Claims:1. A pharmaceutical composition comprising crystalline Rifaximin, Poloxamer, Stearyl polyoxyl-32 glyceride and one or more pharmaceutically acceptable excipient(s) where in Rifaximin has average particle diameter ranging between 10-100 microns.

2. A Pharmaceutical composition comprising crystalline Rifaximin according to claim 1, where in crystalline forms are selected from:
Crystalline Form G characterized by powder X-ray diffraction pattern with characteristic diffraction angle peaks at 5.2, 5.9, 6.6, 7.3, 7.9, 8.6, 12.5, 14.2, 18.5 and 19.1 ± 0.2° 2? and
Crystalline Form GR characterized by powder X-ray diffraction pattern with characteristic diffraction angle peaks at 5.5, 6.6, 6.8, 7.5, 7.7, 11.8, 13.3 and 15.4 ± 0.2° 2?

3. A pharmaceutical composition according to claim 1, wherein Poloxamer and Stearyl polyoxyl-32 glyceride are present individually in the composition in an amount ranging between 0.1 – 10% by weight based on the total weight of composition.

4. The pharmaceutical composition according to claim 1, wherein said one or more pharmaceutically acceptable excipient(s) are selected from microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, glyceryl distearate, talc, and mixtures thereof.

5. A process for preparing pharmaceutical composition comprising crystalline Rifaximin having average particle diameter ranging between 10-100 microns, Poloxamer, Stearyl polyoxyl-32 glyceride and one or more pharmaceutically acceptable excipient(s) where in the process comprise dry granulation process involving either slugging or Roller compaction.

6. A process for preparing pharmaceutical composition comprising crystalline Rifaximin according to claim 5, where in the slugging process for dry granulation comprising the steps of: (a) sifting and blending crystalline Rifaximin with one or more pharmaceutically acceptable excipient(s), (b) compressing the blended mixture of step (a) to form slugs, (c) sizing the slugs to form granules; (d) blending the granules with one or more pharmaceutically acceptable excipient(s), and (e) compressing the granules of step (d) in to tablets.

7. The tablet composition of claim 6, where in film coating is performed using a composition comprising Polyethylene glycol, polyvinyl alcohol, Red iron oxide and Titanium dioxide.

8. A process for preparing pharmaceutical composition comprising crystalline Rifaximin according to claim 5, where in the Roller compaction process for dry granulation comprising the steps of: (a) sifting and blending Rifaximin with one or more pharmaceutically acceptable excipient(s), (b) compacting the blended mixture of step (a) to form compacts, (c) passing the compacts through a sieve to obtain granules; (d) blending the granules with one or more pharmaceutically acceptable excipient(s), and (e) compressing the granules of step (d) in to tablets.

9. The tablet composition of claim 8, where in film coating is performed using a composition comprising Polyethylene glycol, Polyvinyl alcohol, Red iron oxide and Titanium dioxide
, Description:FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition comprising crystalline Rifaximin.

BACKGROUND OF THE INVENTION
Rifaximin is a semi-synthetic, rifamycin-based non-systematic antibiotic. It is chemically termed 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]pyrido[l ,2-(alpha)]-benzimidazole-l, 15(2H)-dione,25-acetate and structurally represented by the following structure:

In the United States Rifaximin is available as 200, 550mg oral tablets under the brand name XIFAXAN® by Salix Pharmaceuticals. It is used for the treatment of Traveller’s diarrhea caused by noninvasive strains of Escherichia coli, Hepatic encephalopathy (HE) recurrence and Irritable bowel syndrome with diarrhea (IBS-D).
It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics. It must be remarked that it is a locally-acting agent, which acts against pathogens present in the gastro-intestinal tract, on the mucosa surface or on the intestinal mucosa.
Rifaximin was first disclosed and claimed in Italian patent IT 1154655 and U.S. Patent No. 4,341,785. These patents disclose a process for the preparation of Rifaximin and a method for the crystallization thereof.
U.S. Patent No. 7,045,620 describes three polymorphic forms a, ß and ? of Rifaximin. Form a and ß show pure crystalline characteristics while the ? form is poorly crystalline. These polymorphic forms are differentiated on the basis of water content and PXRD.
U.S. Patent No. 8,193,196 describes further two polymorphic forms of Rifaximin, designated d and e respectively and U.S. Patent No. 7,709,634 describes an amorphous form of Rifaximin.
U.S. Patent No. 8,568,782 disclose gastro resistant micro granules comprising rifaximin coated with a gastro resistant polymeric material.
US Patent No. 8,383,151 disclose controlled release pharmaceutical composition comprising rifaximin and release controlling agent(s)
WIPO Patent Application WO2015159275 by Vetukuri VNKV, Prasada Raju disclose Novel crystalline form of Rifaximin designated as Form G.
Un Published Indian Patent application IN201741007377 by Vetukuri VNKV, Prasada Raju disclose Novel crystalline form of Rifaximin designated as Form GR.
Rifaximin is poorly water soluble and minimally absorbed drug. There is always a need for stable Pharmaceutical compositions of Rifaximin having similar bioavailability profile in order to retain its therapeutic effect as locally acting agent which acts against pathogens present in the gastro-intestinal tract, on the mucosa surface or on the intestinal mucosa
Accordingly, one object of the present invention is to provide Rifaximin compositions that retain its polymorphic form and stability during manufacturing pharmaceutical process and throughout the shelf life, besides retaining its bioavailability profile of the drug upon administration.
It has been surprisingly found by the inventors that pharmaceutical compositions of Rifaximin according to present invention in the presence of Poloxamer and Stearyl polyoxyl-32 glyceride were found to provide stability and exhibited desired bioavailability which were also found to be comparable with to the marketed formulation.

SUMMARY OF INVENTION
Particular aspect of the present invention relates to stable pharmaceutical composition comprising crystalline Rifaximin.
One aspect of the present invention relates to pharmaceutical composition comprising crystalline Rifaximin, Poloxamer, Stearyl polyoxyl-32 glyceride and one or more pharmaceutically acceptable excipient(s) where in Rifaximin has average particle diameter ranging between 10-100 microns.
In another aspect the present invention relates to process for preparing pharmaceutical composition comprising crystalline Rifaximin having average particle diameter ranging between 10-100 microns, Poloxamer, Stearyl polyoxyl-32 glyceride and one or more pharmaceutically acceptable excipient(s) where in the process comprise dry granulation process involving either slugging or Roller compaction.
In yet another aspect the present invention relates to pharmaceutical composition comprising crystalline Rifaximin wherein crystalline forms are selected from crystalline Form G and crystalline Form GR.
Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF FIGURES:
Fig.1: Represents X-ray powder diffraction pattern of Rifaximin crystalline Form G
Fig.2: Represents X-ray powder diffraction pattern of tablet composition of Rifaximin crystalline Form G.
Fig.3: Represents X-ray powder diffraction pattern of Rifaximin crystalline Form GR
Fig.4: Represents X-ray powder diffraction pattern of Placebo.

