WO2025094081A2

WO2025094081A2 - Solid state forms of deutivacaftor and process thereof

Info

Publication number: WO2025094081A2
Application number: PCT/IB2024/060714
Authority: WO
Inventors: Nikolina JANTON; Zvonimir PERKOVIC
Original assignee: Assia Chemical Industries Ltd
Current assignee: Assia Chemical Industries Ltd
Priority date: 2023-10-30
Filing date: 2024-10-30
Publication date: 2025-05-08
Anticipated expiration: 2026-04-30
Also published as: WO2025094081A3

Abstract

The present disclosure relates to Deutivacaftor solid state forms, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

Description

SOLID STATE FORMS OF DEUTIVACAFTOR AND PROCESS THEREOF

FIELD OF THE INVENTION

[0001] The present disclosure relates to Deutivacaftor solid state forms, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof. BACKGROUND

[0002] Deutivacaftor (CTP-656) which has the chemical name V-[2-/c/7-butyl-4-[ l , 1,1, 3,3,3- hexadeuterio-2-(trideuteriomethyl)propan-2-yl]-5-hydroxyphenyl]-4-oxo-l/f-quinoline-3- carboxamide is a cystic fibrosis transmembrane conductance regulator (CFTR) protein. As described in U.S. Patent No. 9,181,192, Deutivacaftor has the following chemical structure:

[0003] Deutivacaftor preparation is disclosed in U.S. Patent No. 9,181,192.

[0004] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Deutivacaftor, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - “TGA”, or differential scanning calorimetry - “DSC”), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (¹³C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0005] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0006] Discovering new salts and solid state forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New polymorphic forms and new salts of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Deutivacaftor.

SUMMARY OF THE INVENTION

[0007] The present disclosure relates to Deutivacaftor solid state forms or crystalline polymorphs thereof, to processes for preparation thereof, and to pharmaceutical compositions comprising solid state form thereof.

[0008] In particular, the present disclosure provides crystalline forms of Deutivacaftor designated as Forms 1-13 (defined herein).

[0009] The present disclosure further provides process for preparing Deutivacaftor and solid state forms or crystalline polymorphs thereof.

[0010] In another aspect, the present disclosure encompasses the above described solid state forms or crystalline polymorphs of Deutivacaftor for use in the preparation of pharmaceutical compositions and/or formulations, preferably for use in medicine, preferably for treating Cystic Fibrosis.

[0011] In another aspect, the present disclosure encompasses the use of any one of the above described solid state forms or crystalline polymorphs of Deutivacaftor for the preparation of pharmaceutical compositions and/or formulations, preferably for use in medicine, preferably for treating cystic fibrosis. In yet another embodiment, the present disclosure encompasses pharmaceutical compositions comprising any one of the solid state forms or crystalline polymorphs of Deutivacaftor.

[0012] In a specific embodiment, the present disclosure encompasses pharmaceutical formulations comprising the solid state forms or crystalline polymorphs of Deutivacaftor, and at least one pharmaceutically acceptable excipient.

[0013] The present disclosure further encompasses processes to prepare said pharmaceutical formulations of Deutivacaftor, comprising combining any one of the above described solid state forms or crystalline polymorphs of Deutivacaftor, or pharmaceutical compositions comprising it, and at least one pharmaceutically acceptable excipient.

The present disclosure further encompasses processes to prepare solid dispersions of Deutivacaftor, comprising combining any one of the above described solid state forms or crystalline polymorphs of Deutivacaftor with a polymer in order to prepare a solid dispersion. The solid state forms or crystalline polymorphs of Deutivacaftor as defined herein as well as the pharmaceutical compositions or formulations comprising it can be used as medicaments, particularly for treating cystic fibrosis, comprising administering a therapeutically effective amount of the solid state form of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from cystic fibrosis, or otherwise in need of the treatment.

[0014] The present disclosure also provides the uses of the solid state forms or crystalline polymorphs of Deutivacaftor of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating cystic fibrosis.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 shows an X-ray powder diffraction (XRPD) pattern for crystalline Deutivacaftor Form 1.

[0016] Figure 2 shows an XRPD pattern of crystalline Deutivacaftor Form 2.

[0017] Figure 3 shows an XRPD pattern of crystalline Deutivacaftor Form 3.

[0018] Figure 4 shows an XRPD pattern of crystalline Deutivacaftor Form 4 acetone solvate. [0019] Figure 5 shows an XRPD pattern of crystalline Deutivacaftor Form 4 methyl ethyl ketone solvate.

[0020] Figure 6 shows an XRPD pattern of crystalline Deutivacaftor Form 5. [0021] Figure 7 shows an XRPD patern of crystalline Deutivacaftor Form 6. [0022] Figure 8 shows an XRPD patern of crystalline Deutivacaftor Form 7. [0023] Figure 9 shows an XRPD patern of crystalline Deutivacaftor Form 8. [0024] Figure 10 shows an XRPD pattern of amorphous Deutivacaftor.

[0025] Figure 11 shows an XRPD pattern of crystalline Deutivacaftor Form 9.

