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

COMPLEX AND AMORPHOUS PHASE OF LUMACAFTOR AND IVACAFTOR

INTRODUCTION
Aspects of the present application relate to complex and amorphous phase of Lumacaftor and Ivacaftor, and pharmaceutical compositions thereof. Aspects of the present application specifically relate to crystalline complex and amorphous phase of Lumacaftor and Ivacaftor and their preparative processes.
ORKAMBI is approved in US and Europe as a fixed dose combination (FDC) pink immediate-release film-coated tablet for oral administration.
The active ingredients in ORKAMBI tablets are Lumacaftor, which has the chemical name: 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl] carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, and Ivacaftor, a CFTR potentiator, which has the chemical name: N-(2,4-di-tertbutyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide.

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.
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.
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)cyclo propanecarboxamide with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid.
US 8507534 B2 discloses Lumacaftor in crystalline Form I characterized by 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 solvate Form A of Lumacaftor (designated as Form II of Lumacaftor in US 8552034 B2), 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.
US 7495103 B2 discloses Ivacaftor or a pharmaceutically acceptable salt thereof, its pharmaceutical composition and its use for treating or lessening the severity of cystic fibrosis. Ivacaftor made from the procedure exemplified therein was purified by HPLC and no characteristic details of the compound obtained were disclosed.
US 8410274 B2 describes both crystalline (polymorph A and B) and amorphous forms of Ivacaftor. Amorphous Ivacaftor and its amorphous phase with a polymer were described to have superior over their crystalline counterparts.
US 8471029 B2 discloses crystalline Form C of Ivacaftor, while US 8163772 B2 discloses various other the solid forms / co-forms of Ivacaftor, for example, salts, solvates, co-crystals and hydrates of Ivacaftor and exemplified specifically compounds selected from crystalline Ivacaftor.2-methylbutyric acid, Ivacaftor.propylene glycol, Ivacaftor.PEG 400.KOAc, Ivacaftor.lactic acid, Ivacaftor.isobutyric acid, Ivacaftor.propionic acid, Ivacaftor.H2O, Ivacaftor.EtOH, Ivacaftor.2-propanol, Ivacaftor.besylate and Ivacaftor.besylate.H2O and designated them as Form I to XVI
US 8674108 B2 discloses various crystalline solvates of Ivacaftor, wherein the crystalline solvates are designated as a solid form selected from the group consisting of Form D, to Form T, Form W, and Hydrate B and their preparative processes.
There remains a need for alternate solid forms of Lumacaftor and / or Ivacaftor, preparative processes thereof. Specifically, there is a need for a solid form of Lumacaftor and / or Ivacaftor with a higher bioavailability and process ability, which leads to its selection as the final drug substance for pharmaceutical dosage form development. Therefore, it is desirable to have alternate solid forms of Lumacaftor and / or Ivacaftor to meet the needs of drug development and also a reproducible process for their preparation.

SUMMARY
In an aspect, the present application provides a complex of Lumacaftor and Ivacaftor. In specific aspects, the present application provides crystalline complex of Lumacaftor and Ivacaftor.
In another aspect, the present application provides Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor, characterized by a PXRD pattern comprising peaks at about 6.13, 10.36, 10.69, 11.21, 13.55, 14.25 and 20.88 ±0.2° 2?. In an embodiment, the application provides Form LI-1, further characterized by a PXRD pattern having peaks at about 12.33, 15.12, 17.75, 22.64 and 23.92 ±0.2° 2?.
In another aspect, the present application provides Form LI-2 of crystalline complex of Lumacaftor and Ivacaftor, characterized by a PXRD pattern comprising peaks at about 7.44, 8.77, 12.09, 16.45, 17.74 and 20.37 ±0.2° 2?. In an embodiment, the application provides Form LI-2, further characterized by a PXRD pattern having peaks at about 14.77, 21.44, 21.99 and 22.65 ±0.2° 2?.

In another aspect, the present application provides a process for preparing a complex of Lumacaftor and Ivacaftor, which comprises:
a) combining Lumacaftor and Ivacaftor in the presence of a solvent
b) removing the solvent from the mixture of step a);
c) isolating complex of Lumacaftor and Ivacaftor.

