Crystalline forms of CFTR modulators

Abstract

Crystalline forms of Compound I: Formula (I), its pharmaceutically acceptable salts, and solvates and hydrates thereof are disclosed. Pharmaceutical compositions containing them, methods of using them to treat cystic fibrosis, and methods for making them are also disclosed. JPEG2022544383000156.jpg3162

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 886,565, filed August 14, 2019, and U.S. Provisional Patent Application No. 63 / 015,903, filed April 27, 2020, the disclosures of which are incorporated by reference in their entireties.

[0002] Disclosed herein are modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), pharmaceutical compositions containing those modulators, methods of treating cystic fibrosis with those modulators and compositions, and processes for making the modulators. [Background technology]

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

[0004] In patients with CF, mutations in CFTR, which is endogenously expressed in respiratory epithelia, result in reduced apical anion secretion, causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to excessive mucus accumulation in the lungs and associated microbial infections, which ultimately lead to death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, can lead to death. In addition, the majority of men with cystic fibrosis are infertile, and women with cystic fibrosis have reduced fertility.

[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, more than 2,000 mutations in the CFTR gene have been identified. Currently, the CFTR2 database contains information on only 412 of these identified mutations, and sufficient evidence exists to define 346 mutations as disease-causing. The most common disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in nearly all 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 prevents the mutant protein from exiting the endoplasmic reticulum (ER) and transporting to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is much lower than that observed in cells expressing wild-type CFTR, i.e., CFTR without the mutation. In addition to impaired trafficking, the F508del mutation results in abnormal channel gating. The reduced number of channels in the membrane and the abnormal gating together result in reduced anion and fluid transport across epithelia. (Quinton, PM (1990), FASEB J. 4:2709-2727). While still functional, the abnormal channels resulting from the F508del mutation are less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature London. 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 abnormalities in trafficking, synthesis, and / or channel gating alter anion secretion and can be up- or down-regulated to modify disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells. CFTR regulates anion flux across membranes and the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is crucial for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR is composed of 1,480 amino acids that encode a protein composed of tandem repeats 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. Chloride transport is mediated by ENaC (epithelial sodium channel) and CFTR present at the apical membrane, and Na + -K + -ATPase pump and Cl - This occurs through the coordinated activity of the channels. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which is then transported through the Cl - It can passively exit the cell via channels, resulting in vectorial transport. + / 2Cl - / K + Cotransporter, Na + -K + -ATPase pump, and basement membrane K + The positioning of the channel and luminal CFTR coordinates luminal CFTR-mediated chloride secretion. Because water is probably never actively transported itself, its flow across epithelia depends on the small transepithelial osmotic gradient generated by the bulk flow of sodium and chloride. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Cutting, GRet al. (1990) Nature 346:366-369 [Non-patent document 2] Dean, M. et al. (1990) Cell 61:863:870 [Non-patent document 3] Kerem, BS. et al. (1989) Science 245:1073-1080 [Non-patent document 4] Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451 [Non-Patent Document 5] Quinton, PM (1990), FASEB J.4:2709-2727 [Non-patent document 6] Dalemans et al. (1991), Nature Lond.354:526-528, [Non-Patent Document 7] Pasyk and Foskett (1995) J.Cell.Biochem.270:12347-50 Summary of the Invention [Means for solving the problem]

[0009] Several CFTR-modulating compounds have been identified recently. However, there remains a need for compounds that can treat or reduce the severity of cystic fibrosis and other CFTR-mediated diseases, particularly the more severe forms of these diseases.

[0010] Thus, one aspect of the present disclosure provides the CFTR-modulating compound (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I) and pharmaceutically acceptable salts thereof. Compound I can be represented as having the following structure: [ka]

[0011] Compound I was first described as an amorphous (free form) solid and as amorphous calcium, sodium, and potassium salts in PCT Publication No. WO 2019 / 161078 (herein incorporated by reference).

[0012] Crystalline forms are of interest in the pharmaceutical industry, where control of the crystalline form(s) of an active ingredient may be desirable or even necessary. Because different crystalline forms may have different properties, a reproducible process for producing a compound with high purity and a specific crystalline form may be desirable for compounds intended for use in pharmaceuticals. For example, different crystalline forms may have different chemical, physical, and / or pharmaceutical properties. In some embodiments, one or more crystalline forms disclosed herein may exhibit higher purity levels, chemical stability, and / or physical stability compared to the forms produced in WO2019 / 161078. Certain crystalline forms (e.g., the crystalline free form, crystalline salt, crystalline salt solvate, and crystalline salt hydrate forms of Compound I (collectively referred to as "crystalline forms")) may exhibit lower hygroscopicity than the forms produced in WO2019 / 161078. Thus, the crystalline forms of the present disclosure may offer advantages during manufacture, storage, and handling of the drug substance over the amorphous form produced in WO 2019 / 161078. Thus, pharmaceutically acceptable crystalline forms of Compound I may be particularly useful in producing drugs for the treatment of CFTR-mediated diseases.

[0013] In some embodiments, the crystalline form of Compound I is the free form. In some embodiments, the crystalline form of Compound I is Form A of Compound I (free form). In some embodiments, the crystalline form of Compound I is Form B of Compound I (free form). In some embodiments, the crystalline form of Compound I is Form C of Compound I (free form). In some embodiments, the crystalline form of Compound I is Form D of Compound I (free form).

[0014] In some embodiments, the crystalline form of Compound I is a solvate. In some embodiments, the crystalline form of Compound I is a calcium salt solvate. In some embodiments, the crystalline form of Compound I is calcium salt EtOH solvate form A. In some embodiments, the crystalline form of Compound I is calcium salt EtOH solvate form B. In some embodiments, the crystalline form of Compound I is calcium salt EtOH solvate form C.

[0015] In some embodiments, the crystalline form of Compound I is a hydrate. In some embodiments, the crystalline form of Compound I is a calcium salt hydrate. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form A. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form B. In some embodiments, the crystalline form of Compound I is calcium salt hydrate / solvate form B with MeOH. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form C. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form D. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form E. In some embodiments, the crystalline form of Compound I is form F. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form G. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form H.

[0016] In some embodiments, the crystalline form of Compound I is a sodium salt hydrate. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form A. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form C. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form D.

[0017] In some embodiments, the crystalline form of Compound I is Form B of the sodium salt (pure).

[0018] In some embodiments, the crystalline form of Compound I is a potassium salt hydrate. In some embodiments, the crystalline form of Compound I is potassium salt hydrate form A. In some embodiments, the crystalline form of Compound I is potassium salt hydrate form B. In some embodiments, the crystalline form of Compound I is potassium salt hydrate form C. In some embodiments, the crystalline form of Compound I is potassium salt hydrate form D.

[0019] In some embodiments, the crystalline form of Compound I is ammonium salt hydrate Form A.

[0020] Another aspect of the present disclosure provides a pharmaceutical composition comprising any of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein, which may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier. Yet another aspect of the present disclosure is a method for treating the CFTR-mediated disease cystic fibrosis, comprising administering any of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein, optionally as part of a pharmaceutical composition comprising at least one additional component (such as a carrier or an additional active agent), to a subject in need of treatment. A further aspect of the present disclosure provides a process for producing the crystalline forms of Compound I disclosed herein.

[0021] One embodiment is a compound comprising (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I), alone or in combination with (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-( Methods for treating the CFTR-mediated disease cystic fibrosis are provided, comprising administering in combination with 1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II), and / or N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-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).

[0022] In certain embodiments, a method of treating the CFTR-mediated disease cystic fibrosis includes administering Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein in combination with Compound III or III-d and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV).

[0023] In some embodiments, Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in the same composition as Compound II and Compound III. In some embodiments, Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in the same composition as Compound II and Compound III-d. In some embodiments, Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in the same composition as Compound III and Compound IV. In some embodiments, Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in the same composition as Compound III-d and Compound IV.

[0024] In some embodiments, a composition comprising Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein is administered simultaneously with a separate composition comprising Compound II and / or Compound III. In some embodiments, a composition comprising Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein is administered simultaneously with a separate composition comprising Compound II and / or Compound III-d. In some embodiments, a composition comprising Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein is administered simultaneously with a separate composition comprising Compound III and Compound IV. In some embodiments, a composition comprising Compound I in one of the pharmaceutically acceptable crystalline forms disclosed herein is administered simultaneously with a separate composition comprising Compound III-d and Compound IV. [Brief explanation of the drawings]

[0025] [Figure 1] 1 provides an XRPD pattern of Form A of crystalline Compound I (free form). [Figure 2] 1 shows the 13C solid-state NMR spectrum of Form A of crystalline Compound I (free form). [Figure 3] 1 provides an XRPD pattern of Form B of crystalline Compound I (free form). [Figure 4]1 shows the 13C solid-state NMR spectrum of Form B of crystalline Compound I (free form). [Figure 5] 1 provides an XRPD pattern of Form C of crystalline Compound I (free form). [Figure 6] 1 provides an XRPD pattern of crystalline Compound I calcium salt hydrate Form A. [Figure 7] 1 shows the 13C solid-state NMR spectrum of calcium salt hydrate Form A of Compound I. [Figure 8] 1 provides an XRPD pattern of crystalline Compound I calcium salt hydrate Form B. [Figure 9] 1 shows the 13C solid-state NMR spectrum of calcium salt hydrate form B of Compound I. [Figure 10] 1 shows the 13C solid-state NMR spectrum of calcium salt hydrate / solvate form B of Compound I with MeOH. [Figure 11] 1 provides an XRPD pattern of crystalline Compound I calcium salt hydrate Form C. [Figure 12] 1 shows the 13C solid-state NMR spectrum of calcium salt hydrate Form C of Compound I. [Figure 13] 1 provides an XRPD pattern of crystalline Compound I calcium salt hydrate Form D. [Figure 14] 1 shows the 13C solid-state NMR spectrum of calcium salt hydrate form D of Compound I. [Figure 15] 1 provides an XRPD pattern of crystalline Compound I calcium salt hydrate Form E. [Figure 16] 1 provides an XRPD pattern of Form F of crystalline Compound I. [Figure 17] 1 provides an XRPD pattern of crystalline Compound I calcium salt hydrate Form G. [Figure 18] 1 provides an XRPD pattern of crystalline Compound I calcium salt EtOH solvate Form A. [Figure 19] 1 provides an XRPD pattern of crystalline Compound I calcium salt EtOH solvate Form B. [Figure 20]1 provides an XRPD pattern of crystalline Compound I calcium salt EtOH solvate Form C. [Figure 21] 21A and 21B provide XRPD patterns of the calcium salt IPA solvate of crystalline Compound I. Figure 21A shows a wet sample of calcium salt IPA solvate Form A of Compound I. Figure 21B shows an air-dried sample of calcium salt IPA solvate Form B of Compound I. [Figure 22] 22A and 22B provide XRPD patterns of the calcium salt NPA solvate of crystalline Compound I. Figure 22A shows a wet sample of calcium salt NPA solvate Form A of Compound I. Figure 22B shows an air-dried sample of calcium salt NPA solvate Form B of Compound I. [Figure 23] 23A and 23B provide XRPD patterns of the calcium salt 2-BuOH solvate of crystalline Compound I. Figure 23A shows a wet sample of calcium salt 2-BuOH solvate Form A of Compound I. Figure 23B shows an air-dried sample of calcium salt 2-BuOH solvate Form B of Compound I. [Figure 24] 1 provides an XRPD pattern of crystalline Compound I calcium salt acetone solvate Form A. [Figure 25] 1 provides an XRPD pattern of crystalline Compound I calcium salt DCM solvate Form A. [Figure 26] 1 shows the 13C solid-state NMR spectrum of calcium salt DCM solvate Form A of Compound I. [Figure 27] 1 provides an XRPD pattern of crystalline Compound I calcium salt ethylene glycol solvate Form A. [Figure 28] 1 shows the 13C solid-state NMR spectrum of calcium salt ethylene glycol solvate Form A of Compound I. [Figure 29] 1 provides an XRPD pattern of crystalline Compound I calcium salt ethylene glycol solvate Form B. [Figure 30] 1 provides an XRPD pattern of crystalline Compound I calcium salt 1,2-dimethoxyethane solvate Form A. [Figure 31]1 shows the 13C solid-state NMR spectrum of calcium salt 1,2-dimethoxyethane solvate Form A of Compound I. [Figure 32] 1 provides an XRPD pattern of crystalline Compound I calcium salt 1,2-dimethoxyethane solvate Form B. [Figure 33] 1 provides an XRPD pattern of crystalline Compound I calcium salt CPME solvate Form A. [Figure 34] 1 provides an XRPD pattern of crystalline Compound I sodium salt hydrate Form A. [Figure 35] 1 shows the 13C solid-state NMR spectrum of sodium salt hydrate form A of Compound I. [Figure 36] 1 provides an XRPD pattern of pure Form B of the sodium salt of crystalline Compound I. [Figure 37] 1 provides an XRPD pattern of crystalline Compound I sodium salt hydrate Form C. [Figure 38] 1 provides an XRPD pattern of crystalline Compound I sodium salt hydrate Form D. [Figure 39] 1 provides an XRPD pattern of crystalline Compound I potassium salt hydrate Form A. [Figure 40] 1 provides an XRPD pattern of crystalline Compound I potassium salt hydrate Form B. [Figure 41] 1 provides an XRPD pattern of crystalline Compound I potassium salt hydrate Form C. [Figure 42] 1 provides an XRPD pattern of crystalline Compound I potassium salt hydrate Form D. [Figure 43] 1 shows the 13C solid-state NMR spectrum of potassium salt hydrate form D of Compound I. [Figure 44] 1 provides an XRPD pattern of crystalline Compound I ammonium salt hydrate Form A. [Figure 45] 1 provides an XRPD pattern of crystalline Compound I calcium salt hydrate Form H. [Figure 46] 1 shows the 13C solid-state NMR spectrum of calcium salt hydrate form H of Compound I. [Figure 47]1 provides an XRPD pattern of Form D of crystalline Compound I (free form). [Figure 48] 1 shows the 13C solid-state NMR spectrum of Form D of Compound I (free form). [Figure 49] 1 provides an XRPD pattern of crystalline Compound I sodium salt hydrate Form E. [Figure 50] 1 shows the 13C solid-state NMR spectrum of crystalline Compound I sodium salt hydrate Form E. [Figure 51] 1 provides an XRPD pattern of crystalline Compound I sodium salt IPA solvate (wet) Form A. [Figure 52] 1 provides an XRPD pattern of crystalline Compound I sodium salt IPA solvate (dry) Form B. [Figure 53] 1 shows the 13C solid-state NMR spectrum of crystalline Compound I sodium salt IPA solvate (dry) Form B. DETAILED DESCRIPTION OF THE INVENTION

[0026] definition As used throughout this disclosure, "Compound I" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, which may be shown to have the following structure: [ka] Compound I can be a racemic mixture or an enantioenriched mixture of isomers (e.g., greater than 90% ee, greater than 95% ee, greater than 98% ee). Compound I can be in the form of a pharmaceutically acceptable salt, solvate, and / or hydrate. Compound I and methods for making and using Compound I are disclosed in WO2019 / 161078, which is incorporated herein by reference.

[0027] As used throughout this disclosure, "Compound II" refers to (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, which can be shown to have the following structure: [ka] Compound II can be in the form of a pharmaceutically acceptable salt.Compound II and methods for making and using Compound II are disclosed in WO2010 / 053471, WO2011 / 119984 and WO2015 / 160787, each of which is incorporated herein by reference.

[0028] As used throughout this disclosure, "Compound III" refers to N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (also known as N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide), which may be shown to have the following structure: [ka] Compound III can also be in the form of a pharmaceutically acceptable salt. Compound III and methods for making and using Compound III are disclosed in WO2006 / 002421, WO2007 / 079139, and WO2010 / 019239, each of which is incorporated herein by reference.

[0029] In some embodiments, a deuterated derivative of compound III (compound III-d) is used in the compositions and methods disclosed herein. The chemical name of compound III-d is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d)propan-2-yl-1,1,1,3,3,3-d)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, which can be shown to have the following structure: [ka] Compound III-d can be in the form of a pharmaceutically acceptable salt. Compound III-d and methods for making and using compound III-d are disclosed in WO2012 / 158885 and WO2014 / 078842, which are incorporated herein by reference.

[0030] As used herein, "compound IV" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which can be shown to have the following structure: [ka] Compound IV can be in the form of a pharmaceutically acceptable salt.Compound IV and methods for making and using Compound IV are disclosed in WO2007 / 056341, WO2009 / 073757 and WO2009 / 076142, which are incorporated herein by reference.

[0031] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0032] As used herein, the terms "CFTR modulator" and "compound that modulates CFTR" refer interchangeably to compounds that increase the activity of CFTR. Increased activity resulting from a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0033] As used herein, the term "CFTR corrector" refers to a compound that promotes CFTR processing and trafficking to increase the amount of CFTR at the cell surface. Compounds I and II disclosed herein are CFTR correctors.

[0034] As used herein, the term "CFTR potentiator" refers to a compound that enhances ion transport and increases the channel activity of the CFTR protein located on the cell surface. Compounds III and III-d disclosed herein are CFTR potentiators. When a description of the combination of Compound I and another specific CFTR modulator is provided herein, it will be understood that a reference to "Compound III or III-d" in connection with a combination means that either Compound III or Compound III-d is included in the combination, but not both.

[0035] As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") refers to a biologically active compound.

[0036] As used herein, the term "pharmaceutically acceptable crystalline form" refers to a crystalline form of Compound I of the present disclosure, wherein the crystalline forms of Compound I (e.g., crystalline free form, crystalline salt, crystalline salt solvate, and crystalline salt hydrate) are non-toxic and suitable for use in pharmaceutical compositions.

[0037] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0038] As used herein, the terms "treatment," "treating," and the like refer to an improvement in CF or one or more of its symptoms, or a reduction in the severity of CF or one or more of its symptoms in a subject. As used herein, "treatment" includes, but is not limited to, enhancing growth, increasing weight gain, reducing mucus in the lungs, improving pancreatic and / or liver function, reducing lung infections, and / or reducing cough or shortness of breath in a subject. Improvement or a reduction in the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0039] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means that the two or more compounds, agents, or active pharmaceutical ingredients are administered to a patient before, simultaneously with, or after each other.

[0040] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include the specific dose, amount, or weight percent value, or a range of doses, amounts, or weight percents recognized by those skilled in the art to provide a pharmacological effect equivalent to that obtained from the specific dose, amount, or weight percent. The terms "about" and "approximately" can refer to a margin of error for a particular value, as determined by those skilled in the art, which depends in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" means within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

[0041] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are randomly arranged, such that there is no clearly defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions, and do not have a definite melting point. For example, an amorphous material is a solid material that does not have sharp characteristic crystalline peak(s) in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, a solid material may comprise an amorphous compound, and the material may be characterized, for example, by the lack of sharp, characteristic crystalline peak(s) in its XRPD spectrum (i.e., the material is amorphous but not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) may be seen in the XRPD pattern of the material. For a comparison of XRPD of amorphous and crystalline materials, see US 2004 / 0006237. A solid material comprising an amorphous compound may be characterized, for example, by a wider temperature range for melting of the solid material compared to the range of melting of a pure crystalline solid. Other techniques, such as, for example, solid-state NMR, may also be used to characterize crystalline or amorphous forms.

[0042] As used herein, the terms "crystal form," "crystalline form," and "Form" refer interchangeably to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. A crystalline form can be identified by, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and 13 C solid-state nuclear magnetic resonance ( 13C ssNMR). Thus, as used herein, the terms "crystalline form [X] of Compound (I)" and "crystalline form [C] potassium salt of Compound (I)" refer to crystalline forms of the compound (I) that can be identified and distinguished from one another by one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and 13 It refers to unique crystalline forms that can be identified and distinguished from one another by one or more characterization techniques, including C ssNMR. In some embodiments, the novel crystalline forms are characterized by an X-ray powder diffraction pattern having one or more signals at one or more specified 2θ values ​​(°2θ).

[0043] As used herein, the term "free form" refers to the non-ionized version of a compound in the solid state. Examples of free forms include free bases and free acids.

[0044] As used herein, the term "solvate" refers to a crystalline form that contains one or more molecules of a compound of the present disclosure and that contains one or more molecules of a stoichiometric or non-stoichiometric amount of solvent(s) incorporated into the crystal lattice. When the solvent is water, the solvate is referred to as a "hydrate."

[0045] In some embodiments, the solid material may contain a mixture of crystalline solids and amorphous solids. A solid material containing an amorphous compound may contain, for example, up to 30% crystalline solids. In some embodiments, a solid material prepared to contain an amorphous compound may contain, for example, up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solids. In embodiments where the solid material contains a mixture of crystalline solids and amorphous solids, characterization data such as XRPD may contain indicators of both crystalline solids and amorphous solids. In some embodiments, the crystalline form of the present disclosure may contain up to 30% amorphous compound. In some embodiments, a crystalline preparation of Compound I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% amorphous solids.

[0046] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order in the position of its molecules. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity, less than 5% crystallinity, or less than 2% crystallinity). Note that the term "substantially amorphous" also includes the descriptor "amorphous," which refers to a material that has no (0%) crystallinity.

[0047] As used herein, the term "substantially crystalline" refers to a solid material having few or no amorphous molecules. For example, a substantially crystalline material has less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). Note also that the term "substantially crystalline" includes the descriptor "crystalline," which refers to a material that is 100% crystalline.

[0048] As used herein, a crystalline form is "substantially pure" when it accounts for 90% or more by weight of the sum of all solid form(s) in a sample, as determined by art-recognized methods such as quantitative XRPD. In some embodiments, a solid form is "substantially pure" when it accounts for 95% or more by weight of the sum of all solid form(s) in a sample. In some embodiments, a solid form is "substantially pure" when it accounts for 99% or more by weight of the sum of all solid form(s) in a sample.

[0049] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. The XRPD patterns disclosed herein were recorded in transmission or reflection geometry using a diffractometer at ambient conditions.

[0050] As used herein, the term "ambient conditions" refers to room temperature, open air conditions, and uncontrolled humidity conditions. The terms "room temperature" and "ambient temperature" refer to temperatures between 15°C and 30°C.

[0051] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern," and "XRPD spectrum" refer interchangeably to an experimentally obtained pattern plotting signal position (on the abscissa) versus signal intensity (on the ordinate). For amorphous materials, an X-ray powder diffractogram may include one or more broad signals; for crystalline materials, an X-ray powder diffractogram may include one or more signals, each identified by its angular value, measured in degrees 2θ (°2θ), shown on the abscissa of the X-ray powder diffractogram, and may be expressed as "a signal at ⋅⋅°2θ," "a signal at [one (a)] 2θ value(s) of ⋅⋅," and / or "a signal at at least 2θ value(s) selected from ⋅⋅."

[0052] As used herein, a "signal" or "peak" refers to a point in an XRPD pattern where the intensity, as measured in counts, is at a local maximum. Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and, for example, may not be clearly visible to the naked eye. Indeed, those skilled in the art will recognize that several art-recognized methods are possible and suitable for determining whether a signal is present in a pattern, such as Rietveld refinement.

[0053] As used herein, "signal at . . . °2θ" refers to the X-ray reflection position (°2θ) measured and observed in an X-ray powder diffraction experiment.

[0054] The repeatability of the measured angle values ​​is within ±0.2°2θ, i.e., the angle value can be the recited angle value +0.2°2θ, the angle value −0.2°2θ, or any value between those two endpoints (angle value +0.2°2θ and angle value −0.2°2θ).

[0055] The terms "signal intensity" and "peak intensity" refer interchangeably to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect relative signal or peak intensity include sample thickness and preferred orientation (e.g., crystalline grains are not randomly distributed).

[0056] As used herein, an X-ray powder diffractogram is "substantially similar to that in a [particular] diagram" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the signals in the two diffractograms overlap. In determining "substantially similar," one skilled in the art will understand that even for the same crystalline form, there may be variations in intensity and / or signal position in an XRPD diffractogram. Thus, one skilled in the art will understand that signal maxima (°2θ) in an XRPD diffractogram generally mean that the values ​​are identified as ±0.2°2θ of the reported value with art-recognized variances.

[0057] As used herein, 13 A C solid-state nuclear magnetic resonance (ssNMR) spectrum is "substantially similar to that in a [particular] figure" if 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 "substantially similar," one skilled in the art will understand that even for the same crystalline form, there may be variations in intensity and / or signal positions in ssNMR spectra. Thus, one skilled in the art will understand that chemical shifts in ssNMR spectra (referred to herein in parts per million (ppm)) generally mean values ​​are identified as ±0.2 ppm of the reported value with art-recognized variances.

[0058] As used herein, the term "X-ray powder diffractogram having signals at 2θ values" refers to an XRPD pattern containing the positions of X-ray reflections (°2θ) measured and observed in an X-ray powder diffraction experiment.

[0059] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0060] 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).

[0061] 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 greatly (e.g., colloidal particles ranging from nanometer dimensions to several microns in size). Generally, the dispersed phase can be a solid, liquid, or gas. In solid dispersions, both the dispersed and continuous phases are solids. In pharmaceutical applications, a solid dispersion may contain 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, the solid dispersion contains a polymer that constitutes the dispersed phase, and the drug constitutes the continuous phase. Alternatively, the solid dispersion contains a drug that constitutes the dispersed phase and a polymer that constitutes the continuous phase.

[0062] It should be noted that the disclosed amounts of Compound I are based on its Ca salt. Those skilled in the art will recognize that when an amount of Compound I is disclosed, it also refers to the amount of Compound I in a crystalline form that is equivalent or bioequivalent to the concentration of the Ca salt of Compound I. For example, "100 mg of Compound I" should be interpreted as referring not only to 100 mg of Compound I (free form), but also to an amount of any one of the pharmaceutically acceptable crystalline forms disclosed herein that is equivalent or bioequivalent to 100 mg of the Ca salt of Compound I.

[0063] Crystalline Form A of Compound I (free form) In some embodiments, the present invention provides crystalline Compound I (free form) Form A. Figure 1 provides the X-ray powder diffraction diagram of crystalline Compound I (free form) Form A at room temperature.

[0064] In some embodiments, Compound I (free form) is substantially pure crystalline Form A. In some embodiments, Compound I (free form) is substantially crystalline Form A. In some embodiments, crystalline Compound I (free form) Form A is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0065] In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 9.2±0.2 degrees 2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 11.3±0.2 degrees 2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 14.0±0.2 degrees 2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 22.9±0.2 degrees 2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having at least one signal selected from 9.2±0.2 degrees 2θ, 11.3±0.2 degrees 2θ, 14.0±0.2 degrees 2θ, and 22.9±0.2 degrees 2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having at least two signals selected from 9.2±0.2°2θ, 11.3±0.2°2θ, 14.0±0.2°2θ, and 22.9±0.2°2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having at least three signals selected from 9.2±0.2°2θ, 11.3±0.2°2θ, 14.0±0.2°2θ, and 22.9±0.2°2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having signals at 9.2±0.2°2θ, 11.3±0.2°2θ, 14.0±0.2°2θ, and 22.9±0.2°2θ.

[0066] In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern having (a) signals at 9.2±0.2°2θ, 11.3±0.2°2θ, 14.0±0.2°2θ, and / or 22.9±0.2°2θ (i.e., one or more signals from this group), and (b) one, two, three, or four signals selected from 20.0±0.2°2θ, 23.1±0.2°2θ, 16.6±0.2°2θ, and 23.3±0.2°2θ.

[0067] In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having (a) a signal at 9.2±0.2°2θ, (b) a signal at 16.6±0.2°2θ, and (c) a signal at 20.0±0.2°2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having (a) signals at 9.2±0.2°2θ, 16.6±0.2°2θ, and 20.0±0.2°2θ, and (b) signals at 11.3±0.2°2θ, 14.0±0.2°2θ, and / or 22.9±0.2°2θ.

[0068] In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern having (a) signals at 9.2±0.2°2θ, 16.6±0.2°2θ, and 20.0±0.2°2θ, and (b) one, two, three, four, five, or more signals selected from 11.3±0.2°2θ, 14.0±0.2°2θ, 18.1±0.2°2θ, 22.9±0.2°2θ, 23.1±0.2°2θ, and 23.3±0.2°2θ. In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern having signals at 9.2±0.2°2θ, 16.6±0.2°2θ, 20.0±0.2°2θ, 11.3±0.2°2θ, 14.0±0.2°2θ, 18.1±0.2°2θ, 22.9±0.2°2θ, 23.1±0.2°2θ, and 23.3±0.2°2θ.

[0069] In some embodiments, Form A of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0070] In some embodiments, Form A of crystalline Compound I (free form) has one, two, three, four, five, six, seven, or more peaks selected from 163.2±0.2 ppm, 130.2±0.2 ppm, 104.6±0.2 ppm, 103.9±0.2 ppm, 58.3±0.2 ppm, 49.7±0.2 ppm, 43.3±0.2 ppm, and 37.0±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 In some embodiments, Form A of crystalline Compound I (free form) is characterized by having a C ssNMR spectrum with peaks at 163.2±0.2 ppm, 130.2±0.2 ppm, 104.6±0.2 ppm, 103.9±0.2 ppm, 58.3±0.2 ppm, 49.7±0.2 ppm, 43.3±0.2 ppm, and 37.0±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0071] In some embodiments, Form A of crystalline Compound I (free form) has a structure substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0072] In some embodiments, Form A of crystalline Compound I (free form) has a monoclinic crystal system, P21 space group, and Mo K α It is characterized by the following unit cell dimensions measured at 298 K on a Bruker diffractometer equipped with a radiation (λ=0.71073 A) and a (charge-coupled device) CCD detector: [Table 1]

[0073] Another aspect of the present invention provides a method for making crystalline Form A of Compound I (free form), comprising crystallizing amorphous Compound I in toluene and drying under vacuum to obtain crystalline Form A of Compound I (free form).

[0074] Crystalline Form B of Compound I (free form) In some embodiments, the present invention provides crystalline Compound I (free form) Form B. Figure 3 provides the X-ray powder diffraction diagram of crystalline Compound I (free form) Form B at room temperature.

[0075] In some embodiments, Compound I (free form) is substantially pure crystalline Form B. In some embodiments, Compound I (free form) is substantially crystalline Form B. In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0076] In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 16.3±0.2°2θ. In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 17.7±0.2°2θ. In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having signals at 16.3±0.2°2θ and 17.7±0.2°2θ. In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having signals at 5.5±0.2°2θ, 16.3±0.2°2θ, and 17.7±0.2°2θ.

[0077] In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having one or more signals selected from (a) signals at 5.5±0.2°2θ, 16.3±0.2°2θ, and 17.7±0.2°2θ, and (b) 10.8±0.2°2θ, 28.3±0.2°2θ, and 25.9±0.2°2θ. In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having two or more peaks selected from (a) signals at 5.5±0.2°2θ, 16.3±0.2°2θ, and 17.7±0.2°2θ, and (b) 10.8±0.2°2θ, 28.3±0.2°2θ, and 25.9±0.2°2θ. In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern having signals at 5.5±0.2°2θ, 16.3±0.2°2θ, 17.7±0.2°2θ, 10.8±0.2°2θ, 28.3±0.2°2θ, and 25.9±0.2°2θ.

