WO2018037350A1

WO2018037350A1 - Solid forms of lumacaftor, process for its preparation and pharmaceutical compositions thereof

Info

Publication number: WO2018037350A1
Application number: PCT/IB2017/055074
Authority: WO
Inventors: Ram Thaimattam; Suresh Babu RADHAKRISHNAN; Uma Maheswar Rao VASIREDDI
Original assignee: Laurus Labs Pvt Ltd
Current assignee: Laurus Labs Pvt Ltd
Priority date: 2016-08-23
Filing date: 2017-08-23
Publication date: 2018-03-01
Anticipated expiration: 2019-02-23

Abstract

The present invention generally relates to novel solid forms of lumacaftor, including amorphous form, solvates and/or polymorphs, processes for their preparation, pharmaceutical compositions containing the same and to their use in therapy.

Description

"SOLID FORMS OF LUMACAFTOR, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF"

PRIORITY

This application claims the benefit under Indian Provisional Application No(s). 201641028664 filed on 23^rd August 2016 entitled "Amorphous form of lumacaftor and process for the preparation thereof; and 201641031095 filed on 12^th September 2016 entitled "Solid forms of lumacaftor, process for its preparation and pharmaceutical compositions thereof; the content of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to solid forms of lumacaftor, processes for their preparation and use of such solid forms in pharmaceutical compositions and to their use in therapy. In particular, the present invention relates to solid forms of lumacaftor, including amorphous form, solvates and/or polymorphs of solvates, process for their preparation and a pharmaceutical composition comprising the same. BACKGROUND OF THE INVENTION

3- { 6- { [ 1 -(2,2-Difluoro- 1 ,3-benzodioxol-5-yl)cyclopropanecarbonyl] amino } -3-methyl pyridine-2-yl}benzoic acid, commonly known as Lumacaftor having the compound of Formula I, is a modulator of CFTR activity and thus useful in treating CFTR-mediated diseases such as cystic fibrosis (CF).

Formula I

Cystic Fibrosis (CF) is a fatal autosomal recessive disease associated with defective hydration of lung airways due to the loss of function of the CF transmembrane conductance regulator (CFTR) channel at epithelial cell surfaces.

In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea - perhaps explaining the relatively high frequency of the CF gene within the population. Lumacaftor has been demonstrated to restore the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

Lumacaftor is available in a single pill with Ivacaftor combination, lumacaftor/ivacaftor having the brand name Orkambi, is used to treat people with cystic fibrosis who have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR). Lumacaftor was developed by Vertex Pharmaceuticals and the Lumacaftor/Ivacaftr combination was approved by the FDA in 2015.

PCT publication No. WO2007/056341 ("the '341 publication") discloses modulators of ATP-Binding Cassette ("ABC") transporters including Cystic Fibrosis Transmembrane conductance Regulator ("CFTR") such as lumacaftor.

PCT Publication No. WO2009/073757A1 ("the '757 application") discloses crystalline Form I of lumacaftor.

PCT Publication No. WO2011/127290 ("the '290 publication") disclosed crystalline Form A of lumacaftor hydrochloride salt and further disclosed various isostructural solvates of lumacaftor such as methanol solvate, ethanol solvate, acetone solvate, 2- propanol solvate, acetonitrile solvate, THF solvate, methyl acetate solvate, 2-butanone solvate, ethyl formate solvate and 2-methyl tetrahydro furan solvate and process for their preparation, wherein the process for preparing isostructural solvates involves the slurring of solvate reaction mixture for 48 hours.

PCT Publication No. WO2017/025045 ("the Ό45 publication") disclosed crystalline form A of lumacaftor.

PCT Publication No. WO2017/056031 ("the '031 publication") disclosed an amorphous form of lumacaftor. PCT Publication No. WO 2017/056109 ("the Ί09 publication") disclosed an amorphous form of lumacaftor, crystalline lumacaftor acetic acid solvate and crystalline lumacaftor ethyl acetate solvate.

PCT Publication No. WO2017/118915 ("the '915 publication") disclosed an amorphous form of lumacaftor

Obtaining suitable solid forms of a drug is a necessary stage for many orally available drugs. Suitable solid forms possess the desired properties of a particular drug. Such suitable forms often possess more favourable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself or may be used as a drug product intermediate during the preparation of the drug. For example, new drug formulations comprising crystalline forms of a given drug may have superior properties, such as solubility, dissolution, hygroscopicity and storage stability over existing formulations of the drug.

The discovery of new solid forms of active pharmaceutical ingredients ("APIs") provides opportunities to improve the performance characteristics, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products of a pharmaceutical product. Such discoveries enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

In view of the foregoing, it would be desirable to provide new solid forms of lumacaftor. Further, it would be desirable to have reliable processes for producing these solid forms. Therefore, the present invention addresses the need in the art for pharmaceutically useful solid forms of lumacaftor that may have improved physicochemical properties, such as a higher solubility and dissolution rate, enhanced flow properties and enhanced stability. New solid forms of lumacaftor such as amorphous lumacaftor, new solvates and/or polymorphs of solvates of lumacaftor have now been discovered.

SUMMARY OF THE INVENTION Accordingly, the present invention provides solid forms of lumacaftor, including amorphous form, solvates and/or polymorphs of solvates, processes for their preparation, pharmaceutical compositions containing the same and to their use in therapy. In accordance with one embodiment, the present invention provides novel solid forms of lumacaftor.

In accordance with another embodiment, the present invention provides the novel solid forms of lumacaftor exist in an amorphous form.

In accordance with another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 20% of crystalline form. In accordance with another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 10% of crystalline form. In accordance with another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 5% of crystalline form. In accordance with another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 1% of crystalline form.

In accordance with another embodiment, the present invention provides an amorphous form of lumacaftor characterized by a X-ray powder diffraction in accordance with Figure 01.

In accordance with another embodiment, the present invention provides an amorphous form of lumacaftor characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 02.

In accordance with another embodiment, the present invention provides an amorphous form of lumacaftor characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 03.

In accordance with another embodiment, the present invention provides an amorphous form of lumacaftor, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 01, a differential scanning calorimetry (DSC) substantially in accordance with Figure 02 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 03.

In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:

a) providing a solution of lumacaftor in one or more solvents;

b) adding a suitable antisolvent to the step a) solution or vice-versa; and

c) isolating the amorphous form.

a) providing a solution of lumacaftor in one or more solvents;

b) adding a suitable antisolvent to the step a) solution or vice-versa; and

c) isolating the amorphous form; wherein the one or more solvents are selected from the group consisting of organic acids, alcohols, ketones, esters, nitriles and the like and mixtures thereof; wherein the suitable antisolvent is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like; and mixtures thereof.

a) providing a solution of lumacaftor in formic acid; b) adding the solution of step a) into water or vice- versa; and

c) isolating the amorphous form.

a) providing a solution of lumacaftor in acetic acid;

b) adding the solution of step a) into water or vice- versa; and

c) isolating the amorphous form. In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:

a) providing a solution or suspension of lumacaftor in a suitable solvent; and b) removing the solvent from the solution to obtain amorphous form of lumacaftor. In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:

a) providing a solution or suspension of lumacaftor in a suitable solvent; and b) removing the solvent from the solution to obtain amorphous form of lumacaftor; wherein the suitable solvent is selected form the group comprising of alcohols, esters, ethers, ketones, nitriles or mixtures thereof.

In accordance with another embodiment, the present invention provides the novel solid forms of lumacaftor exist in the form of solvates or polymorphs of solvates. In accordance with another embodiment, the present invention provides novel solid forms of lumacaftor, herein designated as lumacaftor Form-Ll, lumacaftor Form-L2, lumacaftor Form-L3, lumacaftor Form-L4, lumacaftor Form-L5, lumacaftor Form-L6, lumacaftor Form-L7, lumacaftor Form-L8, lumacaftor Form-L9, lumacaftor Form-LlO and lumacaftor Form-Ll 1.

In accordance with another embodiment, the present invention provides lumacaftor Form-Ll.

In accordance with another embodiment, the lumacaftor Form-Ll of the present invention is an acetic acid solvate.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-Ll characterized by a X-ray powder diffraction in accordance with Figure 04.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-Ll characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 05. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-Ll characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 06. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-Ll, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 04, a differential scanning calorimetry (DSC) substantially in accordance with Figure 05 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 06.

In accordance with another embodiment, the present invention provides lumacaftor Form-L2.

