DESC:IMPROVED PROCESS FOR PREPARATION OF IVACAFTOR

INTRODUCTION
Aspects of the present application relate to an improved process for preparation of Ivacaftor, crystalline Ivacaftor form I and process for its preparation.
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.
The reported processes suffer from disadvantages including tedious workup procedures and multiple purifications using column chromatography.
There remains a need to provide a simple, economic, industrially viable processes for preparation of Ivacaftor.
SUMMARY
In the first embodiment, the present application provides an improved process for preparation of 2-bromo-4,6-di-tert-butyl-3-nitrophenyl compound of formula V,

wherein R is selected from straight or branched C1-C10 alkyl; or optionally substituted C1-C10 alkyl with one or more halogens; or -OR1 wherein R1 is selected from straight or branched C1-C10 alkyl or optionally substituted aryl or optionally substituted aralkyl; said process comprising:
(a) brominating 2,4-di-tertbutylphenol of formula II to provide 2-bromo-4,6-di-tert-butylphenol of formula III,

(b) protecting alcohol of compound of formula III to provide compound of formula IV, and

wherein R is defined above;
(c) nitrating compound of formula IV with suitable nitrating agent to provide 2-bromo-4,6-di-tert-butyl-3-nitrophenyl compound of formula V.

R is defined above;
wherein the steps (a) to (c) carried out in a single solvent selected from ketones, esters, ethers, unsubstituted or substituted aliphatic or alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles and polar aprotic solvents.
In the second embodiment, the present application further comprises converting the resultant compound of Formula V to Ivacaftor.

wherein R is defined above
In the third embodiment, the present application provides an improved process for preparation of 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate compound of formula Va, , said process comprising:

(a) brominating 2,4-di-tertbutylphenol of formula II to provide 2-bromo-4,6-di-tert-butylphenol of formula III,

(b) protecting alcohol of compound of formula III to provide compound of formula IVa, and

(c) nitrating compound of formula IVa with suitable nitrating agent to provide 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate of formula Va.

wherein the steps (a) to (c) are carried out in a solvent comprising cyclohexane.
In the fourth embodiment, the present application further comprises converting the resultant compound of Formula Va to Ivacaftor.

In the fifth embodiment, the present application provides crystalline Ivacaftor Form R1 characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 4.4 ? 0.2, 8.7 ? 0.2, 9.5 ? 0.2, 9.8 ? 0.2, 12.3 ? 0.2, 13.1 ? 0.2, 15.5 ? 0.2, 16.6 ? 0.2, and 24.8 ? 0.2degrees 2-theta.
In the sixth embodiment, the present application provides a process for the preparation of crystalline Ivacaftor Form R1, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising hexane or methanol or combination thereof; and
b) isolating crystalline Ivacaftor Form R1.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 depicts a PXRD pattern of crystalline Ivacaftor Form R1, obtained by the procedure of Example 4.
Fig 2 depicts a PXRD pattern of 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate, obtained by the procedure of Example 3.

DETAILED DESCRIPTION
In the first embodiment, the present application provides an improved process for preparation of 2-bromo-4,6-di-tert-butyl-3-nitrophenyl compound of formula V,

wherein R is selected from straight or branched C1-C10 alkyl; or optionally substituted C1-C10 alkyl with one or more halogens; or -OR1 wherein R1 is selected from straight or branched C1-C10 alkyl or optionally substituted aryl or optionally substituted aralkyl; said process comprising:
(a) brominating 2,4-di-tertbutylphenol of formula II to provide 2-bromo-4,6-di-tert-butylphenol of formula III,

(b) protecting alcohol of compound of formula III to provide compound of formula IV, and

wherein R is defined above;
(c) nitrating compound of formula IV with suitable nitrating agent to provide 2-bromo-4,6-di-tert-butyl-3-nitrophenyl compound of formula V.

R is defined above;
wherein the steps (a) to (c) carried out in a single solvent selected from ketones, esters, ethers, unsubstituted or substituted aliphatic or alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles and polar aprotic solvents.
Step (a) involves brominating 2,4-di-tertbutylphenol of formula II to provide 2-bromo-4,6-di-tert-butylphenol of formula III,

