CLIAMS:We claim:
1) A process for the preparation of Rifaximin comprising the steps of :
a) reacting rifamycin S with 2-amino-4-methylpyridine in the presence of iodine, acetic acid and acetonitrile at about 30°C for about 30 hours; and
b) obtaining resulted rifaximin as residue; and
c) suspending rifaximin residue in a solvent or mixture of solvents; and
d) heating the suspension of step (c) to about 75°C to obtain a solution; and
e) cooling the solution of step (d) to about 45°C; and
f) optionally seeding the solution of step (e) with seed crystal; and
g) cooling the suspension of step (f) to about 25°C for about 2 hours; and
h) cooling the mass of step (g) further to about 5°C for about 3 hours; and
i) recovering the solid precipitated in step (h) by conventional methods; and
j) drying the solid obtained in step (i) at about 50°C for about 10 hours to afford pure rifaximin.

2) The process of claim 1, wherein the reaction in step (a) is carried out at temperature from about 25°C to about 45°C, preferable at about 30°C and wherein the time period required is from about 20 to about 35 hours, preferably from about 28 to about 30 hours.

3) The process of claim 1, wherein the solvents that can be used in step (c) is selected from water, alcohols selected from methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, amyl alcohol, tertiary butyl alcohol or a mixture thereof at various proportions without limitation, preferably a mixture of ethanol and water.

4) The process of claim 1, wherein the temperature required for obtaining solution in step (d) is from about 60°C to about 75°C or the boiling point of the solvent or mixture of solvents used, preferably from about 65°C to about 75°C.

5) The process of claim 1, wherein the solution in step (e) is cooled to a temperature from about 40°C to about 60°C, preferably to about 50°C.

6) The process of claim 1, wherein the reaction mass in step (g) is cooled to a temperature of about 20°C to about 35°C, preferably to about 25°C and wherein the time period is about 30 mins to about 4 hours, preferably for about 2 hours.

7) The process of claim 1, wherein the reaction mass in step (h) is further cooled to a temperature of about -10°C to about 10°C, preferably to about 5°C and wherein the time period of about 30 minutes to about 5 hours, preferably for about 3 hours.

8) The process of claim 1, wherein the rifaximin obtained is dried at temperature from about 35°C to about 70°C in the presence or absence of vacuum, preferably at about 50°C under vacuum and wherein time period required is from about 5 hours to about 15 hours, preferably 10 hours.

9) A process for the preparation of rifaximin comprising the steps of:
i) providing rifaximin in a solvent or mixture of solvents; and
ii) heating the suspension of step (i) to about 65°C to obtain a solution; and
iii) cooling the solution of step (ii) to about 50°C; and
iv) optionally filtering the solution of step (iii) on celite; and
v) cooling the solution of step (iv) further to about 35°C for about 3 hours; and
vi) cooling the mass of step (v) further to about 5°C for about 12 hours; and
vii) recovering the solid precipitated in step (vi) by conventional methods to afford pure rifaximin.

10) The process of claim 9, wherein the solvents that can be used in step (i) is selected from water, alcohols selected from methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, amyl alcohol, tertiary butyl alcohol or a mixture thereof at various proportions without limitation, preferably a mixture of ethanol and water.

11) The process of claim 9, wherein the temperature for obtaining solution in step (ii) can be from about 55°C to about 70°C or the boiling point of the solvent or mixture of solvents used, preferably from about 60°C to about 65°C.

12) The process of claim 9, wherein the solution in step (iii) is cooled to a temperature of about 45°C to about 55°C, preferably of about 50°C.

13) The process of claim 9, wherein the solution in step (v) is further cooled to a temperature of about 20°C to about 35°C, preferably of about 35°C and the time period of about 30 mins to about 5 hours, preferably for about 3 hours.

14) The process of claim 9, wherein the reaction mass in step (vi) is further cooled to a temperature of about -10°C to about 10°C, preferably to about 5°C and the time period of about 2 hours to about 15 hours, preferably for about 12 hours.

15) The processes of preceding claims, wherein the rifaximin obtained has purity greater than about 99.8 area %, total impurities less than about 0.5 area % and single maximum impurity less than about 0.1 area % by HPLC.
16) The processes of preceding claims, wherein the rifaximin obtained is characterised by powder X- ray diffraction pattern having characteristic peaks at about 5.9, 7.3, 7.9 and 8.6 + 0.2° 2?.

17) The processes of preceding claims, wherein the rifaximin obtained is further characterised by powder X ray diffraction pattern having characteristic peaks at about 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 substantially same as fig.1.

