Crystalline forms of 6-(4-((1s,3s)-1-amino-3-hydroxycyclobutyl)phenyl)-1-ethyl-7-phenyl-1h-pyrido[2,3-b][1,4]oxazin-2(3H)-one salts and free base

Abstract

The present disclosure relates to crystalline forms of 6-(4-((1s,3s)-1-amino-3- hydroxycyclobutyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, (I) or a salt, solvate, or solvate salt thereof.

Description

SALT AND CRYSTALLINE FORMS OF 6-(4-((1S,3S)-1-AMINO-3- HYDROXYCYCLOBUTYL)PHENYL)-1-ETHYL-7-PHENYL-1H-PYRIDO[2,3- B][1,4]OXAZIN-2(3H)-ONE BACKGROUND

[0001] Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disease that affects one in 5,000 to 8,000 people worldwide. 6-(4-((1s,3s)-1-amino-3- hydroxycyclobutyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Compound I) is an allosteric AKT inhibitor useful for the treatment of Hereditary Hemorrhagic Telangiectasia (HHT).

[0002] Crystallization of an active pharmaceutical ingredient can offer benefits for physiochemical properties. Such physicochemical properties include solubility, in vivo bioavailability, stability, melting point, flow properties, hygroscopicity, among others. Therefore, crystalline forms can be advantageous for pharmaceutical products. Thus, there is a need for crystalline forms of AKT inhibitors such as Compound I. SUMMARY

[0003] In aspects, the present disclosure provides a crystalline form of Compound I or a salt thereof.

[0004] In embodiments, the present disclosure provides a tartrate salt of Compound I (“Compound I Tartrate”). In embodiments, Compound I Tartrate is an L-tartrate salt. In embodiments, the present disclosure provides a crystalline form of Compound I Tartrate.

[0005] In embodiments, the present disclosure provides Compound I Tartrate (Form E). In embodiments, Form E is characterized by X-ray powder diffraction (XRPD) peaks at 21.6±0.2, 15.5 ±0.2 and 12.4 ±0.2 °2θ.

[0006] In embodiments, the present disclosure provides a mesylate salt of Compound I (“Compound I Mesylate”). In embodiments, the present disclosure provides a crystalline form of Compound I Mesylate.

[0007] In embodiments, Form M is characterized by XRPD peaks at 7.9±0.2, 22.1 ±0.2 and 20.4 ±0.2 °2θ.

[0008] In embodiments, the present disclosure provides a succinate salt of Compound I (“Compound I Succinate”). In embodiments, the present disclosure provides a crystalline form of Compound I Succinate.

[0009] In embodiments, the present disclosure provides Compound I Succinate (Form K). In embodiments of Form K, the molar ratio of succinate to Compound I is about 2:1. In embodiments, From K is characterized by X-ray powder diffraction (XRPD) peaks at 21.4±0.2, 6.1 ±0.2 and 10.0 ±0.2 °2θ.

[0010] In embodiments, the present disclosure provides Compound I Succinate (Form L). In embodiments of Form L, the molar ratio of succinate to Compound I is about 1:1. In embodiments, Form L is characterized by XRPD peaks at 17.3±0.2, 6.3 ±0.2 and 22.1 ±0.2 °2θ.

[0011] In embodiments, the present disclosure provides a gentisate salt of Compound I (“Compound I Gentisate”). In embodiments, the present disclosure provides a crystalline form of Compound I Gentisate.

[0012] In embodiments, the present disclosure provides Compound I Gentisate (Form P). In embodiments of Form P, the molar ratio of gentisate salt to Compound I is about 1:1. In embodiments, Form P is characterized by XRPD peaks at 6.5±0.2, 7.2±0.2 and 7.4±0.2 °2θ.

[0013] In embodiments, the present disclosure provides a phosphate salt of Compound I (“Compound I Phosphate”). In embodiments, the present disclosure provides a crystalline form of Compound I Phosphate.

[0014] In embodiments, the present disclosure provides Compound I Phosphate (Form T). In embodiments, Form T is characterized by XRPD peaks at 9.1±0.2, 19.2±0.2 and 17.0±0.2 °2θ.

[0015] In embodiments, the present disclosure provides an ethanedisulfonate salt of Compound I (“Compound I Ethanedisulfonate”). In embodiments, the present disclosure provides a crystalline form of Compound I Ethanedisulfonate.

[0016] In embodiments, the present disclosure provides Compound I Ethanedisulfonate (Form D). In embodiments of Form D, the molar ratio of ethanedisulfonate to Compound I is about 1:1. In embodiments, Form D is characterized by XRPD peaks at 9.8±0.2, 21.8 ±0.2 and 26.6±0.2 °2θ.

[0017] In embodiments, the present disclosure provides Compound I Ethanedisulfonate (Form Q). In embodiments, Form Q is characterized by XRPD peaks at 9.4±0.2, 6.5 ±0.2 and 22.4 ±0.2 °2θ.

[0018] In embodiments, the present disclosure provides a sulfate salt of Compound I (“Compound I Sulfate”). In embodiments, the present disclosure provides a crystalline form of Compound I Sulfate.

[0019] In embodiments, the present disclosure provides Compound I Sulfate (Form G). In embodiments, Form G is characterized by XRPD peaks at 10.2±0.2, 20.4±0.2 and 14.6±0.2 °2θ.

[0020] In embodiments, the present disclosure provides a ketoglutarate salt of Compound I (“Compound I Ketoglutarate”). In embodiments, the present disclosure provides a crystalline form of Compound I Ketoglutarate.

[0021] In embodiments, the present disclosure provides Compound I Ketoglutarate (Form I). In embodiments, Form I is characterized by XRPD peaks at 8.3±0.2, 8.1±0.2 and 6.1±0.2 °2θ.

[0022] In embodiments, the present disclosure provides a pyroglutamate salt of Compound I (“Compound I Pyroglutamate”). In embodiments, the present disclosure provides a crystalline form of Compound I Pyroglutamate.

[0023] In embodiments, the present disclosure provides Compound I Pyroglutamate (Form O).In embodiments, Form O is characterized by XRPD peaks at 16.4±0.2, 9.6±0.2 and 19.3±0.2 °2θ.

[0024] In embodiments, the present disclosure provides a malate salt of Compound I (“Compound I Malate”). In embodiments, Compound I Malate is an L-malate. In embodiments, the present disclosure provides a crystalline form of Compound I Malate.

[0025] In embodiments, the present disclosure provides Compound I Malate (Form R). In embodiments, Form R is characterized by XRPD peaks at 18.5±0.2, 9.5±0.2 and 19.1±0.2 °2θ.

[0026] In embodiments, the present disclosure provides an isethionate salt of Compound I (“Compound I Isethionate”). In embodiments, the present disclosure provides a crystalline form of Compound I Isethionate.

[0027] In embodiments, the present disclosure provides Compound I Isethionate (Form S).In embodiments, Form S is characterized by XRPD peaks at 9.1±0.2, 17.2±0.2 and 11.7±0.2 °2θ.

[0028] In embodiments, the present disclosure provides a crystalline form of Compound I free base.

[0029] In embodiments, the crystalline form of Compound I free base is Form B. In embodiments, Compound I of Form B is a dichloromethane solvate. In embodiments, Compound I of Form B is a dichloromethane solvate. In embodiments, Form B is characterized by an XRPD pattern that is substantially similar to FIG. 14A.

[0030] In embodiments, the crystalline form of Compound I free base is Form A. In embodiments, Compound I of Form A is a hydrate. In embodiments, Compound I of Form Ais a hydrate. In embodiments, Form A is characterized by XRPD peaks at 6.1±0.2, 14.8±0.2 and 18.0±0.2 °2θ.

[0031] In embodiments, the crystalline form of Compound I free base is Form C. In embodiments, Form C is an anhydrous form. In embodiments, Form C is characterized by XRPD peaks at 10.4±0.2, 10.2±0.2 and 21.8±0.2 °2θ. In embodiments, the present disclosure provides compositions comprising a crystalline form of Compound I and a pharmaceutically acceptable excipient.

[0032] In embodiments, the present disclosure provides a method of treating Hereditary Hemorrhagic Telangiectasia (HHT) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound I. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1A shows the X-ray powder diffraction (XRPD) diffractogram of a sample of Compound I Tartrate (Form E).

[0034] FIG.1B shows thermogravimetric differential thermal analysis (TG / DTA) thermogram of a sample of Compound I Tartrate (Form E).

[0035] FIG. 1C shows differential scanning calorimetry (DSC) thermogram of a sample of Compound I Tartrate (Form E).

[0036] FIG. 1D shows dynamic vapour sorption (DVS) isotherm of a sample of Compound I Tartrate (Form E).

[0037] FIG. 2A shows the XRPD diffractogram of a sample of Compound I Mesylate (Form M).

[0038] FIG.2B shows TG / DTA thermogram of a sample of Compound I Mesylate (Form M).

[0039] FIG. 2C shows DSC thermogram of a sample of Compound I Mesylate (Form M).

[0040] FIG. 2D shows DVS isotherm of a sample of Compound I Mesylate (Form M).

[0041] FIG. 2E shows intrinsic dissolution rate (IDR) study of Compound I Tartrate, Compound Mesylate and free base forms of Compound I in 0.1M HCl at 37°C.

[0042] FIG. 3A shows the XRPD diffractogram of a sample of Compound I Succinate (Form K).

[0043] FIG. 4A shows the XRPD diffractogram of a sample of Compound I Succinate (Form L).

[0044] FIG. 5A shows the XRPD diffractogram of a sample of Compound I Gentisate (Form P).

[0045] FIG. 6A shows the XRPD diffractogram of a sample of Compound I Phosphate (Form T).

[0046] FIG.7A shows the XRPD diffractogram of a sample of Compound I Ethanedisulfonate (Form D).

[0047] FIG.8A shows the XRPD diffractogram of a sample of Compound I Ethanedisulfonate (Form Q).

[0048] FIG.9A shows the XRPD diffractogram of a sample of Compound I Sulfate (Form G).

[0049] FIG. 10A shows the XRPD diffractogram of a sample of Compound I Ketoglutarate (Form I).

[0050] FIG. 11A shows the XRPD diffractogram of a sample of Compound I Pyroglutamate (Form O).

[0051] FIG. 12A shows the XRPD diffractogram of a sample of Compound I Malate (Form R).

[0052] FIG. 13A shows the XRPD diffractogram of a sample of Compound I Isethionate (Form S).

[0053] FIG. 14A shows the XRPD diffractogram of a sample of Compound I free base (Form B).

[0054] FIG.14B shows TG / DTA thermogram of a sample of Compound I free base (Form B).

[0055] FIG. 15A shows the XRPD diffractogram of a sample of Compound I free base (Form A).

[0056] FIG.15B shows TG / DTA thermogram of a sample of Compound I free base (Form A).

[0057] FIG. 15C shows DSC thermogram of a sample of Compound I free base (Form A).

[0058] FIG. 15D shows DVS isotherm of a sample of Compound I free base (Form A).

[0059] FIG.16A shows the XRPD diffractogram of a sample of Compound I free base (Form C).

[0060] FIG.16B shows TG / DTA thermogram of a sample of Compound I free base (Form C). DETAILED DESCRIPTION

[0061] All publications, patents and patent applications, including any drawings and appendices therein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or appendix wasspecifically and individually indicated to be incorporated by reference in its entirety for all purposes. Definitions

[0062] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0063] Compound I is 6-(4-((1s,3s)-1-amino-3-hydroxycyclobutyl)phenyl)-1-ethyl-7- phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one having the structural formula shown below. Compound I is disclosed in International Patent Publication No. WO2022 / 069552, which is hereby incorporated by reference in its entirety for all purposes.(Compound I).

[0064] All XRPD peaks and patterns are given in °2θ using Cu Kα1 radiation at a wavelength of 1.5406 Å. The values of degree 2θ allow appropriate error margins. For example, the degree 2θ of “17.4±0.2” denotes a range from 17.2 to 17.6 degree 2θ.

[0065] TGA and DSC thermograms for a given crystalline form of the same compound can vary within a margin of error. The values of a single peak, expressed in degree Celsius, allow appropriate error margins. Typically, the error margins are represented by “±”. For example, the single peak characteristic value of “120±5” denotes a range from 115 to 125. Depending on the sample preparation techniques, the calibration techniques applied to the instruments, human operational variations, and etc., those skilled in the art recognize that the appropriate error of margins for a single peak characteristic value can be ±5, which includes any value below ±5 such as ±4, ±3.5, ±3, ±2.5; ±2.0; ±1.5; ±1.0; ±0.5; or less.

[0066] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 22,500” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Similarly, the term “about” when preceding a series of numerical values or a range of values(e.g., "about 10, 20, 30" or "about 10-30") refers, respectively to all values in the series, or the endpoints of the range.

[0067] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or pharmaceutical composition containing the compound or salt) that, when administered to a patient, is capable of performing the intended result. The "effective amount" will vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.

[0068] The term “substantially similar” as used herein with regards to an analytical spectrum, such as an XRPD pattern, means that a spectrum resembles the reference spectrum in the peak locations, while allowing for variability appropriate in the art. Relatively intensities may fluctuate depending on various factors, such as instrumentation. For example, two spectra may be regarded as “substantially similar” when the two spectra share characteristic peaks sufficient to differentiate them from a spectrum obtained for a different solid form, but peak intensities may vary among the two spectra. In embodiments, spectra or characterization data that are substantially similar to those of a reference crystalline form are understood by those of ordinary skill in the art to correspond to the same crystalline form as the particular reference. In analyzing whether spectra or characterization data are substantially similar, a person of ordinary skill in the art understands that particular characterization data points may vary to a reasonable extent while still describing a given solid form, due to, for example, experimental error and routine sample-to-sample analysis.

[0069] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.

[0070] The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art. Salt and Crystalline Forms of Compound I

[0071] In aspects, the present disclosure provides crystalline forms of Compound I or salt, solvate, or solvate salt thereof.

[0072] In embodiments, the crystalline form is Compound I Tartrate (Form E).

[0073] In embodiments, the crystalline form is Compound I Mesylate (Form M).

[0074] In embodiments, the crystalline form is Compound I Succinate (Form K).

[0075] In embodiments, the crystalline form is Compound I Succinate (Form L).

[0076] In embodiments, the crystalline form is Compound I Gentisate (Form P).

[0077] In embodiments, the crystalline form is Compound I Phosphate (Form T).

[0078] In embodiments, the crystalline form is Compound I Ethanedisulfonate (Form D).

[0079] In embodiments, the crystalline form is Compound I Ethanedisulfonate (Form Q).

[0080] In embodiments, the crystalline form is Compound I Sulfate (Form G).

[0081] In embodiments, the crystalline form is Compound I Ketoglutarate (Form I).

[0082] In embodiments, the crystalline form is Compound I Pyroglutamate (Form O).

[0083] In embodiments, the crystalline form is Compound I Malate (Form R).

[0084] In embodiments, the crystalline form is Compound I Isethionate (Form S).

[0085] In embodiments, the crystalline form is Compound I free base (Form B).

[0086] In embodiments, the crystalline form is Compound I free base (Form A).

[0087] In embodiments, the crystalline form is anhydrous Compound I free base (Form C).

[0088] In aspects, the present disclosure provides an amorphous form of Compound I.

[0089] In embodiments, the crystalline form of Compound I is a salt. Examples of salts include, but are not limited to, hydrochloric acid salt, maleic acid salt, fumarate salt, citrate salt, malic salt, malonate salt, sulfate salt, acetate salt, phosphate salt, tartrate salt, L-(+)-tartrate salt, D- glucuronate salt, ketoglutarate salt, pyroglutamate salt, benzoate salt, succinate salt, mesylate salt, ethane sulfonate salt, ethanedisulfonate, gentisate salt, p-toluene sulfonate salt, malonic acid salt, benzene sulfonate salt, isethionate salt, and 1-hydroxy-2-naphthoic acid salt. In embodiments, the crystalline form of Compound I is a tartrate salt. In embodiments, the crystalline form of Compound I is a tartrate salt. In embodiments, the crystalline form of Compound I is a mesylate salt.

[0090] In embodiments, the crystalline form of Compound I is a solvate. Non-limiting examples of suitable solvates include dichloromethane (DCM), dioxane, dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), methanol, isopropanol, ethanol, and ethyl acetate.

[0091] In embodiments, the crystalline form of Compound is an anhydrate.

[0092] In embodiments, the crystalline form of Compound I is a hydrate. Non-limiting examples of hydrates include hemihydrates, monohydrates, dihydrates, trihydrates, hexahydrates.

[0093] In embodiments of the crystalline form of Compound I, Compound I is in a free base form.

[0094] In embodiments, the crystalline form of Compound I may comprise of a mixture of one or more forms Compound I. In embodiments, the crystalline form of Compound I may comprise of substantially pure form of one form of Compound I.

[0095] In embodiments, the crystalline form of Compound I comprises a substantially pure form of one crystalline form of Compound I. In one embodiment, the crystalline form of Compound I comprises over about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of any one of the crystalline forms of Compound I. In another embodiment, the crystalline form of Compound I comprises at least about 99%, at least about 98%, at least about 97%, at least about 96%, at least about 95%, at least about 94%, at least about 93%, at least about 92%, at least about 91%, or at least about 90% of any one of the crystalline forms of Compound I. In embodiments, the crystalline form of Compound I comprises at least about at least about 90%, at least about 85%, at least about 80%, at least about 75%, at least about 70%, at least about 65%, at least about 60%, at least about 55%, at least about 50%, at least about 45%, or at least about 40% of one of any one of the crystalline forms of Compound I.

[0096] In embodiments, the crystalline form of Compound I may comprise of over about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of any combination of any one of the crystalline forms of Compound I. Tartrate Salt

[0097] In embodiments, the present disclosure provides a tartrate salt of Compound I (“Compound I Tartrate”). In embodiments, Compound I Tartrate is an L-tartrate salt. In embodiments, the present disclosure provides a crystalline form of Compound I Tartrate.

[0098] In embodiments, the present disclosure provides Compound I Tartrate (Form E). In embodiments, Form E is characterized by X-ray powder diffraction (XRPD) peaks at 21.6±0.2, 15.5 ±0.2 and 12.4 ±0.2 °2θ. In embodiments, Form E is further characterized by XRPD peaks at 18.7±0.2 and 11.4 ±0.2 °2θ. In embodiments, Form E is further characterized by at least one XRPD peaks at 9.3 ±0.2, 23.0±0.2, 15.7±0.2, 14.9±0.2, 14.1±0.2, 22.7±0.2, 29.8±0.2, 14.8±0.2, 22.4±0.2, 23.5±0.2, 27.5±0.2, 15.5±0.2, 20.9±0.2, 22.8±0.2 and 22.1±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0099] In embodiments, Form E is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 21.6±0.2, 15.5 ±0.2, 12.4 ±0.2, 18.7±0.2, 11.4 ±0.2, 9.3 ±0.2, 23.0±0.2, 15.7±0.2, 14.9±0.2, 14.1±0.2, 22.7±0.2, 29.8±0.2, 14.8±0.2, 22.4±0.2, 23.5±0.2, 27.5±0.2, 15.5±0.2,20.9±0.2, 22.8±0.2 and 22.1±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0100] In embodiments, Form E is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 1A. In embodiments, Form E is characterized by an XRPD pattern substantially similar to that shown in FIG. 1A.

[0101] In embodiments, Form E is characterized by an XRPD pattern comprising peaks show in Table 1.

[0102] Table 1. XRPD peaks of Form E No.Pos.Rel. Int. [°2θ][%] 1 9.3 38.47 2 10.2 2.42 3 11.4 57.39 4 12.2 11.13 5 12.4 59.01 6 13.1 5.84 7 14.1 23.41 8 14.8 20.49 9 14.9 29.19 10 15.1 17.79 11 15.5 85.81 12 15.7 30.07 13 16.2 2.82 14 16.5 1.63 15 17.0 7.89 16 17.7 3.59 17 18.1 2.01 18 18.3 6.30 19 18.8 57.82 20 19.5 7.63 21 20.5 3.70 22 20.9 16.59 23 21.7 100.00 24 22.1 15.16 25 22.4 18.83 26 22.7 21.57 27 22.8 15.43 28 23.0 34.74 29 23.5 18.31 30 24.1 4.80 31 24.5 8.10 32 25.2 3.95 33 26.0 3.5034 26.2 14.28 35 26.9 2.21 36 27.5 17.80 37 27.8 2.92 38 28.0 2.92 39 28.3 8.95 40 28.7 3.57 41 29.6 7.50 42 29.8 21.12 43 30.2 3.61 44 30.5 8.23 45 30.9 3.42 46 31.1 6.89 47 31.7 2.90 48 32.0 4.33 49 32.4 6.64 50 32.7 3.45 51 32.9 3.74 52 33.4 2.24 53 33.8 2.42 54 34.1 2.31 55 34.8 3.62 56 35.9 2.08 57 36.4 2.48 58 36.7 4.91 59 37.3 3.46 60 37.6 4.51 61 38.1 7.17 62 38.5 6.71 63 38.8 3.78 64 39.3 4.77

[0103] In embodiments, Form E exhibits a thermogravimetric differential thermal analysis (TG / DTA) thermogram having an endothermic peak at 210±5 ℃. In embodiments, Form E exhibits a TG / DTA thermogram having an endothermic peak with an onset at 208±5 ℃.

[0104] In embodiments, Form E exhibits a weight loss of about 14.6% from about 175°C to about 300°C as measured by TG / DTA. In embodiments, Form E exhibits a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 210±5 ℃.

[0105] In embodiments, Form E exhibits a TG / DTA thermogram substantially similar to that shown in FIG. 1B. In embodiments, Form E exhibits a DSC thermogram substantially similar to that shown in FIG. 1C.Mesylate Salt

[0106] In embodiments, the present disclosure provides a mesylate salt of Compound I (“Compound I Mesylate”). In embodiments, the present disclosure provides a crystalline form of Compound I Mesylate.

[0107] In embodiments, the present disclosure provides Compound I Mesylate (Form M). In embodiments of Form M, the molar ratio of mesylate to Compound I is about 1:1.

[0108] In embodiments, Form M is characterized by XRPD peaks at 7.9±0.2, 22.1 ±0.2 and 20.4 ±0.2 °2θ. In embodiments, Form M is further characterized by XRPD peaks at 20.1 ±0.2 and 17.2 ±0.2 °2θ. In embodiments, Form M is further characterized by at least one XRPD peaks at 6.8 ±0.2, 15.7 ±0.2, 14.4±0.2, 10.3±0.2, 24.7±0.2, 13.4±0.2, 17.4±0.2, 24.2±0.2, 17.1±0.2, 23.6±0.2, 19.8±0.2, 18.4±0.2, 18.2±0.2, 23.9±0.2, °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0109] In embodiments, Form M is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 7.9±0.2, 22.1 ±0.2, 20.4 ±0.2, 20.1 ±0.2, 17.2 ±0.2, 6.8 ±0.2, 15.7 ±0.2, 14.4±0.2, 10.3±0.2, 24.7±0.2, 13.4±0.2, 17.4±0.2, 24.2±0.2, 17.1±0.2, 23.6±0.2, 19.8±0.2, 18.4±0.2, 18.2±0.2, 23.9±0.2, °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0110] In embodiments, Form M is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 2A. In embodiments, Form M is characterized by an XRPD pattern that is substantially similar to FIG. 2A.

[0111] In embodiments, Form M is characterized by an XRPD pattern comprising peaks show in Table 2.

