.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 7,923,553

« Back to Dashboard

Details for Patent: 7,923,553

Title:Processes for the production of polymorphic forms of rifaximin
Abstract: Crystalline polymorphous forms of rifaximin (INN) antibiotic named rifaximin .alpha. and rifaximin .beta., and a poorly crystalline form named rifaximin .gamma., 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.
Inventor(s): Viscomi; Giuseppe Claudio (Bologna, IT), Campana; Manuela (Bologna, IT), Braga; Dario (Bologna, IT), Confortini; Donatella (Bologna, IT), Cannata; Vincenzo (Bologna, IT), Righi; Paolo (Bologna, IT), Rosini; Goffredo (Bologna, IT)
Assignee: Alfa Wassermann, S.p.A. (Bologna, IT)
Filing Date:May 13, 2008
Application Number:12/119,612
Claims:1. A process for the production of rifaximin in polymorphic form .alpha., comprising: dissolving rifaximin in an alcoholic solvent at a temperature between approximately 45.degree. C. and approximately 65.degree. C.; precipitating the rifaximin by adding water to the alcoholic solvent to form a suspension and by lowering the temperature of the suspension to between approximately 0.degree. C. and approximately 50.degree. C.; and drying the rifaximin for a period of time between approximately 2 and approximately 72 hours to form rifaximin in polymorphic form .alpha..

2. The process according to claim 1, further comprising washing the rifaximin with water after precipitating.

3. The process according to claim 1, wherein the alcoholic solvent is ethyl alcohol.

4. The process according to claim 1, wherein said water added to precipitate the rifaximin is in a weight amount of between approximately 15% and approximately 70% with respect to the weight amount of alcoholic solvent used for the dissolution.

5. The process according to claim 1, wherein after the addition of water, the temperature is lowered to between approximately 28.degree. C. and approximately 32.degree. C.

6. The process according to claim 1, wherein the suspension is stirred at a temperature between approximately 40.degree. C. and approximately 50.degree. C. for a period of time between approximately 6 hours and approximately 24 hours.

7. The process according to claim 1, where the temperature of the suspension is lowered to approximately 0.degree. C. for a period of time between approximately 15 minutes and approximately one hour.

8. The process of claim 1, wherein the drying step is conducted until the rifaximin has a water content of between approximately 2% and approximately 3%.

9. A process for the production of rifaximin in polymorphic form .beta., comprising: dissolving rifaximin in an alcoholic solvent at a temperature between approximately 45.degree. C. and approximately 65.degree. C.; precipitating the rifaximin by adding water to the alcoholic solvent to form a suspension and by lowering the temperature of the suspension to between approximately 0.degree. C. and approximately 50.degree. C.; and drying the rifaximin for a period of time between approximately 2 and approximately 72 hours to form rifaximin in polymorphic form .beta..

10. The process according to claim 9, wherein the alcoholic solvent is ethyl alcohol.

11. The process according to claim 9, wherein after the addition of water, the temperature is lowered to between approximately 28.degree. C. and approximately 32.degree. C.

12. The process according to claim 9, wherein the suspension is stirred at a temperature between approximately 40.degree. C. and approximately 50.degree. C. for a period of time between approximately 6 hours and approximately 24 hours.

13. The process according to claim 9, where the temperature of the suspension is lowered to approximately 0.degree. C. for a period of time between approximately 15 minutes and approximately one hour.

14. The process according to claim 9, wherein the drying step is conducted until the rifaximin has a water content of between approximately 4.5% and approximately 6%.

15. A process for the production of rifaximin in polymorphic form .gamma., comprising: dissolving rifaximin in an alcoholic solvent at a temperature between approximately 45.degree. C. and approximately 65.degree. C.; precipitating the rifaximin by adding water to the alcoholic solvent to form a suspension and by lowering the temperature of the suspension to between approximately 0.degree. C. and approximately 50.degree. C.; and drying the rifaximin for a period of time between approximately 2 and approximately 72 hours to form rifaximin in polymorphic form .gamma..

16. The process according to claim 15, further comprising washing the rifaximin with water after precipitating prior to drying.

17. The process according to claim 15, wherein the alcoholic solvent is ethyl alcohol.

18. The process according to claim 15, wherein said water added to precipitate the rifaximin is in a weight amount of between approximately 15% and approximately 70% with respect to the weight amount of alcoholic solvent used for the dissolution.

19. The process according to claim 15, wherein after the addition of water, the temperature is lowered to between approximately 28.degree. C. and approximately 32.degree. C.

20. The process according to claim 15, wherein the suspension is stirred at a temperature between approximately 40.degree. C. and approximately 50.degree. C. for a period of time between approximately 6 hours and approximately 24 hours.

21. The process according to claim 15, where the temperature of the suspension is lowered to approximately 0.degree. C. for a period of time between approximately 15 minutes and approximately one hour.

