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Patent Analysis of

Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof

Updated Time 12 June 2019

Patent Registration Data

Publication Number

US10150734

Application Number

US15/004034

Application Date

22 January 2016

Publication Date

11 December 2018

Current Assignee

AKEBIA THERAPEUTICS, INC.

Original Assignee (Applicant)

AKEBIA THERAPEUTICS, INC.

International Classification

C07D213/81

Cooperative Classification

C07D213/81

Inventor

HANSELMANN, ROGER,LUONG, ANNE

Patent Images

This patent contains figures and images illustrating the invention and its embodiment.

US10150734 Solid forms 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, 1 US10150734 Solid forms 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, 2 US10150734 Solid forms 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, 3
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Abstract

Provided herein are solid forms comprising 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, methods of making the solid forms, methods of their use for the treatment of various diseases and/or disorders and pharmaceutical compositions comprising the solid forms.

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Claims

1. A crystal form of Compound 1, or a tautomer thereof: which is Form A, and which has an X-ray powder diffraction pattern comprising peaks at approximately 12.1, 23.0 and 26.9° 2θ.

2. The crystal form of claim 1 which has a thermogravimetric analysis thermogram comprising no mass loss of the crystal form before about 155° C. when heated from about 25° C. to about 300° C.

3. The crystal form of claim 1 which has a differential scanning calorimetry thermogram comprising an endotherm event with a maximum at approximately 186° C. when heated from about 25° C. to about 300° C.

4. The crystal form of claim 1 which is anhydrous.

5. A pharmaceutical composition comprising the crystal form of claim 1.

6. The crystal form of claim 1, wherein the X-ray powder diffraction pattern further comprises peaks at approximately 13.1, 14.5, 16.6, 19.6, and 20.1° 2θ.

7. The crystal form of claim 6 which has a thermogravimetric analysis thermogram comprising no mass loss of the crystal form before about 155° C. when heated from about 25° C. to about 300° C.

8. The crystal form of claim 6 which has a differential scanning calorimetry thermogram comprising an endotherm event with a maximum at approximately 186° C. when heated from about 25° C. to about 300° C.

9. The crystal form of claim 6 which is anhydrous.

10. A pharmaceutical composition comprising the crystal form of claim 6.

11. A crystal form comprising Compound 1, or a tautomer thereof: which Form B, and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.3, 8.6, 15.5, and 25.3° 2θ.

12. A crystal form comprising Compound 1, or a tautomer thereof: which is Form C, and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.4, 8.6, 11.4 and 15.6° 2θ.

13. A crystal form comprising Compound 1, or a tautomer thereof: which is Form D and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.3, 7.4, 8.6 and 15.5° 2θ.

14. A crystal form comprising Compound 1, or a tautomer thereof: which is Form E, and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.3, 8.6, 15.5 and 27.9° 2θ.

15. A crystal form comprising Compound 1, or a tautomer thereof: which is Form F and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.0, 4.2 and 15.2° 2θ.

16. A crystal form comprising Compound 1, or a tautomer thereof: which is Form H, and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.2, 8.3, 15.2 and 20.9° 2θ.

17. A crystal form comprising Compound 1, or a tautomer thereof: which Form H, and which has an X-ray powder diffraction pattern comprising peaks at approximately 14.1, 18.8 and 21.4° 2θ.

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Claim Tree

  • 1
    1. A crystal form of Compound 1, or a tautomer thereof: which is Form A, and which has an X-ray powder diffraction pattern comprising
    • peaks at approximately 12.1, 23.0 and 26.9° 2θ.
    • 2. The crystal form of claim 1 which has a thermogravimetric analysis thermogram comprising
      • no mass loss of the crystal form before about 155° C. when heated from about 25° C. to about 300° C.
    • 3. The crystal form of claim 1 which has a differential scanning calorimetry thermogram comprising
      • an endotherm event with a maximum at approximately 186° C. when heated from about 25° C. to about 300° C.
    • 4. The crystal form of claim 1 which is anhydrous.
    • 6. The crystal form of claim 1, wherein
      • the X-ray powder diffraction pattern further comprises
  • 5
    5. A pharmaceutical composition comprising
    • the crystal form of claim 1.
  • 10
    10. A pharmaceutical composition comprising
    • the crystal form of claim 6.
  • 11
    11. A crystal form comprising
    • Compound 1, or a tautomer thereof: which Form B, and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.3, 8.6, 15.5, and 25.3° 2θ.
  • 12
    12. A crystal form comprising
    • Compound 1, or a tautomer thereof: which is Form C, and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.4, 8.6, 11.4 and 15.6° 2θ.
  • 13
    13. A crystal form comprising
    • Compound 1, or a tautomer thereof: which is Form D and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.3, 7.4, 8.6 and 15.5° 2θ.
  • 14
    14. A crystal form comprising
    • Compound 1, or a tautomer thereof: which is Form E, and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.3, 8.6, 15.5 and 27.9° 2θ.
  • 15
    15. A crystal form comprising
    • Compound 1, or a tautomer thereof: which is Form F and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.0, 4.2 and 15.2° 2θ.
  • 16
    16. A crystal form comprising
    • Compound 1, or a tautomer thereof: which is Form H, and which has an X-ray powder diffraction pattern comprising peaks at approximately 4.2, 8.3, 15.2 and 20.9° 2θ.
  • 17
    17. A crystal form comprising
    • Compound 1, or a tautomer thereof: which Form H, and which has an X-ray powder diffraction pattern comprising peaks at approximately 14.1, 18.8 and 21.4° 2θ.
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Description

1. FIELD OF THE INVENTION

Provided herein are solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, methods of making the solid forms, methods of their use for the treatment of various diseases or symptoms thereof, and pharmaceutical compositions thereof.

2. BACKGROUND OF THE INVENTION

The identification and selection of a solid form for making a pharmaceutical composition is complex, given that a change in solid form may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in processing, maintaining, storage, formulation, stability and bioavailability, among other important pharmaceutical characteristics. Potential pharmaceutical solids include crystalline solids, amorphous solids, and mixtures thereof. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability (See, e.g., S. R. Vippagunta et al., Adv. Drug. Deliv. Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48:27-42).

Whether crystalline or amorphous, potential solid forms for making a pharmaceutical composition include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical Compound 1 in the absence of other compounds. Variety among single-component crystalline materials may potentially arise from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound (See, e.g., S. R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The importance of discovering polymorphs was underscored by the case of Ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules. About two years after the product was launched, the unanticipated precipitation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more consistent formulation could be developed (See S. R. Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417).

Additional diversity among the potential solid forms of a pharmaceutical compound may arise from the possibility of multiple-component solids. Crystalline solids comprising two or more ionic species are termed salts (See, e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types of multiple-component solids that may potentially offer other property improvements for a pharmaceutical compound or salt thereof include, e.g., hydrates, solvates, co-crystals and clathrates, among others (See, e.g., S. R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Moreover, multiple-component crystal forms may potentially be susceptible to polymorphism, wherein a given multiple-component composition may exist in more than one three-dimensional crystalline arrangement. The discovery of solid forms is of great importance in the development of a safe, effective, stable and marketable pharmaceutical compound.

Nobel Prize winner Dr. Judah Folkman first proposed in 1971 that all cancer tumors were angiogenesis-dependent and therefore targeting angiogenesis was a potential means for treating cancer. Angiogenesis is the growth of new capillaries from pre-existent microvasculature. A wide range of pathological conditions, from atherosclerosis to cancer, are associated with either excessive or deficient angiogenesis.

It is now widely accepted that tumor growth beyond a few cubic millimeters cannot occur without the induction of a new vascular supply. Therefore, inhibition of new vasculature (antiangiognesis) can provide a non-chemotherapy or non-radiation therapy approach to the treatment of cancer by denying tumors the nutrient supply necessary for the tumors to grow. Although normally quiescent, endothelial cells are responsible for the formation of new vasculature in response to various stimuli. These stimuli can have their genesis in many forms.

The endothelial cells which form new vascular networks in tumors respond to angiogenic stimuli produced by the tumor itself. The best known of these stimuli is vascular endothelial growth factor (VEGF). Found to be ubiquitous in human tumors, increasing levels of VEGF correlate with an increasing rate of tumor growth. Therefore, suppression of VEGF represents a method for controlling the growth rate of tumors (primary and metastatic) and offers a possible means for shrinking existing tumors.

3. SUMMARY OF THE INVENTION

Provided herein are solid forms of Compound 1:

having the name 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, including tautomers thereof. Also provided are methods of preparing, isolating and characterizing the solid forms. 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid (“Compound 1”) is disclosed in United States Patent Application Publication No. 2007/0299086, published Dec. 27, 2007, United States Patent Application Publication No. 2012/0329836, published Dec. 27, 2012 and International Patent Application Publication No. WO 2012/170442, published Dec. 13, 2012, the entireties of which are incorporated by reference herein.

Provided herein are pharmaceutical compositions and dosage units comprising a solid form of Compound 1. In certain embodiments, the pharmaceutical compositions and dosage units comprise a solid form of Compound 1 and a pharmaceutically acceptable diluent, excipient or carrier.

Provided herein are methods for treating or preventing cancer, compromising administering an effective amount of a solid form of Compound 1 to a patient having cancer.

Provided herein are methods for decreasing vascular endothelial growth factor (VEGF) in a cell in vitro, in vivo or ex vivo, comprising contacting the cell with an effective amount of a solid form of Compound 1.

Provided herein are methods for increasing secretion of soluble vascular endothelial growth factor receptor-1 (sVEGF-1) in a cell in vitro, in vivo or ex vivo, comprising contacting the cell with an effective amount of a solid form of Compound 1.

Provided herein are methods for stabilizing hypoxia inducible factor-2 alpha (HIF-2a) in a cell in vitro, in vivo or ex vivo, comprising contacting the cell with an effective amount of a solid form of Compound 1.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts an overlay of X-ray powder diffractogram (XRPD) patterns of Forms A, B, C, D, E, F, G and H of Compound 1.

FIG. 2 depicts an XRPD pattern of Form A of Compound 1.

FIG. 3 depicts an XRPD pattern of Form B of Compound 1.

FIG. 4 depicts an XRPD pattern of Form C of Compound 1.

FIG. 5 depicts an XRPD pattern of Form D of Compound 1.

FIG. 6 depicts an XRPD pattern of Form E of Compound 1.

FIG. 7 depicts an XRPD pattern of Form F of Compound 1.

FIG. 8 depicts an XRPD pattern of Form G of Compound 1.

FIG. 9 depicts an XRPD pattern of Form H of Compound 1.

FIG. 10 depicts a 1H NMR spectrum of Form A of Compound 1.

FIG. 11 depicts a DSC thermogram of Form A of Compound 1.

FIG. 12 depicts a TGA thermogram of Form A of Compound 1.

FIG. 13 depicts a DVS analysis of Form A of Compound 1.

FIG. 14 depicts an XRPD pattern of post-DVS Form A of Compound 1.

FIG. 15 depicts a 1H NMR spectrum of Form B of Compound 1.

FIG. 16 depicts a DSC thermogram of Form B of Compound 1.

FIG. 17 depicts a TGA thermogram of Form B of Compound 1.

FIG. 18 depicts a 1H NMR spectrum of Form C of Compound 1.

FIG. 19 depicts a DSC thermogram of Form C of Compound 1.

FIG. 20 depicts a TGA thermogram of Form C of Compound 1.

FIG. 21 depicts a 1H NMR spectrum of Form D of Compound 1.

FIG. 22 depicts a DSC thermogram of Form D of Compound 1.

FIG. 23 depicts a TGA thermogram of Form D of Compound 1.

FIG. 24 depicts a DVS analysis of Form D of Compound 1.

FIG. 25 depicts a XRPD pattern of post-DVS Form D of Compound 1.

FIG. 26 depicts a 1H NMR spectrum of Form E of Compound 1.

FIG. 27 depicts a DSC thermogram of Form E of Compound 1.

FIG. 28 depicts a TGA thermogram of Form E of Compound 1.

FIG. 29 depicts a 1H NMR spectrum of Form F of Compound 1.

FIG. 30 depicts a DSC thermogram of Form F of Compound 1.

FIG. 31 depicts a TGA thermogram of Form F of Compound 1.

FIG. 32 depicts a 1H NMR spectrum of Form G of Compound 1.

FIG. 33 depicts a DSC thermogram of Form G of Compound 1.

FIG. 34 depicts a TGA thermogram of Form G of Compound 1.

FIG. 35 depicts a DVS analysis of Form G of Compound 1.

FIG. 36 depicts a XRPD pattern of post-DVS of Form G of Compound 1.

FIG. 37 depicts a 1H NMR spectrum of Form H of Compound 1.

FIG. 38 depicts a DSC thermogram of Form H of Compound 1.

FIG. 39 depicts a TGA thermogram of Form H of Compound 1.

FIG. 40 depicts a XRPD Diffractogram of Salt I of Compound 1.

FIG. 41 depicts a XRPD Diffractogram of Salt II of Compound 1.

FIG. 42 depicts a XRPD Diffractogram of Salt III of Compound 1.

FIG. 43 depicts a XRPD Diffractogram of Salt IV of Compound 1.

FIG. 44 depicts a XRPD Diffractogram of Salt V of Compound 1.

FIG. 45 depicts a XRPD Diffractogram of Salt VI of Compound 1.

FIG. 46 depicts a XRPD stackplot of Salt I of Compound 1 before (middle) and after DVS (bottom) analysis.

FIG. 47 depicts a 1H NMR spectrum of Salt I of Compound 1.

FIG. 48 depicts a DSC thermogram of Salt I of Compound 1.

FIG. 49 depicts a TGA thermogram of Salt I of Compound 1.

FIG. 50 depicts a DVS thermogram of Salt I of Compound 1.

FIG. 51 depicts a XRPD stackplot of Salt II of Compound 1 before (middle) and after DVS (bottom) analysis.

FIG. 52 depicts a 1H NMR spectrum of Salt II of Compound 1.

FIG. 53 depicts a DSC thermogram of Salt II of Compound 1.

FIG. 54 depicts a TGA thermogram of Salt II of Compound 1.

FIG. 55 depicts a DVS thermogram of Salt II of Compound 1.

FIG. 56 depicts a XRPD stackplot of Salt III of Compound 1 before (middle) and after DVS (bottom) analysis.

FIG. 57 depicts a 1H NMR spectrum of Salt III of Compound 1.

FIG. 58 depicts a DSC thermogram of Salt III of Compound 1.

FIG. 59 depicts a TGA thermogram of Salt III of Compound 1.

FIG. 60 depicts a DVS thermogram of Salt III of Compound 1.

FIG. 61 depicts a XRPD stackplot of Salt IV of Compound 1 before (middle) and after DVS (bottom) analysis.

FIG. 62 depicts a 1H NMR spectrum of Salt IV of Compound 1.

FIG. 63 depicts a DSC thermogram of Salt IV of Compound 1.

FIG. 64 depicts a TGA thermogram of Salt IV of Compound 1.

FIG. 65 depicts a DVS thermogram of Salt IV of Compound 1.

FIG. 66 depicts a XRPD stackplot of Salt V of Compound 1 before (middle) and after DVS (bottom) analysis.

FIG. 67 depicts a 1H NMR spectrum of Salt V of Compound 1.

FIG. 68 depicts a DSC thermogram of Salt V of Compound 1.

FIG. 69 depicts a TGA thermogram of Salt V of Compound 1.

FIG. 70 depicts a DVS thermogram of Salt V of Compound 1.

FIG. 71 depicts a XRPD stackplot of Salt VI of Compound 1 before (top) and after DVS (bottom) analysis.

FIG. 72 depicts a XRPD stackplot (zoom in) of Salt VI of Compound 1 before (top) and after DVS (bottom) analysis.

FIG. 73 depicts a 1H NMR spectrum of Salt VI of Compound 1.

FIG. 74 depicts a DSC thermogram of Salt VI of Compound 1.

FIG. 75 depicts a TGA thermogram of Salt VI of Compound 1.

FIG. 76 depicts a DVS thermogram of Salt VI of Compound 1.

FIG. 77 depicts a 1H NMR spectrum of 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine.

FIG. 78 depicts a 1H NMR spectrum of 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine.

FIG. 79 depicts a 1H NMR spectrum of 5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxylic acid.

FIG. 80 depicts a 1H NMR spectrum of N-carboxymethyl-5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxamide.

FIG. 81 depicts a 1H NMR spectrum of a mixture of 5-(3-fluorophenyl)-3-methoxypicolinamide and 5-(3-fluorophenyl)-3-methoxypicolinic acid.

FIG. 82 depicts a 1H NMR spectrum of 5-(3-fluorophenyl)-2-(2-methoxy-2-oxoethylcarbamoyl)pyridin-3-yl pivalate.

FIG. 83 depicts a 1H NMR spectrum of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetate.

FIG. 84 depicts a XRPD Diffractogram of Salt VII of Compound 1.

FIG. 85 depicts a 1H NMR spectrum of Salt VII of Compound 1.

FIG. 86 depicts a DSC thermogram of Salt VII of Compound 1.

FIG. 87 depicts a TGA thermogram of Salt VII of Compound 1.

FIG. 88 depicts a microscopy analysis of Salt VII of Compound 1.

FIG. 89 depicts a DVS thermogram of Salt VII of Compound 1.

FIG. 90 depicts a XRPD stackplot of Salt VII of Compound 1 before (top) and after DVS (bottom) analysis.

FIG. 91 depicts a XRPD Diffractogram of Salt VIII of Compound 1.

FIG. 92 depicts a 1H NMR spectrum of Salt VIII of Compound 1.

FIG. 93 depicts a DSC thermogram of Salt VIII of Compound 1.

FIG. 94 depicts a TGA thermogram of Salt VIII of Compound 1.

FIG. 95 depicts a microscopy analysis of Salt VIII of Compound 1.

FIG. 96 depicts a DVS thermogram of Salt VIII of Compound 1.

FIG. 97 depicts a XRPD stackplot of Salt VIII of Compound 1 before (top) and after DVS (bottom) analysis.

FIG. 98 depicts a XRPD Diffractogram of Salt IX of Compound 1.

FIG. 99 depicts a 1H NMR spectrum of Salt IX of Compound 1.

FIG. 100 depicts a DSC thermogram of Salt IX of Compound 1.

FIG. 101 depicts a TGA thermogram of Salt IX of Compound 1.

FIG. 102 depicts a DSC thermogram of Salt IX of Compound 1.

FIG. 103 depicts a microscopy analysis of Salt IX of Compound 1.

FIG. 104 depicts a XRPD stackplot of Salt IX of Compound 1 before (top) and after DVS (bottom) analysis.

FIG. 105 depicts a XRPD Diffractogram of Salt X of Compound 1.

FIG. 106 depicts a 1H NMR spectrum of Salt X of Compound 1.

FIG. 107 depicts a DSC thermogram of Salt X of Compound 1.

FIG. 108 depicts a TGA thermogram of Salt X of Compound 1.

FIG. 109 depicts a microscopy analysis of Salt X of Compound 1.

5. DETAILED DESCRIPTION

5.1 Definitions

As used herein, the terms “prevent”, “preventing” and “prevention” are art-recognized, and when used in relation to a condition, such as a local recurrence, a disease or any other medical condition, such as those described herein, is well understood in the art, and includes administration of a compound, such as a solid form of Compound 1, which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a patient relative to a patient which does not receive the composition.

As used herein, the terms “treat”, “treating” and “treatment” refer to the reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a disease condition, such as those described herein, in manner to improve or stabilize a subject's condition. The terms “treat” and “treatment” also refer to the eradication or amelioration of the disease or symptoms associated with the disease. In certain embodiments, such terms refer to minimizing the spread or worsening of the disease by the administration of a solid form of Compound 1 to a patient with such a disease.

As used herein, the term “hydrate” means 5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or a pharmaceutically acceptable salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

As used herein, the term “solvate” means 5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or a pharmaceutically acceptable salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent, other than water, bound by non-covalent intermolecular forces.

As used herein, the term “HIF prolyl hydroxylase” is art-recognized and may be abbreviated as “PHD”. HIF prolyl hydroxylase is also known as “prolyl hydroxylase domain-containing protein” which may be abbreviated as “PHD”. In this regard, there are three different PHD isoforms, PHD1, PHD2, and PHD3, also referred to as EGLN2, EGLN1, and EGLN3, or HPH3, HPH2, and HPH1, respectively.

The terms “solid form,”“solid forms” and related terms, when used herein to refer to Compound 1, refer to a physical form comprising Compound 1 which is not predominantly in a liquid or a gaseous state. Crystal forms are examples of solid forms. In one embodiment, the solid form is Form A. In another embodiment, the solid form is Form B. In another embodiment, the solid form is Form C. In another embodiment, the solid form is Form D. In another embodiment, the solid form is Form E. In another embodiment, the solid form is Form F. In another embodiment, the solid form is Form G. In another embodiment, the solid form is Form H. In one embodiment, the solid form is Salt I. In one embodiment, the solid form is Salt II. In one embodiment, the solid form is Salt III. In one embodiment, the solid form is Salt IV. In one embodiment, the solid form is Salt V. In one embodiment, the solid form is Salt VI.

The term “crystalline” and related terms used herein, when used to describe a substance, component, product, or form, means that the substance, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington's Pharmaceutical Sciences, 22nd ed., Pharmaceutical Press, (2012); The United States Pharmacopoeia, 30th ed., (2011).

The term “crystal form,”“crystalline form” and related terms herein refer to a crystalline solid form comprising a chemical compound, and may refer to a particular single-component or multiple-component crystal form, including, but not limited to, a polymorph, a solvate, a hydrate or other molecular complex, a salt, a solvate of a salt, a hydrate of a salt, or other molecular complex of a salt, or a polymorph thereof.

The terms “polymorphs,”“polymorphic forms” and related terms herein refer to two or more crystal forms that comprise the same molecule, molecules or ions. Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and/or vibrational spectra as a result of the arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (e.g., particle shape and size distribution might be different between polymorphs).

Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), melting point, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single-crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy (e.g., polaraized light microscopy), hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, dynamic vapor sorption (DVS), and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies.

As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 15%, more specifically within 10%, more specifically within 5%, of the specified dose, amount, or weight percent.

As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or range of values, which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, for example, that describing a melting, dehydration, desolvation or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form. Specifically, the terms “about” and “approximately,” when used in this context, indicate that the numeric value or range of values may vary, in particular embodiments, within 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. With respect to XRPD, values given are ±0.2 degrees 2 theta.

As used herein, and unless otherwise specified, a crystalline that is “pure,” i.e., substantially free of other crystalline or amorphous solids, contains less than about 10% by weight of one or more other crystalline or amorphous solids, less than about 5% by weight of one or more other crystalline or amorphous solids, less than about 3% by weight of one or more other crystalline or amorphous solids, or less than about 1% by weight of one or more other crystalline or amorphous solids.

As used herein, and unless otherwise specified, a solid form that is “substantially physically pure” is substantially free from other solid forms. In certain embodiments, a crystal form that is substantially physically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other solid forms on a weight basis. The detection of other solid forms can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, diffraction analysis, thermal analysis, elemental combustion analysis and/or spectroscopic analysis.

As used herein, and unless otherwise specified, a solid form that is “substantially chemically pure” is substantially free from other chemical compounds (i.e., chemical impurities). In certain embodiments, a solid form that is substantially chemically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other chemical compounds on a weight basis. The detection of other chemical compounds can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, methods of chemical analysis, such as, e.g., mass spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis and/or chromatographic analysis.

As used herein, and unless otherwise indicated, a chemical compound, solid form, or composition that is “substantially free” of another chemical compound, solid form, or composition means that the compound, solid form, or composition contains, in certain embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2% 0.1%, 0.05%, or 0.01% by weight of the other compound, solid form, or composition.

As used herein, an “effective amount” refers to that amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof sufficient to provide a therapeutic benefit in the treatment of the disease or to delay or minimize symptoms associated with the disease, such as any disease or condition described herein.

The terms “subject” and “patient,” unless otherwise specified, are defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In specific embodiments, the patient or patient is a human. In certain embodiments, the patient has a disease or condition as described herein.

“VEGF-dependent cancer,”“VEGF dependent cancers,”“VEGF-dependent tumor” or “VEGF dependent tumors” refers to cancers that rely on VEGF to proliferate.

5.2 Compound 1

The solid forms (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Salt I, Salt II, Salt III, Salt IV, Salt V, Salt VI, Salt VII, Salt VIII, Salt IX and Salt X), formulations and methods of use provided herein relate to Compound 1:

having the name 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, including tautomers thereof.

In certain embodiments, Form A, Form B, Form C, Form D, Form E, Form F, Form G and Form H of Compound 1 exist in the following zwitterionic form:

Compound 1 can be prepared using reagents and methods known in the art, including the methods provided in United States Patent Application Publication No. 2007/0299086, published Dec. 27, 2007, United States Patent Application Publication 2012/0329836, published Dec. 27, 2012 and International Patent Application Publication No. WO 2012/170442, published Dec. 13, 2012, the entireties of which are incorporated by reference herein.

It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

5.3 Solid Forms of Compound 1

In certain embodiments, provided herein are solid forms of Compound 1. In certain embodiments, the solid form is crystalline. In certain embodiments, the solid form is a single-component solid form. In certain embodiments, the solid form is a solvate. In certain embodiments, the solid form is anhydrous. In certain embodiments, the solid form is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Salt I, Salt II, Salt III, Salt IV, Salt V, Salt VI, Salt VII, Salt VIII, Salt IX or Salt X.

While not intending to be bound by any particular theory, certain solid forms are characterized by physical properties, e.g., stability, solubility and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using particular analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in the art.

The solid forms provided herein (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Salt I, Salt II, Salt III, Salt IV, Salt V, Salt VI, Salt VII, Salt VIII, Salt IX and Salt X of Compound 1) may be characterized using a number of methods known to a person skilled in the art, including, but not limited to, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)) and thermal analysis (e.g., thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC)). The particle size and size distribution of the solid form provided herein may be determined by conventional methods, such as laser light scattering technique.

It should be understood that the numerical values of the peaks of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and so the values quoted are not to be construed as absolute, but with an allowable variability, such as ±0.2° 2θ(see United State Pharmacopoeia, page 2228 (2003)).

5.3.1 Form A of Compound 1

In certain embodiments, provided herein is Form A of Compound 1.

In one embodiment, Form A is a solid form of Compound 1. In one embodiment, Form A is anhydrous. In another embodiment, Form A is crystalline.

In certain embodiments, Form A is prepared by single solvent fast cooling crystallization, single solvent slow cooling crystallization, binary solvent fast cooling crystallization or binary solvent slow cooling crystallization experiments (see Table 1-Table 10).

In one embodiment, provided herein are methods for preparing Form A of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the solution to a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is THF, MIBK or MTBE.

In one embodiment, provided herein are methods for preparing Form A of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g., up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the solution to a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is THF, MIBK or MTBE.

In one embodiment, provided herein are methods for preparing Form A of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g, from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the hot solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is THF or MTBE.

In one embodiment, provided herein are methods for preparing Form A of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g, up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the hot solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is THF or MTBE.

In one embodiment, provided herein are methods for preparing Form A of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form. See Table 3, Table 5, Table 7 and Table 9. In certain embodiments, the solvent is MeOH, EtOH, IPA, acetone, DMSO, DMF, NMP, IPAc, MIBK or MTBE. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form A of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form. See Table 3, Table 5, Table 7 and Table 9. In certain embodiments, the solvent is MeOH, EtOH, IPA, acetone, DMSO, DMF, NMP, IPAc, MIBK or MTBE. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form A of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form. See Table 4, Table 6, Table 8 and Table 10. In certain embodiments, the solvent is acetone, DMF, NMP, MeCN, IPAc, MIBK or MTBE. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form A of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form. See Table 4, Table 6, Table 8 and Table 10. In certain embodiments, the solvent is acetone, DMF, NMP, MeCN, IPAc, MIBK or MTBE. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein is Form A prepared by stirring Form G in a solvent for a period of time. See Table 13. In one embodiment, the solvent is IPAc/heptane (e.g., about 1:2 (V:V)) or toluene. In one embodiment, the solvent is acetone/water (e.g., about 1:2 (V:V)). In one embodiment, the period of time is from about 1 day to about 7 days (e.g., about 1 day or about 7 days).

In one embodiment, provided herein is Form A having a DSC thermogram substantially as depicted in FIG. 11. In certain embodiments, the crystalline form exhibits a DSC thermogram comprising an endothermic event with a maximum at about 186° C. when heated from approximately 30° C. to approximately 230° C.

In one embodiment, provided herein is Form A having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 12. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising no mass loss before about 155° C. when heated from approximately 30° C. to approximately 300° C. The TGA thermogram further comprises a decomposition event with an onset temperature at approximately 249.2° C. when heated from approximately 30° C. to approximately 300° C. Thus, in certain embodiments, the crystalline form has no mass loss at a temperature lower than about 100° C.

In one embodiment, provided herein is moderately hygroscopic Form A having about 0% weight moisture uptake at 60% RH and about 6.1% weight moisture uptake at 90% RH. See FIG. 13.

In certain embodiments, a solid form provided herein, e.g., Form A, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 2.

In one embodiment, Form A has one or more characteristic X-ray powder diffraction peaks at approximately 3.73, 3.86, 4.24, 4.39, 5.46, 5.58, 5.77, 6.01, 6.49, 6.86, 7.27, 7.40, 7.83, 8.13, 8.56, 8.67, 8.80, 8.93, 9.91, 10.09, 10.23, 10.41, 11.07, 12.14, 13.05, 14.45, 15.67, 16.20, 16.60, 17.21, 17.70, 18.71, 19.19, 19.59, 20.08, 20.54, 21.60, 22.15, 22.97, 23.34, 24.37, 25.02, 25.55, 25.93, 26.92, 27.55, 29.20, 29.70, 30.10, 31.68, 32.13, 32.59, 33.00, 33.77, 34.18, 34.67, 35.19, 35.88, 36.40, 36.99, 37.46, 38.08, 39.74, 40.38, 40.96, 41.76, 42.12, 42.45, 43.26, 43.87 or 44.52° 2θas depicted in FIG. 2. In a specific embodiment, Form A has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 12.14, 13.05, 14.45, 16.60, 19.59, 20.08, 22.97 or 26.92° 2θ. In another embodiment, Form A has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 12.14, 13.05, 22.97 or 26.92° 2θ. In another embodiment, Form A has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three, sixty-four, sixty-five, sixty-six, sixty-seven, sixty-eight, sixty-nine, seventy or seventy-one characteristic X-ray powder diffraction peaks as set forth in Table 20.

In certain embodiments, a solid form provided herein, e.g., Form A, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 2. In one embodiment, Form A has one or more characteristic X-ray powder diffraction peaks at approximately 3.7, 3.9, 4.2, 4.4, 5.5, 5.6, 5.8, 6.0, 6.5, 6.9, 7.3, 7.4, 7.8, 8.1, 8.6, 8.7, 8.8, 8.9, 9.9, 10.1, 10.2, 10.4, 11., 12.1, 13., 14.5, 15.7, 16.2, 16.6, 17.2, 17.7, 18.7, 19.2, 19.6, 20.1, 20.5, 21.6, 22.2, 23.0, 23.3, 24.4, 25.0, 25.6, 25.9, 26.9, 27.6, 29.2, 29.7, 30.1, 31.7, 32.1, 32.6, 33.0, 33.8, 34.2, 34.7, 35.2, 35.9, 36.4, 37.0, 37.5, 38.1, 39.7, 40.4, 41.0, 41.8, 42.1, 42.5, 43.3, 43.9 or 44.5° 2θas depicted in FIG. 2. In a specific embodiment, Form A has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 12.1, 13.1, 14.5, 16.6, 19.6, 20.1, 23.0 or 26.9° 2θ. In another embodiment, Form A has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 12.1, 13.1, 23.0 or 26.9° 2θ. In another embodiment, Form A has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 12.1, 13.1, 16.6, 20.1, 23.0 or 26.9° 2θ. In another embodiment, Form A has one, two or three characteristic X-ray powder diffraction peaks at approximately 12.1, 23.0 or 26.9° 2θ. In another embodiment, Form A has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three, sixty-four, sixty-five, sixty-six, sixty-seven, sixty-eight, sixty-nine, seventy or seventy-one characteristic X-ray powder diffraction peaks as set forth in Table 20.

In still another embodiment, Form A is substantially pure. In certain embodiments, the substantially pure Form A is substantially free of other solid forms, e.g., Forms B, C, D, E, F, G or H. In certain embodiments, the purity of the substantially pure Form A is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.2 Form B of Compound 1

In certain embodiments, provided herein is Form B of Compound 1.

