Crystalline forms of JAK2 inhibitor

Abstract

To provide crystalline forms of a JAK2 inhibitor, compositions thereof and methods of treating a JAK2-mediated disorder.SOLUTION: A crystalline form of a compound having the following structure is provided.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - reference to related applications This application claims the priority of U.S. Provisional Application No. 62 / 804,332, filed on February 12, 2019, and the entire disclosure of which is incorporated herein by reference in its entirety.

[0002] The present invention provides compounds useful as inhibitors of protein kinases and compositions thereof.

Background Art

[0003] In recent years, the search for new therapeutic agents has been greatly aided by a better understanding of the structures of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive research is protein kinases.

[0004] Protein kinases constitute a large family of structurally related enzymes involved in the control of various intracellular signal transduction processes. Protein kinases are thought to have evolved from a common ancestral gene because their structure and catalytic function are conserved. Almost all kinases contain a similar catalytic domain of 250 - 300 amino acids. Kinases can be classified into families by the substrates they phosphorylate (e.g., protein - tyrosine, protein - serine / threonine, lipids, etc.).

[0005] Generally, protein kinases mediate intracellular signal transduction by effecting phosphorylation transfer from nucleoside triphosphates to protein receptors involved in signal transduction pathways. These phosphorylation events function as on / off switches for molecules that can modulate or regulate the biological functions of target proteins. These phosphorylation events are ultimately triggered in response to various extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte macrophage colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell growth, movement, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, regulation of protein synthesis, and regulation of the cell cycle.

[0006] Many diseases are associated with abnormal cellular responses triggered by events mediated by protein kinases as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there remains a need to find protein kinase inhibitors that are useful as therapeutic agents.

Summary of the Invention

[0007] In some embodiments, the present disclosure provides one or more crystalline forms of Compound 1.

Chemical Formula

[0008] In some embodiments, the present disclosure provides one or more crystalline forms comprising Compound 1 and coformer X, wherein, X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, 1,5-naphthalenedisulfonic acid, (S)-camphor-10-sulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

[0009] In some embodiments, Compound 1, or a crystalline form or complex thereof, is useful for treating a myeloproliferative disorder. In some embodiments, the myeloproliferative disorder is selected from myelofibrosis, polycythemia vera, and essential thrombocythemia. In some embodiments, the myelofibrosis is selected from primary myelofibrosis or secondary myelofibrosis. In some embodiments, the secondary myelofibrosis is selected from myelofibrosis after polycythemia vera and myelofibrosis after essential thrombocythemia.

[0010] In some embodiments, the present disclosure provides a method of inhibiting the activity of JAK2 kinase or a variant thereof in a biological sample, the method comprising contacting the biological sample with Compound 1, or a crystalline form or complex thereof, or a composition thereof.

[0011] In another embodiment, the present disclosure relates to a method of inhibiting the activity of JAK2 kinase or a variant thereof in a patient, comprising the step of administering to the patient compound 1, or a crystalline form or complex thereof, or a composition thereof. In other embodiments, the present disclosure provides a method of treating a JAK2-mediated disease or disorder in a patient in need thereof, the method comprising the step of administering to the patient compound 1, or a crystalline form or complex thereof, or a composition thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0012]

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Mode for Carrying Out the Invention

[0013] General Description of Certain Embodiments of the Invention U.S. Patent No. 7,528,143 (the “‘143 Patent”), issued on May 5, 2009, which is hereby incorporated by reference in its entirety, describes certain 2,4-disubstituted pyrimidine compounds useful for the treatment of myeloproliferative disorders, including polycythemia vera, essential thrombocythemia, and myelofibrosis (e.g., primary myelofibrosis, and secondary myelofibrosis such as post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis). Such compounds include Compound 1.

Chemical formula

[0014] Compound 1, N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-yl ethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide, is designated as Compound Number LVII, and the synthesis of Compound 1 is described in detail in Example 90 of the ‘143 Patent.

[0015] Compound 1 is active in various assays and therapeutic models and exhibits inhibition of Janus kinase 2 (JAK2). Thus, Compound 1, or its crystalline forms or complexes, is useful for treating one or more disorders associated with JAK2 activity.

[0016] Crystalline Forms of Compound 1 In some embodiments, the present disclosure provides crystalline forms of Compound 1. It will be understood that the crystalline forms of Compound 1 may exist in pure or non-solvated forms, hydrated forms, and / or solvated forms. In some embodiments, the crystalline forms of Compound 1 are pure or non-solvated crystalline forms and thus do not have water or solvent incorporated into the crystal structure. In some embodiments, the crystalline forms of Compound 1 are hydrated forms or solvated forms. In some embodiments, the crystalline forms of Compound 1 are hydrate / solvate forms (also referred to herein as “heterosolvates”).

[0017] Accordingly, in some embodiments, the present disclosure provides one or more crystalline anhydrous forms of Compound 1.

Chem.

[0018] In some embodiments, the present disclosure provides one or more crystalline hydrate forms of Compound 1.

Chem.

[0019] In some embodiments, the present disclosure provides one or more crystalline solvate forms of Compound 1.

Chem.

[0020] In some embodiments, the present disclosure provides a substantially impurity-free sample comprising a crystalline form of Compound 1. As used herein, the term "substantially impurity-free" means that the sample contains no significant amount of foreign matter. In some embodiments, a sample comprising a crystalline form of Compound 1 is substantially free of amorphous Compound 1. In certain embodiments, the sample comprises at least about 90% by weight of the crystalline form of Compound 1. In certain embodiments, the sample comprises at least about 95% by weight of the crystalline form of Compound 1. In still other embodiments, the sample comprises at least about 99% by weight of the crystalline form of Compound 1.

[0021] According to some embodiments, the sample comprises at least about 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent (wt%) of the crystalline form of Compound 1, where the percent is based on the total weight of the sample. According to some embodiments, the sample comprising the crystalline form of Compound 1 comprises up to about 5.0% total organic impurities. In some embodiments, the sample comprising the crystalline form of Compound 1 comprises up to about 3.0% total organic impurities. In some embodiments, the sample comprising the crystalline form of Compound 1 comprises up to about 1.5% total organic impurities. In some embodiments, the sample comprising the crystalline form of Compound 1 comprises up to about 1.0% total organic impurities. In some embodiments, the sample comprising the crystalline form of Compound 1 comprises up to about 0.6% total organic impurities. In some embodiments, the sample comprising the crystalline form of Compound 1 comprises up to about 0.5% total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.

[0022] Compound 1 has been found to exist in at least four different crystalline forms, or polymorphs.

[0023] In some embodiments, the present disclosure provides an anhydrous form of Compound 1. In some embodiments, the anhydrous form of Compound 1 is a crystalline anhydrous form of Compound 1. In some embodiments, the crystalline anhydrous form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 9.7, 14.6, 19.5, 24.3, and 25.6 ± 0.2 degrees. In some such embodiments, the crystalline anhydrous form of Compound 1 is Form A.

[0024] In some embodiments, Form A of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 1]

[0025] In some embodiments, Form A of Compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 1.

[0026] In some embodiments, Form A of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern shown in Figure 2A.

[0027] In some embodiments, Form A of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern shown in Figure 2B.

[0028] In some embodiments, Form A of Compound 1 is characterized by the dynamic vapor sorption (DVS) isotherm shown in Figure 2C.

[0029] In some embodiments, the present disclosure provides a solvate form of Compound 1. In some such embodiments, the solvate form of Compound 1 is a 2-methyl-tetrahydrofuran solvate. In some such embodiments, the 2-methyl-tetrahydrofuran solvate form of Compound 1 is a crystalline 2-methyl-tetrahydrofuran solvate form of Compound 1. In some embodiments, the crystalline 2-methyl-tetrahydrofuran solvate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 12.5, 18.3, 18.9, 20.1, and 23.8 ± 0.2 degrees. In some such embodiments, the crystalline 2-methyl-tetrahydrofuran solvate form of Compound 1 is Form B.

[0030] In some embodiments, Form B of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 2

[0031] In some embodiments, Form B of Compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 3.

[0032] In some embodiments, Form B of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern shown in Figure 4A.

[0033] In some embodiments, Form B of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern shown in Figure 4B.

[0034] In some embodiments, the present disclosure provides a hydrate form of Compound 1. In some embodiments, the hydrate form of Compound 1 is a crystalline hydrate form of Compound 1. In some embodiments, the hydrate form of Compound 1 is a monohydrate. In some embodiments, the crystalline monohydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.7, 15.2, 17.3, 18.0, and 19.4 ± 0.2 degrees. In some such embodiments, the crystalline monohydrate form of Compound 1 is Form C.

[0035] In some embodiments, Form C of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 3

[0036] In some embodiments, Form C of Compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 5.

[0037] In some embodiments, Form C of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern shown in Figure 6A.

[0038] In some embodiments, Form C of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern shown in Figure C6B.

[0039] In some embodiments, Form C of Compound 1 is characterized by the dynamic vapor sorption (DVS) isotherm shown in Figure 7.

[0040] In some embodiments, the crystalline hydrate form of Compound 1 is a tetrahydrate. In some embodiments, the crystalline tetrahydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 12.4, 18.5, 19.3, 20.3, and 23.6 ± 0.2 degrees. In some such embodiments, the crystalline tetrahydrate form of Compound 1 is Form D.

[0041] In some embodiments, Form D of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 4]

[0042] In some embodiments, Form D of Compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 8.

[0043] In some embodiments, Form D of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern shown in Figure 9A.

[0044] In some embodiments, Form D of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern shown in Figure 9B.

[0045] In some embodiments, it would be desirable to provide forms of Compound 1 that impart properties such as improved water solubility, stability, and ease of formulation compared to Compound 1. Accordingly, the present invention provides a complex of Compound 1.

[0046] The complex form of Compound 1 In some embodiments, the present disclosure provides a complex comprising Compound 1

Chemical formula

[0047] It will be understood that the complex comprising Compound 1 and coformer X may exist in pure or unsolvated form, hydrated form, solvated form, and / or heterosolvated form. In some embodiments, the complex comprising Compound 1 and coformer is in pure or unsolvated crystalline form and thus has no water or solvent incorporated into the crystal structure. In some embodiments, the complex comprising Compound 1 and coformer is in hydrated or solvated form. In some embodiments, the complex comprising Compound 1 and coformer is in hydrate / solvate form (also referred to herein as "heterosolvate"). In some embodiments, the present disclosure provides Compound 1

Chemical formula

[0048] In some embodiments, the present disclosure provides a hydrate form of a complex comprising Compound 1

Chemical formula

[0049] In some embodiments, the present disclosure provides a solvate form of a complex comprising Compound 1 [Chemical formula] and coformer X, wherein herein X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, 1,5-naphthalenedisulfonic acid, (S)-camphor-10-sulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

[0050] In some embodiments, the present disclosure provides a heterosolvate form of a complex comprising Compound 1 [Chemical formula] and coformer X, wherein herein X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, 1,5-naphthalenedisulfonic acid, (S)-camphor-10-sulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

[0051] In some embodiments, the term "complex" is used herein to refer to a form that includes Compound 1 non-covalently associated with a coformer. Such non-covalent bonds include, by way of example, ionic interactions, dipole-dipole interactions, π-stacking interactions, hydrogen bonding interactions, and the like.

[0052] It will be understood that the term "complex" encompasses salt forms resulting from ionic interactions between Compound 1 and an acid or base, as well as non-ionic associations between Compound 1 and neutral species.

[0053] In some embodiments, the term "complex" is used herein to refer to a form that includes Compound 1 ionically associated with a coformer. Thus, in some such embodiments, the term "complex" is used herein to refer to a salt that includes Compound 1 and an acid or base.

[0054] In some embodiments, the “complex” is an inclusion complex, a salt form, a co-crystal, a clathrate, or their hydrates and / or solvates, etc. In some embodiments, the term “complex” is used to refer to a 1:1 (i.e., stoichiometric) ratio of Compound 1 to the co-former. In some embodiments, the term “complex” does not necessarily indicate a specific ratio of Compound 1 to the co-former. In some embodiments, the complex is a salt form, or its hydrate or solvate. In some embodiments, the complex is a co-crystalline form, or its hydrate or solvate. In some embodiments, the complex is an inclusion complex, or its hydrate or solvate. In some embodiments, the complex is a clathrate, or its hydrate or solvate.

[0055] In some embodiments, co-former X and Compound 1 are ionically associated. In some embodiments, Compound 1 is non-covalently associated with co-former X.

[0056] The complex forms of Compound 1 can exist in various physical forms. For example, the complex of Compound 1 can be in the form of a solution, a suspension, or a solid. In some embodiments, the complex form of Compound 1 is in solution form. In certain embodiments, the complex form of Compound 1 is in solid form. When the complex of Compound 1 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. In some embodiments, the complex form of Compound 1 is an amorphous solid. In some embodiments, the complex form of Compound 1 is a crystalline solid. Exemplary complex forms of Compound 1 are described in more detail below.

[0057] It will be appreciated that the complex comprising Compound 1 and conformer X can contain 1 equivalent of X. Thus, in some embodiments, the complexes described herein comprise Compound 1 and 1 equivalent of X. In some embodiments, the complexes described herein comprise Compound 1 and 2 equivalents of X. In some embodiments, the complexes described herein comprise Compound 1 and 3 equivalents of X. In some embodiments, the complexes described herein comprise Compound 1 and 0.5 to 2.5 equivalents of X (e.g., 0.5, 0.9, 1.2, 1.5 equivalents of X).

[0058] In some embodiments, the present invention provides a substantially impurity-free sample comprising a complex form of Compound 1. In some embodiments, a sample comprising a complex form of Compound 1 is substantially free of excess conformer X, excess Compound 1, residual solvent, or other impurities that may result from the preparation and / or isolation of the complex form of Compound 1. In certain embodiments, the sample comprises at least about 90% by weight of the complex form of Compound 1. In certain embodiments, the sample comprises at least about 95% by weight of the complex form of Compound 1. In yet other embodiments, the sample comprises at least about 99% by weight of the complex form of Compound 1.

[0059] According to some embodiments, the sample comprises at least about 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent (wt%) of the complex form of Compound 1, where the percent is based on the total weight of the sample. According to some embodiments, the sample comprising the complex form of Compound 1 comprises up to about 5.0% total organic impurities. In some embodiments, the sample comprising the complex form of Compound 1 comprises up to about 3.0% total organic impurities. In some embodiments, the sample comprising the complex form of Compound 1 comprises up to about 1.5% total organic impurities. In some embodiments, the sample comprising the complex form of Compound 1 comprises up to about 1.0% total organic impurities. In some embodiments, the sample comprising the complex form of Compound 1 comprises up to about 0.6% total organic impurities. In some embodiments, the sample comprising the complex form of Compound 1 comprises up to about 0.5% total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.

[0060] Structures depicted in the complex form of Compound 1 include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C- or 14 replacement of carbon with 13C-enriched carbon, compounds having the structures of the present invention are within the scope of the present invention.

[0061] In some embodiments, the complex form of Compound 1 is crystalline, and X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, 1,5-naphthalenedisulfonic acid, (S)-camphor-10-sulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glycolic acid, L-malic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, and acetylsalicylic acid.

[0062] In some embodiments, X is selected from the group consisting of 2-naphthalenesulfonic acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, 1,5-naphthalenedisulfonic acid, (S)-camphor-10-sulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, benzenesulfonic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, fumaric acid, L-lactic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glutamic acid, glycolic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, and choline.

[0063] In some embodiments, X is selected from the group consisting of 2-naphthalenesulfonic acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, 1,5-naphthalenedisulfonic acid, (S)-camphor-10-sulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, benzenesulfonic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, fumaric acid, L-lactic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glycolic acid, L-malic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, and acetylsalicylic acid.

[0064] In some embodiments of the complex form of Compound 1, X is hydrobromic acid. In some such embodiments, the complex form of Compound 1 is a hydrobromide salt. In some embodiments, the complex form of Compound 1 contains 1 equivalent of hydrobromic acid. In some embodiments, the hydrobromide salt of Compound 1 is a crystalline hydrobromide salt. In some embodiments, the crystalline hydrobromide salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 9.3, 13.9, 16.6, 19.0, and 20.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A hydrobromide salt.

[0065] In some embodiments, Form A hydrobromide salt is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 5

[0066] In some embodiments, Form A hydrobromide salt is characterized by the FT-Raman spectrum shown in FIG. 10.

[0067] In some embodiments, Form A hydrobromide salt is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 11.

[0068] In some embodiments, the Form A hydrobromide salt is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 12A of FIG. 12.

[0069] In some embodiments, the Form A hydrobromide salt is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 12B of FIG. 12.

[0070] In some embodiments, the complex form of Compound 1 contains 2 equivalents of hydrobromic acid. In some embodiments, the hydrobromide salt of Compound 1 is a hydrate. In some embodiments, the hydrate form of the hydrobromide salt of Compound 1 is a crystalline hydrate form of the hydrobromide salt. In some embodiments, the crystalline hydrate form of the hydrobromide salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.4, 9.8, 18.4, and 25.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B hydrobromide salt.

[0071] In some embodiments, the Form B hydrobromide salt is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 6]

[0072] In some embodiments, the Form B hydrobromide salt is characterized by the FT-Raman spectrum shown in FIG. 13.

[0073] In some embodiments, the Form B hydrobromide salt is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 14.

[0074] In some embodiments, the Form B hydrobromide salt is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 15A of FIG. 15.

[0075] In some embodiments, the Form B hydrobromide salt is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 15B of FIG. 15.

[0076] In some embodiments, the Form B hydrobromide salt is characterized by a dynamic vapor sorption (DVS) isotherm shown in FIG. 16.

[0077] In some embodiments of the complex form of Compound 1, X is sulfuric acid. In some such embodiments, the complex form of Compound 1 is a sulfate. In some embodiments, the sulfate of Compound 1 is a crystalline sulfate.

[0078] In some embodiments, the sulfate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the sulfate of Compound 1 is a crystalline hydrate form of the sulfate. In some embodiments, the crystalline hydrate form of the sulfate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.9, 7.4, 10.8, 11.8, 15.7, 17.1, and 17.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A sulfate.

