Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
View Patent ↗Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin δ and rifaximin ε 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.
1. Rifaximin in polymorphic form δ, wherein the rifaximin polymorphic form δ has x-ray powder diffraction pattern peaks at about 5.7°±0.2, 12.1°±0.2, and 17.0°±0.2 2-θ.
2. The rifaximin in polymorphic form δ of claim 1 , wherein the x-ray powder diffraction pattern further comprises a peak at about 11.3°±0.2 2-θ.
3. The rifaximin in polymorphic form δ of claim 1 , wherein the x-ray powder diffraction pattern further comprises peaks at about 7.1°±0.2 and 21.5°±0.2 2-θ.
4. The rifaximin in polymorphic form δ of claim 1 , wherein the x-ray powder diffraction pattern further comprises a peak at about 6.7°±0.2 2-θ.
5. The rifaximin in polymorphic form δ of claim 1 , wherein the polymorph has x-ray powder diffraction pattern peaks at about 5.7°±0.2, 6.7°±0.2, 7.1°±0.2, 8.0°±0.2, 8.7°±0.2, 10.4°±0.2, 11.3°±0.2, 12.1°±0.2, 17.0°±0.2, 17.3°±0.2, 17.5°±0.2, 18.5°±0.2, 18.8°±0.2, 19.1°±0.2, 21.0°±0.2 and 21.5°±0.2 2-θ.
6. The rifaximin in polymorphic form δ of claim 1 , wherein the polymorph δ has a water content of between 3% and 4.5%.
7. The rifaximin in polymorphic form δ of claim 1 , wherein the polymorph δ has a water content of between 2.5% and 6%.
8. Rifaximin in polymorphic form ε, wherein the rifaximin polymorphic form ε has x-ray powder diffraction pattern peaks at about 8.2°±0.2, 12.4°±0.2, and 16.3°±0.2 2-θ.
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 δ, thereby reducing the bacterial activity in the gastrointestinal tract, wherein the rifaximin polymorphic form δ has x-ray powder diffraction pattern peaks at about 5.7°±0.2, 12.1°±0.2, and 17.0°±0.2 2-θ.
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 ε, thereby reducing the bacterial activity in the gastrointestinal tract, wherein the rifaximin polymorphic form ε has x-ray powder diffraction pattern peaks at about 8.2°±0.2, 12.4°±0.2, and 16.3°±0.2 2-θ.
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 δ of claim 4 , wherein the x-ray powder diffraction pattern further comprises a peak at about 8.7°±0.2 2-θ.
20. The rifaximin in polymorphic form δ of claim 1 , wherein the x-ray powder diffraction pattern further comprises peaks at about 6.7°±0.2 , 8.7°±0.2 10.4°±0.2, 11.3°±0.2, 18.5°±0.2, 21.0°±0.2 and 21.5°±0.2 2-θ.
21. The rifaximin in polymorphic form δ of claim 1 , wherein the x-ray powder diffraction pattern further comprises peaks at about 8.0°±0.2, 10.4°±0.2, 17.3°±0.2, 18.5°±0.2 and 21°±0.2 2-θ.
22. The rifaximin in polymorphic form ε of claim 8 , wherein the x-ray powder diffraction pattern further comprises peaks at about 8.7°±0.2 10.3°±0.2, 11.1°±0.2, and 11.7°±0.2 2-θ.
23. The rifaximin in polymorphic form ε of claim 8 , wherein the x-ray powder diffraction pattern further comprises peaks at about 7.0°±0.2 10.3°±0.2, 14.5°±0.2, and 17.2°±0.2 2-θ.
24. A medicinal preparation for oral administration having antibiotic activity, the medicinal preparation comprising a therapeutically effective amount of rifaximin in polymorphic form δ and pharmaceutically acceptable excipients wherein the rifaximin polymorphic form δ has x-ray powder diffraction pattern peaks at about 5.7°±0.2, 12.1°±0.2, and 17.0°±0.2 2-θ.
25. The medicinal preparation of claim 24 , wherein the x-ray powder diffraction pattern further comprises a peak at about 11.3°±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°±0.2 and 21.5°±0.2 2-θ.