In another aspect, the present application provides a process for preparing a complex of Lumacaftor and Ivacaftor, which comprises:
a) combining Lumacaftor and Ivacaftor in the presence of a solvent
b) contacting an anti-solvent with the mixture of step a);
c) isolating complex of Lumacaftor and Ivacaftor.

In another aspect, the present application provides a process for preparing a complex of Lumacaftor and Ivacaftor, which comprises:
a) combining Lumacaftor and Ivacaftor optionally in the presence of a solvent
b) isolating complex of Lumacaftor and Ivacaftor.

In another aspect, the present application provides a process for the preparation of Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor, comprising the steps
a) providing a solution of Lumacaftor and Ivacaftor in ethanol or a mixture of ethanol and another solvent;
b) removing the solvent of step a);
c) isolating Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor.

In another aspect, the present application provides a process for the preparation of Form LI-2 of crystalline complex of Lumacaftor and Ivacaftor, comprising the step of drying Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor.
In another aspect, the present application provides an amorphous phase of Lumacaftor and Ivacaftor.

In another aspect, the present application provides a process for the preparation of amorphous phase of Lumacaftor and Ivacaftor, comprising the steps of:
a) providing a solution of Lumacaftor and Ivacaftor in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous phase of Lumacaftor and Ivacaftor.
d) optionally combining amorphous phase of Lumacaftor and Ivacaftor of step c) with atleast one additional pharmaceutically acceptable excipient.

In another aspect, the present application provides pharmaceutical composition comprising complex of Lumacaftor and Ivacaftor together with atleast one pharmaceutically acceptable excipient.

In another aspect, the present application provides a pharmaceutical composition comprising crystalline complex of Lumacaftor and Ivacaftor together with atleast one pharmaceutically acceptable excipient.

In another aspect, the present application provides a pharmaceutical composition comprising amorphous phase of Lumacaftor and Ivacaftor together with atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of Form LI-2 of crystalline complex of Lumacaftor and Ivacaftor prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous phase of Lumacaftor and Ivacaftor prepared by the method of Example No 3.

DETAILED DESCRIPTION
In an aspect, the present application provides a complex of Lumacaftor and Ivacaftor. In specific aspects, the present application provides crystalline complex or amorphous phase of Lumacaftor and Ivacaftor.

In another aspect, the present application provides Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor, characterized by a PXRD pattern comprising peaks at about 6.13, 10.36, 10.69, 11.21, 13.55, 14.25 and 20.88 ±0.2° 2?. In an embodiment, the application provides Form LI-1, further characterized by a PXRD pattern having peaks at about 12.33, 15.12, 17.75, 22.64 and 23.92 ±0.2° 2?.
In an embodiment, the present application provides Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor, characterized by a PXRD pattern substantially as shown in figure 1.

In another aspect, the present application provides Form LI-2 of crystalline complex of Lumacaftor and Ivacaftor, characterized by a PXRD pattern comprising peaks at about 7.44, 8.77, 12.09, 16.45, 17.74 and 20.37 ±0.2° 2?. In an embodiment, the application provides Form LI-2, further characterized by a PXRD pattern having peaks at about 14.77, 21.44, 21.99 and 22.65 ±0.2° 2?.
In an embodiment, the present application provides Form LI-2 of crystalline complex of Lumacaftor and Ivacaftor, characterized by a PXRD pattern substantially as shown in figure2.
The ratio of Lumacaftor to Ivacaftor present in the complex according to any aspect of the instant application may vary from about 1:2 to about 2:1. In an embodiment, the ratio of Lumacaftor to Ivacaftor present in the complex may be 1.38:1.

