Gemifloxacin process and polymorphs

Abstract

The present invention provides a novel process for the preparation of gemifloxacin and its pharmaceutically acceptable acid addition salts in high yield. The present invention also relates to novel polymorphs of gemifloxacin free base and its hydrates to the processes for their preparation and to pharmaceutical compositions comprising them. The present invention also relates to infusion solutions of gemifloxacin and to processes for their preparation. Thus, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphth-yridine-3-carboxylic acid is reacted with a mixture of acetic anhydride, acetic acid and boric acid to give borane compound, which is then treated with 4-Aminomethyl-3-methoxyimino-pyrrolidinium dimethanesulfonate in presence of triethylamine, followed by treatment with 3.5% sodium hydroxide solution to give gemifloxacin free base.

1 . A process for preparation of gemifloxacin of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof: 
         which comprises: 
         a) reacting 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of formula II: 
       
       
         
           
           
               
               
           
         
         with boric acid of formula III: 
       
       
         
           
           
               
               
           
         
         in presence of acetic anhydride and acetic acid to give borane compound of formula IV: 
       
       
         
           
           
               
               
           
         
         b) reacting the borane compound of formula IV with 4-aminomethyl-3-methoxyimino-pyrrolidine of formula V: 
       
       
         
           
           
               
               
           
         
         to give the compound of formula VI: 
       
       
         
           
           
               
               
           
         
         c) treating the compound of formula VI with an alkaline metal hydroxide, carbonate or bicarbonate to obtain gemifloxacin of formula I and optionally converted gemifloxacin formed into a pharmaceutically acceptable acid addition salts of gemifloxacin. 
       
     
     
         2 . The process according to  claim 1 , wherein the reaction in step (a) is carried out at about 30° C. to reflux temperature. 
     
     
         3 . The process according to  claim 2 , wherein the reaction is carried out at about 80° C. to reflux temperature. 
     
     
         4 . The process according to  claim 3 , wherein the reaction is carried out at reflux temperature. 
     
     
         5 . The process according to  claim 1 , wherein the reaction in step (b) is carried out in a solvent selected from hydrocarbon solvents, chlorinated hydrocarbon solvents, acetonitrile, tetrahydrofuran, 1,4-dioxane and a mixture thereof. 
     
     
         6 . The process according to  claim 5 , wherein the solvent is n-hexane, cyclohexane, n-heptane, methylene chloride or 1,4-dioxane. 
     
     
         7 . The process according to  claim 6 , wherein the solvent is acetonitrile. 
     
     
         8 . The process according to  claim 1 , wherein the reaction in step (b) is carried out at about 15-100° C. 
     
     
         9 . The process according to  claim 8 , wherein the reaction in step (b) is carried out at about 30-80° C. 
     
     
         10 . The process according to  claim 9 , wherein the reaction in step (b) is carried out at about 50-60° C. 
     
     
         11 . The process according to  claim 1 , wherein the alkaline metal hydroxide is sodium hydroxide or potassium hydroxide, alkaline metal carbonate is sodium carbonate or potassium carbonate, and alkaline metal bicarbonate is sodium bicarbonate or potassium bicarbonate. 
     
     
         12 . The process according to  claim 11 , wherein the alkaline metal hydroxide is sodium hydroxide. 
     
     
         13 . A process for preparation of amorphous gemifloxacin, which comprises:
 a) preparing a solution of gemifloxacin in dimethylformamide or methylene chloride; and   b) isolating amorphous gemifloxacin from the solution.   
     
     
         14 . The process according to  claim 13 , wherein the isolation of amorphous gemifloxacin is performed by the techniques such as cooling, seeding, partial removal of the solvent from the solution, addition of precipitating solvent or a combination thereof. 
     
     
         15 . The process according to  claim 14 , wherein the isolation is performed by cooling. 
     
     
         16 . The process according to  claim 14 , wherein the isolation is performed by using a precipitating solvent. 
     
     
         17 . The process according to  claim 16 , wherein the precipitating solvent is diisopropyl ether. 
     
     
         18 . Compound of formula IV: 
       
         
           
           
               
               
           
         
       
     
     
         19 . Compound of formula VI: 
       
         
           
           
               
               
           
         
       
     
     
         20 . Gemifloxacin hemihydrate. 
     
     
         21 . A process for preparation of gemifloxacin hemihydrate of  claim 20 , which comprises drying wet gemifloxacin at 40-100° C. till the water content is reduced to 1.8-2.4% by weight. 
     
     
         22 . The process according to  claim 21 , wherein the drying is carried out at 50-70° C. 
     
     
         23 . Gemifloxacin monohydrate. 
     
     
         24 . A process for preparation of gemifloxacin monohydrate of  claim 23 , which comprises drying wet gemifloxacin at 40-100° C. till the water content is reduced to 4.0-5.0% by weight. 
     
     
         25 . The process according to  claim 24 , wherein the drying is carried out at 50-70° C. 
     
     
         26 . Gemifloxacin sesquihydrate. 
     
