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Title:
PROCESS FOR THE PREPARATION OF RIFAXIMIN CRYSTALLINE FORM
Document Type and Number:
WIPO Patent Application WO/2018/178777
Kind Code:
A1
Abstract:
The present invention relates to an improved process for the preparation Crystalline Form G2 of Rifaximin of Formula (I). The invention also relates to crystalline Form G2 of Rifaximin (I) obtained by the process of the present invention, the said Form G2 being substantially pure, stable and characterized by X-ray powder diffraction pattern comprising peaks selected from 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 1 1.5, 1 1.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 2θ. The invention also relates to crystalline Form Gl of Rifaximin (I) obtained by the process of the present invention, the said Form Gl being substantially pure, stable and characterized by X-ray powder diffraction pattern comprising peaks selected from 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 1 1.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ± 0.2° 2θ.. The present invention further relates to process for the preparation of substantially pure Rifaximin comprising recrystallization in alcohol or in mixture of water and alcoholic solvents.

Inventors:
VNKV VETUKURI PRASADA RAJU (IN)
VEDANTHAM RAVINDRA (IN)
BOINI AMBAIAH (IN)
GILLA GOVERDHAN (IN)
KANUPARTHY RAMA SESHAIAH (IN)
CHATURVEDI AKSHAY KANT (IN)
Application Number:
PCT/IB2018/051137
Publication Date:
October 04, 2018
Filing Date:
February 23, 2018
Export Citation:
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Assignee:
GRANULES INDIA LTD (IN)
International Classes:
C07D498/22
Domestic Patent References:
WO2017021975A12017-02-09
Foreign References:
US20120116071A12012-05-10
Download PDF:
Claims:
We Claim:

1 ) A process for the preparation of crystalline Form G2 of Rifaximin (I) characterized by X- ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 1 1.0, 1 1.5, 1 1.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 2Θ comprising the steps of:

a. providing a suspension of Rifaximin in water at temperature ranging between 20- 100°C;

b. maintaining the suspension for a time duration ranging between 1 -6 hours at a temperature ranging between 30 - 60°C;

c. cooling the suspension and stirring it for a time duration ranging between 1 -10 hours at a temperature ranging between 0°C to 40°C;

d. separating crystalline Rifaximin followed by drying at temperature range between 30-80°C.

2) The process for the preparation of crystalline Form G2 of Rifaximin (I), according to claim 1 , wherein Rifaximin in step a. utilized as crystalline form or amorphous form.

3) Crystalline Form G2 of Rifaximin (I) characterized by

a. X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 1 1.0, 11.5, 11.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 20.

b. Melting Point: 212-215°C;

c. Water content: < 6%;

d. Purity: > 99.5% (by HPLC).

4) Crystalline Form G2 of Rifaximin according to claim 3, prepared by process comprising the steps of: a. reacting Rifamycin O with 2-amino-4-methylpyridine in mixture of ethanol and water at a temperature 25-100°C for a time duration ranging between 5-15 hours;

b. maintaining the step a. suspension between 8-12 hours at temperature 25-35°C followed by separating crude Rifaximin;

c. dissolving crude Rifaximin in mixture of water and ethanol at 60 - 80°C;

d. cooling the solution at temperature 25-45°C followed by seeding the solution;

e. cooling the solution at temperature ranging between -10 to 10°C and maintaining the solution for 10-12 hours;

f. separating the pure Rifaximin.

g. providing a suspension of crystalline Rifaximin in water at temperature ranging 20- 100°C;

h. maintaining the suspension for a time duration ranging between 1 -6 hours at a temperature ranging between 30 - 60°C;

i. cooling the suspension and stirring it for a time duration ranging between 1-10 hours at a temperature ranging between 0°C to 40°C;

j. separating crystalline Rifaximin followed by drying at temperature range ranging between 30-80°C.

5) A process for the preparation of crystalline Form Gl of Rifaximin (I) characterized by X-ray powder diffraction angle peaks at 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 11.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ± 0.2° 2Θ comprising the steps of:

a. providing a solution of Rifaximin in mixture of water and alcoholic solvents at 30-100°C; b. maintaining the solution for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 100°C; c. cooling the solution and stirring it for a time duration ranging between 5-20 hours at a temperature ranging between 20°C to 40°C;

d. separating crystalline Rifaximin followed by drying in the temperature range between 30- 80°C.

