Polymorphic forms alpha, beta and gamma of rifaximin

Abstract

Crystalline polymorphous forms of rifaximin (INN) antibiotic named rifaximin α and rifaximin β, and a poorly crystalline form named rifaximin γ, useful in the production of medicinal preparations containing rifaximin for oral and topical use and obtained by means of a crystallization carried out by hot-dissolving the raw rifaximin in ethyl alcohol and by causing the crystallization of the product by addition of water at a determinate temperature and for a determinate period of time, followed by a drying carried out under controlled conditions until reaching a settled water content in the end product, are the object of the invention.

1 .- 3 . (canceled) 
     
     
         4 . A polymorph rifaximin preparation having an X-ray powder diffraction pattern peaks at about:
 7.4°±0.2, 7.9°±0.2, and 6.6°±0.2; or   7.4°±0.2, 8.8°±0.2, and 6.6°±0.2; or   7.4°±0.2, 10.5°±0.2, and 6.6°±0.2; or   7.4°±0.2, 11.1°±0.2, and 6.6°±0.2; or   7.4°±0.2, 6.6°±0.2, and 12.9°±0.2; or   7.4°±0.2, 6.6°±0.2, and 17.6°±0.2; or   7.4°±0.2, 6.6°±0.2, and 19.7°±0.2; or   7.4°±0.2, 6.6°±0.2, and 21.4°±0.2; or   7.4°±0.2, 6.6°±0.2, and 22.1°±0.2, or   7.4°±0.2, 11.1°±0.2, and 12.9°±0.2; or   7.4°±0.2, 11.1°±0.2, and 19.7°±0.2; or   7.4°±0.2, 12.9°±0.2, and 19.7°±0.2; or   11.1°±0.2, 6.6°±0.2, and 19.7°±0.2; or   11.1°±0.2, 19.7°±0.2, and 21.4°±0.2; or   11.1°±0.2, 19.7°±0.2, and 22.1°±0.2, or   11.8°±0.2, 12.9°±0.2, and 19.7°±0.2; or   11.8°±0.2, 19.9°±0.2, and 22.1°±0.2, 2θ; and   a halo peak.   
     
     
         5 . The polymorph rifaximin preparation of  claim 4 , wherein the X-ray powder diffraction pattern further comprises peaks at about 5.0°±0.2; 7.1°±0.2; 2θ. 
     
     
         6 . The polymorph rifaximin preparation of  claim 4 , wherein the halo peak is in the range of between about 10° and 25°, 2θ. 
     
     
         7 . The polymorph rifaximin preparation of  claim 4 , wherein the preparation has a water content lower than 6.0%. 
     
     
         8 . The polymorph rifaximin preparation of  claim 4 , wherein the polymorph rifaximin preparation predominately comprises rifaximin polymorphic form α, or predominately comprises rifaximin polymorphic form γ. 
     
     
         9 . The polymorph rifaximin preparation of  claim 4 , wherein the polymorph rifaximin preparation predominately comprises a rifaximin amorphous component. 
     
     
         10 . A medicinal preparation comprising the polymorph rifaximin preparation of  claim 4  and a pharmaceutically acceptable excipient or carrier. 
     
     
         11 . The medicinal preparation of  claim 10 , wherein the polymorph rifaximin preparation predominately comprises rifaximin polymorphic form α or predominately comprises rifaximin polymorphic form γ. 
     
     
         12 . The medicinal preparation of  claim 10 , wherein the polymorph rifaximin preparation predominately comprises a rifaximin amorphous component. 
     
     
         13 . A method for treating gastrointestinal infections, the method comprising administering to a subject in need an effective amount of the medicinal preparation of  claim 10 . 
     
