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

SOLID FORMS OF LUMACAFTOR

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

Lumacaftor partially corrects the fundamental molecular defect caused by F508del-CFTR to increase the amount of functional F508del-CFTR at the cell surface, resulting in enhanced chloride transport. The channel gating activity of F508del-CFTR delivered to the cell surface by Lumacaftor can be potentiated by Ivacaftor to further enhance chloride transport. When added to F508del/F508del-HBE, the magnitude of chloride transport observed with the combination of Lumacaftor and either acute or chronic Ivacaftor treatment was greater than that observed with Lumacaftor alone. Orkambi is approved in US and Europe as a fixed dose combination (FDC) pink immediate-release film-coated tablet for oral administration. Orkambi contains 200 mg of Lumacaftor and 125 mg of Ivacaftor as active substances. US FDA label prescribes two tablets to be taken orally every 12 hours for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.
US 8993600 B2 discloses Lumacaftor as compound-396, its pharmaceutical use for the treatment of cystic fibrosis. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Lumacaftor by reacting N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. However, it is not disclosed about the nature of compound prepared by the process disclosed therein.
US 8507534 B2 discloses a crystalline Form I of Lumacaftor, which was prepared either by dispersing or dissolving a salt form, such as HCl, of Lumacaftor in an appropriate solvent for an effective amount of time (or) directly by treating t-butyl ester intermediate of Lumacaftor with an appropriate acid, such as formic acid. US 8507534 B2 further discloses the reaction of tert-butyl-3-(6-amino-3-methylpyridin-2-yl) benzoate with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride in the presence of base for the preparation of Lumacaftor.
US 8507687 B2 discloses the crystalline solvate Form A of Lumacaftor, which is a isostructural solvate with methanol, ethanol, 2-propanol, acetone, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, 2-methyl tetrahydrofuran and a crystalline Form A of Lumcaftor HCl salt.
The physicochemical properties of a solid form is a critical parameter in the development of pharmaceutical dosage forms of and these properties can affect the bioavailability, stability and processability of the active pharmaceutical ingredient. It is known that a solid active pharmaceutical ingredient can exist in amorphous and crystalline state. Crystalline solids may further exist as various polymorphs and solvates.
The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
Hence there remains a need for alternate solid forms, particularly, need for alternate crystalline forms of Lumacaftor, which are stable, reproducible and can be prepared through an industrially viable manner.

SUMMARY
In an aspect, the present application provides a crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2?. In an embodiment, the application provides crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about, 8.88, 11.10, 16.08, 16.63, 16.85, 17.82, 18.73, 19.79 and 21.54 ±0.2° 2?.

In another aspect, the present application provides a crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?. In an embodiment, the application provides crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 16.45, 17.84, 18.77, 21.64 and 22.43 ±0.2° 2?.

In another aspect, the present application provides a crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?. In an embodiment, the application provides crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 14.87, 15.22, 16.53, 17.85, 18.43, 19.68, 20.44, 21.56 and 22.10 ±0.2° 2?.

In another aspect, the present application provides a crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.39, 12.91, 14.23, 15.98, 23.69, 27.12 and 27.95 ±0.2° 2?. In an embodiment, the application provides crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 7.80, 15.58, 18.71 and 21.6 ±0.2° 2?.

In another aspect, the present application provides a process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2? comprising the step of crystallizing Lumacaftor form SV1 from the solution comprising Lumacaftor and 1,4-dioxane.

In another aspect, the present application provides a process for the preparation of crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?, comprising the step of drying crystalline form SV1 of Lumacaftor.

In another aspect, the present application provides a process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?, comprising the step of treating Lumacaftor with solvent or solvent mixture comprising acetic acid.

In another aspect, the present application provides a process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?, comprising the step of suspending Lumacaftor in a solvent selected from the group comprising of nitromethane, 1,4-dioxane, 1,2-dimethoxy ethane and hexane.

In another aspect, the present application provides a process for the preparation of crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.39, 12.91, 14.23, 15.98, 23.69, 27.12 and 27.95 ±0.2° 2?, comprising the step of crystallizing Lumacaftor from solvent or mixture of solvents comprising 1,2-dimethoxy ethane.

In an aspect, the present application provides a process of converting crystalline form SV1 of Lumacaftor to crystalline form SV3 of Lumacaftor.

In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form of Lumacaftor selected from the group comprising form SV1, form SV2, form SV3, form SV4 or mixtures thereof together with atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form SV1 of Lumacaftor prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form SV2 of Lumacaftor prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form SV3 of Lumacaftor prepared by the method of Example-5.
Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline Form SV4 of Lumacaftor prepared by the method of Example-7.
Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline Form SV3 of Lumacaftor prepared by the method of Example-8.

