STABLE CRYSTAL FORM OF FEBUXOSTAT AND PROCESS FOR THE PREPARATION THEREOF

BACKGROUND OF INVENTION:

Febuxostat(I) is approved under the trademark Uloric ® by the US Food and Drug Administration for the treatment hyperuricemia and gouty arthritis.

PCT publication no. WO 1992/109279 describes Febuxostat. PCT publication no. WO 1999/065885, PCT publication no.WO 2003/082279, PCT publication no. WO 2008/067773, CN 100546985, CN 101139325, CN 101085761, CN 101412700, CN 101386605, CN101648926, CN101671314, CN 101684107 and Heterocycles, 47,2, 857-864 describe various crystalline forms of Febuxostat including forms A,B,C,D,G,H,I,J,K and M as well as an amorphous form.

SUMMARY OF INVENTION:

The present invention relates to the solid state physical properties of Febuxostat, 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxylic acid. Important solid state properties of a pharmaceutical substance are its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences because it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the blood stream. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorph form of a substance. The polymorphic form may give rise to thermal behavior different form that of the amorphous material (or) another polymorphic form.

Thermal behavior is measured in the laboratory by such techniques as capillary melting point, Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC), and may be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct properties that may be detectable by X-Ray Powder Diffraction (XRPD) solid state 13CNMR spectrometry and infrared spectrometry.

The various characteristics and properties of the polymorphic forms of a substance e.g. shape, color, density and the like, will make one polymorphic form preferable over the others for production and /or pharmaceutical compounding. As a result, a very first step in the processes of product development of a new pharmaceutical agent is the determination of whether it exists in polymorphic forms and if so which of such form possesses advantages for the eventual commercial pharmaceutical application.

We undertook a detailed study of the solid state physical properties of the polymorphic forms of Febuxostat. The presumption was that these properties may be influenced by controlling the conditions under Febuxostat are obtained in solid form.

The aim of the current studies is to investigate these aspects and invent a stable and reproducible crystal form having pharmaceutical compatibility and applicability.

Although several crystal forms are reported in literature, no mention is made on the stability or pharmaceutical applicability or solid state characteristics of these forms.

Novel FC-1 form of high HPLC purity (> 99.8%) can be prepared under certain specific conditions with improved physical properties such as greater stability and less hygroscopic etc thereby making it suitable for commercial pharmaceutical applications.

Our detailed studies by carrying out research and development work on polymorphic forms of Febuxostat and their processes for preparation surprisingly revealed the existence of a novel, stable polymorphic form of Febuxostat which is described herein after as FC-1 form having the characteristics mentioned below:

(i) The novel FC-1 form is not meta stable and is stable at room temperature and even at higher temperatures like 70°C. (ii) The novel FC-1 form is stable at normal and accelerated stress conditions like high humidity.

Such a stable highly pure (> 99.8%) FC-1 form of Febuxostat is hither to not known and is a novel polymorphic form. In addition, the form prepared by us now is also suitable for developing a pharmaceutical composition. Such a pharmaceutical composition containing FC-1 form is also not known earlier and is novel.

Accordingly the present invention provides highly pure (> 99.8%) FC-1 crystalline form of Febuxostat which is stable at room temperature and even at higher temperatures like 70°C and accelerated high humidity stress conditions having the XRD characteristics given in the Table-I.

According to still another embodiment of the present invention there is provided a process for the preparation novel crystalline form FC-1 of Febuxostat which is stable at room temperature and even at higher temperatures like 70°C and accelerated high humidity stress conditions, and having the characteristics given in Table 1 which comprises dissolving Febuxostat in solvents like tetrahydrofuran(THF), acetone clarifying the solution with activated carbon and adding the clear solution to an anti solvent like methanol and water at room temperature and maintaining the reaction mixture at room temperature for a period in the range of 3-6hours and, filtering to obtain the FC-1 crystal form. The crystal form FC-I of Febuxostat may also be obtained by crystallizing Febuxostat from solvent mixtures like methanol/n-butanol, methanol/ethyl acetate and isopropanol/water.

Fig.l of the drawings accompanying these specifications shows the X-Ray Powder Diffraction (XRPD) pattern which substantially depicts a typically pure sample of Febuxostat of FC-1 form prepared by the process disclosed in the Example-1 given below. The 29 values and intensities are tabulated in Table-1.

