US7045620B2
Expired / Lapsed
US
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Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations
Assignee: Alfasigma SpA
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Filing: 2003-12-05
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Granted: 2006-05-16
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Expires: 2023-12-05
Abstract
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.
Inventors
- 👤 Giuseppe C. Viscomi
- 👤 Manuela Campana
- 👤 Dario Braga
- 👤 Donatella Confortini
- 👤 Vincenzo Cannata
- 👤 Denis Severini
- 👤 Paolo Righi
- 👤 Goffredo Rosini
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-31 13:51
CPC Classifications
C; C07; C07D; C07D498/00; C07D498/22; H; H05; H05B; H05B6/00; H05B6/02; H05B6/10; H05B6/12; H05B6/1209; H05B6/1236; A; A61; A61P; A61P1/00; A61P1/12; A61P31/00; A61P31/04; A61P31/06; H05B6/1245; H05B6/1263
Claims Analysis
Total Claims: 29
Claim 1
Independent Claim
52 words
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°.
Claim 2
Dependent Claim
52 words
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°.
Claim 3
Dependent Claim
17 words
The rifaximin α according to claim 1 , wherein said water content is between 2.0% and 3.0%.
Claim 4
Dependent Claim
49 words
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°.
Claim 5
Dependent Claim
49 words
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°.
Claim 6
Dependent Claim
17 words
The rifaximin β according to claim 3 , wherein said water content is between 5.0% and 6.0%.
Claim 7
Dependent Claim
47 words
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°.
Claim 8
Dependent Claim
47 words
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°.
Claim 9
Dependent Claim
230 words
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.
Claim 10
Dependent Claim
230 words
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.
Claim 11
Dependent Claim
17 words
The process according to claim 6 , wherein said 2-amino-4-methylpyridine is from 2.0 to 3.5 molar equivalents.
Claim 12
Dependent Claim
38 words
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.
Claim 13
Dependent Claim
107 words
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.
Claim 14
Dependent Claim
16 words
The process according to claim 9 , wherein said water content is between 2.0% and 3.0%.
Claim 15
Dependent Claim
107 words
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.
Claim 16
Dependent Claim
16 words
The process according to claim 11 , wherein said water content is between 5.0% and 6.0%.
Claim 17
Dependent Claim
84 words
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.
Claim 18
Dependent Claim
72 words
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.
Claim 19
Dependent Claim
72 words
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.
Claim 20
Dependent Claim
16 words
The process according to claim 14 , wherein said water content is between 2.0% and 3.0%.
Claim 21
Dependent Claim
72 words
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.
Claim 22
Dependent Claim
72 words
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.
Claim 23
Dependent Claim
16 words
The process according to claim 16 , wherein said water content is between 5.0% and 6.0%.
Claim 24
Dependent Claim
89 words
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.
Claim 25
Dependent Claim
89 words
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.
Claim 26
Dependent Claim
42 words
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.
Claim 27
Dependent Claim
42 words
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.
Claim 28
Dependent Claim
55 words
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.
Claim 29
Dependent Claim
55 words
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.
References Cited (Backward Citations)
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