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

PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM OF LUMACAFTOR

INTRODUCTION
Aspects of the present application relate to processes for the preparation of crystalline form of Lumacaftor, and pharmaceutical compositions thereof. Specific aspects of the present application relate to processes for the preparation of amorphous form and crystalline Form I of Lumacaftor.
The drug compound having the adopted name “Lumacaftor” has chemical name: 3-{6-{[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropane carbonyl]amino}-3-methylpyridin-2-yl}benzoic acid as below.

Lumacaftor partially corrects the fundamental molecular defect caused by F508del-CFTR to increase the amount of functional F508del-CFTR at the cell surface, resulting in enhanced chloride transport. The channel gating activity of F508del-CFTR delivered to the cell surface by Lumacaftor can be potentiated by Ivacaftor to further enhance chloride transport. When added to F508del/F508del-HBE, the magnitude of chloride transport observed with the combination of Lumacaftor and either acute or chronic Ivacaftor treatment was greater than that observed with Lumacaftor alone. Orkambi is approved in US and Europe as a fixed dose combination (FDC) pink immediate-release film-coated tablet for oral administration. Orkambi contains 200 mg of Lumacaftor and 125 mg of Ivacaftor as active substances. US FDA label prescribes two tablets to be taken orally every 12 hours for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.
US 8993600 B2 discloses Lumacaftor as compound-396, its pharmaceutical use for the treatment of cystic fibrosis. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Lumacaftor by reacting N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2- difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. However, it is not disclosed about the nature of compound prepared by the process disclosed therein.
US 8507534 B2 discloses Lumacaftor in crystalline Form I characterized by one or more peaks at 15.2 to 15.6 degrees, 16.1 to 16.5 degrees, and 14.3 to 14.7 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. Lumacaftor Form I was prepared either by dispersing or dissolving a salt form, such as HCl, of Lumacaftor in an appropriate solvent for an effective amount of time (or) directly by treating t-butyl ester intermediate of Lumacaftor with an appropriate acid, such as formic acid. US 8507534 B2 further discloses the reaction of tert-butyl-3-(6-amino-3-methylpyridin-2-yl) benzoate with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride in the presence of base for the preparation of Lumacaftor.
US 8507687 B2 discloses the crystalline Form A of Lumacaftor, which is a isostructural solvate with methanol, ethanol, 2-propanol, acetone, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, 2-methyl tetrahydrofuran and a crystalline Form A of Lumcaftor HCl salt.
Prior art processes does not disclose an amenable process for the preparation of crystalline Form I of Lumacaftor and there remains a need for alternate process for the preparation of crystalline Form I of Lumacaftor in a cost effective and industrially viable manner.

SUMMARY
In an aspect, the present application provides a process for the preparation of crystalline Form I of Lumacaftor, comprising the steps of:
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) optionally contacting the solution obtained in step a) with an anti-solvent;
c) isolating crystalline Form I of Lumcaftor.
In another aspect, the present application provides a process for the preparation of crystalline Form I of Lumacaftor, comprising the step of converting amorphous Lumacaftor to crystalline Form I of Lumacaftor.
In another aspect, the present application provides a process for the preparation of amorphous form of Lumacaftor, comprising the steps of;
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) contacting the solution obtained in step a) with an anti-solvent;
c) isolating amorphous form of Lumacaftor.

In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form I of Lumacaftor obtained by the any of the processes as per the present application with atleast one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form I of Lumacaftor prepared by the method of Example No 2.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous form of Lumacaftor prepared by the method of Example No 5.

DETAILED DESCRIPTION
In the aspects, the present application provides processes for the preparation crystalline Form I of Lumacaftor. In the aspects of the present application, Lumacaftor that is used as starting material may be purified employing any of the purification techniques known in the art or procedures described or exemplified in the instant application, before using.

In an aspect, the present application provides a process for the preparation of crystalline Form I of Lumacaftor, comprising the steps of:
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) optionally contacting the solution obtained in step a) with an anti-solvent;
c) isolating crystalline Form I of Lumcaftor.
In an embodiment, step a) of this aspect may be carried out by providing a solution of Lumacaftor in a suitable solvent or a mixture thereof.
Suitable solvent may be selected from the group comprising of alcohol solvents such as alcohol such methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, iso-butyl acetate; halogenated hydrocarbon such as dichloromethane, chloroform, tetrachloro methane; aromatic hydrocarbon such as toluene, xylene, cumene; ether solvents such as di ethyl ether, di isopropyl ether, tetrahydrofuran, dioxane, anisole; nitrile solvents such as acetonitrile, propionitrile; aprotic solvents such as dimethyl sulphoxide, formamide, dimethyl formamide, dimethyl acetamide, water and mixtures thereof. In an embodiment, the suitable solvent may be selected from the group comprising of, 1-propanol, ethyl acetate, dimethyl sulphoxide, water or mixture thereof.

