FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"NOVEL POLYMORPHIC FORM OF FEBUXOSTAT"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thr, Kesar Solitaire,
Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

NOVEL POLYMORPHIC FORM OF FEBUXOSTAT

FIELD OF THE INVENTION

The present invention relates to novel polymorph of febuxostat hereinafter refer as β-crystalline form. The present invention further relates to processes for preparing β-crystalline form of febuxostat and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION

Chemically Febuxostat is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1, 3-thiazole-5-carboxylic acid. Febuxostat is known from U.S. Patent No. 5,614,520 and is represented by compound of general formula I.

Febuxostat is marketed in USA under proprietary name “ULORIC” and is indicated for the chronic management of hyperuricemia in patients with gout.

U.S. Patent No. 5,614,520 does not describe polymorphism and therefore it was assumed that the crystal form of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1, 3-thiazole-5-carboxylic acid described in the U.S. Patent No. 5,614,520 is an ethanolate.

U.S. Patent No. 6,225,474 disclose six polymorphic forms of febuxostat including an amorphous form and their preparation methods. The disclosed crystalline polymorphic forms referred as crystal A, B, C, D and G.

U.S. Patent Publication No. 2010 / 031770 disclose fourteen polymorphic forms of febuxostat and their preparation methods. The disclosed crystalline forms referred as form F1, form F2, form F3, form F4, form F5, form F6, form F7, form F8, form F9, form F10, form F11, form F12, form F13 and form F14.

PCT Publication No. 2008 / 067773 disclose febuxostat crystal types H, I and J and their preparation methods.

Chinese Patent Publication No. 101386605 discloses crystalline febuxostat polymorphic form K and preparation method thereof.

Chinese Patent Publication No. 101671314 discloses crystalline febuxostat polymorphic form α and preparation method thereof.

Chinese Patent Publication No. 101648926 discloses crystalline febuxostat polymorphic form Q and preparation method thereof.

Chinese Patent Publication No. 101824006 discloses crystalline febuxostat polymorphic form P and preparation method thereof.

Chinese Patent Publication No. 101824007 discloses crystalline febuxostat polymorphic form M and preparation method thereof.

Chinese Patent Publication No. 101928260 discloses crystalline febuxostat polymorphic forms R, S and T and preparation method thereof.

Chinese Patent Publication No. 101684107 discloses crystalline febuxostat polymorphic forms X, Y and Z and preparation method thereof.

Chinese Patent Publication No. 101805310 discloses crystalline febuxostat polymorphic form δ and preparation method thereof.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.

The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solutions, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Therefore, there is a need for additional solid state forms of febuxostat.

The present applicant of the patent has surprisingly found a new crystalline polymorphic form of febuxostat, which is designated as β-crystalline form.

SUMMARY OF THE INVENTION

A first aspect of the present invention is to provide a novel polymorph of febuxostat herein after referred as β crystalline form of febuxostat.

A second aspect of the present invention is to provide processes for preparing β crystalline form of febuxostat.

A third aspect of the present invention is to provide a pharmaceutical composition comprising β crystalline form of febuxostat.

A fourth aspect of the present invention is to provide a process for preparing β crystalline form of febuxostat comprising the steps of:
a. providing a solution of febuxostat in an ether solvent
b. gradually cooling the solution obtained in step a and,
c. isolating β crystalline form of febuxostat.

DETAIL DESCRIPTION OF THE INVENTION

A β crystalline form of febuxostat may be characterized by X-ray diffraction pattern having peaks at 5.8, 7.9, 11.6, 12.7, 16.8, 17.4, 18.2, 18.5, 20.5, 21.0, 23.3, 23.8, 25.9, 26.1 ± 0.1 degrees two theta.

A β crystalline form of febuxostat may be characterized by X-ray diffraction pattern as depicted in Figure 1.

