Processes for the production of polymorphic forms of rifaximin

A process for the production of rifaximin in polymorphic form β, comprising:

• dissolving rifaximin in an alcoholic solvent at a temperature between approximately 45° C. and approximately 65° C.;
• precipitating the rifaximin by adding water to the alcoholic solvent to form a suspension and by lowering the temperature of the suspension to between approximately 0° C. and approximately 50° C.;
• and
• drying the rifaximin for a period of time between approximately 2 and approximately 72 hours to form rifaximin in polymorphic form β.

A process for the production of rifaximin in polymorphic form γ, comprising:

• dissolving rifaximin in an alcoholic solvent at a temperature between approximately 45° C. and approximately 65° C.;
• precipitating the rifaximin by adding water to the alcoholic solvent to form a suspension and by lowering the temperature of the suspension to between approximately 0° C. and approximately 50° C.;
• and
• drying the rifaximin for a period of time between approximately 2 and approximately 72 hours to form rifaximin in polymorphic form γ.

A process for the production of rifaximin α, comprising:

• suspending rifaximin γ in an alcohol/water solvent mixture;
• heating the suspension for a period of time between approximately 6 and approximately 36 hours;
• and
• drying the washed solid to form rifaximin α.

A process for the production of rifaximin β, comprising:

• suspending rifaximin γ in an alcohol/water solvent mixture;
• heating the suspension for a period of time between approximately 6 and approximately 36 hours;
• and
• drying the washed solid to form rifaximin β.

A process for the production of one or more of a Form α, Form β, or Form γ polymorph of rifaximin, comprising:

• reacting an amount 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 raw rifaximin solid with the 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.,
• wherein the rifaximin Form α when free from other polymorphic forms of rifaximin has x-ray powder diffraction pattern peaks at about 7.4°;
• 19.7°;
• 21.0° and 22.1° 2-θ,
• wherein the rifaximin Form β when free from other polymorphic forms of rifaximin has x-ray powder diffraction pattern peaks at about 5.4°;
• 9.0°;
• and 20.9° 2-θ, and
• wherein the rifaximin Form γ when free from other polymorphic forms of rifaximin has x-ray powder diffraction pattern peaks at about 5.0°, 7.1°, and 8.4° 2-θ.

A process for the production of rifaximin O, comprising:

• reacting an amount 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 to obtain rifaximin O.