Field of the invention:

The present invention provides an improved process for the preparation of crystalline forms of Rifaximin compound represented by the following structural formula-1.

Background of the invention:

Rifaximin is a semi-synthetic, non-systemic antibiotic that can be derived from rifamycin O by condensation with 2-amino-4-methylpyridine. Xifaxan* has Rifaximin as the active ingredient. Xifaxan® is used for the treatment of patients with travelers' diarrhea (TD) and the reduction in risk of overt hepatic encephalopathy (HE) recurrence.

The rifaximin (INN; Ref: The Merck Index, XIII Ed., 8304) is an antibiotic pertaining to the rifamycin class, exactly it is a pyrido-imidazo rifamycin described and claimed in the US Patent US4341785, while the European Patent EP 0161534 describes and claims a process for its production starting from the rifamycin 0 (The Merck Index, XIII Ed., 8301).

Both these patents describe the purification of the rifaximin in a generic way saying that the crystallization can be carried out in suitable solvents or solvent systems and summarily showing in some examples that the product coming from the reaction can be crystallized from the 7:3 mixture of ethyl alcohol/vvater and can be dried both under atmospheric pressure and under vacuum without saying in any way neither the experimental conditions of crystallization and drying, nor any distinctive crystallographic characteristic of the obtained product.

The presence of different polymorphs had not been just noticed and therefore the experimental conditions described in both patents had been developed with the goal to get a homogeneous product having a suitable purity from the chemical point of view, apart from the crystallographic aspects of the product itself.

Inventors of the present invention repeated the process exemplified in EP 0161534 and dried the obtained product at different conditions to provide PXRD histograms of Rifaximin.

US7045620, US7612199, US7902206, US8158644, US8158781 and US8193196 provide methods for the synthesis of polymorphic forms-a, P & y of rifaximin. These patents disclosed that the polymorph called rifaximin a is characterized by a water content lower than 4.5%, preferably between 2.0% and 3.0% and from a powder X-ray diffractogram which shows peaks at the values of the diffraction angles 20 of 6.6°; 7.4°; 7.9°; 8.8°; 10.5°; 11.1°; 11.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.4°; 22.1°. The polymorph called rifaximin p is characterized by a water content higher than 4.5%, preferably between 5.0% and 6.0%, and by a powder X-ray diffractogram which shows peaks at the values of the diffraction angles 29 of 5.4°; 6.4°; 7.0°; 7.8°; 9.0°; 10.4°; 13.1°; 14.4°; 17.1°; 17.90; 18.30; 20.9° The polymorph called rifaximin y is characterized by a powder X-ray diffractogram much poorer because of the poor crystallinity; the significant peaks are at the values of the diffraction angles 29 of 5.0°; 7.1°; and 8.4°.

These forms were described as 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 the addition of water at a determinate temperature and for a determinate period of time. The crystallization was followed by drying carried out under controlled conditions until specific water content was reached in the end product. The rifaximin a and rifaximin p crystalline forms were characterized by X-ray diffractogram properties. It is described that the production of rifaximin a and rifaximin P during drying depends on the amount of water remaining at the end, higher or lower than 4.5%, and not from the experimental conditions of pressure and temperature at which this critical limit of water percentage is achieved. In fact, the two polymorphous forms, with higher or lower water content, can be obtained by drying under vacuum or at atmospheric pressure, at room temperature or at high temperatures, in the presence or in the absence of drying agents, provided that the drying is conducted for the amount of time necessary so that the water percent characteristic for each polymorphous form is achieved. It is described in the U.S. Pat. No. 7,045,620 that polymorphous form rifaximin (3 is obtained when the drying of the product, crystallized and washed with water, is stopped at values of water higher than 4.5% and that the polymorphous form rifaximin a is obtained by continuing the drying until values lower than 4.5%, preferably between 2.0% and 3.0%, are reached. The polymorphous form rifaximin a, kept in an ambient environment with a relative humidity higher than 50% for a period of time between 12 and 48 hours, turns into the polymorphous form P, which in turn, by drying until an amount of water lower than 4.5% is reached, preferably comprised between 2.0%> and 3.0%>, turns back into the polymorphous form rifaximin a.

