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WO2024238659A1 - Sels cristallins ou formes amorphes de 2-((1h-pyrazol-3-yl)méthyl)-6-((6-aminopyridin-2-yl)méthyl)-4-méthyl-4,6-dihydro-5h-thiazolo[5',4': 4,5]pyrrolo[2,3-d]pyridazin-5-one - Google Patents

Sels cristallins ou formes amorphes de 2-((1h-pyrazol-3-yl)méthyl)-6-((6-aminopyridin-2-yl)méthyl)-4-méthyl-4,6-dihydro-5h-thiazolo[5',4': 4,5]pyrrolo[2,3-d]pyridazin-5-one Download PDF

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Publication number
WO2024238659A1
WO2024238659A1 PCT/US2024/029471 US2024029471W WO2024238659A1 WO 2024238659 A1 WO2024238659 A1 WO 2024238659A1 US 2024029471 W US2024029471 W US 2024029471W WO 2024238659 A1 WO2024238659 A1 WO 2024238659A1
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Prior art keywords
crystalline form
crystalline
ray powder
powder diffraction
compound
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PCT/US2024/029471
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English (en)
Inventor
Daniel R. Fandrick
Louis Grenier
Benjamin S. Lane
Jaemoon Lee
Cheuk-Yui LEUNG
Hui Li
Karlie E. MELLOTT
Eric Simone
Jacob P. Sizemore
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Agios Pharmaceuticals Inc
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Agios Pharmaceuticals Inc
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Priority to AU2024271856A priority Critical patent/AU2024271856A1/en
Publication of WO2024238659A1 publication Critical patent/WO2024238659A1/fr
Priority to MX2025013731A priority patent/MX2025013731A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • PK Pyruvate kinase
  • L and R isoforms are expressed in liver and red blood cells
  • Ml isoform is expressed in most adult tissues
  • M2 isoform is a splice variant of Ml expressed during embryonic development.
  • a well- known difference between the Ml and M2 isoforms of PK is that M2 is a low-activity enzyme that relies on allosteric activation by the upstream glycolytic intermediate, fructose- 1,6-bisphosphate (FBP), whereas Ml is a constitutively active enzyme.
  • FBP fructose- 1,6-bisphosphate
  • PK activators can be used to treat a number of different disorders including PKD (Pyruvate Kinase Deficiency), thalassemia (e.g., alpha and beta-thalassemia), hereditary elliptocytosis, abetalipoproteinemia or Bassen- Komzweig syndrome, sickle cell disease, paroxysmal nocturnal hemoglobinuria, and various anemias which include congenital anemias (e.g., enzymopathies) and various hemolytic anemias, (e.g.
  • hereditary and/or congenital hemolytic anemia acquired hemolytic anemia, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency, anemia due to MDS (myelodysplastic syndromes) including very low risk, low risk, lower risk and/or intermediate risk MDS, non- spherocytic hemolytic anemia and hereditary spherocytosis).
  • MDS myelodysplastic syndromes
  • Compound 1 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4,6- dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one, herein referred to as Compound 1, is useful for activating pyruvate kinase in a subject in need thereof. See e.g., WO 2019/035865 and WO 2019/035864, the contents of which are incorporated herein by reference.
  • Compound 1 is currently being investigated in clinical trials for use in adult patients with sickle cell disease as well as in patients with anemia due to MDS (lower risk to intermediate risk MDS). See e.g., U.S. clinical trials identifiers NCT04536792 and NCT05490446.
  • the crystalline salt form described herein is a hemi-hydrate hemi-sulfate salt of Compound 1.
  • the hemi-hydrate hemi-sulfate salt of Compound 1 is represented as
  • the crystalline salt form described herein is a phosphate salt of Compound 1.
  • the phosphate salt of Compound 1 is represented as
  • the crystalline salt form described herein is a DL-tartrate salt of Compound 1.
  • the DL-tartrate salt of Compound 1 is represented as
  • the crystalline salt form described herein is an L-tartrate salt of Compound 1.
  • the L-tartrate salt of Compound 1 is represented as
  • the crystalline salt form described herein is a hydrochloride salt of Compound 1.
  • the hydrochloride salt of Compound 1 is represented as
  • the crystalline form described herein is a free base monohydrate form of Compound 1.
  • the free base monohydrate of Compound 1 is represented as
  • compositions comprising one or more of the described crystalline forms or an amorphous form of Compound 1.
  • Methods for the preparation of such forms and uses thereof, including their use for treating conditions such as, e.g., hemolytic anemia, sickle cell disease, and anemia due to MDS (very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS) are also described.
  • FIG. 1 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemihydrate hemi-sulfate salt Form A of Compound 1.
  • XRPD X-ray powder diffraction pattern
  • FIG. 2 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hemi-hydrate hemi- sulfate salt Form A of Compound 1.
  • FIG. 3 depicts the dynamic vapor sorption (DVS) isotherm for crystalline hemi- hydrate hemi-sulfate salt Form A of Compound 1.
  • FIG. 4 depicts an X-ray powder diffraction pattern for crystalline phosphate salt Form B of Compound 1.
  • FIG. 5 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline phosphate salt Form B of Compound 1
  • FIG. 6 depicts the dynamic vapor sorption (DVS) isotherm for crystalline phosphate acid salt Form B.
  • FIG. 7 depicts an X-ray powder diffraction pattern for crystalline DL-tartrate salt Form C of Compound 1.
  • FIG. 8 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline DL-tartrate salt Form C of Compound 1.
  • FIG. 9 depicts the dynamic vapor sorption (DVS) isotherm for crystalline DL- tartrate salt Form C of Compound 1.
  • FIG. 10 depicts an X-ray powder diffraction pattern for crystalline hydrochloride salt Form D of Compound 1.
  • FIG. 11 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hydrochloride salt Form D of Compound 1.
  • FIG. 12 depicts an X-ray powder diffraction pattern for crystalline free base monohydrate Form E of Compound 1.
  • FIG. 13 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline free base monohydrate Form E of Compound 1.
  • FIG. 14 depicts the dynamic vapor sorption (DVS) isotherm for crystalline free base monohydrate Form E of Compound 1.
  • FIG. 15 depicts a graph showing the pH solubility plot of Forms B and C of Compound 1 in pH of 2, 4.5, and 6.8.
  • FIG. 16 depicts an overlay of X-ray powder diffraction patterns of solid residue of Form B of Compound 1 taken at each timestamp in Table 1.
  • FIG. 17 depicts an overlay of X-ray powder diffraction patterns of solid residue of Form C of Compound 1 taken at each timestamp in Table 3.
  • FIG. 18 depicts a graph showing the solubility in bio relevant media plot of Form B and C of Compound 1.
  • FIG. 19 depicts an overlay of X-ray powder diffraction patterns of solid residue of Form B of Compound 1 taken at each timestamp in Table 4.
  • FIG. 20 depicts an overlay of X-ray powder diffraction patterns of solid residue of Form C of Compound 1 taken at each timestamp in Table 5.
  • FIG. 21A depicts mean plasma concentration-time profiles of Compound 1 after a PO (per os) dose of free base monohydrate Form E.
  • FIG. 21B depicts mean plasma concentration-time profiles of Compound 1 after a PO dose of free base monohydrate Form E (unmilled).
  • FIG. 22B depicts mean plasma concentration-time profiles of Compound 1 after a PO dose of Form C.
  • FIG. 23A depicts mean plasma concentration-time profiles of Compound 1 after a PO dose of Form A.
  • FIG. 23B depicts mean plasma concentration-time profiles of Compound 1 after a PO dose of a formulation (SDD with PVPVA and 35% loading of Compound 1) of Compound 1.
  • FIG. 24A depicts mean plasma concentration-time profiles of Compound 1 after a PO dose of a formulation (SDD with HPMC-AS and 35% loading of Compound 1) of Compound 1.
  • FIG. 24B depicts a graph showing the aqueous solubility of Forms A, B, C, and
  • FIG. 25A depicts the solubility of Forms A, B, C, and E.
  • FIG. 25B depicts the stability of two formulations comprising amorphous
  • FIG. 26 depicts an X-ray powder diffraction pattern for a formulation comprising amorphous Compound 1.
  • FIG. 27 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hydrochloride salt Form D-l of Compound 1.
  • FIG. 28 depicts the thermogravimetric analysis (TGA) thermogram for crystalline hydrochloride salt Form D-l of Compound 1.
  • FIG. 29 depicts the differential scanning calorimetry (DSC) thermogram for crystalline hydrochloride salt Form D-l of Compound 1.
  • FIG. 30 depicts the dynamic vapor sorption (DVS) isotherm for crystalline hydrochloride salt Form D-l of Compound 1.
  • FIG. 31 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hydrochloride salt Form D-2 of Compound 1.
  • FIG. 32 depicts the thermogravimetric analysis (TGA) thermogram for crystalline hydrochloride salt Form D-2 of Compound 1.
  • FIG. 33 depicts the differential scanning calorimetry (DSC) thermogram for crystalline hydrochloride salt Form D-2 of Compound 1.
  • FIG. 34 depicts the dynamic vapor sorption (DVS) isotherm for crystalline hydrochloride salt Form D-2 of Compound 1.
  • FIG. 35 depicts an X-ray powder diffraction pattern (XRPD) for crystalline L- tartrate salt Form I of Compound 1.
  • FIG. 36 depicts the thermogravimetric analysis (TGA) thermogram for crystalline L- tartrate salt Form I of Compound 1.
  • FIG. 37 depicts the differential scanning calorimetry (DSC) thermogram for crystalline L-tartrate salt Form I of Compound 1.
  • FIG. 38 depicts the dynamic vapor sorption (DVS) isotherm for crystalline L- tartrate salt Form I of Compound 1.
  • FIG. 39 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hemihydrate hemi-sulfate salt Form H of Compound 1.
  • FIG. 40 depicts the differential scanning calorimetry (DSC) thermogram for crystalline hemi-hydrate hemi-sulfate salt Form H of Compound 1.
  • FIG. 41 depicts the thermogravimetric analysis (TGA) thermogram for crystalline hemi-hydrate hemi-sulfate salt Form L of Compound 1.
  • FIG. 42 depicts an X-ray powder diffraction pattern (XRPD) for crystalline DL- tartrate salt Form F of Compound 1.
  • FIG. 43 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline DL-tartrate salt Form F of Compound 1.
  • FIG. 44 depicts an X-ray powder diffraction pattern (XRPD) for crystalline DL- tartrate salt Form G of Compound 1.
  • FIG. 45 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline DL-tartrate salt Form G of Compound 1.
  • FIG. 46 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hydrochloride salt Form J of Compound 1.
  • FIG. 47 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hydrochloride salt Form J of Compound 1.
  • FIG. 48 depicts an X-ray powder diffraction pattern (XRPD) for crystalline hydrochloride salt Form K of Compound 1.
  • FIG. 49 depicts the combined thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram for crystalline hydrochloride salt Form K of Compound 1.
  • FIG. 50 depicts an X-ray powder diffraction pattern for crystalline DL-tartrate salt Form C-l of Compound 1.
  • FIG. 51 depicts the differential scanning calorimetry (DSC) thermogram for crystalline DL-tartrate salt Form C-l of Compound 1.
  • FIG. 52 depicts the thermogravimetric analysis (TGA) thermogram for crystalline DL-tartrate salt Form C-l of Compound 1.
  • FIG. 53 depicts the dynamic vapor sorption (DVS) isotherm for crystalline DL- tartrate salt Form C-l of Compound 1.
  • compositions comprising crystalline and/or amorphous forms of Compound 1 and methods for preparing and using such formulations comprising crystalline and/or amorphous forms of Compound 1.
  • a range of values is intended to serve as a shorthand method of referring individually to each separate value falling within the range as well as the highest and lowest values that define the range and that each value is incorporated into the specification as if it were individually recited herein, unless expressly stated to the contrary.
  • a range of values from X to Y includes both X and Y and all the values in between X and Y.
  • the terms “Form A”, “Form B”, “Form C”, “Form D”, and “Form E refer to the crystalline forms A, B, C, D, and E of Compound 1, respectively.
  • the terms “Form F”, “Form G”, “Form H”, “Form I”, “Form J”, and “Form K” refer to the crystalline forms F, G, H, I, J, and K.
  • the terms “Form A”, “crystalline Form A”, and “crystalline hemi-hydrate hemi-sulfate salt Form A of Compound 1” are used interchangeably.
  • “Form B”, “crystalline Form B”, and “crystalline phosphate salt Form B of Compound 1” are used interchangeably.
  • Form C “crystalline Form C”, and “crystalline DL-tartrate salt Form C of Compound 1” are used interchangeably.
  • Additional examples of crystalline DL-tartrate salt Form C include crystalline DL-tartrate Forms C-l and C-2.
  • Form C-l may be the same or substantially the same crystalline form as Form C. More specifically, Form C-l may have different water content levels, yet still have the same or substantially the same XRPD as well as other characterization data, including DSC data, as Form C.
  • Form D “crystalline Form D”, and “crystalline hydrochloride salt Form D of Compound 1” are used interchangeably.
  • crystalline hydrochloride salt Form D include crystalline hydrochloride Forms D-l and D-2.
  • Forms D-l and D-2 may be the same or substantially the same crystalline form as Form D. More specifically, Forms D-l and D-2 may have different water content levels, yet still have the same or substantially the same XRPD as well as other characterization data, including DSC data, as Form D.
  • “Form E”, “crystalline Form E”, and “crystalline free base monohydrate Form E of Compound 1” are used interchangeably.
  • “Form F”, “crystalline Form F”, and “crystalline DL-tartrate salt Form F of Compound 1” are used interchangeably.
  • “Pattern A”, “Pattern B”, “Pattern C”, “Pattern D”, and “Pattern E” refer to the X- ray powder diffraction pattern (XRPD) for crystalline Form A, Form B, Form C, Form D, and Form E respectively.
  • “Pattern C”, “Pattern D”, “Pattern F”, “Pattern G”, “Pattern H”, “Pattern I”, “Pattern J”, and “Pattern K” refer to the X-ray powder diffraction pattern (XRPD) for crystalline Form C-l, Form D-l, Form D-2, Form F, Form G, Form H, Form I, Form J, and Form K, respectively.
  • crystalline free base As used herein, the terms “crystalline free base,” “free-base crystalline form of Compound 1,” “crystalline free base form of Compound 1,” and “crystalline free base of Compound 1” are used interchangeably and mean the monohydrate free base (i.e., monohydrate non-salt) Form E of Compound 1, which is present in a crystalline form as Form E, unless expressly stated to the contrary.
  • the crystalline forms described herein are present as a single crystal or a plurality of crystals in which each crystal in the plurality is the same crystal form, i.e., a single crystalline form in which no other detectable amounts of other crystalline forms are present.
  • a crystal form is defined as a specified percentage of one particular single crystalline form of the compound, the remainder is made up of amorphous form and/or crystalline forms other than the one or more particular forms that are specified. In some embodiments this is referred to as “phase purity”.
  • phase purity refers to a determination of the number of crystalline phases of the same material in a sample or composition and can be expressed as a percent by weight of the material or sample.
  • the recited crystalline forms may comprise at least 60% of a single crystalline form, at least 70% of a single crystalline form, at least 80% of a single crystalline form, at least 90% of a single crystalline form, at least 95% of a single crystalline form, or at least 99% of a single crystalline form by weight. Accordingly, for example, if a material is described as comprising at least 60% of a single crystalline form, that material may be described as being at least 60% phase pure or as having a phase purity of at least 60%. Percent by weight of a particular crystal form is determined by the weight of the particular crystalline form divided by the sum weight of the particular crystal, plus the weight of the other crystal forms present plus the weight of amorphous form present multiplied by 100%.
  • anhydrous means that the referenced crystalline form has substantially no water in the crystal lattice e.g., less than about 0.1% by weight as determined by Karl Fisher analysis.
  • the crystalline forms as described herein may have a certain level of hydration or a particular water content but may or may not be a true hydrate of the particular crystalline salt.
  • amorphous means a solid material that is present in a non-crystalline state or form.
  • Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long-range ordering.
  • Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
  • solid state or “solid state form” refers to a compound, composition, formulation, or solid state dispersion that is an amorphous solid or an crystalline solid.