22. The process of claim 15, wherein the drying step is conducted until the rifaximin has a water content of between lower than approximately 2%.

23. A process for the production of rifaximin .alpha., comprising: suspending rifaximin .gamma. in an alcohol/water solvent mixture; heating the suspension for a period of time between approximately 6 and approximately 36 hours; and drying the washed solid to form rifaximin .alpha..

24. The process of claim 23, wherein the drying step is conducted until the rifaximin has a water content of lower than approximately 3%.

25. The process according to claim 23, wherein the drying water content is between approximately 2% and approximately 3.0%.

26. The process according to claim 23, wherein the solvent mixture comprises ethyl alcohol.

27. A process for the production of rifaximin .beta., comprising: suspending rifaximin .gamma. in an alcohol/water solvent mixture; heating the suspension for a period of time between approximately 6 and approximately 36 hours; and drying the washed solid to form rifaximin .beta..

28. The process according to claim 27, further comprising washing the rifaximin with water prior to drying.

29. The process according to claim 27, wherein the drying step is conducted until the rifaximin has a water content between approximately 5.0% and approximately 6.0%.

30. The process according to claim 27, wherein the solvent mixture comprises ethyl alcohol.

31. A process for the production of rifaximin .alpha. comprising, drying .beta. under vacuum at about +30.degree. C. for 8 or more hours to obtain .alpha..

32. A process for the production of rifaximin .beta. comprising, maintaining .alpha. in an atmosphere containing a about 56% relative humidity until .beta. is obtained.

33. A process for the production of rifaximin .gamma. comprising heating .alpha. in ethyl alcohol until dissolution of the solid, adding water to the mixture, cooling the mixture, washing the mixture with water, and drying in a vacuum to obtain .gamma..

34. A process for the production of one or more of a Form .alpha., Form .beta., or Form .gamma. polymorph of rifaximin, comprising: reacting an amount of rifamycin O with an excess of 2-amino-4-methylpyridine in a solvent mixture comprising water and ethyl alcohol in volumetric ratios between about 1:1 and about 2:1 for a time between about 2 and about 8 hours; treating the reaction mixture 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 solution to about 2.0 with hydrochloric acid concentrated aqueous solution, filtering and washing the resulting raw rifaximin solid with the water/ethyl alcohol solvent mixture; purifying the raw rifaximin by dissolution in ethyl alcohol; precipitating rifaximin by addition of water, with between about 15% to about 70% to the weight amount of ethyl alcohol used for the dissolution at a temperature of from between about 50.degree. C. to about 0.degree. C. under stirring for between about 4 to about 36 hours; filtering and washing a resulting solid with water; and drying the rifaximin at a temperature of from between about room temperature to about 105.degree. C., wherein the rifaximin Form .alpha. when free from other polymorphic forms of rifaximin has x-ray powder diffraction pattern peaks at about 7.4.degree.; 19.7.degree.; 21.0.degree. and 22.1.degree. 2-.theta., wherein the rifaximin Form .beta. when free from other polymorphic forms of rifaximin has x-ray powder diffraction pattern peaks at about 5.4.degree.; 9.0.degree.; and 20.9.degree. 2-.theta., and wherein the rifaximin Form .gamma. when free from other polymorphic forms of rifaximin has x-ray powder diffraction pattern peaks at about 5.0.degree., 7.1.degree., and 8.4.degree. 2-.theta..

35. The process of claim 34, wherein the drying is for between about 2 hours and about 72 hours; wherein the reacting of rifamycin O with an excess of 2-amino-4-methylpyridine is at a temperature of from between about 40.degree. C. to about 60.degree. C.; wherein the purifying the raw rifaximin by dissolution in ethyl alcohol is at a temperature of from between about 45.degree. C. to about 65.degree. C.; wherein the rifamycin O is reacted with between about 2.0 to about 3.5 molar equivalents of 2-amino-4-methylpyridine; wherein the precipitating step further comprises lowering the temperature to between about 28.degree. C. to about 32.degree. C. to start crystallization and form a suspension; or wherein the resulting suspension is kept at a temperature of from between about 40.degree. C. to about 50.degree. C. under stifling for a time from between about 6 to about 24 hours.

36. The process of claim 35, further comprising, cooling the suspension to about 0.degree. C. for from between about 15 minutes and about one hour; filtering the resulting solid; and drying the solid to a water content of from between 0% and about 3.0% water to form rifaximin Form .alpha..

37. The process of claim 34, wherein the precipitating step further comprises: cooling the solution to a temperature of from between about 28.degree. C. to about 32.degree. C.; maintaining the solution at from between about 40.degree. C. and about 50.degree. C. under stifling for between about 6 to about 24 hours; cooling the solution to about 0.degree. C. for between about 15 minutes to about one hour; filtering a resulting solid; drying the solid from between about 4.5 to about 100% water content to form rifaximin Form .beta..

