Claims:We Claim:

1. A novel crystalline Form XI of Rifaximin.

2. The novel crystalline Form XI of Rifaximin as claimed in claim 1, which is characterized by X-ray powder diffraction having characteristic peaks expressed in degrees at about 3.02° ±0.2 2? substantially as that as shown in FIG. 1.

3. The novel crystalline Form XI of Rifaximin as claimed in claim 1 and 2, which is further characterized by X-ray powder diffraction having characteristic peaks expressed in degrees at about 5.28°, 6.04°, 7.4°, 8.0°, 8.6°, 10.50°, 12.64°, 14.28°, 15.78°, 18.51° and 22.05°±0.2 2?.

4. The novel crystalline Form XI of Rifaximin as claimed in claim 1, which is characterized by Infrared spectrum having peaks at 777, 726, 631, 500 substantially as that as shown in FIG. 2.

5. The novel crystalline Form XI of Rifaximin as claimed in claim 1 and 4, which is further characterized by Infrared spectrum having peaks at 3436, 2972, 2936, 2883, 1722, 1649, 1604, 1588, 1508, 1465, 1374, 1337, 1321, 1232, 1159, 1120, 1089, 1061, 1049, 1024, 973, 948, 907, 879, 803, 700, 678, 600, 546, 465, 429.

6. A process for the preparation of novel crystalline Form XI of Rifaximin, the process comprising:

a) dissolving crude Rifaximin in alcohol and purified water at 20°C to 30°C,
b) stirring the reaction mixture of step a) at 65°C to 85°C,
c) cooling the slurry of step b) at about 30°C to 45°C, and
d) isolating the Rifaximin Form XI.

7. The process as claimed in claim 6, wherein the alcohol is selected from methanol, ethanol, propanol and isopropyl alcohol.

8. The process as claimed in claim 6, wherein step b) stirring the reaction mixture at 70-80°C.

9. Rifaximin is having mean particle size of D90 50 to 80 microns; Preferably D90 60 to 65 microns.

, Description:CRYSTALLINE FORM XI OF RIFAXIMIN

FIELD OF THE INVENTION

The present invention relates to a novel crystalline Form XI of Rifaximin and also relates to purification process of Rifaximin.

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 8,193,196 B2 discloses polymorphic forms d and e of Rifaximin and methods of their preparation by dissolving Rifaximin in ethyl alcohol at 45 to 65°C., precipitation by adding water to form a suspension, filtering the suspension and washing the resulted solid with demineralized water, followed by drying for a period of time between 2 and 72 hours until a water content in the range 2.5-6% is obtained.

CystEngComm reference article Vol. 10, Pg. 1074-1081 (2008) discloses five crystal forms of Rifaximin and their effect on pharmaceutical properties. Five distinct crystal forms of Rifaximin (a, ß, ?, d and e) have been identified and characterized by X-ray powder diffraction, solid state 13C NMR, and HATR-IR spectroscopy.

US 8,067,429 B2 discloses several polymorphic forms of Rifaximin such as ?, form ?, form-i, form t-dry, form i-dry', form B and amorphous form. Main differentiating point of these polymorphs is respective water content and x-ray powder diffraction pattern.

WO 2013/027227 A1 discloses crystalline Form-I of Rifaximin and process for its preparation.

WO 2015/159275 A2 discloses crystalline Form G of Rifaximin and process for its preparation.
US 7,709,634 B2 discloses amorphous form of Rifaximin characterized by x-ray powder diffraction pattern and it also discloses an amorphous form of Rifaximin and the process for the preparation thereof.

It is evident from above, that Rifaximin can exist in number of polymorphic forms, formation of these polymorphic forms depends upon specific reaction conditions applied during crystallization and drying. In recent times, the solid-state properties of drugs have received great attention as a major contributing factor to both bio-availability and formulation characteristics in the pharmaceutical industry. While polymorphs have the same chemical composition, they differ in packing and geometrical arrangement thereof and exhibit different physical properties such as melting point, shape, particle size, X-ray diffraction pattern, infrared absorption, and solid state NMR spectrum, density, hardness, stability, and dissolution. Depending on their temperature-stability relationship, one crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by techniques such as capillary melting point, thermo gravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.