[0079] In some embodiments, Form A sulfate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 7]

[0080] In some embodiments, Form A sulfate is characterized by an FT-Raman spectrum shown in FIG. 18.

[0081] In some embodiments, Form A sulfate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 19.

[0082] In some embodiments, the Form A sulfate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 20A of FIG. 20.

[0083] In some embodiments, the Form A sulfate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 20B of FIG. 20.

[0084] In some embodiments, the sulfate of Compound 1 is a hetero-solvate. In some embodiments, the hetero-solvate form of the sulfate of Compound 1 is a water:tetrahydrofuran hetero-solvate. In some embodiments, the water:tetrahydrofuran hetero-solvate form of the sulfate of Compound 1 is a crystalline water:tetrahydrofuran hetero-solvate form of the sulfate. In some embodiments, the crystalline water:tetrahydrofuran hetero-solvate form of the sulfate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.3, 6.9, 7.5, 10.5, 18.1, and 18.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B sulfate.

[0085] In some embodiments, the Form B sulfate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 8]

[0086] In some embodiments, the Form B sulfate is characterized by an FT-Raman spectrum shown in FIG. 21.

[0087] In some embodiments, the Form B sulfate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 22.

[0088] In some embodiments, the Form B sulfate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 23A of FIG. 23.

[0089] In some embodiments, the Form B sulfate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 23B of FIG. 23.

[0090] In some embodiments, the crystalline sulfate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.1, 6.5, and 7.1 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C sulfate.

[0091] In some embodiments, Form C sulfate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 9]

[0092] In some embodiments, Form C sulfate is characterized by an FT-Raman spectrum shown in FIG. 24.

[0093] In some embodiments, Form C sulfate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 25.

[0094] In some embodiments, Form C sulfate is characterized by a differential scanning calorimetry (DSC) pattern shown in FIG. 26.

[0095] In some embodiments, the complex form of Compound 1 contains 0.5 equivalents of sulfuric acid. In some embodiments, the sulfate salt of Compound 1 is a solvate. In some embodiments, the solvate form of the sulfate salt of Compound 1 is an acetone solvate. In some embodiments, the solvate form of the sulfate salt of Compound 1 is a bis-acetone solvate. In some embodiments, the bis-acetone solvate form of the sulfate salt of Compound 1 is a crystalline bis-acetone solvate form of the sulfate salt. In some embodiments, the crystalline bis-acetone solvate form of the sulfate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.9, 11.6, 12.1, 16.4, 16.9, and 18.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form D sulfate.

[0096] In some embodiments, Form D sulfate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 10

[0097] In some embodiments, Form D sulfate is characterized by the FT-Raman spectrum shown in Figure 27.

[0098] In some embodiments, Form D sulfate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 28.

[0099] In some embodiments, Form D sulfate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 29A of Figure 29.

[0100] In some embodiments, Form D sulfate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 29B of Figure 29.

[0101] In some embodiments of the complex form of Compound 1, X is p-toluenesulfonic acid. In some such embodiments, the complex form of Compound 1 is a p-toluenesulfonate (also referred to as a "tosylate"). In some embodiments, the tosylate of Compound 1 is a crystalline tosylate.

[0102] In some embodiments, the crystalline tosylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.3, 7.1, 8.6, 9.3, 17.2, and 17.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A tosylate.

[0103] In some embodiments, Form A tosylate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 11

[0104] In some embodiments, Form A tosylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 30.

[0105] In some embodiments, Form A tosylate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 31A of Figure 31.

[0106] In some embodiments, Form A tosylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 31B of Figure 31.

[0107] In some embodiments, the crystalline tosylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.5, 9.3, 11.0, 15.2, and 16.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B tosylate.

[0108] In some embodiments, the Form B tosylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 12]

[0109] In some embodiments, the Form B tosylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 32.

[0110] In some embodiments, the Form B tosylate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 33A of FIG. 33.

[0111] In some embodiments, the Form B tosylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 33B of FIG. 33.

[0112] In some embodiments, the complex form of Compound 1 contains 1 equivalent of p-toluenesulfonic acid. In some embodiments, the crystalline tosylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.6, 12.0, 15.9, 17.9, and 19.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C tosylate.

[0113] In some embodiments, the Form C tosylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 13]

[0114] In some embodiments, the Form C tosylate is characterized by the FT-Raman spectrum shown in FIG. 34.

[0115] In some embodiments, the Form C tosylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 35.

[0116] In some embodiments, the Form C tosylate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 36A of Figure 36.

[0117] In some embodiments, the Form C tosylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 36B of Figure 36.

[0118] In some embodiments, the Form C tosylate is characterized by the dynamic vapor sorption (DVS) isotherm shown in Figure 37.

[0119] In some embodiments, the Form C tosylate is characterized by the X-ray powder diffraction (XRPD) pattern after DVS shown in Figure 38.

[0120] In some embodiments, the Form C tosylate is shown in Figure 39 1 and is characterized by 1H NMR.

[0121] In some embodiments of the complex form of Compound 1, X is methanesulfonic acid. In some such embodiments, the complex form of Compound 1 is a methanesulfonate (also referred to as a "mesylate"). In some embodiments, the complex form of Compound 1 contains 1.2 equivalents of methanesulfonic acid. In some embodiments, the mesylate of Compound 1 is a crystalline mesylate.

[0122] In some embodiments, the crystalline mesylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 12.2, 12.6, 13.2, and 18.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A mesylate.

[0123] In some embodiments, Form A mesylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 14]

[0124] In some embodiments, Form A mesylate is characterized by the FT-Raman spectrum shown in Figure 40.

[0125] In some embodiments, Form A mesylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 41.

[0126] In some embodiments, Form A mesylate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 42A of Figure 42.

[0127] In some embodiments, Form A mesylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 42B of Figure 42.

[0128] In some embodiments, Form A mesylate is shown in Figure 43 1 and is characterized by 1H NMR.

[0129] In some embodiments, the crystalline mesylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 13.4, 13.6, 14.0, and 18.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B mesylate.

[0130] In some embodiments, Form B mesylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 15]

[0131] In some embodiments, Form B mesylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 44.

[0132] In some embodiments, Form B mesylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 46B of FIG. 46.

[0133] In some embodiments, the crystalline mesylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.6, 8.9, 9.1, 13.0, 13.3, 13.6, 17.8, and 18.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C mesylate.

[0134] In some embodiments, Form C mesylate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 16

[0135] In some embodiments, Form C mesylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 45.

[0136] In some embodiments, Form C mesylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 46C of FIG. 46.

[0137] In some embodiments of the complex form of Compound 1, X is 2-naphthalenesulfonic acid. In some such embodiments, the complex form of Compound 1 is 2-naphthalenesulfonate. In some embodiments, the 2-naphthalenesulfonate of Compound 1 is crystalline 2-naphthalenesulfonate.

[0138] In some embodiments, the complex form of Compound 1 comprises 1.5 equivalents of 2-naphthalenesulfonic acid. In some embodiments, the 2-naphthalenesulfonate of Compound 1 is a hemisolvate. In some such embodiments, the hemisolvate of the 2-naphthalenesulfonate of Compound 1 is a hemiacetone solvate. In some embodiments, the hemiacetone solvate of the 2-naphthalenesulfonate of Compound 1 is in the crystalline hemiacetone solvate form of the 2-naphthalenesulfonate.

[0139] In some embodiments, the crystalline hemiacetone solvate form of the 2-naphthalenesulfonate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.6, 10.5, 10.9, 11.1, 12.6, 16.8, and 17.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the 2-naphthalenesulfonate of Form A.

[0140] In some embodiments, the 2-naphthalenesulfonate of Form A is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 17

[0141] In some embodiments, the 2-naphthalenesulfonate of Form A is characterized by the FT-Raman spectrum shown in Figure 47.

[0142] In some embodiments, the 2-naphthalenesulfonate of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 48.

[0143] In some embodiments, the 2-naphthalenesulfonate of Form A is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 50A of Figure 50.

[0144] In some embodiments, the Form A 2-naphthalenesulfonate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 50B of FIG. 50.

[0145] In some embodiments of the complex form of Compound 1, X is phosphoric acid. In some such embodiments, the complex form of Compound 1 is a phosphate. In some embodiments, the phosphate of Compound 1 is a crystalline phosphate.

[0146] In some embodiments, the crystalline phosphate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 9.2, 10.9, 13.5, 15.0, and 16.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A phosphate.

[0147] In some embodiments, Form A phosphate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 18

[0148] In some embodiments, Form A phosphate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 52.

[0149] In some embodiments, Form C phosphate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 56A of FIG. 56.

[0150] In some embodiments, the crystalline phosphate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.9, 8.3, 9.8, 11.0, 17.2, and 19.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B phosphate.

[0151] In some embodiments, the Form B phosphate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 19]

[0152] In some embodiments, the Form B phosphate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 53.

[0153] In some embodiments, the Form B phosphate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 56B of FIG. 56.

[0154] In some embodiments, the crystalline phosphate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.4, 9.9, 10.4, 12.3, and 14.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C phosphate.

[0155] In some embodiments, the Form C phosphate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 20]

[0156] In some embodiments, the Form C phosphate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 54.

[0157] In some embodiments, the Form C phosphate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 56C of FIG. 56.

[0158] In some embodiments, the crystalline phosphate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.1, 11.1, 14.2, 16.9, and 22.3 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form D phosphate.

[0159] In some embodiments, Form D phosphate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 21]

[0160] In some embodiments, Form D phosphate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 55.

[0161] In some embodiments, Form D phosphate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 56D of Figure 56.

[0162] In some embodiments, the complex form of Compound 1 contains 1 equivalent of phosphoric acid. In some embodiments, the phosphate of Compound 1 is a solvate. In some embodiments, the solvate of the phosphate of Compound 1 is a methanol solvate. In some embodiments, the methanol solvate form of the phosphate of Compound 1 is a crystalline methanol solvate. In some embodiments, the crystalline methanol solvate form of the phosphate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.2, 10.1, 10.9, 14.5, 14.8, 18.0, and 19.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form E phosphate.

[0163] In some embodiments, Form E phosphate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 22

[0164] In some embodiments, the Form E phosphate is characterized by the FT-Raman spectrum shown in FIG. 57.

[0165] In some embodiments, the Form E phosphate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 58.

[0166] In some embodiments, the Form E phosphate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 59A of FIG. 59.

[0167] In some embodiments, the Form E phosphate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 59B of FIG. 59.

[0168] In some embodiments of the complex form of Compound 1, X is DL-tartaric acid. In some such embodiments, the complex form of Compound 1 is a DL-tartrate. In some embodiments, the complex form of Compound 1 contains 1 equivalent of DL-tartaric acid. In some embodiments, the DL-tartrate of Compound 1 is a crystalline DL-tartrate.

[0169] In some embodiments, the DL-tartrate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the DL-tartrate of Compound 1 is a crystalline hydrate form of the DL-tartrate. In some embodiments, the crystalline hydrate form of the DL-tartrate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.7, 7.4, 9.3, 11.0, and 13.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the DL-tartrate of Form A.

[0170] In some embodiments, the DL-tartrate of Form A is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 23]

[0171] In some embodiments, the DL-tartrate of Form A is characterized by the FT-Raman spectrum shown in FIG. 60.

[0172] In some embodiments, the DL-tartrate of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 61.

[0173] In some embodiments, the DL-tartrate of Form A is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 62A of FIG. 62.

[0174] In some embodiments, the DL-tartrate of Form A is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 62B of FIG. 62.

[0175] In some embodiments, the DL-tartrate of Form A is characterized by the dynamic vapor sorption (DVS) isotherm shown in FIG. 63.

[0176] In some embodiments, the DL-tartrate of Form A is shown in FIG. 64 1 characterized by 1H NMR.

[0177] In some embodiments, the crystalline DL-tartrate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.9, 9.7, 13.1, 13.4, 16.9, and 17.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the DL-tartrate of Form B.

[0178] In some embodiments, the DL-tartrate of Form B is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 24]

[0179] In some embodiments, the DL-tartrate of Form B is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 65.

[0180] In some embodiments, the DL-tartrate of Form B is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 66A of Figure 66.

[0181] In some embodiments, the DL-tartrate of Form B is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 66B of Figure 66.

[0182] In some embodiments of the complex form of Compound 1, X is succinic acid. In some such embodiments, the complex form of Compound 1 is a succinate. In some embodiments, the succinate of Compound 1 is a crystalline succinate. In some embodiments, the crystalline succinate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.0, 5.4, 6.0, 6.4, 6.8, and 16.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A succinate.

[0183] In some embodiments, Form A succinate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 25]

[0184] In some embodiments, Form A succinate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 67.

[0185] In some embodiments, Form A succinate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 68A of FIG. 68.

[0186] In some embodiments, Form A succinate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 68B of FIG. 68.

[0187] In some embodiments, the complex form of Compound 1 contains 1 equivalent of succinic acid. In some embodiments, the crystalline succinate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.7, 5.8, 6.2, 6.7, 9.4, and 10.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B succinate.

[0188] In some embodiments, Form B succinate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 26]

[0189] In some embodiments, Form B succinate is characterized by the FT-Raman spectrum shown in FIG. 69.

[0190] In some embodiments, Form B succinate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 70.

[0191] In some embodiments, Form B succinate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 71A of FIG. 71.

[0192] In some embodiments, Form B succinate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 71B of FIG. 71.

[0193] In some embodiments, Form B succinate is characterized by 1 1H NMR shown in FIG. 72.

[0194] In some embodiments of the complex form of Compound 1, X is gentiopic acid. In some such embodiments, the complex form of Compound 1 is a gentiopic acid salt. In some embodiments, the complex form of Compound 1 contains 1 equivalent of gentiopic acid. In some embodiments, the gentiopic acid salt of Compound 1 is a crystalline gentiopic acid salt. In some embodiments, the crystalline gentiopic acid salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 3.9, 7.9, 11.9, 15.8, and 17.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A gentiopic acid salt.

[0195] In some embodiments, Form A gentiopic acid salt is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 27]

[0196] In some embodiments, Form A gentiopic acid salt is characterized by an FT-Raman spectrum shown in FIG. 73.

[0197] In some embodiments, Form A gentiopic acid salt is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 74.

[0198] In some embodiments, Form A gentiopic acid salt is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 75A of FIG. 75.

[0199] In some embodiments, the Form A ganciclovir salt is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 75B of FIG. 75.

[0200] In some embodiments, the Form A ganciclovir salt is shown in FIG. 76 1 characterized by 1H NMR.

[0201] In some embodiments of the complex form of Compound 1, X is hippuric acid. In some such embodiments, the complex form of Compound 1 is a hippurate salt. In some embodiments, the complex form of Compound 1 contains 1 equivalent of hippuric acid. In some embodiments, the hippurate salt of Compound 1 is a crystalline hippurate salt. In some embodiments, the crystalline hippurate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.6, 9.7, 11.4, 15.2, and 18.6 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A hippurate salt.

[0202] In some embodiments, the Form A hippurate salt is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 28]

[0203] In some embodiments, the Form A hippurate salt is characterized by an FT-Raman spectrum shown in FIG. 77.

[0204] In some embodiments, the Form A hippurate salt is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 78.

[0205] In some embodiments, the Form A hippurate salt is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 79A of FIG. 79.

[0206] In some embodiments, Form A hippurate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 79B of FIG. 79.

[0207] In some embodiments, Form A hippurate is shown in FIG. 80 1 characterized by 1H NMR.

[0208] In some embodiments of the complex form of Compound 1, X is adipic acid. In some such embodiments, the complex form of Compound 1 is an adipate. In some embodiments, the complex form of Compound 1 contains 0.9 equivalents of adipic acid. In some embodiments, the adipate of Compound 1 is a crystalline adipate. In some embodiments, the crystalline adipate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.0, 8.6, 9.5, 12.0, 12.6, 13.0, 15.4, and 16.1 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A adipate.

[0209] In some embodiments, Form A adipate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 29]

[0210] In some embodiments, Form A adipate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 81.

[0211] In some embodiments, Form A adipate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 82A of FIG. 82.

[0212] In some embodiments, the Form A adipate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 82B of FIG. 82.

[0213] In some embodiments, the crystalline adipate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.1, 9.5, 12.1, 15.7, 16.1, 20.2, and 20.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C adipate.

[0214] In some embodiments, Form C adipate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 30]

[0215] In some embodiments, Form C adipate is characterized by an FT-Raman spectrum shown in FIG. 83.

[0216] In some embodiments, Form C adipate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 84.

[0217] In some embodiments, Form C adipate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 85A of FIG. 85.

[0218] In some embodiments, Form C adipate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 85B of FIG. 85.

[0219] In some embodiments, Form C adipate is shown in FIG. 86 1 characterized by 1H NMR.

[0220] In some embodiments of the complex form of Compound 1, X is galactaric acid. In some such embodiments, the complex form of Compound 1 is a galactarate. In some embodiments, the complex form of Compound 1 contains 1 equivalent of galactaric acid. In some embodiments, the galactarate of Compound 1 is a crystalline galactarate. In some embodiments, the crystalline galactarate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 9.3, 12.1, 12.5, 15.2, 16.6, and 17.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A galactarate.

[0221] In some embodiments, Form A galactarate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 31

[0222] In some embodiments, Form A galactarate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 87.

[0223] In some embodiments, Form A galactarate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 89A of FIG. 89.

[0224] In some embodiments, Form A galactarate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 89B of FIG. 89.

[0225] In some embodiments, Form A galactarate is characterized by the 1 1H NMR shown in FIG. 90.

[0226] In some embodiments of the complex form of Compound 1, X is 1,5-naphthalenedisulfonic acid. In some such embodiments, the complex form of Compound 1 is a 1,5-naphthalenedisulfonate (also referred to as "napadisylate"). In some embodiments, the napadisylate of Compound 1 is a crystalline napadisylate. In some embodiments, the crystalline napadisylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 3.8, 6.5, and 7.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A napadisylate.

[0227] In some embodiments, Form A napadisylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 32]

[0228] In some embodiments, Form A napadisylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 91.

[0229] In some embodiments, Form A napadisylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 94A of Figure 94.

[0230] In some embodiments, the crystalline napadisylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.0, 7.9, and 11.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B napadisylate.