Crystal forms of rifaximin and their effect on pharmaceutical properties are further described in Viscomi G C, et al, The Royal Society of Chemistry, CrystEngComm, 2008, 10, 1074-1081, which is hereby incorporated by reference in its entirety.

US7923553 describes process for the preparation of polymorphous form rifaximin a, rifaximin P & rifaximin y.

Brief description of the invention:

The first aspect of the present invention is to provide an improved process for the preparation of mixture of crystalline rifaximin a and rifaximin p.

The second aspect of the present invention is to provide an improved process for the preparation of crystalline form-P of rifaximin.

The third aspect of the present invention is to provide an improved process for the preparation of crystalline form-a of rifaximin.

The fourth aspect of the present invention is to provide an improved process for the preparation of Rifaximin.

Brief description of the drawings:

Figure 1: Illustrates the PXRD pattern of sample-1 obtained according to reference example- 1.

Figure 2: Illustrates the PXRD pattern of sample-2 obtained according to reference example- 1.

Figure 3: Illustrates the PXRD pattern of sample-3 obtained according to reference example- 1.

Figure 4: Illustrates the PXRD pattern of sample-4 obtained according to reference example- 2.

Figure 5: Illustrates the PXRD pattern of sample-5 obtained according to reference example- 2.

Figure 6: Illustrates the PXRD pattern of sample-6 obtained according to reference example- 2.

Figure 7: Illustrates the PXRD pattern of sample-7 obtained according to reference example- 3.

Figure 8: Illustrates the PXRD pattern of sample-8 obtained according to reference example- 3.

Figure 9: Illustrates the PXRD pattern of sample-9 obtained according to reference example- 3.

Figure 10: Illustrates the PXRD pattern of mixture of crystalline rifaximin a and rifaximin (3 obtained according to example-1.

Detailed description of the invention:

As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, or naphthalene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylfbrmamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1,2.-propanediol (propylene glycol), 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol,. neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.

The mixture of crystalline rifaximin a and rifaximin P wherein the ration of a:(3 rifaximin is in the ratio of 2:98 to 98:2.

The crude rifaximin is taken as input is prepared by the prior art process or prepared according to the present invention.

The first aspect of the present invention provides an improved process for the preparation of mixture of crystalline rifaximin a and rifaximin P, comprising of:

a) Suspending crude rifaximin in an alcoholic solvent,

b) heating the reaction mixture to a suitable temperature,

c) dissolving the compound by addition of water to the reaction mixture,

d) filtering the reaction mixture,

e) stirring the filtrate at a suitable temperature,

f) precipitating the compound by addition of mixture of water & alcoholic solvent,

g) cooling the reaction mixture to a suitable temperature,

h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at a suitable temperature to reach the water content 4.5-7% (W/W) to get mixture of crystalline rifaximin a and rifaximin p.

Wherein in step-a) usage of alcoholic solvent is 2 to 3 times to the quantity of crude rifaximin; preferably 2.5 times.

In step-b) a suitable temperature is about 45°C to reflux temperature of the alcoholic solvent; preferably 55 to 65°C.

In step-c) usage of water is 0.15 to 0.5 times to the quantity of crude rifaximin.

In step-f) mixture of alcoholic & water, wherein the ratio of watenalcoholic solvent is about 1:0 to 1:0.04; preferably 1:0.02.

In step-j) a suitable temperature is about 25-65°C.

Preferred embodiment of the present aspect of the invention provides an improved process for the preparation of mixture of crystalline rifaximin a and rifaximin P, comprising of:

a) Suspending crude rifaximin in isopropanol,

b) heating the reaction mixture to 65-70°C,

c) dissolving the compound by addition of water,

d) filtering the reaction mixture,

e) stirring the filtrate at 55-60°C,

f) precipitating the compound by addition of mixture of water & isopropanol,

g) cooling the reaction mixture to 0-5°C,

h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at 25-30°C for 3 to 4 hours and further drying the compound at 50-55°C to reach the water content 4.5-7% (W/W) to get mixture of crystalline rifaximin a and rifaximin p.

