Field of the Invention

The present invention provides a new polymorphic form of rifaximin designated as DMF solvate and the process for its preparation. It also provides a pharmaceutical composition comprising the same and its use for the treatment of bowel related disorders.

Background of the Invention

Rifaximin is a semi-synthetic, nonsystemic antibiotic which was disclosed in U.S. Patent No. 4,341,785. It is marketed in the United States under the trade name Xifaxan® for the treatment of Travelers' diarrhea and Hepatic Encephalopathy. Rifaximin is designated as (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S, 28E)5,6,21,23,25- pentahydroxy-27-methoxy-2,4, 11 , 16,20,22,24,26-octamethyl-2,7(epoxypenta-deca- [ 1 , 11 , 13]trienimino)benzofuro[4,5-e]pyrido[ 1 ,2-a]-benzimidazole-l,15(2H)dione,25- acetate and is represented by the structural formula as shown below:

Various patent applications describe polymorphic forms of rifaximin, for example,

U.S. Patent Nos. 7,045,620 and 7,612,199 (α, β and γ forms of rifaximin), WO

2006/094662 (ε and δ of rifaximin), WO 2009/108730 (Form ζ, Form γ-1 (ζ), Form η, Form α-dry, Form i, β-l, Form β-2, Form ε-dry, and several amorphous forms of rifaximin having characteristics halo range in X-ray powder diffraction). U.S. Patent No. 7,709,634 and WO 2008/035109 further provide an amorphous form of rifaximin.

Polymorphism is a property exhibited by several compounds and compound complexes, including pharmaceutical compounds, whether by way of crystal forms or solvates. Different crystalline forms or polymorphs of the same pharmaceutical compounds can have different solubility characteristics, and this, in turn, affects bioavailability. Thus, the discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides opportunities to design the performance characteristics of a pharmaceutical product for formulation according to the need. But there is no real way to predict if a compound actually exhibits polymorphism, and if it did what kind of crystal structures it will exhibit. It requires diligent experimentation and analysis.

WO 2009/108730 mentions Form β-l to be an ethanolate/trihydrate of rifaximin but does not provide any example/experimental evidence to support it. The literature does not provide any specific reference related to the solvated forms of rifaximin. The present invention provides Ν,Ν-dimethylformamide solvate of rifaximin which is free flowing, stable, easily reproducible and suitable to develop formulations.

Summary of the Invention

The present invention provides a new polymorphic form of rifaximin designated as

DMF solvate and the process for its preparation. It also provides a pharmaceutical composition comprising the same and its use for the treatment of bowel related disorders.

The first aspect of the present invention provides DMF solvate of the rifaximin.

The second aspect of the present invention provides DMF solvate of the rifaximin characterized by d-spacing (A) values selected from 17.79, 12.31, 11.82, 10.54, 6.74, 5.91, 4.70, 4.22, 4.16, 4.06, 3.98 or 3.53.

The third aspect of the present invention provides a process for the preparation of DMF solvate of the rifaximin, the steps comprising of:

i) heating the reaction mixture containing rifaximin and N,N-dimethylformamide; ii) cooling the mixture to ambient temperature followed by stirring for long hours; and

iii) isolating dimethylformamide solvate of rifaximin.

The fourth aspect of the present invention provides substantially pure DMF solvate of the rifaximin having a purity greater than 99%, when measured by HPLC area percentage. According to a fifth aspect, the present invention provides a pharmaceutical composition comprising DMF solvate of the rifaximin with one or more pharmaceutically acceptable carriers and/or excipients.

According to a sixth aspect, the present invention provides a method for treating, preventing or alleviating bowel related disorders in humans comprising administering to said patient a therapeutically effective amount of DMF solvate of the rifaximin or a pharmaceutical composition comprising the same.

Brief Description of the Drawings

Figure 1 : X-Ray Diffraction (XRD) pattern of DMF solvate of rifaximin

Figure 2: Differential Scanning Calorimetry (DSC) pattern of DMF solvate of rifaximin

Figure 3: Thermal Gravimetric Analysis (TGA) pattern of DMF solvate of

rifaximin

Figure 4: Table I - XRD table for the DMF solvate of rifaximin

Detailed Description of the Invention

Various embodiments and variants of the present invention are described hereinafter.

The term "about", as used herein, refers to variation through ±5 in the defined parameter, like temperature range or stirring time used at different steps during the preparation of dimethylformamide solvate of rifaximin.

"Ambient temperature", as used herein, refers to temperature ranging from about 15°C to about 30°C.

"Substantially pure", as used herein, refers to the DMF solvate of the rifaximin having purity greater than 99%.

The first aspect of the present invention provides DMF solvate of the rifaximin.