[0112] Table 2. XRPD peaks of Form M No. Pos. Rel. Int. [°2θ] [%] 1 8.0 100.00 2 10.3 33.26 3 11.0 10.96 4 12.6 7.10 5 12.9 3.51 6 13.4 28.92 7 13.7 5.02 8 13.9 3.91 9 14.3 8.98 10 14.4 34.05 11 15.0 10.25 12 15.7 34.1015.9 3.25 16.7 5.82 16.8 37.37 17.1 22.75 17.2 38.03 17.4 23.43 17.9 7.35 18.2 17.09 18.3 9.29 18.4 21.18 19.6 14.66 19.8 21.22 20.4 64.83 21.0 45.89 21.5 7.74 22.1 82.19 22.2 11.13 22.6 5.84 23.1 10.82 23.6 9.09 23.6 21.37 23.9 15.97 24.2 23.10 24.3 4.22 24.7 29.34 25.3 8.67 25.5 4.30 25.9 3.81 26.1 7.94 26.6 4.86 26.8 7.76 27.0 5.23 27.4 3.13 27.6 14.37 27.9 3.69 28.5 4.21 28.6 6.83 28.8 8.43 29.1 4.75 29.4 2.90 29.6 5.01 29.9 4.17 30.4 3.64 30.8 2.87 31.2 8.09 31.7 7.4659 32.2 5.83 60 32.5 3.08 61 32.7 6.41 62 32.9 4.31 63 33.2 3.17 64 33.4 6.58 65 34.0 2.85 66 34.3 3.41 67 34.7 3.56 68 35.1 4.08 69 35.4 4.40 70 35.7 2.49 71 36.1 2.84 72 36.3 3.07 73 36.6 2.54 74 37.4 4.06 75 37.9 1.85 76 38.2 2.44 77 38.7 2.07 78 39.4 3.46

[0113] In embodiments, Form M exhibits a TG / DTA thermogram having an endothermic peak at 266±5 ℃. In embodiments, Form M exhibits a TG / DTA thermogram having an endothermic peak with an onset at 261±5 ℃. In embodiments, Form M exhibits a weight loss of less than 1% from about 35 °C to about 240 °C as measured by TG / DTA.

[0114] In embodiments, Form M exhibits a DSC thermogram having an endothermic peak with an onset at 262±5 ℃. In embodiments, Form M exhibits a DSC thermogram comprising an endothermic peak at 265±5 ℃.

[0115] In embodiments, Form M exhibits a TG / DTA thermogram substantially similar to that shown in FIG.2B. In embodiments, Form M exhibits a DSC thermogram substantially similar to that shown in FIG. 2C. Succinate Salt

[0116] In embodiments, the present disclosure provides a succinate salt of Compound I (“Compound I Succinate”). In embodiments, the present disclosure provides a crystalline form of Compound I Succinate.

[0117] In embodiments, the present disclosure provides Compound I Succinate (Form K). In embodiments of Form K, the molar ratio of succinate to Compound I is about 2:1.

[0118] In embodiments, From K is characterized by X-ray powder diffraction (XRPD) peaks at 21.4±0.2, 6.1 ±0.2 and 10.0 ±0.2 °2θ. In embodiments, From K is further characterized byXRPD peaks at 17.4±0.2 and 22.9 ±0.2 °2θ.In embodiments, From K is further characterized by at least one XRPD peaks at 16.0±0.2, 14.7±0.2, 11.4 ±0.2, 16.4±0.2, 20.3±0.2, 23.9±0.2, 17.7 ±0.2, 19.3 ±0.2, 21.9±0.2, 18.9 ±0.2, 24.8±0.2, 26.9 ±0.2 and 9.5±0.2°2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0119] In embodiments, Form K is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 21.4±0.2, 6.1 ±0.2, 10.0 ±0.2, 17.4±0.2, 22.9 ±0.2, 16.0±0.2, 14.7±0.2, 11.4 ±0.2, 16.4±0.2, 20.3±0.2, 23.9±0.2, 17.7 ±0.2, 19.3 ±0.2, 21.9±0.2, 18.9 ±0.2, 24.8±0.2, 26.9 ±0.2 and 9.5±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0120] In embodiments, Form K is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 3A. In embodiments, Form K is characterized by an XRPD pattern that is substantially similar to FIG. 3A.

[0121] In embodiments, Form K is characterized by an XRPD pattern comprising peaks show in Table 3.

[0122] Table 3. XRPD peaks of Form K No. Pos. [°2θ] Rel. Int. [%] 1 6.1 84.38 2 8.8 11.51 3 9.5 18.53 4 10.0 61.12 5 10.3 12.22 6 10.7 17.26 7 10.8 12.08 8 11.4 42.94 9 12.3 12.06 10 12.8 14.18 11 13.3 14.38 12 13.9 16.70 13 14.5 12.89 14 14.7 45.07 15 14.8 15.42 16 15.3 12.40 17 15.7 12.91 18 16.0 46.56 19 16.1 14.66 20 16.4 40.26 21 16.9 15.27 22 17.4 55.16 23 17.7 26.31 24 17.9 12.65 25 18.2 6.9526 18.6 6.90 27 18.9 24.11 28 19.2 14.93 29 19.3 24.94 30 19.7 15.27 31 19.8 10.43 32 20.2 17.04 33 20.3 39.68 34 20.8 17.00 35 21.0 13.57 36 21.4 100.00 37 21.9 24.31 38 22.1 17.51 39 22.3 10.97 40 22.9 47.42 41 23.1 17.13 42 23.3 13.38 43 23.6 9.70 44 23.9 27.60 45 24.2 8.13 46 24.8 22.42 47 25.4 13.19 48 25.8 9.85 49 26.1 10.10 50 26.3 12.04 51 26.9 21.06 52 28.3 7.60 53 28.5 6.20 54 29.2 5.27 55 29.7 5.78 56 29.9 5.14 57 30.5 6.75 58 31.5 6.36 59 32.3 8.63 60 33.0 4.95

[0123] In embodiments, the present disclosure provides Compound I Succinate (Form L). In embodiments of Form L, the molar ratio of succinate to Compound I is about 1:1.

[0124] In embodiments, Form L is characterized by XRPD peaks at 17.3±0.2, 6.3 ±0.2 and 22.1 ±0.2 °2θ. In embodiments, Form L is further characterized by XRPD peaks at 11.0±0.2 and 17.5 ±0.2 °2θ. In embodiments, Form L further characterized by at least XRPD peaks at 10.0±0.2, 14.7 ±0.2, 21.6 ±0.2, 20.2±0.2, 11.6 ±0.2, 22.4 ±0.2, 14.9±0.2, 22.9±0.2, 27.2±0.2,12.7±0.2, 24.4±0.2, 23.2±0.2, 20.6±0.2 and 23.4±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0125] In embodiments, Form L is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 17.3±0.2, 6.3 ±0.2, 22.1 ±0.2, 11.0±0.2, 17.5 ±0.2, 10.0±0.2, 14.7 ±0.2, 21.6 ±0.2, 20.2±0.2, 11.6 ±0.2, 22.4 ±0.2, 14.9±0.2, 22.9±0.2, 27.2±0.2, 12.7±0.2, 24.4±0.2, 23.2±0.2, 20.6±0.2 and 23.4±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0126] In embodiments, Form L is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 4A. In embodiments, Form L is characterized by an XRPD pattern that is substantially similar to FIG. 4A.

[0127] In embodiments, Form L is characterized by an XRPD pattern comprising peaks show in Table 4.

[0128] Table 4. XRPD peaks of Form L No. Pos. [°2θ] Rel. Int. [%] 1 6.3 90.27 2 7.4 9.47 3 8.1 10.14 4 8.4 5.54 5 10.0 55.95 6 11.0 65.06 7 11.6 30.75 8 12.7 21.42 9 14.7 41.89 10 14.9 24.03 11 15.4 10.37 12 16.0 9.15 13 16.3 7.32 14 17.3 100.00 15 17.5 57.15 16 18.7 6.82 17 20.0 12.22 18 20.2 31.69 19 20.6 14.73 20 21.3 10.38 21 21.6 40.44 22 22.1 80.85 23 22.4 25.50 24 22.9 23.94 25 23.2 16.51 26 23.4 14.2727 24.4 17.57 28 24.7 12.24 29 25.0 7.45 30 25.5 11.20 31 25.7 13.87 32 26.2 4.21 33 27.2 22.95 34 27.9 5.90 35 29.2 5.55 36 29.9 5.50 37 30.3 6.99 38 31.1 4.51 39 31.4 6.35 40 31.7 7.51 41 32.5 6.11 Gentisate Salt

[0129] In embodiments, the present disclosure provides a gentisate salt of Compound I (“Compound I Gentisate”). In embodiments, the present disclosure provides a crystalline form of Compound I Gentisate.

[0130] In embodiments, the present disclosure provides Compound I Gentisate (Form P). In embodiments of Form P, the molar ratio of gentisate salt to Compound I is about 1:1.

[0131] In embodiments, Form P is characterized by XRPD peaks at 6.5±0.2, 7.2±0.2 and 7.4±0.2 °2θ. In embodiments, Form P is further characterized by XRPD peaks at 22.9±0.2 and 20.1±0.2 °2θ. In embodiments, Form P is further characterized by at least one XRPD peaks at 16.3±0.2, 13.0 ±0.2, 18.1±0.2, 17.4±0.2, 17.8±0.2, 16.7±0.2, 23.1±0.2, 27.5±0.2, 19.0±0.2, 12.1±0.2, 8.3±0.2, 21.7 ±0.2 and 18.8±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0132] In embodiments, Form P is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 6.5±0.2, 7.2±0.2, 7.4±0.2, 22.9±0.2, 20.1±0.2, 16.3±0.2, 13.0 ±0.2, 18.1±0.2, 17.4±0.2, 17.8±0.2, 16.7±0.2, 23.1±0.2, 27.5±0.2, 19.0±0.2, 12.1±0.2, 8.3±0.2, 21.7 ±0.2 and 18.8±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0133] In embodiments, Form P is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 5A. In embodiments, Form P is characterized by an XRPD pattern that is substantially similar to FIG. 5A.

[0134] In embodiments, Form P is characterized by an XRPD pattern comprising peaks show in Table 5.

[0135] Table 5. XRPD peaks of Form PPos. Rel. Int. No. [°2θ] [%] 1 6.5 100.00 2 7.2 56.00 3 7.4 45.34 4 8.3 11.93 5 10.5 9.96 6 10.9 9.92 7 11.5 5.35 8 12.1 12.38 9 12.4 2.96 10 13.0 29.82 11 13.3 2.75 12 14.2 4.91 13 14.4 7.31 14 14.9 3.11 15 15.1 7.88 16 15.4 5.95 17 16.3 30.78 18 16.7 19.35 19 17.0 4.77 20 17.1 6.05 21 17.4 20.10 22 17.5 8.77 23 17.8 19.74 24 18.1 21.78 25 18.8 11.50 26 19.0 14.77 27 19.5 8.16 28 19.7 4.95 29 19.9 4.32 30 20.1 41.05 31 21.0 11.39 32 21.4 10.04 33 21.7 11.69 34 22.2 7.16 35 22.5 4.81 36 22.9 43.44 37 23.1 16.67 38 23.4 9.39 39 24.0 7.01 40 24.4 8.73 41 24.8 3.27 42 25.1 10.01 43 25.5 3.54 44 26.2 4.8345 26.9 8.55 46 27.5 16.45 47 27.8 8.09 48 28.7 2.50 49 29.0 3.55 50 29.5 8.10 51 29.8 8.87 52 30.5 3.75 53 30.8 2.56 54 31.7 2.68 55 32.0 2.57 56 32.9 2.70 57 33.1 2.48 58 34.4 2.58 59 34.9 2.59 60 35.6 2.43 61 36.7 2.97 Phosphate Salt

[0136] In embodiments, the present disclosure provides a phosphate salt of Compound I (“Compound I Phosphate”). In embodiments, the present disclosure provides a crystalline form of Compound I Phosphate.

[0137] In embodiments, the present disclosure provides Compound I Phosphate (Form T).

[0138] In embodiments, Form T is characterized by XRPD peaks at 9.1±0.2, 19.2±0.2 and 17.0±0.2 °2θ. In embodiments, Form T is further characterized by XRPD peaks at 17.8±0.2 and 20.5±0.2 °2θ. In embodiments, Form T is further characterized by at least one XRPD peaks at 20.4±0.2, 22.4±0.2, 18.3±0.2, 12.3±0.2, 17.6±0.2, 3.9±0.2, 23.4±0.2, 11.6±0.2, 23.0±0.2, 18.7±0.2, 11.3±0.2, 27.2±0.2, 16.3±0.2, 21.8±0.2 and 14.3±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0139] In embodiments, Form T is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 9.1±0.2, 19.2±0.2, 17.0±0.2, 17.8±0.2, 20.5±0.2, 20.4±0.2, 22.4±0.2, 18.3±0.2, 12.3±0.2, 17.6±0.2, 3.9±0.2, 23.4±0.2, 11.6±0.2, 23.0±0.2, 18.7±0.2, 11.3±0.2, 27.2±0.2, 16.3±0.2, 21.8±0.2 and 14.3±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0140] In embodiments, Form T is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 6A. In embodiments, Form T is characterized by an XRPD pattern that is substantially similar to FIG. 6A.

[0141] In embodiments, Form T is characterized by an XRPD pattern comprising peaks show in Table 6.

[0142] Table 6. XRPD peaks of Form T No. Pos. [°2θ] Rel. Int. [%] 1 3.9 22.51 2 7.7 5.92 3 9.1 100.00 4 11.3 14.69 5 11.6 21.03 6 11.9 5.84 7 12.3 25.68 8 13.9 6.71 9 14.3 11.45 10 14.5 3.81 11 16.3 12.20 12 17.0 42.72 13 17.6 25.20 14 17.8 37.21 15 18.1 5.33 16 18.3 26.69 17 18.7 16.46 18 19.2 69.41 19 20.0 10.94 20 20.5 34.24 21 21.0 5.63 22 21.3 4.89 23 21.8 11.70 24 22.4 30.68 25 23.0 17.00 26 23.4 21.66 27 24.0 34.04 28 24.4 4.97 29 24.8 4.83 30 25.1 6.35 31 25.4 11.07 32 25.7 9.61 33 26.1 9.22 34 26.9 5.57 35 27.2 12.25 36 27.4 5.81 37 27.7 8.09 38 28.1 3.41 39 28.8 4.14 40 28.9 3.93 41 29.4 10.5842 29.6 5.43 43 30.0 4.31 44 30.5 6.56 45 30.8 3.14 46 31.3 7.34 47 31.8 5.95 48 33.1 4.10 49 33.7 3.33 50 34.4 3.06 51 34.6 4.67 52 34.9 4.10 53 35.7 4.80 54 36.4 3.77 55 37.1 2.84 56 37.9 5.65 57 38.6 3.72 58 38.9 3.98 59 39.1 4.58 Ethanedisulfonate Salt

[0143] In embodiments, the present disclosure provides an ethanedisulfonate salt of Compound I (“Compound I Ethanedisulfonate”). In embodiments, the present disclosure provides a crystalline form of Compound I Ethanedisulfonate.

[0144] In embodiments, the present disclosure provides Compound I Ethanedisulfonate (Form D). In embodiments of Form D, the molar ratio of ethanedisulfonate to Compound I is about 1:1.

[0145] In embodiments, Form D is characterized by XRPD peaks at 9.8±0.2, 21.8 ±0.2 and 26.6±0.2 °2θ. In embodiments, Form D is further characterized by XRPD peaks at 14.6±0.2 and 21.2±0.2 °2θ. In embodiments, Form D is further characterized by XRPD peaks at 11.0±0.2, 20.7±0.2, 17.8±0.2, 19.0±0.2, 18.6±0.2, 22.1±0.2, 5.7 ±0.2, 20.4±0.2 .25.7±0.2, 29.5±0.2, 16.0±0.2, 24.5±0.2, 23.8±0.2, 24.7±0.2 and 32.2±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0146] In embodiments, Form D is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 9.8±0.2, 21.8 ±0.2, 26.6±0.2, 14.6±0.2, 21.2±0.2, 11.0±0.2, 20.7±0.2, 17.8±0.2, 19.0±0.2, 18.6±0.2, 22.1±0.2, 5.7 ±0.2, 20.4±0.2 .25.7±0.2, 29.5±0.2, 16.0±0.2, 24.5±0.2, 23.8±0.2, 24.7±0.2 and 32.2±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0147] In embodiments, Form D is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 7A. In embodiments, Form D is characterized by an XRPD pattern that is substantially similar to FIG. 7A.

[0148] In embodiments, Form D is characterized by an XRPD pattern comprising peaks show in Table 7.

[0149] Table 7. XRPD peaks of Form D Pos. Rel. Int. No. [°2θ] [%] 1 5.7 17.40 2 9.8 100.00 3 11.0 35.68 4 11.4 7.58 5 13.2 7.10 6 14.6 44.72 7 15.1 2.89 8 16.0 10.64 9 16.1 5.73 10 16.6 2.40 11 17.8 25.91 12 18.6 18.74 13 19.0 20.94 14 19.3 1.84 15 19.7 1.68 16 20.2 4.10 17 20.4 15.29 18 20.7 32.20 19 21.2 42.99 20 21.8 84.21 21 22.1 18.16 22 22.6 4.01 23 23.0 5.20 24 23.2 2.08 25 23.5 6.68 26 23.8 9.12 27 24.1 3.24 28 24.5 9.15 29 24.7 9.07 30 25.7 13.01 31 25.9 4.07 32 26.6 47.93 33 27.0 5.86 34 27.2 3.54 35 27.4 2.49 36 27.6 2.7337 27.8 6.40 38 28.1 5.65 39 28.4 3.47 40 29.0 2.29 41 29.5 13.00 42 30.0 5.62 43 30.6 2.27 44 31.3 4.49 45 32.2 7.73 46 33.3 2.48 47 33.6 1.39 48 34.3 4.71 49 34.7 1.07 50 35.5 2.01 51 35.8 2.04 52 36.1 2.93 53 36.7 2.31 54 37.4 2.82 55 38.1 2.11 56 38.5 2.06 57 39.3 2.14

[0150] In embodiments, the present disclosure provides Compound I Ethanedisulfonate (Form Q).

[0151] In embodiments, Form Q is characterized by XRPD peaks at 9.4±0.2, 6.5 ±0.2 and 22.4 ±0.2 °2θ. In embodiments, Form Q is further characterized by XRPD peaks at 12.1±0.2 and 18.2±0.2 °2θ. In embodiments, Form Q is further characterized by XRPD peaks at 13.7±0.2, 18.9 ±0.2, 25.4±0.2, 20.3±0.2, 20.6±0.2, 24.4 ±0.2, 21.3±0.2, 17.7±0.2, 16.0±0.2, 20.1±0.2, 15.2±0.2, 18.6±0.2, 26.4±0.2, 25.1±0.2 and 7.8±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0152] In embodiments, Form Q is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 9.4±0.2, 6.5 ±0.2, 22.4 ±0.2, 12.1±0.2, 18.2±0.2, 13.7±0.2, 18.9 ±0.2, 25.4±0.2, 20.3±0.2, 20.6±0.2, 24.4 ±0.2, 21.3±0.2, 17.7±0.2, 16.0±0.2, 20.1±0.2, 15.2±0.2, 18.6±0.2, 26.4±0.2, 25.1±0.2 and 7.8±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0153] In embodiments, Form Q is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 8A. In embodiments, Form Q is characterized by an XRPD pattern that is substantially similar to FIG. 8A.

[0154] In embodiments, Form Q is characterized by an XRPD pattern comprising peaks show in Table 8.

[0155] Table 8. XRPD peaks of Form Q No.Pos.Rel. Int. [°2θ] [%] 1 6.5 96.37 2 7.8 15.31 3 8.2 14.40 4 8.8 10.15 5 9.4 100.00 6 12.1 65.17 7 13.7 52.76 8 14.5 8.81 9 14.7 9.91 10 15.2 16.45 11 15.6 14.25 12 16.0 20.52 13 16.8 13.14 14 16.9 8.52 15 17.3 13.38 16 17.7 26.46 17 18.2 58.70 18 18.6 16.26 19 18.9 50.66 20 19.5 8.45 21 19.7 7.81 22 20.1 18.45 23 20.3 36.12 24 20.6 33.59 25 21.3 28.45 26 21.6 13.67 27 21.9 14.05 28 22.4 84.54 29 23.0 8.74 30 23.7 15.24 31 24.4 29.69 32 24.9 12.36 33 25.1 15.53 34 25.4 43.68 35 25.8 12.77 36 26.1 10.84 37 26.4 15.94 38 26.6 13.99 39 27.0 7.35 40 27.5 11.8641 27.9 6.77 42 28.5 11.98 43 29.5 12.36 44 29.9 6.97 45 30.1 6.79 46 30.6 9.46 47 30.8 10.64 48 31.5 10.42 Sulfate Salt

[0156] In embodiments, the present disclosure provides a sulfate salt of Compound I (“Compound I Sulfate”). In embodiments, the present disclosure provides a crystalline form of Compound I Sulfate.

[0157] In embodiments, the present disclosure provides Compound I Sulfate (Form G).

[0158] In embodiments, Form G is characterized by XRPD peaks at 10.2±0.2, 20.4±0.2 and 14.6±0.2 °2θ. In embodiments, Form G is further characterized by XRPD peaks at 21.8±0.2 and 10.4±0.2 °2θ. In embodiments, Form G is further characterized by at least XRPD peaks at 8.2±0.2, 26.4±0.2, 6.7±0.2, 9.5±0.2, 8.5±0.2, 5.6±0.2, 20.8±0.2, 15.3±0.2, 24.8±0.2, 19.0±0.2, 24.0±0.2, 17.0±0.2, 15.9±0.2, 13.4±0.2 and 16.9±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0159] In embodiments, Form G is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 10.2±0.2, 20.4±0.2, 14.6±0.2, 21.8±0.2 and 10.4±0.2, 8.2±0.2, 26.4±0.2, 6.7±0.2, 9.5±0.2, 8.5±0.2, 5.6±0.2, 20.8±0.2, 15.3±0.2, 24.8±0.2, 19.0±0.2, 24.0±0.2, 17.0±0.2, 15.9±0.2, 13.4±0.2 and 16.9±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0160] In embodiments, Form G is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 9A. In embodiments, Form G is characterized by an XRPD pattern that is substantially similar to FIG. 9A.

[0161] In embodiments, Form G is characterized by an XRPD pattern comprising peaks show in Table 9.

[0162] Table 9. XRPD peaks of Form G No.Pos.Rel. Int. [°2θ] [%] 1 5.6 15.08 2 6.7 19.79 3 8.2 23.51 4 8.5 15.168.7 3.90 9.1 5.38 9.5 17.41 10.2 100.00 10.4 26.37 10.9 3.85 11.7 6.99 12.0 5.25 12.3 4.89 13.0 4.39 13.4 8.72 14.6 41.57 15.3 14.01 15.5 6.26 15.9 10.23 16.3 6.71 16.7 6.30 16.9 7.58 17.0 10.30 17.5 3.53 17.9 4.25 18.1 4.86 18.3 5.67 18.6 7.26 19.0 12.63 19.3 6.11 19.7 3.51 20.4 48.15 20.8 14.30 21.8 32.36 22.3 6.33 23.4 6.18 24.0 10.38 24.8 13.15 25.7 5.72 26.4 21.39 26.7 4.98 27.1 5.92 27.4 4.62 27.6 4.32 28.1 3.92 28.4 4.61 28.9 3.94 29.4 5.13 30.7 4.60 31.6 3.4351 32.1 2.57 52 32.8 2.26 53 33.2 2.86 54 33.8 2.02 55 36.7 2.79 56 37.2 2.58 I. Ketoglutarate Salt

[0163] In embodiments, the present disclosure provides a ketoglutarate salt of Compound I (“Compound I Ketoglutarate”). In embodiments, the present disclosure provides a crystalline form of Compound I Ketoglutarate.