In one embodiment, Form B is a solid form of Compound 1. In one embodiment, Form B is anhydrous. In one embodiment, Form B is an anhydrous solid form of Compound 1 retaining residual solvent. In one embodiment, Form B is an anhydrous solid form of Compound 1 retaining residual MEK. In another embodiment, Form B is crystalline.

In certain embodiments, Form B is prepared by single solvent fast cooling crystallization, single solvent slow cooling crystallization, binary solvent fast cooling crystallization or binary solvent slow cooling crystallization experiments (see Table 1-Table 10).

In one embodiment, provided herein are methods for preparing Form B of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the solution to a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is MeOH, THF or acetone.

In one embodiment, provided herein are methods for preparing Form B of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g., up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the solution to a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is MeOH, THF or acetone.

In one embodiment, provided herein are methods for preparing Form B of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g, from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the hot solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is MeOH, MeCN, THF, acetone or MIBK.

In one embodiment, provided herein are methods for preparing Form B of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g, up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the hot solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is MeOH, MeCN, THF, acetone or MIBK.

In one embodiment, provided herein are methods for preparing Form B of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3). In certain embodiments, the solvent is THF. In certain embodiments, the co-solvent is water.

In one embodiment, provided herein are methods for preparing Form B of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3). In certain embodiments, the solvent is THF. In certain embodiments, the co-solvent is water.

In one embodiment, provided herein are methods for preparing Form B of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4 and Table 6). In certain embodiments, the solvent is MeOH, MEK, MIBK or DMF. In certain embodiments, the co-solvent is water or toluene.

In one embodiment, provided herein are methods for preparing Form B of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4 and Table 6). In certain embodiments, the solvent is MeOH, MEK, MIBK or DMF. In certain embodiments, the co-solvent is water or toluene.

In one embodiment, provided herein is Form B having a DSC thermogram substantially as depicted in FIG. 16. In certain embodiments, the crystalline form exhibits a DSC thermogram comprising an endothermic event with a maximum at about 141.5° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 185.2° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at about 146.9° C. when heated from approximately 30° C. to approximately 230° C.

In one embodiment, provided herein is Form B having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 17. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising about 0.64% mass loss before about 155° C. when heated from approximately 30° C. to approximately 300° C. The TGA thermogram further comprises a decomposition event with an onset temperature at approximately 258.0° C. when heated from approximately 30° C. to approximately 300° C.

In one embodiment, provided herein is Form B that can be converted to Form A after being stirred in a solvent for a period of time. See Table 13. In one embodiment, the solvent is IPAc/heptane (e.g., about 1:2 (V:V)) or toluene. In one embodiment, the period of time is from about 1 day to about 7 days (e.g., about 1 day or about 7 days).

In certain embodiments, a solid form provided herein, e.g., Form B, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 3. In one embodiment, Form B has one or more characteristic X-ray powder diffraction peaks at approximately 4.34, 7.46, 8.61, 11.37, 12.90, 14.89, 15.50, 18.76, 19.71, 21.52, 22.15, 22.81, 23.03, 23.77, 24.60, 25.29, 25.73, 26.23, 26.76, 27.49, 28.17, 30.10, 31.76, 32.57, 34.34, 35.94, 37.74, 38.63, 39.27, 41.75, 42.20 or 44.45° 2θas depicted in FIG. 3. In a specific embodiment, Form B has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.34, 8.61, 12.90, 14.89, 15.50, 18.76, 23.77 or 25.29° 2θ. In another embodiment, Form B has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.34, 8.61, 14.89 or 15.50° 2θ. In another embodiment, Form B has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or thirty-two characteristic X-ray powder diffraction peaks as set forth in Table 21.

In certain embodiments, a solid form provided herein, e.g., Form B, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 3. In one embodiment, Form B has one or more characteristic X-ray powder diffraction peaks at approximately 4.3, 7.5, 8.6, 11.4, 12.9, 14.9, 15.5, 18.8, 19.7, 21.5, 22.2, 22.8, 23.0, 23.8, 24.6, 25.3, 25.7, 26.2, 26.8, 27.5, 28.2, 30.1, 31.8, 32.6, 34.3, 35.9, 37.7, 38.6, 39.3, 41.8, 42.2 or 44.5° 2θas depicted in FIG. 3. In a specific embodiment, Form B has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 12.9, 14.9, 15.5, 18.8, 23.8 or 25.3° 2θ. In another embodiment, Form B has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 14.9 or 15.5° 2θ. In another embodiment, Form B has one, two, three, four, five, six or seven characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 12.9, 14.9, 15.5, 18.8 or 25.3° 2θ. In another embodiment, Form B has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 14.9, 15.5, 18.8 or 25.3° 2θ. In another embodiment, Form B has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 15.5 or 25.3° 2θ. In another embodiment, Form B has one, two or three characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6 or 15.5° 2θ. In another embodiment, Form B has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or thirty-two characteristic X-ray powder diffraction peaks as set forth in Table 21.

In still another embodiment, Form B is substantially pure. In certain embodiments, the substantially pure Form B is substantially free of other solid forms, e.g., Forms A, C, D, E, F, G or H. In certain embodiments, the purity of the substantially pure Form B is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.3 Form C of Compound 1

In certain embodiments, provided herein is Form C of Compound 1.

In one embodiment, Form C is a solid form of Compound 1. In one embodiment, Form C is anhydrous. In one embodiment, Form C is an anhydrous solid form of Compound 1 retaining residual solvent. In one embodiment, Form C is an anhydrous solid form of Compound 1 retaining residual EtOH. In another embodiment, Form C is crystalline.

In certain embodiments, Form C is prepared by single solvent fast cooling crystallization, single solvent slow cooling crystallization, binary solvent fast cooling crystallization or binary solvent slow cooling crystallization experiments (see Table 1-Table 10).

In one embodiment, provided herein are methods for preparing Form C of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the solution to a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is EtOH or IPAc.

In one embodiment, provided herein are methods for preparing Form C of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g., up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the solution to a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is EtOH or IPAc.

In one embodiment, provided herein are methods for preparing Form C of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g, from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the hot solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is EtOH or IPAc.

In one embodiment, provided herein are methods for preparing Form C of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g, up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the hot solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is EtOH or IPAc.

In one embodiment, provided herein are methods for preparing Form C of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3, Table 5 and Table 9). In certain embodiments, the solvent is EtOH. In certain embodiments, the co-solvent is water, toluene or cyclohexane.

In one embodiment, provided herein are methods for preparing Form C of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3, Table 5 and Table 9). In certain embodiments, the solvent is EtOH. In certain embodiments, the co-solvent is water, toluene or cyclohexane.

In one embodiment, provided herein are methods for preparing Form C of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 10). In certain embodiments, the solvent is EtOH, EtOAc or IPAc. In certain embodiments, the co-solvent is cyclohexane.

In one embodiment, provided herein are methods for preparing Form C of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 10). In certain embodiments, the solvent is EtOH, EtOAc or IPAc. In certain embodiments, the co-solvent is cyclohexane.

In one embodiment, provided herein is Form C having a DSC thermogram substantially as depicted in FIG. 19. In certain embodiments, the crystalline form exhibits a DSC thermogram comprising an endothermic event with a maximum at about 63.5° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 77.6° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 134.9° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 185.8° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at about 143.0° C. when heated from approximately 30° C. to approximately 230° C.

In one embodiment, provided herein is Form C having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 20. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising about 1.08% mass loss before about 150.0° C. when heated from approximately 30° C. to approximately 300° C. The TGA thermogram further comprises a decomposition event with an onset temperature at approximately 269.1° C. when heated from approximately 30° C. to approximately 300° C.

In one embodiment, provided herein is Form C that can be converted to Form A after being stirred in a solvent for a period of time. See Table 13. In one embodiment, the solvent is IPAc/heptane (e.g., about 1:2 (V:V)) or toluene. In one embodiment, the period of time is from about 1 day to about 7 days (e.g., about 1 day or about 7 days).

In certain embodiments, a solid form provided herein, e.g., Form C, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 4. In one embodiment, Form C has one or more characteristic X-ray powder diffraction peaks at approximately 3.09, 4.35, 7.46, 8.63, 11.41, 12.93, 14.94, 15.55, 18.80, 19.78, 21.60, 22.51, 22.89, 23.31, 24.10, 24.87, 25.25, 26.34, 27.07, 27.77, 28.10, 28.45, 29.09, 29.43, 29.75, 30.37, 30.73, 31.77, 32.24, 32.86, 34.02, 35.67, 37.86, 38.39, 39.35, 41.85, 42.35, 43.28, 43.74 or 44.24° 2θas depicted in FIG. 4. In a specific embodiment, Form C has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.35, 8.63, 11.41, 12.93, 14.94, 15.55, 18.80 or 21.60° 2θ. In another embodiment, Form C has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.35, 8.63, 14.94 or 15.55° 2θ. In another embodiment, Form C has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or forty characteristic X-ray powder diffraction peaks as set forth in Table 22.

In certain embodiments, a solid form provided herein, e.g., Form C, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 4. In one embodiment, Form C has one or more characteristic X-ray powder diffraction peaks at approximately 3.1, 4.4, 7.5, 8.6, 11.4, 12.9, 14.9, 15.6, 18.8, 19.8, 21.6, 22.5, 22.9, 23.3, 24.1, 24.9, 25.3, 26.3, 27.1, 27.8, 28.1, 28.5, 29.1, 29.4, 29.8, 30.4, 30.7, 31.8, 32.2, 32.9, 34.0, 35.7, 37.9, 38.4, 39.4, 41.9, 42.4, 43.3, 43.7 or 44.2° 2θas depicted in FIG. 4. In a specific embodiment, Form C has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.4, 8.6, 11.4, 12.9, 14.9, 15.6, 18.8 or 21.6° 2θ. In another embodiment, Form C has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.4, 8.6, 14.9 or 15.6° 2θ. In another embodiment, Form C has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 4.4, 8.6, 11.4, 14.9, 15.6 or 18.8° 2θ. In another embodiment, Form C has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.4, 8.6, 11.4 or 15.6° 2θ. In another embodiment, Form C has one, two or three characteristic X-ray powder diffraction peaks at approximately 4.4, 8.6 or 15.6° 2θ. In another embodiment, Form C has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or forty characteristic X-ray powder diffraction peaks as set forth in Table 22.

In still another embodiment, Form C is substantially pure. In certain embodiments, the substantially pure Form C is substantially free of other solid forms, e.g., Forms A, B, D, E, F, G or H. In certain embodiments, the purity of the substantially pure Form C is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.4 Form D of Compound 1

In certain embodiments, provided herein is Form D of Compound 1.

In one embodiment, Form D is a solid form of Compound 1. In one embodiment, Form D is anhydrous. In another embodiment, Form D is crystalline.

In certain embodiments, Form D is prepared by single solvent fast cooling crystallization, single solvent slow cooling crystallization, binary solvent fast cooling crystallization or binary solvent slow cooling crystallization experiments (see Table 1-Table 10).

In one embodiment, provided herein are methods for preparing Form D of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the solution to a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is IPA, 1-BuOH, MeCN or EtOAc.

In one embodiment, provided herein are methods for preparing Form D of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g., up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the solution to a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is IPA, 1-BuOH, MeCN or EtOAc.

In one embodiment, provided herein are methods for preparing Form D of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g, from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the hot solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is IPA, EtOAc or MEK.

In one embodiment, provided herein are methods for preparing Form D of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g, up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the hot solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is IPA, EtOAc or MEK.

In one embodiment, provided herein are methods for preparing Form D of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3, Table 5, Table 7 and Table 9). In certain embodiments, the solvent is MeOH, MeCN, n-Propanol, 1-BuOH, THF, 2-MeTHF, EtOAc, IPA, IPAc, acetone, MEK or MIBK. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form D of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3, Table 5, Table 7 and Table 9). In certain embodiments, the solvent is MeOH, MeCN, n-Propanol, 1-BuOH, THF, 2-MeTHF, EtOAc, IPA, IPAc, acetone, MEK or MIBK. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form D of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form. (see Table 4, Table 6, Table 8 and Table 10). In certain embodiments, the solvent is n-propanol, 1-BuOH, MeOH, MeCN, THF, acetone, MEK or MIBK. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form D of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4, Table 6, Table 8 and Table 10). In certain embodiments, the solvent is n-propanol, 1-BuOH, MeOH, MeCN, THF, acetone, MEK or MIBK. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein is Form D having a DSC thermogram substantially as depicted in FIG. 11. In certain embodiments, the crystalline form exhibits a DSC thermogram comprising an endothermic event with a maximum at about 185.2° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at about 118.7° C. when heated from approximately 30° C. to approximately 230° C.

In one embodiment, provided herein is Form D having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 12. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising no mass loss before about 155° C. when heated from approximately 30° C. to approximately 300° C. The TGA thermogram further comprises a decomposition event with an onset temperature at approximately 259.8° C. when heated from approximately 30° C. to approximately 300° C. Thus, in certain embodiments, the crystalline form has no mass loss at a temperature lower than about 100° C.

In one embodiment, provided herein is slightly hygroscopic Form D having about 0.7% weight moisture uptake at 60% RH and about 1.0% weight moisture uptake at 90% RH. See FIG. 24.

In one embodiment, provided herein is Form D that can be converted to Form A after being stirred in a solvent for a period of time. See Table 13. In one embodiment, the solvent is IPAc/heptane (e.g., about 1:2 (V:V)) or toluene. In one embodiment, the period of time is from about 1 day to about 7 days (e.g., about 1 day or about 7 days).

In certain embodiments, a solid form provided herein, e.g., Form D, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 5. In one embodiment, Form D has one or more characteristic X-ray powder diffraction peaks at approximately 4.32, 7.44, 8.59, 11.31, 12.85, 14.85, 15.49, 18.72, 19.71, 21.51, 22.40, 22.75, 23.62, 24.48, 25.17, 26.19, 26.68, 26.96, 27.32, 27.98, 28.35, 29.34, 29.98, 30.30, 32.44, 34.07, 35.81, 37.16, 37.69, 38.44, 39.25, 41.71, 42.19 or 44.35° 2θas depicted in FIG. 5. In a specific embodiment, Form D has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.32, 7.44, 8.59, 11.31, 12.85, 14.85, 15.49 or 18.72° 2θ. In another embodiment, Form D has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.32, 8.59, 14.85 or 15.49° 2θ. In another embodiment, Form D has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or thirty-four characteristic X-ray powder diffraction peaks as set forth in Table 23.

In certain embodiments, a solid form provided herein, e.g., Form D, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 5. In one embodiment, Form D has one or more characteristic X-ray powder diffraction peaks at approximately 4.3, 7.4, 8.6, 11.3, 12.9, 14.9, 15.5, 18.7, 19.7, 21.5, 22.4, 22.8, 23.6, 24.5, 25.2, 26.2, 26.7, 27.0, 27.3, 28.0, 28.4, 29.3, 30.0, 30.3, 32.4, 34.1, 35.8, 37.2, 37.7, 38.4, 39.3, 41.7, 42.2 or 44.4° 2θas depicted in FIG. 5. In a specific embodiment, Form D has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.3, 7.4, 8.6, 11.3, 12.9, 14.9, 15.5 or 18.7° 2θ. In another embodiment, Form D has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 14.9 or 15.5° 2θ. In another embodiment, Form D has one, two, three, four, five, six or seven characteristic X-ray powder diffraction peaks at approximately 4.3, 7.4, 8.6, 12.9, 14.9, 15.5 or 18.7° 2θ. In another embodiment, Form D has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 12.8, 14.9, 15.5 or 18.7° 2θ. In another embodiment, Form D has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.3, 7.4, 8.6 or 15.5° 2θ. In another embodiment, Form D has one, two or three characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6 or 15.5° 2θ. In another embodiment, Form D has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or thirty-four characteristic X-ray powder diffraction peaks as set forth in Table 23.

In still another embodiment, Form D is substantially pure. In certain embodiments, the substantially pure Form D is substantially free of other solid forms, e.g., Forms A, B, C, E, F, G and H. In certain embodiments, the purity of the substantially pure Form D is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.5 Form E of Compound 1

In certain embodiments, provided herein is Form E of Compound 1.

In one embodiment, Form E is a solid form of Compound 1. In one embodiment, Form E is anhydrous. In one embodiment, Form E is an anhydrous solid form of Compound 1 retaining residual solvent. In one embodiment, Form E is an anhydrous solid form of Compound 1 retaining residual EtOAc. In another embodiment, Form E is crystalline.

In certain embodiments, Form E is prepared by single solvent fast cooling crystallization, single solvent slow cooling crystallization, binary solvent fast cooling crystallization or binary solvent slow cooling crystallization experiments (see Table 1-Table 10).

In one embodiment, provided herein are methods for preparing Form E of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the solution to a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is 2-MeTHF, MEK or n-Propanol.

In one embodiment, provided herein are methods for preparing Form E of Compound 1 comprising single solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g., up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the solution to a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 1. In certain embodiments, the solvent is 2-MeTHF, MEK or n-Propanol.

In one embodiment, provided herein are methods for preparing Form E of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 10-55 mg) with a minimum amount of solvents (e.g, from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) cooling the hot solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., from about 6 hours to about 72 hours); (4) isolating the resulting solids; and (5) evaporating the samples without precipitation to dryness and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is 1-BuOH, 2-MeTHF or n-Propanol.

In one embodiment, provided herein are methods for preparing Form E of Compound 1 comprising single solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., approximately 30-35 mg) with a minimum amount of solvents (e.g, up to about 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) cooling the hot solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature over a period of time (e.g., about 24 hours); (4) isolating the resulting solids (e.g., isolating by vacuum filtration); and (5) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen) and collecting the resulting solids. See Table 2. In certain embodiments, the solvent is 1-BuOH, 2-MeTHF or n-Propanol.

In one embodiment, provided herein are methods for preparing Form E of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3, Table 5, Table 7 and Table 9). In certain embodiments, the solvent is IPA, MEK, n-Propanol, EtOH, 1-BuOH, IPA, THF, 2-MeTHF or EtOAc. In certain embodiments, the co-solvent is toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form E of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3, Table 5, Table 7 and Table 9). In certain embodiments, the solvent is IPA, MEK, n-Propanol, EtOH, 1-BuOH, IPA, THF, 2-MeTHF or EtOAc. In certain embodiments, the co-solvent is toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form E of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4, Table 6, Table 8 and Table 10). In certain embodiments, the solvent is EtOH, THF, IPA, 2-MeTHF, EtOAc, n-Propanol, 1-BuOH or MIBK. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein are methods for preparing Form E of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4, Table 6, Table 8 and Table 10). In certain embodiments, the solvent is EtOH, THF, IPA, 2-MeTHF, EtOAc, n-Propanol, 1-BuOH or MIBK. In certain embodiments, the co-solvent is water, toluene, heptane or cyclohexane.

In one embodiment, provided herein is Form E having a DSC thermogram substantially as depicted in FIG. 27. In certain embodiments, the crystalline form exhibits a DSC thermogram comprising an endothermic event with a maximum at about 154.8° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 185.6° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at about 156.7° C. when heated from approximately 30° C. to approximately 230° C.

In one embodiment, provided herein is Form E having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 28. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising about 1.96% mass loss before about 165.0° C. when heated from approximately 30° C. to approximately 300° C. The TGA thermogram further comprises a decomposition event with an onset temperature at approximately 261.6° C. when heated from approximately 30° C. to approximately 300° C.

In one embodiment, provided herein is Form E that can be converted to Form A after being stirred in a solvent for a period of time. See Table 13. In one embodiment, the solvent is IPAc/heptane (e.g., about 1:2 (V:V)) or toluene. In one embodiment, the period of time is from about 1 day to about 7 days (e.g., about 1 day or about 7 days).

In certain embodiments, a solid form provided herein, e.g., Form E, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 6. In one embodiment, Form E has one or more characteristic X-ray powder diffraction peaks at approximately 4.33, 4.66, 5.42, 5.73, 5.99, 6.16, 6.29, 6.50, 7.46, 8.61, 9.32, 10.07, 10.78, 10.93, 11.37, 12.17, 12.89, 13.45, 14.45, 14.89, 15.50, 16.66, 18.74, 19.73, 20.04, 20.56, 21.53, 21.80, 22.19, 22.57, 22.81, 23.45, 23.87, 24.23, 24.97, 25.35, 26.24, 26.47, 26.96, 27.24, 27.85, 28.36, 29.19, 29.57, 29.85, 30.30, 30.81, 31.25, 32.34, 32.93, 34.10, 34.77, 35.74, 36.36, 37.23, 37.71, 38.36, 39.28, 40.74, 41.66, 42.19, 42.61, 43.29, 43.71 or 44.18° 2θas depicted in FIG. 6. In a specific embodiment, Form E has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.33, 8.61, 14.89, 15.50, 18.74, 23.45, 24.97 or 27.85° 2θ. In another embodiment, Form E has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.33, 8.61, 14.89 or 15.50° 2θ. In another embodiment, Form E has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three, sixty-four or sixty-five characteristic X-ray powder diffraction peaks as set forth in Table 24.

In certain embodiments, a solid form provided herein, e.g., Form E, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 6. In one embodiment, Form E has one or more characteristic X-ray powder diffraction peaks at approximately 4.3, 4.7, 5.4, 5.7, 6.0, 6.2, 6.3, 6.5, 7.5, 8.6, 9.3, 10.1, 10.8, 10.9, 11.4, 12.2, 12.9, 13.5, 14.5, 14.9, 15.5, 16.7, 18.7, 19.7, 20.0, 20.6, 21.5, 21.8, 22.2, 22.6, 22.8, 23.5, 23.9, 24.2, 25.0, 25.4, 26.2, 26.5, 27.0, 27.2, 27.9, 28.4, 29.2, 29.6, 29.9, 30.3, 30.8, 31.3, 32.3, 32.9, 34.1, 34.8, 35.7, 36.4, 37.2, 37.7, 38.4, 39.3, 40.7, 41.7, 42.2, 42.6, 43.3, 43.7 or 44.2° 2θ as depicted in FIG. 6. In a specific embodiment, Form E has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 14.9, 15.5, 18.7, 23.5, 25.0 or 27.9° 2θ. In another embodiment, Form E has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 14.9 or 15.5° 2θ. In another embodiment, Form E has one, two, three, four, five, six or seven characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 14.9, 15.5 18.7, 25.0 or 27.9° 2θ. In another embodiment, Form E has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 14.9, 15.5 18.7 or 25.0° 2θ. In another embodiment, Form E has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6, 15.5 or 27.9° 2θ. In another embodiment, Form E has one, two or three characteristic X-ray powder diffraction peaks at approximately 4.3, 8.6 or 15.5° 2θ. In another embodiment, Form E has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three, sixty-four or sixty-five characteristic X-ray powder diffraction peaks as set forth in Table 24.

In still another embodiment, Form E is substantially pure. In certain embodiments, the substantially pure Form E is substantially free of other solid forms, e.g., Forms A, B, C, D, F, G and H. In certain embodiments, the purity of the substantially pure Form E is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.6 Form F of Compound 1

In certain embodiments, provided herein is Form F.

In one embodiment, Form F is a solid form of Compound 1. In one embodiment, Form F is a hydrate solid form of Compound 1. In another embodiment, Form F is crystalline.

In certain embodiments, Form F is prepared by binary solvent fast cooling crystallization or binary solvent slow cooling crystallization experiments (see Table 3 and Table 4).

In one embodiment, provided herein are methods for preparing Form F of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3). In certain embodiments, the solvent is THF, n-Propanol or MIBK. In certain embodiments, the co-solvent is water.

In one embodiment, provided are methods for preparing Form F of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3). In certain embodiments, the solvent is THF, n-Propanol or MIBK. In certain embodiments, the co-solvent is water.

In one embodiment, provided herein are methods for preparing Form F of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4). In certain embodiments, the solvent is THF. In certain embodiments, the co-solvent is water.

In one embodiment, provided herein are methods for preparing Form F of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4). In certain embodiments, the solvent is THF. In certain embodiments, the co-solvent is water.

In one embodiment, provided herein is Form F having a DSC thermogram substantially as depicted in FIG. 30. In certain embodiments, the crystalline form exhibits a DSC thermogram comprising an endothermic event with a maximum at about 64.1° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 91.3° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 185.9° C. when heated from approximately 30° C. to approximately 230° C.

In one embodiment, provided herein is Form F having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 31. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising about 1.86% mass loss before about 110.0° C. when heated from approximately 30° C. to approximately 300° C. The TGA thermogram further comprises a decomposition event with an onset temperature at approximately 268.3° C. when heated from approximately 30° C. to approximately 300° C.

In one embodiment, provided herein is Form F that can be converted to Form A after being stirred in a solvent for a period of time. See Table 13. In one embodiment, the solvent is IPAc/heptane (e.g., about 1:2 (V:V)) or toluene. In one embodiment, the period of time is from about 1 day to about 7 days (e.g., about 1 day or about 7 days).

In certain embodiments, a solid form provided herein, e.g., Form F, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form F has an X-ray powder diffraction pattern substantially as shown in FIG. 7. In one embodiment, Form F has one or more characteristic X-ray powder diffraction peaks at approximately 3.99, 4.23, 7.89, 8.36, 11.81, 15.21, 15.44, 17.39, 17.79, 19.78, 20.87, 22.98, 23.83, 25.17, 26.10, 27.15, 28.53, 30.30, 31.71 or 34.06° 2θas depicted in FIG. 7. In a specific embodiment, Form F has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.99, 4.23, 7.89, 8.36, 15.21, 15.44, 20.87 or 25.17° 2θ. In another embodiment, Form F has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.99, 4.23, 7.89 or 15.21° 2θ. In another embodiment, Form F has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty characteristic X-ray powder diffraction peaks as set forth in Table 25.

In certain embodiments, a solid form provided herein, e.g., Form F, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form F has an X-ray powder diffraction pattern substantially as shown in FIG. 7. In one embodiment, Form F has one or more characteristic X-ray powder diffraction peaks at approximately 4.0, 4.2, 7.9, 8.4, 11.8, 15.2, 15.4, 17.4, 17.8, 19.8, 20.9, 23.0, 23.8, 25.2, 26.1, 27.2, 28.5, 30.3, 31.7 or 34.1° 2θas depicted in FIG. 7. In a specific embodiment, Form F has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.0, 4.2, 7.9, 8.4, 15.2, 15.4, 20.9 or 25.2° 2θ. In another embodiment, Form F has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.0, 4.2, 7.9 or 15.2° 2θ. In another embodiment, Form F has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 4.0, 4.2, 7.9, 8.4, 15.2 or 15.4° 2θ. In another embodiment, Form F has one, two or three characteristic X-ray powder diffraction peaks at approximately 4.0, 4.2 or 15.2° 2θ. In another embodiment, Form F has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty characteristic X-ray powder diffraction peaks as set forth in Table 25.

In still another embodiment, Form F is substantially pure. In certain embodiments, the substantially pure Form F is substantially free of other solid forms, e.g., Forms A, B, C, D, E, G and H. In certain embodiments, the purity of the substantially pure Form F is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.7 Form G of Compound 1

In certain embodiments, provided herein is Form G.

In one embodiment, Form G is a solid form of Compound 1. In one embodiment, Form G is anhydrous. In another embodiment, Form G is crystalline.

In certain embodiments, Form G is prepared by binary solvent fast cooling crystallization or binary solvent slow cooling crystallization experiments (see Table 3 and Table 4).

In one embodiment, provided herein are methods for preparing Form G of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3). In certain embodiments, the solvent is MEK, MIBK or 2-MeTHF. In certain embodiments, the co-solvent is water.

In one embodiment, provided herein are methods for preparing Form G of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) cooling the solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4). In certain embodiments, the solvent is IPA or 2-MeTHF. In certain embodiments, the co-solvent is water.

In one embodiment, provided herein is Form G having a DSC thermogram substantially as depicted in FIG. 33. In certain embodiments, the crystalline form exhibits a DSC thermogram comprising an endothermic event with a maximum at about 90.5° C. when heated from approximately 30° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 184.9° C. when heated from approximately 30° C. to approximately 230° C.

In one embodiment, provided herein is Form G having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 34. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising no mass loss before about 110.0° C. when heated from approximately 30° C. to approximately 300° C. The TGA thermogram further comprises a decomposition event with an onset temperature at approximately 263.5° C. when heated from approximately 30° C. to approximately 300° C.

In one embodiment, provided herein is Form G that can be converted to Form A after being stirred in a solvent for a period of time. See Table 13. In one embodiment, the solvent is IPAc/heptane (e.g., about 1:2 (V:V)) or toluene. In one embodiment, the period of time is from about 1 day to about 7 days (e.g., about 1 day or about 7 days).

In one embodiment, provided herein is slightly hygroscopic Form G having about 0.4% weight moisture uptake at 60% RH and about 7.1% weight moisture uptake at 90% RH. See FIG. 35.

In certain embodiments, a solid form provided herein, e.g., Form G, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form G has an X-ray powder diffraction pattern substantially as shown in FIG. 8. In one embodiment, Form G has one or more characteristic X-ray powder diffraction peaks at approximately 4.19, 8.33, 12.47, 15.19, 15.44, 16.67, 17.81, 19.26, 20.87, 21.33, 22.18, 22.86, 23.71, 24.59, 25.09, 25.89, 27.00, 28.36, 28.63, 29.87, 32.45, 34.70, 39.53 or 42.08° 2θas depicted in FIG. 8. In a specific embodiment, Form G has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.19, 8.33, 15.19, 15.44, 17.81, 20.87, 27.00 or 28.36° 2θ. In another embodiment, Form G has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.19, 8.33, 15.19 or 20.87° 2θ. In another embodiment, Form G has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three or twenty-four characteristic X-ray powder diffraction peaks as set forth in Table 26.

In certain embodiments, a solid form provided herein, e.g., Form G, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form G has an X-ray powder diffraction pattern substantially as shown in FIG. 8. In one embodiment, Form G has one or more characteristic X-ray powder diffraction peaks at approximately 4.2, 8.3, 12.5, 15.2, 15.4, 16.7, 17.8, 19.3, 20.9, 21.3, 22.2, 22.9, 23.7, 24.6, 25.1, 25.9, 27.0, 28.4, 28.6, 29.9, 32.5, 34.7, 39.5 or 42.1° 2θas depicted in FIG. 8. In a specific embodiment, Form G has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.2, 8.3, 15.2, 15.4, 17.8, 20.9, 27.0 or 28.4° 2θ. In another embodiment, Form G has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.2, 8.3, 15.2 or 20.9° 2θ. In another embodiment, Form G has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 4.2, 8.3, 15.2, 15.4, 17.8 or 20.9° 2θ. In another embodiment, Form G has one, two or three characteristic X-ray powder diffraction peaks at approximately 4.2, 8.3 or 15.2° 2θ. In another embodiment, Form G has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three or twenty-four characteristic X-ray powder diffraction peaks as set forth in Table 26.

In still another embodiment, Form G is substantially pure. In certain embodiments, the substantially pure Form G is substantially free of other solid forms, e.g., Forms A, B, C, D, E, F and H. In certain embodiments, the purity of the substantially pure Form G is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.8 Form H of Compound 1

In certain embodiments, provided herein is Form H.

In one embodiment, Form H is a solid form of Compound 1. In one embodiment, Form H is a solvate of Compound 1. In one embodiment, Form H is a DMSO solvate of Compound 1. In one embodiment, Form H is a mono-DMSO solvate of Compound 1. In another embodiment, Form H is crystalline.

In certain embodiments, Form H is prepared by binary solvent fast cooling crystallization or binary solvent slow cooling crystallization experiments (see Table 3 and Table 4).

In one embodiment, provided herein are methods for preparing Form H of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., from about −5° C. to about 10° C.) for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3 and Table 5). In certain embodiments, the solvent is DMSO. In certain embodiments, the co-solvent is toluene.

In one embodiment, provided herein are methods for preparing Form H of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) placing the solution at a second temperature (e.g., about 4° C.) for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3 and Table 5). In certain embodiments, the solvent is DMSO. In certain embodiments, the co-solvent is toluene.