  • the solid state form is an amorphous (i.e., non-crystalline) form.
  • the solid state form is a crystalline form (e.g., a polymorph, salt, free base, solvate, or hydrate).
  • chemical purity refers to the extent by which the disclosed crystalline or amorphous form(s) is free from other materials having a structural formula that is different from the structural formula of the crystalline salts, crystalline free base forms or amorphous forms of Compound 1 disclosed herein and are referred to as impurities.
  • the chemical purity of the disclosed crystalline (or amorphous) form(s) is represented as the weight of the crystalline (or amorphous) form divided by the sum of the weight of the crystalline (or amorphous) form plus the weight of the impurities, multiplied by 100%, i.e., percent by weight.
  • a disclosed crystalline or amorphous form(s) has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight, as measured by HPLC.
  • crystalline refers to a solid form of a compound wherein there exists long-range atomic order in the positions of the atoms.
  • the crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern. If the XRPD of a particular solid compound shows peaks (as opposed to broad, substantially featureless humps that would be expected for an amorphous or non-crystalline material) in the XRPD spectra (or pattern), then the compound is crystalline.
  • solvate refers to a crystalline compound having a stoichiometric or non- stoichiometric amount of solvent, or mixture of solvents, incorporated into its crystal structure or crystal lattice.
  • unsolvated refers to a crystalline compound that has substantially no solvent molecules incorporated into its crystal structure or crystal lattice.
  • hydrate refers to a crystalline compound having a stoichiometric or non- stoichiometric amount of water incorporated into or associated with its crystal structure or crystal lattice.
  • a hydrate is a solvate wherein the solvent incorporated into or associated with the crystal structure or crystal lattice is water.
  • hemi-hydrate hemi-sulfate means the stoichiometric ratio of Compound 1 to H2SO4 and H2O is 2:1:1 in a crystalline form (i.e. a crystalline form contains two molecules of Compound 1 per one molecule of H2SO4 and H2O).
  • the hemi- hydrate hemi-sulfate is also depicted herein as 1 : .5 : .5 or as
  • the terms “substantially the same XRPD pattern” or “an X-ray powder diffraction pattern substantially similar to” when used with reference to a specific figure included in this disclosure mean that for comparison purposes, at least 90% of the peaks shown in the XRPD of the specified figure (i.e., Figures 1, 4, 7, 10, 12, 26, 27, 31, 35, 39, 42, 44, 46, and/or 48) are present.
  • an XRPD pattern or diffractogram may be obtained which has one or more measurement errors depending on the recording conditions, such as the equipment or machine used.
  • intensities in an XRPD pattern may fluctuate depending on measurement conditions or sample preparation as a result of preferred orientation or crystal quality or size.
  • the relative intensity of peaks can also be affected by, for example, particles above 30 pm in size and non-unitary aspect ratios.
  • the skilled person understands that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer, and also the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect on the XRPD pattern or diffractogram.
  • solid forms embodied herein are not limited to those that provide XRPD patterns that are identical to the XRPD pattern shown in the Figures, and any solid forms providing XRPD patterns substantially the same as those shown in the Figures fall within the scope of the corresponding embodiment and claims.
  • a person skilled in the art of XRPD is able to judge the substantial identity of XRPD patterns.
  • a measurement error of a diffraction angle in an XRPD is approximately 29 ( ⁇ 0.2°), and such degree of a measurement error for each “peak” in the diffractogram pattern should be taken into account when considering the X-ray powder diffraction.
  • 2-theta values provided herein were obtained using Cu Kai radiation.
  • a person skilled in the art also understands that the value or range of values observed in a particular compound's DSC thermogram will show variation between batches of different purities. Therefore, whilst for one compound the range may be small, for others the range may be quite large.
  • a measurement error in DSC thermal events is approximately plus or minus 5° C., and such degree of a measurement error should be taken into account when considering the DSC data included herein.
  • TGA thermograms show similar variations, such that a person skilled in the art recognizes that such measurement errors should be taken into account when judging the substantial identity between TGA thermograms.
  • Certain values provided herein may be rounded to avoid reporting insignificant figures.
  • the X-ray diffraction two theta values may be rounded to the tenths.
  • One of skill in the art would readily understand the use of rounding in significant figures. With respect to the number “5” or greater in the hundredth position, the number in the tenth position is rounded up. However, if a value has the number “4” or less in the hundredth position, the number in the tenth position is not changed.
  • the terms “effective amount” or “therapeutically effective amount” are used interchangeably and refer to an amount of a crystalline or amorphous form of Compound 1 described herein that is sufficient to provide a therapeutic benefit in the treatment of a condition or to delay the onset of or to minimize or reduce one or more symptoms associated with the condition.
  • a therapeutically effective amount of a described crystalline or amorphous form of Compound 1 means an amount of the crystalline or amorphous form, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • an effective amount of a crystalline or amorphous form of Compound 1 is between about 0.01 mg to about 100 mg that is administered once or twice daily. In some embodiments an effective amount of a crystalline salt of Compound 1 is an amount that is equivalent to about 0.01 mg to about 100 mg of the non-hydrated non-salt (free base) of Compound 1 that is administered once or twice daily. In some embodiments an effective amount of a crystalline salt form of Compound 1 that is a hydrate or solvate is an amount that is equivalent to about 0.01 mg to about 100 mg of the non-hydrated non-salt (free base) of Compound 1 that is administered once or twice daily.
  • an effective amount of any of the crystalline or amorphous forms of Compound 1 described herein is an amount that is equivalent to about 2 mg, about 5 mg, about 7 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of the non-hydrated non-salt (free base) of Compound 1 that is administered once daily.
  • a therapeutically effective amount is an amount sufficient for regulating 2,3-diphosphoglycerate and/or ATP levels in the blood of a patient in need thereof. In other embodiments, a therapeutically effective amount is an amount sufficient for treating hemolytic anemia.
  • a therapeutically effective amount is an amount sufficient for treating sickle cell disease or acquired hemolytic anemia including anemia due to MDS (including very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS). In other embodiments, a therapeutically effective amount is an amount sufficient for treating acquired PKD. In other embodiments, a therapeutically effective amount is an amount sufficient for treating PKD that is acquired as a result of having another disease such as MDS (e.g. acquired PKD), including very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS.
  • MDS e.g. acquired PKD
  • the MDS described herein is low risk MDS as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS.
  • IVS-R Revised International Prognostic Scoring System
  • Low risk MDS includes, for example, an IPSS-R score of greater than 1.5 to 3.
  • the MDS described herein is very low risk MDS as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS.
  • Very low risk MDS includes, for example, an IPSS-R score of less than or equal to 1.5.
  • the MDS described herein is intermediate risk MDS as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS.
  • Intermediate risk MDS includes, for example, an IPSS-R score of greater than 3 to 4.5.
  • the term “lower risk MDS” used herein to describe MDS encompasses very low risk MDS and low risk MDS as described above.
  • a therapeutically effective amount of a crystalline or amorphous form of Compound 1 is the amount required to generate a hemoglobin (Hb) response in a patient in need thereof is an increase of about >1.0 g/dL, >1.5 g/dL or >2.0 g/dL in Hb concentration from a baseline Hb concentration.
  • a patient in need thereof is a patient that has been diagnosed with hemolytic anemia.
  • a patient in need thereof has been diagnosed with sickle cell disease or acquired hemolytic anemia including anemia due to MDS.
  • a patient in need thereof is a patient that has been diagnosed with PKD that has been acquired as a result of the patient having MDS, including very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS.
  • a therapeutically effective amount of a crystalline or amorphous form of Compound 1 is the amount required to reduce a patient’s transfusion burden over a period of time.
  • the term “reduction in transfusion burden” means at least a 20% reduction in the number of RBC (red blood cell) units transfused within at least 5 weeks of treatment.
  • a reduction in transfusion burden is about a >33% reduction in the number of RBC units transfused within at least 5 weeks of treatment. In certain embodiments, a reduction of transfusion burden is about a >33% reduction in the number of RBC units transfused within at least 10 weeks, at least 20 weeks or at least 24 weeks of treatment.
  • hemolytic anemia refers to a sub-type of anemia where a subject’s low red blood cell count is caused by the destruction — rather than the underproduction — of red blood cells.
  • anemia refers to a low red blood cell count that is caused by underproduction of red blood cells, including ineffective erythropoiesis.
  • MDS-associated anemia As used herein, the terms “MDS-associated anemia”, “anemia associated with MDS”, “anemia due to MDS”, “acquired hemolytic anemia associated with MDS” and “acquired anemia associated with MDS” are used interchangeably and refer to anemia that has developed or has been acquired in a subject as a result of having or suffering from MDS (very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS).
  • anemia associated with acquired PK deficiency PPD
  • PPD-associated anemia or “acquired PK deficiency” and “acquired PKD” are used interchangeably and refer to anemia related to pyruvate kinase deficiency (PKD) which has developed in a subject that has or is suffering from MDS (very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS).
  • MDS very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS
  • the anemia associated with acquired PK deficiency in a subject suffering from MDS is hemolytic anemia.
  • treatment refers to reversing, alleviating, delaying the onset of, reducing the likelihood of developing, or inhibiting the progress of a disease or one or more symptoms of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed (i.e., therapeutic treatment).
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen).
  • treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • treatment includes delaying the onset of at least one symptom of the disorder for a period of time.
  • myelodysplastic syndromes refers to a heterogeneous group of rare hematological malignancies characterized by dysfunctional hematopoiesis, progressive cytopenia, and an increased risk of progression to acute myeloid leukemia (AML). MDS occurs when the blood-forming cells in the bone marrow become abnormal (dysplastic) and have problems making new blood cells.
  • MDS red blood cells
  • transfusions of packed red blood cells is the standard of care for MDS-associated anemia.
  • PRBC packed red blood cells
  • Sickle cell disease is an inherited blood disorder that is characterized by a single-nucleotide mutation in the P-globin chain, encoding the production of an abnormal type of hemoglobin (Hb): hemoglobin S (HbS). HbS polymerizes upon deoxygenation, causing red blood cells (RBC) to sickle. Sickled RBCs are poorly deformable, which leads to vasoocclusion and hemolytic anemia.
  • RBC metabolic intermediates in particular, levels of 2,3-diphosphyglycerate (2,3-DPG) and adenosine triphosphate (ATP).
  • 2,3-DPG is produced in the Rapoport- Luebering shunt, a unique RBC- specific glycolytic bypass, and serves as an important regulator of oxygen affinity of Hb.
  • the increased intracellular 2,3-DPG levels lower oxygen affinity, thereby promoting polymerization of HbS upon deoxygenation and, hence, sickling.
  • ATP is critical for maintaining RBC membrane integrity and deformability, and ⁇ 50% of the cell’s ATP is generated in the last step of glycolysis catalyzed by pyruvate kinase (PK). Decreased levels of ATP have been reported in SCD mice, and ATP depletion has been associated with an increased number of irreversibly sickled cells.
  • the term “activating” means an agent, such as the crystalline and amorphous forms of Compound 1 described herein, that (measurably) increases the activity of wild type pyruvate kinase R (wt PKR) or causes wild type pyruvate kinase R (wt PKR) activity to increase to a level that is greater than wt PKR’s basal levels of activity and/or an agent, such as the crystalline and amorphous forms of Compound 1 described herein, that (measurably) increases the activity of a mutant pyruvate kinase R (mPKR) or causes mutant pyruvate kinase R (mPKR) activity to increase to a level that is greater than that mutant PKR’ s basal levels of activity.
  • wt PKR wild type pyruvate kinase R
  • wt PKR wild type pyruvate kinase R
  • mPKR mutant
  • the increase in activity of wtPKR or mPKR is, for example, about 20%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100% greater than the baseline activity of wtPKR or mPKR, respectively.
  • red blood cells or “RBCs”, “packed red blood cells” and “PRBCs” are used interchangeably and refer to red blood cells made from whole blood by removing the plasma.
  • ex vivo refers to a method that takes place outside an organism.
  • a cell e.g., red blood cells
  • a tissue or blood containing at least red blood cells, plasma and hemoglobin
  • Compound 1 as provided herein or a pharmaceutical composition thereof, optionally under artificially controlled conditions (e.g., temperature).
  • the term “in vitro” refers to a method that takes place outside an organism and is contained within an artificial environment.
  • a cell e.g., red blood cells
  • a tissue or blood containing at least red blood cells, plasma and hemoglobin
  • a pharmaceutical composition thereof in a contained, artificial environment (e.g., a culture system), such as in a test tube, in a culture, in flask, in a microtiter plate, on a Petri dish, and the like.
  • a subject and “patient” are used interchangeably, and mean a mammal in need of treatment, e.g., humans, companion animals e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • a subject or patient is a human in need of treatment.
  • a subject is an adult human (e.g., > 18 years of age).
  • a subject is a human child (e.g., ⁇ 18 years of age).
  • a subject is a human female (adult or child). In yet other embodiments a subject is a human male (adult or child).
  • the term subject may refer to a single subject or may refer to a plurality of subjects (i.e., two or more subjects).
  • a subject is a human in need of treatment of a disease, for example a disease associated with pyruvate kinase.
  • a subject is a human in need of treatment of anemia due to MDS (e.g., very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS).
  • MDS e.g., very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS.
  • a subject is a human in need of treatment of sickle cell disease.
  • a subject is a human in need of treatment of hemolytic anemia.
  • a subject is a human in need of treatment of acquired PKD.
  • a subject is a human in need of treatment of anemia associated with acquired PKD.
  • a subject is a human in need of treatment of hemolytic anemia associated with acquired PKD. In other certain embodiments, a subject is a human suffering from MDS and is in need of treatment of anemia associated with acquired PKD. In still other certain embodiments, a subject is a human suffering from MDS and is in need of treatment of hemolytic anemia associated with acquired PKD.
  • a subject is a patient in need of regular blood transfusions (and is referred to as being “transfusion dependent” or “TD”).
  • regular blood transfusion refers to at least 4 transfusion episodes in a 52- week period prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • a regular blood transfusion refers to at least 5 transfusion episodes in a 52- week period prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein. In certain embodiments, a regular blood transfusion refers to at least 6 transfusion episodes in a 52- week period prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • a regular blood transfusion refers to at least 7 transfusion episodes in a 52-week period prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • the subject has sickle cell disease, or anemia due to MDS (very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS).
  • a subject is referred to as being non-transfusion dependent (NTD) prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • NTD non-transfusion dependent
  • the terms “non-transfusion dependent” or “NTD” and “nontransfused” are used interchangeably and refer to subjects who do not require regular blood transfusions prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • a subject that is NTD refers to a subject that has had ⁇ 3 red blood cell (RBC) units in the 16 week period before treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein and no transfusions in the 8 week period prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • RBC red blood cell
  • the subject is classified as being NTD prior to the administration of a first dose of a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • transfusion independent or “transfusion independence” or “transfusion free” are used interchangeably and refer to a subject that has not had an RBC transfusion for a certain period of time. In some embodiments, a subject who is transfusion independent has not had an RBC transfusion for a period of 16 consecutive weeks. In other embodiments, a subject who is transfusion independent has not had an RBC transfusion for a period of > 8 consecutive weeks. In some embodiments, a subject becomes transfusion independent during treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein. In other embodiments, a subject is transfusion independent prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • HTB high transfusion burden
  • HTB refers to a subject that has had at least 8 RBC units over a 16 week period and has had greater than or equal to (>) 4 transfusion episodes over the course of 8 weeks prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • HTB refers to a subject that has had at least 8 RBC units over a 16 week period and has had greater than or equal to (>) 4 transfusion episodes over the course of 8 weeks in the 16 weeks prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • hemoglobin response and “Hb response” are used interchangeably and refer to an increase from a baseline Hb level (i.e., Hb concentration) of a subject, where the subject’s hemoglobin response is measured over a period of time during treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein or following the administration of a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • Hb concentration i.e., Hb concentration
  • the terms “during treatment” or “following administration” when used in connection with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein refer to ongoing treatment or administration (i.e., the subject will continue to be treated with or administered the disclosed crystalline or amorphous form of Compound 1 or composition comprising a crystalline or amorphous form of Compound 1).