[0164] In embodiments, the present disclosure provides Compound I Ketoglutarate (Form I).

[0165] In embodiments, Form I is characterized by XRPD peaks at 8.3±0.2, 8.1±0.2 and 6.1±0.2 °2θ. In embodiments, Form I is further characterized by XRPD peaks at 11.6±0.2 and 23.9±0.2 °2θ. In embodiments, Form I is further characterized by XRPD peaks at 24.4±0.2, 12.2±0.2, 18.5±0.2, 23.0±0.2, 13.5±0.2, 19.5±0.2, 21.8±0.2, 13.3±0.2, 9.1±0.2, 15.3±0.2, 16.6±0.2, 17.9±0.2, 16.9±0.2, 24.8±0.2 and 8.5±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0166] In embodiments, Form I is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 8.3±0.2, 8.1±0.2, 6.1±0.2, 11.6±0.2, 23.9±0.2, 24.4±0.2, 12.2±0.2, 18.5±0.2, 23.0±0.2, 13.5±0.2, 19.5±0.2, 21.8±0.2, 13.3±0.2, 9.1±0.2, 15.3±0.2, 16.6±0.2, 17.9±0.2, 16.9±0.2, 24.8±0.2 and 8.5±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0167] In embodiments, Form I is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 10A. In embodiments, Form I is characterized by an XRPD pattern that is substantially similar to FIG. 10A.

[0168] In embodiments, Form I is characterized by an XRPD pattern comprising peaks show in Table 10.

[0169] Table 10. XRPD peaks of Form I Pos. Rel. Int. No. [°2θ] [%] 1 6.0522 77.19 2 6.2066 7.69 3 7.4036 11.97 4 8.1377 95.85 5 8.2516 100.00 6 8.4748 15.679.1263 20.48 9.6413 4.60 11.2131 3.86 11.6080 47.99 12.1505 30.51 13.3200 20.63 13.4710 21.61 13.9783 3.58 14.1530 3.46 14.5896 4.21 14.8516 5.30 15.3130 20.18 15.5241 4.46 15.7196 10.14 16.3144 14.24 16.5694 19.14 16.8840 16.87 17.4934 3.60 17.8768 18.40 18.1116 5.11 18.2572 9.82 18.4955 30.02 18.8975 6.09 19.4690 20.95 19.6498 14.08 19.8986 4.59 20.1577 3.83 20.9564 11.40 21.3769 13.92 21.7787 20.66 22.0580 4.02 22.4393 12.38 22.6895 12.63 23.0202 22.80 23.3363 3.22 23.6300 3.59 23.8663 38.46 24.2346 8.17 24.4382 36.35 24.8243 15.75 25.3280 12.36 25.7076 9.08 26.0830 4.41 26.2903 5.10 26.4803 5.13 26.8420 12.7353 27.3714 8.79 54 27.7398 12.46 55 27.9379 4.18 56 28.1625 2.63 57 28.5993 5.21 58 29.2162 2.61 59 29.4581 3.40 60 29.7517 3.91 61 30.8909 4.43 62 31.6692 3.92 63 31.8420 3.98 64 32.2566 2.59 65 32.6081 4.98 66 33.8113 2.28 67 34.4678 2.40 68 35.1760 2.94 69 35.3833 2.60 70 35.8325 3.56 71 36.1952 2.66 72 36.7618 2.54 73 37.0900 3.11 Pyroglutamate Salt

[0170] In embodiments, the present disclosure provides a pyroglutamate salt of Compound I (“Compound I Pyroglutamate”). In embodiments, the present disclosure provides a crystalline form of Compound I Pyroglutamate.

[0171] In embodiments, the present disclosure provides Compound I Pyroglutamate (Form O).

[0172] In embodiments, Form O is characterized by XRPD peaks at 16.4±0.2, 9.6±0.2 and 19.3±0.2 °2θ. In embodiments, Form O is further characterized by XRPD peaks at 18.3±0.2 and 13.5±0.2 °2θ. In embodiments, Form O is further characterized by at least XRPD peaks at 17.5±0.2, 18.9±0.2, 15.0±0.2, 10.8±0.2, 8.5±0.2, 26.2±0.2, 21.8±0.2, 16.9±0.2, 22.3±0.2, 21.2±0.2, 18.5±0.2, 25.8±0.2, 24.1±0.2, 22.9±0.2 and 27.1±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0173] In embodiments, Form O is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 16.4±0.2, 9.6±0.2, 19.3±0.2 18.3±0.2, 13.5±0.2, 17.5±0.2, 18.9±0.2, 15.0±0.2, 10.8±0.2, 8.5±0.2, 26.2±0.2, 21.8±0.2, 16.9±0.2, 22.3±0.2, 21.2±0.2, 18.5±0.2, 25.8±0.2, 24.1±0.2, 22.9±0.2 and 27.1±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0174] In embodiments, Form O is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 11A. In embodiments, Form O is characterized by an XRPD pattern that is substantially similar to FIG. 11A.

[0175] In embodiments, Form O is characterized by an XRPD pattern comprising peaks show in Table 11.

[0176] Table 11. XRPD peaks of Form O Pos. Rel. Int. No. [°2θ] [%] 1 4.5 8.91 2 4.8 10.24 3 8.0 8.47 4 8.5 33.69 5 9.6 76.82 6 10.0 10.26 7 10.2 13.17 8 10.4 6.40 9 10.8 34.48 10 11.1 7.63 11 11.7 5.45 12 13.2 11.53 13 13.5 45.17 14 14.2 6.54 15 15.0 41.09 16 15.5 10.60 17 16.0 10.36 18 16.4 100.00 19 16.9 25.98 20 17.2 16.26 21 17.5 44.57 22 17.9 11.69 23 18.3 45.34 24 18.5 22.48 25 18.9 42.55 26 19.3 64.06 27 19.8 12.14 28 20.1 11.09 29 20.3 9.23 30 20.5 13.96 31 21.2 23.91 32 21.5 9.67 33 21.8 28.38 34 22.3 25.66 35 22.6 12.99 36 22.9 18.2337 23.2 12.59 38 23.6 8.00 39 24.1 18.53 40 24.3 10.76 41 24.7 14.01 42 25.1 15.86 43 25.3 12.27 44 25.8 19.67 45 26.2 31.25 46 26.5 15.14 47 27.1 17.37 48 27.3 14.25 49 27.7 10.16 50 28.7 14.87 51 29.6 5.06 52 30.1 6.42 53 31.1 7.41 54 32.1 6.62 55 33.1 9.62 Malate Salt

[0177] In embodiments, the present disclosure provides a malate salt of Compound I (“Compound I Malate”). In embodiments, Compound I Malate is an L-malate. In embodiments, the present disclosure provides a crystalline form of Compound I Malate.

[0178] In embodiments, the present disclosure provides Compound I Malate (Form R).

[0179] In embodiments, Form R is characterized by XRPD peaks at 18.5±0.2, 9.5±0.2 and 19.1±0.2 °2θ. In embodiments, Form R is further characterized by XRPD peaks at 15.5±0.2 and 24.8±0.2 °2θ. In embodiments, Form R is further characterized by at least one XRPD peaks at 14.9±0.2, 10.3±0.2, 13.0±0.2, 17.4±0.2, 15.9±0.2, 19.7±0.2, 17.7±0.2, 20.5±0.2, 24.2±0.2, 25.4±0.2, 27.3±0.2, 23.9±0.2, 26.9±0.2, 25.1±0.2 and 8.7±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0180] In embodiments, Form R is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 18.5±0.2, 9.5±0.2, 19.1±0.2, 15.5±0.2, 24.8±0.2 14.9±0.2, 10.3±0.2, 13.0±0.2, 17.4±0.2, 15.9±0.2, 19.7±0.2, 17.7±0.2, 20.5±0.2, 24.2±0.2, 25.4±0.2, 27.3±0.2, 23.9±0.2, 26.9±0.2, 25.1±0.2 and 8.7±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0181] In embodiments, Form R is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 12A. In embodiments, Form R is characterized by an XRPD pattern that is substantially similar to FIG. 12A.

[0182] In embodiments, Form R is characterized by an XRPD pattern comprising peaks show in Table 12.

[0183] Table 12. XRPD peaks of Form R No.Pos.Rel. Int. [°2θ] [%] 1 4.3 13.33 2 6.1 11.13 3 8.7 19.47 4 9.5 91.44 5 9.9 9.18 6 10.3 63.27 7 11.3 7.57 8 12.3 13.74 9 13.0 59.65 10 13.5 7.39 11 14.2 7.11 12 14.4 13.04 13 14.9 63.51 14 15.5 79.53 15 15.9 53.17 16 16.8 7.92 17 17.4 58.04 18 17.7 42.57 19 18.5 100.00 20 19.1 79.72 21 19.7 44.07 22 20.5 36.11 23 21.0 13.63 24 21.4 11.88 25 21.9 14.58 26 22.4 18.26 27 22.8 6.42 28 23.2 13.21 29 23.5 12.11 30 23.9 24.18 31 24.2 35.19 32 24.8 65.06 33 25.1 20.26 34 25.4 34.34 35 25.6 19.10 36 26.6 13.36 37 26.9 21.95 38 27.3 24.49 39 27.9 9.06 40 28.2 10.1941 28.8 17.10 42 29.2 10.47 43 29.5 10.62 44 29.8 12.01 45 30.1 12.31 46 31.0 8.29 47 32.8 15.87 48 33.4 9.35 49 35.4 10.34 50 36.4 10.08 51 37.2 12.41 52 37.6 9.73 53 39.1 10.37

[0184] In embodiments, Form R is characterized by having one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty- two, forty-three, forty-four, forty-five, forty-six, forty-seven, forty-eight, forty-nine, fifty, fifty- one, fifty-two or fifty-three XRPD peaks listed in Table 12.

[0185] In one embodiment, Form R is characterized by having about 3 to about 20, from about 5 to about 20, from about 7 to about 20, from about 9 to about 20 or from about 10 to about 20 XRPD peaks listed in Table 12. In another embodiment, Form R is characterized by having about 3 to about 15, from about 5 to about 15, from about 7 to about 15, from about 9 to about 15 or from about 10 to about 15 XRPD peaks listed in Table 12.

[0186] In aspects, this disclosure provides crystalline form of the isethionate salt of Compound I. Isethionate Salt

[0187] In embodiments, the present disclosure provides an isethionate salt of Compound I (“Compound I Isethionate”). In embodiments, the present disclosure provides a crystalline form of Compound I Isethionate.

[0188] In embodiments, the present disclosure provides Compound I Isethionate (Form S).

[0189] In embodiments, Form S is characterized by XRPD peaks at 9.1±0.2, 17.2±0.2 and 11.7±0.2 °2θ. In embodiments, Form S is further characterized by XRPD peaks at 23.2±0.2 and 19.0±0.2 °2θ. In embodiments, Form S is further characterized by XRPD peaks at 11.3±0.2, 20.3±0.2, 22.4±0.2, 17.7±0.2, 21.5±0.2, 25.9±0.2, 23.7±0.2, 3.9±0.2, 12.2±0.2,22.2±0.2, 20.8±0.2, 19.2±0.2, 19.9±0.2, 22.8±0.2 and 23.4±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0190] In embodiments, Form S is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 9.1±0.2, 17.2±0.2, 11.7±0.2, 23.2±0.2, 19.0±0.2, 11.3±0.2, 20.3±0.2, 22.4±0.2, 17.7±0.2, 21.5±0.2, 25.9±0.2, 23.7±0.2, 3.9±0.2, 12.2±0.2, 22.2±0.2, 20.8±0.2, 19.2±0.2, 19.9±0.2, 22.8±0.2 and 23.4±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0191] In embodiments, Form S is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 13A. In embodiments, Form S is characterized by an XRPD pattern that is substantially similar to FIG. 13A.

[0192] In embodiments, Form S is characterized by an XRPD pattern comprising peaks show in Table 13.

[0193] Table 13. XRPD peaks of Form S Pos. Rel. Int. No. [°2θ] [%] 1 3.8726 35.66 2 9.1067 100.00 3 11.3384 49.11 4 11.6744 65.32 5 12.1623 33.29 6 12.4201 9.49 7 13.7576 18.56 8 14.3080 9.23 9 15.6181 9.59 10 16.2574 15.00 11 16.8401 20.63 12 17.2081 91.80 13 17.6812 42.77 14 17.9114 20.01 15 18.4565 19.09 16 18.6821 19.48 17 18.9829 51.93 18 19.1708 29.28 19 19.5482 9.60 20 19.8755 24.39 21 20.2655 44.83 22 20.4607 20.21 23 20.8217 29.32 24 21.4823 38.82 25 21.6743 15.75 26 22.2006 30.5927 22.4253 43.85 28 22.7943 21.96 29 23.2079 55.78 30 23.4342 21.83 31 23.7288 36.52 32 23.9331 11.70 33 24.5124 17.93 34 24.8508 15.49 35 25.0387 19.35 36 25.8940 38.36 37 26.3920 17.20 38 26.6364 16.44 39 27.2942 8.70 40 27.5419 6.54 41 28.1588 12.23 42 28.8167 9.59 43 28.9858 7.29 44 29.3617 8.81 45 29.6249 10.40 46 30.0041 7.89 47 30.3988 9.29 48 30.7902 11.48 49 31.3917 10.67 50 31.7897 8.55 51 32.6510 9.17 52 32.9329 7.37 53 33.4780 7.77 54 33.9479 6.18 55 34.3990 7.78 56 34.6246 7.19 57 35.3952 5.99 58 36.2974 5.20 59 37.5466 13.60 60 37.9999 5.01 Crystalline Free Base

[0194] In embodiments, the present disclosure provides a crystalline form of Compound I free base.

[0195] In embodiments, the crystalline form of Compound I free base is Form B. In embodiments, Compound I of Form B is a dichloromethane solvate.

[0196] In embodiments, Form B is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 14A. In embodiments, Form B is characterized by an XRPD pattern that is substantially similar to FIG. 14A.

[0197] In embodiments, Form B exhibits a TG / DTA thermogram having endothermic peaks at 108±5 ℃, 161±5 ℃ and 188±5 ℃. In embodiments, Form B exhibits a TG / DTA thermogram having endothermic peaks with an onset at 104±5 ℃, 157±5 ℃ and 183±5 ℃.

[0198] In embodiments, Form B exhibits a weight loss at about 1.8 % from 20 °C to 105 °C and a 7.9 % weight loss from 105 °C to 185 °C as measured by TG / DTA.

[0199] In embodiments, Form B exhibits a TG / DTA thermogram substantially similar to that shown in FIG. 14B.

[0200] In embodiments, the crystalline form of Compound I free base is Form A. In embodiments, Compound I of Form A is a hydrate.

[0201] In embodiments, Form A is characterized by XRPD peaks at 6.1±0.2, 14.8±0.2 and 18.0±0.2 °2θ. In embodiments, Form A is further characterized by XRPD peaks at 17.4±0.2 and 10.1±0.2 °2θ. In embodiments, Form A is further characterized by at least one peaks in an XRPD pattern at 12.3±0.2, 10.6±0.2, 22.6±0.2, 22.1±0.2, 21.7±0.2, 21.6±0.2, 16.7±0.2, 18.3±0.2, 22.7±0.2, 27.9±0.2, 26.8±0.2, 15.9±0.2, 7.1±0.2, 24.7±0.2 and 28.2±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0202] In embodiments, Form A is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 6.1±0.2, 14.8±0.2, 18.0±0.2, 17.4±0.2, 10.1±0.2, 12.3±0.2, 10.6±0.2, 22.6±0.2, 22.1±0.2, 21.7±0.2, 21.6±0.2, 16.7±0.2, 18.3±0.2, 22.7±0.2, 27.9±0.2, 26.8±0.2, 15.9±0.2, 7.1±0.2, 24.7±0.2 and 28.2±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0203] In embodiments, Form A is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 15A. In embodiments, Form A is characterized by an XRPD pattern that is substantially similar to FIG. 15A.

[0204] In embodiments, Form A is characterized by an XRPD pattern comprising peaks show in Table 15.

[0205] Table 15. XRPD peaks of Form A No.Pos.Rel. Int. [°2θ] [%] 1 6.1 100.0 2 7.1 11.8 3 8.0 8.2 4 10.1 35.3 5 10.6 32.8 6 12.3 34.5 7 14.8 42.58 15.9 12.5 9 16.1 5.4 10 16.4 5.4 11 16.7 20.3 12 17.4 36.7 13 18.0 37.7 14 18.3 18.4 15 19.1 9.6 16 20.3 8.9 17 20.5 3.4 18 21.6 22.5 19 21.7 24.4 20 22.1 29.1 21 22.6 31.1 22 22.7 16.3 23 23.1 6.8 24 23.3 7.1 25 23.8 4.3 26 24.4 3.7 27 24.7 11.7 28 25.0 7.8 29 25.7 6.1 30 26.8 12.9 31 27.9 13.8 32 28.2 11.7 33 28.7 2.4 34 29.0 2.3 35 29.4 2.7 36 29.7 4.6 37 30.6 5.6 38 31.3 2.6 39 32.1 5.6 40 32.8 4.3 41 34.0 1.5 42 34.7 2.0 43 35.2 2.9 44 35.8 3.3 45 37.9 3.4

[0206] In embodiments, Form A exhibits a TG / DTA (thermogravimetric differential thermal analysis) thermogram having endothermic peaks at 48±5 ℃ and 187±5 ℃. In embodiments, Form A exhibits a TG / DTA thermogram having endothermic peaks with an onset at 33±5 ℃ and 182±5 ℃.

[0207] In embodiments, Form A exhibits about 4.0% weight loss from about 20 °C to about 85 °C, a weight loss less than 1% from about 85 °C to about 170 °C as measured by TG / DTA. In embodiments, Form A exhibits a DSC (differential scanning calorimetry) thermogram having endothermic peaks with an onset at 48±5 ℃, 125±5 ℃ and 183±5℃. In embodiments, Form A exhibits a DSC thermogram comprising endothermic peaks at 76±5 ℃, 130±5 ℃ and 187±5℃.

[0208] In embodiments, Form A exhibits a TG / DTA thermogram substantially similar to that shown in FIG.15B. In embodiments, Form A exhibits a DSC thermogram substantially similar to that shown in FIG. 15C.

[0209] In embodiments, the crystalline form of Compound I free base is Form C. In embodiments, Form C is an anhydrous form.

[0210] In embodiments, Form C is characterized by XRPD peaks at 10.4±0.2, 10.2±0.2 and 21.8±0.2 °2θ. In embodiments, Form C is further characterized by XRPD peaks at 20.4±0.2 and 6.7±0.2 °2θ. In embodiments, Form C is further characterized by at least one XRPD peaks at 26.4±0.2, 20.8±0.2, 14.6±0.2, 9.5±0.2, 16.9±0.2, 18.6±0.2, 19.0±0.2, 18.1±0.2, 13.5±0.2, 22.0±0.2, 15.9±0.2, 22.2±0.2, 16.7±0.2, 25.8±0.2 and 23.5±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0211] In embodiments, Form C is characterized by at least one (e.g., 1, 2, 3, 4, or 5) XRPD peaks at 10.4±0.2, 10.2±0.2, 21.8±0.2, 0.4±0.2 and 6.7±0.2, 26.4±0.2, 20.8±0.2, 14.6±0.2, 9.5±0.2, 16.9±0.2, 18.6±0.2, 19.0±0.2, 18.1±0.2, 13.5±0.2, 22.0±0.2, 15.9±0.2, 22.2±0.2, 16.7±0.2, 25.8±0.2 and 23.5±0.2 °2θ. In some embodiment, the variance at any of the foregoing peaks is ±0.1 °2θ.

[0212] In embodiments, Form C is characterized by having two, three, four, five, six, seven, eight, nine, ten, eleven, or more, XRPD peaks from FIG 16A. In embodiments, Form C is characterized by an XRPD pattern that is substantially similar to FIG. 16A.

[0213] In embodiments, Form C is characterized by an XRPD pattern comprising peaks show in Table 16.

[0214] Table 16. XRPD peaks of Form C Pos. Rel. Int. No. [°2θ] [%] 1 6.7 46.88 2 7.9 7.69 3 9.5 37.34 4 10.2 79.39 5 10.4 100.00 6 11.1 9.217 11.7 9.48 8 13.0 9.42 9 13.5 21.18 10 14.6 39.10 11 15.2 11.89 12 15.9 17.21 13 16.3 14.06 14 16.7 14.17 15 16.9 32.04 16 17.1 8.02 17 17.4 5.50 18 17.5 7.10 19 17.8 4.88 20 18.1 22.66 21 18.6 31.63 22 19.0 25.11 23 19.4 9.25 24 19.7 8.92 25 20.4 56.55 26 20.8 42.17 27 21.4 9.03 28 21.8 57.92 29 22.0 18.44 30 22.2 15.29 31 23.2 6.09 32 23.5 14.13 33 23.9 5.94 34 24.3 13.93 35 24.8 5.54 36 25.1 7.08 37 25.8 14.16 38 26.1 8.34 39 26.4 43.31 40 26.7 12.20 41 27.0 12.55 42 28.1 4.90 43 28.4 5.29 44 28.9 3.56 45 29.4 4.61 46 29.7 3.57 47 30.7 3.60 48 31.4 3.68 49 32.9 4.21

[0215] In embodiments, Form C exhibits a TG / DTA thermogram having an endothermic peak at 114±5 ℃. In embodiments, Form C exhibits a TG / DTA thermogram having an endothermicpeak with an onset at 105±5 ℃. In embodiments, Form C exhibits a 9.0 % weight loss from 50 °C to 160 °C as measured by TG / DTA.

[0216] In embodiments, Form C exhibits a TG / DTA thermogram substantially similar to that shown in FIG. 16B. Pharmaceutical Compositions

[0217] In aspects, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of at least one crystalline form of Compound I or salt, solvate, or solvate salt thereof, and a pharmaceutically acceptable excipient. In embodiments, the excipient is an adjuvant, diluent or carrier.

[0218] In aspects, the present disclosure provides pharmaceutical compositions comprises a therapeutically effective amount of at least one amorphous form of Compound I, and a pharmaceutically acceptable carrier or excipient.

[0219] A crystalline form of Compound I (e.g., Form A, Form B, Form C or any combination thereof), may be used on their own but will generally be administered in the form of a pharmaceutical composition in which Compound I is in association with a pharmaceutically acceptable excipient. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.

[0220] Depending on the mode of administration, the pharmaceutical composition which is used to administer will comprise from 0.05 to 99% w (percent by weight), 0.05 to 80%, 0.10 to 70%, or 0.10 to 50% of one or more of Form A, Form B, Form C or any combination thereof, all percentages by weight being based on total composition.

[0221] The pharmaceutical compositions may be administered topically (e.g., to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g., by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[0222] For oral administration the crystalline forms of Compound I (e.g., Form A, Form B, Form C or any combination thereof) may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone;and / or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.

[0223] In embodiments, the compositions described herein comprise at least one crystalline form of Compound I in an amount from about 1.0 to about 30 wt %; from about 1.0 to about 25 wt %; from about 1.0 to about 20 wt %; from about 1.0 to about 15 wt %; from about 1.0 to about 10 wt %; from about 1.0 to about 5 wt%, or from about 1.0 to about 3 wt %.

