DESC:FIELD OF THE INVENTION
The present invention provides a process for the preparation of stable ivacaftor crystalline form B.

BACKGROUND OF THE INVENTION
Ivacaftor is marketed by Vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO. Ivacaftor has a chemical name N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide and represented by formula I.

The U.S. Patent No. 7495103 discloses modulators of ATP-binding cassette transporters and also discloses methods of treating CFTR transporter mediated diseases using modulators of ATP-binding cassette transporters such as Ivacaftor.

The U.S. Patent No. 8,410,274 discloses solid dispersion of amorphous ivacaftor, crystalline form A of ivacaftor, crystalline ivacaftor form B and process for the preparation and pharmaceutical compositions thereof.

The U.S. Patent No. 8,163,772 and US Patent No. 8,674,108 discloses various solid forms of ivacaftor.

The U.S. Patent No. 8,883,206 discloses a pharmaceutical composition of ivacaftor in form of solid dispersion with HPMCAS along with other excipients.

The U.S. Patent No. 8,471,029 discloses crystalline form C of ivacaftor.

The US Patent No. US 9,701,639 B2 discloses co-crystals of ivacaftor and process for the preparation thereof.

The US Publication No. US2016280654 discloses ivacaftor APO-I form and ivacaftor methylisobutylketone solvate.

The PCT Publication no. WO 2015/128882 and Publication no. WO2016/092561 discloses various solid forms of ivacaftor.

The China Publication no. CN 104725314 describes ivacaftor crystal form D and process for the preparation thereof.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of stable crystalline ivacaftor form B.

The present invention also provides a process for the preparation of stable crystalline ivacaftor form B having HPLC purity more than 99.5% comprising:
a) dissolving ivacaftor in a solvent,
b) optionally adding anti-solvent, and
c) isolating crystalline ivacaftor form B.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts an X-Ray powder diffraction (XRPD) pattern of stable crystalline ivacaftor form B.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention provides a process for the preparation of stable crystalline ivacaftor form B.

Yet another aspect of the present invention provides a process for the preparation of stable crystalline ivacaftor form B comprising the steps of:
a) dissolving ivacaftor in a solvent,
b) optionally adding anti-solvent, and
c) isolating stable crystalline ivacaftor form B from reaction mixture thereof.

In yet another aspect of the present invention provides a process for the preparation of stable crystalline ivacaftor form B having HPLC purity more than 99.9% comprising the steps of:
a) dissolving ivacaftor in a solvent,
b) optionally adding anti-solvent, and
c) isolating stable crystalline ivacaftor form B from reaction mixture thereof.

According to the present invention, wherein solvent is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, polar aprotic solvents such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, protic solvent such as acetic acid and water or a mixture thereof.

According to the present invention, wherein anti-solvent is selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane, pet ether, xylene.
According to the present invention, isolating the ivacaftor form B by removal of the solvent by using suitable techniques such as distillation, distillation by using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, filtration, filtration under vacuum, decantation and centrifugation, or any other technique known in the art.
As used herein, the term “stable” includes ivacaftor form B that after exposure to a relative humidity of 60% at 25°C or 75% at 40°C, for a period of at least six months does not convert to any other polymorphic form or forms.

According to the present invention, wherein stable ivacaftor crystalline form B is characterized by having PXRD pattern substantially as depicted in Figure 1.

According to the present invention, wherein crystalline ivacaftor form B is characterized by having PXRD pattern comprising peaks at diffraction angles (2T) of 6.2 ± 0.2, 7.5 ± 0.2, 8.3 ± 0.2, 12.4 ± 0.2,14.6 ± 0.2, and 17.8 ± 0.2.

According to the present invention, wherein isolating crystalline ivacaftor form B by filtration or centrifugation having a purity more than 99.9% by HPLC method.

According to the present invention, ivacaftor form B is characterized by obtained by the process of the present invention is having a purity of greater than about 95%, or greater than about 98%, or greater than about 99.9%, when measured by using high performance liquid chromatography (HPLC);
Experimental Method:
1) HPLC Instrument and method details:
Instrument : HPLC equipped with Pump, injector, UV detector and Recorder.
Column : Zorbax SB-Aq (4.6 x 250mm), 5µm.
Wavelength : UV Detector 215 nm
Flow rate : 1.5mL/min
Injection volume : 5?L.
Auto sampler temperature: 10°C
Column oven temperature: 20°C.
2) Powder diffraction pattern Instrument and method details:
The X-ray powder diffraction pattern was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.540 Å), running at 45 kV and 40 mA.
The present invention is described in the following examples, however the scope of present invention is not limited by the examples.