  • the terms “hemoglobin (Hb) level” and “hemoglobin concentration” are used interchangeably herein.
  • the term “baseline” refers to a level or concentration that is measured or established prior to treatment or during treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • baseline hemoglobin level refers to a subject’s hemoglobin (Hb) level that is measured or established prior to treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • a subject’s baseline hemoglobin level may be measured or established during treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • hemoglobin response refers to an increase from a baseline Hb level of the subject, where the subject’s hemoglobin response is measured over a period of time during treatment.
  • hemoglobin response refers to an increase from a baseline Hb level of the subject, where the subject’s hemoglobin response is measured over a period of time following administration, e.g., for about 1 week of treatment, about 2 weeks of treatment, about 3 weeks of treatment, about 4 weeks of treatment, about 3 months of treatment, about 6 months of treatment or about 1 year of treatment or longer.
  • the hemoglobin level of the subject being treated increases from baseline over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 30 weeks, at least 40 weeks, or at least 50 weeks during treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • the hemoglobin level of the subject being treated increases from baseline over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, or at least 20 weeks during treatment with a crystalline or amorphous form of Compound 1 as disclosed herein or a composition comprising a crystalline or amorphous form of Compound 1 as disclosed herein.
  • pharmaceutically acceptable refers to a material that is, within the scope of sound medical judgment, suitable for use in humans without undue toxicity, irritation, allergic response, and the like, and such use is commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable excipient” or “excipient” refers to an inert substance, such as a carrier, adjuvant, additive, diluent or vehicle that does not adversely affect the pharmacological activity of the compound (including the crystalline or amorphous forms of Compound 1 as disclosed herein) with which it is formulated.
  • the terms “about” and “approximately” when used in combination with a numeric value or range of values used to characterize, for example, a particular crystal form, amorphous form, or mixture thereof, or weight or a particular analytical measurement such as an endothermic event of a compound, should be understood to mean that the numeric value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while describing a particular crystal form, amorphous form, or mixture thereof or weight or endothermic event of a compound.
  • a crystalline hemi- sulfate salt of Compound 1 having the structural formula:
  • the hemi-sulfate salt described above is a solvate.
  • the hemi-sulfate salt described above is a hydrate.
  • the hemi-sulfate salt described in the first embodiment is a hemi-hydrate.
  • the hemi-sulfate salt described in the first embodiment has the structural formula:
  • the crystalline hemi-hydrate hemi-sulfate salt of Compound 1 described herein is crystalline Form A.
  • crystalline Form A is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 9.8°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 18.4°( ⁇ 0.2°), 22.8 °( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • crystalline Form A is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 9.8°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 18.4°( ⁇ 0.2°), 22.8 °( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • crystalline Form A is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 9.8°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 18.4°( ⁇ 0.2°), 22.8 °( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • crystalline Form A is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 9.8°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 18.4°( ⁇ 0.2°), 22.8 °( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 20 angles selected from 9.8°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 18.4°( ⁇ 0.2°), 22.8 °( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • crystalline Form A is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 9.8° ( ⁇ 0.2°) and one or more peaks selected from 11.3°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 18.4°( ⁇ 0.2°), 22.8 °( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • the crystalline Form A is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angles selected from 9.8°( ⁇ 0.2°) and 13.6°( ⁇ 0.2°) and one or more peaks selected from 11.3°( ⁇ 0.2°), 18.4°( ⁇ 0.2°), 22.8 °( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • crystalline Form A is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angles selected from 9.8°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), and 11.3°( ⁇ 0.2°), and one or more peaks selected from 18.4°( ⁇ 0.2°), 22.8 °( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • crystalline Form A is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angles selected from 9.8°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), and 22.8 °( ⁇ 0.2°), and one or more peaks selected from 18.4°( ⁇ 0.2°), 23.3 °( ⁇ 0.2°), and 28.6°( ⁇ 0.2°).
  • crystalline Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 10 ( ⁇ 0.2°).
  • crystalline Form A is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 10 ( ⁇ 0.2°).
  • the crystalline Form A is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 1.
  • crystalline Form A as described in the first, second and/or third embodiments is characterized by a differential scanning calorimetry (DSC) thermograph comprising endotherm peaks at 117 °C ⁇ 5 °C and 270 °C ⁇ 5 °C.
  • crystalline Form A as described in the first, second or third embodiments is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 2.
  • crystalline Form A as described in the first, second, or third embodiments is characterized by having a moisture content of about 1% to about 4% as measured by Karl- Fischer titration.
  • crystalline Form A as described in any one of the first through fourth embodiments is characterized by a thermo gravimetric analysis (TGA) thermogram comprising a weight loss of 2.1 ⁇ 0.5 % up to 120 °C ⁇ 2 °C and 3.5 ⁇ 0.5 % from 120 °C ⁇ 2 °C to 275 °C ⁇ 2 °C.
  • crystalline Form A as described in any one of the first through fourth embodiments is characterized by a thermogravimetric analysis/differential scanning calorimetry (TGA/DSC) thermogram that is substantially similar to the one depicted in FIG 2.
  • TGA/DSC thermogravimetric analysis/differential scanning calorimetry
  • crystalline Form A as described in any one of the first through fourth embodiments is characterized by a DVS that is substantially similar to the one depicted in FIG 3.
  • the crystalline hemi-hydrate hemi-sulfate salt of Compound 1 described herein is crystalline Form H.
  • crystalline Form H is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 6.9°( ⁇ 0.2°), 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), 19.2°( ⁇ 0.2°), 19.7°( ⁇ 0.2°), 24.5 °( ⁇ 0.2°), and 26.5°( ⁇ 0.2°).
  • crystalline Form H is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 6.9°( ⁇ 0.2°), 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), 19.2°( ⁇ 0.2°), 19.7°( ⁇ 0.2°), 24.5 °( ⁇ 0.2°), and 26.5°( ⁇ 0.2°).
  • crystalline Form H is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 6.9°( ⁇ 0.2°), 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), 19.2°( ⁇ 0.2°), 19.7°( ⁇ 0.2°), 24.5 °( ⁇ 0.2°), and 26.5°( ⁇ 0.2°).
  • crystalline Form H is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 6.9°( ⁇ 0.2°), 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), 19.2°( ⁇ 0.2°), 19.7°( ⁇ 0.2°), 24.5 °( ⁇ 0.2°), and 26.5°( ⁇ 0.2°).
  • crystalline Form H is characterized by x-ray powder diffraction peaks at 20 angles selected from 6.9°( ⁇ 0.2°), 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), 19.2°( ⁇ 0.2°), 19.7°( ⁇ 0.2°), 24.5 °( ⁇ 0.2°), and 26.5°( ⁇ 0.2°).
  • crystalline Form H is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 6.9°( ⁇ 0.2°) and one or more peaks selected from 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), 19.2°( ⁇ 0.2°), 19.7°( ⁇ 0.2°), 24.5 °( ⁇ 0.2°), and 26.5°( ⁇ 0.2°).
  • the crystalline Form H is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angles selected from 6.9°( ⁇ 0.2°) and 26.5°( ⁇ 0.2°) and one or more peaks selected from 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), 19.2°( ⁇ 0.2°), 19.7°( ⁇ 0.2°), and 24.5 °( ⁇ 0.2°).
  • crystalline Form H is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angles selected from 6.9°( ⁇ 0.2°), 24.5 °( ⁇ 0.2°), and 26.5°( ⁇ 0.2°), and one or more peaks selected from 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), 19.2°( ⁇ 0.2°), and 19.7°( ⁇ 0.2°).
  • crystalline Form H is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angles selected from 6.9°( ⁇ 0.2°), 19.7°( ⁇ 0.2°), 24.5 °( ⁇ 0.2°), and 26.5°( ⁇ 0.2°), and one or more peaks selected from 10.1°( ⁇ 0.2°), 16.6°( ⁇ 0.2°), and 19.2°( ⁇ 0.2°).
  • crystalline Form H is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 18 ( ⁇ 0.2°).
  • crystalline Form H is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 18 ( ⁇ 0.2°).
  • the crystalline Form H is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 39.
  • crystalline Form H as described in the first and sixth embodiments is characterized by a differential scanning calorimetry (DSC) thermograph comprising endotherm peaks at 126 °C ⁇ 5 °C and 206 °C ⁇ 5 °C.
  • crystalline Form H as described in the first or sixth embodiments is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 40.
  • crystalline Form H as described in a first, sixth, or seventh embodiment is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 4.2 ⁇ 0.5 % up to 100 °C ⁇ 2 °C and 7.7 ⁇ 0.5 % from 200 °C ⁇ 2 °C.
  • crystalline Form H as described in any one of the first, sixth, or seventh embodiments is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 41.
  • TGA thermogravimetric analysis
  • a ninth embodiment provided is a crystalline form of a phosphate salt of Compound 1.
  • the crystalline phosphate salt described herein is crystalline Form B.
  • crystalline Form B is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), 20.3 °( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), 20.3 °( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), 20.3 °( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), 20.3 °( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by at least six x-ray powder diffraction peaks at 20 angles selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), 20.3 °( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by x-ray powder diffraction peaks at 20 angles selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), 20.3 °( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 20.3° ( ⁇ 0.2°) and one or more peaks selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 20.3°( ⁇ 0.2°) and 16.8 °( ⁇ 0.2°), and one or more peaks selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 20.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), and 13.6°( ⁇ 0.2°), and one or more peaks selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 20.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), 13.6°( ⁇ 0.2°), and 10.2°( ⁇ 0.2°), and one or more peaks selected from 13.4°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), and 21.4°( ⁇ 0.2°).
  • crystalline Form B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 11 ( ⁇ 0.2°).
  • crystalline Form B is characterized by x- ray powder diffraction peaks at 20 angles selected from those in Table 11 ( ⁇ 0.2°).
  • crystalline Form B is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 4.
  • crystalline Form B as described in the ninth or tenth embodiment, is characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm peak at 247 °C ⁇ 5 °C.
  • crystalline Form B as described in the ninth or tenth embodiment, is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 5.
  • crystalline Form B as described in any one of the ninth, tenth, or eleventh embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 1.5 ⁇ 0.5 % up to 260 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form B as described in any one of the ninth, tenth, or eleventh embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 5.
  • crystalline Form B as described in the ninth or tenth embodiments is characterized by having a moisture content of about 3% to about 6% as measured by Karl-Fischer titration.
  • crystalline Form B, as described in any one of the ninth, tenth, or eleventh embodiments is characterized by a DVS that is substantially similar to the one depicted in FIG 6.
  • crystalline Form C is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 20.4°( ⁇ 0.2°), 20.6 °( ⁇ 0.2°), 22.6 °( ⁇ 0.2°), and 25.3°( ⁇ 0.2°).
  • crystalline Form C is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 20.4°( ⁇ 0.2°), 20.6 °( ⁇ 0.2°), 22.6 °( ⁇ 0.2°), and 25.3°( ⁇ 0.2°).
  • crystalline Form C is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 20.4°( ⁇ 0.2°), 20.6 °( ⁇ 0.2°), 22.6 °( ⁇ 0.2°), and 25.3°( ⁇ 0.2°).
  • crystalline Form C is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 20.4°( ⁇ 0.2°), 20.6 °( ⁇ 0.2°), 22.6 °( ⁇ 0.2°), and 25.3°( ⁇ 0.2°).
  • crystalline Form C is characterized by at least six x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 20.4°( ⁇ 0.2°), 20.6 °( ⁇ 0.2°), 22.6 °( ⁇ 0.2°), and 25.3°( ⁇ 0.2°).
  • crystalline Form C is characterized by x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 20.4°( ⁇ 0.2°), 20.6 °( ⁇ 0.2°), 22.6 °( ⁇ 0.2°), and 25.3°( ⁇ 0.2°).
  • crystalline Form C is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 20.6 °( ⁇ 0.2°) and one or more peaks selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 20.4°( ⁇ 0.2°), 22.6 °( ⁇ 0.2°), and 25.3°( ⁇ 0.2°).
  • crystalline Form C is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 20.6 °( ⁇ 0.2°) and 20.4°( ⁇ 0.2°), and one or more peaks selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 22.6 °( ⁇ 0.2°), and 25.3°( ⁇ 0.2°).
  • crystalline Form C is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 20.6 °( ⁇ 0.2°), 20.4°( ⁇ 0.2°), and 25.3°( ⁇ 0.2°), and one or more peaks selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), and 22.6 °( ⁇ 0.2°).
  • crystalline Form C is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 20.6 °( ⁇ 0.2°), 20.4°( ⁇ 0.2°), 25.3°( ⁇ 0.2°), and 15.0°( ⁇ 0.2°), and one or more peaks selected from 8.1°( ⁇ 0.2°), 13.3°( ⁇ 0.2°), and 22.6 °( ⁇ 0.2°).
  • crystalline Form C is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 12 ( ⁇ 0.2°).
  • crystalline Form C is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 12 ( ⁇ 0.2°).
  • crystalline Form C is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 7.
  • crystalline Form C-l is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 13.3°( ⁇ 0.2°),14.9°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), 22.5 °( ⁇ 0.2°), 25.26 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°).
  • crystalline Form C- 1 is characterized by at least three x- ray powder diffraction peaks at 20 angles selected from 13.3°( ⁇ 0.2°),14.9°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), 22.5 °( ⁇ 0.2°), 25.26 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°).
  • crystalline Form C- 1 is characterized by at least four x- ray powder diffraction peaks at 20 angles selected from 13.3°( ⁇ 0.2°),14.9°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), 22.5 °( ⁇ 0.2°), 25.26 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°).
  • crystalline Form C- 1 is characterized by at least five x- ray powder diffraction peaks at 20 angles selected from 13.3°( ⁇ 0.2°),14.9°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), 22.5 °( ⁇ 0.2°), 25.26 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°).
  • crystalline Form C- 1 is characterized by at least six x-ray powder diffraction peaks at 20 angles selected from 13.3°( ⁇ 0.2°),14.9°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), 22.5 °( ⁇ 0.2°), 25.26 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°).
  • crystalline Form C- 1 is characterized by x-ray powder diffraction peaks at 20 angles selected from 13.3°( ⁇ 0.2°),14.9°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), 22.5 °( ⁇ 0.2°), 25.26 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°).
  • crystalline Form C- 1 is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 25.26 °( ⁇ 0.2°) and one or more peaks selected from 13.3°( ⁇ 0.2°),14.9°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), 22.5 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°).
  • crystalline Form C-l is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 20.6°( ⁇ 0.2°), 25.26 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°), and one or more peaks selected from 13.3°( ⁇ 0.2°),14.9°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), and 22.5 °( ⁇ 0.2°).
  • crystalline Form C- 1 is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 14.9°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 25.26 °( ⁇ 0.2°), and 25.6°( ⁇ 0.2°), and one or more peaks selected from 13.3°( ⁇ 0.2°), 22.3°( ⁇ 0.2°), and 22.5 °( ⁇ 0.2°).
  • crystalline Form C-l as described in the thirteenth or fourteenth embodiment, is characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm peak at 218.76 °C ⁇ 5 °C.
  • crystalline Form C-l as described in the thirteenth or fourteenth embodiment, is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 51.
  • crystalline Form C as described in any one of the thirteenth, fourteenth, or fifteenth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 18.2 ⁇ 0.5 % up to 290 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form C as described in any one of the thirteenth, fourteenth, or fifteenth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 8.
  • crystalline Form C as described in any one of the thirteenth, fourteenth, or fifteenth embodiments, is characterized by a DVS that is substantially similar to the one depicted in FIG 9.
  • crystalline Form C as described in the thirteenth, fourteenth, or fifteenth embodiments, is characterized by having a moisture content of about .05 % to about 2% as measured by Karl-Fischer titration.
  • crystalline Form C-l as described in any one of the thirteenth, fourteenth, or fifteenth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 17.4 ⁇ 0.5 % up to 275 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form C-l as described in any one of the thirteenth, fourteenth, or fifteenth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 52.
  • crystalline Form C-l as described in any one of the thirteenth, fourteenth, or fifteenth embodiments, is characterized by a DVS that is substantially similar to the one depicted in FIG 53.
