SOLVATE DE DIMETHYLFORMAMIDE RIFAXIMINE

RIFAXIMIN DIMETHYLFORMAMIDE SOLVATE

Abrégé français

La présente invention concerne une nouvelle forme polymorphe de rifaximine connue sous le nom de solvate DMF et son procédé de préparation. L'invention concerne également une composition pharmaceutique la comprenant ainsi que son utilisation pour le traitement de troubles intestinaux.

Abrégé anglais

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.

Revendications

7
Claims:
1. Rifaximin dimethylformamide solvate.
2. The rifaximin solvate according to claim 1, characterized by d-spacing
(.ANG.) 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.
3. A process for the preparation of rifaximin solvate according to claim 1,
which
comprises the steps 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.
4. The process according to claim 3, wherein the heating of the reaction
mixture in
step i) is carried out from a temperature of about 45°C to about
60°C.
5. The process according to claim 3, wherein cooling is carried out from a
temperature of about 15°C to about 30°C.
6. The process according to claim 3, wherein stirring for long hours in
step ii)
comprises stirring of the mixture from about 12 hours to about 30 hours.
7. The process according to claim 3, wherein isolation of rifaximin solvate
comprises
drying of the solvate for about 8 hours to 15 hours under reduced pressure at
a temperature
range of from about 45°C to about 75°C.
8. Substantially pure rifaximin solvate obtained by the process according
to claim 3
has purity greater than 99%.
9. The substantially pure rifaximin solvate according to claim 8 has water
content in
the range of about 1% to about 3%.
10. A pharmaceutical composition comprising rifaximin solvate according to
claim 1
with one or more pharmaceutically acceptable carriers and/or excipients.

8
11. A
method for treating, preventing or alleviating bowel related disorders in
humans
comprising administering to said patient a therapeutically effective amount of
rifaximin
solvate according to claim 1 or a pharmaceutical composition comprising the
same.

Description

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RIFAXIMIN DIMETHYLFORMAMIDE SOLVATE
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-octamethy1-2,7(epoxypenta-deca-
[1,11,13]trienimino)benzofuro [4,5-e]pyrido [1,2-a]-benzimidazole-
1,15(2H)dione,25-
acetate and is represented by the structural formula as shown below:
!
HOõ, = ,,,,
=
.
Hi H OH '-
e I
=
H
ito
= i \=
1
Various patent applications describe polymorphic forms of rifaximin, for
example,
U.S. Patent Nos. 7,045,620 and 7,612,199 (a, 13 and 7 forms of rifaximin), WO
2006/094662 (e and ö of rifaximin), WO 2009/108730 (Form , Form 7-1 (0, Form
ri,
Form a-dry, Form 1,13-1, Form 13-2, Form e-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

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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 13-1 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 N,N-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.

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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, 11.82,
10.54, 6.74, 5.91, 4.70, 4.22, 4.16, 4.06, 3.98 or 3.53.
SUBSTITUTE SHEET (RULE 26)

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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, 11.26, 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 111.82 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 N,N-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.
SUBSTITUTE SHEET (RULE 26)

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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.
5 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 rifaximin 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.

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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 C18,
(250
EXAMPLE
Example: Preparation of DMF Solvate of Rifaximin
Rifaximin (15.0 gm) was added to N,N-dimethylformamide solvent (25 rnL)
followed by the heating of the reaction mixture to 45 C to 50 C. The reaction
mixture
Yield: 0.916% w/w of DMF