[0231] In some embodiments, Form B napadisylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 33]

[0232] In some embodiments, the Form B napadisylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 92.

[0233] In some embodiments, the Form B napadisylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 94B of FIG. 94.

[0234] In some embodiments, the crystalline napadisylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.6, 13.4, and 14.4 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C napadisylate.

[0235] In some embodiments, Form C napadisylate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 34

[0236] In some embodiments, Form C napadisylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 93.

[0237] In some embodiments, Form C napadisylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 94C of FIG. 94.

[0238] In some embodiments of the complex form of Compound 1, X is (S)-camphor-sulfonic acid. In some such embodiments, the complex form of Compound 1 is the (S)-camphor-sulfonate. In some embodiments, the (S)-camphor-sulfonate of Compound 1 is a crystalline (S)-camphor-sulfonate. In some embodiments, the crystalline (S)-camphor-sulfonate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.0, 9.9, 10.4, 11.1, and 14.3 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the (S)-camphor-sulfonate of Form A.

[0239] In some embodiments, the (S)-camphor-sulfonate of Form A is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 35

[0240] In some embodiments, the (S)-camphor-sulfonate of Form A is characterized by the FT-Raman spectrum shown in Figure 95.

[0241] In some embodiments, the (S)-camphor-sulfonate of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 96.

[0242] In some embodiments, the (S)-camphor-sulfonate of Form A is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 97A of Figure 97.

[0243] In some embodiments, the (S)-camphor-sulfonate of Form A is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 97B of Figure 97.

[0244] In some embodiments, the crystalline (S)-camphor-sulfonate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.9, 10.2, 11.4, and 12.4 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the (S)-camphor-sulfonate of Form B.

[0245] In some embodiments, the (S)-camphor-sulfonate of Form B is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 36

[0246] In some embodiments, the (S)-camphor-sulfonate of Form B is characterized by the FT-Raman spectrum shown in FIG. 98.

[0247] In some embodiments, the (S)-camphor-sulfonate of Form B is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 99.

[0248] In some embodiments, the (S)-camphor-sulfonate of Form B is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 100A of FIG. 100.

[0249] In some embodiments, the (S)-camphor-sulfonate of Form B is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 100B of FIG. 100.

[0250] In some embodiments of the complex form of Compound 1, X is 1,2-ethanedisulfonic acid. In some such embodiments, the complex form of Compound 1 is the 1,2-ethanedisulfonate (also referred to as "edsylate"). In some embodiments, the edsylate of Compound 1 is a crystalline edsylate. In some embodiments, the edsylate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the edsylate of Compound 1 is a crystalline hydrate form of the edsylate. In some embodiments, the crystalline hydrate form of the edsylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 9.1, 10.7, 11.1, 14.0, 14.7, 18.2, and 19.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A edsylate.

[0251] In some embodiments, Form A edsylate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 37

[0252] In some embodiments, Form A edsylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 101.

[0253] In some embodiments, Form A edsylate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 105A of Figure 105.

[0254] In some embodiments, Form A edsylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 105B of Figure 105.

[0255] In some embodiments, the crystalline edisylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 9.8, 10.9, 13.1, 13.6, and 19.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B edisylate.

[0256] In some embodiments, Form B edisylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 38]

[0257] In some embodiments, Form B edisylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 102.

[0258] In some embodiments, Form B edisylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 106B of Figure 106.

[0259] In some embodiments, the crystalline edisylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.0, 12.8, 13.3, 13.7, and 16.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C edisylate.

[0260] In some embodiments, Form C edisylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 39]

[0261] In some embodiments, Form C edisylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 103.

[0262] In some embodiments, the form C esylate is characterized by a differential scanning calorimetry (DSC) pattern shown in trace 106A of FIG. 106.

[0263] In some embodiments, the crystalline esylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.1, 10.2, 10.4, 12.5, 15.8, 16.0, and 17.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is form D esylate.

[0264] In some embodiments, form D esylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 40]

[0265] In some embodiments, form D esylate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 104.

[0266] In some embodiments, form D esylate is characterized by a differential scanning calorimetry (DSC) pattern shown in trace 106C of FIG. 106.

[0267] In some embodiments of the complex form of Compound 1, X is ethanesulfonic acid. In some such embodiments, the complex form of Compound 1 is an esylate. In some embodiments, the esylate of Compound 1 is a crystalline esylate. In some embodiments, the crystalline esylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.4, 17.0, 17.4, 18.2, 18.7, and 25.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is form A esylate.

[0268] In some embodiments, Form A esylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 41]

[0269] In some embodiments, Form A esylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 107.

[0270] In some embodiments, Form A esylate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 109A of Figure 109.

[0271] In some embodiments, Form A esylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 109B of Figure 109.

[0272] In some embodiments, the crystalline esylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.5, 9.8, 12.5, 12.9, and 14.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B esylate.

[0273] In some embodiments, Form B esylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 42]

[0274] In some embodiments, Form B esylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 108.

[0275] In some embodiments, the Form B esylate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 110A of FIG. 110.

[0276] In some embodiments, the Form B esylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 110B of FIG. 110.

[0277] In some embodiments of the complex form of Compound 1, X is benzenesulfonic acid. In some such embodiments, the complex form of Compound 1 is a benzenesulfonate (also referred to as "besylate"). In some embodiments, the besylate of Compound 1 is a crystalline besylate. In some embodiments, the crystalline besylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.5, 7.5, 10.4, 11.0, 12.8, 14.3, and 14.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A besylate.

[0278] In some embodiments, Form A besylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 43]

[0279] In some embodiments, Form A besylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 111.

[0280] In some embodiments, Form A besylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 115A of FIG. 115.

[0281] In some embodiments, the crystalline besylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.5, 9.2, 11.1, 12.1, 14.1, and 15.1 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B besylate.

[0282] In some embodiments, Form B besylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 44]

[0283] In some embodiments, Form B besylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 112.

[0284] In some embodiments, Form B besylate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 115B of FIG. 115.

[0285] In some embodiments, the crystalline besylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.1, 8.2, 12.3, 16.4, and 20.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C besylate.

[0286] In some embodiments, Form C besylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 45]

[0287] In some embodiments, Form C besylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 113.

[0288] In some embodiments, the Form C besylate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 115C of FIG. 115.

[0289] In some embodiments, the besylate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the besylate of Compound 1 is a crystalline hydrate form of the besylate. In some embodiments, the crystalline hydrate form of the besylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.1, 7.2, 11.5, 12.1, 12.6, and 12.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form D besylate.

[0290] In some embodiments, the Form D besylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 46]

[0291] In some embodiments, the Form D besylate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 114.

[0292] In some embodiments, the Form D besylate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 116A of FIG. 116.

[0293] In some embodiments, the Form D besylate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 116B of FIG. 116.

[0294] In some embodiments of the complex form of Compound 1, X is oxalic acid. In some such embodiments, the complex form of Compound 1 is an oxalate. In some embodiments, the oxalate of Compound 1 is a crystalline oxalate. In some embodiments, the oxalate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the oxalate of Compound 1 is a crystalline hydrate form of the oxalate. In some embodiments, the crystalline hydrate form of the oxalate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.7, 6.5, 9.4, 11.0, 11.9, and 12.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A oxalate.

[0295] In some embodiments, Form A oxalate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 47

[0296] In some embodiments, Form A oxalate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 117.

[0297] In some embodiments, Form A oxalate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 119A of Figure 119.

[0298] In some embodiments, Form A oxalate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 119B of Figure 119.

[0299] In some embodiments, the crystalline oxalate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.3, 8.7, and 12.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B oxalate.

[0300] In some embodiments, Form B oxalate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 48]

[0301] In some embodiments, Form B oxalate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 118.

[0302] In some embodiments, Form B oxalate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 120A of FIG. 120.

[0303] In some embodiments, Form B oxalate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 120B of FIG. 120.

[0304] In some embodiments of the complex form of Compound 1, X is maleic acid. In some such embodiments, the complex form of Compound 1 is a maleate. In some embodiments, the maleate of Compound 1 is a crystalline maleate. In some embodiments, the maleate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the maleate of Compound 1 is a crystalline hydrate form of the maleate. In some embodiments, the crystalline hydrate form of the maleate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.7, 11.5, 14.1, 15.4, 15.8, and 16.1 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A maleate.

[0305] In some embodiments, Form A maleate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 49]

[0306] In some embodiments, Form A maleate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 121.

[0307] In some embodiments, Form A maleate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 122A of FIG. 122.

[0308] In some embodiments, Form A maleate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 122B of FIG. 122.

[0309] In some embodiments of the complex form of Compound 1, X is pamoic acid. In some such embodiments, the complex form of Compound 1 is a pamoate. In some embodiments, the pamoate of Compound 1 is a crystalline pamoate. In some embodiments, the crystalline pamoate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.1, 10.7, 13.9, 15.4, 20.86, and 21.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A pamoate.

[0310] In some embodiments, Form A pamoate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 50]

[0311] In some embodiments, Form A pamoate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 123.

[0312] In some embodiments, the Form A pamoate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 124A of FIG. 124.

[0313] In some embodiments, the Form A pamoate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 124B of FIG. 124.

[0314] In some embodiments of the complex form of Compound 1, X is 1-hydroxy-2-naphthoic acid. In some such embodiments, the complex form of Compound 1 is a 1-hydroxy-2-naphthoate. In some embodiments, the 1-hydroxy-2-naphthoate of Compound 1 is a crystalline 1-hydroxy-2-naphthoate. In some embodiments, the crystalline 1-hydroxy-2-naphthoate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.7, 8.4, 9.7, 10.8, and 16.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the Form A 1-hydroxy-2-naphthoate.

[0315] In some embodiments, the Form A 1-hydroxy-2-naphthoate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 51]

[0316] In some embodiments, the Form A 1-hydroxy-2-naphthoate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 125.

[0317] In some embodiments, the Form A 1-hydroxy-2-naphthoate is characterized by the differential scanning calorimetry (DSC) pattern shown in FIG. 126.

[0318] In some embodiments of the complex form of Compound 1, X is malonic acid. In some such embodiments, the complex form of Compound 1 is a malonate. In some embodiments, the malonate of Compound 1 is a crystalline malonate. In some embodiments, the crystalline malonate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.8, 11.7, 13.2, 13.7, and 15.6 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A malonate.

[0319] In some embodiments, Form A malonate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 52

[0320] In some embodiments, Form A malonate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 127.

[0321] In some embodiments, Form A malonate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 128A of Figure 128.

[0322] In some embodiments, Form A malonate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 128B of Figure 128.

[0323] In some embodiments, the crystalline malonate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.6, 7.3, 11.2, 12.3, 14.5, and 16.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B malonate.

[0324] In some embodiments, Form B malonate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 53]

[0325] In some embodiments, Form B malonate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 129.

[0326] In some embodiments, Form B malonate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 130A of FIG. 130.

[0327] In some embodiments, Form B malonate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 130B of FIG. 130.

[0328] In some embodiments, the crystalline malonate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.8, 11.7, 15.7, and 17.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C malonate.

[0329] In some embodiments, Form C malonate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 54]

[0330] In some embodiments, Form C malonate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 131.

[0331] In some embodiments, Form C malonate is characterized by the differential scanning calorimetry (DSC) pattern shown in FIG. 132.

[0332] In some embodiments of the complex form of Compound 1, X is L-tartaric acid. In some such embodiments, the complex form of Compound 1 is an L-tartrate. In some embodiments, the L-tartrate of Compound 1 is a crystalline L-tartrate. In some embodiments, the crystalline L-tartrate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 9.7, 11.1, 14.9, 16.6, 19.8, and 21.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the L-tartrate of Form A.

[0333] In some embodiments, the L-tartrate of Form A is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 55

[0334] In some embodiments, the L-tartrate of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 133.

[0335] In some embodiments, the L-tartrate of Form A is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 134A of FIG. 134.

[0336] In some embodiments, the L-tartrate of Form A is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 134B of FIG. 134.

[0337] In some embodiments, the crystalline L-tartrate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.4, 9.7, 11.2, 11.7, and 14.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the L-tartrate of Form B.

[0338] In some embodiments, the L-tartrate of Form B is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 56]

[0339] In some embodiments, the L-tartrate of Form B is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 135.

[0340] In some embodiments, the L-tartrate of Form B is characterized by the differential scanning calorimetry (DSC) pattern shown in FIG. 136.

[0341] In some embodiments, the crystalline L-tartrate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.4, 9.7, 11.2, 12.5, and 14.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the L-tartrate of Form C.

[0342] In some embodiments, the L-tartrate of Form C is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 57]

[0343] In some embodiments, the L-tartrate of Form C is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 137.

[0344] In some embodiments, the L-tartrate of Form C is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 138A of FIG. 138.

[0345] In some embodiments, the L-tartrate of Form C is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 138B of FIG. 138.

[0346] In some embodiments, the crystalline L-tartrate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.7, 7.4, 9.5, 11.1, 13.1, 13.5, and 18.3 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the L-tartrate of Form D.

[0347] In some embodiments, the L-tartrate of Form D is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 58

[0348] In some embodiments, the L-tartrate of Form D is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 139.

[0349] In some embodiments, the L-tartrate of Form D is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 140A of FIG. 140.

[0350] In some embodiments, the L-tartrate of Form D is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 140B of FIG. 140.

[0351] In some embodiments of the complex form of Compound 1, X is fumaric acid. In some such embodiments, the complex form of Compound 1 is a fumarate. In some embodiments, the fumarate of Compound 1 is a crystalline fumarate. In some embodiments, the crystalline fumarate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.7, 12.3, 13.4, 14.3, and 15.4 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A fumarate.

[0352] In some embodiments, Form A fumarate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 59]

[0353] In some embodiments, Form A fumarate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 141.

[0354] In some embodiments, Form A fumarate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 142A of Figure 142.

[0355] In some embodiments, Form A fumarate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 142B of Figure 142.

[0356] In some embodiments, the crystalline fumarate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.0, 14.1, 14.6, 15.3, and 19.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B fumarate.

[0357] In some embodiments, Form B fumarate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 60]

[0358] In some embodiments, Form B fumarate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 143.

[0359] In some embodiments, Form B fumarate is characterized by the differential scanning calorimetry (DSC) pattern shown in FIG. 144.

[0360] In some embodiments, the crystalline fumarate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.6, 11.4, 15.2, and 19.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C fumarate.

[0361] In some embodiments, Form C fumarate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 61]

[0362] In some embodiments, Form C fumarate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 145.

[0363] In some embodiments, Form C fumarate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 146A of FIG. 146.

[0364] In some embodiments, Form C fumarate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 146B of FIG. 146.

[0365] In some embodiments, the crystalline fumarate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 14.0, 17.6, 23.3, 23.9, and 25.10 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form D fumarate.

[0366] In some embodiments, Form D fumarate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 62]

[0367] In some embodiments, Form D fumarate of Compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 147.

[0368] In some embodiments, Form D fumarate of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 148A of Figure 148.

[0369] In some embodiments, Form D fumarate of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 148B of Figure 148.

[0370] In some embodiments of the complex form of Compound 1, X is citric acid. In some such embodiments, the complex form of Compound 1 is a citrate. In some embodiments, the citrate of Compound 1 is a crystalline citrate. In some embodiments, the crystalline citrate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.5, 11.3, 13.5, 15.1, 18.9, and 19.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A citrate.

[0371] In some embodiments, Form A citrate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 63]

[0372] In some embodiments, Form A citrate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 149.

[0373] In some embodiments, Form A citrate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 150A of Figure 150.

[0374] In some embodiments, Form A citrate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 150B of Figure 150.

[0375] In some embodiments of the complex form of Compound 1, X is L-lactic acid. In some such embodiments, the complex form of Compound 1 is an L-lactate. In some embodiments, the L-lactate of Compound 1 is a crystalline L-lactate. In some embodiments, the crystalline L-citrate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.5, 8.2, 11.2, 12.3, and 16.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A L-lactate.

[0376] In some embodiments, Form A L-lactate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 64]

[0377] In some embodiments, the L-lactate of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 151.

[0378] In some embodiments, the L-lactate of Form A is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 152A of Figure 152.

[0379] In some embodiments, the L-lactate of Form A is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 152B of Figure 152.

[0380] In some embodiments of the complex form of Compound 1, X is acetic acid. In some such embodiments, the complex form of Compound 1 is an acetate. In some embodiments, the acetate of Compound 1 is a crystalline acetate. In some embodiments, the crystalline acetate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.9, 11.6, 11.9, 13.5, 14.1, and 17.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A acetate.

[0381] In some embodiments, Form A acetate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 65

[0382] In some embodiments, Form A acetate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 153.

[0383] In some embodiments, Form A acetate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 154A of Figure 154.

[0384] In some embodiments, the Form A acetate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 154B of FIG. 154.

[0385] In some embodiments, the crystalline acetate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 10.3, 11.6, 12.8, 15.6, 17.6, and 19.1 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B acetate.

[0386] In some embodiments, the Form B acetate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 66]

[0387] In some embodiments, the Form B acetate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 155.

[0388] In some embodiments, the Form B acetate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 156A of FIG. 156.

[0389] In some embodiments, the Form B acetate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 156B of FIG. 156.

[0390] In some embodiments of the complex form of Compound 1, X is propionic acid. In some such embodiments, the complex form of Compound 1 is a propionate. In some embodiments, the propionate of Compound 1 is a crystalline propionate. In some embodiments, the crystalline propionate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.6, 9.7, 12.4, 14.0, 16.4, and 17.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A propionate.

[0391] In some embodiments, Form A propionate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 67

[0392] In some embodiments, Form A propionate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 157.

[0393] In some embodiments, Form A propionate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 158A of Figure 158.

[0394] In some embodiments, Form A propionate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 158B of Figure 158.

[0395] In some embodiments of the complex form of Compound 1, X is DL-lactic acid. In some such embodiments, the complex form of Compound 1 is a DL-lactate. In some embodiments, the DL-lactate of Compound 1 is a crystalline DL-lactate. In some embodiments, the crystalline DL-lactate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.3, 12.4, 15.9, 17.6, and 18.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the DL-lactate of Form A.