In accordance with another embodiment, the lumacaftor Form-L2 of the present invention is a tert-butanol solvate.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L2 characterized by a X-ray powder diffraction in accordance with Figure 07.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 08. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 09.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L2, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 07, a differential scanning calorimetry (DSC) substantially in accordance with Figure 08 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 09. In accordance with another embodiment, the present invention provides lumacaftor Form-L3.

In accordance with another embodiment, the lumacaftor Form-L3 of the present invention is a dichloromethane solvate.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L3 characterized by a X-ray powder diffraction in accordance with Figure 10. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L3, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 10, a differential scanning calorimetry (DSC) substantially in accordance with Figure 11 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 12. In accordance with another embodiment, the present invention provides lumacaftor Form-L4.

In accordance with another embodiment, the lumacaftor Form-L4 of the present invention is an isopropyl acetate solvate.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L4 characterized by a X-ray powder diffraction in accordance with Figure 13. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L4 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L4 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 15.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L4, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 13, a differential scanning calorimetry (DSC) substantially in accordance with Figure 14 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 15.

In accordance with another embodiment, the present invention provides lumacaftor Form-L5.

In accordance with another embodiment, the lumacaftor Form-L5 of the present invention is an ethyl acetate solvate. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L5 characterized by a X-ray powder diffraction in accordance with Figure 16. In accordance with another embodiment, the present invention provides lumacaftor Form-L6.

In accordance with another embodiment, the lumacaftor Form-L6 of the present invention is a cyclopentyl methyl ether solvate.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L6 characterized by a X-ray powder diffraction in accordance with Figure 17. In accordance with another embodiment, the present invention provides lumacaftor Form-L7.

In accordance with another embodiment, the lumacaftor Form-L7 of the present invention is an n-propanol solvate.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L7 characterized by a X-ray powder diffraction in accordance with Figure 18. In accordance with another embodiment, the present invention provides lumacaftor Form-L8.

In accordance with another embodiment, the lumacaftor Form-L8 of the present invention is an n-propyl acetate solvate.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L8 characterized by a X-ray powder diffraction in accordance with Figure 19. In accordance with another embodiment, the present invention provides lumacaftor Form-L9.

In accordance with another embodiment, the lumacaftor Form-L9 of the present invention is an isobutyl acetate solvate.

In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-L9 characterized by a X-ray powder diffraction in accordance with Figure 20.

In accordance with another embodiment, the present invention provides lumacaftor Form-LlO. In accordance with another embodiment, the lumacaftor Form-LlO of the present invention is a dimethylformamide solvate. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-LlO characterized by a X-ray powder diffraction in accordance with Figure 21.

In accordance with another embodiment, the present invention provides lumacaftor Form-Ll l.

In accordance with another embodiment, the lumacaftor Form-Ll l of the present invention is a dimethylsulfoxide solvate. In accordance with another embodiment, the present invention provides crystalline lumacaftor Form-Ll l characterized by a X-ray powder diffraction in accordance with Figure 22.

In accordance with another embodiment, the present invention provides a process for the preparation of novel solvates of lumacaftor.

In accordance with another embodiment, the present invention provides a process for the preparation of crystalline lumacaftor Form LI to LI 1, comprising:

a) suspending or dissolving lumacaftor in a suitable organic solvent;

b) optionally, heating the step a) reaction mixture;

c) optionally, cooling the mixture of step b); and

d) isolating the crystalline lumacaftor Form LI to LI 1.

a) suspending or dissolving lumacaftor in a suitable organic solvent;

b) optionally, heating the step a) reaction mixture;

c) optionally, cooling the mixture of step b); and

d) isolating the crystalline lumacaftor Form LI to LI 1;

wherein the suitable organic solvent is selected from the group consisting of acetic acid, tert-butanol, dichloromethane, isopropyl acetate, ethyl acetate, cyclopentyl methyl ether, n-propanol, n-propyl acetate, isobutyl acetate, dimethyl formamide or dimethyl sulfoxide. In accordance with another embodiment, the present invention provides the use of novel solvate forms of lumacaftor as intermediates to prepare other solid forms of lumacaftor.

In accordance with another embodiment, the present invention provides a process for the preparation of lumacaftor Form I, comprising:

a) suspending or dissolving any crystalline from of lumacaftor selected from LI to

LI 1 in one or more solvents; b) optionally, heating the step a) reaction mixture;

c) optionally, cooling the step b) solution;

d) adding a suitable anti-solvent to the step a) solution or vice versa; and e) isolating the lumacaftor Form I; wherein the crystalline lumacaftor Form LI to LI 1 are characterized by fig. 4 to 22 respectively.

In another embodiment, the present invention provides a process for the preparation of amorphous form of lumacaftor, wherein the process involves the use of one or more novel solvate forms of lumacaftor of the invention as intermediates.

In another embodiment, the present invention provides a process for the preparation of amorphous form of lumacaftor, comprising:

a) suspending or dissolving crystalline lumacaftor in one or more solvents;

b) adding a suitable anti-solvent to the step a) solution or vice versa; and c) isolating the amorphous form; wherein the crystalline lumacaftor is selected from the group consisting of Form LI, L2, L3, L4, L5, L6, L7, L8, L9, L10 and LI 1, which are characterized by fig. 4 to 22 respectively.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention. Figure 1 is the characteristic powder XRD pattern of amorphous form of Lumacaftor.

Figure 2 is the characteristic DSC thermogram of amorphous form of Lumacaftor.

Figure 3 is the characteristic TGA curve of amorphous form of Lumacaftor.

Figure 4 is the characteristic powder XRD pattern of lumacaftor Form-Ll.

Figure 5 is the characteristic DSC thermogram of lumacaftor Form-Ll.

Figure 6 is the characteristic TGA curve of lumacaftor Form-Ll.

Figure 7 is the characteristic powder XRD pattern of lumacaftor Form-L2.

Figure 8 is the characteristic DSC thermogram of lumacaftor Form-L2.

Figure 9 is the characteristic TGA curve of lumacaftor Form-L2.

Figure 10 is the characteristic powder XRD pattern of lumacaftor Form-L3.

Figure 11 is the characteristic DSC thermogram of lumacaftor Form-L3.

Figure 12 is the characteristic TGA curve of lumacaftor Form-L3.

Figure 13 is the characteristic powder XRD pattern of lumacaftor Form-L4. Figure 14 is the characteristic DSC thermogram of lumacaftor Form-L4

Figure 15 is the characteristic TGA curve of lumacaftor Form-L4.

Figure 16 is the characteristic powder XRD pattern of lumacaftor Form- L5.

Figure 17 is the characteristic powder XRD pattern of lumacaftor Form- L6.

Figure 18 is the characteristic powder XRD pattern of lumacaftor Form- ^■L7.

Figure 19 is the characteristic powder XRD pattern of lumacaftor Form- L8.

Figure 20 is the characteristic powder XRD pattern of lumacaftor Form- L9.

Figure 21 is the characteristic powder XRD pattern of lumacaftor Form- ^■L10.

Figure 22 is the characteristic powder XRD pattern of lumacaftor Form- ^■Ll l.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified in this specification, "solid forms" herein used in this specification collectively represents an amorphous form, a crystalline form, solvates or their polymorphic forms.

Unless otherwise specified in this specification, "solvate" herein used in this specification, refers to a crystals form that incorporates a solvent in the crystal structure. The solvent in a solvate may be present in either a stoichiometric or in a non- stoichiometric amount.

The present invention provides novel solid forms of lumacaftor, processes for their preparation and a pharmaceutical composition containing the same.

As used herein in this specification, unless otherwise specified, lumacaftor, which is used as a starting material is known in the art and can be prepared by any known methods, for example lumacaftor may be synthesized as disclosed in international PCT publication WO 2007/056341. The starting lumacaftor may be in any form such as crude obtained directly form the reaction mass, crystalline, amorphous or other forms of lumacaftor, including various solvates and hydrates known in the art as well as the novel solid forms described herein the present invention.

In another embodiment, the present invention provides novel solid forms of lumacaftor, which are characterized by one or more of analytical techniques such as powder X-Ray diffraction (XRD), differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA).

The X-Ray powder diffraction can be measured using PANalytical X'per pro X-ray powder Diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step size=0.01 °.

All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with a empty hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute in the range of 50 to 250°C.

All TGA data reported herein were analyzed using TGA Q500 V 20.13 build 39 in platinum pan with a temperature rise of about 10°C/min in the range of about room temperature to about 250°C.

