DESC:INTRODUCTION
Aspects of the present application relate to an alternate process for preparation of Ivacaftor Form B.
The drug compound having the adopted name Ivacaftor, has a chemical name 4N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4oxoquinoline-3-carboxamide, and is represented by structure of formula I.

I
Ivacaftor is a is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R.
U.S. Patent No. 8,410,274 discloses crystalline Ivacaftor Form B and process for preparation thereof. PCT application No. WO2015/128882A2 discloses processes for preparation of Ivacaftor Form B using mixture of 2-Butanone and water as solvent.
There remains a need to provide a simple, economic, industrially viable processes for preparation of Ivacaftor Form B.

SUMMARY
In the first embodiment, the present application provides a process for the preparation of crystalline Ivacaftor Form B, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising
ethyl acetate;
b) optionally heating the solution or suspension obtained in step (a), and
c) isolating crystalline Ivacaftor Form B.
In the second embodiment, the present application provides a process for the preparation of crystalline Ivacaftor Form B, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising
dimethyl Carbonate;
b) optionally heating the solution or suspension obtained in step (a), and
c) isolating crystalline Ivacaftor Form B.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 depicts a PXRD pattern of crystalline Ivacaftor Form B, obtained by the procedure of Example 1.
Fig 1 depicts a PXRD pattern of crystalline Ivacaftor Form B, obtained by the procedure of Example 2.

DETAILED DESCRIPTION
In the first embodiment, the present application provides a process for the preparation of crystalline Ivacaftor Form B, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising
ethyl acetate;
b) optionally heating the solution or suspension obtained in step (a), and
c) isolating crystalline Ivacaftor Form B.
Providing a solution or suspension in step a) includes:
i) direct use of a reaction mixture containing Ivacaftor that is obtained in the
course of its synthesis; or
ii) dissolving Ivacaftor in ethyl acetate; or
iii) providing a suspension by adding ethyl acetate to the Ivacaftor
Any physical form of Ivacaftor may be utilized for providing the solution or suspension of Ivacaftor in step a). Optionally, when a hydrate of Ivacaftor is used, before or after step a) a water reduction or removal step may be carried out by the techniques known in the art such as distillation, heating, slurring in a suitable solvent and the like.
In embodiments, Ivacaftor obtained in the course of its synthesis may be dissolved or in ethyl acetate.
The dissolution temperatures may range from about 0 °C to about the reflux temperature of the ethyl acetate, or less than about 75 °C, or less than about 65 °C, or less than about 55 °C, less than about 40 °C, or less than about 30 °C, less than about 20 °C, less than about 10 °C, or any other suitable temperatures, as long as a clear solution of Ivacaftor is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step b) involves optionally heating the solution or suspension obtained in step (a). The solution or suspension obtained in step (a) may be heated to about 75 °C or about 70 °C or about 65 °C or about 60 °C or about 55 °C or about 50 °C or about 45 °C or about 40 °C or about 35 °C.
Step c) involves isolating crystalline Ivacaftor Form B from the solution or suspension obtained in step b). Isolation of crystalline Ivacaftor Form B in step c) may involve methods including cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Optionally, isolation may be effected by combining a suitable anti-solvent with the solution or suspension obtained in step b). Anti-solvent as used herein refers to a liquid in which Ivacaftor is less soluble or poorly soluble. An anti-solvent has no adverse effect on the quality of Ivacaftor and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptane, cyclohexane, or methylcyclohexane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; or any mixtures thereof.
The isolated crystalline Ivacaftor Form B may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Ivacaftor is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
In the second embodiment, the present application provides a process for the preparation of crystalline Ivacaftor Form B, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising
dimethyl carbonate;
b) optionally heating the solution or suspension obtained in step (a), and
c) isolating crystalline Ivacaftor Form B.
Providing a solution or suspension in step a) includes:
i) direct use of a reaction mixture containing Ivacaftor that is obtained in
the course of its synthesis; or
ii) dissolving Ivacaftor in dimethyl carbonate; or
iii) providing a suspension by adding dimethyl carbonate to the Ivacaftor

Any physical form of Ivacaftor may be utilized for providing the solution or suspension of Ivacaftor in step a). Optionally, when a hydrate of Ivacaftor is used, before or after step a) a water reduction or removal step may be carried out by the techniques known in the art such as distillation, heating, slurring in a suitable solvent and the like.
In embodiments, Ivacaftor obtained in the course of its synthesis may be dissolved in dimethyl carbonate.
The dissolution temperatures may range from about 0 °C to about the reflux temperature of the dimethyl carbonate, or less than about 85 °C, or less than about 75 °C, or less than about 65 °C, or less than about 55 °C, less than about 40 °C, or less than about 30 °C, less than about 20 °C, less than about 10 °C, or any other suitable temperatures, as long as a clear solution of Ivacaftor is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step b) involves optionally heating the solution or suspension obtained in step (a). The solution or suspension obtained in step (a) may be heated to about 85 °C or about 75 °C or about 70 °C or about 65 °C or about 60 °C or about 55 °C or about 50 °C or about 45 °C or about 40 °C or about 35 °C.
Step c) involves isolating crystalline Ivacaftor Form B from the solution or suspension obtained in step b). Isolation of crystalline Ivacaftor Form B in step c) may involve methods including cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Optionally, isolation may be effected by combining a suitable anti-solvent with the solution or suspension obtained in step b). Anti-solvent as used herein refers to a liquid in which Ivacaftor is less soluble or poorly soluble. An anti-solvent has no adverse effect on the quality of Ivacaftor and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptane, cyclohexane, or methylcyclohexane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; or any mixtures thereof.
The isolated crystalline Ivacaftor Form B may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Ivacaftor is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.

EXAMPLES
EXAMPLE 1: Preparation of Ivacaftor Form B
Ivacaftor (10 g) and ethyl acetate (250 mL) charged in to a round bottom flask, heated to 46 °C and stirred at 46 °C for 26 hours. Filtered the solid at 30 °C, washed with ethyl acetate (40 mL) and dried at 50 °C under vacuum to afford title compound (8.5 g).
EXAMPLE 2: Preparation of Ivacaftor Form B
Ivacaftor (10 g) and dimethyl carbonate (250 mL) charged in to a round bottom flask, heated to 46 °C and stirred at 46 °C for 26 hours. Filtered the solid at 30 °C, washed with dimethyl carbonate (40 mL) and dried at 50 °C under vacuum to afford title compound (8.7 g).
EXAMPLE 3: Preparation of Ivacaftor Form B
Ivacaftor (1 g) and dimethyl carbonate (10 mL) charged in to a round bottom flask at 27 °C and stirred at 27 °C for 26 hours. Filtered the solid at 27 °C, washed with dimethyl carbonate and dried to afford title compound (0.85 g).
EXAMPLE 4: Preparation of Ivacaftor Form B
Ivacaftor (1 g) and ethyl acetate (10 mL) charged in to a round bottom flask at 27 °C and stirred at 27 °C for 26 hours. Filtered the solid at 27 °C, washed with ethyl acetate and dried to afford title compound (0.9 g).
,CLAIMS:WE CLAIM:

1) A process for the preparation of crystalline Ivacaftor Form B, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising ethyl acetate;
b) optionally heating the solution or suspension obtained in step (a), and
c) isolating crystalline Ivacaftor Form B.

2) A process for the preparation of crystalline Ivacaftor Form B, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising dimethyl Carbonate;
b) optionally, heating the solution or suspension obtained in step (a), and
c) isolating crystalline Ivacaftor Form B.