6) Crystalline Form Gl of Rifaximin (I) according to claim 5, characterized by

a. X-ray powder diffraction angle peaks at 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 1 1.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ± 0.2° 20;

b. Water content: 2.5 - 4 %;

c. Purity: > 99.5% (by HPLC).

7) The process for the preparation of crystalline Form Gl of Rifaximin (I), according to claim 5, wherein alcoholic solvent is selected from C1 -C4 alcohol wherein C1-C4 alcohol selected from methanol, ethanol, isopropanol, propanol, n-butanol or mixture thereof.

8) The process for preparing crystalline Form Gl of Rifaximin (I), according to claim 5, wherein mixture of water & alcohol are in the ratio of 1 : 10 (v/v).

Description:
PROCESS FOR THE PREPARATION OF RIFAXIMIN CRYSTALLINE FORM

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation Crystalline Form G2 of Rifaximin of Formula (I).

The invention also relates to crystalline Form G2 of Rifaximin (I) obtained by the process of the present invention, the said Form G2 being substantially pure, stable and characterized by X-ray powder diffraction pattern comprising peaks selected from 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 1 1.5, 1 1.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 2Θ.

The invention also relates to crystalline Form Gl of Rifaximin (I) obtained by the process of the present invention, the said Form Gl being substantially pure, stable and characterized by X-ray powder diffraction pattern comprising peaks selected from 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 1 1.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ± 0.2° 2Θ.

The present invention further relates to process for the preparation of substantially pure Rifaximin comprising recrystallization in alcohol or mixture of water and alcoholic solvents.

BACKGROUND OF THE INVENTION

Rifaximin of formula 1, is chemically known as (2S, 16Z, 18H, 20S, 2 IS, 22R, 23R, 24R, 25S, 26S, 27S, 28E)-5, 6, 21 , 23, 25-pentahydroxy- 27-methoxy-2, 4, 1 1 , 16, 20, 22. 24, 26-octamethyl-2,7-(epoxypentadeca-[l ,1 1 ,13]trienimino)- benzofuro[4, 5-e]- pyrido[l, 2-(alpha)]-benzimidazole-l,15(2H)dione, 25-acetate.

Rifaximin was first described and claimed in Italian patent IT 1 154655 and U.S. Pat. No.4,341 ,785. These patents disclose a process for the preparation of Rifaximin and a method for the crystallisation thereof. U.S. Pat. No. 4,179,438 discloses a process for the preparation of 3-bromorifamycin S which comprises reaction of rifamycin S with at least two equivalents of bromine, per one mole of rifamycin S in the presence of at least one mole of pyridine per each equivalent of bromine and in the presence of ethanol, methanol or mixtures thereof with water at a temperature not above the room temperature. The process for the preparation of Rifaximin is as depicted in scheme I given below:

Hiieg«ate<j Rffamyein-S

R!famycin-S

Scheme I Egidio Marchi et.al. in the patent US 4,341 ,785 discloses a process for the preparation of and a method for crystallization of rifaximin using suitable solvents. However, this patent does not mention the polymorphism of rifaximin.

Vincenzo Cannata et.al. in the patent US 4,557,866 discloses process for the synthesis of pyrido- imidazo-rifamycins. The process comprises reacting the rifamycin O with a 2- aminopyridine which is shown as below Scheme II. This patent also discloses purification of Rifaximin by performing crystallization of crude Rifaximin from a 7:3 mixture of ethyl alcohol and water and followed by drying under vacuum. The crystalline form details are not disclosed.

CMs Oils

Mamyefc-O

Scheme II

G.C.Viscomi et.al. in the patent US 7,045,620 discloses that the polymorph called rifaximin form a is characterized by a water content lower than 4.5%, preferably between 2.0%) and 3.0% and further by powder X-ray diffractogram which shows peaks at the values of the diffraction angles 2Θ of 6.6°; 7.4°; 7.9°; 8.8°; 10.5°; 11 ; 1 1.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.4°; 22.1 °. The other polymorph called rifaximin form β 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 2Θ 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 γ 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 2Θ of 5.0°; 7.1 °; and 8.4°.