[0396] In some embodiments, the DL-lactate of Form A is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 68

[0397] In some embodiments, the DL-lactate of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 159.

[0398] In some embodiments, the DL-lactate of Form A is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 160A of Figure 160.

[0399] In some embodiments, the DL-lactate of Form A is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 160B of Figure 160.

[0400] In some embodiments of the complex form of Compound 1, X is D-gluconic acid. In some such embodiments, the complex form of Compound 1 is a D-gluconate. In some embodiments, the D-gluconate of Compound 1 is a crystalline D-gluconate. In some embodiments, the crystalline D-gluconate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.1, 11.7, 14.7, 16.1, and 16.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the D-gluconate of Form A.

[0401] In some embodiments, the D-gluconate of Form A is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 69

[0402] In some embodiments, the D-gluconate of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 161.

[0403] In some embodiments, the D-gluconate of Form A is characterized by the differential scanning calorimetry (DSC) pattern shown in Figure 162.

[0404] In some embodiments of the complex form of Compound 1, X is DL-malic acid. In some such embodiments, the complex form of Compound 1 is a DL-malate. In some embodiments, the DL-malate of Compound 1 is a crystalline DL-malate. In some embodiments, the crystalline DL-malate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.5, 9.7, 11.3, 15.1, 16.3, and 21.0 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the DL-malate of Form A.

[0405] In some embodiments, the DL-malic acid salt of Form A is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 70]

[0406] In some embodiments, the DL-malic acid salt of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 163.

[0407] In some embodiments, the DL-malic acid salt of Form A is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 164A of FIG. 164.

[0408] In some embodiments, the DL-malic acid salt of Form A is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 164B of FIG. 164.

[0409] In some embodiments, the crystalline DL-malic acid salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.6, 8.3, 11.7, 13.9, and 18.6 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the DL-malic acid salt of Form B.

[0410] In some embodiments, the DL-malic acid salt of Form B is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 71]

[0411] In some embodiments, the DL-malic acid salt of Form B is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 165.

[0412] In some embodiments, the DL-malic acid salt of Form B is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 166A of FIG. 166.

[0413] In some embodiments, the DL-malic acid salt of Form B is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 166B of FIG. 166.

[0414] In some embodiments of the complex form of Compound 1, X is glycolic acid. In some such embodiments, the complex form of Compound 1 is a glycolate. In some embodiments, the glycolate of Compound 1 is a crystalline glycolate. In some embodiments, the crystalline glycolate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.4, 8.6, 10.6, 12.7, and 16.1 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A glycolate.

[0415] In some embodiments, Form A glycolate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 72

[0416] In some embodiments, Form A glycolate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 167.

[0417] In some embodiments, Form A glycolate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 168A of FIG. 168.

[0418] In some embodiments, Form A glycolate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 168B of FIG. 168.

[0419] In some embodiments of the complex form of Compound 1, X is glutaric acid. In some such embodiments, the complex form of Compound 1 is a glutarate. In some embodiments, the galactarate of Compound 1 is a crystalline glutarate. In some embodiments, the crystalline glutarate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.4, 11.1, 14.9, 16.1, 18.6, and 18.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A glutarate.

[0420] In some embodiments, Form A glutarate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 73]

[0421] In some embodiments, Form A glutarate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 169.

[0422] In some embodiments, Form A glutarate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 170A of Figure 170.

[0423] In some embodiments, Form A glutarate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 170B of Figure 170.

[0424] In some embodiments, the crystalline glutarate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.8, 5.8, 9.5, 11.3, and 14.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B glutarate.

[0425] In some embodiments, Form B glutamate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 74]

[0426] In some embodiments, Form B glutamate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 171.

[0427] In some embodiments, Form B glutamate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 172A of FIG. 172.

[0428] In some embodiments, Form B glutamate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 172B of FIG. 172.

[0429] In some embodiments of the complex form of Compound 1, X is L-malic acid. In some such embodiments, the complex form of Compound 1 is an L-malate. In some embodiments, the L-malate of Compound 1 is a crystalline L-malate. In some embodiments, the crystalline L-malate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.5, 9.6, 11.3, 15.1, 16.2, and 16.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A L-malate.

[0430] In some embodiments, Form A L-malate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 75]

[0431] In some embodiments, the L-malate of Form A is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 173.

[0432] In some embodiments, the L-malate of Form A is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 174A of FIG. 174.

[0433] In some embodiments, the L-malate of Form A is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 174B of FIG. 174.

[0434] In some embodiments of the complex form of Compound 1, X is camphoric acid. In some such embodiments, the complex form of Compound 1 is a camphorate. In some embodiments, the camphorate of Compound 1 is a crystalline camphorate. In some embodiments, the crystalline camphorate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.7, 8.3, 9.9, 15.0, and 15.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A camphorate.

[0435] In some embodiments, Form A camphorate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 76]

[0436] In some embodiments, Form A pamoate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 175.

[0437] In some embodiments, Form A camphorate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 176A of FIG. 176.

[0438] In some embodiments, the Form A camphorate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 176B of FIG. 176.

[0439] In some embodiments, the crystalline camphorate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 6.9, 9.9, 11.5, 15.3, 16.1, and 16.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B camphorate.

[0440] In some embodiments, Form B camphorate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 77]

[0441] In some embodiments, Form B camphorate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 177.

[0442] In some embodiments, Form B camphorate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 178A of FIG. 178.

[0443] In some embodiments, Form B camphorate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 178B of FIG. 178.

[0444] In some embodiments, the crystalline camphorate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.9, 10.3, 13.6, 15.5, and 16.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C camphorate.

[0445] In some embodiments, Form C camphorate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 78]

[0446] In some embodiments, Form C camphorate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 179.

[0447] In some embodiments, Form C camphorate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 180A of Figure 180.

[0448] In some embodiments, Form C camphorate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 180B of Figure 180.

[0449] In some embodiments, the crystalline camphorate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.7, 8.6, 9.6, 12.1, 13.5, and 15.3 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form D camphorate.

[0450] In some embodiments, Form D camphorate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 79]

[0451] In some embodiments, Form D camphorate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 181.

[0452] In some embodiments, Form D camphorate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 182A of Figure 182.

[0453] In some embodiments, the Form D camphorate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 182B of FIG. 182.

[0454] In some embodiments of the complex form of Compound 1, X is DL-mandelic acid. In some such embodiments, the complex form of Compound 1 is a DL-mandelate. In some embodiments, the DL-mandelate of Compound 1 is a crystalline DL-mandelate. In some embodiments, the crystalline DL-mandelate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.4, 11.1, 13.8, 14.9, and 16.3 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the Form A DL-mandelate.

[0455] In some embodiments, the Form A DL-mandelate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 80

[0456] In some embodiments, the Form A DL-mandelate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 183.

[0457] In some embodiments, the Form A DL-mandelate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 184A of FIG. 184.

[0458] In some embodiments, the Form A DL-mandelate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 184B of FIG. 184.

[0459] In some embodiments, the crystalline DL-mandelate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.5, 9.2, 11.3, 15.1, and 15.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the DL-mandelate of Form B.

[0460] In some embodiments, the DL-mandelate of Form B is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 81]

[0461] In some embodiments, the DL-mandelate of Form B is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 185.

[0462] In some embodiments, the DL-mandelate of Form B is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 186A of Figure 186.

[0463] In some embodiments, the DL-mandelate of Form B is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 186B of Figure 186.

[0464] In some embodiments, the crystalline DL-mandelate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.4, 9.9, 10.9, 14.0, and 14.6 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is the DL-mandelate of Form C.

[0465] In some embodiments, the DL-mandelate of Form C is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 82]

[0466] In some embodiments, the DL-mandelate of Form C is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 187.

[0467] In some embodiments, the DL-mandelate of Form C is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 188A of FIG. 188.

[0468] In some embodiments, the DL-mandelate of Form C is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 188B of FIG. 188.

[0469] In some embodiments of the complex form of Compound 1, X is saccharin. In some such embodiments, the complex form of Compound 1 is a saccharin co-crystal. In some embodiments, the saccharin co-crystal of Compound 1 is a crystalline saccharin co-crystal. In some embodiments, the complex form of Compound 1 contains 1 equivalent of saccharin. In some embodiments, the saccharin co-crystal of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 3.9, 7.9, 11.8, 15.0, and 15.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A saccharin co-crystal.

[0470] In some embodiments, the Form A saccharin co-crystal is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 83

[0471] In some embodiments, the Form A saccharin co-crystal is characterized by the FT-Raman spectrum shown in FIG. 189.

[0472] In some embodiments, the Form A saccharin cocrystal is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 190.

[0473] In some embodiments, the Form A saccharin cocrystal is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 191A of Figure 191.

[0474] In some embodiments, the Form A saccharin cocrystal is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 191B of Figure 191.

[0475] In some embodiments, the Form A saccharin cocrystal is shown in Figure 192 1 characterized by the 1H NMR spectrum.

[0476] In some embodiments of the complex form of Compound 1, X is nicotinic acid. In some such embodiments, the complex form of Compound 1 is a nicotinate. In some embodiments, the nicotinate of Compound 1 is a crystalline nicotinate. In some embodiments, the complex form of Compound 1 contains 1 equivalent of nicotinic acid. In some embodiments, the crystalline nicotinate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.8, 8.9, 14.0, 16.8, and 17.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A nicotinate.

[0477] In some embodiments, Form A nicotinate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 84

[0478] In some embodiments, Form A nicotinate is characterized by the FT-Raman spectrum shown in FIG. 193.

[0479] In some embodiments, Form A nicotinate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 194.

[0480] In some embodiments, Form A nicotinate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 195A of FIG. 195.

[0481] In some embodiments, Form A nicotinate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 195B of FIG. 195.

[0482] In some embodiments, Form A nicotinate is shown in FIG. 196 1 characterized by the 1H NMR spectrum.

[0483] In some embodiments, the nicotinate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the nicotinate of Compound 1 is a crystalline hydrate form of the nicotinate. In some embodiments, the crystalline hydrate form of the nicotinate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.2, 12.4, 15.3, 17.9, and 18.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B nicotinate.

[0484] In some embodiments, Form B nicotinate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 85

[0485] In some embodiments, Form B nicotinate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 197.

[0486] In some embodiments, Form B nicotinate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 198A of FIG. 198.

[0487] In some embodiments, Form B nicotinate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 198B of FIG. 198.

[0488] In some embodiments, the crystalline nicotinate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 3.8, 7.5, 11.3, 15.0, and 18.7 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form C nicotinate.

[0489] In some embodiments, Form C nicotinate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 86]

[0490] In some embodiments, Form C nicotinate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 199.

[0491] In some embodiments, Form C nicotinate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 200A of FIG. 200.

[0492] In some embodiments, Form C nicotinate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 200B of FIG. 200.

[0493] In some embodiments of the complex form of Compound 1, X is ascorbic acid. In some such embodiments, the complex form of Compound 1 is an ascorbate. In some embodiments, the ascorbate of Compound 1 is a crystalline ascorbate. In some embodiments, the complex form of Compound 1 contains 1 equivalent of ascorbic acid. In some embodiments, the ascorbate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the ascorbate of Compound 1 is a crystalline hydrate form of the ascorbate. In some embodiments, the crystalline hydrate form of the ascorbate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 3.7, 7.5, 11.3, 15.0, and 18.8 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A ascorbate.

[0494] In some embodiments, Form A ascorbate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 87

[0495] In some embodiments, Form A ascorbate is characterized by the FT-Raman spectrum shown in Figure 201.

[0496] In some embodiments, Form A ascorbate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 202.

[0497] In some embodiments, Form A ascorbate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 203A of Figure 203.

[0498] In some embodiments, Form A ascorbate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 203B of Figure 203.

[0499] In some embodiments, Form A ascorbate is characterized by the 1 1H NMR spectrum shown in FIG. 204.

[0500] In some embodiments, the crystalline ascorbate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.4, 9.8, 11.2, 14.9, and 16.1 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B ascorbate.

[0501] In some embodiments, Form B ascorbate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 88

[0502] In some embodiments, Form B ascorbate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 234.

[0503] In some embodiments, Form B ascorbate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 235A of FIG. 235.

[0504] In some embodiments, Form B ascorbate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 235B of FIG. 235.

[0505] In some embodiments of the complex form of Compound 1, X is gallic acid. In some such embodiments, the complex form of Compound 1 is a gallate. In some embodiments, the gallate of Compound 1 is a crystalline gallate. In some embodiments, the complex form of Compound 1 contains 1 equivalent of gallic acid. In some embodiments, the gallate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the gallate of Compound 1 is a crystalline hydrate form of the gallate. In some embodiments, the crystalline hydrate form of the gallate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 3.8, 7.6, 11.5, 15.4, and 19.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A gallate.

[0506] In some embodiments, Form A gallate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 89

[0507] In some embodiments, Form A gallate is characterized by the FT-Raman spectrum shown in Figure 205.

[0508] In some embodiments, Form A gallate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 206.

[0509] In some embodiments, Form A gallate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 207A of Figure 207.

[0510] In some embodiments, Form A gallate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 207B of Figure 207.

[0511] In some embodiments, the Form A gallate is characterized by the 1 H NMR spectrum shown in FIG. 208.

[0512] In some embodiments of the complex form of Compound 1, X is salicylic acid. In some such embodiments, the complex form of Compound 1 is a salicylate. In some embodiments, the salicylate of Compound 1 is a crystalline salicylate. In some embodiments, the salicylate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the salicylate of Compound 1 is a crystalline hydrate form of the salicylate. In some embodiments, the crystalline hydrate form of the salicylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 3.8, 7.6, 11.5, 15.4, and 19.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A salicylate.

[0513] In some embodiments, Form A salicylate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 90

[0514] In some embodiments, Form A salicylate is characterized by the FT-Raman spectrum shown in FIG. 209.

[0515] In some embodiments, Form A salicylate is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 210.

[0516] In some embodiments, Form A salicylate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 211A of FIG. 211.

[0517] In some embodiments, Form A salicylate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 211B of FIG. 211.

[0518] In some embodiments, Form A salicylate is shown in FIG. 212 1 characterized by an 1H NMR spectrum.

[0519] In some embodiments, the crystalline salicylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.1, 7.0, 10.9, 13.9, 15.9, and 16.2 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B salicylate.

[0520] In some embodiments, Form B salicylate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 91

[0521] In some embodiments, Form B salicylate is characterized by an X-ray powder diffraction (XRPD) pattern shown in FIG. 241.

[0522] In some embodiments, Form B salicylate is characterized by a thermogravimetric analysis (TGA) pattern shown in Trace 242A of FIG. 242.

[0523] In some embodiments, Form B salicylate is characterized by a differential scanning calorimetry (DSC) pattern shown in Trace 242B of FIG. 242.

[0524] In some embodiments of Compound 1, X is orotic acid. In some such embodiments, the complex form of Compound 1 is an orotate. In some embodiments, the orotate of Compound 1 is a crystalline orotate. In some embodiments, the complex form of Compound 1 contains 1 equivalent of orotic acid. In some embodiments, the crystalline orotate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.7, 17.6, and 20.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A orotate.

[0525] In some embodiments, Form A orotate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 92

[0526] In some embodiments, Form A orotate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 213.

[0527] In some embodiments, Form A orotate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 214A of Figure 214.

[0528] In some embodiments, Form A orotate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 214B of Figure 214.

[0529] In some embodiments, the crystalline orotate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.8, 8.6, 9.5, 10.0, 15.5, and 21.1 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form D orotate.

[0530] In some embodiments, Form D orotate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 93]

[0531] In some embodiments, Form D orotate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 217.

[0532] In some embodiments, Form D orotate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 218A of Figure 218.

[0533] In some embodiments, Form D orotate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 218B of Figure 218.

[0534] In some embodiments, the crystalline orotate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 4.4, 5.0, 6.2, 9.9, 12.4, and 14.9 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form F orotate.

[0535] In some embodiments, Form F orotate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 94]

[0536] In some embodiments, Form F orotate is characterized by the FT-Raman spectrum shown in Figure 222.

[0537] In some embodiments, Form F orotate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 223.

[0538] In some embodiments, Form F orotate is characterized by the thermogravimetric analysis (TGA) pattern shown in Trace 224A of Figure 224.

[0539] In some embodiments, Form F orotate is characterized by the differential scanning calorimetry (DSC) pattern shown in Trace 224B of Figure 224.

[0540] In some embodiments, Form F orotate is that shown in Figure 225 1 characterized by the 1H NMR spectrum.

[0541] In some embodiments, the crystalline orotate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 5.3, 9.0, 11.9, 13.9, 16.8, and 20.3 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form H orotate.

[0542] In some embodiments, Form H orotate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 95

[0543] In some embodiments, Form H orotate is characterized by the FT-Raman spectrum shown in Figure 226.

[0544] In some embodiments, Form H orotate is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 227.

[0545] In some embodiments, Form H orotate is characterized by a thermogravimetric analysis (TGA) pattern as shown in Trace 228A of FIG. 228.

[0546] In some embodiments, Form H orotate is characterized by a differential scanning calorimetry (DSC) pattern as shown in Trace 228B of FIG. 228.

[0547] In some embodiments, Form H orotate is as shown in FIG. 229 1 characterized by an 1H NMR spectrum.

[0548] In some embodiments of the complex form of Compound 1, X is acetylsalicylic acid. In some such embodiments, the complex form of Compound 1 is an acetylsalicylate. In some embodiments, the acetylsalicylate of Compound 1 is a crystalline acetylsalicylate. In some embodiments, the crystalline acetylsalicylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 7.6, 10.3, 11.4, 13.5, and 15.3 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form A acetylsalicylate.

[0549] In some embodiments, Form A acetylsalicylate is characterized by the following peaks in its X-ray powder diffraction pattern.

Table 96

[0550] In some embodiments, the crystalline acetylsalicylate of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 3.6, 5.0, 5.6, 7.0, 7.9, 9.0, 9.9, and 10.5 ± 0.2 degrees. In some such embodiments, the complex form of Compound 1 is Form B acetylsalicylate.

[0551] In some embodiments, Form B acetylsalicylate is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 97]

[0552] In some embodiments, Form B acetylsalicylate is characterized by an X-ray powder diffraction (XRPD) pattern as shown in FIG. 239.