[0026] Figure 12 shows an XRPD pattern of crystalline Deutivacaftor Form 10. [0027] Figure 13 shows an XRPD pattern of crystalline Deutivacaftor Form 11. [0028] Figure 14 shows an XRPD pattern of crystalline Deutivacaftor Form 12. [0029] Figure 15 shows an XRPD pattern of crystalline Deutivacaftor Form 13.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0030] The present disclosure relates to solid state forms or crystalline polymorphs of Deutivacaftor, to processes for preparation thereof and to pharmaceutical compositions comprising at least one of, or combination of these solid state forms. In particular, the present disclosure relates to solid state forms of Deutivacaftor designated as Form 1 - Form 13 and amorphous Deutivacaftor (defined herein).

[0031] The Deutivacaftor solid state forms, according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, and bulk density. Particularly, Deutivacaftor Forms 1-13 has been shown to be particularly stable to high relative humidity, temperature and compression and hence represents an excellent candidate for incorporating into pharmaceutical compositions.

[0032] A crystal form may be referred to herein as being characterized by graphical data “as depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which can not necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms.

[0033] A crystal form of Deutivacaftor, referred to herein as being characterized by graphical data “as depicted in” a Figure will thus be understood to include any crystal form of Deutivacaftor characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0034] The solid state forms or crystalline polymorphs of Deutivacaftor as described in any aspect or embodiment of the present disclosure may be polymorphically pure, or substantially free of any other solid state forms of Deutivacaftor.

[0035] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% (w/w) of any other forms of the subject compound as measured, for example, by XRPD. Thus, solid states of Deutivacaftor described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject solid state form of Deutivacaftor. Accordingly, in some embodiments of the disclosure, the described solid state form of Deutivacaftor may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more solid state forms of Deutivacaftor.

[0036] The solid state forms or crystalline polymorphs of Deutivacaftor as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds. [0037] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms “chemically pure” or “purified” or “substantially free of any other compounds” refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers. A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1.5% (w/w) or less, about 1% (w/w), about 0.8% (w/w) or less, about 0.6% (w/w) or less about 0.4% (w/w) or less about 0.2% (w/w) or less or less, about 0.1% (w/w) or less or about 0% of any other compound as measured, for example, by HPLC. Alternatively, A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC. Thus, pure or purified Deutivacaftor described herein as substantially free of any compounds would be understood to contain greater than about 90% (w/w), greater than about 95% (w/w), greater than about 96% (w/w), greater than about 97% (w/w), greater than about 98% (w/w), greater than about 98.5% (w/w), greater than about 99% (w/w), greater than about 99.2%, (w/w) greater than about 99.4% (w/w), greater than about 99.6% (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w), or about 100% of the subject Deutivacaftor. Alternatively, pure or purified Deutivacaftor described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2%, area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Deutivacaftor. [0038] As used herein, unless stated otherwise, XRPD peaks reported herein are preferably measured using CuKa radiation, A = 1.5418 A, preferably, XRPD peaks reported herein are measured using CuK a radiation, X = 1.5418 A, at a temperature of 25 ± 3°C.

[0039] As used herein, the term “isolated” in reference to solid state form of Deutivacaftor of the present disclosure corresponds to solid state form of Deutivacaftor that is physically separated from the reaction mixture in which it is formed.

[0040] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature”, often abbreviated “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0041] A process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10 to about 18 hours, typically about 16 hours.

[0042] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline Deutivacaftor which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form does not contain more than about 1% (w/w) of either water or organic solvents as measured for example by TGA, Karl Fischer or by other suitable technique.

[0043] The term “solvate”, as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a “hydrate.” The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0044] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term “v/v” may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding (methyl tert-butyl ether) MTBE (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mb of MTBE was added.

[0045] As used herein the term non-hygroscopic in relation to crystalline Deutivacaftor, refers to less than about 1.0% (w/w) absorption of water at about 25°C and about 80% relative humidity (RH), as determined for example by TGA or other suitable technique.

[0046] As used herein, the term “reduced pressure” refers to a pressure of about 10 mbar to about 500 mbar.

[0047] As used herein, and unless indicated otherwise, the term “thermo-dynamical stability” in relation to solid state forms or crystalline polymorphs of Deutivacaftor refers to resistance of the solid state form or crystalline polymorph to polymorphic conversion under certain conditions, for example, heating, melting or dissolving. In some embodiments, the term refers to less than about 20% (w/w), about 10% (w/w), about 5% (w/w), about 1% (w/w), about 0.5% (w/w), or about 0% (w/w) conversion of crystalline Deutivacaftor to any other solid state form of Deutivacaftor as measured by XRPD. In some embodiments, the conversion is about 1% (w/w) to about 20% (w/w), about 1% (w/w) to about 10% (w/w) or about 1% (w/w) to about 5% (w/w). [0048] The present disclosure comprises a crystalline Deutivacaftor designated as Form 1. Deutivacaftor crystalline Form 1 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.2, 12.4, 18.6 and 24.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 1; or combinations of these data.

[0049] Crystalline Deutivacaftor Form 1 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.2, 12.4, 18.6 and 24.8 degrees two theta ± 0.2 degrees two theta; and also having one, two or three additional peaks selected from 13.6, 15.2 and 24.0 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0050] Crystalline Deutivacaftor Form 1 may alternatively be characterized by XRPD pattern having peaks at 6.2, 12.4, 13.6, 15.2, 18.6, 24.0 and 24.8 degrees two theta ± 0.2 degrees two theta. [0051] Crystalline Deutivacaftor Form 1 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 6.2, 12.4, 18.6 and 24.8 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0052] The present disclosure comprises a crystalline form of Deutivacaftor designated as Form 2. The crystalline Form 2 of Deutivacaftor can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.0, 9.3, 10.0, 15.0 and 15.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 2; or combinations of these data.

