DESC:
FIELD OF INVENTION
The present invention relates to novel polymorph of ivacaftor and process for its preparation.

BACKGROUND OF THE INVENTION
Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula I:

Ivacaftor was approved by FDA and marketed by Vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO® in the form of 150 mg oral tablets.
WO2006/002421 publication discloses modulators of ATP-binding cassette transporters such as ivacaftor. This patent generally discloses a process for the preparation of modulators of ATP-binding cassette transporters such as quinoline compounds; however, specific process for the preparation of ivacaftor and its solid-state details were not specifically disclosed.
WO2007/079139 publication discloses Form A, Form B and amorphous form of ivacaftor characterized by PXRD, DSC and TGA and process for their preparation. Further this publication discloses ethanol solvate of ivacaftor in example part.
WO2009/038683 publication discloses the solid forms of ivacaftor, which are designated as Form-I (2-methylbutyric acid), Form-II (propylene glycol), Form-III (PEG400.KOAc), Form-IV (lactic acid), Form-V (isobutyric acid), Form-VI (propionic acid), Form-VII (ethanol), Form-VIII (2-propanol), Form-IX (monohydrate), Form-X (besylate Form A), Form-XI (besylate Form B), Form-XII (besylate Form D), Form-XIII (besylate Form E), Form-XIV (besylate Form F), Form-XV (besylate (2:1)), Form-XVI (besylate mono hydrate). This publication also discloses the characterization details like PXRD, DSC and TGA for the above forms and process for their preparation.
WO2011/116397 publication discloses crystalline Form C of ivacaftor, process for its preparation and pharmaceutical composition comprising the same. Also discloses characterization details of Form C, such as PXRD, IR, DSC and 13CSSNMR.
WO2013/158121 publication discloses solvated forms of ivacaftor, which are designated as Form D (acetonitrile or acetonitrile/water (75/25) solvate), Form E (Methyl ethyl ketone (MEK), MEK/water (90/1), MEK/water (90/10), MEK/water (80/20) solvate), Form F (acetonitrile/water (75/25) solvate), Form G (isopropyl acetate solvate), Form H (isopropyl acetate/water (95/5) solvate), Form I (MEK solvate), Form J (MEK/water (99/1) solvate), Form K (MEK or MEK/water (99/1) or MEK/water (90/10) or MEK/water (80/20) solvate), Form L (isopropyl acetate/water (95/5) solvate), Form M (MEK or MEK/water (99/1) solvate), Form N (MEK/water (90/10) or MEK/water (80/20) solvate), Form O (MEK or MEK/water (99/1) solvate), Form P (MEK/water (90/10) or MEK/water (80/20) solvate), Form Q (MEK/water (80/20) solvate), Form R (acetonitrile solvate), Form S (MEK/water (80/20) solvate), Form T (isopropyl acetate/water (95/5) solvate), Form W (acetonitrile/water (90/10) solvate), Form XX (from 10% water/acetonitrile) and hydrate B (hydrated form). This patent further discloses characterization details like PXRD and TGA for the above forms and process for their preparation.
WO2014/118805 publication discloses crystalline forms of ivacaftor designated as Form D, Form E, Form E1, Form G and Form G'; amorphous ivacaftor designated as Form I and Form II; crystalline ivacaftor solvates such as n-butanol solvate, methanol solvate, propylene glycol solvate, DMF solvate, THF solvate, DMF: ethyl acetate solvate. This publication further discloses the process for the preparation of said forms along with their characterization details.
WO2015/070336 publication discloses polymorphic form APO-I and MIBK solvate of ivacaftor along with its characteristic PXRD details, process for its preparation and pharmaceutical composition comprising them.
CN 104725314A publication discloses ivacaftor new polymorph D, which is obtained by crystallization of ivacaftor from acetonitrile/water. This publication further discloses characteristic details such PXRD, IR and DSC of ivacaftor new polymorph D.
PCT Publication Nos 2015/128882 and 2016/057730 disclose various crystalline forms of ivacaftor, including co-crystals and the preparation thereof.
Although the above-mentioned crystalline forms have been disclosed, new solid forms of ivacaftor are still needed for enhancing the efficacy of ivacaftor in the treatment of cancers, as well as for improving the processes of preparing them. In particular, new crystalline forms of ivacaftor are needed in the manufacture of pharmaceutical formulations. The present invention meets this need, providing a novel crystalline form of ivacaftor and a process for preparing the crystalline form.