     
         14 . A polymorph rifaximin preparation having an X-ray powder diffraction pattern peaks at about:
 5.4°±0.2, 6.4°±0.2, and 7.0°±0.2; or   5.4°±0.2, 6.4°±0.2, and 7.8°±0.2; or   5.4°±0.2, 6.4°±0.2, and 9.0°±0.2; or   5.4°±0.2, 6.4°±0.2, and 10.4°±0.2; or   5.4°±0.2, 6.4°±0.2, and 13.1°±0.2, or   5.4°±0.2, 7.0°±0.2, and 14.4°±0.2; or   5.4°±0.2 10.4°±0.2, and 18.3°±0.2; or 5.4°±0.2 10.4°±0.2, and 20.9°±0.2; or   5.4°±0.2 10.4°±0.2, and 17.1°±0.2, or   6.4°±0.2 7.0°±0.2, and 10.4°±0.2; or   6.4°±0.2 7.8°±0.2, and 10.4°±0.2; or   6.4°±0.2 9.0°±0.2, and 10.4°±0.2; or   6.4°±0.2 10.4°±0.2, and 14.4°±0.2; or   10.4°±0.2 13.1°±0.2, and 14.4°±0.2; or   10.4°±0.2 17.1°±0.2, and 17.9°±0.2; or   10.4°±0.2 17.9°±0.2, and 18.3°±0.2; or   10.4°±0.2 17.9°±0.2, and 20.9°±0.2; or   10.4°±0.2 18.3°±0.2, and 20.9°±0.2; or   14.4°±0.2 17.1°±0.2, and 18.3°±0.2; or   17.1°±0.2 18.3°±0.2, and 20.9°±0.2; or   14.4°±0.2 17.1°±0.2, and 20.9°±0.2, 2θ; and   a halo peak.   
     
     
         15 . The polymorph rifaximin preparation of  claim 14  wherein the X-ray powder diffraction pattern further comprises peaks at about 5.0°±0.2; 7.1°±0.2; 8.4°±0.2, 2θ. 
     
     
         16 . The polymorph rifaximin preparation of  claim 14 , wherein the halo peak is in the range of between about 10° and 25°, 2θ. 
     
     
         17 . The polymorph rifaximin preparation of  claim 14 , wherein the preparation has a water content higher than 4.5%. 
     
     
         18 . The polymorph rifaximin preparation of  claim 14 , wherein the preparation has a water content in the range between 1.0% and 6.0%. 
     
     
         19 . The polymorph rifaximin preparation of  claim 14 , wherein the polymorph rifaximin preparation predominately comprises rifaximin polymorphic form β, or predominately comprises rifaximin polymorphic form γ. 
     
     
         20 . The polymorph rifaximin preparation of  claim 14 , wherein the polymorph rifaximin preparation predominately comprises a rifaximin amorphous component. 
     
     
         21 . A medicinal preparation comprising the polymorph rifaximin preparation of  claim 14  and a pharmaceutically acceptable excipient and/or carrier. 
     
     
         22 . The medicinal preparation of  claim 21 , wherein the polymorph rifaximin preparation predominately comprises rifaximin polymorphic form β or predominately comprises rifaximin polymorphic form γ. 
     
     
         23 . The medicinal preparation of  claim 21 , wherein the polymorph rifaximin preparation predominately comprises a rifaximin amorphous component. 
     
     
         24 . A method for treating gastrointestinal infections, the method comprising administering to a subject in need an effective amount of the medicinal preparation of  claim 21 . 
     
     
         25 . A polymorph rifaximin preparation having X-ray powder diffraction pattern peaks at about 5.0°±0.2, 7.1°±0.2 and 8.4°±0.2, 2θ and a halo peak. 
     
     
         26 . The polymorph rifaximin preparation of  claim 25 , wherein the halo peak is in the range between about 10.0° and 25.0°, 2θ. 
     
     
         27 . The polymorph rifaximin preparation of  claim 25 , wherein the preparation has a water content in the range between 1.0% and 6.0%. 
     
     
         28 . The polymorph rifaximin preparation of  claim 25 , wherein the preparation has a water content in the range between 1.0% and 4.5%. 
     
     
         29 . The polymorph rifaximin preparation of  claim 25 , wherein the polymorph rifaximin preparation predominately comprises an amorphous component. 
     
     
         30 . A medicinal preparation comprising the rifaximin preparation of  claim 25  and a pharmaceutically acceptable excipient and/or carrier. 
     
     
         31 . The medicinal preparation of  claim 30 , wherein the polymorph rifaximin preparation predominately comprises a rifaximin amorphous component. 
     
     
         32 . A method for treating gastrointestinal infections, the method comprising administering to a subject in need an effective amount of the medicinal preparation of  claim 30 . 
     