Other examples are known, where different crystalline forms behave differently during physical processing like milling and pressing. Many process-induced solid-solid transitions of substances are known, that lead to either other crystalline forms or an amorphous form of the substance. The solid-state experts are in a constant search for crystalline forms that are chemically and physically more stable and can withstand physical stress and still retain their original properties.

Rifaximin exists in a variety of crystalline or amorphous form or a mixture of amorphous and crystalline form having distinct crystal structures and physical properties. Consequently, there is an ongoing search for a new polymorphic form of drug, which may provide improved performance thereof.

SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a novel crystalline Form XI of Rifaximin, which is characterized by X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2? (±0.2° 2?) at 3.02°, 5.28°, 6.04°, 7.4°, 8.0°, 8.6°, 10.50°, 12.64°, 14.28°, 15.78°, 18.51° and 22.05°±0.2 2?.

In an aspect of the present invention, there is provided a crystalline Form XI of Rifaximin, which is characterized by X-ray powder diffraction pattern substantially as same as depicted in FIG. 1.

In another aspect of the present invention, there is provided a novel crystalline Form XI of Rifaximin, which is characterized by Infrared spectrum having peaks at 3436, 2972, 2936, 2883, 1722, 1649, 1604, 1588, 1508, 1465, 1374, 1337, 1321, 1232, 1159, 1120, 1089, 1061, 1049, 1024, 973, 948, 907, 879, 803, 777, 726, 700, 678, 631, 600, 546, 500, 465, 429.

In an aspect of the present invention, there is provided a crystalline Form XI of Rifaximin, which is characterized by Infrared spectrum substantially as same as depicted in FIG. 2.

In another aspect of the present invention, there is provided a process for the preparation of novel crystalline polymorphic Form XI, the process comprising:

(a) Dissolving Crude Rifaximin in alcohol and purified water at 20°C to 30°C,

(b) Stirring the reaction mixture of step a) at 65°C to 85°C,

(c) Cooling the slurry of step b) at about 30°C to 45°C, and

(d) Isolating the Rifaximin Form XI.

In an another aspect of the present invention, the novel crystalline Form XI of Rifaximin range of particle sizes preferred for use in the invention is D90 70-80 µm, more preferably D90 65 µm, even more preferably D90 62.8 µm. The particle sizes stipulated herein and in the claims refer to particle sizes were determined using a laser light scattering technique.

BRIEF DESCRIPTION OF DRAWING

Figure- 1: Represents X-ray powder diffraction pattern (XRPD) of novel crystalline Form XI of Rifaximin.

Figure- 2: Represents infrared absorption spectrum (IR spectrum) of novel crystalline Form XI of Rifaximin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel crystalline Form XI of Rifaximin. And also relates to purification process of Rifaximin.

In one embodiment of the present invention, there is provided a novel crystalline Form XI of Rifaximin, which is characterized by X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2? (±0.2° 2?) at 3.02°, 5.28°, 6.04°, 7.4°, 8.0°, 8.6°, 10.50°, 12.64°, 14.28°, 15.78°, 18.51° and 22.05°±0.2 2?.

The polymorphic Form XI is further characterized by X-ray powder diffraction pattern substantially as that as shown in FIG. 1.

In an embodiment of the present invention, there is provided a novel crystalline Form XI of Rifaximin, which is characterized by Infrared spectrum having peaks at 3436, 2972, 2936, 2883, 1722, 1649, 1604, 1588, 1508, 1465, 1374, 1337, 1321, 1232, 1159, 1120, 1089, 1061, 1049, 1024, 973, 948, 907, 879, 803, 777, 726, 700, 678, 631, 600, 546, 500, 465, 429.