In one embodiment, the present invention provides novel solid forms of lumacaftor. In another embodiment, the present invention provides novel solid forms of lumacaftor exist as an amorphous form.

In another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 20% of crystalline form.

In another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 10% of crystalline form.

In another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 5% of crystalline form. In another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 1% of crystalline form.

In another embodiment, the present invention provides an amorphous form of lumacaftor characterized by a X-ray powder diffraction in accordance with Figure 01.

In another embodiment, the present invention provides an amorphous form of lumacaftor characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 02.

In another embodiment, the present invention provides an amorphous form of lumacaftor characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 03.

In another embodiment, the present invention provides an amorphous form of lumacaftor, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 01, a differential scanning calorimetry (DSC) substantially in accordance with Figure 02 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 03. In another embodiment, the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:

a) providing a solution of lumacaftor in one or more solvents;

b) adding a suitable antisolvent to the step a) solution or vice-versa; and

c) isolating the amorphous form.

The starting material lumacaftor used in the present invention is known in the art and can be prepared by any known methods, for example lumacaftor may be synthesized as disclosed in international PCT publication WO 2007/056341. The starting lumacaftor used herein in step a) may be any crystalline or other form of lumacaftor, including various solvates, hydrates, salts and cocrystals as long as amorphous lumacaftor is produced during the process of the invention or lumacaftor obtaining as existing solution from a previous processing step. Step a) of providing a solution of lumacaftor may include dissolving any form of lumacaftor in one or more solvents at a temperature of about 20°C to about reflux temperature. The one or more solvents include, but are not limited to organic acids selected from formic acid, acetic acid, propionic acid and the like; alcohols selected from methanol, ethanol, isopropanol and the like; ketones selected from acetone, methylisobutylketone, methylethylketone and the like; esters selected methyl acetate, ethyl acetate, isopropyl acetate and the like; nitriles selected from acetonitrile, propionitrile and the like; and mixture thereof, preferably the one or more solvents is formic acid or acetic acid. The step a) reaction may optionally heat to dissolve all solids in one or more solvents. The dissolution temperature for the lumacaftor may range from about 20° C to reflux temperature of the solvent used. Any other temperatures may also be acceptable, provided a clear solution of the concerned materials is obtained in the solvents chosen, and the starting materials are not degraded. It will be understood that the temperatures required will also be determined by the processing conditions for the recovery of the final product, such as the temperature of drying, the boiling point of the solvent, the homogeneity of the solution required after mixing solvents, the viscosity of the solution, the stability of the lumacaftor. Such variations are all included herein without any limitation.

Step b) of the aforementioned process involves precipitation of amorphous form of lumacaftor by either addition of suitable antisolvent to the lumacaftor solution of step a) or addition of step a) solution of lumacaftor into a suitable antisolvent. The suitable antisolvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like; and mixtures thereof. The ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; and mixture thereof; preferably the suitable antisolvent is water. The isolation of the resultant product is accomplished by conventional techniques such as removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution or by cooling to obtain amorphous form. Evaporation can be achieved by a distillation, lyophilisation or freeze-drying technique, rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying, agitated thin-film drying and the like. Preferably the reaction solution may be cooled to obtain amorphous lumacaftor and the resultant amorphous form can be recovered by conventional techniques, for example filtration.

The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

In another embodiment, the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:

a) providing a solution of lumacaftor in formic acid or acetic acid,

b) adding the solution of step a) into water or vice- versa; and

c) isolating the amorphous form.

The lumacaftor in the step a) may be any crystalline or other form of lumacaftor, including various solvates, hydrates, salts and cocrystals as long as amorphous lumacaftor is produced during the process of the invention or lumacaftor obtaining as existing solution from a previous processing step.

The step of providing a solution of lumacaftor may include dissolving any form of lumacaftor in formic acid or acetic acid at a temperature of about 20°C to about reflux temperature. Typically, stirring is involved for about 30 min at the same temperature.

Step b) of the aforementioned process involves addition of lumacaftor solution obtained from step a) into water or water may be added in to step a) solution of lumacaftor.

The isolation of amorphous form of lumacaftor is carried out by any conventional techniques known in the art or methods described just as above, for example filtration. The resultant wet product may optionally be further dried for about 2 hours to 20 hours. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. In another embodiment, the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:

a) providing a solution or suspension of lumacaftor in a suitable solvent; and b) removing the solvent from the solution to obtain amorphous form of lumacaftor.

Step a) of the forgoing process involves the dissolution of lumacaftor in a suitable solvent, wherein the suitable solvent includes but are not limited to alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n- butyl acetate, t-butyl acetate and the like; ethers such as methyl tertiary butyl ether, tetrahydrofuran, dimethyl ether, diisopropyl ether, 1,4-dioxane and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; or mixtures thereof; preferably the suitable solvent is ethanol, isopropanol, n-propanol or t-butanol.

The dissolution temperatures may range from about 10°C to about reflux temperature of the solvent; preferably at a temperature of about 25 °C to about 35°C. The step of removal of solvent may be carried out by one or more techniques known in the art, for example, distillation, distillation under vacuum, spray drying, agitated thin film drying ("ATFD"), and freeze drying (lyophilization). The resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like; preferably the solvent is removed by distillation under vacuum at about 50°C to about 60°C.

The lumacaftor recovered using the process of the present invention is in form of substantially pure amorphous lumacaftor.

The lumacaftor recovered using the process of the present invention is having less than about 20% of any crystalline form; preferably less than about 10%, more preferably less than 5%, most preferably less than about 1%. In another embodiment, the present invention provides the novel solid forms of lumacaftor, which may exist in the form of solvates or polymorphs of solvates.

In another embodiment, the present invention provides novel solvates of lumacaftor, herein after designated as lumacaftor Form-Ll, lumacaftor Form-L2, lumacaftor Form- L3, lumacaftor Form-L4, lumacaftor Form-L5, lumacaftor Form-L6, lumacaftor Form- L7, lumacaftor Form-L8, lumacaftor Form-L9, lumacaftor Form-LlO and lumacaftor Form-Ll 1.

In another embodiment, the present invention provides lumacaftor Form-Ll. In another embodiment, the lumacaftor Form-Ll of the present invention is an acetic acid solvate.

In another embodiment, the present invention provides lumacaftor Form-Ll characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 04.

In another embodiment, the present invention provides lumacaftor Form-Ll characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.02, 7.71, 8.02, 8.78, 10.29, 10.71, 11.18, 12.10, 12.68, 13.79, 14.78, 15.19, 15.62, 16.44, 17.00, 17.76, 18.30, 18.75, 19.62, 20.36, 21.42, 22.01, 22.62, 23.36, 24.10, 24.41, 25.33, 26.24, 27.04, 27.89, 28.59, 29.04, 29.73, 30.61, 31.40, 32.22, 33.57, 34.78, 35.54, 36.13, 37.34, 38.42, 39.06, 39.97 and 41.70 ±0.2° 2Θ. In another embodiment, the present invention provides lumacaftor Form-Ll characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 05.

In another embodiment, the present invention provides lumacaftor Form-Ll characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 06.

In another embodiment, the present invention provides lumacaftor Form-Ll characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 04, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 05 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 06.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-Ll, comprising:

a) mixing lumacaftor with acetic acid to obtain a mixture;

b) optionally, heating the step a) reaction mixture;

c) optionally, cooling the mixture of step b); and

d) isolating the lumacaftor Form-Ll.

The aforementioned process of lumacaftor Form-Ll includes dissolving lumacaftor in acetic acid at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 50°C to about reflux temperature, preferably at about 55°C to about 65°C. Then cooling the reaction mixture to room temperature for sufficient period of time, preferably for about 10 to 20 hours and isolating the lumacaftor Form LI by known methods in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE), filtration under vacuum and the like; preferably filtration under vacuum. In another embodiment, the present invention provides lumacaftor Form-L2.

In another embodiment, the lumacaftor Form-L2 of the present invention is a tert- butanol solvate.

In another embodiment, the present invention provides lumacaftor Form-L2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 07. In another embodiment, the present invention provides lumacaftor Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.44, 6.07, 7.76, 8.23, 8.79, 9.65, 10.77, 11.24, 12.15, 12.73, 13.89, 14.40, 14.79, 15.20, 15.68, 16.48, 17.02, 17.80, 18.40, 18.79, 19.67, 20.34, 20.45, 21.41, 22.10, 22.66, 23.27, 24.39, 25.34, 26.28, 27.07, 27.73, 28.50, 29.04, 29.77, 30.64, 31.33, 32.33, 34.45 and 37.37 ±0.2° 2Θ.