A β crystalline form of febuxostat may be characterized by X-ray diffraction pattern having following peaks:

Pos. [°2Th.] Height [cts] Area [cts*°2Th.] FWHM [°2Th.] d-spacing [Å] Rel. Int. [%]
4.8544 75.66 16.85 0.1506 18.18885 0.52
5.8055 7806.07 1159.30 0.1004 15.21113 53.83
6.8494 44.13 8.74 0.1338 12.89492 0.30
7.9845 14502.46 2153.79 0.1004 11.06416 100.00
9.6307 11.75 3.49 0.2007 9.17626 0.08
11.6341 2139.01 370.61 0.1171 7.60022 14.75
12.7721 4694.43 697.18 0.1004 6.92549 32.37
14.3931 61.88 15.32 0.1673 6.14892 0.43
15.4854 95.69 23.68 0.1673 5.71757 0.66
16.1540 24.65 4.88 0.1338 5.48242 0.17
16.8595 377.48 74.75 0.1338 5.25456 2.60
17.4921 371.52 73.57 0.1338 5.06590 2.56
17.8162 42.85 6.36 0.1004 4.97447 0.30
18.1998 234.89 46.51 0.1338 4.87048 1.62
18.5464 216.09 58.83 0.1840 4.78024 1.49
20.3306 392.01 58.22 0.1004 4.36459 2.70
20.5578 1338.99 232.00 0.1171 4.31684 9.23
21.0080 217.62 48.48 0.1506 4.22534 1.50
22.3223 51.00 17.67 0.2342 3.97946 0.35
23.3406 170.31 33.72 0.1338 3.80808 1.17
23.8830 479.39 83.06 0.1171 3.72282 3.31
24.5759 56.51 8.39 0.1004 3.61940 0.39
25.9047 637.34 110.43 0.1171 3.43668 4.39
26.1754 258.56 44.80 0.1171 3.40175 1.78
26.7132 27.17 4.04 0.1004 3.33447 0.19
27.4104 9.38 2.79 0.2007 3.25122 0.06
28.5708 26.07 5.16 0.1338 3.12175 0.18
28.9146 71.01 21.09 0.2007 3.08541 0.49
29.3593 56.14 8.34 0.1004 3.03969 0.39
30.0816 55.43 10.98 0.1338 2.96832 0.38
30.5655 4.58 1.36 0.2007 2.92242 0.03
31.3081 92.05 22.78 0.1673 2.85478 0.63
32.5658 7.95 3.15 0.2676 2.74734 0.05
33.1322 14.32 5.67 0.2676 2.70165 0.10
34.4757 63.35 12.54 0.1338 2.59939 0.44
35.6618 19.06 3.77 0.1338 2.51560 0.13
36.0878 12.00 1.78 0.1004 2.48688 0.08
36.5487 18.23 4.51 0.1673 2.45657 0.13
36.8111 53.42 13.22 0.1673 2.43966 0.37
37.8524 17.57 4.35 0.1673 2.37490 0.12
38.5973 43.04 12.78 0.2007 2.33077 0.30

A β crystalline form of febuxostat may be characterized by infra-red spectrum as depicted in Figure 2.

The febuxostat used for the present invention may be prepared by methods known in the art such as those described in U.S. Patent No. 5,614,520, U.S. Patent No. 6,225,474; PCT Publication No. 2008 / 067773 and Chinese Patent Publication No. 101386605.

The febuxostat used for the present invention may be in the form of any of the various polymorphic forms known in the prior art including Febuxostat crystalline polymorphic forms A, B, C, D, G, H, I, J, K, Q, α, or febuxostat ethanolate form.

The solution of febuxostat in an ether solvent may be prepared by dissolving febuxostat in an ether solvent at a temperature in the range of 20°C to 80°C to get febuxostat solution in an ether solvent.

The examples of ether solvents may include diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, 1,4-dioxane or mixture(s) thereof.

The β crystalline form of febuxostat may be formed by gradually cooling the febuxostat solution in an ether solvent up to 20-30°C for a period of 4 hours to 20 hours to get β crystalline form of febuxostat.

The β crystalline form of febuxostat may further prepared by dissolving febuxostat in a mixture of ether and aliphatic hydrocarbon solvent at a temperature in the range of 20°C to 80°C and then gradually cooling the febuxostat solution in a mixture of ether and aliphatic hydrocarbon solvent up to 20-30°C for a period of 4 hours to 20 hours to get β crystalline form of febuxostat.