SUMMARY OF THE INVENTION
In one aspect, the invention provides novel crystalline form of ivacaftor, which is characterized by the XRD, TGA, DSC, DVS and NMR data described herein.
In another aspect, the invention provides a process for preparing the novel crystalline form of ivacaftor.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows the characteristic powder X-ray diffraction (XRD) pattern of novel crystalline form of Ivacaftor
Fig. 2 shows the characteristic differential scanning calorimetry (DSC) thermogram of novel crystalline form of Ivacaftor
Fig. 3 shows the characteristic thermogravimetric analysis (TGA) of novel crystalline form of Ivacaftor
Fig. 4 shows the dynamic vapor sorption (DVS) measurement chart recorded for novel crystalline form of Ivacaftor
Fig. 5 shows the nuclear magnetic resonance (1H-NMR) recorded for novel crystalline form of Ivacaftor
Fig. 6 shows the nuclear magnetic resonance (13C-NMR) recorded for novel crystalline form of Ivacaftor

DETAILED DESCRIPTION OF THE INVENTION
In first embodiment, the invention provides a novel crystalline form of Ivacaftor characterized by an X-ray powder diffraction pattern including peaks at 4.8, 9.4 degrees 2? (± 0.2 degrees 2?).
In another embodiment, the invention provides a novel crystalline form of Ivacaftor characterized by an X-ray powder diffraction pattern including further peaks at 11.4, 11.8, 13.4, 22.4 & 29.1 degrees 2? (± 0.2 degrees 2?).
In another embodiment, the present invention provides novel crystalline Ivacaftor, characterized by a X-ray powder diffraction (XRD) substantially in accordance with FIG. 1.
In another embodiment, the present invention provides novel crystalline Ivacaftor, characterized by a differential scanning calorimetry (DSC) substantially in accordance with FIG. 2.
In another embodiment, the present invention provides novel crystalline Ivacaftor, characterized by a thermogravimetric analysis (TGA) substantially in accordance with FIG. 3.
In another embodiment, the present invention provides novel crystalline Ivacaftor, characterized by a dynamic vapor sorption (DVS) substantially in accordance with FIG. 4.
In another embodiment, the present invention provides novel crystalline Ivacaftor, characterized by a nuclear magnetic resonance (1H-NMR) substantially in accordance with FIG. 5.
In another embodiment, the present invention provides novel crystalline Ivacaftor, characterized by a nuclear magnetic resonance (13C-NMR) substantially in accordance with FIG. 6.
In another embodiment, the present invention provides a process for preparation of novel form of Ivacaftor comprising:
a) Dissolving crude Ivacaftor in a suitable solvent at suitable temperature
b) Add the solution of step a) to suitable anti-solvent
c) Isolation of the product from Step b).

In another embodiment, the present invention provides a process for preparation of novel form of Ivacaftor comprising:
a) Dissolving crude Ivacaftor in a suitable solvent at suitable temperature
b) Add the solution of step a) to suitable anti-solvent
c) Stir the solution formed in step b) at suitable temperature
d) Filter the product formed in step c) and dried.
The crude ivacaftor which is used as a starting material is known in the art and can be prepared by any known methods.
A variety of solvents are suitable for dissolving the crude ivacaftor (step a) and can be used for forming the solution in the process of the invention. Examples of suitable solvents include, but are not limited to 2-methyl tetrahydrofuran
A variety of anti-solvents are suitable for step b). Examples of suitable anti-solvents include, but are not limited to n-heptane, n-hexane and the like.

In preferred embodiment, the present invention provides a process for preparation of novel form of Ivacaftor comprising:
a) Dissolving crude Ivacaftor in a 2-methyl tetrahydrofuran at 25°C
b) Add the solution of step a) to n-heptane
c) Stir the solution formed in step b) at 15°C for 3 hours
d) Filter the product formed in step c) and dried.

ADVANTAGES
Involves preparation of novel polymorph via easily scalable process through anti-solvent precipitation method without requirement of special techniques like spray-dryer, lyophilizer.

Example 1: Preparation of N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I)
To a glass vessel equipped with a stirrer and thermometer probe were added 4-oxo-1,4 dihydroquinoline-3 -carboxylic acid (IVF-10, 10.0g, 1.0eq.), HATU (24.11g, 1.2eq.), Triethylamine (16.02g, 3.0eq.), dissolved in DMF (80.0 ml, 8.0 vol.) at 25 oC and stir for 30 minutes. To the reaction mass 5-amino di-tert-butylphenol (IVF-02, 14.04g, 1.2 eq.) added in lot wise fashion at 25 oC and the reaction maintained at same temperature for 5.0 hours. Reaction mass concentrated and ethanol (50ml, 5.0 vol.) was added to the reaction mass and stirred for 2.0 hours at 25 oC, then mass was filtered. The material was dried under vacuum at 90 oC. The dried material (10.0g, 1.0eq.) was dissolved in 2-Methyl THF (220 ml, 22.0 vol.) at 50 -55 oC and it was added slowly to n-heptane (250 ml, cooled at 0-5 oC) by maintaining reaction mass temperature at 0-5 oC. The reaction mass maintained at 15-20 oC for 5.0 hours. The mass was filtered, washed with n-heptane (20.0ml, 2.0 vol.) and dried at 90-95 oC under vacuum to obtain N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I).