[0053] Crystalline Deutivacaftor Form 2 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.0, 9.3, 10.0, 15.0 and 15.6 degrees two theta ± 0.2 degrees two theta; and also having one or two additional peaks selected from 7.8 and 11.9 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0054] Crystalline Deutivacaftor Form 2 may alternatively be characterized by XRPD pattern having peaks at 5.0, 7.8, 9.3, 10.0, 11.9, 15.0 and 15.6 degrees two theta ± 0.2 degrees two theta. [0055] Crystalline Deutivacaftor Form 2 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 5.0, 9.3, 10.0, 15.0 and 15.6 degrees two theta ± 0.2 degrees two theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[0056] According to any aspect or embodiment of the present disclosure, Deutivacaftor Form 2 is preferably anhydrous form.

[0057] The present disclosure comprises a crystalline Deutivacaftor designated as Form 3. Deutivacaftor crystalline Form 3 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2-theta and missing peak at 9.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 3; or combinations of these data.

[0058] Crystalline Deutivacaftor Form 3 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2-theta and also having one, two, three or four additional peaks selected from 7.8, 15.6, 17.7 and 23.7 degrees two theta ± 0.2 degrees two theta; an XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2-theta and missing peak at 9.3 degrees 2-theta ± 0.2 degrees 2-theta; and also having one, two, three or four additional peaks selected from 7.8, 15.6, 17.7 and 23.7 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0059] Crystalline Deutivacaftor Form 3 may alternatively be characterized by XRPD pattern having peaks at 4.9, 7.8, 8.3, 11.6, 15.2, 15.6, 17.7 and 23.7 degrees two theta ± 0.2 degrees two theta.

[0060] Crystalline Deutivacaftor Form 3 may alternatively be characterized by XRPD pattern having peaks at 4.9, 7.8, 8.3, 11.6, 15.2, 15.6, 17.7 and 23.7 degrees two theta ± 0.2 degrees two theta and missing peak at 9.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0061] Crystalline Deutivacaftor Form 3 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by an XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2-theta; XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2-theta and missing peak at 9.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3; and combinations thereof.

[0062] Deutivacaftor Form 3 may be a hydrated form.

[0063] The present disclosure comprises a crystalline Deutivacaftor designated as Form 4. Deutivacaftor crystalline Form 4 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.4, 6.1, 7.0, 8.1 and 10.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 4; an XRPD pattern substantially as depicted in Figure 5; or combinations of these data.

[0064] Crystalline Deutivacaftor Form 4 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.4, 6.1, 7.0, 8.1 and 10.9 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 3.7, 8.7, 12.4, 13.1 and 18.4 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0065] Crystalline Deutivacaftor Form 4 may alternatively be characterized by XRPD pattern having peaks at 3.7, 5.4, 6.1, 7.0, 8.1, 8.7, 10.9 12.4, 13.1 and 18.4 degrees two theta ± 0.2 degrees two theta. [0066] Crystalline Deutivacaftor Form 4 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 5.4,

6.1, 7.0, 8.1 and 10.9 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in Figure 4; an XRD pattern as depicted in Figure 5; and combinations thereof.

[0067] Crystalline Deutivacaftor Form 4 may be isomorphic forms of Deutivacaftor solvates. Crystalline Deutivacaftor Form 4 may be an acetone or a methyl-ethyl ketone solvate of Deutivacaftor.

[0068] The present disclosure comprises a crystalline Deutivacaftor designated as Form 5. Deutivacaftor crystalline Form 5 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks 8.2, 10.1, 12.7, 14.5, 18.8 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 6; or combinations of these data.

[0069] Crystalline Deutivacaftor Form 5 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 8.2, 10.1, 12.7, 14.5, 18.8 and 24.6 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 12.3, 15.3, 16.3, 20.1 and 24.1 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0070] Crystalline Deutivacaftor Form 5 may alternatively be characterized by XRPD pattern having peaks at 8.2, 10.1, 12.3, 12.7, 14.5, 15.3, 16.3, 18.8, 20.1. 24.1 and 24.6 degrees two theta ± 0.2 degrees two theta.

[0071] Crystalline Deutivacaftor Form 5 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 8.2,

10.1, 12.7, 14.5, 18.8 and 24.6 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in Figure 6, and combinations thereof.

[0072] Crystalline Deutivacaftor Form 5 may be a hydrate form.

[0073] The present disclosure comprises a crystalline Deutivacaftor designated as Form 6. Deutivacaftor crystalline Form 6 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks 4.6, 6.9, 9.0 and 11.9 degrees 2-theta ± 0.2 degrees 2- theta; an XRPD pattern substantially as depicted in Figure 7; or combinations of these data.

[0074] Crystalline Deutivacaftor Form 6 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.6, 6.9, 9.0 and 11.9 degrees two theta ± 0.2 degrees two theta; and also having one, two or three additional peaks selected from 13.8, 19.1 and 20.4 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0075] Crystalline Deutivacaftor Form 6 may alternatively be characterized by XRPD pattern having peaks at 4.6, 6.9, 9.0, 11.9 13.8, 19.1 and 20.4 degrees two theta ± 0.2 degrees two theta. [0076] Crystalline Deutivacaftor Form 6 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 4.6, 6.9, 9.0 and 11.9 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in Figure 7, and combinations thereof.