[0553] In some embodiments, Form B acetylsalicylate is characterized by a thermogravimetric analysis (TGA) pattern as shown in Trace 240A of FIG. 240.

[0554] In some embodiments, Form B acetylsalicylate is characterized by a differential scanning calorimetry (DSC) pattern as shown in Trace 240B of FIG. 240.

[0555] Use, Formulation, and Administration Pharmaceutically Acceptable Compositions According to another embodiment, the present disclosure provides a composition comprising Compound 1, or a crystalline form or complex thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of Compound 1, or a crystalline form or complex thereof, in the composition of the present disclosure is such that it is effective to measurably inhibit JAK2 or a variant thereof in a biological sample or patient. In certain embodiments, the composition of the present disclosure is formulated for administration to a patient in need thereof. In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0556] Compounds and compositions are administered according to the methods of the present invention in any amount and by any route of administration effective to treat or reduce the severity of the disorders (i.e., JAK2-mediated diseases or disorders) provided herein. The exact amount required will vary from subject to subject depending on the subject's race, age, and general condition, the severity of the infection, the particular agent, its mode of administration, and the like. Compound 1, or its crystalline forms or complexes, are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage.

[0557] The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally, or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0558] The sterile injectable forms of the compositions of the present disclosure may be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be utilized are water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile fixed oil has conventionally been used as a solvent or suspending medium.

[0559] For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, and similarly, natural pharmaceutically acceptable oils such as olive oil or castor oil are useful, especially in their polyoxyethylated forms. Solutions or suspensions of these oils may contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers, or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for the purposes of the formulation.

[0560] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0561] To extend the effect of Compound 1, or its crystalline form or complex, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance having poor water solubility. The absorption rate of Compound 1, or its crystalline form or complex, thus depends on its dissolution rate, which in turn can depend on crystal size and crystal form. Alternatively, absorption delay of parenterally administered Compound 1, or its crystalline form or complex, is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide - polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating Compound 1, or its crystalline form or complex, in liposomes or microemulsions that are compatible with body tissues.

[0562] In some embodiments, the provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with food or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0563] The pharmaceutically acceptable compositions of the present disclosure can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also generally added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may be added.

[0564] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, Compound 1, or its crystalline form or complex, is combined with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0565] Solid compositions of the same kind can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulation art. These may optionally contain opacifying agents and may also be part of the composition to release the active ingredient(s) only in certain parts of the intestinal tract, i.e., preferentially, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of the same kind can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0566] Compound 1, or its crystalline form or complex, may be in microencapsulated form having one or more of the above excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings, and other coatings well-known in the pharmaceutical formulation art. In such solid dosage forms, Compound 1, or its crystalline form or complex, can be mixed with at least one inert diluent such as sucrose, lactose, or starch. According to conventional methods, such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. They may optionally contain opacifying agents or, preferably, be compositions that release the active ingredient(s) only in certain parts of the intestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes.

[0567] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to Compound 1, or its crystalline forms or complexes, liquid dosage forms may include, for example, inert diluents commonly used in the art such as water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0568] Alternatively, the pharmaceutically acceptable compositions of the present disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing Compound 1, or its crystalline forms or complexes, with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and thereby melt within the rectum to release the drug. Such substances include cocoa butter, suppository wax, and polyethylene glycol.

[0569] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts within the rectal or vaginal cavity and releases the active compound therein, with Compound 1 or its crystalline forms or complexes.

[0570] The pharmaceutically acceptable compositions of the present disclosure may be administered topically, particularly when the target of treatment includes areas or organs that are readily accessible by topical application, such as diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0571] Topical application to the lower intestinal tract can be effected with a rectal suppository formulation (see above) or a suitable enema formulation. Topical transdermal patches may also be used.

[0572] In the case of topical application, the pharmaceutically acceptable compositions provided may be formulated into a suitable ointment containing Compound 1 suspended or dissolved in one or more carriers, or a crystalline form or complex thereof. Carriers for topical administration of Compound 1 or a crystalline form or complex thereof include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated into a suitable lotion or cream containing Compound 1 or a crystalline form or complex thereof suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0573] In the case of ophthalmic use, the pharmaceutically acceptable compositions provided may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as an isotonic, pH-adjusted sterile aqueous solution, with or without a preservative such as benzalkonium chloride. Alternatively, in the case of ophthalmic use, the pharmaceutically acceptable composition may be formulated into an ointment such as petrolatum.

[0574] The pharmaceutically acceptable composition of the present invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and may be prepared as an aqueous saline solution using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0575] Dosage forms for topical or transdermal administration of Compound 1 or its crystalline forms or complexes include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. Compound 1 or its crystalline forms or complexes are mixed under aseptic conditions with a pharmaceutically acceptable carrier and optionally any necessary preservatives or buffers. Ophthalmic formulations, otic drops, and eye drops are also contemplated to be within the scope of the present invention. Further, the present disclosure contemplates the use of transdermal patches which have the further advantage of providing controlled delivery of Compound 1 or its crystalline forms or complexes to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of Compound 1 or its crystalline forms or complexes through the skin. The rate can be controlled either by using a rate controlling membrane or by dispersing Compound 1 or its crystalline forms or complexes in a polymeric matrix or gel.

[0576] In some embodiments, the compositions described herein include a molar amount of Compound 1 or its crystalline forms or complexes equivalent to the free base N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-yl ethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide. For example, a 100 mg formulation of Compound 1 (i.e., the parent N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-yl ethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide of the unsolvated free base, MW = 524.26) contains 117.30 mg of the dihydrochloride monohydrate form of Compound 1 (MW = 614.22).

[0577] In some embodiments, the present disclosure provides a composition comprising Compound 1, or a crystalline form or complex thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients are selected from binders and lubricants.

[0578] In one embodiment, the binder is microcrystalline cellulose. In some such embodiments, the microcrystalline cellulose is siliconized microcrystalline cellulose.

[0579] In some embodiments, the binder is sodium stearyl fumarate.

[0580] In some embodiments, the composition comprises the following. [Table 98]

[0581] In some embodiments, the composition comprises the following. [Table 99]

[0582] Use of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. Examples of kinases inhibited by the compounds and compositions described herein and for which the methods described herein are useful include JAK2 or variants thereof.

[0583] The activity of Compound 1, or its crystalline form or complex, used as an inhibitor of JAK2 kinase or its variants, can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of the phosphorylation activity of activated JAK2 kinase or its variants and / or subsequent functional consequences, or ATPase activity.

[0584] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, the method comprising contacting the biological sample with Compound 1, or its crystalline form or complex, or a composition thereof.

[0585] According to another embodiment, the present invention provides a method for inhibiting the activity of JAK2 kinase or its variants in a biological sample, the method comprising contacting the biological sample with Compound 1, or its crystalline form or complex, or a composition thereof.

[0586] According to another embodiment, the present invention relates to a method for inhibiting the activity of JAK2 kinase or its variants in a patient, the method comprising administering Compound 1, or its crystalline form or complex, or a composition thereof to the patient. In other embodiments, the present disclosure provides a method for treating a JAK2-mediated disease or disorder in a patient in need thereof, the method comprising administering Compound 1, or its crystalline form or complex, or a pharmaceutically acceptable composition thereof to the patient. Such disorders are described in detail herein.

[0587] Compound 1, or its crystalline form or complex, is useful for the treatment of various disorders including, but not limited to, myeloproliferative disorders, proliferative diabetic retinopathy, and other angiogenesis-related disorders including solid tumors and other types of cancer, eye diseases, inflammation, psoriasis, and viral infections. Types of cancer that can be treated include, but are not limited to, gastrointestinal / gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.

[0588] Some examples of diseases and disorders that can be treated include ocular angiogenesis, infantile hemangioma; organ hypoxia, angiogenesis, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes and diabetes complications, inflammatory diseases, acute pancreatitis, chronic pancreatitis, asthma, allergy, adult respiratory distress syndrome, cardiovascular diseases, liver diseases, other blood diseases, asthma, rhinitis, atopic dermatitis, dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, cytokine-related conditions, and glomerulonephritis, sclerodermatitis, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g., allergic asthma, atopic dermatitis, or allergic rhinitis), chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, other autoimmune diseases including graft-versus-host disease, motor neuron diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative diseases including cerebral ischemia, or neurodegenerative diseases caused by traumatic injury, stroke, glutamate neurotoxicity or hypoxia; stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, and ischemic / reperfusion injury in platelet aggregation are also included.

[0589] Some additional diseases and disorders that can be treated include cell-mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjögren's syndrome, scleroderma, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein-Barr virus, hepatitis B, hepatitis C, HIV, HTLV-I, varicella-zoster virus, human papillomavirus), food allergies, skin inflammation, and immunosuppression induced by solid tumors, among others.

[0590] In some embodiments, Compound 1, or a crystalline form or complex thereof, is useful for treating myeloproliferative disorders. In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis, polycythemia vera, and essential thrombocythemia. In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis and secondary myelofibrosis. In some embodiments, the myeloproliferative disorder is secondary myelofibrosis. In some such embodiments, the secondary myelofibrosis is selected from myelofibrosis after polycythemia vera and myelofibrosis after essential thrombocythemia.

[0591] In some embodiments, the provided method includes administering Compound 1, or a crystalline form or complex thereof, to a patient previously treated with a JAK2 inhibitor. In some such embodiments, the provided method includes administering Compound 1, or a crystalline form or complex thereof, to a patient previously treated with ruxolitinib (JAKAFI®).

[0592] In some embodiments, the provided method includes administering Compound 1, or a crystalline form or complex thereof, to a patient having or diagnosed with a myeloproliferative disorder that is non-responsive to ruxolitinib. In some embodiments, the patient has or is diagnosed with a myeloproliferative disorder that is refractory or resistant to ruxolitinib.

[0593] In some embodiments, the patient relapsed during or after treatment with ruxolitinib.

[0594] In some embodiments, the patient is intolerant to ruxolitinib. In some embodiments, the patient's intolerance to ruxolitinib is evidenced by hematological toxicity (e.g., anemia, thrombocytopenia, etc.) or non-hematological toxicity.

[0595] In some embodiments, the patient exhibited an inadequate response to hydroxyurea or was intolerant to hydroxyurea.

[0596] In some embodiments, during treatment with ruxolitinib, the patient has shown or experienced, or may have shown or experienced, one or more of lack of response at any point during ruxolitinib treatment, disease progression, or loss of response. In some embodiments, disease progression is evidenced by an increase in spleen size during ruxolitinib treatment.

[0597] In some embodiments, patients previously treated with ruxolitinib have somatic mutations or clonal markers associated with or indicative of myeloproliferative disorders. In some embodiments, the somatic mutations are selected from JAK2 mutations, CALR mutations, or MPL mutations. In some embodiments, the JAK2 mutation is V617F. In some embodiments, the CALR mutation is a mutation in exon 9. In some embodiments, the MPL mutation is selected from W515K and W515L.

[0598] In some embodiments, the present disclosure provides a method of treating a relapsed or refractory myeloproliferative disorder, wherein the myeloproliferative disorder is relapsed or refractory to ruxolitinib.

[0599] In some embodiments, the myeloproliferative disorder is selected from intermediate-risk myelofibrosis and high-risk myelofibrosis.

[0600] In some embodiments, intermediate-risk myelofibrosis is selected from primary myelofibrosis, myelofibrosis after polycythemia vera (post-PV), and myelofibrosis after essential thrombocythemia (post-ET). In some embodiments, the myelofibrosis is intermediate risk 1 (also referred to as intermediate 1 risk). In some embodiments, the myelofibrosis is intermediate risk 2 (also referred to as intermediate 2 risk).

[0601] In some embodiments, high-risk myelofibrosis is selected from primary myelofibrosis, myelofibrosis after polycythemia vera (post-PV), and myelofibrosis after essential thrombocythemia (post-ET).

[0602] In some embodiments, the present disclosure provides a product comprising a packaging material and a pharmaceutical composition contained within the packaging material. In some embodiments, the packaging material includes a label indicating that the pharmaceutical composition can be used for the treatment of one or more disorders specified above.

[0603] Additional embodiments Embodiment 1. Compound 1 [Chemical formula] The crystalline form thereof.

[0604] Embodiment 2. The crystalline form of Embodiment 1, wherein the form is not solvated.

[0605] Embodiment 3. The crystalline form of Embodiment 2, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 9.7, 14.6, 19.5, 24.3, and 25.6 ± 0.2 degrees.

[0606] Embodiment 4. The crystalline form of Embodiment 2, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 100]

[0607] Embodiment 5. The crystal form of Embodiment 1 in which the form is solvated.

[0608] Embodiment 6. The crystal form of Embodiment 5 in which the form is a 2-methyl-tetrahydrofuran solvate.

[0609] Embodiment 7. The crystal form of Embodiment 6, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 12.5, 18.3, 18.9, 20.1, and 23.8 ± 0.2 degrees.

[0610] Embodiment 8. The crystal form of Embodiment 6, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 101]

[0611] Embodiment 9. The crystal form of Embodiment 1 in which the form is a hydrate.

[0612] Embodiment 10. The crystal form of Embodiment 9 in which the form is a monohydrate.

[0613] Embodiment 11. The crystal form of Embodiment 10, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 8.7, 15.2, 17.3, 18.0, and 19.4 ± 0.2 degrees.

[0614] Embodiment 12. The crystal form of Embodiment 10, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 102]

[0615] Embodiment 13. The crystal form of Embodiment 9 in which the form is a tetrahydrate.

[0616] Embodiment 14. The crystal form of Embodiment 13 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 2θ of 12.4, 18.5, 19.3, 20.3, and 23.6 ± 0.2 degrees.

[0617] Embodiment 15. The crystal form of Embodiment 13 is characterized by the following peaks in its X-ray powder diffraction pattern. [Table 103]

[0618] Embodiment 16. A substantially impurity-free sample containing the crystal form of any one of Embodiments 1 to 15.

[0619] Embodiment 17. The sample of Embodiment 16 containing at least about 99% by weight of Compound 1.

[0620] Embodiment 18. The sample of Embodiment 16 containing at least about 95% by weight of Compound 1.

[0621] Embodiment 19. The sample of Embodiment 16 containing at least about 99% by weight of Compound 1.

[0622] Embodiment 20. The sample of Embodiment 16 containing about 5.0% or less of total organic impurities.

[0623] Embodiment 21. The sample of Embodiment 16 containing about 3.0% or less of total organic impurities.

[0624] Embodiment 22. The sample of Embodiment 16 containing about 1.5% or less of total organic impurities.

[0625] Embodiment 23. The sample of Embodiment 16 containing about 1.0% or less of total organic impurities.

[0626] Embodiment 24. The sample of Embodiment 16 containing about 0.5% or less of total organic impurities.

[0627] Embodiment 25. Compound 1

Chemical formula

[0628] Embodiment 26. Compound 1

Chemical formula

[0629] Embodiment 27. The complex of Embodiment 25, wherein X is hydrobromic acid.

[0630] Embodiment 28. The complex of Embodiment 25, wherein X is sulfuric acid.

[0631] Embodiment 29. The complex of Embodiment 25, wherein X is toluenesulfonic acid.

[0632] Embodiment 30. The complex of Embodiment 25, wherein X is methanesulfonic acid.

[0633] Embodiment 31. The complex of Embodiment 25 or Embodiment 26, wherein X is 2-naphthalenesulfonic acid.

[0634] Embodiment 32. The complex of Embodiment 25, wherein X is phosphoric acid.

[0635] Embodiment 33. The complex of Embodiment 25, wherein X is DL-tartaric acid.

[0636] Embodiment 34. The complex of Embodiment 25 or Embodiment 26, wherein X is succinic acid.

[0637] Embodiment 35. The complex of Embodiment 25 or Embodiment 26, wherein X is genistic acid.

[0638] The complex of Embodiment 25 or Embodiment 26, wherein X is hippuric acid.

[0639] The complex of Embodiment 25 or Embodiment 26, wherein X is adipic acid.

[0640] The complex of Embodiment 25 or Embodiment 26, wherein X is galactaric acid.

[0641] The complex of Embodiment 25 or Embodiment 26, wherein X is 1,5-naphthalenedisulfonic acid.

[0642] The complex of Embodiment 25 or Embodiment 26, wherein X is (S)-camphorsulfonic acid.

[0643] The complex of Embodiment 25 or Embodiment 26, wherein X is 1,2-ethanedisulfonic acid.

[0644] The complex of Embodiment 25 or Embodiment 26, wherein X is ethanesulfonic acid.

[0645] The complex of Embodiment 25 or Embodiment 26, wherein X is benzenesulfonic acid.

[0646] The complex of Embodiment 25, wherein X is oxalic acid.

[0647] The complex of Embodiment 25 or Embodiment 26, wherein X is maleic acid.

[0648] The complex of Embodiment 25 or Embodiment 26, wherein X is pamoic acid.

[0649] The complex of Embodiment 25 or Embodiment 26, wherein X is 1-hydroxy-2-naphthoic acid.

[0650] The complex of Embodiment 25 or Embodiment 26, wherein X is malonic acid.

[0651] Composite of Embodiment 25 where X is L-tartaric acid.

[0652] Composite of Embodiment 25 or Embodiment 26 where X is fumaric acid.

[0653] Composite of Embodiment 25 where X is citric acid.

[0654] Composite of Embodiment 25 or Embodiment 26 where X is L-lactic acid.

[0655] Composite of Embodiment 25 where X is acetic acid.

[0656] Composite of Embodiment 25 or Embodiment 26 where X is propionic acid.

[0657] Composite of Embodiment 25 or Embodiment 26 where X is DL-lactic acid.

[0658] Composite of Embodiment 25 or Embodiment 26 where X is D-gluconic acid.

[0659] Composite of Embodiment 25 or Embodiment 26 where X is DL-malic acid.

[0660] Composite of Embodiment 25 or Embodiment 26 where X is glycolic acid.

[0661] Composite of Embodiment 25 or Embodiment 26 where X is glutaric acid.

[0662] Composite of Embodiment 25 or Embodiment 26 where X is L-malic acid.

[0663] Composite of Embodiment 25 or Embodiment 26 where X is camphoric acid.

[0664] The complex of Embodiment 25, wherein X is DL-mandelic acid.

