin. Further processing of the levofloxacin produced novel levofloxacin forms, including a hemihydrate and Forms A, B, C, F, G and H.

1 . A method for preparing levofloxacin comprising: 
 reacting (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with N-methyl piperazine at an elevated temperature to form levofloxacin;    precipitating the levofloxacin; and    recovering the levofloxacin.    
   
   
       2 . The method of  claim 1 , wherein the yield is about 75% or greater.  
   
   
       3 . The method of  claim 1 , wherein the yield is about 85% or greater.  
   
   
       4 . The method of  claim 1 , wherein the reacting step occurs in a polar solvent.  
   
   
       5 . The method of  claim 4 , wherein the polar solvent is selected from the group consisting of dimethlysulfoxide (DMSO), isobutanol, propylene-glycol-monomethyl-ether (PGME), dimethyl acetamide (DMA), and mixtures thereof.  
   
   
       6 . The method of  claim 4 , wherein the volume of the solvent ranges from about 14 ml to about 4 ml per gram of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.  
   
   
       7 . The method of  claim 5 , wherein the solvent is selected from the group consisting of isobutanol and PGME.  
   
   
       8 . The method of  claim 4 , wherein the volume of solvent is less than about 3 ml per gram of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.  
   
   
       9 . The method of  claim 8 , wherein the solvent is selected from the group consisting of DMSO and DMA.  
   
   
       10 . The method of  claim 1 , wherein N-methyl piperazine is in molar excess over (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid.  
   
   
       11 . The method of  claim 10 , wherein the molar excess is from about 2 to about 4 times.  
   
   
       12 . The method of  claim 10 , wherein the molar excess is from about 2 to about 2.5 times.  
   
   
       13 . The method of  claim 4 , further comprising adding an anti-solvent to the mixture after the reacting step.  
   
   
       14 . The method of  claim 13 , wherein the anti-solvent is selected from the group consisting of n-heptane, hexane, isopropyl alcoho, isopropyl alcohol in water, butanol, acetonitrile, methyl ethyl ketone, and DMSO/water.  
   
   
       15 . The method of  claim 1 , wherein the reacting step occurs in a neat mixture.  
   
   
       16 . The method of  claim 15 , wherein the reacting step is performed at reflux.  
   
   
       17 . The method of  claim 15 , wherein (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid is dissolved in a suspension of N-methyl piperazine.  
   
   
       18 . A method for preparing a levofloxacin form comprising: 
 maintaining levofloxacin at a first elevated temperature in a first solvent; adding a polar solvent to precipitate the levofloxacin form; and    recovering a levofloxacin form selected from the group consisting of Form C, Form A, Form G, Form B, Form H and Form F.    
   
   
       19 . The method of  claim 18 , wherein the amount of the polar solvent is less than about 8 volumes polar solvent/g starting material; and 
 wherein the polar solvent comprises isopropanol and water.    
   
   
       20 . The method of  claim 19 , wherein the recovering step comprises 
 cooling the second mixture to about 0° C. to about 20° C.; and    maintaining the second mixture at 0° C. to about 20° C. for at least about 2 hours.    
   
   
       21 . (canceled)  
   
   
       22 . The method of  claim 18 , 
 wherein a slurry is formed prior to the adding step; and    wherein the polar solvent is isopropanol.    
   
   
       23 . Levofloxacin Form C made by the process of  claim 22 .  
   
   
       24 . The method of  claim 18 , further comprising 
 cooling the levofloxacin-solvent mixture to 0° C. to about 20° C. over a period of at least about 0.5 h;    maintaining the levofloxacin-solvent mixture at 0° C. to about 20° C. for a period of at least about 2 h;    wherein the elevated temperature is about 75° C.; and    wherein the polar solvent is isopropanol.    
   
   
       25 . Levofloxacin Form A made by the process of  claim 24 .  
   