In another embodiment, the present invention provides lumacaftor Form-L2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 08.

In another embodiment, the present invention provides lumacaftor Form-L2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 09. In another embodiment, the present invention provides lumacaftor Form-L2 characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 07, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 08 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 09.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-L2, comprising:

a) mixing lumacaftor with tert-butanol to obtain a mixture;

b) optionally, heating the step a) reaction mixture;

c) optionally, cooling the mixture of step b); and

d) isolating the lumacaftor Form-L2.

The aforementioned process of lumacaftor Form-L2 includes dissolving lumacaftor in tert-butanol at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 50°C to about reflux temperature, preferably at about 75°C to about 85°C. Then cooling the reaction mixture to room temperature and further cooled at about - 20°C for sufficient period of time, preferably for about 10 to 20 hours and finally isolating lumacaftor Form L2 by known methods in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE), filtration under vacuum and the like; preferably filtration under vacuum.

In another embodiment, the present invention provides lumacaftor Form-L3.

In another embodiment, the lumacaftor Form-L3 of the present invention is a dichloromethane solvate.

In another embodiment, the present invention provides lumacaftor Form-L3 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 10.

In another embodiment, the present invention provides lumacaftor Form-L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.02, 7.72, 8.76, 10.78, 11.13, 120.9, 12.84, 13.87, 14.70, 15.72, 16.43, 17.02, 17.78, 18.22, 19.58, 20.34, 21.46, 21.99, 22.90, 23.52, 24.25, 25.40, 26.46, 27.12, 27.39, 27.57, 29.72, 30.67, 32.26, 24.75, 35.63, 37.34, 38.79 and 41.53 ±0.2° 2Θ.

In another embodiment, the present invention provides lumacaftor Form-L3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11.

In another embodiment, the present invention provides lumacaftor Form-L3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.

In another embodiment, the present invention provides lumacaftor Form-L3 characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 10, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-L3, comprising:

a) mixing lumacaftor with dichloromethane to obtain a mixture;

b) optionally, heating the step a) reaction mixture;

c) cooling the mixture of step b); and

d) isolating the lumacaftor Form-L3. The aforementioned process of lumacaftor Form-L3 includes dissolving lumacaftor in dichloromethane at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 30°C to about reflux temperature, preferably at about 35°C to about 45°C. Then cooling the reaction mixture to room temperature and further cooled to 10°C and then to about -20°C for sufficient period of time, preferably for about 10 to 20 hours and finally isolating the lumacaftor Form L3 by known methods in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE), filtration under vacuum and the like; preferably filtration under vacuum.

In another embodiment, the present invention provides lumacaftor Form-L4.

In another embodiment, the lumacaftor Form-L4 of the present invention is an isopropyl acetate solvate.

In another embodiment, the present invention provides lumacaftor Form-L4 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 13. In another embodiment, the present invention provides lumacaftor Form-L4 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.07, 7.73, 8.15, 8.78, 9.56, 10.67, 11.29, 12.11, 12.74, 14.33, 15.18, 15.71, 16.39, 17.55, 18.36, 19.62, 20.45, 21.39, 21.87, 22.06, 22.76, 24.40, 25.47, 26.41, 27.21, 27.91, 30.48 and 32.12 ±0.2° 2Θ.

In another embodiment, the present invention provides lumacaftor Form-L4 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.

In another embodiment, the present invention provides lumacaftor Form-L4 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 15.

In another embodiment, the present invention provides lumacaftor Form-L4 characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 13, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 15.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-L4, comprising:

a) dissolving lumacaftor in isopropyl acetate; and

b) removing the solvent to obtain lumacaftor Form-L4.

The aforementioned process of lumacaftor Form-L4 includes dissolving lumacaftor in isopropyl acetate at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°C. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 50°C to about 60°C. The resulting solid can be dried under vacuum at a temperature of about 45°C to about 55°C for about 10 to 20 hours to obtain lumacaftor Form L4.

In another embodiment, the present invention provides lumacaftor Form-L5.

In another embodiment, the lumacaftor Form-L5 of the present invention is an ethyl acetate solvate.

In another embodiment, the present invention provides lumacaftor Form-L5 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 16.

In another embodiment, the present invention provides lumacaftor Form-L5 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.04, 7.51, 7.73, 8.20, 8.74, 10.76, 11.18, 12.13, 12.66, 14.27, 14.83, 15.70, 16.32, 16.96, 17.81, 18.23, 18.82, 19.48, 19.70, 20.40, 21.27, 21.45, 22.05, 22.73, 23.66, 24.46, 25.44, 26.36, 27.45, 27.90, 28.44, 29.45, 30.57, 32.24, 34.49 and 35.81±0.2° 2Θ.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-L5, comprising:

a) dissolving lumacaftor in ethyl acetate; and

b) removing the solvent to obtain lumacaftor Form-L5.

The aforementioned process of lumacaftor Form-L5 includes dissolving lumacaftor in ethyl acetate at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 50°C to about 60°C to obtain lumacaftor Form L5.

In another embodiment, the present invention provides lumacaftor Form-L6.

In another embodiment, the lumacaftor Form-L6 of the present invention is a cyclopentyl methyl ether solvate.

In another embodiment, the present invention provides lumacaftor Form-L6 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 17.

In another embodiment, the present invention provides lumacaftor Form-L6 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.04, 7.64, 8.20, 8.84, 10.82, 11.24, 12.04, 12.88, 14.77, 15.70, 16.36, 17.67, 18.33, 19.59, 20.36, 21.37, 21.90, 21.91, 22.94, 24.13, 25.46, 26.23, 27.14, 30.63 and 32.03 ±0.2° 2Θ. In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-L6, comprising:

a) dissolving lumacaftor in cyclopentyl methyl ether; and

b) removing the solvent to obtain lumacaftor Form-L6.

The aforementioned process of lumacaftor Form-L6 includes dissolving lumacaftor in cyclopentyl methyl ether at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 50°C to about 60°C to obtain lumacaftor Form L6. In another embodiment, the present invention provides lumacaftor Form-L7.

In another embodiment, the lumacaftor Form-L7 of the present invention is an n- propanol solvate. In another embodiment, the present invention provides lumacaftor Form-L7 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 18.

In another embodiment, the present invention provides lumacaftor Form-L7 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.05, 7.59, 8.11, 8.78, 10.68, 11.10, 12.08, 12.68, 14.75, 15.22, 15.60, 16.71, 17.70, 18.25, 18.83, 19.53, 20.43, 21.22, 220.6, 22.76, 24.26, 25.52, 27.11, 27.86 and 29.69±0.2° 2Θ. In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-L7, comprising:

a) dissolving lumacaftor in n-propanol; and

b) removing the solvent to obtain lumacaftor Form-L7. The aforementioned process of lumacaftor Form-L7 includes dissolving lumacaftor in n-propanol at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 50°C to about 60°C. The resulting solid can be further dried under vacuum at a temperature of about 40°C to about 60°C to obtain lumacaftor Form L7. In another embodiment, the present invention provides lumacaftor Form-L8. In another embodiment, the lumacaftor Form-L8 of the present invention is an n-propyl acetate solvate.

In another embodiment, the present invention provides lumacaftor Form-L8 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 19.

In another embodiment, the present invention provides lumacaftor Form-L8 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.07, 7.60, 8.22, 8.74, 10.65, 11.16, 12.05, 12.71, 14.62, 15.03, 16.51, 17.76, 18.27, 19.63, 20.36, 21.33, 22.04, 22.59, 24.22, 25.26, 26.39, 27.01, 27.94, 30.57, 31.29, 32.12 and 33.51±0.2° 2Θ.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-L8, comprising:

a) dissolving lumacaftor in n-propyl acetate; and

b) removing the solvent to obtain lumacaftor Form-L8.

The aforementioned process of lumacaftor Form-L8 includes dissolving lumacaftor in n-propyl acetate at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 60°C to about 75°C to obtain lumacaftor Form L8.

In another embodiment, the present invention provides lumacaftor Form-L9.

In another embodiment, the lumacaftor Form-L9 of the present invention is an isobutyl acetate solvate.

In another embodiment, the present invention provides lumacaftor Form-L9 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 20.

