Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
DC CAFCFirst Claim
Patent Images
1. A process for the production of the rifaximin polymorphic forms δ
- and ε
, wherein;
reacting a molar equivalent of rifamycin ο
with an excess of 2-amino-4-methylpyridine in a first solvent mixture, comprising water and ethyl alcohol in volumetric ratios between 1;
1 and 2;
1, for between 2 and 8 hours at a temperature between 40°
C. and 60°
C., to obtain a first reaction mixture;
treating the first reaction mixture at room temperature with a solution of ascorbic acid in a mixture of water, ethyl alcohol and concentrated aqueous hydrochloric acid to obtain a second reaction mixture;
adding concentrated aqueous solution of hydrochloric acid to the second reaction mixture to bring the pH to 2.0 thereby obtaining a first suspension;
filtering the first suspension to obtain a first solid;
washing the first solid with the first solvent mixture to obtain raw rifaximin;
dissolving the raw rifaximin in ethyl alcohol at a temperature between 45°
C. and 65°
C.;
forming a precipitate by adding water and lowering the temperature of the mixture to between 50°
C. and 0°
C. while stirring for between 4 and 36 hours to obtain a second suspension;
filtering the second suspension to obtain a second solid;
washing the second solid with water and drying it under vacuum or under normal pressure, with or without a drying agent, at a temperature between room temperature and 105°
C., for between 2 and 72 hours,wherein the rifaximin polymorphic form δ
is free from other polymorphic forms of rifaximin and has x-ray powder diffraction pattern peaks at about 5.7°
±
0.2, 10.8°
±
0.2, 12.1°
±
0.2, and 17.0°
±
0.2 2-θ
, andwherein the rifaximin polymorphic form ε
is free from other polymorphic forms of rifaximin and has x-ray powder diffraction pattern peaks at about 8.2°
±
0.2, 12.4°
±
0.2, and 16.3°
±
0.2 2-θ
.
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Abstract
Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin δ and rifaximin ε useful in the production of medicinal preparations containing rifaximin for oral and topical use and 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 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.
29 Citations
24 Claims
-
1. A process for the production of the rifaximin polymorphic forms δ
- and ε
, wherein;reacting a molar equivalent of rifamycin ο
with an excess of 2-amino-4-methylpyridine in a first solvent mixture, comprising water and ethyl alcohol in volumetric ratios between 1;
1 and 2;
1, for between 2 and 8 hours at a temperature between 40°
C. and 60°
C., to obtain a first reaction mixture;treating the first reaction mixture at room temperature with a solution of ascorbic acid in a mixture of water, ethyl alcohol and concentrated aqueous hydrochloric acid to obtain a second reaction mixture; adding concentrated aqueous solution of hydrochloric acid to the second reaction mixture to bring the pH to 2.0 thereby obtaining a first suspension; filtering the first suspension to obtain a first solid; washing the first solid with the first solvent mixture to obtain raw rifaximin; dissolving the raw rifaximin in ethyl alcohol at a temperature between 45°
C. and 65°
C.;forming a precipitate by adding water and lowering the temperature of the mixture to between 50°
C. and 0°
C. while stirring for between 4 and 36 hours to obtain a second suspension;filtering the second suspension to obtain a second solid; washing the second solid with water and drying it under vacuum or under normal pressure, with or without a drying agent, at a temperature between room temperature and 105°
C., for between 2 and 72 hours,wherein the rifaximin polymorphic form δ
is free from other polymorphic forms of rifaximin and has x-ray powder diffraction pattern peaks at about 5.7°
±
0.2, 10.8°
±
0.2, 12.1°
±
0.2, and 17.0°
±
0.2 2-θ
, andwherein the rifaximin polymorphic form ε
is free from other polymorphic forms of rifaximin and has x-ray powder diffraction pattern peaks at about 8.2°
±
0.2, 12.4°
±
0.2, and 16.3°
±
0.2 2-θ
. - View Dependent Claims (2, 3, 4, 5, 6)
- and ε
-
7. A solid pharmaceutical composition comprising a therapeutically effective amount of rifaximin δ
- , rifaximin ε
, or a combination thereof, and a pharmaceutically acceptable excipient, together disposed in a formulation for oral administration,wherein the rifaximin δ
has x-ray powder diffraction pattern peaks at about 5.7°
±
0.2, 10.8°
±
0.2, 12.1°
±
0.2, and 17.0°
±
0.2, 2-θ
, andwherein the rifaximin ε
has x-ray powder diffraction pattern peaks at about 8.2°
±
0.2, 12.4°
±
0.2, and 16.3°
±
0.2 2-θ
. - View Dependent Claims (8, 9)
- , rifaximin ε
-
10. A solid pharmaceutical composition comprising a therapeutically effective amount of rifaximin δ
- rifaximin ε
, or a combination thereof, in a formulation for topical administration,wherein the rifaximin δ
has x-ray powder diffraction pattern peaks at about 5.7°
±
0.2, 10.8°
±
0.2, 12.1°
±
0.2, and 17.0°
±
0.2, 2-θ
, andwherein the rifaximin ε
has x-ray powder diffraction pattern peaks at about 8.2°
±
0.2, 12.4°
±
0.2, and 16.3°
±
0.2 22-θ
. - View Dependent Claims (11)
- rifaximin ε
-
12. A method of treating bacterial activity in the gastrointestinal tract of a subject, the method comprising:
-
identifying the needed systemic level of rifaximin; and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of rifaximin δ
, rifaximin ε
, or a combination thereof, thereby reducing the bacterial activity in the gastrointestinal tract,wherein the rifaximin δ
has x-ray powder diffraction pattern peaks at about 5.7°
±
0.2, 10.8°
±
0.2, 12.1°
±
0.2, and 17.0°
±
0.2, 2-θ
, andwherein the rifaximin δ
has x-ray powder diffraction pattern peaks at about 8.2°
±
0.2, 12.4°
±
0.2, and 16.3°
±
0.2, 2-θ
. - View Dependent Claims (13, 14, 16)
-
-
15. The method of ctaim 12, wherein the pharmaceutical composition is administered orally.
-
17. Rifaximin in polymorphic form δ
- free from other polymorphic forms of rifaximin not derived from form δ
by moisture absorption or release, wherein the rifaximin form δ
has x-ray powder diffraction pattern peaks at about 5.7°
±
0.2, 10.8°
±
0.2, 12.1°
±
0.2, and 17.0°
±
0.2 2-θ
. - View Dependent Claims (18, 19, 20, 21, 22, 24)
- free from other polymorphic forms of rifaximin not derived from form δ
-
23. Rifaximin in polymorphic form ε
- free from other polymorphic forms of rifaximin not derived from form ε
by moisture absorption or release, wherein the rifaximin form δ
has x-ray powder diffraction pattern peaks at about 8.2°
±
0.2, 12.4°
±
0.2, and 16.3°
±
0.2 2-θ
.
- free from other polymorphic forms of rifaximin not derived from form ε
Specification