In one embodiment, provided herein are methods for preparing Form H of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 10-55 mg) with a minimum amount of solvents (e.g., from about 0.25 mL to about 14.0 mL) at a first temperature (e.g., from about 30° C. to about 90° C.); (2) filtering the hot solution; (3) adding a co-solvent; (4) cooled the solution to ambient temperature at a rate (e.g., from about 5° C./hr to about 40° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., from about 6 hours to about 72 hours); (5) isolating the resulting solids; and (6) evaporating the samples without precipitation to dryness and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 6). In certain embodiments, the solvent is DMSO. In certain embodiments, the co-solvent is toluene.

In one embodiment, provided herein are methods for preparing Form H of Compound 1 comprising binary solvent slow cooling crystallization comprising the steps of: (1) dissolving Compound 1 (e.g., about 30-35 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) filtering the hot solution (e.g., filtering through a 0.45 μm syringe filter); (3) adding a co-solvent; (4) cooled the solution to ambient temperature at a rate (e.g., about 20° C./hr) and allowing to equilibrate at ambient temperature for a period of time (e.g., about 24 hours); (5) isolating the resulting solids (e.g., isolating by vacuum filtration); and (6) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 6). In certain embodiments, the solvent is DMSO. In certain embodiments, the co-solvent is toluene.

In one embodiment, provided herein is Form H having a DSC thermogram substantially as depicted in FIG. 38. In certain embodiments, the crystalline form exhibits a DSC thermogram comprising an endothermic event with a maximum at about 88.0° C. when heated from approximately 30° C. to approximately 230° C.

In one embodiment, provided herein is Form H having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 39. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising about 6.4% mass loss before about 140° C. when heated from approximately 30° C. to approximately 300° C.

In certain embodiments, the TGA thermogram further comprises about 9.8% mass loss before about 240° C. when heated from approximately 30° C. to approximately 300° C. The TGA thermogram further comprises a decomposition event with an onset temperature at approximately 268.1° C. when heated from approximately 30° C. to approximately 300° C.

In one embodiment, provided herein is Form H that can be converted to Form A after being stirred in a solvent for a period of time. See Table 13. In one embodiment, the solvent is IPAc/heptane (e.g., about 1:2 (V:V)) or toluene. In one embodiment, the period of time is from about 1 day to about 7 days (e.g., about 1 day or about 7 days).

In certain embodiments, a solid form provided herein, e.g., Form H, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form H has an X-ray powder diffraction pattern substantially as shown in FIG. 9. In one embodiment, Form H has one or more characteristic X-ray powder diffraction peaks at approximately 3.07, 5.35, 8.56, 10.69, 12.20, 12.62, 13.08, 13.32, 14.08, 15.46, 16.04, 17.18, 17.69, 17.93, 18.76, 19.69, 20.14, 21.19, 21.40, 22.22, 22.99, 24.02, 24.59, 25.18, 25.75, 26.55, 26.93, 27.53, 28.32, 29.07, 31.19, 31.72, 32.05, 33.70, 35.09, 35.76, 37.23, 37.94, 38.67, 39.26, 39.96, 40.36, 43.14 or 44.56° 2θas depicted in FIG. 9. In a specific embodiment, Form H has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.07, 12.62, 14.08, 17.18, 18.76, 21.40, 24.59 or 25.75° 2θ. In another embodiment, Form H has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 14.08, 18.76, 21.40 or 24.59° 2θ. In another embodiment, Form H has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or forty-four characteristic X-ray powder diffraction peaks as set forth in Table 27.

In certain embodiments, a solid form provided herein, e.g., Form H, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form H has an X-ray powder diffraction pattern substantially as shown in FIG. 9. In one embodiment, Form H has one or more characteristic X-ray powder diffraction peaks at approximately 3.1, 5.4, 8.6, 10.7, 12.2, 12.6, 13.1, 13.3, 14.1, 15.5, 16.0, 17.2, 17.7, 17.9, 18.8, 19.7, 20.1, 21.2, 21.4, 22.2, 23.0, 24.0, 24.6, 25.2, 25.8, 26.6, 26.9, 27.5, 28.3, 29.1, 31.2, 31.7, 32.1, 33.7, 35.1, 35.8, 37.2, 37.9, 38.7, 39.3, 40.0, 40.4, 43.1 or 44.6° 2θas depicted in FIG. 9. In a specific embodiment, Form H has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.1, 12.6, 14.1, 17.2, 18.8, 21.4, 24.6 or 25.8° 2θ. In another embodiment, Form H has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 14.1, 18.8, 21.4 or 24.6 °2θ. In another embodiment, Form H has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 14.1, 17.2, 18.8, 21.4, 24.6 or 25.7° 2θ. In another embodiment, Form H has one, two or three characteristic X-ray powder diffraction peaks at approximately 14.1, 18.8 or 21.4° 2θ. In another embodiment, Form H has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or forty-four characteristic X-ray powder diffraction peaks as set forth in Table 27.

In still another embodiment, Form H is substantially pure. In certain embodiments, the substantially pure Form H is substantially free of other solid forms, e.g., Forms A, B, C, D, E, F and G. In certain embodiments, the purity of the substantially pure Form H is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.4 Salts of Compound 1

In certain embodiments, provided herein are salts of Compound 1. In one embodiment, the salt is crystalline.

The salts provided herein (e.g., Salt I, Salt II, Salt III, Salt IV, Salt V and Salt VI of Compound 1) may be characterized using a number of methods known to a person skilled in the art, including, but not limited to, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), thermal gravimetric analysis (TGA), and hot-stage microscopy), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), high performance liquid chromatography (HPLC), and proton nuclear magnetic resonance (1H NMR) spectrum. The particle size and size distribution of the salt provided herein may be determined by conventional methods, such as laser light scattering technique.

It should be understood that the numerical values of the peaks of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and so the values quoted are not to be construed as absolute, but with an allowable variability, such as ±0.2° 2θ(see United State Pharmacopoeia, page 2228 (2003)).

In certain embodiments, provided herein is a method for making a salt of Compound 1, comprising 1) dissolving Compound 1 in a solvent (e.g., CH3OH, CH3CN or acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 30-70° C. or about 50° C.); 3) filtering the mixture at the elevated temperature to yield a solution; 4) adding a basic counter-ion solution (e.g., about 1 or 3 equivalents); 5) cooling the resulting mixture to a temperature (e.g., about 10-30° C. or about 25° C.); 6) collecting precipitation by filtration; and 7) evaporating the solution to yield a solid if no precipitation and collecting the solid. In certain embodiments, the solvent is CH3OH, CH3CN or acetone. In certain embodiments, the basic counter-ion is provided by calcium acetate hydrate, choline hydroxide, potassium hydroxide, sodium hydroxide in, 1-arginine, n-methyl-d-glucamine (meglumine), a mixture of magnesium nitrate and sodium hydroxide or a mixture of calcium nitrate and sodium hydroxide. In certain embodiments, the solvent of the basic counter-ion solution is water, CH3OH or a mixture of water and CH3OH.

5.4.1 Hemi-Calcium Salt of Compound 1 (Salt I)

In one embodiment, provided herein is a calcium salt of Compound 1. In one embodiment, provided herein is a hemi-calcium salt of Compound 1 (“Salt I”). In one embodiment, Salt I is crystalline. In one embodiment, Salt I is moderately hydroscopic. In one embodiment, Salt I is chemically stable.

In certain embodiments, provided herein is a method for making Salt I, comprising 1) dissolving Compound 1 in a solvent (e.g., CH3OH) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 30-70° C.); 3) filtering the mixture at the elevated temperature to yield a solution; 4) contacting the mixture with a calcium acetate solution (e.g., about 0.5-1.5 equivalents); 5) cooling the resulting mixture (e.g., to about 10-30° C.); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the calcium acetate solution is a solution of calcium acetate hydrate in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In certain embodiments, provided herein is a method for making Salt I, comprising 1) dissolving Compound 1 in a solvent (e.g., CH3OH) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 50° C.); 3) filtering the mixture at the elevated temperature with a 0.45 μm syringe filter to yield a solution; 4) contacting the mixture with a calcium acetate solution (e.g., about 1 equivalent); 5) cooling the resulting mixture (e.g., to about 25° C.) (e.g., at a speed of about 20° C./hour); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the calcium acetate solution is a solution of calcium acetate hydrate in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In one embodiment, Salt I has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 49. In certain embodiments, Salt I exhibits a TGA thermogram comprising a total mass loss of approximately 0.34% of the total mass of the sample between approximately 65° C. and approximately 105° C. when heated from approximately 25° C. to approximately 230° C. In one embodiment, the TGA thermogram further comprises a total mass loss of approximately 1.41% of the total mass of the sample between approximately 140° C. and approximately 190° C. when heated from approximately 25° C. to approximately 230° C. In one embodiment, the TGA thermogram further comprises a decomposition event with onset temperature at approximately 213.8° C. when heated from approximately 25° C. to approximately 230° C.

In one embodiment, Salt I has a DSC thermogram as depicted in FIG. 48 comprising an endothermic event with a maximum at approximately 104.0° C. when heated from approximately 25° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 170.6° C. when heated from approximately 25° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 179.1° C. when heated from approximately 25° C. to approximately 230° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 210.6° C. when heated from approximately 25° C. to approximately 230° C.

In certain embodiments, Salt I is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt I has an X-ray powder diffraction pattern substantially as shown in FIG. 40. In one embodiment, Salt I has one or more characteristic X-ray powder diffraction peaks at approximately 3.20, 4.09, 4.51, 4.85, 4.99, 5.19, 5.43, 5.69, 6.01, 6.49, 6.92, 7.21, 8.29, 8.47, 9.17, 9.53, 10.39, 10.58, 11.30, 11.87, 12.10, 12.23, 12.73, 13.23, 14.23, 15.60, 15.97, 17.21, 17.49, 18.08, 18.88, 19.15, 22.00, 22.41, 23.92, 25.25, 25.60, 26.35, 26.67, 27.76, 28.21, 29.29, 31.08, 31.46, 31.82, 33.44, 34.63, 35.58, 37.97, 38.65, 38.96, 41.35, 42.29 or 43.31° 2θas depicted in FIG. 40. In a specific embodiment, Salt I has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.20, 5.43, 9.53, 13.23, 15.60, 15.97, 19.15 or 22.41° 2θ. In another embodiment, Salt I has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.20, 9.53, 15.97 or 22.41° 2θ. In another embodiment, Salt I has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three or fifty-four characteristic X-ray powder diffraction peaks as set forth in Table 38.

In certain embodiments, Salt I is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt I has an X-ray powder diffraction pattern substantially as shown in FIG. 40. In one embodiment, Salt I has one or more characteristic X-ray powder diffraction peaks at approximately 3.2, 4.1, 4.5, 4.9, 5.0, 5.2, 5.4, 5.7, 6.0, 6.5, 6.9, 7.2, 8.3, 8.5, 9.2, 9.5, 10.4, 10.6, 11.3, 11.9, 12.1, 12.2, 12.7, 13.2, 14.2, 15.6, 16.0, 17.2, 17.5, 18.1, 18.9, 19.2, 22.0, 22.4, 23.9, 25.3, 25.6, 26.4, 26.7, 27.8, 28.2, 29.3, 31.1, 31.5, 31.8, 33.4, 34.6, 35.6, 38.0, 38.7, 39.0, 41.4, 42.3 or 43.3° 2θas depicted in FIG. 40. In a specific embodiment, Salt I has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.2, 5.4, 9.5, 13.2, 15.6, 16.0, 19.2 or 22.4° 2θ. In another embodiment, Salt I has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.2, 9.5, 16.0 or 22.4° 2θ. In another embodiment, Salt I has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.2, 9.5, 15.6, 16.0, 19.2 or 22.4° 2θ. In another embodiment, Salt I has one, two or three characteristic X-ray powder diffraction peaks at approximately 3.2, 9.5 or 16.0° 2θ. In another embodiment, Salt I has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three or fifty-four characteristic X-ray powder diffraction peaks as set forth in Table 38.

5.4.2 Dihydrate Hemi-Calcium Salt of Compound 1 (Salt II)

In one embodiment, provided herein is a calcium salt of Compound 1. In one embodiment, provided herein is a hemi-calcium salt of Compound 1. In one embodiment, the hemi-calcium salt is a hydrate. In one embodiment, the hemi-calcium salt is a dihydrate (“Salt II”). In one embodiment, Salt II is crystalline. In one embodiment, Salt II is moderately hydroscopic. In one embodiment, Salt II is chemically stable.

In certain embodiments, provided herein is a method for making Salt II, comprising 1) dissolving Compound 1 in a solvent (e.g., acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 30-70° C.); 3) filtering the mixture at the elevated temperature to yield a solution; 4) contacting the mixture with a calcium acetate solution (e.g., about 0.5-1.5 equivalents); 5) cooling the resulting mixture (e.g., to about 10-30° C.); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the calcium acetate solution is a solution of calcium acetate hydrate in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In certain embodiments, provided herein is a method for making Salt II, comprising 1) dissolving Compound 1 in a solvent (e.g., acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 50° C.); 3) filtering the mixture at the elevated temperature with a 0.45 μm syringe filter to yield a solution; 4) contacting the mixture with a calcium acetate solution (e.g., about 1 equivalent); 5) cooling the resulting mixture (e.g., to about 25° C.) (e.g., at a speed of about 20° C./hour); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the calcium acetate solution is a solution of calcium acetate hydrate in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In one embodiment, Salt II has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 54. In one embodiment, Salt II exhibits a TGA thermogram comprising a total mass loss of approximately 10.98% of the total mass of the sample between approximately 65° C. and approximately 140° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the TGA thermogram further comprises a total mass loss of approximately 0.33% of the total mass of the sample between approximately 150° C. and approximately 180° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the TGA thermogram further comprises a decomposition event with onset temperature at approximately 298° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt II has a DSC thermogram as depicted in FIG. 53 comprising an endothermic event with a maximum at approximately 115.5° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 127.0° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at approximately 200.5° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 220.8° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 311.3° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt II is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt II has an X-ray powder diffraction pattern substantially as shown in FIG. 41. In one embodiment, Salt II has one or more characteristic X-ray powder diffraction peaks at approximately 3.37, 3.81, 3.94, 4.15, 4.33, 4.59, 4.77, 5.12, 5.51, 6.07, 6.25, 7.27, 7.45, 7.82, 8.03, 8.56, 8.83, 10.07, 10.39, 10.71, 11.32, 11.56, 11.70, 13.21, 13.46, 14.10, 14.36, 15.32, 15.58, 16.86, 19.28, 19.51, 20.23, 20.68, 21.32, 22.41, 22.95, 23.71, 24.27, 24.90, 25.87, 26.21, 26.83, 27.15, 27.57, 27.85, 28.12, 28.95, 29.24, 29.53, 29.95, 31.08, 31.47, 31.90, 32.59, 32.97, 33.42, 34.73, 34.97, 35.25, 36.09, 38.09, 39.69, 41.35, 42.56, 42.94 or 44.06° 2θas depicted in FIG. 41. In a specific embodiment, Salt II has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.37, 10.07, 13.21, 16.86, 20.23, 23.71, 31.47 or 38.09° 2θ. In another embodiment, Salt II has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.37, 10.07, 16.86 or 23.71° 2θ. In another embodiment, Salt II has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three, sixty-four, sixty-five, sixty-six or sixty-seven characteristic X-ray powder diffraction peaks as set forth in Table 39.

In certain embodiments, Salt II is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt II has an X-ray powder diffraction pattern substantially as shown in FIG. 41. In one embodiment, Salt II has one or more characteristic X-ray powder diffraction peaks at approximately 3.4, 3.8, 3.9, 4.2, 4.3, 4.6, 4.8, 5.1, 5.5, 6.1, 6.3, 7.3, 7.5, 7.8, 8.0, 8.6, 8.8, 10.1, 10.4, 10.7, 11.3, 11.6, 11.7, 13.2, 13.5, 14.1, 14.4, 15.3, 15.6, 16.9, 19.3, 19.5, 20.2, 20.7, 21.3, 22.4, 23.0, 23.7, 24.3, 24.9, 25.9, 26.2, 26.8, 27.2, 27.6, 27.9, 28.1, 29.0, 29.2, 29.5, 30.0, 31.1, 31.5, 31.9, 32.6, 33.0, 33.4, 34.7, 35.0, 35.3, 36.1, 38.1, 39.7, 41.4, 42.6, 42.9 or 44.1° 2θas depicted in FIG. 41. In a specific embodiment, Salt II has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.4, 10.1, 13.2, 16.9, 20.2, 23.7, 31.5 or 38.1° 2θ. In another embodiment, Salt II has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.4, 10.1, 16.9 or 23.7° 2θ. In another embodiment, Salt II has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.4, 10.1, 13.2, 16.9, 20.2 or 23.7° 2θ. In another embodiment, Salt II has one, two or three characteristic X-ray powder diffraction peaks at approximately 10.1, 16.9 or 23.7° 2θ. In another embodiment, Salt II has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three, sixty-four, sixty-five, sixty-six or sixty-seven characteristic X-ray powder diffraction peaks as set forth in Table 39.

5.4.3 Mono-Potassium Salt of Compound 1 (Salt III)

In one embodiment, provided herein is a potassium salt of Compound 1. In one embodiment, provided herein is a mono-potassium salt of Compound 1 (“Salt III”). In one embodiment, Salt III is crystalline. In one embodiment, Salt III is moderately hydroscopic. In one embodiment, Salt III is chemically stable. In one embodiment, Salt III has a tendency to form hydrates.

In certain embodiments, provided herein is a method for making Salt III, comprising 1) dissolving Compound 1 in a solvent (e.g., acetonitrile) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 30-70° C.); 3) filtering the mixture at the elevated temperature to yield a solution; 4) contacting the mixture with a potassium hydroxide solution (e.g., about 0.5-1.5 equivalents); 5) cooling the resulting mixture (e.g., to about 10-30° C.); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the potassium hydroxide solution is a solution of potassium hydroxide in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In certain embodiments, provided herein is a method for making Salt III, comprising 1) dissolving Compound 1 in a solvent (e.g., acetonitrile) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 50° C.); 3) filtering the mixture at the elevated temperature with a 0.45 μm syringe filter to yield a solution; 4) contacting the mixture with a potassium hydroxide solution (e.g., about 1 equivalent); 5) cooling the resulting mixture (e.g., to about 25° C.) (e.g., at a speed of about 20° C./hour); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the potassium hydroxide solution is a solution of potassium hydroxide in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In one embodiment, Salt III has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 59. In one embodiment, Salt III exhibits a TGA thermogram comprising a total mass loss of approximately 0.91% of the total mass of the sample between approximately 40° C. and approximately 70° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the TGA thermogram further comprises a total mass loss of approximately 0.25% of the total mass of the sample between approximately 100° C. and approximately 120° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the TGA thermogram further comprises a decomposition event with onset temperature at approximately 297.2° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt III has a DSC thermogram as depicted in FIG. 58 comprising an endothermic event with a maximum at approximately 54.3° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 109.3° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 314.4° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt III is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt III has an X-ray powder diffraction pattern substantially as shown in FIG. 42. In one embodiment, Salt III has one or more characteristic X-ray powder diffraction peaks at approximately 4.18, 4.71, 4.98, 5.61, 6.06, 6.41, 6.73, 7.14, 7.39, 8.01, 8.55, 8.78, 9.03, 9.73, 9.88, 10.72, 10.89, 11.76, 11.89, 12.48, 12.97, 13.29, 13.97, 14.54, 14.65, 15.18, 15.29, 16.35, 16.49, 17.01, 17.17, 18.09, 19.70, 21.78, 22.62, 23.13, 23.99, 24.44, 25.16, 25.44, 25.88, 27.37, 28.88, 29.93, 32.09, 34.55, 37.21, 40.15, 40.86 or 41.95° 2θas depicted in FIG. 42. In a specific embodiment, Salt III has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.71, 10.72, 10.89, 14.54, 14.65, 15.18, 15.29 or 16.35° 2θ. In another embodiment, Salt III has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.71, 14.54, 14.65 or 15.29° 2θ. In another embodiment, Salt III has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or fifty characteristic X-ray powder diffraction peaks as set forth in Table 40.

In certain embodiments, Salt III is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt III has an X-ray powder diffraction pattern substantially as shown in FIG. 42. In one embodiment, Salt III has one or more characteristic X-ray powder diffraction peaks at approximately 4.2, 4.7, 5.0, 5.6, 6.1, 6.4, 6.7, 7.1, 7.4, 8.0, 8.6, 8.8, 9.0, 9.7, 9.9, 10.7, 10.9, 11.8, 11.9, 12.5, 13.0, 13.3, 14.0, 14.5, 14.7, 15.2, 15.3, 16.4, 16.5, 17.0, 17.2, 18.1, 19.7, 21.8, 22.6, 23.1, 24.0, 24.4, 25.2, 25.4, 25.9, 27.4, 28.9, 29.9, 32.1, 34.6, 37.2, 40.2, 40.9 or 42.0° 2θas depicted in FIG. 42. In a specific embodiment, Salt III has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.7, 10.7, 10.9, 14.5, 14.6, 15.2, 15.3 or 16.4° 2θ. In another embodiment, Salt III has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.7, 14.5, 14.7 or 15.3° 2θ. In another embodiment, Salt III has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 4.7, 10.9, 14.5, 14.7, 15.2 or 15.3° 2θ. In another embodiment, Salt III has one, two or three characteristic X-ray powder diffraction peaks at approximately 14.5, 14.7 or 15.3° 2θ. In another embodiment, Salt III has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or fifty characteristic X-ray powder diffraction peaks as set forth in Table 40.

5.4.4 Monohydrate Mono-Sodium Salt of Compound 1 (Salt IV)

In one embodiment, provided herein is a sodium salt of Compound 1. In one embodiment, provided herein is a mono-sodium salt of Compound 1. In one embodiment, the mono-sodium salt is a hydrate. In one embodiment, the mono-sodium salt is a mono-hydrate (“Salt IV”). In one embodiment, Salt IV is crystalline. In one embodiment, Salt IV is moderately hydroscopic. In one embodiment, Salt IV is chemically stable. In one embodiment, Salt IV is a stable hydrate.

In certain embodiments, provided herein is a method for making Salt IV, comprising 1) dissolving Compound 1 in a solvent (e.g., acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 30-70° C.); 3) filtering the mixture at the elevated temperature to yield a solution; 4) contacting the mixture with a sodium hydroxide solution (e.g., about 0.5-1.5 equivalents); 5) cooling the resulting mixture (e.g., to about 10-30° C.); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the sodium hydroxide solution is a solution of sodium hydroxide in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In certain embodiments, provided herein is a method for making Salt IV, comprising 1) dissolving Compound 1 in a solvent (e.g., acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 50° C.); 3) filtering the mixture at the elevated temperature with a 0.45 μm syringe filter to yield a solution; 4) contacting the mixture with a sodium hydroxide solution (e.g., about 1 equivalent); 5) cooling the resulting mixture (e.g., to about 25° C.) (e.g., at a speed of about 20° C./hour); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the sodium hydroxide solution is a solution of sodium hydroxide in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In one embodiment, Salt IV has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 64. In one embodiment, Salt IV exhibits a TGA thermogram comprising a total mass loss of approximately 5% of the total mass of the sample between approximately 60° C. and approximately 120° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, Salt IV exhibits a TGA thermogram comprising a total mass loss of approximately 5.43% of the total mass of the sample between approximately 60° C. and approximately 120° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the TGA thermogram further comprises a decomposition event with onset temperature at approximately 302.5° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt IV has a DSC thermogram as depicted in FIG. 63 comprising an endothermic event with a maximum at approximately 107.9° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at approximately 217.2° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 307.4° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt IV is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt IV has an X-ray powder diffraction pattern substantially as shown in FIG. 43. In one embodiment, Salt IV has one or more characteristic X-ray powder diffraction peaks at approximately 3.18, 4.17, 4.78, 5.23, 5.62, 5.86, 5.93, 6.29, 6.44, 6.74, 7.43, 9.45, 9.66, 9.94, 10.63, 11.83, 12.03, 12.62, 13.24, 13.61, 14.57, 14.85, 15.05, 15.80, 16.17, 16.68, 16.98, 17.37, 18.31, 19.00, 19.43, 19.94, 20.72, 22.20, 22.69, 23.63, 24.22, 25.42, 26.01, 26.70, 27.54, 28.35, 28.67, 29.39, 31.24, 31.97, 32.69, 33.18, 34.29, 34.73, 35.82, 37.41, 37.84, 38.27, 38.67, 39.65, 40.64, 41.02, 41.48, 41.90, 42.80, 43.80, 44.32 or 44.59° 2θas depicted in FIG. 43. In a specific embodiment, Salt IV has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.18, 6.29, 9.45, 15.80, 16.17, 19.00, 19.43 or 25.42° 2θ. In another embodiment, Salt IV has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.18, 9.45, 15.80 or 19.00° 2θ. In another embodiment, Salt IV has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three or sixty-four characteristic X-ray powder diffraction peaks as set forth in Table 41.

In certain embodiments, Salt IV is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt IV has an X-ray powder diffraction pattern substantially as shown in FIG. 43. In one embodiment, Salt IV has one or more characteristic X-ray powder diffraction peaks at approximately 3.2, 4.2, 4.8, 5.2, 5.6, 5.9, 6.3, 6.4, 6.7, 7.4, 9.5, 9.7, 9.9, 10.6, 11.8, 12.0, 12.6, 13.2, 13.6, 14.6, 14.9, 15.1, 15.8, 16.2, 16.7, 17.0, 17.4, 18.3, 19.00, 19.4, 19.9, 20.7, 22.2, 22.7, 23.6, 24.2, 25.4, 26.0, 26.7, 27.5, 28.4, 28.7, 29.4, 31.2, 32.0, 32.7, 33.2, 34.3, 34.7, 35.8, 37.4, 37.8, 38.3, 38.7, 39.7, 40.6, 41.0, 41.5, 41.9, 42.8, 43.8, 44.3 or 44.6° 2θas depicted in FIG. 43. In a specific embodiment, Salt IV has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.2, 6.3, 9.5, 15.8, 16.2, 19.0, 19.4 or 25.4° 2θ. In another embodiment, Salt IV has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.2, 9.5, 15.8 or 19.0° 2θ. In another embodiment, Salt IV has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.2, 6.3, 9.5, 15.8, 19.0 or 19.4° 2θ. In another embodiment, Salt IV has one, two or three characteristic X-ray powder diffraction peaks at approximately 3.2, 9.5 or 19.0° 2θ. In another embodiment, Salt IV has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three or sixty-four characteristic X-ray powder diffraction peaks as set forth in Table 41.

5.4.5 Monohydrate Bis-Sodium Salt of Compound 1 (Salt V)

In one embodiment, provided herein is a sodium salt of Compound 1. In one embodiment, provided herein is a bis-sodium salt of Compound 1. In one embodiment, the bis-sodium salt is a hydrate. In one embodiment, the bis-sodium salt is a mono-hydrate (“Salt V”). In one embodiment, Salt V is crystalline. In one embodiment, Salt V is moderately hydroscopic. In one embodiment, Salt V is an unstable hydrate.

In certain embodiments, provided herein is a method for making Salt V, comprising 1) dissolving Compound 1 in a solvent (e.g., acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 30-70° C.); 3) filtering the mixture at the elevated temperature to yield a solution; 4) contacting the mixture with a sodium hydroxide solution (e.g., about 2-4 equivalents); 5) cooling the resulting mixture (e.g., to about 10-30° C.); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the sodium hydroxide solution is a solution of sodium hydroxide in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In certain embodiments, provided herein is a method for making Salt V, comprising 1) dissolving Compound 1 in a solvent (e.g., acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 50° C.); 3) filtering the mixture at the elevated temperature with a 0.45 μm syringe filter to yield a solution; 4) contacting the mixture with a sodium hydroxide solution (e.g., about 3 equivalents); 5) cooling the resulting mixture (e.g., to about 25° C.) (e.g., at a speed of about 20° C./hour); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the sodium hydroxide solution is a solution of sodium hydroxide in water, methanol or a mixture of methanol and water (e.g., about 1:1).

In one embodiment, Salt V has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 69. In one embodiment, Salt V exhibits a TGA thermogram comprising a total mass loss of approximately 5.85% of the total mass of the sample between approximately 40° C. and approximately 130° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the TGA thermogram further comprises a decomposition event with onset temperature at approximately 344.77° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt V has a DSC thermogram as depicted in FIG. 68 comprising an endothermic event with a maximum at approximately 93.3° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt V is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt V has an X-ray powder diffraction pattern substantially as shown in FIG. 44. In one embodiment, Salt V has one or more characteristic X-ray powder diffraction peaks at approximately 3.15, 3.33, 3.51, 3.65, 4.19, 4.45, 4.74, 5.09, 5.24, 5.40, 5.75, 6.00, 6.24, 6.43, 6.64, 7.29, 7.45, 7.58, 7.92, 8.57, 9.21, 9.39, 9.97, 13.02, 13.31, 13.64, 13.97, 16.69, 17.13, 17.65, 18.09, 18.65, 19.51, 20.06, 22.15, 22.50, 22.87, 23.41, 24.54, 25.01, 25.70, 26.29, 26.87, 27.81, 28.89, 29.06, 29.90, 30.29, 30.60, 31.08, 31.97, 32.21, 33.85, 34.24, 35.73, 37.31, 38.39, 39.71, 40.87, 42.01 or 44.30° 2θas depicted in FIG. 44. In a specific embodiment, Salt V has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.15, 9.97, 13.31, 13.64, 13.97, 16.69, 20.06 or 26.87° 2θ. In another embodiment, Salt V has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 9.97, 13.64, 13.97 or 16.69° 2θ. In another embodiment, Salt V has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty or sixty-one characteristic X-ray powder diffraction peaks as set forth in Table 42.

In certain embodiments, Salt V is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt V has an X-ray powder diffraction pattern substantially as shown in FIG. 44. In one embodiment, Salt V has one or more characteristic X-ray powder diffraction peaks at approximately 3.2, 3.3, 3.5, 3.7, 4.2, 4.5, 4.7, 5.1, 5.2, 5.4, 5.8, 6.0, 6.2, 6.4, 6.6, 7.3, 7.5, 7.6, 7.9, 8.6, 9.2, 9.4, 10.0, 13.0, 13.3, 13.6, 14.0, 16.7, 17.1, 17.7, 18.1, 18.7, 19.5, 20.1, 22.2, 22.5, 22.9, 23.4, 24.5, 25.0, 25.7, 26.3, 26.9, 27.8, 28.9, 29.1, 29.9, 30.3, 30.6, 31.1, 32.0, 32.2, 33.9, 34.2, 35.7, 37.3, 38.4, 39.7, 40.9, 42.0 or 44.3° 2θas depicted in FIG. 44. In a specific embodiment, Salt V has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.2, 10.0, 13.3, 13.6, 14.0, 16.7, 20.1 or 26.9° 2θ. In another embodiment, Salt V has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 10.0, 13.6, 14.0 or 16.7° 2θ. In another embodiment, Salt V has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.2, 10.0, 13.3, 13.6, 14.0 or 16.7° 2θ. In another embodiment, Salt V has one, two or three characteristic X-ray powder diffraction peaks at approximately 10.0, 13.6 or 16.7° 2θ. In another embodiment, Salt V has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty or sixty-one characteristic X-ray powder diffraction peaks as set forth in Table 42.

5.4.6 Anhydrous Mono-Sodium Salt of Compound 1 (Salt VI)

In one embodiment, provided herein is a sodium salt of Compound 1. In one embodiment, provided herein is a mono-sodium salt of Compound 1. In one embodiment, the mono-sodium salt is anhydrous (“Salt VI”). In one embodiment, Salt VI is crystalline. In one embodiment, Salt VI is slightly hydroscopic. In one embodiment, Salt VI is chemically stable.

In certain embodiments, provided herein is a method for making Salt VI, comprising 1) heating Salt IV of Compound 1 from a first temperature (e.g., about 160-200° C.) to a second temperature (e.g., about 240-280° C.) at a speed (e.g., about 10° C./minute); 2) holding the solid at the second temperature for a period of time (e.g., about 1-10 minutes); and 3) collecting the resulting solids.

In certain embodiments, provided herein is a method for making Salt VI, comprising 1) heating Salt IV of Compound 1 from a first temperature (e.g., about 180° C.) to a second temperature (e.g., about 260° C.) at a speed (e.g., about 10° C./minute); 2) holding the solid at the second temperature for a period of time (e.g., about 2 minutes); and 3) collecting the resulting solids.