[0078] In some embodiments, Form B of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0079] In some embodiments, Form B of crystalline Compound I (free form) has one or more peaks selected from 142.8±0.2 ppm, 97.8±0.2 ppm, 18.1±0.2 ppm, and 2.3±0.2 ppm. 13 In some embodiments, Form B of crystalline Compound I (free form) is characterized by having a C ssNMR spectrum having: (a) two or more peaks selected from 142.8±0.2 ppm, 97.8±0.2 ppm, 18.1±0.2 ppm, and 2.3±0.2 ppm; and (b) one, two, three, four, five, or six peaks selected from 166.3±0.2 ppm, 137.2±0.2 ppm, 108.1±0.2 ppm, 37.6±0.2 ppm, 25.3±0.2 ppm, and 20.1±0.2 ppm. 13In some embodiments, Form B of crystalline Compound I (free form) is characterized by having a C ssNMR spectrum having peaks selected from 166.3±0.2 ppm, 142.8±0.2 ppm, 137.2±0.2 ppm, 108.1±0.2 ppm, 97.8±0.2 ppm, 37.6±0.2 ppm, 25.3±0.2 ppm, 20.1±0.2 ppm, 18.1±0.2 ppm, and 2.3±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0080] In some embodiments, Form B of crystalline Compound I (free form) has a structure substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0081] Another aspect of the present invention provides a method for making crystalline Form B of Compound I (free form), comprising stirring calcium salt hydrate Form D of Compound I in simulated intestinal fluid as fed, centrifuging the resulting slurry, removing the liquid, and air-drying the solid to obtain crystalline Form B of Compound I (free form).

[0082] Crystalline Form C of Compound I (free form) In some embodiments, the present invention provides crystalline Compound I (free form) Form C. Figure 5 provides the X-ray powder diffraction diagram of crystalline Compound I (free form) Form C at room temperature.

[0083] In some embodiments, Compound I (free form) is substantially pure crystalline Form C. In some embodiments, Compound I (free form) is substantially crystalline Form C. In some embodiments, Form C of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0084] In some embodiments, Form C of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having signals at 6.3±0.2°2θ, 14.8±0.2°2θ, and 20.4±0.2°2θ.

[0085] In some embodiments, Form C of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern having one or more signals selected from (a) signals at 6.3±0.2°2θ, 14.8±0.2°2θ, and 20.4±0.2°2θ, and (b) signals at 15.5±0.2°2θ, 18.5±0.2°2θ, 19.2±0.2°2θ, 20.1±0.2°2θ, 23.8±0.2°2θ, and 26.4±0.2°2θ. In some embodiments, Form C of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern having (a) signals at 6.3±0.2°2θ, 14.8±0.2°2θ, and 20.4±0.2°2θ, and (b) two, three, four, five, or six signals selected from 15.5±0.2°2θ, 18.5±0.2°2θ, 19.2±0.2°2θ, 20.1±0.2°2θ, 23.8±0.2°2θ, and 26.4±0.2°2θ. In some embodiments, Form C of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having signals at 6.3±0.2°2θ, 14.8±0.2°2θ, 15.5±0.2°2θ, 18.5±0.2°2θ, 19.2±0.2°2θ, 20.1±0.2°2θ, 20.4±0.2°2θ, 23.8±0.2°2θ, and 26.4±0.2°2θ.

[0086] In some embodiments, Form C of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0087] Another aspect of the present invention provides a method for making Compound I (free form) crystalline form C, comprising stirring Form A of Compound I (free form) in isopropyl alcohol (IPA) / HO at 25° C. to obtain crystalline form C of Compound I (free form).

[0088] Crystalline Form D of Compound I (free form) In some embodiments, the present invention provides crystalline Compound I (free form) Form D. Figure 47 provides the X-ray powder diffraction diagram of crystalline Compound I (free form) Form D at room temperature.

[0089] In some embodiments, Compound I (free form) is substantially pure crystalline Form D. In some embodiments, Compound I (free form) is substantially crystalline Form D. In some embodiments, crystalline Compound I (free form) Form D is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0090] In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 3.7±0.2°2θ. In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 7.4±0.2°2θ. In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having a signal at 12.2±0.2°2θ. In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having signals at 3.7±0.2°2θ, 7.4±0.2°2θ, and 12.2±0.2°2θ. In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having signals at 3.7±0.2°2θ, 7.4±0.2°2θ, and 17.3±0.2°2θ. In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern having signals at 3.7±0.2°2θ, 7.4±0.2°2θ, 12.2±0.2°2θ, and 17.3±0.2°2θ.

[0091] In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having (a) signals at 3.7±0.2°2θ, 7.4±0.2°2θ, and / or 12.2±0.2°2θ (i.e., any one, any two, or all three from this group), and (b) signals at 7.3±0.2°2θ, 17.3±0.2°2θ, and / or 10.4±0.2°2θ. In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffractogram having (a) signals at 3.7±0.2°2θ, 7.4±0.2°2θ, and / or 12.2±0.2°2θ, and (b) signals at 17.3±0.2°2θ and / or 10.4±0.2°2θ. In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern having signals at 3.7±0.2°2θ, 7.4±0.2°2θ, 12.2±0.2°2θ, 17.3±0.2°2θ, and 10.4±0.2°2θ.

[0092] In some embodiments, Form D of crystalline Compound I (free form) is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0093] In some embodiments, Form D of crystalline Compound I (free form) has two or more peaks selected from 164.6±0.2 ppm, 149.6±0.2 ppm, 135.7±0.2 ppm, 38.9±0.2 ppm, 27.6±0.2 ppm, and 15.7±0.2 ppm. 13 In some embodiments, Form D of crystalline Compound I (free form) is characterized by having a C ssNMR spectrum having three or more peaks selected from 164.6±0.2 ppm, 149.6±0.2 ppm, 135.7±0.2 ppm, 113.6±0.2 ppm, 38.9±0.2 ppm, 27.6±0.2 ppm, and 15.7±0.2 ppm. 13In some embodiments, Form D of crystalline Compound I (free form) is characterized by having a C ssNMR spectrum having four or more peaks selected from 164.6±0.2 ppm, 149.6±0.2 ppm, 135.7±0.2 ppm, 113.6±0.2 ppm, 38.9±0.2 ppm, 27.6±0.2 ppm, and 15.7±0.2 ppm. 13 In some embodiments, Form D of crystalline Compound I (free form) is characterized by having a C ssNMR spectrum with five, six, seven, or eight peaks selected from 164.6±0.2 ppm, 149.6±0.2 ppm, 135.7±0.2 ppm, 113.6±0.2 ppm, 38.9±0.2 ppm, 27.6±0.2 ppm, and 15.7±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0094] In some embodiments, Form D of crystalline Compound I (free form) has a structure substantially similar to that shown in FIG. 13 Characterized by C ssNMR.

[0095] Another aspect of the present invention provides a method for making Form D of crystalline Compound I (free form), comprising adding propanol to Compound I (free form), concentrating the mixture under reduced pressure, and repeating the procedure using toluene.

[0096] Calcium salt hydrate form A of compound I In some embodiments, the present invention provides calcium salt hydrate Form A of crystalline Compound I. Figure 6 provides the X-ray powder diffraction diagram of calcium salt hydrate Form A of Compound I at room temperature.

[0097] In some embodiments, calcium salt hydrate Form A of Compound I is substantially pure crystalline. In some embodiments, calcium salt hydrate of Compound I is substantially crystalline Form A. In some embodiments, calcium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0098] In some embodiments, calcium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ. In some embodiments, calcium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at (a) 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) 10.5±0.2°2θ and / or 10.6±0.2°2θ.

[0099] In some embodiments, calcium salt hydrate Form A of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0100] In some embodiments, the calcium salt hydrate Form A of Compound I has a peak at 17.0±0.2 ppm or 7.8±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum with peaks at 17.0±0.2 ppm and 7.8±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum having (a) peaks at one or both of 17.0±0.2 ppm and 7.8±0.2 ppm, and (b) one or more peaks selected from 178.3±0.2 ppm, 136.8±0.2 ppm, 93.6±0.2 ppm, and 26.4±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0101] In some embodiments, calcium salt hydrate Form A of Compound I has (a) peaks at one or both of 17.0±0.2 ppm and 7.8±0.2 ppm, and (b) two or more peaks selected from 178.3±0.2 ppm, 136.8±0.2 ppm, 93.6±0.2 ppm, and 26.4±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum having (a) peaks at one or both of 17.0±0.2 ppm and 7.8±0.2 ppm, and (b) three or more peaks selected from 178.3±0.2 ppm, 136.8±0.2 ppm, 93.6±0.2 ppm, and 26.4±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum with peaks at 178.3±0.2 ppm, 136.8±0.2 ppm, 93.6±0.2 ppm, 26.4±0.2 ppm, 17.0±0.2 ppm, and 7.8±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0102] In some embodiments, the calcium salt hydrate Form A of Compound I is substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0103] In some embodiments, calcium salt hydrate Form A of Compound I is monoclinic, C2 space group, and Cu K α It is characterized by the following unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with radiation (λ=1.5478 A) and a CCD detector: [Table 2]

[0104] In some embodiments, calcium salt hydrate Form A of Compound I is monoclinic, C2 space group, and Cu Kα It is characterized by the following unit cell dimensions measured at 298 K on a Bruker diffractometer equipped with radiation (λ=1.5478 A) and a CCD detector: [Table 3]

[0105] Another aspect of the present invention provides a method for making calcium salt hydrate Form A of Compound I, comprising charging Form A of Compound I (free form) and Ca(OMe) with IPA / HO at 70° C. to obtain calcium salt hydrate Form A of Compound I.

[0106] Calcium salt hydrate form B of compound I In some embodiments, the present invention provides calcium salt hydrate Form B of crystalline Compound I. Figure 8 provides the X-ray powder diffraction diagram of calcium salt hydrate Form B of Compound I at room temperature.

[0107] In some embodiments, calcium salt hydrate Form B of Compound I is substantially pure crystalline. In some embodiments, calcium salt hydrate of Compound I is substantially crystalline Form B. In some embodiments, calcium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0108] In some embodiments, calcium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 13.1±0.2°2θ, 14.6±0.2°2θ, and 17.7±0.2°2θ. In some embodiments, calcium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 12.2±0.2°2θ, 13.1±0.2°2θ, 14.6±0.2°2θ, and 17.7±0.2°2θ. In some embodiments, calcium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram having one or more signals selected from (a) signals at 12.2±0.2°2θ, 13.1±0.2°2θ, 14.6±0.2°2θ, and 17.7±0.2°2θ, and (b) 16.2±0.2°2θ, 20.4±0.2°2θ, and 21.3±0.2°2θ.

[0109] In some embodiments, calcium salt hydrate Form B of Compound I is characterized by an X-ray powder diffraction pattern having (a) signals at 12.2±0.2°2θ, 13.1±0.2°2θ, 14.6±0.2°2θ, and 17.7±0.2°2θ, and (b) one, two, three, or four signals selected from 16.2±0.2°2θ, 18.1±0.2°2θ, 20.4±0.2°2θ, and 21.3±0.2°2θ. In some embodiments, calcium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 12.2±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 17.7±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, and 21.3±0.2 degrees 2θ.

[0110] In some embodiments, calcium salt hydrate Form B of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0111] In some embodiments, the calcium salt hydrate Form B of Compound I has peaks at 119.6±0.2 ppm and / or 48.7±0.2 ppm. 13 C solid-state nuclear magnetic resonance (13 In some embodiments, calcium salt hydrate Form B of Compound I is characterized by having a C ssNMR spectrum. In some embodiments, calcium salt hydrate Form B of Compound I has (a) a peak at 119.6±0.2 ppm and / or 48.7±0.2 ppm, and (b) one or more peaks selected from 164.7±0.2 ppm, 148.9±0.2 ppm, 114.3±0.2 ppm, 97.7±0.2 ppm, and 25.9±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 In some embodiments, calcium salt hydrate Form B of Compound I is characterized by having a C ssNMR spectrum. In some embodiments, calcium salt hydrate Form B of Compound I has (a) a peak at 119.6±0.2 ppm and / or 48.7±0.2 ppm, and (b) two or more peaks selected from 164.7±0.2 ppm, 148.9±0.2 ppm, 114.3±0.2 ppm, 97.7±0.2 ppm, and 25.9±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 In some embodiments, calcium salt hydrate Form B of Compound I is characterized by having a C ssNMR spectrum. In some embodiments, calcium salt hydrate Form B of Compound I has (a) a peak at 119.6±0.2 ppm and / or 48.7±0.2 ppm, and (b) three or more peaks selected from 164.7±0.2 ppm, 148.9±0.2 ppm, 114.3±0.2 ppm, 97.7±0.2 ppm, and 25.9±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 In some embodiments, calcium salt hydrate Form B of Compound I is characterized by having a C ssNMR spectrum with peaks at 119.6±0.2 ppm, 48.7±0.2 ppm, 164.7±0.2 ppm, 148.9±0.2 ppm, 114.3±0.2 ppm, 97.7±0.2 ppm, and 25.9±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13In some embodiments, calcium salt hydrate Form B of Compound I is characterized by having a C ssNMR spectrum. In some embodiments, calcium salt hydrate Form B of Compound I has one or more peaks selected from (a) 175.8±0.2 ppm, 119.6±0.2 ppm, 48.7±0.2 ppm, 24.4±0.2 ppm, and 22.5±0.2 ppm, and (b) peaks at 164.7±0.2 ppm, 148.9±0.2 ppm, 114.3±0.2 ppm, 97.7±0.2 ppm, and 25.9±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 It is characterized by having a C ssNMR spectrum.

[0112] In some embodiments, calcium salt hydrate Form B of Compound I is substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0113] In some embodiments, isomorphous solvates, solvates / hydrates, and hydrates share the same XRPD pattern as calcium salt hydrate Form B of Compound I. The solvent can be MeOH, EtOH, IPA, and / or water.

[0114] In some embodiments, calcium salt hydrate / solvate Form B of Compound I with MeOH has peaks at 32.9±0.2 ppm and / or 23.3±0.2 ppm. 13 In some embodiments, calcium salt hydrate / solvate Form B of Compound I with MeOH is characterized by having a C ssNMR spectrum having (a) a peak at 32.9±0.2 ppm and / or 23.3±0.2 ppm, and (b) one or more peaks selected from 176.1±0.2 ppm, 164.7±0.2 ppm, 148.9±0.2 ppm, 49.3±0.2 ppm, and 25.9±0.2 ppm. 13In some embodiments, calcium salt hydrate / solvate Form B of Compound I with MeOH is characterized by having a C ssNMR spectrum having (a) peaks at 32.9±0.2 ppm and 23.3±0.2 ppm, and (b) one or more peaks selected from 176.1±0.2 ppm, 164.7±0.2 ppm, 148.9±0.2 ppm, 49.3±0.2 ppm, and 25.9±0.2 ppm. 13 In some embodiments, calcium salt hydrate / solvate Form B of Compound I with MeOH is characterized by having a C ssNMR spectrum with peaks at 32.9±0.2 ppm, 23.3±0.2 ppm, 176.1±0.2 ppm, 164.7±0.2 ppm, 148.9±0.2 ppm, 49.3±0.2 ppm, and 25.9±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0115] In some embodiments, calcium salt hydrate / solvate Form B of Compound I with MeOH is substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0116] In some embodiments, calcium salt hydrate / solvate Form B of Compound I with MeOH has a monoclinic crystal system, P21 space group, and Cu K α It is characterized by the following unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with radiation (λ=1.5478 A) and a CCD detector: [Table 4]

[0117] Another aspect of the present invention provides a method of making calcium salt hydrate Form B of Compound I, comprising slurrying the calcium salt of Compound I in EtOH / water. In some embodiments, the present invention provides a method of making calcium salt hydrate / solvate Form B of Compound I with MeOH, comprising adding MeOH to calcium salt hydrate Form B of Compound I.

[0118] Calcium salt hydrate form C of compound I In some embodiments, the present invention provides calcium salt hydrate Form C of crystalline Compound I. Figure 11 provides the X-ray powder diffraction diagram of calcium salt hydrate Form C of Compound I at room temperature.

[0119] In some embodiments, calcium salt hydrate Form C of Compound I is substantially pure crystalline. In some embodiments, calcium salt hydrate of Compound I is substantially crystalline Form C. In some embodiments, calcium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0120] In some embodiments, calcium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 10.3±0.2°2θ, 15.8±0.2°2θ, and 20.8±0.2°2θ. In some embodiments, calcium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 4.0±0.2°2θ, 10.3±0.2°2θ, 15.8±0.2°2θ, and 20.8±0.2°2θ. In some embodiments, calcium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having one or more signals selected from (a) signals at 4.0±0.2°2θ, 10.3±0.2°2θ, 15.8±0.2°2θ, and 20.8±0.2°2θ, and (b) 13.3±0.2°2θ, 14.3±0.2°2θ, and 19.0±0.2°2θ. In some embodiments, calcium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having two or more signals selected from (a) signals at 4.0±0.2°2θ, 10.3±0.2°2θ, 15.8±0.2°2θ, and 20.8±0.2°2θ, and (b) signals at 13.3±0.2°2θ, 14.3±0.2°2θ, and 19.0±0.2°2θ. In some embodiments, calcium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 4.0±0.2°2θ, 10.3±0.2°2θ, 13.3±0.2°2θ, 14.3±0.2°2θ, 15.8±0.2°2θ, 19.0±0.2°2θ, and 20.8±0.2°2θ.

[0121] In some embodiments, calcium salt hydrate Form C of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0122] In some embodiments, the calcium salt hydrate Form C of Compound I has one or more peaks selected from 115.7±0.2 ppm, 65.9±0.2 ppm, 52.7±0.2 ppm, and 21.4±0.2 ppm. 13In some embodiments, the calcium salt hydrate Form C of Compound I is characterized by having a C ssNMR spectrum having two or more peaks selected from 115.7±0.2 ppm, 65.9±0.2 ppm, 52.7±0.2 ppm, and 21.4±0.2 ppm. 13 In some embodiments, the calcium salt hydrate Form C of Compound I is characterized by having a C ssNMR spectrum having three or more peaks selected from 115.7±0.2 ppm, 65.9±0.2 ppm, 52.7±0.2 ppm, and 21.4±0.2 ppm. 13 In some embodiments, the calcium salt hydrate Form C of Compound I is characterized by having a C ssNMR spectrum having four or more peaks selected from 115.7±0.2 ppm, 65.9±0.2 ppm, 52.7±0.2 ppm, and 21.4±0.2 ppm. 13 In some embodiments, the calcium salt hydrate Form C of Compound I is characterized by having a C ssNMR spectrum with peaks at 115.7±0.2 ppm, 65.9±0.2 ppm, 52.7±0.2 ppm, and 21.4±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0123] In some embodiments, calcium salt hydrate Form C of Compound I has one or more peaks selected from (a) 115.7±0.2 ppm, 65.9±0.2 ppm, 52.7±0.2 ppm, and 21.4±0.2 ppm, and (b) one or more peaks selected from 178.3±0.2 ppm, 155.9±0.2 ppm, 137.7±0.2 ppm, 129.6±0.2 ppm, 112.0±0.2 ppm, 100.0±0.2 ppm, 37.8±0.2 ppm, 26.4±0.2 ppm, and 19.9±0.2 ppm. 13In some embodiments, calcium salt hydrate Form C of Compound I is characterized by having a C ssNMR spectrum. In some embodiments, calcium salt hydrate Form C of Compound I has (a) one or more peaks selected from 115.7±0.2 ppm, 96.0±0.2 ppm, 65.9±0.2 ppm, 52.7±0.2 ppm, and 21.4±0.2 ppm, and (b) two, three, four, five, six, or more peaks selected from 178.3±0.2 ppm, 155.9±0.2 ppm, 137.7±0.2 ppm, 129.6±0.2 ppm, 112.0±0.2 ppm, 100.0±0.2 ppm, 37.8±0.2 ppm, 26.4±0.2 ppm, and 19.9±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0124] In some embodiments, the calcium salt hydrate Form C of Compound I is substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0125] Another aspect of the present invention provides a method for making calcium salt hydrate Form C of Compound I, comprising stirring Form A of Compound I (free form) with calcium methoxide (Ca((OMe)2) in DCM (containing 10% water), isolating and drying the solid.

[0126] Calcium salt hydrate form D of compound I In some embodiments, the present invention provides calcium salt hydrate Form D of crystalline Compound I. Figure 13 provides the X-ray powder diffraction diagram of calcium salt hydrate Form D of Compound I at room temperature.

[0127] In some embodiments, calcium salt hydrate Form D of Compound I is substantially pure crystalline. In some embodiments, calcium salt hydrate of Compound I is substantially crystalline Form D. In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0128] In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ. In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having one or more signals selected from (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) signals at 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ.

[0129] In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having two or more signals selected from (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ. In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) three or more signals selected from 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ. In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having four or more signals selected from (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) signals at 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ.

[0130] In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and 27.6±0.2°2θ. In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 6.1±0.2°2θ, 15.5±0.2°2θ, 16.2±0.2°2θ, 19.7±0.2°2θ, 22.8±0.2°2θ, and 27.6±0.2°2θ.

[0131] In some embodiments, calcium salt hydrate Form D of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0132] In some embodiments, the calcium salt hydrate Form D of Compound I has one or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum having two or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum having three or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm. 13In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum having four or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum having five or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum having six or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0133] In some embodiments, the calcium salt hydrate Form D of Compound I has one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum having two or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum with peaks at 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm. 13It is characterized by having a C ssNMR spectrum.

[0134] In some embodiments, calcium salt hydrate Form D of Compound I has (a) peaks at 130.2±0.2 ppm, 125.6±0.2 ppm, and / or 35.0±0.2 ppm, and (b) peaks at 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and / or 98.6±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum. In some embodiments, calcium salt hydrate Form D of Compound I has (a) peaks at 130.2±0.2 ppm, 125.6±0.2 ppm, and / or 35.0±0.2 ppm, and (b) peaks at 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and 98.6±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum with peaks at (a) 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm, and (b) 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and / or 98.6±0.2 ppm. 13 In some embodiments, calcium salt hydrate Form D of Compound I is characterized by having a C ssNMR spectrum with peaks at 130.2±0.2 ppm, 125.6±0.2 ppm, 35.0±0.2 ppm, 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and 98.6±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0135] In some embodiments, calcium salt hydrate Form D of Compound I is substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0136] In some embodiments, calcium salt hydrate Form D of Compound I is a triclinic crystal, P1 space group, and Cu K α It is characterized by the following unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with a radiation (λ=1.5478 A) and a complementary metal-oxide-semiconductor (CMOS) detector: [Table 5]

[0137] Another aspect of the present invention provides a method for making calcium salt hydrate Form D of Compound I, comprising charging calcium salt hydrate Form A of Compound I with EtOH / water and heating to 65°C.

[0138] Calcium salt hydrate form E of compound I In some embodiments, the present invention provides calcium salt hydrate Form E of crystalline Compound I. Figure 15 provides the X-ray powder diffraction diagram of calcium salt hydrate Form E of Compound I at room temperature.

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

[0140] In some embodiments, calcium salt hydrate Form E of Compound I is characterized by an X-ray powder diffractogram having signals at 8.0±0.2°2θ, 12.0±0.2°2θ, and 24.2±0.2°2θ. In some embodiments, calcium salt hydrate Form E of Compound I is characterized by an X-ray powder diffractogram having signals at 4.0±0.2°2θ, 8.0±0.2°2θ, 12.0±0.2°2θ, and 24.2±0.2°2θ. In some embodiments, calcium salt hydrate Form E of Compound I is characterized by an X-ray powder diffractogram having signals at 4.0±0.2°2θ, 8.0±0.2°2θ, 12.0±0.2°2θ, 24.2±0.2°2θ, and 28.3±0.2°2θ.

[0141] In some embodiments, calcium salt hydrate Form E of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0142] Another aspect of the present invention provides a method for making calcium salt hydrate Form E of Compound I, comprising subjecting calcium salt hydrate Form A of Compound I to solid vapor diffusion in EtOAc.

[0143] Form F of Compound I Elemental analysis data for two batches of Form F of Compound I indicated the presence of both Ca and Na, indicating that Form F of Compound I may be a mixed Ca-Na salt of Compound I, or a mixture of Ca and Na salts of Compound I. In some embodiments, the present invention provides crystalline Form F of Compound I. Figure 16 provides the X-ray powder diffraction diagram of calcium salt hydrate Form F of Compound I at room temperature.

[0144] In some embodiments, Form F of Compound I is substantially pure crystalline. In some embodiments, Compound I is substantially crystalline Form F. In some embodiments, Form F of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0145] In some embodiments, Form F of Compound I is characterized by an X-ray powder diffractogram having signals at 5.3±0.2°2θ, 7.5±0.2°2θ, and 9.1±0.2°2θ. In some embodiments, Compound I is characterized by an X-ray powder diffractogram having signals at 5.3±0.2°2θ, 9.1±0.2°2θ, and 11.9±0.2°2θ. In some embodiments, Form F of Compound I is characterized by an X-ray powder diffractogram having signals at 7.5±0.2°2θ, 9.1±0.2°2θ, and 11.9±0.2°2θ. In some embodiments, Form F of Compound I is characterized by an X-ray powder diffractogram having signals at 5.3±0.2°2θ, 7.5±0.2°2θ, 9.1±0.2°2θ, and 11.9±0.2°2θ.

[0146] In some embodiments, Form F of Compound I is characterized by an X-ray powder diffractogram having signals at 5.3±0.2 degrees 2θ, 7.5±0.2 degrees 2θ, 9.1±0.2 degrees 2θ, 10.6±0.2 degrees 2θ, and 11.9±0.2 degrees 2θ.

[0147] In some embodiments, Form F of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0148] In some embodiments, Form F of Compound I is characterized by: [Table 6]

[0149] Calcium salt hydrate form G of compound I In some embodiments, the present invention provides calcium salt hydrate Form G of crystalline Compound I. Figure 17 provides the X-ray powder diffraction diagram of calcium salt hydrate Form G of Compound I at room temperature.

[0150] In some embodiments, calcium salt hydrate Form G of Compound I is substantially pure crystalline. In some embodiments, calcium salt hydrate of Compound I is substantially crystalline Form G. In some embodiments, calcium salt hydrate Form G of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0151] In some embodiments, calcium salt hydrate Form G of Compound I is characterized by an X-ray powder diffractogram having signals at 5.9±0.2°2θ, 8.8±0.2°2θ, and 26.6±0.2°2θ. In some embodiments, calcium salt hydrate Form G of Compound I is characterized by an X-ray powder diffractogram having one or more signals selected from (a) signals at 5.9±0.2°2θ, 8.8±0.2°2θ, and 26.6±0.2°2θ, and (b) signals at 6.0±0.2°2θ, 11.8±0.2°2θ, 11.9±0.2°2θ, 14.8±0.2°2θ, and 14.7±0.2°2θ. In some embodiments, calcium salt hydrate Form G of Compound I is characterized by an X-ray powder diffractogram having signals at 5.9±0.2°2θ, 6.0±0.2°2θ, 8.8±0.2°2θ, 11.8±0.2°2θ, 11.9±0.2°2θ, 14.8±0.2°2θ, 14.7±0.2°2θ, and 26.6±0.2°2θ.

[0152] In some embodiments, calcium salt hydrate Form G of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0153] Another aspect of the present invention provides a method for making calcium salt hydrate Form G of Compound I, comprising rapid cooling a solution of calcium salt hydrate Form A of Compound I in EtOH:HO (90:10).

[0154] Calcium salt form H of compound I In some embodiments, the present invention provides calcium salt Form H of crystalline Compound I. Figure 45 provides the X-ray powder diffraction diagram of calcium salt Form H of Compound I at room temperature.

[0155] In some embodiments, Compound I is a substantially pure crystalline calcium salt Form H. In some embodiments, Compound I is a substantially crystalline calcium salt Form H. In some embodiments, the calcium salt Form H of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0156] In some embodiments, calcium salt Form H of Compound I is characterized by an X-ray powder diffractogram having signals at 5.8±0.2°2θ, 13.0±0.2°2θ, and 14.5±0.2°2θ. In some embodiments, calcium salt Form H of Compound I is characterized by an X-ray powder diffractogram having one or more signals selected from (a) signals at 5.8±0.2°2θ, 13.0±0.2°2θ, and 14.5±0.2°2θ, and (b) signals at 8.3±0.2°2θ, 12.0±0.2°2θ, 19.5±0.2°2θ, and 27.9±0.2°2θ. In some embodiments, the calcium salt Form H of Compound I is characterized by an X-ray powder diffraction pattern having signals at 5.8±0.2 degrees 2θ, 12.0±0.2 degrees 2θ, 13.0±0.2 degrees 2θ, 14.5±0.2 degrees 2θ, and 27.9±0.2 degrees 2θ.

[0157] In some embodiments, calcium salt Form H of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0158] In some embodiments, the calcium salt Form H of Compound I has peaks at 148.9±0.2 ppm, 27.2±0.2 ppm, and 4.8±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13In some embodiments, the calcium salt Form H of Compound I is characterized by having a C ssNMR spectrum. In some embodiments, the calcium salt Form H of Compound I has one or more peaks selected from (a) 148.9±0.2 ppm, 27.2±0.2 ppm, and 4.8±0.2 ppm, and (b) 164.7±0.2 ppm, 128.3±0.2 ppm, 117.0±0.2 ppm, and 19.4±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 In some embodiments, the calcium salt Form H of Compound I is characterized by having a C ssNMR spectrum. In some embodiments, the calcium salt Form H of Compound I has two, three, or four peaks selected from (a) 148.9±0.2 ppm, 27.2±0.2 ppm, and 4.8±0.2 ppm, and (b) 164.7±0.2 ppm, 128.3±0.2 ppm, 117.0±0.2 ppm, and 19.4±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 It is characterized by having a C ssNMR spectrum.

[0159] In some embodiments, the calcium salt Form H of Compound I is substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0160] In some embodiments, calcium salt Form H of Compound I is characterized by a triclinic crystal system, a P1 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer utilizing synchrotron radiation (0.7288 A) and a CMOS detector: [Table 7]

[0161] Another aspect of the present invention provides a method of making calcium salt Form H of Compound I, comprising mixing calcium salt hydrate Form B of Compound I in IPA / water.

[0162] Calcium Salt EtOH Solvate Form A of Compound I In some embodiments, the present invention provides crystalline calcium salt EtOH solvate Form A of Compound I. Figure 18 provides the X-ray powder diffraction diagram of calcium salt EtOH solvate Form A of Compound I at room temperature.

[0163] In some embodiments, calcium salt EtOH solvate Form A of Compound I is substantially pure crystalline. In some embodiments, calcium salt EtOH solvate Form A of Compound I is substantially crystalline. In some embodiments, calcium salt EtOH solvate Form A of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0164] In some embodiments, calcium salt EtOH solvate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 4.1±0.2°2θ, 8.2±0.2°2θ, and 17.1±0.2°2θ. In some embodiments, calcium salt EtOH solvate Form A of Compound I is characterized by an X-ray powder diffractogram having (a) signals at 4.1±0.2°2θ, 8.2±0.2°2θ, and 17.1±0.2°2θ, and (b) signals at 8.5±0.2°2θ and / or 16.5±0.2°2θ.