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide a stable pharmaceutical composition comprising crystalline Rifaximin.
In one embodiment according to present application, it provides a pharmaceutical composition comprising crystalline Rifaximin, Poloxamer, Stearyl polyoxyl-32 glyceride and one or more pharmaceutically acceptable excipient(s).
In another embodiment according to present invention Poloxamer and Stearyl polyoxyl-32 glyceride are present individually in the composition in an amount ranging between 0.1 – 10% by weight based on the total weight of composition. Presence of Poloxamer and polyoxyl-32 glyceride leads to superior bioavailability characteristics comparable with to the marketed formulations. It has been observed owing to gel forming role besides its surfactant nature, however a full mechanism is still unknown.
In yet another embodiment according to present invention, the pharmaceutical composition comprising crystalline Rifaximin wherein crystalline forms are selected from novel crystalline Form G and crystalline Form GR.
In another embodiment according to present invention crystalline Form G is characterized by powder X-ray diffraction pattern with characteristic diffraction angle peaks at 5.2, 5.9, 6.6, 7.3, 7.9, 8.6, 12.5, 14.2, 18.5 and 19.1 ± 0.2° 2? which is disclosed in PCT application WO2015159275.
Crystalline Form GR is characterized by powder X-ray diffraction pattern with characteristic diffraction angle peaks at 5.5, 6.6, 6.8, 7.5, 7.7, 11.8, 13.3 and 15.4 ± 0.2° 2? which is disclosed in unpublished Indian patent application IN201741007377.
Further, it is well known that particle size can affect the solubility properties of a pharmaceutical compound. Particle size reduction may administer a compound's dissolution rate and consequently its bioavailability. The present invention utilizes crystalline Rifaximin of appropriate particle size, which has solubility well suited for preparing pharmaceutical compositions.
In one aspect, Rifaximin according to the present invention means Rifaximin having Average particle diameter ranging between 10 microns to 100 microns. The drug particles of the desired particle size may be obtained by any of the conventional particle size controlling processes known in the art.
Accordingly "average particle diameter" means volume based distribution median diameter (median diameter: 50% particle diameter from cumulative distribution), unless otherwise specified. It can be measured by, for example, a laser diffraction particle distribution measurement method.
In one embodiment according to present application, it provides a Pharmaceutical composition comprising crystalline Rifaximin, Poloxamer, Stearyl polyoxyl-32 glyceride and one or more pharmaceutically acceptable excipient(s) where in Rifaximin has average particle diameter ranging between 10-100 microns.
In one of the particular embodiment according to present invention the term "excipient" means a pharmacologically inactive component such as a diluent, disintegrant, carrier, etc of a pharmaceutical product. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
Suitable "diluents" include, but are not limited to, either individually or in combination, microcrystalline cellulose, lactose, starch, corn starch, pregelatinized starch, maize starch, potato starch, powdered celluloses, sorbitol, xylitol, dibasic calcium phosphate, calcium phosphate, calcium carbonate, magnesium carbonate and the like.
Suitable "disintegrants" include, but are not limited to, either individually or in combination, sodium starch glycolate, croscarmellose sodium, polacrilin potassium, crospovidone, pregelatinized starch and the like.
Suitable "glidants" include, but are not limited to, either individually or in combination, colloidal silicon dioxide, talc, magnesium silicate, magnesium trisilicate, and other forms of silicon dioxide, such as aggregated silicates, hydrated silica and the like.
Suitable "lubricants" include, but are not limited to, either individually or in combination, Glyceryl distearate, talc, magnesium stearate, stearic acid, fumaric acid, palmitic acid, sodium stearyl fumarate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like.
In one of the particular embodiment the present invention provides a Pharmaceutical composition comprising crystalline Rifaximin, Poloxamer, Stearyl polyoxyl-32 glyceride microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, glyceryl distearate, talc and the like.
In one of the particular embodiment, the present invention provides process for preparing pharmaceutical composition comprising crystalline Rifaximin having average particle diameter ranging between 10-100 microns, Poloxamer, Stearyl polyoxyl-32 glyceride and one or more pharmaceutically acceptable excipient(s) where in the process comprise dry granulation process using slugging or Roller compaction.
In one embodiment according to present invention the Roller compaction process for dry granulation comprising the steps of: (a) sifting and blending Rifaximin with one or more pharmaceutically acceptable excipient(s), (b) compacting the blended mixture of step (a) to form compacts, (c) passing the compacts through a sieve to obtain granules; (d) blending the granules with one or more pharmaceutically acceptable excipient(s), and (e) compressing the granules of step (d) in to tablets.
In another embodiment according to present invention the slugging process for dry granulation comprising the steps of: (a) sifting and blending Rifaximin with one or more pharmaceutically acceptable excipient(s), (b) compressing the blended mixture of step (a) to form slugs, (c) sizing the slugs to form granules; (d) blending the granules with one or more pharmaceutically acceptable excipient(s), and (e) compressing the granules of step (d) in to tablets.
In one of the particular embodiment a tablet of the present invention is provided with a film coating. The film coating is non-functional and provides good appearance to the final dosage form. Accordingly it comprises Polyethylene glycol, polyvinyl alcohol, Red iron oxide and Titanium dioxide.
The invention is further exemplified with following examples which are not intended to limit the scope of the invention.

