FIELD OF THE INVENTION
The present invention relates to a novel crystalline form of rifaximin and process for its preparation.
BACKGROUND OF THE INVENTION
Rifaximin is an antibiotic belonging to rifamycin class of antibiotics and is chemically known as
(2S,16Z,18E,20S,21 S,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[l,2-a]-benzimidazole-l,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, P and y of rifaximin. Form a and P show pure crystalline characteristics while the y form is poorly crystalline. The US '620 discloses that

the formation of the a, P and y 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, P and y 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 P 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 y, 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 P form it should be higher than 4.5% and to obtain y form, water content should be below 2%.
US 8,193,196 B2 discloses polymorphic forms 8 and s 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, P, y, 8 and s) 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 r|, form-i, form t-dry, form i-dry', form B, amorphous form and form 0. Main differentiating point of these polymorphs is respective water content and x-ray powder diffraction pattern.
WO 2013/027227 Al discloses crystalline Form-I of rifaximin and process for its preparation.

5 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 25 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, there is provided a novel crystalline Form X of rifaximin, which is characterized by X-ray powder diffraction pattern having characteristic peaks expressed in degrees 20 (±0.2° 20) at 5.8°, 7.2°, 7.8°, 11.6°, 18.4° and 19.5°±0.2 20.
10 In another aspect, there is provided a crystalline Form X of rifaximin, which is characterized by X-ray powder diffraction pattern substantially as same as depicted in FIG. 1. The polymorphic Form X of Rifaximin is further characterized by Differential Scanning calorimetry (DSC) as shown in FIG. 2.
In another aspect, there is provided a process for the preparation of novel crystalline 15 polymorphic Form X, the process comprising:
(a) Dissolving Crude rifaximin in alcohol at 20°C to 30°C,
(b) Stirring the reaction mixture of step a) at 65°C to 85°C,
(c) adding water to the step b) at 70°C to 80°C,
(d) Cooling the slurry of step c) at about 25°C to 30°C, and 20 (e) Isolating the rifaximin form X.
BRIEF DESCRIPTION OF DRAWING
FIG. 1: X-ray powder diffraction pattern (XRD) of Rifaximin Form X. FIG. 2: Differential Scanning calorimetry (DSC) of Rifaximin Form X. 25
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel polymorphic form X process for the preparation of Rifaximin.

5 In one embodiment of the present invention, there is provided a novel crystalline Form X of rifaximin, which is characterized by X-ray powder diffraction pattern having characteristic peaks expressed in degrees 20 (±0.2° 20) at 5.8°, 7.2°, 7.8°, 11.6°, 18.4° and 19.5°±0.2 20The polymorphic Form X is further characterized by X-ray powder diffraction pattern substantially as that as shown in FIG. 1.
10 In general, the polymorphic form X of is characterized by Differential Scanning calorimetry (DSC) having endothermic peak at about 217.04°Cas shown in FIG. 2.
In an embodiment of the present invention, there is provided a process for the preparation of novel crystalline polymorphic Form X, the process comprising:
(a) Dissolving Crude rifaximin in alcohol at 20°C to 30°C,
15 (b) Stirring the reaction mixture of step a) at 65°C to 85°C,
(c) adding water to the step b) at 70°C to 80°C,
(d) Cooling the slurry of step c) at about 25°C to 30°C, and
(e) Isolating the rifaximin form X.
In general, the alcohol in step (a) comprises one or more of methanol, ethanol, propanol, 20 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 embodiment of the present invention, the crystalline Form X of rifaximin is having water 25 content in the range of 3.0 to 4.0 %
In another embodiment of the present invention, a novel crystalline Form X of rifaximin, which is further characterized by X-ray powder diffraction pattern having characteristic peaks expressed in degrees, is as follows in the table:

5 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.
10 EXAMPLES
Example 1:
Preparation of polymorphic form X of Riaximin:
Example-1:
In round bottomed flask, charge Ethanol (400 ml) and add crude Rifaximin (160 g) at 25°C to 15 30°C, heat the reaction mixture to 70°C to 80°C and allow to stir at 55°C to about 60°C till all solid gets its dissolved, further added distilled mineral water (192 ml) to the reaction mixture at 75°C to about 80°.The resultant mixture was filtered, washed with ethanol (45 ml), the obtain filtrate was allow to stir at 25°C to 28°C for 20 to 40 min and then cool to 10°C to 15°C for 45 to 60 min. The resultant precipitated solid was filtered and dried under vacuum for 16 to 20 hrs at 20 70-75°C to isolate the title product.
Example-2:
In round bottomed flask, charge Ethanol (250 ml) and add crude Rifaximin (80 g) at 25°C to 30°C, heat the reaction mixture to 60°C to 70°C and allow to stir at 35°C to about 40°C till all 25 solid gets its dissolved, further added distilled mineral water (86 ml) to the reaction mixture at 75°C to about 80°.The resultant mixture was filtered, washed with ethanol (25 ml), the obtain filtrate was allow to stir at 25°C to 28°C for 20 to 40 min and then cool to 10°C to 15°C for 45 to 60 min. The resultant precipitated solid was filtered and dried under vacuum for 16 to 20 hrs at 70-75°C to isolate the title product.

5
We Claim:
1. A crystalline Form X of rifaximin characterized by X-ray powder diffraction having
characteristic peaks expressed in degrees 20 (±0.2° 20) at about 5.8°, 7.2°, 7.8°, 11.6°, 18.4° and
10 19.5°±O.2 20.
2. The crystalline Form X of rifaximin according to claim 1, having water content in the range of
3.0 to 4.0%.
15 3. The crystalline Form X of rifaximin according to claim 1, characterized by X-ray powder diffraction substantially as same as that depicted in FIG. 1.
4. The crystalline Form X of rifaximin according to claim 1, characterized by differential
scanning calorimetry having endothermic peak at about 217.04°C.
20
5. A crystalline Form X of rifaximin characterized by X-ray powder diffraction having
characteristic peaks expressed in degrees 20 (±0.2° 20) at about 5.8°, 7.2°, 7.8°, 11.6°, 18.4° and
19.5°± 0.2 20 and having water content from about not more than 4.5%.
25

6. A process for the preparation of crystalline Form X of rifaximin, the process comprising:
(a) Dissolving Crude rifaximin in alcohol at 20°C to 30°C,
(b) Stirring the reaction mixture of step a) at 65°C to 85°C, 10 (c) adding water to the step b) at 70°C to 80°C,
(d) Cooling the slurry of step c) at about 25°C to 30°C, and
(e) Isolating the rifaximin form X.