In another aspect, the present application provides a process for preparing a complex of Lumacaftor and Ivacaftor, which comprises:
a) combining Lumacaftor and Ivacaftor with a suitable solvent;
b) removing the solvent from the mixture of step a);
c) isolating complex of Lumacaftor and Ivacaftor.
Step a) of this aspect may be carried out by combining Lumacaftor and Ivacaftor in the presence of a solvent or a mixture thereof.
In an embodiment, the mixture of Lumacaftor and Ivacaftor may be combined with solvent at any suitable temperatures, such as at about 0°C to about the reflux temperature of the solvent or mixture thereof.
In an embodiment the mixture of Lumacaftor and Ivacaftor in the solvent may be either a heterogeneous or homogeneous phase.
In an embodiment, the mixture of Lumacaftor and Ivacaftor in solvent may be optionally filtered to make particle free solution when it is a homogeneous clear solution and treated with a decolorizing agent, such as carbon, before filtration.
Step b) of this aspect may be carried out by removal of solvent employing any method known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: slow solvent evaporation, fast solvent evaporation under atmospheric pressure or reduced pressure / vacuum using suitable equipment such as Büchi® Rotavapor®, spray drier, thin film drier, sublimation of the components using freez drier and the like.
In an embodiment, solvent may be removed partially or completely from the mixture of step a). In an embodiment, additional solvent may added to the mixture of step b) when the solvent is removed completely.
In an embodiment, the mixture of step a) or step b) may be stirred for sufficient time and suitable temperature to complete the formation of complex of Lumacaftor and Ivacaftor.
Step c) of this aspect may be carried out by isolation of complex of Lumacaftor and Ivacaftor by any methods known in the art or procedures described in the present application. In an embodiment, complex of Lumacaftor and Ivacaftor 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 complex of Lumacaftor and Ivacaftor 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 150°C, less than about 120°C, less than about 100°C, or any other suitable temperatures. 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 preparing a complex of Lumacaftor and Ivacaftor, which comprises:
a) combining Lumacaftor and Ivacaftor in the presence of a solvent;
b) contacting an anti-solvent with the mixture of step a);
c) isolating complex of Lumacaftor and Ivacaftor.
Step a) of this aspect may be carried out by combining Lumacaftor and Ivacaftor in the presence of a solvent or a mixture thereof.
In an embodiment, the mixture of Lumacaftor and Ivacaftor may be combined with solvent at any suitable temperatures, such as at about 0°C to about the reflux temperature of the solvent or mixture thereof.
In an embodiment the mixture of Lumacaftor and Ivacaftor in the solvent may be either a heterogeneous or homogeneous phase.
In an embodiment, the mixture of Lumacaftor and Ivacaftor in solvent may be optionally filtered to make particle free solution when it is a homogeneous clear solution and treated with a decolorizing agent, such as carbon, before filtration.
In an embodiment, the mixture of Lumacaftor and Ivacaftor in solvent may be cooled to suitable temperature for the precipitation of complex of Lumacaftor and Ivacaftor from the mixture. In an embodiment, the mixture of Lumacaftor and Ivacaftor in solvent may be cooled drastically or gradually with either constant rate of cooling or by step-wise cooling periodically to achieve desired complex of Lumacaftor and Ivacaftor.
In an embodiment, the mixture of Lumacaftor and Ivacaftor in solvent may be stirred for sufficient time to complete formation of complex of Lumacaftor and Ivacaftor. In an embodiment, the mixture of Lumacaftor and Ivacaftor in solvent may be stirred for atleast 1hour or more, preferably for atleast 24 hours or more and more preferably atleast 48 hours or more.
In an embodiment, the mixture of Lumacaftor and Ivacaftor in solvent may be stirred at suitable temperature for the formation of complex of Lumacaftor and Ivacaftor. In an embodiment, the mixture of Lumacaftor and Ivacaftor in solvent may be stirred at 0°C and above, preferably between 0°C to reflux temperature of the solvent used, more preferably between 0°C and 50°C.
Step b) of this aspect may be carried out by contacting an anti-solvent with the mixture of step a). In an embodiment, an anti-solvent may be contacted for sufficient time and at suitable temperature to complete the formation of complex of Lumacaftor and Ivacaftor. Anti-solvent is a solvent in which the complex of Lumacaftor and Ivacaftor has minimum solubility and it may include but not limited to water; aliphatic hydrocarbons, such as hexane, heptane, cyclohexane; aromatic hydrocarbons, such as toluene, xylene and chlorobenzene; ethers, such as diethyl ether, di-isopropyl ether, tetrahydrofuran, dioxane; or the like.
In an embodiment, anti-solvent may be added to the mixture of step a) or the mixture of step a) may be added to the anti-solvent. The addition may be carried out either by drastically by one pot addition or in multiple pots or gradually with controlled rate of addition.
In an embodiment, isolation of complex of Lumacaftor and Ivacaftor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, complex of Lumacaftor and Ivacaftor 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 complex of Lumacaftor and Ivacaftor 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 150°C, less than about 120°C, less than about 100°C, or any other suitable temperatures. 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 preparing a complex of Lumacaftor and Ivacaftor, which comprises:
a) combining Lumacaftor and Ivacaftor optionally in the presence of a solvent;
b) isolating complex of Lumacaftor and Ivacaftor.
Step a) of this aspect may be carried out by combining Lumacaftor and Ivacaftor optionally in the presence of a solvent or a mixture thereof.
In an embodiment, Lumacaftor and Ivacaftor may be combined either on the presence or absence of a solvent according to any of the suitable techniques known in the art. Suitable techniques may include, but not limited to blending, grinding or milling the mixture of Lumacaftor and Ivacaftor, optionally in the presence of a solvent such as solvent-drop grinding method or a melt-crystallization of the mixture of Lumacaftor and Ivacaftor.
In an embodiment, the mixture of Lumacaftor and Ivacaftor optionally in the presence of a solvent may be ground in suitable equipment known in the art such as mortar-pestle, ball mill, wet mill or the like.
In an embodiment, the mixture of Lumacaftor and Ivacaftor may be subjected to melt-crystallization i.e., heating the mixture of Lumacaftor and Ivacaftor to obtain molten mass at suitable temperature and cooling it back to crystalize.
In an embodiment, the mixture of Lumacaftor and Ivacaftor may be suspended in a solvent or mixture of solvents for sufficient time and at suitable temperature to afford a complex of Lumacaftor and Ivacaftor.
The complex of Lumacaftor and Ivacaftor obtained by the process of any aspects of the present application is Form LI-1, characterized by a PXRD pattern comprising peaks at about 6.13, 10.36, 10.69, 11.21, 13.55, 14.25 and 20.88 ±0.2° 2?. In an embodiment, Form LI-1 is further characterized by a PXRD pattern having peaks at about 12.33, 15.12, 17.75, 22.64 and 23.92 ±0.2° 2?. In another embodiment, Form LI-1 is characterized by a PXRD pattern substantially as shown in figure 1.
The complex of Lumacaftor and Ivacaftor obtained by the process of any aspects of the present application is Form LI-2, characterized by a PXRD pattern comprising peaks at about 7.44, 8.77, 12.09, 16.45, 17.74 and 20.37 ±0.2° 2?. In an embodiment, Form LI-2 is further characterized by a PXRD pattern having peaks at about 14.77, 21.44, 21.99 and 22.65 ±0.2° 2?. In another embodiment, Form LI-2 is characterized by a PXRD pattern substantially as shown in figure 2.
In another aspect, the present application provides a process for the preparation of Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor, comprising the steps
a) providing a solution of Lumacaftor and Ivacaftor in ethanol or a mixture of ethanol and another solvent;
b) removing the solvent of step a);
c) isolating Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor.
Step a) of this aspect may be carried out by dissolving Lumacaftor and Ivacaftor in ethanol or a mixture of ethanol and another solvent or by dissolving Lumacaftor and Ivacaftor separately in ethanol or a mixture of ethanol and another solvent and combining the two solutions.
Dissolution may be carried out by heating the mixture of Lumacaftor and / or Ivacaftor in ethanol or a mixture thereof from about 25°C to reflux temperature of ethanol or mixture thereof. 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.
Step b) may be carried out by removing the solvent from the solution of step a). Solvent removal may be carried out by evaporating the solvent either under reduced pressure or atmospheric pressure using suitable equipment such as Buchi rotavapour, rotatory cone vacuum drier, spray drier, thin film drier or the like. In an embodiment, the solvent removal may be carried out by sublimation using suitable equipment such as freeze drier or the like.
In an embodiment, the solvent may be partially or completely evaporated from the solution of step a). In embodiments, where the solvent of step a) is completely evaporated, additional amount solvent may be added.
In an embodiment, the mixture of Lumacaftor and Ivacaftor may be suspended in ethanol or a mixture of ethanol and other solvent for sufficient time and at suitable temperature to afford Form LI-1 of the complex of Lumacaftor and Ivacaftor.
In an embodiment, the contents of step b) may be stirred for sufficient time to completely precipitate the complex for atleast one hour or more. In an embodiment, the contents may be stirred at a suitable temperature at about 0°C and above.
Isolation of Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, Form LI-1 of complex 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 Form LI-2 of crystalline complex of Lumacaftor and Ivacaftor, comprising the step of drying Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor.
In an embodiment, drying Form LI-1 of crystalline complex may be carried out in suitable drying equipment such as air drier like tray drier; vacuum driers like tray driers, Buchi rotavapour, rotatory cone vacuum driers; controlled humidifiers or the like.
In an embodiment, drying Form LI-1 of crystalline complex may be carried out at suitable temperatures of about 25°C to 150°C. In an embodiment, drying Form LI-1 may be carried out at about 80°C to 120°C.
In an embodiment, drying Form LI-1 of crystalline complex may be carried out for sufficient time for complete conversion of Form LI-1 to Form LI-2. In an embodiment, drying Form LI-1 may be carried out for atleast 15 minutes or more.