In one embodiment, Salt VI has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 75. In one embodiment, Salt VI exhibits a TGA thermogram comprising a decomposition event with onset temperature at approximately 305.7° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt VI has a DSC thermogram as depicted in FIG. 74 comprising an endothermic event with a maximum at approximately 282.4° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at approximately 283.9° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 308.4° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt VI is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt VI has an X-ray powder diffraction pattern substantially as shown in FIG. 45. In one embodiment, Salt VI has one or more characteristic X-ray powder diffraction peaks at approximately 3.03, 3.39, 4.42, 4.63, 5.01, 5.40, 5.81, 6.23, 6.42, 7.06, 7.66, 8.96, 10.06, 10.68, 11.53, 11.89, 12.42, 13.40, 13.73, 14.04, 14.91, 15.22, 15.67, 16.33, 16.74, 17.10, 17.82, 18.11, 18.48, 19.07, 20.15, 20.94, 21.47, 22.05, 23.37, 24.03, 24.96, 26.38, 26.96, 28.88, 30.07, 31.04, 31.61, 33.20, 33.94, 34.87, 37.20, 38.13, 39.72, 40.29, 40.97, 42.35, 43.41 or 44.38° 2θas depicted in FIG. 45. In a specific embodiment, Salt VI has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.03, 3.39, 10.06, 11.89, 13.40, 15.22, 16.74 or 18.11° 2θ. In another embodiment, Salt VI has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.03, 3.39, 10.06 or 11.89° 2θ. In another embodiment, Salt VI has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or forty-four characteristic X-ray powder diffraction peaks as set forth in Table 43.

In certain embodiments, Salt VI is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt VI has an X-ray powder diffraction pattern substantially as shown in FIG. 45. In one embodiment, Salt VI has one or more characteristic X-ray powder diffraction peaks at approximately 3.0, 3.4, 4.4, 4.6, 5.0, 5.4, 5.8, 6.2, 6.4, 7.1, 7.7, 9.0, 10.1, 10.7, 11.5, 11.9, 12.4, 13.4, 13.7, 14.0, 14.9, 15.2, 15.7, 16.3, 16.7, 17.1, 17.8, 18.1, 18.5, 19.1, 20.2, 20.9, 21.5, 22.1, 23.4, 24.0, 25.0, 26.4, 27.0, 28.9, 30.1, 31.0, 31.6, 33.2, 33.9, 34.9, 37.2, 38.1, 39.7, 40.3, 41.0, 42.4, 43.4 or 44.4° 2θas depicted in FIG. 45. In a specific embodiment, Salt VI has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.0, 3.4, 10.1, 11.9, 13.4, 15.2, 16.7 or 18.1° 2θ. In another embodiment, Salt VI has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.0, 3.4, 10.1 or 11.9° 2θ. In another embodiment, Salt VI has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.0, 3.4, 10.1, 11.9, 16.7 or 18.1° 2θ. In another embodiment, Salt VI has one, two or three characteristic X-ray powder diffraction peaks at approximately 3.0, 3.4 or 10.1° 2θ. In another embodiment, Salt VI has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 or forty-four characteristic X-ray powder diffraction peaks as set forth in Table 43.

5.4.7 Hydrated Mono-Sodium Salt of Compound 1 (Salt VII)

In one embodiment, provided herein is a sodium salt of Compound 1. In one embodiment, provided herein is a mono-sodium salt of Compound 1. In one embodiment, the mono-sodium salt is a hydrate (“Salt VII”). In one embodiment, Salt VII is crystalline. In one embodiment, Salt VII is moderately hydroscopic. In one embodiment, Salt VII is chemically stable. In one embodiment, Salt VII is a stable hydrate.

In certain embodiments, provided herein is a method for making Salt VII, comprising 1) dissolving Compound 1 in a solvent (e.g., methanol) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 30-70° C.); 3) filtering the mixture at the elevated temperature to yield a solution; 4) contacting the mixture with a sodium hydroxide solution (e.g., about 0.5-1.5 equivalents); 5) cooling the resulting mixture (e.g., to about 10-30° C.); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the sodium hydroxide solution is a solution of sodium hydroxide in water, methanol or a mixture of methanol and water.

In certain embodiments, provided herein is a method for making Salt VII, comprising 1) dissolving Compound 1 in a solvent (e.g., methanol) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 50° C.); 3) filtering the mixture at the elevated temperature with a 0.45 μm syringe filter to yield a solution; 4) contacting the mixture with a sodium hydroxide solution (e.g., about 1 equivalent); 5) cooling the resulting mixture (e.g., to about 25° C.) (e.g., at a speed of about 20° C./hour); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the sodium hydroxide solution is a solution of sodium hydroxide in water, methanol or a mixture of methanol and water.

In one embodiment, Salt VII has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 87. In one embodiment, the TGA thermogram comprises a decomposition event with onset temperature at approximately 290.6° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt VII has a DSC thermogram as depicted in FIG. 86 comprising a broad transition event before approximately 90° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises a glass transition event at approximately 160° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt VII is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt VII has an X-ray powder diffraction pattern substantially as shown in FIG. 43. In one embodiment, Salt VII has one or more characteristic X-ray powder diffraction peaks at approximately 3.40, 3.71, 4.08, 4.31, 4.95, 5.07, 5.33, 5.59, 6.11, 6.55, 6.95, 7.27, 7.60, 7.79, 8.49, 8.62, 9.54, 9.96, 10.87, 11.53, 11.88, 12.53, 12.78, 13.28, 13.64, 13.97, 14.31, 14.90, 15.48, 15.73, 16.37, 16.66, 18.02, 18.68, 20.03, 20.76, 20.96, 21.58, 22.15, 24.89, 25.46, 25.82, 26.83, 28.73, 29.35, 31.10, 32.28, 32.84, 33.75, 34.30, 37.27, 38.29, 38.86, 39.67, 40.80 or 44.33° 2θas depicted in FIG. 43. In a specific embodiment, Salt VII has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.40, 3.71, 9.96, 10.87, 14.90, 15.48, 15.73 or 16.66° 2θ. In another embodiment, Salt VII has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.40, 9.96, 14.90 or 16.66° 2θ. In another embodiment, Salt VII has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, or fifty-six characteristic X-ray powder diffraction peaks as set forth in Table 44.

In certain embodiments, Salt VII is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt VII has an X-ray powder diffraction pattern substantially as shown in FIG. 43. In one embodiment, Salt VII has one or more characteristic X-ray powder diffraction peaks at approximately 3.4, 3.7, 4.1, 4.3, 5.0, 5.1, 5.3, 5.6, 6.1, 6.6, 7.0, 7.3, 7.6, 7.8, 8.5, 8.6, 9.5, 10.0, 10.9, 11.5, 11.9, 12.5, 12.8, 13.3, 13.6, 14.0, 14.3, 14.9, 15.5, 15.7, 16.4, 16.7, 18.0, 18.7, 20.0, 20.8, 21.0, 21.6, 22.2, 24.9, 25.5, 25.8, 26.8, 28.7, 29.4, 31.1, 32.3, 32.8, 33.8, 34.3, 37.3, 38.3, 38.9, 39.7, 40.8 or 44.3° 2θas depicted in FIG. 43. In a specific embodiment, Salt VII has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.4, 3.7, 10.0, 10.9, 14.9, 15.5, 15.7 or 16.7° 2θ. In another embodiment, Salt VII has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.4, 10.0, 14.9 or 16.7° 2θ. In another embodiment, Salt VII has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.4, 10.0, 10.9, 14.9, 15.5 or 16.7° 2θ. In another embodiment, Salt VII has one, two or three characteristic X-ray powder diffraction peaks at approximately 3.4, 10.0 or 14.9° 2θ. In another embodiment, Salt VII has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, or fifty-six characteristic X-ray powder diffraction peaks as set forth in Table 44.

5.4.8 Anhydrous Mono-Sodium Salt of Compound 1 (Salt VIII)

In one embodiment, provided herein is a sodium salt of Compound 1. In one embodiment, provided herein is a mono-sodium salt of Compound 1. In one embodiment, the mono-sodium salt is anhydrous (“Salt VIII”). In one embodiment, Salt VIII is crystalline. In one embodiment, Salt VIII is moderately hydroscopic. In one embodiment, Salt VIII is chemically stable.

In certain embodiments, provided herein is a method for making Salt VIII, comprising 1) stirring Salt IV of Compound 1 in a solvent (e.g., methanol) for a period of time (e.g., about 12 hours to about 48 hours) at a temperature (e.g., about 5° C. to about 45° C.); 2) collecting precipitation by filtration; and 3) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid.

In certain embodiments, provided herein is a method for making Salt VIII, comprising 1) stirring Salt IV of Compound 1 in a solvent (e.g., methanol) for a period of time (e.g., about 24 hours) at a temperature (e.g., about 25° C.); 2) collecting precipitation by filtration; and 3) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid.

In one embodiment, Salt VIII has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 94. In one embodiment, the TGA thermogram comprises a decomposition event with onset temperature at approximately 291.2° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt VIII has a DSC thermogram as depicted in FIG. 93 comprising a decomposition event with onset temperature at approximately 294.0° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt VIII is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt VIII has an X-ray powder diffraction pattern substantially as shown in FIG. 91. In one embodiment, Salt VIII has one or more characteristic X-ray powder diffraction peaks at approximately 3.06, 3.39, 3.64, 3.79, 3.95, 4.54, 4.94, 5.07, 5.21, 5.40, 6.02, 6.27, 6.65, 7.18, 8.00, 8.37, 9.32, 10.00, 10.43, 11.04, 11.94, 12.72, 13.01, 13.71, 13.97, 14.66, 15.01, 15.65, 15.73, 16.34, 16.69, 17.14, 17.37, 18.31, 18.91, 19.57, 20.13, 22.17, 24.68, 25.02, 26.92, 28.96, 29.53, 31.12, 32.42, 33.47, 33.76, 34.58, 35.75, 37.25, 39.65, 40.87, 42.36, 43.42 or 44.34° 2θas depicted in FIG. 91. In a specific embodiment, Salt VIII has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.06, 3.39, 3.64, 13.71, 13.97, 15.01, 15.65 or 15.73° 2θ. In another embodiment, Salt VIII has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.06, 3.39, 15.01 or 15.65° 2θ. In another embodiment, Salt VIII has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four or fifty-five characteristic X-ray powder diffraction peaks as set forth in Table 45.

In certain embodiments, Salt VIII is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt VIII has an X-ray powder diffraction pattern substantially as shown in FIG. 91. In one embodiment, Salt VIII has one or more characteristic X-ray powder diffraction peaks at approximately 3.1, 3.4, 3.6, 3.8, 4.0, 4.5, 4.9, 5.1, 5.2, 5.4, 6.0, 6.3, 6.7, 7.2, 8.0, 8.4, 9.3, 10.0, 10.4, 11.0, 11.9, 12.7, 13.0, 13.7, 14.0, 14.7, 15.0, 15.7, 15.7, 16.3, 16.7, 17.1, 17.4, 18.3, 18.9, 19.6, 20.1, 22.2, 24.7, 25.0, 26.9, 29.0, 29.5, 31.1, 32.4, 33.5, 33.8, 34.6, 35.8, 37.3, 39.7, 40.9, 42.4, 43.4 or 44.3° 2θas depicted in FIG. 91. In a specific embodiment, Salt VIII has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.1, 3.4, 3.6, 13.7, 14.0, 15.0, 15.7 or 15.7° 2θ. In another embodiment, Salt VIII has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.1, 3.4, 15.0 or 15.7° 2θ. In another embodiment, Salt VIII has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.1, 3.4, 13.7, 15.0, 15.6 or 15.7° 2θ. In another embodiment, Salt VIII has one, two or three characteristic X-ray powder diffraction peaks at approximately 3.1, 3.4 or 15.0° 2θ. In another embodiment, Salt VIII has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four or fifty-five characteristic X-ray powder diffraction peaks as set forth in Table 45.

5.4.9 Anhydrous Mono-Sodium Salt of Compound 1 (Salt IX)

In one embodiment, provided herein is a sodium salt of Compound 1. In one embodiment, provided herein is a mono-sodium salt of Compound 1. In one embodiment, the mono-sodium salt is anhydrous (“Salt IX”). In one embodiment, Salt IX is crystalline. In one embodiment, Salt IX is moderately hydroscopic. In one embodiment, Salt IX is chemically stable.

In certain embodiments, provided herein is a method for making Salt IX, comprising 1) dissolving Compound 1 in a solvent (e.g., acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 30-70° C.); 3) filtering the mixture at the elevated temperature to yield a solution; 4) contacting the mixture with a sodium hydroxide solution (e.g., about 0.5-1.5 equivalents); 5) cooling the resulting mixture (e.g., to about 10-30° C.); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the sodium hydroxide solution is a solution of sodium hydroxide in water, acetone or a mixture of acetone and water.

In certain embodiments, provided herein is a method for making Salt IX, comprising 1) dissolving Compound 1 in a solvent (e.g., acetone) to yield a mixture; 2) heating the mixture to an elevated temperature (e.g., about 50° C.); 3) filtering the mixture at the elevated temperature with a 0.45 μm syringe filter to yield a solution; 4) contacting the mixture with a sodium hydroxide solution (e.g., about 1 equivalent); 5) cooling the resulting mixture (e.g., to about 25° C.) (e.g., at a speed of about 20° C./hour); 6) collecting precipitation by filtration; and 7) in the absence of precipitation, evaporating the solution to yield a solid and collecting the solid. In one embodiment, the sodium hydroxide solution is a solution of sodium hydroxide in water, acetone or a mixture of acetone and water.

In one embodiment, Salt IX has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 101. In one embodiment, the TGA thermogram comprises a decomposition event with onset temperature at approximately 301.8° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt IX has a DSC thermogram as depicted in FIG. 100 comprising an endothermic event with a maximum at approximately 82.8° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at approximately 229.5° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt IX is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt IX has an X-ray powder diffraction pattern substantially as shown in FIG. 98. In one embodiment, Salt IX has one or more characteristic X-ray powder diffraction peaks at approximately 3.05, 3.19, 4.33, 4.57, 5.11, 5.25, 5.71, 6.32, 7.68, 7.88, 9.47, 9.93, 10.04, 12.63, 13.06, 13.69, 14.01, 14.89, 15.83, 16.31, 16.68, 17.39, 18.33, 19.01, 19.94, 20.72, 20.88, 22.12, 22.27, 22.60, 23.58, 24.21, 24.69, 25.47, 26.26, 26.62, 27.63, 28.42, 28.73, 29.44, 31.25, 31.90, 32.51, 33.23, 34.35, 35.85, 37.39, 38.30, 39.79, 40.61, 41.44, 41.96 or 44.56° 2θas depicted in FIG. 98. In a specific embodiment, Salt IX has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.05, 3.19, 6.32, 9.47, 13.69, 15.83, 19.01 or 25.47° 2θ. In another embodiment, Salt IX has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.05, 3.19, 9.47 or 19.01° 2θ. In another embodiment, Salt IX has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 characteristic X-ray powder diffraction peaks as set forth in Table 46.

In certain embodiments, Salt IX is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt IX has an X-ray powder diffraction pattern substantially as shown in FIG. 98. In one embodiment, Salt IX has one or more characteristic X-ray powder diffraction peaks at approximately 3.1, 3.2, 4.3, 4.6, 5.1, 5.3, 5.7, 6.3, 7.7, 7.9, 9.5, 9.9, 10.0, 12.6, 13.1, 13.7, 14.0, 14.9, 15.8, 16.3, 16.7, 17.4, 18.3, 19.0, 19.9, 20.7, 20.9, 22.1, 22.3, 22.6, 23.6, 24.2, 24.7, 25.5, 26.3, 26.6, 27.6, 28.4, 28.7, 29.4, 31.3, 31.9, 32.5, 33.2, 34.4, 35.9, 37.4, 38.3, 39.8, 40.6, 41.4, 42.0 or 44.6° 2θas depicted in FIG. 98. In a specific embodiment, Salt IX has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.1, 3.2, 6.3, 9.5, 13.7, 15.8, 19.0 or 25.5° 2θ. In another embodiment, Salt IX has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.1, 3.2, 9.5 or 19.0° 2θ. In another embodiment, Salt IX has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.1, 3.2, 6.3, 9.5, 15.8 or 19.0° 2θ. In another embodiment, Salt IX has one, two or three characteristic X-ray powder diffraction peaks at approximately 3.2, 9.5 or 19.0° 2θ. In another embodiment, Salt IX has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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 characteristic X-ray powder diffraction peaks as set forth in Table 46.

5.4.10 Hydrated Mono-Sodium Salt of Compound 1 (Salt X)

In one embodiment, provided herein is a sodium salt of Compound 1. In one embodiment, provided herein is a mono-sodium salt of Compound 1. In one embodiment, the mono-sodium salt is a hydrate (“Salt X”). In one embodiment, Salt X is crystalline. In one embodiment, Salt X is moderately hydroscopic. In one embodiment, Salt X is chemically unstable. In one embodiment, Salt X is an unstable hydrate.

In one embodiment, provided herein are methods for preparing Salt X of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Salt IV of Compound 1 (e.g., about 100-300 mg) with a minimum amount of solvents (e.g., up to 7.0 mL) at a first temperature (e.g., about 50 or 70° C.); (2) adding a co-solvent (e.g., about 5-25 mL); (3) placing the solution at a second temperature (e.g., about 15-35° C.) for a period of time (e.g., about 12-48 hours); and (4) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 47). In certain embodiments, the solvent is water. In certain embodiments, the co-solvent is THF.

In one embodiment, provided herein are methods for preparing Salt X of Compound 1 comprising binary solvent fast cooling crystallization comprising the steps of: (1) dissolving Salt IV of Compound 1 (e.g., about 168 mg) with a minimum amount of solvents (e.g., about 4.3 mL) at a first temperature (e.g., about 60° C.); (2) adding a co-solvent (e.g., about 12.8 mL); (3) placing the solution at a second temperature (e.g., about 25° C.) for a period of time (e.g., about 24 hours); and (4) evaporating the samples without precipitation to dryness (e.g., evaporating under a gentle stream of nitrogen gas) and collecting the resulting solids. All obtained solids were analyzed by XRPD to determine the solid form (see Table 47). In certain embodiments, the solvent is water. In certain embodiments, the co-solvent is THF.

In one embodiment, Salt X has a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 108. In one embodiment, Salt X exhibits a TGA thermogram comprising a total mass loss of approximately 1.3% of the total mass of the sample between approximately 60° C. and approximately 120° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, Salt X exhibits a TGA thermogram comprising a total mass loss of approximately 2.3% of the total mass of the sample between approximately 120° C. and approximately 180° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the TGA thermogram further comprises a decomposition event with onset temperature at approximately 296.7° C. when heated from approximately 25° C. to approximately 350° C.

In one embodiment, Salt IX has a DSC thermogram as depicted in FIG. 107 comprising an endothermic event with a maximum at approximately 91.3° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at approximately 149.3° C. when heated from approximately 25° C. to approximately 350° C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at approximately 230.6° C. when heated from approximately 25° C. to approximately 350° C.

In certain embodiments, Salt X is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt X has an X-ray powder diffraction pattern substantially as shown in FIG. 105. In one embodiment, Salt X has one or more characteristic X-ray powder diffraction peaks at approximately 3.20, 3.74, 4.11, 4.23, 4.36, 4.59, 4.78, 5.03, 5.22, 5.43, 5.62, 5.88, 6.06, 6.28, 6.76, 7.24, 7.41, 7.83, 8.01, 9.50, 10.37, 11.01, 11.15, 11.38, 12.12, 12.75, 13.58, 14.37, 14.87, 15.06, 15.41, 15.78, 16.65, 18.71, 19.70, 20.35, 20.88, 22.16, 22.49, 23.83, 24.73, 25.62, 26.38, 27.11, 28.71, 29.79, 30.65, 31.15, 32.80, 34.52, 35.81, 37.64, 38.77, 41.35, 42.26, 43.70 or 44.25° 2θas depicted in FIG. 105. In a specific embodiment, Salt X has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.20, 3.74, 15.41, 18.71, 19.70, 22.16, 23.83 or 25.62° 2θ. In another embodiment, Salt X has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.20, 3.74, 15.41 or 25.62° 2θ. In another embodiment, Salt X has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three or sixty-four characteristic X-ray powder diffraction peaks as set forth in Table 47.

In certain embodiments, Salt X is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Salt X has an X-ray powder diffraction pattern substantially as shown in FIG. 105. In one embodiment, Salt X has one or more characteristic X-ray powder diffraction peaks at approximately 3.2, 3.7, 4.1, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.9, 6.1, 6.3, 6.8, 7.2, 7.4, 7.8, 8.0, 9.5, 10.4, 11.0, 11.2, 11.4, 12.1, 12.8, 13.6, 14.4, 14.9, 15.0, 15.4, 15.8, 16.7, 18.7, 19.7, 20.4, 20.9, 22.1, 22.5, 23.8, 24.7, 25.6, 26.4, 27.1, 28.7, 29.8, 30.7, 31.2, 32.8, 34.5, 35.8, 37.6, 38.8, 41.4, 42.3, 43.7 or 44.3° 2θas depicted in FIG. 105. In a specific embodiment, Salt X has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.2, 3.7, 15.4, 18.7, 19.7, 22.2, 23.8 or 25.6° 2θ. In another embodiment, Salt X has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.2, 3.7, 15.4 or 25.6° 2θ. In another embodiment, Salt X has one, two, three, four, five or six characteristic X-ray powder diffraction peaks at approximately 3.2, 3.7, 15.4, 18.7, 23.8 or 25.6° 2θ. In another embodiment, Salt X has one, two or three characteristic X-ray powder diffraction peaks at approximately 3.2, 3.7 or 25.6° 2θ. In another embodiment, Salt X has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, 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, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, fifty-eight, fifty-nine, sixty, sixty-one, sixty-two, sixty-three or sixty-four characteristic X-ray powder diffraction peaks as set forth in Table 47.

5.5 Methods for Making Compound 1

By way of example and not limitation, Compound 1 can be prepared as outlined in Scheme 1, as well as in the examples set forth herein.

Provided are methods of preparing Compound 1

comprising contacting compound 10

with an acid (e.g., aq. HCl) in a solvent (e.g., tetrahydrofuran (THF), water or a mixture of THF and water) at about 10° C. to about 35° C. In one embodiment, the solvent is THF, water or a mixture thereof. In one embodiment, the acid is 37% HCl aqueous solution. In one embodiment, the contacting proceeds at about 22° C. In one embodiment, the contacting lasts for about 15 minutes to about 2 hours.

Also provided are methods of preparing compound 10

comprising contacting a mixture of compound 8 and compound 9

with a base (e.g., NaOH) in a solvent (e.g., tetrahydrofuran (THF), water or THF/water) at about 10° C. to about 35° C. In some embodiments, the solvent is THF, water or a mixture thereof. In one embodiment, the base is NaOH. In one embodiment, the contacting proceeds at about 22° C. In one embodiment, the contacting lasts for about 1 hour to about 5 hours.

Also provided are methods of preparing a mixture of compound 8 and compound 9

comprising contacting compound 7

with glycine methyl ester HCl salt in a solvent (e.g., tetrahydrofuran (THF)) in the presence of a base (e.g., diisopropylethylamine) at about 10° C. to about 35° C. In some embodiments, the solvent is THF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the contacting proceeds at about 22° C. In one embodiment, the contacting lasts for about 4 hours to about 16 hours.

Also provided are methods of preparing compound 7

comprising contacting compound 6

with trimethylacetyl chloride in a solvent (e.g., tetrahydrofuran (THF)) in the presence of a base (e.g., diisopropylethylamine) at about −10° C. to about 10° C. In some embodiments, the solvent is THF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the contacting proceeds at about 3° C. In one embodiment, the contacting lasts for about 1 hours to about 3 hours.

Also provided are methods of preparing compound 6

comprising contacting compound 5

with an acid (e.g., 37% HCl aqueous solution) in a solvent (e.g., water) at about 60° C. to about 110° C. In one embodiment, the acid is 37% HCl aqueous solution. In one embodiment, the contacting proceeds at about 100° C. In one embodiment, the contacting lasts for about 10 hours to about 60 hours.

Also provided are methods of preparing compound 5

comprising contacting compound 4

with a methoxide (e.g., sodium methoxide) in a solvent (e.g., methanol) at about 50° C. to about 90° C. In one embodiment, the methoxide is sodium methoxide. In one embodiment, the solvent is methanol. In one embodiment, the contacting proceeds at about 68° C. In one embodiment, the contacting lasts for about 6 hours to about 36 hours.

Also provided are methods of preparing compound 4

comprising contacting compound 2

with (3-fluorophenyl)boronic acid and a catalyst (e.g., DCM adduct PdCl2(dppf) and PdCl2(dppf)) in a solvent (e.g., DMF, water or DMF/water) in the presence of a base (e.g., potassium carbonate) at about 25° C. to about 75° C. In certain embodiments, the catalyst is DCM adduct PdCl2(dppf) or PdCl2(dppf). In some embodiments, the solvent is DMF, water or a mixture thereof. In some embodiments, the base is potassium carbonate. In one embodiment, the contacting proceeds at about 50° C. In one embodiment, the contacting lasts for about 6 hours to about 36 hours.

5.6 Methods of Use

Provided herein are methods for treating or preventing cancer, comprising administering an effective amount of a solid form of Compound 1 to a patient having cancer.

Further provided herein are methods for preventing metastasis of malignant tumors or other cancerous cells, comprising administering an effective amount of a solid form of Compound 1 to a patient having a malignant tumor or cancerous cells.

Further provided herein are methods for reducing the rate of tumor growth or cancer cell growth, comprising administering an effective amount of a solid form of Compound 1 to a patient having a malignant tumor or cancerous cells.

Further provided herein are methods for decreasing tumor angiogenesis, comprising administering an effective amount of a solid form of Compound 1 to a patient having cancer.

Further provided herein are methods for stabilizing hypoxia inducible factor-2 alpha (HIF-2a), comprising administering an effective amount of a solid form of Compound 1 to a patient in need thereof.

Further provided herein are methods for decreasing vascular endothelial growth factor (VEGF) in a cell in vitro, in vivo or ex vivo, by inhibiting the binding of VEGF to vascular endothelial growth factor receptors (VEGFRs), comprising contacting the cell with an effective amount of a solid form of Compound 1. In one embodiment, the cell is a cancer cell. In another embodiment, the cell is a human cell. In as still further embodiment, the cell is a human cancer cell.

Further provided herein are methods for increasing secretion of soluble vascular endothelial growth factor receptor-1 (sVEGF-1) from a cell in vitro, in vivo or ex vivo, comprising contacting the cell with an effective amount of a solid form of Compound 1. In one embodiment, the cell is a tumor associated cell. In another embodiment, the cell is a human tumor associated cell. In as still further embodiment, the cell is a human cancer cell.

Further provided herein are methods for the treatment or prevention of cancer treatable or preventable by decreasing vascular endothelial growth factor (VEGF), comprising administering an effective amount of a solid form of Compound 1 to a patient having cancer treatable or preventable by decreasing VEGF.

Further provided herein are methods for the treatment or prevention of cancer treatable or preventable by increasing secretion of soluble vascular endothelial growth factor receptor-1 (sVEGF-1), comprising administering effective amount of a solid form of Compound 1 to a patient having cancer treatable or preventable by increasing sVEGF-1.

Further provided herein are methods for the treatment or prevention of cancer treatable or preventable by stabilizing hypoxia inducible factor-2 alpha (HIF-2a), comprising administering an effective amount of a solid form of Compound 1 to a patient having cancer treatable or preventable by stabilizing HIF-2a.

Further provided are methods for controlling, inhibiting or decreasing tumor growth in a patient, comprising administering effective amount of a solid form of Compound 1 to a patient having a tumor.

Further provided herein is the use of a solid form of Compound 1 for making a medicament for treating cancer.

Further provided herein is the use of a solid form of Compound 1 for making a medicament for the uses provided herein.

Provided herein is the use of a solid form of Compound 1 for treating or preventing cancer.

Further provided herein is the use of a solid form of Compound 1 for preventing metastasis of malignant tumors or other cancerous cells and for slowing tumor growth.

Further still provided herein is the use of a solid form of Compound 1 for decreasing tumor angiogenesis.

Further provided herein are methods for treating or preventing cancer, comprising administering to a patient having cancer an effective amount of a solid form of Compound 1 and an effective amount of one or more chemotherapeutic agents, wherein a solid form of Compound 1 and the one or more chemotherapeutic agents are administered in any order. Non-limiting examples of chemotherapeutic agents include taxol, IL-2, gemcitabine, erlotinib, doxil, irinortecan, and bevacizumab.

Further provided herein are methods for preventing metastasis of cancer cells, comprising administering to a patient having cancer an effective amount of a solid form of Compound 1 and an effective amount of one or more chemotherapeutic agents, wherein a solid form of Compound 1 and the one or more chemotherapeutic agents are administered in any order. Non-limiting examples of chemotherapeutic agents include taxol, IL-2, gemcitabine, erlotinib, doxil, irinortecan, and bevacizumab.

Further provided herein are methods for treating a patient diagnosed with cancer, comprising administering to a patient diagnosed with cancer an effective amount of a solid form of Compound 1 and an effective amount of one or more chemotherapeutic agents, wherein a solid form of Compound 1 and the one or more chemotherapeutic agents are administered in any order. Non-limiting examples of chemotherapeutic agents include taxol, IL-2, gemcitabine, erlotinib, doxil, irinortecan, and bevacizumab.

The following are non-limiting examples of cancers that can be treated by the disclosed methods and compositions: Acute Lymphoblastic; Acute Myeloid Leukemia; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; Appendix Cancer; Basal Cell Carcinoma; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer; Osteosarcoma and Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Childhood; Central Nervous System Embryonal Tumors; Cerebellar Astrocytoma; Cerebral Astrocytoma/Malignant Glioma; Craniopharyngioma; Ependymoblastoma; Ependymoma; Medulloblastoma; Medulloepithelioma; Pineal Parenchymal Tumors of Intermediate Differentiation; Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma; Visual Pathway and Hypothalamic Glioma; Brain and Spinal Cord Tumors; Breast Cancer; Bronchial Tumors; Burkitt Lymphoma; Carcinoid Tumor; Carcinoid Tumor, Gastrointestinal; Central Nervous System Atypical Teratoid/Rhabdoid Tumor; Central Nervous System Embryonal Tumors; Central Nervous System Lymphoma; Cerebellar Astrocytoma; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Chordoma, Childhood; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Colon Cancer; Colorectal Cancer; Craniopharyngioma; Cutaneous T-Cell Lymphoma; Esophageal Cancer; Ewing Family of Tumors; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Gastrointestinal Stromal Tumor (GIST); Germ Cell Tumor, Extracranial; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma; Glioma, Childhood Brain Stem; Glioma, Childhood Cerebral Astrocytoma; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer; Histiocytosis, Langerhans Cell; Hodgkin Lymphoma; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma; Intraocular Melanoma; Islet Cell Tumors; Kidney (Renal Cell) Cancer; Langerhans Cell Histiocytosis; Laryngeal Cancer; Leukemia, Acute Lymphoblastic; Leukemia, Acute Myeloid; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer; Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoma, AIDS-Related; Lymphoma, Burkitt; Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin; Lymphoma, Non-Hodgkin; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom; Malignant Fibrous Histiocytoma of Bone and Osteosarcoma; Medulloblastoma; Melanoma; Melanoma, Intraocular (Eye); Merkel Cell Carcinoma; Mesothelioma; Metastatic Squamous Neck Cancer with Occult Primary; Mouth Cancer; Multiple Endocrine Neoplasia Syndrome, (Childhood); Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelodysplastic/:Myeloproliferative Diseases; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Small Cell Lung Cancer; Oral Cancer; Oral Cavity Cancer; Oropharyngeal Cancer; Osteosarcoma and Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Islet Cell Tumors; Papillomatosis; Parathyroid Cancer; Penile Cancer; Pharyngeal Cancer; Pheochromocytoma; Pineal Parenchymal Tumors of Intermediate Differentiation; Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Primary Central Nervous System Lymphoma; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer; Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15; Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; Sarcoma, Ewing Family of Tumors; Sarcoma, Kaposi; Sarcoma, Soft Tissue; Sarcoma, Uterine; Sezary Syndrome; Skin Cancer (Nonmelanoma); Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma, Cutaneous; Testicular Cancer; Throat Cancer; Thymoma and Thymic Carcinoma; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sarcoma; Vaginal Cancer; Vulvar Cancer; Waldenstrom Macroglobulinemia; and Wilms Tumor.

The cancer can be any cancer described herein, including VEGF-dependent cancers.

In certain embodiments, provided herein are methods of treating and/or preventing conditions of the eye wherein the methods comprise administering to a subject in need of treatment and/or prevention a solid form of Compound 1. Illustrative conditions of the eye include, but are not limited to, retinopathy (including diabetic retinopathy), radiation retinopathy, macular degeneration, age-related macular degeneration (including early, intermediate, and advanced stage age-related macular degeneration), Wet (exudative) age-related macular degeneration, specific genotypes associated with macular degeneration, cancer, solid or blood borne tumors, choroidal melanoma, sickle cell retinopathy, neovascularization, ocular neovascularization, subretinal neovascularization, vein occlusion, retinopathy of prematurity, chronic uveitis/vitritis, ocular trauma, ocular ischemia, retinal ischemia, Best's disease, chronic retinal detachment, diseases associated with rubeosis, Eales' disease proliferative vitreoretinopathy, familial exudative vitreoretinopathy, Stargardt's disease, presumed ocular histoplasmosis, hyperviscosity syndromes, myopia, post-laser complications, retinopathy of prematurity, infections causing a retinitis or choroiditis, optic pits, pars planitis, toxoplasmosis, choroidal neovascularization (including Type 1, 2, and 3 choroidal neovascularization), macular edema, cystoid macular edema, diabetic macular edema, ocular edema, glaucoma, neovascular glaucoma, surgery-induced edema, surgery-induced neovascularization, retinoschisis, retinal capillary occlusions, retinal angiomatous proliferation, vitreous hemorrhage, retinal neovascularization, polypoidal choroidal vasculopathy (juxtafoveal and subfovial), vitreomacular adhesion, geographic atrophy, retinal hypoxia, pathological myopia, dysregulated para-inflammation, chronic inflammation, chronic wound healing environment in the aging eye, carotid vacernous fistula, idiopathic occlusive arteriolitis, birdshot retinochoroidopathy, retinal vasculitis, incontinentia pigmenti, retinitis pigmentosa, tachyphylaxis, and limbal stem cell deficiency.

5.7 Pharmaceutical Compositions

Pharmaceutical compositions may be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms provided herein comprise a solid form of Compound 1.

In certain embodiment, pharmaceutical compositions and dosage forms comprise a solid form of Compound 1 and one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water.

Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25 NF20 (2002). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. In one embodiment, lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are, in one embodiment, packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.

5.7.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, suspensions and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in which case solid excipients are employed. In another embodiment, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.

Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM. Other suitable forms of microcrystalline cellulose include, but are not limited to, silicified microcrystalline cellulose, such as the materials sold as PROSOLV 50, PROSOLV 90, PROSOLV HD90, PROSOLV 90 LM, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. The binder or filler in pharmaceutical compositions is, in another embodiment, present in from about 20 to about 30 weight percent of the pharmaceutical composition or dosage form. The binder or filler in pharmaceutical compositions is, in another embodiment, present in about 24 weight percent of the pharmaceutical composition or dosage form.

In certain embodiments, fillers may include, but are not limited to block copolymers of ethylene oxide and propylene oxide. Such block copolymers may be sold as POLOXAMER or PLURONIC, and include, but are not limited to POLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and mixtures thereof. In certain embodiments, POLOXAMER or PLURONIC, including, but not limited to POLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and mixtures thereof, are surfactants.

In certain embodiments, fillers may include, but are not limited to isomalt, lactose, lactitol, mannitol, sorbitol xylitol, erythritol, and mixtures thereof.

Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one embodiment, pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, or from about 5 to about 9 weight percent of disintegrant, or from about 1 to about 5 weight percent of disintegrant, or from about 1 to about 7 weight percent of disintegrant, or about 7 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

Glidants and/or lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional glidants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic colloidal silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, glidants and/or lubricants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

In certain embodiments, an oral dosage form comprises the compound, silicified microcrystalline cellulose, sodium starch glycolate, a block copolymer of ethylene oxide and propylene oxide, sodium stearyl fumarate and colloidal silicon dioxide. In certain embodiments, an oral dosage form comprises a solid form of Compound 1 in an amount of about 5% to about 75% by weight, silicified microcrystalline cellulose in an amount of about 15% to about 85%, sodium starch glycolate in an amount of about 2% to about 10%, block copolymer of ethylene oxide and propylene oxide in an amount of about 2% to about 10%, sodium stearyl fumarate in an amount of 0.2% to about 2%, and colloidal silicon dioxide in an amount of about 0.2% to about 2% by weight of the oral dosage form.

In certain embodiments, an oral dosage form comprises the solid form of Compound 1, microcrystalline cellulose, isomalt, sodium starch glycolate, sodium lauryl sulfate, povidone, colloidal silicon dioxide, and magnesium stearate. In certain embodiments, an oral dosage form comprises a solid form of Compound 1 in an amount of about 40% to about 50%, microcrystalline cellulose in an amount of about 40% to about 50%, isomalt in an amount of 0% to about 5%, sodium starch glycolate in an amount of about 5% to about 10%, sodium lauryl sulfate in an amount of 0.2% to about 2%, povidone in an amount of about 2% to about 10%, colloidal silicon dioxide in an amount of 0.1% to about 1%, and magnesium stearate in an amount of about 0.1% to about 1% by weight of the oral dosage form.

In certain embodiments, the invention relates to unit dosage forms that comprise between about 100 mg and about 1,200 mg, about 200 mg and about 1,000 mg, about 400 mg and about 800 mg, or about 450 mg and about 600 mg of a solid form of Compound 1.

In certain embodiments, the invention relates to unit dosage forms that comprise about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150, or even about 1,200 mg of a solid form of Compound 1. In certain such embodiments, the unit dosage form is a capsule comprising about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 250 mg, or about 400 mg of a solid form of Compound 1.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active inhibitor(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

6. EXAMPLES

The following examples are presented by way of illustration, not limitation. The following abbreviations are used in descriptions and examples:

ACN: Acetonitrile

AUC: Area under the curve

CI: Counter Ion

DMF: N,N-Dimethylformide

DMSO: Dimethylsulfoxide

DSC: Differential Scanning Calorimetry

DVS: Dynamic Vapor Sorption

EtOH: Ethanol

Evp: Evaporation

HPLC: High performance liquid chromatography

IC: Ion Chromatography

IPA: 2-Propanol

IPAc: Isopropyl Acetate

LCMS: Liquid Chromatography with Mass Spectroscopy

MEK: Methyl Ethyl Ketone

MeCN: Acetonitrile

MeOH: Methanol

MIBK: Methyl isoButyl Ketone

mp: Melting point

MS: Mass spectrometry

MTBE: tert-Butyl methyl ether

NMP: N-Methyl-2-pyrrolidone

NMR: Nuclear magnetic resonance

ppt: Precipitation

RH: Relative Humidity

RT: Room Temperature

SM: Compound 1

TGA: Thermogravimetric Analysis

THF: Tetrahydrofuran

XRPD: X-Ray Powder Diffraction

6.1 Summary of Polymorph Screen of Compound 1

Eight unique crystal forms (Forms A, B, C, D, E, F, G, and H) were prepared in the polymorph screen, including single solvent and binary solvent crystallization experiments, based on XRPD analysis. The characterization data indicated that Form A is a stable anhydrate polymorph. Forms B, C, D, and E showed high similarity with each other, with small differences between approximately 15 and 30° 2θ. Based on the DSC analysis, all four forms (B, C, D and E) showed similar endotherms at low temperature and recrystallization events at ˜150.0° C. Characterization data showed that Form D is likely a metastable anhydrate polymorph. Forms B, C and E are likely either metastable anhydrate polymorph or solvent inclusion complexes, in which variable amount and type of organic solvents are retained and cause minor changes in crystal lattice. Form F is likely a metastable hydrate polymorph. Although Form G showed similarity to Form F, its TGA analysis did not show significant weight loss so it is possibly a metastable anhydrate polymorph. Form H is a mono-DMSO solvate, harvested when DMSO was used as primary solvent during re-crystallization experiment. Form A was found to be thermodynamically the most stable anhydrate polymorph.

6.1.1 Crystallization Experiments

Both fast cooling (refrigerating at 4° C., 24 hrs) and slow cooling (20° C./hr) approaches were used in attempt to generate crystals via single-solvent and binary solvent crystallization steps. Solvent crystallization experiments were performed as described in Sections 6.1.1.1 and 6.1.1.2 and summarized in Table 1-Table 10.


TABLE 1
Compound 1 single solvent fast cooling crystallization experiments
(refrigerate at 4° C., 24 hrs), no precipitation formed.
Cmpd 1
Solvent
Solid form
amount.
Vol.
Temp.
determined by
(mg)
Solvent
(mL)
(° C.)
XRPD
33.0
MeOH
2.25
50.0
B
33.6
EtOH
2.63
50.0
C
32.5
IPA
4.81
50.0
D
31.2
1-BuOH
4.91
50.0
D + minor
additional peaks
32.8
MeCN
5.06
50.0
D
30.2
THF
3.08
50.0
A + B
32.2
2-MeTHF
5.10
50.0
E
32.1
EtOAc
4.61
50.0
D
35.8
IPAc
4.50
50.0
C
32.9
Acetone
3.85
50.0
B
34.2
MEK
4.64
50.0
E + minor
additional peaks
32.7
MIBK
6.00
50.0
A + minor
additional peaks
35.1
MTBE
6.13
50.0
A
30.3
DMSO
1.04
50.0
31.6
n-Propanol
3.72
50.0
E


TABLE 2
Compound 1 single solvent slow cooling crystallization experiments
(20° C./hr), no precipitation formed.
Cmpd 1
Solvent
amount.
Vol.
Temp.
Solid form by
(mg)
Solvent
(mL)
(° C.)
XRPD
35.6
MeOH
2.25
50.0
B
32.8
EtOH
2.63
50.0
C
31.1
IPA
4.81
50.0
D
31.0
1-BuOH
4.91
50.0
E
31.2
MeCN
5.06
50.0
B
34.7
THF
3.08
50.0
A + B
33.1
2-MeTHF
5.10
50.0
E
32.0
EtOAc
4.61
50.0
D
33.2
IPAc
4.50
50.0
C
30.7
Acetone
3.85
50.0
B
32.1
MEK
4.64
50.0
D
30.0
MIBK
6.00
50.0
B
35.8
MTBE
6.13
50.0
A + minor peak
33.2
DMSO
1.04
50.0
35.3
n-Propanol
3.72
50.0
E


TABLE 3
Compound 1 binary solvent fast cooling crystallization experiments,
water as co-solvent (refrigerate at 4° C., 24 hrs).
Cmpd 1
Solid
amnt.
Primary
Temp.
1° solvent
Co-solvent
Precipitation/
Yield
form by
(mg)
Solvent
(° C.)
Vol. (mL)
Vol. (mL)
Evaporation
(mg)
XRPD
36.5
MeOH
50.0
2.5
3.0
Precipitation
3.99
A + D
32.8
EtOH
70.0
2.6
5.0
Precipitation
12.13
A + C
33.4
IPA
70.0
4.9
10.0
Precipitation
20.6
A
35.0
MeCN
70.0
5.4
10.0
Precipitation
13.49
D
31.3
THF
50.0
3.2
7.5
Evaporation
B + F
with N2
32.5
Acetone
50.0
3.8
8.0
Precipitation
13.06
A
35.5
DMSO
70.0
1.2
1.0
Precipitation
20.86
A
30.1
DMF
70.0
1.1
2.0
Precipitation
7.86
A
33.9
NMP
70.0
1.3
2.0
Precipitation
15.46
A
34.2
n-Propanol
70.0
4.0
8.0
Precipitation
4.91
D + F
30.2
MEK
70.0
4.1
2.0
Evaporation
G
with N2
31.5
MIBK
70.0
5.7
1.0
Evaporation
F + G
with N2
31.8
2-MeTHF
70.0
5.0
1.0
Evaporation
G
with N2
32.5
1-BuOH
70.0
5.1
5.0
Evaporation
D
with N2


TABLE 4
Compound 1 binary solvent slow cooling crystallization
experiments, water as co-solvent (20° C./hr).
Cmpd 1
Solid
amnt.
Primary
Temp.
1° solvent
Co-solvent
Precipitation/
Yield
form by
(mg)
Solvent
(° C.)
Vol. (mL)
Vol. (mL)
Evaporation
(mg)
XRPD
32.6
MeOH
50.0
2.2
3.0
Precipitation
14.35
A + B
35.9
EtOH
70.0
2.8
5.0
Precipitation
12.1 
E
35.1
IPA
70.0
5.2
10.0
Evaporation
G
with N2
34.8
MeCN
70.0
5.4
10.0
Precipitation
12.86
A
36.7
THF
50.0
3.7
7.5
Evaporation
E + F
with N2
36.3
Acetone
50.0
4.2
8.0
Precipitation
16.96
A
30.7
DMSO
70.0
1.1
1.0
Evaporation
Oily
with N2
material
32.2
DMF
70.0
1.2
2.0
Precipitation
 2.66
A
33.5
NMP
70.0
1.3
2.0
Precipitation
11.16
A
34.0
n-Propanol
70.0
4.0
8.0
Evaporation
D
with N2
31.6
MEK
70.0
4.3
2.0
Evaporation
B
with N2
33.4
MIBK
70.0
6.0
1.0
Evaporation
B
with N2
30.1
2-MeTHF
70.0
4.8
1.0
Evaporation
G
with N2
31.9
1-BuOH
70.0
5.0
5.0
Evaporation
D
with N2


TABLE 5
Compound 1 binary solvent fast cooling crystallization experiments,
toluene as co-solvent (refrigerate at 4° C., 24 hrs), no precipitation
formed.
Co-
Cmpd 1
solvent
solvent
amnt.
Primary
Temp.
Vol.
Vol.
Solid form by
(mg)
Solvent
(° C.)
(mL)
(mL)
XRPD
30.0
MeOH
50.0
2.0
4.0
D + extra peak
(5.475° 2θ)
32.0
EtOH
70.0
2.5
5.0
C
35.0
IPA
70.0
5.2
10.0
E
31.3
1-BuOH
70.0
4.9
9.5
E + extra peak
(4.984° 2θ)
35.0
MeCN
70.0
5.4
10.8
D
31.0
THF
50.0
3.2
6.4
D
31.5
2-
70.0
5.0
10.0
D
MeTHF
33.2
EtOAc
70.0
4.7
9.6
D
31.1
IPAc
70.0
3.9
7.6
D
32.8
Acetone
50.0
3.9
7.6
D
32.6
MEK
70.0
4.4
8.8
E
31.2
MIBK
70.0
5.9
11.6
D
32.8
DMSO
70.0
1.1
2.2
H
31.1
DMF
70.0
1.1
2.2
A + extra peaks
(4.32, 15.4° 2θ)
33.1
NMP
70.0
1.3
2.5
Oily material
32.0
n-
70.0
3.8
7.4
E
Propanol


TABLE 6
Compound 1 binary solvent slow cooling crystallization experiments,
toluene as co-solvent (20° C./hr), no precipitation formed.
Cmpd 1
solvent
Co-
amnt.
Primary
Temp.
Vol.
solvent
Solid form by
(mg)
Solvent
(° C.)
(mL)
Vol. (mL)
XRPD
33.2
MeOH
50.0
2.3
4.4
D
31.1
EtOH
70.0
2.4
4.8
E
30.0
IPA
70.0
4.4
8.8
E
32.4
1-BuOH
70.0
5.1
10.0
E + extra peak
(4.984° 2θ)
30.4
MeCN
70.0
4.7
9.3
D
31.5
THF
50.0
3.2
6.4
D
30.4
2-MeTHF
70.0
4.8
9.6
E
34.3
EtOAc
70.0
4.9
9.8
E
32.3
IPAc
70.0
4.0
8.0
A
30.0
Acetone
50.0
3.5
7.0
D
33.9
MEK
70.0
4.6
9.2
D
33.1
MIBK
70.0
6.0
12.0
D
34.3
DMSO
70.0
1.2
2.2
H
31.2
DMF
70.0
1.1
2.2
A + B
34.6
NMP
70.0
1.3
2.6
Oily material
33.5
n-
70.0
3.9
7.8
E
Propanol


TABLE 7
Compound 1 binary solvent fast cooling crystallization experiments,
heptane as co-solvent (refrigerate at 4° C., 24 hrs), no precipitation
formed.
Co-
Cmpd 1
solvent
solvent
amnt.
Primary
Temp.
Vol.
Vol.
Solid form by
(mg)
Solvent
(° C.)
(mL)
(mL)
XRPD
32.0
EtOH
70.0
2.5
5.0
E
34.7
IPA
70.0
5.1
10.0
D
32.5
1-BuOH
70.0
5.1
10.0
E
32.9
THF
50.0
3.4
6.7
D
33.8
2-MeTHF
70.0
5.4
10.8
D
32.1
EtOAc
70.0
4.6
9.0
D
34.3
IPAc
70.0
4.3
8.6
C
32.1
Acetone
50.0
3.8
7.4
D
33.8
MEK
70.0
4.6
9.0
D
35.7
MIBK
70.0
6.5
12.5
A + D
32.7
MTBE
70.0
5.7
11.4
A (with strong
preferred
orientation)
34.0
NMP
70.0
1.3
2.5
Oily material
35.8
n-Propanol
70.0
4.2
8.4
E


TABLE 8
Compound 1 binary solvent slow cooling crystallization
experiments, heptane as co-solvent (20° C./hr).
Cmpd 1
Solid
amnt.
Primary
Temp.
1° solvent
Co-solvent
Precipitation/
Yield
form by
(mg)
Solvent
(° C.)
Vol. (mL)
Vol. (mL)
Evaporation
(mg)
XRPD
32.4
EtOH
70.0
2.5
5.0
Evaporation
E
with N2
30.9
IPA
70.0
4.5
9.0
Evaporation
E
with N2
33.9
1-BuOH
70.0
5.3
10.5
Evaporation
E + extra
with N2
peak
(5.07° 2θ)
30.4
THF
50.0
3.1
6.2
Evaporation
E
with N2
33.0
2-MeTHF
70.0
5.2
10.4
Evaporation
E
with N2
31.9
EtOAc
70.0
4.6
9.0
Evaporation
E
with N2
33.6
IPAc
70.0
4.2
8.4
Precipitation
20.57
A
32.6
Acetone
50.0
3.8
7.6
Evaporation
D
with N2
35.2
MEK
70.0
4.8
9.4
Evaporation
D
with N2
34.8
MIBK
70.0
6.3
12.6
Precipitation
13.01
A
33.1
MTBE
70.0
5.8
11.6
Precipitation
15.49
A
31.3
NMP
70.0
1.2
2.4
Evaporation
Oily
with N2
material
30.8
n-Propanol
70.0
3.6
7.2
Evaporation
E
with N2


TABLE 9
Compound 1 binary solvent fast cooling crystallization experiments,
cyclohexane as co-solvent (refrigerate at 4° C., 24 hrs), no precipitation
formed.
Co-
Cmpd 1
solvent
solvent
amnt.
Primary
Temp.
Vol.
Vol.
Solid form by
(mg)
Solvent
(° C.)
(mL)
(mL)
XRPD
30.5
EtOH
70.0
2.4
4.8
C
33.0
IPA
70.0
4.9
9.8
E
33.4
1-BuOH
70.0
5.2
10.4
E
31.2
THF
50.0
3.2
6.4
E
34.9
2-MeTHF
70.0
5.5
11.0
E
30.4
EtOAc
70.0
4.4
8.8
E
30.5
IPAc
70.0
3.8
7.6
A
35.6
Acetone
50.0
4.2
8.4
D
30.1
MEK
70.0
4.1
8.2
D
32.4
MIBK
70.0
5.9
11.8
D
30.3
NMP
70.0
1.1
2.2
Oily material
30.0
n-Propanol
70.0
3.5
7.0
E


TABLE 10
Compound 1 binary solvent slow cooling crystallization experiments,
cyclohexane as co-solvent (20° C./hr), no precipitation formed.
Co-
Cmpd 1
solvent
solvent
amnt.
Primary
Temp.
Vol.
Vol.
Solid form by
(mg)
Solvent
(° C.)
(mL)
(mL)
XRPD
34.2
EtOH
70.0
2.7
5.4
C
34.2
IPA
70.0
5.0
10.0
E
34.5
1-BuOH
70.0
5.4
10.8
E + extra peak
(5.05° 2θ)
33.5
THF
50.0
3.4
6.8
E
32.6
2-MeTHF
70.0
5.2
10.4
E
31.9
EtOAc
70.0
4.6
9.2
C
32.6
IPAc
70.0
4.1
8.2
A + C
32.8
Acetone
50.0
3.9
7.8
D
30.8
MEK
70.0
4.2
8.4
D
30.0
MIBK
70.0
5.5
11.0
E
31.5
NMP
70.0
1.2
2.4
Oily material
31.3
n-Propanol
70.0
3.7
7.4
E

6.1.1.1 Single Solvent Crystallization

Single solvent crystallizations were conducted at 30-35 mg scale using the primary solvents listed in Table 1 and Table 2. The experiments employed fast and slow cooling profiles as described in Table 1 and Table 2. No precipitates were obtained for all single-solvent crystallization experiments. All 30 crystallization samples had to be evaporated to dryness under a gentle stream of nitrogen to obtain solid for XRPD analysis (Table 1 and Table 2). Five unique XRPD patterns (Forms A, B, C, D, and E, FIG. 1) were observed from 28 crystallization experiments. Forms A, B, C, D, and E were prepared. The remaining two experiments produced an oily material that was not suitable for XRPD analysis.

The method of single solvent fast cooling crystallization comprised the steps of: (1) placing approximately 30-35 mg of Compound 1 into 8 mL clear glass vials equipped with stir bars; (2) dissolving with a minimum amount of solvents (starting with 500 μL increment) at 50° C. (up to 7.0 mL); (3) filtering the hot solution through a 0.45 μm syringe filter into a clean preheated vial; (4) placing the vial in a refrigerator (4° C.) without stirring over 24 hours; (5) isolating the resulting solids by vacuum filtration; and (6) evaporating the samples without precipitation to dryness under a gentle stream of nitrogen. All obtained solids were analyzed by XRPD to determine the solid form. See Table 1.

The method of single solvent slow cooling crystallization comprised the steps of: (1) placing approximately 30-35 mg of Compound 1 into 8 mL clear glass vials equipped with stir bars; (2) dissolving with a minimum amount of solvents (starting with 500 μL increment) at 50° C. (up to 7.0 mL); (3) filtering the hot solution through a 0.45 μm syringe filter into a clean preheated vial; (4) cooling to ambient temperature at a rate of 20° C./hr and allowing to equilibrate with stirring at ambient temperature over 24 hours; (5) isolating the resulting solids by vacuum filtration; and (6) evaporating the samples without precipitation to dryness under a gentle stream of nitrogen. All obtained solids were analyzed by XRPD to determine the solid form. See Table 2.

6.1.1.2 Binary Solvent Crystallization

Binary solvent crystallizations were conducted at ˜30 mg scale. A list of the chosen primary solvent systems is presented in Table 3-Table 10, respectively, to dissolve the Compound 1 at 50 or 70° C. Solvents such as H2O, toluene, heptane and cyclohexane were used as co-solvents as described in Table 3-Table 10. Besides the six patterns (Forms A, B, C, D, E and F), two additional unique XRPD patterns (Forms G and H) were obtained from 110 binary solvent crystallization experiments. Forms A, B, C, D, E, F, G and H were prepared. A representative overlay of XRPD patterns of all eight forms is shown in FIG. 1.

The method of binary solvent fast cooling crystallization comprised the steps of: (1) placing approximately 30.0-35.0 mg of Compound 1 into 8 mL clear glass vials equipped with stir bars; (2) dissolving with a minimum amount of solvents (starting with 500 mL increment) at 50 or 70° C. (up to 7.0 mL); (3) filtering the hot solution through a 0.45 μm syringe filter into a clean preheated vial; (4) adding a co-solvent drop-wise; (5) placing the vials in a refrigerator (4° C.) without stirring over 24 hours; (6) isolating the resulting solids by vacuum filtration; and (7) evaporating the samples without precipitation to dryness under a gentle stream of nitrogen gas. All obtained solids were analyzed by XRPD to determine the solid form (see Table 3, Table 5, Table 7 and Table 9).

The method of binary solvent slow cooling crystallization comprised the steps of: (1) placing approximately 30.0-35.0 mg of Compound 1 into 8 mL clear glass vials equipped with stir bars; (2) dissolving with a minimum amount of solvents (starting with 500 mL increment) at 50 or 70° C. (up to 7.0 mL); (3) filtering the hot solution through a 0.45 μm syringe filter into a clean preheated vial; (4) adding a co-solvent drop-wise; (5) cooling the vial to ambient temperature at a rate of 20° C./hr and allowing to equilibrate with stirring at ambient temperature over 24 hours; (6) isolating the resulting solids by vacuum filtration; and (7) evaporating the samples without precipitation to dryness under a gentle stream of nitrogen gas. All obtained solids were analyzed by XRPD to determine the solid form (see Table 4, Table 6, Table 8 and Table 10).

Water as co-solvent:

Precipitations were isolated by filtration from 15 experiments out of 28 crystallization experiments (Table 3 and Table 4). For the remaining crystallization experiments, solids were obtained in most experiments after the solutions were evaporated to dryness under a gentle stream of nitrogen, followed by XRPD analysis. Five unique XRPD patterns (Forms A, B, D, E and G) and seven XRPD pattern mixtures were observed. Forms A, B, D, E and G were prepared.

Toluene as co-solvent:

No precipitates were obtained for all binary-solvent crystallizations in toluene (Table 5 and Table 6). All the solutions were evaporated to dryness under a gentle stream of nitrogen to obtain solids for XRPD analysis. In 32 crystallization experiments, five unique XRPD patterns (Forms A, C, D, E and H) and one pattern mixture were observed. Forms A, C, D, and E were prepared. New unique Form H was observed and prepared from DMSO/Toluene via both fast and slow cooling methods.

Heptane as co-solvent:

Precipitations were isolated by filtration from 3 experiments out of 26 crystallization experiments (Table 7 and Table 8). For the remaining crystallization samples, solids were obtained in most experiments after the solutions were evaporated to dryness under a gentle stream of nitrogen, followed by XRPD analysis. Four unique XRPD patterns (Forms A, C, D, and E) and one XRPD pattern mixture were observed. Forms A, C, D, and E were prepared.

Cyclohexane as co-solvent:

No precipitates were obtained for all binary-solvent crystallizations in cyclohexane (Table 9 and Table 10). All the solutions were evaporated to dryness under a gentle stream of nitrogen to obtain solids for XRPD analysis. In 24 crystallization experiments, four unique XRPD patterns (Forms A, C, D, and E) and one pattern mixture was observed. Forms A, C, D, and E were prepared.

6.1.2 Scale Up of Crystalline Forms D and G

Forms A, D and G were identified as potential anhydrate polymorphs and prepared for full characterization. The starting material was Form A. A series of experiments were performed to generate a sufficient quantity of Forms D and G materials for further characterization. Details of the experiments are summarized in Table 11.


TABLE 11
Scale up of crystalline Forms D and G with the slow cooling method (20° C./hr).
Cmpd 1
Solid
amnt.
Primary
Temp.
1° solvent
Co-solvent
Precipitation/
Yield
form by
(mg)
Solvent
(° C.)
Vol. (mL)
Co-solvent
Vol. (mL)
Evaporation
(mg)
XRPD
60.7
THF
50.0
6.2
Toluene
12.0
Evaporation
D
with N2
62.5
MEK
70.0
8.5
Toluene
17.0
Evaporation
D
with N2
59.7
IPA
70.0
8.8
Water
17.5
Precipitation
30.2
G
61.4
2-MeTHF
70.0
9.8
Water
12.0
Evaporation
G
with N2

Form D material was scaled up using the binary solvent crystallizations method and conducted at ˜60 mg scale (Table 11). Two batches of Form D materials were generated. Procedures utilized to generate these Form D materials followed the methods used for the two batches in intermediate scale experiments (Table 5 and Table 6).

The scale-up method of binary solvent slow cooling crystallization for preparation of Form D comprised the steps of: (1) placing approximately 60 mg of Compound 1 into 20 mL clear glass vials equipped with stir bars; (2) dissolving with a minimum amount of solvents (THF or MEK, starting with 500 mL increment) at 50 or 70° C.; (3) filtering the hot solution through a 0.45 μm syringe filter into a clean preheated vial; (4) adding a co-solvent (toluene); (5) cooling the vial to ambient temperature at a rate of 20° C./hr and allowing to equilibrate with stirring at ambient temperature over 5 hours; (6) isolating the resulting solids by vacuum filtration; and (7) evaporating the samples without precipitation to dryness under a gentle stream of nitrogen gas. All obtained solids were analyzed by XRPD to determine the solid form (Table 11).

Form G material was scaled up using binary solvent crystallizations method and conducted at ˜60 mg scale (Table 11). Two batches of Form G materials were generated. Procedures utilized to generate these Form G materials followed the methods used for the two batches in intermediate scale experiments (Table 3 and Table 4).

The scale-up method of binary solvent slow cooling crystallization for preparation of Form G comprised the steps of: (1) placing approximately 60 mg of Compound 1 into 20 mL clear glass vials equipped with stir bars; (2) dissolving with a minimum amount of solvents (IPA or 2-MeTHF, starting with 500 mL increment) at 70° C.; (3) filtering the hot solution through a 0.45 μm syringe filter into a clean preheated vial; (4) adding a co-solvent (water); (5) cooling the vial to ambient temperature at a rate of 20° C./hr and allowing to equilibrate with stirring at ambient temperature over 5 hours; (6) isolating the resulting solids by vacuum filtration; and (7) evaporating the samples without precipitation to dryness under a gentle stream of nitrogen gas. All obtained solids were analyzed by XRPD to determine the solid form (Table 11).

6.1.3 Competitive Slurry Experiment of Forms A, D and G

To evaluate relative stability of the anhydrate polymorphs, competitive slurry experiments of Forms A, D and G were conducted as described in below and summarized in Table 12. In all three solvent systems, water, 1:2 v/v IPAc/heptane, and toluene, Form A was the final polymorph after equilibration for 8 days. Therefore, Form A is the most stable anhydrate polymorph among the three polymorphs at ambient temperature.


TABLE 12
Competitive slurry experiment of Forms A, D and G.
Aliquot time
Aliquot time
Parent
Weight
Vol.
Tempt.
point
point
Materials
(mg)
Solvent
(mL)
(° C.)
Day
XRPD
Day
XRPD
Form A
12.54
Water
1.0
RT
1
A + D
8
A
Form D
11.06
Form G
12.00
Form A
12.45
IPAc/Heptane
1.0
RT
1
A
8
A
Form D
12.88
(1:2 V/V)
Form G
12.34
Form A
15.20
Toluene
1.0
RT
1
A
8
A
Form D
16.70
Form G
14.75

Slurry experiments were performed using the following procedure: a mixture of Form A (˜12.0 mg, Compound 1), Form D (˜12.0 mg) and Form G (˜12.0 mg) were weighed into a 20.0 mL clear vial equipped with magnetic stir bars (Table 12). Water, IPAc/Heptane (1:2 V/V) and toluene were used as the solvent systems for these competitive slurry experiments. Three selected solvents, 1.0 mL, were added to achieve free-flowing slurry and allowed to equilibrate at room temperature.

6.1.4 Competitive Slurry Experiment of Forms A Through H

Competitive slurry experiment of all unique Forms A through H were also conducted as described below and summarized in Table 13. Again Form A was detected after one day and seven days equilibration, indicating that it is the most stable polymorph.


TABLE 13
Competitive slurry experiment of Forms A to H.
Aliquot time
Aliquot time
Parent
Weight
Vol.
Tempt.
point
point
Materials
(mg)
Solvent
(mL)
(° C.)
Day
XRPD
Day
XRPD
Form A
4.72
IPAc/Heptane
1.0
RT
1
A
7
A
Form B
3.01
(1:2, V/V)
Form C
1.13, 1.91
Form D
1.65 or 1.70
Form E
3.23
Form F
3.45
Form G
3.43
Form H
3.52
Form A
4.95
Toluene
1.0
RT
1
A
7
A
Form B
3.32
Form C
1.97, 1.80
Form D
1.64 or 1.72
Form E
3.60
Form F
3.22
Form G
3.25
Form H
3.61

Approximately 2 to 3 mg of materials from Forms A to H were weighed into a 20.0 mL clear vial equipped with magnetic stir bars (Table 13). IPAc/Heptane (1:2 V/V) and toluene were used as the solvent systems for these competitive slurry experiments. Two selected solvents, 1.0 mL, were added to achieve free-flowing slurry and allowed to equilibrate at room temperature. All slurries will be isolated via centrifuge filtration after one day and seven days of equilibration.