[0665] The complex of Embodiment 25 or Embodiment 26, wherein X is saccharin.

[0666] The complex of Embodiment 25 or Embodiment 26, wherein X is nicotinic acid.

[0667] The complex of Embodiment 25 or Embodiment 26, wherein X is ascorbic acid.

[0668] The complex of Embodiment 25 or Embodiment 26, wherein X is gallic acid.

[0669] The complex of Embodiment 25 or Embodiment 26, wherein X is salicylic acid.

[0670] The complex of Embodiment 25 or Embodiment 26, wherein X is orotic acid.

[0671] The complex of Embodiment 25 or Embodiment 26, wherein X is acetylsalicylic acid.

[0672] Embodiment 70. A sample substantially free of impurities, comprising the complex of any one of Embodiments 25 to 69.

[0673] Embodiment 71. The sample of Embodiment 70, comprising at least about 90% by weight of the complex.

[0674] Embodiment 72. The sample of Embodiment 70, comprising at least about 95% by weight of the complex.

[0675] Embodiment 73. The sample of Embodiment 70, comprising at least about 99% by weight of the complex.

[0676] Embodiment 74. The sample of Embodiment 70, comprising about 5.0% or less of total organic impurities.

[0677] Embodiment 75. A sample of Embodiment 70 containing up to about 3.0% total organic impurities.

[0678] Embodiment 76. A sample of Embodiment 70 containing up to about 1.5% total organic impurities.

[0679] Embodiment 77. A sample of Embodiment 70 containing up to about 1.0% total organic impurities.

[0680] Embodiment 78. A sample of Embodiment 70 containing up to about 0.5% total organic impurities.

[0681] Embodiment 79. A method for inhibiting the activity of JAK2 kinase or a variant thereof in a biological sample, the method comprising contacting the biological sample with any one of the crystalline forms of Embodiments 1 - 15 or a composition thereof.

[0682] Embodiment 80. A method for inhibiting the activity of JAK2 kinase or a variant thereof in a patient, the method comprising administering to the patient any one of the crystalline forms of Embodiments 1 - 15 or a composition thereof.

[0683] Embodiment 81. A method for treating a JAK2 - mediated disease or disorder in a patient in need thereof, the method comprising administering to the patient any one of the crystalline forms of Embodiments 1 - 15 or a pharmaceutically acceptable composition thereof.

[0684] Embodiment 82. A method for inhibiting the activity of JAK2 kinase or a variant thereof in a biological sample, the method comprising contacting the biological sample with any one of the complexes of Embodiments 25 - 69 or a composition thereof.

[0685] Embodiment 83. A method for inhibiting the activity of JAK2 kinase or a variant thereof in a patient, the method comprising administering to the patient a complex or a composition thereof according to any one of Embodiments 25 to 69.

[0686] Embodiment 84. A method for treating a JAK2-mediated disease or disorder in a patient in need thereof, the method comprising administering to the patient a complex or a pharmaceutically acceptable composition thereof according to any one of Embodiments 25 to 69.

[0687] Embodiment 85. The complex of Embodiment 27 containing 1 equivalent of hydrobromic acid.

[0688] Embodiment 86. The complex of Embodiment 27 containing 2 equivalents of hydrobromic acid.

[0689] Embodiment 87. The complex of Embodiment 28 containing 0.5 equivalent of sulfuric acid.

[0690] Embodiment 88. The complex of Embodiment 29 containing 1 equivalent of toluenesulfonic acid.

[0691] Embodiment 89. The complex of Embodiment 30 containing 1.2 equivalents of methanesulfonic acid.

[0692] Embodiment 90. The complex of Embodiment 31 containing 1.5 equivalents of 2-naphthalenesulfonic acid.

[0693] Embodiment 91. The complex of Embodiment 32 containing 1 equivalent of phosphoric acid.

[0694] Embodiment 92. The complex of Embodiment 33 containing 1 equivalent of DL-tartaric acid.

[0695] Embodiment 93. The complex of Embodiment 34 containing 1 equivalent of succinic acid.

[0696] Embodiment 94. The complex of Embodiment 35 containing 1 equivalent of gentisic acid.

[0697] The complex of Embodiment 36 containing 95.1 equivalents of hippuric acid.

[0698] The complex of Embodiment 37 containing 0.9 equivalents of adipic acid.

[0699] The complex of Embodiment 38 containing 97.1 equivalents of galactaric acid.

[0700] The complex of Embodiment 63 containing 98.1 equivalents of saccharic acid.

[0701] The complex of Embodiment 64 containing 99.1 equivalents of nicotinic acid.

[0702] The complex of Embodiment 65 containing 100.1 equivalents of ascorbic acid.

[0703] The complex of Embodiment 66 containing 101.1 equivalents of gallic acid.

[0704] The complex of Embodiment 68 containing 102.1 equivalents of orotic acid.

[0705] The complex of any one of Embodiments 27, 33, 41, 43, 44, 45, 64, 65, 66, 67, 86, and 92 that is a hydrate.

[0706] The complex of Embodiment 28 that is a hetero-solvate.

[0707] The complex of Embodiment 104, wherein the hetero-solvate is water:tetrahydrofuran.

[0708] The complex of any one of Embodiments 28, 32, and 91 that is a solvate.

[0709] The complex of Embodiment 106, wherein the solvate is an acetone solvate.

[0710] Composite of Embodiment 106, wherein the solvate is a methanol solvate.

Examples

[0711] Measurement FT-Raman spectroscopy: Raman spectra were collected using a Nicolet NXR9650 or NXR 960 spectrometer (Thermo Electron) equipped with a 1064 nm Nd:YVO4 excitation laser, an InGaAs and a liquid N2-cooled Ge detector, and a MicroStage. All spectra were acquired at a resolution of 4 cm -1 with a Happ-Genzel apodization function and two levels of zero filling, and 64 scans.

[0712] X-ray powder diffraction (PXRD or XRPD): PXRD (or XRPD) diffraction patterns were obtained on a PANalytical X’ Pert Pro diffractometer using Ni-filtered CuKa (45 kV / 40 mA) radiation and a step size of 0.02 o 2θ and an X’celeratorTM (registered trademark) RTMS (real-time multistrip) detector. Configuration on the incident beam side: fixed divergence slit (0.25 o ), 0.04 rad Soller slit, anti-scattering slit (0.25 o ), and a 10 mm beam mask. Configuration on the diffracted beam side: fixed divergence slit (0.25 o ) and a 0.04 rad Soller slit. The sample was mounted flat on a zero-background Si wafer.

[0713] Differential scanning calorimetry (DSC): DSC was performed using a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system with a N2 purge of less than 40 mL / min. DSC thermograms were obtained at 15 °C / min in a crimped Al pan.

[0714] Thermogravimetric analysis (TGA): The TGA thermogram was obtained at 15 °C / min with a N2 purge of less than 40 mL / min in Pt or Al pans using a TA Instruments Q500 thermogravimetric analyzer.

[0715] Thermogravimetric analysis with IR off-gas detection (TGA-IR): TGA-IR was performed using a TA Instruments Q5000 thermogravimetric analyzer connected to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGA-IR module having a gas flow cell and a DTGS detector. TGA was performed in Pt or Al pans at a N2 flow rate of 60 mL / min and a heating rate of 15 °C / min. The IR spectra were collected at a resolution of 4 cm -1 and 32 scans at each time point.

[0716] High-performance liquid chromatography (HPLC): HPLC analysis was performed using an HP1100 system equipped with a G1131 quad pump, a G1367A autosampler, and a G1315B diode array detector. Column: Luna C18(2) (50×2.0 mm, 3 μm). Mobile phase: From 100% water (0.05% TFA) to 95% ACN (0.05% TFA) in 8 minutes, and 2 minutes of re-equilibration. Flow rate: 1 mL / min. Detection: 254 nm.

[0717] Proton nuclear magnetic resonance ( 1 1H NMR): A solution for 1H NMR was prepared by dissolving the solid in DMSO-d6. The spectra were collected using an Agilent DD2 500 MHz spectrometer with TMS as the reference substance. 1

[0718] Ion chromatography (IC): Ion chromatography was performed on a Dionex ICS-3000. Column: Dionex IonPac AS12A 4x200 mm. Detection: Suppressed conductivity, ASRS 300 with a suppressor current of 22 mA. Eluent: 1.5 mL / min (2.7 mM Na2CO3 / 0.3 mM NaHCO3).

[0719] Example 1: Compound 1 Free Base (Form C) Compound 1 dihydrochloride (44.5 g) was dissolved in water (498 mL). An aqueous sodium hydroxide solution (2.0 eq; 5 N; 28.9 mL) was added slowly, followed by the addition of acetonitrile (80 mL) and seed crystals of Compound 1 Form C (400 mg). The suspension was stirred at room temperature for 2 hours. The crystalline solid was isolated by vacuum filtration, washed with water (2 × 100 mL) and MTBE (2 × 50 mL), air-dried under vacuum for 1 hour, and dried in a vacuum oven at 40 °C with nitrogen bleed for 24 hours. The yield of the crystalline free base was 97.5% (37 g).

[0720] Compound 1 Form C was a white crystalline powder and was characterized by XRPD (Figure 5), TGA (Figure 6A), DSC (Figure 6B), and DVS (Figure 7). The thermal data indicated that the free base was in the form of a monohydrate with a 3.2% weight loss of water. HPLC analysis showed a purity of 99.5%. IC data did not detect the presence of chloride and confirmed the conversion to the free base.

[0721] The solubility of Compound 1 free base (Form C) was estimated by visually evaluating dissolution in various solvents at room temperature and 40 °C. Aliquots of the solvent were added to 10 mg of the free base at room temperature until complete dissolution or until a maximum volume of 1.8 mL was added. Suspensions that did not dissolve at room temperature were heated to 40 °C to confirm dissolution. Following the visual solubility evaluation, additional Form C was added to the sample and dissolved to obtain a thin suspension. The suspension was stirred at room temperature for 18 hours and the solid was isolated by vacuum filtration. The solid was analyzed by PXRD and compared to the parent group identified during the concurrent salt screening.

[0722] Example 2: Primary Salt Screen of Fedratinib Fedratinib has two basic sites (pK a = 9.3, 6.4) for salt formation. A combination of 53 counterions and stoichiometries was selected. Table 1 shows the additives, pK aShows an overview of the values, administration methods, and the equivalent amounts administered for each additive. Table 1: Additives used in the screening study

Table 104

Table 105

[0723] Multiple modes of crystallization were utilized in the salt screening tests and are as follows: 1. Temperature cycling aging of the solution / suspension for 2 days between 40 °C and 5 °C. 2. High-speed evaporation of the solvent under reduced pressure. 3. Cooling of the solution at 5 °C for up to 2 days. 4. Slow evaporation of the solvent at room temperature for up to 7 days.

[0724] For all samples, the degree of crystallinity was examined by polarized light microscopy (PLM) at the end of each crystallization mode. When birefringence occurred in the experiment, the solid was separated by vacuum filtration and air-dried at room temperature under vacuum for up to 2 hours. The solid was analyzed by FT-Raman spectroscopy and / or PXRD.

[0725] FT-Raman spectra / PXRD patterns of samples prepared using the same additive were compared to determine whether they were in the same crystalline form. Representative samples from each distinct group were further characterized using PXRD, DSC, TGA, and TGA-IR analysis (if necessary).

[0726] The results of the salt screening study are summarized in Table 2. The salt screening experiment yielded crystalline salt hits from 36 out of 42 distinct additives. In all other experiments, amorphous products (gums / amorphous glassy materials) were produced and not isolated. Table 2: Results of the salt screening of fedratinib

Table 106

Table 107

Table 108

[0727] Example 3: Secondary Salt Screen of Fedratinib Of the 36 salt hits, 13 salts of HBr (forms A and B), sulfate (form A), tosylate (form A), mesylate (form A), 2-naphthalenesulfonate (form A / B mixture), phosphate (form D), DL-tartrate (form A), succinate (form A), gentisate (form A), hippurate (form A), adipate (form A) and galactarate (form A) were scaled up to the 200 mg scale.

[0728] Example 3.1: Hydrobromide Two crystalline forms of the hydrobromide were identified from the salt screening experiment and designated as form A and form B. Form A was identified using 1 equivalent of HBr and form B was identified using 2 equivalents of HBr. Both form A and form B have promising thermal properties and were selected for scale-up.

[0729] Preparation of form A: THF (6.3 mL) was combined with crystalline free base form C (315 mg) and aqueous HBr acid solution (1.0 equivalent, 3 M in water, 200 μL). A seed crystal (about 1 mg) of form A hydrobromide was added. The suspension was stirred at room temperature (about 25 °C) for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 1 hour and dried in a vacuum oven at 40 °C for 1 hour. The yield of crystalline form A was 89.9% (327 mg).

[0730] Form A was crystalline by FT-Raman (Figure 10) and PXRD (Figure 11), and the material was birefringent with small irregular particles by PLM. DSC analysis showed two large endotherms at 215 °C and 231 °C (trace 12B in Figure 12), and TGA analysis showed a 0.4% weight loss up to 100 °C (trace 12A in Figure 12). Form A was determined to be a 1.1:1.0 (counterion:parent) salt by ion chromatography. A slight excess of HBr may be due to trace amounts of Form B (di-HBr salt).

[0731] Preparation of Form B: 2-Propanol (6.0 mL) was combined with crystalline free base Form C (300 mg) and aqueous HBr acid (2.0 equivalents, 3 M in water, 381 μL). A seed crystal of the HBr salt (ca. 1 mg) was added. The suspension was stirred at room temperature (ca. 25 °C) for 16 h. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 h, and dried in a vacuum oven at 40 °C for 1 h. The yield of crystalline Form B was 83.8% (329 mg).

[0732] Form B was crystalline by FT-Raman (Figure 13) and PXRD (Figure 14), and the material was birefringent with small needles by PLM. In DSC analysis, a small broad endotherm at 72 °C and a large sharp endotherm at 233 °C were shown (trace 15B in Figure 15), and in TGA-IR analysis, a 2.4% weight loss of water with trace IPA up to 100 °C was shown (trace 15A in Figure 15). In DVS analysis, a 0.9% water uptake was shown between 5 - 95% relative humidity (Figure 16). No change in the crystalline form was seen in the PXRD pattern of the sample after DVS (Figure 17). Form B was determined to be a 2.0:1.0 (counterion:parent) salt by ion chromatography.

[0733] Example 3.2: Sulfate At least three crystalline forms of the sulfate were identified from the salt screening experiments and designated as Form A, B, and C. Form A was characterized by FT-Raman (Figure 18), PXRD (Figure 19), TGA-IR (trace 20A in Figure 20), and DSC (trace 20B in Figure 20). Form B was characterized by FT-Raman (Figure 21), PXRD (Figure 22), TGA-IR (trace 23A in Figure 23), and DSC (trace 23B in Figure 23). Form C was characterized by FT-Raman (Figure 24), PXRD (Figure 25), and DSC (Figure 26).

[0734] Form A had the most promising thermal properties and was selected for scale-up. From the scale-up experiments, a new form, namely Form D, was identified.

[0735] Preparation of Form D: Acetone (7.4 mL) was combined with crystalline free base Form C (372 mg) and aqueous sulfuric acid solution (0.5 equivalent, 2.5 M, 142 μL). Seed crystals of the sulfate (about 1 mg) were added. The suspension was stirred at room temperature (about 25 °C) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour, and dried in a vacuum oven at 40 °C for 4 hours. The yield of the crystalline sulfate was 77.4% (315 mg).

[0736] Form D was crystalline as determined by FT-Raman (Figure 27) and PXRD (Figure 28), but did not match Form A. DSC analysis showed multiple complex endotherms (trace 29B in Figure 29), and TGA-IR analysis showed a weight loss of 1.0% water followed by 6.7% acetone up to 160 °C (trace 29A in Figure 29). The thermal data suggest that Form D is an acetone solvate. Form D was determined to be a 0.5:1.0 (counterion:parent) salt by ion chromatography.

[0737] Example 3.3: Tosylate Two crystalline forms were identified from the salt screening experiments and designated as Form A and Form B. Form A was identified using 1 equivalent of p-toluenesulfonic acid, and Form B was identified using 2 equivalents of p-toluenesulfonic acid. Form A was characterized by PXRD (Figure 30), TGA-IR (trace 31A in Figure 31), and DSC (trace 31B in Figure 31). Form B was characterized by PXRD (Figure 32), TGA-IR (trace 33A in Figure 33), and DSC (trace 33B in Figure 33).

[0738] Form A had the most promising thermal properties and was selected for scale-up. From the scale-up experiments, a new form, namely Form C, was identified.

[0739] Preparation of Form C: Acetone (5.3 mL) was combined with crystalline free base Form C (265 mg) and aqueous tosylate solution (1.0 equivalent, 3 M, 168 μL). Seed crystals of the tosylate (Form A, ~1 mg) were added. The suspension was stirred at room temperature (ca. 25 °C) for 16 h. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 h, and dried in a vacuum oven at 40 °C for 4 h. The yield of the crystalline sulfate was 86.7% (305 mg).

[0740] The tosylate was crystalline as determined by FT-Raman (Figure 34) and PXRD (Figure 35), but did not match Form A. DSC analysis (trace 36B in Figure 36) showed a sharp endotherm at 241 °C, and TGA analysis (trace 36A in Figure 36) showed a 0.1% weight loss up to 100 °C. The thermal data suggest that Form C is less solvated and more stable than Form A. DVS analysis (Figure 37) showed a 1.2% water uptake between 5 - 95% relative humidity. No change in the crystalline form was seen in the PXRD pattern of the sample after DVS (Figure 38). Form C was 1 determined to be a 1.0:1.0 (counterion:parent) tosylate by 1H NMR (Figure 39).

[0741] Example 3.4: Mesylate Three crystalline forms were identified from the salt screening experiments and designated as Form A, B, and C. Forms A and B were identified using 1 equivalent of methanesulfonic acid, and Form C was identified using 2 equivalents of methanesulfonic acid. Form B was characterized by PXRD (Figure 44) and DSC (trace 46B in Figure 46). Form C was characterized by PXRD (Figure 45) and DSC (trace 46C in Figure 46). Form A had the most promising thermal properties and was selected for scale-up.