   
       26 . The method of  claim 18 , further comprising 
 cooling the levofloxacin-solvent mixture to 0° C. to about 20° C. over a period of at least about 0.5 h;    maintaining the levofloxacin-solvent mixture at 0° C. to about 20° C. for a period of at least about 2 h;    wherein the recovering step comprises drying the levofloxacin for about 3 to about 6 hours at about 40° C. and for about 3 hours at about 60° C.;    wherein the elevated temperature is about 75° C.; and    wherein the polar solvent is isopropanol.    
   
   
       27 . Levofloxacin Form G made by the process of  claim 26 .  
   
   
       28 . The method of  claim 18 , further comprising 
 cooling the levofloxacin-solvent mixture to 0° C. to about 20° C. over a period of at least about 0.5 h;    maintaining the levofloxacin-solvent mixture at 0° C. to about 20° C. for a period of at least about 2 h;    wherein the recovering step comprises drying the levofloxacin for about 20 hours at about 40° C. and for at least about 6 hours at about 60° C.;    wherein the elevated temperature is about 75° C.; and    wherein the polar solvent is isopropanol.    
   
   
       29 . Levofloxacin Form B made by the process of  claim 28 .  
   
   
       30 . The method of  claim 18 , further comprising 
 cooling the levofloxacin-solvent mixture to 0° C. to about 20° C. over a period of at least about 0.5 h;    maintaining the levofloxacin-solvent mixture at 0° C. to about 20° C. for a period of at least about 2 h;    wherein the elevated temperature is about 75° C.; and    wherein the polar solvent is isopropanol containing about 0.3% to about 0.4% by volume water.    
   
   
       31 . Levofloxacin Form H made by the process of  claim 30 .  
   
   
       32 . A method for preparing levofloxacin Form F comprising: 
 maintaining a first mixture of levofloxacin and a polar solvent at a first elevated temperature for at least about 15 minutes;    cooling the first mixture to less than about 80° C.;    adding additional polar solvent to the cooled first mixture to form a second mixture;    maintaining the second mixture at a second elevated temperature;    adding additional polar solvent to the second mixture during the maintaining step;    cooling the second mixture to form a levofloxacin form; and    recovering levofloxacin Form F.    
   
   
       33 . The method of  claim 32 , 
 wherein the first elevated temperature is the reflux temperature; and    wherein the polar solvent is isobutyl alcohol.    
   
   
       34 . Levofloxacin Form F made by the process of  claim 32 .  
   
   
       35 . A method for preparing a levofloxacin form comprising: 
 reacting (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with N-methyl piperazine at an elevated temperature to form levofloxacin;    adding a polar solvent to precipitate the levofloxacin form; and    recovering a levofloxacin form selected from the group consisting of Form C, Form A, Form G, Form B, Form H and Form F.    
   
   
       36 . (canceled)  
   
   
       37 . Levofloxacin Form C.  
   
   
       38 . The form of  claim 37 , wherein the Form C comprises about 30-50% by weight DMSO and about 3.5% by weight water.  
   
   
       39 . The form of  claim 37 , wherein the Form C is characterized by peaks at 12.2, 17.6, 18.0, 21.7, 22.4, 23.4, each peak being ±0.3 deg. 2θ.  
   
   
       40 . The form of  claim 39 , wherein the Form C is further characterized by peaks at 7.8, 10.8, 15.6, 17.2, 20.0, 20.6, 23.9, 24.5, 27.5, 27.8, each peak being ±0.3 deg. 2θ.  
   
   
       41 . A pharmaceutical composition comprising a therapeutically effective amount of the form of  claim 39  and a pharmaceutically acceptable carrier.  
   
   
       42 . Levofloxacin Form A.  
   
   
       43 . The form of  claim 42 , wherein the Form A is characterized by peaks at 5.5, 11.3, 12.6, 18.8, each peak being ±0.3 deg. 2θ.  
   
   
       44 . The form of  claim 43 , wherein the Form C is further characterized by peaks at 2.9, 8.1, 10.8, 15.9, 16.1, 20.7, 21.5, 21.9, 23.2, 25.7, 29.4, 29.7, each peak being 0.3 deg. 2θ.  
   