[0224] In embodiments, the compositions described herein comprise at least one crystalline form of Compound I in an amount from about 1.5 to about 30 wt%; from about 1.5 to about 25 wt%; from about 1.5 to about 20 wt%; from about 1.5 to about 15 wt%; from about 1.5 to about 10 wt %; or from about 1.5 to about 5 wt%.

[0225] In embodiments, the compositions described herein comprise at least one crystalline form of Compound I in an amount from about 3 to about 30 wt%; from about 3 to about 25 wt %; from about 3 to about 20 wt%; from about 3 to about 15 wt %; from about 3 to about 10 wt %; or from about 3 to about 5 wt%.

[0226] In one embodiment, the compositions described herein comprise at least one crystalline form of Compound I in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt% or about 30 wt%.

[0227] In embodiments, the compositions described herein comprise at least one crystalline form of Compound I in an amount of 1 mg to 100 mg, 20 mg to 75 mg, 10 mg to 50 mg, 20 mg to 40 mg, or 20 mg to 40 mg. In embodiments, the compositions described herein comprise at least one crystalline form of Compound I in an amount of about 20 mg, about 30 mg or about 40 mg. In embodiments, the compositions described herein comprise at least one crystalline form of Compound I in an amount of about 20 mg. In embodiments, the compositions described herein comprise at least one crystalline form of Compound I in an amount of about 30 mg. In embodiments, the compositions described herein comprise at least one crystalline form of Compound I in an amount of about 40 mg.

[0228] The pharmaceutical composition of the present disclosure may be in any solid dosage form suitable for oral administration to a human being.

[0229] In embodiments, the pharmaceutical composition of the present disclosure is a pharmaceutical tablet. Pharmaceutical tablets may be prepared using methods known to thoseskilled in the art including, for example, dry mixing / direct compression process as described herein.

[0230] In embodiments, pharmaceutical tablet comprises a tablet core wherein the tablet core comprises the pharmaceutical composition as defined herein and wherein the tablet core has a coating. In embodiments, the coating is a film coating.

[0231] The dosage of the crystalline form of Compound I or salt, solvate, or solvate salt thereof will, of course, vary with the mode of administration, the treatment desired and the disorder indicated.

[0232] In embodiments, one or more of the pharmaceutical compositions provided herein is used in a method to treat Hereditary Hemorrhagic Telangiectasia (HHT) in a subject in need thereof. In embodiments of the methods, the subject is a human. Therapeutic Methods

[0233] In aspects, the present disclosure provides methods of using at least one crystalline form of Compound I or amorphous form for treating Hereditary Hemorrhagic Telangiectasia (HHT) in a subject in need thereof. In aspects, the present disclosure provides methods of treating Hereditary Hemorrhagic Telangiectasia (HHT) in a subject in need thereof, comprising administering at least one crystalline form of Compound I to the subject.

[0234] In embodiments, the treatment of HHT provides a reduction in the frequency, duration or intensity of bleeding associated with HHT. In some such embodiments, the bleeding associated with HHT is gastrointestinal (GI) bleeding. In embodiments, the bleeding associated with HHT is nosebleeds.

[0235] In embodiments, the treatment of HHT provides an increase in haemoglobin levels in the subject.

[0236] In embodiments, the treatment of HHT comprises reducing the number of telangiectasia in the subject. In embodiments, the treatment of HHT comprises reducing the size of telangiectasia in the subject. In embodiments, the telangiectasia are skin telangiectasia. In embodiments, the telangiectasia are nasal telangiectasia. In embodiments, the telangiectasia are oral telangiectasia. In embodiments, the telangiectasia are gastrointestinal telangiectasia.

[0237] In embodiments, the treatment of HHT comprises reducing number and or size of arteriovenous malformations (AVMs) in the subject. In embodiments, the treatment of HHT comprises preventing the formation of AVMs in the subject. In some such embodiments, the arteriovenous malformations are pulmonary AVMs. In embodiments, the arteriovenousmalformations are cerebral (brain) AVMs. In embodiments, the arteriovenous malformations are visceral AVMs.

[0238] In embodiments, the treatment of HHT comprises reduction in cardiac insufficiency and pulmonary arterial hypertension (PAH). In embodiments, the treatment of HHT comprises prevention of cardiac insufficiency and pulmonary arterial hypertension (PAH).

[0239] In embodiments, the treatment of HHT comprises prevention of right to left shunt induced by pulmonary AVMs in the subject. In embodiments, the treatment of HHT comprises reduction in the grade of right to left shunt induced by pulmonary AVMs in the subject. In embodiments, the treatment of HHT comprises a reduction in the need for iron supplementation in the subject, for example a reduction of the number of iron infusions required by the subject. In embodiments, the treatment of HHT comprises a reduction of the number of blood transfusions required by the subject.

[0240] In embodiments, the treatment of HHT comprises a decrease in hepatic blood flow.

[0241] In embodiments, the treatment of HHT reduces the need for liver transplantation in the subject.

[0242] In embodiments, the treatment of HHT comprises a reduction in the frequency and / or severity of additional symptoms of HHT. Such additional symptoms may include dyspnea, migraine, fatigue, neurological events, and embolic events.

[0243] In embodiments, the method of treating HHT results in an improvement in the quality of life of the subject.

[0244] In embodiments, the method of treating HHT results in a reduction in cardiac insufficiency and pulmonary arterial hypertension (PAH). In embodiments, the method of treating HHT results in the prevention of cardiac insufficiency and pulmonary arterial hypertension (PAH).

[0245] In embodiments, the method of treating HHT prevents right to left shunt induced by pulmonary AVMs in the subject. In embodiments, the method of treating HHT results in a reduction in the grade of right to left shunt induced by pulmonary AVMs in the subject.

[0246] In embodiments, the method of treating HHT results in a reduction in the need for iron supplementation in the subject, for example a reduction of the number of iron infusions required by the subject. In embodiments, the method of treating HHT results in a reduction of the number of blood transfusions required by the subject.

[0247] In embodiments, the method of treating HHT results in a decrease in hepatic blood flow.

[0248] In embodiments, the method of treating HHT reduces the need for liver transplantation in the subject.

[0249] In embodiments, the method of treating HHT results in a reduction in the frequency and / or severity of additional symptoms of HHT. Such additional symptoms may include dyspnea, migraine, fatigue, neurological events, and embolic events. In embodiments, the method of treating HHT results in an overall improvement in the quality of life of the subject. Examples

[0250] Compound I can be prepared according to the methods disclosed in International Patent Publication No. WO2022 / 069552, which is incorporated herein for all purposes. The following examples are used to assist in describing the present disclosure, but should not be seen as limiting the present disclosure in any way. Experimental techniques:

[0251] Unless otherwise specified, all characterization data were obtained using the following procedures: X-ray Powder Diffraction (XRPD)

[0252] XRPD analyses were performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. The isothermal samples were analysed in transmission mode and held between low density polyethylene films. The XRPD program used includes: range 3-40°2θ, step size 0.013°, counting time 99sec, ~22min run time. XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software. Differential Scanning Calorimetry (DSC)

[0253] DSC analyses were carried out on a Perkin Elmer Jade Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminium pans. Each sample was heated under nitrogen at a rate of 10°C / minute to a maximum of 300°C. Indium metal was used as the calibration standard. Temperatures were reported at the transition onset to the nearest 0.01 degree.. Thermogravimetric Differential Thermal Analysis (TG / DTA)

[0254] Thermogravimetric analyses were carried out on a Mettler Toledo TGA / DSC1 STARe. The calibration standard was indium. Samples were placed in an aluminium sample pan, inserted into the TG furnace and accurately weighed. The samples were heated from 25°C to 300°C in a stream of nitrogen at a rate of 10°C / minute.Dynamic Vapour Sorption (DVS)

[0255] Dynamic Vapour Sorption (DVS) was performed using a Hiden Analytical Instruments IGAsorp Vapour Sorption Balance. Approximately 30mg of sample was placed into a wire- mesh vapour sorption balance pan, loaded into the IGAsorp vapour sorption balance and held at 25°C ± 0.1°C. The sample was subjected to a step profile from 0 to 90%RH at 10% increments, followed by desorption from 80%RH to 0%RH at 10% increments. The equilibrium criterion was set to 99.0% step completion within a minimum of 60 minutes and a maximum of 5 hours for each increment. The weight change during the sorption cycle was monitored, allowing for the hygroscopic nature of the sample to be determined. The data collection interval was in seconds. Solubility estimation

[0256] Aliquots of the test solvent were added to an accurately weighed sample (~5mg-20mg) of Compound I (free base, DCM solvate or salt form) at ambient temperature. The aliquot volumes were typically 50-100μL. Complete dissolution of the test material was determined by visual inspection. The solubility was estimated from these experiments based on the total solvent used to provide complete dissolution.

[0257] In the case of Compound I DCM solvate, where dissolution did not occur after the last aliquot of solvent was added (typically ~50 volumes of solvent), the sample was subjected to two cycles of the following temperature cycling regime on the Clarity crystallisation station: • Heat from 20°C to within 3°C of solvent boiling point (or 100°C, whichever was lower) at 0.5°C / minute. • Cool to 20°C at 0.2°C / minute. • Stirrer speed 800 rpm.

[0258] From the infrared (IR) transmission data of the sample vials, dissolution and precipitation events were recorded as the point of complete transmission of IR and the onset of turbidity by IR respectively.

[0259] Samples were held at ambient temperature for 18 hours. In some cases, solids were analyzed by XRPD. The solubility values for all forms of Compound I were expressed as a range and rounded to the nearest whole number. Proton Nuclear Magnetic Resonance spectroscopy (NMR)

[0260] NMR analyses were carried out on a Bruker 500MHz instrument in CD3OD.Instrumentalparameters are listed on the relevant spectrum plots. Polarised Light Microscopy

[0261] Microscopy analyses were carried out on a Smiths IlluminatIR II instrument. Photomicrographs of Compound I (free base and salts) were obtained at objective lens magnifications x10 or x20 using a polarised light source. High Performance Liquid Chromatography (HPLC)

[0262] HPLC analyses were carried out using the method described in Table 4 for equilibrium solubility measurements and for chemical purity of salts.

[0263] The retention time of Compound I was typically 7.08±0.2min and no new peaks were detected during the analysis of experimental samples. Example 1: Salt preparation methods

[0264] Experiments were carried out at a scale of ~20mg with 1:1 stoichiometry and 2:1 stoichiometry (Compound I (API): acid). Preparation of stock solutions

[0265] Compound I DCM solvate (896.1mg) was added to a 50mL volumetric flask and THF was added to the 50mL mark to form a 0.04M solution. This was sonicated in the water bath to ensure complete dissolution. The acid solutions were prepared as described in Table 17. Table 17: Preparation of stock solutions of acids Acid Mw Amount of Solvent Molarity Volume acid (mg) (M) (mL) Citric 192.12 193.9 MeOH 0.10 10 Ethanedisulfonic acid 208.20 206.9 MeOH 0.10 10 hydrate Gentisic 154.12 154.1 MeOH 0.10 10 Glucuronic 194.14 194.5 MeOH / H2O, THF 0.10 10 Ketoglutaric 146.10 144.0 MeOH 0.10 10 Malic 134.09 132.5 MeOH 0.10 10 Malonic 104.06 107.7 MeOH 0.10 10 Nicotinic 123.11 126.1 MeOH / H2O, THF 0.10 10 Pyroglutamic 129.11 129.8 MeOH 0.10 10 Succinic 118.09 114.5 MeOH 0.10 10 Tartaric 150.09 145.3 MeOH 0.10 10Isethionic 126.13 128.7 MeOH 0.10 10 Methanesulfonic 96.11 509.1 THF 0.53 10 Sulfuric (0.5M) 98.08 2 (mL) THF 0.10 10 Phosphoric (85 wt%) 98.00 678.2 MeOH 0.69 10 Acetic 60.05 57.0 MeOH 0.10 10 Precipitation

[0266] Compound I solution (1.16mL) was added to each of sixteen vials and the required acid solution was added to each vial (1:1 ratio). The mixtures were stirred at 20°C for 16 hrs. Any solids which precipitated were isolated by centrifugation, decantation of solvent and drying of the solid with filter paper. Any samples which remained as solutions were uncapped, placed in a desiccator under vacuum and any solids were analysed by XRPD. Salt formation at 40°C

[0267] Compound I solution (1.16mL) and the required acid solution (1 equivalent) were added to each vial and heated at 40°C for 6 days. The solutions were evaporated and solids analysed by XRPD. Salt formation by evaporation

[0268] Compound I solution (1.16mL) and the required acid solution (1 equivalent) were added to each vial and the solutions were stirred, uncapped, for 16 hrs. Any solids were analysed by XRPD. Salts which remained as oils were triturated in either MTBE / dioxane or EtOAc / dioxane for 3-7 days. Solids were recovered by centrifugation and decantation of solvent. The solids were dried with filter paper and analysed by XRPD. Slurry experiments

[0269] Acid solution (1 eq) was added to an HPLC vial and allowed to evaporate to dryness. Compound I DCM solvate (20mg) and EtOAc:MeOH (95:5, v / v, 150µL) were added to each acid and the mixtures stirred at 20°C for 48 hrs. A further portion of EtOAc (100 µL) was added to each salt formation and the reaction heated to 40°C over 1 hr. The mixtures were stirred at 40°C for 1 hr and cooled to 20°C over 3 hrs. They were stirred at 20°C for a further 7 days. The solids were recovered by centrifugation and air dried prior to XRPD analysis.Humidity stress

[0270] Compound I (salts) were added to individual vials and placed unsealed into a vial containing a saturated solution of sodium chloride at 40°C (75% relative humidity). The salts were stored for 5-7 days prior to visual inspection for deliquescence. Example 2: Salt preparation results

[0271] A salt preparation of Compound I in the free base form was carried out using 16 acids and different crystallisation techniques, stoichiometry and conditions. Crystalline forms of Compound I obtained from the salt preparation experiments are summarized in Table 18. Table 18. Summary of Crystalline forms obtained from salt preparation experiments Crystalline Form Cauterization Form A Hydrate of free base of Compound I Form B DCM solvate free base of Compound I Form C Anhydrous form free base of Compound I Form D Ethanedisulfonate salt (1:1) Form E L-tartrate salt (1:1) Form F Phosphate salt Form G Sulphate salt Form H Dioxane solvate of free base of Compound I Form I ketoglutarate salt Form J acetate salt Form K Succinate salt (2:1, API : acid) Form L Succinate salt (1:1) Form M Mesylate salt (1:1) Form N acetate salt Form O pyroglutamate salt Form P Gentisate salt (1:1) Form Q ethanedisulfonate salt Form R malic salt Form S isethionate salt Form T phosphate salt Form U phosphate salt Form V malonate saltSolvent based preparation techniques

[0272] Solvent based experiments were performed on approximately 20–40mg scale in glass vials. The methods employed are described in detail in example 1. Precipitation

[0273] The precipitation experiments involved mixing two solutions and isolating any precipitated solids (see example 1). Only 2 experiments precipitated solids. The remainder of the solutions were evaporated and any solids analysed by XRPD. A further 3 experiments yielded solids, one of which was XRPD amorphous. The results of precipitation experiments are included in table 19. Table 19: Results from precipitation experiments Acid Solvent Compound I Result XRPD of XRPD after conc precipitate evaporation (mg / mL) Citric THF / MeOH 17.9 Oil - - Ethanedisulfonic THF / MeOH 17.9 Solid Form D - Gentisic THF / MeOH 17.9 Oil - - Glucuronic THF / MeOH 17.9 Oil - - Ketoglutaric THF / MeOH 17.9 Oil - - Malic THF / MeOH 17.9 No precipitation - - (ppt) Malonic THF / MeOH 17.9 No ppt - - Nicotinic THF / MeOH 17.9 Solid after evap. - amorphous Pyroglutamic THF / MeOH 17.9 No ppt - - Succinic THF / MeOH 17.9 No ppt - - Tartaric THF / MeOH 17.9 Solid after evap. - Form E Methanesulfonic THF / MeOH 17.9 No ppt - - Sulfuric THF / MeOH 17.9 Solid after evap. - Form G Phosphoric THF 17.9 Solid Form F - Acetic THF / MeOH 17.9 No ppt - -

[0274] The solids were analysed by1H-NMR spectroscopy to confirm salt formation. The NMR spectrum of Form D material corresponded to formation of an ethyldisulfonate salt witha 1:1 molar ratio of API to co-former. Form E was confirmed as a 1:1 tartrate salt by1H-NMR spectroscopy. As the phosphate and sulphate counterions are not detectable by1H-NMR spectroscopy, salt formation was assessed by peak shifting. In the free base, CH2 protons were observed at 2.16-2.20 ppm and 2.91-2.94 ppm. In the phosphate salt, these protons had shifted to 2.49- 2.53 ppm and 3.05-3.09 ppm. The CH2 protons were observed at 2.60-2.63 ppm and 3.03- 3.07 ppm in the sulphate salt. Salt formation at 40°C

[0275] The salt formations were carried out at 40°C (see example 1). The results are shown in Table 20. The ethane disulfonate, tartrate and phosphate salts were formed. Table 20: Results from slurry experiments at 40°C Acid Solvent Result Crystalline forms obtained Ethanedisulfonic THF / MeOH (3:1) Solid Form D Tartaric THF / MeOH (3:1) Solid Form E Sulfuric THF Solution - Phosphoric THF / MeOH (15:1) Solid Form F Evaporation in vials

[0276] Evaporation of a mixture of Compound I and the acid solution (1:1 ratio) was conducted as described in section example 1. The results are shown in Table 21. XRPD patterns were observed with ketoglutaric acid, acetic acid, succinic acid and isethionic acid.1H-NMR analysis showed the succinate salt to have formed in a 2:1 molar ratio (API:acid). Table 21: Results from evaporations Sample Acid Solvent Result XRPD after XRPD evaporation after slurry 01 Citric EtOAc / dioxane Gum - - azeotrope (91:9%v / v) 02 Ethane THF / MeOH Solid after evap. Form D - disulfonic 03 Gentisic MTBE / dioxane Oil - - azeotrope (96:4%v / v) 04 Glucuronic MTBE / dioxane Oil - - azeotrope (91:9%v / v)05 Ketoglutaric THF / MeOH Solid after evap. Form I - (disordered) 06 Malic MTBE / dioxane Solid after - Form R azeotrope slurry (91:9%v / v) 07 Malonic EtOAc / dioxane Solid / gum after - Form V + azeotrope slurry amorphou (91:9%v / v) s 08 Nicotinic MTBE / dioxane Solid / gum after - Form A azeotrope slurry (91:9%v / v) 09 Pyroglutamic THF / MeOH Solid after evap. free base of - Compound I + amorphous 10 Succinic EtOAc / dioxane Solid after slurry - Form K azeotrope (91:9%v / v) 11 Tartaric THF / MeOH Solid after evap. Form E - 033-01 Isethionic methanol Solid after evap. Form S - 13 Methane MTBE / dioxane Gum - - sulfonic azeotrope (91:9%v / v) 14 Sulfuric THF / MeOH Solid after evap. Form G - 15 Phosphoric THF / MeOH Solid after evap. Amorphous - 16 Acetic MTBE / dioxane Solid after slurry - Form J azeotrope (91:9%v / v) Slurry experiments Slurry experiments were carried out as described in example 1. Results are shown in Table 22.1H-NMR analyses of selected patterns demonstrated salt formation in a 1:1 molar ratio with gentisic, methanesulfonic and succinic acid. All of the NMR spectra showed EtOAc to be present. Table 22: Results from slurry experiments at 20°C Sample Acid Solvent Resul Crystalline forms t determined by XRPD 01 Citric EtOAc / MeOH (95:5) Solid Disordered 02 Ethane disulfonic EtOAc / MeOH (95:5) Solid Form Q 03 Gentisic EtOAc / MeOH (95:5) Solid Form P 04 Glucuronic EtOAc / MeOH (95:5) Solid N / A 05 Ketoglutaric EtOAc / MeOH (95:5) Solid Form I 06 Malic EtOAc / MeOH (95:5) Solid Compound I -free base (FB)07 Malonic EtOAc / MeOH (95:5) Solid Disordered 08 Nicotinic EtOAc / MeOH (95:5) Gel - 09 Pyroglutamic EtOAc / MeOH (95:5) Solid Form O 10 Succinic EtOAc / MeOH (95:5) Solid Form L 11 Tartaric EtOAc / MeOH (95:5) Solid Form E 13 Methane sulfonic EtOAc / MeOH (95:5) Solid Form M 14 Sulfuric EtOAc / MeOH (95:5) Solid Form G + amorphous 15 Phosphoric EtOAc / MeOH (95:5) Solid Form U 16 Acetic EtOAc / MeOH (95:5) Solid Form N Humidity stress

[0277] Certain crystalline solids were stressed under 40°C / 75%RH conditions for seven days and visually examined for evidence of deliquescence. The results are shown in Table 25. None of the solids tested appeared to be deliquescent. Table 23: Results from humidity stress experiments (40°C / 75%RH, 7 days) Sample Acid Result Sample 02 of table 5 Ethanedisulfonic Slightly damp solid Sample 05 of table 5 Ketoglutaric Free flowing solid Sample 07 of table 5 Malonic Sticky / glassy solid Sample 08 of table 5 Nicotinic Slightly sticky solid Sample 10 of table 5 Succinic Free flowing solid Sample 11 of table 5 Tartaric Free flowing solid Sample 11 of table 5 Tartaric Free flowing solid Sample 13 of table 5 Methanesulfonic Free flowing solid Sample 14 of table 5 Sulfuric Slightly sticky solid Sample 15 of table 5 Phosphoric Free flowing solid Sample 16 of table 5 Acetic Free flowing solid Solubility / pH of Compound I salts in water

[0278] The aqueous solubility of the five Compound I salts was tested and compared to that of the Compound I HCl salt. Solution pH was also recorded (Table 10) for each salt.Table 24: Solubility estimates of Compound I salts in water Salt Solubility range (mg / mL) pH Compound I succinate 10-11 6 Compound I tartrate 9-10 4 Compound I phosphate 4-4.5 6 Compound I gentisate 3-3.5 6 Compound I 22-30 3-4 methanesulfonate Compound I HCl 23-32 6 Example 3: Form E (L-Tartrate salt)

[0279] Crystalline Form E was prepared through precipitation experiments, slurry experiments and evaporation experiments as detailed in Examples 2 and 3. Form E is characterized to be a crystalline form of L-tartrate salt of Compound I. Gram-scale preparation of Form E was conducted. Gram-scale preparation of Form E

[0280] Compound I free base DCM solvate (1.0g, 2.0mmol) was charged to a 50mL round bottomed flask. L-tartaric acid (328mg, 2.0mmol) was added followed by EtOH / water (95:5, 20mL). The mixture was stirred and heated at 70°C. Dissolution took place almost immediately followed quickly by precipitation. The reaction mixture was seeded with Compound I tartrate salt and heating at 40°C continued overnight. A sample removed and analysed by XRPD showed that salt formation was complete. The flask was removed from the heat and allowed to cool to ambient temperature. The flask was then placed in an ice / water bath for ~10 mins. The reaction mixture was filtered by vacuum filtration (filtration rate of 2.5s / mL). The cake was washed with EtOH / water (95:5, 5mL), followed by diethyl ether (2 x 5mL). The tartrate salt was afforded as an off white solid (919mg, 75%). The slow filtration rate could prove problematic on scale up. Chemical purity was 99.05% by HPLC analysis.

[0281] The XRPD pattern obtained for Compound I L-tartrate salt (FIG. 1A) matched that prepared on small scale and is indicative of a crystalline material. Optical microscopy confirmed crystallinity, showing birefringent particles and the formation of aggregates and / or agglomerates.

