Note: Descriptions are shown in the official language in which they were submitted.
WO 2011/107911 PCT/IB2011/050785
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POLYMORPH OF 2-[3-CYANO-4-(2-METHYLPROPOXY)PHENYL]-4-
METHYLTHIAZOLE-5-CARBOXYLIC ACID
Field of the Invention
The present invention provides for crystalline Form R of 2-[3-cyano-4-(2-
methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, and process for its
preparation. The present invention also includes a pharmaceutical composition,
which
includes Form R and its use in the chronic management of hyperuricemia in
patients with
gout.
Background of the Invention
2-[3-Cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid
(febuxostat) is a non-purine xanthine oxidase inhibitor having the structure
as represented
by Formula I.
x
CO-H,
Formula I
Febuxostat is disclosed in U.S. Patent No. 5,614,520 and is marketed in the
United
States under the brand name Uloric for the chronic management of
hyperuricemia in
patients with gout. Crystalline forms of febuxostat are disclosed in U.S.
Patent No.
6,225,474; WO 2008/067773; CN 101139325; CN 101085761; CN 101386605; and CN
101412700.
U.S. Patent No. 6,225,474 discloses crystalline Forms A, B, C, D and G of
febuxostat prepared using a mixture of methanol, ethanol or propanol with
water.
WO 2008/067773 discloses crystalline Forms H, I and J of febuxostat prepared
using acetonitrile.
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CN 101139325, CN 101085761, CN 101386605 and CN 101412700 disclose
crystalline forms of febuxostat prepared using ethanol, ethyl acetate, acetone
or 1,4-
dioxane.
Summary of the Invention
In one general aspect, the present invention provides for crystalline Form R
of
febuxostat, which includes X-ray diffraction peaks at d-spacing of about
15.62, 15.23,
11.08, 6.93 and 3.43 A
Embodiments of this aspect may include one or more of the following features.
For example, the crystalline Form may further include X-ray diffraction peaks
at d-spacing
of about 7.61, 7.04, 5.25, 4.32 and 3.40 A.
In another general aspect, the present invention provides for crystalline Form
R of
febuxostat characterized by X-ray diffraction pattern as depicted in Figure-1.
In another general aspect, the present invention provides for Crystalline Form
R of
febuxostat characterized by DSC as depicted in Figure-2.
In another general aspect, the present invention provides for Crystalline Form
R of
febuxostat characterized by TGA as depicted in Figure-3.
In another general aspect, the present invention provides for Crystalline Form
R of
febuxostat characterized by IR spectrum as depicted in Figure 4.
In another general aspect, the present invention provides for a process for
the
preparation of crystalline Form R of febuxostat. The process includes:
i) contacting febuxostat with a ketone to form a reaction mixture; and
ii) isolating crystalline Form R.
Embodiments of this aspect may include one or more of the following features.
For example, the ketone is acetone, dimethyl ketone, ethyl methyl ketone or
methyl iso-
butyl ketone. The ketone may be ethyl methyl ketone.
The febuxostat may be contacted with the solvent at room temperature. The
reaction mixture may be heated to about 40 C to the reflux temperature of the
solvent.
The reaction mixture may be stirred for about 5 minutes to about 30 minutes.
The reaction
WO 2011/107911 PCT/IB2011/050785
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mixture may also be further cooled to about 5 C to about 25 C. The reaction
mixture may
also be further dried under reduced pressure at a temperature of about 35 C to
about 60 C.
In yet another general aspect, the present invention provides for a
pharmaceutical
composition, which includes crystalline Form R of febuxostat and one or more
pharmaceutically acceptable carriers, diluents or excipients.
In another general aspect, the present invention also provides for the use of
crystalline Form R of febuxostat in the manufacture of a medicament for use in
chronic
management of hyperuricemia in patients with gout.
Brief Description of the Figures
Figure-1: X-ray diffraction pattern (XRD) of crystalline Form R
Figure-2: Differential Scanning Calorimetry (DSC) of crystalline Form R
Figure-3: Thermogravimetric Analysis (TGA) of crystalline Form R
Figure-4: Infra-red spectrum (IR) of crystalline Form R
Detailed Description of the Invention
Crystalline Form R of the present invention may be characterized by primary
XRD
peaks at about 5.65 (d-spacing at 15.62 A), 5.80 (15.23 A), 7.97 (11.08 A),
12.76 (6.93
A) and 25.92 (3.43 A) 0.2 20. It may be further characterized by XRD peaks
at about
11.62 (7.61 A), 12.56 (7.04 A), 16.88 (5.25 A), 20.54 (4.32 A) and 26.19 (3.40
A) 0.2
20. Crystalline Form R may also be characterized by an endothermic maximum at
201
20 2 C observed during thermal analysis using DSC. It may be characterized by
XRD
pattern, DSC, TGA and IR as depicted in Figures 1, 2, 3 and 4, respectively.