  • crystalline Form F is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 4.8°( ⁇ 0.2°), 9.6°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 18.2°( ⁇ 0.2°), 19.3°( ⁇ 0.2°), 20.2°( ⁇ 0.2°), and 22.8°( ⁇ 0.2°).
  • crystalline Form F is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 4.8°( ⁇ 0.2°), 9.6°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 18.2°( ⁇ 0.2°), 19.3°( ⁇ 0.2°), 20.2°( ⁇ 0.2°), and 22.8°( ⁇ 0.2°).
  • crystalline Form F is characterized by an x- ray powder diffraction pattern comprising a peak at 20 angle 22.8°( ⁇ 0.2°) and one or more peaks selected from 4.8°( ⁇ 0.2°), 9.6°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 18.2°( ⁇ 0.2°), 19.3°( ⁇ 0.2°), and 20.2°( ⁇ 0.2°).
  • crystalline Form F is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 19.3°( ⁇ 0.2°) and 22.8°( ⁇ 0.2°), and one or more peaks selected from 4.8°( ⁇ 0.2°), 9.6°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 18.2°( ⁇ 0.2°), and 20.2°( ⁇ 0.2°).
  • crystalline Form F is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 9.6°( ⁇ 0.2°), 19.3°( ⁇ 0.2°) 20.2°( ⁇ 0.2°), and 22.8°( ⁇ 0.2°), and one or more peaks selected from 4.8°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), and 18.2°( ⁇ 0.2°).
  • crystalline Form F is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 19 ( ⁇ 0.2°).
  • crystalline Form F is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 19 ( ⁇ 0.2°).
  • crystalline Form F is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 42.
  • crystalline Form F as described in the thirteenth or seventeenth embodiments, is characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm peak at 217 °C ⁇ 5 °C.
  • crystalline Form F as described in the thirteenth or seventeenth embodiment, is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 43.
  • crystalline Form G is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 5.7°( ⁇ 0.2°), 7.2°( ⁇ 0.2°), 7.7°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 18.3°( ⁇ 0.2°), and 20.1°( ⁇ 0.2°).
  • crystalline Form G is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 5.7°( ⁇ 0.2°), 7.2°( ⁇ 0.2°), 7.7°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 18.3°( ⁇ 0.2°), and 20.1°( ⁇ 0.2°).
  • crystalline Form G is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 5.7°( ⁇ 0.2°), 7.2°( ⁇ 0.2°), 7.7°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 18.3°( ⁇ 0.2°), and 20.1°( ⁇ 0.2°).
  • crystalline Form G is characterized by x-ray powder diffraction peaks at 20 angles selected from 5.7°( ⁇ 0.2°), 7.2°( ⁇ 0.2°), 7.7°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 18.3°( ⁇ 0.2°), and 20.1°( ⁇ 0.2°).
  • crystalline Form G is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 7.7°( ⁇ 0.2°) and one or more peaks selected from 5.7°( ⁇ 0.2°), 7.2°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 18.3°( ⁇ 0.2°), and 20.1°( ⁇ 0.2°).
  • crystalline Form G is characterized by an x- ray powder diffraction pattern comprising a peak at a 20 angle selected from 7.2°( ⁇ 0.2°), 7.7°( ⁇ 0.2°), 18.3°( ⁇ 0.2°), and one or more peaks selected from 5.7°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), and 20.1°( ⁇ 0.2°).
  • crystalline Form G is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 7.2°( ⁇ 0.2°), 7.7°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 18.3°( ⁇ 0.2°), and one or more peaks selected from 5.7°( ⁇ 0.2°), 11.3°( ⁇ 0.2°), and 20.1°( ⁇ 0.2°).
  • crystalline Form G is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 20 ( ⁇ 0.2°).
  • crystalline Form G is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 20 ( ⁇ 0.2°). In yet another alternative, as part of a twentieth embodiment, crystalline Form G is characterized by an x- ray powder diffraction pattern that is substantially the same as depicted in FIG. 44.
  • crystalline Form G is characterized by a differential scanning calorimetry (DSC) thermograph comprising endotherm peaks at 63 °C ⁇ 5 °C, 138 °C ⁇ 5 °C, and 202 °C ⁇ 5 °C.
  • crystalline Form G is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 45.
  • crystalline Form G as described in any one of the thirteenth, twentieth, or twenty-first embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 3.428 ⁇ 0.01 % up to 110 °C ⁇ 2 °C and a weight loss of 2.797 ⁇ 0.01 % up to 170 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form G as described in the thirteenth, twentieth, or twenty- first embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 45.
  • crystalline L-tartrate salt described herein as crystalline Form I.
  • crystalline Form I is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 8.0°( ⁇ 0.2°), 10.8°( ⁇ 0.2°), 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), 16.7°( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form I is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 8.0°( ⁇ 0.2°), 10.8°( ⁇ 0.2°), 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), 16.7°( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form I is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 8.0°( ⁇ 0.2°), 10.8°( ⁇ 0.2°), 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), 16.7°( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form I is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 8.0°( ⁇ 0.2°), 10.8°( ⁇ 0.2°), 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), 16.7°( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form I is characterized by at least six x-ray powder diffraction peaks at 20 angles selected from 8.0°( ⁇ 0.2°), 10.8°( ⁇ 0.2°), 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), 16.7°( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form I is characterized by x-ray powder diffraction peaks at 20 angles selected from 8.0°( ⁇ 0.2°), 10.8°( ⁇ 0.2°), 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), 16.7°( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form I is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 8.0 °( ⁇ 0.2°) and one or more peaks selected from 10.8°( ⁇ 0.2°), 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), 16.7°( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form I is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 8.0°( ⁇ 0.2°) and 25.2°( ⁇ 0.2°), and one or more peaks selected from 10.8°( ⁇ 0.2°), 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), and 16.7°( ⁇ 0.2°).
  • crystalline Form I is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 8.0 °( ⁇ 0.2°), 25.2 °( ⁇ 0.2°), and 10.8 °( ⁇ 0.2°), and one or more peaks selected from 13.8°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), and 16.7°( ⁇ 0.2°).
  • crystalline Form I is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 8.0°( ⁇ 0.2°), 25.2 °( ⁇ 0.2°), 10.8°( ⁇ 0.2°), and 13.8°( ⁇ 0.2°), and one or more peaks selected from 15.0°( ⁇ 0.2°), 16.0 °( ⁇ 0.2°), and 16.7°( ⁇ 0.2°).
  • crystalline Form I is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 17 ( ⁇ 0.2°). In yet another alternative, as part of a twenty-third embodiment, crystalline Form I is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 17 ( ⁇ 0.2°). In yet another alternative, as part of a twenty- third embodiment, crystalline Form I is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 35.
  • crystalline Form I as described in the thirteenth or twenty-third embodiments, is characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm peak at 65 °C ⁇ 5 °C and 180 °C ⁇ 5 °C.
  • DSC differential scanning calorimetry
  • crystalline Form I as described in the thirteenth or twenty-third embodiment, is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 37.
  • crystalline Form I as described in the thirteenth or twenty-third embodiment, is characterized by having a moisture content of about .05 % to about 5% as measured by Karl-Fischer titration.
  • crystalline Form I as described in any one of the thirteenth, twenty-third , or twenty-fourth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 4.0 ⁇ 0.5 % up to 141 °C ⁇ 2 °C and a weight loss of 19.5 ⁇ 0.5 % up to 297 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form I as described in the thirteenth, twenty-third , or twenty-fourth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 36.
  • crystalline Form I is characterized by a DVS that is substantially similar to the one depicted in FIG 38.
  • a crystalline hydrochloride salt of Compound 1 having the structural formula: [00147]
  • crystalline Form D is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 10.6°( ⁇ 0.2°), 14.4°( ⁇ 0.2°), 24.6( ⁇ 0.2°), 24.8°( ⁇ 0.2°), 25.2 °( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form D is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 10.6°( ⁇ 0.2°), 14.4°( ⁇ 0.2°), 24.6( ⁇ 0.2°), 24.8°( ⁇ 0.2°), 25.2 °( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form D is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 10.6°( ⁇ 0.2°), 14.4°( ⁇ 0.2°), 24.6( ⁇ 0.2°), 24.8°( ⁇ 0.2°), 25.2 °( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form D is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 10.6°( ⁇ 0.2°), 14.4°( ⁇ 0.2°), 24.6( ⁇ 0.2°), 24.8°( ⁇ 0.2°), 25.2 °( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form D is characterized by x-ray powder diffraction peaks at 20 angles selected from 10.6°( ⁇ 0.2°), 14.4°( ⁇ 0.2°), 24.6( ⁇ 0.2°), 24.8°( ⁇ 0.2°), 25.2 °( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form D is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 25.2 °( ⁇ 0.2°) and one or more peaks selected from 10.6°( ⁇ 0.2°), 14.4°( ⁇ 0.2°), 24.6( ⁇ 0.2°), 24.8°( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form D is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 25.2 °( ⁇ 0.2°) and 10.6°( ⁇ 0.2°), and one or more peaks selected from 14.4°( ⁇ 0.2°), 24.6( ⁇ 0.2°), 24.8°( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form D is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 25.2 °( ⁇ 0.2°), 10.6°( ⁇ 0.2°), and 14.4°( ⁇ 0.2°), and one or more peaks selected from 24.6( ⁇ 0.2°), 24.8°( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form D is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 13 ( ⁇ 0.2°).
  • crystalline Form D is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 13 ( ⁇ 0.2°).
  • crystalline Form D is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 10.
  • crystalline Form D as described in the twentysixth or twenty- seventh embodiment, is characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm peak at 190 °C ⁇ 5 °C.
  • DSC differential scanning calorimetry
  • crystalline Form D as described in the twenty-sixth or twenty- seventh embodiments, is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 11.
  • DSC differential scanning calorimetry
  • crystalline Form D as described in the twenty-sixth or twenty- seventh embodiment, is characterized by having a moisture content of about 1.0 % to about 9% as measured by Karl-Fischer titration.
  • crystalline Form D as described in any one of the twenty-sixth, twenty-seventh, or twenty-eighth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 8.5 ⁇ 0.5 % up to 180 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form D as described in any one of the twenty-sixth, twenty- seventh, or twenty-eighth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG. 11.
  • crystalline Form D-l is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 15.6 °( ⁇ 0.2°), 21.0 °( ⁇ 0.2°), 24.4 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form D- 1 is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 15.6 °( ⁇ 0.2°), 21.0 °( ⁇ 0.2°), 24.4 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form D-l is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 15.6 °( ⁇ 0.2°), 21.0 °( ⁇ 0.2°), 24.4 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form D-l is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 15.6 °( ⁇ 0.2°), 21.0 °( ⁇ 0.2°), 24.4 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form D-l is characterized by x-ray powder diffraction peaks at 20 angles selected from 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 15.6 °( ⁇ 0.2°), 21.0 °( ⁇ 0.2°), 24.4 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form D-l is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 25.2 °( ⁇ 0.2°) and one or more peaks selected from 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 15.6 °( ⁇ 0.2°), 21.0 °( ⁇ 0.2°), and 24.4 °( ⁇ 0.2°).
  • crystalline Form D- 1 is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angles selected from 25.2 °( ⁇ 0.2°) and 10.7°( ⁇ 0.2°), and one or more peaks selected from 9.5°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 15.6 °( ⁇ 0.2°), 21.0 °( ⁇ 0.2°), and 24.4 °( ⁇ 0.2°).
  • crystalline Form D-l is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angles selected from 25.2 °( ⁇ 0.2°), 10.7°( ⁇ 0.2°), and 14.5°( ⁇ 0.2°), and one or more peaks selected from 9.5°( ⁇ 0.2°), 15.0°( ⁇ 0.2°), 15.6 °( ⁇ 0.2°), 21.0 °( ⁇ 0.2°), and 24.4 °( ⁇ 0.2°).
  • crystalline Form D-l is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 15 ( ⁇ 0.2°).
  • crystalline Form D- 1 is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 15 ( ⁇ 0.2°).
  • crystalline Form D- 1 is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 27.
  • crystalline Form D-l as described in the twentysixth or thirtieth embodiment, is characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm peak at 194 °C ⁇ 5 °C, an exotherm peak at 208 °C ⁇ 5 °C, an exotherm peak at 235°C ⁇ 5 °C, and an endotherm peak at 276 °C ⁇ 5 °C.
  • DSC differential scanning calorimetry
  • crystalline Form D-l as described in the twenty-sixth or thirtieth embodiments, is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 29.
  • DSC differential scanning calorimetry
  • crystalline Form D-l as described in any one of the twenty-sixth , thirtieth , or thirty-first embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 5.3 ⁇ 0.5 % up to 206 °C ⁇ 2 °C and a weight loss of 7.4 ⁇ 0.5 % up to 290 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form (D-2) is characterized by at least two x- ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 24.2 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 24.2 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 24.2 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 24.2 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by at least six x-ray powder diffraction peaks at 20 angles selected from 8.1°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.7°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 24.2 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 10.7 °( ⁇ 0.2°) and one or more peaks selected from 8.1°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 14.5°( ⁇ 0.2°), 24.2 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 10.7°( ⁇ 0.2°) and 14.5°( ⁇ 0.2°), and one or more peaks selected from 8.1°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 24.2 °( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 10.7°( ⁇ 0.2°), 14.5 °( ⁇ 0.2°), and 24.2°( ⁇ 0.2°), and one or more peaks selected from 8.1°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), and 25.2°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 10.7°( ⁇ 0.2°), 14.5 °( ⁇ 0.2°), 24.2°( ⁇ 0.2°), and 25,2°( ⁇ 0.2°), and one or more peaks selected from 8.1°( ⁇ 0.2°) and 9.5°( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 16 ( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 16 ( ⁇ 0.2°).
  • crystalline Form (D-2) is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 31.
  • crystalline Form (D-2) is characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm peak at 208 °C ⁇ 5 °C and 277 °C ⁇ 5 °C.
  • crystalline Form (D-2) is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 33.
  • crystalline Form (D-2) is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 7.5 ⁇ 0.5 % up to 205 °C ⁇ 2 °C and a weight loss of 7.1 ⁇ 0.5 % up to 290 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form (D-2) is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 32.
  • crystalline Form (D-2) is characterized by a DVS that is substantially similar to the one depicted in FIG 34.
  • crystalline Form (D-2) is characterized by having a moisture content of about 5% to about 10% as measured by Karl- Fischer titration.
  • a hydrochloride salt described herein as crystalline Form J is provided.
  • crystalline Form J is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 15.0°( ⁇ 0.2°), 15.6°( ⁇ 0.2°), 20.4( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 21.1°( ⁇ 0.2°), 24.1°( ⁇ 0.2°), and 24.7°( ⁇ 0.2°).
  • crystalline Form J is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 15.0°( ⁇ 0.2°), 15.6°( ⁇ 0.2°), 20.4( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 21.1°( ⁇ 0.2°), 24.1°( ⁇ 0.2°), and 24.7°( ⁇ 0.2°).
  • crystalline Form J is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 15.0°( ⁇ 0.2°), 15.6°( ⁇ 0.2°), 20.4( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 21.1°( ⁇ 0.2°), 24.1°( ⁇ 0.2°), and 24.7°( ⁇ 0.2°).
  • crystalline Form J is characterized by x-ray powder diffraction peaks at 20 angles selected from 15.0°( ⁇ 0.2°), 15.6°( ⁇ 0.2°), 20.4( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 21.1°( ⁇ 0.2°), 24.1°( ⁇ 0.2°), and 24.7°( ⁇ 0.2°).
  • crystalline Form J is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 24.1°( ⁇ 0.2°), and one or more peaks selected from 15.0°( ⁇ 0.2°), 15.6°( ⁇ 0.2°), 20.4( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 21.1°( ⁇ 0.2°), and 24.7°( ⁇ 0.2°).
  • crystalline Form J is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 15.6°( ⁇ 0.2°) and 24.1°( ⁇ 0.2°), and one or more peaks selected from 15.0°( ⁇ 0.2°), 20.4( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 21.1°( ⁇ 0.2°), and 24.7°( ⁇ 0.2°).