The examples of aliphatic hydrocarbons solvent may include but not limited to pentane, hexane, heptane, octane, nonane or mixture(s) thereof.

The β crystalline form of febuxostat may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.

The isolated β crystalline form of febuxostat may be dried at a temperature in the range of 40°C to 110°C for a period of 2 hours to 8 hours under reduced pressure.

A pharmaceutical composition of febuxostat comprising β crystalline form of febuxostat and pharmaceutically acceptable excipients

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts X-ray diffraction pattern of β crystalline form of febuxostat
Figure 2 depicts infra-red spectra of β crystalline form of febuxostat

XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: Continuous;
Step size [°2-theta]: 0.0170°;
Scan step time[s]: 51.04 seconds;
Sample spin: 15 rpm;
Sample holder: glass;
Measurement Temperature [°C]: 25
Anode Material: Cu
K-Alpha [Å]: 1.54060

Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

EXAMPLE
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example 1: Preparation of β crystalline form of febuxostat

Febuxostat (10gm) was dissolved in mixture of 1, 4-dioxane (800ml) and diethyl ether (350ml) at 70-80°C to get transparent solution. The resulting solution was cooled to 20-30°C and maintain at same temperature for 18 hours. The resulting solids were filter, washed with diethyl ether (5ml) and dried at 60-70°C for 6 hours to get title compound.
Yield: 9.8gm
Purity: 99.9% (By HPLC)
XRD: As depicted in Figure 1
IR: As depicted in Figure 2

Example 2: Preparation of β crystalline form of febuxostat

Febuxostat (10gm) was dissolved in mixture of 1, 4-dioxane (750ml) and heptane (400ml) at 70-80°C to get transparent solution. The resulting solution was cooled to 20-30°C and maintain at same temperature for 17 hours. The resulting solids were filter, washed with heptane (10ml) and dried at 60-70°C for 6 hours to get title compound.
Yield: 9.7gm
Purity: 99.9% (By HPLC)
XRD: As depicted in Figure 1
IR: As depicted in Figure 2

WE CLAIM

1. A compound which is β crystalline form of febuxostat having substantially the same X-ray diffraction pattern as shown in Figure 1.

2. The compound of claim 1, having X-ray diffraction pattern comprising the peaks at 5.8, 7.9, 11.6, 12.7, 16.8, 17.4, 18.2, 18.5, 20.5, 21.0, 23.3, 23.8, 25.9, 26.1 ± 0.1 degrees two theta.

3. The compound of claim 1, having substantially the same infrared spectrum as shown in Figure 2.

4. A process for preparing β crystalline form of febuxostat comprising the steps of:
a. providing a solution of febuxostat in an ether solvent
b. gradually cooling the solution obtained in step a and,
c. isolating β crystalline form of febuxostat.

5. The process according to claim no. 4 wherein, the solution of febuxostat in an ether solvent is prepared by dissolving febuxostat in an ether solvent at a temperature in the range of 20°C to 80°C.

6. The process according to claim nos. 4 and 5 wherein, the examples of ether solvents is selected from the group comprising of diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, 1,4-dioxane or mixture(s) thereof.

7. The process according to claim no. 5 wherein, β crystalline form of febuxostat is formed by gradually cooling the febuxostat solution in an ether solvent up to 20-30°C for a period of 4 hours to 20 hours to get β crystalline form of febuxostat.

8. A process for preparing β crystalline form of febuxostat comprises dissolving febuxostat in a mixture of ether and aliphatic hydrocarbon solvent such as pentane, hexane, heptane, octane, nonane at a temperature in the range of 20°C to 80°C and then gradually cooling the febuxostat solution in a mixture of ether and aliphatic hydrocarbon solvent up to 20-30°C for a period of 4 hours to 20 hours.

9. The process according to claim nos. 4 and 8 wherein, the β crystalline form of febuxostat is dried at a temperature in the range of 40°C to 110°C for a period of 2 hours to 8 hours under reduced pressure.

10. A pharmaceutical composition of febuxostat comprising β crystalline form of febuxostat and pharmaceutically acceptable excipients.