Example 2 : Preparation of N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I)
To a glass vessel equipped with a stirrer and thermometer probe were added 4-oxo-1,4 dihydroquinoline-3 -carboxylic acid (IVF-10, 10.0g, 1.0eq.), HATU (24.11g, 1.2eq.), Triethylamine (16.02g, 3.0eq.), dissolved in DMF (80.0 ml, 8.0 vol.) at 25 oC and stir for 30 minutes. To the reaction mass 5-amino di-tert-butylphenol (IVF-02, 14.04g, 1.2 eq.) added in lot wise fashion at 25 oC and the reaction maintained at same temperature for 5.0 hours. Reaction mass concentrated and ethanol (50ml, 5.0 vol.) was added to the reaction mass and stirred for 2.0 hours at 25 oC, then mass was filtered. The material was dried under vacuum at 90 oC. The dried material (10.0g, 1.0eq.) was dissolved in 2-Methyl THF (220 ml, 22.0 vol.) at 50 -55 oC and n-heptane (250 ml, 25V) was added to the reaction mass at 50-55 0C. The reaction was maintained at 15-200 C for 5 hours. The mass was filtered, washed with n-heptane (20.0ml, 2.0 vol.), and dried at 90-950 C under vacuum to obtain N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I).

Example 3 : Preparation of N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide.(Formula I)
To a glass vessel equipped with a stirrer and thermometer probe were added 4-oxo-1,4 dihydroquinoline-3 -carboxylic acid (IVF-10, 10.0g, 1.0eq.), HATU (24.11g, 1.2eq.), Triethylamine (16.02g, 3.0eq.), dissolved in DMF (80.0 ml, 8.0 vol.) at 25 oC and stir for 30 minutes. To the reaction mass 5-amino di-tert-butylphenol (IVF-02, 14.04g, 1.2 eq.) added in lot wise fashion at 25 oC and the reaction maintained at same temperature for 5.0 hours. Reaction mass concentrated and ethanol (50ml, 5.0 vol.) was added to the reaction mass and stirred for 2.0 hours at 25 oC, then mass was filtered. The material was dried under vacuum at 90 oC. The dried material (10.0g, 1.0eq.) was dissolved in 2-Methyl THF (220 ml, 22.0 vol.) at 50 -55 oC and it was added slowly to n-hexane (250 ml, cooled at 0-5 oC) by maintaining reaction mass temperature at 0-5 oC. The reaction mass maintained at 15-20 oC for 5.0 hours. The mass was filtered, washed with n-hexane (20.0ml, 2.0 vol.) and dried at 90-95 oC under vacuum to obtain N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I).

Example 4 : Preparation of N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I)
To a glass vessel equipped with a stirrer and thermometer probe were added 4-oxo-1,4 dihydroquinoline-3 -carboxylic acid (IVF-10, 10.0g, 1.0eq.), HATU (24.11g, 1.2eq.), Triethylamine (16.02g, 3.0eq.), dissolved in DMF (80.0 ml, 8.0 vol.) at 25 oC and stir for 30 minutes. To the reaction mass 5-amino di-tert-butylphenol (IVF-02, 14.04g, 1.2 eq.) added in lot wise fashion at 25 oC and the reaction maintained at same temperature for 5.0 hours. Reaction mass concentrated and ethanol (50ml, 5.0 vol.) was added to the reaction mass and stirred for 2.0 hours at 25 oC, then mass was filtered. The material was dried under vacuum at 90 oC. The dried material (10.0g, 1.0eq.) was dissolved in 2-Methyl THF (220 ml, 22.0 vol.) at 50 -55 oC and n-hexane (250 ml, 25V) was added to the reaction mass at 50-55 0C. The reaction was maintained at 15-200 C for 5 hours. The mass was filtered, washed with n-hexane (20.0ml, 2.0 vol.), and dried at 90-950 C under vacuum to obtain N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I).