DETAILED DESCRIPTION

In an aspect, the present application provides a crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2?. In an embodiment, the application provides crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about, 8.88, 11.10, 16.08, 16.63, 16.85, 17.82, 18.73, 19.79 and 21.54 ±0.2° 2?.
In an embodiment, the present application provides crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern substantially as shown in figure 1.

In another aspect, the present application provides a crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?. In an embodiment, the application provides crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 16.45, 17.84, 18.77, 21.64 and 22.43 ±0.2° 2?.
In an embodiment, the present application provides crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern substantially as shown in figure 2.

In another aspect, the present application provides a crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?. In an embodiment, the application provides crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 14.87, 15.22, 16.53, 17.85, 18.43, 19.68, 20.44, 21.56 and 22.10 ±0.2° 2?.
In an embodiment, the present application provides crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern substantially as shown in figure 3.

In another aspect, the present application provides a crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.39, 12.91, 14.23, 15.98, 23.69, 27.12 and 27.95 ±0.2° 2?. In an embodiment, the application provides crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern having one or more additional peaks at about 7.80, 15.58, 18.71 and 21.6 ±0.2° 2?.
In an embodiment, the present application provides crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern substantially as shown in figure 4.

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

In another aspect, the present application provides a process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2? comprising the step of crystallizing Lumacaftor form SV1 from the solution comprising Lumacaftor and 1,4-dioxane.

In an embodiment, solution comprising Lumacaftor and 1,4-dioxane may obtained by dissolving Lumacaftor in a solvent or mixture of solvents comprising 1,4-dioxane, optionally by heating.
In an embodiment, dissolution of Lumacaftor may be carried out by optionally heating a mixture of Lumacaftor and a solvent or mixture of solvents comprising 1,4-dioxane at about 30°C to reflux temperature of the solvent. The solution may be made particle free by filtering the solution, optionally the solution may be treated with carbon, hydrose or any decolorizing agent before filtration.
In an embodiment, crystallization of Lumacaftor form SV1 may be carried out according to any methods known in the art for the reduction of solubility of Lumacaftor such as lowering the temperature (i.e., cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof.
In an embodiment, crystallization of Lumacaftor form SV1 may be carried out by lowering the temperature of the solution comprising Lumacaftor and 1,4-dioxane to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
In an embodiment, temperature lowering may be carried out slowly or drastically. In an embodiment, drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath. In further embodiments, temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
In an embodiment, after lowering the temperature, the solution comprising Lumacaftor and 1,4-dioxane may be stirred at the same temperature for time sufficient to obtain crystalline form SV1 of Lumacaftor.
Isolation of crystalline form SV1 of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form SV1 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In another aspect, the present application provides a process for the preparation of crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?, comprising the step of drying crystalline form SV1 of Lumacaftor.
In an embodiment, drying crystalline form SV1 of Lumacaftor may be carried out in suitable drying equipment such as a tray drier optionally under reduced pressure or other drying conditions known in the art such as Buchi rotavapour vacuum drying, rotatory cone vacuum drying; fluid bed drying optionally under nitrogen atmosphere, thin film drying; or the like.
In an embodiment, drying crystalline form SV1 of Lumacaftor may be carried out at suitable temperatures of about 25°C and above, optionally under reduced pressure. In an embodiment, drying may be carried out at about 100°C and above.
In an embodiment, drying crystalline form SV1 of Lumacaftor may be carried out for sufficient time to complete its conversion to crystalline form SV2 of Lumacaftor. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another aspect, the present application provides a process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?, comprising the step of treating Lumacaftor with solvent or solvent mixture comprising acetic acid.
In an embodiment, crystalline form SV3 of Lumacaftor may be obtained by treating Lumacaftor with solvent or solvent mixture comprising acetic acid, wherein the mixture of Lumacaftor and the solvent is either heterogeneous or homogeneous.
In an embodiment, crystalline form SV3 of Lumacaftor may be obtained by suspending Lumacaftor in a solvent or mixture of solvents comprising acetic acid for at suitable temperature and sufficient time.
In an embodiment, crystalline form SV3 of Lumacaftor may be obtained by crystallizing it from the solution comprising Lumacaftor and solvent or mixture of solvents comprising acetic acid.
In embodiments, crystallization of Lumacaftor form SV3 may be carried out according to any method known in the art for the reduction of solubility of Lumacaftor such as lowering the temperature (i.e., cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof. Crystallization may be carried out by any method described in any aspect or according to procedures exemplified in the instant application.
In an embodiment, crystallization of Lumacaftor form SV3 may be carried out by lowering the temperature of the solution comprising Lumacaftor and solvent or mixture of solvents comprising acetic acid to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
In an embodiment, temperature lowering may be carried out slowly or drastically. In an embodiment, drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath. In further embodiments, temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
In an embodiment, after lowering the temperature, the solution comprising Lumacaftor and solvent or mixture of solvents comprising acetic acid may be stirred at the same temperature for time sufficient to obtain crystalline form SV3 of Lumacaftor.
Isolation of crystalline form SV3 of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form SV3 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, isolated crystalline form SV3 of Lumacaftor may be optionally dried in a suitable drying equipment for times sufficient to achieve desired quality of product at suitable temperatures.