6.1.5 Single Form Slurry Experiments

Single form slurry experiments were conducted for Forms A, D and G in three solvents stems, water, 1:2 v/v IPAc/heptane, and toluene to evaluate their physical form stability as a single polymorph (Table 14). Form A remained unchanged at six day time point. Form G converted to Form A after three day time points. Form D remained unchanged for three days in water but converted to a mixture A and D at six days. In 1:2 IPAc/heptane and toluene, Form D converted to a mixture of A and D at three days and then Form A at six days. These results showed that Form G is a metastable polymorph and readily converts to Form A under slurry conditions at ambient temperature. Form D is also a metastable polymorph but its conversion to Form A is kinetically slower than Form G. The conversion was the slowest in water partly due to low solubility.


TABLE 14
Single form slurry experiment of Forms A, D and G
Aliquot time
Aliquot time
Parent
Weight
Vol.
Tempt.
point
point
Materials
(mg)
Solvent
(mL)
(° C.)
Day
XRPD
Day
XRPD
Form A
16.33
Water
1.0
RT
3
A
6
A
Form A
17.80
IPAc/Heptane
1.0
RT
3
A
6
A
(1:2 V/V)
Form A
16.28
Toluene
1.0
RT
3
A
6
A
Form D
10.01
Water
1.0
RT
3
D
6
A + D
Form D
11.70
IPAc/Heptane
1.0
RT
3
A + D
6
A
(1:2 V/V)
Form D
10.90
Toluene
1.0
RT
3
A + D
6
A
Form G
27.01
Water
1.0
RT
3
A
6
A
Form G
21.32
IPAc/Heptane
1.0
RT
3
A
6
A
(1:2 V/V)
Form G
21.29
Toluene
1.0
RT
3
A
6
A

Approximately 10-20 mg of Forms A, D and G were weighed into 8 mL clear vials equipped with magnetic stir bars (Table 14). Water, IPAc/Heptane (1:2 V/V) and toluene were used as the solvent systems for these competitive slurry experiments. Three selected solvents, 1.0 mL, were added to achieve free-flowing slurry and allowed to equilibrate at room temperature. All slurries will be isolated via centrifuge filtration after three day and six days of equilibration.

Thermal stability experiments of Forms A, D and G were conducted and summarized in Table 15.


TABLE 15
Thermal Stability Experiments
Aliquot time
Aliquot time
Parent
Weight
Tempt.
point
point
Parent Material
HPLC
Material
(mg)
(° C.)
Day
XRPD
Day
XRPD
HPLC (% AUC)
(% AUC)
Form A
27.0
60.0
1
A
7
A
>99.9
>99.9
Form D
26.5
60.0
1
D
7
D
>99.9
>99.9
Form G
27.3
60.0
1
A + G
7
A
>99.3
>99.9

6.1.6 Aqueous Solubility

Approximately 14-25 mg of Forms A, D and G were transferred to 20 mL vials equipped with magnetic stir bars. 1.0 mL of deionized water was added and the resulting free flowing slurry was allowed to equilibrate over 1 and 7 days period with stirring at room temperature. The slurries were filtered through 0.45 micron centrifuge filters and the resulting solids analyzed by XRPD (Table 16). The filtrates were analyzed by HPLC to determine solubility.


TABLE 16
Aqueous solubility of Forms A, D and G
DI H2O
Solid form
Solid form
Initial
Mass
vol.
by XRPD
by XRPD
Solubility
form
(mg)
(mL)
Condition
after 1 day
after 7 day
(mg/mL)
A
25.93
1.0
free flowing
A
A
(0.0026)*
D
13.88
1.0
slurry was
A
A
(0.49)*
G
21.94
1.0
allowed to
A
A
0.061
equilibrate
with stirring
at room
temperature
*Extrapolated values based on the standard curve (0.008-0.2 mg/mL).

6.2 Instrumentation

The vendor and model information of the instruments used for analysis are provided below in Table 17.


TABLE 17
Instrument vendors and models
Instrument
Vendor/Model #
Differential Scanning Calorimeter
Mettler DSC1
Thermal Gravimetric Analyzer
Mettler 851e TGA
X-Ray Powder Diffractometer
CubiX-Pro
Nuclear Magnetic Resonance
Bruker 500 MHz AVANCE
Spectrometer

6.2.1 Differential Scanning Calorimetry (DSC)

DSC analysis was performed on the sample “as is.” Sample was weighed in an aluminum pan, covered with a pierced lid, and then crimped and analyzed from 30-230° C. at 10° C./min.

6.2.2 Thermal Gravimetric Analysis (TGA)

TGA was carried out on the sample “as is.” Sample was weighed in an alumina crucible and analyzed from 30-300° C. at 10° C./min.

6.2.3 X-Ray Powder Diffraction

Samples were analyzed “as is.” Sample was placed on Si zero-return ultra-micro sample holders. Analysis was performed using a 10 mm irradiated width and the following parameters were set within the hardware/software:

X-ray tube: Cu Kα, 45 kV, 40 mA

Detector: X'Celerator

ASS Primary Slit: Fixed 10

Divergence Slit (Prog): Automatic—5 mm irradiated length

Soller Slits: 0.02 radian

Scatter Slit (PASS): Automatic—5 mm observed length

Scan Range: 3.0-45.0°

Scan Mode: Continuous

Step Size: 0.02°

Time per Step: 10 s

Active Length: 2.54°

Following analysis the data was converted from adjustable to fixed slits using the X'Pert HighScore Plus software with the following parameters:

Fixed Divergence Slit Size: 1.00°, 1.59 mm

6.2.4 Nuclear Magnetic Resonance

Samples were dissolved in DMSO-d6 with 0.05% tetramethylsilane (TMS) for internal reference. 1H-NMR spectra were acquired at 500 MHz using 5 mm broadband (1H-X) Z gradient probe. A 30 degree pulse with 20 ppm spectral width, 1.0 s repetition rate, and 64 transients were utilized in acquiring the spectra.

Weight percent purity determination by 1H NMR using 1,4 Dimethoxybenzene in DMSO-d6 with 0.05% tetramethylsilane (TMS). Sample preparation, 1H-NMR spectra acquiring and sample purity was calculated accordingly.

6.2.5 Dynamic Vapour Sorption (DVS)

Dynamic vapour sorption experiment was carried out by first holding the sample at 40% RH and 25.0° C. until an equilibrium weight was reached or for a maximum of four hours. The sample was then subjected to an isothermal (at 25.0° C.) adsorption scan from 40 to 90% RH in steps of 10%. The sample was allowed to equilibrate to an asymptotic weight at each point for a maximum of four hours. Following adsorption, a desorption scan from 85 to 5% RH (at 25.0° C.) was run in steps of 10% again allowing a maximum of four hours for equilibration to an asymptotic weight. An adsorption scan was then performed from 0 to 40% RH in steps of 10%. The sample was then dried for no less than two hours at 60.0° C. and the resulting solid analyzed by XRPD.

6.2.6 HPLC

HPLC conditions are listed in Table 18.


TABLE 18
HPLC conditions
System:
Agilent 1100 Series HPLC
Column:
Agilent Zorbax SB-C18, (SN: USEG012031)
4.6 mm × 150 mm, 3.5 μm
Column
30.0° C.
Temperature:
Auto Sampler
Ambient
Temp:
Flow Rate:
1.0 mL/min.
Injection Volume:
15.0 μL
Run Time:
40 minutes
Detection:
263 nm
Sample
Standard reference:
Preparation:
1.0 mg/mL
Dissolved 2.333 mg of Compound 1 in 2.333 mL of
diluent and stirred at 25.0° C. for 10 minutes
API aqueous solubility samples:
Filtrates from aqueous solubility experiments
Thermal Stability Experiments:
API
Diluent volume
weight (mg)
(mL)
Compound 1, Form A
3.284
3.284
Compound 1, Form D
3.549
3.549
Compound 1, Form G
2.586
2.586
Dissolved polymorphs in diluent and stirred
at 25.0° C. for 10 minutes
Mobile Phases:
A - 0.1% TEA and TFA in H2O, adjusted pH
to 1.3 using HCl solution
B - 100% ACN
Diluent:
50:50 (V/V) ACN:H2O

6.2.7 Characterization of Compound 1 Polymorphs

All unique XRPD forms of Compound 1 were characterized to evaluate their physical form and stability. Table 19 summarizes the characterization results for each polymorph of Compound 1. A stackplot of representative XRPD Patterns of Forms A, B, C, D, E, F, G and H is shown in FIG. 1. X-ray powder diffraction pattern and peak list of each unique polymorph are shown in FIG. 2-FIG. 9.


TABLE 19
Summary of Compound 1 Polymorphs.
Solid
Moisture
form
DSC (° C.)
TGA (Weight loss)
NMR
Sorption
Comments
A
Endotherm
onset of
No detectable
60% RH:
Anhydrate
at 186.0
decomposition at
solvent, no
0%
249.2° C.
degradation
90% RH:
6.1 wt %
B
Endotherm
0.64% @ 135-155° C.,
No
N/A
Metastable
at 141.5,
onset decomposition
degradation,
anhydrate (or
185.2
at 258.0° C.
0.48 wt %
possible
Exotherm
MEK
inclusion
at 146.9
complex)
C
Endotherm
1.08% @ 120-150° C.,
Additional
N/A
Metastable
at 63.5,
onset decomposition
NMR peaks
anhydrate (or
77.6,
at 269.1° C.
1.98 wt %
possible
134.9,
EtOH
inclusion
185.8
complex)
Exotherm
at 143.0
D
Endotherm
onset of
No detectable
60% RH:
Metastable
at 185.2
decomposition at
solvent, no
0.7%
anhydrate
Exotherm
259.8° C.
degradation
90% RH:
at 118.7
1.0 wt %
E
Endotherm
1.96% @ 130-165° C.,
1.66 wt %
N/A
Metastable
at 154.8,
onset decomposition
EtOAc, no
anhydrate (or
185.6
at 261.6° C.
degradation
possible
Exotherm
inclusion
at 156.7
complex)
F
Endotherm
1.86% @ 50-110° C.,
No detectable
N/A
metastable
at 64.1,
onset decomposition
solvent, no
hydrate
91.3, 185.9
at 268.3° C.
degradation
G
Endotherm
onset of
No detectable
60% RH:
metastable
at 90.5,
decomposition at
solvent, no
0.4%
anhydrate
184.9
263.5° C.
degradation
90% RH:
7.1 wt %
H
Endotherm
6.4% @ 70-140° C.,
18.9 wt %
N/A
mono-
at 88.0
9.8% @ 145-240° C.,
DMSO, no
DMSO
onset decomposition
degradation
solvate
at 268.1° C.

6.2.8 Form A of Compound 1

Form A was harvested from the binary solvent recrystallization experiment using acetone as primary solvent and water as co-solvent (Table 3 and Table 4). Form A was also isolated in other single solvent and binary solvents recrystallization experiments in multiple solvent systems (Table 1-Table 10). The 1H NMR (d6-DMSO) spectrum of Form A is provided in FIG. 10. Thermal analysis by DSC showed a single endothermic transition at 186.0° C. (FIG. 11). Further analysis by TGA indicated no weight loss before the onset of decomposition at 249.2° C. (FIG. 12). The material adsorbed 0 wt % moisture at 60% RH and 6.1 wt % moisture at 90% RH (FIG. 13). Although the material is moderately hygroscopic, no deliquescence was observed. The XRPD analysis of the post-DVS material after drying at 60° C. for 2 hours, recorded an XRPD pattern consistent with the starting material (FIG. 14). Aqueous solubility of Form A was determined to be 0.0026 mg/mL, which is extrapolated value based on the standard curve (Table 16).

In the single form and competitive slurry experiments, Form A was found to be the most stable polymorph at ambient temperature under all tested conditions. In addition, DSC did not show any noticeable endothermic event prior to 186° C. and TGA did not show any weight loss at low temperature range (<100.0° C.). No chemical and physical form changes were observed for Form A after storing the material at 60° C. for seven days (Table 15).

Characterization results of Form A are consistent with a stable anhydrate polymorph.

FIG. 2 provides an XRPD pattern of Form A. A list of X-Ray Diffraction Peaks for Form A is provided below in Table 20.


TABLE 20
X-Ray Diffraction Peaks for Form A
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.73
23.68
0.99
3.86
22.92
1.14
4.24
20.86
2.46
4.39
20.13
1.24
5.46
16.19
1.25
5.58
15.85
0.78
5.77
15.31
1.04
6.01
14.70
1.21
6.49
13.61
11.74
6.86
12.89
0.62
7.27
12.16
0.63
7.40
11.94
0.26
7.83
11.29
0.77
8.13
10.88
0.98
8.56
10.34
0.85
8.67
10.20
0.57
8.80
10.05
0.44
8.93
9.91
1.18
9.91
8.92
1.34
10.09
8.76
0.79
10.23
8.65
0.01
10.41
8.50
0.17
11.07
7.99
1.37
12.14
7.29
58.99
13.05
6.78
33.11
14.45
6.13
17.61
15.67
5.66
0.64
16.20
5.47
4.48
16.60
5.34
19.83
17.21
5.15
4.65
17.70
5.01
2
18.71
4.74
15.15
19.19
4.63
12.76
19.59
4.53
19
20.08
4.42
28.19
20.54
4.33
9.63
21.60
4.11
1.1
22.15
4.01
2.09
22.97
3.87
84.6
23.34
3.81
15.95
24.37
3.65
1.22
25.02
3.56
6.03
25.55
3.49
0.72
25.93
3.44
1.66
26.92
3.31
100
27.55
3.24
1.69
29.20
3.06
10.29
29.70
3.01
3.15
30.10
2.97
1.34
31.68
2.82
11.82
32.13
2.79
8.52
32.59
2.75
16.15
33.00
2.71
2.88
33.77
2.65
1.79
34.18
2.62
0.43
34.67
2.59
0.64
35.19
2.55
3.41
35.88
2.50
1.01
36.40
2.47
0.33
36.99
2.43
1.57
37.46
2.40
1.86
38.08
2.36
0.68
39.74
2.27
0.84
40.38
2.23
0.39
40.96
2.20
0.79
41.76
2.16
1.44
42.12
2.15
1.48
42.45
2.13
0.83
43.26
2.09
0.54
43.87
2.06
1.84
44.52
2.03
0.81

6.2.9 Form B of Compound 1

Form B was prepared in the binary solvent recrystallization experiment using MEK as primary solvent and water as co-solvent, (Table 3 and Table 4). Form B was also isolated in other single solvent and binary solvents recrystallization experiments in multiple solvent systems (Table 1-Table 4). An estimated 0.48 wt % of MEK and no degradation were observed by 1H NMR (d6-DMSO) (FIG. 15). DSC analysis presented two endotherms at 141.5 and 185.2° C., and an exotherm at 146.9° C. (FIG. 16). TGA analysis indicated a weight loss of 0.64%, attributed to loss of MEK, before 155° C. and onset decomposition at 258.0° C. (FIG. 17). In the competitive slurry experiment, Form B converted to Form A (Table 13).

Characterization results of Form B are mostly consistent with a metastable anhydrate polymorph retaining residual solvent. The residual solvents was not released until melt and Form B showed similarity to several other forms (i.e., Forms C, D and E), indicating that Form B might be an inclusion complex in which non-stoichiometry amount of solvent was retained and caused minor changes in crystal lattice.

FIG. 3 provides an XRPD pattern of Form B. A list of X-Ray Diffraction Peaks for Form B is provided below in Table 21.


TABLE 21
X-Ray Diffraction Peaks for Form B
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
4.34
20.37
82.64
7.46
11.86
17.24
8.61
10.27
100
11.37
7.78
12.06
12.90
6.86
19.52
14.89
5.95
34.65
15.50
5.72
78.65
18.76
4.73
28.42
19.71
4.50
10.4
21.52
4.13
11.25
22.15
4.01
4.18
22.81
3.90
13.48
23.03
3.86
8.41
23.77
3.74
19.1
24.60
3.62
6.72
25.29
3.52
22.84
25.73
3.46
5.58
26.23
3.40
7.14
26.76
3.33
10.88
27.49
3.24
3.85
28.17
3.17
18.3
30.10
2.97
7.77
31.76
2.82
6.67
32.57
2.75
5.14
34.34
2.61
1.74
35.94
2.50
2.24
37.74
2.38
1.68
38.63
2.33
1.36
39.27
2.29
2.07
41.75
2.16
1.36
42.20
2.14
0.81
44.45
2.04
0.87

6.2.10 Form C of Compound 1

Form C was prepared in the binary solvent recrystallization experiment using EtOH as primary solvent and cyclohexane as co-solvent (Table 9 and Table 10). Form C was also isolated in other single solvent and binary solvents recrystallization experiments usually when EtOH and IPAc were used (Table 1-Table 10). An estimated 1.98 wt % of EtOH and additional peaks were observed by 1H NMR (d6-DMSO) (FIG. 18). Additional peaks indicated by asterisk in FIG. 18 were noted in the 1H NMR. These resonances are likely attributed to a degradation product due to esterification of the carboxylic acid group. Therefore, alcoholic solvents may present the risk of degradation through ester formation. DSC analysis presented four endotherms at 63.5, 77.6, 134.9 and 185.8° C., and an exotherm at 143.0° C. (FIG. 19). TGA analysis indicated a weight loss of 1.08%, attributed to loss of EtOH, before 150.0° C. and onset decomposition at 269.1° C. (FIG. 20). In the competitive slurry experiment, Form C converted to Form A (Table 13).

Characterization results of Form C are mostly consistent with a metastable anhydrate polymorph retaining residual solvent. The residual solvents was not released until melt and Form C showed similarity to several other forms (i.e., Forms B, D and E), indicating that Form C might be an inclusion complex in which non-stoichiometry amount of solvent was retained and caused minor changes in crystal lattice.

FIG. 4 provides an XRPD pattern of Form C. A list of X-Ray Diffraction Peaks for Form C is provided below in Table 22.


TABLE 22
X-Ray Diffraction Peaks for Form C
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.09
28.62
5.24
4.35
20.32
100
7.46
11.85
8.25
8.63
10.25
76.25
11.41
7.76
15.09
12.93
6.85
10.8
14.94
5.93
23.35
15.55
5.70
62.12
18.80
4.72
19.03
19.78
4.49
8.2
21.60
4.11
11.12
22.51
3.95
2.83
22.89
3.89
8.58
23.31
3.82
5.08
24.10
3.69
1.43
24.87
3.58
6.48
25.25
3.53
1.75
26.34
3.38
10.28
27.07
3.29
4.33
27.77
3.21
7.03
28.10
3.18
1.59
28.45
3.14
5.36
29.09
3.07
0.87
29.43
3.04
1.09
29.75
3.00
3.84
30.37
2.94
1.5
30.73
2.91
0.36
31.77
2.82
2.07
32.24
2.78
1.97
32.86
2.73
0.55
34.02
2.64
1.66
35.67
2.52
1.44
37.86
2.38
0.98
38.39
2.34
0.8
39.35
2.29
1.72
41.85
2.16
1.01
42.35
2.13
0.61
43.28
2.09
0.68
43.74
2.07
0.55
44.24
2.05
0.73

6.2.11 Form D of Compound 1

Form D was prepared in the binary solvent recrystallization experiment using THF as primary solvent and toluene as co-solvent (Table 5 and Table 6). Form D was also isolated in other single solvent and binary solvents recrystallization experiments in multiple solvent systems (Table 1-Table 10). No detectable solvent or degradation was observed by 1H NMR (d6-DMSO) (FIG. 21). DSC analysis presented an endotherm at 185.2° C., and an exotherm at 118.7° C. (FIG. 22). Further analysis by TGA indicated no weight loss before the onset of decomposition at 259.8° C. (FIG. 23). The material adsorbed 0.7 wt % moisture at 60% RH and 1.0 wt % moisture at 90% RH (FIG. 24). This material is considered slightly hygroscopic. The XRPD analysis of the post-DVS material, after drying at 60° C. for 2 hours, recorded an XRPD pattern consistent with the starting material (FIG. 25). Once formed, Form D maintained its chemical and physical form even after storing the material at 60° C. for seven days (Table 15). Aqueous solubility of Form D was not achieved because Form D converted to Form A in aqueous equilibrium (Table 16). The obtained solubility of 0.49 mg/mL represents solubility of Form A. The discrepancy compared to the Form A solubility value described in Table 16 (0.0026 mg/mL) was possibly due to insufficient equilibrium or different residual solvent/impurity profile. In the single form and competitive slurry experiments, Form D converted to Form A at ambient temperature under all tested conditions.

Characterization results of Form D are mostly consistent with metastable anhydrate polymorph.

FIG. 5 provides an XRPD pattern of Form D. A list of X-Ray Diffraction Peaks for Form D is provided below in Table 23.


TABLE 23
X-Ray Diffraction Peaks for Form D
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
4.32
20.45
92.9
7.44
11.88
17.03
8.59
10.30
100
11.31
7.82
13.88
12.85
6.89
17.13
14.85
5.96
34.18
15.49
5.72
68.51
18.72
4.74
27.1
19.71
4.50
10.18
21.51
4.13
10.6
22.40
3.97
3.16
22.75
3.91
13.28
23.62
3.77
7.61
24.48
3.64
1.81
25.17
3.54
11.43
26.19
3.40
6.39
26.68
3.34
6.01
26.96
3.31
2.19
27.32
3.27
1.33
27.98
3.19
9.25
28.35
3.15
8.91
29.34
3.04
1.4
29.98
2.98
5.45
30.30
2.95
2.44
32.44
2.76
3.55
34.07
2.63
0.75
35.81
2.51
1.34
37.16
2.42
1.12
37.69
2.39
2.33
38.44
2.34
1.07
39.25
2.30
2.46
41.71
2.17
1.41
42.19
2.14
0.91
44.35
2.04
0.88

6.2.12 Form E of Compound 1

Form E was prepared in the binary solvent recrystallization experiment using EtOAc as primary solvent and toluene as co-solvent (Table 5 and Table 6). Form E was also isolated in other single solvent and binary solvents recrystallization experiments in multiple solvent systems (Table 1-Table 10). An estimated 1.66 wt % of EtOAc and no degradation were observed by 1H NMR (d6-DMSO) (FIG. 26). DSC analysis presented two endotherms at 154.8 and 185.6° C., and an exotherm at 156.7° C. (FIG. 27). Further analysis by TGA indicated a weight loss of 1.96%, attributed to loss of EtOAc, before 165.0° C. and onset of decomposition at 261.6° C. (FIG. 28). In the competitive slurry experiment, Form E converted to Form A (Table 13).

Characterization results of Form E are mostly consistent with a metastable anhydrate polymorph retaining residual solvent. The residual solvents was not released until melt and Form E showed similarity to several other forms (i.e., Forms B, C and D), indicating that Form E might be an inclusion complex in which non-stoichiometry amount of solvent was retained and caused minor changes in crystal lattice.

FIG. 6 provides an XRPD pattern of Form E. A list of X-Ray Diffraction Peaks for Form E is provided below in Table 24.


TABLE 24
X-Ray Diffraction Peaks for Form E
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
4.33
20.40
100
4.66
18.96
1.11
5.42
16.31
0.89
5.73
15.43
0.2
5.99
14.76
0.67
6.16
14.36
0.78
6.29
14.06
0.27
6.50
13.59
0.76
7.46
11.85
11.12
8.61
10.27
90.7
9.32
9.49
1.07
10.07
8.78
0.37
10.78
8.21
0.49
10.93
8.09
0.33
11.37
7.78
14.51
12.17
7.27
0.99
12.89
6.87
13.92
13.45
6.58
0.54
14.45
6.13
0.44
14.89
5.95
27.33
15.50
5.72
66.57
16.66
5.32
0.78
18.74
4.74
22.56
19.73
4.50
9.11
20.04
4.43
0.58
20.56
4.32
0.47
21.53
4.13
11.42
21.80
4.08
3.21
22.19
4.01
2.72
22.57
3.94
5.03
22.81
3.90
13.03
23.45
3.79
14.55
23.87
3.73
1.37
24.23
3.67
4.18
24.97
3.57
18.47
25.35
3.51
4.98
26.24
3.40
8.36
26.47
3.37
8.99
26.96
3.31
4.6
27.24
3.27
2.52
27.85
3.20
15.23
28.36
3.15
7.68
29.19
3.06
2.43
29.57
3.02
2.49
29.85
2.99
6.95
30.30
2.95
2.02
30.81
2.90
1.47
31.25
2.86
0.42
32.34
2.77
4.49
32.93
2.72
0.8
34.10
2.63
1.64
34.77
2.58
0.22
35.74
2.51
2.35
36.36
2.47
0.37
37.23
2.41
0.48
37.71
2.39
1.97
38.36
2.35
1.17
39.28
2.29
2.17
40.74
2.21
0.39
41.66
2.17
1.45
42.19
2.14
0.82
42.61
2.12
0.43
43.29
2.09
0.4
43.71
2.07
0.63
44.18
2.05
1.05

6.2.13 Form F of Compound 1

Form F was prepared in binary solvent crystallization using water as an anti-solvent (Table 3 and Table 4). Form F was not isolated from single solvent and binary solvent crystallization experiments but a mixture of Forms F and B, or D, or E, or G was encountered in binary solvent crystallization. The 1H NMR (DMSO-d6) spectrum was consistent with the structure of Compound 1 with no significant residual solvent (FIG. 29). DSC analysis presented three endotherms at 64.1, 91.3 and 185.9° C. (FIG. 30). Further analysis by TGA indicated a weight loss of 1.86% before 110.0° C. and onset of decomposition at 268.3° C. (FIG. 31). In the competitive slurry experiment, Form F converted to Form A (Table 13).

Characterization results of Form F are mostly consistent with a metastable hydrate polymorph.

FIG. 7 provides an XRPD pattern of Form F. A list of X-Ray Diffraction Peaks for Form F is provided below in Table 25.


TABLE 25
X-Ray Diffraction Peaks for Form F
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.99
22.15
100
4.23
20.91
42.6
7.89
11.20
35.92
8.36
10.58
30.55
11.81
7.50
19.52
15.21
5.82
37.6
15.44
5.74
33.4
17.39
5.10
10.19
17.79
4.99
12.96
19.78
4.49
13.97
20.87
4.26
22.28
22.98
3.87
12.77
23.83
3.73
11.45
25.17
3.54
20.19
26.10
3.41
12.71
27.15
3.28
8.58
28.53
3.13
10.53
30.30
2.95
5.79
31.71
2.82
12.17
34.06
2.63
1.29

6.2.14 Form G of Compound 1

Form G was prepared in the binary solvent recrystallization experiment using IPA as primary solvent and water as co-solvent (Table 3 and Table 4). Form G showed a high degree of similarity to Form F (FIG. 1). No detectable solvent or degradation was observed by 1H NMR (d6-DMSO) (FIG. 32). DSC analysis presented two endotherms at 90.5 and 184.9° C. (FIG. 33). Analysis by TGA indicated no weight loss before the onset of decomposition at 263.5° C. (FIG. 34). The material adsorbed 0.4 wt % moisture at 60% RH and 7.1 wt % moisture at 90% RH (FIG. 35). This material is considered as moderately hygroscopic. The XRPD analysis of the post-DVS material after drying at 60° C. for 2 hours, afforded Form A (FIG. 36). Since no apparent hysteresis was observed on DVS, Form G is not a hydrate form. Because it converted to Form A after the DVS experiment and drying, it is likely a metastable anhydrate polymorph. Aqueous slurry experiment also supported that Form G is not a hydrate form because Form G converted to Form A after one day in water (Table 12). When storing Form G at 60° C. for 24 hours a form mixture was observed at day 1, and at day 7 only Form A was obtained (Table 15). Aqueous solubility of Form G was not achieved because Form G converted to Form A in aqueous equilibrium (Table 16). The obtained solubility of 0.061 mg/mL represents solubility of Form A. The discrepancy compared to the Form A solubility value described in Table 16 (0.0026 mg/mL) was possibly due to insufficient equilibrium or different residual solvent/impurity profile. In the single form and competitive slurry experiments, Form G converted to Form A at ambient temperature under all tested conditions.

Characterization results of Form G are mostly consistent with a metastable anhydrate polymorph.

FIG. 8 provides an XRPD pattern of Form G. A list of X-Ray Diffraction Peaks for Form G is provided below in Table 26.


TABLE 26
X-Ray Diffraction Peaks for Form G
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
4.19
21.07
100
8.33
10.61
80.94
12.47
7.10
11.24
15.19
5.83
36.87
15.44
5.74
22.1
16.67
5.32
4.11
17.81
4.98
24.01
19.26
4.61
1.69
20.87
4.26
34.66
21.33
4.17
4.01
22.18
4.01
5.07
22.86
3.89
7.24
23.71
3.75
4.57
24.59
3.62
3.4
25.09
3.55
9.73
25.89
3.44
4.8
27.00
3.30
19.8
28.36
3.15
20.89
28.63
3.12
16.14
29.87
2.99
2.25
32.45
2.76
1.52
34.70
2.59
1.57
39.53
2.28
1.34
42.08
2.15
1.27

6.2.15 Form H of Compound 1

Form H was prepared in the binary solvent recrystallization experiment using DMSO as primary solvent and toluene as co-solvent (Table 5 and Table 6). Form H was isolated from conditions where DMSO was used. An estimated 18.9 wt % of DMSO and no degradation were observed by 1H NMR (MeOD) (FIG. 37). DSC analysis presented an endotherm at 88.0° C. (FIG. 38). Analysis by TGA indicated two weight losses of 6.4% before 140° C. and 9.8% before 240° C., and the onset of decomposition at 268.1° C. (FIG. 39).

Based on characterization results, Form H is consistent with a mono-DMSO solvate polymorph.

FIG. 9 provides an XRPD pattern of Form H. A list of X-Ray Diffraction Peaks for Form H is provided below in Table 27.


TABLE 27
X-Ray Diffraction Peaks for Form H
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.07
28.81
20.05
5.35
16.53
12.44
8.56
10.33
2.24
10.69
8.28
18.25
12.20
7.26
6.45
12.62
7.01
21.51
13.08
6.77
5.27
13.32
6.65
10.86
14.08
6.29
100
15.46
5.73
3.68
16.04
5.53
2.76
17.18
5.16
29.96
17.69
5.01
4.89
17.93
4.95
15.41
18.76
4.73
44.25
19.69
4.51
17.85
20.14
4.41
2.51
21.19
4.19
10.15
21.40
4.15
72.29
22.22
4.00
3.08
22.99
3.87
6.26
24.02
3.70
5.81
24.59
3.62
31.18
25.18
3.54
18.49
25.75
3.46
29.33
26.55
3.36
7.81
26.93
3.31
8.85
27.53
3.24
17.48
28.32
3.15
2.33
29.07
3.07
1.97
31.19
2.87
1.53
31.72
2.82
6.13
32.05
2.79
6.34
33.70
2.66
1.26
35.09
2.56
3.94
35.76
2.51
6.55
37.23
2.42
2.48
37.94
2.37
1.06
38.67
2.33
2.67
39.26
2.29
1.16
39.96
2.26
0.82
40.36
2.23
1.88
43.14
2.10
0.79
44.56
2.03
3.62

6.2.16 Conclusion

During the polymorph study, eight unique polymorphs (Forms A, B, C, D, E, F, G and H) were observed. Form A is characterized as a moderately hygroscopic, anhydrate polymorph and was determined to be the most stable polymorph from slurry experiments, thermal stability and aqueous solubility. Forms B, C, D and E shared many common XRPD diffraction peaks between 15 and 30° 2θ. The small variation in diffraction patterns is probably due to minor changes in crystal lattice due to presence of variable amount of residual solvents. Forms F and G also shared some similarity. Based on NMR and TGA analysis, Forms D and G are likely metastable anhydrate polymorphs. Form H was found to be a DMSO solvate. All the polymorphs converted to Form A in competitive and single form slurry experiments. All four polymorphs showed similar endotherm/exotherm at low temperature, attributed to a melt/recrystallization event, followed by an endothermic event at ˜150.0° C. in the DSC analysis. Forms A, D and G were found to be chemically stable over storage as solid at 60° C. for 7 days. However, potential ester degradation product was detected in the solid isolated from EtOH, indicating that alcoholic solvents should be avoided to reduce the potential risk of degradation.