[0077] Crystalline Deutivacaftor Form 6 may be a hydrate form.

[0078] The present disclosure comprises a crystalline Deutivacaftor designated as Form 7. Deutivacaftor crystalline Form 7 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks 7.3, 10.8, 19.8, 20.5 and 20.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 8; or combinations of these data.

[0079] Crystalline Deutivacaftor Form 7 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.3, 10.8, 19.8, 20.5 and 20.9 degrees two theta ± 0.2 degrees two theta; and also having one, two, three or four additional peaks selected from 13.1, 14.0, 18.0, 23.5 and 25.5 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0080] Crystalline Deutivacaftor Form 7 may alternatively be characterized by XRPD pattern having peaks at 7.3, 10.8, 13.1, 14.0, 18.0, 19.8, 20.5, 20.9, 23.5 and 25.5 degrees two theta ± 0.2 degrees two theta.

[0081] Crystalline Deutivacaftor Form 7 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 7.3, 10.8, 19.8, 20.5 and 20.9 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in Figure 8, and combinations thereof.

[0082] The present disclosure comprises a crystalline Deutivacaftor designated as Form 8. Deutivacaftor crystalline Form 8 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks 5.9, 7.7, 8.8, 9.7 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 9; or combinations of these data.

[0083] Crystalline Deutivacaftor Form 8 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.9, 7.7, 8.8, 9.7 and 22.7 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 13.7, 17.8, 18.3, 24.0 and 26.9 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0084] Crystalline Deutivacaftor Form 8 may alternatively be characterized by XRPD pattern having peaks at 5.9, 7.7, 8.8, 9.7, 13.7, 17.8, 18.3, 22.7, 24.0 and 26.9 degrees two theta ± 0.2 degrees two theta.

[0085] Crystalline Deutivacaftor Form 8 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 5.9, 7.7, 8.8, 9.7 and 22.7 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in Figure 9, and combinations thereof.

[0086] Crystalline Deutivacaftor Form 8 may be anhydrous form.

[0087] The present disclosure comprises Amorphous Deutivacaftor. Amorphous Deutivacaftor can be characterized by absence of crystalline peak in the XRPD pattern; an XRPD pattern substantially as depicted in Figure 10; or combinations of these data.

[0088] The present disclosure comprises a crystalline form of Deutivacaftor designated as Form 9. The crystalline Form 9 of Deutivacaftor can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.4, 7.4, 10.6, 14.3 and 16.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 11; or combinations of these data.

[0089] Crystalline Deutivacaftor Form 9 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.4, 7.4, 10.6, 14.3 and 16.0 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 13.8, 17.0, 18.1, 19.4 and 20.2 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0090] Crystalline Deutivacaftor Form 9 may alternatively be characterized by XRPD pattern having peaks at 5.4, 7.4, 10.6, 13.8, 14.3, 16.0, 17.0, 18.1, 19.4, and 20.2 degrees two theta ± 0.2 degrees two theta. [0091] Crystalline Deutivacaftor Form 9 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 5.4, 7.4, 10.6, 14.3 and 16.0 degrees two theta ± 0.2 degrees two theta; an XRPD pattern as depicted in Figure 11, and combinations thereof.

[0092] The present disclosure further comprises a crystalline form of Deutivacaftor designated as Form 10. The crystalline Form 10 of Deutivacaftor can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.6, 13.5 and 15.4 degrees 2- theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 12; or combinations of these data.

[0093] Crystalline Deutivacaftor Form 10 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.6, 13.5 and 15.4 degrees two theta ± 0.2 degrees two theta; and also having one or two additional peaks selected from 9.0 and 11.9 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0094] Crystalline Deutivacaftor Form 10 may alternatively be characterized by XRPD pattern having peaks at 4.6, 9.0, 11.9, 13.5, and 15.4 degrees two theta ± 0.2 degrees two theta.

[0095] Crystalline Deutivacaftor Form 10 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 4.6, 13.5 and 15.4 degrees two theta ± 0.2 degrees two theta; an XRPD pattern as depicted in Figure 12, and combinations thereof.

[0096] The present disclosure further comprises a crystalline form of Deutivacaftor designated as Form 11. The crystalline Form 11 of Deutivacaftor can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.3, 13.7 and 14.5 degrees 2- theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 13; or combinations of these data.

[0097] Crystalline Deutivacaftor Form 11 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.3, 13.7 and 14.5 degrees two theta ± 0.2 degrees two theta; and also having one or two additional peaks selected from 11.4 and 19.7 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0098] Crystalline Deutivacaftor Form 11 may alternatively be characterized by XRPD pattern having peaks at 5.3, 11.4, 13.7, 14.5 and 19.7 degrees two theta ± 0.2 degrees two theta. [0099] Crystalline Deutivacaftor Form 11 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 5.3, 13.7 and 14.5 degrees two theta ± 0.2 degrees two theta; an XRPD pattern as depicted in Figure 13, and combinations thereof.

[00100] Crystalline Deutivacaftor Form 8 may be hydrated.