Suitable brominating agents that may be used in step (a) include N-Bromosuccinimide, bromine, N-Bromosaccharin, Tetrabutylammonium tribromide and the like or any other suitable reagents.
The reaction mixture obtained from step (a) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, the resulting product may be directly used for step (b) with or without isolation or it may be further purified, if isolated, to improve the purity of the product.
Step (b) involves protecting alcohol of compound of formula III to provide compound of formula IV, and

wherein R is selected from straight or branched C1-C10 alkyl; or optionally substituted C1-C10 alkyl with one or more halogens; or -OR1 wherein R1 is selected from straight or branched C1-C10 alkyl or optionally substituted aryl or optionally substituted aralkyl;
Suitable bases that may be used in step (b) include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, alkoxides such as sodium methoxide, potassium methoxide; organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, collidine 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, piperidine, 2-methylimidazole, 4-methylimidazole and the like or any other suitable bases known in the art.
The reaction mixture obtained from step (b) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other suitable techniques for the removal of solids. The product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (c) with or without isolation or it may be further purified, if isolated, to improve the purity of the product.
Step (c) involves nitrating compound of formula IV with suitable nitrating agent to provide 2-bromo-4,6-di-tert-butyl-3-nitrophenyl compound of formula V.

Suitable nitrating agents that may be used in step (c) include, mixture of nitric acid and sulfuric acid or any other suitable nitrating agents known in the art.
The reaction mixture obtained from step (c) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other suitable techniques for the removal of solids. The product of step (c) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, the resulting product may be directly used for next step with or without isolation or it may be further purified, if isolated, to improve the purity of the product.
Steps (a) to (c) may be carried out in a single solvent system comprising ketones, esters, ethers, unsubstituted or substituted aliphatic or alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents.
In the second embodiment, the present application further comprises converting the resultant compound of Formula V to Ivacaftor.

wherein R is defined above
In the third embodiment, the present application provides an improved process for preparation of 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate compound of formula Va, , said process comprising:

(a) brominating 2,4-di-tertbutylphenol of formula II to provide 2-bromo-4,6-di-tert-butylphenol of formula III,

(b) protecting alcohol of compound of formula III to provide compound of formula IVa, and

(c) nitrating compound of formula IVa with suitable nitrating agent to provide 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate of formula Va.

wherein the steps (a) to (c) are carried out in a solvent comprising cyclohexane.
In the fourth embodiment, the present application further comprises converting the resultant compound of Formula Va to Ivacaftor.

In the fifth embodiment, the present application provides crystalline Ivacaftor Form R1 characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 4.4 ? 0.2, 8.7 ? 0.2, 9.5 ? 0.2, 9.8 ? 0.2, 12.3 ? 0.2, 13.1 ? 0.2, 15.5 ? 0.2, 16.6 ? 0.2, and 24.8 ? 0.2degrees 2-theta.
In the sixth embodiment, the present application provides a process for the preparation of crystalline Ivacaftor Form R1, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising hexane or methanol or combination thereof; and
b) isolating crystalline Ivacaftor Form R1.
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 hexane or methanol or combination thereof; or
iii) providing a suspension by adding hexane or methanol or combination thereof 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 methanol or hexane or combination thereof.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the hexane or methanol or combination thereof, or less than about 60°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 crystalline Ivacaftor Form R1 from the solution obtained in step a). Isolation of crystalline Ivacaftor Form R1 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 crystalline Ivacaftor Form R1 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.
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 “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol and 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 “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate 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.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride and the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones and the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include acetonitrile, propionitrile, butanenitrile and the like.
A “polar aprotic solvents” include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, acetonitrile 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 2-bromo-4,6-di-tert-butylphenol. N-Bromosuccinamide (104 g) was added to the reaction mass containing 2,4-di-tertbutylphenol (100 g) in cyclohexane (1000 mL) at 12 °C and the resultant reaction mixture was stirred at 12 °C for 2 hours followed by stirred at 26 °C for 4 hours 15 minutes. Reaction mass was filtered and washed with cyclohexane (200 mL). Filtrate washed with water (200 mL), 5% sodium thio sulphate solution (500 mL), 5% sodium bicarbonate solution (500 mL) and concentrated in vacuo to afford title compound (72 g).
EXAMPLE 2: Preparation of 2-bromo-4,6-di-tert-butylphenyl methyl carbonate.
Solution of methyl chloroformate (23.85 g) in cyclohexane (48 mL) was slowly added to the reaction mixture containing 2-bromo-4,6-di-tert-butylphenol (48 g) cyclohexane (192 mL), dimethylformamide (24 mL) and triethylamine (34 g) at 28 °C. The resultant reaction mixture was stirred at 31 °C for 20 minutes. Water (96 mL) was added to the reaction mass at 32 °C and stirred for 10 minutes. Layers were separated, organic layer washed with aqueous hydrochloride solution (14.4 mL of concentrated HCl in 96 mL of water), sodium bicarbonate solution (4.24 g of sodium bicarbonate in 96 mL of water) and the resultant organic layer concentrated in vacuo to afford title compound (55 g).
EXAMPLE 3: Preparation of 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate
70% Nitric acid (184 g) was slowly added to the Sulfuric acid (400 g) at 10 °C and stirred for 15 minutes. Solution of 2-bromo-4,6-di-tert-butylphenyl methyl carbonate (200 g) and cyclohexane (800 mL) was slowly added to the mixture of sulfuric acid and nitric acid at 30 °C. The resultant reaction mixture was stirred at 45 °C for 2 hours 30 minutes. Layers were separated, organic layer quenched with sodium bicarbonate solution (78 g of sodium bicarbonate in 1000 mL of water) and stirred at 5 °C for 1 hour. Separated solid was filtered, washed with water (400 mL) cyclohexane (400 mL) and wet compound dried in in vacuo to afford title compound (170g).The above obtained compound (65 g) and cyclohexane (260 mL) was charged into a round bottom flask and stirred at 70 °C for 1 hour. Cooled to 28 °C and stirred at 28 °C for 3 hours. Separated solid was filtered, washed with cyclohexane (20 mL) and wet compound dried at 50 °C to afford title compound (55 g).
EXAMPLE 4: Preparation of Ivacaftor Form R1
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa?uorophosphate (12.03 g) was added to the reaction mass containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5 g), dimethylformamide (10 mL) and ethyl acetate (100 mL) at 26 °C and stirred for 10 minutes. Triethylamine (5.35 g) was slowly added to the reaction mass at 26 °C and stirred at 26 °C for 1 hour 30 minutes. 5-amino-2,4-di-tert-butylphenol (7.02 g) was added at 26 °C and the resultant reaction mass was stirred at 28 °C for 18 hours. Water (40 mL) was added to the reaction mass at 26 ° C and stirred for 15 minutes. Layers separated, organic layer washed with saturated aqueous sodium chloride solution (25 mL) and the resultant organic layer concentrated in vacuo. Hexane (25 mL) was added to the residue at 27 °C and stirred at 27 °C for 15 minutes. Separated solid was filtered and washed with hexane (10 mL). The obtained wet compound, methanol (30 mL) charged into flask and heated to 55 °C. Reaction mass was filtered through Hyflow at 50 °C and washed with methanol (10 mL). Cyclohexane (25 mL) was added to the filtrate at 27 °C, stirred at 27 °C for 10 minutes. Separated solid was filtered, washed with cyclohexane and dried at 50 °C to afford title compound (4.0 g).
,CLAIMS:1. An improved process for preparation of 2-bromo-4,6-di-tert-butyl-3-nitrophenyl compound of formula V,