EXAMPLES:
The following examples further describe and demonstrate particular embodiments within the scope of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Table 1: Examples 1-4: Rifaximin tablet composition prepared by dry granulation process using Roller compaction.
Ingredients mg/tab
Ex-1 Ex- 2 Ex- 3 Ex- 4
Core
Rifaximin 550 550 550 550
Crystalline Form of Rifaximin G GR G GR
Microcrystalline cellulose 265 125 75 120
Poloxamer 5 (0.5%) 75 (7.5%) 100 (10%) 75 (7.5%)
Stearoyl polyoxyl-32 glycerides 5
(0.5%) 75
(7.5%) 100
(10%) 100
(10%)
Sodium starch glycolate 60 60 60 50
Colloidal silicon dioxide 25 25 25 15
Glyceryl distearate 15 15 15 25
Talc 50 50 50 40
Coating
Polyethylene Glycol 5 5 5 5
Polyvinyl Alcohol 12.5 12.5 12.5 12.5
Red iron oxide 4 4 4 4
Titanium dioxide 3.5 3.5 3.5 3.5
Tablet Weight (mg) 1000 1000 1000 1000
Manufacturing process:
1. Stearoyl polyoxyl-32 glycerides and poloxamer were milled through 0.5mm screen and sifted through #40 mesh.
2. Rifaximin, colloidal silicon dioxide, microcrystalline cellulose and sodium starch glycolate were sifted (which constitute 3 parts of total tablet weight) separately through# 40 mesh and glyceryl distearate, talc through #60 mesh.
3. The sifted materials of step 1 & 2 (excluding glyceryl distearate and talc) were blended and further lubricated with glyceryl distearate and talc to form the pre-mix.
4. The pre-mix of step 3 was charged in roller compactor to form compacts, which are further sieved to form granules.
5. Microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide materials (constituting 1 part of total tablet weight) were sifted through #40 mesh and were added to the compacted granules formed in step 4 and blended.
6. Glyceryl distearate and talc (constituting 1 part of total tablet weight) were sifted through #60 mesh and lubricated with the blend of step 5.
7. Lubricated blend was compressed into tablets with the desired physical parameters and coated with the coating solution.
Dissolution data for Examples 1-4:
The dissolution data of the compositions made according to the present invention were tested by using the following method were represented in Table 2
Apparatus: USP Type II (paddle)
Media: pH 7.4 phosphate buffer + 0.8% Sodium lauryl sulphate
Rpm: 75; Temperature: 37 ± 0.5°C
Volume: 1000ml
Time points: 90 minutes
Specification: Not less than 75% (Q) of labelled amount of Rifaximin is dissolved.

Tale 2: Dissolution Profile
Time (in minutes) % Drug Release
Ex-1 Ex- 2 Ex- 3 Ex- 4
90 93 94 96 92

Table 3: Example 5: Rifaximin tablet composition prepared by dry granulation process using Slugging.
Ingredients mg/tab
Rifaximin crystalline Form G 550
Microcrystalline cellulose 125
Poloxamer 75
(7.5%)
Stearoyl polyoxyl-32 glycerides 75
Sodium starch glycolate 60
Colloidal silicon dioxide 25
Glyceryl distearate 15
Talc 50
Coating Composition
Polyethylene Glycol 5
Polyvinyl Alcohol 12.5
Red iron oxide 4
Titanium dioxide 3.5
Tablet Weight (mg) 1000

Manufacturing process:
1. Stearoyl polyoxyl-32 glycerides and poloxamer were milled through 0.5mm screen and sifted through #40 mesh.
2. Rifaximin, colloidal silicon dioxide, microcrystalline cellulose and sodium starch glycolate were sifted (which constitute 3 parts of total tablet weight) separately through #40 mesh and glyceryl distearate, talc through #60 mesh.
3. The sifted materials of step 1 & 2 (excluding glyceryl distearate and talc) were blended and further lubricated with glyceryl distearate and talc to form the pre-mix.
4. The pre-mix of step 3 was compressed into slugs and milled through 1.0mm screen in multi mill. The granules were then sifted through #20 mesh.
5. Microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide materials (constituting 1 part of total tablet weight) were sifted through #40 mesh and were added to the granules formed in step 4 and blended.
6. Glyceryl distearate and talc (constituting 1 part of total tablet weight) were sifted through #60 mesh and lubricated with the blend of step 5.
7. Lubricated blend was compressed into tablets with the desired physical parameters and coated with the coating solution.
Dissolution data for Example 5
Apparatus: USP Type II
Media: pH 7.4 phosphate buffer + 0.8% Sodium lauryl sulphate
Rpm: 75; Temperature: 37 ± 0.5°C
Volume: 1000ml
Time points: 90 minutes
Specification: Not less than 75% (Q) of labelled amount of Rifaximin (C43H51N3O11) is dissolved.

Table 4: Dissolution Profile
Time (in minutes) % Drug Release
90 96

Stability Information:
X-ray powder diffraction pattern of pharmaceutical composition prepared according to the present invention (Example 3) reveals that crystalline stability is retained in the final tablet composition (Fig.2)

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.