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EP1557421A1
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EP
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Polymorphous forms of rifaximin as antibiotics
Assignee: Alfa Wasserman SpA
•
Filing: 2004-03-09
•
Granted: —
•
Expires: 2024-03-09
Abstract
Abstract Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin alpha and rifaximin beta , and a poorly crystalline form named rifaximin y 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
- 👤 Guiseppe C. Viscomi
- 👤 Manuela Campana
- 👤 Dario Braga
- 👤 Donatella Confortini
- 👤 Vincenzo Cannata
- 👤 Denis Severini
- 👤 Paolo Righi
- 👤 Goffredo Rosini
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-01 04:58
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: 28
Claim 1
Independent Claim
52 words
A purified rifaximin α, a polymorph of the antibiotic rifaximin, wherein
said rifaximin α has a water content lower than 4.5%, and produces a powder
X-ray diffractogram showing peaks at values of the diffraction angles 2 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
16 words
The rifaximin α according to claim 1, wherein said water content is
between 2.0% and 3.0%.
Claim 3
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 2 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 4
Dependent Claim
16 words
The rifaximin β according to claim 3, wherein said water content is
between 5.0% and 6.0%.
Claim 5
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 2 of 5.0°; 7.1°; 8.4°.
Claim 6
Dependent Claim
212 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.
Claim 7
Dependent Claim
16 words
The process according to claim 6, wherein said 2-amino-4-methylpyridine
is from 2.0 to 3.5 molar equivalents.
Claim 8
Dependent Claim
37 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 9
Dependent Claim
102 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 10
Dependent Claim
15 words
The process according to claim 9, wherein said water content is between
2.0% and 3.0%.
Claim 11
Dependent Claim
102 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 12
Dependent Claim
15 words
The process according to claim 11, wherein said water content is
between 5.0% and 6.0%.
Claim 13
Dependent Claim
81 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 14
Dependent Claim
70 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 15
Dependent Claim
15 words
The process according to claim 14, wherein said water content is
between 2.0% and 3.0%.
Claim 16
Dependent Claim
70 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 17
Dependent Claim
15 words
The process according to claim 16, wherein said water content is
between 5.0% and 6.0%.
Claim 18
Dependent Claim
85 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 19
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 20
Dependent Claim
54 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 21
Dependent Claim
22 words
A composition comprising a predetermined amount of rifaximin α,
rifaximin β or rifaximin γ in combination with excipients suitable for oral
administration.
Claim 22
Dependent Claim
32 words
The composition according to claim 21, wherein said excipients are
suitable for the production of coated and uncoated tablets, hard and soft
gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets and/or
powders.
Claim 23
Dependent Claim
22 words
A composition comprising a predetermined amount of rifaximin α,
rifaximin β or rifaximin γ in combination with excipients suitable for topical
administration.
Claim 24
Dependent Claim
21 words
The composition according to claim 23, wherein said excipients are
suitable for the production of ointments, pomades, creams, gels and lotions.
Claim 25
Dependent Claim
23 words
A composition comprising predetermined amounts of rifaximin α,
rifaximin β, or rifaximin γ or any combination thereof, in combination with
pharmaceutically acceptable excipients.
Claim 26
Dependent Claim
16 words
A composition comprising the rifaximin α according to claim 1 in
combination with pharmaceutically acceptable excipients.
Claim 27
Dependent Claim
16 words
A composition comprising the rifaximin β according to claim 3 in
combination with pharmaceutically acceptable excipients.
Claim 28
Dependent Claim
16 words
A composition comprising the rifaximin γ according to claim 5 in
combination with pharmaceutically acceptable excipients.
References Cited (Backward Citations)
EP0161534A2
Cited
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