G.C.Viscomi et.al. in US 7,923,553 discloses process for the preparation polymorphous form rifaximin a, rifaximin β & rifaximin γ. G.C.Viscomi et.al. in US 8, 193, 196 discloses two polymorphic forms of Rifaximin, designated δ characterized by x-ray powder diffraction pattern peaks at about 5.7°±0.2, 10.8°±0.2, 12.1 °±0.2, and 17.0°±0.2, 2Θ and ε respectively. Form δ has water content within the range from 2.5 to 6% by weight (preferably from 3 to 4.5%) and characterized by x-ray powder diffraction pattern peaks at about 8.2°±0.2, 12.4°±0.2, and 16.3°±0.2 2Θ.

Karen S. Gushurst et.al. in the patent US 8,067,429 describes Form ζ characterized by x-ray powder diffraction pattern peaks at about 4.7 (doublet), 7.6 (doublet), and 9.5° 2-Θ; or 4.7 (doublet), 7.3, and 8.2° 2-Θ; or 7.6 (doublet), 8.6, and 10.5° 2-Θ; or 8.2, 8.6, and 9.5° 2-Θ; or 10.2 (triplet), 12.6 (quintet), and 13.2° (doublet) 2-Θ; or 7.3, 10.5, and 12.9° (doublet) 2-Θ; or 7.3, 7.6 (doublet), 8.2, 8.6° 2-Θ; or 4.7 (doublet), 7.3, 7.6 (doublet), 9.5, and 10.5° 2-Θ; or 8.2, 8.6, 9.5, 10.2 (triplet), and 10.5° 2-Θ; or 8.6, 9.5, 10.2 (triplet), 10.5, and 1 1 .2 (doublet) 0 2-0; or 4.7 (doublet), 6.3, 6.4, 7.3, 7.6 (doublet), 8.2, 8.6, 9.5, 10.2 (triplet), 10.5, 11.2 (doublet), 11.9 (doublet), 12.2 (weak), 12.6 (quintet), 12.9 (doublet), 13.2 (doublet) 0 2-Θ and Form η exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in 20° (+/-0.20 0 Θ) at 6.1, 7.3, and 7.5° 2-0; or 6.1, 7.3, and 7.9° 2-0; or 6.1, 7.3, and 8.8° 2-Θ; or 6.1, 7.3, and 12.7° 2-0; or 6.1, 7.5, and 8.8° 2-0; or 6.1, 7.5, and 7.9° 2-0; or 5.3, 6.1, and 7.3° 2-0; or 5.3, 6.1, and 7.9° 2-0; or 5.3, 6.1, and 12.7° 2-0; or 5.3, 6.1, and 7.5° 2-0; or 5.3, 6.1 , and 8.8° 2-0; or 6.1, 7.3, 7.5, 7.9, 8.8, and 12.7° 2-0; or 5.3, 6.1, 7.3, 7.5, 7.9, 8.8, 12.7° 2-0; or 5.3, 6.1, 7.3, 7.9, 8.8, and 12.7° 2-0; or 5.3, 6.1, 7.3, 7.5, 8.8, and 12.7° 2-0; or 5.3, 6.1, 7.3, 7.5, 7.9, 8.8, and 12.7° 20 and polymorph Form ι exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in 20° (+/-0.20 0 0) at 5.9+0.1 ; 7.9+0.1 ; 9.0±0.1; or 12.7±0.1 ; 13.9±0.1 ; 14.9±0.1 ; or 5.9±0.1; 7.9±0.1; 12.7±0.1 ; or 5.9±0.1 ; 9.0±0.1; 12.7±0.1 ; or 5.9±0.1 ; 13.9±0.1 ; 14.9+0.1 ; or 5.9±0.1 ; 7.9±0.1; 14.9±0.1 ; or 9.0±0.1 ; 12.7±0.1 ; 14.9±0.1 ; or 5.9±0.1; 7.9±0.1; 9.0±0.1 ; 14.9±0.1 ; or 5.9±0.1; 7.9±0.1; 9.0±0.1 ; 12.7±0.1; or 5.9±0.1 ; 7.9±0.1; 9.0±0.1 ; 12.7±0.1 ; 13.9±0.1 ; 14.9+0.1 and mesylate Form of rifaximin exhibits X-ray powder diffraction pattern having characteristic peaks expressed in 20° (+/-0.20 0 0) at 5.34±0.10; 8.46±0.10; 10.95±0.10; or 5.34±0.10; 6.93±0.10; 8.46±0.10; or 5.34±0.10; 10.95±0.10; 16.23±0.10; 17.70±0.10; or 7.41±0.10; 8.46±0.10; 10.62±0.10; 10.95±0.10; or 16.23±0.10; 17.70+0.10; 17.94±0.10; 19.29±0.10; 22.77+0.10; or 16.23±0.10; 17.70±0.10; 19.29±0.10; 22.77±0.10; or 5.34±0.10; 16.23+0.10; 17.70±0.10; or 5.34±0.10; 6.93+0.10; 7.41+0.10; 8.46+0.10; 10.62+0.10; 10.95+0.10; 16.23+0.10; 17.70+0.10; 17.94+0.10; 19.29+0.10; 22.77+0.10.. Further this patent discloses β-1, β-2, ε-dry and amorphous forms of Rifaximin. Kiran Kumar Kothakonda et.al. in the patent US7709634 B2 discloses amorphous form of Rifaximin.