Examples
Example 1
Process for the preparation of stable crystalline ivacaftor form B.
Ivacaftor (65 g; purity 99.3% by HPLC) was dissolved in mixture of 2-Methyl THF(325 ml) and aqueous sodium chloride solution (325 ml) at room temperature, stirred the mass and separate both the layers. Activated carbon (3 gm) was added to organic layers, filtered the mass through celite and distill off 2-Methyl THF. Added ethyl acetate (234 ml) and water (26 ml) to the residue, heat the mass to 60 to 70°C and cooled the mass to room temperature and added n-heptane (260 ml). The solid was filtered and washed with mixture of ethyl acetate and n-heptane. The obtained solid was dried under vacuum to give title compound.
Yield: 54 gm
Purity: 99.9% (by HPLC);

Example 2
Process for the preparation of stable crystalline ivacaftor form B.
Ivacaftor (120 g; purity 99.3% by HPLC) having purity 99.3% by HPLC was dissolved in a mixture of 2-Methyl THF (325 ml) and aqueous sodium chloride solution (325 ml) at room temperature, stirred the mass and separate both the layers. Activated carbon (3 gm) was added to organic layers, filtered the mass through celite and distill off 2-Methyl THF. Added ethyl acetate (216 ml) and water (24 ml) to the residue, heat the mass to 60 to 70°C and cooled the mass to 0-10°C.The solid was filtered and washed with mixture of ethyl acetate and water. The obtained solid was dried under vacuum to give title compound.
Yield: 90 gm; Purity: 99.98% (by HPLC).

Example 3
Process for the preparation of stable crystalline ivacaftor form B.
Ivacaftor (110 g) was dissolved in a mixture of 2-Methyl THF (325 ml) and water at room temperature, stirred the mass and separate both the layers. Activated carbon (3 gm) was added to organic layers, filtered the mass through celite and distill off 2-Methyl THF. Added Acetonitrile (500 ml) to the residue, heat the mass to 70°C and cooled the mass to 25-35°C.The solid was filtered and washed with Acetonitrile. The obtained solid was dried under vacuum to give title compound.
Yield: 80 gm; Purity: 99.27% (by HPLC).
,CLAIMS:1. A process for the preparation of stable crystalline ivacaftor form B comprising the steps of:
a) dissolving ivacaftor in a solvent,
b) optionally adding anti-solvent, and
c) isolating stable crystalline ivacaftor form B from reaction mixture thereof.

2. The process as claimed in claim 1, wherein the suitable solvent is selected from one or more tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, acetonitrile, butyronitrile, isobutyronitrile and water or mixtures thereof.

3. The process as claimed in claim 1, wherein, the anti-solvent is selected from n-hexane, n-heptane, cyclohexane.

4. A process for the preparation of stable crystalline ivacaftor form B comprising the steps of:
a) dissolving ivacaftor in 2-methyl THF,
b) optionally adding sodium chloride solution,
c) removing the 2-methylTHF and adding mixture of ethyl acetate and water,
d) heating the reaction mass to 60-70°C and cool the reaction mass,
e) adding n-heptane, and
f) isolating stable crystalline ivacaftor form B.

5. A process for the preparation of stable crystalline ivacaftor form B comprising:
a) dissolving ivacaftor in 2-methyl THF,
b) optionally adding sodium chloride solution,
c) removing the 2-methylTHF,
d) adding mixture of ethyl acetate and water,
e) heating the reaction mass to 60-70°C,cooling the reaction mass and
f) isolating stable crystalline ivacaftor form B.

6. A process for the preparation of stable crystalline ivacaftor form B comprising:
a) dissolving ivacaftor in 2-methyl THF,
b) removing the 2-methylTHF,
c) adding acetonitrile to the step b residue,
d) heating the reaction mass to 70°C, and
e) isolating stable crystalline ivacaftor form B.

7. The process as claimed in claim 1-6, wherein the stable crystalline ivacaftor form B having HPLC purity more than 99.9%.

8. The process as claimed in claim 1-6, wherein the stable crystalline ivacaftor form B having PXRD pattern comprising peaks at diffraction angles (2T) of 6.2 ± 0.2, 7.5 ± 0.2, 8.3 ± 0.2, 12.4 ± 0.2,14.6 ± 0.2, and 17.8 ± 0.2.

9. The process as claimed in claim 1-6, wherein the stable ivacaftor crystalline form B is characterized by having PXRD pattern substantially as depicted in Figure 1.