CRYSTALLINE FORMS AND COMPOSITIONS OF CFTR MODULATORS

Description

[0001] This application claims priority to U.S. Provisional Application No. 62 / 574,677, filed October 19, 2017; U.S. Provisional Application No. 62 / 574,670, filed October 19, 2017; and U.S. Provisional Application No. 62 / 650,057, filed March 29, 2018.

[0002] Disclosed herein are crystalline forms of Compound I and pharmaceutically acceptable salts thereof, which are modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), compositions comprising the same, methods of using the same, and processes for making the same.

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.

[0004] In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with cystic fibrosis are infertile, and fertility is reduced among females with cystic fibrosis.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to define 281 mutations as disease causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with severe disease.

[0006] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum (ER) and traffic to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is far less than observed in cells expressing wild-type CFTR, i.e., CFTR having no mutations. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion and fluid transport across epithelia. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). The channels that are defective because of the F508del mutation are still functional, albeit less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease-causing mutations in CFTR that result in defective trafficking, synthesis, and / or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

[0008] Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na +< -K +< -ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl -< channels, resulting in a vectorial transport. Arrangement of Na +< / 2Cl -< / K +< co-transporter, Na +< -K +< -ATPase pump and the basolateral membrane K +< channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

[0009] US2016095858A1 relates to a compound for the treatment of CFTR mediated diseases, and also relates to pharmaceutical compositions, methods of treating and kits for the treatment of such diseases.

[0010] Compound I and pharmaceutically acceptable salts thereof are potent CFTR modulators. Compound I is N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, and has the following structure:

[0011] Crystalline forms are of interest in the pharmaceutical industry, where the control of the crystalline form(s) of the active ingredient may be desirable or even required. Reproducible processes for producing a compound with a particular crystalline form in high purity may be desirable for compounds intended to be used in pharmaceuticals, as different crystalline forms may possess different properties. For example, different crystalline forms may possess different chemical, physical, and / or pharmaceutical properties.

[0012] Accordingly, there is a need for novel crystalline forms of compounds useful for treatment of CFTR mediated diseases.

[0013] The invention is defined in the appended claims. Any references in the description to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).

[0014] Disclosed herein are novel crystalline forms of Compound I and pharmaceutically acceptable salts thereof, compositions comprising the same, and methods of using and making the same.

[0015] Also, disclosed are pharmaceutical compositions comprising combinations of Compound I and / or pharmaceutically acceptable salts thereof with (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II) and / or pharmaceutically acceptable salts thereof and / or with N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound III) or N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-d)

[0016] Also disclosed are methods of using a crystalline form of Compound I and / or pharmaceutically acceptable salts thereof disclosed herein alone or in combination with other CFTR modulators to treat cystic fibrosis. In certain embodiments, the crystalline form of Compound I and / or pharmaceutically acceptable salts thereof is administered with Compound II and / or Compound III or Compound III-d, either in a single pharmaceutical composition or in multiple compositions to treat cystic fibrosis.Brief Description of the Drawings

[0017] FIG. 1A shows a selection from an X-ray powder diffractogram of crystalline Form B of a potassium salt of Compound I, and FIG. 1B shows a full scan view of an X-ray powder diffractogram of crystalline Form B of a potassium salt of Compound I. FIG. 2 shows an X-ray powder diffractogram of crystalline Form B of a potassium salt of Compound I at 3% relative humidity (RH) (red) initial and 100%RH (blue). FIG. 3 shows a a dynamic vapor sorption (DVS)- plot of crystalline Form B of a potassium salt of Compound I . FIG. 4 shows a differential scanning calorimetry (DSC) plot of crystalline Form B of a potassium salt of Compound I . FIG. 5 shows a TGA plot of crystalline Form B of a potassium salt of Compound I . FIG. 6 shows a ball and stick plot of crystalline Form B of a potassium salt of Compound I . FIG. 7A shows a selection from an X-ray powder diffractogram of crystalline Form C of a potassium salt / co-crystal of Compound I, and FIG. 7B shows a full scan view of an X-ray powder diffractogram of crystalline Form C of a potassium salt / co-crystal of Compound I. FIG. 8A shows a selection from an X-ray powder diffractogram of crystalline Form A of a sodium salt of Compound I, and FIG. 8B shows a full scan view of an X-ray powder diffractogram of crystalline Form A of a sodium salt of Compound I. FIG. 9A shows a selection from an X-ray powder diffractogram of crystalline Form D of a sodium salt of Compound I, and FIG. 9B shows a full scan view of an X-ray powder diffractogram of crystalline Form D of a sodium salt of Compound I. FIG. 10A shows a selection from an X-ray powder diffractogram of crystalline Form M of a sodium salt of Compound I, and FIG. 10B shows a full scan view of an X-ray powder diffractogram of crystalline Form M of a sodium salt of Compound I . FIG. 11A shows a selection from an X-ray powder diffractogram of crystalline Form H of a sodium salt of Compound I, and FIG. 11B shows a full-scan view of an X-ray powder diffractogram of crystalline Form H of a sodium salt of Compound I . FIG. 12A shows a selection from an X-ray powder diffractogram of crystalline Form E of a sodium salt of Compound I, and FIG. 12B shows a full scan view of an X-ray powder diffractogram of crystalline Form E of a sodium salt of Compound I . FIG. 13A shows a selection from an X-ray powder diffractogram of crystalline Form A of Compound I, and FIG. 13B shows a full scan view of an X-ray powder diffractogram of crystalline Form A of Compound I . FIG. 14 shows the X-ray powder diffractogram of a spray-dried dispersion (SDD) of 50 wt% Compound I in HPMCAS-HG. FIG. 15 is spectrum showing modulated differential scanning calorimetry (MDSC) plot of a SDD of 50 wt% Compound I in HPMCAS-HG. FIG. 16 shows the X-ray powder diffractogram spectrum of an amorphous sodium salt of Compound I. FIG. 17 is a representative list of CFTR genetic mutations. FIG. 18 shows tablet dissolution of Compound I of a Control tablet comprising a spray dried dispersion of Compound I, and a fixed dose combination (FDC) tablet comprising a potassium salt of Compound I, a spray dried dispersion of Compound II and a spray dried dispersion of Compound III. FIG. 19 shows tablet dissolution of Compound II of a Control tablet comprising a spray dried dispersion of Compound II and a spray dried dispersion of Compound III, and of an FDC tablet comprising a potassium salt of Compound I, a spray dried dispersion of Compound II and a spray dried dispersion of Compound III. FIG. 20 shows tablet dissolution of Compound III of a Control tablet comprising a spray dried dispersion of Compound II and a spray dried dispersion of Compound III, and of an FDC tablet comprising a potassium salt of Compound I, a spray dried dispersion of Compound II and a spray dried dispersion of Compound III. FIG. 21 shows bioavailability of Compound I of a Control tablet comprising a spray dried dispersion of Compound I, and an FDC tablet comprising a potassium salt of Compound I, a spray dried dispersion of Compound II and a spray dried dispersion of Compound III in a dog. FIG. 22 shows bioavailability of Compound II of a Control tablet comprising a spray dried dispersion of Compound II and a spray dried dispersion of Compound III, and of an FDC tablet comprising a potassium salt of Compound I, a spray dried dispersion of Compound II and a spray dried dispersion of Compound III in a dog. FIG. 23 shows bioavailability of Compound III of a Control tablet comprising a spray dried dispersion of Compound II and a spray dried dispersion of Compound III, and of an FDC tablet comprising a potassium salt of Compound I, a spray dried dispersion of Compound II and a spray dried dispersion of Compound III in a dog. FIG. 24 shows tablet dissolution data of K salt of Compound I of FDC Tablets C1, C2, C3, C4, and C5. The tablet dissolution data were obtained using dissolution media 1, which included 0.8 wt% SDS in pH 6.8 sodium phosphate buffer. FIG. 25 shows tablet dissolution data for Compound II of FDC Tablets C1, C2, C3, C4, and C5. The tablet dissolution data were obtained using dissolution media 2, which included 0.1 wt% SDS in 0.1 N HCl. FIG. 26 shows tablet dissolution data for Compound III of FDC Tablets C1, C2, C3, C4, and C5. The tablet dissolution data were obtained using dissolution media 1, which included 0.8 wt% SDS in pH 6.8 sodium phosphate buffer. FIG. 27 shows tablet dissolution data of the potassium salt of Compound I of FDC Tablets D3, D4, D5, and D6. The tablet dissolution data were obtained using dissolution media 1, which included 1.0% SDS in 50 mM sodium phosphate monobasic buffer at pH 6.8. FIG. 28 shows tablet dissolution data for Compound II of FDC Tablets D3, D4, D5, and D6. The tablet dissolution data were obtained using dissolution media 2, which included 0.07% SDS in 0.1 N HCl. FIG. 29 shows tablet dissolution data for Compound III of FDC Tablets D3, D4, D5, and D6. The tablet dissolution data were obtained using dissolution media 1, which included 1.0% SDS in 50 mM sodium phosphate monobasic buffer at pH 6.8. Definitions

[0018] As used herein, "Compound I" refers to a compound having a chemical name N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which has the following structure:

[0019] As used herein, "Compound II" refers to a compound having a chemical name (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, which has the following structure:

[0020] As used herein, "Compound III" refers to a compound having a chemical name N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, which has the following structure:

[0021] As used herein, "Compound III-d" refers to a compound having a chemical name N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, which has the following structure:

[0022] As used herein, "Compound IV" refers to a compound having a chemical name 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which has the following structure:

[0023] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound of this disclosure wherein the salt is nontoxic. Pharmaceutically acceptable salts of Compound I, Compound II, Compound III, Compound III-d, and Compound IV of this disclosure include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0024] Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, that article provides the following pharmaceutically acceptable salts: AcetateIodideBenzathineBenzenesulfonateIsethionateChloroprocaineBenzoateLactateCholineBicarbonateLactobionateDiethanolamineBitartrateMalateEthylenediamineBromideMaleateMeglumineCalcium edetateMandelateProcaineCamsylateMesylateAluminumCarbonateMethylbromideCalciumChlorideMethylnitrateLithiumCitrateMethylsulfateMagnesiumDihydrochlorideMucatePotassiumEdetateNapsylateSodiumEdisylateNitrateZincEstolatePamoate (Embonate)EsylatePantothenateFumaratePhosphate / diphosphateGluceptatePolygalacturonateGluconateSalicylateGlutamateStearateGlycollylarsanilateSubacetateHexylresorcinateSuccinateHydrabamineSulfateHydrobromideTannateHydrochlorideTartrateHydroxynaphthoateTeociateTriethiodide

[0025] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N +< (C 1-4 alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0026] As used herein, the term "co-crystal" is a crystalline material composed of two or more different molecules, typically the compound and co-crystal formers (or coformers), in the same crystal lattice. Co-crystals components are in a neutral state and interact nonionically.

[0027] As used herein, the term "ambient conditions" means room temperature, open air condition and uncontrolled humidity condition.

[0028] As used herein, the terms "crystal form," "crystalline form," and "Form" interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). Accordingly, as used herein, the terms "crystalline Form [X] of Compound I " and "crystalline Form [C] of a [pharmaceutically acceptable] salt of Compound I " refer to unique crystalline forms that can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (° 2θ).

[0029] As used herein, the terms "solvate" and "pseudo-polymorph" interchangeably refer to a crystal form comprising one or more molecules of a compound of the present disclosure and, incorporated into the crystal lattice, one or more molecules of a solvent or solvents in stoichiometric or nonstoichiometric amounts. When the solvent is water, the solvate is referred to as a "hydrate".

[0030] As used herein, a "variable hydrate" is a crystal form comprising nonstoichiometric water in the crystal lattice. The amount of water present in a variable hydrate varies as a function of at least the relative humidity ("RH") in the environment of the variable hydrate. Since the positions of the signals in the X-ray powder diffractogram of a crystalline form correlate to the dimensions of its unit cell, a change in the size of the unit cell due to the presence (or absence) of water can be determined by comparison of X-ray diffractograms under different RH environments.

[0031] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

[0032] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern" interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate). For an amorphous material, an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2θ (° 2θ), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as "a signal at ... degrees two-theta," "a signal at [a] two-theta value(s)of ..." and / or "a signal at at least ... two-theta value(s) chosen from ...." The term "X-ray powder diffractogram having a signal at ... two-theta values" as used herein refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2θ).

[0033] A "signal" or "peak" as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local. One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.

[0034] As used herein, "a signal at ... degrees two-theta," "a signal at [a] two-theta value[s] of ..." and / or "a signal at at least ... two-theta value(s) chosen from ...." refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2θ).

[0035] The repeatability of the angular values is in the range of ±0.2° 2θ, i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).

[0036] The terms "signal intensities" and "peak intensities" interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

[0037] As used herein, an X-ray powder diffractogram is "substantially similar to that in [a particular] Figure" when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variation in the intensities and / or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta (°2θ) referred to herein) generally mean that value reported ±0.2 degrees 2θ of the reported value, an art-recognized variance.

[0038] As used herein, a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by a method in accordance with the art, such as quantitative XRPD. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample.

[0039] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0040] As used herein, the term "onset of decomposition" refers to the intersection point of the baseline before transition and the interflection tangent.

[0041] As used herein, the term "glass transition temperature" or "Tg" refers to the temperature above which a glassy amorphous solid becomes rubbery.

[0042] As used herein, the term "TGA" refers to the analytical method of Thermo Gravimetric (or thermogravimetric) Analysis.

[0043] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (solubility of product >1 g / l).

[0044] As used herein, the term "anti-solvent" refers to any liquid in which the product is insoluble or at maximum sparingly soluble (solubility of product <0.01 mol / l).

[0045] As used herein, the term "anti-solvent crystallization" refers to a process wherein supersaturation is achieved and, as a result thereof, crystallization is induced by addition of an antisolvent to the product solution.

[0046] As used herein, the term "amorphous" refers to a solid material having no long range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order. For example, an amorphous material is a solid material having no sharp characteristic signal(s) in its X-ray power diffractogram (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its diffractogram. Broad peaks are characteristic of an amorphous solid. See, e.g., US 2004 / 0006237 for a comparison of diffractograms of an amorphous material and crystalline material.

[0047] As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than 15% crystallinity (e.g., less than 10% crystallinity or less than 5% crystallinity). It is also noted that the term 'substantially amorphous' includes the descriptor, 'amorphous', which refers to materials having no (0%) crystallinity.

[0048] As used herein, the term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g. colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, a solid dispersion includes the polymer constituting the dispersed phase, and the drug constitute the continuous phase. Or, a solid dispersion includes the drug constituting the dispersed phase, and the polymer constituting the continuous phase.

[0049] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0050] As used herein, "mutations" can refer to mutations in the CFTR gene or the CFTR protein. A "CFTR gene mutation" refers to a mutation in the CFTR gene, and a "CFTR protein mutation" refers to a mutation in the CFTR protein. A genetic defect or mutation, or a change in the nucleotides in a gene in general results in a mutation in the CFTR protein translated from that gene, or a frame shift(s).

[0051] The term "F508del" refers to a mutant CFTR protein which is lacking the amino acid phenylalanine at position 508.

[0052] As used herein, a patient who is "homozygous" for a particular gene mutation has the same mutation on each allele.

[0053] As used herein, a patient who is "heterozygous" for a particular gene mutation has this mutation on one allele, and a different mutation on the other allele.

[0054] As used herein, the term "modulator" refers to a compound that increases the activity of a biological compound such as a protein. For example, a CFTR modulator is a compound that increases the activity of CFTR. The increase in activity resulting from a CFTR modulator includes but is not limited to compounds that correct, potentiate, stabilize and / or amplify CFTR.

[0055] As used herein, the term "CFTR corrector" refers to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface. Compound I, Compound II, Compound IV, and their pharmaceutically acceptable salts thereof disclosed herein are CFTR correctors.

[0056] As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport. Compound III and Compound III-d disclosed herein are CFTR potentiators.

[0057] As used herein, the term "active pharmaceutical ingredient" ("API") refers to a biologically active compound.

[0058] The terms "patient" and "subject" are used interchangeably and refer to an animal including humans.

[0059] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0060] As used herein, the terms "treatment," "treating," and the like generally mean the improvement of CF or a CFTR mediated disease or its symptoms or lessening the severity of CF or a CFTR mediated disease or its symptoms in a subject. "Treatment," as used herein, includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and / or liver function, reduction of chest infections, and / or reductions in coughing or shortness of breath. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0061] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other in a single composition or in multiple compositions.

[0062] The terms "about" and "approximately", when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In some embodiments, the term "about" modifies a specified number by + or - 10%. In some embodiments, the term "about" modifies a specified number by + or - 5%. In some embodiments, the term "about" modifies a specified number by + or - 2%. In some embodiments, the term "about" modifies a specified number by + or - 1%.

[0063] As used herein, the term "room temperature" or "ambient temperature" means 15 °C to 30 °C.Crystalline Form B of a Potassium Salt of Compound I

[0064] As stated above, disclosed herein are crystalline forms of Compound I: and pharmaceutically acceptable salts thereof.

[0065] In some embodiments, the present disclosure provides crystalline Form B of a potassium salt of Compound I. Crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2, obtained using Cu Kα radiation

[0066] FIG. 1A shows an X-ray powder diffractogram of crystalline Form B of a potassium salt of Compound I at ambient conditions.

[0067] FIG. 2 shows an overlay of the X-ray powder diffractogram of crystalline Form B of a potassium salt of Compound I at 3%RH (red) initial and at 100%RH (blue).

[0068] FIG. 3 shows the results of dynamic vapor sorption (DVS) plot of crystalline Form B of a potassium salt of Compound I. In some embodiments, the crystalline Form B of a potassium salt of Compound I is characterized by a weight change ranging from 1% to 2% or1.5% to 1.8% in a dynamic vapor sorption experiment, while varying the relative humidity from 0-95% RH at 25 °C

[0069] FIG. 4 shows a DSC trace of the crystalline Form B of a potassium salt of Compound I. In some embodiments, the crystalline Form B of a potassium salt of Compound I is characterized by a DSC having an onset of decomposition temperature of 254 °C and / or a peak temperature of 256 °C.

[0070] FIG. 5 shows TGA results of crystalline Form B of a potassium salt of Compound I. In some embodiments, the crystalline Form B of a potassium salt of Compound I is characterized by a TGA having an onset of decomposition temperature of 322 °C.

[0071] In some embodiments, the crystalline Form B of a potassium salt of Compound I is a variable hydrate. In some embodiments, the crystalline Form B of a potassium salt of Compound I comprises 71% water (molar %). In some embodiments, the crystalline Form B of a potassium salt of Compound I comprises 26% water (molar %). In some embodiments, the crystalline Form B of a potassium salt of Compound I comprises 38% water (molar %).

[0072] In some embodiments, crystalline Form B of a potassium salt of Compound I is in substantially pure form. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation.

[0073] In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 5.8 ± 0.2 degrees two-theta. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 8.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.6 ± 0.2 degrees two-theta. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 10.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 13.8 ± 0.2 degrees two-theta. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 15.1 ± 0.2 degrees two-theta. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 16.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 17.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 19.1 ± 0.2 degrees two-theta.

[0074] In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2.

[0075] In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 16.3 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.8 ± 0.2, 10.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.8 ± 0.2, 10.2 ± 0.2, and 19.1 ± 0.2. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.8 ± 0.2, 8.2 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 16.3 ± 0.2, and 19.1 ± 0.2.

[0076] In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 1A.

[0077] In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by an orthorhombic crystal system. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized as belonging to a P212121 space group. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by having a unit cell characterized by three edges of 9.0058 ± 0.0009 Å, 11.5389 ± 0.0012Å, and 30.9399 ± 0.003 Å. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by having a unit cell characterized by three edges of 9.006 ± 0.005 Å, 11.539 ± 0.005 Å, and 30.940 ± 0.005 Å. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by having a unit cell characterized by three edges of 9.01 ± 0.09 Å, 11.54 ± 0.09 Å, and 30.9 ± 0.2 Å. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by having a unit cell characterized by three edges of 9.0± 0.2 Å, 11.5 ± 0.2 Å, and 31.0 ± 0.2 Å. In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by having a unit cell of an orthorhombic crystal system characterized by three edges of 9.0± 0.2 Å, 11.5 ± 0.2 Å, and 31.0 ± 0.2 Å.

[0078] In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by having a unit cell with the following characteristics measured at 298°K and 1.54178 Å: Crystal System:OrthorhombicSpace Group:P212121a (Å):9.0058(3)b (Å):11.5389(4)c (Å):30.9399(10)α (°):90β (°):90γ (°)90V (Å3):3215.18(19)Z / Z':4 / 1

[0079] In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by having a unit cell characterized by three angles of 90°.

[0080] In some embodiments, crystalline Form B of a potassium salt of Compound I is characterized by having a unit cell with volume of 3215 Å 3< .

[0081] In some embodiments, the present disclosure provides crystalline Form B of a potassium salt of Compound I prepared by a process comprising reacting Compound I with a potassium base.

[0082] In some embodiments, the present disclosure provides methods of preparing crystalline Form B of a potassium salt of Compound I, comprising reacting Compound I with a potassium base. In some embodiments, the potassium base is chosen from potassium hydroxide, potassium t-butoxide, potassium acetate, potassium bicarbonate, potassium carbonate, potassium methoxide, and potassium ethoxide. In some embodiments, the potassium base is chosen from potassium hydroxide. In some embodiments, the potassium base is chosen from potassium carbonate. In some embodiments, the reaction is performed at room temperature.

[0083] Crystalline Form B of a potassium salt of Compound I , is a crystalline channel / variable-hydrate that has been found to be thermodynamically stable during development. The potassium salt Form B of Compound I is stable across a wide humidity range. In addition, it was found to be particularly amenable to scale up manufacturing processes.Crystalline Form C of a Potassium Salt / Co-Crystal of Compound I

[0084] In some embodiments, the present disclosure provides crystalline form of a potassium salt or co-crystal of Compound I, designated as Form C. Crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12.4 ± 0.2, and 16.0 ± 0.2, obtained using Cu Kα radiation.

[0085] FIG. 7A shows an X-ray powder diffractogram of Form C of a potassium salt / co-crystal of Compound I at ambient conditions.

[0086] In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is in substantially pure form. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation.

[0087] In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 3.7 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 7.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 7.4 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 8.7 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.5 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 11.4 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 11.5 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 12.4 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at 16.0 ± 0.2 degrees two-theta.

[0088] In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta.

[0089] In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12. 4 ± 0.2, and 16.0 ± 0.2 degrees two-theta.

[0090] In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, and 11.5 ± 0.2.

[0091] In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 3.7 ± 0.2, 7.0 ± 0.2, and 11.4 ± 0.2. In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, and 11.5 ± 0.2.

[0092] In some embodiments, crystalline Form C of a potassium salt / co-crystal of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 7A.

[0093] In some embodiments, the present disclosure provides crystalline Form C of a potassium salt / co-crystal of Compound I prepared by a process comprising stirring a potassium salt of Compound I with a solvent system comprising at least one source of water. In some embodiments, the solvent system comprises water. In some embodiments, the solvent system comprises at least one organic solvent miscible with water. In some embodiments, the solvent system comprises acetonitrile. In some embodiments, the solvent system comprises at least one alcohol chosen from C 1 -C 4 alcohols. In some embodiments, the solvent system comprises at least one alkane chosen from C 5 -C 8 alcohols. In some embodiments, the solvent system comprises at least one alkane chosen from pentane, hexane and heptane. In some embodiments, the solvent system comprises water. In some embodiments, the at least one source of water is water. In some embodiments, the at least one source of water is a hydrate of a potassium salt of Compound I. In some embodiments, stirring occurs at a temperature ranging from 20 °C to 100 °C.

[0094] In some embodiments, the present disclosure provides methods of preparing crystalline Form C of a potassium salt / co-crystal Compound I comprising stirring a potassium salt of Compound I with a solvent system comprising at least one source of water. In some embodiments, the solvent system comprises water. In some embodiments, the solvent system comprises at least one organic solvent miscible with water. In some embodiments, the solvent system comprises acetonitrile. In some embodiments, the solvent system comprises at least one alcohol chosen from C 1 -C 4 alcohols. In some embodiments, the solvent system comprises at least one alkane chosen from C 5 -C 8 alcohols. In some embodiments, the solvent system comprises at least one alkane chosen from pentane, hexane and heptane. In some embodiments, the solvent system comprises water. In some embodiments, the at least one source of water is water. In some embodiments, the solvent system is a 1:10 v / v mixture of acetonitrile and water.

[0095] In some embodiments, the at least one source of water is a hydrate of a potassium salt of Compound I. In some embodiments, stirring occurs at a temperature ranging from 20 °C to 100 °C. In some embodiments, stirring occurs at a temperature ranging from 60 °C to 80 °C. In some embodiments, stirring occurs in 1:10 v / v acetonitrile: water at a temperature ranging from 60 °C to 90 °C. In some embodiments, stirring occurs in 1:10 v / v acetonitrile: water at a temperature ranging from 70 °C to 80 °C (e.g, at 75°C).Crystalline Form A of a Sodium Salt of Compound I

[0096] In some embodiments, the present disclosure provides crystalline Form A of a sodium salt of Compound I. Crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2, obtained using Cu Kα radiation.

[0097] FIG. 8A shows an X-ray powder diffractogram of crystalline Form A of a sodium salt of Compound I at ambient conditions.

[0098] In some embodiments, crystalline Form A of a sodium salt of Compound I is in substantially pure form.

[0099] In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation.

[0100] In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 4.7 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 4.9 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 6.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 8.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 8.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 11.1 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 12.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 12.6 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 14.0 ± 0.2 degrees two-theta.

[0101] In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2.

[0102] In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 12.2 ± 0.2, and 12.6 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 4.7 ± 0.2, 8.0 ± 0.2, and 12.2 ± 0.2. In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 4.7 ± 0.2, 4.9 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 12.2 ± 0.2, and 12.6 ± 0.2.

[0103] In some embodiments, crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 8A.

[0104] In some embodiments, the present disclosure provides crystalline Form A of a sodium salt of Compound I prepared by a process comprising reacting Compound I with a sodium base. In some embodiments, the sodium base is chosen from sodium hydroxide, sodium t-butoxide, sodium acetate, sodium bicarbonate, sodium carbonate, sodium methoxide, and sodium ethoxide. In some embodiments, the sodium base is sodium hydroxide. In some embodiments, the sodium base is sodium methoxide. In some embodiments, the reaction is performed at room temperature. In some embodiments, Compound I in acetonitrile solution is reacted with a sodium base in solvent system comprising water. In some embodiments, Compound I in acetonitrile solution is reacted with a sodium base in solvent system comprising water at room temperature.

[0105] In some embodiments, the present disclosure provides methods for preparing crystalline Form A of a sodium salt of Compound I comprising reacting Compound I with a sodium base. In some embodiments, the sodium base is sodium hydroxide. In some embodiments, the sodium base is sodium methoxide. In some embodiments, Compound I in acetonitrile solution is reacted with a sodium base in solvent system comprising water. In some embodiments, Compound I in acetonitrile solution is reacted with a sodium base in solvent system comprising water at room temperature. In some embodiments, the reaction is performed at room temperature.Crystalline Form D of a Sodium Salt of Compound I

[0106] In some embodiments, the present disclosure provides crystalline Form D of a sodium salt of Compound I. Crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2, obtained using Cu Kα radiation.

[0107] FIG. 9A shows an X-ray powder diffractogram of crystalline Form D of a sodium salt of Compound I at ambient conditions.

[0108] In some embodiments, crystalline Form D of a sodium salt of Compound I is in substantially pure form. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation.

[0109] In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 4.9 ± 0.2 degrees two-theta. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 5.7 ± 0.2 degrees two-theta. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 7.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 8.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.8 ± 0.2 degrees two-theta. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 11.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 12.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 14.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 16.0 ± 0.2 degrees two-theta.

[0110] In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2.

[0111] In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 12.2 ± 0.2, and 14.0 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 4.9 ± 0.2, 8.0 ± 0.2, and 12.2 ± 0.2. In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 4.9 ± 0.2, 5.7 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 12.2 ± 0.2, and 14.0 ± 0.2.

[0112] In some embodiments, crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 9A.

[0113] In some embodiments, the present disclosure provides crystalline Form D of a sodium salt of Compound I prepared by a process comprising heating a crystalline Form M or crystalline Form E of the sodium salt of Compound I at a temperature in a range from 280 °C to 300 °C under an anhydrous condition. In some embodiments, the anhydrous condition is under dry N 2 or Ar 2 . In some embodiments, the anhydrous condition is under dry N 2 . In some embodiments, crystalline Form M or crystalline Form E is heated to a temperature ranging from 290 °C to295 °C.

[0114] In some embodiments, the present disclosure provides methods of preparing crystalline Form D of a sodium salt Compound I comprising heating an ethanol solvate of the sodium salt of Compound I at a temperature in a range from 280 °C to 300 °C under an anhydrous condition. In some embodiments, the anhydrous condition is under dry N 2 or Ar 2 . In some embodiments, the anhydrous condition is under dry N 2 . In some embodiments, the heating temperature is 290 °C -295 °C. Crystalline Form D of a sodium salt of Compound I was obtained by heating either Form M of a sodium salt of Compound I or Form E of a sodium salt of Compound I at 290°C under dry N 2 . In one example, 8 mg of crystalline Form E of a sodium salt of Compound I was heated in a TGA pan at a 10 °C / minute rate from room temperature to 290 °C and was then maintained at 290 °C for 2 minutes under dry N 2 (50 mL per minute).Crystalline Form M of a Sodium Salt of Compound I

[0115] Also disclosed but not defined in the claims is crystalline Form M of a sodium salt of Compound I: FIG. 10A shows an X-ray powder diffractogram of crystalline Form M of a sodium salt of Compound I at ambient conditions.

[0116] Crystalline Form M is a solvate of a sodium salt of Compound I comprising up to 1 mole of solvent chosen from methanol, water, and mixtures thereof. Accordingly, crystalline Form M can comprise up to 1 mole of methanol, up to 1 mole of water, or up to 1 mole of a mixture of methanol and water.

[0117] In some embodiments, crystalline Form M of a sodium salt of Compound I is in substantially pure form. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation.

[0118] In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.9 ± 0.2 degrees two-theta. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 10.5 ± 0.2 degrees two-theta. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 11.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 13.9 ± 0.2 degrees two-theta. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 15.1 ± 0.2 degrees two-theta. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 18.8 ± 0.2 degrees two-theta. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 19.5 ± 0.2 degrees two-theta. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 19.9 ± 0.2 degrees two-theta.

[0119] In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of

[0120] Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2.

[0121] In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, and 18.8 ± 0.2.

[0122] In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 9.3 ± 0.2, 11.3 ± 0.2, and 15.1 ± 0.2. In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 9.3 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, and 18.8 ± 0.2.

[0123] In some embodiments, crystalline Form M of a sodium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 10A.

[0124] In some embodiments, the present disclosure provides crystalline Form M of a sodium salt of Compound I prepared by a process comprising reacting Compound I with a sodium base in methanol. In some embodiments, the sodium base is chosen from sodium hydroxide, sodium t-butoxide, sodium acetate, sodium bicarbonate, sodium carbonate, sodium methoxide, and sodium ethoxide. In some embodiments, the sodium base is chosen from sodium hydroxide. In some embodiments, the sodium base is sodium methoxide. In some embodiments, Compound I in methanol is reacted with a sodium base, such as sodium hydroxide or sodium methoxide, to generate crystalline Form M of a sodium salt of Compound I. In some embodiments, the reaction is performed at room temperature.

[0125] In some embodiments, the present disclosure provides methods of preparing crystalline Form M of a sodium salt of Compound I comprising reacting Compound I with a sodium base in methanol. In some embodiments, the sodium base is chosen from sodium hydroxide, sodium t-butoxide, sodium acetate, sodium bicarbonate, sodium carbonate, sodium methoxide, and sodium ethoxide. In some embodiments, the sodium base is sodium methoxide. In some embodiments, Compound I in methanol is reacted with a sodium base, such as sodium hydroxide or sodium methoxide, to generate crystalline Form M of a sodium salt of Compound I. In some embodiments, the reaction is performed at room temperature.Crystalline Form H of a Sodium Salt of Compound I

[0126] Also disclosed but not defined in the claims is crystalline Form H of a sodium salt of Compound I .

[0127] FIG. 11A shows an X-ray powder diffractogram of crystalline Form H of a sodium salt of Compound I at ambient conditions. In some embodiments, the present disclosure provides crystalline Form H of Compound I prepared by a process comprising de-solvating Form M of a sodium salt of Compound I disclosed herein.

[0128] In some embodiments, crystalline Form H of a sodium salt of Compound I is in substantially pure form. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation. In some embodiments, crystalline Form H of a sodium salt of Compound I is the methanol solvate, crystalline Form H of a sodium salt of Compound I.

[0129] In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.9 ± 0.2 degrees two-theta. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 10.5 ± 0.2 degrees two-theta. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 11.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 13.9 ± 0.2 degrees two-theta. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 15.1 ± 0.2 degrees two-theta. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 18.8 ± 0.2 degrees two-theta. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 19.5 ± 0.2 degrees two-theta. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 19.9 ± 0.2 degrees two-theta.

[0130] In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2.

[0131] In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, 18.8 ± 0.2, 19.5 ± 0.2, and 19.9 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.3 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, and 18.8 ± 0.2.

[0132] In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 9.3 ± 0.2, 11.3 ± 0.2, and 15.1 ± 0.2. In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 9.3 ± 0.2, 9.9 ± 0.2, 11.3 ± 0.2, 13.9 ± 0.2, 15.1 ± 0.2, and 18.8 ± 0.2.

[0133] In some embodiments, crystalline Form H of a sodium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 11A.

[0134] In some embodiments, the present disclosure provides crystalline Form H of a sodium salt of Compound I prepared by a process comprising de-solvating crystalline Form M or Form E of a sodium salt of Compound I in the presence of at least one source of water. In some embodiments, the at least one source of water is water. In some embodiments, the at least one source of water is moisture in air.

[0135] In some embodiments, the present disclosure provides methods of preparing crystalline Form H of a sodium salt of Compound I comprising de-solvating crystalline Form M or Form E of a sodium salt of Compound I in the presence of at least one source of water. In some embodiments, the at least one source of water is water. In some embodiments, the at least one source of water is moisture in air.Crystalline Form E of a Sodium Salt of Compound I

[0136] In some embodiments, the present disclosure provides crystalline Form E of a sodium salt of Compound I. Crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.7± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2, obtained using Cu Kα radiation.

[0137] FIG. 12A shows an X-ray powder diffractogram of crystalline Form E of a sodium salt of Compound I at ambient conditions.

[0138] Crystalline Form E is a solvate of a sodium salt of Compound I comprising up to 1 mole of solvent chosen from ethanol, water, and mixtures thereof. Accordingly, crystalline Form E can comprise up to 1 mole of ethanol, up to 1 mole of water, or up to 1 mole of a mixture of ethanol and water.

[0139] In some embodiments, crystalline Form E of a sodium salt of Compound I is in substantially pure form. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation.

[0140] In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 5.7 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.9 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 11.4 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 14.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 15.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 16.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 17.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 19.0 ± 0.2 degrees two-theta.

[0141] In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 5.7 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 9.9 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 10.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 11.4 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 14.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 15.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 16.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 17.3 ± 0.2 degrees two-theta. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 19.0 ± 0.2 degrees two-theta.

[0142] In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2.

[0143] In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 5.7 ± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 5.7 ± 0.2, 9.0 ± 0.2, 10.0 ± 0.2, 10.2 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2.

[0144] In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.7 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 15.2 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 11.4 ± 0.2, 15.2 ± 0.2, and 19.0 ± 0.2. In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.7 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 15.2 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2.

[0145] In some embodiments, crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 12A.

[0146] In some embodiments, the present disclosure provides crystalline Form E of a sodium salt of Compound I prepared by a process comprising reacting Compound I with a sodium base in ethanol. In some embodiments, the sodium base is chosen from sodium hydroxide, sodium t-butoxide, sodium acetate, sodium bicarbonate, sodium carbonate, sodium methoxide, and sodium ethoxide. In some embodiments, the sodium base is sodium hydroxide. In some embodiments, the sodium base is sodium methoxide. In some embodiments, Compound I in ethanol is reacted with a sodium base, such as sodium hydroxide or sodium methoxide, to generate crystalline Form E of a sodium salt of Compound I. In some embodiments, the reaction is performed at room temperature.

[0147] In some embodiments, the present disclosure provides methods of preparing crystalline Form E of a sodium salt of Compound I comprising reacting Compound I with a sodium base in ethanol. In some embodiments, the sodium base is chosen from sodium hydroxide, sodium t-butoxide, sodium acetate, sodium bicarbonate, sodium carbonate, sodium methoxide, and sodium ethoxide. In some embodiments, the sodium base is sodium hydroxide. In some embodiments, the sodium base is sodium methoxide. In some embodiments, Compound I in ethanol is reacted with a sodium base, such as sodium hydroxide or sodium methoxide, to generate crystalline Form E of a sodium salt of Compound I. In some embodiments, the reaction is performed at room temperature.Crystalline Form A of Compound I

[0148] In some embodiments, the present disclosure provides crystalline Form A of Compound I. Crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 5.3 to 5.5, from 7.2 to 7.5, from 11.8 to 12.2, from 14.7 to 15.0, from 16.7 to 17.1, from 17.4 to 17.7, from 18.5 to 18.8, and from 19.5 to 19.8 degrees two-theta, obtained using Cu Kα radiation.

[0149] FIG. 13A shows an X-ray powder diffractogram of crystalline Form A of Compound I at ambient conditions.

[0150] In some embodiments, the present disclosure provides crystalline Form A of Compound I prepared by a process comprising de-solvating a methanol or ethanol solvate of crystalline Form A of Compound I. In some embodiments, the present disclosure provides crystalline Form A of Compound I prepared by a process comprising de-solvating a methanol solvate of crystalline Form A of Compound I. In some embodiments, the present disclosure provides crystalline Form A of Compound I prepared by a process comprising de-solvating an ethanol solvate of crystalline Form A of Compound I.

[0151] In some embodiments, crystalline Form A of Compound I is in substantially pure form. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation.

[0152] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram wherein one or more of the signals may shift from batch to batch. As would be recognized by one of ordinary skill in the art, this is likely due to the collapse of the solvate structure from which crystalline Form A of Compound I is produced.

[0153] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 5.3 ± 0.2 to 5.5 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 7.2 ± 0.2 to 7.5 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 11.8 ± 0.2 to 12.2 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 14.7 ± 0.2 to 15.0 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 16.7 ± 0.2 to 17.1 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 17.4 ± 0.2 to 17.7 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 18.5 ± 0.2 to 18.8 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0154] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal ranging from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0155] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least eight of the following ranges from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0156] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least seven of the following ranges chosen from: from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least six of the following ranges chosen from: from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0157] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least five of the following ranges chosen from: from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0158] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least four of the following ranges chosen from: from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0159] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three of the following ranges chosen from: from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0160] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two of the following ranges chosen from: from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0161] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one of the following ranges chosen from: from 5.3 ± 0.2 to 5.5 ± 0.2, from 7.2 ± 0.2 to 7.5 ± 0.2, from 11.8 ± 0.2 to 12.2 ± 0.2, from 14.7 ± 0.2 to 15.0 ± 0.2, from 16.7 ± 0.2 to 17.1 ± 0.2, from 17.4 ± 0.2 to 17.7 ± 0.2, from 18.5 ± 0.2 to 18.8 ± 0.2, and from 19.5 ± 0.2 to 19.8 ± 0.2 degrees two-theta.

[0162] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.5 ± 0.2, 7.6 ± 0.2, 15.1 ± 0.2, 16.7 ± 0.2, 18.9 ± 0.2, and 19.6 ± 0.2. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at three two-theta values of 7.6 ± 0.2, 15.1 ± 0.2, and 16.7 ± 0.2. In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at two-theta values of 5.5 ± 0.2, 7.6 ± 0.2, 15.1 ± 0.2, 16.7 ± 0.2, 18.9 ± 0.2, and 19.6 ± 0.2.

[0163] In some embodiments, crystalline Form A of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 13A. In some embodiments, the present disclosure provides methods of preparing crystalline Form A of Compound I comprising de-solvating at least one solvate of Compound I chosen from ethanol solvates of Compound I and methanol solvates of Compound I .Solvates

[0164] In some embodiments, the present disclosure provides at least one solvate of Compound I chosen from 1,4-dioxane solvates, 2-methyl tetrahydrofuran solvates, ethanol solvates, nitromethane solvates, 1-propanol solvates, tetrahydrofuran solvates, toluene solvates, pyridine solvates, chlorobenzene solvates, diethyl ether solvates, 2-propanol solvates, 2-butanol solvates, hexane solvates, heptane solvates, ethyl acetate solvates, methanol solvates, dichloromethane solvates, acetone solvates, methyl tert-butyl ether solvates, n-butanol solvates, N-methyl-2-pyrrolidone solvates, and t-butanol solvates of Compound I. Such solvates of Compound I can be prepared by stirring Compound I in a relevant solvent.

[0165] In some embodiments, the present disclosure provides at least one solvate of a sodium salt of Compound I chosen from ethanol solvates and methanol solvates of a sodium salt of Compound I. Such solvates of Compound I can be prepared by stirring a sodium salt of Compound I in a relevant solvent or reacting Compound I with a sodium base in a relevant solvent. In some embodiments, ethanol solvates of a sodium salt of Compound I are prepared by reacting Compound I with a sodium base in ethanol. In some embodiments, methanol solvates of a sodium salt of Compound I are prepared by reacting Compound I with a sodium base in methanol. Examples of suitable sodium bases are as described above for crystalline Form M and Form E of a sodium salt of Compound I .