  • crystalline Form J is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 15.6°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), and 24.1°( ⁇ 0.2°), and one or more peaks selected from 15.0°( ⁇ 0.2°), 20.4( ⁇ 0.2°), 21.1°( ⁇ 0.2°), and 24.7°( ⁇ 0.2°).
  • crystalline Form J is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 21 ( ⁇ 0.2°).
  • crystalline Form J is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 21 ( ⁇ 0.2°).
  • crystalline Form J is characterized by an x- ray powder diffraction pattern that is substantially the same as depicted in FIG. 46.
  • crystalline Form J as described in any one of the twenty-sixth, thirty-sixth, or thirty-seventh embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 0.92 ⁇ 0.05 % up to 250 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form J as described in the twenty- sixth, thirty- sixth, or thirty- seventh embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 47.
  • a hydrochloride salt described herein as crystalline Form K is provided.
  • crystalline Form K is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 7.2°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.6( ⁇ 0.2°), 14.0°( ⁇ 0.2°), 17.4°( ⁇ 0.2°), 26.0°( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form K is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 7.2°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.6( ⁇ 0.2°), 14.0°( ⁇ 0.2°), 17.4°( ⁇ 0.2°), 26.0°( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form K is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 7.2°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.6( ⁇ 0.2°), 14.0°( ⁇ 0.2°), 17.4°( ⁇ 0.2°), 26.0°( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form K is characterized by x-ray powder diffraction peaks at 20 angles selected from 7.2°( ⁇ 0.2°), 9.5°( ⁇ 0.2°), 10.6( ⁇ 0.2°), 14.0°( ⁇ 0.2°), 17.4°( ⁇ 0.2°), 26.0°( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form K is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 7.2°( ⁇ 0.2°), and 26.0°( ⁇ 0.2°), and one or more peaks selected from 9.5°( ⁇ 0.2°), 10.6( ⁇ 0.2°), 14.0°( ⁇ 0.2°), 17.4°( ⁇ 0.2°), and 27.0°( ⁇ 0.2°).
  • crystalline Form K is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 22 ( ⁇ 0.2°).
  • crystalline Form K is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 22 ( ⁇ 0.2°).
  • crystalline Form K is characterized by an x-ray powder diffraction pattern that is substantially the same as depicted in FIG. 48.
  • crystalline Form K is described in the twenty-sixth and thirty-ninth embodiment, is characterized by a differential scanning calorimetry (DSC) thermograph comprising exotherm peaks at 55 °C ⁇ 5 °C, 234 °C ⁇ 5 °C, and 284 °C ⁇ 5 °C.
  • crystalline Form K as described in the twenty- sixth and thirty-ninth embodiment, is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 49.
  • crystalline Form K as described in any one of the twenty-sixth, thirty-ninth, and fortieth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 10.06 ⁇ 0.05 % up to 180 °C ⁇ 2 °C.
  • crystalline Form K as described in the twenty-sixth, thirty-ninth, and fortieth embodiments, is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 49.
  • crystalline Form E is described herein as crystalline Form E.
  • crystalline Form E is characterized by at least two x-ray powder diffraction peaks at 20 angles selected from 11.6°( ⁇ 0.2°), 16.0°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 23.8 °( ⁇ 0.2°), 26.0 °( ⁇ 0.2°), and 27.4°( ⁇ 0.2°).
  • crystalline Form E is characterized by at least three x-ray powder diffraction peaks at 20 angles selected from 11.6°( ⁇ 0.2°), 16.0°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 23.8 °( ⁇ 0.2°), 26.0 °( ⁇ 0.2°), and 27.4°( ⁇ 0.2°).
  • crystalline Form E is characterized by at least four x-ray powder diffraction peaks at 20 angles selected from 11.6°( ⁇ 0.2°), 16.0°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°),
  • crystalline Form E is characterized by at least five x-ray powder diffraction peaks at 20 angles selected from 11.6°( ⁇ 0.2°), 16.0°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°),
  • crystalline Form E is characterized by at least six x-ray powder diffraction peaks at 20 angles selected from 11.6°( ⁇ 0.2°), 16.0°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°),
  • crystalline Form E is characterized by x-ray powder diffraction peaks at 20 angles selected from 11.6°( ⁇ 0.2°), 16.0°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 23.8 °( ⁇ 0.2°), 26.0 °( ⁇ 0.2°), and 27.4°( ⁇ 0.2°).
  • crystalline Form E is characterized by an x-ray powder diffraction pattern comprising a peak at 20 angle 26.0 °( ⁇ 0.2°) and one or more peaks selected from 11.6°( ⁇ 0.2°), 16.0°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), 23.8 °( ⁇ 0.2°), and 27.4°( ⁇ 0.2°).
  • crystalline Form E is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 26.0°( ⁇ 0.2°) and 23.8 °( ⁇ 0.2°), and one or more peaks selected from 11.6°( ⁇ 0.2°), 16.0°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), and 27.4°( ⁇ 0.2°).
  • crystalline Form E is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 26.0°( ⁇ 0.2°), 23.8 °( ⁇ 0.2°), and 16.0°( ⁇ 0.2°), and one or more peaks selected from 11.6°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), 20.6°( ⁇ 0.2°), and 27.4°( ⁇ 0.2°).
  • crystalline Form E is characterized by an x-ray powder diffraction pattern comprising a peak at a 20 angle selected from 26.0°( ⁇ 0.2°), 23.8 °( ⁇ 0.2°), 16.0°( ⁇ 0.2°), and 20.6°( ⁇ 0.2°), and one or more peaks selected from 11.6°( ⁇ 0.2°), 16.8°( ⁇ 0.2°), and 27.4°( ⁇ 0.2°).
  • crystalline Form E is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight or at least nine x-ray powder diffraction peaks at 20 angles selected from those in Table 14 ( ⁇ 0.2°). In yet another alternative, as part of a forty-third embodiment, crystalline Form E is characterized by x-ray powder diffraction peaks at 20 angles selected from those in Table 14 ( ⁇ 0.2°). In yet another alternative, as part of a forty-third embodiment, crystalline Form E is characterized by an x- ray powder diffraction pattern that is substantially the same as depicted in FIG. 12.
  • crystalline Form E as described in the forty- second-fourth or forty-third embodiments, is characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm peak at 112 °C ⁇ 5 °C, 156 °C ⁇ 5 °C, and 219 °C ⁇ 5 °C, and an exotherm peak at 160 °C ⁇ 5 °C.
  • crystalline Form E as described in the forty-second or forty-third embodiments, is characterized by a differential scanning calorimetry (DSC) thermogram that is substantially similar to the one depicted in FIG. 13.
  • crystalline Form E is characterized by a thermogravimetric analysis (TGA) thermogram comprising a weight loss of 4.0 ⁇ 0.5 % up to 100 °C ⁇ 2 °C.
  • TGA thermogravimetric analysis
  • crystalline Form E is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially similar to the one depicted in FIG 13.
  • crystalline Form E is characterized by a DVS that is substantially similar to the one depicted in FIG 14.
  • the crystalline forms described herein (e.g., in any one of the first to forty-fifth embodiments) have a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight as determined by HPLC.
  • spray dried dispersions that are prepared using a crystalline form as described herein (e.g., such as any one of those in the first to forty-fourth embodiments), comprising dissolving a crystalline form as described herein (e.g., such as any one of those in the first to forty-fourth embodiments), and a dispersion polymer in a solvent to form a feed solution; and removing the solvent to form the spray dried dispersion.
  • spray dried dispersions that are prepared using at least one crystalline form described herein (e.g., such as any one of those in the first to forty-fifth embodiments) and that such resultant spray dried dispersions comprise Compound 1 that is substantially amorphous.
  • spray dried dispersions prepared using at least one crystalline form described herein e.g., such as any one of those in the first to forty-fifth embodiments
  • the resultant spray dried dispersions are formulated in a tablet and comprise Compound 1 that is substantially amorphous.
  • the spray dried dispersions are prepared using the crystalline hemi-hydrate hemi-sulfate salt Form A (e.g., those described in any one of the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments) and at least one polymer.
  • the spray dried dispersions are prepared using the crystalline hemihydrate hemi-sulfate salt Form A, the crystalline phosphate salt Form B, the crystalline DL- tartrate salt form C, the crystalline hydrochloride salt Form D, or the crystalline free base monohydrate Form E, and at least one polymer.
  • tablets comprising the spray dried dispersions comprise about 55% by weight, about 50% by weight, about 45% by weight, about 40% by weight, about 35%, by weight, about 30% by weight, about 25% by weight, or about 20% by weight of Compound 1.
  • the tablets comprising a spray dried dispersion are prepared using at least one of the crystalline forms described herein.
  • the tablets comprising a spray dried dispersion are prepared using crystalline hemi-hydrate hemi- sulfate salt Form A.
  • the tablets comprising the spray dried dispersion are prepared using crystalline phosphate salt Form B.
  • the tablets comprising the spray dried dispersion are prepared using the crystalline hemi-hydrate hemi-sulfate salt Form A, the crystalline phosphate salt Form B, the crystalline DL-tartrate salt form C, the crystalline hydrochloride salt Form D, or the crystalline free base monohydrate Form E.
  • the tablets comprising the spray dried dispersion are prepared using the crystalline hemi-hydrate hemi- sulfate salt Form H, the crystalline DL-tartrate salt Form C-l, the crystalline DL-tartrate salt Form F, the crystalline DL-tartrate salt Form G, the crystalline hydrochloride salt Form D (i.e., Forms D, D-l, and D-2), the crystalline hydrochloride salt Form J, the crystalline hydrochloride salt Form K, or the crystalline L-tartrate salt Form I.
  • the tablets comprise at least one crystalline form of Compound 1 as described herein.
  • the tablets comprise crystalline hemi-hydrate hemi-sulfate salt Form A.
  • the tablets comprise crystalline phosphate salt Form B.
  • the tablets comprise crystalline DL- tartrate salt Form C.
  • the tablets comprise crystalline hydrochloride salt Form D.
  • the tablets comprise crystalline monohydrate free base Form E.
  • the tablets comprise amorphous Compound 1.
  • the tablets comprise at least one crystalline form of Compound 1 as described herein.
  • the tablets comprise the crystalline hemi-hydrate hemi-sulfate salt Form H, the crystalline DL-tartrate salt Form C-l , the crystalline DL-tartrate salt Form F, the crystalline DL-tartrate salt Eorm G, the crystalline L-tartrate salt Eorm I, the crystalline hydrochloride salt Eorm D (i.e., Forms D, D- 1, and D-2), the crystalline hydrochloride salt Form J, the crystalline hydrochloride salt Form K, or crystalline L-tartrate salt Form I.
  • the tablets comprise amorphous Compound 1.
  • the tablets comprise amorphous Compound 1.
  • the tablets comprise an amorphous solid dispersion of Compound 1.
  • the tablets comprise an amorphous solid dispersion of a salt of Compound 1.
  • capsules comprising the spray dried dispersions comprise about 55% by weight, about 50% by weight, about 45% by weight, about 40% by weight, about 35%, by weight, about 30% by weight, about 25% by weight, or about 20% by weight of Compound 1.
  • the capsules comprising a spray dried dispersion are prepared using at least one of the crystalline forms described herein.
  • the capsules comprising a spray dried dispersion are prepared using crystalline hemi-hydrate hemi-sulfate salt Form A.
  • the capsules comprising the spray dried dispersion are prepared using crystalline phosphate salt Form B.
  • the capsules comprising the spray dried dispersion are prepared using the crystalline hemi- hydrate hemi-sulfate salt Form A, the crystalline phosphate salt Form B, the crystalline DL- tartrate salt form C, the crystalline hydrochloride salt Form D, or the crystalline free base monohydrate Form E.
  • the capsules comprising the spray dried dispersion are prepared using the crystalline hemi-hydrate hemi- sulfate salt Form H, the crystalline DL-tartrate salt Form C-l , the crystalline DL-tartrate salt Form F, the crystalline DL-tartrate salt Form G, the crystalline hydrochloride salt Form D (i.e., Forms D, D-l, and D-2), the crystalline hydrochloride salt Form J, the crystalline hydrochloride salt Form K, or the crystalline L-tartrate salt Form I.
  • the capsules comprise at least one crystalline form of Compound 1 as described herein.
  • the capsules comprise crystalline hemi-hydrate hemi-sulfate salt Form A.
  • the capsules comprise crystalline phosphate salt Form B.
  • the capsules comprise crystalline DL- tartrate salt Form C.
  • the capsules comprise crystalline hydrochloride salt Form D.
  • the capsules comprise crystalline monohydrate free base Form E.
  • the capsules comprise amorphous Compound 1.
  • the capsules comprise at least one crystalline form of Compound 1 as described herein.
  • the capsules comprise the crystalline hemi-hydrate hemi-sulfate salt Form H, the crystalline DL-tartrate salt form C- 1, the crystalline DL-tartrate salt Form F, the crystalline DL-tartrate salt Eorm G, the crystalline hydrochloride salt Eorm D (i.e., Forms D, D-l, and D-2), the crystalline hydrochloride salt Form J, the crystalline hydrochloride salt Form K, or crystalline L-tartrate salt Form I.
  • the capsules comprise amorphous Compound 1.
  • the capsules comprise amorphous Compound 1.
  • the capsules comprise an amorphous solid dispersion of Compound 1.
  • the capsules comprise an amorphous solid dispersion of a salt of Compound 1.
  • granules comprising the spray dried dispersions comprise about 55% by weight, about 50% by weight, about 45% by weight, about 40% by weight, about 35%, by weight, about 30% by weight, about 25% by weight, or about 20% by weight of Compound 1.
  • the granules comprising a spray dried dispersion are prepared using at least one of the crystalline forms described herein.
  • the granules comprising a spray dried dispersion are prepared using crystalline hemi-hydrate hemi-sulfate salt Form A.
  • the granules comprising the spray dried dispersion are prepared using crystalline phosphate salt Form B.
  • the granules comprising the spray dried dispersion are prepared using the crystalline hemi- hydrate hemi-sulfate salt Form A, the crystalline phosphate salt Form B, the crystalline DL- tartrate salt form C, the crystalline hydrochloride salt Form D, or the crystalline free base monohydrate Form E.
  • the granules comprising the spray dried dispersion are prepared using the crystalline hemi-hydrate hemi-sulfate salt Form H, the crystalline DL-tartrate salt Form C-l, the crystalline DL-tartrate salt Form F, the crystalline DL-tartrate salt Form G, the crystalline hydrochloride salt Form D (i.e., Forms D, D-l, and D-2), the crystalline hydrochloride salt Form J, the crystalline hydrochloride salt
  • the granules comprise at least one crystalline form of Compound 1 as described herein.
  • the granules comprise the crystalline hemi-hydrate hemi-sulfate salt Form H, the crystalline DL-tartrate salt Form C-l, the crystalline DL-tartrate salt Form F, the crystalline DL-tartrate salt Eorm G, the crystalline hydrochloride salt Eorm D (i.e., Forms D, D-l, and D-2), the crystalline hydrochloride salt Form J, the crystalline hydrochloride salt Form K, or crystalline L-tartrate salt Form I.
  • the granules comprise amorphous Compound 1.
  • the granules comprise amorphous Compound 1.
  • the granules comprise an amorphous solid dispersion of Compound 1.
  • the granules comprise an amorphous solid dispersion of a salt of Compound 1.
  • a solid oral dosage form comprising one or more crystalline forms of Compound 1 as described herein.
  • the solid oral dosage form comprises crystalline hemi-hydrate hemi-sulfate salt Form A.
  • the solid oral dosage form comprises crystalline phosphate salt Form B.
  • the solid oral dosage form comprises crystalline DL-tartrate salt Form C.
  • the solid oral dosage form comprises crystalline hydrochloride salt Form D.
  • the solid oral dosage form comprises crystalline monohydrate free base Form E.
  • the solid oral dosage form comprises amorphous Compound 1.
  • a solid oral dosage form comprising one or more crystalline forms of Compound 1 as described herein.
  • the solid oral dosage form comprises crystalline hemi-hydrate hemi-sulfate salt Form H.
