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Claims for Patent: 7,045,620

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Claims for Patent: 7,045,620

Title:Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations
Abstract:Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin .alpha. and rifaximin .beta., and a poorly crystalline form named rifaximin .gamma. 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.
Inventor(s): Viscomi; Giuseppe C. (Bologna, IT), Campana; Manuela (Bologna, IT), Braga; Dario (Bologna, IT), Confortini; Donatella (Bologna, IT), Cannata; Vincenzo (Bologna, IT), Severini; Denis (Bologna, IT), Righi; Paolo (Bologna, IT), Rosini; Goffredo (Bologna, IT)
Assignee: Alfa Wassermann, S.p.A. (Alanno, IT)
Application Number:10/728,090
Patent Claims: 1. A purified rifaximin .alpha., a polymorph of the antibiotic rifaximin, wherein said rifaximin .alpha. has a water content of 3% or less, and produces a powder X-ray diffractogram showing peaks at values of the diffraction angles 2.theta. of 6.6.degree.; 7.4.degree.; 7.9.degree.; 8.8.degree.; 10.5.degree.; 11.1.degree.; 11.8.degree.; 12.9.degree.; 17.6.degree.; 18.5.degree.; 19.7.degree.; 21.0.degree.; 21.4.degree.; 22.1.degree..

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

3. A purified rifaximin .beta., a polymorph of the antibiotic rifaximin wherein said rifaximin .beta. has a water content higher than 4.5% and produces a powder X-ray diffractogram showing peaks at values of the diffraction angles 2.theta. of 5.4.degree.; 6.4.degree.; 7.0.degree.; 7.8.degree.; 9.0.degree.; 10.4.degree.; 13.1.degree., 14.4.degree.; 17.1.degree.; 17.9.degree.; 18.3.degree.; 20.9.degree..

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

5. A purified rifaximin .gamma., a polymorph of the antibiotic rifaximin wherein said rifaximin .gamma. 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 2.theta. of 5.0.degree.; 7.1.degree.; 8.4.degree..

6. A process for the production of rifaximins .alpha., .beta. and .gamma., 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.degree. C. and 60.degree. 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.degree. C. and 65.degree. C., precipitating the raw rifaximin by adding water and by lowering the temperature of the suspension to between 0.degree. C. to 50.degree. 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.degree. C., for a period of time between 2 and 72 hours to the water content required to form rifaximin .alpha., .beta. or .gamma..

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 .alpha., wherein after the addition of water to the raw rifaximin, the temperature is lowered to a value between 28.degree. C. and 32.degree. C. in order to cause the beginning of the crystallization, stirring the resulting suspension at a temperature between 40.degree. C. and 50.degree. C. for a period of time between 6 and 24 hours, cooling the suspension to 0.degree. 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 .beta., wherein after the addition of water to the raw rifaximin, the temperature is lowered to a value between 28.degree. C. and 32.degree. C. in order to cause the beginning of the crystallization, stirring the resulting suspension at a temperature between 40.degree. C. and 50.degree. C. for a period of time between 6 and 24 hours, cooling the suspension to 0.degree. 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 .gamma., wherein after the addition of water to the raw rifaximin, the temperature is lowered to a value between 28.degree. C. and 32.degree. C. in order to cause the beginning of the crystallization, cooling the suspension to 0.degree. 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 .alpha., comprising suspending rifaximin .gamma. in a solvent mixture of ethyl alcohol/water in a volumetric ratio of 7:3, heating the suspension at a temperature between 38.degree. C. and 50.degree. 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 .beta., comprising suspending rifaximin .gamma. in a solvent mixture of ethyl alcohol/water in a volumetric ratio of 7:3, heating the suspension at a temperature between 38.degree. C. and 50.degree. 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 .gamma., comprising dissolving rifaximin .alpha. or .beta. in ethyl alcohol at a temperature between 50.degree. C. and 60.degree. C., adding demineralized water until an ethyl alcohol/water volumetric ratio equal to 7:3 is reached, cooling the solution to 30.degree. C. under strong stirring, further cooling the resulting suspension to 0.degree. 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 .beta., comprising keeping rifaximin .alpha. in an ambient environment having a relative humidity higher than 50% for a period of time between 12 and 48 hours until said rifaximin .alpha. is converted into rifaximin .beta..

20. A process for the production of rifaximin .alpha., comprising drying rifaximin .beta. under atmospheric pressure, or under vacuum, or in the presence of a drying agent, at a temperature between the room temperature and 105.degree. C., for a period of time between 2 and 72 hours until said rifaximin .beta. is converted into rifaximin .alpha..
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