In another embodiment, the present invention provides lumacaftor Form-L9 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.06, 7.72, 8.20, 8.78, 10.78, 11.23, 12.21, 12.71, 14.41, 14.84, 15.65, 16.34, 17.83, 18.36, 19.72, 20.42, 21.41, 22.09, 22.74, 24.46, 25.42, 26.25, 27.16, 27.88, 28.71, 30.46, 32.07 and 34.59 ±0.2° 2Θ.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-L9, comprising:

a) dissolving lumacaftor in isobutyl acetate; and

b) removing the solvent to obtain lumacaftor Form-L9. The aforementioned process of lumacaftor Form-L9 includes dissolving lumacaftor in isobutyl acetate at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 60°C to about 75°C obtain lumacaftor Form L9.

In another embodiment, the present invention provides lumacaftor Form-LlO.

In another embodiment, the lumacaftor Form-LlO of the present invention is a dimethyl formamide solvate.

In another embodiment, the present invention provides lumacaftor Form-LlO characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 21.

In another embodiment, the present invention provides lumacaftor Form-LlO characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.06, 7.72, 8.12, 8.71, 10.82, 11.06, 12.14, 12.83, 13.65, 14.63, 15.02, 15.33, 15.78, 16.29, 16.95, 17.90, 18.20, 18.65, 19.51, 20.27, 21.29, 21.47, 21.97, 22.85, 24.34, 25.42, 26.63, 26.96, 27.45, 28.18, 29.60, 29.83, 31.70, 31.26, 32.04, 34.59, 35.64, 38.44 and 41.17±0.2° 2Θ. In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-LlO, comprising:

a) dissolving lumacaftor in dimethyl formamide; and

b) removing the solvent to obtain lumacaftor Form-LlO. The aforementioned process of lumacaftor Form-LlO includes dissolving lumacaftor in dimethyl formamide at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 50°C to about reflux temperature, preferably at about 50°C to about 70°C. Then cooling the reaction mixture to room temperature and then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at less than about 90°C. The resulting solid can be dried under vacuum at a temperature of less than about 80°C to obtain lumacaftor Form L10.

In another embodiment, the present invention provides lumacaftor Form-Ll 1.

In another embodiment, the lumacaftor Form-Ll 1 of the present invention is a dimethyl sulfoxide solvate. In another embodiment, the present invention provides lumacaftor Form-Ll l characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 22. In another embodiment, the present invention provides lumacaftor Form-Ll l characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.05, 7.73, 8.19, 8.77, 10.74, 11.18, 12.12, 12.79, 12.98, 13.86, 14.35, 14.72, 15.14, 15.47, 15.65, 16.43, 16.98, 17.77, 18.31, 19.62, 20.37, 21.43, 22.02, 22.70, 22.97, 24.06, 24.39, 25.36, 26.27, 27.06, 27.94, 28.51, 28.98, 29.66, 30.59, 31.43, 32.14, 33.67, 34.78, 36.07, 37.35, 39.89 and 41.61 ±0.2° 2Θ.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form-Ll 1, comprising:

a) dissolving lumacaftor in dimethyl sulfoxide; and

b) removing the solvent to obtain lumacaftor Form-Ll 1.

The aforementioned process of lumacaftor Form-Ll l includes dissolving lumacaftor in dimethyl sulfoxide at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 50°C to about reflux temperature, preferably at about 50°C to about 70°C. Then cooling the reaction mixture to room temperature and then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at less than about 90°C. The resulting solid can be dried under vacuum at a temperature of less than about 80°C to obtain lumacaftor Form LI 1.

In another embodiment, the present invention provides the use of novel solvate forms of lumacaftor as intermediates to prepare other solid forms of lumacaftor.

In another embodiment, the present invention provides a process for the preparation of lumacaftor Form I, comprising:

a) suspending or dissolving any crystalline form of lumacaftor selected from Form

LI to LI 1 in one or more solvents;

b) optionally, heating the step a) reaction mixture;

c) optionally, cooling the step b) solution;

d) adding a suitable anti-solvent to the step a) solution or vice versa; and

e) isolating the lumacaftor Form I; wherein the crystalline lumacaftor Form LI to

LI 1 are characterized by fig. 4 to - 22 respectively.

The Lumacaftor Form I is a known compound and is disclosed in the literature, for example, disclosed in the US Patent No. 8,507,534. The starting material of Lumacaftor solvates, used herein is known in the art or can be obtained by any of the methods known in the art or can be prepared according to the process of present invention described herein above. The one or more solvents include, but are not limited to organic acids selected from formic acid, acetic acid, propionic acid and the like; alcohols selected from methanol, ethanol, isopropanol and the like; ketones selected from acetone, methylisobutylketone, methylethylketone and the like; esters selected methyl acetate, ethyl acetate, isopropyl acetate and the like; nitriles selected from acetonitrile, propionitrile and the like; and mixtures thereof, preferably the one or more solvent is acetic acid or formic acid.

The step a) of providing a solution or suspension of lumacaftor solvates in one or more solvents may include heating the reaction mass to a temperature of about 50°C to about reflux temperature, preferably to a temperature of 65 °C to about 75°C.

In another embodiment, the lumacaftor solvates used herein as a starting material is selected from the group consisting of lumacaftor acetic acid solvate (Form-Ll), lumacaftor tert-butanol solvate (Form-L2), lumacaftor dichloromethane solvate (Form- L3), lumacaftor isopropylacetate solvate (Form-L4), lumacaftor ethylacetate solvate (Form-L5), lumacaftor cyclopentyl methyl ether solvate (Form-L6), lumacaftor n- propanol solvate (Form-L7), lumacaftor n-propyl acetate solvate (Form-L8), lumacaftor isobutyl acetate solvate (Form-L9), lumacaftor dimethyl formamide solvate (Form L10) or lumacaftor dimethyl sulfoxide solvate (Form LI 1) and the like. The step c) of cooling the reaction mass may include cooling the reaction mass initially to a temperature of about 30°C or less and later to a temperature of about 0°C to about 10°C.

Step d) of the aforementioned process involves the isolation of lumacaftor Form I by either addition of suitable antisolvent to the lumacaftor solution of step c) or addition of step c) solution of lumacaftor into a suitable antisolvent.

The suitable antisolvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like; and mixtures thereof. The ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; and mixture thereof; preferably the suitable antisolvent is water.

The isolation of lumacaftor Form I is carried out by any conventional techniques known in the art or methods described just as above, for example filtration. The resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

a) suspending or dissolving crystalline lumacaftor in one or more solvents;

b) adding a suitable anti-solvent to the step a) solution or vice versa; and

c) isolating the amorphous form; wherein the crystalline lumacaftor is selected from the group consisting of Form LI, L2, L3, L4, L5, L6, L7, L8, L9, L10 and LI 1, which are characterized by fig. 4 to 22 respectively.

In another embodiment, the lumacaftor solvates used herein as a starting material is selected from the group consisting of lumacaftor acetic acid solvate (Form-Ll), lumacaftor tert-butanol solvate (Form-L2), lumacaftor dichloromethane solvate (Form- L3), lumacaftor isopropylacetate solvate (Form-L4), lumacaftor ethylacetate solvate (Form-L5), lumacaftor cyclopentyl methyl ether solvate (Form-L6), lumacaftor n- propanol solvate (Form-L7), lumacaftor n-propyl acetate solvate (Form-L8), lumacaftor isobutyl acetate solvate (Form-L9), lumacaftor dimethyl formamide solvate (Form L10) or lumacaftor dimethyl sulfoxide solvate (Form LI 1) and the like. The one or more solvents include, but are not limited to organic acids selected from formic acid, acetic acid, propionic acid and the like; alcohols selected from methanol, ethanol, isopropanol and the like; ketones selected from acetone, methylisobutylketone, methylethylketone and the like; esters selected methyl acetate, ethyl acetate, isopropyl acetate and the like; nitriles selected from acetonitrile, propionitrile and the like; and mixture thereof, preferably the one or more solvent is acetic acid or formic acid.

Step c) of the aforementioned process involves the isolation of lumacaftor Form I by either addition of suitable antisolvent to the lumacaftor solution of step a) or addition of step a) solution of lumacaftor into a suitable antisolvent. Before addition of anti-solvent to the step a) reaction solution, step a) reaction solution may cooled initially to a temperature of about 30°C or less and later to a temperature of about 0°C to about 10°C.