The second aspect of the present invention provides an improved process for the preparation of crystalline form- P of rifaximin, comprising of:

a) Suspending crude rifaximin to alcoholic solvent,

b) heating the reaction mixture to a suitable temperature,

c) dissolving the compound by addition of water to the reaction mixture,

d) filtering the reaction mixture,

e) stirring the filtrate at a suitable temperature,

f) precipitating the compound by addition of mixture of water & alcoholic solvent,

g) cooling the reaction mixture to a suitable temperature,

h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at a suitable temperature to reach the water content >7% (W/W) to get crystalline form-(3 of rifaximin.

Wherein in step-a) usage of alcoholic solvent is 2 to 3 times to the quantity of crude rifaximin; preferably 2.5 times.

In step-b) a suitable temperature is about 45°C to reflux temperature of the alcoholic solvent; preferably 55 to 65°C.

In step-c) usage of water is 0.15 to 0.5 times to the quantity of crude rifaximin.

In step-f) mixture of alcoholic & water, wherein the ratio of wateralcoholic solvent is about 1:0 to 1:0.04; preferably 1:0.02.

In step-j) a suitable temperature is about 25-65°C.

Preferred embodiment of the present aspect of the invention provides an improved process for the preparation of crystalline form-P of rifaximin, comprising of:

a) Suspending crude rifaximin in isopropanol,

b) heating the reaction mixture to 65-70°C,

c) dissolving the compound by addition of water,

d) filtering the reaction mixture,

e) stirring the filtrate at 55-60°C,

f) precipitating the compound by addition of mixture of water & isopropanol,

g) cooling the reaction mixture to 0-5°C,

h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at 25-30°C for 3 to 4 hours and further drying the compound at 30-4Q°C to reach the water content >7% (W/W) to provide crystalline form-|3 of rifaximin.

The third aspect of the present invention provides an improved process for the preparation of crystalline form-a of rifaximin, comprising of:

a) Suspending crude rifaximin in an alcoholic solvent,

b) heating the reaction mixture to a suitable temperature,

c) dissolving the compound by addition of water,

d) filtering the reaction mixture,

e) stirring the filtrate at a suitable temperature,

f) precipitating the compound by addition of mixture of water & alcoholic solvent at a suitable temperature,

g) cooling the reaction mixture to a suitable temperature,

h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at a suitable temperature to reach the water content <4% (W/W) to get crystalline form-a of rifaximin. Wherein in step-a) usage of alcoholic solvent is 2 to 3 times to the quantity of crude rifaximin; preferably 2.5 times.

In step-b) a suitable temperature is about 45°C to reflux temperature of the alcoholic solvent; preferably 55 to 65°C.

In step-c) usage of water is 0.15 to 0.5 times to the quantity of crude rifaximin. In step-f) mixture of alcoholic & water, wherein the ratio of water : alcoholic solvent is about 1:0 to 1:0.04; preferably 1:0.02. In step-j) a suitable temperature is about 25-65°C.

Preferred embodiment of the present aspect of the invention provides an improved process for the preparation of crystalline form-a of rifaximin, comprising of:

a) Suspending crude rifaximin in isopropanol,

b) heating the reaction mixture to 65-70°C,

c) dissolving the compound by addition of water,

d) filtering the reaction mixture,

e) stirring the filtrate at 55-60°C,

f) precipitating the compound by addition of mixture of water & isopropanol,

g) cooling the reaction mixture to 0-5°C, h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at 25-30°C for 3 to 4 hours and further drying the compound at 50-55°C to reach the water content <4% (W/W) to provide crystalline form-a of rifaximin.