38. The process of claim 34, wherein the precipitating step further comprises: cooling the solution to a temperature of from between about 28.degree. C. to about 32.degree. C.; cooling the solution to about 0.degree. C., under stirring, for between about 6 to about 24 hours; filtering a resulting solid; and drying the solid to a water content of between about 1.0% and about 2.0% to form rifaximin Form .gamma..

39. The process of claim 34, wherein the rifaximin Form .alpha. has a water content of less than 4.5%.

40. The process of claim 34, wherein the rifaximin Form .beta. has a water content of greater than or equal to 4.5%.

41. The method of claim 34, wherein the rifaximin Form .gamma. has a water content from about 0% to about 2%.

42. A process for the production of rifaximin O, comprising: reacting an amount of rifamycin O with an excess of 2-amino-4-methylpyridine in a solvent mixture comprising water and ethyl alcohol to form a reaction mixture; treating the reaction mixture with a solution of a weak acid, water, and alcohol to lower the pH of the solution to form a suspension; filtering the suspension and washing the resulting solid with a water, alcohol, and solvent mixture to form raw rifaximin; purifying the raw rifaximin by dissolution in an alcohol at a temperature between about 45.degree. C. and about 65.degree. C.; precipitating the raw rifaximin by the addition of water; lowering of the temperature of the suspension to between about 50.degree. C. to about 0.degree. C. under stirring to form a second suspension; filtering the second suspension; and washing a resulting solid with water and drying to obtain rifaximin O.

43. The process of claim 42, wherein the rifamycin O is reacted with between about 2.0 to about 3.5 molar equivalents of 2-amino-4-methylpyridine; wherein the reacting a solvent mixture comprising water and ethyl alcohol is in volumetric ratios from between about 1:1 to about 2:1; wherein the alcohol is one or more of ethyl alcohol, menthol, propanol, or 2-butanol; wherein the reacting a solvent mixture comprising water and ethyl alcohol is for a time from between about 2 to about 8 hours; wherein the reacting a solvent mixture comprising water and alcohol is at a temperature from between about 40.degree. C. to about 60.degree. C.; wherein the treating the reaction mixture is at about room temperature; wherein the solution to treat the reaction mixture comprises a weak reducing agent in a mixture of water, alcohol and a strong acid; wherein the weak acid is ascorbic acid; wherein the strong acid is hydrochloric acid; wherein when treating the reaction mixture the pH is lowered to about 2.0; wherein the drying is by one or more of under vacuum, under conditions of normal pressure, or in the presence of a drying agent; wherein the drying is at a temperature between about room temperature to about 105.degree. C.; wherein the drying is for a time from between about 2 to about 72 hours; wherein the precipitating the rifaximin is by the addition of water in weight amounts of from between about 15% to about 70% of the weight amount of ethyl alcohol used for the reacting; or wherein the second suspension is formed under stifling for a time from between about 4 to about 36 hours.

44. The process of claim 42, wherein after the precipitation of raw rifaximin the method further comprises: lowering the temperature to between about 28.degree. C. to about 32.degree. C.; maintaining the temperature at between about 40.degree. C. to about 50.degree. C. under stirring for between about 6 to about 24 hours; cooling to about 0.degree. C. for between about 15 minutes to about one hour; filtering a resulting solid; and drying the resulting solid to a water content from between about 3.0% to 0% to form rifaximin Form .alpha., wherein the rifaximin Form .alpha. has x-ray powder diffraction pattern peaks at about 7.4.degree.; 19.7.degree.; 21.0.degree. and 22.1.degree. 2-.theta..

45. The process of claim 42, wherein after the precipitation of raw rifaximin the method further comprises: lowering the temperature to between about 28.degree. C. to about 32.degree. C.; maintaining the temperature at between about 40.degree. C. to about 50.degree. C. under stifling for between about 6 to about 24 hours; cooling to about 0.degree. C. for between about 15 minutes and about one hour; filtering a resulting solid; and drying the solid to a water content greater than or equal to about 4.5% to form rifaximin Form .beta., wherein the rifaximin Form .beta. has x-ray powder diffraction pattern peaks at about 5.4.degree.; 9.0.degree.; and 20.9.degree. 2-.theta..

46. The process of claim 42, wherein after the precipitation of raw rifaximin the method further comprises: lowering the temperature to between about 28.degree. C. to about 32.degree. C.; cooling the temperature to about 0.degree. C. under stifling for between about 6 to about 24 hours; filtering a resulting solid; and drying the solid to a water content of between about 1.0% to about 2.0% to form rifaximin Form .gamma., wherein the rifaximin Form .gamma. has x-ray powder diffraction pattern peaks at about 5.0.degree., 7.1.degree., and 8.4.degree. 2-.theta..
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc