Details for Patent: 8,741,904

Title:	Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
Abstract:	Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin .delta. and rifaximin .epsilon. useful in the production of medicinal preparations containing rifaximin for oral and topical use and obtained by means of a crystallization process 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.
Inventor(s):	Viscomi; Giuseppe Claudio (Sasso Marconi, IT), Campana; Manuela (Bologna, IT), Confortini; Donatella (Calderara di Reno, IT), Barbanti; Maria (Bologna, IT), Braga; Dario (Bologna, IT)
Assignee:	Alfa Wassermann S.p.A. (IT)
Filing Date:	Jul 25, 2013
Application Number:	13/950,642
Claims:	1. Rifaximin in polymorphic form .delta., wherein the rifaximin polymorphic form .delta. has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2 2-.theta.. 2. The rifaximin in polymorphic form .delta. of claim 1, wherein the x-ray powder diffraction pattern further comprises a peak at about 11.3.degree..+-.0.2 2-.theta.. 3. The rifaximin in polymorphic form .delta. of claim 1, wherein the x-ray powder diffraction pattern further comprises peaks at about 7.1.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 4. The rifaximin in polymorphic form .delta. of claim 1, wherein the x-ray powder diffraction pattern further comprises a peak at about 6.7.degree..+-.0.2 2-.theta.. 5. The rifaximin in polymorphic form .delta. of claim 1, wherein the polymorph has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 6.7.degree..+-.0.2, 7.1.degree..+-.0.2, 8.0.degree..+-.0.2, 8.7.degree..+-.0.2, 10.4.degree..+-.0.2, 11.3.degree..+-.0.2, 12.1.degree..+-.0.2, 17.0.degree..+-.0.2, 17.3.degree..+-.0.2, 17.5.degree..+-.0.2, 18.5.degree..+-.0.2, 18.8.degree..+-.0.2, 19.1.degree..+-.0.2, 21.0.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 6. The rifaximin in polymorphic form .delta. of claim 1, wherein the polymorph .delta. has a water content of between 3% and 4.5%. 7. The rifaximin in polymorphic form .delta. of claim 1, wherein the polymorph .delta. has a water content of between 2.5% and 6%. 8. Rifaximin in polymorphic form .epsilon., wherein the rifaximin polymorphic form .epsilon. has x-ray powder diffraction pattern peaks at about 8.2.degree..+-.0.2, 12.4.degree..+-.0.2, and 16.3.degree..+-.0.2 2-.theta.. 9. A method of treating bacterial activity in the gastrointestinal tract of a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of rifaximin .delta., thereby reducing the bacterial activity in the gastrointestinal tract, wherein the rifaximin polymorphic form .delta. has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2 2-.theta.. 10. The method of claim 9, wherein the bacterial activity causes infectious diarrhea. 11. The method of claim 9, wherein the bacteria are anaerobic bacteria. 12. The method of claim 9, wherein the pharmaceutical composition is administered orally. 13. The method of claim 9, wherein the bacteria are gastrointestinal bacteria. 14. A method of treating bacterial activity in the gastrointestinal tract of a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of rifaximin .epsilon., thereby reducing the bacterial activity in the gastrointestinal tract, wherein the rifaximin polymorphic form .epsilon. has x-ray powder diffraction pattern peaks at about 8.2.degree..+-.0.2, 12.4.degree..+-.0.2, and 16.3.degree..+-.0.2 2-.theta.. 15. The method of claim 14, wherein the bacterial activity causes infectious diarrhea. 16. The method of claim 14, wherein the bacteria are anaerobic bacteria. 17. The method of claim 14, wherein the pharmaceutical composition is administered orally. 18. The method of claim 14, wherein the bacteria are gastrointestinal bacteria. 19. The rifaximin in polymorphic form .delta. of claim 4, wherein the x-ray powder diffraction pattern further comprises a peak at about 8.7.degree..+-.0.2 2-.theta.. 20. The rifaximin in polymorphic form .delta. of claim 1, wherein the x-ray powder diffraction pattern further comprises peaks at about 6.7.degree..+-.0.2 , 8.7.degree..+-.0.2 10.4.degree..+-.0.2, 11.3.degree..+-.0.2, 18.5.degree..+-.0.2, 21.0.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 21. The rifaximin in polymorphic form .delta. of claim 1, wherein the x-ray powder diffraction pattern further comprises peaks at about 8.0.degree..+-.0.2, 10.4.degree..+-.0.2, 17.3.degree..+-.0.2, 18.5.degree..+-.0.2 and 21.degree..+-.0.2 2-.theta.. 22. The rifaximin in polymorphic form .epsilon. of claim 8, wherein the x-ray powder diffraction pattern further comprises peaks at about 8.7.degree..+-.0.2 10.3.degree..+-.0.2, 11.1.degree..+-.0.2, and 11.7.degree..+-.0.2 2-.theta.. 23. The rifaximin in polymorphic form .epsilon. of claim 8, wherein the x-ray powder diffraction pattern further comprises peaks at about 7.0.degree..+-.0.2 10.3.degree..+-.0.2, 14.5.degree..+-.0.2, and 17.2.degree..+-.0.2 2-.theta.. 