Field of the invention

The present invention relates to an improved process for the preparation of Rifaximin. More particularly the present invention relates to the preparation of amorphous form of Rifaximin.

Background of the invention

Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic pertaining to the rifamycin class. The antimicrobial spectrum (in vitro) includes most gram-positive and gram-negative bacteria; and both aerobes and anaerobes. Rifaximin is approved in certain countries for the treatment of pathologies whose etiology is in part or totally due to intestinal acute and chronic infections sustained by gram-positive and gram-negative bacteria, with diarrhea syndromes, altered intestinal microbial flora, summer diarrhea-like episodes, traveler's diarrhea and enterocolitis; pre- and post-surgery prophylaxis of the infective complications in gastro intestinal surgery; and hyperammonaemia therapy as coadjutant. The drug has been found to have no significant side effects.

The antibiotic Rifaximin was originally disclosed in U.S. Pat. No. 4,341,785. This patent disclosed imidazo-rifamycin derivatives having antibacterial utility, and the related process for preparing it. This patent also disclosed a pharmaceutical antibacterial composition and a method of using it to treat antibacterial diseases of the gastrointestinal tract (GIT).

IN 3181/DELNP/2005 discloses three polymorphic forms of Rifaximin, namely, alpha, beta, and gamma. The patent describes that the gamma form has high content of amorphous component and obtained by dissolution of Rifaximin in ethanol followed by the addition of water.

U.S. Pat. No. 7,709,634 discloses a process for preparing amorphous form of Rifaximin. The said process involves dissolving Rifaximin in a solvent selected from the group consisting of C3.6 alkyl esters, C2.4 alcohols, C3.7 alkyl ketones and mixtures thereof followed by addition of anti-solvents selected from C5.10 hydrocarbons, C4.8 alkyl ethers to yield amorphous material.

IN 756/MUMNP/2009 discloses a process in which amorphous Rifaximin is obtained by stirring the crude Rifaximin with a mixture of 20% dichloromethane and heptane at room temperature.

IN 389/CHENP/2010 discloses a process for the preparation of amorphous form of Rifaximin, which comprises dissolving crude Rifaximin in absolute ethanol at high temperature followed by cooling the resulting solution to yield amorphous Rifaximin which is isolated by filtration. The process uses ascorbic acid while dissolving the crude Rifaximin. IN 2651/CHE/2010 discloses similar process in which the amorphous Rifaximin is prepared by dissolving crude Rifaximin in a solvent selected from Ci_4 alcohols; precipitating the amorphous Rifaximin by cooling the solution without adding water or an antisolvent.IN 6001/CHENP/2010 discloses a processes for producing amorphous Rifaximin comprising lyophilization in p-dioxane:water 1:1, and fast evaporation from acetone.
IN 2046/DEL/2011 discloses process in which Form I of Rifaximin is dissolved in dimethylformamide followed by the addition of water to yield amorphous Rifaximin.

US 2012/0289532 and US 2013/0004576 disclose a process in which amorphous form is obtained by spray drying a solution of Rifaximin.

WO 2012/060675 discloses a process in which the amorphous form of Rifaximin is prepared by dissolving crystalline Rifaximin a, P or y in acetone, followed by addition of water. The isolation process involves distilling 75% of solvent followed by cooling.

IPCOM000225321D discloses a process for the preparation of amorphous Rifaximin prepared by a process comprising:

(a) contacting Rifaximin in a suitable organic solvent selected from alcohols (e.g., methyl alcohol, isopropyl alcohol, butyl alcohol, pentyl alcohol, and hexyl alcohol), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, and butyl acetate), ketones (e.g., methyl ethyl ketone, methyl isobutyl ketone, and methyl tert-butyl ketone), or mixtures thereof at ambient temperature, or mixtures of solvents;

(b) removing the solvent by spray drying, flash evaporation, or a combination thereof.; and

(c) isolating amorphous Rifaximin.

Considering the importance of amorphous form of Rifaximin, there is need for a simple, economical and industrially viable process for the synthesis of amorphous form of Rifaximin. With a view to find a simple process, the present applicant diligently worked and identified a robust and economical process for the preparation of Rifaximin in amorphous form.

Objectives of the invention

The main objective of the present invention is to provide an improved process for the preparation of Rifaximin in amorphous form.

Another objective of the present invention is to provide a robust process for the preparation of Rifaximin in amorphous form with high purity and yield.

Summary of the invention

Accordingly, there is provided an improved process for the preparation of Rifaximin which comprises dissolving the Rifaximin in C3-C6 alkyl ketones solvent followed by removing the solvent by distillation.

Detailed description of the invention

In an embodiment of the present invention, the solvent used for dissolving Rifaximin is C3-C6 alkyl ketones selected from acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) or mixtures thereof. Since the solvent used herein belong to ICH class-3 solvents, it is possible to have higher limits of residual solvent. The volume of solvent used for dissolution can be in the range of 1 to 6 volume with respect to weight of the Rifaximin taken, preferably about 2 volume used.

In another embodiment of the present invention, the distillation may be carried out either at atmospheric pressure or at reduced pressure. Preferably the solvent is removed at a pressure of about 760 mm Hg or less, more preferably at about 300 mm Hg or less.

In still another embodiment of the present invention, the distillation is carried out at a temperature in the range of 20 °C to reflux temperature of the solvent used. The distillation may be carried out until the solvent is almost completely distilled off, specifically completely distilled off. The solvent is removed from the solution to dryness, thereby leaving a solid residue containing amorphous Rifaximin.