  • the solid oral dosage form comprises crystalline DL-tartrate salt Form C (i.e., C and C-l .
  • the solid oral dosage form comprises crystalline DL-tartrate salt Form F.
  • the solid oral dosage form comprises crystalline DL-tartrate salt Form G.
  • the solid oral dosage form comprises crystalline L-tartrate salt Form I.
  • the solid oral dosage form comprises crystalline hydrochloride salt Form D (i.e., D, D-l, and D-2).
  • the solid oral dosage form comprises crystalline hydrochloride salt Form J.
  • the solid oral dosage form comprises crystalline hydrochloride salt Form K.
  • the solid oral dosage form comprises amorphous Compound 1.
  • the H2SO4 solution used in the method described above in the fifty-third embodiment is part of an alcoholic solution comprising a ratio of alcohol to water of about 2:2, about 4:2, about 6:2, about 8:2, or about 10:2 v/v.
  • the alcohol described in the fifty-third or fifty-fourth embodiment is selected from methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, or isobutanol, propylene glycol, ethylene glycol, /-amyl alcohol, diethylene glycol, n-pentanol, benzyl alcohol, or cyclohexanol or any combination thereof.
  • the alcohol described in the fifty-third or fifty-fourth embodiment is n- propanol.
  • the polar aprotic solvent used in the method described above in the fifty- sixth embodiment is selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, or tetrahydrofuran, or any combination thereof.
  • the polar aprotic solvent described in the fifty-sixth embodiment is dimethylsulfoxide.
  • the method described in the fifty-sixth embodiment further comprises a second step of adding an antisolvent.
  • the antisolvent used in the fifty- sixth embodiment is an alcoholic solution.
  • the alcoholic solution used in the fifty-sixth embodiment further comprises water.
  • the ratio of alcohol to water as described in the fiftyeighth embodiment is about 2:2, about 4:2, about 6:2, about 8:2, or about 10:2 v/v.
  • the ratio of alcohol to water as described in the fifty- eighth embodiment is about 8:2 v/v.
  • the alcohol as described in the fifty-eighth and fiftyninth embodiments is selected from methanol, ethanol, n-propanol, isopropyl alcohol, n- butanol, or isobutanol, propylene glycol, ethylene glycol, /-amyl alcohol, diethylene glycol, 77-pcntanol, benzyl alcohol, or cyclohexanol or any combination thereof.
  • the alcohol as described in the fifty-eighth and fifty-ninth embodiments is ethanol.
  • the polar aprotic solvent used in the method described above in the sixty-first embodiment is selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, or tetrahydrofuran, or any combination thereof.
  • the polar aprotic solvent described in the sixty-first embodiment is tetrahydrofuran.
  • the solvent as described in the sixty-second embodiment is a mixture further comprising water.
  • the ratio of solvent to water is about 99:1, about 95:5, about 90:10, about 80:20, or about 60:40 v/v.
  • the ratio of solvent to water as described in the is about 95:5 v/v.
  • the solution comprising L-tartaric acid used in the method described above in the sixty-fifth embodiment comprises an alcoholic solution comprising water, e.g. a solution comprising L-tartaric acid, alcohol, and water.
  • the L-tartaric acid solution used in the method described above in the sixty-fifth embodiment is part of an alcoholic solution comprising a ratio of alcohol to water of about 99:1, about 95:5, about 90:10, about 80:20, or about 60:40 v/v.
  • the L-tartaric acid solution used in the method described above in the sixty-fifth embodiment is part of an alcoholic solution comprising a ratio of alcohol to water of about 95:5 v/v.
  • the alcohol described in the sixty-sixth or sixtyseventh embodiment is selected from methanol, ethanol, n-propanol, isopropyl alcohol, n- butanol, or isobutanol, propylene glycol, ethylene glycol, /-amyl alcohol, diethylene glycol, 77-pcntanol, benzyl alcohol, or cyclohexanol or any combination thereof.
  • the alcohol described in the sixty-sixth or sixty-seventh embodiment is ethanol.
  • a method of forming a hydrochloride salt of Compound 1 in an alternative embodiment provided herein is a method of forming a hydrochloride salt of a compound having the structure: the method comprising reacting Compound 1 : with a solution comprising hydrochloric acid and at least one polar aprotic solvent.
  • the polar aprotic solvent used in the method described above in the sixty-ninth embodiment is selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, or tetrahydrofuran, or any combination thereof.
  • the polar aprotic solvent described in the sixty-ninth embodiment is tetrahydrofuran.
  • compositions comprising one or more of the disclosed crystalline forms (e.g. crystalline Form C-l, D-l, D-2, E, F, G, H, I, J, or K) of Compound 1 together with a pharmaceutically acceptable excipient.
  • the amount of crystalline form in a provided composition is an amount that is effective to measurably activate PKR in a subject.
  • composition is used interchangeably with the term “pharmaceutical composition” and are comprised of the crystalline forms (e.g. crystalline Form C-l, D-l, D-2, E, F, G, H, I, J, or K) of Compound 1, including salts, solvates, hydrates, anhydrous, and non-solvated forms, and zero, one, or more excipients as described herein.
  • crystalline forms e.g. crystalline Form C-l, D-l, D-2, E, F, G, H, I, J, or K
  • the pharmaceutical composition may be a pharmaceutical composition suitable for oral consumption or oral administration.
  • Pharmaceutical compositions containing a compound of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or as liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the crystalline form (e.g.
  • crystalline Form A, B, C, or D of the disclosure into association with an excipient, such as a carrier, which constitutes one or more necessary ingredients.
  • excipient such as a carrier
  • Such dosage forms can also be prepared by any of the methods of pharmacy, but all methods include the step of bringing the crystalline form (e.g. crystalline Form A, B, C, or D) of the disclosure into association with an excipient, such as a carrier, which constitutes one or more necessary ingredients.
  • Such dosage forms can also be prepared by any of the methods of pharmacy, but all methods include the step of bringing the crystalline form (e.g. crystalline Form C-l, D-l, D-2, E, F, G, H, I, J, or K) of the disclosure into association with an excipient, such as a carrier, which constitutes one or more necessary ingredients.
  • Such dosage forms can also be prepared by any of the methods of pharmacy, but all methods include the step of bringing the crystalline form (e.g. crystalline Form C-l, D-l, D-2, E, F, G, H, I, J, or K) of the disclosure into association with an excipient, such as a carrier, which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the crystalline form of the disclosure with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients (excipients).
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more excipients such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the crystalline forms of the disclosure can be combined in an intimate admixture with one or more pharmaceutical excipients according to conventional pharmaceutical compounding techniques.
  • the excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as excipients, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable oral dosage forms include powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Carriers such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, silicified microcrystalline cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cell
  • polyoxyethylene monostearate Myrj 45
  • polyoxyethylene hydrogenated castor oil polyethoxylated castor oil, polyoxymethylene stearate, and Solutol
  • sucrose fatty acid esters polyethylene glycol fatty acid esters (e.g., CremophorTM)
  • polyoxyethylene ethers e.g., polyoxyethylene lauryl ether (Brij 30)
  • diethylene glycol monolaurate triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, silicified microcrystalline cellulose, cellulose acetate, polyvinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), silicified microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle.
  • Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form.
  • a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein.
  • the amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, betacarotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl.
  • BHA butylated hydroxyanisol
  • BHT butylated hydroxytoluened
  • SLS sodium lauryl sulfate
  • SLES sodium lauryl ether sulfate
  • sodium bisulfite sodium metabisulfite
  • potassium sulfite potassium metabisulfite
  • Glydant Plus Phenoni
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 2 weight percent of the pharmaceutical composition.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Film coatings may be used, for example, Opadry® II Blue film coat [polyvinyl alcohol, titatnium dioxide, macrogol/polyethylene glycol, talc, FD&C blue #2/indigo carmine aluminum lake/E 132].
  • Surfactants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value).
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical, and cosmetic emulsions.
  • ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di- glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate
  • Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macro golglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; poly glycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyalkylene al
  • hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyce
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol (PEG), polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; polyethylene glycol 660 12-hydroxystearate, amides and other nitrogen-containing compounds such
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG having an average molecular weight of about 100 to about 8000 g/mole, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of less than about 10%, less than about 25%, less than about 50%, about 100%, or up to less than about 200% by weight, based on the combined weight of the drug, and other excipients.
  • solubilizer may also be used, such as less than about 5%, less than about 2%, less than about 1% or even less.
  • the solubilizer may be present in an amount of less than about 1% to about 100%, more typically less than about 5% to less than about 25% by weight.
  • compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, transmucosally, or in an ophthalmic preparation.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions provided herewith are orally administered in an orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • the excipient is selected from one or more of silicified microcrystalline cellulose, Croscarmellose Sodium, Sodium Stearyl Fumarate, polyvinyl alcohol, titatnium dioxide, macrogol/polyethylene glycol, talc, FD&C blue #2/indigo carmine aluminum lake/E132.
  • the excipient is selected from one or more of silicified microcrystalline cellulose, croscarmellose Sodium, Sodium Stearyl Fumarate, and Opadry® II Blue film coat.
  • the excipient is selected from one or more of mannitol, pregelatinized starch (starch 1500), hydrogenated vegetable oil, and Opadry® II Blue film coat.
  • the excipient is selected from one or more of sorbitol, crosssodium carboxymethyl starch (sodium starch glycolate), zinc stearate, and Opadry® II Blue film coat.
  • the excipient is selected from one or more of silicified microcrystalline cellulose, Croscarmellose Sodium, Sodium Stearyl Fumarate, polyvinyl alcohol, titatnium dioxide, macrogol/polyethylene glycol, talc, FD&C blue #2/indigo carmine aluminum lake/E132, olyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol.
  • silicified microcrystalline cellulose Cro
  • the amount of a crystalline or amorphous form of Compound 1 that may be combined with one or more excipients to produce a composition in a single dosage form will vary depending upon the subject to be treated and the particular mode of administration. For example, a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a crystalline or amorphous form of Compound 1 in the composition will also depend upon the particular crystalline form (e.g., Form A, B, C, D, or E) in the composition.
  • crystalline form e.g., Form A, B, C, D, or E
  • the amount of a crystalline or amorphous form of Compound 1 in the composition will also depend upon the particular crystalline form (e.g. crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K ) in the composition.
  • the dose refers to the amount of Compound 1 in a particular crystalline form.
  • the amount of the particular crystalline form will be calculated based on the equivalence to the non-hydrated free -base (non-salt) form of Compound 1.
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 0.5 mg to about 30 mg of the non-hydrated free base (non-salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 0.5 mg to about 7 mg of the non-hydrated free base (non-salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 0.5 mg to about 5 mg of the non-hydrated free base (non-salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 1 mg of the non-hydrated free base (non-salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 2 mg of the non-hydrated free base (non-salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 5 mg of the non-hydrated free base (non- salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 15 mg of the non-hydrated free base (non-salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 25 mg of the non-hydrated free base (non-salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • a disclosed crystalline form e.g., crystalline Form A, B, C, D, or E
  • amorphous form of Compound 1 is formulated for administration at a dose that is equivalent to about 30 mg of the non-hydrated free base (non- salt) form of Compound 1.
  • a crystalline form e.g., crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K
  • crystalline Form A, B, C, D, or E is present in the tablet composition in an amount equivalent to about 0.5 to about 6 mg of Compound 1.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K is present in the tablet composition in an amount equivalent to about 0.5 to about 6 mg of Compound 1.
  • crystalline Form A, B, C, D, or E is present in the tablet composition in an amount equivalent to about 0.5 to about 10 mg of Compound 1.
  • crystalline Form C- 1, D-l, D-2, F, G, H, I, J, or K is present in the tablet composition in an amount equivalent to about 0.5 to about 10 mg of Compound 1.
  • crystalline Form A, B, C, D, or E is present in the tablet composition in an amount equivalent to about 0.5 mg of Compound 1.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K is present in the tablet composition in an amount equivalent to about 0.5 mg of Compound 1.
  • crystalline Form A, B, C, D, or E is present in the tablet composition in an amount equivalent to about 1 to about 5 mg of Compound 1.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K is present in the tablet composition in an amount equivalent to about 1 to about 5 mg of Compound 1.
  • crystalline Form A, B, C, D, or E is present in the tablet composition in an amount equivalent to about 10 mg of Compound 1.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K is present in the tablet composition in an amount equivalent to about 10 mg of Compound 1.
  • the amount of crystalline Form A, B, C, D, or E (or amorphous form of Compound 1) is based on the equivalence to the non-hydrated free-base form of Compound 1.
  • the amount of crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K is based on the equivalence to the nonhydrated free -base form of Compound 1.
  • “crystalline Form A is present in the composition in an amount equivalent to about 1.0 mg of Compound 1” means that about 1.18 mg of crystalline Form A is present in the composition and is equivalent to about 1.0 mg of the non-hydrated free base (non- salt) form of Compound 1.
  • the tablet composition comprises about 2% w/w ( ⁇ 1%) of a crystalline or amorphous form of Compound 1 and about 98% w/w ( ⁇ 2%) comprising one or more excipients.
  • any of crystalline forms A, B, C ,D, and E as described herein may be used.
  • any of crystalline forms C-l, D-l, D-2, F, G, H, I, J, or K as described herein may be used.
  • the tablet composition comprises about 5% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form A, B, C, D, or E, as described herein) or amorphous form of Compound 1 and about 95% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 7% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K, as described herein) or amorphous form of Compound 1 and about 93% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 10% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form A, B, C, D, or E as described herein) or amorphous form of Compound 1 and about 90% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 10% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein) or amorphous form of Compound 1 and about 90% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 12% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form A, B, C, D, or E as described herein) or amorphous form of Compound 1 and about 88% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 12% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein) or amorphous form of Compound 1 and about 88% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 15% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form A, B, C, D, or E as described herein) or amorphous form of Compound 1 and about 85% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 15% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein) or amorphous form of Compound 1 and about 85% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 18% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form A, B, C, D, or E as described herein) or amorphous form of Compound 1 and about 82% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 20% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form A, B, C, D, or E as described herein) or amorphous form of Compound 1 and about 80% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 20% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein) or amorphous form of Compound 1 and about 80% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 25% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form A, B, C, D, or E as described herein) or amorphous form of Compound 1 and about 75% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 25% w/w ( ⁇ 1%) of a crystalline (any of crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein) or amorphous form of Compound 1 and about 75% w/w ( ⁇ 2%) comprising one or more excipients.
  • a pharmaceutical composition comprising any of the crystalline forms Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient that has been processed to generate particles of a consistent size (“milled powder”).
  • a pharmaceutical composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K, as described herein and a pharmaceutically acceptable excipient that has been processed to generate particles of a consistent size (“milled powder”).
  • processing the milled powder comprises milling for an amount of time suitable to bring about a desired particle size.
  • the particle size of the milled powder is less than about 200 pm. In some embodiments, the particle size of the milled powder is less than about 100 pm. In some embodiments, the particle size of the milled powder is less than about 75 pm. In some embodiments, the particle size of the milled powder is less than about 50 pm. In some embodiments, the particle size of the milled powder is less than about 45 pm. In some embodiments, the particle size of the milled powder is less than about 40 pm. In some embodiments, the particle size of the milled powder is less than about 35 pm. In some embodiments, the particle size of the milled powder is less than about 30 pm. In some embodiments, the particle size of the milled powder is less than about 25 pm.
  • the particle size of the milled powder is less than about 20 pm. In some embodiments, the particle size of the milled powder is less than about 15 pm. In some embodiments, the particle size of the milled powder is less than about 10 pm. In some embodiments, the particle size of the milled powder is less than about 5 pm. In some embodiments, the particle size of the milled powder is less than about 1 pm. In some embodiments, the particle size of the milled powder is less than about 500 nm. In some embodiments, the particle size of the milled powder ranges from about 500 nm to about 200 pm. In some embodiments, the particle size of the milled powder ranges from about 500 nm to about 100 pm.