27. The medicinal preparation of claim 24 , wherein the x-ray powder diffraction pattern further comprises a peak at about 6.7°±0.2 and 8.7°±0.2 2-θ.
28. The medicinal preparation of claim 24 , wherein the polymorph has x-ray powder diffraction pattern peaks at about 5.7°±0.2, 6.7°±0.2, 7.1°±8.0°±0.2, 8.7°±0.2, 10.4°±0.2, 11.3°±0.2, 12.1°±0.2, 17.0°±0.2, 17.3°±0.2, 17.5°±0.2, 18.5°±0.2, 18.8°±0.2, 19.1°±0.2, 21.02°±0.2 and 21.5°±0.2 2-θ.
29. The medicinal preparation of claim 24 , wherein the x-ray powder diffraction pattern further comprises peaks at about 6.7°±0.2 , 8.7°±0.2 10.4°±0.2, 11.3°±0.2, 18.5°±0.2, 21.0°±0.2 and 21.5°±0.2 2-θ.
30. The medicinal preparation of claim 24 , wherein the x-ray powder diffraction pattern further comprises peaks at about 8.0°±0.2, 10.4°±0.2, 17.3°±0.2, 18.5 °±0.2 and 21°±0.2 2-θ.
31. The medicinal preparation of claim 24 , wherein the polymorph δ has a water content of between 3% and 4.5%.
32. The medicinal preparation of claim 24 , wherein the polymorph δ 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 ε and pharmaceutically acceptable excipients wherein the rifaximin in polymorphic form ε has x-ray powder diffraction pattern peaks at about 8.2°±0.2, 12.4°±0.2, and 16.3°±0.2 2-θ.
34. The medicinal preparation of claim 33 , wherein the x-ray powder diffraction pattern further comprises peaks at about 8.7°±0.2 10.3°±0.2, 11.1°±0.2, and 11.7°±0.2 2-θ.
35. The medicinal preparation of claim 33 , wherein the x-ray powder diffraction pattern further comprises peaks at about 7.0°±0.2 10.3°±0.2, 14.5°±0.2, and 17.2°±0.2 2-θ.
36. A medicinal preparation for topical administration having antibiotic activity, the medicinal preparation comprising a therapeutically effective amount of rifaximin in polymorphic form δ and pharmaceutically acceptable excipients wherein the rifaximin polymorphic form δ has x-ray powder diffraction pattern peaks at about 5.7°±0.2, 12.1°±0.2, and 17.0°±0.2 2-θ.
37. The medicinal preparation of claim 36 , wherein the x-ray powder diffraction pattern further comprises a peak at about 11.3°±0.2 2-θ.
38. The medicinal preparation of claim 36 , wherein the x-ray powder diffraction pattern further comprises peaks at about 7.1°±0.2 and 21.5°±0.2 2-θ.
39. The medicinal preparation of claim 36 , wherein the x-ray powder diffraction pattern further comprises a peak at about 6.7°±0.2 and 8.7°±0.2 2-θ.
40. The medicinal preparation of claim 36 , wherein the polymorph has x-ray powder diffraction pattern peaks at about 5.7°±0.2, 6.7°±0.2, 7.1°±0.2, 8.0°±0.2, 8.7°±0.2, 10.4°±0.2, 11.3°±0.2, 12.1°±0.2, 17.0°±0.2, 17.3°±0.2, 17.5°±0.2, 18.5°±0.2, 18.8°±0.2, 19.1°±0.2, 21.0°±0.2 and 21.5°±0.2 2-θ.
41. The medicinal preparation of claim 36 , wherein the x-ray powder diffraction pattern further comprises peaks at about 6.7°±0.2, 8.7°±0.2 10.4°±0.2, 11.2 ±0.2, 18.5°±0.2, 21°±0.2 and 21.5°±0.2 2-θ.
42. The medicinal preparation of claim 36 , wherein the x-ray powder diffraction pattern further comprises peaks at about 8.0°±0.2, 10.4°±0.2, 17.3°±0.2, 18.5°±0.2 and 21°±0.2 2-θ.
43. The medicinal preparation of claim 37 , wherein the polymorph δ has a water content of between 3% and 4.5%.
44. The medicinal preparation of claim 38 , wherein the polymorph δ has a water content of between 2.5% and 6%.