DESC:PRODUCTION CRYSTALLINE FORMS OF RIFAXIMIN

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of mixed crystalline Rifaximin a and Rifaximin ß

BACKGROUND OF THE INVENTION

Rifaximin is an antibiotic belonging to Rifamycin class of antibiotics and is chemically known as (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13] trienimino) benzofuro [4,5-e] pyridop [1,2-a]-benzimidazole-1,15(2H)-dione-25-acetate. And it has the following chemical structure.

Rifaximin is an antibiotic pertaining to the Rifamycin class, specifically it is a pyrido-imdazo rifamycin which is described in Italian patent IT 1154655. US 4,341,785 and 4,557,866 disclose a process for the preparation of Rifaximin starting from rifamycin S or O. The above patents describe purification steps of Rifaximin by performing crystallization of crude Rifaximin from a 7:3 mixture of ethyl alcohol / water and drying under atmospheric pressure and vacuum. These patents do not disclose the exact crystallization and drying conditions as well as any characterization data for confirmation on polymorphic forms of Rifaximin.

US 7,045,620 discloses three polymorphic forms a, ß and ? of Rifaximin. Form a and ß show pure crystalline characteristics while the ? form is poorly crystalline. The US '620 discloses that the formation of the a, ß and ? forms depends on the presence of water within the crystallization solvent, on the temperature at which the product is crystallized and on the amount of water present into the product at the end of the drying phase.

The polymorphic forms a, ß and ? are characterized on the basis of water content and XRPD. This patent also discloses processes for preparation of these polymorphs which involve use of specific reaction conditions during crystallization like dissolving Rifaximin in ethyl alcohol at 45 to 65°C, precipitation by adding water to form a suspension, filtering suspension and washing the resulted solid with water, followed by drying at room temperature under vacuum for a period of time between 2 and 72 hours. The purely crystalline forms a and ß are obtained by immediate filtration of suspension when temperature of reaction mixture is brought finally to 0°C. Whereas in order to obtain the poorly crystalline form ?, the reaction mixture is stirred for 5-6 hours after temperature is set to 0°C. and then filtered the suspension. The a form has water content lower than 4.5%, for ß form it should be higher than 4.5% and to obtain ? form, water content should be below 2%.

US 9,186,355 B2 discloses a Rifaximin composition comprising mixed crystalline polymorphs Rifaximin a and Rifaximin ß containing about 3-12% (w/w) of the Rifaximin ß crystalline polymorph in mixture with a remaining percentage of the Rifaximin a crystalline polymorph.

Our inventors have developed unexpectedly discovered that the mixed forms of a and ß of Rifaximin. The mixed crystalline Rifaximin a and Rifaximin ß has been found to be stable over the time and reproducible, wherein ß form less than 3%. The present invention mixture provides a stable pharmaceutical formulation.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of mixed crystalline Rifaximin a and Rifaximin ß.

The present invention provides an improved process for the preparation of mixed crystalline Rifaximin a and Rifaximin ß, which comprises the steps of:

(a) crude Rifaximin is dissolved in an ethanol,
(b) heating the reaction mixture to 70-80°C,
(c) adding purified water to reaction mixture,
(d) filtering the reaction mixture and wash with ethanol,
(e) cooling the reaction mixture to 35-40ºC and stirring the reaction mixture for 20-30 minutes,
(f) cooling the reaction mixture to 25-30ºC and stirring the reaction mixture for 4-5 hours,
(g) filtering the solid and wash with ethanol,
(h) drying the compound at 80-85ºC to reach the water content less than 3% (w/w) to obtain the mixed crystalline Rifaximin a and Rifaximin ß, wherein the mixed crystalline polymorphs Rifaximin a and Rifaximin ß contains less than 3% (w/w) of the Rifaximin ß.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of mixed crystalline Rifaximin a and Rifaximin ß.

The present invention provides an improved process for the preparation of mixed crystalline Rifaximin a and Rifaximin ß, which comprises the steps of:

(a) crude Rifaximin is dissolved in an ethanol,
(b) heating the reaction mixture to 70-80°C,
(c) adding purified water to reaction mixture,
(d) filtering the reaction mixture and wash with ethanol,
(e) cooling the reaction mixture to 35-40ºC and stirring the reaction mixture for 20-30 minutes,
(f) cooling the reaction mixture to 25-30ºC and stirring the reaction mixture for 4-5 hours,
(g) filtering the solid and wash with ethanol,
(h) drying the compound at 80-85ºC to reach the water content less than 3% (w/w) to obtain the mixed crystalline Rifaximin a and Rifaximin ß, wherein the mixed crystalline polymorphs Rifaximin a and Rifaximin ß contains less than 3% (w/w) of the Rifaximin ß.
According to the embodiment of the present invention, an improved process for the preparation of mixed crystalline Rifaximin a and Rifaximin ß, which comprises the steps of, Crude Rifaximin is dissolved in an ethanol, heating the reaction mixture to 70-80°C, adding purified water to reaction mixture, filtering the reaction mixture and wash with ethanol, cooling the reaction mixture to 35-40ºC and stirring the reaction mixture for 20-30 minutes, cooling the reaction mixture to 25-30ºC and stirring the reaction mixture for 4-5 hours, filtering the solid and wash with ethanol, drying the compound at 80-85ºC to reach the water content less than 3% (w/w) to obtain the mixed crystalline Rifaximin a and Rifaximin ß, wherein the mixed crystalline polymorphs Rifaximin a and Rifaximin ß contains less than 3% (w/w) of the Rifaximin ß.