In another aspect, the present application provides an amorphous phase of Lumacaftor and Ivacaftor.
In an embodiment, the amorphous phase of Lumacaftor and Ivacaftor may optionally comprise atleast one pharmaceutically acceptable excipient and / or anti-oxidant.
In an embodiment, the present application provides an amorphous phase of Lumacaftor and Ivacaftor, characterized by a PXRD pattern substantially as shown in figure 3.
In an embodiment, amorphous phase of Lumacaftor and Ivacaftor may be obtained by combining desired ratios of Lumacaftor and Ivacaftor to obtain a stable and suitable product for development. In an embodiment, amorphous phase of Lumacaftor and Ivacaftor may be obtained by combining amorphous Lumacaftor with amorphous Ivacaftor in desired ratio.
The ratio of Lumacaftor to Ivacaftor present in the amorphous phase of Lumacaftor and Ivacaftor according to instant application may vary from about 1:2 to about 2:1. In an embodiment, the ratio of Lumacaftor to Ivacaftor present in amorphous phase of Lumacaftor and Ivacaftor may be 1.38:1.
In an embodiment, amorphous phase of Lumacaftor and Ivacaftor may be obtained either by blending of Lumacaftor and Ivacaftor or by combining both these components in the presence of a solvent and suitable conditions. Lumacaftor and Ivacaftor may be combined according to methods known in the art or by the procedures described or exemplified in any aspect of instant application.
In an embodiment, amorphous phase of Lumacaftor and Ivacaftor may be obtained by physical blending of Lumacaftor and Ivacaftor in suitable blending equipment known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure or inert atmosphere such as nitrogen at suitable temperature and sufficient time to obtain uniform amorphous phase of Lumacaftor and Ivacaftor.
In an embodiment, amorphous phase of Lumacaftor and Ivacaftor may be obtained by combining amorphous Lumacaftor with amorphous Ivacaftor in desired mole ratio such as 1: 2 to 2: 1 according to suitable methods such as physical blending. In an embodiment, amorphous phase of Lumacaftor and Ivacaftor may be obtained by blending amorphous Lumacaftor with amorphous Ivacaftor physically in mole ratio of 1.38:1, respectively.
In an alternative embodiment, amorphous phase of Lumacaftor and Ivacaftor may be obtained by the suspending or dissolving Lumacaftor and Ivacaftor in a solvent and isolating amorphous phase of Lumacaftor and Ivacaftor.
In another aspect, the present application provides a process for the preparation of amorphous phase of Lumacaftor and Ivacaftor, comprising the steps of:
a) providing a solution of Lumacaftor and Ivacaftor in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous phase of Lumacaftor and Ivacaftor.
d) optionally combining amorphous phase of Lumacaftor and Ivacaftor of step c) with atleast one additional pharmaceutically acceptable excipient.