The suitable antisolvent used herein is same as described just above; preferably the suitable antisolvent is water. The isolation of amorphous lumacaftor is carried out by any conventional techniques known in the art or methods described just as above, for example filtration. The resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

In another embodiment, the present invention provides lumacaftor prepared by the processes described above, having a chemical purity of 98% or more as measured by HPLC, preferably 99% or more, more preferably 99.5% or more.

In another embodiment, the present invention provides a pharmaceutical composition comprising at least one of the novel solid forms of lumacaftor described above and at least one or more pharmaceutically acceptable excipients. In a specific embodiment, the amorphous form of lumacaftor is stable during storage. This property is important and advantageous for the desired use of lumacaftor in pharmaceutical product formulations.

The amorphous form of lumacaftor of the present invention has commercially acceptable pharmacokinetic characteristics, solubility, flow properties, stability, and the like. The products may optionally be milled to get the desired particle size distributions. Milling or micronization may be performed prior to drying, or after the completion of drying of the products. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.

The present invention also encompasses a pharmaceutical composition comprising a therapeutically effective amount of an amorphous form of lumacaftor with at least one pharmaceutically acceptable carrier or other excipients. The present invention further provides, when a pharmaceutical composition comprising amorphous from of lumacaftor prepared according to the present invention is formulated for oral administration or parenteral administration. Accordingly, Dso and D90 particle size of the unformulated amorphous lumacaftor of the present invention used as starting material in preparing a pharmaceutical composition generally is less than 500 microns preferably less than about 300 microns, more preferably less than 150 microns, still more preferably less than about 50 microns and still more preferably less than about 10 microns.

Any milling, grinding, micronizing or other particle size reduction method known in the art can be used to bring the solid state amorphous lumacaftor of the present invention into any desired particle size range as set forth above.

Amorphous lumacaftor described in the present invention may be formulated into solid pharmaceutical products for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active ingredient is combined with one or more pharmaceutically acceptable excipients. The drug substance also may be formulated into liquid compositions for oral administration including for example solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffins.

Compositions for parenteral administration may be suspensions, emulsions or aqueous or non-aqueous, sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.

Suitable pharmaceutical compositions are solid dosage forms, such as tablets with immediate release or sustained release of the active principle, effervescent tablets or dispersion tablets and capsules. Optionally, the pharmaceutical compositions of the invention may be combination products comprising one or more additional pharmaceutically active components in addition to lumacaftor.

Pharmaceutically acceptable excipients include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol and sugar; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropylmethyl celluloses and pregelatinized starch; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium and colloidal silicon dioxide; lubricants such as stearic acid, talc, magnesium stearate and zinc stearate; glidants such as colloidal silicon dioxide; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, and waxes. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, film coating agents, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, and antioxidants. EXAMPLES

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLE 1; Preparation of amorphous form of lumacaftor (Formic acid + water)

Formic acid (2.5 mL) and lumacaftor (1.4 gms) were added in to a round bottom flask at 24°C to 28°C, stirred the solution at same temperature for about 5-10 minutes and the resulting solution was added to pre cooled water at 0°C to 5°C (500 mL). Stirred for about 30 minutes at this temperature and the precipitated solid was filtered and dried the solid in an oven under vacuum at 40°C for about 16 hrs. Yield: 1.22 gms.

The PXRD is set forth in Figure 1, The DSC thermogram is set forth in Figure 2 and The TGA is set forth in Figure 3.

EXAMPLE 2: Preparation of amorphous form of lumacaftor (Formic acid + water)

Formic acid (0.833 mL) and lumacaftor (500 mg) were added in to a round bottom flask at 24°C to 28°C, stirred the solution at same temperature for about 5-10 minutes. Pre cooled water at 0°C to 5°C (50 ml) was added to the resulting solution and stirred for about 30 minutes at same temperature. The precipitated solid was filtered and dried the solid under vacuum at 50 C for about 16 hrs. Yield: 362 mg.

EXAMPLE 3: Preparation of amorphous form of lumacaftor (Acetic acid + water)

Acetic acid (1.5 mL) and lumacaftor (300 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was heated to 58°C to 62°C and stirred for about 10 minutes and allowed to cool to room temperature. Pre cooled water at 0°C to 5°C (30 mL) was added to the reaction solution and the precipitated solid was filtered and dried the solid in an oven under vacuum at about 45°C for about 6 hrs. Output: 275 mg.

EXAMPLE 4: Preparation of amorphous form of lumacaftor (Acetic acid + water)

Acetic acid (1.5 mL) and Lumacaftor (300 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was heated to 58°C to 62°C and allowed to cool to room temperature. The resultant solution was added to pre cooled water at 0°C to 5°C (30 mL) and stirred for about 30 minutes and the precipitated solid was filtered and dried the solid under vacuum at 45°C for 6 hrs. Yield: 280 mg.

EXAMPLE 5: Preparation of amorphous form of lumacaftor (Ethanol)

Ethanol (20 mL) and Lumacaftor (250 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 55°C to get title compound. Yield: 260 mg. EXAMPLE 6: Preparation of amorphous form of lumacaftor (Isopropanol)

Isopropanol (30 mL) and Lumacaftor (225 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 55°C to get the title compound. Yield: 260 mg.

EXAMPLE 7: Preparation of amorphous form of lumacaftor (n-propanol) n-propanol (20 mL) and Lumacaftor (235 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 55°C to get the title compound. Yield: 245 mg. EXAMPLE 8: Preparation of amorphous form of lumacaftor (tert-butanol)

Tert-butanol (30 mL) and Lumacaftor (225 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 55°C to get the title compound. Yield: 234 mg.

EXAMPLE 9: Preparation of Lumacaftor Form-Ll

Acetic acid (1.5ml) and Lumacaftor (300 mg) were added in to a round bottom flask at 24°C to 28°C.The resulting solution was heated to about 55-65°C, stirred and then cooled to room temperature for 16 hours. The obtained solid was filtered and suck dried. The wet solid was further dried at 40-50°C under vacuum for 16 hours to obtain lumacaftor Form-Ll. Yield: 210 mg.

The PXRD is set forth in Figure 04, the DSC thermogram is set forth in Figure 05, and the TGA is set forth in Figure 06.

EXAMPLE 10: Preparation of Lumacaftor Form-L2

Tert-butanol (7.5 ml) and Lumacaftor (1.0 g) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was heated to about 55-65°C, stirred the solution and then cooled to room temperature and further cooled to about -20°C for 16 hours, filtered and suck dried the solids obtained. The wet solid obtained was dried at 40-50°C under vacuum for 6 hours to obtain lumacaftor Form-L2. Yield: 880 mg.

The PXRD is set forth in Figure 07, the DSC thermogram is set forth in Figure 08, and the TGA is set forth in Figure 09.

EXAMPLE 11: Preparation of Lumacaftor Form-L3

Dichloromethane (20 ml) and Lumacaftor (1.0 g) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was heated to about 35-45°C, stirred the solution and then cooled to room temperature and further cooled to about -20°C for 16 hours, filtered and suck dried the solids obtained. The wet solid obtained was dried at 40-50°C under vacuum for 16 hours to obtain lumacaftor Form-L3. Yield: 845 mg. The PXRD is set forth in Figure 10, the DSC thermogram is set forth in Figure 11, and the TGA is set forth in Figure 12.

EXAMPLE 12: Preparation of Lumacaftor Form-L4

Isopropyl acetate (76 ml) and Lumacaftor (508 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 50-60°C. The solid obtained was further dried under vacuum at about 50-60 °C for 16 hours to get lumacaftor Form L4. Yield: 470 mg.

The PXRD is set forth in Figure 13, the DSC thermogram is set forth in Figure 14, and the TGA is set forth in Figure 15. EXAMPLE 13: Preparation of Lumacaftor Form-L5

Ethyl acetate (20 ml) and Lumacaftor (293 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 50-60°C to get lumacaftor Form L5. Yield: 300 mg. The PXRD is set forth in Figure 16.

EXAMPLE 14: Preparation of Lumacaftor Form-L6 Cyclopentyl methyl ether (20 ml) and Lumacaftor (200 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 50-60°C to get lumacaftor Form L6. Yield: 220 mg. The PXRD is set forth in Figure 17. EXAMPLE 15: Preparation of Lumacaftor Form-L7

Lumacaftor (468 mg) and n-propanol (40 mL) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 50-60°C. The solid obtained was further dried under vacuum at about 45-55 °C for 16 hours to yield lumacaftor Form L7. Yield: 439 mg. The PXRD is set forth in Figure 18.