[0282] A summary of the XRPD peaks of Form E is found below in Table 25. Table 25. XRPD peaks of Form E Pos. d-spacing Height Rel. Int. No. [°2θ] [Å] [cts] [%] Derivation 1 9.3419 9.4671 2467.94 38.47 KA1 + KA2 2 10.1754 8.6862 155.29 2.42 Pure KA1 3 11.4432 7.7330 3681.76 57.39 KA1 + KA2 4 12.2202 7.2430 714.07 11.13 KA1 + KA2 5 12.4419 7.1144 3785.74 59.01 KA1 + KA2 6 13.0828 6.7673 374.45 5.84 KA1 + KA2 7 14.0967 6.2828 1501.94 23.41 KA1 + KA2 8 14.7988 5.9862 1314.35 20.49 KA1 + KA2 9 14.9453 5.9279 1872.93 29.19 KA1 + KA2 10 15.1265 5.8573 1141.63 17.79 KA1 + KA2 11 15.4830 5.7232 5505.60 85.81 KA1 + KA2 12 15.6641 5.6575 1929.39 30.07 KA1 + KA2 13 16.1704 5.4769 180.93 2.82 Pure KA1 14 16.5141 5.3637 104.54 1.63 Pure KA1 15 16.9665 5.2260 506.36 7.89 KA1 + KA2 16 17.6575 5.0230 230.05 3.59 KA1 + KA2 17 18.0560 4.9089 128.70 2.01 Pure KA1 18 18.2866 4.8516 403.88 6.30 KA1 + KA2 19 18.7555 4.7313 3709.60 57.82 KA1 + KA2 20 19.4629 4.5609 489.60 7.63 KA1 + KA2 21 20.4607 4.3407 237.28 3.70 KA1 + KA2 22 20.8604 4.2584 1064.36 16.59 KA1 + KA2 23 21.6531 4.1043 6415.83 100.00 KA1 + KA2 24 22.0555 4.0303 972.34 15.16 KA1 + KA2 25 22.4308 3.9637 1208.29 18.83 KA1 + KA2 26 22.6774 3.9212 1383.89 21.57 KA1 + KA2 27 22.7739 3.9016 990.26 15.43 Pure KA1 28 23.0142 3.8646 2229.13 34.74 KA1 + KA2 29 23.5093 3.7843 1174.76 18.31 KA1 + KA2 30 24.0930 3.6909 308.17 4.80 Pure KA1 31 24.4777 3.6367 519.48 8.10 KA1 + KA2 32 25.2339 3.5294 253.63 3.95 KA1 + KA2 33 26.0068 3.4234 224.39 3.50 Pure KA1 34 26.2104 3.4001 916.50 14.28 KA1 + KA2 35 26.9487 3.3059 141.78 2.21 Pure KA1 36 27.4677 3.2473 1141.87 17.80 KA1 + KA2 37 27.8162 3.2047 187.20 2.92 Pure KA1 38 27.9684 3.1876 187.24 2.92 Pure KA1 39 28.2864 3.1551 574.08 8.95 KA1 + KA2 40 28.7174 3.1087 228.80 3.57 KA1 + KA2 41 29.6330 3.0122 481.49 7.50 Pure KA142 29.8287 2.9954 1355.01 21.12 KA1 + KA2 43 30.2373 2.9534 231.56 3.61 Pure KA1 44 30.5005 2.9309 527.77 8.23 KA1 + KA2 45 30.8782 2.8935 219.63 3.42 Pure KA1 46 31.1178 2.8742 441.87 6.89 KA1 + KA2 47 31.6665 2.8233 185.86 2.90 Pure KA1 48 31.9696 2.7995 277.61 4.33 KA1 + KA2 49 32.4473 2.7594 425.89 6.64 KA1 + KA2 50 32.7166 2.7350 221.58 3.45 Pure KA1 51 32.9209 2.7185 240.23 3.74 Pure KA1 52 33.4253 2.6786 143.77 2.24 Pure KA1 53 33.7840 2.6510 155.36 2.42 Pure KA1 54 34.0723 2.6292 148.50 2.31 Pure KA1 55 34.8158 2.5769 232.32 3.62 KA1 + KA2 56 35.8737 2.5033 133.62 2.08 KA1 + KA2 57 36.4126 2.4654 159.04 2.48 Pure KA1 58 36.7217 2.4474 314.90 4.91 KA1 + KA2 59 37.3257 2.4072 222.25 3.46 Pure KA1 60 37.5700 2.3941 289.03 4.51 KA1 + KA2 61 38.0650 2.3641 459.85 7.17 KA1 + KA2 62 38.4899 2.3390 430.69 6.71 KA1 + KA2 63 38.8315 2.3172 242.84 3.78 Pure KA1 64 39.2672 2.2944 305.97 4.77 KA1 + KA2

[0283] Thermogravimetric / Differential Thermal Analysis (TG / DTA) and Differential Scanning Calorimetry (DSC) were performed to determine the thermal profile and associated % weight changes of Compound I tartrate salt.

[0284] TG / DTA (FIG. 1B) shows a single endothermic event at onset temperature ~208°C. No weight loss was observed prior to the melt, indicating the salt was anhydrous. DSC data (FIG 1C) agreed with TG / DTA results showing a single broad endothermic event at ~208°C, due to the melt with decomposition. The1H-NMR spectrum confirms mono- salt formation and solvents were not detected. Hygroscopicity and the sorption properties Form E

[0285] The hygroscopicity and the sorption properties of Form E were determined using Dynamic Vapour Sorption (DVS). The sample was dried at 0%RH prior to performing sorption and desorption. The isotherm (FIG. 1D) showed that the material had gained ~0.4% up to 80% RH, which indicated that the sample was slightly hygroscopic, according to the European Pharmacopoeia classification (Table 28). Post-DVS XRPD analysis did not detect change in physical form.Table 26: Hygroscopicity Classifications (Ph. Eur.) Classification Weight increase at 80% RH (25°C) Non hygroscopic <0.2 % Slightly hygroscopic ≥0.2 % and <2 % Hygroscopic ≥2 % and <15% Very hygroscopic ≥15% Deliquescent sufficient water is absorbed to form a liquid Stability assessment for Compound I L-tartrate salt

[0286] Form E was stressed at 20°C / 60%RH and 40°C / 75%RH for 13 days and Form E was physically and chemically stable under the conditions tested (Table 27).

[0287] Humidity stressing was carried out at 20°C / 60%RH (saturated solution of sodium bromide) and 40°C / 75%RH (saturated solution of sodium chloride) to assess weight gain, appearance, physical stability by XRPD and chemical stability by HPLC. Samples were analysed after 4 days and 13 days.

[0288] Stability testing showed the tartrate salt to be both physically (XRPD) and chemically stable under the timeframe and RH conditions tested. Table 27: Hygroscopicity & stability results for Compound I L-tartrate salt Conditions Weight Change XRPD HPLC %purity 4d 13d 4d 13d 4d 13d 40°C / 75%RH 0.2% 0.9% No apparent No apparent 99.02 98.95 change change 20°C / 60%RH -0.8% 1.1% No apparent No apparent 98.98 98.96 change change Example 4: Form M (Mesylate salt of Compound I)

[0289] Crystalline Form M was prepared through slurry experiments as detailed in Examples 2 and 3. Form M is characterized to be a crystalline form of mesylate salt of Compound I.Gram-scale preparation of Form M

[0290] Compound I free base DCM solvate (1.0g, 2mmol) was added to MeTHF (10mL, 10vol) in a 50ml round-bottomed flask. Methanesulfonic acid (142mL, 2mmol) was added and a sticky gum ball formed. The mixture was seeded with Compound I mesylate salt (1897- 043-02) and heated to 60°C for 4 hours.

[0291] The mixture was cooled to ambient temperature and the product was isolated by vacuum filtration (filtration rate of 0.3s / mL). The product cake was washed with diethyl ether (2 x 5mL) to aid drying and help remove residual solvent. The mesylate salt was obtained as an off white solid (890mg, 80%). Chemical purity was 98.2% by HPLC analysis.

[0292] The XRPD pattern obtained for Compound I mesylate salt was highly crystalline and matched that observed for the mesylate salt when generated on a small scale. Polarised light microscopy showed the presence of some aggregation or agglomeration.

[0293] A summary of the XRPD peaks of Form M is included in Table 30. Table 28. XRPD peaks of Form M No. Pos. d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 7.9528 11.1173 6059.69 100.00 KA1 + KA2 2 10.2679 8.6154 2015.59 33.26 KA1 + KA2 3 10.9939 8.0480 664.32 10.96 KA1 + KA2 4 12.5750 7.0394 430.19 7.10 KA1 + KA2 5 12.9246 6.8441 212.99 3.51 Pure KA1 6 13.4119 6.6020 1752.64 28.92 KA1 + KA2 7 13.6593 6.4776 304.08 5.02 Pure KA1 8 13.8711 6.3791 237.10 3.91 Pure KA1 9 14.3264 6.1774 544.43 8.98 Pure KA1 10 14.4123 6.1459 2063.38 34.05 KA1 + KA2 11 15.0481 5.8876 620.90 10.25 KA1 + KA2 12 15.7202 5.6374 2066.46 34.10 KA1 + KA2 13 15.9468 5.5532 196.99 3.25 Pure KA1 14 16.6544 5.3188 352.44 5.82 Pure KA1 15 16.8043 5.2761 2264.80 37.37 KA1 + KA2 16 17.1006 5.1810 1378.85 22.75 Pure KA1 17 17.1872 5.1594 2304.66 38.03 KA1 + KA2 18 17.4420 5.0846 1419.90 23.43 KA1 + KA2 19 17.9124 4.9521 445.48 7.35 KA1 + KA2 20 18.2302 4.8665 1035.55 17.09 KA1 + KA2 21 18.3252 4.8375 562.79 9.29 Pure KA1 22 18.4130 4.8186 1283.63 21.18 KA1 + KA2 23 19.5749 4.5351 888.31 14.66 KA1 + KA2 24 19.7843 4.4876 1285.76 21.22 KA1 + KA220.4300 4.3472 3928.74 64.83 KA1 + KA2 20.9994 4.2306 2780.82 45.89 KA1 + KA2 21.4859 4.1359 469.29 7.74 KA1 + KA2 22.0926 4.0236 4980.73 82.19 KA1 + KA2 22.2433 3.9934 674.40 11.13 Pure KA1 22.6366 3.9282 353.97 5.84 KA1 + KA2 23.0869 3.8525 655.56 10.82 KA1 + KA2 23.5730 3.7711 551.06 9.09 Pure KA1 23.6390 3.7638 1295.03 21.37 KA1 + KA2 23.9153 3.7209 967.57 15.97 KA1 + KA2 24.1520 3.6850 1399.72 23.10 KA1 + KA2 24.3392 3.6541 255.54 4.22 Pure KA1 24.6891 3.6060 1777.68 29.34 KA1 + KA2 25.2711 3.5243 525.13 8.67 KA1 + KA2 25.5246 3.4870 260.64 4.30 Pure KA1 25.8626 3.4422 230.63 3.81 Pure KA1 26.1180 3.4119 481.44 7.94 KA1 + KA2 26.5702 3.3521 294.62 4.86 Pure KA1 26.7912 3.3277 470.11 7.76 KA1 + KA2 27.0029 3.2994 316.88 5.23 Pure KA1 27.3964 3.2528 189.90 3.13 Pure KA1 27.6203 3.2297 870.81 14.37 KA1 + KA2 27.9089 3.1943 223.33 3.69 Pure KA1 28.4668 3.1329 255.29 4.21 Pure KA1 28.6471 3.1136 413.75 6.83 Pure KA1 28.8361 3.0962 510.65 8.43 KA1 + KA2 29.0572 3.0706 287.74 4.75 Pure KA1 29.3614 3.0395 175.56 2.90 Pure KA1 29.6019 3.0178 303.79 5.01 KA1 + KA2 29.8776 2.9881 252.47 4.17 Pure KA1 30.3869 2.9392 220.36 3.64 Pure KA1 30.8480 2.8963 173.88 2.87 Pure KA1 31.1791 2.8687 490.06 8.09 KA1 + KA2 31.7324 2.8199 452.09 7.46 KA1 + KA2 32.1789 2.7818 353.28 5.83 KA1 + KA2 32.4771 2.7546 186.47 3.08 Pure KA1 32.7252 2.7366 388.62 6.41 KA1 + KA2 32.9259 2.7181 261.22 4.31 Pure KA1 33.2011 2.6962 192.08 3.17 Pure KA1 33.4494 2.6790 398.52 6.58 KA1 + KA2 33.9802 2.6362 172.83 2.85 Pure KA1 34.3234 2.6106 206.62 3.41 Pure KA1 34.7471 2.5797 215.86 3.56 Pure KA1 35.0851 2.5556 247.45 4.08 Pure KA1 35.4322 2.5314 266.46 4.40 Pure KA1 35.7409 2.5102 150.79 2.49 Pure KA171 36.0727 2.4879 172.22 2.84 Pure KA1 72 36.2513 2.4760 186.33 3.07 Pure KA1 73 36.6079 2.4527 153.71 2.54 Pure KA1 74 37.3636 2.4068 245.83 4.06 KA1 + KA2 75 37.8589 2.3745 112.31 1.85 Pure KA1 76 38.1778 2.3554 147.65 2.44 Pure KA1 77 38.7054 2.3245 125.15 2.07 Pure KA1 78 39.4003 2.2851 209.91 3.46 Pure KA1

[0294] Thermogravimetric / Differential Thermal Analysis (TG / DTA) and Differential Scanning Calorimetry (DSC) were performed to determine the thermal profile and associated % weight changes of Compound I mesylate salt (FIG. 2B). DSC analysis (FIG. 2C) also showed one endothermic event at onset ~262°C. These results indicate the material is a thermally stable anhydrous salt. The1H-NMR spectrum conforms to the structure and confirms formation of a mono-mesylate salt. The hygroscopicity and the sorption properties of Form M

[0295] The hygroscopicity and the sorption properties of Compound I mesylate salt were determined using Dynamic Vapour Sorption (DVS). The sample was dried at 0%RH prior to performing sorption and desorption. The isotherm (FIG.2D) showed the material exhibits a gradual uptake of moisture from 0%RH to 80%RH, with a sharper uptake between 80%RH and 90%RH. The isotherm showed the total weight gain observed between 0%RH and 80%RH to be 0.95%w / w which indicated that the sample was slightly hygroscopic, according to the European Pharmacopoeia classification (Table 11). All moisture gained was lost by 0% RH. XRPD analysis was performed on the post DVS sample (Figure 48) and the diffractogram was identical to that of the starting material, indicating that no changes to physical form had occurred. Stability assessment for Compound I mesylate salt

[0296] Under the conditions and timeframe tested, the mesylate salt was physically (XRPD) and chemically stable (Table 29). Table 29: Hygroscopicity & stability results for mesylate salts Conditions Weight Chg XRPD HPLC %purity 4d 13d 4d 13d 4d 13d 40°C / 75%RH - -0.2% No apparent No apparent 98.1 98.08 0.6% change change 920°C / 60%RH 0.7% -0.1% No apparent No apparent 98.2 97.86 change change 1 Example 5: Intrinsic dissolution rate study of Form E, Form M and free base of Compound

[0297] An intrinsic dissolution rate (IDR) study was conducted using Compound I L-tartrate, mesylate and HCl salt as well as Compound I free base. The dissolution medium was 0.1M HCl at 37°C. The Results are summarised in FIG. 2E. Example 6: Form A (monohydrate)

[0298] Crystalline Form A was prepared through evaporation, sonification experiments as detailed in Examples 2 and 3.

[0299] The XRPD spectrum for Form A is shown in FIG. 15A and is indicative of a crystalline material. Polarised light microscopy confirmed this showing birefringent small, irregularly shaped particle.

[0300] A summary of the XRPD peaks of Form A is included in Table 30. Table 30. XRPD peaks of Form A No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 6.1219 14.4374 4269.8 100.0 KA1 + KA2 2 7.1372 12.3858 504.6 11.8 KA1 + KA2 3 8.0222 11.0214 351.2 8.2 KA1 + KA2 4 10.0569 8.7956 1507.7 35.3 KA1 + KA2 5 10.5845 8.3584 1400.2 32.8 KA1 + KA2 6 12.2887 7.2028 1471.0 34.5 KA1 + KA2 7 14.7698 5.9979 1815.4 42.5 KA1 + KA2 8 15.8783 5.5816 534.9 12.5 KA1 + KA2 9 16.1485 5.4843 232.5 5.4 Pure KA1 10 16.3986 5.4012 228.3 5.4 Pure KA1 11 16.7016 5.3083 868.7 20.3 KA1 + KA2 12 17.3575 5.1091 1565.7 36.7 KA1 + KA2 13 18.0159 4.9239 1610.2 37.7 KA1 + KA2 14 18.3045 4.8469 784.6 18.4 KA1 + KA2 15 19.1061 4.6453 408.3 9.6 KA1 + KA2 16 20.2553 4.3843 381.2 8.9 KA1 + KA2 17 20.5166 4.3254 144.1 3.4 Pure KA1 18 21.5946 4.1153 961.9 22.5 KA1 + KA2 19 21.7227 4.0913 1040.9 24.4 KA1 + KA2 20 22.0641 4.0288 1241.6 29.1 KA1 + KA221 22.5758 3.9386 1329.0 31.1 KA1 + KA2 22 22.7066 3.9130 694.6 16.3 Pure KA1 23 23.1331 3.8418 290.5 6.8 Pure KA1 24 23.3096 3.8131 303.0 7.1 Pure KA1 25 23.7803 3.7387 182.7 4.3 Pure KA1 26 24.3538 3.6519 155.8 3.7 Pure KA1 27 24.7470 3.5977 498.1 11.7 KA1 + KA2 28 24.9863 3.5609 333.4 7.8 Pure KA1 29 25.6990 3.4666 259.7 6.1 KA1 + KA2 30 26.8015 3.3264 549.9 12.9 KA1 + KA2 31 27.8577 3.2027 590.7 13.8 KA1 + KA2 32 28.1667 3.1682 497.3 11.7 KA1 + KA2 33 28.7410 3.1037 103.8 2.4 Pure KA1 34 29.0204 3.0744 100.1 2.3 Pure KA1 35 29.3680 3.0388 117.1 2.7 Pure KA1 36 29.7201 3.0061 194.3 4.6 KA1 + KA2 37 30.5752 2.9239 240.3 5.6 KA1 + KA2 38 31.3398 2.8520 111.3 2.6 Pure KA1 39 32.0616 2.7917 238.5 5.6 KA1 + KA2 40 32.7993 2.7306 181.4 4.3 KA1 + KA2 41 34.0356 2.6320 64.1 1.5 Pure KA1 42 34.6975 2.5833 85.6 2.0 Pure KA1 43 35.2416 2.5446 123.0 2.9 Pure KA1 44 35.8152 2.5052 141.7 3.3 Pure KA1 45 37.9184 2.3709 143.3 3.4 Pure KA1

[0301] Thermogravimetric / Differential Thermal Analysis (TG / DTA) was performed to determine the thermal profile and associated % weight changes of Compound I free base (FIG. 15B). Weight loss of 3.98% was noted from ~25°C to 70°C suggesting the presence of moisture or solvent. No solvent was observed in the1H-NMR spectrum and the weight loss was attributed to water. The weight loss corresponds to 0.96 moles of water and drying the material caused a phase change, which indicates that it is a hydrate. A second weight loss at temperatures greater than 240°C corresponds to initiation of material decomposition. A large endotherm was observed at onset temperature 182.3°C.

[0302] . The1H-NMR spectrum conforms to the structure.

[0303] The DSC thermogram obtained for Form A is shown in FIG. 15C.

[0304] The hygroscopicity and the sorption properties of Compound I free base were determined using Dynamic Vapour Sorption (DVS). The isotherm obtained is shown in FIG. 15D. The sample was dried at 0%RH prior to sorption and desorption cycles. The isotherm showed the total weight gain observed between 0%RH and 80%RH to be 5%w / w, whichindicates that the sample is hygroscopic, according to the European Pharmacopoeia classification.

[0305] The desorption curve showed that the Form A loses moisture gradually with decreasing humidity, creating slight hysteresis between the sorption and desorption curves. The rate of desorption was comparable with that of sorption but a large weight loss was observed below 10%, which is characteristic of dehydration of a hydrate.

[0306] The diffractogram of the post DVS sample is indicates that the material has undergone change during DVS analysis. Based on thermal and DVS data, Form A appears to be a monohydrate. Example 7: Form B (DCM solvate)

[0307] Preparation of Form B

[0308] Compound I (3.0g) and dichloromethane (300mL) were added to a flask and stirred to form a fine suspension. Saturated aqueous NaHCO3 solution (200mL) was added and the mixture was stirred for ~5 minutes to form a solution. The layers were separated and the aqueous layer was extracted with CH2Cl2 (100mL). The organics were combined, washed with saturated aqueous brine solution, dried (MgSO4), filtered and concentrated to dryness to yield a pale yellow solid. This was confirmed as a DCM solvate of Compound I. Crystalline Form B was also prepared through slurry or sonification experiments as detailed in Examples 2 and 3.

[0309] The XRPD pattern for Form B is shown in FIG. 14A. This corresponds to a crystalline material. The microscope image shows the material to consist of plate like crystals.

[0310] Thermogravimetric / Differential Thermal Analysis (TG / DTA) was performed to determine the thermal profile and associated % weight changes of Form B solvate (FIG.14 B). A weight loss of 1.82% from ~25-100°C suggested the presence of surface adsorbed moisture or solvent. Three endothermic events were observed, the first at onset 104.5°C has an associated weight loss of 7.86%, which equates to 0.42 moles of DCM. The second endothermic event occurs at onset 157.1°C with no associated weight loss. The largest endothermic event was observed at onset temperature 183.3°C and is most likely due to the melt of the free base, anhydrate. Weight loss above 240°C corresponds to material decomposition. The TG / DTA and1H-NMR data confirm the presence of 0.4-0.5 moles of DCM, indicating that the material is a DCM solvate of the free base of Compound I.Example 8: Form C (anhydrous)

[0311] Crystalline Form C was prepared through heating and desolvation of Form B at 165°C in a TG instrument.

[0312] The TG analysis data indicated that the Form C did not lose weight after 165°C and was determined to be anhydrous. XRPD spectrum of Form C is shown in FIG. 16A.