[0166] In some embodiments, the present disclosure provides at least one solvate of a potassium salt of Compound I chosen from 1-pentanol solvates, isopropyl acetate solvates, 1-propanol solvates, acetone solvates, acetonitrile solvates, 2-methyl tetrahydrofuran solvates, ethyl acetate solvates, methanol solvates, ethanol solvates, methyl tert-butyl ether solvates, and methyl ethyl ketone solvates of a potassium salt of Compound I. In some embodiments, a solvate of a potassium salt of Compound I is chosen from 1-pentanol solvates, isopropyl acetate solvates, acetone solvates, acetonitrile solvates, 2-methyl tetrahydrofuran solvates, ethyl acetate solvates, methyl tert-butyl ether solvates, and methyl ethyl ketone solvates of a potassium salt of Compound I. Such solvates of Compound I can be prepared by stirring a potassium salt of Compound I in a relevant solvent or reacting Compound I with a potassium base in a relevant solvent. In some embodiments, ethanol solvates of a postassium salt of Compound I are prepared by reacting Compound I with a potassium base in ethanol. In some embodiments, methanol solvates of a potassium salt of Compound I are prepared by reacting Compound I with a potassium base in methanol. Examples of suitable potassium bases are as described above for crystalline Form B of a potassium salt of Compound I .Isotopically Enriched Compounds

[0167] Disclosed are isotope-labelled compounds of the afore-mentioned compounds, which have the same structures as disclosed herein except that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled). Examples of isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2< H, 3< H, 13< C, 14< C, 15< N, 18< O, 17< O, 31< P, 32< P, 35< S, 18< F and 36< Cl, respectively.

[0168] Isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and / or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3< H)- and / or carbon-14 ( 14< C)-labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability. For example, deuterium ( 2< H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non- 2< H-labelled compounds. In general, deuterium ( 2< H)-labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which could be desired. Isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

[0169] Isotope-labelled compounds and salts may be deuterium ( 2< H)-labelled ones. Isotope-labelled compounds and salts may be deuterium ( 2< H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium. In chemical structures, deuterium is represented as " 2< H" or "D."

[0170] Deuterium ( 2< H)-labelled compounds and salts can manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of k M / k D = 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417; and T.G. Gant "Using deuterium in drug discovery: leaving the label in the drug" J. Med. Chem. 2014, 57, 3595-3611.

[0171] The concentration of the isotope(s) (e.g., deuterium) incorporated into isotope-labelled compounds and salt may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0172] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It may be reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.

[0173] One of ordinary skill in the art would understand that deuteration of one or more metabolically labile positions on a compound or active metabolite may lead to improvement of one or more superior DMPK properties while maintaining biological activity as compared to the corresponding hydrogen analogs. The superior DMPK property or properties may have an impact on the exposure, half-life, clearance, metabolism, and / or even food requirements for optimal absorption of the drug product. Deuteration may also change the metabolism at other non-deuterated positions of the deuterated compound.

[0174] In some embodiments, the pharmaceutical compositions are a tablet. In some embodiments, the tablets are suitable for oral administration. In some embodiments, the tablets can be administered concurrently with, prior to, or subsequent to, at least one active pharmaceutical ingredients or medical procedures.Exemplary Embodiments of Crystalline Forms of Compound I

[0175] Exemplary embodiments of crystalline forms of Compound I and pharmaceutically acceptable salts and solvates thereof include: 1. Crystalline Form B of a potassium salt of Compound I: characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2, obtained using Cu Kα radiation. 2. Crystalline Form B according to embodiment 1 in substantially pure form, wherein a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by quantitative XRPD. 3. Crystalline Form B according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 16.3 ± 0.2, and 19.1 ± 0.2. 4. Crystalline Form B according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at three two-theta values of 5.8 ± 0.2, 10.2 ± 0.2, and 19.1 ± 0.2. 5. Crystalline Form B according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at six two-theta values of 5.8 ± 0.2, 8.2 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 16.3 ± 0.2, and 19.1 ± 0.2. 6. Crystalline Form B of embodiment 1, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 1A, wherein "substantially similar" means that at least 90% of the signals in the two diffractograms overlap. 7. Crystalline Form B of embodiment 1 having a unit cell characterized by three edges of 9.0 ± 0.2 Å, 11.5 ± 0.2 Å, and 31.0 ± 0.2 Å. 8. Crystalline Form B of a potassium salt of Compound I prepared by a process comprising reacting Compound I with a potassium base. 9. A method of preparing Crystalline Form B of a potassium salt of Compound I, comprising reacting Compound I with a potassium base. 10. The method of embodiment 9, wherein said potassium base is KOH. 11. Crystalline Form C of a potassium salt / co-crystal of Compound I, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12.4 ± 0.2, and 16.0 ± 0.2, obtained using Cu Kα radiation. 12. Crystalline Form C according to embodiment 11 in substantially pure form, wherein a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by quantitative XRPD. 13. Crystalline Form C according to embodiment 11, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, and 11.5 ± 0.2. 14. Crystalline Form C according to embodiment 11, characterized by an X-ray powder diffractogram having a signal at three two-theta values of 3.7 ± 0.2, 7.0 ± 0.2, and 11.4 ± 0.2. 15. Crystalline Form C according to embodiment 11, characterized by an X-ray powder diffractogram having a signal at six two-theta values of 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, and 11.5 ± 0.2. 16. Crystalline Form C of embodiment 11, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 7A, wherein "substantially similar" means that at least 90% of the signals in the two diffractograms overlap. 17. Crystalline Form C of a potassium salt / co-crystal of Compound I prepared by a process comprising stirring a potassium salt of Compound I with a solvent system comprising at least one source of water. 18. A method of preparing Crystalline Form C of a potassium salt / co-crystal of Compound I, comprising stirring a potassium salt of Compound I with a solvent system comprising at least one source of water. 19. Crystalline Form A of a sodium salt of Compound I, characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2, obtained using Cu Kα radiation. 20. Crystalline Form A according to embodiment 19 in substantially pure form, wherein a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by quantitative XRPD. 21. Crystalline Form A according to embodiment 19, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 12.2 ± 0.2, and 12.6 ± 0.2. 22. Crystalline Form A according to embodiment 19, characterized by an X-ray powder diffractogram having a signal at three two-theta values of 4.7 ± 0.2, 8.0 ± 0.2, and 12.2 ± 0.2. 23. Crystalline Form A according to embodiment 19, characterized by an X-ray powder diffractogram having a signal at six two-theta values of 4.7 ± 0.2, 4.9 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 12.2 ± 0.2, and 12.6 ± 0.2. 24. Crystalline Form A of embodiment 19, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 8A, wherein "substantially similar" means that at least 90% of the signals in the two diffractograms overlap. 25. A method of preparing crystalline Form A of a sodium salt of Compound I comprising reacting Compound I with a sodium base. 26. Crystalline Form D of a sodium salt of Compound I, characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2, obtained using Cu Kα radiation. 27. Crystalline Form D according to embodiment 26 in substantially pure form, wherein a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by quantitative XRPD. 28. Crystalline Form D according to embodiment 26, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 12.2 ± 0.2, and 14.0 ± 0.2. 29. Crystalline Form D according to embodiment 26, characterized by an X-ray powder diffractogram having a signal at three two-theta values of 4.9 ± 0.2, 8.0 ± 0.2, and 12.2 ± 0.2. 30. Crystalline Form D according to embodiment 26, characterized by an X-ray powder diffractogram having a signal at six two-theta values of 4.9 ± 0.2, 5.7 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 12.2 ± 0.2, and 14.0 ± 0.2. 31. Crystalline Form D of embodiment 26, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 9A, wherein "substantially similar" means that at least 90% of the signals in the two diffractograms overlap. 32. A method of preparing crystalline Form D of a sodium salt Compound I, comprising heating a crystalline Form M or Form E of a sodium salt of Compound I at a temperature in a range from 280 °C to 300 °C under anhydrous conditions. 33. Crystalline Form A of Compound I, characterized by an X-ray powder diffractogram having a signal ranging from 5.3 to 5.5, from 7.2 to 7.5, from 11.8 to 12.2, from 14.7 to 15.0, from 16.7 to 17.1, from 17.4 to 17.7, from 18.5 to 18.8, and from 19.5 to 19.8 degrees two-theta, obtained using Cu Kα radiation. 34. Crystalline Form A according to embodiment 33 in substantially pure form, wherein a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by quantitative XRPD. 35. Crystalline Form A according to embodiment 33, characterized by an X-ray powder diffractogram having at least three signals chosen from signals in the following two-theta value ranges: from 5.3 to 5.5, from 7.2 to 7.5, from 11.8 to 12.2, from 14.7 to 15.0, from 16.7 to 17.1, from 17.4 to 17.7, from 18.5 to 18.8, and from 19.5 to 19.8 degrees two-theta. 36. Crystalline Form A of embodiment 33, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 13A, wherein "substantially similar" means that at least 90% of the signals in the two diffractograms overlap. 37. A method of preparing crystalline Form A of Compound I comprising de-solvating at least one solvate of Compound I chosen from ethanol solvates of Compound I and methanol solvates of Compound I. 38. Crystalline Form E of a sodium salt of Compound I, characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.7± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2, obtained using Cu Kα radiation. 39. Crystalline Form E according to embodiment 38 in substantially pure form, wherein a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by quantitative XRPD. 40. Crystalline Form E according to embodiment 38, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.7± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 15.2 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. 41. Crystalline Form E according to embodiment 38, characterized by an X-ray powder diffractogram having a signal at three two-theta values of 11.4 ± 0.2, 15.2 ± 0.2, and 19.0 ± 0.2. 42. Crystalline Form E according to embodiment 38, characterized by an X-ray powder diffractogram having a signal at sixtwo-theta values of 5.7± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 15.2 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2. 43. Crystalline Form E of embodiment 38, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 12A, wherein "substantially similar" means that at least 90% of the signals in the two diffractograms overlap. 44. A method of preparing crystalline Form E of a sodium salt of Compound I comprising reacting Compound I with a sodium base in ethanol. 45. A pharmaceutical composition comprising at least one crystalline form according to any one of embodiments 1 - 44 and a pharmaceutically acceptable carrier. 46. A crystalline form according to any one of embodiments 1 - 44 or pharmaceutical composition of embodiment 45 for use in treating cystic fibrosis comprising administering to a patient in need thereof at least one crystalline form according to any one of embodiments 1 - 44 or pharmaceutical composition of embodiment 45. 47. At least one solvate of Compound I chosen from 1,4-dioxane solvates, 2-methyl tetrahydrofuran solvates, ethanol solvates, nitromethane solvates, 1-propanol solvates, tetrahydrofuran solvates, toluene solvates, pyridine solvates, chlorobenzene solvates, diethyl ether solvates, 2-propanol solvates, 2-butanol solvates, hexane solvates, heptane solvates, ethyl acetate solvates, methanol solvates, dichloromethane solvates, acetone solvates, methyl tert-butyl ether solvates, n-butanol solvates, N-methyl-2-pyrrolidone solvates, and t-butanol solvates of Compound I. 48. At least one solvate of a sodium salt Compound I chosen from ethanol solvates and methanol solvates of the sodium salt of Compound I. 49. At least one solvate of a potassium salt Compound I chosen from 1-pentanol solvates, isopropyl acetate solvates, 1-propanol solvates, acetone solvates, acetonitrile solvates, 2-methyl tetrahydrofuran solvates, ethyl acetate solvates, methanol solvates, ethanol solvates, methyl tert-butyl ether solvates, and methyl ethyl ketone solvates of a potassium salt of Compound I. Compositions

[0176] In some embodiments, the present disclosure provides compositions comprising at least one crystalline form of Compound I as defined in the claims and pharmaceutically acceptable salts thereof disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the compositions of the invention comprise at least one crystalline form of salt / co-crystal of Compound I as defined in the claims and a pharmaceutically acceptable carrier. In some embodiments, these compositions comprise one or more additional CFTR modulating agents.

[0177] In some embodiments, the pharmaceutical compositions disclosed herein comprise a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B), either as a mixture with other forms (crystalline and / or amorphous) or a substantially pure form. In some embodiments, the pharmaceutical compositions disclosed herein comprise substantially pure crystalline Form B of a potassium salt of Compound I as defined in the claims.

[0178] In some embodiments, the pharmaceutical compositions disclosed herein comprise crystalline Form C of a potassium salt / co-crystal of Compound I as defined in the claims, either as a mixture with other forms (crystalline and / or amorphous) or a substantially pure form. In some embodiments, the pharmaceutical compositions disclosed herein comprise substantially pure crystalline Form C of a potassium salt / co-crystal of Compound I as defined in the claims.

[0179] In some embodiments, the pharmaceutical compositions disclosed herein comprise a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B), either alone or in combination with one or more CFTR modulating agents. In some embodiments, the pharmaceutical composition comprises a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B), in combination with Compound II and optionally one or more additional CFTR modulating agents. In some embodiments, the pharmaceutical composition comprises a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B) in combination with Compound III and optionally one or more additional CFTR modulating agents. In some embodiments, the pharmaceutical compositions disclosed herein comprise a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B) in combination with Compound II and / or Compound III or III-d. Solid Dispersions

[0180] In some embodiments, the pharmaceutical compositions disclosed herein comprise a potassium salt of Compound I in a crystalline form as defined in the claims (in some embodiments, potassium salt crystalline Form B), either as a mixture with other forms (crystalline and / or amorphous) or a substantially pure form together with a first solid dispersion and / or a second solid dispersion. In some embodiments, the first solid dispersion is a spray dried dispersion comprising Compound II. In some embodiments, the second solid dispersion is selected from a spray-dried dispersion comprising Compound III or Compound III-d. In some embodiments, the first solid dispersion is a spray dried dispersion comprising Compound II and the second solid dispersion is a spray dried dispersion comprising Compound III or Compound III-d.

[0181] In some embodiments, each of the first and second solid dispersions, such as the first and second spray dried dispersions, independently comprises a plurality of particles having a mean particle diameter of 5 to 100 microns. In some embodiments, each of the first and second solid dispersions, such as the first and secondspray dried dispersions, independently comprises a plurality of particles having a mean particle diameter of 5 to 30 microns. In some embodiments, each of the first and second solid dispersions, such as the first and second spray dried dispersions, independently comprises a plurality of particles having a mean particle diameter of 15 microns.

[0182] In some embodiments, the first solid dispersions and the first spray dried dispersions of the disclosure independently comprises substantially amorphous Compound II. In some embodiments, the second solid dispersions and the second spray dried dispersions of the disclosure independently comprises substantially amorphous Compound III or Compound III-d.

[0183] In some embodiments, the solid dispersions and the spray dried dispersions of the disclosure can comprise other excipients, such as polymers and / or surfactants. Any suitable polymers and surfactants known in the art can be used in the disclosure. Certain exemplary polymers and surfactants are as described below.

[0184] Solid dispersions of any one of Compounds II, Compound III and Compound III-d may be prepared by any suitable method know in the art, e.g., spray drying, lyophilizing, hot melting, or cyrogrounding / cryomilling techniques. For example, see WO2015 / 160787. Typically such spray drying, lyophilizing, hot melting or cyrogrounding / cryomilling techniques generates an amorphous form of API (e.g., Compound II or Compound III, or Compound III-d).

[0185] Spray drying is a process that converts a liquid feed to a dried particulate form. Optionally, a secondary drying process such as fluidized bed drying or vacuum drying may be used to reduce residual solvents to pharmaceutically acceptable levels. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot gasto produce evaporation and drying of the liquid droplets. The preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray drying apparatus. In one procedure, the preparation is sprayed into a current of warm filtered gas that evaporates the solvent and conveys the dried product to a collector (e.g. a cyclone). The spent gas is then exhausted with the solvent, or alternatively the spent air is sent to a condenser to capture and potentially recycle the solvent. Commercially available types of apparatus may be used to conduct the spray drying. For example, commercial spray dryers are manufactured by Buchi Ltd. And Niro (e.g., the PSD line of spray driers manufactured by Niro) (see, US 2004 / 0105820; US 2003 / 0144257).

[0186] Techniques and methods for spray drying may be found in Perry's Chemical Engineering Handbook, 6th Ed., R. H. Perry, D. W. Green & J. O. Maloney, eds.), McGraw-Hill book co. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

[0187] Removal of the solvent may require a subsequent drying step, such as tray drying, fluid bed drying, vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying.

[0188] In one embodiment, the solid dispersions and the spray dried dispersions of the disclosure are fluid bed dried.

[0189] In one process, the solvent includes a volatile solvent, for example a solvent having a boiling point of less than 100 °C. In some embodiments, the solvent includes a mixture of solvents, for example a mixture of volatile solvents or a mixture of volatile and non-volatile solvents. Where mixtures of solvents are used, the mixture can include one or more non-volatile solvents, for example, where the non-volatile solvent is present in the mixture at less than 15%, e.g., less than 12%, less than 10%, less than 8%, less than 5%, less than 3%, or less than 2%.

[0190] In some processes, solvents are those solvents where the API(s) (e.g., Compound II and / or Compound III) has solubilities of at least 10 mg / ml, (e.g., at least 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, or greater). In other processes, solvents include those solvents where the API(s) (e.g., Compound II and / or Compound III) has a solubility of at least 20 mg / ml.

[0191] Exemplary solvents that could be tested include acetone, cyclohexane, dichloromethane or methylene chloride (DCM), N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropyl alcohol, isopropyl acetate, and toluene. Exemplary co-solvents include DCM / methanol, acetone / DMSO, acetone / DMF, acetone / water, MEK / water, THF / water, dioxane / water. In a two solvent system, the solvents can be present in of from 0.1% to 99.9% w / w. In some preferred embodiments, water is a co-solvent with acetone where water is present from 0.1% to 15%, for example 9% to 11%, e.g., 10%. In some preferred embodiments, water is a co-solvent with MEK where water is present from 0.1% to 15%, for example 9% to 11%, e.g., 10%. In some embodiments the solvent system includes three solvents. Certain exemplary solvents include those described above, for example, MEK, DCM, water, methanol, IPA, and mixtures thereof.

[0192] The particle size and the temperature drying range may be modified to prepare an optimal solid dispersion. As would be appreciated by skilled practitioners, a small particle size would lead to improved solvent removal. Applicants have found however, that smaller particles can lead to fluffy particles that, under some circumstances do not provide optimal solid dispersions for downstream processing such as tableting.

[0193] A solid dispersion (e.g., a spray dried dispersion) dislcosed herein may optionally include a surfactant. A surfactant or surfactant mixture would generally decrease the interfacial tension between the solid dispersion and an aqueous medium. An appropriate surfactant or surfactant mixture may also enhance aqueous solubility and bioavailability of the API(s) (e.g., Compound II and / or Compound III) from a solid dispersion. The surfactants for use in connection with the disclosure include, but are not limited to, sorbitan fatty acid esters (e.g., Spans ®< ), polyoxyethylene sorbitan fatty acid esters (e.g., Tweens ®< ), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS) dioctyl sodium sulfosuccinate (Docusate sodium), dioxycholic acid sodium salt (DOSS), Sorbitan Monostearate, Sorbitan Tristearate, hexadecyltrimethyl ammonium bromide (HTAB), Sodium N-lauroylsarcosine, Sodium Oleate, Sodium Myristate, Sodium Stearate, Sodium Palmitate, Gelucire 44 / 14, ethylenediamine tetraacetic acid (EDTA), Vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), Lecithin, MW 677-692, Glutanic acid monosodium monohydrate, Labrasol, PEG 8 caprylic / capric glycerides, Transcutol, diethylene glycol monoethyl ether, Solutol HS-15, polyethylene glycol / hydroxystearate, Taurocholic Acid, Pluronic F68, Pluronic F108, and Pluronic F127 (or any other polyoxyethylene-polyoxypropylene co-polymers (Pluronics ®< ) or saturated polyglycolized glycerides (Gelucirs ®< )). Specific example of such surfactants that may be used in connection with this disclosure include, but are not limited to, Span 65, Span 25, Tween 20, Capryol 90, Pluronic F108, sodium lauryl sulfate (SLS), Vitamin E TPGS, pluronics and copolymers.

[0194] In some embodiments, SLS is used as a surfactant in the solid dispersion of Compound III.

[0195] In some embodiments, SLS is used as a surfactant in the solid dispersion of Compound III-d.

[0196] The amount of the surfactant (e.g., SLS) relative to the total weight of the solid dispersion may be between 0.1 - 15% w / w. For example, it is from 0.5% to 10%, such as from 0.5 to 5%, e.g., 0.5 to 4%, 0.5 to 3%, 0.5 to 2%, 0.5 to 1%, or 0.5%.

[0197] In certain embodiments, the amount of the surfactant relative to the total weight of the solid dispersion is at least 0.1% or at least 0.5%. In these embodiments, the surfactant would be present in an amount of no more than 15%, or no more than 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. In some mebodiments, the surfactant is in an amount of 0.5% by weight.

[0198] Candidate surfactants (or other components) can be tested for suitability for use in the disclosure in a manner similar to that described for testing polymers.

[0199] One aspect of the disclosure provides a method of generating a spray dried dispersion comprising (i) providing a mixture of one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle and subjecting the mixture to spray drying conditions to generate the spray dried dispersion.