In an embodiment, providing a solution at step a) may be carried out by dissolving Lumacaftor in a suitable solvent or by taking the reaction mixture containing Lumacaftor directly. Lumacaftor used in providing the solution of step a) may be in any solid form such as crystalline, amorphous or a mixture thereof. In an embodiment, a solution of Lumacaftor can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Lumacaftor may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
Step b) of this aspect may be carried out optionally by contacting the solution of step a) with an anti-solvent. The anti-solvent may be a solvent in which Lumacaftor has low solubility and which include, but not limited to water; hydrocarbons like n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane; ethers like diethyl ether, di isopropyl ether or mixtures thereof.
In an embodiment, the anti-solvent of step (b) may be contacted either by adding anti-solvent to the solution of step (a) or by adding the solution of step (a) to the anti-solvent.
In an embodiment, the anti-solvent of step (b) may be contacted with solution of step (a) for sufficient time for the crystallization of Form I of Lumacaftor. In embodiments, the anti-solvent of step (b) may be contacted with solution of step (a) either in one portion or multiple small portions or by drop wise addition.
In an embodiment, anti-solvent of step (b) may be contacted with solution of step a) at suitable temperature of about 0°C and reflux temperature of the solvent used.
In an embodiment, anti-solvent may be contacted in sufficient quantity to crystallize Form I of Lumacaftor from the reaction mixture.
In an embodiment, the mixture of step a) or step b) may be cooled to relatively lower temperatures to crystallize or complete the formation of crystalline Form I of Lumacaftor.
In an embodiment, the solution of Lumacaftor of step a) may be cooled to suitable temperature at which crystalline Form I is stable and / or readily crystallizes out from the solution. Solution of Lumacaftor of step a) may be cooled either drastically or gradually, at a constant or step wise cooling rate based on the required quality of the product such as chemical purity, particle size or shape.
In another embodiment, the mixture of step b) may be cooled to suitable temperature at which crystalline Form I is stable and / or completely crystallizes out.
The mixture of step a) or step b) may be stirred under suitable conditions in which crystalline Form I. In an embodiment, the mixture of step a) or step b) may be stirred at suitable temperature and for sufficient time to completely crystallize Form I of Lumacaftor. In an embodiment, the mixture may be stirred at a suitable temperature of about 0°C and above for atleast 0.5 hour or more.
Step c) of this aspect may be carried out by isolating crystalline Form I of Lumacaftor by employing any of the techniques known to a person skilled in art. Techniques for the isolation of crystalline Form I of Lumacaftor include, but not limited to: decantation, filtration by gravity or suction,
Crystalline Form I of Lumacaftor isolated at step c) may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In another aspect, the present application provides a process for the preparation of crystalline Form I of Lumacaftor, comprising the step of converting amorphous Lumacaftor to crystalline Form I of Lumacaftor.
In an embodiment, the step of converting amorphous Lumacaftor to crystalline Form I may be carried out by suspending or re-crystallizing amorphous Lumacaftor in a suitable solvent or mixture of solvents.
Re-crystallizing amorphous Lumacaftor may be carried out by according previous aspect or any of the methods or procedures described in the present application.
In an embodiment, amorphous Lumacaftor may be suspended in a suitable solvent or mixture of solvents under suitable conditions in which crystalline Form I is stable.
In an embodiment, suitable solvent may be selected from the group consisting of alcohol solvents such as water; aprotic solvents such as dimethyl sulphoxide, formamide, dimethyl formamide, dimethyl acetamide; alcohol such methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, iso-butyl acetate; halogenated hydrocarbon such as dichloromethane, chloroform, tetrachloro methane; aromatic hydrocarbon such as toluene, xylene, cumene; ether solvents such as di ethyl ether, di isopropyl ether, tetrahydrofuran, dioxane, anisole; nitrile solvents such as acetonitrile, propionitrile; and mixtures thereof.
In an embodiment, amorphous Lumacaftor may be suspended in water or aquesous organic solvent mixture under suitable conditions in which crystalline Form I is stable.
In an embodiment, amorphous Lumacaftor may be suspended in the solvent at suitable temperature between 0°C and reflux temperature of the solvent used. In an embodiment, amorphous Lumacaftor may be suspended in the solvent for sufficient time to complete the conversion of amorphous form to crystalline Form I of Lumcaftor for atleast 0.5 hours or more.
In an embodiment, the isolation of crystalline Form I of Lumacaftor may be carried out by employing any of the techniques known to a person skilled in art. Techniques for the isolation of Lumacaftor include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
Crystalline Form I of Lumacaftor may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In another aspect, the present application provides crystalline Form I of Lumacaftor obtained according any of the previous aspects. The present application provides a crystalline Form I of Lumacaftor having x-ray diffraction pattern as depicted in figure – 1.

