DESC:The following specification particularly describes the invention and the manner in
which it is to be performed:

SOLID FORMS OF IVACAFTOR
INTRODUCTION
Aspects of the present application relate to solid forms of ivacaftor and process for preparation thereof.
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. 7,495,103 and U.S. Patent No. 8, 476, 442 discloses process for preparation of ivacaftor and intermediates thereof.
U.S. Patent No. 9,139,530, U.S. Patent No. 8,471,029, U.S. Patent No. 8,163,772, U.S. Patent No. 8,674,108, U.S. Patent No. 9,550,735, U.S. Patent application No. 2016/280654, PCT application No. WO2015/128882A2 and WO2016/092561A2 discloses different crystalline forms of Ivacaftor.
The occurrence of different polymorphs is possible for some compounds. A single compound may give rise to a variety of solid forms having distinct physical properties. This variation in solid forms may be significant and may result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties. Because polymorphic forms can vary in their physical properties, regulatory authorities require that efforts shall be made to identify all polymorphic forms, e.g., crystalline, solvated, etc., of new drug substances.
The existence and possible number of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. However, new forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of pharmaceutical products. For example, in some cases, different forms of the same drug can exhibit very different solubility and dissolution rates. The discovery of new polymorphic forms enlarges selection of materials with which formulation scientists can design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, there remains a need for preparing new and stable polymorphic form of ivacaftor.
SUMMARY
In the first embodiment, the present application provides ivacaftor Form-R2 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 6.5 ? 0.2, 9.7 ? 0.2, 13.2 ? 0.2, 13.9 ? 0.2, 14.9 ? 0.2, 16.2 ? 0.2, 18.4 ? 0.2, 19.8 ? 0.2, 23.1 ? 0.2 and 23.7 ? 0.2 degrees 2theta.
In the second embodiment, the present application provides ivacaftor Form-R2 characterized by its PXRD pattern as illustrated by Figure 1.
In the third embodiment, the present application provides a process for preparation of ivacaftor Form-R2, comprising the steps of:
a) providing a solution or suspension of ivacaftor in a solvent comprising hexafluoroisopropanol; and
b) isolating ivacaftor Form-R2.
In the fourth embodiment, the present application provides amorphous ivacaftor characterized by its PXRD pattern as illustrated by Figure 2.
In the fifth embodiment, the present application provides a process for preparation of amorphous ivacaftor, wherein said process comprises heating ivacaftor Form-R2 to about 150 °C and cooling to room temperature.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 depicts a PXRD pattern of crystalline Ivacaftor Form R2, obtained by the procedure of Example 1.
Fig 2 depicts a PXRD pattern of amorphous Ivacaftor, obtained by the procedure of Example 2.
DETAILED DESCRIPTION
In the first embodiment, the present application provides ivacaftor Form-R2 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 6.5 ? 0.2, 9.7 ? 0.2, 13.2 ? 0.2, 13.9 ? 0.2, 14.9 ? 0.2, 16.2 ? 0.2, 18.4 ? 0.2, 19.8 ? 0.2, 23.1 ? 0.2 and 23.7 ? 0.2 degrees 2theta.
In the second embodiment, the present application provides ivacaftor Form-R2 characterized by its PXRD pattern as illustrated by Figure 1.
In the third embodiment, the present application provides a process for preparation of ivacaftor Form-R2, comprising the steps of:
a) providing a solution or suspension of ivacaftor in a solvent comprising hexafluoroisopropanol; and
b) isolating ivacaftor Form-R2.
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 a solvent comprising hexafluoroisopropanol; or
iii) providing a suspension of ivacaftor in a solvent comprising hexafluoroisopropanol.
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 hexafluoroisopropanol.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the hexafluoroisopropanol, or less than about 55°C, less than about 40°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 isolating Ivacaftor Form R2 from the solution or suspension obtained in step a). Isolation of Ivacaftor Form R2 in step b) 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 obtained in step a). 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 Ivacaftor Form R2 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 fourth embodiment, the present application provides amorphous ivacaftor characterized by its PXRD pattern as illustrated by Figure 2.
In the fifth embodiment, the present application provides a process for preparation of amorphous ivacaftor, wherein said process comprises heating ivacaftor Form-R2 to about 150 °C and cooling to room temperature.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, and the like.
An “aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has delocalized conjugated p system. Examples of an aromatic hydrocarbon solvent include benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C12 aromatic hydrocarbons and the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like.
An “alicyclic hydrocarbons” is an organic compound containing both aliphatic and cyclic carbon atoms. They contain one or more all-carbon rings which may be either saturated or unsaturated, but do not have aromatic character. Alicyclic hydrocarbons include cyclohexane, methylcyclohexane, cycloheptane and the like.
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 R2
Ivacaftor (5.0 g) and hexafluoroisopropanol (100 mL) charged into a round bottom flask at 24 °C, heated to 50 °C and stirred at 50 °C for 24 hours. Cooled to 30 °C and stirred at 30 °C for 30 minutes. Separated solid was filtered, washed with hexafluoroisopropanol (10 mL) and dried at 50 °C to afford title compound (4.9 g).
EXAMPLE 2: Preparation of amorphous Ivacaftor.
Ivacaftor Form-R2 (500 mg) was heated to 150 °C and slowly cooled to 28 °C to afford title compound.
EXAMPLE 3: Preparation of Ivacaftor Form R2
2-(1H-benzotriazol-1-yl)-1, 1, 3, 3-tetramethyluronium hexa?uorophosphate (48.1 g) was added to the reaction mass containing 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (20 g) and ethyl acetate (400 mL) at 26 °C. Triethylamine (21.4 g) was slowly added to the reaction mass at 26 °C, heated to 45 °C and stirred at 45 °C for 2 hours. 5-amino-2,4-di-tert-butylphenol (28.1 g) was added at 45 °C and the resultant reaction mass was stirred at 45 °C for 21 hours. 10% hydrochloric acid solution (100 mL) was slowly added to the reaction mass and stirred for 10 minutes. Layers were separated, organic layer washed with water (120 mL), 10% sodium bicarbonate solution (100 mL), the resultant organic layer divided in to two equal parts and one part of organic layer was concentrated in vacuo. Hexafluoroisopropanol (200 mL) was added to the crude at 26 °C, heated to 50 °C and stirred at 50 °C for 10 hour, at 30 °C for 3 hours. Separated solid was filtered at 30 °C, washed with hexafluoroisopropanol (40 mL) and dried at 50 °C to afford title compound (20.3 g).
,CLAIMS:WE CLAIM:

1. A process for preparation of ivacaftor Form-R2, comprising the steps of:
a) providing a solution or suspension of ivacaftor in a solvent comprising hexafluoroisopropanol; and
b) isolating ivacaftor Form-R2.

2. The process according to claim 1, wherein the solution or suspension of ivacaftor is provided at a temperature 0-60 °C.

3. The process according to claim 1, wherein the solution or suspension of ivacaftor is provided at 25-35 °C.

4. The process according to claim 1, wherein isolation of ivacaftor Form-R2 is isolated at 0-40 °C.

5. The process according to claim 1, wherein the isolation of ivacaftor Form-R2 is isolated at 25-35 °C.