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

INTRODUCTION
Aspects of the present application relate to processes for the crystalline forms of Lumacaftor. Specific aspects relate to processes for the preparation of crystalline form SV1 and SV2 of Lumacaftor.
The drug compound having the adopted name “Lumacaftor” has chemical name: 3-{6-{[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclo propane 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)cyclopropane carboxamide 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 a crystalline Form I of Lumacaftor, which 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)-cyclopropane carbonyl chloride in the presence of base for the preparation of Lumacaftor.
US 8507687 B2 discloses the crystalline solvate 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 hydrochloride salt of Lumcaftor.
The physicochemical properties of a solid form is a critical parameter in the development of pharmaceutical dosage forms of and these properties can affect the bioavailability, stability and processability of the active pharmaceutical ingredient. It is known that a solid active pharmaceutical ingredient can exist in amorphous and crystalline state. Crystalline solids may further exist as various polymorphs and solvates.
The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
Hence there remains a need for alternate solid forms, particularly, need for alternate crystalline forms of Lumacaftor, which are stable, reproducible and can be prepared through an industrially viable manner.

SUMMARY
In an aspect, the present application provides a process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2? comprising the step of treating Lumacaftor with 1,4-dioxane or a mixture thereof.
In another aspect, the present application provides a process for the preparation of crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?, comprising the step of drying crystalline form SV1 of Lumacaftor.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form SV1 of Lumacaftor prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form SV1 of Lumacaftor prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form SV2 of Lumacaftor prepared by the method of Example-3.

DETAILED DESCRIPTION
Aspects of the present application relate to the processes for the preparation of crystalline forms SV1 and SV2 of Lumacaftor.
Lumacaftor that is used as starting material for the preparation of any of the solid forms of present application may be purified before using employing any of the purification techniques known in the art such as recrystallization, slurrying or chromatography or according to the procedures described or exemplified in the instant application.
Starting material may be either in a crystalline or amorphous state. In embodiments, crystalline form of Lumacaftor that may be used may include but not limited to crystalline form I or solvate form A of Lumacaftor or an alternate crystalline form of Lumacaftor known in the art.

In an aspect, the present application provides a process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2? comprising the step of treating Lumacaftor with 1,4-dioxane or a mixture thereof.
In an embodiment, treating Lumacaftor with 1,4-dioxane or a mixture thereof may be carried out by combining Lumacaftor and 1,4-dioxane or a mixture thereof.
In an embodiment, the mixture of Lumacaftor and 1, 4-dioxane or a mixture thereof may form a homogeneous or heterogeneous mixture.
In an embodiment, the mixture of Lumacaftor and 1,4-dioxane or a mixture thereof is a heterogeneous mixture in the form a suspension.
In an embodiment, crystalline form SV1 of Lumacaftor may be obtained by treating Lumacaftor with a mixture of 1, 4-dioxane and atleast one additional solvent. In an embodiment, additional solvent may be selected from the group comprising of water, methanol, ethanol, 2-propanol, acetone, methyl isobutyl ketone, diethyl ether, di isopropyl ether, methyl tert-butyl ether or a mixture thereof.
In an embodiment, combining Lumacaftor with 1,4-dioxane or a mixture thereof may be carried out optionally by heating a mixture of Lumacaftor and 1,4-dioxane or a mixture thereof at about 30°C to reflux temperature.
In an embodiment, the mixture of Lumacaftor and 1,4-dioxane or a mixture thereof may be stirred for sufficient time to complete the formation of form SV1 and at suitable temperature where crystalline form SV1 is stable and do not convert to any other form of Lumacaftor.
In an embodiment, optionally seeds of crystalline form SV1 of Lumacaftor may be added to the mixture of Lumacaftor and 1,4-dioxane or a mixture thereof, in case the mixture forms a homogenous solution. In an embodiment, seeds may be added at a suitable temperature and sufficient quantity such that the seeds are not dissolved.
In an embodiment, the mixture of Lumacaftor and 1,4-dioxane or a mixture thereof may be stirred for atleast one hour or more. In an embodiment, the mixture of Lumacaftor and 1,4-dioxane or a mixture thereof may be stirred at a temperature of about 0°C to reflux temperature.
In an embodiment, optionally anti-solvent may be added to the mixture of Lumacaftor and 1,4-dioxane or a mixture thereof, in case the mixture forms a homogenous solution. 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 mixture of Lumacaftor and 1,4-dioxane or a mixture may be optionally cooled to a suitable temperature before or after formation of Form SV1.
In an optional embodiment, the mixture of Lumacaftor and 1,4-dioxane or a mixture thereof may be cooled to a relatively lower temperature. In an embodiment, after lowering the temperature, the mixture comprising Lumacaftor and 1,4-dioxane or a mixture thereof may be stirred at the same temperature for time sufficient to obtain crystalline form SV1 of Lumacaftor.
Isolation of crystalline form SV1 of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form SV1 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In another aspect, the present application provides a process for the preparation of crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?, comprising the step of heating or drying the crystalline form SV1 of Lumacaftor.
In an embodiment, heating or drying of crystalline form SV1 of Lumacaftor may be carried out in suitable equipment such as a tray drier optionally under reduced pressure or other drying conditions known in the art such as Buchi rotavapour vacuum drying, rotatory cone vacuum drying; fluid bed drying optionally under nitrogen atmosphere, thin film drying; or the like.
In an embodiment, heating or drying of crystalline form SV1 of Lumacaftor may be carried out at suitable temperatures of about 25°C and above, optionally under reduced pressure. In an embodiment, drying may be carried out at about 100°C and above.
In an embodiment, drying crystalline form SV1 of Lumacaftor may be carried out for sufficient time to complete its conversion to crystalline form SV2 of Lumacaftor. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product. 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 an aspect the present application provides a crystalline form SV2 of Lumacaftor. In an embodiment, the crystalline form SV2 is stable under humidity of about 60% RH, under both closed or packed and open conditions. In an embodiment, the crystalline form SV2 of Lumacaftor is stable for atleast a week when placed under open atmospheric conditions. In an embodiment, the crystalline form SV2 of Lumacaftor is stable for atleast 5 months when stored in closed amber colored bottle.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form of Lumacaftor selected from the group comprising form SV1, form SV2 or mixtures thereof together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides crystalline forms of Lumacaftor or their pharmaceutical compositions comprising Lumacaftor having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In another aspect, the present application provides crystalline forms of Lumacaftor or their 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 terms “crystalline form" indicates that the Lumacaftor is present in substantially crystalline Form. "Substantially" crystalline denotes that atleast 80 %, preferably 90 % or 95 %, more preferably all of the Lumacaftor is crystalline form. In other words, "crystalline form" 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.
X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?) ±0.2° of 6.3°" means "having a diffraction peak at a diffraction angle (2?) of 6.1° to 6.5°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks may vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors may slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments may vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).