In another aspect, the present application provides a process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?, comprising the step of suspending Lumacaftor in a solvent or mixture of solvents, wherein solvent is selected from the group comprising of nitromethane, 1,4-dioxane, ,2-dimethoxy ethane and hexane.
In embodiments, crystalline form SV3 of Lumacaftor may be obtained by suspending Lumacaftor in the solvent with suitable concentrations such that the mixture of Lumacaftor and the solvent remain heterogeneous throughout the transformation.
In embodiments, crystalline form SV3 of Lumacaftor may be obtained by suspending Lumacaftor in the solvent at suitable temperature of about 0°C and above for sufficient time to complete the formation of crystalline form SV3, for atleast 1 hour or more.
In an embodiment, crystalline form SV3 of Lumacaftor may be obtained by suspending Lumacaftor in the solvent at 25°C and above for sufficient time to complete the formation of crystalline form SV3, for more than 10 hours.

In another aspect, the present application provides a process for the preparation of crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at about 9.39, 12.91, 14.23, 15.98, 23.69, 27.12 and 27.95 ±0.2° 2?, comprising the step of crystallizing Lumacaftor from solvent or mixture of solvents comprising 1,2-dimethoxy ethane.
In an embodiment, solution comprising Lumacaftor and solvent or mixture of solvents comprising 1,2-dimethoxy ethane may obtained by dissolving Lumacaftor in a solvent or mixture of solvents, optionally by heating.
In an embodiment, dissolution of Lumacaftor may be carried out by optionally heating a mixture of Lumacaftor and a solvent or mixture of solvents comprising 1,2-dimethoxy ethane at about 30°C to reflux temperature of the solvent. The solution may be made particle free by filtering the solution, optionally the solution may be treated with carbon, hydrose or any decolorizing agent before filtration.
In an embodiment, crystallization of Lumacaftor form SV4 may be carried out according to any methods known in the art for the reduction of solubility of Lumacaftor such as lowering the temperature (i.e., cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof.
In an embodiment, crystallization of Lumacaftor form SV4 may be carried out by lowering the temperature of the solution comprising Lumacaftor and 1,2-dimethoxy ethane to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
In an embodiment, temperature lowering may be carried out slowly or drastically. In an embodiment, drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath. In further embodiments, temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
In an embodiment, after lowering the temperature, the solution comprising Lumacaftor and 1,2-dimethoxy ethane may be stirred at the same temperature for time sufficient to obtain crystalline form SV4 of Lumacaftor.
Isolation of crystalline form SV4 of Lumacaftor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form SV4 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In an aspect, the present application provides a process of converting crystalline form SV1 of Lumacaftor to crystalline form SV3 of Lumacaftor.
In an embodiment, the conversion of crystalline form SV1 may be carried out by holding crystalline form SV1 under closed condition at suitable temperature of about 0°C to 40°C. In an embodiment, crystalline form SV1 may be held under closed condition for sufficient time to complete the conversion for atleast 24 hours or more. In an embodiment, crystalline form SV1 may be held under suitable packing condition.
In an embodiment, the present application provides crystalline form SV3 of Lumacaftor obtained according to the process of this aspect may be, characterized by a PXRD pattern substantially as shown in figure 5.

In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form of Lumacaftor selected from the group comprising form SV1, form SV2, form SV3, form SV4 or mixtures thereof together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides crystalline forms of Lumacaftor or their pharmaceutical compositions comprising Lumacaftor having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In another aspect, the present application provides crystalline forms of Lumacaftor or their pharmaceutical composition, wherein particle size (D90) of Lumacaftor may be less than 100 microns or less than 50 microns or less than 20 microns.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Definitions
The term "about" when used in the present application preceding a number and
referring to it, is meant to designate any value which lies within the range of ±10%,
preferably within a range of ±5%, more preferably within a range of ±2%, still more
preferably within a range of ±1 % of its value. For example "about 10" should be
construed as meaning within the range of 9 to 11 , preferably within the range of 9.5
to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably
within the range of 9.9 to 10.1.
The terms “crystalline form" indicates that the Lumacaftor is present in substantially crystalline Form. "Substantially" crystalline denotes that atleast 80 %, preferably 90 % or 95 %, more preferably all of the Lumacaftor is crystalline form. In other words, "crystalline form" of Lumacaftor denotes Lumacaftor, which does not contain substantial amounts, preferably does not contain noticeable amounts, of any other crystalline portions of Lumacaftor e.g. measurable upon X-ray powder diffraction analysis.