6.3 Polymorph Conversion

The conversion of Form G to Form A was conducted initially on a 2.0 g scale of Compound 1 in seven volumes of 33% acetone in water (2.3 vol of acetone and 4.7 vol of water) with 5.4% w/w of form A seeds of Compound 1. The desired Form A of Compound 1 was recovered in 97% yield. Following this successful trial experiment, a 72.4 g conversion of Form G to Form A was completed in seven volumes of 33% acetone in water and seeding with 2.3% w/w of Form A. The scale up experiment yielded 73.9 g in 97% yield (including added seeds) of Form A.

6.3.1 2.0 g Trial Experiment

To a 25-mL, three-neck, round-bottom flask equipped with an overhead stirrer were charged Form G of Compound 1 (2.0 g, 6.9 mmol), acetone (4.6 mL, 2.3 vol), and H2O (9.4 mL, 4.7 vol) at 18° C. (room temperature). The slurry was stirred for 10 min at which Form A seeds (0.107 g, 5.4% w/w, lot #1150-041) were added. After 24 h of stirring at 17-18° C., the mixture was filtered in a Buchner funnel and washed with H2O (4 mL, 2 vol). The wet cake was dried in vacuum oven at 20-25° C. for 16 h to afford 1.90 g of Form A of Compound 1 in 97% yield as a white solid.

6.3.2 74.2 g Scale Up Experiment

To a 1-L, three-neck, round-bottom flask equipped with an overhead stirrer were charged Form G of Compound 1 (74.2 g, 0.26 mol), acetone (171 mL, 2.3 vol), and H2O (349 mL, 4.7 vol) at 18-20° C. (room temperature). The slurry was stirred for 10 min at which Form A seeds (1.71 g, 2.3% w/w) were added. After 28 h of stirring at 18-20° C., the mixture was filtered in a Buchner funnel and washed with H2O (140 mL, 2 vol). The wet cake was dried in vacuum oven at 20-25° C. for 42 h to afford 73.9 g of Form A in 97% yield as a white solid.

6.4 Summary of Salt Screen of Compound 1

Following counterions were selected for initial salt formation experiments, based on the pKa of Compound 1 and safety/acceptance in pharmaceutical drug products: Calcium acetate, choline hydroxide, potassium hydroxide, sodium hydroxide, arginine, meglumine, magnesium hydroxide and calcium hydroxide. Solids isolated from the salt formation experiments were characterized. Based on the salt stoichiometry and preliminary stability evaluation by thermal analysis and competitive slurry, five salts (Salt I, Salt II, Salt III, Salt IV and Salt V) were selected for scale up and full characterization. Salt I and Salt II provided poor aqueous solubility at 0.01 mg/mL and 0.03 mg/mL, respectively. All sodium and potassium salts (Salt III, Salt IV and Salt V) showed good solubility (>19 mg/mL). The five salts all had endothermic events at low temperature. Salt II, Salt IV and Salt V exhibited 5-10% weight loss which started below 100° C. DVS of Salt IV showed that it is a stable hydrate throughout humidity range at 25° C. Therefore Salt IV has good solubility and relative stability. Although some endothermic events were observed, Salt III also showed good stability. From thermal holding experiment, Salt VI was discovered. Salt VI was found to be an anhydrate form and only slightly hygroscopic. This form showed more favorable physical property than Salt IV. However, preparation of Salt VI involved thermal holding at 260° C.

6.4.1 Salt Formation on 30 mg Scale

Approximately 30 mg of Compound 1 was weight into 4 mL glass vials equipped with stir bar. Solvent (1.0 or 2.0 mL) was added and the mixture was heated to elevated temperatures 50° C., and then the acetone and MeCN solution was polish filtered through a 0.45 m syringe filter into a clean preheated vial. After hot filtration, basic counterion solution was added drop-wise as summarized in Table 28 and the resulting mixture was cooled to RT at 20° C./h. The vial was inspected for precipitation. If no precipitation or very little precipitation was discovered, the content was evaporated under nitrogen. All precipitates were isolated by filtration.


TABLE 28
Counterion lists
Safety
Name
M.W.
Solvent
Class
Calcium acetate hydrate
176.18
Water
1
Choline hydroxide
121.18
Water
1
Potassium hydroxide
56.11
Water/MeOH
1
Sodium hydroxide in
40
Water/MeOH
1
or Water
l-Arginine
174.2
Water
1
n-methyl-d-glucamine (meglumine)
195.21
Water/MeOH
1
Magnesium nitrate + Sodium
256.41
Water
1
hydroxide
Calcium nitrate + Sodium hydroxide
236.15
Water
1

The details of 30 mg scale salt formation experiments are summarized in Table 29, Table 30, Table 31, Table 32, Table 33 and Table 34. The reaction was performed at elevated temperature and filtered to ensure complete dissolution of the free acid. If precipitation did not occur instantaneously, crystallization of the potential salts was attempted by cooling or evaporation crystallization. The majority of experiments afforded solids isolable by filtration. The solids from filtration or evaporation were analyzed by XRPD for crystallinity and form. Salt stoichiometry was examined by NMR or IC. The results are summarized in Table 35.


TABLE 29
Salt formation experiments (1:1 equiv.) part 1
CI Actual
SM
Conc.
CI Amt
After CI
After
(mg)
CI Solution
(M)
(mL)
Addition
Cooling
Isolation
32.5
Calcium acetate
0.25
0.41
ppt
ppt
Filtration,
hydrate in water
white solid
29.9
Choline hydroxide
0.5
0.21
Clear
Clear
Evaporation,
in water
gel solid
30.1
Potassium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in water
white solid
29.7
Potassium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in MeOH
white solid
29.8
Sodium hydroxide
0.5
0.21
Clear
ppt
Filtration,
in water
white solid
29.7
Sodium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in MeOH:water
white solid
(3/2)
29.3
l-Arginine
0.5
0.21
Clear
Clear
Evaporation,
in water
white solid
30
Meglumine
0.5
0.21
Clear
Clear
Evaporation,
in water
gel solid
30.2
Meglumine in
0.5
0.21
Clear
ppt,
Evaporation,
MeOH:water
small
white solid
(1/1)
quant.
30.7
Magnesium itrate +
0.5
0.21/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
30.8
Calcium nitrate +
0.5
0.21/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
Solvent = CH3OH;
Solvent Amount = 1 mL;
Temperature = 50° C.;
Equivalent = 1.


TABLE 30
Salt formation experiments (1:1 equiv.) part 2
CI Actual
SM
Conc.
CI Amt
After CI
After
(mg)
CI Solution
(M)
(mL)
Addition
Cooling
Isolation
30.5
Calcium acetate
0.25
0.41
ppt
ppt
Filtration,
hydrate in water
white solid
28.8
Choline hydroxide
0.5
0.21
ppt
ppt,
Evaporation,
in water
small
gel solid
quant.
30.6
Potassium hydroxide
0.5
0.21
Clear
ppt
Filtration,
in water
white solid
31
Potassium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in MeOH
white solid
28.7
Sodium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in water
white solid
30.7
Sodium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in MeOH:water
white solid
(3/2)
30.4
l-Arginine
0.5
0.21
ppt
ppt,
Filtration,
in water
small
not enough
quant.
solid
31.3
Meglumine
0.5
0.21
Clear
Clear
Evaporation,
in water
gel solid
29.9
Meglumine in
0.5
0.21
Clear
ppt
Filtration,
MeOH:water
white solid
(1/1)
31.7
Magnesium nitrate +
0.5
0.21/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
29.6
Calcium nitrate +
0.5
0.21/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
Solvent = Acetone;
Solvent Amount = 1 mL;
Temperature = 50° C.;
Equivalent = 1.


TABLE 31
Salt formation experiments (1:1 equiv.) part 3
CI Actual
SM
Conc.
CI Amt
After CI
After
(mg)
CI Solution
(M)
(mL)
Addition
Cooling
Isolation
31.1
Calcium acetate
0.25
0.41
ppt
ppt
Filtration,
hydrate in water
white solid
31
Choline hydroxide
0.5
0.21
ppt
ppt,
Evaporation,
in water
small
gel solid
quant.
29.6
Potassium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in water
white solid
31.3
Potassium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in MeOH
white solid
30.7
Sodium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in water
white solid
29.8
Sodium hydroxide
0.5
0.21
ppt
ppt
Filtration,
in MeOH:water
white solid
(3/2)
30.8
l-Arginine
0.5
0.21
ppt
ppt,
Evaporation,
in water
gel solid
white solid
30.6
Meglumine
0.5
0.21
ppt
ppt,
Evp,
in water
gel solid
gel solid
31.4
Meglumine in
0.5
0.21
ppt
ppt
Filtration,
MeOH:water
white solid
(1/1)
30.4
Magnesium nitrate +
0.5
0.21/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
30.1
Calcium nitrate +
0.5
0.21/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
Solvent = CH3CN;
Solvent Amount = 2 mL;
Temperature = 50° C.;
Equivalent = 1.


TABLE 32
Salt formation experiments (2:1 or 1:2 equiv.) part 1
CI Actual
SM
CI
Conc.
CI Amt
After CI
After
(mg)
Solution
(M)
Equiv.
(mL)
addition
cooling
Isolation
29.2
Calcium acetate
0.25
2.1
0.87
ppt
ppt
Filtration,
hydrate in water
white solid
32.3
Choline hydroxide
0.5
0.43
Clear
Clear
Evaporation,
in water
gel solid
31.3
Potassium hydroxide
0.5
0.43
Clear
Clear
Evaporation,
in water
yellow solid
33.0
Potassium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in MeOH
white solid
29.9
Sodium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in water
white solid
32.9
Sodium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in MeOH:water
white solid
(3/2)
30.6
1-Arginine
0.5
0.43
Clear
Clear
Evaporation,
in water
white solid
30.2
Meglumine
0.5
0.43
Clear
Clear
Evaporation,
in water
gel solid
32.2
Meglumine in
0.5
0.43
Clear
Clear
Evaporation,
MeOH:water
gel solid
(1/1)
30.8
Magnesium nitrate +
0.5
0.43/0.87
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
31.5
Calcium nitrate +
0.5
0.43/0.87
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
32.4
Calcium acetate
0.25
0.51
0.21
ppt
ppt
Filtration,
hydrate in water
white solid
30.7
Calcium nitrate +
0.5
0.11/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
Solvent = CH3OH;
Solvent Amount = 1 mL;
Temperature = 50° C.


TABLE 33
Salt formation experiments (2:1 or 1:2 equiv.) part 2
CI Actual
SM
Conc.
CI Amt
After CI
After
(mg)
CI Solution
(M)
Equiv.
(mL)
addition
cooling
Isolation
30.3
Calcium acetate
0.25
2.1
0.87
ppt
ppt
Filtration,
hydrate in water
white solid
29.7
Choline hydroxide
0.5
0.43
Clear
Clear
Evaporation,
in water
gel solid
28.8
Potassium hydroxide
0.5
0.43
Clear
Clear
Evaporation,
in water
yellow solid
30.7
Potassium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in MeOH
white solid
29.3
Sodium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in water
white solid
31.4
Sodium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in MeOH:water
white solid
(3/2)
31.5
1-Arginine
0.5
0.43
Clear
Clear
Evaporation,
in water
white solid
28.8
Meglumine
0.5
0.43
Clear
Clear
Evaporation,
in water
gel solid
29.3
Meglumine in
0.5
0.43
Clear
Clear
Evaporation,
MeOH:water
gel solid
(1/1)
29.3
Magnesium nitrate +
0.5
0.43/0.87
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
28.8
Calcium nitrate +
0.5
0.43/0.87
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
31.3
Calcium acetate
0.25
0.51
0.21
ppt
ppt
Filtration,
hydrate in water
white solid
29.7
Calcium nitrate +
0.5
0.11/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
Solvent = Acetone;
Solvent Amount = 1 mL;
Temperature = 50° C.


TABLE 34
Salt formation experiments (2:1 or 1:2 equiv.) part 3
CI Actual
SM
Conc.
CI Amt
After CI
After
(mg)
CI Solution
(M)
Equiv.
(mL)
addition
cooling
Isolation
33.9
Calcium acetate
0.25
2.1
0.87
ppt
ppt
Filtration,
hydrate in water
white solid
32.5
Choline hydroxide
0.5
0.43
Clear
Clear
Evaporation,
in water
gel solid
30.1
Potassium hydroxide
0.5
0.43
Clear
Clear
Evaporation,
in water
yellow solid
31.1
Potassium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in MeOH
white solid
30.4
Sodium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in water
white solid
30.7
Sodium hydroxide
0.5
0.43
ppt
ppt
Filtration,
in MeOH:water
white solid
(3/2)
30.5
1-Arginine
0.5
0.43
ppt
ppt
Evaporation,
in water
white solid
33.2
Meglumine
0.5
0.43
Clear
Clear
Evaporation,
in water
gel solid
29.7
Meglumine in
0.5
0.43
ppt
ppt
Evaporation,
MeOH:water
white solid
(1/1)
32.4
Magnesium nitrate +
0.5
0.43/0.87
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
29.7
Calcium nitrate +
0.5
0.43/0.87
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
29.5
Calcium acetate
0.25
0.51
0.21
ppt
ppt
Filtration,
hydrate in water
white solid
30.0
Calcium nitrate +
0.5
0.11/0.21
ppt
ppt
Filtration,
Sodium hydroxide
white solid
in water
Solvent = CH3CN;
Solvent Amount = 2 mL;
Temperature = 50° C.


TABLE 35
Salt formation experiments - characterization summary (1:1 equiv.)
API:CI
CI Solution (0.5M
Ratio by
Solvent
unless specified)
XRPD
NMR
IC
MeOH
calcium acetate in
Salt I
No degradation
1:0.56
water
calcium nitrate +
No degradation
1:0.52
sodium hydroxide in
water
calcium acetate
hydrate in water
acetone
calcium acetate in
Salt II
No degradation
1:0.50
water
calcium nitrate +
No degradation
1:0.51
Sodium hydroxide in
water
Calcium acetate in
water
Calcium acetate in
water
Calcium nitrate +
Salt II +
Sodium hydroxide in
impurity
water
MeOH
Calcium acetate in
Salt II
water
MeCN
calcium acetate in
water
calcium nitrate +
sodium hydroxide in
water
Calcium acetate
hydrate in water
Calcium acetate
hydrate in water
MeCN
Calcium nitrate +
Salt II +
Sodium hydroxide in
impurity
water
MeOH
potassium hydroxide
Salt III
in MeOH
MeCN
potassium hydroxide
Salt III
No degradation
1:0.65
in water
potassium hydroxide
in MeOH
acetone
Sodium hydroxide in
Salt IV
No degradation
1:1
water
Sodium hydroxide in
Salt IV
MeOH
MeCN
Sodium hydroxide in
Salt IV
water
Sodium hydroxide in
Salt IV +
No degradation
1:0.84
MeOH
impurity
MeOH
Sodium hydroxide in
Salt V
No degradation
1:1.48
water
Sodium hydroxide in
MeOH
acetone
Sodium hydroxide in
water
Sodium hydroxide in
MeOH
MeCN
Sodium hydroxide in
water
Sodium hydroxide in
MeOH

Overall salt formation was confirmed with counterion ratio of approximately 0.5 to 1.5 equivalents. Most salts exhibited polymorphism with observation of multiple unique XRPD patterns: four for calcium salts, two for choline salts, seven for potassium salts, and eight for sodium salts. A crystalline salt was obtained using meglumine but only 0.38 equivalents of meglumine were detected. Magnesium also afforded a crystalline mono-salt.

6.4.2 Slurry Experiments

Calcium, sodium, and potassium salts were used to setup different competitive slurry experiments. For competitive slurry of calcium salts (˜5-6 mg of Salt I and Salt II) were weighed into a 5.0 mL clear vial equipped with magnetic stir bars. These steps were repeated for potassium salt material (˜5-6.5 mg of Salt III) and sodium salt materials (˜2.6-6.4 mg of Salt IV and Salt V). Acetone, 1.0 mL, was added to each vial to achieve free-flowing slurry and allowed to equilibrate at room temperature. 50 μL of water was added to the potassium and sodium salt mixtures to increase solubility. All slurries, 400 μL, were filtered through 0.45 micron centrifuge filters after one and seven days of equilibration. The solids were analyzed by XRPD to check for salt conversion (Table 36).

It was found that Salt I, Salt III and Salt V were the most stable polymorphs in these solvent systems. These three salts were selected for scale up and full characterization.


TABLE 36
Competitive Slurry
Aliquot time
Aliquot time
Parent
Weight
Vol.
Temp.
point
point
Salt
Materials
(mg)
Solvent
(mL)
(° C.)
Day
XRPD
Day
XRPD
Ca2+
Salt I,
5.36
Acetone
1.0
RT
1
Salt I
7
Salt I
(filtration)
Salt II,
6.53
(filtration)
K+
Salt III,
6.57
Acetone
1.5
RT
1
Salt III
7
Salt III
(filtration)
Water
0.05
Na+
Salt IV,
6.36
Acetone
1.0
RT
1
Salt V +
7
Salt V
(filtration)
Water
0.05
impurity
Salt V,
6.31
(filtration)

6.4.3 Characterization Summary of Salts I, II, III, IV, V, VI, VII, VIII, IX and X

Salt I, Salt II, Salt III, Salt IV, Salt V, Salt VI, Salt VII, Salt VIII, Salt IX and Salt X were characterized to evaluate its physical form and stability. Since all these salt forms showed low temperature endothermic events, except Salt VIII, thermal holding experiments were performed in an attempt to isolate high melting salt form. Salt VI was obtained from the thermal holding experiments (Table 50) and characterized. Table 37 summarizes the characterization results for each salt.


TABLE 37
Characterization summary of Salts I, II, III, IV, V, VI, VII, VIII, IX and X
Salt
Salt I
Salt II
Salt III
DSC (° C.)
Endotherm at
Endotherm at
Endotherm at 54.3,
104.0, 170.6,
115.5, 127.0,
109.3, 314.4
179.1 and 210.6
220.8, 311.3
Exotherm at
200.5
TGA (Weight loss)
0.34% @ 65-105° C.
10.98% @ 65-140° C.,
0.91% @ 40-70° C.,
1.41% @ 140-190° C.
0.33% @ 150-180° C.
0.25% @ 100-120° C.,
onset of
onset
onset
decomposition at
decomposition at
decomposition at
213.8° C.
298.0° C.
297.2° C.
NMR
0.24 wt % MeOH
0.32 wt %
0.24 wt % MeCN
Acetone
Cmpd 1:CI ratio by IC
1:0.37
1:0.69
1:0.94
Moisture
60% RH: 1.0 wt %
60% RH: 11.9 wt %
60% RH: 2.1 wt %
Sorption
90% RH: 4.1 wt %
90% RH: 12.0 wt %
90% RH: 4.5 wt %
(moderately
(moderately
(moderately
hygroscopic)
hygroscopic)
hygroscopic)
Aqueous
Solubility
0.01
0.03
35.8
Solubility
(mg/mL)
Standard curve linear range 0.008 to 0.2 mg/mL.
XRPD (1
Salt I + Extra
Salt II
Salt IX
day)
peaks
hydration property
anhydrate (60%
di-hydrate
hemi-(60% RH)
RH) to
to mono-hydrate
monohydrate
(90% RH)
(90% RH)
Comment
Hemi-calcium
Hemi-calcium
Mono-potassium
Salt
Salt
Salt
Salt
Salt IV
Salt V
Salt VI
DSC (° C.)
Endotherm at
Endotherm at
Endotherm at
107.9, 307.4
93.3 (no melting
282.4 and 308.4,
Exotherm at
was observed
Exotherm at 283.9
217.2
between 70-320° C.)
TGA (Weight loss)
5.43% @ 60-120° C.
5.85% @ 40-130° C.,
onset
onset of
onset
decomposition at
decomposition at
decomposition at
305.7° C.
302.5° C.
344.77° C.
NMR
0.29 wt %
2.26 wt %
No degradation
Acetone
Acetone
Cmpd 1:CI ratio by IC
1:1.12
1:1.86
N/A
Moisture
60% RH: 6.1 wt %
60% RH: 6.0 wt %
60% RH: 0.3 wt %
Sorption
90% RH: 6.5 wt %
90% RH: 6.4 wt %
90% RH: 0.7 wt %
(moderately
(moderately
hygroscopic)
hygroscopic)
Aqueous
Solubility
19
79.8
N/A
Solubility
(mg/mL)
Standard curve linear range 0.008 to 0.2 mg/mL.
XRPD (1
Salt IV + Extra
Salt V + Extra
N/A
day)
peaks
peaks
hydration property
monohydrate
monohydrate
anhydrate
Comment
Mono-sodium
Bis-sodium Salt
Mono-sodium Salt
Salt
Salt
Salt VII
Salt VIII
Salt IX
DSC (° C.)
Broad transition
No thermic
Endothermic at
before 90 (might
change before
82.8; Exotherm at
be water loss),
onset
229.5; Onset
Possible glass
decomposition at
decomposition at
transition at 160,
294.1
293.9
onset
decomposition at
294.9
TGA (Weight loss)
onset
onset
onset
decomposition at
decomposition at
decomposition at
290.6
291.2
301.8
NMR
No detectable
No detectable
0.01 wt % Acetone
solvent, no
solvent, no
degradation
degradation
Cmpd 1:CI ratio by IC
1:1.15
1:1.09
1:1.09
Moisture
60% RH: 0.9 wt %
60% RH: 1.0 wt %
60% RH: 0.3 wt %
Sorption
90% RH: 2.9 wt %
90% RH: 2.7 wt %
90% RH: 0.3 wt %
Aqueous
Solubility
Solubility
(mg/mL)
XRPD (1
day)
hydration property
Comment
Mono-sodium
Mono-sodium
Mono-sodium Salt
Salt
Salt
Salt
Salt X
DSC (° C.)
Endothermic at
91.3 and 149.3;
Exotherm at
230.6; Onset
decomposition at
294.7
TGA (Weight loss)
onset 1.3 wt %
loss at 79.2; onset
2.3 wt % loss at
135.1; onset
decomposition at
296.7
NMR
3.5 wt % of 4-
hydroxybutanoic
acid
Cmpd 1:CI ratio by IC
1:1.00
Moisture
Sorption
Aqueous
Solubility
Solubility
(mg/mL)
XRPD (1
day)
hydration property
Comment
Mono-sodium
Salt

6.4.4 Salt I of Compound 1

Salt I of Compound 1 is a hemi-calcium salt. Salt I was obtained in filtration from the salt formation experiment using methanol as primary solvent (Table 48, FIG. 40). An estimated 0.24 wt % of MeOH was observed by 1H NMR (d6-DMSO) (Table 37, FIG. 47). From IC analysis, Compound 1 free acid:calcium ratio was determined to be 1.0:0.4, consistent with a hemi-calcium salt. DSC analysis presented four endotherms at 104.0, 170.6, 179.1 and 210.6° C. (FIG. 48). TGA analysis indicated a two weight losses: 0.34% at 65-105° C. (attributed to loss of residual MeOH), and 1.41% at 140-190° C. and onset decomposition at 213.8° C. (FIG. 49). To further investigate the material's moisture sorption behavior, DVS analysis was carried out. The material adsorbed 1.0 wt % moisture at 60% RH, and 4.1 wt % moisture at 90% RH, indicating that it is moderately hygroscopic (FIG. 50). The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, recorded a consistent XRPD pattern as the starting material (FIG. 46).

Salt I exhibited no change in physical form upon exposure to 60° C. for a period of seven days (Table 49). It was also chemically stable based on HPLC analysis. It was found that Salt I is sparingly soluble in the aqueous solubility study, where a solubility of 0.01 mg/mL was obtained.

FIG. 40 provides an XRPD pattern of Salt I. A list of XRPD Peaks for Salt I is provided below in Table 38.


TABLE 38
X-Ray Diffraction Peaks for Salt I
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.20
27.61
90.18
4.09
21.60
1.21
4.51
19.58
7.6
4.85
18.23
4.2
4.99
17.70
4.19
5.19
17.04
8
5.43
16.27
9.32
5.69
15.54
6.49
6.01
14.71
5.98
6.49
13.61
5.32
6.92
12.77
2.72
7.21
12.27
3.38
8.29
10.67
5.25
8.47
10.44
3.08
9.17
9.64
2.21
9.53
9.28
32.9
10.39
8.51
4.58
10.58
8.37
5.32
11.30
7.83
2.4
11.87
7.45
3.31
12.10
7.31
4.51
12.23
7.23
4.1
12.73
6.95
5.94
13.23
6.69
17.06
14.23
6.22
5.17
15.60
5.68
23.52
15.97
5.55
100
17.21
5.15
2.21
17.49
5.07
3.54
18.08
4.91
3.02
18.88
4.70
4.87
19.15
4.63
18.36
22.00
4.04
3.38
22.41
3.97
31.57
23.92
3.72
7.89
25.25
3.53
5.93
25.60
3.48
6.38
26.35
3.38
3.02
26.67
3.34
2.1
27.76
3.21
4.32
28.21
3.16
5.53
29.29
3.05
9.13
31.08
2.88
2.7
31.46
2.84
2.95
31.82
2.81
3.11
33.44
2.68
2.71
34.63
2.59
1.81
35.58
2.52
3.51
37.97
2.37
1.24
38.65
2.33
3.26
38.96
2.31
5.02
41.35
2.18
6.64
42.29
2.14
4.11
43.31
2.09
0.84

6.4.5 Salt II of Compound 1

Salt II of Compound 1 is a dihydrated hemi-calcium salt. Salt II was obtained in filtration from the salt formation experiment using acetone as primary solvent (Table 48, FIG. 51). An estimated 0.32 wt % of acetone was observed by 1H NMR (d6-DMSO) (Table 37, FIG. 52). The ratio of Compound 1 free acid to calcium counterion was 1.0:0.69, indicating it is a hemi-calcium salt.

DSC analysis presented four endotherms at 115.5, 127.0, 220.8, 311.3° C. and an exotherm at 220.5° C. (FIG. 53). TGA analysis indicated a two weight losses: 10.98% at 65-140° C. (attributed to water loss), 0.33% at 150-180° C. and onset decomposition at 298.0° C. (FIG. 54). The material adsorbed 11.9 wt % moisture at 60% RH, and 12.0 wt % moisture at 90% RH, indicating that it is moderately hygroscopic (FIG. 55). Slight hysteresis was observed at 0-40% RH. The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, recorded a new XRPD pattern (bottom) (FIG. 51). TGA and DVS results indicated that Salt II is a dihydrate, which is stable above 40% RH.

Salt II exhibited no change in physical form upon exposure to 60° C. for a period of seven days (Table 49). Chemical purity of the thermally stressed solid was assessed by HPLC and no significant reduction in purity was observed. It was found that Salt II remained sparingly soluble in the aqueous solubility study, where a solubility of 0.03 mg/mL was obtained.

FIG. 41 provides an XRPD pattern of Salt II. A list of XRPD Peaks for Salt II is provided below in Table 39.


TABLE 39
X-Ray Diffraction Peaks for Salt II
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.37
26.19
23.10
3.81
23.16
0.13
3.94
22.45
2.32
4.15
21.28
4.74
4.33
20.43
4.51
4.59
19.25
1.91
4.77
18.54
2.30
5.12
17.28
1.77
5.51
16.03
1.14
6.07
14.55
2.22
6.25
14.15
1.09
7.27
12.16
1.77
7.45
11.86
1.82
7.82
11.31
1.77
8.03
11.01
1.75
8.56
10.32
0.22
8.83
10.02
2.15
10.07
8.78
100.00
10.39
8.52
3.22
10.71
8.26
1.84
11.32
7.82
1.04
11.56
7.66
0.73
11.70
7.56
1.49
13.21
6.70
7.45
13.46
6.58
3.58
14.10
6.28
1.43
14.36
6.17
0.80
15.32
5.78
0.93
15.58
5.69
0.44
16.86
5.26
27.14
19.28
4.60
2.06
19.51
4.55
3.28
20.23
4.39
9.96
20.68
4.29
0.15
21.32
4.17
2.82
22.41
3.97
1.76
22.95
3.88
1.05
23.71
3.75
26.87
24.27
3.67
2.66
24.90
3.58
1.19
25.87
3.44
3.47
26.21
3.40
0.61
26.83
3.32
2.54
27.15
3.28
3.24
27.57
3.24
0.57
27.85
3.20
2.38
28.12
3.17
2.44
28.95
3.08
0.53
29.24
3.05
0.64
29.53
3.02
0.48
29.95
2.98
1.62
31.08
2.88
0.60
31.47
2.84
6.68
31.90
2.81
2.70
32.59
2.75
1.65
32.97
2.72
0.47
33.42
2.68
3.66
34.73
2.58
2.95
34.97
2.57
2.37
35.25
2.55
1.08
36.09
2.49
0.62
38.09
2.36
4.79
39.69
2.27
0.70
41.35
2.18
0.91
42.56
2.12
1.54
42.94
2.11
2.32
44.06
2.05
0.86

6.4.6 Salt III of Compound 1

Salt III of Compound 1 is a mono-potassium salt. Salt III was obtained in filtration from the salt experiment using acetonitrile as primary solvent (Table 36, FIG. 56). An estimated 0.24 wt % of CH3CN was observed by 1H NMR (Table 50, FIG. 52). The ratio of Compound 1 free acid:potassium was determined by IC analysis to be 1.0:0.9 indicating it is a mono-potassium salt. DSC analysis presented three endotherms at 54.3, 109.3 and 314.4° C. (FIG. 58). TGA analysis indicated two weight losses: 0.91% at 40-70° C., and 0.25% at 100-120° C. and onset decomposition at 297.2° C. (FIG. 59). The material adsorbed 2.1 wt % moisture at 60% RH, and 4.5 wt % moisture at 90% RH, indicating it is moderately hygroscopic (FIG. 60). Mild hysteresis was observed indicating presence of potential hydrate form. The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, recorded a similar XRPD pattern as the starting material (FIG. 56).

Salt III exhibited no change in physical form upon exposure to 60° C. for a period of seven days (Table 48). Chemical purity of the thermally stressed solid was assessed by HPLC and no reduction in purity was observed. Aqueous solubility measurement of potassium salt in deionized water was carried out in room temperature. The materials after 24 hour equilibrium converted from Salt III to Salt IX, and remained as Salt IX on day seven. Collected filtrate was subjected to HPLC analysis and a solubility of 35.8 mg/mL was attained.

Multiple thermal transitions (endothermic) were observed on DSC analysis with some occur at low temperature. In an effort to isolate a high melt crystal form, the material was held at 130° C. for 2 minutes followed by cooling to ambient temperature. XRPD analysis of the resulting solid was consistent with Salt III.

Based on the characterization results, Salt III showed a tendency to form hydrate form. Although several low temperature thermal events were observed, the material appeared to be stable under thermal stress.

FIG. 42 provides an XRPD pattern of Salt III. A list of XRPD Peaks for Salt III is provided below in Table 40.


TABLE 40
X-Ray Diffraction Peaks for Salt III
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
4.18
21.14
2.11
4.71
18.77
65.00
4.98
17.76
18.65
5.61
15.75
17.46
6.06
14.60
34.64
6.41
13.80
11.03
6.73
13.14
7.69
7.14
12.39
7.87
7.39
11.96
12.77
8.01
11.04
11.19
8.55
10.34
4.72
8.78
10.07
5.16
9.03
9.80
9.46
9.73
9.09
20.42
9.88
8.95
34.85
10.72
8.26
39.75
10.89
8.12
50.42
11.76
7.53
8.26
11.89
7.44
9.01
12.48
7.09
25.58
12.97
6.83
8.88
13.29
6.66
4.99
13.97
6.34
27.99
14.54
6.09
90.90
14.65
6.05
100.00
15.18
5.84
62.41
15.29
5.79
66.49
16.35
5.42
49.40
16.49
5.37
37.96
17.01
5.21
2.87
17.17
5.16
6.63
18.09
4.90
22.64
19.70
4.51
4.56
21.78
4.08
6.45
22.62
3.93
6.14
23.13
3.85
3.58
23.99
3.71
6.61
24.44
3.64
7.47
25.16
3.54
2.65
25.44
3.50
4.44
25.88
3.44
2.22
27.37
3.26
6.45
28.88
3.09
16.07
29.93
2.99
3.52
32.09
2.79
2.50
34.55
2.60
7.41
37.21
2.42
1.67
40.15
2.25
3.75
40.86
2.21
4.58
41.95
2.16
1.21

6.4.7 Salt IV of Compound 1

Salt IV of Compound 1 is a monohydrated mono-sodium salt. Salt IV was obtained in filtration from the recrystallization experiment using acetone as primary solvent (Table 36, FIG. 61). IC analysis of this material indicated the material had a Compound 1 free acid:sodium ratio of 1.0:1.1, consistent with a mono-sodium salt. An estimated 0.29 wt % of acetone was observed by 1H NMR (Table 50, FIG. 62). DSC analysis presented two endotherms at 107.9, 307.4° C. and an exotherm at 217.2° C. (FIG. 63). TGA analysis indicated a weight loss of 5.43% at 60-120° C. attributed to water loss followed by an onset decomposition at 302.5° C. (FIG. 64). The material adsorbed 6.1 wt % moisture at 60% RH, and 6.5 wt % moisture at 90% RH, indicating it is moderately hygroscopic (FIG. 65). The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, recorded a consistent XRPD pattern as the starting material (FIG. 61). DVS analysis showed that Salt IV is a stable hydrate.