18) The processes of preceding claims, wherein the rifaximin obtained is further characterised by differential scanning calorimetry (DSC) having endothermic peak at 236.68°C with onset temperature of 221.6°C which is substantially same as fig.2.

19) Novel Rifaximin Form G characterised by powder X- ray diffraction pattern having characteristic peaks at about 5.9, 7.3, 7.9 and 8.6 + 0.2° 2?

20) Novel Rifaximin Form G further characterised by powder X ray diffraction pattern having characteristic peaks at about 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 substantially same as fig.1.
,TagSPECI: FORM 2

THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“IMPROVED PROCESSES FOR THE PREPARATION OF RIFAXIMIN”

Granules India Limited,
an Indian Company having its registered office at
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad (A.P) 500 081- India.

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to improved processes for the preparation of Rifaximin. Particularly, the present invention relates to improved processes for the preparation of Rifaximin from Rifamycin O and S. More particularly the present invention relates to a novel polymorph of Rifaximin and process for its preparation.

BACKGROUND OF THE INVENTION
Rifaximin is a broad-spectrum antibiotic belonging to the family of rifamycins and shows its antibacterial activity, in the gastrointestinal tract against localized bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn’s disease, and/or pancreatic insufficiency.
Rifaximin is marketed in the United States under the trade name Xifaxan® for the treatment of Travelers’ diarrhea and Hepatic Encephalopathy.
Rifaximin is structurally represented by compound of Formula I.

BRIEF DESCRIPTION OF THE RELATED ART
IT 1154655 and U.S. Patent. No. 4,341,785 describes Rifaximin and discloses a process for the preparation of Rifaximin, and a method for the crystallisation thereof. There is no disclosure on Rifaximin polymorphism.
The process for the preparation of Rifaximin is as depicted in scheme I given below:

Scheme -I
U.S.Patent No.4,557,866 discloses a process for one step synthesis of Rifaximin from Rifamycin O, which is shown in scheme II given below:

Scheme -II
US ‘866 patent also discloses purification of Rifaximin by performing crystallization of crude Rifaximin from a 7:3 mixture of ethyl alcohol/water followed by drying both under atmospheric pressure and under vacuum. The crystalline form which is obtained has not been characterized. However, the XRD pattern of product obtained as per the procedure of Example 9 of EP 0 161 534 B1 is provided during the examination of EP 1 557 421 B1.
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. 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 45-65°C, precipitation by adding water to form a suspension, filtering suspension and washing the resulted solid with demineralized water, followed by drying at room temperature under vacuum for a period of time between 2 and 72 hours. Crystalline forms a and ß are obtained by immediate filtration of suspension when temperature of reaction mixture is brought to 0°C and poorly crystalline form ? is obtained when the reaction mixture is stirred for 5-6 hours at 0°C and then filtered the suspension. In addition to above these forms are also characterized by specific water content. For a form water content should be lower than 4.5%, for ß form it should be higher than 4.5% and to obtain ? form, water content should be below 2%.
U.S.Patent No. 7,709,634 describes an amorphous form of Rifaximin which is prepared by dissolving Rifaximin in solvents such as alkyl esters, alkanols and ketones and precipitating by addition of anti-solvents selected from hydrocarbons, ethers or mixtures thereof.
U.S.Patent No. 8,193,196 describes two polymorphic forms of Rifaximin, designated d and e respectively. Form d has water content within the range from 2.5 to 6% by weight (preferably from 3 to 4.5%).
U.S.Patent No 8,067,429 describes a-dry, ß-1, ß-2, e-dry and amorphous forms of Rifaximin.
U.S. Patent No. 8,227,482 describes polymorphs Form µ, Form p, Form Omicron, Form Zeta, Form Eta, Form Iota and Form Xi of Rifaximin.
International application publications WO 2008/035109, WO 2008/155728, WO 2012/035544, WO 2012/060675, and WO 2012/156533 describes various amorphous or poorly crystalline forms of Rifaximin.
These polymorphic forms are obtained under different experimental conditions and are characterized by XRPD pattern.
The polymorphic forms of Rifaximin obtained from the prior art methods have specific water content. Transition between different polymorphic forms of Rifaximin occurs by drying or wetting of the synthesized Rifaximin. Hence, 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.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One polymorph may give rise to thermal behaviour different from that of another polymorph. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms.
The differences in the physical properties of different polymorphs results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphs of the same composition or complex. Hence there remains a need for polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale. The inventors of the present invention during their continuous efforts developed a novel polymorphic form of Rifaximin.
Objectives of the Invention
The main objective of the present invention is to provide improved processes for the preparation of Rifaximin.
Another objective of the present invention is to provide novel crystalline Form of Rifaximin which has better solubility, reproducibility, chemical and polymorphic stabilities.
Yet another objective of the present invention is to provide a process for the preparation of Rifaximin novel crystalline Form G.
SUMMARY OF THE INVENTION
The present invention relates to improved processes for the preparation of Rifaximin. Particularly, the present invention relates to improved processes for the preparation of Rifaximin from Rifamycin O and S. More particularly the present invention relates to a novel polymorph of Rifaximin and process for its preparation.
In one aspect, the present invention relates to an improved process for the preparation of Rifaximin comprising the steps of :
a) reacting rifamycin S with 2-amino-4-methylpyridine in the presence of iodine, acetic acid and solvent acetonitrile at about 30°C for about 30 hours; and
b) obtaining resulted rifaximin as residue; and
c) suspending rifaximin residue in a solvent or mixture of solvents; and
d) heating the suspension of step (c) to about 75°C to obtain a solution; and
e) cooling the solution of step (d) to about 45°C; and
f) optionally seeding the solution of step (e) with seed crystal; and
g) cooling the suspension of step (f) further to about 25°C for about 2 hours; and
h) cooling the mass of step (g) further to about 5°C for about 3 hours; and
i) recovering the solid precipitated in step (h) by conventional methods; and
j) drying the solid obtained in step (i) at about 50°C for about 10 hours to afford pure rifaximin.
In another aspect, the present invention relates to a process for the preparation of rifaximin comprising the steps of:
i) providing rifaximin in a solvent or mixture of solvents; and
ii) heating the suspension of step (i) to about 65°C to obtain a solution; and
iii) cooling the solution of step (ii) to about 50°C; and
iv) optionally filtering the solution of step (iii) on celite; and
v) cooling the solution of step (iv) further to about 5°C; and
vi) recovering the solid precipitated in step(v) by conventional methods to afford pure rifaximin.
BRIEF DESCRIPTION OF DRAWINGS
Fig.1: Represents X-ray powder diffraction pattern of Rifaximin novel crystalline Form G
Fig.2: Represents Differential Scanning Calorimetry (DSC) endotherm peak of
Rifaximin novel crystalline Form G.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to improved processes for the preparation of Rifaximin. Particularly, the present invention relates to improved processes for the preparation of Rifaximin from Rifamycin O and S. More particularly the present invention relates to a novel polymorph of Rifaximin and process for its preparation.
In one embodiment, the present invention provides an improved process for the preparation of Rifaximin comprising the steps of:
a) reacting rifamycin S with 2-amino-4-methylpyridine in the presence of iodine, acetic acid and acetonitrile at about 30°C for about 30 hours; and
b) obtaining resulted rifaximin as residue; and
c) suspending rifaximin residue in a solvent or mixture of solvents; and
d) heating the suspension of step (c) to about 75°C to obtain a solution; and
e) cooling the solution of step (d) to about 45°C; and
f) optionally seeding the solution of step (e) with seed crystal; and
g) cooling the suspension of step (f) further to about 25°C for about 2 hours; and
h) cooling the mass of step (g) further to about 5°C for about 3 hours; and
i) recovering the solid precipitated in step (h) by conventional methods; and
j) drying the solid obtained in step (i) at about 50°C for about 10 hours to afford pure rifaximin.
In preferred embodiments, the reaction time in step (a) can be from about 20 to about 35 hours, preferably from about 28 to about 30 hours is optimum.
The solvents that can be used in step (c) include but are not limited to water, alcohols selected from methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, amyl alcohol, tertiary butyl alcohol or a mixture thereof at various proportions without limitation. Preferably a mixture of ethanol and water is being used.
As used herein a mixture of solvents refers to a composition comprising more than one solvent.
Preferably, in step c) the residue is suspended in a mixture of solvents such as ethanol and water comprising at least 95% ethyl alcohol per volume.
The mixture of ethanol and water used for preparing a solution of rifaximin in step (c) typically may contain at least 95%, 96%, 97%, 97.5%, 98% or 99% of ethanol per volume.
The volumetric ratio in mixture of ethyl alcohol and water can be from about 1: 1 to 1:9. Preferably a ratio of 1:1 is used.
The temperature for obtaining solution in step (d) can be from about 60°C to about 75°C or the boiling point of the solvent or mixture of solvents used, preferably from about 65°C to about 75°C.
The solution of step (e) can be cooled from about 40°C to about 60°C, preferably to about 50°C.
In step (g) the reaction mass of step (f) is further cooled from about 20°C to about 35°C, preferably to about 25°C and maintained for a period of about 30 mins to about 4 hours, preferably for about 2 hours.
In step (h), the reaction mass of step (g) is further cooled from about -10°C to about 10°C, preferably to about 5°C and maintained for a period of about 30 mins to about 5 hours, preferably for about 3 hours.
The solid rifaximin is precipitated according to any known technique. Typically, the solids resulting from the reaction are precipitated by cooling the solution. Precipitating the solid is for example performed by cooling the solution to a temperature comprised between 0°C -15°C preferably between 5°C-10°C in a period of time comprised between 15 - 60 minutes preferably between 25 - 40 minutes.
In preferred embodiments the solution is cooled to 5°C in 60 minutes.
In another embodiment, the present invention provides a process for the preparation of rifaximin comprising the steps of:
i) providing rifaximin in a solvent or mixture of solvents; and
ii) heating the suspension of step (i) to about 65°C to obtain a solution; and
iii) cooling the solution of step (ii) to about 50°C; and
iv) optionally filtering the solution of step (iii) on celite; and
v) cooling the solution of step (iv) further to about 35°C for about 3 hours; and
vi) cooling the mass of step (v) further to about 5°C for about 12 hours; and
vii) recovering the solid precipitated in step (vi) by conventional methods to afford pure rifaximin.
The solvents that can be used in step (i) include but are not limited to water, alcohols selected from methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, amyl alcohol, tertiary butyl alcohol or a mixture thereof at various proportions without limitation. Preferably a mixture of ethanol and water is being used.
The temperature for obtaining solution in step (ii) can be from about 55°C to about 70°C or the boiling point of the solvent or mixture of solvents used, preferably from about 60°C to about 65°C.
The solution in step (iii) is cooled from about 45°C to about 55°C, preferably to about 50°C.
The reaction mass of step (v) is further cooled from about 20°C to about 35°C, preferably to about 35°C and maintained for a period of about 30 mins to about 5 hours, preferably for about 3 hours.
The reaction mass of step (vi) is further cooled from about -10°C to about 10°C, preferably to about 5°C and maintained for a period of about 2 hours to about 15 hours, preferably for about 12 hours.
The precipitated solids are recovered by conventional method such as filteration or centrifugation and the recovered solid rifaximin is washed.
Washing usually includes washing with a mixture of ethyl alcohol and water.
In an embodiment, the mixture of ethyl alcohol and water in a volumetric ratio 1 : 1 is being used. However other ratios are also contemplated within this present invention.
After washing, the rifaximin can be dried according to any appropriate method.
The rifaximin obtained by the above described processes of present invention may be dried under vacuum or under normal pressure, in the presence of drying agents or not and at any appropriate temperature. Preferably, drying is performed under vacuum at 50°C and for a period from about 5 hours to about 15 hours preferably 10 hours.
Advantageously, the processes of present invention provides rifaximin with high yield and purity.
Preferably, the yield of the rifaximin is greater than about 80%, or more, more preferably, the yield is greater than about 85%, most preferably, the yield is greater than about 90%, or more, by weight.
Advantageously, the rifaximin obtained by the processes described above has at purity preferably purity of at least about 99.5%, or more preferably at least about 99.9 area% and impurities less than about 1% more preferably less than about 0.5%, and most preferably less than about 0.1% by HPLC.