[0165] In some embodiments, calcium salt EtOH solvate Form A of Compound I is characterized by an X-ray powder diffractogram having at least two signals selected from 8.2±0.2 degrees two-theta, 8.5±0.2 degrees two-theta, 16.5±0.2 degrees two-theta, and 17.1±0.2 degrees two-theta. In some embodiments, calcium salt EtOH solvate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 8.2±0.2 degrees two-theta, 8.5±0.2 degrees two-theta, 16.5±0.2 degrees two-theta, and 17.1±0.2 degrees two-theta.

[0166] In some embodiments, calcium salt EtOH solvate Form A of Compound I is characterized by an X-ray powder diffractogram having (a) signals at 8.2±0.2°2θ, 8.5±0.2°2θ, 16.5±0.2°2θ, and / or 17.1±0.2°2θ, and (b) at least one signal selected from 4.1±0.2°2θ, 4.8±0.2°2θ, 5.6±0.2°2θ, and 20.3±0.2°2θ.

[0167] In some embodiments, calcium salt EtOH solvate Form A of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0168] Another aspect of the present invention provides a method for making the calcium salt EtOH solvate Form A of Compound I, comprising rapid cooling a solution of the calcium salt of Compound I in EtOH:HO (85:15).

[0169] Calcium Salt EtOH Solvate Form B of Compound I In some embodiments, the present invention provides crystalline calcium salt EtOH solvate Form B of Compound I. Figure 19 provides the X-ray powder diffraction diagram of calcium salt EtOH solvate Form B of Compound I at room temperature.

[0170] In some embodiments, calcium salt EtOH solvate Form B of Compound I is substantially pure crystalline. In some embodiments, calcium salt EtOH solvate Form B of Compound I is substantially crystalline. In some embodiments, calcium salt EtOH solvate Form B of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0171] In some embodiments, calcium salt EtOH solvate Form B of Compound I is characterized by an X-ray powder diffractogram having a signal at 15.4±0.2°2θ. In some embodiments, calcium salt EtOH solvate Form B of Compound I is characterized by an X-ray powder diffractogram having (a) a signal at 15.4±0.2°2θ, and (b) signals at 4.5±0.2°2θ and / or 5.0±0.2°2θ. In some embodiments, calcium salt EtOH solvate Form B of Compound I is characterized by an X-ray powder diffractogram having (a) a signal at 15.4±0.2°2θ, and (b) at least two signals selected from 4.5±0.2°2θ, 5.0±0.2°2θ, and 20.3±0.2°2θ. In some embodiments, calcium salt EtOH solvate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 4.5±0.2 degrees 2θ, 5.0±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, and 20.3±0.2 degrees 2θ.

[0172] In some embodiments, calcium salt EtOH solvate Form B of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0173] Another aspect of the present invention provides a method for making calcium salt EtOH solvate Form B of Compound I, comprising temperature cycling of calcium salt hydrate Form A of Compound I in EtOH:n-heptane (1:1) from 60°C to 5°C at a cooling rate of 0.2°C / min.

[0174] Calcium Salt EtOH Solvate Form C of Compound I In some embodiments, the present invention provides crystalline calcium salt EtOH solvate Form C of Compound I. Figure 20 provides the X-ray powder diffraction diagram of calcium salt EtOH solvate Form C of Compound I at room temperature.

[0175] In some embodiments, calcium salt EtOH solvate Form C of Compound I is substantially pure crystalline. In some embodiments, calcium salt EtOH solvate Form C of Compound I is substantially crystalline. In some embodiments, calcium salt EtOH solvate Form C of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0176] In some embodiments, calcium salt EtOH solvate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 4.2±0.2 degrees 2θ, 5.0±0.2 degrees 2θ, and 5.7±0.2 degrees 2θ.

[0177] In some embodiments, calcium salt EtOH solvate Form C of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0178] Another aspect of the present invention provides a method for making the calcium salt EtOH solvate Form C of Compound I, comprising making a slurry of amorphous calcium salt of Compound I with EtOH:HO (9:1) at room temperature.

[0179] Sodium Salt Hydrate Form A of Compound I In some embodiments, the present invention provides sodium salt hydrate Form A of crystalline Compound I. Figure 34 provides the X-ray powder diffraction diagram of sodium salt hydrate Form A of Compound I at room temperature.

[0180] In some embodiments, sodium salt hydrate Form A of Compound I is substantially pure crystalline. In some embodiments, sodium salt hydrate Form A of Compound I is substantially crystalline. In some embodiments, sodium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0181] In some embodiments, sodium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 5.4±0.2°2θ, 15.9±0.2°2θ, and 17.6±0.2°2θ. In some embodiments, sodium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having at least one, at least two, at least three, at least four, or at least five signals selected from (a) signals at 5.4±0.2°2θ, 15.9±0.2°2θ, and 17.6±0.2°2θ, and (b) signals at 15.3±0.2°2θ, 18.6±0.2°2θ, 21.3±0.2°2θ, 23.9±0.2°2θ, 20.0±0.2°2θ, and 26.7±0.2°2θ. In some embodiments, sodium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 5.4±0.2°2θ, 15.9±0.2°2θ, 17.6±0.2°2θ, 15.3±0.2°2θ, 18.6±0.2°2θ, 21.3±0.2°2θ, 23.9±0.2°2θ, 20.0±0.2°2θ, and 26.7±0.2°2θ.

[0182] In some embodiments, sodium salt hydrate Form A of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0183] In some embodiments, the sodium salt hydrate Form A of Compound I has at least one peak selected from 177.0±0.2 ppm, 159.6±0.2 ppm, 138.5±0.2 ppm, 107.0±0.2 ppm, 96.4±0.2 ppm, 38.3±0.2 ppm, and 28.9±0.2 ppm. 13 In some embodiments, the sodium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum having at least two peaks selected from 177.0±0.2 ppm, 159.6±0.2 ppm, 138.5±0.2 ppm, 107.0±0.2 ppm, 96.4±0.2 ppm, 38.3±0.2 ppm, and 28.9±0.2 ppm. 13In some embodiments, the sodium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum having at least three peaks selected from 177.0±0.2 ppm, 159.6±0.2 ppm, 138.5±0.2 ppm, 107.0±0.2 ppm, 96.4±0.2 ppm, 38.3±0.2 ppm, and 28.9±0.2 ppm. 13 In some embodiments, the sodium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum having at least four peaks selected from 177.0±0.2 ppm, 159.6±0.2 ppm, 138.5±0.2 ppm, 107.0±0.2 ppm, 96.4±0.2 ppm, 38.3±0.2 ppm, and 28.9±0.2 ppm. 13 In some embodiments, the sodium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum having at least five peaks selected from 177.0±0.2 ppm, 159.6±0.2 ppm, 138.5±0.2 ppm, 107.0±0.2 ppm, 96.4±0.2 ppm, 38.3±0.2 ppm, and 28.9±0.2 ppm. 13 In some embodiments, the sodium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum with peaks at 177.0±0.2 ppm, 159.6±0.2 ppm, 138.5±0.2 ppm, 107.0±0.2 ppm, 96.4±0.2 ppm, 38.3±0.2 ppm, and 28.9±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum.

[0184] In some embodiments, the sodium salt hydrate Form A of Compound I is substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0185] In some embodiments, sodium salt hydrate Form A of Compound I is characterized by an orthorhombic crystal system, P212121 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer using synchrotron radiation (0.7288 A): [Table 8]

[0186] Another aspect of the present invention provides a method for making sodium salt hydrate Form A of Compound I, comprising mixing amorphous sodium salt of Compound I with IPA / water at room temperature for two weeks.

[0187] Sodium salt pure form B of compound I In some embodiments, the present invention provides pure Form B of the sodium salt of crystalline Compound I. Figure 36 provides the X-ray powder diffraction diagram of pure Form B of the sodium salt of Compound I at room temperature.

[0188] In some embodiments, pure Form B of the sodium salt of Compound I is substantially pure crystalline. In some embodiments, pure Form B of the sodium salt of Compound I is substantially crystalline. In some embodiments, pure Form B of the sodium salt of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0189] In some embodiments, pure Form B of the sodium salt of Compound I is characterized by an X-ray powder diffractogram having signals at 11.0±0.2°2θ, 18.1±0.2°2θ, and 20.5±0.2°2θ. In some embodiments, pure Form B of the sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 12.8±0.2°2θ. In some embodiments, pure Form B of the sodium salt of Compound I is characterized by an X-ray powder diffractogram having (a) a signal at 12.8±0.2°2θ, and (b) signals at 11.0±0.2°2θ, 18.1±0.2°2θ, and / or 20.5±0.2°2θ. In some embodiments, the sodium salt pure form B of Compound I is characterized by an X-ray powder diffraction pattern having signals at 11.0±0.2 degrees 2θ, 12.8±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, and 20.5±0.2 degrees 2θ.

[0190] In some embodiments, pure Form B of the sodium salt of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0191] Another aspect of the present invention provides a method for making sodium salt pure Form B of Compound I, comprising desolvating / dehydrating sodium salt hydrate Form C of Compound I.

[0192] Sodium salt hydrate form C of compound I In some embodiments, the present invention provides sodium salt hydrate Form C of crystalline Compound I. Figure 37 provides the X-ray powder diffraction diagram of sodium salt hydrate Form C of Compound I at room temperature.

[0193] In some embodiments, the sodium salt hydrate Form C of Compound I is substantially pure crystalline. In some embodiments, the sodium salt hydrate Form C of Compound I is substantially crystalline. In some embodiments, the sodium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0194] In some embodiments, sodium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 6.1±0.2°2θ, 13.4±0.2°2θ, and 19.2±0.2°2θ. In some embodiments, sodium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 4.5±0.2°2θ and / or 10.3±0.2°2θ. In some embodiments, sodium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having (a) signals at 4.5±0.2°2θ and / or 10.3±0.2°2θ, and (b) signals at 6.1±0.2°2θ, 13.4±0.2°2θ, and / or 19.2±0.2°2θ. In some embodiments, sodium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 4.5±0.2 degrees 2θ, 6.1±0.2 degrees 2θ, 10.3±0.2 degrees 2θ, 13.4±0.2 degrees 2θ, and 19.2±0.2 degrees 2θ.

[0195] In some embodiments, sodium salt hydrate Form C of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0196] Another aspect of the present invention provides a method for making sodium salt hydrate Form C of Compound I, comprising stirring amorphous sodium salt of Compound I with ACN at room temperature.

[0197] Sodium Salt Hydrate Form D of Compound I In some embodiments, the present invention provides sodium salt hydrate Form D of crystalline Compound I. Figure 38 provides the X-ray powder diffraction diagram of sodium salt hydrate Form D of Compound I at room temperature.

[0198] In some embodiments, sodium salt hydrate Form D of Compound I is substantially pure crystalline. In some embodiments, sodium salt hydrate Form D of Compound I is substantially crystalline. In some embodiments, sodium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0199] In some embodiments, sodium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 7.8±0.2°2θ, 18.5±0.2°2θ, and 19.9±0.2°2θ. In some embodiments, sodium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 9.3±0.2°2θ, 14.8±0.2°2θ, 27.3±0.2°2θ, and / or 29.1±0.2°2θ. In some embodiments, sodium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at (a) 7.8±0.2°2θ, 18.5±0.2°2θ, and 19.9±0.2°2θ, and (b) 9.3±0.2°2θ, 14.8±0.2°2θ, and / or 27.3±0.2°2θ. In some embodiments, sodium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 7.8±0.2°2θ, 9.3±0.2°2θ, 14.8±0.2°2θ, 18.5±0.2°2θ, and 19.9±0.2°2θ, and 27.3±0.2°2θ.

[0200] In some embodiments, sodium salt hydrate Form D of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0201] Another aspect of the present invention provides a method for making sodium salt hydrate Form D of Compound I, comprising drying sodium salt hydrate Form C of Compound I under vacuum at 80°C.

[0202] Sodium salt hydrate form E of compound I In some embodiments, the present invention provides sodium salt hydrate Form E of crystalline Compound I. Figure 49 provides the X-ray powder diffraction diagram of sodium salt hydrate Form E of Compound I at room temperature.

[0203] In some embodiments, sodium salt hydrate Form E of Compound I is substantially pure crystalline. In some embodiments, sodium salt hydrate Form E of Compound I is substantially crystalline. In some embodiments, sodium salt hydrate Form E of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0204] In some embodiments, sodium salt hydrate Form E of Compound I is characterized by an X-ray powder diffractogram having signals at 4.3±0.2°2θ, 13.0±0.2°2θ, and 14.9±0.2°2θ. In some embodiments, sodium salt hydrate Form E of Compound I is characterized by an X-ray powder diffractogram having signals at: (a) 4.3±0.2°2θ, 13.0±0.2°2θ, and 14.9±0.2°2θ, and (b) 10.6±0.2°2θ, 11.7±0.2°2θ, 13.4±0.2°2θ, 14.1±0.2°2θ, 14.2±0.2°2θ, 17.3±0.2°2θ, 18.3±0.2°2θ, 19.3±0.2°2θ, 20.3±0.2°2θ, 21.3±0.2°2θ, 22.3±0.2°2θ, 23.3±0.2°2θ, 24.3±0.2°2θ, 25.3±0.2°2θ, 26.3±0.2°2θ, 27.3±0.2°2θ, 28.3±0.2°2θ, 29.3±0.2°2θ, 30.3±0.2°2θ, 31.3±0.2°2θ, 32.3±0.2°2θ, 33.3±0.2°2θ, 34.3±0.2°2θ, 35.3±0.2°2θ, 36.3±0.2°2θ, 37.3±0.2°2θ, 38.3±0.2°2θ, 39.3±0.2°2θ, 40.3 and characterized by an X-ray powder diffractogram having at least one signal selected from signals at 18.1±0.2°2θ, 18.8±0.2°2θ, 19.2±0.2°2θ, 20.0±0.2°2θ, 21.4±0.2°2θ, 21.5±0.2°2θ, 22.3±0.2°2θ, and 23.1±0.2°2θ. In some embodiments, the sodium salt hydrate Form E of Compound I exhibits (a) signals at 4.3±0.2°2θ, 13.0±0.2°2θ, and 14.9±0.2°2θ, and (b) signals at 10.6±0.2°2θ, 11.7±0.2°2θ, 13.4±0.2°2θ, 14.1±0.2°2θ, 14.2±0.2°2θ, 17.3±0.2°2θ, 18.1 and 23.1±0.2°2θ.

[0205] In some embodiments, sodium salt hydrate Form E of Compound I is characterized by an X-ray powder diffractogram having signals at 4.3±0.2 degrees 2θ, 13.0±0.2 degrees 2θ, and 23.1±0.2 degrees 2θ.

[0206] In some embodiments, sodium salt hydrate Form E of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0207] In some embodiments, the sodium salt hydrate Form E of Compound I has at least one peak selected from 165.2±0.2 ppm, 155.4±0.2 ppm, 142.7±0.2 ppm, 128.4±0.2 ppm, 121.3±0.2 ppm, 101.0±0.2 ppm, 93.1±0.2 ppm, 69.5±0.2 ppm, 62.6±0.2 ppm, 55.2±0.2 ppm, 50.6±0.2 ppm, 50.0±0.2 ppm, 21.1±0.2 ppm, 17.2±0.2 ppm, 7.2±0.2 ppm, and 2.1±0.2 ppm. 13 In some embodiments, the sodium salt hydrate Form E of Compound I is characterized by having a C ssNMR spectrum having two, three, four, five, six, seven, or more peaks selected from 165.2±0.2 ppm, 155.4±0.2 ppm, 142.7±0.2 ppm, 128.4±0.2 ppm, 121.3±0.2 ppm, 101.0±0.2 ppm, 93.1±0.2 ppm, 69.5±0.2 ppm, 62.6±0.2 ppm, 55.2±0.2 ppm, 50.6±0.2 ppm, 50.0±0.2 ppm, 21.1±0.2 ppm, 17.2±0.2 ppm, 7.2±0.2 ppm, and 2.1±0.2 ppm. 13 In some embodiments, the sodium salt hydrate Form E of Compound I is characterized by having a C ssNMR spectrum of 165.2±0.2 ppm, 155.4±0.2 ppm, 142.7±0.2 ppm, 128.4±0.2 ppm, 121.3±0.2 ppm, 101.0±0.2 ppm, 93.1±0.2 ppm, 69.5±0.2 ppm, 62.6±0.2 ppm, 55.2±0.2 ppm, 50.6±0.2 ppm, 50.0±0.2 ppm, 21.1±0.2 ppm, 17.2±0.2 ppm, 7.2±0.2 ppm, and 2.1±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum peak.

[0208] In some embodiments, the sodium salt hydrate Form E of Compound I has an RI of 177.4±0.2 ppm, 165.2±0.2 ppm, 155.4±0.2 ppm, 142.7±0.2 ppm, 128.4±0.2 ppm, 121.3±0.2 ppm, 101.0±0.2 ppm, 69.5±0.2 ppm, 62.6±0.2 ppm, 55.2±0.2 ppm, 50.0±0.2 ppm, 30.9±0.2 ppm, 30.2±0.2 ppm, 27.8±0.2 ppm, 21.1±0.2 ppm, 17.2±0.2 ppm, 7.2±0.2 ppm, and 2.1±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum peak.

[0209] In some embodiments, the sodium salt hydrate Form E of Compound I is substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0210] In some embodiments, the sodium salt hydrate Form E of Compound I has an orthorhombic crystal system, a C2221 space group, and the following Cu K α It is characterized by its unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with a 1.54178 A radiation beam. [Table 9]

[0211] Another aspect of the present invention provides a method for making sodium salt hydrate Form E of Compound I, comprising heating sodium salt hydrate Form A of Compound I in IPA and water at 65° C., cooling the mixture to 45° C., seeding with crystals of sodium salt hydrate Form A of Compound I, cooling the mixture to 20° C., collecting the solid, then washing with IPA:water (1:3 v:v), air-drying, then adding IPA, NaOH, and water to the solid, heating to 73° C., polish-filtering the solution, cooling to 58° C., adding water, seeding with crystals of sodium salt hydrate Form E of Compound I at 40° C., cooling to 5° C., collecting the solid, washing the solid with a mixture of water and IPA, and drying under vacuum at 40° C. to obtain sodium salt hydrate Form E of Compound I.

[0212] Another aspect of the present invention provides a method for making sodium salt hydrate Form E of Compound I, comprising dissolving sodium salt hydrate Form A of Compound I in IPA / water at 65° C., cooling the solution to 45° C., seeding with a mixture of sodium salt hydrate Form A and Form E of Compound I, adding water, cooling to 20° C., collecting the solid, washing the solid with a mixture of water and IPA, and drying under vacuum to obtain sodium salt hydrate Form E of Compound I.

[0213] Sodium Salt IPA (Wet) Solvate Form A of Compound I In some embodiments, the present invention provides sodium salt IPA (wet) solvate Form A of Compound I. Figure 51 provides the X-ray powder diffraction diagram of sodium salt IPA (wet) solvate Form A of Compound I at room temperature.

[0214] In some embodiments, sodium salt IPA (wet) solvate Form A of Compound I is substantially pure crystalline. In some embodiments, sodium salt IPA (wet) solvate Form A of Compound I is substantially crystalline. In some embodiments, sodium salt IPA (wet) solvate Form A of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0215] In some embodiments, sodium salt IPA (wet) solvate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 3.5±0.2 degrees 2θ and / or 3.6±0.2 degrees 2θ. In some embodiments, sodium salt IPA (wet) solvate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at (a) 3.5±0.2 degrees 2θ and / or 3.6±0.2 degrees 2θ, and (b) 9.5±0.2 degrees 2θ.

[0216] In some embodiments, the sodium salt IPA (wet) solvate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 3.6±0.2 degrees 2θ, 3.5±0.2 degrees 2θ, and 9.5±0.2 degrees 2θ.

[0217] In some embodiments, the sodium salt IPA (wet) solvate Form A of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0218] Another aspect of the present invention provides a method for making the sodium salt IPA (wet) solvate Form A of Compound I, comprising slurrying amorphous sodium salt hydrate Form A of Compound I in IPA.

[0219] Sodium Salt IPA (Dry) Solvate Form B of Compound I In some embodiments, the present invention provides sodium salt IPA (dry) solvate Form B of Compound I. Figure 52 provides the X-ray powder diffraction diagram of sodium salt IPA (dry) solvate Form B of Compound I at room temperature.

[0220] In some embodiments, sodium salt IPA (dry) solvate Form B of Compound I is substantially pure crystalline. In some embodiments, sodium salt IPA (dry) solvate Form B of Compound I is substantially crystalline. In some embodiments, sodium salt IPA (dry) solvate Form B of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0221] In some embodiments, sodium salt IPA (dry) solvate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 4.0±0.2°2θ and 5.3±0.2°2θ. In some embodiments, sodium salt IPA (dry) solvate Form B of Compound I is characterized by an X-ray powder diffractogram having at least one signal selected from (a) signals at 4.0±0.2°2θ and 5.3±0.2°2θ, and (b) signals at 7.9±0.2°2θ, 9.7±0.2°2θ, 11.0±0.2°2θ, 13.9±0.2°2θ, 18.5±0.2°2θ, and 20.0±0.2°2θ. In some embodiments, sodium salt IPA (dry) solvate Form B of Compound I is characterized by an X-ray powder diffraction pattern having (a) signals at 4.0±0.2°2θ and 5.3±0.2°2θ, and (b) one, two, three, or four signals at 7.9±0.2°2θ, 9.7±0.2°2θ, 11.0±0.2°2θ, 13.9±0.2°2θ, 18.5±0.2°2θ, and 20.0±0.2°2θ.

[0222] In some embodiments, sodium salt IPA (dry) solvate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 4.0±0.2 degrees 2θ, 7.9±0.2 degrees 2θ, and 9.7±0.2 degrees 2θ.

[0223] In some embodiments, the sodium salt IPA (dry) solvate Form B of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0224] In some embodiments, the sodium salt IPA (dry) solvate Form B of Compound I has a NA of 180.3±0.2 ppm, 178.7±0.2 ppm, 164.7±0.2 ppm, 135.9±0.2 ppm, 127.0±0.2 ppm, 117.0±0.2 ppm, 105.4±0.2 ppm, 95.5±0.2 ppm, 94.4±0.2 ppm m, 68.9±0.2 ppm, 67.6±0.2 ppm, 64.1±0.2 ppm, 59.5±0.2 ppm, 54.5±0.2 ppm, 53.6±0.2 ppm, 32.7±0.2 ppm, 24.6±0.2 ppm, 20.2±0.2 ppm, 5.1±0.2 ppm, 3.6±0.2 ppm 13 In some embodiments, the sodium salt IPA (dry) solvate Form B of Compound I is characterized by having a C ssNMR spectrum of 180.3±0.2 ppm, 178.7±0.2 ppm, 164.7±0.2 ppm, 135.9±0.2 ppm, 127.0±0.2 ppm, 117.0±0.2 ppm, 105.4±0.2 ppm, 95.5±0.2 ppm, 94.4±0.2 ppm, 68.9±0.2 ppm. 2 ppm, 67.6 ± 0.2 ppm, 64.1 ± 0.2 ppm, 59.5 ± 0.2 ppm, 54.5 ± 0.2 ppm, 53.6 ± 0.2 ppm, 32.7 ± 0.2 ppm, 24.6 ± 0.2 ppm, 20.2 ± 0.2 ppm, 5.1 ± 0.2 ppm, 3.6 ± 0.2 ppm, or more peaks selected from the following: 13It is characterized by having a C ssNMR spectrum. In some embodiments, the sodium salt IPA (dry) solvate Form B of Compound I has an NA of 180.3±0.2 ppm, 178.7±0.2 ppm, 164.7±0.2 ppm, 135.9±0.2 ppm, 127.0±0.2 ppm, 117.0±0.2 ppm, 105.4±0.2 ppm, 95.5±0.2 ppm, 94.4±0.2 ppm, 68.9±0.2 ppm, 67.6±0.2 ppm, 64.1±0.2 ppm, 59.5±0.2 ppm, 54.5±0.2 ppm, 53.6±0.2 ppm, 32.7±0.2 ppm, 24.6±0.2 ppm, 20.2±0.2 ppm, 5.1±0.2 ppm, 3.6±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum peak.

[0225] In some embodiments, the sodium salt IPA (dry) solvate Form B of Compound I has an NA of 180.3±0.2 ppm, 178.7±0.2 ppm, 164.7±0.2 ppm, 135.9±0.2 ppm, 127.0±0.2 ppm, 117.0±0.2 ppm, 105.4±0.2 ppm, 95.5±0.2 ppm, 94.4±0.2 ppm, 67.6±0.2 ppm, 59.5±0.2 ppm, 53.6±0.2 ppm, 32.7±0.2 ppm, 27.2±0.2 ppm, 24.6±0.2 ppm, and 3.6±0.2 ppm. 13 It is characterized by having a C ssNMR spectrum peak.

[0226] In some embodiments, the sodium salt IPA (dry) solvate Form B of Compound I has a structure substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0227] Another aspect of the present invention provides a method for making sodium salt IPA (dry) solvate Form B of Compound I, comprising slurrying amorphous sodium salt hydrate Form A of Compound I in IPA, followed by drying under vacuum at 40° C. to obtain sodium salt IPA (dry) solvate Form B of Compound I.

[0228] Potassium salt hydrate form A of compound I In some embodiments, the present invention provides potassium salt hydrate Form A of crystalline Compound I. Figure 39 provides the X-ray powder diffraction diagram of potassium salt hydrate Form A of Compound I at room temperature.

[0229] In some embodiments, potassium salt hydrate Form A of Compound I is substantially pure crystalline. In some embodiments, potassium salt hydrate Form A of Compound I is substantially crystalline. In some embodiments, potassium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0230] In some embodiments, potassium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at 10.7±0.2°2θ. In some embodiments, potassium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at 10.7±0.2°2θ, and signals at 15.3±0.2°2θ and / or 20.4±0.2°2θ. In some embodiments, potassium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 10.7±0.2°2θ, 15.3±0.2°2θ, and 20.4±0.2°2θ.

[0231] In some embodiments, potassium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having (a) a signal at 10.7±0.2 degrees 2θ, and (b) one or more signals selected from 15.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, and 29.1±0.2 degrees 2θ. In some embodiments, potassium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 10.7±0.2 degrees 2θ, 15.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, and 29.1±0.2 degrees 2θ.

[0232] In some embodiments, potassium salt hydrate Form A of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0233] Another aspect of the present invention provides a method for making potassium salt hydrate Form A of Compound I, comprising reacting Form A of Compound I (free form) with potassium hydride / water and subjecting it to two heating and cooling cycles from 60° C. to room temperature.

[0234] Potassium salt hydrate form B of compound I In some embodiments, the present invention provides potassium salt hydrate Form B of crystalline Compound I. Figure 40 provides the X-ray powder diffraction diagram of potassium salt hydrate Form B of Compound I at room temperature.

[0235] In some embodiments, potassium salt hydrate Form B of Compound I is substantially pure crystalline. In some embodiments, potassium salt hydrate Form B of Compound I is substantially crystalline. In some embodiments, potassium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0236] In some embodiments, potassium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 4.7±0.2°2θ, 6.8±0.2°2θ, and 21.5±0.2°2θ. In some embodiments, potassium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 4.7±0.2°2θ, 6.8±0.2°2θ, 14.8±0.2°2θ, and 21.5±0.2°2θ.

[0237] In some embodiments, potassium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram having at least one signal selected from (a) 4.7±0.2°2θ, 6.8±0.2°2θ, and 21.5±0.2°2θ, and (b) 14.8±0.2°2θ, 15.2±0.2°2θ, 16.1±0.2°2θ, and 19.0±0.2°2θ. In some embodiments, potassium salt hydrate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at 4.7±0.2°2θ, 6.8±0.2°2θ, 14.8±0.2°2θ, 15.2±0.2°2θ, 16.1±0.2°2θ, 19.0±0.2°2θ, and 21.5±0.2°2θ.

[0238] In some embodiments, potassium salt hydrate Form B of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0239] Another aspect of the present invention provides a method for making potassium salt hydrate Form B of Compound I, comprising making a slurry of amorphous potassium salt of Compound I in ACN at room temperature and then at 60°C.

[0240] Potassium salt hydrate form C of compound I In some embodiments, the present invention provides potassium salt hydrate Form C of crystalline Compound I. Figure 41 provides the X-ray powder diffraction diagram of potassium salt hydrate Form C of Compound I at room temperature.

[0241] In some embodiments, potassium salt hydrate Form C of Compound I is substantially pure crystalline. In some embodiments, potassium salt hydrate Form C of Compound I is substantially crystalline. In some embodiments, potassium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0242] In some embodiments, potassium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 4.8±0.2°2θ, 6.3±0.2°2θ, and 14.2±0.2°2θ. In some embodiments, potassium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at 4.8±0.2°2θ, 6.3±0.2°2θ, 14.2±0.2°2θ, 13.5±0.2°2θ, and 27.1±0.2°2θ. In some embodiments, potassium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at: (a) 6.3±0.2°2θ, 4.8±0.2°2θ, 14.2±0.2°2θ, 13.5±0.2°2θ, and 27.1±0.2°2θ, and (b) 19.0±0.2°2θ and / or 15.8±0.2°2θ. In some embodiments, potassium salt hydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at: 6.3±0.2°2θ, 4.8±0.2°2θ, 14.2±0.2°2θ, 13.5±0.2°2θ, 27.1±0.2°2θ, 19.0±0.2°2θ, and 15.8±0.2°2θ.

[0243] In some embodiments, potassium salt hydrate Form C of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0244] Another aspect of the present invention provides a method for making potassium salt hydrate Form C of Compound I, comprising mixing amorphous potassium salt of Compound I with ACN at room temperature.

[0245] Potassium salt hydrate form D of compound I In some embodiments, the present invention provides potassium salt hydrate Form D of crystalline Compound I. Figure 42 provides the X-ray powder diffraction diagram of potassium salt hydrate Form D of Compound I at room temperature.

[0246] In some embodiments, potassium salt hydrate Form D of Compound I is substantially pure crystalline. In some embodiments, potassium salt hydrate Form D of Compound I is substantially crystalline. In some embodiments, potassium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0247] In some embodiments, potassium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 4.4±0.2 degrees 2θ, 15.3±0.2 degrees 2θ, and 13.1±0.2 degrees 2θ.

[0248] In some embodiments, potassium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at (a) 4.4±0.2°2θ, 15.3±0.2°2θ, and 13.1±0.2°2θ, and (b) 8.8±0.2°2θ. In some embodiments, potassium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 4.4±0.2°2θ, 8.8±0.2°2θ, 13.1±0.2°2θ, and 15.3±0.2°2θ.

