Polymorphic forms of rifaximin, processes for their production and uses thereof

Abstract

The present invention relates to rifaximin polymorphic forms α, β and γ, the processes for their preparation and the use thereof in the manufacture of medicinal preparations for the oral or topical route.

1 . A compound formula (I)  
       
         
           
           
               
               
           
         
         in polymorphic form α.  
       
     
     
         2 . The compound of  claim 1 , wherein the polymorph in Form α has an x-ray powder diffraction pattern peak position at about 11.8°; 12.9°; °; and 19.7° degrees 2-θ.  
     
     
         3 . The compound of  claim 1 , wherein the polymorph in Form α has an x-ray powder diffraction pattern peak position at about 6.6°; 7.4°; 7.9°; 8.8°; 10.5°; 11.1°; 11.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.4°; and 22.1° degrees 2-θ.  
     
     
         4 . The compound of  claim 1 , wherein the polymorph has a water content of from between about 0 to about 3.0%.  
     
     
         5 . The compound of  claim 1 , wherein the C max  is from between about 2.3 ng/ml to about 2.7 ng/ml.  
     
     
         6 . The compound of  claim 1 , wherein the t max  is from between about 3.5 h to about 9.5 h.  
     
     
         7 . The compound of  claim 1 , wherein the AUC 0-24 h  is between about 10 and about 20 ng·h/ml.  
     
     
         8 . The compound of  claim 1 , wherein the AUC 0-inf  is between about 10 and about 25 ng·h/ml.  
     
     
         9 . A compound of formula (I) in polymorphic Form β.  
     
     
         10 . The compound of  claim 9 , wherein the polymorph in Form β has an x-ray powder diffraction pattern peak position at about 5.4°; 10.4°; 18.3° and 20.9° degrees 2-θ.  
     
     
         11 . The compound of  claim 9 , wherein the polymorph in Form β has an x-ray powder diffraction pattern peak position at about 5.4°; 6.4°; 7.0°; 7.8°; 9.0°; 10.4°; 13.1°, 14.4°; 17.1°; 17.9°; 18.3°; 20.9° degrees 2-θ.  
     
     
         12 . The compound of  claim 9 , wherein the polymorph in Form β has a water content of from between about 4.5 to about 100%.  
     
     
         13 . The compound of  claim 9 , wherein the C max  is between about 0.9 and about 1.3 ng/ml.  
     
     
         14 . The compound of  claim 9 , wherein the t max  is between about 3.5 and about 4.5 h.  
     
     
         15 . The compound of  claim 9 , wherein the AUC 0-24 h  is between about 8 to about 12 ng·h/ml.  
     
     
         16 . The compound of  claim 9 , wherein the AUC 0-inf  is between about 10 to about 25 ng·h/ml.  
     
     
         17 . The compound of  claim 9 , wherein the intrinsic dissolution rate is from between about 0.001 to about 0.016 mg/min/cm 2 .  
     
     
         18 . A compound of formula (I) in polymorphic Form γ.  
     
     
         19 . The compound of  claim 18 , wherein the polymorph in Form γ has an x-ray powder diffraction pattern peak position at about 5.0°; 7.1°; 8.4° degrees 2-θ.  
     
     
         20 . The compound of  claim 18 , wherein the polymorph in Form γ has a water content of from between 0% to about 2%.  
     
     
         21 . The compound of  claim 18 , wherein the C max  is from between about 660 to about 1100 ng/ml.  
     
     
         22 . The compound of  claim 18 , wherein the t max  is from between about 1.5 h to about 4.0 h.  
     
     
         23 . The compound of  claim 18 , wherein the AUC 0-24 h  is from between about 3600 to about 5000 ng·h/ml.  
     
     
         24 . The compound of  claim 18 , wherein the AUC 0-inf  is from between about 3700 to about 5000 ng·h/ml.  
     
     
         25 . The polymorph of rifaximin according to  claim 18 , wherein the intrinsic dissolution rate is from between about 0.1 to about 0.16 mg/min/cm 2 .  
     
     
         26 . A pharmaceutical composition comprising one or more of a Form α, Form β, or Form γ polymorph of rifaximin and a pharmaceutically acceptable carrier.  
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein the pharmaceutical composition further comprises excipients.  
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the excipients are one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, colouring agent, flavouring agent or sweetening agent.  
     
     
         29 . The pharmaceutical composition of  claim 26 , wherein the composition is formulated for selected coated and uncoated tablets, hard and soft gelatine capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in sealed packet.  
     
     
         30 . The pharmaceutical composition of  claim 26 , wherein the composition is formulated for topical use.  
     