The improved methods of the present invention provides rifaximin with fewer impurities, in preferred embodiments, the processes of the present invention results in a crystalline polymorph which possesses advantageous physicochemical properties which render its processing as a medicament beneficial.
In one of the embodiment, the novel crystalline form of rifaximin obtained by the processes of the present invention was characterised by powder X- ray diffraction pattern having characteristic peaks at about 5.9, 7.3, 7.9 and 8.6 + 0.2° 2?. The said novel crystalline Form obtained herein is designated as Form G.
The crystalline Form of rifaximin obtained by the processes of the present invention was further characterized by powder X ray diffraction pattern having characteristic peaks at about 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 substantially same as fig.1.
The crystalline Form G of rifaximin obtained by the processes of the present invention was further characterized by differential scanning calorimetry (DSC) having endothermic peak at 236.68°C with onset temperature of 221.6°C which is substantially same as fig.2.
The crystalline Form G of rifaximin obtained by the processes of the present invention was characterised by powder X-ray diffractography using Powder XRD make: Bruker model D2 Phaser Goniometer type theta – 2 theta; X-ray source: Copper Ka; Detector: Lynx Eye Detector.
Rifaximin samples data was collected using PMMA holder with the scan parameter details as follows:
2?range: 3-40°; Step size: 0.012; Time for step: 72 S; Generator KV: 30; Generator Ma: 10; Spinner: 15 rpm;
Method of analysis:
Sample preparation: If required sample is finely grind using a mortar and pestle, then pack the sample in a suitable sample holders. Selection of the sample holder depends on the sample quantity.
Ex: a) 25mm/49mm dia, sample holders made up of PMMA will be used if the sample quantity is more than 500mg.
b) 8.5mm dis. Silicon zero background holders will be used if the sample quantity is less than 100mg.
The crystalline Form of rifaximin obtained by the processes of the present invention was further characterised by differential scanning calorimetry (DSC) using instrument make: TA instruments, software: Universal analysis, Model: Q100.
Method of analysis:
Sample preparation: Weigh accurately about 2.0-5.0 mg of test sample and transfer into aluminium hermetic pan, close with lid and seal with a crimper. Hold it in the sample compartment with furnace temperature programme: 30°C to 300°C and at ramp rate of
5°C / min.
Rifaximin used herein as starting material in one of the embodiment of present invention can be made from rifamycin S or rifamycin O or obtained from any of processes reported in the literature for example crude rifaximin can be prepared as per example 4 of U.S. Pat. No. 4,557,866.
Rifaximin used herein can be crystalline or amorphous or mixture thereof.
The starting compounds rifamycin S or rifamycin O used herein the processes of rifaximin can be obtained from any of the processes reported in the literature and can be of any polymorph or mixture of polymorphs.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
EXAMPLES
PROCESSES FOR THE PREPARATION OF RIFAXIMIN
Example 1: 5g of Rifamycin S, 3.1 gms of 2-amino-4-methyl pyridine, 0.45 g of iodine, 1.65 ml of acetic acid and 20ml of acetonitrile were charged in a clean and dry round bottom flask followed by stirring the resultant reaction mixture at about 30°C for about 30 hours. The reaction progress was monitored by TLC, after completion of reaction, the reaction mass was quenched by adding a mixture of 4.0g of ascorbic acid dissolved in 20 ml of water. The resultant reaction suspension was stirred at about 25°C for about 15mins. 25 ml of dichloromethane was charged and stirred for about 15mins. followed by separation of organic and aqueous phases. The aqueous phase was extracted with 25 ml of dichloromethane followed by separation of organic and aqueous phases. The organic phases were combined and distilled at below about 50°C to yield Rifaximin as residue. 11.25ml of purified water and 11.25ml of ethanol were charged to the residue and stirred at about 30°C for about 15 mins. The resultant reaction suspension was heated to about 75°C and stirred for about 30mins. The resultant reaction solution further cooled to about 25°C and stirred for about 2 hours followed by further cooling to about 5°C for about 3 hours. The solid precipitated was filtered and the solid was washed with a mixture of 2.5ml of ethanol and 2.5 ml of purified water. The solid obtained was dried at about 50°C for about 10 hours to afford 3 g. of Rifaximin as crystalline form.
Purity by HPLC: 99.85 area %.
Example 2: 10g of Rifamycin O and 4.3g of 2-amino-4-methyl pyridine, and ( 25.8 ml) of purified water and (19.4 ml) of ethanol were charged into a clean and dry R.B. Flask followed by heating to about 45°C. The resultant suspension was stirred at about 45°C for about 8 hours. The resultant solution was cooled to about 25-35°C and stirred at 25-35°C for about 12 hours. The solid separated was filtered and washed the solid with (3.2 ml) of ethanol and (3.2 ml) of purified water. The solid obtained was dried at about 50°C for about 10 hours to afford 9 g of rifaximin as crystalline form.
Purity by HPLC: 99.89 area%.
Example 3: 10g of Rifaximin, (71.0ml) of ethanol and (30.6 ml ) of purified water were charged into a clean and dry R.B. Flask followed by heating to about 65°C. The resultant suspension was stirred at about 65°C for about 2 hours. The resultant solution was cooled to about 50°C and filtered through a microfilter and seeded with seed crystal. The solution was further cooled to about 35°C and stirred at about 30°C for about 3 hours. The resultant mass was further cooled to about 5°C and stirred for about 12 hours. The solid separated was filtered and the solid was washed with (4.8 ml) of ethanol and (1.6 ml) of purified water. The solid obtained was dried at about 50°C for about 10 hours to afford 9.5 g of rifaximin as crystalline form.
Purity by HPLC: 99.87 area %.