[0200] Another aspect of the disclosure provides a method of generating a spray dried dispersion comprising: (i) providing a mixture comprising one or more APIs and a solvent(s); and (ii) forcing the mixture out of a nozzle under spray dry drying conditions to generate a spray dried dispersion.

[0201] Another aspect of the disclosure provides a method of generating a spray dried dispersion comprising (i) spraying a mixture through a nozzle, wherein the mixture comprises one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate a particle that comprises the APIs.

[0202] Another aspect of the disclosure provides a spray dried dispersion comprising one or more APIs, wherein the dispersion is substantially free of a polymer, and wherein the spray dried dispersion is generated by (i) providing a mixture that consists essentially of one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.

[0203] Another aspect of the disclosure provides a spray dried dispersion comprising one or more APIs, wherein the dispersion is generated by (i) providing a mixture that comprising one or more APIs, a polymer(s), and a solvent(s); and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.

[0204] Another aspect of the disclosure provides a spray dried dispersion comprising a particle, wherein the particle comprises one or more APIs and a polymer(s), and wherein the spray dried dispersion is generated by (i) spraying a mixture through a nozzle, wherein the mixture comprises one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.

[0205] Another aspect of the disclosure provides a spray dried dispersion comprising a particle, wherein the particle comprises one or more APIs, and the particle is substantially free of a polymer, and wherein the spray dried dispersion is generated by (i) spraying a mixture through a nozzle, wherein the mixture comprises one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.

[0206] In some embodiments, the one or more APIs are selected from Compound II and Compound III. In some embodiments, the one or more APIs are selected from Compound II and Compound III-d.

[0207] Some embodiments further comprise further drying the spray dried dispersion. For example, the spray dried dispersion is dried under reduced pressure. In other examples, the spray dried dispersion is dried at a temperature of from 50 °C to 100 °C.

[0208] In some embodiments, the solvent comprises a polar organic solvent. Examples of polar organic solvents include methylethyl ketone, THF, DCM, methanol, or IPA, or any combination thereof, such as, for example DCM / methanol. In other examples, the solvent further comprises water. In other examples, the solvent further comprises water. For instance, the solvent could be methylethyl ketone / water, THF / water, or methylethyl ketone / water / IPA. For example, the ratio of the polar organic solvent to water is from 70:30 to 95:5 by volume. In other instances, the ratio of the polar organic solvent to water is 90:10 by volume.

[0209] Some embodiments further comprise filtering the mixture before it is forced through the nozzle. Such filtering can be accomplished using any suitable filter media having a suitable pore size.

[0210] Some embodiments further comprise applying heat to the mixture as it enters the nozzle. This heating can be accomplished using any suitable heating element.

[0211] In some embodiments, the nozzle comprises an inlet and an outlet, and the inlet is heated to a temperature that is less than the boiling point of the solvent. For example, the inlet is heated to a temperature of from 90 °C to 150 °C.

[0212] In some embodiments, the mixture is forced through the nozzle by a pressurized gas. Examples of suitable pressurized gases include those pressurized gas that are inert to the first agent, the second agent, and the solvent. In one example, the pressurized gas comprises elemental nitrogen.

[0213] In some embodiments, the pressurized gas has a positive pressure of from 90 psi to 150 psi.

[0214] Some embodiments further comprise further drying the spray dried dispersion. For example, the spray dried dispersion is dried under reduced pressure. In other examples, the spray dried dispersion is dried at a temperature of from 50 °C to 100 °C.

[0215] In some embodiments, the solvent comprises a polar organic solvent. Examples of polar organic solvents include methylethyl ketone, THF, DCM, methanol, or IPA, or any combination thereof. In other examples, the solvent further comprises water. In other examples, the solvent further comprises water. For instance, the solvent could be methylethyl ketone / water, THF / water, or methylethyl ketone / water / IPA. For example, the ratio of the polar organic solvent to water is from 70:30 to 95:5 by volume. In other instances, the ratio of the polar organic solvent to water is 90:10 by volume.

[0216] In some embodiments, a pharmaceutically acceptale composition of the disclosure comprising substantially amorphous API(s) (e.g., Compound II and / or Compound III or III-d) may be prepared by non-spray drying techniques, such as, for example, cyrogrounding / cryomilling techniques. A composition comprising substantially amorphous API(s) (e.g., Compound II and / or Compound III or III-d) may also be prepared by hot melt extrusion techniques.

[0217] In some embodiments, the solid dispersions (e.g., spray dried dispersions) of the disclosure comprise a polymer(s). Any suitable polymers known in the art can be used in the disclosure. Exemplary suitable polymers include polymers selected from cellulose-based polymers, polyoxyethylene-based polymers, polyethylene-propylene glycol copolymers, vinyl-based polymers, PEO-polyvinyl caprolactam-based polymers, and polymethacrylate-based polymers.

[0218] The cellulose-based polymers include a methylcellulose, a hydroxypropyl methylcellulose (HPMC) (hypromellose), a hypromellose phthalate (HPMC-P), a hypromellose acetate succinate, and co-polymers thereof. The polyoxyethylene-based polymers include a polyethylene-propylene glycol, a polyethylene glycol, a poloxamer, and co-polymers thereof. The vinyl-based polymers include a polyvinylpyrrolidine (PVP), and PVP / VA. The PEO-polyvinyl caprolactam-based polymers include a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer (e.g., Soluplus ®< ). The polymethacrylate-based polymers are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Several types are commercially available and may be obtained as the dry powder, aqueous dispersion, or organic solution. Examples of such polymethacrylate-based polymers include a poly(methacrylic acid, ethyl acrylate) (1:1), a dimethylaminoethyl methacrylate-methylmethacrylate copolymer, and a Eudragit ®< .

[0219] In some embodiments, the cellulose-based polymer is a hypromellose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate or HMPCAS) and a hypromellose (also known as hydroxypropyl methylcellulose or HPMC), or a combination of hypromellose acetate succinate and a hypromellose. HPMCAS is available in various grades based on the content of acetyl and succinoyl groups (wt%) in the HPMCAS molecule and on particle size. For example, HPMCAS grades L, M, and H are available. HPMCAS-H is a grade that contains about 10-14 wt% of acetyl groups and about 4-8 wt% of succinoyl groups. Each HPMCAS grade is available in two particle sizes, F (fine) and G (granular). HPMC comes in various types (for example, HPMC E, F, J, and K-types). HPMC E type means that there are about 28-30% methoxy groups and about 7-12% hydroxpropoxy groups. There are various E grades ranging from low to high viscosity. For example, E3 means the viscosity is about 2.4-3.6 millipascal seconds (mPa·s) for HPMC measured at 2% in water at 20°C; E15 means the viscosity is about 12-18 mPa·s for the HPMC measured at 2% in water at 20°C; and E50 means the viscosity is about 40-60 mPa·s for the HPMC measured at 2% in water at 20°C.

[0220] In some embodiments, the cellulose-based polymer is hypromellose E15, hypromellose acetate succinate L or hypromellose acetate succinate H.

[0221] In some embodiments, the polyoxyethylene-based polymer or polyethylene-propylene glycol copolymer is a polyethylene glycol or a pluronic.

[0222] In some embodiments, the polyoxyethylene-based polymer or polyethylene-propylene glycol copolymer is polyethylene glycol 3350 or poloxamer 407.

[0223] In some embodiments, the vinyl-based polymer is a vinylpolyvinylpyrrolidine-based polymer, such as polyvinylpyrrolidine K30 or polyvinylpyrrolidine VA 64.

[0224] In some embodiments, the polymethacrylate polymer is Eudragit L100-55 or Eudragit ®< E PO.

[0225] In some embodiments, the polymer(s) is selected from cellulosic polymers such as HPMC and / or HPMCAS.

[0226] In one embodiment, a polymer is able to dissolve in aqueous media. The solubility of the polymers may be pH independent or pH dependent. The latter include one or more enteric polymers. The term "enteric polymer" refers to a polymer that is preferentially soluble in the less acidic environment of the intestine relative to the more acid environment of the stomach, for example, a polymer that is insoluble in acidic aqueous media but soluble when the pH is above 5-6. An appropriate polymer is chemically and biologically inert. In order to improve the physical stability of the solid dispersions, the glass transition temperature (Tg) of the polymer is as high as possible. For example, polymers have a glass transition temperature at least equal to or greater than the glass transition temperature of the API. Other polymers have a glass transition temperature that is within 10 to 15 °C of the API.

[0227] Additionally, the hygroscopicity of the polymers is as low, e.g., less than 10%. For the purpose of comparison in this application, the hygroscopicity of a polymer or composition is characterized at 60% relative humidity. In some preferred embodiments, the polymer has less than 10% water absorption, for example less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, or less than 2% water absorption. The hygroscopicity can also affect the physical stability of the solid dispersions. Generally, moisture adsorbed in the polymers can greatly reduce the Tg of the polymers as well as the resulting solid dispersions, which will further reduce the physical stability of the solid dispersions as described above.

[0228] In one embodiment, the polymer is one or more water-soluble polymer(s) or partially water-soluble polymer(s). Water-soluble or partially water-soluble polymers include but are not limited to, cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as polymethacrylate (e.g., Eudragit ®< E); cyclodextrins (e.g., β-cyclodextin) and copolymers and derivatives thereof, including for example PVP-VA (polyvinylpyrollidone-vinyl acetate).

[0229] In some embodiments, the polymer is hydroxypropylmethylcellulose (HPMC), such as HPMC E50, HPMC E15, or HPMC E3.

[0230] As discussed herein, the polymer can be a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methyl cellulose phthalates (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or a salt thereof (e.g., a sodium salt such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), or polymethacrylates (e.g., Eudragit ®< S). In some embodiments, the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS). In some embodiments, the polymer is hydroxypropyl methyl cellulose acetate succinate HG grade (HPMCAS-HG).

[0231] In yet another embodiment, the polymer is a polyvinylpyrrolidone co-polymer, for example, avinylpyrrolidone / vinyl acetate co-polymer (PVP / VA).

[0232] In embodiments where Compound II, Compound III and / or Compound III-d forms a solid dispersion with a polymer, for example with an HPMC, HPMCAS, or PVP / VA polymer, the amount of polymer relative to the total weight of the solid dispersion ranges from 0.1% to 99% by weight. Unless otherwise specified, percentages of drug, polymer and other excipients as described within a dispersion are given in weight percentages. The amount of polymer is typically at least 20%, and preferably at least 30%, for example, at least 35%, at least 40%, at least 45%, or 0% (e.g., 49.5%). The amount is typically 99% or less, and preferably 80% or less, for example 75% or less, 70% or less, 65% or less, 60% or less, or 55% or less. In one embodiment, the polymer is in an amount of up to 50% of the total weight of the dispersion (and even more specifically, between 40% and 50%, such as 49%, 49.5%, or 50%).

[0233] In some embodiments, the API (e.g., Compound II or Compound III) and polymer are present in roughly equal amounts in weight, for example each of the polymer and the drug make up half of the percentage weight of the dispersion. For example, the polymer is present in 49.5 wt % and Compound II, Compound III, or Compound III-d is present in 50 wt%. In another embodiment Compound II, Compound III, or Compound III-d is present in an amount greater than half of the percentage weight of the dispersions. For example, the polymer is present in 20 wt% and Compound II, Compound III, or Compound III-d is present in 80 wt%. In other embodiments, the polymer is present in 19.5 wt% and Compound II, Compound III, or Compound III-d is present in 80 wt%.

[0234] In some embodiments, the API (e.g., Compound II or Compound III) and the polymer combined represent 1% to 20% w / w total solid content of the spray drying solution prior to spray drying. In some embodiments, Compound II, Compound III, or Compound III-d, and the polymer combined represent 5% to 15% w / w total solid content of the spray drying solution prior to spray drying. In some embodiments, Compound II, Compound III, or Compound III-d, and the polymer combined represent 11% w / w total solid content of the spray drying solution prior to spray drying.

[0235] In some embodiments, the dispersion further includes other minor ingredients, such as a surfactant (e.g., SLS). In some embodiments, the surfactant is present in less than 10% of the dispersion, for example less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, 1%, or 0.5%.

[0236] In embodiments including a polymer, the polymer is present in an amount effective for stabilizing the solid dispersion. Stabilizing includes inhibiting or preventing, the crystallization of an API (e.g., Compound II or Compound III). Such stabilizing would inhibit the conversion of the API from amorphous to crystalline form. For example, the polymer would prevent at least a portion (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or greater) of the API from converting from an amorphous to a crystalline form. Stabilization can be measured, for example, by measuring the glass transition temperature of the solid dispersion, measuring the amount of crystalline material, measuring the rate of relaxation of the amorphous material, or by measuring the solubility or bioavailability of the API.

[0237] In some embodiments, the polymers for use in the disclosure have a glass transition temperature of no less than 10-15 °C lower than the glass transition temperature of API. In some instances, the glass transition temperature of the polymer is greater than the glass transition temperature of API, and in general at least 50°C higher than the desired storage temperature of the drug product. For example, at least 100 °C, at least 105 °C, at least 105 °C, at least 110 °C, at least 120 °C, at least 130 °C, at least 140 °C, at least 150 °C, at least 160 °C, at least 160 °C, or greater.

[0238] In some embodiments, the polymers for use in the disclosure have similar or better solubility in solvents suitable for spray drying processes relative to that of an API (e.g., Compound II or Compound III). In some embodiments, the polymer will dissolve in one or more of the same solvents or solvent systems as the API.

[0239] In some embodiments, the polymers for use in the disclosure can increase the solubility of an API (e.g., Compound II or Compound III) in aqueous and physiologically relative media either relative to the solubility of the API in the absence of polymer or relative to the solubility of the API when combined with a reference polymer. For example, the polymers can increase the solubility of Compound II, Compound III, or Compound III-d by reducing the amount of amorphous Compound II, Compound III, or Compound III-d that converts to a crystalline form(s), either from a solid amorphous dispersion or from a liquid suspension.

[0240] In some embodiments, the polymers for use in the disclosure can decrease the relaxation rate of the amorphous substance.

[0241] In some embodiments, the polymers for use in the disclosure can increase the physical and / or chemical stability of an API (e.g., Compound II or Compound III).

[0242] In some embodiments, the polymers for use in the disclosure can improve the manufacturability of an API (e.g., Compound II or Compound III).

[0243] In some embodiments, the polymers for use in the disclosure can improve one or more of the handling, administration or storage properties of an API (e.g., Compound II or Compound III).

[0244] In some embodiments, the polymers for use in the disclosure have little or no unfavorable interaction with other pharmaceutical components, for example excipients.

[0245] The suitability of a candidate polymer (or other component) can be tested using the spray drying methods (or other methods) described herein to form an amorphous composition. The candidate composition can be compared in terms of stability, resistance to the formation of crystals, or other properties, and compared to a reference preparation, e.g., a preparation of neat amorphous Compound II, Compound III, or Compound III-d. For example, a candidate composition could be tested to determine whether it inhibits the time to onset of solvent mediated crystallization, or the percent conversion at a given time under controlled conditions, by at least 50 %, 75 %, or 100% as well as the reference preparation, or a candidate composition could be tested to determine if it has improved bioavailability or solubility relative to crystalline Compound II, Compound III, or Compound III-d.

[0246] In one aspect, the disclosure provides pharmaceutical compositions comprising neat Compound I-potassium salt (in some embodiments, potassium salt crystalline Form B), a first solid dispersion comprising Compound II, and a second solid dispersion compirising Compound III.

[0247] In another aspect, the disclosure provides pharmaceutical compositions comprising neat Compound I -potassium salt (in some embodiments, potassium salt crystalline Form B), a first solid dispersion comprising Compound II, and a second solid dispersion compirising Compound III-d.

[0248] In some embodiments, the first solid dispersion comprises a cellulose polymer. For example, the first solid dispersion comprises a hydroxypropyl methylcellulose (HPMC). In some embodiments, the first solid dispersion comprises a weight ratio of HPMC to Compound II ranging from 1:10 to 1:1. In some instances, the ratio of HPMC to Compound II is from 1:3 to 1:5.

[0249] In some embodiments, the second solid dispersion comprises a cellulose polymer. For example, the second solid dispersion comprises a hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0250] In some embodiments, each of the first and second solid dispersions comprises a plurality of particles having a mean particle diameter of 5 to 100 microns. In some embodiments, the particles have a mean particle diameter of 5 to 30 microns. In some embodiments, the particules have a mean particle diameter of 15 microns.

[0251] In some embodiments, the first solid dispersion comprises from 70 wt% to 90 wt% (e.g., from 75 wt% to 85 wt%) of Compound II.

[0252] In some embodiments, the second solid dispersion comprises from 70 wt% to 90 wt% (e.g., from 75 wt% to 85 wt%) of Compound III.

[0253] In some embodiments, the second solid dispersion comprises from 70 wt% to 90 wt% (e.g., from 75 wt% to 85 wt%) of Compound III-d.

[0254] In some embodiments, each of the first and second solid dispersions is a spray dried dispersion.

[0255] In some embodiments, the compositions of the invention comprise 100 to 260 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), and optionally comprise one or more additional CFTR modulating agents. In some embodiments, the compositions comprise about 128 mg or about 255-256 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), and optionally comprise one or more additional CFTR modulating agents. In some embodiments, the compositions comprise about 128 mg or about 255-256 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), together with 100 mg of Compound II and 150 mg of Compound III or 200 mg of Compound III-d. In some embodiments the compositions comprise about 128 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 50 mg of Compound II, and 75 mg of Compound III. In some embodiments the compositions comprise about 64 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), about 25 mg of Compound II, and about 35 mg to 40 mg of Compound III. Exemplary Formulations

[0256] In some embodiments, the pharmaceutical compositions disclosed herein further comprise one or more pharmaceutically acceptable excipients, such as pharmaceutically acceptable vehicles, adjuvants, or carriers.

[0257] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure.

[0258] In one embodiment, the pharmaceutical compositions of the disclosure comprise one or more fillers, a disintegrant, and a lubricant.

[0259] Fillers suitable for the pharmaceutical compositions disclosed herein are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical compositions. Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., mannitol, lactose, sucrose, or the like), or any combination thereof. In one embodiment, the filler is microcrystalline cellulose.

[0260] In some embodiments, the pharmaceutical compositions comprises one or more fillers in an amount of at least 5 wt% (e.g., at least 20 wt%, at least 30 wt%, or at least 40 wt%) by weight of the pharmaceutical composition. For example, the pharmaceutical compositions comprise from 10 wt% to 60 wt% (e.g., from 20 wt% to 55 wt%, from 25 wt% to 50 wt%, or from 27 wt% to 45 wt%) of filler, by weight of the tablet. In another example, the pharmaceutical compositions comprise at least 20 wt% (e.g., at least 30 wt% or at least 40 wt%) of microcrystalline cellulose, for example MCC Avicel PH102 or Avicel PH101, by weight of the pharmaceutical composition. In yet another example, the pharmaceutical compositions comprise from 10 wt% to 60 wt% (e.g., from 20 wt% to 55 wt% or from 25 wt% to 45 wt%) of microcellulose, by weight of the pharmaceutical composition.

[0261] Disintegrants suitable for the pharmaceutical compositions disclosed herein can enhance the dispersal of the pharmaceutical compositions and are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical compositions. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, crospovidone or a combination thereof. In one embodiment, the disintegrant is croscarmellose sodium.

[0262] In some embodiments, the pharmaceutical compositions discosed herein comprise disintegrant in an amount of 10 wt% or less (e.g., 7 wt% or less, 6 wt% or less, or 5 wt% or less) by weight of the pharmaceutical composition. For example, the pharmaceutical compositionscomprise from 1 wt% to 10 wt% (e.g., from 1.5 wt% to 7.5 wt% or from 2.5 wt% to 6 wt%) of disintegrant, by weight of the pharmaceutical composition. In another example, the pharmaceutical compositions comprise 10 wt% or less (e.g., 7 wt% or less, 6 wt% or less, or 5 wt% or less) of croscarmellose sodium, by weight of the pharmaceutical composition. In yet another example, the pharmaceutical compositions comprise from 1 wt% to 10 wt% (e.g., from 1.5 wt% to 7.5 wt% or from 2.5 wt% to 6 wt%) of croscarmellose sodium, by weight of the pharmaceutical composition. In some examples, the pharmaceutical compositions comprise from 0.1% to 10 wt% (e.g., from 0.5 wt% to 7.5 wt% or from 1.5 wt% to 6 wt%) of disintegrant, by weight of the pharmaceutical composition. In still other embodiments, the pharmaceutical compositions comprise from 0.5% to 10 wt% (e.g., from 1.5 wt% to 7.5 wt% or from 2.5 wt% to 6 wt%) of disintegrant, by weight of the pharmaceutical composition.

[0263] In some embodiments, the pharmaceutical compositions disclosed herein comprise a lubricant. A lubricant can prevent adhesion of a mixture compoent to a surface (e.g., a surface of a mixing bowl, a granulation roll, a compression die and / or punch). A lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a granulator and / or die press. A suitable lubricant for the pharmaceutical compositions disclosed herein is compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical compositions. Exemplary lubricants include magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof. In embodiment, the lubricant is magnesium stearate.