[00101] The present disclosure further comprises a crystalline form of Deutivacaftor designated as Form 12. The crystalline Form 12 of Deutivacaftor can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.4, 7.4, 13.0 and

17.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 14; or combinations of these data.

[00102] Crystalline Deutivacaftor Form 12 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.4, 7.4, 13.0 and 17.5 degrees two theta ± 0.2 degrees two theta; and also having one or two additional peaks selected from

18.6 and 19.7 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[00103] Crystalline Deutivacaftor Form 12 may alternatively be characterized by XRPD pattern having peaks at 6.4, 7.4, 13.0, 17.5, 18.6 and 19.7 degrees two theta ± 0.2 degrees two theta.

[00104] Crystalline Deutivacaftor Form 12 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 6.4, 7.4, 13.0 and 17.5 degrees two theta ± 0.2 degrees two theta; an XRPD pattern as depicted in Figure 14, and combinations thereof.

[00105] Crystalline Deutivacaftor Form 12 may be anhydrous.

[00106] The present disclosure further comprises a crystalline form of Deutivacaftor designated as Form 13. The crystalline Form 13 of Deutivacaftor can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.2, 12.4, 13.5, 14.1 and 22.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in Figure 15; or combinations of these data.

[00107] Crystalline Deutivacaftor Form 13 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.2, 12.4, 13.5, 14.1 and 22.5 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 10.4, 17.8, 19.8, 23.4 and 27.2 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[00108] Crystalline Deutivacaftor Form 13 may alternatively be characterized by XRPD pattern having peaks at 6.2, 10.4, 12.4, 13.5, 14.1, 17.8, 19.8, 22.5, 23.4 and 27.2 degrees two theta ± 0.2 degrees two theta.

[00109] Crystalline Deutivacaftor Form 13 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 6.2, 12.4, 13.5, 14.1 and 22.5 degrees two theta ± 0.2 degrees two theta; an XRPD pattern as depicted in Figure 15, and combinations thereof.

[00110] Crystalline Deutivacaftor Form 13 may be an isopropanol solvate.

[00111] In any aspect or embodiment of the present invention, crystalline Deutivacaftor Forms 1- 13 described herein may be substantially free of any other solid state forms of Deutivacaftor. Preferably, crystalline Forms 1 - 13 of Deutivacaftor according to any aspect or embodiment of the present invention contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w), about 0.2% (w/w) or less, or about 0% (w/w) of any other forms of Deutivacaftor as measured, for example, by XRPD. Thus, according to any aspect or embodiment of the present invention, the crystalline forms 1-13 of Deutivacaftor comprise greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the specific form of Deutivacaftor. Preferably, crystalline Deutivacaftor Forms 1- 13 according to any aspect or embodiment of the present invention contain no detectable amounts of other solid state forms of Deutivacaftor (preferably as measured by XRPD).

[00112] In another embodiment of the present disclosure, crystalline Deutivacaftor Forms 1- 13 are polymorphically pure.

[00113] In another embodiment of the present disclosure, crystalline Deutivacaftor Forms 1- 13 are isolated.

[00114] As described above, depending on which other solid state it is compared with, Deutivacaftor Forms 1- 13 according to the present disclosure may have advantageous properties as described above. [00115] The present disclosure also relates to crystalline forms of Deutivacaftor Forms 1- 13 which are obtainable by any process as described herein. The said process can include the process set out in the examples herein below.

[00116] The present disclosure also relates to a pharmaceutical composition comprising one or more of crystalline Deutivacaftor Forms 1- 13 or amorphous Deutivacaftor as described herein, or one or more crystalline Deutivacaftor Forms 1- 13 or amorphous Deutivacaftor, which are obtainable by any process as described herein below.

[00117] The invention further comprises a process for preparing a pharmaceutical composition comprising one or more of crystalline Deutivacaftor Forms 1- 13 or amorphous Deutivacaftor, wherein the process comprises combining one or more of crystalline Deutivacaftor Forms 1 -13 or amorphous Deutivacaftor with at least one pharmaceutically acceptable excipient. The invention further comprises a process for preparing any of crystalline Deutivacaftor Forms 1 - 13 or amorphous Deutivacaftor as described herein below and further comprising combining one or more of crystalline Deutivacaftor Forms 1 -13 or amorphous Deutivacaftor with at least one pharmaceutically acceptable excipient.

[00118] The present disclosure also provides processes for the preparation of the above described solid state forms of Deutivacaftor. The said process can include the process set out in the examples herein below.

[00119] In another aspect, the present disclosure encompasses any of the above described solid state forms of Deutivacaftor for use in the preparation of pharmaceutical compositions and/or formulations, preferably for use in medicine, preferably for treating cystic fibrosis.

[00120] In another aspect, the present disclosure encompasses the use of any of the above described solid state forms of Deutivacaftor for the preparation of pharmaceutical compositions and/or formulations, preferably for use in medicine, preferably for treating complement mediated diseases, preferably for the treatment of cystic fibrosis.

[00121] In another aspect, the present disclosure encompasses the use of any of the above described solid state forms of Deutivacaftor for the preparation of solid dispersions. Solid dispersions can be prepared by combining any of the above described solid state forms of Deutivacaftor with a polymer in order to prepare a solid dispersion. Solid dispersions can be prepared by spray drying or hot melt extrusion. [00122] In yet another embodiment, the present disclosure encompasses pharmaceutical compositions comprising one or more of the above described solid state forms of Deutivacaftor. [00123] In specific embodiment, the present disclosure encompasses pharmaceutical formulation comprising one or more of the above described solid state forms of Deutivacaftor, and at least one pharmaceutically acceptable excipient.