The other figures correspond to the data as detailed below: Figure -1- XRD spectrum of FC-1 form prepared as per Example -1 Figure - 2 - IR spectrum of FC-1 form prepared as per Example - 1 Figure - 3 - DSC thermo gram of FC-1 form prepared as per Example -1 Figure - 4 - TGA curve of FC-1 form prepared as per example-1 Figure - 5 - Crystal morphology of FC-1 form prepared as per example-1 Table-2 shows the heat stability of FC-1 form over the temperature range 70-75°C. The FC-1 form is shown to be non-meta stable and stable when heated at 70°C for 40 hours.

STABILITY OF FC-1 CRYSTAL FORM

Pure FC-1 crystal polymorph (1 gm) prepared by the process described in Example 1 was taken in a boiling test tube and heated gradually in oil bath the substance was examined by XRPD. The results are tabulated below The above data suggest that FC-1 form of Febuxostat is not meta stable and is fairly stable to heat even at 70°C/ 40hours.

Table-3 shows suitable ranges of active ingredients and excipients (weight %) and the preferred amounts for the present pharmaceutical formulations.

Table-4 shows the stability of FC-1 form of Febuxostat formulation and API under accelerated stress conditions (45±2°C, 75 ±5% RH, 6 months).

The stability of FC-1 form of Febuxostat in API and formulation in accelerated high humidity stress conditions is thus established.

The details of the invention are provided in the examples given below which are provided to illustrate the invention only and therefore they should not be construed to limit the scope of the invention.

EXAMPLES

Preparation of highly pure(>99.8%) 2-[3-cyano-4-(2-Methyl-propoxy)phenyl]-4-methyl-5-thiazole carboxylic acid (Febuxostat):

Example-1:

Ethyl 2-(3- cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate (17.0g, 0.045mol) was hydrolyzed using aqueous (4.0%) sodium hydroxide (4.08g, 0.102mol) solution in THF(170ml)and methanol( 127ml). The reaction was performed at 60-65°C for 30minutes. After reaction completion water (340ml) was added to the reaction mixture at room temperature, which then was acidified to about pH 2-3 with 1 N HC1 (90ml). The precipitated febuxostat was separated by filtration to yield crude wet product (23g, purity by HPLC-99.55%).

The crude wet product was dissolved in THF(72ml) at 50-55°C. Activated carbon(0.5) was charged to the clear solution and maintained at 50-55°C for 30minutes. The reaction mass was filtered and washed with THF(29ml). The filtrate was brought to room temperature and added slowly during one hour to the mixture of methanol(17ml) and water( 100ml) and stirred for 6hours . The product was filtered and washed with water(80ml) and vacuum dried at 60-65°C to yield Febuxostat (13g, 92%) of 99.92% HPLC purity. The product was identified as polymorphic form FC-1 by XRD, IR, DSC, TGA, crystal morphology (Figures-1 to 5). Water by Karl-fischer: 1.9%

Example-2:

Ethyl 2-(3- cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate (30.0g, 0.0788mol) was hydrolyzed using aqueous (4.0%) sodium hydroxide (7.2g, 0.180mol) solution in Acetone(350ml). The reaction was performed at 50°C for 60minutes. After completion of reaction, water (600ml) was added to the reaction mixture at room temperature, which then was acidified to about pH 2-3 with IN HC1 (150ml). The precipitated Febuxostat was separated by filtration to yield crude wet product(48g, purity by HPLC-99.57%).

The crude wet product was dissolved in acetone(300ml) at 50-55°C. Activated carbon(0.5) was charged to the clear solution and maintained at 50-55°C for 30minutes. The reaction mass was filtered and washed with acetone(60ml). Filtrate was brought to room temperature and water(3 60ml)was added slowly during one hour . The reaction mass was stirred for 6hours, filtered and washed with water( 150ml) . Filtered product was vacuum dried at 60-65°C to yield Febuxostat (22g, 88.3%) of 99.80% HPLC purity. The product was identified as FC-1 by XRD, IR, DSC, TGA, crystal morphology. Water by Karl-fischer: 1.8%

Example-3:

Ethyl 2-(3- cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate (20.0g, 0.0525mol) was hydrolyzed using aqueous (4.0%) sodium hydroxide (4.8g, 0.120mol) solution in THF(200ml)and methanol( 150ml). The reaction was performed at 60-65°C for 30minutes. After completion of reaction water (400ml) was added to the reaction mixture at room temperature, which then was acidified to about pH 2-3 with IN HC1 (100ml). The precipitated Febuxostat was separated by filtration and dried at 60-65°C to yield crude product(16g, purity by HPLC-99.5%).