24. A medicinal preparation for oral administration having antibiotic activity, the medicinal preparation comprising a therapeutically effective amount of rifaximin in polymorphic form .delta. and pharmaceutically acceptable excipients wherein the rifaximin polymorphic form .delta. has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2 2-.theta.. 25. The medicinal preparation of claim 24, wherein the x-ray powder diffraction pattern further comprises a peak at about 11.3.degree..+-.0.2 2-9. 26. The medicinal preparation of claim 24, wherein the x-ray powder diffraction pattern further comprises peaks at about 7.1.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 27. The medicinal preparation of claim 24, wherein the x-ray powder diffraction pattern further comprises a peak at about 6.7.degree..+-.0.2 and 8.7.degree..+-.0.2 2-.theta.. 28. The medicinal preparation of claim 24, wherein the polymorph has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 6.7.degree..+-.0.2, 7.1.degree..+-.8.0.degree..+-.0.2, 8.7.degree..+-.0.2, 10.4.degree..+-.0.2, 11.3.degree..+-.0.2, 12.1.degree..+-.0.2, 17.0.degree..+-.0.2, 17.3.degree..+-.0.2, 17.5.degree..+-.0.2, 18.5.degree..+-.0.2, 18.8.degree..+-.0.2, 19.1.degree..+-.0.2, 21.02.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 29. The medicinal preparation of claim 24, wherein the x-ray powder diffraction pattern further comprises peaks at about 6.7.degree..+-.0.2 , 8.7.degree..+-.0.2 10.4.degree..+-.0.2, 11.3.degree..+-.0.2, 18.5.degree..+-.0.2, 21.0.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 30. The medicinal preparation of claim 24, wherein the x-ray powder diffraction pattern further comprises peaks at about 8.0.degree..+-.0.2, 10.4.degree..+-.0.2, 17.3.degree..+-.0.2, 18.5 .degree..+-.0.2 and 21.degree..+-.0.2 2-.theta.. 31. The medicinal preparation of claim 24, wherein the polymorph .delta. has a water content of between 3% and 4.5%. 32. The medicinal preparation of claim 24, wherein the polymorph .delta. has a water content of between 2.5% and 6%. 33. A medicinal preparation for oral administration having antibiotic activity, the medicinal preparation comprising a therapeutically effective amount of rifaximin in polymorphic form .epsilon. and pharmaceutically acceptable excipients wherein the rifaximin in polymorphic form .epsilon. has x-ray powder diffraction pattern peaks at about 8.2.degree..+-.0.2, 12.4.degree..+-.0.2, and 16.3.degree..+-.0.2 2-.theta.. 34. The medicinal preparation of claim 33, wherein the x-ray powder diffraction pattern further comprises peaks at about 8.7.degree..+-.0.2 10.3.degree..+-.0.2, 11.1.degree..+-.0.2, and 11.7.degree..+-.0.2 2-.theta.. 35. The medicinal preparation of claim 33, wherein the x-ray powder diffraction pattern further comprises peaks at about 7.0.degree..+-.0.2 10.3.degree..+-.0.2, 14.5.degree..+-.0.2, and 17.2.degree..+-.0.2 2-.theta.. 36. A medicinal preparation for topical administration having antibiotic activity, the medicinal preparation comprising a therapeutically effective amount of rifaximin in polymorphic form .delta. and pharmaceutically acceptable excipients wherein the rifaximin polymorphic form .delta. has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 12.1.degree..+-.0.2, and 17.0.degree..+-.0.2 2-.theta.. 37. The medicinal preparation of claim 36, wherein the x-ray powder diffraction pattern further comprises a peak at about 11.3.degree..+-.0.2 2-.theta.. 38. The medicinal preparation of claim 36, wherein the x-ray powder diffraction pattern further comprises peaks at about 7.1.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 39. The medicinal preparation of claim 36, wherein the x-ray powder diffraction pattern further comprises a peak at about 6.7.degree..+-.0.2 and 8.7.degree..+-.0.2 2-.theta.. 40. The medicinal preparation of claim 36, wherein the polymorph has x-ray powder diffraction pattern peaks at about 5.7.degree..+-.0.2, 6.7.degree..+-.0.2, 7.1.degree..+-.0.2, 8.0.degree..+-.0.2, 8.7.degree..+-.0.2, 10.4.degree..+-.0.2, 11.3.degree..+-.0.2, 12.1.degree..+-.0.2, 17.0.degree..+-.0.2, 17.3.degree..+-.0.2, 17.5.degree..+-.0.2, 18.5.degree..+-.0.2, 18.8.degree..+-.0.2, 19.1.degree..+-.0.2, 21.0.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 41. The medicinal preparation of claim 36, wherein the x-ray powder diffraction pattern further comprises peaks at about 6.7.degree..+-.0.2, 8.7.degree..+-.0.2 10.4.degree..+-.0.2, 11.2 .+-.0.2, 18.5.degree..+-.0.2, 21.degree..+-.0.2 and 21.5.degree..+-.0.2 2-.theta.. 42. The medicinal preparation of claim 36, wherein the x-ray powder diffraction pattern further comprises peaks at about 8.0.degree..+-.0.2, 10.4.degree..+-.0.2, 17.3.degree..+-.0.2, 18.5.degree..+-.0.2 and 21.degree..+-.0.2 2-.theta.. 43. The medicinal preparation of claim 37, wherein the polymorph .delta. has a water content of between 3% and 4.5%. 44. The medicinal preparation of claim 38, wherein the polymorph .delta. has a water content of between 2.5% and 6%.