[00124] The present disclosure further encompasses processes to prepare said pharmaceutical formulations of Deutivacaftor, comprising combining one or more of the above described solid state forms of Deutivacaftor, or pharmaceutical compositions comprising them, and at least one pharmaceutically acceptable excipient.

[00125] The present disclosure comprises processes for preparing the above mentioned pharmaceutical compositions. The processes comprise combining the above crystalline polymorph of Deutivacaftor, of the present disclosure with at least one pharmaceutically acceptable excipient.

[00126] The present disclosure further comprises processes for preparing solid dispersions by combining the above described solid state forms of Deutivacaftor with a polymer in order to prepare a solid dispersion. Solid dispersions can be prepared by spray drying. The process for preparing a solid dispersion by spray drying comprises: (a) forming a mixture comprising the above described solid state form of Deutivacaftor, a polymer, and a solvent; and (b) spray drying the mixture to form a solid dispersion. Polymers can be selected from cellulosic polymers such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose acetate succinate (HPMCAS) or pyrrolidone containing polymers such as polyvinylpyrrolidone co-polymer, such as a vinylpyrrolidone/vinyl acetate co-polymer. Preferably, a cellulosic polymer such as HPMC or HPMCAS is used. Solid dispersions can also be prepared by hot melt extrusion. The process for preparing a solid dispersion by hot melt extrusion comprises: (a) mixing the above described solid state form of Deutivacaftor, one or more polymers and optionally one or more additional additives such as plasticizers in a mixer; (b) feeding the mixed material into a hot melt extruder at a controlled rate and at a controlled temperature; (c) cooling the extruded material; (d) recovering the cooled, hot melt extruded material; (e) grinding or milling the extruded material into a form suitable for blending with additional pharmaceutical excipients.

[00127] Pharmaceutical formulations of the present invention contain one or more of the crystalline polymorph of Deutivacaftor of the present invention, particularly one or more of crystalline Deutivacaftor Forms 1 - 13. In addition to the active ingredient, the pharmaceutical formulations of the present invention can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[00128] Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[00129] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[00130] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), and starch.

[00131] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate. [00132] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. [00133] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[00134] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[00135] In liquid pharmaceutical compositions of the present invention, Deutivacaftor and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[00136] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[00137] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouthfeel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum. [00138] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[00139] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[00140] According to the present invention, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00141] The solid compositions of the present invention include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[00142] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [00143] The dosage form of the present invention can be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

[00144] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00145] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant. [00146] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[00147] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00148] A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[00149] The solid state forms of Deutivacaftor as defined herein as well as the pharmaceutical compositions or formulations comprising them can be used as medicaments, particularly for treating cystic fibrosis, comprising administering a therapeutically effective amount of the solid state form of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from cystic fibrosis, or otherwise in need of the treatment. [00150] The present disclosure also provides the uses of the solid state form of Deutivacaftor of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating cystic fibrosis.

[00151] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure. ANALYTICAL METHODS

[00152] Powder X-ray Diffraction was performed on Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.5418 A (Angstrom), X’Celerator (2.022° 20) detector.

[00153] Measurement parameters: Scan range: 3 - 40 degrees 2-theta; step size 0.0167, time per step 37 s, continuous scan.

EXAMPLES

[00154] Deutivacaftor can be obtained by any procedure described in the literature, for example using the syntheses procedure reported in US patent No 9,512,079 (Example 3).

Example 1: Preparation of Deutivacaftor Form 1

[00155] Deutivacaftor (10 grams) was dissolved in N, N-dimethylformamide : ethanol (150 mL, 450 mL, 1 :3) at 70°C for few seconds. Heating was discontinued and the solution was cooled to room temperature (RT) (precipitation occurred during cooling at about 40°C). The suspension was stirred at RT overnight and the obtained solid was isolated by vacuum filtration and dried at 70°C for 12 hours. The obtained Deutivacaftor was designated Form 1 by XRPD (Figure 1).

Example 2: Preparation of Deutivacaftor Form 2

[00156] Deutivacaftor form 1 (0.1 grams) was placed in chamber ('Anton Paar TTK 450’) on Philips X'Pert PRO X-ray powder diffractometer. The sample was heated up to 250°C by heating rate 10°C/min under air and analyzed by XRPD to obtain Deutivacaftor designated as Form 2 (Figure 2).

Example 3. Preparation of Deutivacaftor Form 3

[00157] Deutivacaftor form 1 (0.05 grams, prepared by Example 1) was suspended in hexane (6 mL) at reflux temperature (about 69°C) and stirred for 5 minutes. The solid was isolated by vacuum filtration and analyzed by XRPD to obtain Deutivacaftor designated as Form 3 (Figure 3).

Example 4. Preparation of Deutivacaftor Form 4 acetone solvate

[00158] Deutivacaftor (0.05 grams) was dissolved in acetone (4 mL) at room temperature (25°C). Crystallization flask was left open at room conditions for 1 day to obtained precipitation which was isolated by vacuum filtration and analyzed by XRPD to confirm Deutivacaftor Form

4 acetone solvate (Figure 4).