     
         33 . A polymorph rifaximin preparation having at least one X-ray powder diffraction pattern peak at about:
 7.4°±0.2, 7.9°±0.2, and 6.6°±0.2; or   7.4°±0.2, 8.8°±0.2, and 6.6°±0.2; or   7.4°±0.2, 10.5°±0.2, and 6.6°±0.2; or   7.4°±0.2, 11.1°±0.2, and 6.6°±0.2; or   7.4°±0.2, 6.6°±0.2, and 12.9°±0.2; or   7.4°±0.2, 11.8°±0.2, and 17.6°±0.2; or   7.4°±0.2, 11.8°±0.2, and 19.7°±0.2; or   7.4°±0.2, 11.8°±0.2, and 21.4°±0.2; or   7.4°±0.2, 11.8°±0.2, and 22.1°±0.2, or   7.4°±0.2, 11.1°±0.2, and 12.9°±0.2; or   7.4°±0.2, 11.1°±0.2, and 19.7°±0.2; or   7.4°±0.2, 12.9°±0.2, and 19.7°±0.2; or   11.1°±0.2, 11.8°±0.2, and 19.7°±0.2; or   11.1°±0.2, 19.7°±0.2, and 21.4°±0.2; or   11.1°±0.2, 19.7°±0.2, and 22.1°±0.2, or   11.8°±0.2, 12.9°±0.2, and 19.7°±0.2; or   11.8°±0.2, 19.7°±0.2, and 22.1°±0.2, 2θ,   at least one X-ray powder diffraction pattern peak at about   5.4°±0.2, 6.4°±0.2, and 7.0°±0.2, or   5.4°±0.2, 6.4°±0.2, and 7.8°±0.2; or   5.4°±0.2, 6.4°±0.2, and 9.0°±0.2; or   5.4°±0.2, 6.4°±0.2, and 10.4°±0.2; or   5.4°±0.2, 6.4°±0.2, and 13.1°±0.2, or   5.4°±0.2, 7.0°±0.2, and 14.4°±0.2; or   5.4°±0.2 10.4°±0.2, and 18.3°±0.2; or   5.4°±0.2 10.4°±0.2, and 20.9°±0.2; or   5.4°±0.2 10.4°±0.2, and 17.1°±0.2, or   6.4°±0.2 7.0°±0.2, and 10.4°±0.2; or   6.4°±0.2 7.8°±0.2, and 10.4°±0.2; or   6.4°±0.2 9.0°±0.2, and 10.4°±0.2; or   6.4°±0.2 10.4°±0.2, and 14.4°±0.2; or   10.4°±0.2 13.1°±0.2, and 14.4°±0.2; or   10.4°±0.2 17.1°±0.2, and 17.9°±0.2; or   10.4°±0.2 17.9°±0.2, and 18.3°±0.2; or   10.4°±0.2 17.9°±0.2, and 20.9°±0.2; or   10.4°±0.2 18.3°±0.2, and 20.9°±0.2; or   14.4°±0.2 17.1°±0.2, and 18.3°±0.2; or   17.1°±0.2 18.3°±0.2, and 20.9°±0.2; or   14.4°±0.2 17.1°±0.2, and 20.9°±0.2, 2θ,   Or at least one X-ray powder diffraction pattern peaks at about:   5.0°±0.2, 7.1 and 8.4°±0.2, 2θ; and   a halo peak.   
     
     
         34 . The polymorph rifaximin preparation of  claim 33 , wherein the halo peak is in the range of between about 10°±0.2 and 25°±0.2, 2θ. 
     
     
         35 . The polymorph rifaximin preparation of  claim 33 , where the preparation has a water content in the range between 1.0% and 6.0%. 
     
     
         36 . The polymorph rifaximin preparation of  claim 33 , wherein the polymorph rifaximin preparation predominately comprises rifaximin polymorphic form α, or predominately comprises rifaximin polymorphic form γ 
     
     
         37 . The polymorph rifaximin preparation of  claim 33 , wherein the polymorph rifaximin preparation predominately comprises rifaximin polymorphic form β, or predominately comprises rifaximin polymorphic form γ. 
     
     
         38 . The polymorph rifaximin preparation of  claim 34 , wherein the polymorph rifaximin preparation predominately comprises a rifaximin amorphous component. 
     
     
         39 . A medicinal preparation comprising the rifaximin preparation of  claim 33  and a pharmaceutically acceptable excipient and/or carrier. 
     
     
         40 . The medicinal preparation of  claim 39 , wherein the polymorph rifaximin preparation predominately comprises a rifaximin amorphous component. 
     
     
         41 . A method for treating gastrointestinal infections, the method comprising administering to a subject in need an effective amount of the medicinal preparation of  claim 39 .