[0264] In one embodiment, the pharmaceutical compositions comprise a lubricant in an amount of 5 wt% or less (e.g., 4.75 wt%, 4.0 wt% or less, or 3.00 wt% or less, or 2.0 wt% or less) by weight of the pharmaceutical composition. For example, the pharmaceutical compositions comprise from 5 wt% to 0.10 wt% (e.g., from 4.5 wt% to 0.5 wt% or from 3 wt% to 1 wt%) of lubricant, by weight of the pharmaceutical composition. In another example, the pharmaceutical compositions comprise 5 wt% or less (e.g., 4.0 wt% or less, 3.0 wt% or less, or 2.0 wt% or less, or 1.0 wt% or less) of magnesium stearate, by weight of thepharmaceutical composition. In yet another example, the pharmaceutical compositionscomprise from 5 wt% to 0.10 wt% (e.g., from 4.5 wt% to 0.15 wt% or from 3.0 wt% to 0.50 wt%) of magnesium stearate, by weight of the pharmaceutical composition.

[0265] Any suitable spray dried dispersions of Compound II, Compound III, and Compound III-d can be used for the pharmaceutical compositions disclosed herein. Some examples for Compound II and its pharmaceutically acceptable salts can be found in WO 2011 / 119984 and WO 2014 / 015841. Some examples for Compound III and its pharmaceutically acceptable salts can be found in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731, and WO 2013 / 130669. Spray dried dispersions of Compound III-d can be prepared as those of Compound III as described in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731, and WO 2013 / 130669.

[0266] Pharmaceutical compositions comprising Compound II and Compound III are disclosed in PCT Publication No. WO 2015 / 160787. An exemplary embodiment is shown in the following Table 1 for administration with crystalline Form B of the potassium salt of Compound I. Table 1: Exemplary Tablet Comprising 100 mg of Compound II and 150 mg of Compound III Ingredient Amount per tablet (mg) Intra-granularCompound II SDD (spray dried dispersion)125(80 wt % Compound II; 20 wt % HPMC)Compound III SDD187.5(80 wt % Compound III; 19.5 wt% HPMCAS-HG; 0.5 wt% sodium lauryl sulfate)Microcrystalline cellulose131.4Croscarmellose Sodium29.6Total 473.5 Extra-granularMicrocrystalline cellulose112.5Magnesium Stearate5.9Total 118.4 Total uncoated Tablet 591.9 Film coatOpadry17.7Total coated Tablet 609.6

[0267] Pharmaceutical compositions comprising Compound III are disclosed in PCT Publication No. WO 2010 / 019239. An exemplary embodiment is shown in the following Table 2 for administration with crystalline Form B of the potassium salt of Compound I alone or in combination with Compound II. Table 2: Ingredients for Exemplary Tablet of Compound III Tablet Formulation Percent Dose % Wt. / Wt Dose (mg) Batch (g) Compound III SDD(80 wt % Compound III; 19.5 wt% HPMCAS-HG; 0.5 wt% sodium lauryl sulfate)34.09%187.523.86Microcrystalline cellulose30.51%167.821.36Lactose30.40%167.221.28Sodium croscarmellose3.000%16.502.100SLS0.500%2.7500.3500Colloidal silicon dioxide0.500%2.7500.3500Magnesium stearate1.000%5.5000.7000Total 100% 550 70

[0268] Additional pharmaceutical compositions comprising Compound III are disclosed in PCT Publication No. WO 2013 / 130669. Exemplary mini-tablets (~2 mm diameter, ~2 mm thickness, each mini-tablet weighing 6.9 mg) was formulated to have 50 mg of Compound III per 26 mini-tablets and 75 mg of Compound III per 39 mini-tablets using the amounts of ingredients recited in Table 3, below for administration with crystalline Form B of the potassium salt of Compound I alone or in combination with Compound II. Table 3: Ingredients for mini-tablets for 50 mg and 75 mg potencyTablet Formulation Percent Dose %Wt. / Wt. Dose (mg) 50 mg potency Dose (mg) 75 mg potency Batch (g) Compound III SDD3562.593.81753.4(80 wt % Compound III; 19.5 wt% HPMCAS-HG; 0.5 wt% sodium lauryl sulfate)Mannitol13.524.136.2675.2Lactose4173.2109.82050.2Sucralose2.03.65.4100.06Croscarmellose sodium6.010.716.1300.1Colloidal silicon dioxide1.01.82.750.0Magnesium stearate1.52.74.074.19Total 100 178.6 268 5003.15

[0269] In some embodiments, the pharmaceutical compositions disclosed herein comprise one of the following formulations: Table 4: Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)200 mg to 215 mgsolid dispersion containing 80% Compound II, 20% hypromellose60 mg to 65 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate90 mg to 95 mgmicrocrystalline cellulose175 mg to 215 mgcroscarmellose sodium (CCS)15 mg to 30 mgmagnesium stearate3 mg to 7 mg Table 5 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)212.9 mgsolid dispersion containing 80% Compound II, 20% hypromellose62.5 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate93.8 mgmicrocrystalline cellulose196.7 mgcroscarmellose sodium24.7 mgmagnesium stearate5.3 mg Table 6 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)115 mg to 140 mgsolid dispersion containing 80% Compound II, 20% hypromellose60 mg to 65 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate90 mg to 95 mgmicrocrystalline cellulose120 mg to 135 mgcroscarmellose sodium15 mg to 25 mgmagnesium stearate2 mg to 7 mg Table 7 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127.7 mgsolid dispersion containing 80% Compound II, 20% hypromellose62.5 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate93.8 mgmicrocrystalline cellulose130.6 mgcroscarmellose sodium18.1 mgmagnesium stearate3.9 mg

[0270] In some embodiments, the pharmaceutical compositions disclosed herein comprise an intra-granular part and an extragranular part, and the intra-granular part and the extra-granular part comprise components as shown in the tables below: Table 8 Component Amount (mg) per compositionIntra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)200 mg to 215 mgsolid dispersion containing 80% Compound II, 20% hypromellose60 mg to 65 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate90 mg to 95 mgmicrocrystalline cellulose (e.g., PH101)120 mg to 150 mgcroscarmellose sodium (CCS)10 mg to 20 mgmagnesium stearate3 mg to 7 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)55 mg to 65 mgcroscarmellose sodium5 mg to 10 mg Table 9 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)115 mg to 140 mgsolid dispersion containing 80% Compound II, 20% hypromellose60 mg to 65 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose90 mg to 95 mgacetate succinate, and 0.5% sodium lauryl sulfatemicrocrystalline cellulose (e.g., PH101)80 mg to 90 mgcroscarmellose sodium10 mg to 15 mgmagnesium stearate2 mg to 7 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)40 mg to 45 mgcroscarmellose sodium5 mg to 10 mg Table 10 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)115 mg to 140 mgsolid dispersion containing 80% Compound II, 20% hypromellose60 mg to 65 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate90 mg to 95 mgmicrocrystalline cellulose (e.g., PH101)80 mg to 90 mgcroscarmellose sodium10 mg to 15 mgmagnesium stearate1 mg to 3 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)40 mg to 45 mgcroscarmellose sodium5 mg to 10 mgmagnesium stearate1 mg to 3 mg Table 11 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)115 mg to 140 mgsolid dispersion containing 80% Compound II, 20% hypromellose60 mg to 65 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose90 mg to 95 mgacetate succinate, and 0.5% sodium lauryl sulfatemicrocrystalline cellulose (e.g., PH101)80 mg to 90 mgcroscarmellose sodium8 mg to 15 mgmagnesium stearate0.5 mg to 5 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)35 mg to 50 mgcroscarmellose sodium5 mg to 10 mgmagnesium stearate0.5 mg to 5 mg Table 12 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)115 mg to 140 mgsolid dispersion containing 80% Compound II, 20% hypromellose60 mg to 65 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate90 mg to 95 mgmicrocrystalline cellulose (e.g., PH101)80 mg to 90 mgcroscarmellose sodium8 mg to 15 mgmagnesium stearate0.5 mg to 5 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)35 mg to 50 mgcroscarmellose sodium5 mg to 10 mg Table 13 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)115 mg to 140 mgsolid dispersion containing 80% Compound II, 20% hypromellose60 mg to 65 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose90 mg to 95 mgacetate succinate, and 0.5% sodium lauryl sulfatemicrocrystalline cellulose (e.g., PH101)80 mg to 90 mgcroscarmellose sodium8 mg to 15 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)35 mg to 50 mgcroscarmellose sodium5 mg to 10 mgmagnesium stearate0.5 mg to 5 mg Table 14 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)212-213 mgsolid dispersion containing 80% Compound II, 20% hypromellose62-63 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate93-94 mgmicrocrystalline cellulose (e.g., PH101)137-138 mgcroscarmellose sodium15-16 mgmagnesium stearate5-6 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)59-60 mgcroscarmellose sodium8-9 mg Table 15 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)212.9 mgsolid dispersion containing 80% Compound II, 20% hypromellose62.5 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose93.8 mgacetate succinate, and 0.5% sodium lauryl sulfatemicrocrystalline cellulose (e.g., PH101)137.1 mgcroscarmellose sodium15.8 mgmagnesium stearate5.3 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)59.6 mgcroscarmellose sodium8.9 mgUncoated Tablet595.9 mgCoating18.4 mg Table 16 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127-128 mgsolid dispersion containing 80% Compound II, 20% hypromellose62-63 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate93-94 mgmicrocrystalline cellulose (e.g., PH101)86-87 mgcroscarmellose sodium11-12 mgmagnesium stearate3-4 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)43-44 mgcroscarmellose sodium6-7 mg Table 17 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127.7 mgsolid dispersion containing 80% Compound II, 20% hypromellose62.5 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate93.8 mgmicrocrystalline cellulose (e.g., PH101)86.9 mgcroscarmellose sodium11.6 mgmagnesium stearate3.9 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)43.7 mgcroscarmellose sodium6.5 mgUncoated Tablet436.6 mgCoating13.5 mg Table 18 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127-128 mgsolid dispersion containing 80% Compound II, 20% hypromellose62-63 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate93-94 mgmicrocrystalline cellulose (e.g., PH101)86-87 mgcroscarmellose sodium11-12 mgmagnesium stearate1-2 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)43-44 mgcroscarmellose sodium6-7 mgmagnesium stearate1-2 mg Table 19 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127.7 mgsolid dispersion containing 80% Compound II, 20% hypromellose62.5 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate93.8 mgmicrocrystalline cellulose (e.g., PH101)86.3 mgcroscarmellose sodium11.5 mgmagnesium stearate1.9 mgExtra-granular partmicrocrystalline cellulose (e.g., PH102)43.6 mgcroscarmellose sodium6.5 mgmagnesium stearate.1.9 mgUncoated tablet435.8 mgCoating13.5mg

[0271] In some embodiments, the pharmaceutical compositions disclosed herein comprise a formulation selected from one of the following: Table 20 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)45-80 mgsolid dispersion containing 80% Compound II, 20% hypromellose20-50 mgsolid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate30-70 mgmicrocrystalline cellulose60-150 mgcroscarmellose sodium5-25 mgmagnesium stearate1-7 mg Table 21 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 45 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III or Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10-40 wt% Table 22 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 45 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III or Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 40 wt%microcrystalline cellulose5 - 50 wt%croscarmellose sodium (CCS)1 - 10 wt%Optionally magnesium stearate in an amount of 0.05 wt% - 2 wt% Table 23 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 45 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III or Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 40 wt%microcrystalline cellulose5 - 50 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% Table 24 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 35 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 40 wt%microcrystalline cellulose20 - 40 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% Table 25 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)20 - 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 25 wt%microcrystalline cellulose20 - 40 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% Table 26 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)30 - 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 15 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 20 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05 - 2 wt% Table 27 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)33 - 38 wt%solid dispersion containing 80% Compound II, 20% hypromellose8 - 13 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate13 - 18 wt%microcrystalline cellulose30 - 35 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05- 2 wt% Table 28 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)25 - 35 wt%solid dispersion containing 80% Compound II, 20% hypromellose10 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 25 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05 - 2 wt% Table 29 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)27 - 32 wt%solid dispersion containing 80% Compound II, 20% hypromellose12 - 17 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate18 - 23 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)3 - 6 wt%magnesium stearate0.05- 1.5 wt% Table 30 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)207 - 217solid dispersion containing 80% Compound II, 20% hypromellose58 - 68solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate182-193microcrystalline cellulose (e.g., PH101)125 - 145croscarmellose sodium10 - 20magnesium stearate3 - 9Extra-granular partmicrocrystalline cellulose (e.g., PH102)50-70croscarmellose sodium5 - 15 Table 31 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)212 - 213solid dispersion containing 80% Compound II, 20% hypromellose62 - 63solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate187-188microcrystalline cellulose (e.g., PH101)136 - 138croscarmellose sodium15 - 16magnesium stearate5 - 6Extra-granular partmicrocrystalline cellulose (e.g., PH102)59 - 60croscarmellose sodium8-9 Table 32 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)28 - 33 wt%solid dispersion containing 80% Compound II, 20% hypromellose7 - 12 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate25 - 30 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% Table 33 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)122 - 132solid dispersion containing 80% Compound II, 20% hypromellose58 - 68solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate182 - 193microcrystalline cellulose110 - 145croscarmellose sodium13 - 25magnesium stearate1.5 - 8 Table 34 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127 - 128solid dispersion containing 80% Compound II, 20% hypromellose62 - 63solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate187 - 188microcrystalline cellulose (e.g., PH101)86 - 87croscarmellose sodium11 - 12magnesium stearate1 - 2.5Extra-granular partmicrocrystalline cellulose (e.g., PH102)43 - 44croscarmellose sodium6-7magnesium stearate1 - 2.5 Table 35 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127 - 128solid dispersion containing 80% Compound II, 20% hypromellose62 - 63solid dispersion containing 80% Compound III, 19.5% hypromellose187-188acetate succinate, and 0.5% sodium lauryl sulfatemicrocrystalline cellulose (e.g., PH101)86 - 88croscarmellose sodium13 - 16magnesium stearate1 - 1.5Extra-granular partmicrocrystalline cellulose (e.g., PH102)48 - 50croscarmellose sodium7-9magnesium stearate4 - 5.5 Table 36 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)62 - 65solid dispersion containing 80% Compound II, 20% hypromellose30 - 33solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate90 - 95microcrystalline cellulose (e.g., PH101)42 - 45croscarmellose sodium7-8magnesium stearate0.5 -1Extra-granular partmicrocrystalline cellulose (e.g., PH102)23 - 26croscarmellose sodium3-5magnesium stearate2 - 3.5 Table 37 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)58 - 68solid dispersion containing 80% Compound II, 20% hypromellose25 - 35solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate87 - 97microcrystalline cellulose60 - 100croscarmellose sodium5 - 15magnesium stearate1.5 - 7 Table 38 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)50 - 80solid dispersion containing 80% Compound II, 20% hypromellose20 - 40solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate70 - 120microcrystalline cellulose60 - 300croscarmellose sodium5 - 25magnesium stearate1-7 Table 39 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)20- 30 wt%solid dispersion containing 80% Compound II, 20% hypromellose7 - 15 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate30 - 40 wt%microcrystalline cellulose15 - 40 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05 - 1.5 wt% Table 40 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)22 - 27 wt%solid dispersion containing 80% Compound II, 20% hypromellose8 - 13 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate32 - 37 wt%microcrystalline cellulose20 - 30 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% Table 41 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)207-217solid dispersion containing 80% Compound II, 20% hypromellose58 - 68solid dispersion containing 80% Compound III -d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate120 - 130microcrystalline cellulose (e.g., PH101)125 - 150croscarmellose sodium10 - 20magnesium stearate3 - 8Extra-granular partmicrocrystalline cellulose (e.g., PH102)50 - 70croscarmellose sodium5 -12 Table 42 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)212-213solid dispersion containing 80% Compound II, 20% hypromellose62 - 63solid dispersion containing 80% Compound III-d, 19.5% hypromellose124 - 126acetate succinate, and 0.5% sodium lauryl sulfatemicrocrystalline cellulose (e.g., PH101)137 - 138croscarmellose sodium15 - 16magnesium stearate5 - 6Extra-granular partmicrocrystalline cellulose (e.g., PH102)59 - 60croscarmellose sodium8 -9 Table 43 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)25- 40 wt%solid dispersion containing 80% Compound II , 20% hypromellose7 - 15 wt%solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 35 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% Table 44 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)29 - 36 wt%solid dispersion containing 80% Compound II , 20% hypromellose8 - 13 wt%solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 25 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% Table 45 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)122 - 132solid dispersion containing 80% Compound II , 20% hypromellose58 - 68solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate124 - 126microcrystalline cellulose129 - 131croscarmellose sodium17 - 19magnesium stearate3 - 5 Table 46 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)122 - 132solid dispersion containing 80% Compound II , 20% hypromellose58 - 68solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate124 - 126microcrystalline cellulose (e.g., PH101)86 - 87croscarmellose sodium11 - 12magnesium stearate3 - 4Extra-granular partmicrocrystalline cellulose (e.g., PH102)43 - 44croscarmellose sodium6 - 7 Table 47 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)122 - 132solid dispersion containing 80% Compound II , 20% hypromellose58 - 68solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate124 - 126microcrystalline cellulose (e.g., PH101)86 - 87croscarmellose sodium11 - 12magnesium stearate1.5 - 2.5Extra-granular partmicrocrystalline cellulose (e.g., PH102)43 - 44croscarmellose sodium6 - 7magnesium stearate1.5 - 2.5 Table 48 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)122-132solid dispersion containing 80% Compound II, 20% hypromellose58 -68solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate120-130Microcrystalline cellulose75-95Croscarmellose sodium5-20Magnesium Stearate1-6Extra-granular partMicrocrystalline cellulose35-50Croscarmellose sodium3-10 Table 49 Component Amount (mg) per composition Intra-granular partpotassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127-128solid dispersion containing 80% Compound II , 20% hypromellose62 -63solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate124-126Microcrystalline cellulose84-85Croscarmellose sodium11-12Magnesium Stearate3-4Extra-granular partMicrocrystalline cellulose43-44Croscarmellose sodium6-7 Table 50 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)250-260solid dispersion containing 80% Compound II , 20% hypromellose120-130solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate245-255Microcrystalline cellulose80-110Croscarmellose sodium15-30optionally magnesium stearate0.01-10 Table 51 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)255-256solid dispersion containing 80% Compound II , 20% hypromellose124-126solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate249-251microcrystalline cellulose89 -98mroscarmellose sodium22-23optionally magnesium stearate in an amount of 0.01 - 10 mg per composition Table 52 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)122-132solid dispersion containing 80% Compound II , 20% hypromellose57-67solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate120-130microcrystalline cellulose275 -305croscarmellose sodium10 -25optionally magnesium stearate in an amount of 0.05 - 10 mg per composition Table 53 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127-128solid dispersion containing 80% Compound II , 20% hypromellose62-63solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate124-126Microcrystalline cellulose289 -297Croscarmellose sodium18 -19optionally magnesium stearate in an amount of 0.01 - 10 mg per composition Table 54 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)122 - 132solid dispersion containing 80% Compound II , 20% hypromellose58 - 68solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate120 - 130microcrystalline cellulose110 - 130croscarmellose sodium10 - 20optionally magnesium stearate in an amount of 0.01 - 10 mg per composition Table 55 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)127 - 128solid dispersion containing 80% Compound II , 20% hypromellose62 - 63solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate124 - 126Microcrystalline cellulose117 - 122Croscarmellose sodium13 - 14optionally magnesium stearate in an amount of 0.01 - 10 mg per composition Table 56 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15- 40 wt%solid dispersion containing 80% Compound II , 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 40 wt%microcrystalline cellulose10 - 50 wt%croscarmellose sodium (CCS)2 - 7 wt%optionally magnesium stearate in an amount of 0.01 wt% - 2 wt% based on the total weight of composition Table 57 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)20 - 30 wt%solid dispersion containing 80% Compound II , 20% hypromellose8-18 wt%solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 30 wt%microcrystalline cellulose20 - 30 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition Table 58 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)28 - 38 wt%solid dispersion containing 80% Compound II , 20% hypromellose10 -20 wt%solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate27 - 37 wt%microcrystalline cellulose5 - 20 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition Table 59 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 25 wt%solid dispersion containing 80% Compound II , 20% hypromellose5-15 wt%solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 25 wt%microcrystalline cellulose40 - 50 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition Table 60 Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)22 - 32 wt%solid dispersion containing 80% Compound II , 20% hypromellose10-20 wt%solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 30 wt%microcrystalline cellulose20 - 30 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition Table 61 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)50 - 80solid dispersion containing 80% Compound II , 20% hypromellose20 - 40solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate45 - 80microcrystalline cellulose60 - 300croscarmellose sodium5 - 25optionally magnesium stearate in an amount of 0.01 - 10 mg per composition Table 62 Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)95-160solid dispersion containing 80% Compound II , 20% hypromellose45-80solid dispersion containing 80% Compound III-d , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate95-155Microcrystalline cellulose60 -300Croscarmellose sodium5-25optionally magnesium stearate in an amount of 0.01 - 10 mg per composition Processes of Making Tablets

[0272] The tablets of the disclosure can be produced by compacting or compressing an admixture or composition, for example, powder or granules, under pressure to form a stable three-dimensional shape (e.g., a tablet). As used herein, "tablet" includes compressed pharmaceutical dosage unit forms of all shapes and sizes, whether coated or uncoated. In some embodiments, the methods of preparing the tablets disclosed herein comprise (a) mixing a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) and the first and second solid dispersions to form a first mixture; and (b) compressing a tablet mixture comprising the first mixture into a tablet. As used herein, the term "mixing" include mixing, blending and combinding. In some embodiments, the tablet mixture further comprises one or more pharmaceutically acceptable excipients, and the methods further comprise mixing the first mixture with said one or more excipients to form the tablet mixture. Mixing the first mixture with one or more excipients can be performed in one or more steps. In one embodiment, the one or more excipients are mixed to form a second mixture; and the first and second mixtures are mixed together to form the tablet mixture prior to the compression step. In one embodiment, the one or more excipients can be mixed with the first mixture in more than one parts, for example, some excipients mixed with the first mixture first and the other excipients followed later. In some embodiments, the tablets disclosed herein an intra-granular part and an extra-grandular part as described above, and one or more excipients included in the intra-granular part are mixed to form a second mixture, and one or more excipients included in the extra-granular part are mixed to form a third mixture, and the first mixture are combined with the second mixture, and the combined first and second mixtures are combined with the third mixture to form a tablet mixture.