[0313] A summary of the XRPD peaks of Form C is included in Table 31. Table 31. XRPD peaks of Form C Pos. d-spacing Height Rel. Int. No. [°2θ] [Å] [cts] [%] Derivation 1 6.7048 13.1837 669.96 46.88 KA1 + KA2 2 7.9060 11.1738 109.93 7.69 Pure KA1 3 9.4626 9.3466 533.65 37.34 KA1 + KA2 4 10.2275 8.6493 1134.55 79.39 KA1 + KA2 5 10.3529 8.5447 1429.08 100.00 KA1 + KA2 6 11.0708 7.9857 131.63 9.21 Pure KA1 7 11.6576 7.5849 135.51 9.48 Pure KA1 8 12.9675 6.8215 134.58 9.42 Pure KA1 9 13.4617 6.5777 302.61 21.18 KA1 + KA2 10 14.6052 6.0651 558.80 39.10 KA1 + KA2 11 15.2288 5.8182 169.92 11.89 KA1 + KA2 12 15.8698 5.5846 245.99 17.21 KA1 + KA2 13 16.2829 5.4393 200.97 14.06 Pure KA1 14 16.7413 5.2914 202.48 14.17 Pure KA1 15 16.8845 5.2512 457.86 32.04 KA1 + KA2 16 17.0892 5.1844 114.68 8.02 Pure KA1 17 17.3635 5.1032 78.64 5.50 Pure KA1 18 17.5159 5.0591 101.46 7.10 Pure KA1 19 17.7901 4.9817 69.70 4.88 Pure KA1 20 18.1275 4.8938 323.79 22.66 KA1 + KA2 21 18.6311 4.7627 452.04 31.63 KA1 + KA2 22 19.0156 4.6672 358.83 25.11 KA1 + KA2 23 19.3743 4.5778 132.16 9.25 Pure KA1 24 19.7411 4.4936 127.43 8.92 Pure KA1 25 20.4124 4.3509 808.21 56.55 KA1 + KA2 26 20.7842 4.2739 602.68 42.17 KA1 + KA2 27 21.3653 4.1555 129.06 9.03 Pure KA1 28 21.7944 4.0780 827.69 57.92 KA1 + KA2 29 22.0409 4.0296 263.50 18.44 Pure KA1 30 22.2295 3.9959 218.54 15.29 Pure KA1 31 23.1517 3.8387 86.99 6.09 Pure KA1 32 23.5477 3.7782 201.93 14.13 KA1 + KA2 33 23.9376 3.7145 84.82 5.94 Pure KA1 34 24.2658 3.6680 199.03 13.93 KA1 + KA235 24.7701 3.5915 79.20 5.54 Pure KA1 36 25.1346 3.5402 101.12 7.08 Pure KA1 37 25.7661 3.4577 202.38 14.16 KA1 + KA2 38 26.1068 3.4105 119.22 8.34 Pure KA1 39 26.3981 3.3763 618.97 43.31 KA1 + KA2 40 26.6502 3.3422 174.29 12.20 Pure KA1 41 26.9557 3.3050 179.33 12.55 Pure KA1 42 28.0665 3.1767 70.09 4.90 Pure KA1 43 28.4123 3.1388 75.53 5.29 Pure KA1 44 28.9440 3.0823 50.87 3.56 Pure KA1 45 29.4012 3.0355 65.92 4.61 Pure KA1 46 29.6754 3.0080 50.96 3.57 Pure KA1 47 30.7246 2.9077 51.51 3.60 Pure KA1 48 31.3820 2.8482 52.59 3.68 Pure KA1 49 32.8990 2.7203 60.18 4.21 Pure KA1 Example 9: Form D (ethanedisulfonate salt)

[0314] Crystalline Form D was prepared through precipitation, slurry, evaporation or slurrying crystal salt experiments as detailed in Examples 2 and 3. XRPD spectrum of Form D is shown in FIG. 17A.

[0315] The NMR spectrum of Form D corresponded to formation of an ethyldisulfonate salt with a 1:1 molar ratio of API to coformer.

[0316] A summary of the XRPD peaks of Form B is included in Table 32. Table 32. XRPD peaks of Form D Pos. d-spacing Height Rel. Int. No. [°2θ] [Å] [cts][%]Derivation1 5.6875 15.5391 1134.75 17.40 KA1 + KA2 2 9.8123 9.0143 6522.12 100.00 KA1 + KA2 3 11.0378 8.0161 2327.00 35.68 KA1 + KA2 4 11.4135 7.7531 494.34 7.58 KA1 + KA2 5 13.1991 6.7079 462.96 7.10 KA1 + KA2 6 14.5691 6.0801 2916.84 44.72 KA1 + KA2 7 15.1358 5.8537 188.56 2.89 KA1 + KA2 8 15.9639 5.5519 694.14 10.64 KA1 + KA2 9 16.0742 5.5095 373.44 5.73 Pure KA1 10 16.5792 5.3428 156.81 2.40 Pure KA1 11 17.7524 4.9964 1690.03 25.91 KA1 + KA2 12 18.5881 4.7736 1222.49 18.74 KA1 + KA2 13 18.9581 4.6812 1366.05 20.94 KA1 + KA2 14 19.3373 4.5865 119.88 1.84 Pure KA1 15 19.7258 4.4970 109.77 1.68 Pure KA1 16 20.1726 4.3984 267.15 4.10 Pure KA120.4162 4.3501 997.03 15.29 KA1 + KA2 20.6932 4.2925 2100.29 32.20 KA1 + KA2 21.1904 4.1929 2804.02 42.99 KA1 + KA2 21.7960 4.0777 5492.12 84.21 KA1 + KA2 22.1273 4.0174 1184.44 18.16 KA1 + KA2 22.6004 3.9344 261.79 4.01 KA1 + KA2 22.9751 3.8710 338.89 5.20 KA1 + KA2 23.1530 3.8385 135.72 2.08 Pure KA1 23.4634 3.7916 435.38 6.68 KA1 + KA2 23.8420 3.7322 594.99 9.12 KA1 + KA2 24.1047 3.6891 211.17 3.24 Pure KA1 24.4726 3.6375 596.81 9.15 KA1 + KA2 24.7479 3.5976 591.37 9.07 KA1 + KA2 25.6940 3.4673 848.32 13.01 KA1 + KA2 25.9054 3.4366 265.16 4.07 Pure KA1 26.6080 3.3502 3125.79 47.93 KA1 + KA2 27.0114 3.3011 382.40 5.86 KA1 + KA2 27.2319 3.2721 230.70 3.54 Pure KA1 27.4262 3.2494 162.41 2.49 Pure KA1 27.5953 3.2299 178.24 2.73 Pure KA1 27.8136 3.2077 417.54 6.40 KA1 + KA2 28.1172 3.1737 368.60 5.65 KA1 + KA2 28.3585 3.1446 226.15 3.47 Pure KA1 29.0480 3.0715 149.37 2.29 Pure KA1 29.4634 3.0317 847.76 13.00 KA1 + KA2 29.9774 2.9809 366.42 5.62 KA1 + KA2 30.6153 2.9202 148.28 2.27 KA1 + KA2 31.3124 2.8568 293.09 4.49 KA1 + KA2 32.1715 2.7824 504.17 7.73 KA1 + KA2 33.2604 2.6915 161.85 2.48 Pure KA1 33.5809 2.6666 90.57 1.39 Pure KA1 34.2805 2.6159 307.18 4.71 KA1 + KA2 34.6783 2.5847 69.75 1.07 Pure KA1 35.4844 2.5278 130.99 2.01 Pure KA1 35.8049 2.5059 133.16 2.04 Pure KA1 36.0662 2.4904 191.05 2.93 KA1 + KA2 36.7042 2.4485 150.42 2.31 KA1 + KA2 37.4433 2.4019 183.91 2.82 KA1 + KA2 38.0981 2.3602 137.51 2.11 Pure KA1 38.4574 2.3389 134.46 2.06 Pure KA1 39.3315 2.2889 139.30 2.14 Pure KA1Example 10: Form F (phosphate salt)

[0317] Crystalline Form F was prepared through precipitation or slurry experiments as detailed in Examples 2 and 3. Example 11: Form G (sulfate salt)

[0318] Crystalline Form G was prepared through precipitation, slurry or evaporation experiments as detailed in Examples 2 and 3.

[0319] XRPD spectrum of Form G is shown in FIG. 9A.

[0320] A summary of the XRPD peaks of Form G is included in Table 33. Table 33. XRPD peaks of Form G No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 5.6411 15.6670 356.16 15.08 KA1 + KA2 2 6.7462 13.1027 467.44 19.79 KA1 + KA2 3 8.1795 10.8098 555.53 23.51 KA1 + KA2 4 8.4606 10.4512 358.08 15.16 KA1 + KA2 5 8.7116 10.1422 92.18 3.90 Pure KA1 6 9.0678 9.7446 126.99 5.38 Pure KA1 7 9.4727 9.3367 411.35 17.41 KA1 + KA2 8 10.2156 8.6593 2362.52 100.00 KA1 + KA2 9 10.3530 8.5447 623.05 26.37 KA1 + KA2 10 10.9336 8.0855 91.07 3.85 Pure KA1 11 11.6624 7.5819 165.21 6.99 Pure KA1 12 12.0095 7.3635 124.03 5.25 Pure KA1 13 12.2823 7.2006 115.44 4.89 Pure KA1 14 12.9941 6.8077 103.68 4.39 Pure KA1 15 13.4229 6.5911 206.05 8.72 Pure KA1 16 14.6142 6.0614 982.16 41.57 KA1 + KA2 17 15.3102 5.7874 331.07 14.01 KA1 + KA2 18 15.4809 5.7192 147.97 6.26 Pure KA1 19 15.9231 5.5660 241.61 10.23 KA1 + KA2 20 16.2992 5.4339 158.48 6.71 Pure KA1 21 16.6959 5.3057 148.91 6.30 Pure KA1 22 16.8769 5.2492 179.00 7.58 Pure KA1 23 17.0026 5.2150 243.42 10.30 KA1 + KA2 24 17.5024 5.0630 83.33 3.53 Pure KA1 25 17.9034 4.9504 100.29 4.25 Pure KA1 26 18.1266 4.8900 114.79 4.86 Pure KA1 27 18.2889 4.8470 133.85 5.67 Pure KA1 28 18.5933 4.7683 171.47 7.26 Pure KA1 29 19.0124 4.6680 298.49 12.63 KA1 + KA2 30 19.3439 4.5849 144.43 6.11 Pure KA131 19.6686 4.5100 82.84 3.51 Pure KA1 32 20.4487 4.3432 1137.55 48.15 KA1 + KA2 33 20.7980 4.2711 337.78 14.30 KA1 + KA2 34 21.8082 4.0755 764.51 32.36 KA1 + KA2 35 22.2858 3.9859 149.58 6.33 Pure KA1 36 23.3814 3.8015 146.04 6.18 Pure KA1 37 23.9619 3.7138 245.20 10.38 KA1 + KA2 38 24.8492 3.5832 310.76 13.15 KA1 + KA2 39 25.7349 3.4590 135.13 5.72 Pure KA1 40 26.4275 3.3727 505.25 21.39 KA1 + KA2 41 26.7291 3.3325 117.55 4.98 Pure KA1 42 27.0943 3.2884 139.83 5.92 Pure KA1 43 27.3986 3.2526 109.04 4.62 Pure KA1 44 27.5812 3.2315 102.05 4.32 Pure KA1 45 28.1087 3.1720 92.60 3.92 Pure KA1 46 28.3725 3.1431 109.03 4.61 Pure KA1 47 28.8797 3.0891 92.97 3.94 Pure KA1 48 29.3666 3.0389 121.22 5.13 Pure KA1 49 30.7463 2.9057 108.69 4.60 Pure KA1 50 31.5596 2.8326 81.01 3.43 Pure KA1 51 32.1074 2.7855 60.78 2.57 Pure KA1 52 32.8378 2.7252 53.39 2.26 Pure KA1 53 33.1828 2.6977 67.60 2.86 Pure KA1 54 33.7711 2.6520 47.72 2.02 Pure KA1 55 36.7333 2.4446 65.93 2.79 Pure KA1 56 37.2202 2.4138 61.01 2.58 Pure KA1 Example 12: Form H (Dioxane solvate of free base of Compound I)

[0321] Crystalline Form H was prepared through the solubility studies using dioxane and MAD solvent mixture. The experimental procedure of solubility studies is detailed in Example 1. Example 13: Form (ketoglutarate salt)

[0322] Crystalline Form I was prepared through evaporation or slurry experiments as detailed in Examples 2 and 3.

[0323] XRPD spectrum of Form I is shown in FIG. 10A.

[0324] A summary of the XRPD peaks of Form I is included in Table 34. Table 34. XRPD peaks of Form I No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 6.0522 14.6036 2463.46 77.19 KA1 + KA2 2 6.2066 14.2289 245.51 7.69 Pure KA17.4036 11.9407 381.99 11.97 KA1 + KA2 8.1377 10.8651 3058.86 95.85 KA1 + KA2 8.2516 10.7154 3191.34 100.00 KA1 + KA2 8.4748 10.4337 500.12 15.67 KA1 + KA2 9.1263 9.6903 653.45 20.48 KA1 + KA2 9.6413 9.1662 146.80 4.60 Pure KA1 11.2131 7.8846 123.07 3.86 Pure KA1 11.6080 7.6235 1531.50 47.99 KA1 + KA2 12.1505 7.2844 973.76 30.51 KA1 + KA2 13.3200 6.6473 658.33 20.63 KA1 + KA2 13.4710 6.5731 689.62 21.61 KA1 + KA2 13.9783 6.3304 114.25 3.58 Pure KA1 14.1530 6.2527 110.52 3.46 Pure KA1 14.5896 6.0666 134.28 4.21 Pure KA1 14.8516 5.9601 169.13 5.30 Pure KA1 15.3130 5.7863 644.13 20.18 KA1 + KA2 15.5241 5.7034 142.32 4.46 Pure KA1 15.7196 5.6376 323.56 10.14 KA1 + KA2 16.3144 5.4334 454.39 14.24 KA1 + KA2 16.5694 5.3503 610.72 19.14 KA1 + KA2 16.8840 5.2513 538.44 16.87 KA1 + KA2 17.4934 5.0655 114.78 3.60 Pure KA1 17.8768 4.9619 587.16 18.40 KA1 + KA2 18.1116 4.8940 163.22 5.11 Pure KA1 18.2572 4.8553 313.29 9.82 Pure KA1 18.4955 4.7973 957.92 30.02 KA1 + KA2 18.8975 4.6922 194.23 6.09 Pure KA1 19.4690 4.5595 668.69 20.95 KA1 + KA2 19.6498 4.5180 449.36 14.08 KA1 + KA2 19.8986 4.4584 146.37 4.59 Pure KA1 20.1577 4.4016 122.32 3.83 Pure KA1 20.9564 4.2391 363.79 11.40 KA1 + KA2 21.3769 4.1567 444.26 13.92 KA1 + KA2 21.7787 4.0809 659.31 20.66 KA1 + KA2 22.0580 4.0265 128.18 4.02 Pure KA1 22.4393 3.9622 395.18 12.38 KA1 + KA2 22.6895 3.9191 402.98 12.63 KA1 + KA2 23.0202 3.8636 727.73 22.80 KA1 + KA2 23.3363 3.8088 102.66 3.22 Pure KA1 23.6300 3.7621 114.52 3.59 Pure KA1 23.8663 3.7285 1227.43 38.46 KA1 + KA2 24.2346 3.6696 260.61 8.17 Pure KA1 24.4382 3.6425 1159.91 36.35 KA1 + KA2 24.8243 3.5867 502.64 15.75 KA1 + KA2 25.3280 3.5165 394.60 12.36 KA1 + KA2 25.7076 3.4655 289.71 9.08 KA1 + KA249 26.0830 3.4136 140.64 4.41 Pure KA1 50 26.2903 3.3871 162.87 5.10 Pure KA1 51 26.4803 3.3633 163.62 5.13 Pure KA1 52 26.8420 3.3215 406.35 12.73 KA1 + KA2 53 27.3714 3.2585 280.55 8.79 KA1 + KA2 54 27.7398 3.2160 397.65 12.46 KA1 + KA2 55 27.9379 3.1910 133.53 4.18 Pure KA1 56 28.1625 3.1661 84.02 2.63 Pure KA1 57 28.5993 3.1213 166.26 5.21 KA1 + KA2 58 29.2162 3.0542 83.20 2.61 Pure KA1 59 29.4581 3.0297 108.53 3.40 Pure KA1 60 29.7517 3.0005 124.65 3.91 Pure KA1 61 30.8909 2.8948 141.23 4.43 KA1 + KA2 62 31.6692 2.8230 125.26 3.92 Pure KA1 63 31.8420 2.8081 127.07 3.98 Pure KA1 64 32.2566 2.7730 82.58 2.59 Pure KA1 65 32.6081 2.7461 158.83 4.98 KA1 + KA2 66 33.8113 2.6489 72.86 2.28 Pure KA1 67 34.4678 2.6000 76.50 2.40 Pure KA1 68 35.1760 2.5492 93.71 2.94 Pure KA1 69 35.3833 2.5348 82.87 2.60 Pure KA1 70 35.8325 2.5040 113.64 3.56 Pure KA1 71 36.1952 2.4797 84.88 2.66 Pure KA1 72 36.7618 2.4428 80.97 2.54 Pure KA1 73 37.0900 2.4220 99.21 3.11 Pure KA1 Example 14: Form J (acetate salt)

[0325] Crystalline Form J was prepared through slurrying crystalline salt experiments as detailed in Examples 2 and 3. Example 15: Form K (Succinate salt (2:1, API : acid))

[0326] Crystalline Form K was prepared through slurrying crystalline salt experiments as detailed in Examples 2 and 3.

[0327] XRPD spectrum of Form K is shown in FIG. 3A.

[0328] A summary of the XRPD peaks of Form K is included in Table 35. Table 35. XRPD peaks of Form K No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 6.139 14.397 837.62 84.38 KA1 + KA2 2 8.768 10.078 114.26 11.51 Pure KA1 3 9.548 9.255 183.95 18.53 Pure KA110.021 8.827 606.73 61.12 KA1 + KA2 10.272 8.605 121.35 12.22 Pure KA1 10.672 8.283 171.31 17.26 Pure KA1 10.844 8.152 119.89 12.08 Pure KA1 11.399 7.763 426.25 42.94 KA1 + KA2 12.329 7.173 119.70 12.06 Pure KA1 12.767 6.928 140.80 14.18 Pure KA1 13.263 6.670 142.75 14.38 Pure KA1 13.910 6.361 165.74 16.70 Pure KA1 14.501 6.104 127.91 12.89 Pure KA1 14.674 6.037 447.38 45.07 KA1 + KA2 14.825 5.971 153.10 15.42 Pure KA1 15.320 5.779 123.13 12.40 Pure KA1 15.720 5.633 128.16 12.91 Pure KA1 16.000 5.539 462.22 46.56 KA1 + KA2 16.139 5.488 145.50 14.66 Pure KA1 16.413 5.401 399.69 40.26 KA1 + KA2 16.863 5.254 151.58 15.27 Pure KA1 17.442 5.085 547.58 55.16 KA1 + KA2 17.662 5.017 261.20 26.31 Pure KA1 17.910 4.949 125.54 12.65 Pure KA1 18.215 4.867 69.03 6.95 Pure KA1 18.609 4.764 68.54 6.90 Pure KA1 18.924 4.690 239.30 24.11 KA1 + KA2 19.162 4.628 148.17 14.93 Pure KA1 19.290 4.598 247.61 24.94 Pure KA1 19.657 4.513 151.59 15.27 Pure KA1 19.840 4.471 103.58 10.43 Pure KA1 20.164 4.400 169.16 17.04 Pure KA1 20.314 4.372 393.86 39.68 KA1 + KA2 20.800 4.267 168.76 17.00 Pure KA1 20.980 4.231 134.69 13.57 Pure KA1 21.432 4.146 992.69 100.00 KA1 + KA2 21.904 4.054 241.35 24.31 Pure KA1 22.095 4.020 173.87 17.51 Pure KA1 22.267 3.989 108.94 10.97 Pure KA1 22.891 3.885 470.72 47.42 KA1 + KA2 23.102 3.847 170.04 17.13 Pure KA1 23.257 3.822 132.80 13.38 Pure KA1 23.618 3.764 96.25 9.70 Pure KA1 23.932 3.718 274.01 27.60 KA1 + KA2 24.193 3.676 80.69 8.13 Pure KA1 24.842 3.584 222.59 22.42 KA1 + KA2 25.409 3.503 130.92 13.19 Pure KA1 25.790 3.452 97.73 9.85 Pure KA1 26.056 3.417 100.22 10.10 Pure KA150 26.323 3.383 119.48 12.04 Pure KA1 51 26.873 3.318 209.05 21.06 KA1 + KA2 52 28.264 3.155 75.47 7.60 Pure KA1 53 28.549 3.124 61.57 6.20 Pure KA1 54 29.235 3.052 52.31 5.27 Pure KA1 55 29.654 3.010 57.35 5.78 Pure KA1 56 29.949 2.981 51.02 5.14 Pure KA1 57 30.473 2.931 67.02 6.75 Pure KA1 58 31.537 2.835 63.11 6.36 Pure KA1 59 32.340 2.766 85.69 8.63 Pure KA1 60 32.987 2.713 49.12 4.95 Pure KA1 Example 16: Form L (Succinate salt (1:1))

[0329] Crystalline Form L was prepared through slurry experiments as detailed in Examples 2 and 3.

[0330] XRPD spectrum of Form L is shown in FIG. 4A.

[0331] A summary of the XRPD peaks of Form L is included in Table 36. Table 36. XRPD peaks of Form L No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 6.3045 14.0198 1481.15 90.27 KA1 + KA2 2 7.4157 11.9114 155.35 9.47 Pure KA1 3 8.0838 10.9284 166.44 10.14 Pure KA1 4 8.4020 10.5153 90.85 5.54 Pure KA1 5 9.9644 8.8771 918.05 55.95 KA1 + KA2 6 11.0179 8.0305 1067.56 65.06 KA1 + KA2 7 11.6365 7.6049 504.58 30.75 KA1 + KA2 8 12.6521 6.9967 351.54 21.42 KA1 + KA2 9 14.7338 6.0125 687.34 41.89 KA1 + KA2 10 14.9204 5.9377 394.32 24.03 KA1 + KA2 11 15.4125 5.7444 170.22 10.37 Pure KA1 12 15.9640 5.5472 150.14 9.15 Pure KA1 13 16.2588 5.4473 120.07 7.32 Pure KA1 14 17.3111 5.1227 1640.87 100.00 KA1 + KA2 15 17.4998 5.0679 937.81 57.15 KA1 + KA2 16 18.7145 4.7377 111.99 6.82 Pure KA1 17 20.0186 4.4319 200.49 12.22 Pure KA1 18 20.2168 4.3925 520.03 31.69 KA1 + KA2 19 20.5506 4.3219 241.64 14.73 KA1 + KA2 20 21.2876 4.1705 170.25 10.38 Pure KA1 21 21.6224 4.1101 663.63 40.44 KA1 + KA2 22 22.1291 4.0171 1326.65 80.85 KA1 + KA223 22.4498 3.9604 418.44 25.50 KA1 + KA2 24 22.9470 3.8757 392.86 23.94 KA1 + KA2 25 23.1647 3.8366 270.93 16.51 Pure KA1 26 23.3768 3.8023 234.09 14.27 Pure KA1 27 24.3847 3.6504 288.22 17.57 KA1 + KA2 28 24.6812 3.6042 200.77 12.24 Pure KA1 29 25.0406 3.5533 122.17 7.45 Pure KA1 30 25.4765 3.4935 183.84 11.20 Pure KA1 31 25.7311 3.4595 227.61 13.87 Pure KA1 32 26.2373 3.3939 69.13 4.21 Pure KA1 33 27.1787 3.2811 376.57 22.95 KA1 + KA2 34 27.9001 3.1953 96.86 5.90 Pure KA1 35 29.1833 3.0576 91.09 5.55 Pure KA1 36 29.9257 2.9834 90.21 5.50 Pure KA1 37 30.2756 2.9497 114.64 6.99 Pure KA1 38 31.0710 2.8760 74.02 4.51 Pure KA1 39 31.4316 2.8438 104.25 6.35 Pure KA1 40 31.7073 2.8197 123.16 7.51 Pure KA1 41 32.5464 2.7512 100.28 6.11 KA1 + KA2 Example 17: Form N (acetate salt)

[0332] Crystalline Form N was prepared through slurry experiments as detailed in Examples 2 and 3. Example 18: Form O (pyroglutamate salt)

[0333] Crystalline Form O was prepared through slurry experiments as detailed in Examples 2 and 3.