EXAMPLES

Example-1: Preparation of crystalline form SV1 of Lumacaftor.
Lumacaftor (3 g) was dissolved in 1,4-dioxane (15 mL) at 50°C and rapidly cooled to -78°C to precipitate solid. The reaction mixture was allowed to attain 25°C and solid was filtered to obtain 1.6 g of the title compound.
Example-2: Preparation of crystalline form SV2 of Lumacaftor
Crystalline form SV1 of Lumcaftor (0.8 g) obtained in example-1 was dried under vacuum at 100°C for 1 hour to obtain the title compound.
Example-3: Preparation of crystalline form SV1 of Lumacaftor.
Lumacaftor (0.5 g) was dissolved in 1,4-dioxane (2 mL) at 25°C and rapidly cooled to -78°C to precipitate solid. The precipitated solid was allowed to attain 25°C and solid was filtered to obtain title compound.
Example-4: Preparation of crystalline form SV2 of Lumacaftor
Crystalline form SV1 of Lumacaftor that was obtained in example- 3 was heated to 140°C and cooled to 25°C in a thermo gravimetric analyzer to obtain title compound.
Example-5: Preparation of crystalline form SV3 of Lumacaftor
Lumacaftor (2 g) was dissolved in acetic acid (20 mL) at 60°C and rapidly cooled to -78°C. The reaction mixture was then allowed to attain 26°C and maintained for 1 hour at the same temperature. The solid was filtered and dried under vacuum for 2 hours at 100°C to obtain title compound.
Example-6: Preparation of crystalline form SV3 of Lumacaftor
Lumacaftor (4x 0.1 g) was stirred with 0.7 mL of each solvent (i.e., Nitromethane, 1,4-dioxane, 1,2-dimethoxy ethane and hexane) at 30°C for 24 hours to obtain title compound.
Example-7: Preparation of crystalline form SV4 of Lumacaftor
Lumacaftor (0.5 g) was dissolved in 1,2-dimethoxy ethane (10 mL) at 60°C and rapidly cooled to -70°C and maintained for 10 minutes at the same temperature. The solution was then allowed to evaporate the solvent under atmospheric pressure at 26°C in an open beaker for 20 hours to obtain title compound.
Example-8: Preparation of crystalline form SV3 of Lumacaftor
Crystalline form SV1 of Lumacaftor obtained at example-1 was packed in an amber colour glass vial and stored for 12 days at 25°C to obtain the title compound.
,CLAIMS:We Claim:
1. A crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2?.
2. A crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?.
3. A crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?.
4. A crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 9.39, 12.91, 14.23, 15.98, 23.69, 27.12 and 27.95 ±0.2° 2?.
5. A process for the preparation of crystalline form SV1 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 6.52, 9.30, 10.45, 10.73, 11.88, 17.19, 19.46, 20.28 and 24.7 ±0.2° 2? comprising the step of crystallizing Lumacaftor form SV1 from the solution comprising Lumacaftor and 1,4-dioxane.
6. A process for the preparation of crystalline form SV2 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 9.67, 10.74, 11.32, 13.85, 19.25, 20.34, 26.47 and 27.25 ±0.2° 2?, comprising the step of drying crystalline form SV1 of Lumacaftor.
7. A process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?, comprising the step of treating Lumacaftor with solvent or solvent mixture comprising acetic acid.
8. A process for the preparation of crystalline form SV3 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 6.13, 12.19, 12.83, 17.08, 22.78, 24.20, 25.47, 26.39 and 28.02 ±0.2° 2?, comprising the step of suspending Lumacaftor in a solvent selected from the group comprising of nitromethane, 1,2-dimethoxy ethane and hexane.
9. A process for the preparation of crystalline form SV4 of Lumacaftor, characterized by a PXRD pattern comprising the peaks at 9.39, 12.91, 14.23, 15.98, 23.69, 27.12 and 27.95 ±0.2° 2?, comprising the step of crystallizing Lumacaftor from solvent or mixture of solvents comprising 1,2-dimethoxy ethane.
10. A pharmaceutical composition comprising Lumacaftor according to any of the preceding claims together with one or more pharmaceutically acceptable carriers.