Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
  • B65B31/00—Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers

Definitions

• the present invention relates to novel crystalline Form of Febuxostat, i.e. 2-[3-cyano-4- (2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, denominated as Form- Mi.
• Present invention also relates to process for the preparation of Febuxostat Form .
• Febuxostat i.e. 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I is approved by USFDA for the treatment of hyperuricemia in patients with gout under the brand name of ULORIC.
• ULORIC is recommended at 40 mg or 80 mg once daily.
• US 6225474 discloses crystalline Forms A, B, C, D, G and amorphous form of Febuxostat. This patent also discloses method of producing crystalline Forms A, B, C, D, G and amorphous Form of Febuxostat.
• Crystalline Forms Fl, F2, F10, R, Rl, R2, R3, R4 and R5 of Febuxostat are disclosed US 20100317702, WO 201 110791 1 and WO 201 1080651.
• CN 101817801 discloses crystalline Form-K characterized by powder X-ray diffraction pattern having peaks at 5.65, 7.91, 11.52, 12.77, 14.29, 15.42, 16.75, 17.44, 18.14, 18.39, 20.47, 20.98, 22.23, 23.31, 23.81, 24.45, 25.89, 26.08, 28.92, 31.26 and 34.41 ⁇ 0.2 2 ⁇ .
• the present invention provides stable and industrially scalable crystalline form of Febuxostat and an improved process for the preparation of Febuxostat crystalline Form- K. OBJECT AND SUMMARY OF THE INVENTION:
• Principle object of the present invention is to provide novel crystalline Form-Mi of Febuxostat, i.e. 2-(3-cyano-4-isobutyloxyphenyI)-4-methyl-5-thiazolecarboxylic acid. Another object of the present invention also provides an improved process for the preparation of Febuxostat crystalline Form-K.
• One aspect of the present invention provides, a process for the preparation of Febuxostat crystalline Form-Mj comprising the steps of:
• One more aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• Another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• Yet another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• Figure 1 illustrates the powder X-ray diffraction pattern of Febuxostat Form-Mi.
• Figure 2 illustrates DSC thermogram of Febuxostat Form-Mi.
• Figure 3 illustrates the powder X-ray diffraction pattern of Febuxostat Form-K
• Figure 4 illustrates DSC thermogram of Febuxostat Form-K.
• Figure 5 illustrates TGA thermogram of Febuxostat Form-K.
• Figure 6 illustrates thermal ellipsoid plot of Febuxostat Form-K with atomic numbering scheme.
• Figure 7 illustrates powder X-ray diffraction patterns of Febuxostat Form-K (Experimental and Simulated pattern).
• the present invention relates to novel crystalline Form-Mi of Febuxostat, i.e. 2-(3-cyano- 4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
• Powder X-ray Diffraction The said polymorph of the present invention is characterized by their X-ray powder diffraction pattern.
• the X-ray diffraction patterns of said polymorphs of the invention were measured on 1) PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector and 2) Bruker AXS D8 Discover powder X-ray diffractometer equipped with a goniometer of ⁇ /2 ⁇ configuration, Variol monochromator and Lynx-Eye detector.
• the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
• DSC Differential Scanning Calorimetry
• the DSC measurements were carried out on TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30 - 300 °C purging with nitrogen at a flow rate of 50 mL/min. Standard aluminum crucibles covered by lids with three pin holes were used.
• TGA/DTA was recorded using the instrument TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30 - 300 °C purging with nitrogen at a flow rate of 25 mL/min.
• the main aspect of the present invention is to provide novel crystalline Form-Mi of Febuxostat.
• crystalline Febuxostat Form Mi is characterized by the powder X- ray diffraction having characteristic peaks 6.13, 9.06, 12.29, 17.44 and 25.81 ⁇ 0.2° 2 ⁇ .
• crystalline Form-Mi of Febuxostat is further characterized by the Powder X-ray diffraction as depicted in Figure 1.
• crystalline Form-Miof Febuxostat is further characterized by the DSC thermogram as depicted in Figure 2.
• Another aspect of the present invention provides a process for the preparation of Febuxostat crystalline Form-Mi comprising the steps of:
• the ester solvent used herein is Ethyl acetate.
• the input Febuxostat used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
• Febuxostat crystal is dissolved in ester solvent such as ethyl acetate at 50 - 60 °C and cooled to room temperature.
• ester solvent such as ethyl acetate
• the obtained solution optionally filtered to remove any undissolved particulate, and the clear solution is subjected to spray drying in a buchi mini spray dryer (Model B-290) to obtain crystalline Febuxostat Form-M i .
• One more aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• the ester solvent used herein is Ethyl acetate.
• the input Febuxostat used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
• Febuxostat is dissolved in ester solvent such as ethyl acetate at 50 - 60 °C and cooled to room temperature.
• ester solvent such as ethyl acetate
• the obtained solution optionally filtered to remove any undissolved particulate, and the clear solution is evaporated on agitated thin film dryer (ATFD) instrument, at 50 °C under reduced pressure (120 mm- Hg) to obtain Febuxostat Form-K.