[0273] In some embodiments, the methods of preparing the tablets disclosed herein comprise:(a) mixing a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) and the first and second solid dispersions to form a first mixture; (b) mixing the first mixture with a microcrystalline cellulose, croscarmellose sodium and magnesium stearate to form a tablet mixture; and (c) compressing the tablet mixture into a tablet.

[0274] In some embodiments, the methods of preparing the tablets disclosed herein comprise: (a) mixing a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) and the first and second solid dispersions described above to form a first mixture; (b) mixing a microcrystalline cellulose, croscarmellose sodium and magnesium stearate in an intra-granular part to form a second mixture; (c) mixing a microcrystalline cellulose and croscarmellose sodium in an extra-granular part to form a third mixture; (d) mixing the first, second, and third mixtures to form a tablet mixture; and (e) compressing the tablet mixture comprising the first, second and third mixtures into a tablet. It is noted that step (a) can occur prior to step (b) or step (b) can occur prior to step (a).

[0275] In some embodiments, the methods of preparing the tablets disclosed herein comprise: (a) mixing a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) and the first and second solid dispersions to form a first mixture; (b) mixing a microcrystalline cellulose, croscarmellose sodium and magnesium stearate in an intra-granular part to form a second mixture; (c) mixing a microcrystalline cellulose, croscarmellose sodium, and magnesium stearate comprised in an extra-granular part to form a third mixture; (d) mixing the first, second, and third mixtures to form a tablet mixture; (e) compressing the tablet mixture comprising the first, second and third mixtures into a tablet.

[0276] In some embodiments, the methods disclosed herein further comprise coating the tablet.

[0277] In some embodiments, the methods disclosed herein further comprise granulating the first, second, and / or third mixtures prior to the compression the tablet mixture. Any suitable methods known in the art for granulation and compression of pharmaceutical compositions can be used. It is noted that step (a) can occur prior to step (b) or step (b) can occur prior to step (a).Granulation and Compression

[0278] In some embodiments, solid forms, including powders comprising one or more APIs (e.g., Compound I, Compound II, and / or Compound III or III-d) and the included pharmaceutically acceptable excipients (e.g. filler, diluent, disintegrant, surfactant, glidant, binder, lubricant, or any combination thereof) can be subjected to a dry granulation process. The dry granulation process causes the powder to agglomerate into larger particles having a size suitable for further processing. Dry granulation can improve the flowability of a mixture to produce tablets that comply with the demand of mass variation or content uniformity.

[0279] In some embodiments, formulations can be produced using one or more mixing and dry granulations steps. The order and the number of the mixing by granulation. At least one of the excipients and the API(s) can be subject to dry granulation or wet high shear granulation or twin screw wet granulation before compression into tablets. Dry granulation can be carried out by a mechanical process, which transfers energy to the mixture without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof) in contrast to wet granulation processes, also contemplated herein. Generally, the mechanical process requires compaction such as the one provided by roller compaction. An example of an alternative method for dry granulation is slugging. In some embodiments, wet granulations instead of the dry granulation can be used.

[0280] In some embodiments, roller compaction is a granulation process comprising mechanical compacting of one or more substances. In some embodiments, a pharmaceutical composition comprising an admixture of powders is pressed, that is roller compacted, between two rotating rollers to make a solid sheet that is subsequently crushed in a sieve to form a particulate matter. In this particulate matter, a close mechanical contact between the ingredients can be obtained. An example of roller compaction equipment is Minipactor ®< a Gerteis 3W-Polygran from Gerteis Maschinen+ Processengineering AG.

[0281] In some embodiments, tablet compression according to the disclosure can occur without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof), i.e., a dry granulation process. In a typical embodiment the resulting core or tablet has a compressive strength in the range of from 1kp to 15 kP; such as 1.5 to 12.5 kP, preferably in the range of 2 to 10 kP.

[0282] In some embodiments, the ingredients are weighed according to the formula set herein. Next, all of the intragranular ingredients are sifted and mixed well. The ingredients can be lubricated with a suitable lubricant, for example, magnesium stearate. The next step can comprise compaction / slugging of the powder admixture and sized ingredients. Next, the compacted or slugged blends are milled into granules and sifted to obtain the desired size. Next, the granules can be further lubricated with, for example, magnesium stearate. Next, the granular composition of the disclosure can be compressed on suitable punches into various pharmaceutical formulations in accordance with the disclosure. Optionally the tablets can be coated with a film coat.

[0283] Another aspect of the disclosure provides a method for producing a pharmaceutical composition comprising an admixture of a composition comprising one or more APIs (e.g., Compound I, Compound II and / or Compound III); and one or more excipients selected from: one or more fillers, a diluent, a binder, a glidant, a surfactant, a lubricant, a disintegrant, and compressing the composition into a tablet.Coating

[0284] In some embodiments, the tablets disclosed herein can be coated with a film coating and optionally labeled with a logo, other image and / or text using a suitable ink. In still other embodiments, the tablets disclosed herein can be coated with a film coating, waxed, and optionally labeled with a logo, other image and / or text using a suitable ink. Suitable film coatings and inks are compatible with the other ingredients of the tablets, e.g., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the tablets. The suitable colorants and inks can be any color and are water based or solvent based. In one embodiment, the tablets disclosed herein are coated with a colorant and then labeled with a logo, other image, and / or text using a suitable ink.

[0285] In some embodiments, the tablets disclosed herein are coated with a film that comprises 2-6 wt% by the weight of the uncoated tablet. In some embodiments, the film comprises one or more colorants and / or pigments. In some embdodiments, the tablets disclosed herein are coated with a film that comprises one or more colorants and / or pigments and wherein the film comprises 2 - 5 wt% by the weight of the uncoated tablet. In some embodiments, the tablets disclosed herein are coated with a film that comprises one or more colorants and / or pigments and wherein the film comprises 2 - 4 wt% by the weight of the uncoated tablet. The colored tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink.Methods of Treatment

[0286] One aspect of the invention provides crystalline forms and compositions for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of at least one crystalline form of Compound I or pharmaceutically acceptable salt thereof as defined in the claims, alone or in combination with one or more additional CFTR modulating agents to the patient. In some embodiments, the method comprises administering at least one crystalline form of Compound I or pharmaceutically acceptable salt thereof disclosed herein, in combination with Compound II, and / or Compound III or Compound III-d. In some embodiments, the combination may include 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid ("Compound IV"):

[0287] In some embodiments, the method comprises administering a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), alone or in combination with one or more additional CFTR modulating agents, to the patient in need thereof. In some embodiments, the method comprises administering a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) in combination Compound II, and optionally, one or more additional CFTR modulating agents. In some embodiments, the method comprises administering a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) in combination Compound III, and optionally, one or more additional CFTR modulating agents. In some embodiments, the method comprises administering a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), in combination with Compound II, and Compound III or III-d. In some embodiments, the combination may include Compound IV.

[0288] In one embodiment, the method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering an effective amount of at least one crystalline form, including crystalline salt forms, of Compound I as disclosed herein, in combination with one or more additional CFTR modulating agents, wherein the at least one crystalline form of Compound I as disclosed herein and the additional modulating agent(s) are administered together in a single composition. In some embodiment, the at least one crystalline form of Compound I as disclosed herein and the additional modulating agent(s) are administered as two or more separate compositions.

[0289] In some embodiments, the method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering an effective amount of at least one crystalline form, including crystalline salt forms, of Compound I as disclosed herein, in combination with Compound II and / or Compound III or III-d, wherein the at least one crystalline form of Compound I as disclosed herein and Compound II and / or Compound III or III-d are administered together in a single composition. In some embodiment, the at least one crystalline form of Compound I as disclosed herein and Compound II and / or Compound III or III-d are administered as two or more separate compositions.

[0290] In some embodiments, the method comprises administering an effective amount of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) in combination with one or more additional CFTR modulating agents, wherein the potassium salt of Compound I and the additional modulating agent(s) are administered together in a single composition. In some embodiments, the potassium salt of Compound I and the additional modulating agent(s) are administered as two or more separate compositions.

[0291] In some embodiments, the method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering an effective amount of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) in combination with Compound II and / or Compound III or III-d, wherein the potassium salt of Compound I and Compound II and / or Compound III or III-d are administered together in a single composition. In some embodiments, the potassium salt of Compound I and Compound II and / or Compound III or III-d are administered in two or more separate compositions.

[0292] In some embodiments, the patient has a F508del heterozygous or homozygous genotype. In some embodiments, the patient is homozygous or heterozygous for the CFTR genetic mutation G551D. In some embodiments, the patient is heterozygous for the G551D genetic mutation on one allele and the other CF-causing genetic mutation on the other allele is any one of F508del, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ΔI507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In some embodiments, the patient is heterozygous for the G551D genetic mutation, and the other CFTR genetic mutation is F508del. In some embodiments, the patient is heterozygous for the G551D genetic mutation, and the other CFTR genetic mutation is R117H.

[0293] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation F508del. In some embodiments, the patient is homozygous for the F508del genetic mutation. In some embodiments, the patient is heterozygous for the F508del genetic mutation wherein the patient has the F508del genetic mutation on one allele and any CF-causing genetic mutation on the other allele. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation, including, but not limited to G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ΔI507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is GSS1D. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is R117H.

[0294] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G, 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K, F1016S, F1099L, F191V, F311del, F311L, F508C, F575Y, G1061R, G1249R, G126D, G149R, G194R, G194V, G27R, G314E, G458V, G463V, G480C, G622D, G628R, G628R(G->A), G91R, G970D, H1054D, H1085P, H1085R, H1375P, H139R, H199R, H609R, H939R, 11005R, 11234V, 11269N, 11366N, 1175V, I502T, I506S, I506T, I601F, I618T, I807M, 1980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, M1T, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L, T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V456F, V5621, W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.In some embodiments, the patient has at least one combination mutation chosen from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G.

[0295] In some embodiments, the patient has at least one combination mutation chosen from: 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K, F1016S, F1099L, F191V, F311del, F311L, F508C, F575Y, G1061R, G1249R, G126D, G149R, G194R, G194V, G27R, G314E, G458V, G463V, G480C, G622D, G628R, G628R(G->A), G91R, G970D, H1054D, H1085P, H1085R, H1375P, H139R, H199R, H609R, H939R, I1005R, I1234V, 11269N, I1366N, I175V, I502T, I506S, I506T, I601F, 1618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, M1T, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L, T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V456F, V5621, W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.

[0296] In some embodiments, the patient has at least one combination mutation chosen from: D443Y; G576A; R668C, F508C;S 1251N, G576A; R668C, G970R; M470V, R74W; D1270N, R74W; V201M, and R74W; V201M; D1270N.

[0297] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In some embodiments, this disclosure provides a method of treating CFTR comprising administering a compound of Formula (I), (II), (III), (IV), (V), or a pharmaceutically acceptable salt thereof to a patient possessing a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from E193K, F1052V and G1069R. In some embodiments, the method produces an increase in chloride transport relative to baseline chloride transport of the patient of the patient.

[0298] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H. In some embodiments, the method produces an increase in chloride transport above the baseline chloride transport of the patient.

[0299] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G.

[0300] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTR mutation selected from F508del, R117H, and G551D.

[0301] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from E193K, F1052V and G1069R, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, the method produces an increase in chloride transport relative to baseline chloride transport of the patient.

[0302] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, the method produces an increase in chloride transport which is above the baseline chloride transport of the patient.

[0303] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G, and a human CFTR mutation selected from F508del, R117H.

[0304] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTR mutation selected from F508del, R117H, and G551D.

[0305] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from E193K, F1052V and G1069R. In some embodiments, the method produces an increase in chloride transport relative to baseline chloride transport of the patient.

[0306] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H. In some embodiments, the method produces an increase in chloride transport which is above the baseline chloride transport of the patient.

[0307] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G.

[0308] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTR mutation selected from F508del, R117H, and G551D, and one or more human CFTR mutations selected from F508del, R117H, and G551D.

[0309] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and one or more human CFTR mutations selected from F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and one or more human CFTR mutations selected from F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from E193K, F1052V and G1069R, and one or more human CFTR mutations selected from F508del, R117H, and G551D. In some embodiments, the method produces an increase in chloride transport relative to baseline chloride transport of the patient.

[0310] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H, and one or more human CFTR mutations selected from F508del, R117H, and G551D. In some embodiments, the method produces an increase in chloride transport which is above the baseline chloride transport of the patient.

[0311] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and one or more human CFTR mutations selected from F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T, and one or more human CFTR mutations selected from F508del, R117H, and G551D. In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G, and one or more human CFTR mutations selected from F508del, R117H, and G551D.

[0312] In some embodiments, the patient is heterozygous having one CF-causing mutation on one allele and another CF-causing mutation on the other allele. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation, including, but not limited to F508del on one CFTR allele and a CFTR mutation on the second CFTR allele that is associated with minimal CFTR function, residual CFTR function, or a defect in CFTR channel gating activity.

[0313] In some embodiments, the CF-causing mutation is selected from Table 63. In some embodiments, the patient is heterozygous having one CF-causing mutation on one CFTR allele selected from the mutations listed in the table from FIG. 17 and another CF-causing mutation on the other CFTR allele is selected from the CFTR mutations listed in Table 63. Table 63. CFTR Mutations Criteria: Truncation mutations• %PI >50% and / or SwCl -< >86 mmol / L• no full-length proteinS4XC276XG542XR792XE1104XG27XQ290XG550XE822XR1158XQ39XG330XQ552XW846XR1162XW57XW401XR553XY849XS1196XE60XQ414XE585XR851XW1204XR75XS434XG673XQ890XL1254XE92XS466XQ685XS912XS1255XQ98XS489XR709XY913XW1282XY122XQ493XK710XW1089XQ1313XE193XW496XL732XY1092XE1371XL218XC524XR764XW1098XQ1382XQ220XQ525XR785XR1102XQ1411XCriteria : Splice Mutations• %PI >50% and / or SwCl -< >86 mmol / L• no or little mature mRNA185+1G→T711+5G→A1717-8G→A2622+1G→A3121-1G→A296+1G→A712-1G→T1717-1G→A2790-1G→C3500-2A→G405+1G→A1248+1G→A1811+1G→C3040G→C (G970R)3600+2insT405+3A→C1249-1G→A1811+1.6kbA→ G3850-1G→A406-1G→A1341+1G→A1812-1G→A3120G→A4005+1G→A621+1G→T1525-2A→G1898+1G→A3120+1G→A4374+1G→T711+1G→T1525-1G→A1898+1G→C3121-2A→GCriteria : Small (≤3 nucleotide) insertion / deletion (ins / del) frameshift mutations• %PI >50% and / or SwCl -< >86 mmol / L• garbled and / or truncated protein182delT1119delA1782delA2732insA3876delA306insA1138insG1824delA2869insG3878delG365-366insT1154insTC2043delG2896insAG3905insT394delTT1161delC2143delT2942insT4016insT442delA1213delT2183AA→G a< 2957delT4021dupT444delA1259insA2184delA3007delG4040delA457TAT→G1288insTA2184insA3028delA4279insA541delC1471delA2307insA3171delC4326delTC574delA1497delGG2347delG3659delC663delT1548delG2585delT3737delA935delA1609del CA2594delGT3791delC1078delT1677delTA2711delT3821delTNote: a< = Also known as 2183delAA→G.Criteria: Non-small (>3 nucleotide) insertion / deletion (ins / del) frameshift mutations• %PI >50% and / or SwCl -< >86 mmol / L• garbled and / or truncated proteinCFTRdele2,31461ins42991del32CFTRdele22,231924del73667ins4124del23bp2055del9→A4010del4852del222105-2117dell3insAGAAA4209TGTT-AA991del52721del11Criteria: Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II or Compound IV • %PI>50% and / or SwCl >86 mmol / L and• Not responsive in vitro to Compound III alone or in combination with Compound II or Compound IVA46D b< V520FY569D b< N1303KG85EA559T b< L1065PR347PR560TR1066CL467P b< R560SL1077P b< 1507delA561EM1101KNote: %PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic insufficient; SwCl -< : mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry b< = Unpublished data. Additional CFTR Mutations4382delAS341PG178R2789+5G→A3600+2insTR1066MS549N3849+10kbC→TT338IH1085RS549R3272-26A→GL927PF1052VG551D711+3A→GA455ER1070WG551SE56KD579GF1074LG1244EP67LE831XD1152HS1251NR74WS945LD1270NS1255PD110ES977FR117HG1349DD110HR117CL206WR347HR352QG178RG551DG1244ES1255PS549NG551SS1251NG1349DS549R

[0314] Table 63 above includes certain exemplary CFTR minimal function mutations, which are detectable by an FDA-cleared genotyping assay, but does not include an exhaustive list.

[0315] In some embodiments, the patient has F508del / MF (F / MF) genotypes; with F508del / F508del (F / F) genotype (homozygous for F508del); and / or with F508del / gating (F / G) genotypes (heterozygous for F508del and a gating mutation known to be CFTR modulator-responsive (e.g., Compound III -responsive). In some embodiments, a patient with F508del / MF (F / MF) genotypes has any one of the MF mutations in Table 63.

[0316] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation, including truncation mutations, splice mutations, small (≤3 nucleotide) insertion or deletion (ins / del) frameshift mutations; non-small (>3 nucleotide) insertion or deletion (ins / del) frameshift mutations; and Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II or Compound IV.

[0317] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a truncation mutation. In some specific embodiments, the truncation mutation is a truncation mutation listed in Table 63.

[0318] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a splice mutation. In some specific embodiments, the splice mutation is a splice mutation listed in Table 63.

[0319] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a small (≤3 nucleotide) insertion or deletion (ins / del) frameshift mutation. In some specific embodiments, the small (≤3 nucleotide) insertion or deletion (ins / del) frameshift mutation is a small (≤3 nucleotide) insertion or deletion (ins / del) frameshift mutation listed in Table 63.

[0320] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation expected to be and / or is responsive to, based on in vitro and / or clinical data, the combination of a crystalline form of Compound I, or pharmaceutically acceptable salt thereof disclosed herein, Compound II (or a pharmaceutically acceptable salts thereof), and / or Compound III or Compound III-d (or a pharmaceutically acceptable salt thereof).

[0321] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation expected to be and / or is responsive, based on in vitro and / or clinical data, to the triple combination of a crystalline form of Compound I, or pharmaceutically acceptable salt thereof disclosed herein, Compound II (or pharmaceutically acceptable salt thereof) and / or Compound III or Compound III-d (or a pharmaceutically acceptable salts thereof).

[0322] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a non-small (>3 nucleotide) insertion or deletion (ins / del) frameshift mutation. In some specific embodiments, the non-small (>3 nucleotide) insertion or deletion (ins / del) frameshift mutation is a non-small (>3 nucleotide) insertion or deletion (ins / del) frameshift mutation listed in Table 63.

[0323] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II. In some specific embodiments, the Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II is a Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II or Compound IV listed in Table 63.

[0324] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any mutation listed in Table 63.

[0325] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any mutation listed in FIG. 17.

[0326] In some embodiments, the patient is homozygous for F508del.

[0327] In some embodiments, the patient is heterozygous having one CF-causing mutation on one CFTR allele selected from the mutations listed in the table from FIG. 17 and another CF-causing mutation on the other CFTR allele is selected from the CFTR mutations listed in Table 63.