[0742] Preparation of Form A: Acetone (6.0 mL) was combined with crystalline free base Form C (298 mg) and aqueous methanesulfonic acid solution (1.0 equivalent, 3 M, 189 μL). A seed crystal of the mesylate salt (Form A, ~1 mg) was added to the solution, and the solution was concentrated until dry under vacuum. Acetone (3.0 mL) was added, and the suspension was reseeded with Form A. The suspension was stirred at room temperature (about 25 °C) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour, and dried in a vacuum oven at 40 °C for 4 hours. The yield of the crystalline mesylate salt was 91.3% (322 mg).

[0743] The mesylate salt was crystalline as determined by FT-Raman (Figure 40) and PXRD (Figure 41), and was in good agreement with Form A. DSC analysis (trace 42B in Figure 42) showed a sharp endotherm at 207 °C, and TGA analysis (trace 42A in Figure 42) showed a 0.3% weight loss up to 100 °C. Form A was 1 determined to be a 1.2:1.0 (counterion:parent) mesylate salt by 1H NMR (Figure 43). 1 The 1H NMR data suggest that the minor extra peaks in the PXRD of Form A may be due to dimesylate impurities and that it may be difficult to control the stoichiometry.

[0744] Example 3.5: 2-Naphthalenesulfonate One crystalline form (Form A) of 2-naphthalenesulfonic acid was identified from salt screening experiments using 1 or 2 equivalents of 2-naphthalenesulfonic acid. Form A had promising thermal properties and was selected for scale-up.

[0745] Preparation of Form A: Acetone (5.0 mL) was combined with crystalline free base Form C (252 mg) and an aqueous solution of 2-naphthalenesulfonic acid (1.0 equivalent, 3 M in THF, 160 μL). A seed crystal of 2-naphthalenesulfonate (Form A, ~1 mg) was added. The suspension was stirred at room temperature (about 25 °C) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour, and dried in a vacuum oven at 40 °C for 4 hours. The yield of crystalline 2-naphthalenesulfonate was 86.8% (349 mg).

[0746] The 2-naphthalenesulfonate was crystalline by FT-Raman (Figure 47) and PXRD (Figure 48). Form A was found to be a mixture with Group B (acetone solvate) (Figure 49). The thermal data was very complex, showing that 0.9% water was lost stepwise up to 75 °C and 2.6% acetone was lost between 75 - 175 °C (Figure 50). Form A was 1 found by 1H NMR to be a 1.5:1.0 (counterion:parent) 2-naphthalenesulfonate and was determined to contain 0.5 equivalent of acetone (Figure 51). The thermal and 1 1H NMR data suggest the presence of acetone solvate impurities (Form B) and that it may be difficult to control the stoichiometry.

[0747] Example 3.6: Phosphate Four crystal forms of the sulfate were identified from the salt screening experiments and designated Form A, B, C, and D. Form A was characterized by PXRD (Figure 52) and DSC (trace 56A in Figure 56). Form B was characterized by PXRD (Figure 53) and DSC (trace 56B in Figure 56). Form C was characterized by PXRD (Figure 54) and DSC (trace 56C in Figure 56). Form D was characterized by PXRD (Figure 55) and DSC (trace 56D in Figure 56).

[0748] Form D has the most promising thermal properties and was selected for scale-up. From the scale-up experiments, a new form, namely Form E, was identified.

[0749] Preparation of Form E: Methanol (7.0 mL) was combined with crystalline free base Form C (350 mg) and aqueous phosphoric acid solution (1.0 equivalent, 3 M, 222 μL). A phosphate seed crystal (Form D, approximately 1 mg) was added to the solution, and the solution was concentrated until dry under vacuum. Methanol (3.0 mL) was added and the suspension was reseeded. The suspension was stirred at room temperature (about 25 °C) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour, and dried in a vacuum oven at 40 °C for 4 hours. The yield of the crystalline phosphate was 81.4% (338 mg).

[0750] The phosphate was crystalline by FT-Raman (Figure 57) and PXRD (Figure 58), but did not match the target form. DSC analysis showed multiple complex endotherms (Trace 59B in Figure 59), and TGA-IR analysis showed a 3.8% weight loss of water and methanol up to 125 °C (Trace 59A in Figure 59). The thermal data suggest that Form E is a methanol solvate. Form E was determined to be a 1.0:1.0 (counterion:parent) phosphate by ion chromatography.

[0751] Example 3.7: DL-Tartrate Crystalline DL-tartrate hits were isolated from all 8 salt formation experiments. These 8 hits were classified into 2 groups based on FT-Raman spectral matches (designated as Form A and Form B). Form A was isolated from 7 out of 8 experiments and scaled up at a 200 mg scale. Form B was characterized by PXRD (Figure 65), TGA (Trace 66A in Figure 66), and DSC (Trace 66B in Figure 66).

[0752] Preparation of Form A: THF (4.0 mL) was combined with crystalline free base Form C (198.88 mg) and DL-tartaric acid (1.0 equivalent, administered as a solid). Seed crystals of the DL-tartrate (approx. 1 mg) were added. The suspension was heated to 50 °C, stirred at 50 °C for 15 minutes, cooled slowly to 25 °C (0.1 °C / min), and stirred at 25 °C for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours, and dried in a vacuum oven at 40 °C for 4 hours. The yield of crystalline DL-tartrate was 66.8% (171 mg).

[0753] Form A was crystalline as determined by FT-Raman (Figure 60) and PXRD (Figure 61). DSC data showed a small, broad endotherm starting at 25.4 °C followed by a second sharp endotherm at 194.4 °C (trace 62B in Figure 62). TGA data showed a loss of approximately 3 wt% from 30 - 85 °C (trace 62A in Figure 62). TGA-IR analysis of the evolved gas showed loss of water, suggesting that Form A of the DL-tartrate is a hydrate. DVS analysis (Figure 63) showed an uptake of approximately 2.2% moisture between 5 - 95% relative humidity. The PXRD pattern of the sample after DVS showed no change in the crystalline form. The stoichiometry of the DL-tartrate was 1 shown to be 1.0:1.0 (counterion:parent) by 1H NMR analysis (Figure 64).

[0754] Example 3.8: Succinate Hits of crystalline succinate were isolated from 4 out of 8 salt formation experiments. The FT-Raman spectra of all 4 hits were in agreement with each other and showed a single crystal form (designated as Form A). Form A was characterized by PXRD (Figure 67), TGA (trace 68A in Figure 68), and DSC (trace 68B in Figure 68). Attempts to prepare Form A of the succinate on a 200 mg scale failed, and a new crystal form (designated as Form B) was obtained.

[0755] Preparation of Form B: IPA (7.5 mL) was combined with crystalline free base Form C (213.26 mg) and succinic acid (1.0 equivalent, administered as a solid). Seed crystals of the succinate (approx. 1 mg) were added. The suspension was heated to 40 °C, stirred at 40 °C for 5 hours, cooled slowly to 25 °C (0.1 °C / min), and stirred at 25 °C for 16 hours. MeOH (0.75 mL) was added to the suspension. The suspension was heated to 50 °C, stirred at 50 °C for 5 hours, cooled slowly to 25 °C (0.1 °C / min), and stirred at 25 °C for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours, and dried in a vacuum oven at 40 °C for 4 hours. The yield of the crystalline succinate was 76.2% (199.3 mg).

[0756] Form B was crystalline as determined by FT-Raman (Figure 69) and PXRD (Figure 70). DSC data (trace 71B in Figure 71) showed a single endotherm at 153.2 °C. TGA data (trace 71A in Figure 71) showed a loss of approximately 0.8 wt% from 30 - 165 °C, suggesting that Form B is likely the non-solvated form. The stoichiometry of the succinate was 1 shown to be 1.0:1.0 (counterion:parent) by 1H NMR analysis (Figure 72).

[0757] Example 3.9: Gentisic acid salt Crystalline gentisic acid salt hits were isolated from 6 out of 8 salt formation experiments. Gum / oil was obtained in the remaining experiments. The FT-Raman spectra of all 6 hits were in agreement with each other, indicating a single crystal form (designated as Form A). Form A was scaled up at the 200 mg scale.

[0758] Preparation of Form A: IPA (7.5 mL) was combined with crystalline free base Form C (230.82 mg) and gentisic acid (1.0 equivalent, administered as a solid). Seed crystals of the gentisate (approx. 1 mg) were added. The suspension was heated to 40 °C, stirred at 40 °C for 5 hours, cooled slowly to 25 °C (0.1 °C / min), and stirred at 25 °C for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours, and dried in a vacuum oven at 40 °C for 4 hours. The yield of crystalline gentisate was 79.3% (237.2 mg).

[0759] Form A was crystalline as determined by FT-Raman (Figure 73) and PXRD (Figure 74). DSC data showed a single endotherm at 200.2 °C (trace 75B in Figure 75). TGA data showed a loss of approximately 0.8 wt% from 30 - 196 °C, suggesting that Form A gentisate is likely in the non-solvated form (trace 75A in Figure 75). The stoichiometry of the gentisate was 1 shown to be 1.0:1.0 (counterion:parent) by 1H NMR analysis (Figure 76).

[0760] Example 3.10: Hippurate Hits of crystalline hippurate were isolated from 6 out of 8 salt formation experiments. Gum / oil was obtained in the remaining experiments. The FT-Raman spectra of all 6 hits were in agreement with each other, indicating a single crystal form (designated as Form A). Form A hippurate was scaled up at the 200 mg scale.

[0761] Preparation of Form A: Acetone (7.5 mL) was combined with crystalline free base Form C (218.98 mg) and hippuric acid (1.0 equivalent, administered as a solid). Seed crystals of the hippurate (approx. 1 mg) were added. The suspension was heated to 40 °C, stirred at 40 °C for 5 hours, cooled slowly to 25 °C (0.1 °C / min), and stirred at 25 °C for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours, and dried in a vacuum oven at 40 °C for 4 hours. The yield of crystalline hippurate was 73.7% (217 mg).

[0762] Form A was crystalline as determined by FT-Raman (Figure 77) and PXRD (Figure 78). DSC data showed a single endotherm at 170.1 °C (trace 79B in Figure 79). TGA data showed a loss of approximately 0.1 wt% from 30 - 157 °C, suggesting that Form A hippurate is in the non-solvated form (trace 79A in Figure 79). The stoichiometry of the hippurate was 1 shown to be 1.0:1.0 (counterion:parent) by 1H NMR analysis (Figure 80).

[0763] Example 3.11: Adipate Crystalline adipate hits were isolated from 6 out of 8 salt formation experiments. The FT-Raman spectra of 5 out of 6 crystalline hits were in agreement with each other, indicating a single crystal form (designated as Form A), while the FT-Raman spectrum of the sample isolated from acetone suggested a mixture of forms. Form A was characterized by PXRD (Figure 81), TGA (trace 82A in Figure 82), and DSC (trace 82B in Figure 82). Attempts to prepare Form A on a 200 mg scale failed, and a new crystal form (designated as Form C) was obtained.

[0764] Preparation of Group C: EtOAc (7.5 mL) was combined with crystalline free base Form C (210.27 mg) and adipic acid (1.0 equiv, administered as a solid). A seed crystal of the adipate (ca. 1 mg) was added. The suspension was heated to 40 °C, stirred at 40 °C for 5 h, cooled slowly to 25 °C (0.1 °C / min), and stirred at 25 °C for 16 h. The suspension was heated to 50 °C, stirred at 50 °C for 5 h, cooled slowly to 25 °C (0.1 °C / min), and stirred at 25 °C for 16 h. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 2 h, and dried in a vacuum oven at 40 °C for 4 h. The yield of crystalline adipate was 76.2% (205.2 mg).

[0765] Form C was crystalline by FT-Raman (Figure 83) and PXRD (Figure 84). DSC data showed a small endotherm starting at 93.2 °C, followed by two sharp endotherms at 132.6 °C and 171.2 °C (trace 85B in Figure 85). TGA data showed a loss of approximately 0.9 wt% from 30 to 180 °C (trace 85A in Figure 85). The stoichiometry of the adipate was 1 shown to be 0.9:1.0 (counterion:parent) by 1H NMR analysis (Figure 86).

[0766] Example 3.12: Galactarate Hits of crystalline galactarate were isolated from 5 out of 8 salt formation experiments. In the remaining experiments, gums / oils, free bases, or counterions were obtained. The FT-Raman spectra of all 5 salt hits were in agreement with each other and showed a single crystal form (designated as Form A). Form A galactarate was scaled up on a 200 mg scale.

[0767] Preparation of Form A: Acetone (7.5 mL) was combined with crystalline free base Form C (194.89 mg) and galactaric acid (1.0 equivalent, administered as a solid). A seed crystal of galactarate (ca. 1 mg) was added. The suspension was heated to 40 °C, stirred at 40 °C for 5 h, cooled slowly to 25 °C (0.1 °C / min), and stirred at 25 °C for 16 h. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 h, and dried in a vacuum oven at 40 °C for 4 h. The yield of crystalline galactarate was 86.9% (237.5 mg).

[0768] Form A was crystalline by FT-Raman (Figure 87) and PXRD (Figure 88). DSC data showed a single endotherm at 184.4 °C (trace 89B in Figure 89). TGA data showed a loss of approximately 0.7 wt% from 30 to 157 °C, suggesting that Form A galactarate is in the non-solvated form (trace 89A in Figure 89). The stoichiometry of the galactarate was 1 shown to be 1.0:1.0 (counterion:parent) by 1H NMR analysis (Figure 90).

[0769] Example 3.13: Crystalline Salt Hits In addition to the crystalline salts discussed in Examples 3.1 to 3.12, salts were also obtained from various additives in the salt screening tests. The characterization data of these salt hits are shown in Table 3. Table 3: Crystal Hits from the Screen

Table 109

Table 110

Table 111

Table 112

[0770] Example 4: Primary Cocrystal Screen of Fedratinib Based on the tendency of hydrogen bonding, molecular diversity, and pharmaceutical acceptability, a total of 24 cocrystal formers (CCFs) were selected. One equivalent of CCF was administered in all screening experiments. Table 4 shows the set of CCFs used. Table 4: Cocrystal Formers Used in the Screen

Table 113

[0771] In the presented cocrystal screening experiments, a total of five pure solvents and two binary mixtures of THF, EtOAc, DCM, MIBK, MeOH, THF / cyclohexane (2:8 v / v), and IPA:water (9:1 v / v) were used. This selection was based on the diversity of the molecular structure and properties of the solvents (e.g., polarity, chemical diversity), and the solubility of the free base form C ("API") from visual solubility evaluations.

[0772] A total of approximately 240 co-crystal screening experiments were carried out using 24 CCFs and a combination of i) solvent drop grinding (SDG) with 4 solvents, ii) slurry ripening (SR) with 6 solvents, and iii) evaporation of the solution obtained in step ii.

[0773] Solvent Drop Grinding (SDG): Several preliminary experiments were conducted to determine the milling parameters suitable for the SDG experiments. The results of these experiments are summarized in Table 5 (grinding for 15 minutes at 15 Hz with one milling ball). This data indicates that grinding for 15 minutes at 15 Hz using one milling ball is suitable for 100 mg API using 2 - 15 μL of solvent. The specific (initial) solvent amounts selected for the 4 solvents were THF - 5 μL; EtOAc, DCM, and MIBK - 15 μL. Table 5: Determination of appropriate solvent drop grinding (SDG) parameters

Table 114

[0774] For the SDG experiments, the API (approx. 100 mg), stoichiometric amount of CCF (1 equivalent), and the solvents THF, EtOAc, DCM, or MIBK were mixed in a stainless - steel milling jar (10 mL). Grinding was carried out at room temperature (approx. 23 °C) using one milling ball (7 mm) at 15 Hz for 15 minutes on a Retsch Mill (model MM301). If these parameters were observed or predicted (based on the properties of the CCF) to result in low yields or gumming, the grinding time was shortened to 10 minutes or manual grinding with a mortar and pestle was used.

[0775] Slurry Ripening (SR): Using the product of the SDG experiment, except that THF: cyclohexane (2:8 v / v) was used instead of THF, an SR test was carried out in combination with the same four pure solvents used in the SDG experiment. In the case of CCFs that produce potential co-crystals (or salts) from SDG, a saturated solution of the CCF was prepared in the specific solvent that produces the potential co-crystal or salt and used in the SR experiment.

[0776] Two additional solvents (MeOH and IPA: water (9:1 v / v)) and a 1:1 (API: CCF) equivalent mixture were prepared and combined with these two solvent systems.

[0777] The saturated solution of CCF was prepared by combining CCF (an estimated amount to achieve a suspension) with 2 mL of solvent and mixing at 23 °C for 16 h. The suspension was filtered through a 0.20 μm PTFE filter membrane to obtain a saturated solution.

[0778] The SR experiment was carried out in a 2 mL vial containing a tumbling stir disk, using a maximum of 1.9 mL of solvent [THF: cyclohexane (2:8 v / v), EtOAc, DCM, MIBK, MeOH, or IPA: water (9:1 v / v)]. The samples were mixed and temperature cycled between 40 °C and 5 °C for 7 days and then mixed at 25 °C for 5 days. During this processing time, additional solvent was added to produce a mixable suspension containing sufficient solids for isolation and analysis. The suspended solids were isolated by filtration and air dried for 18 h.

[0779] Evaporation (EV): The solution obtained from the slurry ripening experiment was slowly evaporated (by loosening the vial cap) until dry in a draft. The product was first examined by PLM for birefringence and, in the case of birefringence, further analyzed by PXRD.

[0780] All solid outputs of the screen were analyzed by PXRD to evaluate cocrystal formation. Potential cocrystals were analyzed by additional techniques (FT-Raman, DSC, TGA-IR, PLM, etc.) as needed and as sample amounts permitted.

[0781] From the experiments conducted, potential cocrystals (pure or mixtures with the parent and / or CCF) of Form C free base with isonicotinamide, pyrogallol, saccharin, and xylitol, as well as potential salts with L-ascorbic acid, nicotinic acid, gallic acid, orotic acid, salicylic acid, and acetylsalicylic acid were obtained. Most potential cocrystals (or salts) were obtained from SR / EV experiments. The PXRD patterns of salicylic acid Form A and acetylsalicylic acid Form A were observed to be identical. Proton NMR analysis confirmed that acetylsalicylate Form A corresponded to salicylate Form A since no acetyl groups were observed. This may be because acetylsalicylic acid was hydrolyzed to salicylic acid during slurry aging.