The polymorphic Form XI is further characterized by Infrared spectrum substantially as that as shown in FIG. 2.

In another embodiment of the present invention, there is provided a process for the preparation of novel crystalline polymorphic Form XI, the process comprising:

(a) Dissolving Crude Rifaximin in alcohol and purified water at 20°C to 30°C,

(b) Stirring the reaction mixture of step a) at 65°C to 85°C,

(c) Cooling the slurry of step b) at about 30°C to 45°C, and

(d) Isolating the Rifaximin Form XI.

According to the embodiment of the present invention, purification process for the preparation of novel crystalline Form XI of Rifaximin comprising, crude Rifaximin is dissolved in ethanol and water at 25-30°C. Raise the reaction mixture temperature to 70-80°C and stir the mixture for 10 min at same temperature. Cool the temperature to 35-40°C, further cool to 25-30°C and stir for 8-10 hrs. Isolating the Rifaximin Form XI.

In general, the alcohol in step (a) comprises one or more of methanol, ethanol, propanol, isopropanol and butanol. In particular, the alcohol is ethanol. And the reaction is performed at temperature about 20°C to 35° C. In particular, the temperature is about 25°C to about 30°C.

In general, the step (b) of reaction is performed at temperature about 65°C to 85° C. In particular, the temperature is about 70°C to about 80°C.

In an another embodiment of the present invention, the novel crystalline Form XI of Rifaximin range of particle sizes preferred for use in the invention is D90 70-80 µm, more preferably D90 65 µm, even more preferably D90 62.8 µm. The particle sizes stipulated herein and in the claims refer to particle sizes were determined using a laser light scattering technique.

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 novel crystalline Form XI of Rifaximin:

Example-1:

Charge ethanol lot-1 (375 ml) and purified water lot-1 (100 ml) into the flask. Charge rifaximin crude solid (100 gm) at 25-30°C. Raise mass temperature to 70-80°C stir the mass for 10 min at 70-80°C to dissolve solid completely. Filter the mass through the hyflow bed and wash with ethanol lot-2 (25 ml). Cool the mass temperature to 35-40°C. Seed the material at 35-40°C. Further cool to 25-30°C. Stir for 8-10 hrs at 25-30°C. Filter the solid at 25-30°C wash the material with mixture of solvent ethanol lot-3 (15 ml) + purified water lot-2 (5.0 ml). Suck dry the material for 45-60 min. Load the material into the tray drier, dry for 2 hrs at 25-30°C. Raise the dryer temperature to 70-75°C. Dry the material for 4-5 hours at 70-75°C. Further raise the dryer temperature to 80-85°C and maintain for 17 hours at 80-85°C, send sample to ADL for water content. (Limit NMT: 4.0%). Unload the material into a poly cover.

Dry wt: 75.0-85.0 gm

Example-2:

Charge isopropyl alcohol lot-1 (375 ml) and purified water lot-1 (100 ml) into the flask. Charge rifaximin crude solid (100 gm) at 25-30°C. Raise mass temperature to 70-80°C stir the mass for 10 min at 70-80°C to dissolve solid completely. Filter the mass through the hyflow bed and wash with isopropyl alcohol lot-2 (25 ml). Cool the mass temperature to 35-40°C. Seed the material at 35-40°C. Further cool to 25-30°C. Stir for 8-10 hrs at 25-30°C. Filter the solid at 25-30°C wash the material with mixture of solvent isopropyl alcohol lot-3 (15 ml) + purified water lot-2 (5.0 ml). Suck dry the material for 45-60 min. Load the material into the tray drier, dry for 2 hrs at 25-30°C. Raise the dryer temperature to 70-75°C. Dry the material for 4-5 hours at 70-75°C. Further raise the dryer temperature to 80-85°C and maintain for 17 hours at 80-85°C, send sample to ADL for water content. (Limit NMT: 4.0%). Unload the material into a poly cover.

Dry wt: 75.0-85.0 gm