Table-1
provides XRD peaks of crystalline Form R.
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Table-1: X-Ray Diffraction Peaks of Crystalline Form R
Position ( 20) d-spacing (A) Relative Intensity (%)
5.65 15.62 28.29
5.80 15.23 70.59
7.97 11.08 100.00
11.62 7.61 18.87
12.56 7.04 8.63
12.76 6.93 36.73
12.94 6.84 3.81
14.40 6.15 1.38
15.53 5.71 2.08
16.16 5.49 1.10
16.88 5.25 7.59
17.46 5.08 5.48
18.19 4.88 5.66
18.49 4.80 6.63
20.54 4.32 12.74
21.01 4.23 3.82
22.34 3.98 1.15
23.38 3.81 2.65
23.86 3.73 6.53
24.40 3.65 3.74
24.63 3.62 2.99
25.92 3.43 19.38
26.19 3.40 10.36
26.76 3.33 1.22
27.50 3.24 1.09
28.09 3.18 1.09
28.57 3.12 1.79
28.92 3.09 3.66
30.10 2.97 1.68
31.36 2.85 1.93
32.67 2.74 0.98
33.49 2.68 0.78
34.48 2.60 1.92
35.68 2.52 1.11
36.12 2.49 0.95
36.72 2.45 1.14
37.85 2.38 1.09
38.69 2.33 1.20
The febuxostat used for the preparation of the crystalline Form R of the
present
invention may be obtained by any of the methods known in the literature such
as those
described in U.S. Patent No. 5,614,520; U.S. Publication 2009/0203919; and
U.S. Patent
WO 2011/107911 PCT/IB2011/050785
No. 7,541,475, which are incorporated herein by reference. Febuxostat, to be
used as
starting material for the preparation of crystalline forms of the present
invention, may be
obtained as a solution directly from a reaction in which it is formed and used
as such
without isolation.
5 The term "contacting" may include dissolving, slurrying, stirring or a
combination
thereof.
The term "about", as used herein, includes variations in the range of 10% in
the
temperature and time period.
The term "room temperature", as used herein, includes temperature in the range
of
about 15 C to about 35 C.
Febuxostat may be contacted with a solvent at about room temperature. The
solvent may be selected from the group comprising of C3-C10 alcohols,
carboxylic acids,
chlorinated hydrocarbons, ketones, amides, sulphoxides, ethers, alkyl
acetates, water or
mixtures thereof. Examples of C3-C10 alcohols may include 1-propanol, 1-
butanol or 2-
butanol. Examples of carboxylic acids may include formic acid, acetic acid or
propionic
acid. Examples of chlorinated hydrocarbons may include dichloromethane or
chloroform.
Examples of ketones may include acetone, dimethyl ketone, ethyl methyl ketone
or methyl
iso-butyl ketone. Examples of ethers may include diethyl ether, ethyl methyl
ether, di-
isopropyl ether, tetrahydrofuran or 1,4-dioxane. Examples of amides may
include N, N-
dimethylformamide or N, N-dimethylacetamide. Examples of sulphoxides may
include
dimethyl sulfoxide or diethyl sulphoxide. Examples of cyclic ethers may
include
tetrahydrofuran. Examples of alkyl acetates may include methyl acetate, ethyl
acetate,
propyl acetate or butyl acetate.
The reaction mixture may be stirred for a period of about 1 minute to about 15
minutes followed by heating to a temperature of about 40 C to the reflux
temperature of
the solvent and further stirring for about 2 minutes to about 30 minutes. It
may be cooled
to a temperature of about 5 C to about 25 C, preferably, to about 15 C to
about 20 C,
over a period of about 10 minutes to about 2 hours, preferably, over a period
of about 30
minutes. It may be further stirred for about 30 minutes to about 5 hours,
preferably, for
about 2 hours, and dried. Any suitable method of drying may be employed, such
as,
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drying under reduced pressure, vacuum tray drying, air drying, or a
combination thereof.
Drying may be carried out at a temperature of about 20 C to about 60 C,
preferably, at
about 45 C, for a period of about 1 hour to about 8 hours, preferably, for
about 5 hours.