According to the embodiment of the present invention, drying the crystallized material to a water content less than 3% and the mixed crystalline polymorphs Rifaximin a and Rifaximin ß contains less than 3% (w/w) of the Rifaximin ß. The present invention mixture to a stable, equilibrium composition at the stated water content and this mixture provide a stable pharmaceutical composition.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Preparation of Crude Rifaximin:

Example 1:
Rifamycin-O (100 g; 0.132 mol) was added to the reaction mixture of 2-Methyl-4-amino pyridine (43 g; 0.3976) in a solution of ethanol and purified water mixture (1.5:1.9 vol) at 25-30°C and stirred the reaction mixture for 4-5 hours at 45-50°C, after completion of reaction monitoring by HPLC. The reaction mixture was cooled to 20-30°C and add ascorbic acid solution (2.6 g; 0.014 mol), PH was adjusted to 2.0-3.0 with hydrochloric acid (0.12 vol). The obtained solid was filtered and washed with purified water and ethanol mixture (0.4: 0.5 vol). The resultant wet solid for further purification with ethanol (2.7 vol) and heat the mass to 60-65°C observe clear solution, cool the clear solution to 25-30°C. The resultant solid was cooled to 0-5°C. Filter the obtained solid and wash with ethanol gives the tech grade solid, and obtained material was dried at 70-75°C to give Rifaximin tech grade solid.
Yield: 81.52% (85 gm).

Preparation of pure mixed crystalline Rifaximin a and Rifaximin ß
Example 2:
Rifaximin tech solid (85 gm) was dissolved in ethanol (2.5 vol) at 25-30°C, heat the reaction mass to 70-80°C and add purified water (1.2 vol) at same temperature. Filter the clear solution through celite, wash with ethanol (0.3 vol) and cool the reaction mass to 35-40°C, stir the reaction mass 20-30 min. The reaction mixture was again cooled to 25-30°C and stir the reaction mass 4-5 hrs at 25-30°C. The obtained solid filtered and wash with ethanol (0.2 vol) to gives the pure solid. The obtained material was dried at 80-85°C for 20-24 hrs to obtain pure mixed crystalline Rifaximin a and Rifaximin ß, contains less than 3% (w/w) of the Rifaximin ß & water content less than 3% (w/w).
Yield: 70.58% (60 gm).
Purity: 99.66 %.

Example 3:
Rifaximin tech solid (80) was dissolved in ethanol (2.5 vol) at 25-30°C; heat the reaction mass to 70-80°C and add purified water (1.2 vol) at 70-80°C. Filter the clear solution through celite, wash with ethanol (0.3 vol) and cool the reaction mass to 35-40°C, stir the reaction mass 20-30 min. The reaction mixture was again cooled to 25-30°C and stir the reaction mass 4-5 hrs at 25-30°C. The obtained solid filtered and wash with ethanol (0.2 vol) to gives the pure solid. The obtained material was dried at 80-85°C for 20-24 hrs to obtain pure mixed crystalline Rifaximin a and Rifaximin ß, contains less than 3% (w/w) of the Rifaximin ß & water content less than 3% (w/w).
Yield: 75.0% (60 gm).
Purity: 99.66 %.

Example 4:
Rifaximin tech solid (85 gm) was dissolved in ethanol (2.5 vol) at 25-30°C; heat the reaction mass to 70-80°C and add purified water (1.2 vol) at 70-80°C. Filter the clear solution through celite, wash with ethanol (0.3 vol) and cool the reaction mass to 35-40°C, stir the reaction mass 20-30 min. The reaction mixture was again cooled to 25-30°C and stir the reaction mass 4-5 hrs at 25-30°C. The obtained solid filtered and wash with ethanol (0.2 vol) to obtain the pure solid. The obtained material was dried at 80-85°C for 20-24 hrs to obtain pure mixed crystalline Rifaximin a and Rifaximin ß, contains less than 3% (w/w) of the Rifaximin ß & water content less than 3% (w/w).
Yield: 77.64% (66 gm).
Purity: 99.66 %.
,CLAIMS:WE CLAIM:
1. An improved process for the preparation of mixed crystalline Rifaximin a and Rifaximin ß, which comprises the steps of:

(a) crude Rifaximin is dissolved in an ethanol,
(b) heating the reaction mixture to 70-80°C,
(c) adding purified water to reaction mixture,
(d) filtering the reaction mixture and wash with ethanol,
(e) cooling the reaction mixture to 35-40ºC and stirring the reaction mixture for 20-30 minutes,
(f) cooling the reaction mixture to 25-30ºC and stirring the reaction mixture for 4-5 hours,
(g) filtering the solid and wash with ethanol,
(h) drying the compound at 80-85ºC to reach the water content less than 3% (w/w) to obtain the mixed crystalline Rifaximin a and Rifaximin ß.
2. The process as claimed in claim 01, wherein the mixed crystalline polymorphs Rifaximin a and Rifaximin ß contains less than 3% (w/w) of the Rifaximin ß.