  • the particle size of the milled powder ranges from about 500 nm to about 75 pm. In some embodiments, the particle size of the milled powder ranges from about 500 nm to about 50 pm. In some embodiments, the particle size of the milled powder ranges from about 500 nm to about 45 pm. In some embodiments, the particle size of the milled powder ranges from about 500 nm to about 40 pm. In some embodiments, the particle size of the milled powder ranges from about 500 nm to about 35 pm. In some embodiments, the particle size of the milled powder ranges from about 1 pm to about 45 pm. In some embodiments, the particle size of the milled powder ranges from about 1 pm to about 40 pm.
  • the particle size of the milled powder ranges from about 1 pm to about 35 pm. In some embodiments, the particle size of the milled powder is about 45 pm. In some embodiments, the particle size of the milled powder is about 40 pm. In some embodiments, the particle size of the milled powder is about 35 pm. In some embodiments, the particle size of the milled powder is about 30 pm. In some embodiments, the particle size of the milled powder is about 25 pm. In some embodiments, the particle size of the milled powder is about 5 pm. In some embodiments, the particle size of the milled powder is about 4 pm. In some embodiments, the particle size of the milled powder is about 3 pm. In some embodiments, the particle size of the milled powder is about 2 pm. In some embodiments, the particle size of the milled powder is about 1 pm. The term “about,” as used herein with respect to particle size, means +/- 5 pm.
  • the pharmaceutical composition comprises amorphous Compound 1. In some embodiments, the pharmaceutical composition comprises amorphous Compound 1 and at least one excipient. In some embodiments, the pharmaceutical composition comprises a solid dispersion. In still other embodiments, the pharmaceutical composition comprises amorphous Compound 1 in a spray dried dispersion.
  • the solid dispersion or pharmaceutical composition containing the solid dispersion comprises Compound 1 or a salt thereof and one or more polymer(s).
  • the solid dispersion is a spray dried dispersion.
  • the solid dispersion comprises Compound 1 or a salt thereof, one or more polymer(s), and one or more surfactant(s).
  • the solid dispersion or pharmaceutical composition containing the solid dispersion comprises Compound 1 or a salt thereof and at least one polymer.
  • the solid dispersion or pharmaceutical composition containing the solid dispersion comprises Compound 1 or a salt thereof, at least one polymer, and at least one surfactant.
  • the non- salt (free form) of Compound 1 is used in the solid dispersion or pharmaceutical composition containing the solid dispersion.
  • a pharmaceutically acceptable salt of Compound 1 is used in the solid dispersion or pharmaceutical composition containing the solid dispersion.
  • the amorphous form of Compound 1 is used in the solid dispersion or pharmaceutical composition containing the solid dispersion.
  • the solid dispersion or pharmaceutical composition containing the solid dispersion comprises the monohydrate free form of Compound 1.
  • the solid dispersion or pharmaceutical composition containing the solid dispersion comprises non-hydrated free form of Compound 1.
  • the pharmaceutically acceptable salt of Compound 1 used in the solid dispersion or pharmaceutical composition containing the solid dispersion is the phosphate salt of Compound 1.
  • the pharmaceutically acceptable salt of Compound 1 used in the solid dispersion or pharmaceutical composition containing the solid dispersion is the hemi-hydrate hemi-sulfate salt of Compound 1.
  • the pharmaceutically acceptable salt of Compound 1 used in the solid dispersion or pharmaceutical composition containing the solid dispersion is the DL-tartrate salt of Compound 1.
  • the pharmaceutically acceptable salt of Compound 1 used in the solid dispersion or pharmaceutical composition containing the solid dispersion is the hydrochloride salt of Compound 1.
  • the pharmaceutically acceptable salt of Compound 1 used in the solid dispersion or pharmaceutical composition containing the solid dispersion is the L-tartrate salt of Compound 1.
  • the solid dispersion comprises at least one polymer that is methylcellulose (MC); ethylcellulose (EC); hydroxyethylcellulose (HEC); hydroxypropyl methyl cellulose (HPMC) such as HPMC 606 or HPMC E5; hydroxypropyl cellulose (HPC); carboxymethyl ethyl cellulose (CMEC); hydroxypropyl methyl cellulose acetosuccinate (HPMCAS) such as HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, HPMCAS/SLS, HPMCAS AS-MF, HPMCAS-HF; hydroxypropyl methyl cellulose phthalate (HPMCP); cellulose acetate phthalate (CAP); cellulose acetate groups having at least a half of cellulose acetate in hydrolyzed form; polyvinylpyrrolidone such as PVP K-12, PVPVA, PVP K30, PVP K 29/32, or PVPVA 64; polyoxyethylene-polyoxypropy
  • the solid dispersion comprises one or more polymers selected from hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, and polyvinylpyrrolidone (PVP), and mixtures thereof.
  • HPMC hydroxypropyl methyl cellulose
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • HPMCP hydroxypropyl methyl cellulose phthalate
  • HPPC hydroxypropyl cellulose
  • ethylcellulose cellulose acetate phthalate
  • PVP polyvinylpyrrolidone
  • one or more polymers in the solid dispersion is a cellulose-based polymer such as HPMC, HPMCAS, HPC, and ethylcellulose.
  • at least one polymer in the solid dispersion is HPMCAS
  • At least one polymer in the solid dispersion is HPMC. In yet further embodiments at least one polymer in the solid dispersion is PVP. In still further embodiments at least one polymer in the solid dispersion is ethylcellulose. In additional embodiments at least one polymer in the solid dispersion is copovidone.
  • the polymer is (or the one or more polymers are) present in the solid dispersion in an amount of about 10% w/w to 90% w/w (e.g., about 20% w/w to about 80% w/w; about 30% w/w to about 70% w/w; about 40% w/w to about 60% w/w; or between about 15% w/w and about 35% w/w).
  • the polymer is (or the one or more polymers are) present in the solid dispersion in an amount of from about 10% w/w to about 80% w/w, for example from about 30% w/w to about 75% w/w, or from about 40% w/w to about 65% w/w, or from about 45% w/w to about 55% w/w, for example, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w, about 51% w/w, about 52% w/w, about 53% w/w, or about 54% w/w.
  • the polymer is (or the one or more polymers are) present in the solid dispersion in an amount of about 48% w/w, about 48.5% w/w, about 49% w/w, about 49.5% w/w, about 50% w/w, about 50.5% w/w, about 51% w/w, about 51.5% w/w, about 52% w/w, or about 52.5% w/w.
  • the solid state form of Compound 1 is present in the solid dispersion in an amount of from about 10% w/w and 90% w/w (equivalent to the amount of non-hydrated free form Compound 1) (e.g., about 20% w/w to about 80% w/w; about 30% w/w to about 70% w/w; about 40% w/w to about 60% w/w; or about 15% w/w to about 35% w/w).
  • the solid state form of Compound 1 is present in the solid dispersion in an amount of from about 10% w/w to about 90% w/w, for example from about 20% w/w to about 80% w/w, or from about 30% w/w to about 70% w/w.
  • the solid state form of Compound 1 is present in the solid dispersion in an amount of from about, for example, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w, about 30% w/w, about 31% w/w, about 32% w/w, about 33% w/w, about 34% w/w, about 35% w/w, about 36% w/w, about 37% w/w, about 38% w/w, about 39% w/w, or about 40% w/w.
  • the solid dispersion further comprises a surfactant.
  • the surfactant is selected from sodium lauryl sulfate (SLS), vitamin E or a derivative thereof (e.g., vitamin E TPGS), docusate sodium, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), poloxamers (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, pluronic copolymers (e.g., Pluronic F108, Pluronic P-123), and mixtures thereof.
  • the surfactant is SLS.
  • the surfactant is vitamin E or a derivative thereof (e.g., vitamin E TPGS).
  • the surfactant is present in the solid dispersion in an amount of from about 0.1% w/w to about 10% w/w, for example from about 0.5% w/w to about 2% w/w, or from about 1% w/w to about 3% w/w, from about 1% w/w to about 4% w/w, or from about 1% w/w to about 5% w/w.
  • the surfactant is present in the solid dispersion in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, or about 1% w/w.
  • the surfactant is present in the solid dispersion in an amount of about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w.
  • the disclosure relates to processes for preparing a solid dispersion using any of the solid state forms disclosed herein.
  • the process comprises spray-drying a mixture prepared using a solid state form of Compound 1 as described herein, a polymer, and an appropriate solvent or solvent mixture.
  • the solid dispersion prepared according to the processes disclosed herein comprises Compound 1 (or a salt of Compound 1) in substantially amorphous form.
  • the process comprises combining a solid state form of Compound 1 (or a salt of Compound 1) as described herein with a polymer and a solvent to form a mixture that is an emulsion, solution, or suspension; and spray-drying the mixture to produce the solid dispersion.
  • the at least one polymer utilized is described above.
  • the solvent is methylene chloride, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or a mixture thereof.
  • the solvent is methylene chloride and methanol.
  • a solid state form of Compound 1 as described herein may be used as the starting material in a process to prepare the solid dispersion.
  • the solid state form used as a starting material in the process to prepare the solid dispersion is one of the crystalline forms described herein.
  • the solid dispersion is prepared by spray drying.
  • solid state form of Compound 1 refers to a crystalline salt form or a crystalline non salt form of Compound 1 crystalline Form A, B, C, D, or E) or an amorphous form of Compound 1.
  • solid state form of Compound 1 refers to a crystalline salt form or a crystalline non salt form of Compound 1 crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K) or an amorphous form of Compound 1.
  • Spray drying involves atomization of a liquid solution containing, e.g., a solid and a solvent or solvent mixture, and removal of the solvent or solvent mixture. Atomization may be done, for example, through a two-fluid or pressure or electrosonic nozzle or on a rotating disk. Removal of the solvent or solvent mixture may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 °C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200 °C). Techniques and methods for spray-drying may be found in Perry's Chemical Engineering Handbook, 6th Ed., R. H. Perry, D. W. Green & J. O.
  • a method for treating a disease, condition or disorder as described herein comprising administering crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or a pharmaceutical composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • a method for treating a disease, condition or disorder as described herein comprising administering crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein or a pharmaceutical composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient.
  • a method for increasing the lifetime of red blood cells (RBCs) in a subject in need thereof comprising administering an effective amount of (1) crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • RBCs red blood cells
  • a method for increasing the lifetime of red blood cells (RBCs) in a subject in need thereof comprising administering an effective amount of (1) crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising a crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient.
  • a method for reducing 2,3-diphosphoglycerate levels in the blood of a subject in need thereof comprising administering an effective amount of (1) crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • a method for reducing 2,3-diphosphoglycerate levels in the blood of a subject in need thereof comprising administering an effective amount of (1) crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient.
  • a method for increasing the level of hemoglobin (Hb) in a subject in need thereof comprising administering an effective amount of (1) crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • Hb hemoglobin
  • a method for increasing the level of hemoglobin (Hb) in a subject in need thereof comprising administering an effective amount of (1) crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising a crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient.
  • a method for treating sickle cell disease comprising administering to a subject in need thereof an effective amount of (1) crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • a method for treating sickle cell disease comprising administering to a subject in need thereof an effective amount of (1) crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient.
  • a method of treating acquired pyruvate kinase deficiency (PKD) in a subject comprising administering to the subject in need thereof an effective amount of (1) crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • PTD acquired pyruvate kinase deficiency
  • a method of treating acquired pyruvate kinase deficiency (PKD) in a subject comprising administering to the subject in need thereof an effective amount of (1) crystalline Form C-l, D-l, D-2, F, G, H, I, J, or Kas described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or Kas described herein and a pharmaceutically acceptable excipient.
  • PTD acquired pyruvate kinase deficiency
  • anemia in one embodiment provided is a method of treating anemia in a subject comprising administering to the subject in need thereof an effective amount of (1) crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein; or (2) a pharmaceutically acceptable composition comprising a crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • the anemia is hemolytic anemia.
  • the hemolytic anemia is associated with MDS (e.g., very low risk MDS, low risk MDS, lower risk MDS, and/or intermediate risk MDS).
  • the hemolytic anemia is acquired PKD associated with MDS (e.g., very low risk MDS, low risk MDS, lower risk MDS, and/or intermediate risk MDS).
  • a method of treating anemia associated with MDS (e.g., very low risk MDS, low risk MDS, lower risk MDS, and/or intermediate risk MDS) in a subject comprising administering to the subject in need thereof an effective amount of (1) crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • a method of treating anemia in a subject comprising administering to the subject in need thereof an effective amount of (1) crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient.
  • the anemia is hemolytic anemia.
  • the hemolytic anemia is associated with MDS (e.g., very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS).
  • the hemolytic anemia is acquired PKD associated with MDS (e.g., very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS).
  • a method of treating anemia associated with MDS (e.g., very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS) in a subject comprising administering to the subject in need thereof an effective amount of (1) crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient.
  • anemia refers to a deficiency of red blood cells (RBCs) and/or hemoglobin.
  • anemia includes all types of clinical anemia, for example (but not limited to): microcytic anemia, iron deficiency anemia, hemoglobinopathies, heme synthesis defect, globin synthesis defect, sideroblastic defect, normocytic anemia, anemia of chronic disease, aplastic anemia, hemolytic anemia, macrocytic anemia, megaloblastic anemia, pernicious anemia, dimorphic anemia, anemia of prematurity, Fanconi anemia, hereditary spherocytosis, sickle cell disease, warm autoimmune hemolytic anemia, cold agglutinin hemolytic anemia, osteopetrosis, thalassemia, and myelodysplastic syndrome.
  • anemia refers to hemolytic anemia.
  • anemia refers to hemolytic anemia
  • anemia can be diagnosed on a complete blood count.
  • anemia can be diagnosed based on the measurement of one or more markers of hemolysis (e.g., RBC count, hemoglobin, reticulocytes, schistocytes, lactate Dehydrogenase (LDH), haptoglobin, bilirubin, and ferritin) and/or hemosiderinuria mean corpuscular volume (MCV) and/or red cell distribution width (RDW).
  • markers of hemolysis e.g., RBC count, hemoglobin, reticulocytes, schistocytes, lactate Dehydrogenase (LDH), haptoglobin, bilirubin, and ferritin
  • MCV mean corpuscular volume
  • RW red cell distribution width
  • a method for treating hemolytic anemia in a subject comprising administering to a subject in need thereof an effective amount of (1) crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein; or (2) a pharmaceutically acceptable composition comprising a crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient.
  • a method for treating hemolytic anemia in a subject comprising administering to a subject in need thereof an effective amount of (1) crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient.
  • crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient for increasing the lifetime of red blood cells (RBCs) in a subject in need thereof.
  • RBCs red blood cells
  • crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient for reducing 2,3-diphosphoglycerate levels in the blood of a subject in need thereof.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient for reducing 2,3-diphosphoglycerate levels in the blood of a subject in need thereof.
  • the hemolytic anemia is anemia associated with MDS (very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS). In other certain embodiments, the hemolytic anemia is associated with acquired PKD in a subject suffering from MDS (very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS).
  • the anemia is hemolytic anemia.
  • the hemolytic anemia is a congenital and/or hereditary form of hemolytic anemia.
  • the hemolytic anemia is acquired hemolytic anemia.
  • the hemolytic anemia is anemia associated with MDS (very low MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS). In other certain embodiments, the hemolytic anemia is associated with acquired PKD in a subject suffering from MDS (very low MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS).
  • crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein, and a pharmaceutically acceptable excipient for the preparation of a medicament for treating hemolytic anemia in a subject in need thereof.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein, and a pharmaceutically acceptable excipient for the preparation of a medicament for treating hemolytic anemia in a subject in need thereof.
  • crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for treating sickle cell disease in a subject in need thereof.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for treating sickle cell disease in a subject in need thereof.
  • crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for treating acquired pyruvate kinase deficiency (PKD) in a subject in need thereof.
  • PTD acquired pyruvate kinase deficiency
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for treating acquired pyruvate kinase deficiency (PKD) in a subject in need thereof.
  • PTD acquired pyruvate kinase deficiency
  • crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for treating acquired hemolytic anemia.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein ; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for treating acquired hemolytic anemia.
  • crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for activating mutant or wild-type PKR in red blood cells in a subject in need thereof.
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for activating mutant or wild-type PKR in red blood cells in a subject in need thereof.
  • crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein or (2) a pharmaceutically acceptable composition comprising crystalline Form A, B, C, D, or E or an amorphous form of Compound 1 as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for treating anemia associated with MDS (very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS) in a subject in need thereof.
  • MDS very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS
  • crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein; or (2) a pharmaceutically acceptable composition comprising crystalline Form C-l, D-l, D-2, F, G, H, I, J, or K as described herein and a pharmaceutically acceptable excipient for the preparation of a medicament for treating anemia associated with MDS (very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS) in a subject in need thereof.
  • MDS very low risk MDS, low risk MDS, lower risk MDS and/or intermediate risk MDS
  • the crystalline forms may be prepared according to the following general procedures.
  • a Rigaku SmartLab X-Ray Diffractometer was configured in Bragg-Brentano reflection geometry equipped with a beam stop and knife edge to reduce incident beam and air scatter. Typical parameters for XRPD are listed below.
  • Thermogravimetric analysis was carried out using a TA Instruments Q5500 Discovery Series instrument.
  • the instrument balance was calibrated using class M weights and the temperature calibration was performed using alumel.
  • the nitrogen purge was ⁇ 40 mL per minute at the balance and ⁇ 60 mL per minute at the furnace.
  • Each sample was placed into a pre-tared platinum pan and heated from approximately 25 °C to 300 °C at a rate of 10 °C per minute.
  • Dynamic Vapor Sorption was carried out using a TA Instruments Q5000 Dynamic Vapor Sorption analyzer. The instrument was calibrated with standard weights and a sodium bromide standard for humidity. Approximately 10-25 mg of sample was loaded into a metal-coated quartz pan for analysis. The sample was analyzed at 25 °C with a maximum equilibration time of one hour in 10% relative humidity (RH) steps from 5 to 95% RH (adsorption cycle) and from 95 to 5% RH (desorption cycle). The movement from one step to the next occurred either after satisfying the equilibrium criterion of 0.01% weight change or, if the equilibrium criterion was not met, after one hour. The percent weight change values were calculated using Microsoft Excel®.
  • Compound 1 can be prepared following the procedures described in WO 2019/035865, the entirety of which is incorporated by reference.
  • Salt formation was conducted by slurrying Compound 1, in n-PrOH/FFO (8:2 v/v). The slurry was then heated to 80 °C and stirred for 15 minutes. Full dissolution was observed after 15 minutes. Sulfuric acid (98%, 0.55 eq.) was added slowly to the solution dropwise. Spontaneous nucleation occurred in less than 5 minutes. Slurry was then stirred at 80 °C for 1 hour. After, the slurry was cooled to 25 °C over the course of 1 hour. The slurry was filtered, washed 3 times with two volumes of n-PrOH and dried in vacuum oven overnight at 50 °C. The slurry was filtered and then analyzed by XRPD.
  • crystalline Form A of a hemi- hydrate hemi-sulfate salt of Compound 1 was found to have a variety of favorable physicochemical properties, including high crystallinity, stability in multiple solvent systems (e.g. especially containing water), relatively small particle size (e.g. below 20 pm under microscope so as to potentially avoid the subsequent micronization), and stability in humidity (e.g. at least 20% RH or at least a water activity of 0.2), and demonstrate favorable plasma concentration-time profiles and pharmacokinetic parameters.
  • Salt formation was conducted by adding 451.6 mg of Compound 1 hydrate to 18.1 mL n-PrOH/thO (8:2 v/v) in a 20 mL scintillation vial.
  • the vial was heated to 80 °C and 82.4 p L phosphoric acid solution (85%) was added after 15 minutes.
  • a seed crystal of the free base form was added to the vial and the system became a viscous slurry within 1-2 minutes.
  • the system was stirred at 80 °C for 45 minutes and left to cool to room temperature and stir overnight.
  • the slurry was filtered and the wet cake was washed three times with two volumes of n-PrOH.
  • the wet cake was dried in a vacuum oven at 50 °C for 5 hours.
  • Salt formation was conducted by adding 39.5 mg of Compound 1, 7 mL of 95:5 TtffithO, and 15.1 mg of tartaric acid to a 2-dram vial.
  • the slurry was sonicated, resulting in a clear solution.
  • the solution was left at room temperature overnight, and remained clear the next day.
  • the sample was then placed in a refrigerator at 5 °C overnight and remained clear the next day.
  • the sample was then placed in a freezer at -15 °C for 4 days. Crystals were observed to form in this time.
  • the slurry was centrifuged, the mother liquor decanted, and the solids allowed to air dry at room temperature.
  • DL-Tartrate Salt Form F can be obtained from a slurry of material in a variety of solvents including THF (slurry at ambient temperature), methyl ethyl ketone (slurry at 50 C), isopropyl alcohol and 2-Me THF.
  • solvents including THF (slurry at ambient temperature), methyl ethyl ketone (slurry at 50 C), isopropyl alcohol and 2-Me THF.
  • Salt formation was conducted by adding 10.6 mg of Compound 1, 0.25 mL of THF, and 3.2 pL of hydrochloric acid (aqueous, 37%). The resulting slurry was centrifuged, the mother liquor decanted, and the solids allowed to air dry at room temperature.
  • a spray dried dispersion of Compound 1 to HPMCAS (15/85) was prepared according to the Table below:
  • Solubility samples were prepared by weighing about 10 mg of each salt and adding 1 mL of media and vortexed briefly to obtain suspensions. For low pH media (pH 1 and simulated gastric fluid), the solid dissolved instantly and therefore 100 uL increments of the media was added to estimate the solubility. For such instances, the solubility is calculated as greater than (>).
  • pH 2 buffer USP Mixed 50 mL of 0.2M potassium chloride and 13 mL 0.2M HC1, diluted to 200 mL with water.
  • pH 4.5 buffer USP 5.44g of potassium dihydrogen phosphate was diluted to lOOOmL with water.
  • pH 6.8 buffer USP Mixed 50 mL of 0.2M potassium phosphate and 22.4 mL 0.2M sodium hydroxide. Diluted with water to 200mL.
  • SGF 2.0109 g of NaCl was dissolved in water, added 7 mL of cone. HC1 and diluted to 1 L.
  • FeSSIF 4.0321 g of NaOH and 11.8726 g of NaCl were dissolved in water, added 8.65 mL of glacial acetic acid, adjusted the pH to 5.0 and diluted to 1 L.
  • FaSSIF 0.4247 g of NaOH, 3.9548 g of sodium phosphate monobasic monohydrate and 6.1900 g of NaCl were dissolved in water, adjusted the pH to 6.5 and diluted to 1 L. pH Solubility
  • pH solubility was determined in buffers ranging from pH 1 to pH 6.8 at 2 hours and 24 hours. At each time point, the solution was analyzed by HPLC and residue was vacuum dried and analyzed by XRPD. The pH of the solution was measured at 24 hours. [00359] Overall, Form C exhibited highest solubility, with Form B exhibiting similar level of solubility. In 0.1N HC1, both Form B and From C dissolved instantly, and therefore the solubility was estimated by adding 100 uL aliquots to about 10 mg of weighed solid. XRPD analysis showed salt disproportionation at pH 4.5 and higher.
  • Kinetic solubility was determined in biorelevant media. At each time point, the solution was analyzed by HPLC. The solid residue was analyzed by XRPD at selected time points. The pH of the solution was measured at 24 hours.
  • Form C exhibited highest solubility in all media tested.
  • SGF simulated gastric fluid
  • both Form B and Form C dissolved instantly, and therefore the solubility was evaluated by adding 100 uL aliquots to about 10 mg of weighed solid.
  • the solubility in the table is given as greater than “>”, calculated based on the total volume of media added to fully dissolve the solid.
  • HP-P-CD Hydroxypropyl-beta-cyclodextrin
  • HPMCAS-MF Hydroxypropylmethylcellulose acetate succinate
  • PVP K30 Polyvinylpyrrolidone
  • Blood was serially collected from each animal at 0 (pre-dose), 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h post-dose. For each collection, the animal was restrained manually, and approximately 150 pL of blood sample was collected via the tail vein into K2EDTA tubes. Plasma samples were stored at approximately -70°C until analysis.
  • Compound 1 was formulated as a solution in 10% N-methyl-2-pyrrolidone, 10% Solutol HS 15, and 80% saline and administered at 1 mg/kg as intravenous (IV) bolus dose to a separate group of male Sprague Dawley rats, and blood samples were collected at similar timepoints to those shown above. Further, plasma samples were obtained from the collected samples and stored at approximately -70°C until analysis.
  • IV intravenous
  • a 20 pL aliquot of each plasma sample was mixed with 200 p L of acetonitrile containing glipizide as an internal standard (40 ng/mL). The resulting mixture was vortexed at 1500 rpm for 2 min and centrifuged at 5800 rpm for 10 min. A 1 pL sample from the supernatant was injected into LC-MS/MS.
  • Historical data for the IV administration of Compound 1 is provided in Table 9.
  • the absolute bioavailability of each form of Compound 1 was determined by dividing the AUCinf of the form in question by the AUCinf obtained historical data by IV administration of Compound 1.
  • TGA of Form A showed about 2.1% weight loss up to 120 °C. See FIG. 2. Two thermal events were observed in DSC thermogram with the first peak at 117.3 °C and the second peak at 270.3 °C. See FIG. 2. Dynamic vapor sorption of salt Form A at 25 °C showed that the solid picks up about 0.08% moisture from 5% to 95% relative humidity. See FIG. 3. Form A shows about 2% water content via Karl Fischer analysis. Form B
  • TGA of Form B showed about 0.3% weight loss up to 125 °C. See FIG. 5.
  • One thermal event was observed in the DSC thermogram at about 247.0 °C. See FIG. 5.
  • Dynamic vapor sorption of salt Form B at 25 °C showed that the solid picks up about 0.9% moisture from 5% to 95% relative humidity. See FIG. 6.
  • Form B shows about 4.4% water content via Karl Fischer analysis.
  • TGA of Form C showed about 18.2% weight loss up to 270 °C. See FIG. 8.
  • One thermal event was observed in the DSC thermogram at about 224.2 °C. See FIG. 8.
  • Dynamic vapor sorption of salt Form C at 25 °C showed that the solid picks up about 0.06% moisture from 5% to 95% relative humidity. See FIG. 9.
  • Form C shows about 0.11% water content via Karl Fischer analysis.
  • TGA of Form D showed about 8.4% weight loss up to 180 °C. See FIG. 11. Two thermal events were observed in the DSC thermogram the first at about 120.6 °C and the second at about 190.32 °C. See FIG. 11. Form D shows about 2.4% to about 7.4% water content via Karl Fischer analysis.
  • TGA of Form E showed about 4.4% weight loss up to 100 °C. See FIG. 13.
  • Four thermal events were observed in the DSC thermogram the first at about 112.3 °C, the second at about 156.1 °C, the third at about 160.4 °C, and the fourth at 219.6 °C. See FIG. 13.
  • TGA of Form D-l showed about 2.1% weight loss up to 115 °C, about 5.2% weight loss up to 206 °C, and about 7.4% weight loss up to 290 °C. See FIG. 28.
  • Four thermal events were observed in the DSC thermogram the first at about 194.4 °C, the second at about 208.9 °C, the third at about 235.8 °C, and the fourth at 276.6 °C. See FIG. 29.
  • TGA of Form D-2 showed about 2.2% weight loss up to 138 °C, about 7.5% weight loss up to 206 °C, and about 7.1% weight loss up to 290 °C. See FIG. 32. Two thermal events were observed in the DSC thermogram the first at about 208.6 °C and the second at about 277.8 °C. See FIG. 33. Dynamic vapor sorption of salt Form D-2 at 25 °C showed that the solid picks up about 1.1% moisture from 2% to 95% relative humidity. See FIG. 34. Form G shows about 7.36% water content via Karl Fischer analysis.
  • TGA of Form I showed about 4.3% weight loss up to 141 °C and about 19.4% weight loss up to 297 °C. See FIG. 36.
  • Two thermal events were observed in the DSC thermogram the first at about 65.7 °C and the second at about 180.7 °C. See FIG. 37.
  • TGA of Form H showed a weight loss of 4.2 ⁇ 0.5 % up to 100 °C ⁇ 2 °C and 7.7 ⁇ 0.5 % from 200 °C ⁇ 2 °C. See FIG. 41.
  • Two thermal events were observed in DSC thermogram the first at about 126 °C and the second at about 206 °C. See FIG. 40.
  • TGA of Form F showed a weight loss of 0.03 ⁇ 0.01 % up to 200 °C ⁇ 2 °C.
  • FIG. 43 One thermal event was observed in DSC thermogram at about 217 °C. See FIG. 43. Form G
  • TGA of Form G showed a weight loss of 3.428 ⁇ 0.01 % up to 110 °C ⁇ 2 °C and a weight loss of 2.797 ⁇ 0.01 % up to 170 °C ⁇ 2 °C. See FIG. 45.
  • Three thermal events were observed in DSC thermogram the first at about 63 °C, the second at about 138 °C, and the third at about 202 °C. See FIG. 45.
  • TGA of Form J showed a weight loss of 0.92 ⁇ 0.05 % up to 250 °C ⁇ 2 °C. See FIG. 47.
  • Two thermal events were observed in the DSC thermogram the first at about 76 °C and the second at about 229°C. See FIG. 47.
  • Form K
  • TGA of Form K showed a weight loss of 10.06 ⁇ 0.05 % up to 180 °C ⁇ 2 °C. See FIG. 49.
  • Three thermal events were observed in the DSC thermogram the first at about 55 °C, the second at about 234 °C, and the third at about 284 °C. See FIG. 49.
  • TGA of Form I showed about 17.4% weight loss up to 275 °C. See FIG. 52.
  • One thermal event was observed in the DSC thermogram the first at about 218.76 °C. See FIG. 52.

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Abstract

L'invention concerne des sels cristallins et des formes de base libres ainsi que des formes amorphes du composé ayant la formule : (I). L'invention concerne également des compositions pharmaceutiques comprenant de telles formes cristallines et amorphes, des procédés pour leur fabrication, et leurs utilisations pour traiter diverses affections telles que l'anémie hémolytique, la drépanocytose et le MDS (MDS à très faible risque, MDS à faible risque, MDS à risque inférieur et/ou MDS à risque intermédiaire).
PCT/US2024/029471 2023-05-15 2024-05-15 Sels cristallins ou formes amorphes de 2-((1h-pyrazol-3-yl)méthyl)-6-((6-aminopyridin-2-yl)méthyl)-4-méthyl-4,6-dihydro-5h-thiazolo[5',4': 4,5]pyrrolo[2,3-d]pyridazin-5-one Pending WO2024238659A1 (fr)

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AU2024271856A AU2024271856A1 (en) 2023-05-15 2024-05-15 Crystalline salts or amorphous forms of 2-((1h-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4,6-dihydro -5h-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one
MX2025013731A MX2025013731A (es) 2023-05-15 2025-11-14 Sales cristalinas o formas amorfas de 2-((1h-pirazol-3-il)metil)-6-((6-aminopiridin-2-il)metil)-4-metil-4,6-dihidro-5h-thiazolo[5',4':4,5]pirrolo[2,3-d]piridazin-5-ona

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Citations (2)

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WO2019035865A1 (fr) 2017-08-15 2019-02-21 Agios Pharmaceuticals Inc. Modulateurs de la pyruvate kinase et leur utilisation
WO2023091414A1 (fr) * 2021-11-16 2023-05-25 Agios Pharmaceuticals, Inc. Composés pour le traitement d'anémies associées au mds et d'autres affections

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WO2019035865A1 (fr) 2017-08-15 2019-02-21 Agios Pharmaceuticals Inc. Modulateurs de la pyruvate kinase et leur utilisation
WO2019035864A1 (fr) 2017-08-15 2019-02-21 Agios Pharmaceuticals, Inc. Activateurs de la pyruvate kinase destinés à être utilisés dans le traitement de troubles sanguins
WO2023091414A1 (fr) * 2021-11-16 2023-05-25 Agios Pharmaceuticals, Inc. Composés pour le traitement d'anémies associées au mds et d'autres affections

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