Rifaximin

Abstract

Amorphous rifaximin, methods of making it, and pharmaceutical compositions containing it. Also described are methods of converting amorphous rifaximin to crystalline rifaximin and vice versa.

1 . Rifaximin in an amorphous form. 
     
     
         2 . Rifaximin in an amorphous form characterised by the XRPD pattern shown in  FIG. 1 . 
     
     
         3 . Rifaximin in an amorphous form characterised by the FT-IR spectrum shown in  FIG. 2 . 
     
     
         4 . Rifaximin according to  claim 1 ,  2  or  3  having a purity level of at least 99 wt %. 
     
     
         5 . Rifaximin according to any preceding claim, essentially free of crystalline rifaximin. 
     
     
         6 . Rifaximin according to any preceding claim having a bulk density in the range greater than 0.3 to 0.4 g/ml. 
     
     
         7 . A composition comprising at least 99 wt % amorphous rifaximin according to any preceding claim. 
     
     
         8 . A pharmaceutical composition comprising rifaximin according to any one of  claims 1  to  7  in combination with a pharmaceutically acceptable carrier. 
     
     
         9 . Rifaximin according to any one of  claims 1  to  5 , for use as a medicament. 
     
     
         10 . The use of Rifaximin according to any one of  claims 1  to  5 , for use in the manufacture of a medicament for treating bowel related disorders like irritable bowel syndrome, diarrhea, traveler's diarrhea, microbe associated diarrhea, Crohn's disease, chronic pancreatitis, pancreatic insufficiency and/or colitis. 
     
     
         11 . A method of treating diarrhea, comprising administering a therapeutically effective amount of rifaximin according to any preceding claim to a patient in need thereof. 
     
     
         12 . A process for manufacturing amorphous rifaximin as defined in any one of  claims 1  to  5  comprising:
 a) reacting Rifamycin S with 2-amino-4-picoline in presence of suitable solvent 
 b) adding iodine dissolved in suitable solvent to the above reaction mass followed by reducing agent 
 c) adjusting the pH of the reaction mass between 1.5-2.5 under stirring 
 d) extracting with water immiscible organic solvent and concentrating the organic layer to form a residue 
 e) stripping the residue obtained in step d) with a water immiscible solvent or mixture of water immiscible solvents to residue. 
 f) stirring the residue obtained in step e) with a water immiscible solvent or mixtures thereof to get a solid 
 g) Filtering the solid and washing with the same solvent/s and 
 h) drying the solid at a temperature below 40° C. 
 
     
     
         13 . A process according to  claim 12 , wherein the solvent or solvents used in step (e) is selected from one or more of: n-heptane, n-hexane, di-isopropyl ether, dichloromethane, dichloroethylene, chloroform and ethyl acetate. 
     
     
         14 . A process according to  claim 12  or  13 , wherein the solvents in step (f) are selected from at least two of: n-heptane, n-hexane, di-isopropyl ether, dichloromethane, dichloroethylene, chloroform and ethyl acetate 
     
     
         15 . A process for converting amorphous rifaximin, as defined in any one of  claims 1  to  5 , to crystalline γ form rifaximin, said process comprising combining the amorphous rifaximin with a mixture of an organic acid and water, then drying the rifaximin mixture at a temperature from 100 to 110° C. to yield γ form rifaximin. 
     
     
         16 . A process according to  claim 15 , wherein the organic acid is acetic acid or formic acid. 
     
     
         17 . A process according to  claim 15  or  16 , wherein prior to combining the amorphous rifaximin with the organic acid/water mixture, the rifaximin is dissolved in an organic solvent at 40-60° C., combined with water, allowed to cool, and filtered to produce a rifaximin residue which is combined with the organic acid and water. 
     
     
         18 . A process for converting amorphous rifaximin, as defined in any one of  claims 1  to  5 , to crystalline β form rifaximin, said process comprising combining the amorphous rifaximin with a mixture of a water-miscible organic solvent and water, then drying the rifaximin mixture at a temperature from 80 to 110° C. to yield β form rifaximin. 
     
     
         19 . A process according to  claim 18 , wherein the water-miscible solvent is at least one of acetone, acetonitrile, and one or more C 1-4  alcohols. 
     
     
         20 . A process according to  claim 18  or  19 , wherein prior to combining the amorphous rifaximin with the mixture of organic solvent and water, the amorphous rifaximin is dissolved in an organic solvent at 40-60° C., combined with water, allowed to cool, and filtered to produce a rifaximin residue which is combined with the water miscible solvent and water. 
     
     
         21 . A process for converting a crystalline form of rifaximin to an amorphous form of rifaximin as defined in any one of  claims 1  to  7 , said process comprising dissolving the crystalline rifaximin in a suitable solvent, filtering the solution, washing the filtrate with a suitable solvent, and concentrating the residue at 40-60° C. to form a rifaximin residue followed by the steps of:
 (a) stripping rifaximin residue with a water-immiscible solvent, or a mixture of water-immiscible solvents; 
 (b) stirring the residue obtained in step (a) with water immiscible solvents or mixtures thereof to get a solid 
 (c) filtering the solid and washing with the same solvent/s and 
 (d) drying the solid at a temperature below 40° C. 
 
     
     
         22 . A process according to  claim 21 , wherein the solvent used in step (b) is selected from one or more of: n-heptane, n-hexane, di-isopropyl ether, dichloromethane, dichloroethylene, chloroform and ethyl acetate.