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

AMORPHOUS LUMACAFTOR AND PROCESS FOR ITS PREPARATION

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

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

SUMMARY
In an aspect, the present application provides an amorphous form of Lumacaftor.
In another aspect, the present application provides a process for the preparation of an amorphous form of Lumacaftor, comprising the steps of:
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Lumcaftor.
d) optionally combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides amorphous solid dispersion of Lumacaftor together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Lumacaftor, comprising the steps of:
a) providing a solution of Lumacaftor and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Lumacaftor.
d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
In another aspect, the present application provides a pharmaceutical composition comprising amorphous form of Lumacaftor or the amorphous solid dispersion of Lumacaftor together with atleast one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous form of Lumacaftor prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous form of Lumacaftor prepared by the method of Example No 3.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous form of Lumacaftor prepared by the method of Example No 4.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Lumacaftor with povidone K-30 prepared by the method of Example No 5.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Lumacaftor with co-povidone NF prepared by the method of Example No 6.
Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Lumacaftor with povidone K-30 and Syloid-244 FP NF prepared by the method of Example No 5.
Figure 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Lumacaftor with co-povidone NF and Syloid-244 FP NF prepared by the method of Example No 6.
Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Lumacaftor with HPMC and Syloid-244 FP NF prepared by the method of Example No 7.
Figure 9 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Lumacaftor with HPMC by the method of Example No 8.

DETAILED DESCRIPTION
In an aspect, the present application provides an amorphous form of Lumacaftor.
In an embodiment, the present application provides an amorphous form of Lumacaftor characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 1, 2 or 3.
The present application provides a stable amorphous form of Lumacaftor suitable for powder handling and downstream processes.
In an embodiment, the amorphous form of Lumacaftor is stable for atleast 2 months when packed in amber colored bottle and stored at ambient conditions.
In an embodiment, the amorphous form of Lumacaftor is stable for atleast 1 month in all ICH storage conditions including (i) 25°C ± 2°C and 65%RH ± 5RH (ii) 35°C±2°C and 75%RH ± 5RH (iii) 40°C±2°C and 75%RH ± 5RH and (iv) 2°C - 8°C, using the below packing method.
Packing method: Flush the clear anti-static polyethylene bag with Nitrogen gas. Keep the sample in a clear anti-static polyethylene bag and tie it properly with plastic strip. Keep the above in a black polythene bag along with Molecular sieve pouch, fill it with Nitrogen gas and tie it properly with plastic strip. Keep the above in a triple laminated bag and seal it with VNS (Vacuuming Nitrogen filling and sealing). Finally keep the packet in HDPE container and store in the related stability chamber.
Amorphous form of Lumacaftor of the present application which was surprisingly found to be also stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH. In an embodiment, the present application provides a stable amorphous form of Lumacaftor with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably devoid of crystallinity as per X-ray diffraction analysis.