The fourth aspect of the present invention provides an improved process for the preparation of Rifaximin.

a) Adding Rifamycin O compound of formula-2 to the mixture of water & alcoholic solvent,

b) adding 2-Amino-4-methyl pyridine compound of formula-3 to the above reaction mixture,

c) stirring the reaction mixture at a suitable temperature,

d) cooling the reaction mixture,

e) filtering the reaction mixture,

f) drying the obtained compound to get rifaximin.

Wherein in

step-a) the alcoholic solvent is methanol, ethanol, isopropanol, butanol; preferably methanol. The mixture of alcoholic solvent and water is used in the ratio between about 5.5:4.5 to 6:4; preferably 6:4.

In step-c) a suitable temperature is selected from about 15 to 30°C; preferably 20 to 25°C. In step-d) the reaction mixture was cooled to about 0-10°C; preferably 0-5°C.

All prior art processes discloses the isolation of the compound by neutralizing with acids and extracting the reaction mixture using solvents.

Whereas, as per the present invention there no usage of acid and does not required extractions with solvents. This process is less expensive by avoiding the usage of acid & extracting solvents.

By practicing a method of the present invention as disclosed and claimed herein, mixture of crystalline forms of rifaximin can be obtained rather than only a single crystalline polymorph. The composition can be suitable for use in the formulation of medicaments, such as for the treatment of infections of the gastrointestinal (GI) tract.

A composition containing rifaximin a and P mixture useful for the preparation of formulation with a suitable pharmaceutical carrier for oral administration.

HPLC Method of Analysis:

Rifaximin and its related substances were analyzed by HPLC with the following chromatographic conditions:

Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector. Column: Alltima CI8, 250 x 4.6 mm, 5 um (or) Equivalent; Wavelength: 276 nm; Column temperature: 40°C; Injection volume: 20 uX; Elution: Isocartic; Needle wash: Diluent. Mobile phase: Mix 37 volumes of a 3.16 g/L solution of ammonium formate, adjust its pH to 7.2 with diluent ammonia solution and 63 volumes of a mixture of equal volumes of acetonitrile and methanol.

PXRD analysis of crystalline forms of Rifaximin were carried out using Bruker-AXS/ D8 advance X-Ray diffractometer using Cu Kal, radiation of wavelength 1.5406 A0 and continuous scan speed of 0.03°/min.

Milled the crystalline forms of Rifaximin obtained according to the present invention by passing through mesh under nitrogen atmosphere to get desired particle size and further dried the compound to reach the required water content. Crystalline polymorphs of Rifaximin obtained according to the present invention having particle size about less than 500um, preferably <300 u.m, most preferably <200 um, more preferably <100 um.

The present invention represented in the scheme-1.

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples: Reference Example-1:

The 2-Amino-4-methyl pyridine (6.55 gms) was added to the mixture of Rifamycin 0 (20 gms) and dichloromethane (100 ml) at 25-30°C. Stirred the reaction mixture for 40 hours at the same temperature. IN hydrochloride solution (90 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was extracted with dichloromethane and the organic layer was dried with sodium sulfate. The organic layer was distilled off and 30 ml of mixture of ethanol & water (7:3) was added at 40-45°C. Cooled the reaction mixture to 25-30 and stirred the reaction mixture. Solid formation not observed. Further the reaction mixture was cooled to 0-5°C and stirred for 1 1/2 hours at the same temperature. Filtered the precipitated solid and washed the compound with mixture of ethanol & water. The obtained wet compound (sample-1) has water content 14.58% w/w and its PXRD pattern is depicted in the figure-1 and it is matched with crystalline form-p.

The above wet compound dried at 25-30°C for 4 hours. Water content of the obtained compound (sample-2) is 7.62% w/w and its PXRD pattern is depicted in figure-2 and it is matched with crystalline form-p.

Further the above compound was dried at 50-55°C for 3 1/2 hours. Water content of the obtained compound (sample-3) is 4.62%) w/w arid its PXRD pattern is depicted in figure-3 and it is matched with mixture of crystalline rifaximin a and p.