[0249] In some embodiments, potassium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having at least one signal selected from (a) 4.4±0.2°2θ, 8.8±0.2°2θ, 13.1±0.2°2θ, and 15.3±0.2°2θ, and (b) 7.0±0.2°2θ, 8.1±0.2°2θ, and 21.9±0.2°2θ. In some embodiments, potassium salt hydrate Form D of Compound I is characterized by an X-ray powder diffractogram having signals at 4.4±0.2°2θ, 7.0±0.2°2θ, 8.1±0.2°2θ, 8.8±0.2°2θ, 13.1±0.2°2θ, and 15.3±0.2°2θ, and 21.9±0.2°2θ.

[0250] In some embodiments, potassium salt hydrate Form D of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0251] Another aspect of the present invention provides a method for making potassium salt hydrate Form D of Compound I, comprising mixing amorphous potassium salt of Compound I with ACN at room temperature and drying under vacuum at 29°C.

[0252] Ammonia salt hydrate form A of compound I In some embodiments, the present invention provides crystalline ammonia salt hydrate Form A of Compound I. Figure 44 provides the X-ray powder diffraction diagram of ammonia salt hydrate Form A of Compound I at room temperature.

[0253] In some embodiments, the ammonia salt hydrate Form A of Compound I is substantially pure crystalline. In some embodiments, the ammonia salt hydrate Form A of Compound I is substantially crystalline. In some embodiments, the ammonia salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0254] In some embodiments, the ammonia salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at 5.5±0.2°2θ. In some embodiments, the ammonia salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at 15.3±0.2°2θ. In some embodiments, the ammonia salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at 17.7±0.2°2θ. In some embodiments, the ammonia salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 5.5±0.2°2θ, 15.3±0.2°2θ, and / or 17.7±0.2°2θ. In some embodiments, the ammonia salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 5.5±0.2°2θ, 15.3±0.2°2θ, and 17.7±0.2°2θ.

[0255] In some embodiments, the ammonium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having (a) signals at 5.5±0.2°2θ, 15.3±0.2°2θ, and / or 17.7±0.2°2θ, and (b) at least one signal selected from 19.6±0.2°2θ, 20.9±0.2°2θ, and 18.0±0.2°2θ. In some embodiments, the ammonium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having (a) signals at 5.5±0.2°2θ, 15.3±0.2°2θ, and / or 17.7±0.2°2θ, and (b) signals at 18.0±0.2°2θ, 19.6±0.2°2θ, and / or 20.9±0.2°2θ. In some embodiments, the ammonium salt hydrate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at 5.5±0.2 degrees 2θ, 15.3±0.2 degrees 2θ, 17.7±0.2 degrees 2θ, 18.0±0.2 degrees 2θ, 19.6±0.2 degrees 2θ, and 20.9±0.2 degrees 2θ.

[0256] In some embodiments, the ammonium salt hydrate Form A of Compound I is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0257] Another aspect of the present invention provides a method for making the ammonium salt hydrate Form A of Compound I, comprising mixing Form A of amorphous Compound I (free form) with ammonium hydroxide in water.

[0258] Treatment methods Compound I, in its amorphous form or any one of the pharmaceutically acceptable crystalline forms disclosed herein, acts as a CFTR modulator, i.e., regulates CFTR activity in the body. Individuals suffering from mutations in the gene encoding CFTR may benefit from receiving a CFTR modulator. CFTR mutations can affect CFTR mass, i.e., the number of CFTR channels on the cell surface, or CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations that affect CFTR mass include those that cause defective synthesis (Class I defects), defective processing and trafficking (Class II defects), reduced synthesis of CFTR (Class V defects), and reduced surface stability of CFTR (Class VI defects). Mutations that affect CFTR function include those that cause abnormal gating (Class III defects) and defective conductance (Class IV defects). Some CFTR mutations exhibit characteristics of multiple classes. Specific mutations in the CFTR gene result in cystic fibrosis.

[0259] Therefore, in some embodiments, the present invention provides a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of Compound I, either as an amorphous solid or in any one of the pharmaceutically acceptable crystalline forms disclosed herein, alone or in combination with another active ingredient, such as another CFTR modulator. In some embodiments, the patient has the F508del / minimal function (MF) genotype, the F508del / F508del genotype (homozygous for the F508del mutation), the F508del / gating genotype, or the F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0260] In some embodiments, the patient is heterozygous and carries the F508del mutation in one allele and a mutation selected from Table 1 in the other allele. Table 1: CFTR mutations [Table 10-1] [Table 10-2]

[0261] In some embodiments, the present invention provides a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of Compound I as crystalline free form Form A of Compound I. In some embodiments, the method employs crystalline free form Form B of Compound I. In some embodiments, the method employs crystalline free form Form C of Compound I.

[0262] In some embodiments, the present invention provides a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of crystalline Compound I in the form of a calcium salt hydrate. In some embodiments, the crystalline form of Compound I is calcium salt hydrate Form A. In some embodiments, the crystalline form of Compound I is calcium salt hydrate Form B. In some embodiments, the crystalline form of Compound I is calcium salt hydrate Form C. In some embodiments, the crystalline form of Compound I is calcium salt hydrate Form D. In some embodiments, the crystalline form of Compound I is calcium salt hydrate Form E. In some embodiments, the crystalline form of Compound I is Form F. In some embodiments, the crystalline form of Compound I is calcium salt hydrate Form G. In some embodiments, the crystalline form of Compound I is calcium salt Form H.

[0263] In some embodiments, the present invention provides a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of a crystalline form of Compound I, wherein the crystalline form is a calcium salt solvate. In some embodiments, crystalline Compound I is calcium salt EtOH solvate Form A. In some embodiments, crystalline Compound I is calcium salt EtOH solvate Form B. In some embodiments, crystalline Compound I is calcium salt EtOH solvate Form C.

[0264] In some embodiments, the present invention provides a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of a crystalline form of Compound I, wherein the crystalline form is sodium salt hydrate form A. In some embodiments, the crystalline form of Compound I is sodium salt pure form B. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form C. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form D.

[0265] In some embodiments, a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of a crystalline form of Compound I, wherein the crystalline form is potassium salt hydrate Form A. In some embodiments, the crystalline form of Compound I is potassium salt hydrate Form A.

[0266] In some embodiments, the crystalline form of Compound I used in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis of the present invention is potassium salt hydrate Form C. In some embodiments, the crystalline form of Compound I used in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis of the present invention is potassium salt hydrate Form D.

[0267] In some embodiments, the crystalline form of Compound I used in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis of the present invention is ammonium salt hydrate Form A.

[0268] Combination therapy One aspect disclosed herein provides a method for treating cystic fibrosis and other CFTR-mediated diseases using Compound I in combination with other pharmaceutically active agents, including CFTR modulators. In some embodiments, Compound I is in amorphous form and can be administered in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from (a) Compound II and a pharmaceutically acceptable salt thereof, and (b) Compound III or Compound III-d and a pharmaceutically acceptable salt thereof. Thus, in some embodiments, the combination therapy provided herein comprises amorphous Compound I and at least one compound selected from Compound II, (Compound III or III-d), and a pharmaceutically acceptable salt thereof. In some embodiments, the combination therapy provided herein comprises at least one compound selected from amorphous Compound I and a pharmaceutically acceptable salt thereof, and at least one compound selected from (Compound III or III-d), Compound IV, and / or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein is administered in combination with at least one compound selected from Compound II and a pharmaceutically acceptable salt thereof. In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein is administered in combination with at least one compound selected from Compound III and a pharmaceutically acceptable salt thereof. In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein is administered in combination with at least one compound selected from Compound III-d and a pharmaceutically acceptable salt thereof. In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein is administered in combination with Compound II or a pharmaceutically acceptable salt thereof, and at least one compound selected from Compound III and a pharmaceutically acceptable salt thereof. In some embodiments, at least one compound selected from compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in combination with at least one compound selected from compound II and pharmaceutically acceptable salts thereof, and at least one compound selected from compound III-d and pharmaceutically acceptable salts thereof.

[0270] Each of Compound I (in any one of the pharmaceutically acceptable crystalline forms disclosed herein), II, and III or III-d, and their pharmaceutically acceptable salts, can be independently administered once a day, twice a day, or three times a day. In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein is administered once a day. In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein is administered twice a day. In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein and at least one compound selected from Compound II, and their pharmaceutically acceptable salts, are administered once a day. In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein and at least one compound selected from Compound II, and their pharmaceutically acceptable salts, are administered twice a day. In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein and at least one compound selected from Compound III or III-d, and pharmaceutically acceptable salts thereof, is administered once daily. In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein and at least one compound selected from Compound III or III-d, and pharmaceutically acceptable salts thereof, is administered twice daily.

[0271] In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein, at least one compound selected from Compound II, and their pharmaceutically acceptable salts, and at least one compound selected from Compound III or III-d, and their pharmaceutically acceptable salts, are administered once a day. In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein, at least one compound selected from Compound III or III-d, and their pharmaceutically acceptable salts, and at least one compound selected from Compound IV, and their pharmaceutically acceptable salts, are administered once a day. In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein, at least one compound selected from Compound II, and their pharmaceutically acceptable salts, and at least one compound selected from Compound III or III-d, and their pharmaceutically acceptable salts, are administered twice a day. In some embodiments, at least one compound selected from compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein, at least one compound selected from compound III or III-d, and pharmaceutically acceptable salts thereof, and at least one compound selected from compound IV, and pharmaceutically acceptable salts thereof, is administered twice daily.

[0272] In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein and at least one compound selected from Compound II, and pharmaceutically acceptable salts thereof, are administered once daily, and at least one compound selected from Compound III-d, and pharmaceutically acceptable salts thereof, are administered twice daily. In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein and at least one compound selected from Compound IV, and pharmaceutically acceptable salts thereof, are administered once daily, and at least one compound selected from Compound III-d, and pharmaceutically acceptable salts thereof, are administered twice daily.

[0273] In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein is administered in an amount of 5 mg to 100 mg. In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein is administered daily in an amount of 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments, at least one compound selected from any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein is administered once daily in an amount of 5 mg, 10 mg, or 20 mg. In some embodiments, 5 mg or 10 mg of any one of the pharmaceutically acceptable crystalline forms of Compound I disclosed herein is administered twice daily.

[0274] Compound I (any one of the pharmaceutically acceptable crystalline forms disclosed herein), II, (III or III-d), and their pharmaceutically acceptable salts can be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Such pharmaceutical compositions can be administered once a day or multiple times a day, such as twice a day. As used herein, the phrase "a given amount of API (e.g., compound I, II, (III, III-d), or a pharmaceutically acceptable salt thereof) is administered once or twice a day or daily" means that the given amount is administered once or twice a day per dose. For example, the phrase 50 mg of Compound II or a pharmaceutically acceptable salt thereof administered twice daily or every other day means that 50 mg of Compound II or an equivalent amount of a pharmaceutically acceptable salt thereof is administered twice daily per dose (e.g., 50 mg of Compound II or an equivalent amount of a pharmaceutically acceptable salt thereof is administered in the morning and 50 mg of Compound II or an equivalent amount of a pharmaceutically acceptable salt thereof is administered in the evening).

[0275] In some embodiments, at least one compound selected from compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in a first pharmaceutical composition, at least one compound selected from compound II and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition, and at least one compound selected from compound III and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0276] In some embodiments, at least one compound selected from compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in a first pharmaceutical composition, at least one compound selected from compound II and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition, and at least one compound selected from compound III-d and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0277] In some embodiments, at least one compound selected from compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in a first pharmaceutical composition, at least one compound selected from compound III or III-d and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition, and at least one compound selected from compound IV and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0278] In some embodiments, at least one compound selected from Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein is administered in a first pharmaceutical composition, and at least one compound selected from Compound II and a pharmaceutically acceptable salt thereof, and at least one compound selected from Compound III or III-d and a pharmaceutically acceptable salt thereof, are administered in a second pharmaceutical composition. In some embodiments, the second pharmaceutical composition comprises half of the daily dose of the at least one compound selected from Compound III, III-d, and a pharmaceutically acceptable salt thereof, and the remaining half of the at least one compound selected from Compound III, III-d, and a pharmaceutically acceptable salt thereof is administered in a third pharmaceutical composition.

[0279] In some embodiments, at least one compound selected from compound I, at least one compound selected from compound II and their pharmaceutically acceptable salts, and at least one compound selected from compound III, III-d and their pharmaceutically acceptable salts, are administered in a first pharmaceutical composition. In some embodiments, the first pharmaceutical composition is administered to a patient twice a day. In some embodiments, the first pharmaceutical composition is administered once a day. In some embodiments, the first pharmaceutical composition is administered once a day, and the second composition containing only compound III is administered once a day.

[0280] Any suitable pharmaceutical composition known in the art can be used for Compound I (any one of the pharmaceutically acceptable crystalline forms disclosed herein), Compound II, Compound III, Compound III-d, and their pharmaceutically acceptable salts.Some exemplary pharmaceutical compositions of Compound I and its pharmaceutically acceptable salts are described in Examples.Some exemplary pharmaceutical compositions of Compound II and its pharmaceutically acceptable salts can be found in WO2011 / 119984 and WO2014 / 014841, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of Compound III and pharmaceutically acceptable salts thereof can be found in WO2007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, and WO2013 / 130669, and some exemplary pharmaceutical compositions of Compound III-d and pharmaceutically acceptable salts thereof can be found in US8,865,902, US9,181,192, US9,512,079, WO2017 / 053455, and WO2018 / 080591, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions of Compound IV and pharmaceutically acceptable salts thereof can be found in WO2010 / 037066, WO2011 / 127421, and WO2014 / 071122, which are incorporated herein by reference.

[0281] In some embodiments, the crystalline form of Compound I used in the combination therapy of the invention is free form Compound I, Form A. In some embodiments, the combination therapy employs crystalline free form Compound I, Form B. In some embodiments, the combination therapy employs crystalline free form Compound I, Form C.

[0282] In some embodiments, the crystalline form of Compound I used in the combination therapy of the invention is a calcium salt hydrate. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form A. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form B. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form C. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form D. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form E. In some embodiments, the crystalline form of Compound I is form F. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form G. In some embodiments, the crystalline form of Compound I is calcium salt form H.

[0283] In some embodiments, the combination therapy of the present invention utilizes a crystalline form of Compound I, wherein the crystalline form is a calcium salt solvate. In some embodiments, crystalline Compound I is calcium salt EtOH solvate Form A. In some embodiments, crystalline Compound I is calcium salt EtOH solvate Form B. In some embodiments, crystalline Compound I is calcium salt EtOH solvate Form C.

[0284] In some embodiments, the combination therapy of the present invention comprises a crystalline form of Compound I, wherein the crystalline form is sodium salt hydrate form A. In some embodiments, the crystalline form of Compound I is sodium salt pure form B. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form C. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form D.

[0285] In some embodiments, the combination therapy of the present invention comprises a crystalline form of Compound I, wherein the crystalline form is potassium salt hydrate form A. In some embodiments, the crystalline form of Compound I is potassium salt hydrate form B.

[0286] In some embodiments, the crystalline form of Compound I used in the combination therapy of the invention is potassium salt hydrate form C. In some embodiments, the crystalline form of Compound I used in the combination therapy of the invention is potassium salt hydrate form D.

[0287] In some embodiments, the crystalline form of Compound I used in the combination therapy of the present invention is ammonium salt hydrate Form A.

[0288] Coordination structure of a particular crystal form One particular crystalline form involves Compound I being coordinated to a Ca ion. The coordinated structure has the chemical structure shown below: [ka] wherein R1 and R2 are the remainder of Compound I.

[0289] In each case, the calcium ion is coordinated by either 6, 7, or 8 atoms, with at least two atoms being two oxygen atoms from Compound I, and other atoms in the coordination sphere may include other atoms from the Compound I molecule, atoms from different Compound I molecules, water, or alcohol solvent.

[0290] Pharmaceutical Compositions Another aspect of the present invention provides pharmaceutical compositions comprising Compound I as an amorphous solid or in any one of the pharmaceutically acceptable crystalline forms disclosed herein. In some embodiments, the present invention provides pharmaceutical compositions comprising Compound I as an amorphous solid or in any one of the pharmaceutically acceptable crystalline forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the pharmaceutical composition comprises Compound I as an amorphous solid or in any one of the pharmaceutically acceptable crystalline forms disclosed herein and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator.

[0291] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective, and an anti-inflammatory agent.

[0292] In some embodiments, the present invention provides pharmaceutical compositions comprising at least one compound selected from Compound I, either as an amorphous solid or in any one of the pharmaceutically acceptable crystalline forms disclosed herein, and at least one pharmaceutically acceptable carrier.

[0293] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) 5 mg to 20 mg of Compound I (Compound I is any one of the pharmaceutically acceptable crystalline forms disclosed herein); (b) at least one compound selected from Compound II and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0294] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) 5 mg to 20 mg of compound I (compound I is any one of the pharmaceutically acceptable crystalline forms disclosed herein); (b) at least one compound selected from compound III, III-d, and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0295] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) 5 mg to 20 mg of Compound I (Compound I is any one of the pharmaceutically acceptable crystalline forms disclosed herein); (b) at least one compound selected from Compound II and pharmaceutically acceptable salts thereof; (c) at least one compound selected from Compound III and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0296] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) 5 mg to 20 mg of compound I (compound I is any one of the pharmaceutically acceptable crystalline forms disclosed herein); (b) at least one compound selected from compound II and pharmaceutically acceptable salts thereof; (c) at least one compound selected from compound III-d and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0297] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) 5 mg to 20 mg of compound I (compound I is any one of the pharmaceutically acceptable crystalline forms disclosed herein); (b) at least one compound selected from compound III or III-d and pharmaceutically acceptable salts thereof; (c) at least one compound selected from compound IV and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0298] In some embodiments, the disclosure provides pharmaceutical compositions comprising 5 mg to 20 mg of Compound I (wherein Compound I is in any one of the pharmaceutically acceptable crystalline forms disclosed herein), and optionally one or more additional CFTR modulators. In some embodiments, the compositions comprise about 5 mg, about 10 mg, or about 20 mg of Compound I and a pharmaceutically acceptable salt thereof, and optionally one or more additional CFTR modulators. In some embodiments, the compositions comprise: (a) 5 mg to 20 mg of at least one compound selected from Compound I (wherein Compound I is in any one of the pharmaceutically acceptable crystalline forms disclosed herein); (b) 50 mg to 100 mg of Compound II; and (c) 150 mg to 300 mg of Compound III or 50 mg to 150 mg of Compound III-d. In some embodiments, the composition comprises: (a) 5 mg to 20 mg of Compound I (Compound I is any one of the pharmaceutically acceptable crystalline forms disclosed herein); (b) 100 mg of Compound II; and (c) 150 mg of Compound III or 150 mg of Compound III-d.

[0299] In some embodiments, the disclosure provides a pharmaceutical composition comprising 5 mg of Compound I (Compound I is in any one of the pharmaceutically acceptable crystalline forms disclosed herein), and optionally one or more additional CFTR modulators. In some embodiments, the composition comprises 10 mg of Compound I (Compound I is in any one of the pharmaceutically acceptable crystalline forms disclosed herein), and optionally one or more additional CFTR modulators. In some embodiments, the disclosure provides a pharmaceutical composition comprising 20 mg of Compound I (Compound I is in any one of the pharmaceutically acceptable crystalline forms disclosed herein), and optionally one or more additional CFTR modulators. In some embodiments, the composition comprises: (a) 5 mg, 10 mg, or 20 mg of compound I (compound I is any one of the pharmaceutically acceptable crystalline forms disclosed herein); (b) 50 mg or 100 mg of compound II; and (c) 150 mg or 300 mg of compound III, or 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg of compound III-d.

[0300] Any pharmaceutical composition disclosed herein can comprise at least one pharmaceutically acceptable carrier.In some embodiments, at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicle and pharmaceutically acceptable adjuvant.In some embodiments, at least one pharmaceutically acceptable is selected from pharmaceutically acceptable filler, disintegrant, surfactant, binder, lubricant.

[0301] In some embodiments, the crystalline form of Compound I in a pharmaceutical composition of the present invention is free form Compound I, Form A. In some embodiments, the pharmaceutical composition comprises crystalline free form Compound I, Form B. In some embodiments, the pharmaceutical composition comprises crystalline free form Compound I, Form C.

[0302] In some embodiments, the crystalline form of Compound I in the pharmaceutical compositions of the present invention is a calcium salt hydrate. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form A. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form B. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form C. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form D. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form E. In some embodiments, the crystalline form of Compound I is form F. In some embodiments, the crystalline form of Compound I is calcium salt hydrate form G. In some embodiments, the crystalline form of Compound I is calcium salt form H.

[0303] In some embodiments, the pharmaceutical compositions of the present invention comprise a crystalline form of Compound I, wherein the crystalline form is a calcium salt solvate. In some embodiments, the crystalline Compound I is calcium salt EtOH solvate Form A. In some embodiments, the crystalline Compound I is calcium salt EtOH solvate Form B. In some embodiments, the crystalline Compound I is calcium salt EtOH solvate Form C.

[0304] In some embodiments, the pharmaceutical compositions of the present invention comprise a crystalline form of Compound I, wherein the crystalline form is sodium salt hydrate form A. In some embodiments, the crystalline form of Compound I is sodium salt pure form B. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form C. In some embodiments, the crystalline form of Compound I is sodium salt hydrate form D.

[0305] In some embodiments, the pharmaceutical compositions of the present invention comprise a crystalline form of Compound I, wherein the crystalline form is potassium salt hydrate form A. In some embodiments, the crystalline form of Compound I is potassium salt hydrate form B.

[0306] In some embodiments, the crystalline form of Compound I in a pharmaceutical composition of the invention is potassium salt hydrate form C. In some embodiments, the crystalline form of Compound I in a pharmaceutical composition of the invention is potassium salt hydrate form D.

[0307] In some embodiments, the crystalline form of Compound I in the pharmaceutical compositions of the present invention is ammonium salt hydrate Form A.

[0308] The pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR-mediated diseases.

[0309] As mentioned above, the pharmaceutical compositions disclosed herein can optionally further comprise at least one pharmaceutically acceptable carrier.At least one pharmaceutically acceptable carrier can be selected from adjuvants and vehicles.As used herein, at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants that are suitable for the specific dosage form desired.Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and JC B. Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, e.g., produces any undesired biological effect, or interacts in a deleterious manner with any component(s) of the other pharmaceutically acceptable compositions, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose), and the like. Ingredients include, but are not limited to, cellulose acetate, sodium cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, larkspur, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavors, fragrances, preservatives, and antioxidants.