     
         31 . A method of treating, preventing, or alleviating a bowel related disorder comprising administering to a subject in need thereof a cell infected with a virus with an effective amount of one or more of a Form α, Form β, or Form γ polymorph of rifaximin.  
     
     
         32 . The method of  claim 31 , wherein the bowel related disorder is one or more of irritable bowel syndrome, travelers' diarrhea, small intestinal bacterial overgrowth, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, or colitis.  
     
     
         33 . A method of assessing the efficacy of a bowel related disorder treatment in a subject, monitoring the progress of a subject being treated for a bowel related disorder, or a method of selecting a subject for treatment of a bowel disorder, comprising: 
 determining a pre-treatment level of bacterial overgrowth;    administering a therapeutically effective amount of one or more of a Form α, Form β, or Form γ polymorph of rifaximin to the subject; and    determining a post-treatment level of bacterial overgrowth after an initial period of treatment with the one or more of Form α, Form β, or Form γ polymorph of rifaximin.    
     
     
         34 . The method of  claim 33 , wherein the modulation of the level of bacterial overgrowth indicates efficacy of the treatment.  
     
     
         25 . The method of  claim 33 , wherein a decrease in bacterial overgrowth indicates that the treatment is efficacious.  
     
     
         36 . The method of  claim 33 , wherein the modulation of the bacterial overgrowth is an indication that the subject is likely to have a favourable clinical response to the treatment.  
     
     
         37 . A kit for treating a bowel disorder in a subject, comprising: 
 one or more of a Form α, Form β, or Form γ polymorph of rifaximin and instructions for use.    
     
     
         38 . A packaged composition comprising, a therapeutically effective amount of one or more of a Form α, Form β, or Form γ polymorph of rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for treating a subject suffering from or susceptible to a bowel disorder, and packaged with instructions to treat a subject suffering from or susceptible to a bowel disorder.  
     
     
         39 . A process for the production of one or more of a Form α, Form β, or Form γ polymorph of rifaximin, comprising: 
 reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine in a solvent mixture comprising water and ethyl alcohol in volumetric ratios between about 1:1 and about 2:1 for a time between about 2 and about 8 hours;    treating the reaction mixture at room temperature with a solution of ascorbic acid in a mixture of water, ethyl alcohol and concentrated aqueous hydrochloric acid;    adjusting the pH of the solution to about 2.0 with hydrochloric acid concentrated aqueous solution,    filtering and washing the resulting solid with the same water/ethyl alcohol solvent mixture;    purifying the raw rifaximin by dissolution in ethyl alcohol;    precipitating rifaximin by addition of water, with between about 15% to about 70% to the weight amount of ethyl alcohol used for the dissolution at a temperature of from between about 50° C. to about 0° C. under stirring for between about 4 to about 36 hours;    filtering and washing a resulting solid with water; and    drying the rifaximin at a temperature of from between about room temperature to about 105° C.    
     
     
         40 . The method of  claim 39 , wherein the drying is for form between about 2 hours and about 72 hours.  
     
     
         41 . The method of  claim 39 , wherein the reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine is at a temperature of from between about 40° C. to about 60° C.  
     
     
         42 . The method of  claim 39 , wherein the purifying the raw rifaximin by dissolution in ethyl alcohol is at a temperature of from between about 45° C. to about 65° C.  
     
     
         43 . The method of  claim 39 , wherein the reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine is from between about 2.0 to about 3.5 molar equivalents.  
     
     
         44 . A method according to  claim 39 , wherein after precipitating rifaximin by addition of water, the method further comprises lowering the temperature to between about 28° C. to about 32° C. to start crystallization.  
     
     
         45 . The method according to  claim 44 , wherein the resulting suspension is kept at a temperature of from between about 40° C. to about 50° C. under stirring for a time from between about 6 to about 24 hours.  
     
     
         46 . The method according to  claim 45 , further comprising, cooling the suspension to about 0° C. for from between about 15 minutes and about one hour; 
 filtering the resulting solid; and    drying the solid to a water content of from between 0% and about 3.0% water to form Form α.    
     
     
         47 . The method according to  claim 39 , wherein after precipitating rifaximin by addition of water, the method further comprises: 
 cooling the solution to a temperature of from between about 28° C. to about 32° C.;    maintaining the solution at from between about 40° C. and about 50° C. under stirring for between about 6 to about 24 hours;    cooling the solution to about 0° C. for between about 15 minutes to about one hour;    filtering a resulting solid;    drying the solid from between about 4.5 to about 100% water content to form Form β.    
     