Reference Example-2:

The 2-Amino-4-methyl pyridine (6.55 gms) was added to the mixture of Rifamycin O (20 gms) and dichloromethane (100 ml) at 25-30°C. Stirred the reaction mixture for 40 hours at the same temperature. IN hydrochloride solution (90 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was extracted with dichloromethane and the organic layer was dried with sodium sulfate. The organic layer was distilled off and cooled the obtained compound to 25-30°C. Added 30 ml of mixture of ethanol & water (7:3) at 25-30°C and stirred the reaction mixture for 4 hours at the same temperature. Filtered the precipitated solid and washed the compound with mixture of ethanol & water. The obtained wet compound (sample-4) has water content 15.12% w/w and its PXRD pattern is depicted in the figure-4 and it is matched with crystalline form-(3.

The above wet compound dried at 25-30°C for 16 hours. Water content of the obtained compound (sample-5) is 7.98% w/w and its PXRD pattern is depicted in figure-5 and it is matched with crystalline form-(3.

Further the above compound was dried at 50-55°C for 3 hours. Water content of the obtained compound (sample-6) is 4.68% w/w and its PXRD pattern is depicted in figure-6 and it is matched with mixture of crystalline rifaximin a and p.

Reference Example-3:

The 2-Amino-4-methyl pyridine (6.55 gms) was added to the mixture of Rifamycin 0 (20 gms) and dichloromethane (100 ml) at 25-30°C. Stirred the reaction mixture for 40 hours at the same temperature. IN hydrochloride solution (90 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was extracted with dichloromethane and the organic layer was dried with sodium sulfate. The organic layer was distilled off and cooled the obtained compound to 25-30°C. Added 30 ml of mixture of ethanol & water (7:3) at 25-30°C and stirred the reaction mixture for 4 hours at the same temperature. Filtered the precipitated solid and washed the compound with mixture of ethanol & water. The obtained wet compound (sample-7) has water content 17.08% w/w and its PXRD pattern is depicted in the figure-7 and it is matched with crystalline form-p.

The above wet compound dried at 25-30°C for 16 hours. Water content of the obtained compound (sample-8) is 8.19% w/w and its PXRD pattern is depicted in figure-8 and it is matched with crystalline form-p.

Further the above compound was dried at 50-55°C for 10 hours. Water content of the obtained compound (sample-9) is 2.0% w/w and its PXRD pattern is depicted in figure-9 and it is matched with crystalline form-a.

Example-1: Preparation of crude rifaximin

2-Amino-4-methyl pyridine compound of formula-3 (86 gms) was added to the reaction mixture of Rifamycin O compound of formula-2 (200 gms) in a mixture of methanol (2400 ml) and water (1600 ml) at 20-25°C and stirred the reaction mixture for 24 hours at the same temperature. The reaction mixture was cooled to 0-5°C and stirred for 30 minutes at the

same temperature. Filtered the precipitated solid, washed with water and dried to get crude rifaximin. Yield: 168 gms; HPLC Purity: 98.46%, 0.25 % D&H impurities; Water content: 6.5% w/w.

ExampIe-2: Preparation of pure crystalline mixture of rifaximin a and 0:

Crude Rifaximin (100 gms) was suspended in isopropanol (250 ml) to at 25-30°C and heated to 65-70°C. Completely dissolved the compound by addition of water (15 ml) to the reaction mixture at 65-7Q°C and stirred the reaction mixture for 15 minutes. Filtered the reaction mixture on hiflow bed and washed with isopropanol (50 ml). Slowly added a mixture of isopropanol (10 ml) and water (450 ml) to the filtrate at 55-60°C. Cooled the reaction mixture to 0-5°C and stirred for 5 hours. Filtered the precipitated solid, washed with water and dried the obtained compound at 25-30°C for 5 hours and further the compound was dried at 50-55°C for 3.5 hours. Milled the material through #0.5mm mesch under nitrogen atmosphere and further sifting the material through 40 mesch dried the compound at 50-55°C for 3 hours to get the title compound.