[0310] Illustrative Embodiments 1. Compound I (free form), [ka] Compound I (free form), wherein Compound I is substantially crystalline Form A (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, and less than 5% of Compound I is in amorphous form). 2. Compound I according to embodiment 1, wherein compound I is 100% crystalline form A. 3. Compound I according to embodiment 1 or embodiment 2, wherein Form A of compound I (free form) is characterized by an X-ray powder diffraction pattern having signals at 9.2±0.2 degrees 2θ, 11.3±0.2 degrees 2θ, 14.0±0.2 degrees 2θ, and / or 22.9±0.2 degrees 2θ. 4. Compound I according to embodiment 1 or embodiment 2, wherein Form A of compound I (free form) is characterized by an X-ray powder diffraction pattern with signals at 9.2±0.2 degrees 2θ, 16.6±0.2 degrees 2θ, and / or 20.0±0.2 degrees 2θ. 5. Compound I according to embodiment 1 or embodiment 2, wherein Form A of compound I (free form) is characterized by an X-ray powder diffraction pattern having (a) signals at 9.2±0.2°2θ, 16.6±0.2°2θ, and 20.0±0.2°2θ, and (b) signals at 11.3±0.2°2θ, 14.0±0.2°2θ, 22.9±0.2°2θ, 23.1±0.2°2θ, and / or 23.3±0.2°2θ. 6. Compound I according to embodiment 1 or embodiment 2, wherein Form A of compound I (free form) is characterized by an X-ray powder diffraction pattern substantially similar to Figure 1. 7. Monoclinic system, P21 space group, and Mo K α Form A of compound I (free form) according to any one of embodiments 1 to 6, characterized by the following unit cell dimensions measured at 298 K on a Bruker diffractometer with radiation (λ=0.71073 A): [Table 11] 8. Form A of Compound I (free form) has one, two, three, four, five, six, seven, or more peaks selected from 163.2±0.2 ppm, 130.2±0.2 ppm, 104.6±0.2 ppm, 103.9±0.2 ppm, 58.3±0.2 ppm, 49.7±0.2 ppm, 43.3±0.2 ppm, and 37.0±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13Form A of compound I (free form) according to any one of embodiments 1 to 7, characterized by a C ssNMR spectrum. 9. Form A of Compound I (free form) has peaks at 163.2±0.2 ppm, 130.2±0.2 ppm, 104.6±0.2 ppm, 103.9±0.2 ppm, 58.3±0.2 ppm, 49.7±0.2 ppm, 43.3±0.2 ppm, and 37.0±0.2 ppm. 13 Form A of compound I (free form) according to any one of embodiments 1 to 7, characterized by C ssNMR spectrum. 10. Form A of Compound I (free form) is substantially similar to Figure 2 13 Form A of compound I (free form) according to any one of embodiments 1 to 7, characterized by C ssNMR. 11. Form A of compound I (free form) according to any one of embodiments 1 to 10, prepared by a process comprising crystallizing amorphous compound I in toluene and drying under vacuum to obtain crystalline form A of compound I (free form). 12. A pharmaceutical composition comprising Form A of compound I (free form) according to any one of embodiments 1 to 11, and optionally further comprising one or more additional CFTR-modulating compounds. 13. One or more additional CFTR modulating compounds are a. (a) Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 12, wherein the compound is (i) compound II and (ii) compound III or compound III-d. 14. Form A of compound I (free form) as defined in any one of embodiments 1 to 11, or a pharmaceutical composition as defined in embodiment 12 or embodiment 13, for use in the treatment of cystic fibrosis. 15. Use of Form A of compound I (free form) as defined in any one of embodiments 1 to 11, or a composition as defined in embodiment 12 or embodiment 13, in the manufacture of a medicament for the treatment of cystic fibrosis. 16. A method for treating cystic fibrosis, comprising administering Form A of compound I (free form) as described in any one of embodiments 1 to 11, or a pharmaceutical composition as described in embodiment 12 or embodiment 13, to a subject in need of treatment. 17. The compound of use according to embodiment 14, the use according to embodiment 15, or the method according to embodiment 19, wherein Form A of compound I (free form) according to any one of embodiments 1 to 11 is administered in combination with at least one additional CFTR-modulating compound. 18. Form A of compound I (free form) according to any one of embodiments 1 to 11 is a.(a) Compound III or Compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 17, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 19. The composition, method, use, or compound according to any one of embodiments 13 to 18, wherein compound II and / or compound III are in the form of a solid dispersion. 20. A method for preparing Form A of Compound I (free form) according to any one of embodiments 1 to 10, comprising crystallizing amorphous Compound I in toluene and drying under vacuum to obtain crystalline Form A of Compound I (free form). 21. Compound I (free form), wherein Compound I is substantially crystalline Form B (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, and less than 5% of Compound I is in amorphous form). 22. Compound I according to embodiment 21, wherein compound I is 100% crystalline form B. 23. Compound I according to embodiment 21 or embodiment 22, wherein form B of compound I (free form) is characterized by an X-ray powder diffraction pattern with signals at 16.3±0.2° 2θ, and / or 17.7±0.2° 2θ. 24. Compound I according to embodiment 21 or embodiment 22, wherein form B of compound I (free form) is characterized by an X-ray powder diffraction pattern having (a) signals at 16.3±0.2° 2θ and / or 17.7±0.2° 2θ, and (b) a signal at 5.5±0.2° 2θ. 25. Compound I according to embodiment 21 or embodiment 22, wherein form B of compound I (free form) is characterized by an X-ray powder diffraction pattern substantially similar to Figure 3. 26. Form B of Compound I (free form) has one, two, three, or four peaks selected from 142.8±0.2 ppm, 97.8±0.2 ppm, 18.1±0.2 ppm, and 2.3±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 Compound I according to any one of embodiments 21 to 25, characterized by a C ssNMR spectrum. 27. Form B of Compound I (free form) has (a) one, two, three, or four peaks selected from 142.8±0.2 ppm, 97.8±0.2 ppm, 18.1±0.2 ppm, and 2.3±0.2 ppm, and (b) one, two, three, four, five, or six peaks selected from 166.3±0.2 ppm, 137.2±0.2 ppm, 108.1±0.2 ppm, 37.6±0.2 ppm, 25.3±0.2 ppm, and 20.1±0.2 ppm. 13 Compound I according to any one of embodiments 21 to 25, characterized by a C ssNMR spectrum. 28. Form B of Compound I (free form) has peaks at 142.8±0.2 ppm, 108.1±0.2 ppm, 97.8±0.2 ppm, 37.6±0.2 ppm, 18.1±0.2 ppm, and 2.3±0.2 ppm. 13 Compound I according to any one of embodiments 21 to 25, characterized by a C ssNMR spectrum. 29. Form B of Compound I (free form) has peaks at 142.8±0.2 ppm, 166.3±0.2 ppm, 137.2±0.2 ppm, 25.3±0.2 ppm, and 20.1±0.2 ppm. 13Compound I according to any one of embodiments 21 to 25, characterized by a C ssNMR spectrum. 30. Form B of Compound I (free form) has peaks at 37.6±0.2 ppm, 166.3±0.2 ppm, 137.2±0.2 ppm, 25.3±0.2 ppm, and 20.1±0.2 ppm. 13 Compound I according to any one of embodiments 21 to 25, characterized by a C ssNMR spectrum. 31. Form B of Compound I (free form) is substantially similar to FIG. 13 Compound I according to any one of embodiments 21 to 25, characterized by C ssNMR. 32. Form B of compound I (free form) according to any one of embodiments 21-31, prepared by a process comprising stirring calcium salt hydrate Form D of compound I in simulated intestinal fluid as fed. 33. A method for preparing Form B of Compound I (free form) according to any one of embodiments 21-31, comprising stirring calcium salt hydrate Form D of Compound I in simulated intestinal fluid as fed. 34. A pharmaceutical composition comprising Form B of compound I (free form) according to any one of embodiments 21-32, optionally further comprising one or more additional CFTR-modulating compounds. 35. One or more additional CFTR modulating compounds are a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 34, wherein the compound is (i) compound II and (ii) compound III or compound III-d. 36. Form B of compound I (free form) as defined in any one of embodiments 21-32, or a pharmaceutical composition as defined in embodiment 34 or embodiment 35, for use in the treatment of cystic fibrosis. 37. Use of form B of compound I (free form) as defined in any one of embodiments 21 to 32, or a pharmaceutical composition as defined in embodiment 34 or embodiment 35, in the manufacture of a medicament for the treatment of cystic fibrosis. 38. A method for treating cystic fibrosis, comprising administering form B of compound I (free form) as described in any one of embodiments 21 to 32, or a pharmaceutical composition as described in embodiment 34 or embodiment 35, to a subject in need of treatment. 39. Compound I according to any one of embodiments 21 to 32, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound for use according to embodiment 36, the use according to embodiment 37, or the method according to embodiment 38, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 40. The composition, use, or method or compound according to any one of embodiments 35 to 39, wherein compound II and / or compound III is in the form of a solid dispersion. 41. Compound I (free form), wherein Compound I is substantially crystalline Form C (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, and less than 5% of Compound I is in amorphous form). 42. Compound I according to embodiment 41, wherein compound I is 100% crystalline form C. 43. Compound I according to embodiment 41 or embodiment 42, wherein form C of compound I (free form) is characterized by an X-ray powder diffraction pattern with a signal at 6.3±0.2° 2θ. 44. Compound I according to embodiment 41 or embodiment 42, wherein Form C of compound I (free form) is characterized by an X-ray powder diffraction pattern with signals at 6.3±0.2° 2θ, 14.8±0.2° 2θ, and 20.4±0.2° 2θ. 45. Compound I according to embodiment 41 or embodiment 42, wherein Form C of compound I (free form) is characterized by an X-ray powder diffraction pattern having (a) a signal at 6.3±0.2°2θ, and (b) one, two, three, four, five, six, or more signals selected from 14.8±0.2°2θ, 15.5±0.2°2θ, 18.5±0.2°2θ, 19.2±0.2°2θ, 20.1±0.2°2θ, 20.4±0.2°2θ, 23.8±0.2°2θ, and 26.4°2θ. 46. ​​Compound I according to any one of embodiments 41 or 42, wherein form C of compound I (free form) is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 5. 47. Form C of compound I (free form) according to any one of embodiments 41-46, prepared by a process comprising stirring Form A of compound I (free form) in IPA / H2O at 25°C. 48. A method for preparing Form C of compound I (free form) according to any one of embodiments 41-46, comprising stirring Form A of compound I (free form) in IPA / H2O at 25°C. 49. A pharmaceutical composition comprising Form C of compound I (free form) according to any one of embodiments 41 to 47, optionally further comprising one or more additional CFTR-modulating compounds. 50. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 49, wherein the compound is (i) compound II and (ii) compound III or compound III-d. 51. Compound I as defined in any one of embodiments 41 to 47, or the pharmaceutical composition as defined in embodiment 49 or embodiment 50, for use in the treatment of cystic fibrosis. 52. Use of Form C of compound I (free form) as defined in any one of embodiments 41 to 47, or a pharmaceutical composition as defined in embodiment 49 or embodiment 50, in the manufacture of a medicament for the treatment of cystic fibrosis. 53. A method for treating cystic fibrosis, comprising administering Form C of compound I (free form) as described in any one of embodiments 41 to 47, or a pharmaceutical composition as described in embodiment 49 or embodiment 50, to a subject in need of treatment. 54. The compound for use according to embodiment 51, the use according to embodiment 52, or the method according to embodiment 53, wherein Form C of compound I (free form) according to any one of embodiments 41 to 47 is administered in combination with at least one additional CFTR-modulating compound. 55. Form C of compound I (free form) according to any one of embodiments 41 to 47 is a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 54, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 56. The composition, use, or method or compound according to any one of embodiments 50 to 55, wherein compound II and / or compound III are in the form of a solid dispersion. 57. Compound I (free form), wherein Compound I is substantially crystalline form D (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, and less than 5% of Compound I is in amorphous form). 58. Compound I according to embodiment 57, wherein compound I is 100% crystalline form D. 59. Compound I according to embodiment 57 or embodiment 58, wherein form D of compound I (free form) is characterized by an X-ray powder diffraction pattern with signals at 3.7±0.2° 2θ, 7.4±0.2° 2θ, and / or 12.2±0.2° 2θ. 60. Compound I according to embodiment 57 or embodiment 58, wherein form D of compound I (free form) is characterized by an X-ray powder diffraction pattern with signals at 3.7±0.2° 2θ, 7.4±0.2° 2θ, and 17.3±0.2° 2θ. 61. Compound I according to any one of embodiments 57 or 58, wherein form D of compound I (free form) is characterized by an X-ray powder diffraction pattern substantially similar to Figure 47. 62. Form D of Compound I (free form) has two, three, four, five, six, seven, or eight peaks selected from 164.6±0.2 ppm, 149.6±0.2 ppm, 135.7±0.2 ppm, 113.6±0.2 ppm, 63.0±0.2 ppm, 38.9±0.2 ppm, 27.6±0.2 ppm, and 15.7±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 Compound I according to any one of embodiments 57 to 61, characterized by a C ssNMR spectrum. 63. Form D of Compound I (free form) is substantially similar to Figure 48 13 Compound I according to any one of embodiments 57-61, characterized by C ssNMR. 64. Form D of compound I (free form) according to any one of embodiments 57-63, prepared by a process comprising adding propanol to compound I (free form), concentrating the mixture under reduced pressure, and repeating the procedure using toluene. 65. A method for preparing Form D of compound I (free form) according to any one of embodiments 57-63, comprising adding propanol to compound I (free form), concentrating the mixture under reduced pressure, and repeating the procedure using toluene. 66. A pharmaceutical composition comprising Form D of compound I (free form) according to any one of embodiments 57-64, optionally further comprising one or more additional CFTR-modulating compounds. 67. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 64, wherein the compound is (i) compound II and (ii) compound III or compound III-d. 68. Form D of compound I (free form) as defined in any one of embodiments 57-64, or a pharmaceutical composition as defined in embodiment 66 or embodiment 67, for use in the treatment of cystic fibrosis. 69. Use of form D of compound I (free form) as defined in any one of embodiments 57-64, or a pharmaceutical composition as defined in embodiment 66 or embodiment 67, in the manufacture of a medicament for the treatment of cystic fibrosis. 70. A method for treating cystic fibrosis, comprising administering form D of compound I (free form) as described in any one of embodiments 57-64, or a pharmaceutical composition as described in embodiment 66 or embodiment 67, to a subject in need of treatment. 71. The compound for use according to embodiment 68, the use according to embodiment 69, or the method according to embodiment 70, wherein form D of compound I (free form) according to any one of embodiments 57 to 64 is administered in combination with at least one additional CFTR-modulating compound. 72. Form D of compound I (free form) according to any one of embodiments 57 to 64 is a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 71, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 73. The composition, use, method, or compound according to any one of embodiments 67-72, wherein compound II and / or compound III are in the form of a solid dispersion. 74. Substantially crystalline calcium salt hydrate Form A of Compound I (i.e., less than 15% of Compound I is in amorphous form). 75. The substantially crystalline calcium salt hydrate Form A of Compound I according to embodiment 74, wherein less than 10% is in amorphous form. The substantially crystalline calcium salt hydrate Form A of Compound I according to embodiment 74, wherein less than 76.5% is in amorphous form. 77. Calcium salt hydrate form A of crystalline Compound I. 78. The calcium salt hydrate form A of crystalline Compound I according to any one of embodiments 74 to 77, wherein the calcium salt hydrate form A of Compound I is characterized by an X-ray powder diffraction pattern with signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ. 79. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) one or more signals at 10.5±0.2°2θ, 10.6±0.2°2θ, and 17.8±0.2°2θ. 80. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having two or more of: (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) signals at 10.5±0.2°2θ, 10.6±0.2°2θ, and 17.8±0.2°2θ. 81. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) signals at 10.5±0.2°2θ, 10.6±0.2°2θ, and 17.8±0.2°2θ. 82. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) one or more signals selected from 10.5±0.2°2θ, 10.6±0.2°2θ, 17.8±0.2°2θ, 20.7±0.2°2θ, and 25.1±0.2°2θ. 83. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having two or more signals selected from (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) signals at 10.5±0.2°2θ, 10.6±0.2°2θ, 17.8±0.2°2θ, 20.7±0.2°2θ, and 25.1±0.2°2θ. 84. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) three or more signals selected from 10.5±0.2°2θ, 10.6±0.2°2θ, 17.8±0.2°2θ, 20.7±0.2°2θ, and 25.1±0.2°2θ. 85. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having four or more signals selected from (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) signals at 10.5±0.2°2θ, 10.6±0.2°2θ, 17.8±0.2°2θ, 20.7±0.2°2θ, and 25.1±0.2°2θ. 86. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74-77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) one or more signals selected from 10.6±0.2°2θ, 14.8±0.2°2θ, 17.8±0.2°2θ, 19.6±0.2°2θ, 20.7±0.2°2θ, 24.4±0.2°2θ, and 25.1±0.2°2θ. 87. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) two or more signals selected from 10.6±0.2°2θ, 14.8±0.2°2θ, 17.8±0.2°2θ, 19.6±0.2°2θ, 20.7±0.2°2θ, 24.4±0.2°2θ, and 25.1±0.2°2θ. 88. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) three or more signals selected from 10.6±0.2°2θ, 14.8±0.2°2θ, 17.8±0.2°2θ, 19.6±0.2°2θ, 20.7±0.2°2θ, 24.4±0.2°2θ, and 25.1±0.2°2θ. 89. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) four or more signals selected from 10.6±0.2°2θ, 14.8±0.2°2θ, 17.8±0.2°2θ, 19.6±0.2°2θ, 20.7±0.2°2θ, 24.4±0.2°2θ, and 25.1±0.2°2θ. 90. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern having (a) signals at 4.2±0.2°2θ, 18.0±0.2°2θ, and 19.7±0.2°2θ, and (b) five or more signals selected from 10.6±0.2°2θ, 14.8±0.2°2θ, 17.8±0.2°2θ, 19.6±0.2°2θ, 20.7±0.2°2θ, 24.4±0.2°2θ, and 25.1±0.2°2θ. 91. Calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74 to 77, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 6. 92. Monoclinic, C2 space group, and Cu K α Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 91, characterized by the following unit cell dimensions measured at 100 K on a Bruker diffractometer with radiation (λ=1.5478 A): [Table 12] 93. Monoclinic system, C2 space group, and Cu K α Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 92, characterized by the following unit cell dimensions measured at 298 K on a Bruker diffractometer equipped with radiation (λ=1.5478 A) and a CCD detector: [Table 13] It has a peak of 94.17.0±0.2 ppm 13 Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by C ssNMR spectrum. It has a peak of 95.7.8±0.2 ppm 13 Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by a C ssNMR spectrum. 96.1 with peaks of 7.0±0.2 ppm and 7.8±0.2 ppm 13 Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by a C ssNMR spectrum. 97. (a) A peak at 17.0±0.2 ppm and / or a peak at 7.8±0.2 ppm, and (b) one or more peaks selected from 178.3±0.2 ppm, 136.8±0.2 ppm, 93.6±0.2 ppm, and 26.4±0.2 ppm. 13Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by a C ssNMR spectrum. 98. (a) A peak at 17.0±0.2 ppm and / or a peak at 7.8±0.2 ppm, and (b) two or more peaks selected from 178.3±0.2 ppm, 136.8±0.2 ppm, 93.6±0.2 ppm, and 26.4±0.2 ppm. 13 Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by a C ssNMR spectrum. 99. (a) A peak at 17.0±0.2 ppm and / or a peak at 7.8±0.2 ppm, and (b) three or more peaks selected from 178.3±0.2 ppm, 136.8±0.2 ppm, 93.6±0.2 ppm, and 26.4±0.2 ppm. 13 Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by a C ssNMR spectrum. 100. (a) having a peak at 17.0 ± 0.2 ppm and / or a peak at 7.8 ± 0.2 ppm, and (b) having peaks at 178.3 ± 0.2 ppm, 136.8 ± 0.2 ppm, 93.6 ± 0.2 ppm, and 26.4 ± 0.2 ppm. 13 Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by a C ssNMR spectrum. with peaks at 101.17.0±0.2 ppm, 7.8±0.2 ppm, 178.3±0.2 ppm, 136.8±0.2 ppm, 93.6±0.2 ppm, and 26.4±0.2 ppm. 13 Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by a C ssNMR spectrum. 102. Substantially similar to FIG. 13 Calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 93, characterized by C ssNMR. 103. The calcium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 74-102, prepared by a process comprising charging Form A of Compound I (free form) and Ca(OMe)2 with IPA / H2O at 70°C. 104. A method for preparing crystalline calcium salt hydrate Form A of Compound I according to any one of embodiments 74-102, comprising charging Form A of Compound I (free form) and Ca(OMe)2 with IPA / H2O at 70°C. 105. A pharmaceutical composition comprising calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74-103. 106. The pharmaceutical composition of embodiment 105, further comprising one or more additional CFTR-modulating compounds. 107. The pharmaceutical composition according to embodiment 105 or embodiment 106, further comprising compound III or compound III-d. 108. The pharmaceutical composition according to embodiment 105 or embodiment 106, further comprising (a) compound II and (b) compound III or compound III-d. 109. Calcium salt hydrate Form A of crystalline Compound I as described in any one of embodiments 74-103, or a pharmaceutical composition as described in any one of embodiments 105-108, for use in the treatment of cystic fibrosis. 110. Use of crystalline calcium salt hydrate Form A of Compound I as described in any one of embodiments 74-103, or a composition as described in any one of embodiments 105-108, in the manufacture of a medicament for the treatment of cystic fibrosis. 111. A method for treating cystic fibrosis, comprising administering calcium salt hydrate Form A of compound I as described in any one of embodiments 74-103, or a pharmaceutical composition as described in any one of embodiments 105-108, to a subject in need of treatment. 112. The method of embodiment 111, wherein calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 103 is administered in combination with at least one additional CFTR-modulating compound. 113. The method of embodiment 112, wherein calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 103 is administered in combination with Compound III or Compound III-d. 114. The method of embodiment 112, wherein calcium salt hydrate Form A of crystalline Compound I according to any one of embodiments 74 to 103 is administered in combination with (a) Compound II and (b) Compound III or Compound III-d. 115. The method of embodiment 112, wherein calcium salt hydrate Form A of crystalline Compound I as described in any one of embodiments 74 to 103 is administered in combination with (a) Compound IV and (b) Compound III or Compound III-d. 116. The method of any one of embodiments 107, 108, and 113-115, wherein compound II and / or compound III are in the form of a solid dispersion. 117. A substantially crystalline calcium salt hydrate Form B of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 118. Compound I according to embodiment 117, wherein compound I is 100% crystalline calcium salt hydrate form B. 119. The calcium salt hydrate form B of crystalline Compound I, as described in embodiment 117 or embodiment 118, characterized by an X-ray powder diffraction pattern with signals at 13.1±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 17.7±0.2 degrees 2θ. 120. Calcium hydrate Form B of crystalline Compound I according to embodiment 117 or embodiment 118, characterized by an X-ray powder diffraction pattern having (a) signals at 12.2±0.2°2θ, 13.1±0.2°2θ, 14.6±0.2°2θ, and 17.7±0.2°2θ, and (b) one, two, three, or four signals at 16.2±0.2°2θ, 18.1±0.2°2θ, 20.4±0.2°2θ, and 21.3±0.2°2θ. 121. Calcium salt hydrate form B of crystalline compound I, according to embodiment 117 or embodiment 118, characterized by an X-ray powder diffraction pattern substantially similar to Figure 8. 122.175.8±0.2ppm, 119.6±0.2ppm, 48.7±0.2ppm, 24.4±0.2ppm, 22.5±0.2ppm with one, two, three, four, or five peaks 13 Calcium salt hydrate Form B of crystalline Compound I according to any one of embodiments 117-121, characterized by C ssNMR spectrum. 123. (a) Having one, two, three, four, or five peaks selected from 175.8 ± 0.2 ppm, 119.6 ± 0.2 ppm, 48.7 ± 0.2 ppm, 24.4 ± 0.2 ppm, and 22.5 ± 0.2 ppm, and (b) having one, two, three, or four peaks selected from 164.7 ± 0.2 ppm, 148.9 ± 0.2 ppm, 97.7 ± 0.2 ppm, and 25.9 ± 0.2 ppm. 13 Calcium salt hydrate Form B of crystalline Compound I according to any one of embodiments 117-121, characterized by C ssNMR spectrum. 124. Substantially similar to FIG. 13 Calcium salt hydrate Form B of crystalline Compound I according to any one of embodiments 117-121, characterized by C ssNMR. 125.3 with peaks of 2.9 ± 0.2 ppm and / or 23.3 ± 0.2 ppm 13 Calcium salt hydrate / solvate form B of crystalline Compound I with MeOH, characterized by C ssNMR spectrum. 126. (a) A peak at 32.9±0.2 ppm and / or a peak at 23.3±0.2 ppm, and (b) one, two, three, four, or five peaks selected from 176.1±0.2 ppm, 164.7±0.2 ppm, 148.9±0.2 ppm, 49.3±0.2 ppm, and 25.9±0.2 ppm. 13Calcium salt hydrate / solvate Form B of crystalline Compound I with MeOH according to embodiment 125, characterized by C ssNMR spectrum. 127. Substantially similar to FIG. 13 Calcium salt hydrate / solvate Form B of crystalline Compound I with MeOH according to embodiment 125, characterized by C ssNMR spectrum. 128. Monoclinic system, P21 space group, and Cu K α 128. The calcium salt hydrate / solvate Form B of crystalline Compound I with MeOH according to any one of embodiments 125-127, characterized by the following unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with radiation (λ=1.5478 A) and a CCD detector: [Table 14] 129. Crystalline calcium salt hydrate Form B of Compound I, as described in any one of embodiments 117-125, prepared by a process comprising slurrying the calcium salt of Compound I in EtOH / water; or calcium salt hydrate / solvate Form B of Compound I with MeOH, as described in any one of embodiments 126-128, prepared by a process comprising adding MeOH to calcium salt hydrate Form B of Compound I. 130. A method for preparing crystalline calcium salt hydrate Form B of Compound I as described in any one of embodiments 117-125, comprising slurrying the calcium salt of Compound I in EtOH / water, or calcium salt hydrate / solvate Form B of Compound I with MeOH as described in any one of embodiments 126-128, comprising adding MeOH to calcium salt hydrate Form B of Compound I. 131. A pharmaceutical composition comprising crystalline Compound I calcium salt hydrate Form B or crystalline Compound I calcium salt hydrate / solvate Form B with MeOH according to any one of embodiments 117-129, optionally further comprising one or more additional CFTR-modulating compounds. 132. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 131, which is (i) compound II and (ii) compound III or compound III-d. 133. Calcium salt hydrate Form B of Compound I or crystalline calcium salt hydrate / solvate Form B with MeOH according to any one of embodiments 117-129, or a pharmaceutical composition according to embodiment 131 or embodiment 132, for use in the treatment of cystic fibrosis. 134. Calcium salt hydrate Form B of Compound I or crystalline calcium salt hydrate / solvate Form B with MeOH according to any one of embodiments 117-129, or a pharmaceutical composition according to embodiment 131 or embodiment 132, in the manufacture of a medicament for the treatment of cystic fibrosis. 135. A method for treating cystic fibrosis, comprising administering calcium salt hydrate Form B of Compound I or crystalline calcium salt hydrate / solvate Form B with MeOH of Compound I as described in any one of embodiments 117-129, or a pharmaceutical composition as described in embodiment 131 or embodiment 132, to a subject in need of treatment. 136. The compound for use according to embodiment 133, the use according to embodiment 134, or the method according to embodiment 135, wherein calcium salt hydrate Form B of compound I according to any one of embodiments 117 to 129 is administered in combination with at least one additional CFTR-modulating compound. 137. The calcium salt hydrate form B of Compound I or crystalline calcium salt hydrate / solvate form B of Compound I with MeOH according to any one of embodiments 117-129, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 136, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 138. The composition, use, method or compound according to any one of embodiments 132-137, wherein compound II and / or compound III are in the form of a solid dispersion. 139. A substantially crystalline calcium salt hydrate Form C of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 140. Compound I according to embodiment 139, wherein compound I is 100% crystalline calcium salt hydrate form C. 141. The calcium salt hydrate Form C of crystalline Compound I, as described in embodiment 139 or embodiment 140, characterized by an X-ray powder diffractogram having signals at 10.3±0.2 degrees 2θ, 15.8±0.2 degrees 2θ, and 20.8±0.2 degrees 2θ. 142. Calcium salt hydrate Form C of crystalline Compound I, as described in embodiment 139 or embodiment 140, characterized by an X-ray powder diffraction pattern having (a) signals at 4.0±0.2°2θ, 10.3±0.2°2θ, 15.8±0.2°2θ, and 20.8±0.2°2θ, and (b) one or more signals at 19.0±0.2°2θ, 14.3±0.2°2θ, and 13.3±0.2°2θ. 143. The calcium salt hydrate form C of crystalline Compound I, as described in embodiment 139 or embodiment 140, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 11. 144.115.7±0.2 ppm, 65.9±0.2 ppm, 52.7±0.2 ppm, and / or 21.4±0.2 ppm peaks 13 Calcium salt hydrate Form C of crystalline Compound I according to any one of embodiments 139 to 143, characterized by a C ssNMR spectrum. 145. (a) having peaks at 115.7 ± 0.2 ppm, 65.9 ± 0.2 ppm, 52.7 ± 0.2 ppm, and / or 21.4 ± 0.2 ppm, and (b) having peaks at 178.3 ± 0.2 ppm, 155.9 ± 0.2 ppm, 137.7 ± 0.2 ppm, 129.6 ± 0.2 ppm, 112.0 ± 0.2 ppm, 100.0 ± 0.2 ppm, 37.8 ± 0.2 ppm, 26.4 ± 0.2 ppm, and / or 19.9 ± 0.2 ppm. 13 Calcium salt hydrate Form C of crystalline Compound I according to any one of embodiments 139 to 143, characterized by a C ssNMR spectrum. 146. Substantially similar to FIG. 13 Calcium salt hydrate Form C of crystalline Compound I, as described in embodiment 139 or embodiment 140, characterized by C ssNMR. 147. Calcium salt hydrate Form C of crystalline Compound I, according to any one of embodiments 139-146, prepared by a process comprising stirring Form A of Compound I (free form) with calcium methoxide in dichloromethane (containing 10% water), and isolating and drying the solid. 148. A method for preparing crystalline calcium salt hydrate Form C of Compound I according to any one of embodiments 139-146, prepared by a process comprising stirring Form A of Compound I (free form) with calcium methoxide in dichloromethane (containing 10% water), and isolating and drying the solid. 149. A pharmaceutical composition comprising calcium salt hydrate Form C of crystalline Compound I according to any one of embodiments 139-147, optionally further comprising one or more additional CFTR-modulating compounds. 150. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 149, which is (i) compound II and (ii) compound III or compound III-d. 151. Calcium salt hydrate Form C of compound I as defined in any one of embodiments 139-147, or a pharmaceutical composition as defined in embodiment 149 or embodiment 150, for use in the treatment of cystic fibrosis. 152. Use of calcium salt hydrate Form C of compound I as defined in any one of embodiments 139-147, or a pharmaceutical composition as defined in embodiment 149 or embodiment 150, in the manufacture of a medicament for the treatment of cystic fibrosis. 153. A method for treating cystic fibrosis, comprising administering calcium salt hydrate Form C of compound I as described in any one of embodiments 117-129, or a pharmaceutical composition as described in embodiment 149 or embodiment 150, to a subject in need of treatment. 154. The compound for use according to embodiment 151, the use according to embodiment 152, or the method according to embodiment 153, wherein calcium salt hydrate Form C of compound I according to any one of embodiments 139 to 147 is administered in combination with at least one additional CFTR-modulating compound. 155. The calcium salt hydrate form C of compound I according to any one of embodiments 139-147 is a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 154, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 156. The composition, use, method, or compound according to any one of embodiments 150-155, wherein compound II and / or compound III are in the form of a solid dispersion. 157. Substantially crystalline calcium salt hydrate Form D of Compound I (i.e., less than 15% of Compound I is in amorphous form). The substantially crystalline calcium salt hydrate Form D of Compound I according to embodiment 74, wherein less than 158.10% is in amorphous form. The substantially crystalline calcium salt hydrate Form D of Compound I according to embodiment 74, wherein less than 159.5% is in amorphous form. 160. Calcium salt hydrate form D of crystalline Compound I. Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-160, characterized by an X-ray powder diffraction pattern with signals at 161.6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ. 162. Calcium salt hydrate Form D of crystalline Compound I, according to any one of embodiments 157-160, characterized by an X-ray powder diffraction pattern having (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) one or more signals selected from 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ. 163. Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-160, characterized by an X-ray powder diffraction pattern having (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) two or more signals selected from 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ. 164. Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-160, characterized by an X-ray powder diffraction pattern having (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) three or more signals selected from 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ. 165. Calcium salt hydrate Form D of crystalline Compound I, according to any one of embodiments 157-160, characterized by an X-ray powder diffraction pattern having (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) four or more signals selected from 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ. 166. Calcium salt hydrate Form D of crystalline Compound I, according to any one of embodiments 157-160, characterized by an X-ray powder diffraction pattern having (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) five or more signals selected from 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ. Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-160, characterized by an X-ray powder diffractogram with signals at 167.6.1±0.2°2θ, 16.2±0.2°2θ, 22.8±0.2°2θ, and 27.6±0.2°2θ. Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-160, characterized by an X-ray powder diffractogram with signals at 168.6.1±0.2°2θ, 15.5±0.2°2θ, 16.2±0.2°2θ, 19.7±0.2°2θ, 22.8±0.2°2θ, and 27.6±0.2°2θ. 169. Calcium salt hydrate form D of crystalline Compound I, according to any one of embodiments 157-160, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 13. 170. Triclinic system, P1 space group, and Cu K α Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157 to 169, characterized by the following unit cell dimensions measured at 100 K on a Bruker diffractometer with radiation (λ=1.5478 A): [Table 15] It has a peak of 171.130.2±0.2 ppm 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by a C ssNMR spectrum. It has a peak of 172.125.6±0.2 ppm 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by a C ssNMR spectrum. It has a peak of 173.35.0±0.2 ppm 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by a C ssNMR spectrum. with peaks at 174.130.2±0.2 ppm, 125.6±0.2 ppm, and / or 35.0±0.2 ppm 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by a C ssNMR spectrum. 175. (a) having peaks at 130.2 ± 0.2 ppm, 125.6 ± 0.2 ppm, and / or 35.0 ± 0.2 ppm, and (b) having peaks at 176.9 ± 0.2 ppm, 160.9 ± 0.2 ppm, 142.0 ± 0.2 ppm, and / or 98.6 ± 0.2 ppm. 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by a C ssNMR spectrum. 176. (a) having peaks at 130.2 ± 0.2 ppm, 125.6 ± 0.2 ppm, and 35.0 ± 0.2 ppm, and (b) having peaks at 176.9 ± 0.2 ppm, 160.9 ± 0.2 ppm, 142.0 ± 0.2 ppm, and / or 98.6 ± 0.2 ppm. 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by a C ssNMR spectrum. 177. (a) having peaks at 130.2 ± 0.2 ppm, 125.6 ± 0.2 ppm, and / or 35.0 ± 0.2 ppm, and (b) having peaks at 176.9 ± 0.2 ppm, 160.9 ± 0.2 ppm, 142.0 ± 0.2 ppm, and 98.6 ± 0.2 ppm. 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by a C ssNMR spectrum. 178. (a) has a peak at 35.0 ± 0.2 ppm, and (b) peaks at 176.9 ± 0.2 ppm, 160.9 ± 0.2 ppm, 142.0 ± 0.2 ppm, and 98.6 ± 0.2 ppm. 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by a C ssNMR spectrum. 179. Substantially similar to FIG. 13 Calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-170, characterized by C ssNMR. 180. Crystalline calcium salt hydrate Form D of Compound I, according to any one of embodiments 157-179, prepared by a process comprising charging calcium salt hydrate Form A of Compound I with EtOH / water and heating to 65°C. 181. A method for preparing crystalline calcium salt hydrate Form D of Compound I according to any one of embodiments 157-179, comprising charging calcium salt hydrate Form A of Compound I with EtOH / water and heating to 65°C. 182. A pharmaceutical composition comprising calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157-180. 183. The pharmaceutical composition of embodiment 182, further comprising one or more additional CFTR-modulating compounds. 184. The pharmaceutical composition according to embodiment 182 or embodiment 183, further comprising compound III or compound III-d. 185. The pharmaceutical composition according to embodiment 182 or embodiment 183, further comprising (a) compound II and (b) compound III or compound III-d. 186. Calcium salt hydrate Form D of crystalline Compound I as described in any one of embodiments 157-180, or a pharmaceutical composition as described in any one of embodiments 182-185, for use in the treatment of cystic fibrosis. 187. Use of calcium salt hydrate Form D of crystalline Compound I as described in any one of embodiments 157-180, or a composition as described in any one of embodiments 182-185, in the manufacture of a medicament for the treatment of cystic fibrosis. 188. A method for treating cystic fibrosis, comprising administering calcium salt hydrate Form D of crystalline Compound I as described in any one of embodiments 157-180, or a pharmaceutical composition as described in any one of embodiments 182-185, to a subject in need of treatment. 189. The method of embodiment 188, wherein calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157 to 180 is administered in combination with at least one additional CFTR-modulating compound. 190. The method of embodiment 189, wherein calcium salt hydrate Form D of crystalline Compound I according to any one of embodiments 157 to 180 is administered in combination with Compound III or Compound III-d. 191. The method of embodiment 189, wherein calcium salt hydrate Form D of crystalline Compound I as described in any one of embodiments 157-180 is administered in combination with (a) Compound II and (b) Compound III or Compound III-d. 192. The method of embodiment 189, wherein calcium salt hydrate Form D of crystalline Compound I as described in any one of embodiments 157-180 is administered in combination with (a) Compound IV and (b) Compound III or Compound III-d. 193. The method of any one of embodiments 184, 185, and 190-192, wherein compound II and / or compound III are in the form of a solid dispersion. 194. A substantially crystalline calcium salt hydrate Form E of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 195. The compound I according to embodiment 194, wherein compound I is a 100% crystalline calcium salt hydrate form E. Calcium salt hydrate Form E of crystalline Compound I, as described in embodiment 194 or embodiment 195, characterized by an X-ray powder diffractogram with signals at 196.8.0±0.2 degrees 2θ, 12.0±0.2 degrees 2θ, and 24.2±0.2 degrees 2θ. 197. Calcium salt hydrate Form E of crystalline Compound I, as described in embodiment 194 or embodiment 195, characterized by an X-ray powder diffraction pattern having (a) signals at 8.0±0.2°2θ, 12.0±0.2°2θ, and 24.2±0.2°2θ, and (b) signals at 4.0±0.2°2θ and / or 28.3±0.2°2θ. Calcium salt hydrate Form E of crystalline Compound I, as described in embodiment 194 or embodiment 195, characterized by an X-ray powder diffraction pattern with signals at 198.8.0±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, 24.2±0.2 degrees two-theta, and 4.0±0.2 degrees two-theta. 199. The calcium salt hydrate form E of crystalline Compound I, as described in embodiment 194 or embodiment 195, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 15. 200. Crystalline calcium salt hydrate Form E of Compound I, according to any one of embodiments 195-199, prepared by a process comprising subjecting calcium salt hydrate Form A of Compound I to solid vapor diffusion in EtOAc. 201. A method for preparing crystalline calcium salt hydrate Form E of Compound I according to any one of embodiments 195-199, prepared by a process comprising subjecting calcium salt hydrate Form A of Compound I to solid vapor diffusion in EtOAc. 202. A pharmaceutical composition comprising calcium salt hydrate Form E of crystalline Compound I according to any one of embodiments 195-200, optionally further comprising one or more additional CFTR-modulating compounds. 203. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 202, which is (i) compound II and (ii) compound III or compound III-d. 204. Calcium salt hydrate form E of compound I, as defined in any one of embodiments 195-200, or the pharmaceutical composition as defined in embodiment 202 or embodiment 203, for use in the treatment of cystic fibrosis. 205. Use of calcium salt hydrate form E of compound I as defined in any one of embodiments 195-200, or of a pharmaceutical composition as defined in embodiment 202 or embodiment 203, in the manufacture of a medicament for the treatment of cystic fibrosis. 206. A method for treating cystic fibrosis, comprising administering calcium salt hydrate Form E of compound I as described in any one of embodiments 195-200, or a pharmaceutical composition as described in embodiment 202 or embodiment 203, to a subject in need of treatment. 207. The compound for use according to embodiment 204, the use according to embodiment 205, or the method according to embodiment 206, wherein calcium salt hydrate Form E of compound I according to any one of embodiments 195 to 200 is administered in combination with at least one additional CFTR-modulating compound. 208. The calcium salt hydrate form E of compound I according to any one of embodiments 195-200 is a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 207, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 209. The composition, use, method, or compound according to any one of embodiments 203-208, wherein compound II and / or compound III are in the form of a solid dispersion. 210. Form F of Compound I that is substantially crystalline (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 211. Compound I according to embodiment 210, wherein compound I is 100% crystalline form F. 212. Form F of crystalline compound I according to embodiment 210 or embodiment 211, characterized by an X-ray powder diffractogram with signals at 5.3±0.2 degrees 2θ, 7.5±0.2 degrees 2θ, and 9.14±0.2 degrees 2θ. 213. F of crystalline compound I according to embodiment 210 or embodiment 211, characterized by an X-ray powder diffraction pattern having (a) signals at 5.3±0.2°2θ, 7.5±0.2°2θ, and 9.1±0.2°2θ, and (b) signals at 10.6±0.2°2θ and / or 11.9±0.2°2θ. 214. Form F of crystalline compound I, as described in embodiment 210 or embodiment 211, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 16. 215. Form F of crystalline Compound I, according to any one of embodiments 210-214, prepared by a process comprising mixing calcium salt hydrate Form A of Compound I with MEK at room temperature. 216. A method for preparing Form F of crystalline Compound I according to any one of embodiments 210-214, prepared by a process comprising mixing calcium salt hydrate Form A of Compound I with MEK at room temperature. 217. A pharmaceutical composition comprising form F of crystalline compound I according to any one of embodiments 210-215, optionally further comprising one or more additional CFTR-modulating compounds. 218. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 217, which is (i) compound II and (ii) compound III or compound III-d. 219. Form F of compound I as defined in any one of embodiments 210-215, or the pharmaceutical composition as defined in embodiment 217 or embodiment 218, for use in the treatment of cystic fibrosis. 220. Use of form F of compound I according to any one of embodiments 210-215, or of a pharmaceutical composition according to embodiment 217 or embodiment 218, in the manufacture of a medicament for the treatment of cystic fibrosis. 221. A method for treating cystic fibrosis, comprising administering form F of compound I as described in any one of embodiments 210-215, or a pharmaceutical composition as described in embodiment 217 or embodiment 218, to a subject in need of treatment. 222. The compound for use according to embodiment 219, the use according to embodiment 220, or the method according to embodiment 221, wherein form F of compound I according to any one of embodiments 210 to 215 is administered in combination with at least one additional CFTR-modulating compound. 223. Form F of compound I according to any one of embodiments 210-215 is a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 222, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 224. The composition, use, method, or compound according to any one of embodiments 218-223, wherein compound II and / or compound III are in the form of a solid dispersion. 225. A substantially crystalline calcium salt hydrate Form G of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 226. The compound I according to embodiment 225, wherein compound I is a 100% crystalline calcium salt hydrate form G. 227. The calcium salt hydrate form G of crystalline Compound I, as described in embodiment 225 or embodiment 226, characterized by an X-ray powder diffractogram with signals at 227.5.9±0.2 degrees 2θ, 8.8±0.2 degrees 2θ, and 26.6±0.2 degrees 2θ. 228. The calcium salt hydrate form G of crystalline Compound I, according to embodiment 225 or embodiment 226, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 17. 229. Crystalline calcium salt hydrate Form G of Compound I, according to any one of embodiments 225-228, prepared by a process comprising subjecting calcium salt hydrate Form A of Compound I to solid vapor diffusion in EtOAc. 230. A method for preparing crystalline calcium salt hydrate Form G of Compound I, according to any one of embodiments 225-228, prepared by a process comprising subjecting calcium salt hydrate Form A of Compound I to solid vapor diffusion in EtOAc. 231. A pharmaceutical composition comprising calcium salt hydrate Form G of crystalline Compound I according to any one of embodiments 225-229, optionally further comprising one or more additional CFTR-modulating compounds. 232. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 231, which is (i) compound II and (ii) compound III or compound III-d. 233. The calcium salt hydrate form G of compound I as defined in any one of embodiments 225-229, or the pharmaceutical composition as defined in embodiment 231 or embodiment 232, for use in the treatment of cystic fibrosis. 234. Use of calcium salt hydrate form G of compound I as defined in any one of embodiments 225-229, or of a pharmaceutical composition as defined in embodiment 231 or embodiment 232, in the manufacture of a medicament for the treatment of cystic fibrosis. 235. A method for treating cystic fibrosis, comprising administering calcium salt hydrate Form G of compound I as described in any one of embodiments 225-229, or a pharmaceutical composition as described in embodiment 231 or embodiment 232, to a subject in need of treatment. 236. The compound for use according to embodiment 233, the use according to embodiment 234, or the method according to embodiment 235, wherein calcium salt hydrate Form G of compound I according to any one of embodiments 225 to 229 is administered in combination with at least one additional CFTR-modulating compound. 237. The calcium salt hydrate form G of compound I according to any one of embodiments 225-229 is a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 236, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 238. The composition, use, method, or compound according to any one of embodiments 232-237, wherein compound II and / or compound III are in the form of a solid dispersion. 239. A substantially crystalline calcium salt hydrate Form H of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 240. The compound I according to embodiment 239, wherein compound I is a 100% crystalline calcium salt hydrate form H. The calcium salt hydrate form H of crystalline Compound I, as described in embodiment 239 or embodiment 240, characterized by an X-ray powder diffraction pattern with signals at 241.5.8±0.2 degrees 2θ, 13.0±0.2 degrees 2θ, and 14.5±0.2 degrees 2θ. 242. Calcium salt hydrate Form H of crystalline Compound I, according to embodiment 239 or embodiment 240, characterized by an X-ray powder diffraction pattern having (a) signals at 5.8±0.2°2θ, 13.0±0.2°2θ, and 14.5±0.2°2θ, and (b) one or more signals selected from 8.3±0.2°2θ, 12.0±0.2°2θ, 19.5±0.2°2θ, and 27.9±0.2°2θ. 243. The calcium salt hydrate form H of crystalline Compound I, as described in embodiment 239 or embodiment 240, characterized by an X-ray powder diffraction pattern substantially similar to Figure 45. 244. Calcium salt hydrate form H of crystalline Compound I, according to any one of embodiments 239-243, characterized by a triclinic crystal system, a P1 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer using synchrotron radiation (λ=0.7288 A): [Table 16] with peaks at 245.148.9±0.2 ppm, 27.2±0.2 ppm, and 4.8±0.2 ppm 13 Calcium salt hydrate Form H of crystalline Compound I, according to any one of embodiments 239-244, characterized by a C ssNMR spectrum. 246. (a) having peaks at 148.9 ± 0.2 ppm, 27.2 ± 0.2 ppm, and 4.8 ± 0.2 ppm, and (b) having peaks at 164.7 ± 0.2 ppm, 128.3 ± 0.2 ppm, 117.0 ± 0.2 ppm, and / or 19.4 ± 0.2 ppm. 13 Calcium salt hydrate Form H of crystalline Compound I, according to any one of embodiments 239-244, characterized by a C ssNMR spectrum. 247. Substantially similar to FIG. 13 Calcium salt hydrate Form H of crystalline Compound I, according to any one of embodiments 239-244, characterized by C ssNMR. 248. Crystalline calcium salt hydrate Form H of Compound I, according to any one of embodiments 239-244, prepared by a process comprising mixing calcium salt Form A of Compound I in IPA / H2O. 249. A method for preparing crystalline calcium salt hydrate Form H of Compound I according to any one of embodiments 239-244, comprising mixing the calcium salt of Compound I in IPA / H2O. 250. A pharmaceutical composition comprising calcium salt hydrate Form H of crystalline Compound I according to any one of embodiments 239-245, optionally further comprising one or more additional CFTR-modulating compounds. 251. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 250, which is (i) compound II and (ii) compound III or compound III-d. 252. Calcium salt hydrate form H of compound I as described in any one of embodiments 239-245, or the pharmaceutical composition as described in embodiment 250 or embodiment 251, for use in the treatment of cystic fibrosis. 253. Use of calcium salt hydrate form H of compound I as defined in any one of embodiments 239-245, or of a pharmaceutical composition as defined in embodiment 250 or embodiment 251, in the manufacture of a medicament for the treatment of cystic fibrosis. 254. A method for treating cystic fibrosis, comprising administering calcium salt hydrate Form H of compound I as described in any one of embodiments 239-245, or a pharmaceutical composition as described in embodiment 250 or embodiment 251, to a subject in need of treatment. 255. The compound for use according to embodiment 252, the use according to embodiment 253, or the method according to embodiment 254, wherein calcium salt hydrate Form H of compound I according to any one of embodiments 239 to 245 is administered in combination with at least one additional CFTR-modulating compound. 256. The calcium salt hydrate form H of compound I according to any one of embodiments 239-245 is a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 255, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 257. The composition, use, method, or compound according to any one of embodiments 251-256, wherein compound II and / or compound III are in the form of a solid dispersion. 258. A substantially crystalline calcium salt EtOH solvate Form A of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, and less than 5% of Compound I is in amorphous form). 259. Compound I according to embodiment 258, wherein compound I is a 100% crystalline calcium salt EtOH solvate form A. Calcium salt EtOH solvate Form A of crystalline Compound I, as described in embodiment 258 or embodiment 259, characterized by an X-ray powder diffractogram having signals at 260.4.1±0.2 degrees two-theta, 8.2±0.2 degrees two-theta, and 17.1±0.2 degrees two-theta. 261. Calcium salt EtOH solvate Form A of crystalline Compound I, as described in embodiment 258 or embodiment 259, characterized by an X-ray powder diffraction pattern having (a) signals at 4.1±0.2 degrees 2θ, 8.2±0.2 degrees 2θ, and 17.1±0.2 degrees 2θ, and (b) signals at 8.5±0.2 degrees 2θ and / or 16.5±0.2 degrees 2θ. 262. The calcium salt EtOH solvate Form A of crystalline Compound I, as described in embodiment 258 or embodiment 259, characterized by an X-ray powder diffraction pattern having (a) signals at 4.1±0.2°2θ, 8.2±0.2°2θ, and 17.1±0.2°2θ, and (b) one or more signals at 4.1±0.2°2θ, 4.8±0.2°2θ, 5.6±0.2°2θ, 8.5±0.2°2θ, 16.5±0.2°2θ, and 20.3±0.2°2θ. 263. The calcium salt EtOH solvate Form A of crystalline Compound I, as described in embodiment 258 or embodiment 259, characterized by an X-ray powder diffraction pattern substantially similar to Figure 18. 264. Crystalline Compound I calcium salt EtOH solvate Form A according to any one of embodiments 258-263, prepared by a process comprising rapid cooling of a solution of the calcium salt of Compound I in EtOH:H2O (85:15). 265. A method for preparing crystalline Compound I calcium salt EtOH solvate Form A according to any one of embodiments 225-228, prepared by a process comprising rapid cooling of a solution of the calcium salt of Compound I in EtOH:H2O (85:15). 266. A pharmaceutical composition comprising the calcium salt EtOH solvate Form A of crystalline Compound I according to any one of embodiments 258-264, optionally further comprising one or more additional CFTR modulating compounds. 267. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 266, which is (i) compound II and (ii) compound III or compound III-d. 268. The calcium salt EtOH solvate Form A of compound I as described in any one of embodiments 258-264, or the pharmaceutical composition as described in embodiment 266 or embodiment 267, for use in the treatment of cystic fibrosis. 269. Use of the calcium salt EtOH solvate Form A of compound I according to any one of embodiments 258-264, or the pharmaceutical composition according to embodiment 266 or embodiment 267, in the manufacture of a medicament for the treatment of cystic fibrosis. 270. A method for treating cystic fibrosis, comprising administering calcium salt EtOH solvate Form A of compound I as described in any one of embodiments 258-264, or a pharmaceutical composition as described in embodiment 266 or embodiment 267, to a subject in need of treatment. 271. The compound for use according to embodiment 268, the use according to embodiment 269, or the method according to embodiment 270, wherein calcium salt EtOH solvate Form A of compound I according to any one of embodiments 258 to 264 is administered in combination with at least one additional CFTR-modulating compound. 272. The calcium salt EtOH solvate form A of compound I according to any one of embodiments 258-264, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 271, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 273. The composition, use, method, or compound according to any one of embodiments 267-272, wherein compound II and / or compound III are in the form of a solid dispersion. 274. A substantially crystalline calcium salt EtOH solvate Form B of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 275. The compound I according to embodiment 274, wherein compound I is a 100% crystalline calcium salt EtOH solvate form B. The calcium salt EtOH solvate Form B of crystalline Compound I, as described in embodiment 274 or embodiment 275, characterized by an X-ray powder diffractogram with signals at 276.15.4±0.2° 2θ. The calcium salt EtOH solvate Form B of crystalline Compound I, as described in embodiment 274 or embodiment 175, characterized by an X-ray powder diffractogram having signals at 277.4.5±0.2 degrees 2θ, 5.0±0.2 degrees 2θ, and 15.4±0.2 degrees 2θ. 278. The calcium salt EtOH solvate form B of crystalline compound I, as described in embodiment 274 or embodiment 175, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 19. 279. Crystalline calcium salt EtOH solvate Form B of Compound I according to any one of embodiments 274-278, prepared by a process comprising temperature cycling calcium salt hydrate Form A of Compound I in EtOH:n-heptane (1:1) at a cooling rate of 0.2°C / min from 60°C to 5°C. 280. A method for preparing crystalline calcium salt EtOH solvate Form B of Compound I according to any one of embodiments 274-278, prepared by a process comprising temperature cycling calcium salt hydrate Form A of Compound I in EtOH:n-heptane (1:1) at a cooling rate of 0.2°C / min between 60°C and 5°C. 281. A pharmaceutical composition comprising the calcium salt EtOH solvate Form B of crystalline Compound I according to any one of embodiments 274-279, optionally further comprising one or more additional CFTR modulating compounds. 282. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 281, which is (i) compound II and (ii) compound III or compound III-d. 283. The calcium salt EtOH solvate Form B of compound I as described in any one of embodiments 274-279, or the pharmaceutical composition as described in embodiment 281 or embodiment 282, for use in the treatment of cystic fibrosis. 284. Use of the calcium salt EtOH solvate Form B of compound I according to any one of embodiments 274-279, or the pharmaceutical composition according to embodiment 281 or embodiment 282, in the manufacture of a medicament for the treatment of cystic fibrosis. 285. A method for treating cystic fibrosis, comprising administering calcium salt EtOH solvate Form B of compound I as described in any one of embodiments 274-279, or a pharmaceutical composition as described in embodiment 281 or embodiment 282, to a subject in need of treatment. 286. The compound for use according to embodiment 283, the use according to embodiment 284, or the method according to embodiment 285, wherein calcium salt EtOH solvate Form B of compound I according to any one of embodiments 274 to 279 is administered in combination with at least one additional CFTR-modulating compound. 287. The calcium salt EtOH solvate form B of compound I according to any one of embodiments 274-279, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 286, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 288. The composition, use, method, or compound according to any one of embodiments 282-287, wherein compound II and / or compound III are in the form of a solid dispersion. 289. A substantially crystalline calcium salt EtOH solvate Form C of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, and less than 5% of Compound I is in amorphous form). 290. The compound I according to embodiment 289, wherein compound I is a 100% crystalline calcium salt EtOH solvate form C. 291. The calcium salt EtOH solvate Form C of crystalline Compound I, as described in embodiment 289 or embodiment 290, characterized by an X-ray powder diffractogram having signals at 4.2±0.2 degrees two-theta, 5.0±0.2 degrees two-theta, and 5.7±0.2 degrees two-theta. 292. The calcium salt EtOH solvate Form C of crystalline Compound I, as described in embodiment 289 or embodiment 290, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 20. 293. Crystalline calcium salt EtOH solvate Form C of Compound I according to any one of embodiments 289-292, prepared by a process comprising making a slurry of amorphous calcium salt of Compound I with EtOH:H2O (9:1) at room temperature. 294. A method for preparing crystalline Compound I calcium salt EtOH solvate Form C according to any one of embodiments 289-292, prepared by a process comprising making a slurry of amorphous Compound I calcium salt with EtOH:H2O (9:1) at room temperature. 295. A pharmaceutical composition comprising the calcium salt EtOH solvate Form C of crystalline Compound I according to any one of embodiments 289-293, optionally further comprising one or more additional CFTR-modulating compounds. 296. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 295, which is (i) compound II and (ii) compound III or compound III-d. 297. The calcium salt EtOH solvate Form C of compound I as described in any one of embodiments 289-293, or the pharmaceutical composition as described in embodiment 295 or embodiment 296, for use in the treatment of cystic fibrosis. 298. Use of the calcium salt EtOH solvate Form C of compound I according to any one of embodiments 289-293, or the pharmaceutical composition according to embodiment 295 or embodiment 296, in the manufacture of a medicament for the treatment of cystic fibrosis. 299. A method for treating cystic fibrosis, comprising administering calcium salt EtOH solvate Form C of compound I as described in any one of embodiments 289-293, or a pharmaceutical composition as described in embodiment 295 or embodiment 296, to a subject in need of treatment. 300. The compound for use according to embodiment 297, the use according to embodiment 298, or the method according to embodiment 299, wherein calcium salt EtOH solvate Form C of compound I according to any one of embodiments 289 to 293 is administered in combination with at least one additional CFTR-modulating compound. 301. The calcium salt EtOH solvate form C of compound I according to any one of embodiments 289-293, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 300, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 302. The composition, use, method, or compound according to any one of embodiments 296-301, wherein compound II and / or compound III are in the form of a solid dispersion. 303. A substantially crystalline sodium salt hydrate Form A of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 304. Compound I according to embodiment 303, wherein compound I is 100% crystalline sodium salt hydrate form A. 305. The sodium salt hydrate Form A of crystalline Compound I, as described in embodiment 303 or embodiment 304, characterized by an X-ray powder diffractogram with signals at 5.4±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, and 17.6±0.2 degrees 2θ. 306. The sodium salt hydrate Form A of crystalline Compound I, as described in embodiment 303 or embodiment 304, characterized by an X-ray powder diffraction pattern having (a) signals at 5.4±0.2°2θ, 15.9±0.2°2θ, and 17.6±0.2°2θ, and (b) signals at 15.3±0.2°2θ, 18.6±0.2°2θ, 20.0±0.2°2θ, 21.3±0.2°2θ, 23.9±0.2°2θ, and / or 26.7±0.2°2θ. 307. The sodium salt hydrate form A of crystalline Compound I, as described in embodiment 303 or embodiment 304, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 34. 308.Having peaks at 177.0±0.2 ppm, 159.6±0.2 ppm, 138.5±0.2 ppm, 107.0±0.2 ppm, 96.4±0.2 ppm, 38.3±0.2 ppm, and / or 28.9±0.2 ppm 13The sodium salt hydrate Form A of crystalline Compound I according to any one of embodiments 303 to 307, characterized by a C ssNMR spectrum. 309. Substantially similar to FIG. 13 The sodium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 303 to 307, characterized by C ssNMR. 309(a) Sodium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 303 to 309, characterized by an orthorhombic crystal system, a P212121 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer using synchrotron radiation (λ=0.7288 A): [Table 17] 310. The sodium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 303-309, prepared by a process comprising mixing amorphous Compound I sodium salt with IPA / water at room temperature for 2 weeks. 311. A method for preparing crystalline Compound I sodium salt hydrate Form A according to any one of embodiments 303-309, prepared by a process comprising mixing amorphous Compound I sodium salt with IPA / water at room temperature for 2 weeks. 312. A pharmaceutical composition comprising the sodium salt hydrate Form A of crystalline Compound I according to any one of embodiments 303-310, optionally further comprising one or more additional CFTR-modulating compounds. 313. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 312, which is (i) compound II and (ii) compound III or compound III-d. 314. Sodium salt hydrate form A of compound I, as defined in any one of embodiments 303-310, or a pharmaceutical composition as defined in embodiment 312 or embodiment 313, for use in the treatment of cystic fibrosis. 315. Use of the sodium salt hydrate form A of compound I as defined in any one of embodiments 303-310, or of the pharmaceutical composition as defined in embodiment 312 or embodiment 313, in the manufacture of a medicament for the treatment of cystic fibrosis. 316. A method for treating cystic fibrosis, comprising administering sodium salt hydrate Form A of compound I as described in any one of embodiments 303 to 310, or a pharmaceutical composition as described in embodiment 312 or embodiment 313, to a subject in need of treatment. 317. The compound for use according to embodiment 314, the use according to embodiment 315, or the method according to embodiment 316, wherein the sodium salt hydrate form A of compound I according to any one of embodiments 303 to 310 is administered in combination with at least one additional CFTR-modulating compound. 318. The sodium salt hydrate form A of compound I according to any one of embodiments 303 to 310, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 317, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 319. The composition, use, method, or compound according to any one of embodiments 313-318, wherein compound II and / or compound III are in the form of a solid dispersion. 320. A substantially crystalline sodium salt pure form B of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 321. The compound I according to embodiment 320, wherein compound I is 100% crystalline sodium salt pure form B. 322. Pure form B of the sodium salt of crystalline Compound I, according to embodiment 320 or embodiment 321, characterized by an X-ray powder diffraction pattern with signals at 11.0±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, and 20.5±0.2 degrees two-theta. 323. Pure form B of the sodium salt of crystalline Compound I, according to embodiment 320 or embodiment 321, characterized by an X-ray powder diffraction pattern having (a) a signal at 12.8±0.2 degrees 2θ, and (b) signals at 20.5±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, and / or 11.0±0.2 degrees 2θ. 324. The sodium salt pure form B of crystalline compound I according to embodiment 320 or embodiment 321, characterized by an X-ray powder diffraction pattern substantially similar to that in FIG. 36. 325. Crystalline Compound I sodium salt pure form B according to any one of embodiments 320-324, prepared by a process comprising desolvating / dehydrating sodium salt hydrate form C of Compound I. 326. A method for preparing crystalline sodium salt pure form B of Compound I according to any one of embodiments 320-324, prepared by a process comprising desolvating / dehydrating sodium salt hydrate form C of Compound I. 327. A pharmaceutical composition comprising the sodium salt pure form B of crystalline Compound I according to any one of embodiments 320-325, optionally further comprising one or more additional CFTR-modulating compounds. 328. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 327, which is (i) compound II and (ii) compound III or compound III-d. 329. The sodium salt pure form B of compound I as defined in any one of embodiments 320-325, or the pharmaceutical composition as defined in embodiment 327 or embodiment 328, for use in the treatment of cystic fibrosis. 330. Use of the sodium salt pure form B of compound I according to any one of embodiments 320-325, or the pharmaceutical composition according to embodiment 327 or embodiment 328, in the manufacture of a medicament for the treatment of cystic fibrosis. 331. A method for treating cystic fibrosis, comprising administering to a subject in need thereof sodium salt pure form B of compound I as described in any one of embodiments 320-325, or a pharmaceutical composition as described in embodiment 327 or embodiment 328. 332. The compound for use according to embodiment 329, the use according to embodiment 330, or the method according to embodiment 331, wherein the sodium salt pure form B of compound I according to any one of embodiments 320 to 325 is administered in combination with at least one additional CFTR-modulating compound. 333. The sodium salt pure form B of compound I according to any one of embodiments 320 to 325, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 332, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 334. The composition, use, method, or compound according to any one of embodiments 328-333, wherein compound II and / or compound III are in the form of a solid dispersion. 335. A substantially crystalline sodium salt hydrate Form C of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 336. The compound I according to embodiment 335, wherein compound I is 100% crystalline sodium salt hydrate form C. The sodium salt hydrate form C of crystalline Compound I, as described in embodiment 335 or embodiment 336, characterized by an X-ray powder diffraction pattern with signals at 337.6.1±0.2 degrees 2θ, 13.4±0.2 degrees 2θ, and 19.2±0.2 degrees 2θ. 338. The sodium salt hydrate form C of crystalline Compound I, as described in embodiment 335 or embodiment 336, characterized by an X-ray powder diffractogram having (a) signals at 10.3±0.2°2θ and / or 4.5±0.2°2θ, and (b) signals at 19.2±0.2°2θ, 13.4±0.2°2θ, and / or 6.1±0.2°2θ. 339. The sodium salt hydrate form C of crystalline compound I, as described in embodiment 335 or embodiment 336, characterized by an X-ray powder diffraction pattern substantially similar to Figure 37. 340. The crystalline sodium salt hydrate Form C of Compound I, according to any one of embodiments 335-339, prepared by a process comprising stirring amorphous sodium salt of Compound I with ACN at room temperature. 341. A method for preparing crystalline Compound I sodium salt hydrate Form C, according to any one of embodiments 335-339, prepared by a process comprising stirring amorphous sodium salt of Compound I with ACN at room temperature. 342. A pharmaceutical composition comprising the sodium salt hydrate Form C of crystalline Compound I according to any one of embodiments 335-340, optionally further comprising one or more additional CFTR-modulating compounds. 343. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 342, which is (i) compound II and (ii) compound III or compound III-d. 344. Sodium salt hydrate form C of compound I as described in any one of embodiments 335-340, or a pharmaceutical composition as described in embodiment 342 or embodiment 343, for use in the treatment of cystic fibrosis. 345. Use of the sodium salt hydrate form C of compound I as defined in any one of embodiments 335-340, or the pharmaceutical composition as defined in embodiment 342 or embodiment 343, in the manufacture of a medicament for the treatment of cystic fibrosis. 346. A method for treating cystic fibrosis, comprising administering sodium salt hydrate form C of compound I as described in any one of embodiments 335-340, or a pharmaceutical composition as described in embodiment 342 or embodiment 343, to a subject in need of treatment. 347. The compound for use according to embodiment 344, the use according to embodiment 345, or the method according to embodiment 346, wherein the sodium salt hydrate form C of compound I according to any one of embodiments 335 to 340 is administered in combination with at least one additional CFTR-modulating compound. 348. The sodium salt hydrate form C of compound I according to any one of embodiments 335-340, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 347, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 349. The composition, use, method, or compound according to any one of embodiments 343-348, wherein compound II and / or compound III are in the form of a solid dispersion. 350. A substantially crystalline sodium salt hydrate Form D of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 351. The compound I according to embodiment 350, wherein compound I is 100% crystalline sodium salt hydrate form D. The sodium salt hydrate form D of crystalline Compound I, as described in embodiment 350 or embodiment 351, characterized by an X-ray powder diffraction pattern with signals at 352.7.8±0.2 degrees 2θ, 18.5±0.2 degrees 2θ, and 19.9±0.2 degrees 2θ. 353. The sodium salt hydrate form D of crystalline Compound I, as described in embodiment 350 or embodiment 351, characterized by an X-ray powder diffraction pattern having (a) signals at 7.8±0.2 degrees 2θ, 18.5±0.2 degrees 2θ, and 19.9±0.2 degrees 2θ, and (b) signals at 9.3±0.2 degrees 2θ, 14.8±0.2 degrees 2θ, and / or 27.3±0.2 degrees 2θ. 354. The sodium salt hydrate form D of crystalline Compound I, as described in embodiment 350 or embodiment 351, characterized by an X-ray powder diffraction pattern substantially similar to Figure 38. 355. Crystalline sodium salt hydrate form D of Compound I, according to any one of embodiments 350-354, prepared by a process comprising drying sodium salt hydrate form C of Compound I under vacuum at 80°C. 356. A method for preparing crystalline sodium salt hydrate form D of Compound I according to any one of embodiments 350-354, prepared by a process comprising drying sodium salt hydrate form C of Compound I under vacuum at 80°C. 357. A pharmaceutical composition comprising the sodium salt hydrate form D of crystalline Compound I according to any one of embodiments 350-355, optionally further comprising one or more additional CFTR modulating compounds. 358. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 357, which is (i) compound II and (ii) compound III or compound III-d. 359. Sodium salt hydrate form D of compound I as described in any one of embodiments 350-355, or a pharmaceutical composition as described in embodiment 357 or embodiment 358, for use in the treatment of cystic fibrosis. 360. Use of the sodium salt hydrate form D of compound I as defined in any one of embodiments 350-355, or the pharmaceutical composition as defined in embodiment 357 or embodiment 358, in the manufacture of a medicament for the treatment of cystic fibrosis. 361. A method for treating cystic fibrosis, comprising administering sodium salt hydrate form D of compound I as described in any one of embodiments 350-355, or a pharmaceutical composition as described in embodiment 357 or embodiment 358, to a subject in need of treatment. 362. The compound for use according to embodiment 359, the use according to embodiment 360, or the method according to embodiment 361, wherein the sodium salt hydrate form D of compound I according to any one of embodiments 350 to 355 is administered in combination with at least one additional CFTR-modulating compound. 363. The sodium salt hydrate form D of compound I according to any one of embodiments 350-355, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 362, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 364. The composition, use, method, or compound according to any one of embodiments 358-363, wherein compound II and / or compound III are in the form of a solid dispersion. 365. A substantially crystalline potassium salt hydrate Form A of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 366. The compound I according to embodiment 365, wherein compound I is 100% crystalline potassium salt hydrate form A. The potassium salt hydrate Form A of crystalline Compound I, as described in embodiment 365 or embodiment 366, characterized by an X-ray powder diffractogram having a signal at 367.10.7±0.2 degrees 2θ. 368. The potassium salt hydrate Form A of crystalline Compound I, as described in embodiment 365 or embodiment 366, characterized by an X-ray powder diffractogram having (a) a signal at 10.7±0.2 degrees 2θ, and (b) signals at 15.3±0.2 degrees 2θ and / or 20.4±0.2 degrees 2θ. 369. The potassium salt hydrate form A of crystalline Compound I, as described in embodiment 365 or embodiment 366, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 39. 370. The potassium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 365-369, prepared by a process comprising reacting Form A of Compound I (free form) with potassium hydride / H2O and two cycles of heating and cooling from 60°C to room temperature. 371. A method for preparing crystalline potassium salt hydrate Form A of Compound I according to any one of embodiments 365-369, prepared by a process comprising reacting Form A of Compound I (free form) with potassium hydride / H2O and performing two cycles of heating and cooling from 60°C to room temperature. 372. A pharmaceutical composition comprising potassium salt hydrate Form A of crystalline Compound I according to any one of embodiments 365-370, optionally further comprising one or more additional CFTR-modulating compounds. 373. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 372, which is (i) compound II and (ii) compound III or compound III-d. 374. Potassium salt hydrate Form A of compound I, as defined in any one of embodiments 365-370, or a pharmaceutical composition as defined in embodiment 372 or embodiment 373, for use in the treatment of cystic fibrosis. 375. Use of potassium salt hydrate Form A of compound I, as defined in any one of embodiments 365-370, or a pharmaceutical composition as defined in embodiment 372 or embodiment 373, in the manufacture of a medicament for the treatment of cystic fibrosis. 376. A method for treating cystic fibrosis, comprising administering potassium salt hydrate Form A of compound I as described in any one of embodiments 365-370, or a pharmaceutical composition as described in embodiment 372 or embodiment 373, to a subject in need of treatment. 377. The compound for use according to embodiment 374, the use according to embodiment 375, or the method according to embodiment 376, wherein potassium salt hydrate Form A of compound I according to any one of embodiments 365 to 370 is administered in combination with at least one additional CFTR-modulating compound. 378. The potassium salt hydrate form A of compound I according to any one of embodiments 365-370, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 377, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 379. The composition, use, method, or compound according to any one of embodiments 374-378, wherein compound II and / or compound III are in the form of a solid dispersion. 380. A substantially crystalline potassium salt hydrate Form B of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 381. The compound I according to embodiment 380, wherein compound I is 100% crystalline potassium salt hydrate form B. The potassium salt hydrate form B of crystalline Compound I, as described in embodiment 380 or embodiment 381, characterized by an X-ray powder diffractogram having a signal at 382.14.8±0.2 degrees 2θ. 383. The potassium salt hydrate Form B of crystalline Compound I, as described in embodiment 380 or embodiment 381, characterized by an X-ray powder diffractogram having signals at 4.7±0.2 degrees 2θ, 6.8±0.2 degrees 2θ, and 21.5±0.2 degrees 2θ. 384. The potassium salt hydrate Form B of crystalline Compound I, as described in embodiment 380 or embodiment 381, characterized by an X-ray powder diffraction pattern having (a) signals at 4.7±0.2°2θ, 6.8±0.2°2θ, 14.8±0.2°2θ, 21.5±0.2°2θ, and (b) signals at 15.2±0.2°2θ, 16.1±0.2°2θ, and / or 19.0±0.2°2θ. 385. The potassium salt hydrate form B of crystalline Compound I, as described in embodiment 380 or embodiment 381, characterized by an X-ray powder diffraction pattern substantially similar to Figure 40. 386. The crystalline potassium salt hydrate Form B of Compound I, according to any one of embodiments 380-385, prepared by a process comprising making a slurry of amorphous potassium salt of Compound I in ACN at room temperature, then at 60°C. 387. A method for preparing crystalline potassium salt hydrate Form B of Compound I according to any one of embodiments 380-385, prepared by a process comprising making a slurry of amorphous potassium salt of Compound I in ACN at room temperature, then at 60°C. 388. A pharmaceutical composition comprising potassium salt hydrate Form B of crystalline Compound I according to any one of embodiments 380-386, optionally further comprising one or more additional CFTR-modulating compounds. 389. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 388, which is (i) compound II and (ii) compound III or compound III-d. 390. The potassium salt hydrate form B of compound I, as defined in any one of embodiments 380-386, or the pharmaceutical composition as defined in embodiment 388 or embodiment 389, for use in the treatment of cystic fibrosis. 391. Use of potassium salt hydrate form B of compound I, as defined in any one of embodiments 380-386, or a pharmaceutical composition as defined in embodiment 388 or embodiment 389, in the manufacture of a medicament for the treatment of cystic fibrosis. 392. A method for treating cystic fibrosis, comprising administering potassium salt hydrate Form B of compound I as described in any one of embodiments 380-386, or a pharmaceutical composition as described in embodiment 388 or embodiment 389, to a subject in need of treatment. 393. The compound for use according to embodiment 390, the use according to embodiment 391, or the method according to embodiment 392, wherein potassium salt hydrate Form B of compound I according to any one of embodiments 380 to 386 is administered in combination with at least one additional CFTR-modulating compound. 394. The potassium salt hydrate form B of compound I according to any one of embodiments 380-386, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 393, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 395. The composition, use, method, or compound according to any one of embodiments 389-394, wherein compound II and / or compound III are in the form of a solid dispersion. 396. A substantially crystalline potassium salt hydrate Form C of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 397. The compound I according to embodiment 396, wherein compound I is 100% crystalline potassium salt hydrate form C. 398. The potassium salt hydrate Form C of crystalline Compound I, as described in embodiment 396 or embodiment 397, characterized by an X-ray powder diffractogram having signals at 4.8±0.2 degrees 2θ, 6.3±0.2 degrees 2θ, and 14.2±0.2 degrees 2θ. 399. Potassium hydrate Form C of crystalline Compound I, according to embodiment 396 or embodiment 397, characterized by an X-ray powder diffraction pattern having (a) signals at 4.8±0.2°2θ, 6.3±0.2°2θ, and 14.2±0.2°2θ, and (b) one or more signals selected from 13.5±0.2°2θ, 14.2±0.2°2θ, 15.8±0.2°2θ, 19.0±0.2°2θ, and 27.1±0.2°2θ. 400. The potassium salt hydrate form C of crystalline Compound I, as described in embodiment 396 or embodiment 397, characterized by an X-ray powder diffraction pattern substantially similar to Figure 41. 401. The crystalline potassium salt hydrate Form C of Compound I, according to any one of embodiments 396-400, prepared by a process comprising mixing amorphous potassium salt of Compound I with ACN at room temperature. 402. A method for preparing crystalline potassium salt hydrate Form C of Compound I, according to any one of embodiments 396-400, prepared by a process comprising mixing amorphous potassium salt of Compound I with ACN at room temperature. 403. A pharmaceutical composition comprising potassium salt hydrate Form C of crystalline Compound I according to any one of embodiments 396-401, optionally further comprising one or more additional CFTR-modulating compounds. 404. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 403, which is (i) compound II and (ii) compound III or compound III-d. 405. The potassium salt hydrate form C of compound I as described in any one of embodiments 396-401, or the pharmaceutical composition as described in embodiment 403 or embodiment 404, for use in the treatment of cystic fibrosis. 406. Use of potassium salt hydrate Form C of compound I as defined in any one of embodiments 396-401, or of a pharmaceutical composition as defined in embodiment 403 or embodiment 404, in the manufacture of a medicament for the treatment of cystic fibrosis. 407. A method for treating cystic fibrosis, comprising administering potassium salt hydrate Form C of compound I as described in any one of embodiments 396-401, or a pharmaceutical composition as described in embodiment 403 or embodiment 404, to a subject in need of treatment. 408. The compound for use according to embodiment 405, the use according to embodiment 406, or the method according to embodiment 407, wherein potassium salt hydrate Form C of compound I according to any one of embodiments 396 to 401 is administered in combination with at least one additional CFTR-modulating compound. 409. The potassium salt hydrate form C of compound I according to any one of embodiments 396-401, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 408, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 410. The composition, use, method, or compound according to any one of embodiments 404-409, wherein compound II and / or compound III are in the form of a solid dispersion. 411. A substantially crystalline potassium salt hydrate Form D of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 412. The compound I according to embodiment 411, wherein compound I is 100% crystalline potassium salt hydrate form D. 413. The potassium salt hydrate form D of crystalline Compound I, as described in embodiment 411 or embodiment 412, characterized by an X-ray powder diffractogram with signals at 4.4±0.2 degrees two-theta, 13.1±0.2 degrees two-theta, and 15.3±0.2 degrees two-theta. 414. The potassium salt hydrate form D of crystalline Compound I, as described in embodiment 411 or embodiment 412, characterized by an X-ray powder diffraction pattern having (a) a signal at 8.8±0.2°2θ, and (b) signals at 4.4±0.2°2θ, 13.1±0.2°2θ, and / or 15.3±0.2°2θ. 415. The potassium salt hydrate form D of crystalline Compound I, as described in embodiment 411 or embodiment 412, characterized by an X-ray powder diffraction pattern having (a) signals at 4.4±0.2°2θ, 8.8±0.2°2θ, 13.1±0.2°2θ, and 15.3±0.2°2θ, and (b) signals at 7.0±0.2°2θ, 8.1±0.2°2θ, and / or 21.9±0.2°2θ. 416. The potassium salt hydrate form D of crystalline compound I, as described in embodiment 411 or embodiment 412, characterized by an X-ray powder diffraction pattern substantially similar to Figure 42. 417. The crystalline potassium salt hydrate Form D of Compound I, according to any one of embodiments 411-416, prepared by a process comprising mixing amorphous potassium salt of Compound I with ACN at room temperature and drying under vacuum at 29 °C. 418. A method for preparing crystalline potassium salt hydrate Form D of Compound I according to any one of embodiments 411-416, prepared by a process comprising mixing amorphous potassium salt of Compound I with ACN at room temperature and drying under vacuum at 29 °C. 419. A pharmaceutical composition comprising potassium salt hydrate Form D of crystalline Compound I according to any one of embodiments 411-417, optionally further comprising one or more additional CFTR-modulating compounds. 420. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 419, which is (i) compound II and (ii) compound III or compound III-d. 421. Potassium salt hydrate form D of compound I as described in any one of embodiments 411-417, or a pharmaceutical composition as described in embodiment 419 or embodiment 420, for use in the treatment of cystic fibrosis. 422. Use of potassium salt hydrate form D of compound I as defined in any one of embodiments 411-417, or of a pharmaceutical composition as defined in embodiment 419 or embodiment 420, in the manufacture of a medicament for the treatment of cystic fibrosis. 423. A method for treating cystic fibrosis, comprising administering potassium salt hydrate form D of compound I as described in any one of embodiments 411 to 417, or a pharmaceutical composition as described in embodiment 419 or embodiment 420, to a subject in need of treatment. 424. The compound for use according to embodiment 421, the use according to embodiment 422, or the method according to embodiment 423, wherein potassium salt hydrate Form D of compound I according to any one of embodiments 411 to 417 is administered in combination with at least one additional CFTR-modulating compound. 425. The potassium salt hydrate form D of compound I according to any one of embodiments 411 to 417 is a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 408, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 426. The composition, use, method, or compound according to any one of embodiments 420-425, wherein compound II and / or compound III are in the form of a solid dispersion. 427. A substantially crystalline ammonium salt hydrate Form A of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 428. Compound I according to embodiment 427, wherein compound I is 100% crystalline ammonium salt hydrate form A. 429. The ammonium salt hydrate Form A of crystalline Compound I, as described in embodiment 427 or embodiment 428, characterized by an X-ray powder diffractogram having signals at 5.5±0.2 degrees 2θ, 15.3±0.2 degrees 2θ, and / or 17.7±0.2 degrees 2θ. 430. The ammonium salt hydrate Form A of crystalline Compound I, as described in embodiment 427 or embodiment 428, characterized by an X-ray powder diffraction pattern having (a) signals at 5.5±0.2 degrees 2θ, 15.3±0.2 degrees 2θ, and 17.7±0.2 degrees 2θ, and (b) signals at 18.0±0.2 degrees 2θ, 19.6±0.2 degrees 2θ, and / or 20.9±0.2 degrees 2θ. 431. The ammonium salt hydrate form A of crystalline Compound I, as described in embodiment 427 or embodiment 428, characterized by an X-ray powder diffraction pattern substantially similar to Figure 44. 432. The ammonium salt hydrate Form A of crystalline Compound I, according to any one of embodiments 427-431, prepared by a process comprising mixing Form A of amorphous Compound I (free form) with ammonium hydroxide in water. 433. A method for preparing crystalline ammonium salt hydrate Form A of Compound I, according to any one of embodiments 427-431, prepared by a process comprising mixing Form A of amorphous Compound I (free form) with ammonium hydroxide in water. 434. A pharmaceutical composition comprising the ammonium salt hydrate Form A of crystalline Compound I according to any one of embodiments 427-432, optionally further comprising one or more additional CFTR-modulating compounds. 435. One or more additional CFTR modulating compounds a. Compound III or Compound III-d, or b. The pharmaceutical composition of embodiment 434, which is (i) compound II and (ii) compound III or compound III-d. 436. The ammonium salt hydrate form A of compound I as defined in any one of embodiments 427-432, or the pharmaceutical composition as defined in embodiment 434 or embodiment 435, for use in the treatment of cystic fibrosis. 437. Use of the ammonium salt hydrate form A of compound I according to any one of embodiments 427-432, or the pharmaceutical composition according to embodiment 434 or embodiment 435, in the manufacture of a medicament for the treatment of cystic fibrosis. 438. A method for treating cystic fibrosis, comprising administering to a subject in need thereof an ammonium salt hydrate form A of compound I as described in any one of embodiments 427-432, or a pharmaceutical composition as described in embodiment 434 or embodiment 435. 439. The compound for use according to embodiment 436, the use according to embodiment 437, or the method according to embodiment 438, wherein the ammonium salt hydrate Form A of compound I according to any one of embodiments 427 to 432 is administered in combination with at least one additional CFTR-modulating compound. 440. The ammonium salt hydrate form A of compound I according to any one of embodiments 427-432, a. Compound III or compound III-d, b. (i) Compound II and (ii) Compound III or Compound III-d, or c. The compound, use, or method of embodiment 439, administered in combination with (i) compound IV and (ii) compound III or compound III-d. 441. The composition, use, method, or compound according to any one of embodiments 435-440, wherein compound II and / or compound III are in the form of a solid dispersion. 442. Substantially crystalline sodium salt hydrate form E of Compound I. 443. The sodium salt hydrate form E of compound I according to embodiment 442, characterized by an X-ray powder diffraction pattern with signals at 4.3±0.2 degrees 2θ, 13.0±0.2 degrees 2θ, and 14.9±0.2 degrees 2θ. 444.(a) Signals at 4.3 ± 0.2° 2θ, 13.0 ± 0.2° 2θ, and 14.9 ± 0.2° 2θ, and (b) The sodium salt hydrate Form E of compound I of embodiment 442 or embodiment 443, characterized by an X-ray powder diffraction pattern having one, two, three, or four signals at 10.6±0.2°2θ, 11.7±0.2°2θ, 13.4±0.2°2θ, 14.1±0.2°2θ, 14.2±0.2°2θ, 17.3±0.2°2θ, 18.1±0.2°2θ, 18.8±0.2°2θ, 19.2±0.2°2θ, 20.0±0.2°2θ, 21.4±0.2°2θ, 21.5±0.2°2θ, 22.3±0.2°2θ, and 23.1±0.2°2θ. 445. The sodium salt hydrate form E of compound I according to embodiment 442, characterized by an X-ray powder diffraction pattern with signals at 4.3±0.2 degrees 2θ, 13.0±0.2 degrees 2θ, and 23.1±0.2 degrees 2θ. 446. Sodium salt hydrate form E of compound I, according to any one of embodiments 442-445, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 49. 447. Sodium salt hydrate Form E of Compound I has one, two, three, four, five, six, seven, or more peaks selected from 165.2±0.2 ppm, 155.4±0.2 ppm, 142.7±0.2 ppm, 128.4±0.2 ppm, 121.3±0.2 ppm, 101.0±0.2 ppm, 93.1±0.2 ppm, 69.5±0.2 ppm, 62.6±0.2 ppm, 55.2±0.2 ppm, 50.6±0.2 ppm, 50.0±0.2 ppm, 21.1±0.2 ppm, 17.2±0.2 ppm, 7.2±0.2 ppm, and 2.1±0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 The sodium salt hydrate form E of compound I according to any one of embodiments 442 to 446, characterized by a C ssNMR) spectrum. 448. Sodium salt hydrate form E of Compound I has peaks at 165.2 ± 0.2 ppm, 155.4 ± 0.2 ppm, 142.7 ± 0.2 ppm, 128.4 ± 0.2 ppm, 121.3 ± 0.2 ppm, 101.0 ± 0.2 ppm, 93.1 ± 0.2 ppm, 69.5 ± 0.2 ppm, 62.6 ± 0.2 ppm, 55.2 ± 0.2 ppm, 50.6 ± 0.2 ppm, 50.0 ± 0.2 ppm, 21.1 ± 0.2 ppm, 17.2 ± 0.2 ppm, 7.2 ± 0.2 ppm, and 2.1 ± 0.2 ppm. 13 Sodium salt hydrate form E of compound I according to any one of embodiments 442 to 447, characterized by C ssNMR spectrum. 449. Sodium salt hydrate form E of Compound I has peaks at 177.4 ± 0.2 ppm, 165.2 ± 0.2 ppm, 155.4 ± 0.2 ppm, 142.7 ± 0.2 ppm, 128.4 ± 0.2 ppm, 121.3 ± 0.2 ppm, 101.0 ± 0.2 ppm, 69.5 ± 0.2 ppm, 62.6 ± 0.2 ppm, 55.2 ± 0.2 ppm, 50.0 ± 0.2 ppm, 30.9 ± 0.2 ppm, 30.2 ± 0.2 ppm, 27.8 ± 0.2 ppm, 21.1 ± 0.2 ppm, 17.2 ± 0.2 ppm, 7.2 ± 0.2 ppm, and 2.1 ± 0.2 ppm. 13 C solid-state nuclear magnetic resonance ( 13 The sodium salt hydrate form E of compound I according to any one of embodiments 442 to 446, characterized by a C ssNMR) spectrum. 450. Substantially similar to FIG. 13 Sodium salt hydrate form E of compound I, according to any one of embodiments 442 to 449, characterized by a C solid-state NMR spectrum. 451. The sodium salt hydrate form E of compound I has an orthorhombic crystal system, C2221 space group, and the following Cu K α The sodium salt hydrate form E of compound I according to any one of embodiments 442 to 450, characterized by the following unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with radiation (λ=1.54178 A): [Table 18] 452.i. Heating sodium salt hydrate Form A of Compound I in IPA and water at 65°C; ii. cooling the mixture to 45°C; iii. Seeding with sodium salt hydrate Form A crystals of Compound I; iv. cooling the mixture to 20°C; v. Collecting solids; vi. Washing the solid with IPA:water (1:3 v:v) and air drying; vii. adding IPA, NaOH, and water to the solid; viii. Heating to 73°C; ix. abrasive filtering the solution; Cooling to 58°C, xi. adding water; xii. Seeding sodium salt hydrate Form E crystals of Compound I at 40°C; cooling to xiii.5°C; xiv. Collecting the solids; xv. washing the solid with a mixture of water and IPA; and xvi. Drying under vacuum at 40°C, The sodium salt hydrate form E of compound I according to any one of embodiments 442 to 451, prepared by a process comprising obtaining sodium salt hydrate form E of compound I. 453.i. Heating sodium salt hydrate Form A of Compound I in IPA and water at 65°C; ii. cooling the mixture to 45°C; iii. Seeding with sodium salt hydrate Form A crystals of Compound I; iv. cooling the mixture to 20°C; v. Collecting solids; vi. Washing the solid with IPA:water (1:3 v:v) and air drying; vii. adding IPA, NaOH, and water to the solid; viii. Heating to 73°C; ix. abrasive filtering the solution; Cooling to 58°C, xi. adding water; xii. Seeding sodium salt hydrate Form E crystals of Compound I at 40°C; cooling to xiii.5°C; xiv. Collecting the solids; xv. washing the solid with a mixture of water and IPA; and xvi. A method for preparing sodium salt hydrate form E of compound I, according to any one of embodiments 442-451, prepared by a process comprising drying under vacuum at 40°C. 454.i. Dissolving sodium salt hydrate Form A of Compound I in IPA / water at 65°C; ii. cooling the solution to 45°C; iii. Seeding with a mixture of sodium salt hydrate Form A and Form E of Compound I; iv. adding water; v. Cooling to 20°C; vi. collecting the solids; vii. washing the solid with a mixture of water and IPA; and viii. By drying under vacuum The sodium salt hydrate form E of compound I according to any one of embodiments 442 to 451, prepared by a process comprising obtaining sodium salt hydrate form E of compound I. 455.i. Dissolving sodium salt hydrate Form A of Compound I in IPA / water at 65°C; ii. cooling the solution to 45°C; iii. Seeding with a mixture of sodium salt hydrate Form A and Form E of Compound I; iv. adding water; v. Cooling to 20°C; vi. collecting the solids; vii. washing the solid with a mixture of water and IPA; and viii. A method for preparing sodium salt hydrate Form E of Compound I according to any one of embodiments 442-451, comprising drying under vacuum. 456. Substantially crystalline sodium salt IPA (wet) solvate Form A of Compound I. 457. The sodium salt IPA solvate (wet) Form A of compound I according to embodiment 456, characterized by an X-ray powder diffraction pattern with signals at 3.5±0.2° 2θ and / or 3.6±0.2° 2θ. 458.(a) signals at 3.5±0.2°2θ and / or 3.6±0.2°2θ, and (b) Sodium salt IPA solvate (wet) Form A of compound I, as described in embodiment 456 or embodiment 457, characterized by an X-ray powder diffraction pattern with a signal at 9.5±0.2 degrees 2θ. 459. The sodium salt IPA solvate (wet) Form A of compound I according to any one of embodiments 456 to 458, characterized by an X-ray powder diffraction pattern having signals at 3.6±0.2°2θ, 3.5±0.2°2θ, and 9.5±0.2°2θ. 460. Sodium salt IPA solvate (wet) Form A of compound I, as described in any one of embodiments 456-459, characterized by an X-ray powder diffraction pattern substantially similar to FIG. 51. 461. The sodium salt solvate (wet) Form A of Compound I according to any one of embodiments 456-460, prepared by a process comprising slurrying amorphous sodium salt hydrate Form A of Compound I in IPA. 462. A method for preparing sodium salt solvate (wet) Form A of Compound I according to any one of embodiments 456-460, comprising slurrying amorphous sodium salt hydrate Form A of Compound I in IPA. 463. Substantially crystalline sodium salt IPA (dry) solvate Form B of Compound I. 464. The sodium salt IPA solvate (dried) Form B of compound I according to embodiment 463, characterized by an X-ray powder diffraction pattern with signals at 4.0±0.2 degrees 2θ and 5.3±0.2 degrees 2θ. 465.(a) Signals at 4.0±0.2°2θ and 5.3±0.2°2θ, and (b) Sodium salt IPA solvate (dried) Form B of compound I, as described in embodiment 463 or embodiment 464, characterized by an X-ray powder diffraction pattern having one, two, three, or four signals at 7.9±0.2°2θ, 9.7±0.2°2θ, 11.0±0.2°2θ, 13.9±0.2°2θ, 18.5±0.2°2θ, and 20.0±0.2°2θ. 466. The sodium salt IPA solvate (dried) Form B of compound I according to embodiment 463, characterized by an X-ray powder diffraction pattern with signals at 4.0±0.2°2θ, 7.9±0.2°2θ, and 9.7±0.2°2θ. 467. Sodium salt IPA solvate (wet) Form B of compound I, according to any one of embodiments 463-466, characterized by an X-ray powder diffraction pattern substantially similar to Figure 52. 468. Compound I sodium salt IPA solvate (dry) Form B had the following concentrations: 180.3±0.2 ppm, 178.7±0.2 ppm, 164.7±0.2 ppm, 135.9±0.2 ppm, 127.0±0.2 ppm, 117.0±0.2 ppm, 105.4±0.2 ppm, 95.5±0.2 ppm, 94.4±0.2 ppm, 68.9±0.2 ppm, 6 Having one, two, three, four, five, six, seven, or more peaks selected from 7.6±0.2 ppm, 64.1±0.2 ppm, 59.5±0.2 ppm, 54.5±0.2 ppm, 53.6±0.2 ppm, 32.7±0.2 ppm, 24.6±0.2 ppm, 20.2±0.2 ppm, 5.1±0.2 ppm, 3.6±0.2 ppm 13 C solid-state nuclear magnetic resonance ( 13 Sodium salt IPA solvate (dry) Form B of compound I according to any one of embodiments 463 to 467, characterized by a C ssNMR spectrum. 469. Compound I sodium salt IPA solvate (dry) Form B showed the following concentrations: 180.3±0.2 ppm, 178.7±0.2 ppm, 164.7±0.2 ppm, 135.9±0.2 ppm, 127.0±0.2 ppm, 117.0±0.2 ppm, 105.4±0.2 ppm, 95.5±0.2 ppm, 94.4±0. 2 ppm, 68.9±0.2 ppm, 67.6±0.2 ppm, 64.1±0.2 ppm, 59.5±0.2 ppm, 54.5±0.2 ppm, 53.6±0.2 ppm, 32.7±0.2 ppm, 24.6±0.2 ppm, 20.2±0.2 ppm, 5.1±0.2 ppm, and 3.6±0.2 ppm peaks. 13 Sodium salt IPA solvate (dried) Form B of compound I according to any one of embodiments 463-468, characterized by C ssNMR spectrum. 470. Sodium salt IPA solvate (dry) Form B of Compound I has peaks at 180.3±0.2 ppm, 178.7±0.2 ppm, 164.7±0.2 ppm, 135.9±0.2 ppm, 127.0±0.2 ppm, 117.0±0.2 ppm, 105.4±0.2 ppm, 95.5±0.2 ppm, 94.4±0.2 ppm, 67.6±0.2 ppm, 59.5±0.2 ppm, 53.6±0.2 ppm, 32.7±0.2 ppm, 27.2±0.2 ppm, 24.6±0.2 ppm, and 3.6±0.2 ppm. 13 Sodium salt IPA solvate (dried) Form B of compound I according to any one of embodiments 463 to 467, characterized by C ssNMR spectrum. 471. Substantially similar to Figure 53 13 Sodium salt IPA solvate (dried) Form B of compound I according to any one of embodiments 463 to 470, characterized by a C solid-state NMR spectrum. 472. Sodium salt IPA solvate (dried) Form B of Compound I, according to any one of embodiments 463-471, prepared by a process comprising slurrying amorphous sodium salt hydrate Form A of Compound I in IPA, followed by drying under vacuum at 40°C. 473. A method for preparing sodium salt IPA solvate (dried) Form B of Compound I according to any one of embodiments 463-471, comprising slurrying amorphous sodium salt hydrate Form A of Compound I in IPA, followed by drying under vacuum at 40°C.