Vetukuri Vnkv et. al. in the patent application WO/2015/159275 describes crystalline form G of Rifaximin, characterised by powder X- ray diffraction pattern having characteristic peaks at about 5.9, 7.3, 7.9 and 8.6 + 0.2° 2Θ.

Vetukuri Vnkv et. al. in the patent application IN 201741007377 describes crystalline form GR of Rifaximin, characterised by powder X- ray diffraction pattern having characteristic peaks at about 5.5, 6.6, 6.8, 7.5, 7.7, 1 1.8, 13.3 and 15.4 ± 0.2° 20.

Rifaximin is an important therapeautic agent for the treatment of patients with travelers' diarrhea (TD) and the reduction in risk of overt hepatic encephalopathy (HE) recurrence. Additional and improved ways of preparing new polymorphic forms of Rifaximin may provide an opportunity to improve the drug performance characteristics of such products. Hence, there exists a need for the further development of new stable crystalline form of Rifaximin and commercially viable processes for its preparation, which may be up scalable, safer for handling, less time consuming and with better and consistent quality parameters.

The inventors of this application have developed a process which provides a stable polymorphic crystalline form of Rifaximin, designated as Form G2 which is stable and thus has easy handling properties. The process of this invention provides the crystalline Form G2 of Rifaximin in substantially pure form.

The inventors of this application have also developed a process which provides a stable polymorphic crystalline form of Rifaximin, designated as Form Gl which is stable and thus has easy handling properties. The process of this invention provides the crystalline Form Gl of Rifaximin in substantially pure form.

SUMMARY OF INVENTION

Particular aspects of the present invention relates to a process for the preparation of crystalline Form G2 of Rifaximin (1). Crystalline Form G2 of Rifaximin obtained by the process of the present invention is found to be substantially pure and stable.

In one aspect of the present invention, it relates to process for the preparation of crystalline Form G2 of Rifaximin (I), characterized by X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 1 1.0, 1 1.5, 1 1.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 20 comprising the steps of

a. providing a suspension of Rifaximin in water at temperature ranging 20- 100°C;

b. maintaining the suspension for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 60°C;

c. cooling the suspension and stirring it for a time duration ranging between 1-10 hours at a temperature ranging between 0°C to 40°C;

d. separating crystalline Rifaximin followed by drying at temperature range

between 30-80°C.

In another aspect of the present invention relates to crystalline Form G2 of

Rifaximin, which is characterized by

a. X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 11.5, 11.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 20.

b. Melting Point: 212-215°C

c. Water content: < 6%

d. Purity: > 99.5% (by HPLC).