wherein R is selected from straight or branched C1-C10 alkyl; or optionally substituted C1-C10 alkyl with one or more halogens; or -OR1 wherein R1 is selected from straight or branched C1-C10 alkyl or optionally substituted aryl or optionally substituted aralkyl; said process comprising:
(a) brominating 2,4-di-tertbutylphenol of formula II to provide 2-bromo-4,6-di-tert-butylphenol of formula III,

(b) protecting alcohol of compound of formula III to provide compound of formula IV, and

wherein R is defined above;
(c) nitrating compound of formula IV with suitable nitrating agent to provide 2-bromo-4,6-di-tert-butyl-3-nitrophenyl compound of formula V.

R is defined above;
wherein the steps (a) to (c) carried out in a single solvent selected from ketones, esters, ethers, unsubstituted or substituted aliphatic or alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles and polar aprotic solvents.
2. The process according to claim 1, further comprises converting the resultant compound of Formula V to Ivacaftor.

wherein R is defined above
3. An improved process for preparation of 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate compound of formula Va, , said process comprising:

(a) brominating 2,4-di-tertbutylphenol of formula II to provide 2-bromo-4,6-di-tert-butylphenol of formula III,

(b) protecting alcohol of compound of formula III to provide compound of formula IVa, and

(c) nitrating compound of formula IVa with suitable nitrating agent to provide 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate of formula Va.

wherein the steps (a) to (c) are carried out in a solvent comprising cyclohexane.
4. The process according to claim 3, further comprises converting the resultant compound of Formula Va to Ivacaftor.

5. Crystalline Ivacaftor Form R1 characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 4.4 ? 0.2, 8.7 ? 0.2, 9.5 ? 0.2, 9.8 ? 0.2, 12.3 ? 0.2, 13.1 ? 0.2, 15.5 ? 0.2, 16.6 ? 0.2, and 24.8 ? 0.2degrees 2-theta.
6. A process for the preparation of crystalline Ivacaftor Form R1, comprising:
a) providing a solution or suspension of Ivacaftor in a solvent comprising hexane or methanol or combination thereof; and
b) isolating crystalline Ivacaftor Form R1.