Example 5. Preparation of Deutivacaftor Form 4 methyl ethyl ketone solvate

[00159] Deutivacaftor (0.05 grams) was dissolved in methyl ethyl ketone (4 mL) at room temperature (25°C). Crystallization flask was left open at room conditions for 3 days and the obtained solid was isolated by vacuum filtration over the black ribbon and analyzed by XRPD to obtain Deutivacaftor designated Form 4 methyl ethyl ketone solvate (Figure 5).

Example 6. Preparation of Deutivacaftor Form 5

[00160] Amorphous Deutivacaftor (0.05 grams) was suspended in water (0.5 mL) and kept for

5 days at room temperature under stirring. The obtained solid was isolated by vacuum filtration and analyzed by XRPD to produce Deutivacaftor form 5 (Figure 6).

Example 7. Preparation of Deutivacaftor Form 6

[00161] Amorphous Deutivacaftor (0.05 grams) was suspended in acetonitrile (0.5 mL) and kept for 5 days at room temperature under stirring. The obtained solid was isolated by vacuum filtration and analyzed by XRPD to produce Deutivacaftor form 6 (Figure 7).

Example 8. Preparation of Deutivacaftor Form 7

[00162] Deutivacaftor (0.2 grams) was dissolved in methanol (24 mL) at 75°C. Heating was discontinued and the solution was left to cool at room temperature under stirring to observe precipitation (crystallization was observed after about 2 hours). The solid was isolated by vacuum filtration and analyzed by XRPD to produce Deutivacaftor form 7 (Figure 8).

Example 9. Preparation of Deutivacaftor Form 8

[00163] Deutivacaftor (0.2 grams) was suspended in acetone (2 mL) at 40°C and kept for 3 days under stirring. The obtained solid was isolated by vacuum filtration and analyzed by XRPD to produce Deutivacaftor form 8 (Figure 9).

Example 10. Preparation of amorphous Deutivacaftor

[00164] Deutivacaftor (1 gram) was grinded in a zirconium oxide jar with 5 zirconium oxide beads. Experiment was performed on a planetary micro mill Pulverisette (Fritsch®) for 5 hours and the obtained solid was analyzed by XRPD to obtain amorphous Deutivacaftor (Figure 10).

Example 11. Preparation of Deutivacaftor Form 9

[00165] Deutivacaftor form 6 (0.5 grams) was suspended in acetic acid (25 mL) at 60°C and stirred for 1 hour. Heating was discontinued, the suspension was cooled to RT and stirred for 1 hour. The obtained solid was isolated by vacuum filtration and analyzed by XRPD (Figure 11). Deutivacaftor Form 9 was obtained.

Example 12. Preparation of Deutivacaftor Form 10

[00166] Deutivacaftor (0.05 grams) was dissolved in 2-methyltetrahydrofuran (2 mL) and left at room temperature (25 °C) to evaporate. Obtained solid was isolated by vacuum filtration and analyzed by XRPD (Figure 12). Deutivacaftor form 10 was obtained.

Example 13. Preparation of Deutivacaftor Form 11

[00167] Deutivacaftor (0.1 grams) was dissolved in acetone with 10% water (7 mL) at 40°C. Heating was discontinued and the solution was left to cool to room temperature with stirring. Crystallization occurred at -5°C. Obtained solid was isolated by vacuum filtration and analyzed by XRPD (Figure 13). Deutivacaftor form 11 was obtained.

Example 14 Preparation of Deutivacaftor Form 12

[00168] Deutivacaftor form 11 (0.1 grams) was dried in vacuum oven at 80°C for 12 hours at 10 mbar. Obtained solid was analyzed by XRPD (Figure 14). Deutivacaftor form 12 was obtained.

Example 15 Preparation of Deutivacaftor Form 13

[00169] Deutivacaftor form 1 (0.2 grams) was dissolved in 2-propanol (13 mL) at 78°C. Heating was discontinued and the solution was cooled to RT. Solution was stirred at RT overnight and a suspension was obtained. Solid was isolated by vacuum filtration and analyzed by XRPD (Figure 15). Deutivacaftor form 13 was obtained.

Example 16 Preparation of amorphous Deutivacaftor

[00170] Deutivacaftor form 9 (0.5 grams) was dried in vacuum oven at 100°C for 8 hours at 10 mbar. The solid was analyzed by ROD and amorphous Deutivacaftor was obtained.

Example 17 Preparation of amorphous Deutivacaftor

[00171] Deutivacaftor form 6 (4.9 g) was dissolved in 400 mL of acetone. The solution was filtered over the black ribbon and spray dried under the below conditions. The solid was analyzed by XRPD and amorphous Deutivacaftor was obtained.

Claims

1. Crystalline Form of Deutivacaftor designated as Form 2, which is characterized by data including at least one of: i) an XRPD pattern having peaks at 5.0, 9.3, 10.0, 15.0 and 15.6 degrees 2-theta ± 0.2 degrees 2-theta; or ii) an XRPD pattern substantially as depicted in Figure 2.

2. A crystalline form of Deutivacaftor according to claim 1, which is characterized by an XRPD pattern having peaks at 5.0, 9.3, 10.0, 15.0 and 15.6 degrees 2-theta ± 0.2 degrees 2- theta, and also having one or two additional peaks selected from 7.8 and 11.9 degrees 2- theta ± 0.2 degrees 2-theta.