In another aspect of the present invention relates to process for the preparation of crystalline Form Gl of Rifaximin (I) characterized by X-ray powder diffraction angle peaks at 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 1 1.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ± 0.2° 20 comprising the steps of: a. providing a solution of Rifaximin in mixture of water and alcoholic solvents at 30-

100°C;

b. maintaining the solution for a time duration ranging between 1 -6 hours at a temperature ranging between 30 - 100°C;

c. cooling the solution and stirring it for a time duration ranging between 5-20 hours at a temperature ranging between 20°C to 40°C;

d. separating crystalline Rifaximin followed by drying in the temperature range between 30-80°C. Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline Form G2 of Rifaximin.

Fig. 2 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline crystalline Form Gl of Rifaximin (I).

Fig. 3 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline Form G of Rifaximin (I).

Fig 4 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline

Form GR of Rifaximin (1).

Fig 5 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline Amorphous form of Rifaximin (I). DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention provide a reproducible and efficient process for the preparation of crystalline Form G2 of Rifaximin (I). Crystalline Form G2. of Rifaximin obtained by the process of the present invention is found to be substantially pure and stable.

In one embodiment of the present invention, it relates to process for the preparation of crystalline Form G2 of Rifaximin (I), characterized by X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 11.5, 1 1.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 20 comprising the steps of: a. providing a suspension of Rifaximin in water at temperature ranging 20- 100°C;

b. maintaining the suspension for a time duration ranging between 1 -6 hours at a temperature ranging between 30 - 60°C;

c. cooling the suspension and stirring it for a time duration ranging between 1-10 hours at a temperature ranging between 0°C to 40°C;

d. separating crystalline Rifaximin followed by drying at temperature range

between 30-80°C.

Individual step of the embodiment is detailed herein below.

According to present invention, in the step a of the present invention, water is added to Rifaximin at temperature 20-100°C to obtain suspension of Rifaximin. Preferably, suspension is prepared at temperature 40-45°C.

In one of the particular embodiment of the present invention, Rifaximin utilized in step a. is in the form of crystalline form or amorphous form.

In the step b of the present invention, suspension is maintained for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 60°C. Preferably, suspension is maintained at temperature 40-45°C for 2 hours.

In the step c of the present invention, suspension is cooled and stirred for a time duration ranging between 1-10 hours at a temperature ranging between 0°C to 40°C. Preferably, suspension is cooled 25-35°C and stirred for 2 hours.

In the step d of the present invention, separating Rifaximin by various conventional methods like distillations, filtering, drying, ccntrifugation etc. followed by drying the separated compound at a temperature 30-80°C to give crystalline Form G2, preferably at temperature until a water content with below 4.0%.

In one of the embodiment of the present invention, relates to process for the preparation of crystalline Form G2 of Rifaximin (I), characterized by X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 11.5, 11.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 20 comprising the steps of:

a. reacting Rifamycin O with 2-amino-4-methylpyridine in a mixture of ethanol and water at a temperature 25-100°C for 5-15 hours;

b. maintaining the step a. suspension between 8-12 hours at temperature 25-35°C followed by separating crude Rifaximin;

c. dissolving crude Rifaximin in mixture of water and ethanol at 60 - 80°C; d. cooling the solution at temperature 25-45°C followed by seeding the solution; e. cooling the solution at temperature ranging between -10 to 10°C and maintaining the solution for 10-12 hours;

f. separating the pure Rifaximin.

g. providing a suspension of crystalline Rifaximin in water at temperature ranging 20-

100°C;

h. maintaining the suspension for a time duration ranging between 1 -6 hours at a temperature ranging between 30 - 60°C;

i. cooling the suspension and stirring it for a time duration ranging between 1-10 hours at a temperature ranging between 0°C to 40°C;

j. separating crystalline Rifaximin followed by drying at temperature range ranging between 30-80°C.

Individual steps of the embodiment are detailed herein below.

Accordingly, in the step of reacting Rifamycin O with 2-amino-4-methylpyridine in a mixture of ethanol and water at a temperature 25-100°C for 8 hours, it comprises the source of Rifamycin O that may be obtained according lo any of prior disclosed processes. The solution obtained is maintained for 12 hours at temperature 25-35°C followed by separating crude Rifaximin. Crude Rifaximin obtained is dissolved in mixture of water and ethanol at temperature ranging between 60-80°C. The solution obtained is cooled at temperature 25- 45 °C and followed by seeded with crystalline form of Rifaximin. The solution obtained is cooled at temperature -10 to 10°C and maintained for 12 hours. Preferably, the solution is cooled at -5 to 5°C for 12 hours. The solid obtained is separated to obtain pure Rifaximin.