In a particular embodiment, crystalline Form R of the present invention is
prepared
by contacting febuxostat with a ketone solvent at a temperature of about 15 C
to about
35 C. The reaction mixture is stirred for about 1 minute to about 15 minutes,
and the
reaction mixture is heated to a temperature of about 40 C to the reflux
temperature of the
solvent. This is stirred for about 5 minutes to about 30 minutes. This is then
cooled to a
temperature of about 5 C to about 25 C in a period of about 10 minutes to
about 2 hours,
and then for about 30 minutes to about 5 hours; followed by drying. The ketone
solvent
may be acetone, dimethyl ketone, ethyl methyl ketone or methyl iso-butyl
ketone.
In another embodiment, crystalline Form R of the present invention is prepared
by
contacting febuxostat with ethyl iso-butyl ketone at room temperature,
stirring the reaction
mixture for about 1 minute to about 15 minutes. The reaction mixture is then
heated to a
temperature of about 40 C to the reflux temperature of the solvent, and
stirred for about 5
minutes to about 30 minutes. This is then cooled to a temperature of about 15
C to about
C over a period of 30 minutes. Finally, the reaction mixture is stirred for
about 2 hours
and then dried under reduced pressure at a temperature of about 45 C for about
5 hours.
Crystalline Form R of the present invention is a highly pure, easy to filter,
free-
20 flowing solid. Preferably, crystalline Form R has a particle size of less
than 100 m.
Variations in dissolution profiles may arise due to larger particle size.
Crystalline Form R
of the present invention is free of residual solvents, is stable towards
polymorphic
conversion and shows little or no variation in dissolution profile.
The term "free of residual solvents", as used herein, refers to crystalline
Form R of
febuxostat containing less than 5000 ppm, preferably, less than 1000 ppm and
more
preferably, less than 500 ppm of residual solvents.
The crystalline Form R of febuxostat of the present invention may be converted
into an amorphous form of febuxostat by evaporation of the solvent, spray
drying, freeze-
drying or lyophilization.
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Solvates, pseudomorphs and hydrates of crystalline Form R of the present
invention are also included within the scope of the present invention.
The crystalline Form R of febuxostat of the present invention may be
administered
as part of a pharmaceutical composition for the chronic management of
hyperuricemia in
patients with gout. Any suitable route of administration may be employed for
example
peroral or parental.
The present invention also provides for a pharmaceutical composition which
includes crystalline Form R of febuxostat, one or more pharmaceutically
acceptable
carriers, diluents or excipients and optionally other therapeutic ingredients.
The excipients
may be vegetable oils, oily esters, glycerin esters, alcohols, physiological
saline, glycols,
animal fat and oil, cellulose derivatives, polyvinyl pyrrolidone, dextrin,
lactose, mannitol,
sorbitol or starch. Examples of vegetable oils may include corn oil, cotton
seed oil,
coconut oil, almond oil, peanut oil or olive oil. Examples of oily esters may
include
glyceride oils or mineral oils. Examples of glycerin esters may include
tricaprylin or
triacetin. Examples of alcohols may include methanol, ethanol or propanol.
Examples of
glycols may include propylene glycol or polyethylene glycol. Examples of
cellulose
derivatives may include crystalline cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose or methyl cellulose. The diluents may be calcium
carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.
The
crystalline Form R of febuxostat of the present invention may be formulated
into capsules,
hard capsules, tablets, granules, powder, suspension, solutions and syrups,
injections,
suppositories and external preparations.
Embodiments of the present invention are described by way of example to
illustrate the process of invention. However, this is not intended in any way
to limit the
scope of the present invention. Several variants of the example would be
evident to
persons ordinarily skilled in the art which are within the scope of the
present invention.
Methods
The X-ray diffraction patterns were recorded using Panalytical Expert PRO with
Xcelerator as detector, 3-40 as scan range, 0.02 as step size and 3-40 20 as
range.
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DSC and TGA were recorded using Mettler Toledo DSC 821e and Perkin Elmer
TGA 7 instruments, respectively.
IR spectrum was recorded using Perkin Elmer Spectrum one FT-IR spectrometer.
Example: Preparation of Crystalline Form R of Febuxostat
Febuxostat (3 g) was added to a round-bottomed flask containing ethyl methyl
ketone (21 mL) at room temperature. The reaction mixture was stirred for about
3
minutes, followed by heating to about 50 C to about 55 C. The reaction mixture
was
stirred for about 5 minutes, cooled to about 15 C to about 20 C over a period
of about 30
minutes, stirred for about 2 hours, filtered, washed with ethyl methyl ketone
(3 mL) and
dried under reduced pressure at a temperature of about 45 C for about 5 hours
to obtain
crystalline Form R of febuxostat.
Yield: 2.4 g