3. Crystalline Form of Deutivacaftor designated as Form 3, which is characterized by data including at least one of: i) an XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2-theta; ii) an XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2-theta and missing peak at 9.3 degrees 2-theta ± 0.2 degrees 2-theta; or iii) an XRPD pattern substantially as depicted in Figure 3.

4. A crystalline form of Deutivacaftor according to claim 3, which is characterized by an XRPD pattern having peaks at 4.9, 8.3, 11.6, 14.0 and 15.2 degrees 2-theta ± 0.2 degrees 2- theta, and also having one, two, three or four additional peaks selected from 7.8, 15.6, 17.7 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta.

5. Crystalline Form of Deutivacaftor designated as Form 5, which is characterized by data including at least one of: i) an XRPD pattern having peaks at 8.2, 10.1, 12.7, 14.5, 18.8 and 24.6 degrees 2- theta ± 0.2 degrees 2-theta; or ii) an XRPD pattern substantially as depicted in Figure 6.

6. A crystalline form of Deutivacaftor according to claim 5, which is characterized by an XRPD pattern having peaks at 8.2, 10.1, 12.7, 14.5, 18.8 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks selected from 12.3, 15.3, 16.3, 20.1 and 24.1 degrees 2-theta ± 0.2 degrees 2-theta.

7. Crystalline Form of Deutivacaftor designated as Form 6, which is characterized by data including at least one of: i) an XRPD pattern having peaks at 4.6, 6.9, 9.0 and 11.9 degrees 2-theta ± 0.2 degrees 2-theta; or ii) an XRPD pattern substantially as depicted in Figure 7.

8. A crystalline form of Deutivacaftor according to claim 7, which is characterized by an XRPD pattern having peaks at 4.6, 6.9, 9.0 and 11.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two or three additional peaks selected from 13.8, 19.1 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta.

9. Crystalline Form of Deutivacaftor designated as Form 8, which is characterized by data including at least one of: i) an XRPD pattern having peaks at 5.9, 7.7, 8.8, 9.7 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta; or ii) an XRPD pattern substantially as depicted in Figure 9.

10. A crystalline form of Deutivacaftor according to claim 9, which is characterized by an XRPD pattern having peaks at 5.9, 7.7, 8.8, 9.7 and 22.7 degrees 2-theta ± 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks selected from 13.7, 17.8, 18.3, 24.0 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

11. Crystalline Form of Deutivacaftor designated as Form 11, which is characterized by data including at least one of: i) an XRPD pattern having peaks at 5.3, 13.7 and 14.5 degrees 2-theta ± 0.2 degrees 2-theta; or ii) an XRPD pattern substantially as depicted in Figure 13.

12. A crystalline form of Deutivacaftor according to claim 11, which is characterized by an XRPD pattern having peaks at 5.3, 13.7 and 14.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having one or two additional peaks selected from 11.4 and 19.7 degrees 2-theta ± 0.2 degrees 2-theta.

13. Crystalline Form of Deutivacaftor designated as Form 12, which is characterized by data including at least one of: i) an XRPD pattern having peaks at 6.4, 7.4, 13.0 and 17.5 degrees 2-theta ± 0.2 degrees 2-theta; or ii) an XRPD pattern substantially as depicted in Figure 14.

14. A crystalline form of Deutivacaftor according to claim 13, which is characterized by an XRPD pattern having peaks at 6.4, 7.4, 13.0 and 17.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having one or two additional peaks selected from 18.6 and 19.7 degrees 2-theta ± 0.2 degrees 2-theta.

15. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 14.

16. Use of a crystalline form according to any one of claims 1 to 14 in the preparation of a pharmaceutical composition and/or formulation.

17. A pharmaceutical formulation comprising a crystalline form according to any one of claims 1 to 14, or a pharmaceutical composition of claim 15, and at least one pharmaceutically acceptable excipient.

18. A crystalline form according to any one of claims 1 to 14, a pharmaceutical composition according to claim 15, or a pharmaceutical formulation according to claim 17, for use as a medicament.

19. A crystalline form according to any one of claims 1 to 14, a pharmaceutical composition according to claim 15, or a pharmaceutical formulation according to claim 17, for use in the treatment of cystic fibrosis.

20. A process for preparing a solid state form of Deutivacaftor, comprising preparing a crystalline form of Deutivacaftor according to any one of claims 1 to 14 and converting it to another solid state form of Deutivacaftor.

21. A process for preparing a solid dispersion of Deutivacaftor comprising combining a solid state form of Deutivacaftor according to any one of claims 1 to 14 with a polymer in order to prepare a solid dispersion.

22. A process for preparing a solid dispersion of Deutivacaftor by spray drying comprising: (a) forming a mixture comprising a solid state form of Deutivacaftor according to any one of claims 1 to 14, a polymer, and a solvent; and (b) spray drying the mixture to form a solid dispersion.

23. A process for preparing a solid dispersion of Deutivacaftor according to claims 22, wherein the polymer is selected from cellulosic polymers such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose acetate succinate (HPMCAS) or pyrrolidone containing polymers such as polyvinylpyrrolidone co-polymer, such as a vinylpyrrolidone/vinyl acetate co-polymer.

24. A solid dispersion of Deutivacaftor prepared according to process of claim 22.

25. A solid dispersion of Deutivacaftor prepared according to process of claim 23.