In another aspect, the present application provides a process for the preparation of an amorphous form of Lumacaftor, comprising the steps of:
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Lumcaftor.
d) optionally combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient
In an embodiment, suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, suitable solvent at step a) may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; or mixtures thereof.
In an embodiment, providing a solution at step a) may be carried out by dissolving Lumacaftor in a suitable solvent or by taking the reaction mixture containing Lumacaftor directly. In an embodiment, a solution of Lumacaftor can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Lumacaftor may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying and the like.
In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous form of Lumacaftor at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. In an embodiment, the amorphous form of Lumacaftor obtained from step b) may be optionally dried before or after isolating it at step c).
Amorphous form of Lumacaftor obtained at step c) may be optionally combined with atleast one pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous form of Lumacaftor may be combined with excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous form of Lumacaftor may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of Lumacaftor and atleast one pharmaceutically acceptable excipient.
In an embodiment, amorphous form of Lumacaftor may be combined with the excipient by evaporating the suspension or solution of amorphous form of Lumacaftor and atleast one pharmaceutically acceptable excipient.
In an embodiment, pharmaceutically acceptable excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene or polyvinyl alcohol copolymer, polyethylene or polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
In preferred embodiment, pharmaceutically acceptable excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica; copolymers, such as polyethylene or polyvinyl alcohol copolymer, polyethylene or polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.
Amorphous form of Lumacaftor isolated at step c) or d) may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In an aspect, the present application provides pharmaceutical composition comprising amorphous form of Lumacaftor and atleast one pharmaceutically acceptable excipient.
In an aspect, the present application provides amorphous solid dispersion of Lumacaftor together with atleast one pharmaceutically acceptable excipient.
In an embodiment, the present application provides amorphous solid dispersion of Lumacaftor together with atleast one pharmaceutically acceptable excipient characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 4, 5, 6 or 7.
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Lumacaftor, comprising the steps of:
a) providing a solution of Lumacaftor and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Lumacaftor.
d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
In an embodiment, suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group consisting of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, suitable solvent at step a) may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; or mixtures thereof.
In an embodiment, atleast one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone,povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose SL, hydroxyethyl cellulose, gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.
In an embodiment, providing a solution at step a) may be carried out by dissolving Lumacaftor and atleast one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
In an embodiment, a solution of Lumacaftor and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Lumacaftor and the excipient may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, agitated thin film drying and the like.
In preferred embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous solid dispersion of Lumacaftor and excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In an embodiment, the amorphous solid dispersion of Lumacaftor and excipient obtained from step b) may be optionally dried before or after isolating at step c).
Amorphous solid dispersion of Lumacaftor obtained at step c) may be optionally combined with atleast one additional pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous solid dispersion of Lumacaftor may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous solid dispersion of the present application may be combined with additional excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous solid dispersion of Lumacaftor with pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
In an embodiment, amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of Lumacaftor and additional excipient.
In an embodiment, pharmaceutically acceptable additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of Lumacaftor. Additional excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene or polyvinyl alcohol copolymer, polyethylene or polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
In preferred embodiment, pharmaceutically acceptable additional excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica; copolymers, such as polyethylene or polyvinyl alcohol copolymer, polyethylene or polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.
Amorphous solid dispersion of Lumacaftor isolated at step c) or d) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In an aspect, the present application provides pharmaceutical composition comprising amorphous solid dispersion of Lumacaftor with atleast one pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
In an aspect, the present application provides pharmaceutical compositions comprising amorphous Lumacaftor and atleast one pharmaceutically acceptable excipient, in particular in the form of solid dispersions and adsorbates, and a process for preparing the same. In embodiments, the pharmaceutically acceptable excipient is selected from the excipients at any aspect of present application.
In embodiments, the present application provides adsorbates, wherein Lumacaftor is associated with a suitable substrate. Suitable substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Lumacaftor and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption. In embodiments, the suitable substrate is selected from the excipients at any aspect of present application.
Amorphous form of Lumacaftor or its solid dispersion may be obtained alternatively either by employing a melt-extrusion technique or by combining a solution of Lumacaftor as obtained any of the aspects of present application with a suitable anti-solvent. In embodiment, amorphous product may be obtained by employing suitable melt-extrusion conditions or any of the procedures known in the art for obtaining amorphous product by melt-extrusion technique. In embodiment, solution of Lumacaftor may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product. Suitable anti-solvent is a solvent, wherein Lumacaftor has low solubility and it may include, but not limited to aliphatic or cyclic ethers solvents, aliphatic or aromatic hydrocarbons or the like.
In another aspect, the present application provides amorphous Lumacaftor, its solid dispersion or pharmaceutical composition comprising Lumacaftor having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and
referring to it, is meant to designate any value which lies within the range of ±10%,
preferably within a range of ±5%, more preferably within a range of ±2%, still more
preferably within a range of ±1 % of its value. For example "about 10" should be
construed as meaning within the range of 9 to 11 , preferably within the range of 9.5
to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably
within the range of 9.9 to 10.1.
The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
The terms “amorphous form of Lumacaftor" and “amorphous Lumcaftor” indicate that the Lumacaftor is present in substantially amorphous state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition). "Substantially" amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the Lumacaftor being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous. In other words, an "amorphous" Lumacaftor composition denotes a Lumacaftor-containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Lumacaftor e.g. measurable upon X-ray powder diffraction analysis.
The term "solid dispersion" when used in the present application, denotes a state where most of the Lumacaftor, preferably 90%, 95% or all of the Lumacaftor of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
The term "adsorbate" when used in the present application, specifies that the Lumacaftor is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