According to the second aspect of the present invention, DMF solvate of the rifaximin having characteristics d-spacing (A) values selected from 17.79, 12.31, 1 1.82, 10.54, 6.74, 5.91, 4.70, 4.22, 4.16, 4.06, 3.98 or 3.53. DMF solvate of rifaximin may be characterized by d-spacing (A) values at about 17.79, 14.91, 13.41, 12.31, 11.82, 10.54, 10.13, 8.83, 8.28, 7.86, 7.18, 6.74, 6.42, 6.16, 5.91, 5.71, 5.65, 5.26, 5.10, 4.98, 4.70, 4.50, 4.32, 4.22, 4.16, 4.06, 3.98, 3.83, 3.66, 3.53, 3.39, 3.18, 3.04, 2.95, 2.78 and the corresponding 2-theta values at about 4.97, 5.93, 6.59, 7.18, 7.48, 8.39, 8.73, 10.02, 10.69, 1 1.26, 12.32, 13.14, 13.79, 14.38, 15.00, 15.51, 15.67, 16.85, 17.39, 17.83, 18.90, 19.71, 20.56, 21.04, 21.34, 21.89, 22.32, 23.24, 24.29, 25.22, 26.32, 28.05, 29,39, 30.25, 32.15 ± 0.2

DMF solvate of the rifaximin can also be characterized by (i) XRD having substantially the same pattern as depicted in Figure 1, (ii) DSC having substantially the same pattern as depicted in Figure 2, (iii) TGA having substantially the same pattern as depicted in Figure 3.

The DSC shows two characteristic endotherm peaks. The first endothermal peak is in the range from about 45.60°C to about 71.59°C and the second endothermal peak is from about 110.15°C to about 1 11.82°C.

The DMF solvate of the rifaximin has water content from about 0% to about 5%, when measured by Karl-Fischer analysis. Preferably, water content can be in between 1% to 3%.

The rifaximin, used herein, for the preparation of DMF solvate can be obtained by any of the methods known in literature such as those described in U.S. Patent Nos.

4,557,866; 4,341,785; 7,045,620; and 7,612, 199.

The mixture of rifaximin in Ν,Ν-dimethylformamide solvent may be heated at a temperature of about 45°C to about 60°C followed by optional stirring of the mixture, if required for complete dissolution of the mixture.

The reaction mixture obtained may be cooled to ambient temperature, preferably to about 20°C to 30°C, followed by stirring.

The stirring of the cooled mixture can be carried out for long hours, for about 30 hours, preferably for about 12 hours to about 24 hours for complete precipitation of the solid.

The solid thus formed can be isolated by conventional means known to a person of ordinary skill in the art including, for example, decantation, filtration or centrifugation. The isolated solid, designated as DMF solvate of the rifaximin, can be washed with solvent if desired, followed by drying, wherein the drying can be carried out by any drying means known to a person of ordinary skill in the art including, for example, under reduced pressure, vacuum tray drying, air drying and/or combinations thereof.

In a particular embodiment, DMF solvate of rifaximin can be dried for a certain period of time, for example, for about 8 hours to 15 hours under reduced pressure at a temperature range of from about 45°C to about 75°C. The drying time can be changed accordingly depending on drying temperature, preferably, drying is done at 45°C to 50°C.

The isolated crystalline solid refers to substantially pure DMF solvate of the rifaximin.

The DMF solvate of the rifaximin can be formulated into pharmaceutical compositions with excipients or carriers. The various dosage forms which include, but are not limited to, coated or uncoated tablets, hard or soft gelatin capsules, sugar coated pills, lozenges, wafer sheets, pellets, or powders in a sealed packet. The DMF solvate of the rifaximin can also be formulated as a topical composition. Preferably, the pharmaceutical composition comprises an amount of DMF solvate of rif-iximin effective to treat, prevent or alleviate the desired indication, i.e., bowel related disorders in an animal, such as a human.

Also presented herein, the use of DMF solvate of the rifaximin as a medicament for treatment, prevention, alleviating bowel related disorders, preferably Travelers' diarrhea and Hepatic encephalopathy.

The packaging of the DMF solvate of the rifaximin can be done in self sealing polybags under vacuum after nitrogen flushing, or under nitrogen atmosphere, optionally including a desiccant to improve stability of the material. In the following section, preferred embodiments are described by way of examples to illustrate the process. However, these are not intended in any way to limit the scope of the claims. Several variants of these examples would be evident to persons ordinarily skilled in the art. Method:

The DMF solvate of the rifaximin obtained by the present invention has an HPLC purity greater than 99.1% as measured by area percentage. Typically, high performance liquid chromatography (HPLC) was carried out using column name: Alltima CI 8, (250 mm x 4.6 mm), 5μιη; Temperature: 40°C; Flow rate: 1.4 mL/min; Injection Volume: 20μί; Run time: 55 minutes; buffer: ammonium formate and ammonia solution in water, solvent mixture of buffer, acetonitrile and methanol (50:50) as mobile phase and water and acetonitrile (60:40) as diluents. The XRD pattern was recorded using a PANalytical XPert PRO. The TGA and DSC patterns were recorded using TA instruments-Q500 and Mettler DSC 821 e Perkin Elmer, respectively.

EXAMPLE

Example: Preparation of DMF Solvate of Rifaximin

Rifaximin (15.0 gm) was added to Ν,Ν-dimethylformamide solvent (25 mL) followed by the heating of the reaction mixture to 45°C to 50°C. The reaction mixture was stirred to get a clear solution followed by the cooling of the solution to 22°C to 25°C. The cooled mixture was stirred at the same temperature for 18 hours followed by filtration of the solid. The solid so obtained was dried at 45°C to 50°C under reduced pressure for 10 hours to 12 hours to get DMF solvate of rifaximin.

Yield: 0.916% w/w of DMF

Chromatographic purity %: 99.18%

Water content by KF: 2.28%