Yield: 96.5 gms; HPLC Purity: 99.54, 0.24% (sum of D&H impurities); Water content is 5.7% w/w and its PXRD pattern is depicted in figure-10. Particle size: D(0.1): 1.315 um, D(0.5): 19.338 urn, D(0.9): 52.293 urn.

Example-3: Preparation of pure crystalline form-p of rifaximin:

Crude Rifaximin (100 gms) was suspended in isopropanol (250 ml) to at 25-30°C and heated to 65-70°C. Completely dissolved the compound by addition of water (15 ml) to the reaction mixture at 65-70°C and stirred the reaction mixture for 15 minutes. Filtered the reaction mixture on hiflow bed and washed with isopropanol (50 ml). Slowly added a mixture of isopropanol (10 ml) and water (450 ml) to the filtrate at 55-60°C. Cooled the reaction mixture to 0-5°C and stirred for 5 hours. Filtered the precipitated solid, washed with water and dried the obtained compound at 25-30°C for 5 hours and further the compound was dried at 35-40°C for 2 hours. Milled the material through #0.5mm mesch under nitrogen atmosphere and further sifting the material through 40 mesch dried the compound at 35-40°C for 2 hours to get the title compound.

Yield: 96 gms; HPLC Purity: 99.57, 0.23% (sum of D&H impurities): Water content is 9.98% w/w.

Particle size: D(0.1): 4.7 um, D(0.5): 31.9 urn, D(0.9): 70.6 urn.

Example-4: Preparation of pure crystalline form-a of rifaximin:

Crude Rifaximin (100 gms) was suspended in isopropanol (250 ml) to at 25-30°C and heated to 65-70°C. Completely dissolved the compound by addition of water (15 ml) to the reaction mixture at 65-70°C and stirred the reaction mixture for 15 minutes. Filtered the reaction mixture on hiflow bed and washed with isopropanol (50 ml). Slowly added a mixture of isopropanol (10 ml) and water (450 ml) to the filtrate at 55-60°C. Cooled the reaction mixture to 0-5°C and stirred for 5 hours. Filtered the precipitated solid, washed with water and dried the obtained compound at 25-30°C for 5 hours and further the compound was dried at 50-55°C for 8 hours. Milled the material through #0.5mm mesch under nitrogen atmosphere and further sifting the material through 40 mesch dried the compound at 50-55°C for 3 hours to get the title compound.

Yield: 90 gms; HPLC Purity: 99.63, 0.23% (sum of D&H impurities); Water content is 1.8% w/w. Particle size: D(0.1): 1.753 um, D(0.5): 22.346 um, D(0.9): 53.687 um.

We claim:

1. An improved process for the preparation of mixture of crystalline rifaximin a and rifaximin P, comprising of:

a) Suspending crude rifaximin in an alcoholic solvent,

b) heating the reaction mixture to a suitable temperature,

c) dissolving the compound by addition of water to the reaction mixture,

d) filtering the reaction mixture,

e) stirring the filtrate at a suitable temperature,

f) solidifying the compound by addition of mixture of water & alcoholic solvent,

g) cooling the reaction mixture to a suitable temperature, h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at a suitable temperature to reach the water content 4.5-7% (W/W) to provide mixture of crystalline rifaximin a and rifaximin (3.

2. An improved process for the preparation of crystalline form-(3 of rifaximin, comprising of:

a) Suspending crude rifaximin in an alcoholic solvent,

b) heating the reaction mixture to a suitable temperature,

c) dissolving the compound by addition of water to the reaction mixture,

d) filtering the reaction mixture,

e) stirring the filtrate at a suitable temperature,

f) solidifying the compound by addition of mixture of water & alcoholic solvent,

g) cooling the reaction mixture to a suitable temperature, h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at a suitable temperature to reach the water content >7% (W/W) to provide crystalline form-P of rifaximin.