In an embodiment, providing a solution at step a) may be carried out by dissolving Lumacaftor and Ivacaftor 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 step a) may be prepared optionally in the presence of a pharmaceutically acceptable excipient.
In an embodiment, a solution of Lumacaftor and Ivacaftor 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 Ivacaftor 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 amorphous phase of Lumacaftor and Ivacaftor 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 phase of Lumacaftor and Ivacaftor obtained from step b) may be optionally dried before or after isolating at step c).
Amorphous phase of Lumacaftor and Ivacaftor obtained at step c) may be optionally combined with atleast one additional pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous phase of Lumacaftor and Ivacaftor may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
In an embodiment, amorphous phase of Lumacaftor and Ivacaftor of the present application may be combined with the 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 physical blending in 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 phase of Lumacaftor and Ivacaftor.
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 ellulose acetate succinate, hydroxypropylmethyl ellulose, 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 inorganic oxide such as Syloid, 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/polyvinyl alcohol copolymer, polyethylene/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. 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.
Solvent that may be used in any aspect of the present application may include, but not limited to water; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; alcohols, such as methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol; nitriles, such as acetonitrile and propionitrile; halogenated hydrocarbons, such as dichloromethane, chloroform and carbontetrachloride;, and dimethoxyethane; aprotic non-poplar solvents such as dimethylsulfoxide; formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl- 2-pyrrolidone; any mixtures of two or more thereof.
The ratio of Lumacaftor to Ivacaftor that may be used in the preparation of the complex or amorphous phase of Lumacaftor and Ivacaftor according to any aspect of the instant application may vary from about 1:2 to about 2:1. In an embodiment, the complex or amorphous phase of Lumacaftor and Ivacaftor may be obtained by combining Lumacaftor and Ivacaftor in the mole ratio of 1: 2 to 2: 1.
In an embodiment, Lumacaftor and Ivacaftor may be combined in the mole ratio of 1.38: 1. Alternatively, in an embodiment, amorphous phase of Lumacaftor and Ivacaftor may be obtained by combining 0.442 moles of Lumacaftor with 0.318 moles of Ivacaftor.
Lumacaftor and / or Ivacaftor that may be used as starting material for the preparation of complex or amorphous phase of Lumacaftor and Ivacaftor in any of the aspects of the present application may be either in a crystalline or amorphous form or in any other solid form reported in the literature. In an embodiment, amorphous forms of starting materials, Lumacaftor and/ or Ivacaftor may be obtained according to any methods known in the art.
Lumacaftor and / or Ivacaftor that may be used in any aspect of the present application may be purified by any methods known in the art such as column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In another aspect, the present application provides pharmaceutical composition comprising complex or amorphous phase of Lumacaftor and Ivacaftor together with atleast one pharmaceutically acceptable excipient. In an embodiment, the present application provides a pharmaceutical composition comprising crystalline forms of complex of Lumacaftor and Ivacaftor together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides pharmaceutical composition comprising complex of Lumacaftor and Ivacaftor and atleast one pharmaceutically acceptable excipient, wherein complex of Lumacaftor and Ivacaftor may be selected from group comprising of Form LI-1, Form LI-2 and amorphous form of complex of Lumacaftor and Ivacaftor or mixtures thereof.
In another aspect, the present application provides complex or amorphous phase of Lumacaftor and Ivacaftor or its pharmaceutical composition comprising Lumacaftor and / or Ivacaftor having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.