[0311] Methods of Preparing Compounds and Forms General experimental procedure Definitions of certain abbreviations in the following examples are summarized below. [Table 19-1] [Table 19-2]

[0312] Compounds II, III, III-d, and IV can be prepared by any suitable method in the art, for example, PCT Publication Nos. 2011 / 133751, 2011 / 133951, 2015 / 160787, and U.S. Patent No. 8,865,902.

[0313] Solid-state NMR experiments (applicable to all crystalline forms): A Bruker-Biospin 400 MHz wide-angle spectrometer equipped with a Bruker-Biospin 4 mm HFX probe was used. Samples were packed into a 4 mm rotor and spun under magic angle spinning (MAS) conditions, with a typical spinning speed set at 12.5 kHz. Proton relaxation times were 1 Estimated from H MAS T1 saturation recovery relaxation experiments, 13 A C cross-polarization (CP) probe was used to set the appropriate recycle delay for the MAS experiment. The CP contact time for the MAS experiment was set to 2 ms. A CP proton pulse with a linear ramp (50%-100%) was used. All spectra were externally referenced by adjusting the magnetic field to set the adamantane carbon resonance at 29.5 ppm. A TPPM15 proton decoupling sequence with a magnetic field strength of approximately 100 kHz was used.

[0314] Although the specific crystalline forms of Compound I described in the Examples are non-pharmaceutical, they are useful in the preparation of other forms. Accordingly, some embodiments of the present invention provide crystalline Compound I calcium salt IPA solvate Form A (wet) or Form B (dry). In some embodiments, crystalline Compound I is calcium salt NPA solvate Form A (wet) or Form B (dry). In some embodiments, crystalline Compound I is calcium salt 2-BuOH solvate Form A (wet) or Form B (dry). In some embodiments, crystalline Compound I is calcium salt acetone solvate Form A. In some embodiments, crystalline Compound I is calcium salt DCM solvate Form A. In some embodiments, crystalline Compound I is calcium salt ethylene glycol solvate Form A. In some embodiments, crystalline Compound I is calcium salt ethylene glycol solvate Form B. In some embodiments, crystalline Compound I is calcium salt 1,2-dimethoxyethane solvate Form A. In some embodiments, crystalline Compound I is calcium salt 1,2-dimethoxyethane solvate Form B. In some embodiments, the crystalline Compound I is calcium salt CPME solvate Form A. [Example]

[0315] Example 1: Synthesis of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trionene (Compound I) Reagents and starting materials were obtained from commercial sources and used without purification unless otherwise noted.

[0316] Proton and carbon NMR spectra (as applied in Example 1) were obtained at 400 MHz and 100 MHz, respectively. 1 H and 13Spectra were acquired either on a Bruker Biospin DRX 400 MHz FTNMR spectrometer operating at the C resonance frequency or on a 300 MHz NMR spectrometer. One-dimensional proton and carbon spectra were acquired using a broadband observer (BBFO) probe with 20 Hz sample rotation at digital resolutions of 0.1834 and 0.9083 Hz / Pt, respectively. All proton and carbon spectra were acquired with temperature control at 30 °C using standard, previously published pulse sequences and routine processing parameters.

[0317] Part A: Synthesis of 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid [ka] Step 1: 7-(Bromomethyl)dipyro[2.0.2.1]heptane [ka] A 1000 mL three-neck round-bottom flask was equipped with a mechanical stirrer, cooling bath, addition funnel, J-Kem temperature probe, and nitrogen inlet / outlet. The vessel was charged with triphenylphosphine (102.7 mL, 443.2 mmol) and dichloromethane (1 L) under a nitrogen atmosphere to provide a clear, colorless solution. Stirring was initiated, and the cooling bath was charged with acetone. Dry ice was added portionwise to the cooling bath until a pot temperature of −15° C. was obtained. The addition funnel was charged with a solution of bromine (22.82 mL, 443.0 mmol) in dichloromethane (220 mL, 10 mL / g), which was subsequently added dropwise over 1 hour. Dry ice was added portionwise to the cooling bath during the addition to maintain a pot temperature of −15° C. After the addition of bromine, the pale yellow suspension continued to stir at −15° C. for 15 minutes, at which point the suspension was cooled to −30° C. An addition funnel was charged with a solution of dispiro[2.0.2.1]heptan-7-ylmethanol (50 g, 402.6 mmol), pyridine (35.82 mL, 442.9 mmol), and dichloromethane (250 mL, 5 mL / g). The clear, pale yellow solution was then added dropwise over 1.5 hours, maintaining the pot temperature at −30° C. The resulting clear, pale yellow reaction mixture was gradually warmed to a pot temperature of −5° C. and then continued to stir at −5° C. for 1 hour. The reaction mixture was then poured into hexane (2000 mL), resulting in the formation of a precipitate. The suspension was stirred at room temperature for 30 minutes and then filtered through a glass-fritted Buchner funnel with a 20 mm layer of Celite. The clear filtrate was concentrated under reduced pressure (water bath temperature 20° C.) to give a yellow oil with some precipitate present. The oil was diluted with some hexane, allowed to stand at room temperature for 15 minutes, and then filtered through a glass-fritted Buchner funnel with a 20 mm layer of Celite. The clear filtrate was concentrated under reduced pressure (water bath temperature 20 °C) to give 7-(bromomethyl)dispiro[2.0.2.1]heptane (70 g, 93%) as a clear yellow oil. 1 H NMR(400MHz,chloroform-d)δ3.49(d,J=7.5Hz,2H),1.90(t,J=7.5Hz,1H),1.06-0.84( m,4H),0.71(ddd,J=9.1,5.1,4.0Hz,2H),0.54(dddd,J=8.6,4.8,3.8,1.0Hz,2H).