     
         27 . A process for preparation gemifloxacin sesquihydrate of  claim 26 , which comprises drying wet gemifloxacin at 40-100° C. till the water content is reduced to 5.8-6.5% by weight. 
     
     
         28 . The process according to  claim 27 , wherein the drying is carried out at 50-70° C. 
     
     
         29 . A crystalline gemifloxacin lactate, characterized by an X-ray powder diffraction spectrum having peaks expressed as 2θ at about 7.4, 7.7, 8.2, 9.1, 12.4, 18.5, 19.8, 23.6, 25.7 and 26.8 degrees. 
     
     
         30 . A process for preparation of crystalline gemifloxacin lactate of  claim 29 , which comprises contacting gemifloxacin with lactic acid in a solvent medium and crystallizing the gemifloxacin lactate from the solution. 
     
     
         31 . The process according to  claim 30 , wherein the solvent is selected from chlorinated hydrocarbon solvent, alcoholic solvent and a mixture thereof. 
     
     
         32 . The process according to  claim 31 , wherein the chlorinated hydrocarbon solvents are methylene chloride, ethylene chloride, chloroform and a mixture thereof. 
     
     
         33 . The process according to  claim 32 , wherein the chlorinated hydrocarbon solvent is methylene chloride. 
     
     
         34 . The process according to  claim 31 , wherein the alcoholic solvents are methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and a mixture thereof. 
     
     
         35 . The process according to  claim 34 , wherein the alcoholic solvent is ethanol. 
     
     
         36 . A crystalline gemifloxacin formate. 
     
     
         37 . A process for preparation of crystalline gemifloxacin formate of  claim 36 , which comprises contacting gemifloxacin with formic acid in a solvent medium and crystallizing the gemifloxacin formate from the solution. 
     
     
         38 . The process according to  claim 37 , wherein the solvent is selected from chlorinated hydrocarbon solvent, alcoholic solvent and a mixture thereof. 
     
     
         39 . The process according to  claim 38 , wherein the chlorinated hydrocarbon solvents are methylene chloride, ethylene chloride, chloroform and a mixture thereof. 
     
     
         40 . The process according to  claim 39 , wherein the chlorinated hydrocarbon solvent is methylene chloride. 
     
     
         41 . The process according to  claim 38 , wherein the alcoholic solvents are methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and a mixture thereof. 
     
     
         42 . The process according to  claim 41 , wherein the alcoholic solvent is ethanol. 
     
     
         43 . A pharmaceutical composition comprising gemifloxacin hemihydrate of  claim 20  and a pharmaceutically acceptable excipient. 
     
     
         44 . A pharmaceutical composition comprising gemifloxacin monohydrate of  claim 23  and a pharmaceutically acceptable excipient. 
     
     
         45 . A pharmaceutical composition comprising gemifloxacin sesquihydrate of  claim 26  and a pharmaceutically acceptable excipient. 
     
     
         46 . A pharmaceutical composition comprising crystalline gemifloxacin lactate of  claim 29  and a pharmaceutically acceptable excipient. 
     
     
         47 . A pharmaceutical composition comprising crystalline gemifloxacin formate of  claim 36  and a pharmaceutically acceptable excipient. 
     
     
         48 . An aqueous infusion solution comprising 0.015 to 0.5 gm of gemifloxacin per 100 ml of aqueous solution and an amount of at least one physiologically tolerated acid which suffices to dissolve gemifloxacin, wherein there are 1.33 to 2.2 moles per mole of gemifloxacin, of the physiologically tolerated acid. 
     
     
         49 . An infusion solution according to  claim 48 , wherein the physiologically tolerated acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, propionic acid, succinic acid, glutaric acid, citric acid, fumaric acid, maleic acid, tartaric acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid, ascorbic acid, phosphoric acid, nitric acid, acetic acid, maleic acid, L-aspartic acid, lactic acid and a mixture thereof. 
     
     
         50 . An infusion solution according to  claim 49 , wherein the physiologically tolerated acid is lactic acid, hydrochloric acid or a mixture thereof. 
     
     
         51 . An infusion solution according to  claim 50 , wherein the physiologically tolerated acid is lactic acid. 
     
     
         52 . An infusion solution according to  claim 51 , wherein the lactic acid is present in 1.33 to 1.50 moles per mole of gemifloxacin. 
     
     
         53 . An infusion solution according to  claim 48 , having a pH from 3.0 to 5.2. 
     
     
         54 . An infusion solution according to  claim 53 , having a pH from 3.6 to 4.7. 
     
     
         55 . An infusion solution according to  claim 54 , having a pH from 3.9 to 4.5. 
     
     
         56 . An infusion solution according to  claim 55 , having a pH from 4.1 to 4.3. 
     
     
         57 . An infusion solution according to  claim 48 , which is substantially isotonic. 
     
     
         58 . An infusion solution according to  claim 48 , containing 1.33 to 2.2 moles of lactic acid and 0.0 to 0.80 moles of hydrochloric acid per mole of gemifloxacin, and relative to 100 ml of solution, 0.6 to 2.2 gm of NaCl.