EXAMPLES
Example-1: Preparation of crystalline form SV1 of Lumacaftor.
Lumacaftor (1 g) was dissolved in a mixture of 1, 4-dioxane (5 mL) and water (1 mL) and a crystalline form SV1 seed (100 mg) at 26°C. The mixture was stirred for 5.5 hours at the same temperature and the solid was filtered to obtain the title compound.

Example-2: Preparation of crystalline form SV1 of Lumacaftor.
A suspension of Lumacaftor (1 g) in 1,4-dioxane (7 mL) was stirred at 26°C for 2 hours and the solid was filtered to obtain title compound.
Example-3: Preparation of crystalline form SV2 of Lumacaftor
Crystalline form SV1(100 mg) was heated to 100°C in 1 hour under reduced pressure in a tray drier to obtain the title compound.

Example-4: Preparation of crystalline form SV2 of Lumacaftor
Crystalline form SV1(100 mg) was dried in tray drier at 70°C for 13 hours under reduced pressure to obtain the title compound.
,CLAIMS:We Claim:
1. A process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2? comprising the step of treating Lumacaftor with 1,4-dioxane or a mixture thereof.
2. A process according to claim 1, wherein crystalline form SV1 of Lumacaftor obtained by treating Lumacaftor with a mixture of 1, 4-dioxane and at least one additional solvent.
3. A process according to claim 2, wherein additional solvent may be selected from the group comprising of water, methanol, ethanol, 2-propanol, acetone, methyl isobutyl ketone, diethyl ether, di isopropyl ether, methyl tert-butyl ether or a mixture thereof.
4. A process according to claim 1 and 2, wherein optionally seeds of crystalline form SV1 of Lumacaftor may be added to the mixture of Lumacaftor and 1,4-dioxane or a mixture thereof.
5. A process for the preparation of crystalline form SV1 of Lumacaftor comprising the stirring a suspension of Lumacaftor in 1,4-dioxane.
6. A process for the preparation of crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?, comprising the step of drying crystalline form SV1 of Lumacaftor.
7. A process according to claim 6, wherein heating or drying of crystalline form SV1 of Lumacaftor carried out at temperatures of about 25°C and above, optionally under reduced pressure