3. An improved process for the preparation of crystalline form-a of rifaximin, comprising of:

a) Suspending crude rifaximin in an alcoholic solvent,

b) heating the reaction mixture to a suitable temperature,

c) dissolving the compound by addition of water,

d) filtering the reaction mixture,

e) stirring the filtrate at a suitable temperature,

f) solidifying the compound by addition of mixture of water & alcoholic solvent at a suitable temperature,

g) cooling the reaction mixture to a suitable temperature,

h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at a suitable temperature to reach the water content <4% (W/W) to provide crystalline form-a of rifaximin.

4. The process according to claims 1 to 3, Wherein in step-a) usage of alcoholic solvent is 2 to 3 times to the quantity of crude rifaximin; preferably 2.5 times; in step-b) a suitable temperature is about 45°C to reflux temperature of the alcoholic solvent; preferably 55 to 65°C; in step-c) usage of water is 0.15 to 0.5 times to the quantity of crude rifaximin; in step-f) mixture of alcoholic & water, wherein the ratio of watenalcoholic solvent is about 1:0 to 1:0.04; preferably 1:0.02.

5. An improved process for the preparation of mixture of crystalline rifaximin a and rifaximin P, comprising of:

a) Suspending crude rifaximin in isopropanol,

b) heating the reaction mixture to 65-70°C,

c) dissolving the compound by addition of water,

d) filtering the reaction mixture,

e) stirring the filtrate at 55-60°C,

f) precipitating the compound by addition of mixture of water & isopropanol,

g) cooling the reaction mixture to 0-5°C, h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at 25-30°C for 3 to 4 hours and further drying the compound at 50-55°C to reach the water content 4.5-7% (W/W) to get mixture of crystalline rifaximin a and rifaximin (3.

6. An improved process for the preparation of crystalline form-(3 of rifaximin, comprising of:

a) Suspending crude rifaximin in isopropanol,

b) heating the reaction mixture to 65-70°C,

c) dissolving the compound by addition of water,

d) filtering the reaction mixture,

e) stirring the filtrate at 55-60°C,

f) precipitating the compound by addition of mixture of water & isopropanol,

g) cooling the reaction mixture to 0-5°C,

h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at 25-30°C for 3 to 4 hours and further drying the compound at 30-40°C to reach the water content >7% (W/W) to provide crystalline form-P of rifaximin.

7. An improved process for the preparation of crystalline form-a of rifaximin, comprising of:

a) Suspending crude rifaximin in isopropanol,

b) heating the reaction mixture to 65-70°C,

c) dissolving the compound by addition of water,

d) filtering the reaction mixture,

e) stirring the filtrate at 55-60°C,

f) precipitating the compound by addition of mixture of water & isopropanol,

g) cooling the reaction mixture to 0-5°C,

h) stirring the reaction mixture,

i) filtering the obtained solid, washing with water,

j) drying the compound at 25-30°C for 3 to 4 hours and further drying the compound at 50-55°C to reach the water content <4% (W/W) to provide crystalline form-a of rifaximin.

8. An improved process for the preparation of Rifaximin, comprising of:

a) Adding Rifamycin 0 compound of formula-2 to the mixture of water & alcohol solvent,

b) adding 2-Amino-4-methyl pyridine compound of formula-3 to the above reaction mixture,

c) stirring the reaction mixture at a suitable temperature,

d) cooling the reaction mixture,

e) filtering the reaction mixture,

f) drying the obtained compound to get rifaximin.

9. The process according to claim-8, wherein in step-a) the alcohol solvent is methanol, ethanol, isopropanol, butanol; and the mixture of alcohol and water is used in the ratio between about 5.5:4.5 to 6:4; in step-c) a suitable temperature is selected from about 15 to 30°C; in step-d) the reaction mixture was cooled to about 0-10°C.

10. The process according to claims 8 to 9, wherein in step-a) the alcohol solvent is methanol; and the mixture of alcohol and water is used in the ratio between about 6:4; in step-c) a suitable temperature is selected from about 20 to 25°C; in step-d) the reaction mixture was cooled to about 0-5°C.