• ATD agitated thin film dryer
• Another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• ester solvent used herein is Ethyl acetate.
• the solvent removed in step b is at temperature 70 - 80 °C.
• the input Febuxostat used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
• Febuxostat is dissolved in ester solvent such as ethyl acetate at 50 - 60 °C, cooled to room temperature (25 - 30 °C). The resulting solution is filtered through hyflow to remove any undissolved particulate and the solution was heated to 70 - 80 °C. The solvent was distilled out at the same temperature under reduced pressure to obtain Febuxostat Form-K.
• ester solvent such as ethyl acetate
• Yet another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• the ester solvent used herein is Ethyl acetate. In one more embodiment, the solvent removed in step b, is at temperature 70 - 80 °C.
• hydrocarbon solvents used herein are selected from cyclohexane and toluene.
• the input Febuxostat used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
• Febuxostat is dissolved in ester solvent such as ethyl acetate at 50 - 60 °C, cooled to room temperature (25 - 30 °C).
• ester solvent such as ethyl acetate
• the resulting solution is filtered through hyflow to remove any undissolved particulate and the solution was heated to 70 - 80 °C.
• the solvent is distilled out at the same temperature under reduced pressure and hydrocarbon solvents such as toluene or cyclohexane is added to the residue.
• the resulting is slurred, filtered and dried to obtain Febuxostat Form- .
• Yet another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• ester solvent used herein is Ethyl acetate.
• the reaction mass is filtered to separate any undissolved particulate.
• the filtrate is maintained for 30-120 minutes, preferably 60-90 minutes at 50 - 80 °C.
• the solvent is removed at a temperature of 30 - 70 °C under reduced pressure.
• hydrocarbon solvent used herein is selected from cyclohexane and toluene.
• the input Febuxostat used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
• Yet another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• the organic solvent is selected from ethanol, methanol, isopropanol, tetrahydrofuran or mixtures thereof.
• base is selected from alkali or alkali earth metal hydroxides like sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
• acid used in this invention for the neutralization is selected from acetic acid, formic acid, hydrochloric acid, sulfuric acid or phosphoric acid.
• ester solvent used herein is Ethyl acetate.
• hydrocarbon solvents used herein are selected from cyclohexane or toluene.
• the input Febuxostat used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
• Febuxostat is dissolved in organic solvents such as ethanol and tetrahydrofuran at 25 - 30 °C.
• organic solvents such as ethanol and tetrahydrofuran at 25 - 30 °C.
• this base such as sodium hydroxide is added and the solvent is distilled out at 60 - 70 °C.
• the reaction mass is cooled to 25 - 30 °C and water is added. This is neutralized with hydrochloric acid and ester solvent like ethyl acetate is added.
• the reaction mass is completely distilled out at 75 - 80 °C under reduced pressure and cooled to 25 - 30 °C.
• To the solid mass cyclohexane is added and filtered. The resulting solid is dried to obtain Febuxostat crystalline Form-K.
• Yet another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• alkyl ester of Febuxostat is selected from methyl or ethyl ester, preferably ethyl ester.
• the organic solvent is selected from ethanol, methanol, isopropanol, tetrahydrofuran or mixtures thereof.
• base is selected from alkali or alkali earth metal hydroxides like sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
• acid used in this invention for the neutralization is selected from acetic acid, formic acid, hydrochloric acid, sulfuric acid and phosphoric acid.
• ester solvent used herein is Ethyl acetate.
• hydrocarbon solvents used herein are selected from cyclohexane and toluene.
• ethyl ester of Febuxostat is dissolved in organic solvents such as ethanol and tetrahydrofuran at 25 - 30 °C.
• organic solvents such as ethanol and tetrahydrofuran at 25 - 30 °C.
• base such as sodium hydroxide is added and the solvent is distilled out at 60 - 70 °C.
• the reaction mass is cooled to 25 - 30 °C and water is added. This is neutralized with hydrochloric acid and ester solvent like ethyl acetate is added.
• the reaction mass is completely distilled out at 75 - 80 °C under reduced pressure and cooled to 25 - 30 °C.
• To the solid mass cyclohexane is added and filtered. The resulting solid is dried to obtain Febuxostat crystalline Form-K.
• Yet another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• the ester solvent used herein is Ethyl acetate.
• hydrocarbon solvents used herein are selected from cyclohexane and toluene.
• the input Febuxostat used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
• Yet another aspect of the present invention is to provide an improved process for the preparation of crystalline Form-K of Febuxostat comprising the steps of:
• the ester solvent used herein is Ethyl acetate and hydrocarbon solvent used herein is selected from cyclohexane and toluene.
• the preferable mixture of solvent is mixture of ethyl acetate and toluene.
• step b 30-70 % preferably 40-55 % of solvent is removed at a temperature of 50 - 100 °C preferably at atmospheric pressure.