In one of the particular embodiment of the present invention, step f of the present invention can be performed by separating crystalline Rifaximin (I) by various conventional methods like distillations, filtering, drying, centrifugation etc. to obtain Form G2 of Rifaximin (I).

In the step g of the present invention, water is added to crystalline Rifaximin at temperature 20-100°C to obtain suspension of Rifaximin. Preferably, suspension is prepared at temperature 40-45°C.

In the step h of the present invention, suspension is maintained for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 60°C. Preferably, suspension is maintained at temperature 40-45 °C for 2 hours. In the step i of the present invention, suspension is cooled and stirred for a time duration ranging between 1-10 hours at a temperature ranging between 0°C to 40°C. Preferably, suspension is cooled 25-35°C and stirred for a 2 hours.

In the step j of the present invention, separating Rifaximin by various conventional methods like distillations, filtering, drying, centrifugation etc. followed by drying the separated compound at a temperature 30-80°C to give crystalline Form G2. Drying the final crystalline form G2 at a temperature until a water content lower than 6.0% wherein the X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 1 1.0, 11.5, 11.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ± 0.2° 2Θ.

In one of the particular embodiment of the present invention that the production of rifaximin form G2 depends on drying conditions such that water remaining at the end, lower than 6.0%), and not from the experimental conditions of pressure and temperature at which this critical limit of water percentage is achieved.

In another embodiment of the present invention provides a process for preparation of Form G2 of Rifaximin (I) having water content in range of 2 - 6% as determined by the Karl Fischer method.

In another embodiment of the present invention relates to process for the preparation of crystalline Form Gl of Rifaximin (I) characterized by X-ray powder diffraction angle peaks at 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 1 1.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ± 0.2° 2Θ comprising the steps of:

a. providing a solution of Rifaximin in mixture of water and alcoholic solvents at 30- 100°C;

b. maintaining the solution for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 100°C;

c. cooling the solution and stirring it for a time duration ranging between 5-20 hours at a temperature ranging between 20°C to 40°C;

d. separating crystalline Rifaximin followed by drying in the temperature range between 30-80°C.

Individual steps of the embodiment are detailed herein below.

In a one of the particular embodiment according to present application, making solution is in the temperature range of 30 - 100°C.

In one of the particular embodiment according to present invention in step a, C1-C4 alcoholic solvents are selected from methanol, ethanol, isopropanol, propanol, n-butanol. In another embodiment of the present invention provides process for the preparation of substantially pure Rifaximin comprising recrystallization using alcohol or mixture of water and alcoholic solvent wherein mixture of water and alcoholic solvents is in the ratio of 1 : 10 (v/v).

In a particular embodiment of the present invention, Rifaximin utilized in step a as crystalline form or amorphous form.

In another embodiment of the present invention Crystalline form of Rifaximin is any of the crystalline form known in the prior art.

In the Step b of present embodiment, maintaining the solution for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 100°C

In one of the particular embodiment of the present invention, step b. is maintained for 2 hours at temperature ranging between 75-85°C.

In the Step c of present embodiment, cooling the solution and stirring it for a time duration ranging between 5-30 hours at a temperature ranging between 20°C to 40°C.

In one of the particular embodiment of the present invention, step c maintained for 20 hours at temperature 25-35°C.

In one of the particular embodiment of the present invention, step d of the present invention can be performed by separating crystalline Rifaximin (I) by various conventional methods like distillations, filtering, drying, eentrifugation etc. to obtain Form Gl of Rifaximin (I). Drying the final crystalline form G2 at a temperature until a water content near 4.0% wherein the X-ray powder diffraction angle peaks at 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 1 1.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ± 0.2° 2Θ.

In one of the particular embodiment of the present invention crystalline form of Rifaximin is selected from Crystalline Form Gl, Crystalline Form G and Crystalline Form GR.

In one of the embodiment of the present invention provides crystalline Form Gl of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 2.