EXAMPLES
Example-1: Preparation of Amorphous form of Lumacaftor
Lumacaftor (0.5 g) was dissolved in methanol (30 mL) at 45°C and filtered the solution to make it particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely using rotavapour under vacuum at 55°C to obtain the title compound. XRPD: Amorphous.
Example-2: Preparation of Amorphous form of Lumacaftor.
Lumacaftor (0.5 g) was dissolved in acetone (20 mL) at 50°C and filtered the solution to make it particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely using rotavapour under vacuum at 55°C to obtain the title compound. XRPD: Amorphous.
Example-3: Preparation of Amorphous form of Lumacaftor
Lumacaftor (0.5 g) was dissolved in methanol (30 mL) at 50°C and filtered the solution to make it particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely using rotavapour under vacuum at 55°C. Syloid-244 FP NF (0.5 g) was added to it and blended at 25°C for 25 minutes to obtain title compound. XRPD: Amorphous
Example-4: Preparation of Amorphous form of Lumacaftor
Lumacaftor (2 g) was dissolved in methanol (100 mL) at 50°C and filtered the solution to make it particle free. The clear solution was spray dried with 70% aspirator, flow rate of 9 mL/ minute and inlet temperature of 80°C and out let temperature of 46°C to obtain the title compound. XRPD: Amorphous.
Example-5: Preparation of Amorphous solid dispersion of Lumacaftor and Povidone
Lumacaftor (0.5 g) was dissolved in methanol (60 mL) at 50°C and filtered the solution to make it particle free. Povidone K-30 solution (0.5 g in 20 mL of methanol) was added to above Lumacaftor solution. The combined solution was taken into a Buchi flask and evaporated the solvent completely using rotavapour under vacuum at 55°C to obtain amorphous solid dispersion. Syloid-244 FP NF (0.5 g) was added to it and blended at 25°C for 13 minutes to obtain title compound. XRPD: Amorphous.
Example-6: Preparation of Amorphous solid dispersion of Lumacaftor and Co-povidone.
Lumacaftor (0.5 g) was dissolved in methanol (60 mL) at 50°C and filtered the solution to make it particle free. Co-povidone NF solution (0.5 g in 20 mL of methanol) was added to above Lumacaftor solution. The combined solution was taken into a Buchi flask and evaporated the solvent completely using rotavapour under vacuum at 55°C to obtain amorphous solid dispersion. Syloid-244 FP NF (0.5 g) was added to it and blended at 25°C for 19 minutes to obtain title compound. XRPD: Amorphous.

Example-7: Preparation of Amorphous solid dispersion of Lumacaftor and hydroxypropylmethylcellulose (HPMC).
Lumacaftor (0.5 g) was dissolved in methanol (10 mL) at 50°C and filtered the solution to make it particle free. HPMC solution (0.5 g in 20 mL of methanol) was added to above Lumacaftor solution. The combined solution was taken into a Buchi flask and evaporated the solvent completely using rotavapour under vacuum at 55°C to obtain amorphous solid dispersion. Syloid-244 FP NF (0.5 g) was added to it and blended at 25°C for 10 minutes to obtain title compound. XRPD: Amorphous.
Example-8: Preparation of Amorphous solid dispersion of Lumacaftor and hydroxypropylmethylcellulose (HPMC).
Lumacaftor (2 g) was dissolved in methanol (30 mL) at 55°C and filtered the solution to make it particle free. HPMC solution (2 g in 30 mL of methanol) was added to above Lumacaftor solution. The clear solution was spray dried with 65% aspirator, flow rate of 6 mL/ minute and inlet temperature of 70°C and out let temperature of 42°C to obtain the title compound. XRPD: Amorphous.
,CLAIMS:We Claim:
1. An amorphous form of Lumacaftor.
2. A process for the preparation of an amorphous form of Lumacaftor, comprising the steps of:
a) providing a solution of Lumacaftor in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Lumcaftor.
d) optionally combining the amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
3. A process of claim 2, wherein the suitable solvent at step a) may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; or mixtures thereof.
4. A process of claims 2, wherein the pharmaceutically acceptable excipient at step d) is selected from the group comprising of silicon dioxide such as colloidal or fumed silicon dioxide or porous silica; copolymers such as polyethylene or polyvinyl alcohol copolymer, polyethylene or polyvinyl pyrrolidinone copolymer; and cellulose such as microcrystalline cellulose.
5. An amorphous solid dispersion of Lumacaftor together with atleast one pharmaceutically acceptable excipient.
6. An amorphous solid dispersion of Lumacaftor of claim 3, wherein the pharmaceutically acceptable excipient is selected from the group comprising of polyvinyl pyrrolidine, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMC phthalate), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropyl cellulose SL (HPC), hydroxy ethyl cellulose (HEC) and ethyl cellulose (EC).
7. A process for the preparation of an amorphous solid dispersion of Lumacaftor with atleast one pharmaceutically acceptable excipient, comprising the steps of:
a) providing a solution of Lumacaftor and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a) and
c) isolating the amorphous solid dispersion of Lumacaftor.
d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
8. A process of claims 5, wherein the suitable solvent at step a) may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; or mixtures thereof.
9. A process of claims 5, wherein the pharmaceutically acceptable excipient at step d) is selected from the group comprising of silicon dioxide such as colloidal or fumed silicon dioxide or porous silica; copolymers such as polyethylene or polyvinyl alcohol copolymer, polyethylene or polyvinyl pyrrolidinone copolymer; and cellulose such as microcrystalline cellulose.
10. A pharmaceutical composition comprising an amorphous form of Lumacaftor and atleast one pharmaceutically acceptable excipient.