Example 5 :Preparation of N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide.(Fomula I)
To a glass vessel equipped with a stirrer and thermometer probe were added 4-oxo-1,4 dihydroquinoline-3 -carboxylic acid (IVF-10, 10.0g, 1.0eq.), HATU (24.11g, 1.2eq.), Triethylamine (16.02g, 3.0eq.), dissolved in DMF (80.0 ml, 8.0 vol.) at 25 oC and stir for 30 minutes. To the reaction mass 5-amino di-tert-butylphenol (IVF-02, 14.04g, 1.2 eq.) added in lot wise fashion at 25 oC and the reaction maintained at same temperature for 5.0 hours. Reaction mass concentrated and ethanol (50ml, 5.0 vol.) was added to the reaction mass and stirred for 2.0 hours at 25 oC, then mass was filtered. The material was dried under vacuum at 90 oC. The dried material (10.0g, 1.0eq.) was dissolved in 2-Methyl THF (120 ml, 12.0 vol.) at 50 -55 oC and it was added slowly to n-heptane (120 ml, cooled at 0-5 oC) by maintaining reaction mass temperature at 0-5 oC. The reaction mass maintained at 15-20 oC for 5.0 hours. The mass was filtered, washed with n-heptane (20.0ml, 2.0 vol.) and dried at 90-95 oC under vacuum to obtain N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I).

Example 6:Preparation of N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide.(Fomula I)
To a glass vessel equipped with a stirrer and thermometer probe were added 4-oxo-1,4 dihydroquinoline-3 -carboxylic acid (IVF-10, 10.0g, 1.0eq.), HATU (24.11g, 1.2eq.), Triethylamine (16.02g, 3.0eq.), dissolved in DMF (80.0 ml, 8.0 vol.) at 25 oC and stir for 30 minutes. To the reaction mass 5-amino di-tert-butylphenol (IVF-02, 14.04g, 1.2 eq.) added in lot wise fashion at 25 oC and the reaction maintained at same temperature for 5.0 hours. Reaction mass concentrated and ethanol (50ml, 5.0 vol.) was added to the reaction mass and stirred for 2.0 hours at 25 oC, then mass was filtered. The material was dried under vacuum at 90 oC. The dried material (10.0g, 1.0eq.) was dissolved in 2-Methyl THF (160 ml, 16.0 vol.) at 50 -55 oC and it was added slowly to n-heptane (120 ml, cooled at 0-5 oC) by maintaining reaction mass temperature at 0-5 oC. The reaction mass maintained at 15-20 oC for 5.0 hours. The mass was filtered, washed with n-heptane (20.0ml, 2.0 vol.) and dried at 90-95 oC under vacuum to obtain N-(2,4 di-tert-butyl-5- hydroxyphenyl)-4-oxo-1,4-dihyroquinoline-3-carboxamide (Formula I).
,CLAIMS:
1. A novel crystalline form of Ivacaftor characterized by an X-ray powder diffraction pattern including peaks at 4.8, 9.4 degrees 2? (± 0.2 degrees 2?).

2. The novel crystalline form of Ivacaftor according to claim 1, characterized by an X-ray powder diffraction pattern including further peaks at 4.8, 9.4, 11.4, 11.8, 13.4, 22.4 & 29.1 degrees 2? (± 0.2 degrees 2?).

3. The novel crystalline form of Ivacaftor according to claim 1, characterized by a X-ray powder diffraction (XRD) substantially in accordance with FIG. 1.

4. The novel crystalline form of Ivacaftor according to claim 1, characterized by a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) substantially in accordance with FIG. 2 and FIG. 3.

5. The novel crystalline form of Ivacaftor according to claim 1, characterized by a dynamic vapor sorption (DVS) substantially in accordance with FIG. 4.

6. The novel crystalline form of Ivacaftor according to claim 1, characterized by a nuclear magnetic resonance (1H-NMR) and (13C-NMR) substantially in accordance with FIG. 5 and FIG. 6.

7. A process for preparation of novel form of Ivacaftor comprising,
a) dissolving crude Ivacaftor in a suitable solvent at suitable temperature,
b) adding the solution of step a) into suitable anti-solvent; and
c) isolation of the product from Step b).

8. The process for preparation of Ivacaftor novel form according to claim 7, comprising,
a) dissolving crude Ivacaftor in a suitable solvent at suitable temperature,
b) adding the solution of step a) to suitable anti-solvent,
c) stirring the solution formed in step b) at suitable temperature; and
d) filtering the product formed in step c) and dried.

9. The process according to claim 7, wherein the suitable solvents is 2-methyl tetrahydrofuran and suitable anti-solvents include n-heptane and n-hexane.

10. The process for preparation of Ivacaftor novel form according to claim 7, comprising,
a) dissolving crude Ivacaftor in a 2-methyl tetrahydrofuran at 25°C,
b) adding the solution of step a) to n-heptane,
c) stirring the solution formed in step b) at 15°C for 3 hours; and
d) filtering the product formed in step c) and dried.