EXAMPLE 16: Preparation of Lumacaftor Form-L8 Lumacaftor (300 mg) and n-propyl acetate (30 mL) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 60-70°C to yield lumacaftor Form L8. Yield: 300 mg. The PXRD is set forth in Figure 19. EXAMPLE 17: Preparation of Lumacaftor Form-L9

Isobutyl acetate (30 mL) and Lumacaftor (219 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 60-70°C to yield lumacaftor Form L9. Yield: 219 mg. The PXRD is set forth in Figure 20.

EXAMPLE 18: Preparation of Lumacaftor Form-LlO

Dimethyl formamide (0.4 ml) and Lumacaftor (500 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was heated to about 55-65°C, stirred the solution and then cooled to room temperature for 16 hours. The solvent was evaporated by passing nitrogen gas for 2 hours to obtain lumacaftor Form-LlO. Yield: 340 mg. The PXRD is set forth in Figure 21. EXAMPLE 19: Preparation of Lumacaftor Form-Ll 1 Dimethyl sulfoxide (0.4 ml) and Lumacaftor (500 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was heated to about 55-65°C, stirred the solution and then cooled to room temperature for 16 hours. The solvent was evaporated by passing nitrogen gas for 2 hours to obtain lumacaftor Form-Ll 1. Yield: 360 mg. The PXRD is set forth in Figure 22

EXAMPLE 20: Preparation of Lumacaftor form-I from Lumacaftor DCM solvate:

Lumacaftor DCM solvate (5g) and formic acid (20mL) were added into a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to 65-75°C

and maintained for 10-20 min. The solution was gradually cooled to 2-8°C and then added to water (375 ml). The precipitated material was slurred for 5-10 min, filtered and dried at 60°C to obtain Lumacaftor Form-I. Yield: 4.2g; HPLC purity 99.95%. EXAMPLE 21: Preparation of amorphous Lumacaftor from Lumacaftor DCM solvate:

Lumacaftor DCM solvate (5g) and formic acid (15 mL) were added into a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to 65-75°C and maintained for 10-20 min. The solution was gradually cooled to 2-8°C and then added to pre-cooled water (500 ml). The precipitated material was slurred for 5-10 min, filtered and dried at 60°C to obtain amorphous Lumacaftor. Yield: 3.9g; HPLC purity 99.67%.

Claims

WE CLAIM:

Claim 1: An amorphous form of Lumacaftor. Claim 2: The Amorphous form of lumacaftor of claim 1, further characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 01, a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 02 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 03.

Claim 3: A process for the preparation of amorphous form of lumacaftor, the process comprising:

a) providing a solution of lumacaftor in one or more solvents;

b) adding a suitable antisolvent to the step a) solution or vice-versa; and

c) isolating the amorphous form.

Claim 4: The process of claim 3, wherein the one or more solvents are selected from the group consisting of organic acids selected from formic acid, acetic acid, propionic acid; alcohols selected from methanol, ethanol, isopropanol; ketones selected from acetone, methylisobutylketone, methylethylketone; esters selected methyl acetate, ethyl acetate, isopropyl acetate; nitriles selected from acetonitrile, propionitrile; and mixture thereof.

Claim 5: The process of claim 4, wherein the one or more solvent is formic acid or acetic acid.

Claim 6: The process of claim 3, wherein the suitable antisolvent is selected from the group consisting of water, ethers selected from tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane; aliphatic hydrocarbons selected from hexane, heptane, propane; alicyclic hydrocarbons selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane; and mixture thereof.

Claim 7: The process of claim 6, wherein the suitable antisolvent is water.

Claim 8: A process for the preparation of amorphous form of lumacaftor, the process comprising:

a) providing a solution or suspension of lumacaftor in a suitable solvent;

b) removing the solvent from the solution; and

c) isolating the amorphous form of lumacaftor.

Claim 9: The process of claim 8, wherein the suitable solvent is selected from the group consisting of alcohols selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, esters selected from methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers selected from methyl tertiary butyl ether, tetrahydrofuran, dimethyl ether, diisopropyl ether, 1,4- dioxane; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles selected from acetonitrile, propionitrile; and mixtures thereof. Claim 10: The process of claim 9, wherein the suitable solvent is ethanol, isopropanol, n-propanol or t-butanol.

Claim 11: Lumacaftor Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.02, 7.71, 8.02, 8.78, 10.29, 10.71, 11.18, 12.10, 12.68, 13.79, 14.78, 15.19, 15.62, 16.44, 17.00, 17.76, 18.30, 18.75, 19.62, 20.36, 21.42, 22.01, 22.62, 23.36, 24.10, 24.41, 25.33, 26.24, 27.04, 27.89, 28.59, 29.04, 29.73, 30.61, 31.40, 32.22, 33.57, 34.78, 35.54, 36.13, 37.34, 38.42, 39.06, 39.97 and 41.70 ±0.2° 2Θ. Claim 12: Lumacaftor Form-Ll of claim 11, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 04.

Claim 13: Lumacaftor Form-Ll of claim 11, further characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 05.

Claim 14: Lumacaftor Form-Ll of claim 11, further characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 06.

Claim 15: Lumacaftor Form-Ll characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 04, a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 05 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 06.

Claim 16: A process for the preparation of lumacaftor Form-Ll of claim 11, comprising:

a) mixing lumacaftor with acetic acid to obtain a mixture;

b) optionally, heating the step a) reaction mixture to about 50°C to about reflux temperature;

c) optionally, cooling the mixture of step b); and

d) isolating the lumacaftor Form-Ll.

Claim 17: Lumacaftor Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 4.44, 6.07, 7.76, 8.23, 8.79, 9.65, 10.77, 11.24, 12.15, 12.73, 13.89, 14.40, 14.79, 15.20, 15.68, 16.48, 17.02, 17.80, 18.40, 18.79, 19.67, 20.34, 20.45, 21.41, 22.10, 22.66, 23.27, 24.39, 25.34, 26.28, 27.07, 27.73, 28.50, 29.04, 29.77, 30.64, 31.33, 32.33, 34.45 and 37.37 +0.2° 2Θ.

Claim 18: Lumacaftor Form-L2 of claim 17, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 07. Claim 19: Lumacaftor Form-L2 of claim 17, further characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 08.

Claim 20: Lumacaftor Form-L2 of claim 17, further characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 09.

Claim 21: Lumacaftor Form-L2 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 07, a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 08 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 09.

Claim 22: A process for the preparation of lumacaftor Form-L2 of claim 17, comprising:

a) mixing lumacaftor with tert-butanol to obtain a mixture;

c) optionally, cooling the mixture of step b); and

d) isolating the lumacaftor Form-L2. Claim 23: Lumacaftor Form-L3 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.02, 7.72, 8.76, 10.78, 11.13, 120.9, 12.84, 13.87, 14.70, 15.72, 16.43, 17.02, 17.78, 18.22, 19.58, 20.34, 21.46, 21.99, 22.90, 23.52, 24.25, 25.40, 26.46, 27.12, 27.39, 27.57, 29.72, 30.67, 32.26, 24.75, 35.63, 37.34, 38.79 and 41.53 ±0.2° 2Θ.

Claim 24: Lumacaftor Form-L3 of claim 23, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 10.

Claim 25: Lumacaftor Form-L3 of claim 23, further characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 11.

Claim 26: Lumacaftor Form-L3 of claim 23, further characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 12. Claim 27: Lumacaftor Form-L3 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 10, a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 11 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 12. Claim 28: A process for the preparation of lumacaftor Form-L3 of claim 23, comprising:

a) mixing lumacaftor with dichloromethane to obtain a mixture;

b) optionally, heating the step a) reaction mixture to about 30°C to about reflux temperature;

c) cooling the mixture of step b) to less than 10°C; and d) isolating the lumacaftor Form-L3.

Claim 29: Lumacaftor Form-L4 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.07, 7.73, 8.15, 8.78, 9.56, 10.67, 11.29, 12.11, 12.74, 14.33, 15.18, 15.71, 16.39, 17.55, 18.36, 19.62, 20.45, 21.39, 21.87, 22.06,

22.76, 24.40, 25.47, 26.41, 27.21, 27.91, 30.48 and 32.12 ±0.2° 2Θ.

Claim 30: Lumacaftor Form-L4 of claim 29, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 13.

Claim 31: Lumacaftor Form-L4 of claim 29, further characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 14.

Claim 32: Lumacaftor Form-L4 of claim 29, further characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 15.

