Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations

• US 7,045,620 B2
• Filed: 12/05/2003
• Issued: 05/16/2006
• 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: Righi, Paolo, Braga, Dario, Viscomi, Giuseppe C., Confortini, Donatella, Rosini, Goffredo, Cannata, Vincenzo, Campana, Manuela, Severini, Denis
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US10/728,090
• Publication Number:
  US 20050101598A1
• Time in Patent Office: 893 Days
• Field of Search: 540/456, 514/393
• US Class Current: 540/456
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

Abstract

Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin α and rifaximin β, and a poorly crystalline form named rifaximin γ have been discovered. These forms are useful in the production of medicinal preparations for oral and topical use and can be 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 the addition of water at a determinate temperature and for a determinate period of time. The crystallization is followed by drying carried out under controlled conditions until a specific water content is reached in the end product.

Claims

1. A purified rifaximin α

, a polymorph of the antibiotic rifaximin, wherein said rifaximin α

has a water content of 3% or less, and produces a powder X-ray diffractogram showing peaks at values of the diffraction angles 2θ

of 6.6°

;

7.4°

;

7.9°

;

8.8°

;

10.5°

;

11.1°

;

11.8°

;

12.9°

;

17.6°

;

18.5°

;

19.7°

;

21.0°

;

21.4°

;

22.1°

.

2. The rifaximin α

according to claim 1, wherein said water content is between 2.0% and 3.0%.

3. A purified rifaximin β

, a polymorph of the antibiotic rifaximin wherein said rifaximin β

has a water content higher than 4.5% and produces a powder X-ray diffractogram showing peaks at values of the diffraction angles 2θ

of 5.4°

;

6.4°

;

7.0°

;

7.8°

;

9.0°

;

10.4°

;

13.1°

, 14.4°

;

17.1°

;

17.9°

;

18.3°

;

20.9°

.

4. The rifaximin β

according to claim 3, wherein said water content is between 5.0% and 6.0%.

5. A purified rifaximin γ

, a polymorph of the antibiotic rifaximin wherein said rifaximin γ

has a water content between 1.0% and 2.0% and produces a powder X-ray diffractogram showing a mainly amorphous profile and few significant peaks at values of diffraction angles 2θ

of 5.0°

;

7.1°

;

8.4°

.

6. A process for the production of rifaximins α

, β and

γ

, comprising;

reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine in a solvent mixture of water and ethyl alcohol in a volumetric ratio between 1;

1 and 2;

1, for a period of time between 2 and 8 hours, at a temperature between 40°

C. and 60°

C.,

treating the reaction mass 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 reaction mass to pH 2.0 with a concentrated aqueous solution of hydrochloric acid,

filtering the suspension,

washing any resulting solid with the water/ethyl alcohol solvent mixture to obtain raw rifaximin,

purifying the raw rifaximin by dissolving it in ethyl alcohol at a temperature between 45°

C. and 65°

C.,

precipitating the raw rifaximin by adding water and by lowering the temperature of the suspension to between 0°

C. to 50°

C. under stirring for a period of time between 4 and 36 hours,

filtering the suspension,

washing the resulting solid with water, and

drying it under vacuum or under conditions of normal pressure, with or without a drying agent, at a temperature between room temperature and 105°

C., for a period of time between 2 and 72 hours to the water content required to form rifaximin α

, β

or γ

.

7. The process according to claim 6, wherein said 2-amino-4-methylpyridine is from 2.0 to 3.5 molar equivalents.

8. The process according to claim 6, wherein said water added to precipitate the raw rifaximin is in a weight amount between 15% and 70% with respect to the weight amount of ethyl alcohol used for the dissolution.

9. The process according to claim 6 for the production of rifaximin α

, wherein after the addition of water to the raw rifaximin, the temperature is lowered to a value between 28°

C. and 32°

C. in order to cause the beginning of the crystallization,

stirring the resulting suspension at a temperature between 40°

C. and 50°

C. for a period of time between 6 and 24 hours,

cooling the suspension to 0°

C. for a period of time between 15 minutes and one hour,

filtering the suspension, washing the resulting solid with water, and

drying the washed solid until a water content lower than 4.5% is reached.

10. The process according to claim 9, wherein said water content is between 2.0% and 3.0%.

11. The process according to claim 6 for the production of rifaximin β

,

wherein after the addition of water to the raw rifaximin, the temperature is lowered to a value between 28°

C. and 32°

C. in order to cause the beginning of the crystallization,

stirring the resulting suspension at a temperature between 40°

C. and 50°

C. for a period of time between 6 and 24 hours,

cooling the suspension to 0°

C. for a period of time between 15 minutes and one hour,

filtering the suspension, washing the resulting solid with water, and drying the washed solid until a water content higher than 4.5% is reached.

12. The process according to claim 11, wherein said water content is between 5.0% and 6.0%.

13. The process according to claim 6 for the production of rifaximin γ

, wherein after the addition of water to the raw rifaximin, the temperature is lowered to a value between 28°

C. and 32°

C. in order to cause the beginning of the crystallization,

cooling the suspension to 0°

C. for a period of time between 6 and 24 hours,

filtering the suspension, washing the resulting solid with water and

drying the washed solid until a water content between 1.0% and 2.0% is reached.

14. A process for the production of rifaximin α

, comprising suspending rifaximin γ

in a solvent mixture of ethyl alcohol/water in a volumetric ratio of 7;

3,

heating the suspension at a temperature between 38°

C. and 50°

C., under stirring, for a period of time between 6 and 36 hours,

filtering the suspension,

washing the resulting solid with water, and

drying the washed solid until a water content lower than 4.5% is reached.

15. The process according to claim 14, wherein said water content is between 2.0% and 3.0%.

16. A process for the production of rifaximin β

, comprising

suspending rifaximin γ

in a solvent mixture of ethyl alcohol/water in a volumetric ratio of 7;

3,

heating the suspension at a temperature between 38°

C. and 50°

C., under stirring, for a period of time between 6 and 36 hours,

filtering the suspension,

washing the resulting solid with water, and

drying the washed solid until a water content higher than 4.5% is reached.

17. The process according to claim 16, wherein said water content is between 5.0% and 6.0%.

18. A process for the production of rifaximin γ

, comprising

dissolving rifaximin α

or β

in ethyl alcohol at a temperature between 50°

C. and 60°

C.,

adding demineralized water until an ethyl alcohol/water volumetric ratio equal to 7;

3 is reached,

cooling the solution to 30°

C. under strong stirring,

further cooling the resulting suspension to 0°

C. for a period of time between 6 and 24 hours,

filtering said suspension,

washing the resulting solid with water, and

drying the solid until a water content lower than 2.0% is reached.

19. A process for the production of rifaximin β

, comprising keeping rifaximin α

in an ambient environment having a relative humidity higher than 50% for a period of time between 12 and 48 hours until said rifaximin α

is converted into rifaximin β

.

20. A process for the production of rifaximin α

, comprising drying rifaximin β

under atmospheric pressure, or under vacuum, or in the presence of a drying agent, at a temperature between the room temperature and 105°

C., for a period of time between 2 and 72 hours until said rifaximin β

is converted into rifaximin α

.