After evaporation of the solvent, the residual solid may optionally be treated with an organic solvent. Organic solvent may be selected from the hydrocarbon such as hexane, heptane, toluene and benzene. The solid obtained is dried at a temperature in the range of 50 °C to 95 °C

In a preferred embodiment, the present invention provides an improved process for the preparation of Rifaximin which comprises the steps of

i) dissolving Rifaximin in solvent selected from acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) or mixtures thereof, ii) removing the solvent by distillation at reduced pressure and iii) isolating amorphous Rifaximin.

In a more preferred embodiment, the present invention provides an improved process for the preparation of Rifaximin which comprises the steps of i) dissolving Rifaximin in solvent selected from acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) or mixtures thereof, ii) removing the solvent by distillation at reduced pressure and iii) drying the amorphous Rifaximin at a temperature in the range of 50°C to 95°C and iv) isolating amorphous Rifaximin by conventional methods.

In yet another embodiment of the present invention, the Rifaximin obtained is substantially free from residual organic solvents and polymorphically stable.

The XRD pattern and DSC thermogram of amorphous Rifaximin of the present invention is depicted in Figures 1 and 2.

The staring material Rifaximin is prepared by utilizing the process disclosed in the prior art.

The present invention is exemplified by following examples, which are provided for illustration only and should not be construed to limit the scope of the invention.

Example 1

Rifaximin (12 g) was dissolved in acetone (24 ml), at ambient temperature. The solution was filtered to remove any foreign particle. The filtrate was distilled out completely under reduced pressure at 25-30 °C till dryness of the compound. The solid obtained was further dried at 80 ° C and cooled to ambient temperature. To the resulting free flowing solid, cyclohexane was added and the solid was filtered to yield amorphous Rifaximin (11.6 gm).

Example 2;

Rifaximin (100 g) was dissolved in acetone (200 ml) at ambient temperature. The solution was filtered to remove any foreign particle. The filtrate was distilled out completely under reduced pressure at around 20 °C till dryness of the compound. The solid obtained was further dried at 80 ° C and cooled to ambient temperature. The resulting free flowing solid was isolated to yield amorphous Rifaximin (95 g).

Example 3:

Rifaximin (100 g) was dissolved in methyl ethyl ketone (200 ml) at ambient temperature. The solution was filtered to remove any foreign particle. The filtrate was distilled out completely under reduced pressure at 40 °C till dryness of the compound. The solid obtained was further dried at 80° C and cooled to ambient temperature. To the resulting free flowing solid cyclohexane was added and the solid was filtered to yield amorphous Rifaximin (98ngm).

Example 4:

Rifaximin (100 g) was dissolved in diethyl ketone (200 ml) at ambient temperature. The solution was filtered to remove any foreign particle. The filtrate was distilled out completely under reduced pressure at 40 °C till dryness of the compound. The solid obtained was further dried at 80° C and cooled to ambient temperature. To the resulting free flowing solid cyclohexane was added and the solid was filtered to yield amorphous Rifaximin (98ngm).

Example 5:

Rifaximin (100 g) was dissolved in methyl isobutyl ketone (200 ml) at ambient temperature. The solution was filtered to remove any foreign particle. The filtrate was distilled out completely under reduced pressure at 50°C till dryness of the compound. The solid obtained was further dried at 80° C and cooled to ambient temperature. To the resulting free flowing solid cyclohexane was added and the solid was filtered to yield amorphous Rifaximin (97 gm).

TABLE - 1

From the above table, it is clearly evident that yield of amorphous of Rifaximin prepared according to the present invention is significantly higher than the one prepared according to the prior art. In addition the present invention uses less amount of solvent for dissolution hence the productivity is increased.

Advantages of process:

1. Use of environmental friendly and human non toxic solvents.

2. The present invention is simple, operation friendly process and does not require any special equipments such as spray drier, lyophilizer, Agitated Thin Film Dryer etc.

3. The present invention provides robust, consistent and reproducible process for the production of amorphous Rifaximin.

4. Avoids the use of anti-solvent.

5. Because of complete distillation almost quantitative yield is obtained where as the yield obtained with the prior art process of solvent/anti-solvent technique, is less.

6. The present invention can be workable even at high temperature hence required residual solvent limit can be easily achieved.

We claim:

1. An improves process for the preparation of Rifaximin in amorphous form which comprises dissolving Rifaximin in C3-C6 alkyl ketone solvent, followed by removing the solvent by distillation.

2. The process as claimed in claim 1, wherein the C3-C6 alkyl ketone solvent is selected from acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) and mixtures thereof.

3. The process as claimed in claim 1, wherein the distillation is carried out at a temperature in the range of 20 °C to reflux temperature of the solvent used.

4. The process as claimed in claim 1, further comprising drying the amorphous Rifaximin at a temperature in the range of 50°C to 95°C.

5. The process as claimed in claim 2, wherein the distillation is carried out at a reduced pressure.

6. In a preferred embodiment, the present invention provides an improved process for the preparation of Rifaximin which comprises the steps of

i) dissolving Rifaximin in solvent selected from acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) or mixtures thereof, ii) removing the solvent by distillation at reduced pressure and iii) isolating amorphous Rifaximin.

7. In a more preferred embodiment, the present invention provides an improved process for the preparation of Rifaximin which comprises the steps of

i) dissolving Rifaximin in solvent selected from acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone (MIBK) or mixtures thereof,

ii) removing the solvent by distillation at reduced pressure and

iii) drying the amorphous Rifaximin at a temperature in the range of 50°C to 95°C and

iv) isolating amorphous Rifaximin.

8. An improved process for the preparation of amorphous Rifaximin, prepared according to the examples as described herein.