The crude product was dissolved in a mixture of methanol(260ml)and n-butanol(130ml) at 50-55°C. Activated carbon(0.5) was charged to the clear solution and maintained at 50-55°C for 30minutes. The reaction mass was filtered and washed with methanol(40ml). Filtrate was brought to room temperature and cooled to 0-5°C for 3hours, filtered and washed with chilled methanol(40ml) . Filtered product was vacuum dried at 60-65°C to yield Febuxostat (llg, 66%) of 99.8% HPLC purity. The product was identified as FC-1 by XRD, IR, DSC, TGA, crystal morphology. Water by Karl-fischer: 1.9%

Example-4:

Ethyl 2-(3- cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate (20.0g, 0.0525mol) was hydrolyzed using aqueous (4.0%) sodium hydroxide (4.8g, 0.120mol) solution in THF(200ml)and methanol( 150ml). The reaction was performed at 60-65°C for 30minutes. After completion of reaction water (400ml) was added to the reaction mixture at room temperature, which then was acidified to about pH 2-3 with IN HC1 (100ml). The precipitated Febuxostat was separated by filtration and dried at 60-65°C to yield crude product(16g, purity by HPLC-99.5%).

The crude product was dissolved in a mixture of methanol(80ml)and ethyl acetate(80ml) at 50-55°C. Activated carbon(0.5) was charged to the clear solution and maintained at 50-55°C for 30minutes. Reaction mass was filtered and washed with methanol(40ml). Filtrate was brought to room temperature and stirred for 3hours, filtered and washed with chilled methanol(40ml) . Filtered product was vacuum dried at 60-65°C to yield febuxostat (9g, 54.2%) of 99.8% HPLC purity. The polymorph is identified as FC-1 by XRD, IR, DSC, TGA, crystal morphology. Water by Karl-fischer: 1.8%

Example-5:

Ethyl 2-(3- cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate (20.0g, 0.0525mol) was hydrolyzed using aqueous (4.0%) sodium hydroxide (4.8g, 0.120mol) solution in THF(200ml)and methanol( 150ml). The reaction was performed at 60-65°C for 30minutes. After completion of reaction water (400ml) was added to the reaction mixture at room temperature, which then was acidified to about pH 2-3 with IN HC1 (100ml). The precipitated Febuxostat was separated by filtration and dried at 60-65°C to yield crude product(16g, purity by HPLC-99.5%).

The crude product was dissolved in a mixture of isopropanol(640ml) at 50-55°C and water (640ml) . The reaction mass temperature was raised to 80°Cand maintained at the same temperature for 30minutes. Clear solution was brought to room temperature, filtered and washed with isopropanol(40ml). Filtered product was vacuum dried at 60-65°C to yield Febuxostat (9g, 54.1%) of 99.81% HPLC purity. The polymorph is identified as FC-1 by XRD, IR, DSC, TGA, crystal morphology. Water by Karl-fischer : 2.1%

ADVANTAGES OF THE INVENTION

1. The FC-1 polymorphic form of Febuxostat is stable at room temperature and at accelerated high humidity stress conditions (40oC, 75% RH, 6months).

2. The novel FC-1 polymorph of febuxostat is stable even at high temperatures like 70°C (40hours).
3. The novel FC-1 form prepared is suitable for pharmaceutical applications.

4. The process produces novel stable FC-1 polymorphic form of Febuxostat consistently

CLAIMS We Claim

1. A crystalline form FC-1 of Febuxostat of formula-(I)

2. A crystalline form FC-1 according to claim 1, which substantially shows the X-ray diffraction pattern depicted in figure-1.

3. A crystalline form FC-1 according to any one of the claims 1 to 2 is characterized by the Infra- red spectrum depicted in figure-2.

4. A crystalline form FC-1 according to any one of the claims 1 to 3 , which has a melting point of about 198°C defined as the peak temperature in differential scanning calorimetry depicted in figure-3.

5. A crystalline form FC-1 according to any one of the claims 1 to 4 is characterized by the Thermal gravimetric curve depicted in figure-4.

6. A crystalline form FC-1 according to claim 1 to 5 having needle-shaped crystals depicted by figure-5.

7. A process for the preparation of a novel FC-1 crystalline form of Febuxostat as claimed in claims 1-6 comprises crystallization or precipitation of crude Febuxostat from solvents THF, methanol, isopropanol, ethyl acetate, n-butanol, acetone, water and mixtures thereof.

8. A crystal form FC-1 of Febuxostat as claimed in claims 1-7 is stable at room temperature and under accelerated high humidity stress conditions (40°C, 75% RH, 6months).

9. A process for the preparation of a novel, stable FC-1 crystalline form of Febuxostat substantially as herein described with reference to the Example 1 to 5.