[0328] Patients with an F508del / gating mutation genotype are defined as patients that are heterozygous F508del-CFTR with a second CFTR allele that contains a mutation associated with a gating defect and clinically demonstrated to be responsive to Compound III. Examples of such mutations include: G178R, S549N, S549R, G551D, G551S, G1244E, S1251N, S1255P, and G1349D.

[0329] Patients with an F508del / residual function genotype are defined as patients that are heterozygous F508del-CFTR with a second CFTR allele that contains a mutation that results in reduced protein quantity or function at the cell surface which can produce partial CFTR activity. CFTR gene mutations known to result in a residual function phenotype include in some embodiments, a CFTR residual function mutation selected from 2789+5G→ A, 3849+10kbC→T, 3272-26A→ G, 711+3A→ G, E56K, P67L, R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K, and K1060T. In some embodiments, the CFTR residual function mutation is selected from R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, A1067T, E193K, or K1060T. In some embodiments, the CFTR residual function mutation is selected from R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, or A1067T.

[0330] In some embodiments, disclosed herein is a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this disclosure to the patient, such as a mammal, wherein the patient possesses a CFTR genetic mutation selected from the mutations listed in FIG. 17.

[0331] In some embodiments, the composition disclosed herein is useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cl -< concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected for patients that are heterozygous or homozygous for a variety of different mutations, including patients heterozygous for the most common mutation, F508del, as well as other mutations such as the G551D mutation, or the R117H mutation. In some embodiments, compositions disclosed herein are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little to no residual CFTR activity. In some embodiments, compositions disclosed herein are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little to no residual CFTR activity in the apical membrane of respiratory epithelia.

[0332] In some embodiments, the compositions disclosed herein are useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity using pharmacological methods. Such methods increase the amount of CFTR present at the cell surface, thereby inducing a hitherto absent CFTR activity in a patient or augmenting the existing level of residual CFTR activity in a patient.

[0333] In some embodiments, the compositions disclosed herein are useful for treating or lessening the severity of cystic fibrosis in patients with certain genotypes exhibiting residual CFTR activity.

[0334] In some embodiments, compositions disclosed herein are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients within certain clinical phenotypes, e.g., a mild to moderate clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia. Such phenotypes include patients exhibiting pancreatic sufficiency.

[0335] In some embodiments, the compositions disclosed herein are useful for treating, lessening the severity of, or symptomatically treating patients diagnosed with pancreatic sufficiency, idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease wherein the patient exhibits residual CFTR activity.

[0336] In some embodiments, this disclosure relates to a method of augmenting or inducing anion channel activity in vitro or in vivo, comprising contacting the channel with a composition disclosed herein. In some embodiments, the anion channel is a chloride channel or a bicarbonate channel. In some embodiments, the anion channel is a chloride channel.

[0337] The exact amount of a pharmaceutical composition required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like. The compounds of this disclosure may be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of this disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, such as a mammal, and even further such as a human.

[0338] In some embodiments, the disclosure also is directed to methods of treatment using isotope-labelled compounds of the afore-mentioned compounds, which have the same structures as disclosed herein except that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled). Examples of isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2< H, 3< H, 13< C, 14< C, 15< N, 18< O, 17< O, 31< P, 32< P, 35< S, 18< F and 38< Cl, respectively. In some embodiments, the isotope-labelled compounds and salts are deuterium ( 2< H)-labelled ones. In some specific embodiments, the isotope-labelled compounds and salts are deuterium ( 2< H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium. In chemical structures, deuterium is represented as " 2< H" or "D."

[0339] In some embodiments, the pharmaceutical compositions are a tablet. In some embodiments, the tablets are suitable for oral administration. In some embodiments, the tablets can be administered concurrently with, prior to, or subsequent to, at least one active pharmaceutical ingredients or medical procedures.

[0340] The compositions disclosed herein comprising a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), alone or in combination with Compound II and / or Compound III or Compound III-d can be administered once a day, twice a day, or three times a day. In some embodiments, one or more of the tablets are administered per dosing. In some embodiments, two tablets per dosing are administered. In some embodiments, two tablets per dosing are administered twice a day. An effective amount of the APIs (e.g., Compound I) is administered to the patient with or using one or more tablets disclosed herein.

[0341] In some embodiments, methods of treating, lessening the severity of, or symptomatically treating patients diagnosed with cystic fibrosis or a CFTR mediated disease comprise admininstering a crystalline form of Compound I as disclosed herein, in a daily dosage amount of 100 mg to 260 mg. In some embodiments, a 100 mg to 260 mg daily dose of a crystalline form of Compound I, or pharmaceutically acceptable salt thereof disclosed herein, is administered with 50 mg to 150 mg / day of Compound II and / or 50 mg to 300 mg / day of Compound III or III-d.

[0342] In some embodiments, methods of treating, lessening the severity of, or symptomatically treating patients diagnosed with cystic fibrosis or a CFTR mediated disease comprise admininstering 100 mg to 260 mg of Compound I potassium salt (in some embodiments, potassium salt crystalline Form B) daily. In some embodiments, the 100 mg to 260 mg daily dose of Compound I potassium salt is administered with 50 mg to 150 mg / day of Compound II and / or 50 mg to 300 mg / day of Compound III or III-d either in a single composition or in separate compositions.

[0343] In some embodiments, methods of treating, lessening the severity of, or symptomatically treating patients diagnosed with cystic fibrosis or a CFTR mediated disease comprise admininstering about 128 mg or about 255-256 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) daily. In some embodiments, the about 128 mg or about 255-256 mg daily dose of Compound I potassium salt is administered with 50 mg or 100 mg / day of Compound II and / or 75 mg, 150 mg, 200 mg, or 300 mg / day of Compound III or III-d either in a single composition or in separate compositions.

[0344] In some embodiments, about 255-256 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) is administered daily with 100 mg of Compound II and either 300 mg of Compound III or 200 mg of Compound III-d. In some embodiments, the methods of treating, lessening the severity of, or symptomatically treating patients diagnosed with cystic fibrosis or a CFTR mediated disease comprise admininstering about 128 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 50 mg of Compound II, and 75 mg of Compound III and optionally administering an additional 150 mg of Compound III daily. For example, two compositions each comprising about 128 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 50 mg of Compound II, and 75 mg of Compound III may be administered in the morning and one composition comprising 150 mg of Compound III may be administered in the evening. In some embodiments, the methods comprise administering about 128 mg of a crystalline potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B). In some embodiments, the methods comprise administering two compositions, each with about 128 mg of a crystalline potassium salt of Compound I in Form B.

[0345] In some embodiments, about 128 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B) is administered with 50 mg of Compound II and 150 mg of Compound III daily. In some embodiments, the methods of treating, lessening the severity of, or symptomatically treating patients diagnosed with cystic fibrosis or a CFTR mediated disease comprise administering daily two pharmaceutical compositions, each comprising about 64 mg of crystalline Form B of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 25 mg of Compound II, and 35 mg to 40 mg of Compound III and optionally administering an additional 75 mg of Compound III daily. For example, two compositions each comprising about 64 mg of crystalline Form B of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 25 mg of Compound II, and 35 mg to 40 mg of Compound III may be administered in the morning and 75 mg of Compound III may be administered in the evening.

[0346] Some embodiments of the invention provide a method of treating, lessening the severity of, or symptomatically treating patients diagnosed with cystic fibrosis or a CFTR mediated disease comprising administering a fixed dose composition comprising about 128 mg of a crystalline form of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 50 mg of Compound II, and 150 mg of Compound III twice a day, e.g., morning and evening or every 12 hours. In an alternate embodiment, the methods comprise administering a fixed dose composition comprising about 128 mg of a crystalline form of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 50 mg of Compound II, and 100 mg of Compound III-d twice a day. In an alternate embodiment, the methods comprise administering two fixed dose compositions, each comprising about 128 mg of a crystalline form of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 50 mg of Compound II, and 100 mg of Compound III-d, once a day. In an alternate embodiment, the methods comprise administering a fixed dose composition comprising about 255-256 mg of a crystalline form of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B), 100 mg of Compound II, and 200 mg of Compound III-d once a day.Exemplary Embodiments

[0347] Exemplary embodiments of the invention include: 1. A pharmaceutical composition comprising (a) 50 mg to 600 mg of a crystalline form selected from a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B), a sodium salt of Compound I as defined in the claims (Form A, D, or E) and crystalline Form A of Compound I: (b) a first solid dispersion comprising 25 mg to 125 mg of Compound II: and 10 wt% to 30 wt% of a polymer relative to the total weight of the first solid dispersion; and (c) a second solid dispersion comprising 5 mg to 300 mg of Compound III or Compound III-d : and 10 wt% to 30 wt% of a polymer relative to the total weight of the second solid dispersion. 2. The pharmaceutical composition of embodiment 1, wherein at least one of the first or second solid dispersions is a spray-dried dispersion. 3. The pharmaceutical composition of embodiment 1, wherein both of the first and second solid dispersions are spray-dried dispersions. 4. The pharmaceutical composition of embodiment 1, wherein said polymer for the first solid dispersion is hypromellose; and said polymer for the second solid dispersion is hypromellose acetate succinate. 5. The pharmaceutical composition of embodiment 1, wherein said polymer for the first solid dispersion is HPMC E15; and said polymer for the second solid dispersion is hypromellose acetate succinate H. 6. The pharmaceutical composition of embodiment 1, wherein said polymer for the first solid dispersion is HPMC E15; and said polymer for the second solid dispersion is hypromellose acetate succinate HG. 7. The pharmaceutical composition of any one of embodiments 1-6, comprising 50 mg to 500 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B). 8. The pharmaceutical composition of any one of embodiments 1-6, comprising 50 mg to 400 mg, 50 mg to 300 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 150 mg, or 200 mg to 250 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B). 9. The pharmaceutical composition of any one of embodiments 1-6, comprising 100 mg to 250 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B). 10. The pharmaceutical composition of any one of embodiments 1-6, comprising 100 mg to 150 mg or 150 mg to 250 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B). 11. The pharmaceutical composition of any one of embodiments 1-10, wherein the first solid dispersion comprises 25 mg to 75 mg of Compound II. 12. The pharmaceutical composition of any one of embodiments 1-10, wherein the first solid dispersion comprises 30 mg to 60 mg of Compound II. 13. The pharmaceutical composition of any one of embodiments 1-10, wherein the second solid dispersion comprises 25 mg to 50 mg, 25 mg to 75 mg, 50 mg to 100 mg, 75 mg to 125 mg, or 125 mg to 175 mg of Compound III or Compound III-d. 14. The pharmaceutical composition of any one of embodiments 1-10, wherein the second solid dispersion comprises 50 mg to 100 mg of Compound III or Compound III-d. 15. The pharmaceutical composition of any one of embodiments 1-6, comprising 100 mg to 250 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); and wherein the first solid dispersion comprises 25 mg to 75 mg of Compound II; and the second solid dispersion comprises 50 mg to 100 mg of Compound III or Compound III-d. 16. The pharmaceutical composition of any one of embodiments 1-6, comprising 100 mg to 150 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); and wherein the first solid dispersion comprises 50 mg of Compound II; and the second solid dispersion comprises 75 mg or 150 mg of Compound III or 100 mg of Compound III-d . 17. The pharmaceutical composition of any one of embodiments 1-6, comprising 170 mg to 250 mg of a potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); and wherein the first solid dispersion comprises 50 mg or 100 mg of Compound II; and the second solid dispersion comprises 75 mg or 150 mg of Compound III or 100 mg or 200 mg of Compound III-d . 18. The pharmaceutical composition of any one of embodiments 1-17, wherein the second solid dispersion further comprises 0.5% sodium lauryl sulfate relative to the total weight of the second solid dispersion. 19. The pharmaceutical composition of any one of embodiments 1-18, further comprising one or more pharmaceutically acceptable excipients selected from one or more fillers, a disintegrant, and a lubricant. 20. The pharmaceutical composition of embodiment 19, wherein one or more fillers are selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, dicalcium phosphate, mannitol, copovidone, hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, starch, Maltodextrin, agar, and guar gum. 21. The pharmaceutical composition of embodiment 19, wherein the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn or pre-gelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and microcrystalline cellulose. 22. The pharmaceutical composition of embodiment 19, wherein the lubricant is selected from magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium stearate, stearic acid, and talc. 23. The pharmaceutical composition of any one of embodiments 1-22, wherein the potassium salt of Compound I is crystalline, and wherein each of Compound II, Compound III and Compound III-d are independently substantially amorphous wherein "substantially amorphous" referes to a solid material having less that 15% crystallinity. 24. A pharmaceutical composition comprising: (a) 15 wt% to 45 wt% of a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B): relative to the total weight of the pharmaceutical composition; (b) 5 wt% to 20 wt% of a first solid dispersion relative to the total weight of the pharmaceutical composition, wherein the first solid dispersion comprises 70 wt% to 90 wt% of Compound II relative to the total weight of the first solid dispersion: and 10 wt% to 30 wt% of a polymer relative to the total weight of the first solid dispersion; and (c) 10 wt% to 40 wt% of a second solid dispersion relative to the total weight of the pharmaceutical composition; wherein the second solid dispersion comprises 70 wt% to 90 wt% of Compound III or Compound III-d relative to the total weight of the second solid dispersion: and 10 wt% to 30 wt% of a polymer relative to the total weight of the second solid dispersion. 25. The pharmaceutical composition of embodiment 24, wherein at least one of the first or second solid dispersions is a spray-dried dispersion. 26. The pharmaceutical composition of embodiment 24, wherein both of the first and second solid dispersions are spray-dried dispersions. 27. The pharmaceutical composition of embodiment 24, wherein said polymer for the first solid dispersion is hypromellose; and said polymer for the second solid dispersion is hypromellose acetate succinate. 28. The pharmaceutical composition of embodiment 24, wherein said polymer for the first solid dispersion is hypromellose (HPMC E15); and said polymer for the second solid dispersion is hypromellose acetate succinate H. 29. The pharmaceutical composition of embodiment 24, wherein: the first solid dispersion comprises 70 wt% to 85 wt% of Compound II relative to the total weight of the first solid dispersion, and the polymer is a hydroxypropyl methylcellulose in an amount of 15 wt% to 30 wt% relative to the total weight of the first solid dispersion; and the second solid dispersion comprises 70 wt% to 85 wt% of Compound III or Compound III-d relative to the total weight of the second solid dispersion, 0.5% sodium lauryl sulfate relative to the total weight of the second solid dispersion, and the polymer is hypromellose acetate succinate in an amount of 14.5 wt% to 29.5 wt% relative to the total weight of the second solid dispersion. 30. The pharmaceutical composition of any one of embodiments 24-29, wherein the first solid dispersion comprises 75 wt% to 85 wt% of Compound II relative to the total weight of the first solid dispersion. 31. The pharmaceutical composition of any one of embodiments 24-29, wherein the first solid dispersion comprises 80 wt% of Compound II relative to the total weight of the first solid dispersion; and 20 wt% of a hydroxypropyl methylcellulose relative to the total weight of the first solid dispersion. 32. The pharmaceutical composition of any one of embodiments 24-31, wherein the second solid dispersion comprises 75 wt% to 85 wt% of Compound III or Compound III-d relative to the total weight of the second solid dispersion. 33. The pharmaceutical composition of any one of embodiments 24-32, wherein the second solid dispersion comprises 80 wt% of Compound III or Compound III-d relative to the total weight of the second solid dispersion; 0.5% of sodium lauryl sulfate relative to the total weight of the second solid dispersion, and 19.5 wt% of hypromellose acetate succinate relative to the total weight of the second solid dispersion. 34. The pharmaceutical composition of any one of embodiments 24-33, further comprising one or more pharmaceutically acceptable excipients selected from fillers, disintegrants, and lubricants. 35. The pharmaceutical composition of embodiment 34, wherein the filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, dicalcium phosphate, mannitol, copovidone, hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, starch, Maltodextrin, agar, and guar gum. 36. The pharmaceutical composition of embodiment 34, wherein the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn or pre-gelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and microcrystalline cellulose. 37. The pharmaceutical composition of embodiment 34, wherein the lubricant is selected from magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium stearate, stearic acid, and talc. 38. The pharmaceutical composition of any one of embodiments 24-37, the potassium salt of Compound I is crystalline, and wherein each of Compound II, Compound III and Compound III-d is independently substantially amorphous wherein "substantially amorphous" referes to a solid material having less that 15% crystallinity. 39. A single tablet comprising: (a) 200 mg to 215 mg of a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B); (b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt% Compound II relative to the total weight of the first solid dispersion and 20 wt% of a hypromellose relative to the total weight of the first solid dispersion; and (c) 90 mg to 95 mg of a second solid dispersion comprising 80 wt% of Compound III relative to the total weight of the second solid dispersion, 0.5 wt% of sodium lauryl sulfate relative to the total weight of the second solid dispersion; and 19.5 wt% of a hypromellose acetate succinate to the total weight of the second solid dispersion (d) 175 mg to 215 mg of a microcrystalline cellulose; (e) 20 mg to 30 mg of a croscarmellose sodium; and (f) 3 mg to 7 mg of magnesium stearate. 40. The single tablet of embodiment 39, wherein the tablet comprises: (a) 200 mg to 215 mg of said potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); (b) 60 mg to 65 mg of said first solid dispersion; (c) 90 mg to 95 mg of said second solid dispersion; (d) 175 mg to 215 mg of said microcrystalline cellulose; (e) 15 mg to 30 mg of said croscarmellose sodium; and (f) 3 mg to 7 mg of magnesium stearate. 41. The single tablet of embodiment 39, wherein the tablet comprises an intra-granular part and extra-granular part, and (a) wherein the intra-granular part comprises: (i) 200 mg to 215 mg of said potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); (ii) 60 mg to 65 mg of said first solid dispersion; (iii) 90 mg to 95 mg of said second solid dispersion; (iv) 120 mg to 150 mg of said microcrystalline cellulose; (v) 10 mg to 20 mg of said croscarmellose sodium; and (vi) 3 mg to 7 mg of magnesium stearate; and (b) wherein the extra-granular part comprises: (i) 55 mg to 65 mg of said microcrystalline cellulose; and (ii) 5 mg to 10 mg of said croscarmellose sodium. 42. The single tablet of embodiment 39, wherein the tablet comprises: (a) 210 mg to 215 mg of said potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); (b) 60 mg to 65 mg of said first solid dispersion; (c) 90 mg to 95 mg of said second solid dispersion; (d) 193 mg to 203 mg of said microcrystalline cellulose; (e) 21 mg to 27 mg of said croscarmellose sodium; and (f) 4 mg to 7 mg of magnesium stearate. 43. The single tablet of embodiment 39, wherein the tablet comprises an intra-granular part and extra-granular part, and (a) wherein the intra-granular part comprises: (i) 210 mg to 215 mg of said potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); (ii) 60 mg to 65 mg of said first solid dispersion; (iii) 90 mg to 95 mg of said second solid dispersion; (iv) 135 mg to 140 mg of said microcrystalline cellulose; (v) 14 mg to 17 mg of said croscarmellose sodium; and (vi) 4 mg to 7 mg of magnesium stearate; and (b) wherein the extra-granular part comprises: (i) 58 mg to 63 mg of said microcrystalline cellulose; and (ii) 7 mg to 10 mg of said croscarmellose sodium. 44. A single tablet comprising: (a) 115 mg to 140 mg of a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B); (b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt% Compound II relative to the total weight of the first solid dispersion and 20 wt% of a hypromellose relative to the total weight of the first solid dispersion; and (c) 90 mg to 95 mg of a second solid dispersion comprising 80 wt% of Compound III relative to the total weight of the second solid dispersion, 0.5 wt% of sodium lauryl sulfate relative to the total weight of the second solid dispersion; and 19.5 wt% of a hypromellose acetate succinate to the total weight of the second solid dispersion; (d) 120 mg to 135 mg of a microcrystalline cellulose; (e) 15 mg to 25 mg of a croscarmellose sodium; and (f) 2 mg to 6 mg of magnesium stearate. 45. The single tablet of embodiment 44, wherein the tablet comprises: (a) 115 mg to 140 mg of said potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); (b) 60 mg to 65 mg of said first solid dispersion; (c) 90 mg to 95 mg of said second solid dispersion; (d) 120 mg to 135 mg of said microcrystalline cellulose; (e) 15 mg to 25 mg of said croscarmellose sodium; and (f) 3 mg to 5 mg of magnesium stearate. 46. The single tablet of embodiment 44, wherein the tablet comprises an intra-granular part and extra-granular part, and (a) wherein the intra-granular part comprises: (i) 115 mg to 140 mg of said potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); (ii) 60 mg to 65 mg of said first solid dispersion; (iii) 90 mg to 95 mg of said second solid dispersion; (iv) 80 mg to 90 mg of said microcrystalline cellulose; (v) 10 mg to 15 mg of said croscarmellose sodium; and (vi) 3 mg to 5 mg of magnesium stearate; and (b) wherein the extra-granular part comprises: (i) 40 mg to 45 mg of said microcrystalline cellulose; and (i) 5 mg to 10 mg of said croscarmellose sodium. 47. The single tablet of embodiment 44, wherein the tablet comprises: (a) 115 mg to 140 mg of said potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); (b) 60 mg to 65 mg of said first solid dispersion; (c) 90 mg to 95 mg of said second solid dispersion; (d) 125 mg to 140 mg of said microcrystalline cellulose; (e) 15 mg to 25 mg of said croscarmellose sodium; and (f) 2 mg to 6 mg of magnesium stearate. 48. The single tablet of embodiment 44, wherein the tablet comprises an intra-granular part and extra-granular part, and (a) wherein the intra-granular part comprises: (i) 115 mg to 140 mg of said potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B); (ii) 60 mg to 65 mg of said first solid dispersion; (iii) 90 mg to 95 mg of said second solid dispersion; (iv) 85 mg to 95 mg of said microcrystalline cellulose; (v) 10 mg to 15 mg of said croscarmellose sodium; and (vi) 1 mg to 3 mg of magnesium stearate; and (b) wherein the extra-granular part comprises: (i) 40 mg to 45 mg of said microcrystalline cellulose; and (ii) 5 mg to 10 mg of said croscarmellose sodium; and (iii) 1 mg to 3 mg of magnesium stearate. 49. The pharmaceutical composition of any one of embodiments 1-48, wherein the pharmaceutical composition is a single tablet. 50. The pharmaceutical composition of any one of embodiments 1-49, further comprising a microcrystalline cellulose in an amount 20 wt % - 40 wt% relative to the total weight of the pharmaceutical composition. 51. The pharmaceutical composition of embodiment 50, further comprising a croscarmellose sodium in an amount 1 wt % - 10 wt% relative to the total weight of the pharmaceutical composition. 52. The pharmaceutical composition of embodiment 51, further comprising a magnesium stearate in an amount 0.5 wt % - 1.5 wt% relative to the total weight of the pharmaceutical composition. 53. A pharmaceutical composition comprising: (a) 20 wt% to 35 wt% of a potassium salt of Compound I as defined in the claims (in some embodiments, potassium salt crystalline Form B) relative to the total weight of the pharmaceutical composition; (b) 5 wt% to 20 wt% of a first solid dispersion relative to the total weight of the pharmaceutical composition, wherein the first solid dispersion comprises 70 wt% to 90 wt% of Compound II relative to the total weight of the first solid dispersion and 10 wt% to 30 wt% of a polymer relative to the total weight of the first solid dispersion; and (c) 20 wt% to 40 wt% of a second solid dispersion relative to the total weight of the pharmaceutical composition, wherein the second solid dispersion comprises 70 wt% to 90 wt% of Compound III relative to the total weight of the second solid dispersion, and 10 wt% to 30 wt% of a polymer relative to the total weight of the second solid dispersion. 54. The pharmaceutical composition of embodiment 53, wherein at least one of the first or second solid dispersions is a spray-dried dispersion. 55. The pharmaceutical composition of embodiment 53, wherein both of the first and second solid dispersions are spray-dried dispersions. 56. The pharmaceutical composition of embodiment 53, wherein said polymer for the first solid dispersion is hypromellose; and said polymer for the second solid dispersion is hypromellose acetate succinate. 57. The pharmaceutical composition of embodiment 53, wherein said polymer for the first solid dispersion is hypromellose (HPMC E15); and said polymer for the second solid dispersion is hypromellose acetate succinate H. 58. The pharmaceutical composition of embodiment 53, wherein: the first solid dispersion comprises 70 wt% to 85 wt% of Compound II relative to the total weight of the first solid dispersion, and the polymer is a hydroxypropyl methylcellulose in an amount of 15 wt% to 30 wt% relative to the total weight of the first solid dispersion; and the second solid dispersion comprises 70 wt% to 85 wt% of Compound III relative to the total weight of the second solid dispersion, 0.5% sodium lauryl sulfate relative to the total weight of the second solid dispersion, and the polymer is hypromellose acetate succinate in an amount of 14.5 wt% to 29.5 wt% relative to the total weight of the second solid dispersion. 59. The pharmaceutical composition of any one of embodiments 53-58, wherein the first solid dispersion comprises 75 wt% to 85 wt% of Compound II relative to the total weight of the first solid dispersion. 60. The pharmaceutical composition of embodiment 59, wherein the first solid dispersion comprises 80 wt% of Compound II relative to the total weight of the first solid dispersion; and 20 wt% of a hydroxypropyl methylcellulose relative to the total weight of the first solid dispersion. 61. The pharmaceutical composition of any one of embodiments 53-60, wherein the second solid dispersion comprises 75 wt% to 85 wt% of Compound III relative to the total weight of the second solid dispersion. 62. The pharmaceutical composition of embodiment 61, wherein the second solid dispersion comprises 80 wt% of Compound III relative to the total weight of the second solid dispersion; 0.5% of sodium lauryl sulfate relative to the total weight of the second solid dispersion, and 19.5 wt% of a hypromellose acetate succinate relative to the total weight of the second solid dispersion. 63. The pharmaceutical composition of any one of embodiments 53-62, further comprising one or more pharmaceutically acceptable excipients selected from fillers, disintegrants, and lubricants. 64. The pharmaceutical composition of embodiment 63, wherein the filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, dicalcium phosphate, mannitol, copovidone, hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, starch, Maltodextrin, agar, and guar gum. 65. The pharmaceutical composition of embodiment 64, wherein the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn or pre-gelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and microcrystalline cellulose. 66. The pharmaceutical composition of embodiment 65, wherein the lubricant is selected from magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium stearate, stearic acid, and talc. 67. The pharmaceutical composition of any one of embodiments 53-66, the potassium salt of Compound I is substantially crystalline, and wherein each of Compound II and Compound III is independently substantially amorphous. 68. The pharmaceutical composition of any one of embodiments 1-38 and 49-52, wherein said potassium salt of Compound I, said Compound II, and said Compound III are present in a ratio of 8:2:3 based on the respective weight of free base Compound I: Compound II: Compound III. 69. The pharmaceutical composition of any one of embodiments 1-38 and 49-52, wherein said potassium salt of Compound I, said Compound II, and said Compound III are present in a ratio of 24:10:15 based on the respective weight of free base Compound I: Compound II: Compound III. 70. The pharmaceutical composition of any one of embodiments 1-38 and 49-52, wherein said potassium salt of Compound I, said Compound II, and said Compound III-d are present in a ratio of 4:1:2 based on the respective weight of free base Compound I: Compound II: Compound III-d. 71. The pharmaceutical composition of any one of embodiments 1-38 and 49-52, wherein said potassium salt of Compound I, said Compound II, and said Compound III-d are present in a ratio of 12:5:10 based on the respective weight of free base Compound I: Compound II: Compound III-d. 72. The pharmaceutical composition of any one of embodiments 1-38 and 53-67, wherein said potassium salt of Compound I, said Compound II, and said Compound III are present in a ratio of 4:1:3 based on the respective weight of free base Compound I: Compound II: Compound III. 73. The pharmaceutical composition of any one of embodiments 1-38 and 53-67, wherein said potassium salt of Compound I, said Compound II, and said Compound III are present in a ratio of 12:5:15 based on the respective weight of free base Compound I: Compound II: Compound III. 74. The pharmaceutical composition of embodiment 24, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)20 - 45 wt%solid dispersion containing 80% Compound II , 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10-30 wt% 75. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 45 wt%solid dispersion containing 80% Compound II , 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III or Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 40 wt%microcrystalline cellulose5 - 50 wt%croscarmellose sodium (CCS)1 - 10 wt%optionally magnesium stearate in an amount of 0.01 wt% - 2 wt% based on the total weight of composition 76. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 45 wt%solid dispersion containing 80% Compound II , 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III or Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 40 wt%microcrystalline cellulose5 - 50 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% 77. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 35 wt%solid dispersion containing 80% Compound II , 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III , 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 40 wt%microcrystalline cellulose20 - 40 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% 78. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)20 - 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 25 wt%microcrystalline cellulose20 - 40 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% 79. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)30 - 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 15 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 20 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05 - 2 wt% 80. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)33 - 38 wt%solid dispersion containing 80% Compound II, 20% hypromellose8 - 13 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate13 - 18 wt%microcrystalline cellulose30 - 35 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05- 2 wt% 81. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)28 - 33 wt%solid dispersion containing 80% Compound II, 20% hypromellose7 - 12 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate25 - 30 wt%microcrystalline cellulose25 -35 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% 82. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)25 - 35 wt%solid dispersion containing 80% Compound II, 20% hypromellose10 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 25 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05 - 2 wt% 83. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)27 - 32 wt%solid dispersion containing 80% Compound II, 20% hypromellose12 - 17 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate18 - 23 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)3 - 6 wt%magnesium stearate0.05 - 1.5 wt% 84. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)20- 30 wt%solid dispersion containing 80% Compound II, 20% hypromellose7 - 15 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate30 - 40 wt%microcrystalline cellulose15 - 40 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05 - 1.5 wt% 85. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)22 - 27 wt%solid dispersion containing 80% Compound II, 20% hypromellose8 - 13 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate32 - 37 wt%microcrystalline cellulose20 - 30 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% 86. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)25- 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose7 - 15 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 35 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% 87. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)29 - 36 wt%solid dispersion containing 80% Compound II, 20% hypromellose8 - 13 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 25 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% 88. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and optionally magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15- 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 40 wt%microcrystalline cellulose10 - 50 wt%croscarmellose sodium (CCS)2 - 7 wt%optionally magnesium stearate in an amount of 0.01 wt% - 2 wt% based on the total weight of composition 89. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and optionally magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)20 - 30 wt%solid dispersion containing 80% Compound II, 20% hypromellose8-18 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 30 wt%microcrystalline cellulose20 - 30 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition 90. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and optionally magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)28 - 38 wt%solid dispersion containing 80% Compound II, 20% hypromellose10 -20 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate27 - 37 wt%microcrystalline cellulose5 - 20 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition 91. The pharmaceutical composition of embodiment 24, further comprising microcrystalline cellulose, croscarmellose sodium and optionally magnesium stearate, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)15 - 25 wt%solid dispersion containing 80% Compound II, 20% hypromellose5-15 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 25 wt%microcrystalline cellulose40 - 50 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition 92. The pharmaceutical composition of embodiment 24, wherein the pharmaceutical composition comprises: Component weight % based on the total weight of composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)22 - 32 wt%solid dispersion containing 80% Compound II, 20% hypromellose10-20 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 30 wt%microcrystalline cellulose20 - 30 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition 93. The pharmaceutical composition of embodiment 1, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component Amount (mg) per composition potassium salt of Compound I (in some embodiments, potassium salt crystalline Form B)207 - 217solid dispersion containing 80% Compound II, 20% hypromellose58 - 68solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate182-193microcrystalline cellulose (e.g., PH101)175 - 215croscarmellose sodium15 - 35magnesium stearate3 - 9 94. The pharmaceutical composition of embodiment 1, further comprising microcrystalline cellulose, croscarmellose sodium and magnesium stearate, wherein the pharmaceutical composition comprises: Component Amount (mg) per composition potassium s...

