Polymorphic forms α, β and γ of rifaximin

• US 8,835,452 B2
• Filed: 11/19/2012
• Issued: 09/16/2014
• Est. Priority Date: 11/07/2003
• Status: Active Grant

• Current Assignee: Alfasigma S.p.A.
• Original Assignee: ALFA Wassermann BV (Alfasigma S.p.A.)
• Inventors: Viscomi, Giuseppe Claudio, Campana, Manuela, Braga, Dario, Confortini, Donatella, Cannata, Vincenzo, Righi, Paolo, Rosini, Goffredo
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/680,967
• Publication Number:
  US 20130281697A1
• Time in Patent Office: 666 Days
• Field of Search: 540/456, 514/279
• US Class Current: 514/279
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

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.

Claims

1. A polymorph rifaximin preparation comprising a polymorph rifaximin in form α

, β and

/or γ

wherein the polymorph rifaximin in form a has x-ray powder diffraction pattern peaks at about;

7.4°

, 7.9°

, and 11.8°

;

or

7.4°

, 8.8°

, and 11.8°

;

or

7.4°

, 10.5°

, and 11.8°

;

or

7.4°

, 11.1°

, and 11.8°

;

or

7.4°

, 11.8°

, and 12.9°

;

or

7.4°

, 11.8°

, and 17.6°

;

or

7.4°

, 11.8°

, and 19.7°

;

or

7.4°

, 11.8°

, and 21.4°

;

or

7.4°

, 11.8°

, and 22.1°

, or

7.4°

,11.1°

, and 12.9°

;

or

7.4°

, 11.1°

, and 19.7°

;

or

7.4°

, 12.9°

, and 19.7°

;

or

11.1°

, 11.8°

, and 19.7°

;

or

11.1°

, 19.7°

, and 21.4°

;

or

11.1°

, 19.7°

, and 22.1°

, or

11.8°

, 12.9°

, and 19.7°

;

or

11.8°

, 19.9°

, and 22.1°

, 2θ

.

the polymorph rifaximin in form β

has x-ray powder diffraction pattern peaks at about;

5.4°

, 6.4°

, and 7.0°

, or

5.4°

, 6.4°

, and 7.8°

;

or

5.4°

, 6.4°

, and 9.0°

;

or

5.4°

, 6.4°

, and 10.4°

;

or

5.4°

, 6.4°

, and 13.1°

, or

5.4°

, 7.0°

, and 14.4°

;

or

5.4°

10.4°

, and 18.3°

;

or

5.4°

10.4°

, and 20.9°

;

or

5.4°

10.4°

, and 17.1°

, or

6.4°

7.0°

, and 10.4°

;

or

6.4°

7.8°

, and 10.4°

;

or

6.4°

9.0°

, and 10.4°

;

or

6.4°

10.4°

, and 14.4°

;

or

10.4°

13.1°

, and 14.4°

;

or

10.4°

17.1°

, and 17.9°

;

or

10.4°

17.9°

, and 18.3°

;

or

10.4°

17.9°

, and 20.9°

;

or

10.4°

18.3°

, and 20.9°

;

or

14.4°

17.1°

, and 18.3°

;

or

17.1°

18.3°

, and 20.9°

;

or

14.4°

17.1°

, and 20.9°

, 2θ

;

and the polymorph rifaximin in form γ

as x-ray powder diffraction pattern peaks at about;

5.0°

, 7.1°

, and 8.4°

2θ

.

2. The polymorph rifaximin preparation of claim 1, wherein the preparation comprises rifaximin polymorph in form α

and β

.

3. The polymorph rifaximin preparation of claim 1, wherein the preparation comprises rifaximin polymorph in form α

and γ

.

4. The polymorph rifaximin preparation of claim 1, wherein the preparation comprises rifaximin polymorph in form β

and γ

.

5. The polymorph rifaximin preparation of claim 1, wherein the preparation comprises rifaximin polymorph in form a free from other polymorphic forms of rifaximin.

6. The polymorph rifaximin preparation of claim 1, wherein the preparation comprises rifaximin polymorph in form β

free from other polymorphic forms of rifaximin.

7. The polymorph rifaximin preparation of claim 1, wherein the preparation comprises rifaximin polymorph in form γ

free from other polymorphic forms of rifaximin.

8. A pharmaceutical composition comprising the rifaximin preparation of claim 1 and a pharmaceutically acceptable excipient or carrier.

9. The pharmaceutical composition of claim 8, wherein the rifaximin preparation comprises rifaximin polymorph in form a free from other polymorphic forms of rifaximin.

10. The pharmaceutical composition of claim 8, wherein the rifaximin preparation comprises rifaximin polymorph in form β

free from other polymorphic forms of rifaximin.

11. The pharmaceutical composition of claim 8, wherein the rifaximin preparation comprises rifaximin polymorph in form γ

free from other polymorphic forms of rifaximin.

12. The pharmaceutical composition of claim 8, wherein the excipient is selected from the group consisting of a diluting agent, a binding agent, a lubricating agent, a disintegrating agent, a coloring agent, a flavoring agent, and a sweetening agent.

13. The pharmaceutical composition of claim 12, wherein the composition is for oral use and is in a form selected from the group consisting of coated or uncoated tablets, hard or soft gelatine capsules, sugar-coated pills, lozenges, wafer sheets, pellets, and powders in sealed packet.

14. The pharmaceutical composition of claim 13, wherein the composition comprises colloidal silicon dioxide.

15. The pharmaceutical composition of claim 14, wherein the composition comprises cellulose.

16. The pharmaceutical composition of claim 14, wherein the composition comprises microcrystalline cellulose.

17. The pharmaceutical composition of claim 14, wherein the composition comprises sodium starch glycolate.

18. The pharmaceutical composition of claim 12 wherein the composition is for topical use and is in a form selected from the group consisting of ointments, pomades, creams, gels and lotions.

19. The pharmaceutical composition of claim 10, wherein the composition comprises hydroxypropyl methylcellulose.

20. The pharmaceutical composition of claim 10, wherein the composition comprises colloidal silicon dioxide.

21. The pharmaceutical composition of claim 10, wherein the composition comprises propylene glycol.