[0334] XRPD spectrum of Form O is shown in FIG. 11A.

[0335] A summary of the XRPD peaks of Form O is included in Table 37. Table 37. XRPD peaks of Form O No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 4.4943 19.6452 109.85 8.91 Pure KA1 2 4.8047 18.3771 126.23 10.24 Pure KA1 3 7.9670 11.0884 104.42 8.47 Pure KA1 4 8.4939 10.4103 415.26 33.69 KA1 + KA2 5 9.5837 9.2288 946.83 76.82 KA1 + KA2 6 10.0210 8.8197 126.49 10.26 Pure KA1 7 10.2131 8.6543 162.29 13.17 Pure KA1 8 10.4052 8.4949 78.91 6.40 Pure KA1 9 10.8146 8.1810 425.04 34.48 KA1 + KA211.1285 7.9444 94.06 7.63 Pure KA1 11.6875 7.5656 67.20 5.45 Pure KA1 13.1685 6.7179 142.09 11.53 Pure KA1 13.4556 6.5806 556.76 45.17 KA1 + KA2 14.2252 6.2212 80.55 6.54 Pure KA1 14.9852 5.9122 506.44 41.09 KA1 + KA2 15.5256 5.7029 130.63 10.60 Pure KA1 16.0132 5.5303 127.75 10.36 Pure KA1 16.3902 5.4084 1232.58 100.00 KA1 + KA2 16.8581 5.2593 320.19 25.98 KA1 + KA2 17.1510 5.1659 200.46 16.26 Pure KA1 17.4539 5.0811 549.35 44.57 KA1 + KA2 17.9047 4.9501 144.13 11.69 Pure KA1 18.3330 4.8394 558.88 45.34 KA1 + KA2 18.5253 4.7856 277.02 22.48 Pure KA1 18.9469 4.6840 524.51 42.55 KA1 + KA2 19.2582 4.6089 789.57 64.06 KA1 + KA2 19.7961 4.4812 149.67 12.14 Pure KA1 20.1065 4.4127 136.67 11.09 Pure KA1 20.2542 4.3809 113.80 9.23 Pure KA1 20.5054 4.3278 172.06 13.96 Pure KA1 21.1605 4.1987 294.74 23.91 KA1 + KA2 21.4807 4.1334 119.23 9.67 Pure KA1 21.7940 4.0781 349.86 28.38 KA1 + KA2 22.3200 3.9832 316.23 25.66 KA1 + KA2 22.6333 3.9255 160.06 12.99 Pure KA1 22.8698 3.8854 224.74 18.23 Pure KA1 23.2096 3.8293 155.20 12.59 Pure KA1 23.5718 3.7713 98.64 8.00 Pure KA1 24.1110 3.6881 228.43 18.53 Pure KA1 24.2811 3.6627 132.65 10.76 Pure KA1 24.7392 3.5959 172.65 14.01 Pure KA1 25.0643 3.5500 195.45 15.86 Pure KA1 25.2860 3.5194 151.29 12.27 Pure KA1 25.7709 3.4571 242.47 19.67 KA1 + KA2 26.1824 3.4037 385.17 31.25 KA1 + KA2 26.4977 3.3611 186.63 15.14 Pure KA1 27.0740 3.2909 214.09 17.37 Pure KA1 27.3104 3.2629 175.69 14.25 Pure KA1 27.6798 3.2202 125.19 10.16 Pure KA1 28.6556 3.1153 183.31 14.87 KA1 + KA2 29.5537 3.0201 62.32 5.06 Pure KA1 30.1300 2.9637 79.13 6.42 Pure KA1 31.0757 2.8756 91.37 7.41 Pure KA1 32.0510 2.7903 81.55 6.62 Pure KA1 33.1298 2.7019 118.53 9.62 Pure KA1Example 19: Form P (gentisate salt (1:1))

[0336] Crystalline Form P was prepared through slurry experiments as detailed in Examples 2 and 3.

[0337] XRPD spectrum of Form P is shown in FIG. 5A.

[0338] A summary of the XRPD peaks of Form P is included in Table 38. Table 38. XRPD peaks of Form P Pos. d-spacing Height Rel. Int. No. [°2θ] [Å] [cts][%]Derivation1 6.4772 13.6463 6558.33 100.00 KA1 + KA2 2 7.2029 12.2730 3672.55 56.00 KA1 + KA2 3 7.4203 11.9139 2973.84 45.34 KA1 + KA2 4 8.3244 10.6218 782.18 11.93 KA1 + KA2 5 10.4706 8.4490 653.28 9.96 KA1 + KA2 6 10.9186 8.1033 650.35 9.92 KA1 + KA2 7 11.4872 7.7035 350.59 5.35 KA1 + KA2 8 12.1495 7.2850 811.83 12.38 KA1 + KA2 9 12.4310 7.1147 194.40 2.96 Pure KA1 10 12.9733 6.8242 1955.60 29.82 KA1 + KA2 11 13.3077 6.6479 180.36 2.75 Pure KA1 12 14.1636 6.2481 321.93 4.91 Pure KA1 13 14.4342 6.1366 479.26 7.31 KA1 + KA2 14 14.8629 5.9556 203.98 3.11 Pure KA1 15 15.1126 5.8626 516.74 7.88 KA1 + KA2 16 15.4459 5.7369 390.35 5.95 KA1 + KA2 17 16.2771 5.4457 2018.85 30.78 KA1 + KA2 18 16.6704 5.3181 1269.32 19.35 KA1 + KA2 19 16.9608 5.2234 313.08 4.77 Pure KA1 20 17.1174 5.1760 396.48 6.05 Pure KA1 21 17.3575 5.1091 1318.36 20.10 KA1 + KA2 22 17.5140 5.0596 574.88 8.77 Pure KA1 23 17.7542 4.9959 1294.84 19.74 KA1 + KA2 24 18.1447 4.8892 1428.56 21.78 KA1 + KA2 25 18.8478 4.7084 754.11 11.50 KA1 + KA2 26 19.0464 4.6597 968.79 14.77 KA1 + KA2 27 19.5168 4.5485 535.11 8.16 KA1 + KA2 28 19.7275 4.4966 324.60 4.95 Pure KA1 29 19.8945 4.4593 283.06 4.32 Pure KA1 30 20.1498 4.4070 2692.14 41.05 KA1 + KA2 31 21.0372 4.2231 747.23 11.39 KA1 + KA2 32 21.3838 4.1554 658.47 10.04 KA1 + KA2 33 21.7240 4.0911 766.96 11.69 KA1 + KA2 34 22.2308 3.9989 469.77 7.16 KA1 + KA2 35 22.5247 3.9442 315.41 4.81 Pure KA136 22.9023 3.8832 2849.14 43.44 KA1 + KA2 37 23.1433 3.8433 1093.49 16.67 KA1 + KA2 38 23.4459 3.7944 615.95 9.39 KA1 + KA2 39 24.0121 3.7062 459.68 7.01 KA1 + KA2 40 24.4019 3.6478 572.26 8.73 KA1 + KA2 41 24.7792 3.5902 214.43 3.27 Pure KA1 42 25.1339 3.5432 656.42 10.01 KA1 + KA2 43 25.4576 3.4960 231.99 3.54 Pure KA1 44 26.1624 3.4062 317.06 4.83 KA1 + KA2 45 26.8534 3.3201 560.47 8.55 KA1 + KA2 46 27.5038 3.2431 1078.99 16.45 KA1 + KA2 47 27.8075 3.2083 530.76 8.09 KA1 + KA2 48 28.7285 3.1050 164.21 2.50 Pure KA1 49 29.0417 3.0722 232.98 3.55 Pure KA1 50 29.5241 3.0256 531.31 8.10 KA1 + KA2 51 29.7783 3.0003 581.92 8.87 KA1 + KA2 52 30.4649 2.9343 246.17 3.75 KA1 + KA2 53 30.7951 2.9012 168.09 2.56 Pure KA1 54 31.7241 2.8183 175.60 2.68 Pure KA1 55 31.9746 2.7968 168.30 2.57 Pure KA1 56 32.8931 2.7208 176.92 2.70 Pure KA1 57 33.1280 2.7020 162.64 2.48 Pure KA1 58 34.4327 2.6025 169.09 2.58 Pure KA1 59 34.9128 2.5678 169.94 2.59 Pure KA1 60 35.6121 2.5190 159.20 2.43 Pure KA1 61 36.7491 2.4457 194.63 2.97 KA1 + KA2 Example 20: Form Q (ethanedisulfonate salt)

[0339] Crystalline Form Q was prepared through slurry experiments as detailed in Examples 2 and 3.

[0340] XRPD spectrum of Form Q is shown in FIG. 8A.

[0341] A summary of the XRPD peaks of Form Q is included in Table 39. Table 39. XRPD peaks of Form Q No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 6.477 13.647 950.78 96.37 KA1 + KA2 2 7.823 11.293 151.05 15.31 Pure KA1 3 8.191 10.786 142.11 14.40 Pure KA1 4 8.797 10.045 100.15 10.15 Pure KA1 5 9.398 9.410 986.55 100.00 KA1 + KA2 6 12.146 7.287 642.96 65.17 KA1 + KA2 7 13.710 6.459 520.54 52.76 KA1 + KA214.474 6.115 86.89 8.81 Pure KA1 14.705 6.019 97.75 9.91 Pure KA1 15.246 5.807 162.24 16.45 Pure KA1 15.592 5.679 140.59 14.25 Pure KA1 15.982 5.541 202.47 20.52 Pure KA1 16.761 5.285 129.60 13.14 Pure KA1 16.922 5.235 84.06 8.52 Pure KA1 17.302 5.121 131.99 13.38 Pure KA1 17.656 5.023 261.07 26.46 KA1 + KA2 18.192 4.877 579.15 58.70 KA1 + KA2 18.557 4.777 160.44 16.26 Pure KA1 18.904 4.694 499.81 50.66 KA1 + KA2 19.496 4.550 83.40 8.45 Pure KA1 19.728 4.497 77.04 7.81 Pure KA1 20.094 4.415 181.99 18.45 Pure KA1 20.330 4.368 356.32 36.12 KA1 + KA2 20.565 4.319 331.43 33.59 KA1 + KA2 21.324 4.167 280.63 28.45 KA1 + KA2 21.609 4.109 134.88 13.67 Pure KA1 21.933 4.049 138.58 14.05 Pure KA1 22.427 3.964 834.01 84.54 KA1 + KA2 23.044 3.856 86.19 8.74 Pure KA1 23.715 3.749 150.31 15.24 Pure KA1 24.417 3.646 292.95 29.69 KA1 + KA2 24.862 3.578 121.90 12.36 Pure KA1 25.057 3.551 153.21 15.53 Pure KA1 25.396 3.507 430.97 43.68 KA1 + KA2 25.771 3.454 125.97 12.77 Pure KA1 26.117 3.409 106.99 10.84 Pure KA1 26.355 3.379 157.23 15.94 Pure KA1 26.615 3.347 137.98 13.99 Pure KA1 26.998 3.300 72.56 7.35 Pure KA1 27.524 3.238 116.98 11.86 Pure KA1 27.914 3.194 66.80 6.77 Pure KA1 28.511 3.131 118.15 11.98 KA1 + KA2 29.472 3.028 121.91 12.36 Pure KA1 29.926 2.983 68.78 6.97 Pure KA1 30.079 2.969 66.96 6.79 Pure KA1 30.619 2.917 93.34 9.46 Pure KA1 30.814 2.899 104.95 10.64 Pure KA1 31.550 2.833 102.85 10.42 Pure KA1Example 21: Form R (malic salt)

[0342] Crystalline Form R was prepared through evaporation experiments as detailed in Examples 2 and 3.

[0343] XRPD spectrum of Form R is shown in FIG. 12A.

[0344] A summary of the XRPD peaks of Form R is included in Table 40. Table 40. XRPD peaks of Form R No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 4.304 20.514 149.34 13.33 Pure KA1 2 6.051 14.595 124.70 11.13 Pure KA1 3 8.671 10.190 218.11 19.47 Pure KA1 4 9.501 9.309 1024.21 91.44 KA1 + KA2 5 9.862 8.962 102.78 9.18 Pure KA1 6 10.327 8.566 708.72 63.27 KA1 + KA2 7 11.323 7.808 84.79 7.57 Pure KA1 8 12.323 7.177 153.90 13.74 Pure KA1 9 13.048 6.785 668.13 59.65 KA1 + KA2 10 13.510 6.549 82.81 7.39 Pure KA1 11 14.229 6.220 79.68 7.11 Pure KA1 12 14.427 6.135 146.03 13.04 Pure KA1 13 14.948 5.927 711.36 63.51 KA1 + KA2 14 15.496 5.719 890.81 79.53 KA1 + KA2 15 15.858 5.589 595.56 53.17 KA1 + KA2 16 16.774 5.281 88.76 7.92 Pure KA1 17 17.444 5.084 650.15 58.04 KA1 + KA2 18 17.737 5.001 476.85 42.57 KA1 + KA2 19 18.535 4.787 1120.10 100.00 KA1 + KA2 20 19.057 4.657 892.92 79.72 KA1 + KA2 21 19.732 4.499 493.63 44.07 KA1 + KA2 22 20.544 4.323 404.45 36.11 KA1 + KA2 23 20.971 4.233 152.62 13.63 Pure KA1 24 21.430 4.143 133.05 11.88 Pure KA1 25 21.888 4.057 163.27 14.58 Pure KA1 26 22.365 3.975 204.54 18.26 KA1 + KA2 27 22.796 3.898 71.92 6.42 Pure KA1 28 23.166 3.836 147.93 13.21 Pure KA1 29 23.502 3.782 135.60 12.11 Pure KA1 30 23.907 3.719 270.89 24.18 Pure KA1 31 24.158 3.684 394.19 35.19 KA1 + KA2 32 24.782 3.593 728.71 65.06 KA1 + KA2 33 25.054 3.551 226.89 20.26 Pure KA1 34 25.414 3.505 384.68 34.34 KA1 + KA2 35 25.636 3.472 213.90 19.10 Pure KA136 26.606 3.348 149.62 13.36 Pure KA1 37 26.903 3.314 245.83 21.95 KA1 + KA2 38 27.324 3.264 274.30 24.49 KA1 + KA2 39 27.893 3.196 101.51 9.06 Pure KA1 40 28.193 3.163 114.19 10.19 Pure KA1 41 28.807 3.099 191.53 17.10 KA1 + KA2 42 29.181 3.058 117.33 10.47 Pure KA1 43 29.498 3.026 118.96 10.62 Pure KA1 44 29.798 2.996 134.55 12.01 Pure KA1 45 30.080 2.968 137.94 12.31 Pure KA1 46 31.015 2.881 92.85 8.29 Pure KA1 47 32.820 2.729 177.80 15.87 KA1 + KA2 48 33.449 2.677 104.69 9.35 Pure KA1 49 35.429 2.534 115.82 10.34 KA1 + KA2 50 36.358 2.471 112.87 10.08 KA1 + KA2 51 37.223 2.414 139.06 12.41 Pure KA1 52 37.629 2.389 109.03 9.73 Pure KA1 53 39.128 2.300 116.18 10.37 Pure KA1 Example 22: Form S (isethionate salt)

[0345] Crystalline Form S was prepared through evaporation experiments as detailed in Examples 2 and 3.

[0346] XRPD spectrum of Form S is shown in FIG. 13A.

[0347] Isethionic acid was prepared from its sodium salt by ion exchange chromatography. The ion exchange resin was washed with water (4 x 50mL) and filtered. Isethionic acid sodium salt (1.09g) in water (30mL) was added to the washed resin and the mixture stirred at ambient temperature for 15 minutes. The mixture was filtered and the resin washed with water (30mL). The aqueous filtrates were concentrated in vacuo to afford the acid as an orange liquid (0.82g, 89%).

[0348] A summary of the XRPD peaks of Form S is included in Table 41. Table 41. XRPD peaks of Form S No.Pos.d-spacing Height Rel. Int. Derivation [°2θ] [Å] [cts] [%] 1 3.8726 22.8169 329.58 35.66 KA1 + KA2 2 9.1067 9.7110 924.24 100.00 KA1 + KA2 3 11.3384 7.8042 453.92 49.11 KA1 + KA2 4 11.6744 7.5804 603.72 65.32 KA1 + KA2 5 12.1623 7.2774 307.71 33.29 KA1 + KA2 6 12.4201 7.1210 87.75 9.49 Pure KA1 7 13.7576 6.4315 171.54 18.56 Pure KA114.3080 6.1853 85.30 9.23 Pure KA1 15.6181 5.6693 88.66 9.59 Pure KA1 16.2574 5.4478 138.61 15.00 Pure KA1 16.8401 5.2606 190.70 20.63 Pure KA1 17.2081 5.1532 848.46 91.80 KA1 + KA2 17.6812 5.0163 395.28 42.77 KA1 + KA2 17.9114 4.9482 184.92 20.01 Pure KA1 18.4565 4.8033 176.47 19.09 Pure KA1 18.6821 4.7458 180.07 19.48 Pure KA1 18.9829 4.6752 479.92 51.93 KA1 + KA2 19.1708 4.6259 270.61 29.28 Pure KA1 19.5482 4.5375 88.76 9.60 Pure KA1 19.8755 4.4672 225.42 24.39 KA1 + KA2 20.2655 4.3821 414.29 44.83 KA1 + KA2 20.4607 4.3371 186.82 20.21 Pure KA1 20.8217 4.2663 270.94 29.32 KA1 + KA2 21.4823 4.1365 358.77 38.82 KA1 + KA2 21.6743 4.0969 145.58 15.75 Pure KA1 22.2006 4.0010 282.72 30.59 Pure KA1 22.4253 3.9647 405.25 43.85 KA1 + KA2 22.7943 3.9013 202.98 21.96 KA1 + KA2 23.2079 3.8327 515.53 55.78 KA1 + KA2 23.4342 3.7931 201.73 21.83 Pure KA1 23.7288 3.7498 337.52 36.52 KA1 + KA2 23.9331 3.7151 108.14 11.70 Pure KA1 24.5124 3.6286 165.72 17.93 Pure KA1 24.8508 3.5800 143.18 15.49 Pure KA1 25.0387 3.5535 178.80 19.35 Pure KA1 25.8940 3.4409 354.53 38.36 KA1 + KA2 26.3920 3.3743 158.99 17.20 Pure KA1 26.6364 3.3439 151.97 16.44 Pure KA1 27.2942 3.2648 80.37 8.70 Pure KA1 27.5419 3.2360 60.47 6.54 Pure KA1 28.1588 3.1665 113.00 12.23 Pure KA1 28.8167 3.0957 88.59 9.59 Pure KA1 28.9858 3.0780 67.34 7.29 Pure KA1 29.3617 3.0394 81.43 8.81 Pure KA1 29.6249 3.0130 96.10 10.40 Pure KA1 30.0041 2.9758 72.94 7.89 Pure KA1 30.3988 2.9381 85.91 9.29 Pure KA1 30.7902 2.9016 106.07 11.48 Pure KA1 31.3917 2.8474 98.61 10.67 Pure KA1 31.7897 2.8126 79.01 8.55 Pure KA1 32.6510 2.7404 84.74 9.17 Pure KA1 32.9329 2.7175 68.11 7.37 Pure KA1 33.4780 2.6745 71.86 7.77 Pure KA154 33.9479 2.6386 57.09 6.18 Pure KA1 55 34.3990 2.6050 71.94 7.78 Pure KA1 56 34.6246 2.5886 66.41 7.19 Pure KA1 57 35.3952 2.5339 55.37 5.99 Pure KA1 58 36.2974 2.4730 48.04 5.20 Pure KA1 59 37.5466 2.3955 125.67 13.60 KA1 + KA2 60 37.9999 2.3660 46.35 5.01 Pure KA1 Example 23: Form T (phosphate salt)

[0349] Crystalline Form T was prepared through slurrying crystal salt experiments as detailed in Examples 2 and 3.

[0350] XRPD spectrum of Form T is shown in FIG. 6A.

[0351] A summary of the XRPD peaks of Form T is included in Table 42. Table 42. XRPD peaks of Form T Pos. d-spacing Height Rel. Int. No. [°2θ] [Å] [cts][%]Derivation1 3.8674 22.8472 652.54 22.51 KA1 + KA2 2 7.7180 11.4455 171.68 5.92 Pure KA1 3 9.1265 9.6901 2899.34 100.00 KA1 + KA2 4 11.3288 7.8108 425.77 14.69 KA1 + KA2 5 11.6310 7.6085 609.87 21.03 KA1 + KA2 6 11.8818 7.4423 169.26 5.84 Pure KA1 7 12.3330 7.1770 744.69 25.68 KA1 + KA2 8 13.8713 6.3790 194.64 6.71 Pure KA1 9 14.2869 6.1995 332.02 11.45 KA1 + KA2 10 14.5462 6.0846 110.35 3.81 Pure KA1 11 16.2515 5.4542 353.61 12.20 KA1 + KA2 12 17.0365 5.2047 1238.49 42.72 KA1 + KA2 13 17.6096 5.0366 730.66 25.20 KA1 + KA2 14 17.8281 4.9753 1078.87 37.21 KA1 + KA2 15 18.0870 4.9006 154.50 5.33 Pure KA1 16 18.3185 4.8432 773.75 26.69 KA1 + KA2 17 18.6679 4.7534 477.36 16.46 KA1 + KA2 18 19.1819 4.6271 2012.34 69.41 KA1 + KA2 19 20.0165 4.4360 317.14 10.94 KA1 + KA2 20 20.4585 4.3412 992.81 34.24 KA1 + KA2 21 21.0171 4.2236 163.17 5.63 Pure KA1 22 21.3347 4.1614 141.64 4.89 Pure KA1 23 21.7514 4.0860 339.22 11.70 KA1 + KA2 24 22.3709 3.9742 889.57 30.68 KA1 + KA2 25 22.9886 3.8688 492.86 17.00 KA1 + KA2 26 23.3627 3.8077 627.98 21.66 KA1 + KA227 23.9676 3.7129 987.01 34.04 KA1 + KA2 28 24.4311 3.6405 144.22 4.97 Pure KA1 29 24.7884 3.5889 139.92 4.83 Pure KA1 30 25.1457 3.5387 184.07 6.35 Pure KA1 31 25.3895 3.5081 321.01 11.07 KA1 + KA2 32 25.7193 3.4639 278.60 9.61 KA1 + KA2 33 26.1486 3.4080 267.20 9.22 KA1 + KA2 34 26.8925 3.3127 161.54 5.57 Pure KA1 35 27.1802 3.2810 355.12 12.25 KA1 + KA2 36 27.4085 3.2514 168.41 5.81 Pure KA1 37 27.7099 3.2194 234.62 8.09 KA1 + KA2 38 28.1443 3.1681 98.94 3.41 Pure KA1 39 28.7534 3.1023 120.13 4.14 Pure KA1 40 28.8940 3.0876 114.05 3.93 Pure KA1 41 29.3691 3.0412 306.73 10.58 KA1 + KA2 42 29.5969 3.0158 157.42 5.43 Pure KA1 43 30.0420 2.9721 125.06 4.31 Pure KA1 44 30.4729 2.9335 190.12 6.56 KA1 + KA2 45 30.7983 2.9009 91.18 3.14 Pure KA1 46 31.2528 2.8621 212.75 7.34 KA1 + KA2 47 31.7720 2.8165 172.37 5.95 KA1 + KA2 48 33.0643 2.7071 118.94 4.10 Pure KA1 49 33.7437 2.6541 96.52 3.33 Pure KA1 50 34.4063 2.6045 88.67 3.06 Pure KA1 51 34.6340 2.5879 135.30 4.67 Pure KA1 52 34.9386 2.5660 118.81 4.10 Pure KA1 53 35.6904 2.5157 139.19 4.80 KA1 + KA2 54 36.3743 2.4679 109.19 3.77 Pure KA1 55 37.1006 2.4213 82.34 2.84 Pure KA1 56 37.9460 2.3712 163.77 5.65 KA1 + KA2 57 38.6000 2.3306 107.80 3.72 Pure KA1 58 38.8577 2.3157 115.41 3.98 Pure KA1 59 39.1154 2.3011 132.84 4.58 Pure KA1 Example 24: Form V (malonate salt)

[0352] Crystalline Form V was prepared through evaporation experiments as detailed in Examples 2 and 3.