In another aspect, the present application provides a process for the preparation of amorphous Lumacaftor, comprising the steps of;
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) contacting the solution obtained in step a) with an anti-solvent;
c) isolating amorphous form of Lumacaftor.
In an embodiment, step a) of this aspect may be carried out by providing a solution of Lumacaftor in a suitable solvent or a mixture thereof.
Suitable solvent may be selected from the group comprising of alcohol solvents such as alcohol such methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, iso-butyl acetate; halogenated hydrocarbon such as dichloromethane, chloroform, tetrachloro methane; aromatic hydrocarbon such as toluene, xylene, cumene; ether solvents such as di ethyl ether, di isopropyl ether, tetrahydrofuran, dioxane, anisole; nitrile solvents such as acetonitrile, propionitrile; aprotic solvents such as dimethyl sulphoxide, formamide, dimethyl formamide, dimethyl acetamide, water and mixtures thereof.
In an embodiment, providing a solution at step a) may be carried out by dissolving Lumacaftor in a suitable solvent or by taking the reaction mixture containing Lumacaftor directly. Lumacaftor used in providing the solution of step a) may be in any solid form such as crystalline, amorphous or a mixture thereof. In an embodiment, a solution of Lumacaftor can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Lumacaftor may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
Step b) of this aspect may be carried out optionally by contacting the solution of step a) with an anti-solvent. The anti-solvent may be a solvent in which Lumacaftor has low solubility and which include, but not limited to water; hydrocarbons like n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane; ethers like diethyl ether, di isopropyl ether or mixtures thereof.
In an embodiment, the anti-solvent of step (b) may be contacted either by adding anti-solvent to the solution of step (a) or by adding the solution of step (a) to the anti-solvent.
In an embodiment, the anti-solvent of step (b) may be contacted with solution of step (a) for sufficient time for the precipitation of amorphous Lumacaftor. In embodiments, the anti-solvent of step (b) may be contacted with solution of step (a) either in one portion or multiple small portions or by drop wise addition.
In an embodiment, anti-solvent of step (b) may be contacted with solution of step a) at suitable temperature of about 0°C and reflux temperature of the solvent used. In preferred embodiment, anti-solvent of step (b) may be contacted with solution of step a) at temperature of about 50°C and above.
In an embodiment, anti-solvent may be contacted in sufficient quantity to precipitate amorphous Lumacaftor from the reaction mixture.
In an embodiment, the mixture of a) or step b) may be cooled to relatively lower temperatures to complete the formation of amorphous form Lumacaftor.
In an embodiment, the mixture of step a) or step b) may be cooled to suitable temperature at which amorphous Lumacaftor is stable and / or does not crystallize. Mixture of step a) or step b) may be cooled either drastically or gradually, at a constant or step wise cooling rate based on the required quality of the product such as chemical purity, particle size or shape.
The mixture of step a) or step b) may be stirred under suitable conditions at which amorphous Lumacaftor is stable and / or does not crystallize. In an embodiment, the mixture of step a) or step b) may be stirred at suitable temperature and for sufficient time to complete precipitation of amorphous Lumacaftor.
Step c) of this aspect may be carried out by isolating amorphous form of Lumacaftor by employing any of the techniques known to a person skilled in art. Techniques for the isolation of amorphous of Lumacaftor include, but not limited to: decantation, filtration by gravity or suction,
Amorphous form of Lumacaftor isolated at step c) may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form I of Lumacaftor obtained according any of the previous aspects and atleast one additional pharmaceutically acceptable excipient.
The prior art exemplified the processes involving either the conversion of a salt of Lumacaftor such as HCl salt or the hydrolysis of an ester of Lumacaftor such as t. Bu ester to obtain crystalline Form I of Lumacaftor which are different from the processes of the present application. Further, the processes of present application are simple and industrially viable procedures to obtain crystalline Form I of Lumacaftor.
Amorphous form, its preparation methods or the process of converting amorphous form to crystalline form of Lumacaftor are not reported in the literature.
The processes of the aspects of the present application may be useful to enhance the chemical purity and stability of the product obtained.
In another aspect, the present application provides crystalline Form I of Lumacaftor or its pharmaceutical composition, wherein the chemical purity of Lumacaftor may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another aspect, the present application provides crystalline Form I of Lumacaftor or its pharmaceutical composition, wherein particle size (D90) of Lumacaftor may be less than 100 microns or less than 50 microns or less than 20 microns.
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. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and
referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
The terms “crystalline Form I of Lumacaftor" indicates that the Lumacaftor is present in substantially crystalline Form I. "Substantially" crystalline denotes that atleast 80 %, preferably 90 % or 95 %, more preferably all of the Lumacaftor is crystalline Form I. In other words, "crystalline Form I" of Lumacaftor denotes Lumacaftor, which does not contain substantial amounts, preferably does not contain noticeable amounts, of any other crystalline portions of Lumacaftor e.g. measurable upon X-ray powder diffraction analysis.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, ethylene glycol, diethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, 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-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, 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, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, 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, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