In one of the embodiment of the present invention provides crystalline Form G of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 3. In one of the embodiment of the present invention provides crystalline Form GR of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 4.

In one of the embodiment of the present invention provides Amorphous Form of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 5.

The remaining steps of the embodiment shall be construed in line with the exemplified disclosure.

Substantially pure crystalline Form G2 of Rifaximin (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% and preferably greater than 99.5%. The purity of the Form G2 of Rifaximin (I) samples was measured using Chromatography, Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.

Pharmaceutically acceptable excipients used in the compositions of crystalline Form G2 of Rifaximin (I) of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The invention was further defined by reference to the following examples describing in detail by the preparation of the compounds of the 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. EXAMPLES:

Example 1: Process for the preparation of Form G2 of Rifaximin using Rifamycin O:

50g of Rifamycin O and 21.5g of 2-amino-4-methyl pyridine, and (130.0 ml) of purified water and (100.0 ml) of ethanol were heated to 40-45°C. The resultant suspension was stirred at 40-45°C for 8-9 hours and then cooled and stirred at 25-35°C for 10-12 hours. The solid separated was filtered and washed with (2.5 ml) of ethanol and (2.5 ml) of purified water followed by drying at 55-65 °C for 5-8 hours to afford 46.9 g of rifaximin crude. lOg of Rifaximin crude, 70 ml of ethanol and 30 ml of purified water were heated to 75-85° C. The resultant suspension was stirred at 75-85° C about for about 2 hours and then cooled to 50- 60° C and passed through a micro filter for to make particle free. The solution was further cooled to about 25-35 °C and seeded with rifaximin, stirred for 2-3 hours. The resultant mass was further cooled to 0±5°C and stirred for 10-12 hours. The solid separated was filtered and washed with the chilled mixture (3.5 mL) of ethanol and (1.5 mL) of water. The solid obtained was dried at about 60-65°C for about 6-8 hours to afford 7.5 g of rifaximin as crystalline form. 7.5 grams of crystalline Rifaximin and 30.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated al 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35°C and stirring continued for another 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain Rifaximin Form G2.

Water content by KF: 2.96%

Purity by HPLC: 99.60%

Example 2: Process for the preparation of Form G2 of Rifaximin using Rifamycin S: lOOg of Rifamycin S was charged into toluene (1000 ml) and cooled to -15 to -5°C. To this reaction mixture was added slowly of mixture ethanol (500.0 ml), 40.0 gm of molecular bromine and 40.0 gm of pyridine and maintained the reaction mass for 15-30 minutes at same temperature. Charge 200.0 mL of chilled aqueous HC1 at below 0°C then separate the layers after stirring continued for 10-15 minutes. Isolated the material by using 1580.0 mL of 0.5N HC1 and after 2-3 hours maintenance the resulting of 3-BromoRifamycin S. The solid obtained was added to a mixture of dichloromethane (1000.0 mL) and 33.0 gm of 2-amino-4- methyl pyridine and stirring continued for 5-7 hours at 5-15 °C. Raise the temperature to 25- 35°C and add 25.0 gm of Ascorbic acid was charged to the reaction mixture and maintained for 6-8 hours at 25-35° C to give crude Rifaximin compound which was isolated by washing the with 400.0 mL of water, 0.5N HC1 (2x300.0 mL) solution and water (2X400.0 mL) followed by distillation of dichloromethane and isolated the material by using 30% aq. Ethanol solution with recrystallization technique to give substantially pure Rifaximin (60.0 g). lOg of Rifaximin crude, 70 ml of ethanol and 30 ml of purified water were heated to 75- 85° C. The resultant suspension was stirred at 75-85° C about for about 2 hours and then cooled to 50-60° C and passed through a micro filter for to make particle free. The solution was further cooled to about 25-35 °C and seeded with rifaximin, stirred for 2-3 hours. The resultant mass was further cooled to 0±5°C and stirred for 10-12 hours. The solid separated was filtered and washed with the chilled mixture (3.5 mL) of ethanol and (1.5 mL) of water. The solid obtained was dried at about 60-65°C for about 6-8 hours to afford 7.5 g of rifaximin as crystalline form. 7.5 grams of crystalline form of Rifaximin and 30.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated at 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35°C and stirring continued for another 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain to obtain Rifaximin Form G2.