Claims

CLAIMS:

1. A crystalline form of the tartrate salt of Compound I:(Compound I).

2. The crystalline form of claim 1, wherein the crystalline form is characterized by X-ray powder diffraction (XRPD) peaks at 21.6±0.2, 15.5 ±0.2 and 12.4 ±0.2 °2θ.

3. The crystalline form of claim 1 or 2, wherein the crystalline form is further characterized by XRPD peaks at 18.7±0.2 and 11.4 ±0.2 °2θ.

4. The crystalline form of any one of claims 1-3, wherein the crystalline form is further characterized by at least one XRPD peaks at 9.3 ±0.2, 23.0±0.2, 15.7±0.2, 14.9±0.2, 14.1±0.2, 22.7±0.2, 29.8±0.2, 14.8±0.2, 22.4±0.2, 23.5±0.2, 27.5±0.2, 15.5±0.2, 20.9±0.2, 22.8±0.2, 22.1±0.2 °2θ.

5. The crystalline form of any one of claims 1-4, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 1A.

6. The crystalline form of any one of claims 1-5, wherein the crystalline form exhibits a thermogravimetric differential thermal analysis (TG / DTA) thermogram having an endothermic peak at 210±5 ℃.

7. The crystalline form of any one of claims 1-6, wherein the crystalline form exhibits a TG / DTA thermogram having an endothermic peak with an onset at 208±5 ℃.

8. The crystalline form of claims 1-7, wherein the crystalline form exhibits a weight loss of about 14.6% from about 175°C to about 300°C as measured by TG / DTA.

9. The crystalline form of any one of claims 1-8, wherein the crystalline form exhibits a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 210±5 ℃.

10. The crystalline form of any one of claims 1-9, wherein tartrate is L-tartrate salt.

11. The crystalline form of any one of claims 1-10, wherein the molar ratio of tartrate to Compound I is about 1:

1.

12. A crystalline form of the mesylate salt of Compound (I).

13. The crystalline form of claim 12, wherein the crystalline form is characterized by XRPD peaks at 7.9±0.2, 22.1 ±0.2 and 20.4 ±0.2 °2θ.

14. The crystalline form of claim 12 or 13, wherein the crystalline form is further characterized by XRPD peaks at 20.1 ±0.2 and 17.2 ±0.2 °2θ.

15. The crystalline form of any one of claims 12-14, wherein the crystalline form is further characterized by at least one XRPD peaks at 6.8 ±0.2, 15.7 ±0.2, 14.4±0.2, 10.3±0.2, 24.7±0.2, 13.4±0.2, 17.4±0.2, 24.2±0.2, 17.1±0.2, 23.6±0.2, 19.8±0.2, 18.4±0.2, 18.2±0.2, 23.9±0.2, °2θ.

16. The crystalline form of any one of claims 12-15, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 2A.

17. The crystalline form of any one of claims 12-16, wherein the crystalline form exhibits a TG / DTA thermogram having an endothermic peak at 266±5 ℃.

18. The crystalline form of any one of claims 12-17, wherein the crystalline form exhibits a TG / DTA thermogram having an endothermic peak with an onset at 261±5 ℃.

19. The crystalline form of claims 12-18, wherein the crystalline form exhibits a weight loss of less than 1% from about 35 °C to about 240 °C as measured by TG / DTA.

20. The crystalline form of any one of claims 12-19, wherein the crystalline form exhibits a DSC thermogram having an endothermic peak with an onset at 262±5 ℃.

21. The crystalline form of any one of claims 12-20, wherein the crystalline form exhibits a DSC thermogram comprising an endothermic peak at 265±5 ℃.

22. The crystalline form of any one of claims 12-21, wherein the molar ratio of mesylate to Compound I is about 1:

1.

23. A crystalline form of the succinate salt of Compound I.

24. The crystalline form of claim 23, wherein the crystalline form is characterized by X- ray powder diffraction (XRPD) peaks at 21.4±0.2, 6.1 ±0.2 and 10.0 ±0.2 °2θ.

25. The crystalline form of claim 23 or 24, wherein the crystalline form is further characterized by XRPD peaks at 17.4±0.2 and 22.9 ±0.2 °2θ.

26. The crystalline form of any one of claims 23-25, wherein the crystalline form is further characterized by at least one XRPD peaks at 16.0±0.2, 14.7±0.2, 11.4 ±0.2, 16.4±0.2, 20.3±0.2, 23.9±0.2, 17.7 ±0.2, 19.3 ±0.2, 21.9±0.2, 18.9 ±0.2, 24.8±0.2, 26.9 ±0.2 and 9.5±0.2°2θ.

27. The crystalline form of any one of claims 23-26, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 3A.

28. The crystalline form of any one of claims 23-27, wherein the molar ratio of succinate to Compound I is about 2:

1.

29. The crystalline form of the succinate salt of claim 23, wherein the crystalline form is characterized by XRPD peaks at 17.3±0.2, 6.3 ±0.2 and 22.1 ±0.2 °2θ.

30. The crystalline form of claim 23 or 29, wherein the crystalline form is further characterized by XRPD peaks at 11.0±0.2 and 17.5 ±0.2 °2θ.

31. The crystalline form of any one of claims 23 or 29-30, wherein the crystalline form is further characterized by at least XRPD peaks at 10.0±0.2, 14.7 ±0.2, 21.6 ±0.2, 20.2±0.2, 11.6 ±0.2, 22.4 ±0.2, 14.9±0.2, 22.9±0.2, 27.2±0.2, 12.7±0.2, 24.4±0.2, 23.2±0.2, 20.6±0.2 and 23.4±0.2 °2θ.

32. The crystalline form of any one of claims 23 or 29-31, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 4A.

33. The crystalline form of any one of claims 23 or 29-32, wherein the molar ratio of succinate to Compound I is about 1:

1.

34. A crystalline form of the gentisate salt of Compound I.

35. The crystalline form of claim 34, wherein the crystalline form is characterized by XRPD peaks at 6.5±0.2, 7.2±0.2 and 7.4±0.2 °2θ.

36. The crystalline form of claim 34 or 35, wherein the crystalline form is further characterized by XRPD peaks at 22.9±0.2 and 20.1±0.2 °2θ.

37. The crystalline form of any one of claims 34-36, wherein the crystalline form is further characterized by at least one XRPD peaks at 16.3±0.2, 13.0 ±0.2, 18.1±0.2, 17.4±0.2, 17.8±0.2, 16.7±0.2, 23.1±0.2, 27.5±0.2, 19.0±0.2, 12.1±0.2, 8.3±0.2, 21.7 ±0.2 and 18.8±0.2 °2θ.

38. The crystalline form of any one of claims 34-37, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 5A.

39. The crystalline form of any one of claims 34-38, wherein the molar ratio of gentisate salt to Compound I is about 1:

1.

40. A crystalline form of the phosphate salt of Compound I.

41. The crystalline form of claim 40, wherein the crystalline form is characterized by XRPD peaks at 9.1±0.2, 19.2±0.2 and 17.0±0.2 °2θ.

42. The crystalline form of claim 40 or 41, wherein the crystalline form is further characterized by XRPD peaks at 17.8±0.2 and 20.5±0.2 °2θ.

43. The crystalline form of any one of claims 40-42, wherein the crystalline form is further characterized by at least one XRPD peaks at 20.4±0.2, 22.4±0.2, 18.3±0.2, 12.3±0.2, 17.6±0.2, 3.9±0.2, 23.4±0.2, 11.6±0.2, 23.0±0.2, 18.7±0.2, 11.3±0.2, 27.2±0.2, 16.3±0.2, 21.8±0.2 and 14.3±0.2 °2θ.

44. The crystalline form of any one of claims 40-43, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 6A.

45. A crystalline form of the ethanedisulfonate salt of Compound I.

46. The crystalline form of claim 45, wherein the crystalline form is characterized by XRPD peaks at 9.8±0.2, 21.8 ±0.2 and 26.6±0.2 °2θ.

47. The crystalline form of claim 45 or 46, wherein the crystalline form is further characterized by XRPD peaks at 14.6±0.2 and 21.2±0.2, °2θ.

48. The crystalline form of any one of claims 45-47, wherein the crystalline form is further characterized by XRPD peaks at 11.0±0.2, 20.7±0.2, 17.8±0.2, 19.0±0.2, 18.6±0.2, 22.1±0.2, 5.7 ±0.2, 20.4±0.2 .25.7±0.2, 29.5±0.2, 16.0±0.2, 24.5±0.2, 23.8±0.2, 24.7±0.2 and 32.2±0.2 °2θ.

49. The crystalline form of any one of claims 45-48, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 7A.

50. The crystalline form of any one of claims 45-49, wherein the molar ratio of ethanedisulfonate to Compound I is about 1:

1.

51. The crystalline of claim 45, wherein the crystalline form is characterized by XRPD peaks at 9.4±0.2, 6.5 ±0.2 and 22.4 ±0.2 °2θ.

52. The crystalline form of claim 45 or 51, wherein the crystalline form is further characterized by XRPD peaks at 12.1±0.2 and 18.2±0.2 °2θ.

53. The crystalline form of any one of claims 45 or 51-52, wherein the crystalline form is further characterized by XRPD peaks at 13.7±0.2, 18.9 ±0.2, 25.4±0.2, 20.3±0.2, 20.6±0.2, 24.4 ±0.2, 21.3±0.2, 17.7±0.2, 16.0±0.2, 20.1±0.2, 15.2±0.2, 18.6±0.2, 26.4±0.2, 25.1±0.2 and 7.8±0.2 °2θ.

54. The crystalline form of any one of claims 45 or 51-53, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 8A.

55. A crystalline form of the sulfate salt of Compound I.

56. The crystalline form of claim 55, wherein the crystalline form is characterized by XRPD peaks at 10.2±0.2, 20.4±0.2 and 14.6±0.2 °2θ.

57. The crystalline form of claim 55 or 56, wherein the crystalline form is further characterized by XRPD peaks at 21.8±0.2 and 10.4±0.2 °2θ.

58. The crystalline form of any one of claims 55-57, wherein the crystalline form is further characterized by at least XRPD peaks at 8.2±0.2, 26.4±0.2, 6.7±0.2, 9.5±0.2, 8.5±0.2, 5.6±0.2, 20.8±0.2, 15.3±0.2, 24.8±0.2, 19.0±0.2, 24.0±0.2, 17.0±0.2, 15.9±0.2, 13.4±0.2 and 16.9±0.2 °2θ.

59. The crystalline form of any one of claims 55-58, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 9A.

60. A crystalline form of the ketoglutarate salt of Compound I.

61. The crystalline form of claim 60, wherein the crystalline form is characterized by XRPD peaks at 8.3±0.2, 8.1±0.2 and 6.1±0.2 °2θ.

62. The crystalline form of claim 60 or 61, wherein the crystalline form is further characterized by XRPD peaks at 11.6±0.2 and 23.9±0.2 °2θ.

63. The crystalline form of any one of claims 60-62, wherein the crystalline form is further characterized by XRPD peaks at 24.4±0.2, 12.2±0.2, 18.5±0.2, 23.0±0.2, 13.5±0.2, 19.5±0.2, 21.8±0.2, 13.3±0.2, 9.1±0.2, 15.3±0.2, 16.6±0.2, 17.9±0.2, 16.9±0.2, 24.8±0.2 and 8.5±0.2 °2θ.

64. The crystalline form of any one of claims 60-63, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 10A.

65. A crystalline form of the pyroglutamate salt of Compound I.

66. The crystalline form of claim 65, wherein the crystalline form is characterized by XRPD peaks at 16.4±0.2, 9.6±0.2 and 19.3±0.2 °2θ.

67. The crystalline form of claim 65 or 66, wherein the crystalline form is further characterized by XRPD peaks at 18.3±0.2 and 13.5±0.2 °2θ.

68. The crystalline form of any one of claims 65-67, wherein the crystalline form is further characterized by at least XRPD peaks at 17.5±0.2, 18.9±0.2, 15.0±0.2, 10.8±0.2, 8.5±0.2, 26.2±0.2, 21.8±0.2, 16.9±0.2, 22.3±0.2, 21.2±0.2, 18.5±0.2, 25.8±0.2, 24.1±0.2, 22.9±0.2 and 27.1±0.2 °2θ.

69. The crystalline form of any one of claims 65-68, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 11A.

70. A crystalline form of the malic salt of Compound I.

71. The crystalline form of claim 70, wherein the crystalline form is characterized by XRPD peaks at 18.5±0.2, 9.5±0.2 and 19.1±0.2 °2θ.

72. The crystalline form of claim 70 or 71, wherein the crystalline form is further characterized by XRPD peaks at 15.5±0.2 and 24.8±0.2 °2θ.

73. The crystalline form of any one of claims 70-72, wherein the crystalline form is further characterized by at least one XRPD peaks at 14.9±0.2, 10.3±0.2, 13.0±0.2, 17.4±0.2, 15.9±0.2, 19.7±0.2, 17.7±0.2, 20.5±0.2, 24.2±0.2, 25.4±0.2, 27.3±0.2, 23.9±0.2, 26.9±0.2, 25.1±0.2 and 8.7±0.2 °2θ.

74. The crystalline form of any one of claims 70-73, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 12A.

75. A crystalline form of the isethionate salt of Compound I.

76. The crystalline form of claim 75, wherein the crystalline form is characterized by XRPD peaks at 9.1±0.2, 17.2±0.2 and 11.7±0.2 °2θ.

77. The crystalline form of claim 75 or 76, wherein the crystalline form is further characterized by XRPD peaks at 23.2±0.2 and 19.0±0.2 °2θ.

78. The crystalline form of any one of claims 75-77, wherein the crystalline form is further characterized by XRPD peaks at 11.3±0.2, 20.3±0.2, 22.4±0.2, 17.7±0.2, 21.5±0.2, 25.9±0.2, 23.7±0.2, 3.9±0.2, 12.2±0.2, 22.2±0.2, 20.8±0.2, 19.2±0.2, 19.9±0.2, 22.8±0.2 and 23.4±0.2 °2θ.

79. The crystalline form of any one of claims 75-78, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 13A.

80. A crystalline form of the free base form of Compound I.

81. The crystalline form of claim 80, wherein the crystalline form is a solvate of Compound I.

82. The crystalline form of claim 80 or 81, wherein the crystalline form is a the crystalline form is a solvate of Compound I solvate.

83. The crystalline form of any one of claims 80-82, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 14A.

84. The crystalline form of any one of claims 80-83, wherein the crystalline form exhibits a TG / DTA thermogram having endothermic peaks at 108±5 ℃, 161±5 ℃ and 188±5 ℃.

85. The crystalline form of any one of claims 80-84, wherein the crystalline form exhibits a TG / DTA thermogram having endothermic peaks with an onset at 104±5 ℃, 157±5 ℃ and 183±5 ℃.

86. The crystalline form of claims 80-85, wherein the crystalline form exhibits a 1.8 % weight loss from 20 °C to 105 °C and a 7.9 % weight loss from 105 °C to 185 °C as measured by TG / DTA.

87. The crystalline form of claim 80, wherein the crystalline form is a hydrate of Compound I.

88. The crystalline form of any one of claims 80 or 87, wherein the crystalline form is characterized by XRPD peaks at 6.1±0.2, 14.8±0.2 and 18.0±0.2 °2θ.

89. The crystalline form of any one of claims 80 or 87-88, wherein the crystalline form is further characterized by XRPD peaks at 17.4±0.2 and 10.1±0.2 °2θ.

90. The crystalline form of any one of claims 80 or 87-89, wherein the crystalline form is further characterized by at least one peaks in an XRPD pattern at 12.3±0.2, 10.6±0.2, 22.6±0.2, 22.1±0.2, 21.7±0.2, 21.6±0.2, 16.7±0.2, 18.3±0.2, 22.7±0.2, 27.9±0.2, 26.8±0.2, 15.9±0.2, 7.1±0.2, 24.7±0.2 and 28.2±0.2 °2θ.

91. The crystalline form of any one of claims 80 or 87-90, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 15A.

92. The crystalline form of any one of claims 80 or 87-91, wherein the crystalline form exhibits a TG / DTA (thermogravimetric differential thermal analysis) thermogram having endothermic peaks at 48±5 ℃ and 187±5 ℃.

93. The crystalline form of any one of claims 80 or 87-92, wherein the crystalline form exhibits a TG / DTA thermogram having endothermic peaks with an onset at 33±5 ℃ and 182±5 ℃.

94. The crystalline form of claims 80 or 87-93, wherein the crystalline form exhibits about 4.0% weight loss from about 20 °C to about 85 °C, a weight loss less than 1% from about 85 °C to about 170 °C as measured by TG / DTA.

95. The crystalline form of any one of claims 80 or 87-94, wherein the crystalline form exhibits a DSC (differential scanning calorimetry) thermogram having endothermic peaks with an onset at 48±5 ℃, 125±5 ℃ and 183±5℃.

96. The crystalline form of any one of 80 or 87-95, wherein the crystalline form exhibits a DSC thermogram comprising endothermic peaks at 76±5 ℃, 130±5 ℃ and 187±5℃.

97. The crystalline form of claim 80, wherein the crystalline form is an anhydrous of compound I.

98. The crystalline form of claim 80 or 97, wherein the crystalline form is characterized by XRPD peaks at 10.4±0.2, 10.2±0.2 and 21.8±0.2 °2θ.

99. The crystalline form of any one of claims 80 or 97-98, wherein the crystalline form is further characterized by XRPD peaks at 20.4±0.2 and 6.7±0.2 °2θ.

100. The crystalline form of any one of claims 80 or 97-99, wherein the crystalline form is further characterized by at least one XRPD peaks at 26.4±0.2, 20.8±0.2, 14.6±0.2, 9.5±0.2, 16.9±0.2, 18.6±0.2, 19.0±0.2, 18.1±0.2, 13.5±0.2, 22.0±0.2, 15.9±0.2, 22.2±0.2, 16.7±0.2, 25.8±0.2 and 23.5±0.2 °2θ.

101. The crystalline form of any one of claims 80 or 97-100, wherein the crystalline form is characterized by an XRPD pattern that is substantially similar to FIG. 16A.

102. The crystalline form of any one of claims 80 or 97-101, wherein the crystalline form exhibits a TG / DTA thermogram having an endothermic peak at 114±5 ℃.

103. The crystalline form of any one of claims 80 or 97-102, wherein the crystalline form exhibits a TG / DTA thermogram having an endothermic peak with an onset at 105±5 ℃.

104. The crystalline form of claims 80 or 97-103, wherein the crystalline form exhibits a 9.0 % weight loss from 50 °C to 160 °C as measured by TG / DTA.

105. A composition comprising a crystalline form of any one of claims 1-104 and a pharmaceutically acceptable excipient.

106. A method of treating Hereditary Hemorrhagic Telangiectasia (HHT) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of any one of claims 1-104 or a combination thereof.

107. A method of treating Hereditary Hemorrhagic Telangiectasia (HHT) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 105.

108. The method of claim 106 or 107, wherein the subject is a human.

109. The method of any one of claims 106-108, wherein the subject is an adult.

110. The method of claim 106 or 107, wherein 20 mg to 75 mg of the crystalline form of the composition is administered to the subject once a day.

111. The method of claim 106 or 107, wherein 10 mg to 50 mg of the crystalline form of the composition is administered to the subject once a day.

112. The method of claim 106 or 107, wherein 20 mg to 40 mg of the crystalline form of the composition is administered to the subject once a day.

113. The method of claim 106 or 107, wherein 20 mg to 30 mg of the crystalline form of the composition is administered to the subject once a day.

114. The method of claim 106 or 107, wherein about 30 mg of the crystalline form of the composition is administered to the subject once a day.

115. The method of claim 106 or 107, wherein about 40 mg of the crystalline form of the composition is administered to the subject once a day.

116. The method of claim 106 or 107, wherein about 50 mg of the crystalline form of the composition is administered to the subject once a day.

117. The method of claim 106 or 107, wherein the administration provides a reduction in the frequency, duration or intensity of bleeding associated with HHT.

118. The method of claim 117, wherein the administration provides a reduction in the gastrointestinal (GI) bleeding associated with HHT.

119. The method of claim 106 or 107, wherein the administration provides a reduction in the epistaxis associated with HHT.

120. The method of claim 106 or 107, wherein the administration provides an increase in the subject’s hemoglobin levels.

121. The method of claim 106 or 107, wherein the treatment of HHT comprises reducing the number of telangiectasia.

122. The method of claim 106 or 107, wherein the treatment of HHT comprises reducing the size of telangiectasia.

123. The method of claim 106 or 107, wherein the telangiectasia is skin telangiectasia.

124. The method of claim 106 or 107, wherein the telangiectasia is nasal telangiectasia.

125. The method of claim 106 or 107, wherein the telangiectasia is oral telangiectasia.

126. The method of claim 106 or 107, wherein the telangiectasia is gastrointestinal telangiectasia.

127. The method of claim 106 or 107, wherein the treatment of HHT comprises reducing the number of arteriovenous malformations (AVMs).

128. The method of claim 106 or 107, wherein the treatment of HHT comprises reducing the size of arteriovenous malformations (AVMs).

129. The method of claim 106 or 107, wherein the treatment of HHT comprises preventing the formation of arteriovenous malformations (AVMs).

130. The method of any one of claims 124-129, wherein the arteriovenous malformations are pulmonary AVMs.

131. The method of any one of claims 127-129, wherein the arteriovenous malformations are cerebral (brain) AVMs.

132. The method of any one of claims 127-129, wherein the arteriovenous malformations are visceral AVMs.

133. The method of claim 106 or 107, wherein the treatment of HHT comprises reduction in cardiac insufficiency and pulmonary arterial hypertension (PAH).

134. The method of claim 106 or 107, wherein the treatment of HHT comprises prevention of cardiac insufficiency and pulmonary arterial hypertension (PAH).

135. The method of claim 106 or 107, wherein the treatment of HHT comprises prevention of right to left shunt induced by pulmonary AVMs.

136. The method of claim 106 or 107, wherein the treatment of HHT comprises reduction in the grade of right to left shunt induced by pulmonary AVMs.

137. The method of claim 106 or 107, wherein the treatment of HHT comprises a reduction in the need for iron supplementation.

138. The method of claim 106 or 107, wherein the treatment of HHT comprises a reduction of the number of blood transfusions required.

139. The method of claim 106 or 107, wherein the treatment of HHT comprises a decrease in hepatic blood flow.

140. The method of claim 106 or 107, wherein the treatment of HHT reduces the need for liver transplantation.

141. The method of claim 106 or 107, wherein the treatment of HHT comprises a reduction in the frequency or severity of additional symptoms of HHT.

142. The method of claim 141, wherein the additional symptoms are dyspnea, migraine, fatigue, neurological events, or embolic events.

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