POLYMORPH OF 2-[3-CYANO-4-(2-METHYLPROPOXY)PHENYL]-4-
METHYLTHIAZOLE-5-CARBOXYLIC ACID
Field of the Invention
The present invention provides 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 crystalline 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.
CH3
H3C ^ ^ ]C02H
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.
CN 101139325, CN 101085761, CN 101386605 and CN 101412700 disclose crystalline
forms of febuxostat prepared using ethanol, ethyl acetate, acetone or 1,4-dioxane.
^ 3
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 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 29
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° 26. 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° 26. Crystalline
Form R may also be characterized by an endothermic maximum at 201 ± 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.
Table-1: X-Ray Diffraction Peaks of Crystalline Form R
Position (°28) d-spacing (A) Relative Intensity (%)
5,65 1162 28.29
180 15.23 70.59
Z97 1L08 100.00
\L62 7^61 18.87
12.56 7M 8^63
12/76 6^93 36/73
12.94 6M 18]
1440 6A5 138
1^53 5/71 208
16J6 549 U0
16J58 125 7^59
1X46 108 548
18.19 4J58 166
1849 480 6^63
20.54 432 12/74
21.01 423 182
22.34 198 L15
23.38 181 265
23.86 173 6^53
24.40 165 174
24.63 162 299
25.92 143 1938
26.19 140 1036
26.76 333 L22
27.50 124 L09
28.09 118 L09
28.57 112 1/79
28.92 109 166
30.10 297 L68
3136 2/85 L93
32.67 274 098
33.49 268 078
34.48 260 L92
35.68 252 Ul
36.12 249 095
36.72 245 U4
37.85 238 L09
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 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.
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, 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 20°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-flowing
solid. Preferably, crystalline Form R has a particle size of less than 100 um. 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.
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° 26 as range.
DSC and TGA were recorded using Mettler Toledo DSC 82 le 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

WE CLAIM:
1. Crystalline Form R of febuxostat comprising X-ray diffraction peaks at d-spacing of
about 15.62, 15.23, 11.08, 6.93 and 3.43 A
2. The crystalline Form R according to claim 1 further comprising X-ray diffraction peaks
at d-spacing of about 7.61, 7.04, 5.25, 4.32 and 3.40 A.
3. Crystalline Form R of febuxostat characterized by X-ray diffraction pattern as depicted
in Figure-1.
4. Crystalline Form R of febuxostat characterized by DSC as depicted in Figure-2.
5. Crystalline Form R of febuxostat characterized by TGA as depicted in Figure-3.
6. Crystalline Form R of febuxostat characterized by IR spectrum as depicted in Figure-4.
7. A process for the preparation of crystalline Form R of febuxostat comprising:
i) contacting febuxostat with a ketone to form a reaction mixture; and
ii) isolating crystalline Form R.
8. The process according to claim 7, wherein the ketone consists of acetone, dimethyl
ketone, ethyl methyl ketone or methyl iso-butyl ketone.
9. The process according to claim 8, wherein the ketone consists of ethyl methyl ketone.
10. The process according to claim 7, wherein the febuxostat is contacted with the solvent at
room temperature.
11. The process according to claim 7, wherein the reaction mixture is heated to about 40°C
to the reflux temperature of the solvent and/or is stirred for about 5 minutes to about 30
minutes.
12. The process according to claim 7, wherein the reaction mixture is further cooled to about
5°C to about 25°C.
13. The process according to claim 7, wherein the reaction mixture is further dried under
reduced pressure at a temperature of about 35°C to about 60°C.
14. A pharmaceutical composition comprising crystalline Form R of febuxostat and one or
more pharmaceutically acceptable carriers, diluents or excipients.
15. Crystalline Form R of febuxostat, as defined in any of claims 1-6, in the manufacture of
a medicament for use in chronic management of hyperuricemia in patients with gout.