X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?) ±0.2° of 6.3°" means "having a diffraction peak at a diffraction angle (2?) of 6.1° to 6.5°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks may vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors may slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments may vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).
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 “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 “complex of Lumacaftor and Ivacaftor” or “complex” includes a molecular entity formed by association of two or more component molecular entities (ionic or uncharged), or by association of two or more chemical species. The bonding between the components may be non-covalent and is normally weaker than covalent bonding. Accordingly, the complex of Lumacaftor and Ivacaftor described herein is a molecular entity formed by the association between Lumacaftor and Ivacaftor. The Lumacaftor-Ivacaftor complex may in some embodiments exist as a solid state form that is referred to herein as a salt or an inclusion complex or supra-molecular complex or co-crystal form of Lumacaftor-Ivacaftor complex or as an Lumacaftor-Ivacaftor co-crystal or as a crystalline Lumacaftor-Ivacaftor complex.
The terms “crystalline complex of Lumacaftor and Ivacaftor” or “crystalline complex” includes solvates, hydrates, and anhydrates of complex of Lumacaftor and Lumacaftor. The percent crystallinity of any of the crystalline forms of complex described herein can vary with respect to the total amount of complex. In particular, certain embodiments provide for the percent crystallinity of a crystalline form of comlex being at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least, 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some embodiments, the percent crystallinity can be substantially 100%, where substantially 100% indicates that the entire amount of complex appears to be crystalline as best can be determined using methods known in the art.
The term "amorphous phase of Lumacaftor and Ivacaftor" when used in the present application, denotes a state where most of the Lumacaftor and Ivacaftor, preferably 90%, 95% or all of the Lumacaftor and / or Ivacaftor of the amorphous phase, is homogeneously molecularly dispersed. Preferably amorphous phase, relates to a molecular dispersion where the component molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in an amorphous phase, the two components form a homogeneous one-phase system. In a preferred embodiment, in the amorphous phase of Lumacaftor and Ivacaftor according to the present invention no chemical bonds can be detected between the components. The amorphous phase of Lumacaftor and Ivacaftor may in some embodiments exist as a solid state form that is referred to herein as a solid dispersion or a premix of Lumacaftor and Ivacaftor or as an amorphous solid dispersion of Lumacaftor and Ivacaftor.
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 Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor
A mixture of Lumacaftor (1.0 g) and Ivacaftor (0.867 g) was dissolved in ethanol (100 mL) at 60°C for 24 minutes. The clear solution was evaporated under reduced pressure at 60°C to remove the solvent. Ethanol (50 mL) was added and stirred the suspension for 21 hours at 25°C. Solids were filtered to obtain the title compound.
Example-2: Preparation of Form LI-2 of crystalline complex of Lumacaftor and Ivacaftor
Form LI-1 obtained in example-1 was dried in air tray drier at 120°C for 2 hours to obtain the title compound.
Example-3: Preparation of amorphous phase of Lumacaftor and Ivacaftor
Lumacaftor (2.0 g) and Ivacaftor (1.25 g) were dissolved in methanol (200 mL) at 60°C and filtered the solution to make it particle free. Evaporated the solvent from the above solution using a spray drier at 30% feed pump flow, 70% aspirator at 70°C and 42°C of inlet and outlet temperatures respectively to obtain title compound.
,CLAIMS:We Claim:
1. A complex of Lumacaftor and Ivacaftor.
2. A crystalline complex of Lumacaftor and Ivacaftor.
3. A crystalline complex of claim 2, characterized by a PXRD pattern comprising peaks at 6.13, 10.36, 10.69, 11.21, 13.55, 14.25 and 20.88 ±0.2° 2?.
4. A crystalline complex of claim 2, characterized by a PXRD pattern comprising peaks at 7.44, 8.77, 12.09, 16.45, 17.74 and 20.37 ±0.2° 2?.
5. An amorphous phase of Lumacaftor and Ivacaftor.
6. A process for the preparation of a complex of Lumacaftor and Ivacaftor, which comprising the steps of:
a. combining Lumacaftor and Ivacaftor in the presence of a solvent;
b. removing the solvent from the mixture of step a);
c. isolating complex of Lumacaftor and Ivacaftor.
7. A process for the preparation of a complex of Lumacaftor and Ivacaftor, which comprising the steps of:
a. combining Lumacaftor and Ivacaftor in the presence of a solvent
b. contacting an anti-solvent with the mixture of step a);
c. isolating complex of Lumacaftor and Ivacaftor.
8. A process for the preparation of a complex of Lumacaftor and Ivacaftor, which comprising the steps of:
a. combining Lumacaftor and Ivacaftor optionally in the presence of a solvent
b. isolating complex of Lumacaftor and Ivacaftor.
9. A process for the preparation of Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor, comprising the steps
a. providing a solution of Lumacaftor and Ivacaftor in ethanol or a mixture of ethanol and another solvent;
b. removing the solvent of step a);
c. isolating Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor.
10. A process for the preparation of Form LI-2 of crystalline complex of Lumacaftor and Ivacaftor, comprising the step of drying Form LI-1 of crystalline complex of Lumacaftor and Ivacaftor.
11. A process for the preparation of amorphous phase of Lumacaftor and Ivacaftor, comprising the steps of:
a. providing a solution of Lumacaftor and Ivacaftor in a suitable solvent or a mixture thereof;
b. removing the solvent from the solution obtained in step a), and
c. isolating the amorphous phase of Lumacaftor and Ivacaftor.
d. optionally, combining amorphous phase of Lumacaftor and Ivacaftor of step c) with atleast one additional pharmaceutically acceptable excipient.