[0782] Cocrystallization formers that did not produce potential cocrystals included urea, caffeine, nicotinamide, L-prolinamide, vanillin, methylparaben, propylparaben, butylated hydroxyanisole, chrysin, resveratrol, quercetin, aspartame, sucralose, and D-mannitol. These cocrystallization formers resulted in amorphous substances, parent forms, CCFs, or combinations thereof. The products obtained from the SDG and SR / EV experiments are shown in Tables 6 and 7, respectively. Table 6: Cocrystal or Salt Screening Products from the SDG Approach

Table 115

Table 116

[0783] Example 5: Scale - up of Cocrystals Of the potential cocrystal (or salt) hits, seven, namely saccharin form A, nicotinic acid form A, ascorbic acid form A, gallic acid form A, salicylic acid form A, and orotic acid forms F and H, showed desirable physicochemical properties and were scaled up at the 250 mg scale. The results are described in detail below.

[0784] Example 5.1: Saccharin Cocrystal The saccharin co-crystal hits were obtained from six SR experiments. In the PXRD analysis of the samples, one form designated as Form A was shown. Form A (unsolvated) was scaled up (250 mg scale) and characterized in detail.

[0785] Preparation of Form A (unsolvated): Form C free base (244.5 mg) was combined with saccharin (83.1 mg; 1 equivalent) and solvent (DCM, 3.5 mL), and mixed at 40 °C for 30 minutes to obtain a suspension. A seed (about 5 mg) was added, and the suspension was mixed at 40 °C for 2 hours, gradually cooled to 20 °C, and mixed at 20 °C for 60 hours to obtain a moderately thick slurry. The solid was isolated by vacuum filtration for 2 hours and dried in a vacuum oven at 40 °C for 18 hours. The weight of the product was 287 mg of Form A (87% yield for the co-crystal).

[0786] Form A was determined to be a crystalline powder by FT-Raman (Figure 189) and PXRD (Figure 190). DSC analysis showed an endothermic melting starting at 183.8 °C (ΔH = 104.2 J / g) (Trace 191B in Figure 191). TGA analysis showed a 0.1% weight loss from 26 to 174 °C, indicating an unsolvated form (Trace 191A in Figure 191). Proton NMR analysis of Form A showed that Form A contains 1 equivalent of saccharin (Figure 192).

[0787] Example 5.2: Nicotinate The nicotinate hits were obtained from three SR experiments and one EV experiment. In the PXRD analysis of the samples, three forms designated as Form A, Form B, and Form C were shown. Form A (unsolvated) was scaled up (250 mg scale) and characterized in detail. Form B was characterized by PXRD (Figure 197), TGA (Trace 198A in Figure 198), and DSC (Trace 198B in Figure 198). Form C was characterized by PXRD (Figure 199), TGA (Trace 200A in Figure 200), and DSC (Trace 200B in Figure 200).

[0788] Preparation of Form A (non-solvate): Morphological C free base (252.8 mg) was combined with nicotinic acid (57.9 mg, 1 equivalent) and a solvent (THF / cyclohexane (2:8), 3.0 mL), and mixed at 40 °C for 30 minutes to obtain a suspension. A seed (about 5 mg) was added, and the suspension was mixed at 40 °C for 2 hours, gradually cooled to 20 °C, and mixed at 20 °C for 60 hours to obtain a moderately thick slurry. The solid was isolated by vacuum filtration for 2 hours and dried in a vacuum oven at 40 °C for 18 hours. The weight of the product was 247 mg of nicotinic acid salt Form A (79% yield based on the salt).

[0789] Form A was determined to be a crystalline powder by FT-Raman (Figure 193) and PXRD (Figure 194). DSC analysis showed an endothermic melting starting at 179.9 °C (ΔH = 120.4 J / g) (trace 195B in Figure 195). TGA analysis showed a 0.2% weight loss at 29 - 168 °C, indicating an unsolvated form (trace 195A in Figure 195). Proton NMR analysis of Form A showed that Form A contained 1 equivalent of nicotinic acid (Figure 196).

[0790] Example 5.3: L-ascorbate Ascorbate hits were obtained from six SR experiments. PXRD analysis of the samples showed two forms designated as Form A and Form B. Form A (hydrate) was scaled up (250 mg scale) and characterized in detail.

[0791] Preparation of Form A (hydrate): Morphological C free base (249.7 mg) was combined with L-ascorbic acid (81.6 mg; 1 equivalent) and a solvent (IPA / water (9:1) v / v, 6.0 mL), and mixed at 40 °C for 30 minutes to obtain a suspension. A seed (about 5 mg) was added, and the suspension was mixed at 40 °C for 2 hours, gradually cooled to 20 °C, and mixed at 20 °C for 60 hours to obtain a moderately thick slurry. The solid was isolated by vacuum filtration for 4 hours and left open in a draft at 40 °C for 18 hours. The weight of the product was 294 mg of ascorbate Form A (83% yield based on the salt).

[0792] Form A was determined to be a crystalline powder by FT-Raman (Figure 201) and PXRD (Figure 202). DSC analysis showed an endothermic dehydration starting at 46.0 °C (ΔH = 168.5 J / g), followed by a small endotherm at 116.8 °C (ΔH = 7.5 J / g), and an endothermic melting starting at 157.0 °C (presumably two fusing) (ΔH = 71.4 J / g) (trace 203B in Figure 203). TGA analysis showed a 5.4% weight (2.2 equivalents) loss of water between 29 and 140 °C, indicating a hydrated form (trace 203A in Figure 203). Proton NMR analysis of Form A indicated that Form A contains 1 equivalent of L-ascorbic acid (Figure 204).

[0793] Example 5.4: Gallate The gallate hits were obtained from four SR experiments. PXRD analysis of the samples showed two forms designated Form A and Form B. Form A was obtained in pure form, while Form B was only obtained as a mixture with Form A. The hydrated Form A of gallate was scaled up (250 mg scale) and characterized in detail.

[0794] Preparation of Form A (hydrate): The Form C free base (245.0 mg) was combined with gallic acid (77.0 mg; 1 equivalent) and solvent (MeOH, 4.0 mL) and mixed at 40 °C for 30 minutes to obtain a suspension. Seed (ca. 5 mg) was added and the suspension was mixed at 40 °C for 2 hours, slowly cooled to 20 °C, and mixed at 20 °C for 60 hours to obtain a moderately thick slurry. The solid was isolated by vacuum filtration for 4 hours and left open in a draft at 40 °C for 18 hours. The weight of the product was 256 mg of gallate Form A (77% yield based on the salt).

[0795] Form A was determined to be a crystalline powder by FT-Raman (Figure 205) and PXRD (Figure 206). DSC analysis showed an endothermic dehydration starting at 48.5 °C (ΔH = 79.8 J / g), followed by an endothermic melting starting at 193.5 °C (ΔH = 176.1 J / g) (trace 207B in Figure 207). TGA analysis showed a 2.4% weight (1 equivalent) water loss between 22 and 89 °C, indicating a hydrated form (trace 207A in Figure 207). Proton NMR analysis of Form A indicated that Form B contains 1 equivalent of gallic acid (Figure 208).

[0796] Example 5.5: Salicylates Salicylate hits were obtained from one SDG experiment and six SR experiments. However, the hits from SDG were a mixture of potential salts, parents, and CCFs. PXRD analysis of the six SR hits showed two forms designated Form A and Form B. Most of the hits (5 / 6) were consistent with Form A. Form A (hydrate) of the salicylate was scaled up (250 mg scale) and characterized in detail.

[0797] Preparation of Form A (hydrate): Form C free base (253.8 mg) was combined with salicylic acid (64.7 mg; 1 equivalent) and solvent (IPA / water 9:1, 4.5 mL) and mixed at 40 °C for 30 minutes to obtain a suspension. Seed (ca. 5 mg) was added and the suspension was mixed at 40 °C for 2 hours, slowly cooled to 20 °C, and mixed at 20 °C for 60 hours to obtain a moderately thick slurry. The solid was isolated by vacuum filtration for 18 hours. The weight of the product was 272 mg of salicylate Form A (83% yield based on the salt).

[0798] Form A was determined to be a crystalline powder by FT-Raman (Figure 209) and PXRD (Figure 210). DSC analysis showed an endothermic dehydration starting at 34.9 °C (ΔH = 71.0 J / g), followed by an endothermic melting starting at 159.8 °C (ΔH = 83.8 J / g) (trace 211B in Figure 211). TGA analysis showed a 2.5% weight (1 equivalent) water loss between 26 and 96 °C, indicating a hydrated form (trace 211A in Figure 211). Proton NMR analysis of Form A indicated that Form A contains 1 equivalent of salicylic acid (Figure 212).

[0799] Example 5.6: Orotic Acid Salt The hits for orotic acid salt were obtained from six SR experiments. PXRD analysis of the hits showed six forms designated as Form A, Form B, Form C, Form D, Form E, and Form F. Scale-up experiments (250 mg) were performed on Forms E and F (hydrates), and the other groups were down-prioritized due to solvation or being mixtures of the two groups shown in Table 7. The scale-up experiment for Form E failed, generating two new groups, Form G and Form H. Form G is a MeOH / water solvate that desolvates under ambient conditions to form Form H, which is a hydrate. Form A was characterized by PXRD (Figure 213), TGA (trace 214A in Figure 214), and DSC (trace 214B in Figure 214). The mixture of Form B and Form E was characterized by PXRD (Figure 215). The mixture of Form C and Form E was characterized by PXRD (Figure 216). Form D was characterized by PXRD (Figure 217), TGA (trace 218A in Figure 218), and DSC (trace 218B in Figure 218). Form E was characterized by PXRD (Figure 219), TGA (trace 220A in Figure 220), and DSC (trace 220B in Figure 220). Form G was characterized by XRPD (Figure 221). Forms F and H (hydrates) of orotic acid salt were scaled up (250 mg) and characterized in detail.

[0800] Preparation of Form F (Hydrate): Morphology C free base (250.0 mg) was combined with orotic acid (77.0 mg, 1 equivalent) and a solvent (IPA / water 9:1, 10.0 mL), and mixed at 40 °C for 30 minutes to obtain a suspension. A seed (about 5 mg) was added, and the suspension was mixed at 40 °C for 2 hours, gradually cooled to 20 °C, and mixed at 20 °C for 60 hours to obtain a moderately thick slurry. The solid was isolated by vacuum filtration for 22 hours. The weight of the product was 297 mg of Form A (82% yield based on the cocrystal).

[0801] Form F was determined to be a crystalline powder by FT-Raman (Figure 222) and PXRD (Figure 223). DSC analysis showed two endothermic dehydrations starting at 56.5 °C (ΔH = 86.1 J / g) and 104.7 °C (ΔH = 15. J / g), respectively, followed immediately by an endothermic melting (ΔH = 12.3 J / g) starting at 135.2 °C (trace 224B in Figure 224). TGA analysis showed a 10.8% weight loss (4.5 equivalents) of water from 24 to 129 °C, indicating a hydrated form (trace 224A in Figure 224). Proton NMR analysis of Form F showed that Form F contained 1 equivalent of orotic acid (Figure 225).

[0802] PXRD analysis of the heated sample showed a significant decrease in crystallinity but no change in form.

[0803] Preparation of Form H (Hydrate): Morphology C free base (251.7 mg) was combined with orotic acid (72.7 mg, 1 equivalent) and a solvent (MeOH, 1.0 mL), and mixed at 40 °C for 10 minutes to obtain a nearly clear solution. When a seed (Group E, about 5 mg) was added, the suspension became very thick, so additional solvent (MeOH, 1.5 mL) was added. The suspension was mixed at 40 °C for 2 hours, gradually cooled to 20 °C, and mixed at 20 °C for 18 hours to obtain a moderately thick slurry. PXRD showed a new form, and DSC / TGA-IR showed a solvate of MeOH / water, which was designated as Form G. The batch solid was isolated by vacuum filtration for 18 hours. The weight of the product was 178 mg. PXRD showed a further new form, and DSC / TGA-IR showed a hydrate, which was designated as Form H (53% yield based on the salt).

[0804] Form H was determined to be a crystalline powder by FT-Raman (Figure 226) and PXRD (Figure 227). DSC analysis showed a broad endotherm for dehydration starting at 34.3 °C (ΔH = 23.4 J / g), followed by two small endotherms at 134.5 °C and 144.4 °C respectively, a large endotherm starting at 165.8 °C (ΔH = 44.6 J / g), and a broad endotherm starting at 203.4 °C (ΔH = 11.1 J / g) (trace 228B in Figure 228). TGA analysis showed a 3.2% weight (2 equivalents) loss of moisture between 23 and 95 °C, indicating a hydrated form (trace 228A in Figure 228). Proton NMR analysis of Form H indicated that Form H contains 1 equivalent of orotic acid (Figure 229).

[0805] PXRD analysis of the heated sample showed some loss of crystallinity and some loss of the major peaks.

[0806] Example 5.7: Other cocrystal or salt hits Acetylsalicylate Form A was scaled up, and its PXRD pattern was observed to be the same as that of Salicylate Form A. Proton NMR analysis confirmed that Acetylsalicylate Form A was identical to Salicylate Form A since no acetyl group was observed. This may be due to the hydrolysis of acetylsalicylic acid to salicylic acid during slurry aging.

[0807] In addition to the scaled-up cocrystals (or salts), several other potential cocrystals were obtained from the screening. These hits - limited sample amounts, - undesirable physicochemical properties (poor crystallinity / poor thermal properties) - identified as mixtures with the parent and / or CCF were not fully characterized and / or not scaled up due to the reasons of

[0808] A representative sample of these co-crystal (or salt) hits is summarized in Table 9. Table 9: Attributes of Other Co-crystals or Salt Hits Identified by Screening

Table 121

Table 122

[0809] Example 6: Water Solubility of a Particular Complex The solid / salt form (about 20 - 30 mg) was transferred to a clear glass vial (4 ml). To each vial containing the solid form, water (about 0.2 - 2 ml) was separately added. The amount of water added and the weight of the solid / salt form were appropriately adjusted to produce an excess of undissolved solid / salt form. The vials containing the solid / salt form / water mixture were transferred to a rack maintained at rotation, and the samples were stirred at ambient temperature for 24 hours to equilibrate. At the end of the equilibration process, a visual observation of the suspension was made, the samples were removed, and centrifuged (14,000 rpm for 3 minutes) through a Costar SPIN-X polypropylene centrifuge tube (2.0 ml) filter (0.22 mm nylon filter) to separate the undissolved drug. The clear filtrate was assayed for drug content and appropriately diluted with acetonitrile / water (50:50) if necessary, and then the solubility of the active substance in the solution was determined. A standard curve in the concentration range of 0.126 mg / ml to 0.001 mg / ml was prepared using the free base. Samples and standards were analyzed for drug content using HPLC. The results are described in Table 10. Table 10: Solubility of Particular Forms of Compound 1

Table 123

Claims

1. Crystalline forms of Compound 1. 【Chemistry 1】

2. 2. The crystalline form of claim 1, wherein said form is unsolvated.

3. 3. The crystalline form of claim 2, wherein said form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.6, 19.5, 24.3, and 25.6±0.2 degrees 2θ.

4. 3. The crystalline form of claim 2, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern: 【Table 1】

5. 2. The crystalline form of claim 1, wherein the form is solvated.

6. 6. The crystalline form of claim 5, wherein said form is a 2-methyl-tetrahydrofuran solvate.

7. 7. The crystalline form of claim 6, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 12.5, 18.3, 18.9, 20.1, and 23.8±0.2 degrees 2θ.

8. 7. The crystalline form of claim 6, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern: 【Table 2】

9. 2. The crystalline form of claim 1, wherein the form is a hydrate.

10. 10. The crystalline form of claim 9, wherein the form is a monohydrate.

11. 11. The crystalline form of claim 10, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.7, 15.2, 17.3, 18.0, and 19.4±0.2 degrees 2θ.

12. 11. The crystalline form of claim 10, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern: 【Table 3】

13. 10. The crystalline form of claim 9, wherein the form is a tetrahydrate.

14. 14. The crystalline form of claim 13, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 12.4, 18.5, 19.3, 20.3, and 23.6±0.2 degrees 2θ.

15. 14. The crystalline form of claim 13, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern: 【Table 4】

16. 16. A substantially impurity-free sample comprising the crystalline form of any one of claims 1 to 15.

17. Compound 1 【Chemistry 2】 and a coformer X, wherein the complex is crystalline, X is hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, 1,5-naphthalenedisulfonic acid, (S)-camphor-10-sulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, The complex is selected from the group consisting of malic acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

18. Compound 1 【Chemistry 3】 and a coformer X, Where: The complex, wherein X is selected from the group consisting of 2-naphthalenesulfonic acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, 1,5-naphthalenedisulfonic acid, (S)-camphor-10-sulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, benzenesulfonic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, fumaric acid, L-lactic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glutamic acid, glycolic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, and choline.

19. 19. A substantially impurity-free sample comprising the complex of claim 17 or claim 18.

20. 16. A method of inhibiting activity of JAK2 kinase or a mutant thereof in a biological sample, comprising contacting said biological sample with a crystalline form or composition thereof according to any one of claims 1 to 15.

21. 16. A method of inhibiting activity of JAK2 kinase or a mutant thereof in a patient, comprising administering to said patient a crystalline form or composition thereof of any one of claims 1-15.

22. 16. A method for treating a JAK2-mediated disease or disorder in a patient in need thereof, comprising administering to the patient a crystalline form of any one of claims 1-15 or a pharma- ceutically acceptable composition thereof.

23. 20. A method for inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, comprising contacting the biological sample with a complex or composition thereof of claim 17 or claim 18.

24. 20. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, comprising administering to the patient a complex or composition thereof of claim 17 or claim 18.

25. A method for treating a JAK2-mediated disease or disorder in a patient in need thereof, comprising administering to the patient a complex of claim 17 or claim 18 or a pharma- ceutical acceptable composition thereof.

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