Claims

1. Crystalline Form B of a potassium salt of Compound I: characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, and 19.1 ± 0.2, obtained using Cu Kα radiation.

2. Crystalline Form B according to claim 1, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.8 ± 0.2, 8.2 ± 0.2, 10.2 ± 0.2, 13.8 ± 0.2, 16.3 ± 0.2, and 19.1 ± 0.2, obtained using Cu Kα radiation.

3. Crystalline Form B according to claim 1, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 1A, wherein "substantially similar" means that at least 90% of the signals in the two diffractograms overlap.

4. Crystalline Form B of claim 1 having a unit cell characterized by three edges of 9.0 ± 0.2 Å, 11.5 ± 0.2 Å, and 31.0 ± 0.2 Å, when measured by X-ray powder diffraction at 298°K and 1.54178 Å.

5. Crystalline Form C of a potassium salt / co-crystal of Compound I, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 11.5 ± 0.2, 12.4 ± 0.2, and 16.0 ± 0.2, obtained using Cu Kα radiation.

6. Crystalline Form C according to claim 5, characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 7.0 ± 0.2, 7.4 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, and 11.5 ± 0.2, obtained using Cu Kα radiation.

7. Crystalline Form C according to claim 5, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 7A, wherein "substantially similar" means that at least 90% of the signals in the two diffractograms overlap.

8. A crystalline form of a sodium salt of compound I wherein the crystalline form of a sodium salt of compound I is: (a) Crystalline Form A of a sodium salt of Compound I characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.7 ± 0.2, 4.9 ± 0.2, 6.3 ± 0.2, 8.0 ± 0.2, 8.3 ± 0.2, 11.1 ± 0.2, 12.2 ± 0.2, 12.6 ± 0.2, and 14.0 ± 0.2, obtained using Cu Kα radiation; (b) Crystalline Form D of a sodium salt of Compound I characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.9 ± 0.2, 5.7 ± 0.2, 7.0 ± 0.2, 8.0 ± 0.2, 9.8 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 14.0 ± 0.2, and 16.0 ± 0.2, obtained using Cu Kα radiation; or (c) Crystalline Form E of a sodium salt of Compound I characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.7± 0.2, 9.0 ± 0.2, 9.9 ± 0.2, 11.4 ± 0.2, 14.0 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, and 19.0 ± 0.2, obtained using Cu Kα radiation.

9. Crystalline Form A of Compound I characterized by an X-ray powder diffractogram having a signal ranging from 5.3 to 5.5, from 7.2 to 7.5, from 11.8 to 12.2, from 14.7 to 15.0, from 16.7 to 17.1, from 17.4 to 17.7, from 18.5 to 18.8, and from 19.5 to 19.8 degrees two-theta, obtained using Cu Kα radiation.

10. The crystalline form according to any one of the claims 1-9 where the crystalline form is in substantially pure form, wherein a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by quantitative XRPD.

11. A pharmaceutical composition comprising at least one crystalline form according to any one of claims 1-9 and a pharmaceutically acceptable carrier.

12. At least one crystalline form according to any one of claims 1-9, or the pharmaceutical composition of claim 11, for use in treating cystic fibrosis comprising administering to a patient in need thereof.

13. At least one solvate of: (a) Compound I chosen from 1,4-dioxane solvates, 2-methyl tetrahydrofuran solvates, ethanol solvates, nitromethane solvates, 1-propanol solvates, tetrahydrofuran solvates, toluene solvates, pyridine solvates, chlorobenzene solvates, diethyl ether solvates, 2-propanol solvates, 2-butanol solvates, hexane solvates, heptane solvates, ethyl acetate solvates, methanol solvates, dichloromethane solvates, acetone solvates, methyl tert-butyl ether solvates, n-butanol solvates, N-methyl-2-pyrrolidone solvates, and t-butanol solvates of Compound I; (b) a sodium salt of Compound I chosen from ethanol solvates and methanol solvates of the sodium salt of Compound I; or (c) a potassium salt of Compound I chosen from 1-pentanol solvates, isopropyl acetate solvates, 1-propanol solvates, acetone solvates, acetonitrile solvates, 2-methyl tetrahydrofuran solvates, ethyl acetate solvates, methanol solvates, ethanol solvates, methyl tert-butyl ether solvates, and methyl ethyl ketone solvates of a potassium salt of Compound I.

14. The pharmaceutical composition of claim 11 comprising: (a) (i) 50 mg to 600 mg of crystalline Form B of a potassium salt of Compound I as defined in claim 1: (ii) a first solid dispersion comprising 25 mg to 125 mg of Compound II: and 10 wt% to 30 wt% of a polymer relative to the total weight of the first solid dispersion; and (iii) a second solid dispersion comprising 5 mg to 300 mg of Compound III: or Compound III-d: and 10 wt% to 30 wt% of a polymer relative to the total weight of the second solid dispersion; (b) (i) 15 wt% to 45 wt% of crystalline Form B of a potassium salt of Compound I as defined in claim 1 relative to the total weight of the pharmaceutical composition; (ii) 5 wt% to 20 wt% of a first solid dispersion relative to the total weight of the pharmaceutical composition, wherein the first solid dispersion comprises 70 wt% to 90 wt% of Compound II relative to the total weight of the first solid dispersion and 10 wt% to 30 wt% of a polymer relative to the total weight of the first solid dispersion; and (iii) 10 wt% to 40 wt% of a second solid dispersion relative to the total weight of the pharmaceutical composition, wherein the second solid dispersion comprises 70 wt% to 90 wt% of Compound III or Compound III-d relative to the total weight of the second solid dispersion, and 10 wt% to 30 wt% of a polymer relative to the total weight of the second solid dispersion; or (c) (i) 20 wt% to 35 wt% of crystalline Form B of a potassium salt of Compound I as defined in claim 1 relative to the total weight of the pharmaceutical composition; (ii) 5 wt% to 20 wt% of a first solid dispersion relative to the total weight of the pharmaceutical composition, wherein the first solid dispersion comprises 70 wt% to 90 wt% of Compound II relative to the total weight of the first solid dispersion, and 10 wt% to 30 wt% of a polymer relative to the total weight of the first solid dispersion; and (iii) 20 wt% to 40 wt% of a second solid dispersion relative to the total weight of the pharmaceutical composition, wherein the second solid dispersion comprises 70 wt% to 90 wt% of Compound III relative to the total weight of the second solid dispersion, and 10 wt% to 30 wt% of a polymer relative to the total weight of the second solid dispersion.

15. The pharmaceutical composition of claim 14, wherein: (a) at least one of the first or second solid dispersions is a spray-dried dispersion; (b) both of the first and second solid dispersions are spray-dried dispersions; (c) said polymer for the first solid dispersion is hypromellose; and said polymer for the second solid dispersion is hypromellose acetate succinate; (d) said polymer for the first solid dispersion is HPMC E15; and said polymer for the second solid dispersion is hypromellose acetate succinate H; or (e) said polymer for the first solid dispersion is HPMC E15; and said polymer for the second solid dispersion is hypromellose acetate succinate HG.

16. The pharmaceutical composition of any one of claims 14 or 15, wherein the potassium salt of Compound I is crystalline, and wherein each of Compound II, Compound III and Compound III-d are independently substantially amorphous wherein "substantially amorphous" referes to a solid material having less that 15% crystallinity, optionally wherein said potassium salt of Compound I, said Compound II, and said Compound III are present in a ratio of 8:2:3 based on the respective weight of free base Compound I: Compound II: Compound III.

17. The pharmaceutical composition of claim 14 comprising any one of the following: (a) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 120 - 45 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10-30 wt% (b) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 115 - 45 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III or Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 40 wt%microcrystalline cellulose5 - 50 wt%croscarmellose sodium (CCS)1 - 10 wt%optionally magnesium stearate in an amount of 0.01 wt% - 2 wt% based on the total weight of composition (c) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 115 - 45 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III or Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 40 wt%microcrystalline cellulose5 - 50 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% (d) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 115 - 35 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 40 wt%microcrystalline cellulose20 - 40 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% (e) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 120 - 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate10 - 25 wt%microcrystalline cellulose20 - 40 wt%croscarmellose sodium (CCS)1 - 10 wt%magnesium stearate0.05 - 2 wt% (f) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 125 - 35 wt%solid dispersion containing 80% Compound II, 20% hypromellose10 - 20 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 25 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 7 wt%magnesium stearate0.05 - 2 wt% (g) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 127 - 32 wt%solid dispersion containing 80% Compound II, 20% hypromellose12 - 17 wt%solid dispersion containing 80% Compound III, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate18 - 23 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)3 - 6 wt%magnesium stearate0.05 - 1.5 wt% (h) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 125- 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose7 - 15 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate15 - 35 wt%microcrystalline cellulose25 - 35 wt%croscarmellose sodium (CCS)2 - 5 wt%magnesium stearate0.05 - 1.5 wt% (i) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 115- 40 wt%solid dispersion containing 80% Compound II, 20% hypromellose5 - 20 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 40 wt%microcrystalline cellulose10 - 50 wt%croscarmellose sodium (CCS)2 - 7 wt%optionally magnesium stearate in an amount of 0.01 wt% - 2 wt% based on the total weight of composition (j) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 120 - 30 wt%solid dispersion containing 80% Compound II, 20% hypromellose8-18 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 30 wt%microcrystalline cellulose20 - 30 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition (k) Componentweight % based on the total weight of compositionCrystalline Form B of a potassium salt of Compound I as defined in claim 122 - 32 wt%solid dispersion containing 80% Compound II, 20% hypromellose10-20 wt%solid dispersion containing 80% Compound III-d, 19.5% hypromellose acetate succinate, and 0.5% sodium lauryl sulfate20 - 30 wt%microcrystalline cellulose20 - 30 wt%croscarmellose sodium (CCS)2 - 5 wt%optionally magnesium stearate in an amount of 0.01 wt% - 1.5 wt% based on the total weight of composition18. A pharmaceutical composition of any one of claims 14 to 17, for use in treating cystic fibrosis in a patient comprising orally administering the pharmaceutical composition to the patient.

19. The pharmaceutical composition for use according to claim 18, wherein the pharmaceutical composition is administered: (a) once daily; or (b) twice daily.

20. The pharmaceutical composition of any one of claims 14 to 17, wherein the pharmaceutical composition is a single tablet.