     
         48 . The method according to  claim 39 , wherein after precipitating rifaximin by addition of water, the method further comprises: 
 cooling the solution to a temperature of from between about 28° C. to about 32° C.;    cooling the solution to about 0° C., under stirring, for between about 6 to about 24 hours;    filtering a resulting solid; and    drying the sold to a water content of between about 1.0% and about 2.0% to form Form γ.    
     
     
         49 . A method for the production of rifaximin O, comprising: 
 reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine in a solvent mixture comprising water and ethyl alcohol to form a reaction mixture;    treating the reaction mixture with a solution of a weak acid, water, and alcohol to lower the pH of the solution to form a suspension;    filtering the suspension and washing the resulting solid with a water, alcohol, and solvent mixture to form raw rifaximin;    purifying the raw rifaximin by dissolution in an alcohol at a temperature between about 45° C. and about 65° C.;    precipitating the raw rifaximin by the addition of water;    lowering of the temperature of the suspension to between about 50° C. to about 0° C. under stirring to form a second suspension;    filtering the second suspension; and    washing a resulting solid with water and drying.    
     
     
         50 . The method of  claim 49 , wherein the reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine is from between about 2.0 to about 3.5 molar equivalents.  
     
     
         51 . The method of  claim 49 , wherein the reacting a solvent mixture comprising water and ethyl alcohol is in volumetric ratios from between about 1:1 to about 2:1.  
     
     
         52 . The method of  claim 51 , wherein the alcohol is one or more of ethyl alcohol, menthol, propanol, or 2-butanol.  
     
     
         53 . The method of  claim 49 , wherein the reacting a solvent mixture comprising water and ethyl alcohol is for a time from between about 2 to about 8 hours.  
     
     
         54 . The method of  claim 49 , wherein the reacting a solvent mixture comprising water and alcohol is at a temperature from between about 40° C. to about 60° C.  
     
     
         55 . The method of  claim 49 , wherein the treating the reaction mixture is at about room temperature.  
     
     
         56 . The method of  claim 49 , wherein the solution to treat the reaction mixture comprises a weak reducing agent in a mixture of water, alcohol and a strong acid.  
     
     
         57 . The method of  claim 56 , wherein the weak acid is one or more of ascorbic acid, sodium dithionate, or sodium thiosulphate.  
     
     
         58 . The method of  claim 55 , wherein the strong acid is one or more of hydrochloric acid, sulphuric acid, phosphoric acid.  
     
     
         59 . The method of  claim 49 , wherein when treating the reaction mixture the pH is lowered to about 2.0.  
     
     
         60 . The method of  claim 49 , wherein the drying is by one or more of under vacuum, under conditions of normal pressure, or in the presence of a drying agent.  
     
     
         61 . The method of  claim 49 , wherein the drying is at a temperature between about room temperature to about 105° C.  
     
     
         62 . The method of  claim 49 , wherein the drying is for a time from between about 2 to about 72 hours.  
     
     
         63 . The method of  claim 49 , wherein the precipitating the rifaximin is by the addition of water in weight amounts of from between about 15% to about 70% of the weight amount of ethyl alcohol used for the reacting.  
     
     
         64 . The method of  claim 49 , wherein the under stirring for a time from between about 4 to about 36 hours.  
     
     
         65 . The method of  claim 49 , wherein after the precipitation of raw rifaximin the method further comprises: 
 lowering the temperature to between about 28° C. to about 32° C.;    maintaining the temperature at between about 40° C. to about 50° C. under stirring for between about 6 to about 24 hours;    cooling to about 0° C. for between about 15 minutes to about one hour;    filtering a resulting solid; and    drying the resulting solid to a water content from between about 3.0% to 0%, wherein the method forms Form α of rifaximin.    
     
     
         66 . The method of  claim 49 , wherein after the precipitation of raw rifaximin the method further comprises: 
 lowering the temperature to between about 28° C. to about 32° C.;    maintaining the temperature at between about 40° C. to about 50° C. under stirring for between about 6 to about 24 hours;    cooling to about 0° C. for between about 15 minutes and about one hour;    filtering a resulting solid; and    drying the solid to a water content greater than about 4.5% to form Form β of rifaximin.    
     
     
         67 . The method of  claim 49 , wherein after the precipitation of raw rifaximin the method further comprises: 
 lowering the temperature to between about 28° C. to about 32° C.;    cooling the temperature to about 0° C. under stirring for between about 6 to about 24 hours;    filtering a resulting solid; and    drying the solid to a water content of between about 1.0% to about 2.0%, wherein the method produces Form γ of rifaximin.