   
       45 . A pharmaceutical composition comprising a therapeutically effective amount of the form of  claim 43  and a pharmaceutically acceptable carrier.  
   
   
       46 . Levofloxacin Form G.  
   
   
       47 . The form of  claim 46 , wherein the Form G is characterized by peaks at 5.3, 6.7, 13.1, 13.4, 26.4, 26.7, each peak being ±0.3 deg. 2θ.  
   
   
       48 . The form of  claim 47 , wherein the Form G is further characterized by peaks at 2.8, 9.9, 16.1, 18.7, 19.6, 20.1, 21.5, 29.6, 33.1, 33.8, 34.5, 35.0, each peak being ±0.3 deg. 2θ.  
   
   
       49 . A pharmaceutical composition comprising a therapeutically effective amount of the form of  claim 47  and a pharmaceutically acceptable carrier.  
   
   
       50 . Levofloxacin Form B.  
   
   
       51 . The form of  claim 50 , wherein the Form B is characterized by peaks at 15.2, 15.8, 25.5, 25.8, each peak being ±0.3 deg. 2θ.  
   
   
       52 . The form of  claim 51 , wherein the Form B is further characterized by peaks at 5.3, 6.0, 6.7, 9.7, 13.1, 19.4, 20.0, 26.3, 26.7, each peak being ±0.3 deg. 2θ.  
   
   
       53 . A pharmaceutical composition comprising a therapeutically effective amount of the form of  claim 51  and a pharmaceutically acceptable carrier.  
   
   
       54 . Levofloxacin Form H.  
   
   
       55 . The form of  claim 54 , wherein the Form H comprises a solvate such that the ratio of levofloxacin: solvate is about 2:1.  
   
   
       56 . The form of  claim 55 , wherein the solvate is isopropanol.  
   
   
       57 . The form of  claim 54 , wherein the Form H is characterized by peaks at 4.9, 5.2, 5.5, 18.7, each peak being ±0.3 deg. 2θ.  
   
   
       58 . The form of  claim 57 , wherein the Form H is further characterized by peaks at 2.8, 6.7, 8.1, 10.7, 13.4, 16.1, 18.7, 20.1, 20.7, 21.4, 29.6, 35.1, each peak being ±0.3 deg. 2θ.  
   
   
       59 . A pharmaceutical composition comprising a therapeutically effective amount of the form of  claim 58  and a pharmaceutically acceptable carrier.  
   
   
       60 . Levofloxacin Form F.  
   
   
       61 . The form of  claim 60 , wherein the Form F is characterized by peaks at 11.9, 17.8, 18.4, each peak being ±0.3 deg. 2θ.  
   
   
       62 . The form of  claim 61 , wherein the Form F is further characterized by peaks at 5.3, 6.0, 6.7, 9.7, 10.6, 13.2, 13.4, 13.7, 15.5, 15.9, 19.4, 20.1, 25.3, 26.4, 26.8, each peak being ±0.3 deg. 2θ.  
   
   
       63 . A pharmaceutical composition comprising a therapeutically effective amount of the form of  claim 61  and a pharmaceutically acceptable carrier.  
   
   
       64 . (canceled)  
   
   
       65 . A method for preparing a levofloxacin form comprising: 
 reacting (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with N-methyl piperazine at an elevated temperature to form levofloxacin;    precipitating the levofloxacin;    maintaining the levofloxacin at a first elevated temperature in a first solvent;    adding a polar solvent to precipitate the levofloxacin form; and    recovering a levofloxacin form selected from the group consisting of Form C, Form A, Form G, Form B, Form H and Form F.    
   
   
       66 . The method of  claim 1 , wherein the elevated temperature is from about 70-120° C.  
   
   
       67 . The method of  claim 14 , wherein the polar solvent is PGME or isobutanol and the anti-solvent is heptane or hexane.  
   
   
       68 . The method of  claim 14 , wherein the polar solvent is DMSO and the anti-solvent is isopropanol.  
   
   
       69 - 73 . (canceled)  
   
   
       74 . The method of  claim 1 , wherein the recovered levofloxacin is levofloxacin hemihydrate.