EXAMPLES
Example-1: Preparation of crystalline Form I of Lumacaftor.
Lumacaftor (0.5 g) was dissolved in ethyl acetate (10 mL) at 70°C and cooled the mixture to 27°C. This mixture was stirred at the same temperature for 1 hour and filtered the solid to obtain the title compound.
Example-2: Preparation of crystalline form I of Lumacaftor
Lumacaftor (0.5 g) was dissolved in 1-propanol (15 mL) at 65°C and cooled the mixture to 27°C. This mixture was stirred for 1 hour at the same temperature and filtered the solid to obtain title compound.
Example-3: Preparation of crystalline form I of Lumacaftor
Lumacaftor (0.5 g) was dissolved in methanol (20 mL) at 70°C and filtered the solution to make it particle free. This clear solution was added to water (30 mL) at 27°C and stirred for 4 hours at the same temperature. The solid was filtered to obtain the title compound.
Example-4: Preparation of crystalline form I of Lumacaftor
Amorphous Lumacaftor (0.2 g) was suspended in water (4 mL) at 27°C and stirred at the same temperature for 24 hours. The solid was filtered to obtain the title compound.
Example-5: Preparation of amorphous Lumacaftor.
Lumacaftor (0.2 g) was dissolved in dimethyl sulphoxide (1.2 mL) at 78°C and water (3 mL) was added at 80°C to this clear solution. This mixture was cooled to 25°C and stirred at the same temperature for 2.5 hours. Some of the reaction mass was filtered to obtain amorphous form of Lumacaftor.
Example-6: Preparation of crystalline form I of Lumacaftor
The remaining suspension of example-5 containing amorphous Lumacaftor in the mixture of dimethyl sulphoxide and water was stirred at 27°C for 5 hours and the solid was filtered to obtain the title compound.
,CLAIMS:1. A process for the preparation of crystalline Form I of Lumacaftor, comprising the steps of:
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) optionally, contacting the solution obtained in step a) with an anti-solvent;
c) isolating crystalline Form I of Lumcaftor.
2. A process of claim 1, wherein suitable solvent of step a) is selected from the group comprising of methanol, 1-propanol, ethyl acetate, dimethyl sulphoxide, water or mixture thereof.
3. A process of claim 2, wherein anti- solvent of step b) is selected from the group comprising of water, n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, diethyl ether, di isopropyl ether or mixtures thereof.
3. A process for the preparation of crystalline Form I of Lumacaftor, comprising the step of converting amorphous Lumacaftor to crystalline Form I of Lumacaftor.
4. A process of claim 3, wherein converting amorphous Lumacaftor to crystalline Form I may be carried out by re-crystallizing amorphous Lumacaftor in a suitable solvent or mixture of solvents.
5, A process of claim 3, wherein converting amorphous Lumacaftor to crystalline Form I may be carried out by suspending amorphous Lumacaftor in a suitable solvent or mixture of solvents.
6. A process of claim 4 or 5, wherein suitable solvent is selected from the group comprising water, dimethyl sulphoxide, formamide, dimethyl formamide, dimethyl acetamide, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, iso-butyl acetate, dichloromethane, chloroform, tetrachloro methane, toluene, xylene, cumene, di ethyl ether, di isopropyl ether, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile or mixtures thereof.
7. A process for the preparation of amorphous form of Lumacaftor, comprising the steps of;
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) contacting the solution obtained in step a) with an anti-solvent;
c) isolating amorphous form of Lumacaftor.
8. A process of claim 7, wherein the suitable solvent of step a) is selected from the group comprising of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, iso-butyl acetate, dichloromethane, chloroform, tetrachloro methane, toluene, xylene, cumene, di ethyl ether, di isopropyl ether, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile; dimethyl sulphoxide, formamide, dimethyl formamide, dimethyl acetamide, water or mixtures thereof.
9. A process of claim 7, wherein the suitable solvent of step a) is selected from dimethyl sulphoxide, formamide, dimethyl formamide, dimethyl acetamide, water or mixtures thereof.
10. A process of claim 7, wherein anti- solvent of step b) is selected from the group comprising of water, n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, diethyl ether, di isopropyl ether or mixtures thereof.