Claim 33: Lumacaftor Form-L4 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 13, a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 14 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 15.

Claim 34: A process for the preparation of lumacaftor Form-L4 of claim 29, comprising:

a) dissolving lumacaftor in isopropyl acetate; and

b) removing the solvent to obtain lumacaftor Form-L4.

Claim 35: Lumacaftor Form-L5 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.04, 7.51, 7.73, 8.20, 8.74, 10.76, 11.18, 12.13, 12.66, 14.27, 14.83, 15.70, 16.32, 16.96, 17.81, 18.23, 18.82, 19.48, 19.70, 20.40, 21.27, 21.45, 22.05, 22.73, 23.66, 24.46, 25.44, 26.36, 27.45, 27.90, 28.44, 29.45, 30.57, 32.24, 34.49 and 35.81±0.2° 2Θ.

Claim 36: Lumacaftor Form-L5 of claim 35, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 16.

Claim 37: A process for the preparation of lumacaftor Form-L5 of claim 35, comprising:

a) dissolving lumacaftor in ethyl acetate; and

b) removing the solvent to obtain lumacaftor Form-L5.

Claim 38: Lumacaftor Form-L6 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.04, 7.64, 8.20, 8.84, 10.82, 11.24, 12.04, 12.88,

14.77, 15.70, 16.36, 17.67, 18.33, 19.59, 20.36, 21.37, 21.90, 21.91, 22.94, 24.13, 25.46, 26.23, 27.14, 30.63 and 32.03 ±0.2° 2Θ. Claim 39: Lumacaftor Form-L6 of claim 38, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 17.

Claim 40: A process for the preparation of lumacaftor Form-L6 of claim 38, comprising:

a) dissolving lumacaftor in cyclopentyl methyl ether; and

b) removing the solvent to obtain lumacaftor Form-L6.

Claim 41: Lumacaftor Form-L7 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.05, 7.59, 8.11, 8.78, 10.68, 11.10, 12.08, 12.68, 14.75, 15.22, 15.60, 16.71, 17.70, 18.25, 18.83, 19.53, 20.43, 21.22, 220.6, 22.76, 24.26, 25.52, 27.11, 27.86 and 29.69±0.2° 2Θ.

Claim 42: Lumacaftor Form-L7 of claim 41, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 18.

Claim 43: A process for the preparation of lumacaftor Form-L7 of claim 41, comprising:

a) dissolving lumacaftor in n-propanol; and

b) removing the solvent to obtain lumacaftor Form-L7.

Claim 44: Lumacaftor Form-L8 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.07, 7.60, 8.22, 8.74, 10.65, 11.16, 12.05, 12.71, 14.62, 15.03, 16.51, 17.76, 18.27, 19.63, 20.36, 21.33, 22.04, 22.59, 24.22, 25.26, 26.39, 27.01, 27.94, 30.57, 31.29, 32.12 and 33.51±0.2° 2Θ.

Claim 45: Lumacaftor Form-L8 of claim 44, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 19. Claim 46: A process for the preparation of lumacaftor Form-L8 of claim 44, comprising:

a) dissolving lumacaftor in n-propyl acetate; and

b) removing the solvent to obtain lumacaftor Form-L8. Claim 47: Lumacaftor Form-L9 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.06, 7.72, 8.20, 8.78, 10.78, 11.23, 12.21, 12.71,

14.41, 14.84, 15.65, 16.34, 17.83, 18.36, 19.72, 20.42, 21.41, 22.09, 22.74, 24.46,

25.42, 26.25, 27.16, 27.88, 28.71, 30.46, 32.07 and 34.59 ±0.2° 2Θ. Claim 48: Lumacaftor Form-L9 of claim 47, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 20.

Claim 49: A process for the preparation of lumacaftor Form-L9 of claim 47, comprising:

a) dissolving lumacaftor in isobutyl acetate; and

b) removing the solvent to obtain lumacaftor Form-L9. Claim 50: Lumacaftor Form-LlO characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.06, 7.72, 8.12, 8.71, 10.82, 11.06, 12.14, 12.83, 13.65, 14.63, 15.02, 15.33, 15.78, 16.29, 16.95, 17.90, 18.20, 18.65, 19.51, 20.27, 21.29, 21.47, 21.97, 22.85, 24.34, 25.42, 26.63, 26.96, 27.45, 28.18, 29.60, 29.83, 31.70, 31.26, 32.04, 34.59, 35.64, 38.44 and 41.17±0.2° 2Θ.

Claim 51: Lumacaftor Form-LlO of claim 50, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 21. Claim 52: A process for the preparation of lumacaftor Form-LlO of claim 50, comprising:

a) dissolving lumacaftor in dimethyl formamide; and

b) removing the solvent to obtain lumacaftor Form-LlO. Claim 53: Lumacaftor Form-Ll 1 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 6.05, 7.73, 8.19, 8.77, 10.74, 11.18, 12.12, 12.79, 12.98, 13.86, 14.35, 14.72, 15.14, 15.47, 15.65, 16.43, 16.98, 17.77, 18.31, 19.62, 20.37, 21.43, 22.02, 22.70, 22.97, 24.06, 24.39, 25.36, 26.27, 27.06, 27.94, 28.51, 28.98, 29.66, 30.59, 31.43, 32.14, 33.67, 34.78, 36.07, 37.35, 39.89 and 41.61 ±0.2° 2Θ.

Claim 54: Lumacaftor Form-Ll 1 of claim 53, further characterized by a powder X- Ray diffraction (PXRD) pattern substantially in accordance with Figure 22.

Claim 55: A process for the preparation of lumacaftor Form-Ll 1 of claim 53, comprising:

a) dissolving lumacaftor in dimethyl sulfoxide; and

b) removing the solvent to obtain lumacaftor Form-Ll 1.

Claim 56: A process for the preparation of crystalline Form I of Lumacaftor, comprising:

a) suspending or dissolving any crystalline from of lumacaftor selected from LI to LI 1 in one or more solvents;

b) optionally, heating the step a) reaction mixture;

c) optionally, cooling the step b) solution;

d) adding a suitable anti-solvent to the step a) solution or vice versa; and

e) isolating the lumacaftor Form I; wherein the crystalline lumacaftor Form LI to LI 1 are characterized by fig. 4 to 22 respectively.

Claim 57: The process of claim 56, wherein the step a) one or more solvents selected from the group consisting of organic acids selected from formic acid, acetic acid, propionic acid; alcohols selected from methanol, ethanol, isopropanol; ketones selected from acetone, methylisobutylketone, methylethylketone; esters selected methyl acetate, ethyl acetate, isopropyl acetate; nitriles selected from acetonitrile, propionitrile; and mixtures thereof. Claim 58: The process of claim 56, wherein the suitable anti-solvent is selected from the group consisting of water; ethers selected from tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane; aliphatic hydrocarbons selected from hexane, heptane, propane; alicyclic hydrocarbons selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane; and mixtures thereof.

Claim 59: The process of claim 56, wherein the solvent is formic acid or acetic acid and the anti- solvent is water.

Claim 60: A process for the preparation of amorphous of Lumacaftor, comprising: a) suspending or dissolving crystalline lumacaftor in one or more solvents;

b) adding a suitable anti-solvent to the step a) solution or vice versa; and c) isolating the amorphous form; wherein the crystalline lumacaftor is selected from the group consisting of Form LI, L2, L3, L4, L5, L6, L7, L8, L9, L10 and

LI 1, which are characterized by fig. 4 to 22 respectively.

Claim 61: The process of claim 60, wherein the one or more solvents are selected from the group consisting of organic acids selected from formic acid, acetic acid or propionic acid; alcohols selected from methanol, ethanol or isopropanol; ketones selected from acetone, methylisobutylketone or methylethylketone; esters selected from methyl acetate, ethyl acetate or isopropyl acetate; nitriles selected from acetonitrile, or propionitrile; and mixture thereof;

Claim 62: The process of claim 60, wherein the antisolvent is selected from water, ethers selected from tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether or 1,4-dioxane; aliphatic hydrocarbons selected from hexane, heptane or propane; alicyclic hydrocarbons selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane or cyclooctane. Claim 63: The process of claim 60, wherein the one or more solvents are formic acid or acetic acid and the anti-solvent is water.

Claim 64: A pharmaceutical composition comprising novel solid forms of lumacaftor according to claim 1 to 63, and at least one pharmaceutically acceptable excipient.