• Febuxostat crystalline Form K is isolated by cooling the reaction temperature to 10 -40 °C, preferably 20- 35 °C followed by filtration.
• the input Febuxostat used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.
• Febuxostat Form K is characterized by single crystal X-ray diffraction as shown in Figure 6.
• the crystallographic data and atomic coordinates are incorporated respectively in Table 1 and Table 2.
• Table 1 Crystallographic Data of Febuxostat Form K from single crystal X-ray diffraction.
• Table 2 Atomic coordinates of Febuxostat Form K obtained from single crystal diffraction.
• the experimental PXRD pattern was matched with the simulated PXRD pattern obtained from single crystal X-ray diffraction as shown in Figure 7, which shows the phase purity of Form K.
• a further aspect of the present invention is to provide packaging conditions for the stable crystalline Form-K of Eebuxostat in a way to attain the polymorphic stability, there by increasing the shelf life of the product.
• the method for packaging crystalline Febuxostat Form-K comprises of placing Febuxostat Form-K in LDPE (low density polyethylene) bag under nitrogen atmosphere, placing the sealed bag in Triple laminated aluminum liner bag with vacuumised nitrogen sealing, placing the above Triple laminated aluminum bag into the outer bag of triple laminated aluminum bag and vacuumised nitrogen sealing and enclosing the triple laminated bag in closed HDPE (high density polyethylene) drums.
• LDPE low density polyethylene
• Example - 1 Process for the Preparation of crystalline Febuxostat Form-Mi
• Example - 2 Process for the Preparation of crystalline Febuxostat Form-Mi
• Example - 3 Process for the preparation of Febuxostat crystal Form-K
• Febuxostat Crystal A 5 g was dissolved in ethyl acetate (200 mL) at 50 - 60 °C and cooled to room temperature (25 - 30 °C). The resulting solution was filtered through hyflow to remove any undissolved particulate. The clear solution was evaporated on agitated thin film dryer (ATFD) instrument, at 50 °C under reduced pressure (120 mm- Hg). The resulted solid was collected and identified as crystalline febuxostat Form K.
• ATFD agitated thin film dryer
• Example - 4 Process for the preparation of Febuxostat crystal Form-K
• Febuxostat Crystal G 5g was dissolved in ethyl acetate (200 mL) at 50 - 60 °C and cooled to room temperature (25 - 30 °C). The resulting solution was filtered through hyflow to remove any undissolved particulate. The clear solution was evaporated on ATFD instrument at 65 °C under reduced pressure (120 mm-Hg). The resulted solid was collected and identified as crystalline febuxostat Form K.
• Example - 5 Process for the preparation of Febuxostat crystal Form-K 5 g of Febuxostat was dissolved in ethyl acetate (200 mL) at 70 - 80 °C and the solvent was removed on rotary evaporator at same temperature under reduced pressure. The resulted solid was collected and identified as crystalline febuxostat Form K.
• Example - 6 Process for the preparation of Febuxostat crystal Form-
• Example - 8 Process for the preparation of Febuxostat crystal Form-K
• Example - 10 Process for the preparation of Febuxostat crystal Form-K
• Example - 11 Process for the preparation of Febuxostat crystal Form-K
• Example - 12 Process for the preparation of Febuxostat crystal Form-K
• Example - 13 Process for the preparation of Febuxostat crystal Form-K
• the aqueous layer was extracted using ethyl acetate (100 mL) and dried over anhydrous Na 2 S0 4
• the reaction mass was distilled out completely at 75 - 80 °C under reduced pressure and cooled to 25 - 30°C.
• cyclohexane 100 mL was added, slurred for 2 hours at 25-30°C and filtered.
• the isolated solid was dried at 60°C under vacuum for 12 - 15h.
• the product obtained was identified as crystalline Febuxostat Form K.
• Example - 14 Process for the preparation of Febuxostat crystal Form-K
• reaction mass was cooled to 25 - 30°C, added water (100 mL) and neutralized with IN HC1. Then ethyl acetate (400 mL) was added to the reaction mass and stirred for 10 - 15 minutes at 25 - 30°C. The aqueous layer was extracted using ethyl acetate (100 mL) and dried over anhydrous Na 2 S0 4 . The reaction mass was distilled out completely at 75 - 80 °C under reduced pressure and cooled to 25
• Example - 15 Process for the preparation of Febuxostat crystal Form-K
• Example - 16 Process for the preparation of Febuxostat crystal Form-K
• Febuxostat Form-K was packed in LDPE bag under nitrogen atmosphere, twisted and tied with plastic fastener. It was inserted in Triple laminated aluminum liner bag with vacuumised nitrogen sealing. Both these bags were then put into the outer bag of triple laminated aluminum bag and vacuumised nitrogen sealing. Such poly bags were further packed in HDPE drums, closed with plastic lids having rubber gasket followed by locking ring and a metal seal and labeled.

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• 2012
  • 2012-11-14 EP EP12823213.9A patent/EP2780335B1/en active Active
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