Water content by KF: 3.45%

Purity by HPLC: 99.67% Example-3: Process for the preparation of Rifaximin Form Gl:

10.0 grams of Rifaximin Form G and 45.0 mL of aqueous ethanol with the ratio of 7:3 added at room temperature into a three-necked flask equipped with mechanical stirrer, thermometer and condenser, then the suspension is heated at 75-85° C. until complete dissolution of the solid and it is kept under stirring at this temperature for 1-2 hours, then cooled the solution to 25-35° C during 10-14 hours. Maintain the suspension for 20 hours under stirring at 25-35° C after which product was separated by filtration. The solid washed with mixture of 1.5 mL of water and 3.5 mL of ethanol and dried under vacuum at 60-65° C until water content obtained is near 4% to obtain Rifaximin Form Gl .

Water content by KF: 3.81%

Purity by HPLC: 99.85%

Example-4: Process for the preparation of Rifaximin Form Gl:

10.0 grams of Rifaximin Form GR and 45.0 mL of aqueous ethanol with the ratio of 7:3 added at room temperature into a three-necked flask equipped with mechanical stirrer, thermometer and condenser, then the suspension is heated at 75-85° C. until complete dissolution of the solid and it is kept under stirring at this temperature for 1-2 hours, then cooled the solution to 25-35° C during 10-14 hours. Maintain the suspension for 20 hours under stirring at 25-35° C after which product was separated by filtration. The solid washed with mixture of 1 .5 mL of water and 3.5 mL of ethanol and dried under vacuum at 60-65" C until constant weight obtaining 6.9 g of rifaximin Form-Gl with below 4.5% of water content.

Water content by KF: 3.02%

Purity by HPLC: 99.92% Example-5: Process for the preparation of Rifaximin Form G2:

10.0 grams of Rifaximin Form Gl and 50.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated at 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35°C and stirring continued for another 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 33-38° C until water content obtained is near 4% to obtain Rifaximin Form G2.

Purity by HPLC: 99.83%

ExampIe-6: Process for the preparation of Rifaximin Form G2:

10.0 grams of Rifaximin Form G and 50.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated at 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35°C and stirring continued for another 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain to obtain Rifaximin Form G2.

Water content by KF: 3.45%

Purity by HPLC: 99.67%

Example-7: Process for the preparation of Rifaximin Form G2:

10.0 grams of Rifaximin Form G and 50.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated at 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35°C and stirring continued for another 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain Rifaximin Form G2.

Water content by KF: 2.96%

Purity by HPLC: 99.60%

ExampIe-8: Process for the preparation of Rifaximin Form G2:

10.0 grams of Rifaximin Form GR and 50.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated at 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35°C and Stirling continued for another 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to to obtain Rifaximin Form G2.

Purity by HPLC: 99.64% Example-9: Process for the preparation of Rifaximin Form G2:

10.0 grams of Rifaximin Form G and 50.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated at 70-75° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35° C and stirring continued for another 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain Rifaximin Form G2.

Water content by KF: 3.39%

Purity by HPLC: 99.74% ExampIe-10: Process for the preparation of Rifaximin Form G2:

10.0 grams of Rifaximin Form G and 50.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is stirred at 25-35° C and kept under stirring for 3 hours. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain Rifaximin Form G2.

Water content by KF: 3.63%

Purity by HPLC: 99.75%

Example-11: Process for the preparation of Rifaximin Form G2:

10.0 grams of Rifaximin Form G and 50.0 mL of water into a three-necked flask equipped with mechanical stiner, thermometer and reflux condenser, then the suspension is heated at 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 0-5° C and stirring continued for extra 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain Rifaximin Form G2.

Water content by KF: 2.85%

Purity by HPLC: 99.55% Example-12: Process for the preparation of Rifaximin Form G2:

10.0 grams of Amorphous form of Rifaximin and 50.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated at 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35°C and stirring continued for another 1 hour. The product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain Rifaximin Form G2.

Purity by HPLC: 99.47%

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 with non-limiting scope. 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 with respect to the invention scope.