[0318] Step 2: 2-Dispiro[2.0.2.1]heptan-7-ylacetonitrile [ka] A 1000 mL three-neck round-bottom flask was equipped with a mechanical stirrer, a cooling bath (used as a cross-contaminant), a J-Kem temperature probe, and a nitrogen inlet / outlet. The vessel was charged with 7-(bromomethyl)dipyrro[2.0.2.1]heptane (35 g, 187.1 mmol) and dimethyl sulfoxide (245 mL) under a nitrogen atmosphere, providing a clear, amber solution. Stirring was initiated, and the pot temperature was recorded at 19 °C. The vessel was then charged with sodium cyanide (11.46 g, 233.8 mmol) added as a solid in one portion, resulting in a dark solution that gradually exothermed to 49 °C over 15 minutes. After several minutes, the pot temperature began to decrease, and the mixture was allowed to stir at room temperature overnight (approximately 15 hours). The dark reaction mixture was quenched with ice-cold saturated sodium carbonate solution (500 mL), then transferred to a separatory funnel and partitioned with diethyl ether (500 mL). The organics were removed, and the remaining aqueous solution was extracted with diethyl ether (2 × 250 mL). The combined organics were washed with water (500 mL), dried over sodium sulfate (200 g), and then filtered through a glass-fritted Buchner funnel. The clear amber filtrate was concentrated under reduced pressure (water bath temperature 20 °C) to give 2-dispiro[2.0.2.1]heptan-7-ylacetonitrile (21 g, 84%) as a clear, dark amber oil. 1 H NMR (400 MHz, chloroform-d) δ 2.42 (d, J = 6.6 Hz, 2H), 1.69 (t, J = 6.6 Hz, 1H), 1.02-0.88 (m, 4H), 0.79-0.70 (m, 2H), 0.66-0.55 (m, 2H).

[0319] Step 3: 2-Dispiro[2.0.2.1]heptan-7-yl acetic acid [ka] To a solution of 2-dispiro[2.0.2.1]heptan-7-ylacetonitrile (2.1 g, 14.19 mmol) in EtOH (32 mL) was added sodium hydroxide (5.12 g, 128.0 mmol), followed by water (13 mL), and the resulting solution was stirred and heated to 70 °C overnight. The mixture was then cooled to room temperature, diluted with water, and extracted with diethyl ether. The aqueous phase was adjusted to pH = 1 by adding 6 N hydrochloric acid (resulting in a cloudy precipitate) and extracted with diethyl ether (three times). The organic phase was dried (magnesium sulfate), filtered, and concentrated to give 2-dispiro[2.0.2.1]heptan-7-ylacetic acid (2.19 g, 99% yield, 98% purity) as an orange solid, which was used in the next step without further purification. 1 H NMR (400MHz, chloroform-d) δ2.44(d,J=6.9Hz,2H),1.67(t,J=6.9Hz,1H),0.91(ddd,J=9.0,5.2,3.9Hz ,2H),0.81(dddd,J=8.9,5.2,3.9,0.5Hz,2H),0.69(ddd,J=8.9,5.2,3.9Hz,2H),0.56-0.44(m,2H).

[0320] Step 4: 2-Dispiro[2.0.2.1]heptan-7-ylethanol [ka] To lithium aluminum hydride (827.4 mg, 902.3 μL, 21.80 mmol) dissolved in tetrahydrofuran (33.71 mL) cooled in an ice / water bath was added 2-dispiro[2.0.2.1]heptan-7-ylacetic acid (2.552 g, 16.77 mmol) in tetrahydrofuran (7.470 mL) dropwise over 15 minutes, keeping the reaction temperature below 20° C. The mixture was stirred for a total of 18 hours, gradually warming to ambient temperature. The mixture was cooled in an ice / water bath and quenched sequentially by the slow addition of water (838.4 mg, 838.4 μL, 46.54 mmol), followed by sodium hydroxide (1.006 mL of 5 M, 5.031 mmol), and then water (2.493 g, 2.493 mL, 138.4 mmol), yielding a white granular slurry that was filtered over Celite. The filtered solid was washed with diethyl ether. The filtrate was concentrated in a vacuum of approximately 300 mbar and a 30°C water bath. The residue was diluted with diethyl ether, dried (magnesium sulfate), filtered, and concentrated in a vacuum of approximately 300 mbar and a 30°C water bath, followed by concentration under vacuum for approximately 30 seconds to give 2-dispiro[2.0.2.1]heptan-7-ylethanol (2.318 g, 100%), which was used directly in the next step without further purification. 1 H NMR (400MHz, chloroform-d) δ3.64(s,2H),1.68(d,J=6.7Hz,2H),1.39(s,1H),1.31(s,1H),0.82(d,J=14.0Hz,4H),0.65(s,2H),0.50(d,J=3.6Hz,2H).

[0321] Step 5: tert-Butyl 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate [ka] To a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (2.942 g, 15.97 mmol) and 2-dispiro[2.0.2.1]heptan-7-ylethanol (2.318 g, 16.77 mmol) in tetrahydrofuran (36.78 mL) was added triphenylphosphine (4.399 g, 16.77 mmol). To the mixture was added diisopropyl azodicarboxylate (3.391 g, 3.302 mL, 16.77 mmol) slowly dropwise over 10 minutes (a mild exotherm was observed). The reaction mixture was stirred at room temperature for 30 minutes and then at 50°C for 30 minutes. Tetrahydrofuran was removed in vacuo. To the crude residue was added toluene (23.54 mL), and the mixture was stirred overnight as a precipitate gradually crystallized. The precipitate was then slurried through Celite, filtered, washed with toluene (8.705 mL), and washed again with toluene (8.705 mL). The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography using a shallow gradient of 100% hexane to 100% ethyl acetate to give tert-butyl 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate (3.449 g, 71%). ESI-MS m / z calculated 304.17868, found 305.1 (M+1). + ; Retention time: 0.82 min (LC method A).

[0322] Step 6: 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-1H-pyrazole [ka] tert-Butyl 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate (5.304 g, 17.43 mmol) was dissolved in dichloromethane (53.04 mL) containing trifluoroacetic acid (29.81 g, 20.14 mL, 261.4 mmol), and the reaction was stirred at room temperature for 120 minutes. The reaction was evaporated, and the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution, and the layers were separated. The aqueous portion was extracted twice more with ethyl acetate, and the organics were then combined, washed with brine, dried over sodium sulfate, filtered, and evaporated to give 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-1H-pyrazole (3.56 g, 100%) as an oil. ESI-MS m / z calculated 204.12627, observed 205.1 (M+1) + ; Retention time: 0.59 min (LC method A).

[0323] Step 7: tert-Butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylate [ka] tert-Butyl 2,6-dichloropyridine-3-carboxylate (4.322 g, 17.42 mmol), 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-1H-pyrazole (3.559 g, 17.42 mmol), and potassium carbonate (2.891 g, 20.92 mmol) were combined in anhydrous dimethyl sulfoxide (71.18 mL). 1,4-Diazabicyclo[2.2.2]octane (391.1 mg, 3.487 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (136.9 mL) and stirred for 15 minutes. The resulting white solid was filtered and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and evaporated to give tert-butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylate (5.69 g, 79%) as a white solid. 1 H NMR (400MHz, chloroform-d) δ8.35(d,J=2.9Hz,1H),8.18(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),5.94(d,J=2.9Hz,1H),4.25(s,2H) ,1.90(d,J=6.8Hz,2H),1.62(s,9H),1.49(t,J=6.6Hz,1H),0.85(d,J=1.5Hz,4H),0.65(d,J=1.5Hz,2H),0.52(d,J=1.1Hz,2H). ESI-MS m / z calculated value 415.16626, observed value 360.0 (M-tBu)+; retention time: 2.09 minutes (LC method B).

[0324] Step 8: 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid [ka] tert-Butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylate (5.85 g, 14.07 mmol) was dissolved in dichloromethane (58.5 mL) containing trifluoroacetic acid (16.26 mL, 211.1 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction was evaporated, ether was added to the resulting solid, and the ether was then removed under reduced pressure. This evaporation from ether was repeated two more times to give a white solid, 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (5.06 g, 100%). 1 H NMR(400MHz,chloroform-d)δ 8.41(d,J=8.5Hz,1H),8.37(d,J=2.9Hz,1H),7.75(d,J=8.5Hz,1H),5.97(d,J=2.9Hz,1H),4.27(s,2H) ),1.91(d,J=6.7Hz,2H),1.50(s,1H),0.85(d,J=1.5Hz,4H),0.71-0.62(m,2H),0.52(d,J=1.1Hz,2H). ESI-MS m / z calculated value 359.10367, measured value 360.2(M+1) + ; Retention time: 2.16 minutes (LC method B).

[0325] Part B: Synthesis of tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate [ka] Step 1: (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt) [ka] A 5 L, three-neck round-bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe / controller, and nitrogen inlet / outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w / w, 1.498 mol) followed by heptane (1.5 L), resulting in a gray suspension. Stirring was initiated, and the pot temperature was recorded at 19 °C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe, resulting in gas evolution. The addition funnel was charged with a clear, pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 hour, resulting in gas evolution and a gradual exotherm to 45 °C. The resulting thick white suspension was then heated to 65 °C for 2 hours and then cooled to room temperature. The mixture was allowed to stir overnight (approximately 10 hours) at room temperature. The reaction mixture was vacuum filtered through a glass-fritted Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was washed with heptane (2 x 250 mL) and strained for several minutes. The slightly damp heptane cake was transferred to a glass tray and dried in a vacuum oven at 45 °C for 15 hours to give the desired product, (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt), as a white solid (205 g, 1.36 mol, 91% yield).

[0326] Step 2: 3-Methylenetetrahydropyran-2-one [ka] A 5 L, three-neck round-bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe / controller, and nitrogen inlet / outlet. The vessel was charged with (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt) (205 g, 1.366 mol) and tetrahydrofuran (1640 mL) under a nitrogen atmosphere to give a white suspension. Stirring was started, and the pot temperature was recorded at 19 °C. The vessel was then charged in one portion with paraformaldehyde (136.6 g, 4.549 mol), added as a solid. The resulting suspension was heated to 63 °C and maintained at these conditions for 15 hours. Upon heating, the reaction mixture became slightly gelatinous. The white gelatinous mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The remaining residue was partitioned in a separatory funnel with ethyl acetate (1000 mL), saturated sodium chloride (500 mL), and saturated sodium bicarbonate (500 mL). The organics were removed, and the remaining aqueous solution was extracted with ethyl acetate (5 × 300 mL). The combined organics were dried over sodium sulfate (500 g) and then vacuum filtered through a glass-fritted Buchner funnel with a 20 mm layer of Celite. The filter cake was displacement washed with ethyl acetate (250 mL). The clear filtrate was concentrated under reduced pressure to give a clear, pale yellow oil (135 g) as the desired crude product. The material was purified by silica gel column flash chromatography (liquid load) eluting with a gradient of 100% hexane to 60% ethyl acetate in hexane over 1 hour, collecting 450 mL fractions. The product was detected by TLC analysis on silica gel eluting with 3:1 hexane / ethyl acetate and visualized under UV. The product fractions were combined and concentrated under reduced pressure to give the desired product, 3-methylenetetrahydropyran-2-one, as a clear, colorless oil (132 g, 1.18 mol, 72% yield, containing 16 wt% residual ethyl acetate by NMR). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 6.18 (q, J = 1.9 Hz, 1H), 5.60 (q, J = 1.9 Hz, 1H), 4.40-4.26 (m, 2H), 2.61 (ddt, J = 7.0, 6.3, 2.0 Hz, 2H), 1.90-1.75 (m, 2H).

[0327] Step 3: 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one [ka] A 5000 mL, three-neck, round-bottom flask was equipped with a mechanical stirrer, a cooling bath used as secondary containment, a J-Kem temperature probe, and a nitrogen inlet / outlet. The vessel was charged with 2-nitropropane (104.9 g, 1.177 mol) under a nitrogen atmosphere. Stirring was initiated, and the pot temperature was recorded at 19 °C. 1,8-diazabicyclo[5.4.0]undec-7-ene (22.41 g, 147.2 mmol) was then added neat to the vessel in one portion, resulting in a clear, pale yellow solution. No exotherm was observed. The addition funnel was charged with a solution of 3-methylenetetrahydropyran-2-one (110 g, 981.0 mmol) in acetonitrile (1100 mL), which was added dropwise over 1 hour, resulting in a clear, pale yellow solution that gradually exothermed to 24 °C. The reaction mixture was continued to stir at room temperature for 3.5 hours and then concentrated under reduced pressure. The remaining residue was dissolved in dichloromethane (1000 mL) and partitioned with 500 mL of a 3:2 mixture of 1 molar citric acid solution and saturated sodium chloride solution. The resulting organic phase was a clear, pale blue solution, and the aqueous phase was a slightly cloudy, very pale blue solution. The organics were removed, and the remaining aqueous solution was extracted with dichloromethane (300 mL). The combined organics were washed with saturated sodium chloride solution (300 mL), dried over sodium sulfate (250 g), and then filtered through a glass-fritted Buchner funnel. The filtrate was concentrated under reduced pressure to a volume of approximately 200 mL. The clear, pale blue dichloromethane solution was diluted with methyl tert-butyl ether (1500 mL), and the cloudy solution was concentrated under reduced pressure to a volume of approximately 200 mL, resulting in a suspension. The mixture was again diluted with methyl tert-butyl ether (1500 mL) and concentrated under reduced pressure to a volume of approximately 250 mL. The resulting suspension was allowed to stand overnight (approximately 12 hours) at room temperature. The solid was collected by vacuum filtration in a glass-fritted Buchner funnel, and the filter cake was displacement washed with cold methyl tert-butyl ether (2 × 150 mL) and then suctioned for 30 minutes. The material was further dried in a vacuum oven at 45 °C for 5 hours to give the desired product as a white solid, 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (160 g, 0.795 mol, 81% yield). 1H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 4.34 (ddd, J = 11.1, 9.3, 4.3 Hz, 1H), 4.20 (dt, J = 11.1, 5.1 Hz, 1H), 2.75-2.62 (m, 1H), 2.56 (dd, J = 14.9, 5.2 Hz, 1H), 2.01-1.89 (m, 2H), 1.89-1.67 (m, 2H), 1.55 (d, J = 6.0 Hz, 6H), 1.44 (dddd, J = 12.8, 11.5, 8.1, 6.6 Hz, 1H).

[0328] Step 4: 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one [ka] A 1000 mL three-neck round-bottom flask was equipped with a Teflon stir bar, heating mantle, J-Kem temperature probe / controller, and rubber septum. The vessel was charged with 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (25 g, 124.2 mmol) and ethyl alcohol (375 mL), resulting in a white suspension. Stirring was initiated, and the suspension was heated to 40°C for 10 minutes, resulting in a clear, colorless solution. The vessel was then equipped with a gas dispersion tube, and the solution was degassed with nitrogen for 15 minutes. The vessel was then charged with Raney nickel (8.019 g, 68.31 mmol of 50% w / w), and the vessel was then equipped with a septum. The vessel was evacuated and placed under a hydrogen atmosphere. This process was repeated three times. The vessel was then placed under 1 atmosphere of hydrogen, and the reaction mixture was gradually heated to 60°C. The reaction was allowed to stir at 60°C for 24 hours. After cooling to room temperature, the vessel was equipped with a gas dispersion tube, and the reaction mixture was degassed with nitrogen for 15 minutes. The mixture was vacuum filtered through a glass-fritted Buchner funnel with a 20 mm layer of Celite. The filter cake was displacement washed with ethanol (2 × 100 mL), suctioned until the ethyl alcohol was slightly wet, and then wetted with water, and the spent Raney nickel catalyst was discarded in water. The clear, pale amber filtrate was concentrated under reduced pressure to give a clear, viscous, pale amber oil. The oil was diluted with methyl tert-butyl ether (1500 mL), and the cloudy solution was concentrated under reduced pressure to a volume of approximately 150 mL, resulting in a suspension. The mixture was again diluted with methyl tert-butyl ether (1500 mL) and concentrated under reduced pressure to a volume of approximately 150 mL. The resulting suspension was allowed to stand overnight (approximately 12 hours) at room temperature. The solid was collected by vacuum filtration in a glass-fritted Buchner funnel, and the filter cake was displacement washed with cold methyl tert-butyl ether (2 × 50 mL) and then suctioned for 30 minutes. The material was further dried in a vacuum oven at 45 °C for 3 hours to give 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one as a white solid (19 g, 0.111 mol, 89% yield) as the product. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 7.63 (s, 1H), 3.38 (t, J = 6.5 Hz, 2H), 2.37 (tdd, J = 9.8, 8.5, 4.4 Hz, 1H), 2.02 (dd, J = 12.3, 8.6 Hz, 1H), 1.72 (tdd, J = 9.6, 7.5, 4.4 Hz, 1H), 1.52-1.32 (m, 3H), 1.28-1.03 (m, 7H).

[0329] Step 5: 3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol [ka] A 5 L, three-neck round-bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe / controller, and nitrogen inlet / outlet. The vessel was charged with lithium aluminum hydride pellets (19.39 g, 510.9 mmol) under a nitrogen atmosphere. Tetrahydrofuran (500 mL, 20 mL / g) was then added to the vessel. Stirring was initiated, and the pot temperature was recorded at 20°C. The mixture was stirred at room temperature for 0.5 hours to dissolve the pellets. The pot temperature of the resulting gray suspension was recorded at 24°C. The addition funnel was charged with a solution of 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (25 g, 146.0 mmol) in tetrahydrofuran (500 mL), and the clear, pale yellow solution was added dropwise over 90 minutes. Slight heating was required to achieve homogeneity. After the addition was complete, the pot temperature of the resulting gray suspension was recorded at 24°C. The mixture was then heated to a pot temperature of 65°C and maintained at these conditions for 72 hours. Analysis of the reaction mixture at this point indicated that some residual starting material still remained and that there was no change in product formation. The reaction was then stopped at this point. The heating mantle was removed and a cooling bath was installed. The suspension was cooled to 0°C with a crushed ice / water cooling bath and then quenched by the very slow dropwise addition of water (19.93 mL), followed by the dropwise addition of 15 wt% sodium hydroxide solution (19.93 mL), and finally with water (59.79 mL). The pot temperature of the resulting white suspension was recorded at 5°C. The cooling bath was removed and the vessel was again equipped with a heating mantle. The suspension was warmed to 60°C and maintained at these conditions for 30 minutes. The warm suspension was vacuum filtered through a glass-fritted Buchne...

Claims

1. A crystal of Compound I, 【Chemical 33】 The crystal of Compound I is calcium salt hydrate form D and is characterized by an X-ray powder diffraction pattern having signals at 6.1±0.2° 2θ, 16.2±0.2° 2θ, and 22.8±0.2° 2θ.

2. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern having one or more signals selected from: (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ; and (b) signals at 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ.

3. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern having two or more signals selected from: (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ, and (b) signals at 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ.

4. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern having three or more signals selected from: (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ; and (b) signals at 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ.

5. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern having four or more signals selected from: (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ; and (b) signals at 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ.

6. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern having five or more signals selected from: (a) signals at 6.1±0.2°2θ, 16.2±0.2°2θ, and 22.8±0.2°2θ; and (b) signals at 5.5±0.2°2θ, 15.5±0.2°2θ, 19.7±0.2°2θ, 21.5±0.2°2θ, 22.1±0.2°2θ, 23.0±0.2°2θ, and 27.6±0.2°2θ.

7. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern having signals at 6.1±0.2°2θ, 16.2±0.2°2θ, 22.8±0.2°2θ, and 27.6±0.2°2θ.

8. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern having signals at 6.1±0.2°2θ, 15.5±0.2°2θ, 16.2±0.2°2θ, 19.7±0.2°2θ, 22.8±0.2°2θ, and 27.6±0.2°2θ.

9. The following diagram 【Chemical 34】 The crystal of claim 1 characterized by the X-ray powder diffraction pattern shown in

10. Triclinic system, P1 space group, and Cu K α The following was measured at 100 K on a Bruker diffractometer with radiation (λ = 1.5478 Å): 【Chemical 35】 2. The crystal of claim 1, characterized by unit cell dimensions of:

11. It has a peak at 130.2±0.2 ppm １３ 2. The crystal of claim 1 characterized by a C ssNMR spectrum.

12. It has a peak at 125.6±0.2 ppm １３ 2. The crystal of claim 1 characterized by a C ssNMR spectrum.

13. It has a peak at 35.0±0.2 ppm １３ 2. The crystal of claim 1 characterized by a C ssNMR spectrum.

14. having peaks at 130.2±0.2 ppm, 125.6±0.2 ppm, and / or 35.0±0.2 ppm １３ 2. The crystal of claim 1 characterized by a C ssNMR spectrum.

15. (a) peaks at 130.2±0.2 ppm, 125.6±0.2 ppm, and / or 35.0±0.2 ppm, and (b) peaks at 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and / or 98.6±0.2 ppm. １３ 2. The crystal of claim 1 characterized by a C ssNMR spectrum.

16. (a) peaks at 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm, and (b) peaks at 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and / or 98.6±0.2 ppm. １３ 2. The crystal of claim 1 characterized by a C ssNMR spectrum.

17. (a) peaks at 130.2±0.2 ppm, 125.6±0.2 ppm, and / or 35.0±0.2 ppm, and (b) peaks at 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and 98.6±0.2 ppm. １３ 2. The crystal of claim 1 characterized by a C ssNMR spectrum.

18. (a) a peak at 35.0±0.2 ppm, and (b) peaks at 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and 98.6±0.2 ppm. １３ 2. The crystal of claim 1 characterized by a C ssNMR spectrum.

19. The following diagram 【Chemical 36】 As shown in １３ The crystal of claim 1 characterized by C ssNMR.

20. A crystal of Compound I, 【Chemical 37】 The crystal of Compound I is Form A, characterized by an X-ray powder diffraction pattern having signals at 9.2±0.2° 2θ, 11.3±0.2° 2θ, 14.0±0.2° 2θ, and 22.9±0.2° 2θ.

21. A crystal of Compound I, 【Chemical 38】 The crystalline form of Compound I is Form B, characterized by an X-ray powder diffraction pattern having signals at 16.3±0.2° 2θ, 17.7±0.2° 2θ, and 5.5±0.2° 2θ.

22. A crystal of Compound I, 【Chemical 39】 The crystalline form of Compound I is Form C, characterized by an X-ray powder diffraction pattern having signals at 6.3±0.2° 2θ, 14.8±0.2° 2θ, and 20.4±0.2° 2θ.

23. A crystal of Compound I, 【Chemistry 40】 The crystal of Compound I is calcium salt hydrate form A and is characterized by an X-ray powder diffraction pattern having signals at 4.2±0.2° 2θ, 18.0±0.2° 2θ, and 19.7±0.2° 2θ.

24. A crystal of Compound I, 【Chemistry 41】 The crystal of Compound I is calcium salt hydrate form B and is characterized by an X-ray powder diffraction pattern having signals at 13.1±0.2° 2θ, 14.6±0.2° 2θ, and 17.7±0.2° 2θ.

25. A crystal of Compound I, 【Chemistry 43】 The crystal of Compound I is calcium salt hydrate form C and is characterized by an X-ray powder diffraction pattern having signals at 10.3±0.2° 2θ, 15.8±0.2° 2θ, and 20.8±0.2° 2θ.

26. A crystal of Compound I, 【Chemical 44】 The crystal of Compound I is calcium salt hydrate form E and is characterized by an X-ray powder diffraction pattern having signals at 8.0±0.2° 2θ, 12.0±0.2° 2θ, and 24.2±0.2° 2θ.

27. A crystal of Compound I, 【Chemistry 45】 The crystalline form of Compound I is Form F, characterized by an X-ray powder diffraction pattern having signals at 5.3±0.2° 2θ, 7.5±0.2° 2θ, and 9.14±0.2° 2θ.

28. A crystal of Compound I, 【Chemistry 46】 The crystal of Compound I is calcium salt hydrate form G and is characterized by an X-ray powder diffraction pattern having signals at 5.9±0.2° 2θ, 8.8±0.2° 2θ, and 26.6±0.2° 2θ.

29. A crystal of Compound I, 【Chemistry 47】 The crystalline form of Compound I is calcium salt form H and is characterized by an X-ray powder diffraction pattern having signals at 5.8±0.2° 2θ, 13.0±0.2° 2θ, and 14.5±0.2° 2θ.

30. A crystal of Compound I, 【Chemistry 48】 The crystal of Compound I is calcium salt ethanol (EtOH) solvate form A, characterized by an X-ray powder diffraction pattern having signals at 4.1±0.2°2θ, 8.2±0.2°2θ, and 17.1±0.2°2θ.

31. A crystal of Compound I, 【Chemistry 49】 The crystal of Compound I is calcium salt ethanol (EtOH) solvate form B, characterized by an X-ray powder diffraction pattern having signals at 4.5±0.2° 2θ, 5.0±0.2° 2θ, and 15.4±0.2° 2θ.

32. A crystal of Compound I, 【Chemistry 50】 The crystalline form of Compound I is calcium salt EtOH solvate Form C, characterized by an X-ray powder diffraction pattern having signals at 4.2±0.2° 2θ, 5.0±0.2° 2θ, and 5.7±0.2° 2θ.

33. A crystal of Compound I, 【Chemistry 51】 The crystal of Compound I is sodium salt hydrate form A and is characterized by an X-ray powder diffraction pattern having signals at 5.4±0.2° 2θ, 15.9±0.2° 2θ, and 17.6±0.2° 2θ.

34. A crystal of Compound I, 【Chemistry 52】 The crystal of Compound I is sodium salt pure form B, characterized by an X-ray powder diffraction pattern having signals at 11.0±0.2° 2θ, 18.1±0.2° 2θ, and 20.5±0.2° 2θ.

35. A crystal of Compound I, 【Chemistry 53】 The crystal of Compound I is sodium salt hydrate form C and is characterized by an X-ray powder diffraction pattern having signals at 6.1±0.2° 2θ, 13.4±0.2° 2θ, and 19.2±0.2° 2θ.

36. A crystal of Compound I, 【Chemical 54】 The crystal of Compound I is sodium salt hydrate form D and is characterized by an X-ray powder diffraction pattern having signals at 7.8±0.2° 2θ, 18.5±0.2° 2θ, and 19.9±0.2° 2θ.

37. A crystal of Compound I, 【Chemistry 55】 The crystal of Compound I is potassium salt hydrate form A and is characterized by an X-ray powder diffraction pattern having signals at 10.7±0.2° 2θ, 15.3±0.2° 2θ, and 20.4±0.2° 2θ.

38. A crystal of Compound I, 【Chemical Formula 56】 The crystal of Compound I is potassium salt hydrate form B, characterized by an X-ray powder diffraction pattern having signals at 4.7±0.2° 2θ, 6.8±0.2° 2θ, and 21.5±0.2° 2θ.

39. A crystal of Compound I, 【Chemical Formula 57】 The crystalline form of Compound I is potassium salt hydrate form C and is characterized by an X-ray powder diffraction pattern having signals at 4.8±0.2° 2θ, 6.3±0.2° 2θ, and 14.2±0.2° 2θ.

40. A crystal of Compound I, 【Chemistry 58】 The crystalline form of Compound I is potassium salt hydrate form D and is characterized by an X-ray powder diffraction pattern having signals at 4.4±0.2° 2θ, 13.1±0.2° 2θ, and 15.3±0.2° 2θ.

41. A crystal of Compound I, 【Chemical Formula 59】 The crystal of Compound I is ammonium salt hydrate form A and is characterized by an X-ray powder diffraction pattern having signals at 5.5±0.2° 2θ, 15.3±0.2° 2θ, and 17.7±0.2° 2θ.

42. A pharmaceutical composition comprising a crystal of Compound I according to any one of claims 1 to 41.

43. 43. The pharmaceutical composition of claim 42, further comprising one or more additional CFTR-modulating compounds.

44. 44. The pharmaceutical composition of claim 43, wherein the at least one additional CFTR modulating compound is a CFTR potentiator.

45. 44. The pharmaceutical composition of claim 43, wherein the at least one additional CFTR modulating compound is a CFTR corrector.

46. The one or more additional CFTR modulating compounds are (a) Compound II: 【Chemistry 60】 (b) Compound III: 【Hua 61】 or compound III-d: 【Hua 62】 and (c) Compound IV: 【Chemistry 63】 44. The pharmaceutical composition of claim 43, wherein the pharmaceutical composition is selected from:

47. Use of a crystal of compound I according to any one of claims 1 to 41 in the manufacture of a medicament for the treatment of cystic fibrosis.

48. 48. The use of claim 47, wherein the medicament further comprises one or more additional CFTR-modulating compounds.

49. The one or more additional CFTR modulating compounds are (a) Compound II: 【Hua 64】 (b) Compound III: 【Chemistry 65】 or compound III-d: 【Hua 66】 and (c) Compound IV: 【Chemical 67】 49. The use according to claim 48, wherein the compound is selected from the group consisting of:

50. 43. The pharmaceutical composition of claim 42 for use in the treatment of cystic fibrosis.

51. 51. The pharmaceutical composition for use in treating cystic fibrosis of claim 50, wherein the pharmaceutical composition is formulated for administration before, after, or simultaneously with one or more additional CFTR-modulating compounds.

52. The one or more additional CFTR modulating compounds are (a) Compound II: 【Chemistry 68】 (b) Compound III: 【Chemical Formula 69】 or compound III-d: 【Chemistry 70】 and (c) Compound IV: 【Chemical 71】 52. The pharmaceutical composition for use in the treatment of cystic fibrosis according to claim 51, selected from:

53. (a) crystallizing amorphous Compound I in toluene and drying under vacuum to obtain Form A of Compound I; (b) Compound I Form A and calcium methoxide (Ca(OMe) ２ ) with IPA / H ２ 0 at 70°C to obtain calcium salt hydrate Form A of Compound I; and (e) charging calcium salt hydrate Form A of Compound I with EtOH / water and heating to 65° C. to obtain calcium salt Form D of Compound I; 20. A method for preparing a crystal of Compound I according to any one of claims 1 to 19, comprising:

54. A solid of Compound I, 【Chemical Formula 72】 A solid, wherein an amount of 90% or more by weight of said solid is calcium salt hydrate form D of compound I according to any one of claims 1 to 19.

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