In an effort to isolate a high melt crystal form through a dehydration/recrystallization process, Salt IV was held at 130° C. for 2 minutes followed by cooling to ambient temperature. XRPD analysis of the resulting solid was consistent with Salt IV. The holding experiment was repeated by holding the material at 260° C., a temperature higher than the exothermic event at 217.2° C. A conversion to a new salt (Salt VI) was observed.

In the aqueous solubility study, no form change was observed after slurring Salt IV in water for 13 days (Table 49). A solubility of 19.0 mg/mL was attained. When storing Salt IV at 60° C., no polymorph conversion or degradation of the material was observed at day 1, and 7 (Table 48).

FIG. 43 provides an XRPD pattern of Salt IV. A list of XRPD Peaks for Salt IV is provided below in Table 41.


TABLE 41
X-Ray Diffraction Peaks for Salt IV
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.18
27.83
100.00
4.17
21.18
0.82
4.78
18.50
0.36
5.23
16.91
0.58
5.62
15.74
0.54
5.86
15.08
0.21
5.93
14.91
0.36
6.29
14.04
9.51
6.44
13.73
5.33
6.74
13.11
0.33
7.43
11.90
0.15
9.45
9.36
30.33
9.66
9.16
5.46
9.94
8.90
1.64
10.63
8.33
0.56
11.83
7.48
0.30
12.03
7.36
0.07
12.62
7.01
1.03
13.24
6.68
0.45
13.61
6.50
0.86
14.57
6.08
0.13
14.85
5.97
0.32
15.05
5.89
0.07
15.80
5.61
26.27
16.17
5.48
6.01
16.68
5.32
0.55
16.98
5.22
0.03
17.37
5.11
0.69
18.31
4.85
0.85
19.00
4.67
30.80
19.43
4.57
7.57
19.94
4.45
0.92
20.72
4.29
0.55
22.20
4.00
2.92
22.69
3.92
1.22
23.63
3.77
0.28
24.22
3.68
0.26
25.42
3.50
6.32
26.01
3.43
1.49
26.70
3.34
0.73
27.54
3.24
1.09
28.35
3.15
0.53
28.67
3.11
2.01
29.39
3.04
1.15
31.24
2.86
0.43
31.97
2.80
1.32
32.69
2.74
0.75
33.18
2.70
0.20
34.29
2.61
0.79
34.73
2.58
0.32
35.82
2.51
0.33
37.41
2.40
1.04
37.84
2.38
0.12
38.27
2.35
1.51
38.67
2.33
0.46
39.65
2.27
0.13
40.64
2.22
1.05
41.02
2.20
0.41
41.48
2.18
0.47
41.90
2.16
0.40
42.80
2.11
0.10
43.80
2.07
0.23
44.32
2.04
0.65
44.59
2.04
0.92

6.4.8 Salt V of Compound 1

Salt V of Compound 1 is a monohydrated bis-sodium salt. Salt V was obtained in filtration from the recrystallization experiment using acetone as primary solvent (Table 36, FIG. 66). IC analysis of this material indicated the material had a Compound 1 free acid:sodium ratio of 1.0:1.9, consistent with a bis-sodium salt. An estimated 2.26 wt % of acetone was observed by 1H NMR (Table 50, FIG. 67). DSC analysis presented an endotherm at 93.3° C. (FIG. 68). TGA analysis indicated a weight loss of 5.85% at 40-130° C. attributed to water loss, followed by an onset of decomposition at 344.8° C. (FIG. 69). The material adsorbed 6.0 wt % moisture at 60% RH, and 6.4 wt % moisture at 90% RH, indicating it is moderately hygroscopic (FIG. 70). Significant hysteresis was observed at 0-40% RH, indicating it is not a stable hydrate that may lose water at low humidity. The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, recorded a XRPD pattern mostly consistent with Salt V with a few missing peaks (FIG. 66).

No melting event was observed for this bis-sodium salt when subject to heating between 70-410° C. at the rate of 1° C./min on melting apparatus. The white crystalline Salt V remained unchanged until it reached the decomposition temperature (>320° C.) as shown in Table 51. The material showed a high solubility at 80.0 mg/mL.

FIG. 44 provides an XRPD pattern of Salt V. A list of XRPD Peaks for Salt V is provided below in Table 42.


TABLE 42
X-Ray Diffraction Peaks for Salt V
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.15
28.01
33.88
3.33
26.55
20.18
3.51
25.19
3.70
3.65
24.18
1.01
4.19
21.10
1.34
4.45
19.86
0.31
4.74
18.66
1.46
5.09
17.35
2.23
5.24
16.87
1.10
5.40
16.37
2.15
5.75
15.38
2.50
6.00
14.73
1.57
6.24
14.18
1.74
6.43
13.75
1.73
6.64
13.32
2.14
7.29
12.13
1.51
7.45
11.87
1.27
7.58
11.66
1.44
7.92
11.16
1.53
8.57
10.32
1.38
9.21
9.61
1.32
9.39
9.42
0.71
9.97
8.87
100.00
13.02
6.80
12.96
13.31
6.65
33.72
13.64
6.49
39.41
13.97
6.34
37.17
16.69
5.31
63.51
17.13
5.18
3.63
17.65
5.03
1.29
18.09
4.90
0.97
18.65
4.76
0.53
19.51
4.55
2.67
20.06
4.43
28.05
22.15
4.01
16.77
22.50
3.95
0.78
22.87
3.89
0.48
23.41
3.80
0.40
24.54
3.63
1.23
25.01
3.56
1.99
25.70
3.47
0.20
26.29
3.39
10.34
26.87
3.32
23.31
27.81
3.21
3.07
28.89
3.09
8.62
29.06
3.07
9.74
29.90
2.99
0.54
30.29
2.95
2.38
30.60
2.92
2.03
31.08
2.88
21.52
31.97
2.80
0.89
32.21
2.78
0.56
33.85
2.65
4.03
34.24
2.62
3.76
35.73
2.51
0.64
37.31
2.41
2.39
38.39
2.34
1.09
39.71
2.27
1.60
40.87
2.21
6.46
42.01
2.15
0.67
44.30
2.04
8.24

6.4.9 Salt VI of Compound 1

Salt VI of Compound 1 is an anhydrous mono-sodium salt. Salt VI was isolated from the thermal holding experiment (Table 50, FIG. 71). No degradation was observed by 1H NMR (Table 50, FIG. 73). DSC analysis presented two endothermic peaks at 282.4 and 308.4° C. and an exothermic peak at 283.9° C. (FIG. 74). No weight loss was observed by TGA, and the onset decomposition temperature is 305.7° C. (FIG. 75). The material adsorbed 0.3 wt % moisture at 60% RH, and 0.7 wt % moisture at 90% RH, indicating it is slightly hygroscopic material (FIG. 76).

The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, recorded a consistent XRPD diffractogram (FIG. 72). These results indicated that Salt VI is a stable anhydrate form of mono-sodium salt.

FIG. 45 provides an XRPD pattern of Salt VI. A list of XRPD Peaks for Salt VI is provided below in Table 43.


TABLE 43
X-Ray Diffraction Peaks for Salt VI
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.03
29.12
100.00
3.39
26.05
41.75
4.42
19.99
1.12
4.63
19.08
1.77
5.01
17.62
2.09
5.40
16.37
2.37
5.81
15.21
1.21
6.23
14.19
0.78
6.42
13.77
0.58
7.06
12.52
0.74
7.66
11.55
0.95
8.96
9.87
0.82
10.06
8.79
9.02
10.68
8.28
1.75
11.53
7.67
0.14
11.89
7.45
8.37
12.42
7.13
2.13
13.40
6.61
3.37
13.73
6.45
1.19
14.04
6.31
2.74
14.91
5.94
2.99
15.22
5.82
4.62
15.67
5.65
0.68
16.33
5.43
2.07
16.74
5.30
6.01
17.10
5.19
0.92
17.82
4.98
2.82
18.11
4.90
7.43
18.48
4.80
0.20
19.07
4.65
3.04
20.15
4.41
2.67
20.94
4.24
1.42
21.47
4.14
0.36
22.05
4.03
1.14
23.37
3.81
0.40
24.03
3.70
0.27
24.96
3.57
0.53
26.38
3.38
0.03
26.96
3.31
2.44
28.88
3.09
0.42
30.07
2.97
2.24
31.04
2.88
1.20
31.61
2.83
0.78
33.20
2.70
0.73
33.94
2.64
0.24
34.87
2.57
0.41
37.20
2.42
0.75
38.13
2.36
0.29
39.72
2.27
0.18
40.29
2.24
0.31
40.97
2.20
0.51
42.35
2.13
0.63
43.41
2.08
0.31
44.38
2.04
0.40

6.4.10 Salt VII of Compound 1

Salt VII of Compound 1 is a mono-sodium salt and a possible hydrate form. It was obtained from the salt formation experiment in MeOH. IC analysis of this material indicated the material had a free acid:sodium ratio of 1.0:1.2, consistent with a mono-sodium salt. 1H NMR (D2O) analysis was consistent with the chemical structure and no solvent was detected (FIG. 85). DSC analysis showed a broad transition before 90° C., which might be from water loss and a possible glass transition at 160° C. (FIG. 86). TGA analysis indicated no weight loss and onset decomposition at 290.6° C. (FIG. 87). Polarized microscopy analysis revealed birefringent particles, ˜10.0 μm to 80.0 μm (FIG. 88).

In the moisture sorption analysis, the material adsorbed 0.9 wt % moisture at 60% RH, and 2.9 wt % moisture at 90% RH (FIG. 89). The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, recorded a XRPD pattern consistent with the starting material (FIG. 90). DVS analysis showed minor hysteresis indicating that Salt VII of Compound 1 is a possible hydrate with variable water content depending on the environment humidity.

The polymorph form was stable after seven days of stirring in acetone and no change in XRPD pattern was observed. After seven days of storage at 60° C., no change in XRPD pattern and no degradation were observed by HPLC.

Approximately 160 mg of Compound 1 was weighed in a 20.0 mL clear vial equipped with magnetic stir bars and dissolved with minimum amount of methanol at 50° C. Prior to CI addition, each solution was polish filtered through a 0.45 μm syringe filter into clean preheated vials. After hot filtration, 1.2 mL of 0.5 M aqueous sodium hydroxide was added drop-wise. The vials were cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate with stirring at ambient temperature overnight with slow cooling. The resulting solids were transferred into a Bichner funnel (with grade 1 Whatman paper) and isolated by filtration. All obtained solids were dried under vacuum (˜30 inches Hg) and analyzed by XRPD to determine the solid pattern, 1H NMR to confirm structure and IC for salt stoichiometry (Table 37).

FIG. 84 provides an XRPD pattern of Salt VII. A list of XRPD Peaks for Salt VII is provided below in Table 44.


TABLE 44
X-Ray Diffraction Peaks for Salt VII
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.40
25.96
100.00
3.71
23.80
48.20
4.08
21.67
27.72
4.31
20.50
29.20
4.95
17.86
29.21
5.07
17.43
35.50
5.33
16.58
33.39
5.59
15.82
25.36
6.11
14.46
33.91
6.55
13.49
22.93
6.95
12.72
18.29
7.27
12.15
21.19
7.60
11.64
17.55
7.79
11.35
16.23
8.49
10.42
18.29
8.62
10.26
18.46
9.54
9.27
21.65
9.96
8.88
94.70
10.87
8.14
48.51
11.53
7.67
20.75
11.88
7.45
23.67
12.53
7.06
36.50
12.78
6.92
27.31
13.28
6.67
34.98
13.64
6.49
28.43
13.97
6.34
32.67
14.31
6.19
28.60
14.90
5.94
86.48
15.48
5.72
54.80
15.73
5.63
39.86
16.37
5.41
33.98
16.66
5.32
60.39
18.02
4.92
20.75
18.68
4.75
15.27
20.03
4.43
27.28
20.76
4.28
7.31
20.96
4.24
7.06
21.58
4.12
6.69
22.15
4.01
13.35
24.89
3.58
5.75
25.46
3.50
6.34
25.82
3.45
5.02
26.83
3.32
11.50
28.73
3.11
6.55
29.35
3.04
7.21
31.10
2.88
12.92
32.28
2.77
2.27
32.84
2.73
3.85
33.75
2.66
2.21
34.30
2.61
2.49
37.27
2.41
3.03
38.29
2.35
2.09
38.86
2.32
0.56
39.67
2.27
1.86
40.80
2.21
7.08
44.33
2.04
3.68

6.4.11 Salt VIII of Compound 1

Salt VIII of Compound 1 is a mono-sodium salt and a stable anhydrate polymorph. It was obtained from the slurry experiment using MeOH as solvent (FIG. 91). IC analysis of this material indicated the material had a free acid:sodium ratio of 1.0:1.1, consistent with a mono-sodium salt. No degradation was observed by 1H NMR (D2O) (FIG. 92). DSC analysis showed no thermic change before onset decomposition at 294.0° C. (FIG. 93). TGA analysis showed no weight loss and an onset decomposition at 291.2° C. (FIG. 94). Polarized microscopy analysis revealed birefringent particles, ˜20.0 μm to 80.0 μm (FIG. 95).

Salt VIII of Compound 1 adsorbed 1.0 wt % moisture at 60% RH, and 2.7 wt % moisture at 90% RH (FIG. 96). The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, showed an XRPD pattern consistent with the starting material (FIG. 97).

Salt VIII of Compound 1 was stable after seven days of stirring in acetone and no change in XRPD pattern was observed. In competitive slurry experiments, Salt VIII of Compound 1 was stable in an acetone slurry after seven days of equilibration. After seven days of storage at 60° C., no change in XRPD pattern and no degradation were observed by HPLC.

Approximately 150 mg of Salt IV of Compound 1 was placed into a 20.0 mL clear vial equipped with magnetic stir bars. Methanol (10.0 mL) was added to achieve free-flowing slurry and allowed to equilibrate at room temperature. The slurry was transferred into a Büchner funnel (with grade 1 Whatman paper) after one day of equilibration. The resulting solid was dried under vacuum (˜30 inches Hg) and analyzed by XRPD to determine the solid pattern, 1H NMR to confirm structure and IC for salt stoichiometry (Table 37).

FIG. 91 provides an XRPD pattern of Salt VIII. A list of XRPD Peaks for Salt VIII is provided below in Table 45.


TABLE 45
X-Ray Diffraction Peaks for Salt VIII
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.06
28.86
100.00
3.39
26.07
73.24
3.64
24.29
31.30
3.79
23.31
27.13
3.95
22.36
24.85
4.54
19.47
16.91
4.94
17.89
27.50
5.07
17.44
23.21
5.21
16.95
18.18
5.40
16.37
16.87
6.02
14.69
17.08
6.27
14.11
14.06
6.65
13.28
15.61
7.18
12.31
12.13
8.00
11.06
6.23
8.37
10.56
10.79
9.32
9.49
9.06
10.00
8.85
22.09
10.43
8.48
13.83
11.04
8.01
30.28
11.94
7.41
9.98
12.72
6.96
21.11
13.01
6.80
18.85
13.71
6.46
35.02
13.97
6.34
31.38
14.66
6.04
24.16
15.01
5.90
54.69
15.65
5.66
43.71
15.73
5.63
34.23
16.34
5.42
15.36
16.69
5.31
16.66
17.14
5.17
10.36
17.37
5.11
6.32
18.31
4.84
16.85
18.91
4.69
8.79
19.57
4.54
5.57
20.13
4.41
13.39
22.17
4.01
10.89
24.68
3.61
3.20
25.02
3.56
3.44
26.92
3.31
5.68
28.96
3.08
6.20
29.53
3.02
6.68
31.12
2.87
6.69
32.42
2.76
1.62
33.47
2.68
1.24
33.76
2.66
0.81
34.58
2.59
1.21
35.75
2.51
1.74
37.25
2.41
2.01
39.65
2.27
1.30
40.87
2.21
1.65
42.36
2.13
1.62
43.42
2.08
1.57
44.34
2.04
1.72

6.4.12 Salt IX of Compound 1

Salt IX of Compound 1 is a mono-sodium salt and an anhydrate polymorph. It was obtained from salt formation experiments in acetone (FIG. 98). IC analysis of this material indicated the material had a free acid:sodium ratio of 1.0:1.1, consistent with a mono-sodium salt. An estimated 0.01 wt % of acetone was observed by 1H NMR (D2O) (FIG. 99). DSC analysis showed an endotherm at 82.8° C. and exotherm at 229.5° C. (FIG. 100). However, DSC analysis of the post thermal holding experiment at 150° C. showed no endothermic change before 180° C. (FIG. 102). XRPD analysis of the post thermal holding experiment gave material consistent with the starting material, which indicated the endothermic change was not related to a form change. TGA analysis indicated no weight loss and an onset decomposition of 301.8° C. (FIG. 101). Polarized microscopy analysis revealed birefringent particles, ˜10.0 μm to 40.0 μm (FIG. 103).

The material adsorbed 0.3 wt % moisture at 60% RH, and 0.3 wt % moisture at 90% RH (FIG. 104). The XRPD analysis of the post-DVS material after drying at 60.0° C. for two hours, showed an XRPD pattern consistent with Salt IV of Compound 1.

After seven days of stirring in water and acetone, all Salt IX of Compound 1 had converted to Salt VIII or Salt IV. After seven days of storage at 60° C., no change in XRPD pattern and no degradation were observed by HPLC.

Approximately 1.6 g of Compound 1 was placed into a 250 mL round bottom flask equipped with stir bar and dissolved with 123.0 mL of acetone at 50° C. The solution was polish filtered through a 0.45 M syringe filter into clean preheated flask. After hot filtration, 12.7 mL of 0.5 M sodium hydroxide was added drop-wise to generate a white color suspension. After stirred at 50° C. for 10 minutes, the flask was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate with stirring at ambient temperature overnight with slow cooling. The resulting solids were transferred into a Büchner funnel (with grade 1 Whatman paper) and isolated by filtration. The clear solutions were kept at ambient temperature. The obtained solid was dried under vacuum (˜30 inches Hg) and analyzed by XRPD to determine the solid pattern, 1H NMR to confirm structure and IC for salt stoichiometry.

FIG. 98 provides an XRPD pattern of Salt IX. A list of XRPD Peaks for Salt IX is provided below in Table 46.


TABLE 46
X-Ray Diffraction Peaks for Salt IX
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.05
28.95
78.75
3.19
27.68
100.00
4.33
20.41
6.91
4.57
19.34
6.24
5.11
17.30
4.92
5.25
16.82
4.17
5.71
15.47
5.57
6.32
13.98
35.72
7.68
11.51
4.25
7.88
11.22
4.40
9.47
9.34
99.14
9.93
8.91
7.57
10.04
8.81
9.36
12.63
7.01
4.96
13.06
6.78
6.44
13.69
6.47
21.62
14.01
6.32
13.40
14.89
5.95
3.86
15.83
5.60
65.85
16.31
5.44
4.42
16.68
5.32
4.05
17.39
5.10
5.60
18.33
4.84
2.89
19.01
4.67
79.21
19.94
4.45
4.88
20.72
4.29
4.76
20.88
4.25
2.57
22.12
4.02
7.77
22.27
3.99
6.70
22.60
3.93
5.31
23.58
3.77
2.40
24.21
3.68
2.54
24.69
3.61
2.16
25.47
3.50
17.07
26.26
3.39
2.92
26.62
3.35
4.83
27.63
3.23
10.05
28.42
3.14
4.76
28.73
3.11
5.48
29.44
3.03
5.15
31.25
2.86
2.74
31.90
2.81
3.89
32.51
2.75
1.25
33.23
2.70
1.41
34.35
2.61
3.94
35.85
2.50
1.23
37.39
2.41
4.41
38.30
2.35
6.23
39.79
2.27
0.81
40.61
2.22
4.40
41.44
2.18
2.34
41.96
2.15
1.04
44.56
2.03
3.89

6.4.13 Salt X of Compound 1

Salt X of Compound 1 is a mono-sodium salt and an unstable hydrate polymorph. It was obtained from the binary solvent crystallization experiment, using water as primary solvent and THF as anti-solvent (FIG. 105). IC analysis of this material indicated the material had a free acid:sodium ratio of 1.0:1.0, consistent with a mono-sodium salt. 1H NMR (D2O) analysis indicated this material contained an estimated 3.5 wt % of 4-hydroxybutanoic acid, which was the contamination of tetrahydrofuran peroxides (FIG. 106). DSC analysis showed two endotherms at 91.3° C. and 149.3° C., respectively and an exotherm at 230.6° C. (FIG. 107). TGA analysis indicated a 1.3% weight loss at 60-120° C. and a 2.3% weight loss at 120-180° C., followed by an onset decomposition at 296.7° C. (FIG. 108). Polarized microscopy analysis revealed birefringent particles, ˜10.0 μm to 40.0 μm (FIG. 109).

After seven days of stirring in water and acetone, all Salt X converted to Salt VII or Salt IV. After seven days of storage at 60° C., no change in XRPD pattern and no degradation were observed by HPLC.

Approximately 168 mg of Salt IV of Compound 1 was placed into a 50.0 mL clear glass vial equipped with stir bar and dissolved in 4.3 mL of water at 60° C. Tetrahydrofuran, 12.8 mL, was added drop-wise at the same temperature. The vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate with stirring at ambient temperature over 24 hours. The solvent was evaporated to dryness under a gentle stream of nitrogen gas. The obtained solid was dried under vacuum (˜30 inches Hg) and analyzed by XRPD to determine the solid form, 1H NMR to confirm structure and IC for salt stoichiometry.

FIG. 105 provides an XRPD pattern of Salt X. A list of XRPD Peaks for Salt X is provided below in Table 47.


TABLE 47
X-Ray Diffraction Peaks for Salt X
Relative
Two-theta angle (°)
d Space (Å)
Intensity (%)
3.20
27.65
60.05
3.74
23.61
100.00
4.11
21.51
11.05
4.23
20.90
8.87
4.36
20.28
6.93
4.59
19.26
5.18
4.78
18.48
7.24
5.03
17.59
6.96
5.22
16.92
5.19
5.43
16.27
5.79
5.62
15.72
5.24
5.88
15.04
8.05
6.06
14.58
7.87
6.28
14.08
10.30
6.76
13.08
5.00
7.24
12.20
5.19
7.41
11.92
4.33
7.83
11.30
4.33
8.01
11.03
4.13
9.50
9.31
14.32
10.37
8.53
3.76
11.01
8.04
3.65
11.15
7.93
7.58
11.38
7.78
3.38
12.12
7.30
2.94
12.75
6.94
3.38
13.58
6.52
7.26
14.37
6.16
7.76
14.87
5.96
5.54
15.06
5.88
7.16
15.41
5.75
44.42
15.78
5.62
11.20
16.65
5.32
4.31
18.71
4.74
31.15
19.70
4.51
15.61
20.35
4.36
11.27
20.88
4.26
13.46
22.16
4.01
14.64
22.49
3.95
10.09
23.83
3.73
20.69
24.73
3.60
9.74
25.62
3.48
60.92
26.38
3.38
8.68
27.11
3.29
11.10
28.71
3.11
10.22
29.79
3.00
8.15
30.65
2.92
4.71
31.15
2.87
6.76
32.80
2.73
4.49
34.52
2.60
2.50
35.81
2.51
0.77
37.64
2.39
0.99
38.77
2.32
1.44
41.35
2.18
1.24
42.26
2.14
2.24
43.70
2.07
3.25
44.25
2.05
2.30

6.4.14 400 mg Scale Preparation of Salt I, Salt II, Salt III, Salt IV and Salt V

Approximately 400 mg of Compound 1 was placed into 20 mL clear glass vials equipped with stir bars and dissolved with a minimum amount of solvents at 50° C. Methanol was used as the primary solvent to dissolve Compound 1 before addition of counter ion (CI) (0.25 M calcium acetate hydrate/H2O) to generate Salt I. Acetone was used as primary solvent for dissolving Compound 1 before addition of CI to generate Salt II. Prior to CI addition, each solution was polish filtered through a 0.45 μm syringe filter into clean preheated vials. After hot filtration, 5.8 mL of 0.25 M calcium acetate hydrate was added drop-wise. The vials were cooled to ambient temperature at a rate of 20° C./hr and allowed to equilibrate with stirring at ambient temperature overnight with slow cooling. The resulting solids were transferred into a Büchner funnel (with grade 1 Whitman paper) and isolated by filtration. The clear solutions were kept in RT. All obtained solids were analyzed by XRPD to characterize the solid (Table 48)

Approximately 400 mg of Compound 1 was placed into 20 mL clear glass vial equipped with stir bar and dissolved with a minimum amount of solvent at 50° C. Acetonitrile was used as the primary solvent to dissolve Compound 1 before addition of counter ion (CI) (0.5 M potassium hydroxide/H2O) to generate Salt III. Prior to CI addition, the solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, 1.9 mL of 0.5 M potassium hydroxide was added drop-wise. The vial was cooled to ambient temperature at a rate of 20° C./hr and allowed to equilibrate with stirring at ambient temperature overnight with slow cooling. The resulting solid was transferred into a Buchner funnel (with grade 1 Whitman paper) and isolated by filtration. The clear solution was kept in RT. Obtained solid was analyzed by XRPD to characterize the solid (Table 48)

Approximately ˜250 to 400 mg of Compound 1 was placed into 20 mL clear glass vials equipped with stir bars and dissolved with a minimum amount of solvents at 50° C. Acetone was used as the primary solvent to dissolve Compound 1 before addition of CI (0.5 M sodium hydroxide/H2O) to generate Salt IV and Salt V. Prior to CI addition, each solution was polish filtered through a 0.45 μm syringe filter into clean preheated vials. After hot filtration, 1.8 mL of 0.5 M sodium hydroxide was added drop-wise to generate Salt IV, and 5.8 mL of 0.5 M sodium hydroxide was added drop-wise to generate Salt V. The vials were cooled to ambient temperature at a rate of 20° C./hr and allowed to equilibrate with stirring at ambient temperature overnight with slow cooling. The resulting solids were transferred into a Buchner funnel (with grade 1 Whitman paper) and isolated by filtration. The clear solutions were kept in RT. All obtained solids were analyzed by XRPD to characterize the solid (Table 48)

Details of the experiments are summarized in Table 48.


TABLE 48
Scale up of Salts I, II, III, IV and V
Primary
API
solvent
amnt.
Primary
Temp.
Vol.
CI Vol.
Precipitation/
pH of
Recovery
Yield (%,
Salt
(mg)
Solvent
(° C.)
(mL)
(mL)
Isolation
Filtrate
(mg)
filtration)
XRPD
Ca2+
398.9
MeOH
50.0
13.3
4.8
PPT
6.07
407.1
91.9
Salt I
formed,
Filtration
Ca2+
402.3
Acetone
50.0
23.4
5.8
PPT
6.56
561.8
116.4
Salt II
formed,
Filtration
K+
396.7
MeCN
50.0
27.7
1.9
PPT
9.74
149
32.9
Salt III
formed,
Filtration
K+
320.4
MeCN
50.0
22.7
2.3
PPT
7.50
273.4
74.8
Salt III +
formed,
H
Filtration
Na+
251.2
Acetone
50.0
18.4
1.8
PPT
8.54
241.4
80.1
Salt IV
formed,
Filtration
Na+
405.3
Acetone
50.0
23.5
5.8
PPT
9.24
400.5
82.3
Salt V
formed,
Filtration
*Cooling method - Slow Cooling (20° C./hr)

Table 49 provides thermal stability data. Table 50 provides TGA thermal data. Table 51 provides stability of crystalline materials from selected salts in different humidity.


TABLE 49
Thermal Stability Experiments
Parent
Aliquot time
Aliquot time
Material
Parent
Weight
Temp
point
point
HPLC
HPLC
Material
(mg)
(° C.)
Day
XRPD
Day
XRPD
(% AUC)
(% AUC)
Filtration,
42.4
60.0
1
Salt I
7
Salt I
N/A*
N/A*
Salt I
Filtration,
47.2
60.0
1
Salt II
7
Salt II
99.9
99.9
Salt II
Filtration,
35.6
60.0
1
Salt III
7
Salt III
99.9
99.9
Salt III
Filtration,
37.8
60.0
1
Salt IV
7
Salt IV
99.9
99.9
Salt IV
Filtration,
3.6.4
60.0
1
Salt V
7
Salt V
99.9
99.9
Salt V
*Materials poorly dissolved in D2O, DMSO, or diluent for HPLC analysis. No degradation of the materials (before and after thermal stress analysis) based on 1H NMR.


TABLE 50
TGA thermal hold experiments of crystalline materials from selected salts
XRPD
Post thermal
Thermal Hold
Pre-
Post
hold, sample
Parent
Weight
Temperature
Holding
thermal
thermal
left on bench
Material
(mg)
range, ° C.
Temp./time
hold
hold
top, 24 hrs*
Filtration,
6.184
30-130, at
130° C./
Salt IV
Salt IV
Salt IV
Salt IV
10° C./min
2 min
Filtration,
4.957
180-260, at
260° C./
Salt IV
Salt VI
Salt VI
Salt IV
10° C./min
2 min
Filtration,
8.84
30-160, at
160° C./
Salt V
Salt V +
Salt V +
Salt V
10° C./min
2 min
missing peaks
missing peaks
Filtration,
8.208
30-130, at
130° C./
Salt III +
Salt III
Salt III
Salt III
10° C./min
2 min
Salt IX


TABLE 51
Stability of Crystalline materials from selected salts in different
humidity.
XRPD
Parent
Weight
Humidity
Post humidity
Material
(mg)
condition
Initial
exposure
Filtration,
4.35
 0% RH, RT
Salt V
Salt V + missing
Salt V
peaks
Filtration,
7.12
65% RH, RT
Salt V
Salt V
Salt V
Filtration,
11.5
65% RH, RT
Salt IV
Salt IV + missing
Salt IV
peaks
Filtration,
19.23
65% RH, RT
Salt III + Salt IX
Salt III + Salt IX
Salt III

6.5 Synthesis of Compound 1

6.5.1 Preparation of 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4)

Potassium carbonate (1785 g, 1.49 eq), 3,5-dichloro-2-cyanopyridine (1500 g, 1.0 eq), (3-fluorophenyl)boronic acid (1069.5 g, 1.0 eq), dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium (II) (DCM adduct PdCl2(dppf)) (30 g, 0.004 eq) and dimethylformamide (10.6 kg) were charged to a 30 L reactor equipped with an over-head agitator, condenser, thermocouple and nitrogen sparger. The mixture was agitated and sparged with nitrogen gas through the dip-tube for ca. 30 minutes. Degassed water (969 g) was slowly charged to the mixture while maintaining a temperature of less than 45° C.

The reaction mixture was agitated at 20 to 45° C. and sparged with nitrogen gas through the dip-tube for 30 minutes, followed by agitation at 50° C. (between 47 to 53° C.) for 12 to 24 hours until the reaction was determined to be complete due to the disappearance of compound 2 as measured by HPLC.

The reaction mixture was cooled to 22° C. (between 19 to 25° C.). n-Heptane (2.2 kg) and water (12.9 kg) were charged to the reaction mixture while keeping the temperature at no more than 45° C. After the mixture was agitated at 22° C. (between 19 to 25° C.) for 1 to 2 hours, crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was isolated as a solid by filtration.

The crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was transferred into an empty reactor with water (12.9 kg). The mixture was agitated at 22° C. (between 19 to 25° C.) for 2 hours. Crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was isolated as a solid by filtration and washed with water (3 kg).

The crude 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was transferred into an empty reactor with 2-propanol (14.25 kg). The mixture was agitated at reflux at 82° C. for 1 to 2 hours. After cooling to 22° C. (19 to 25° C.), the mixture was agitated at 22° C. (19 to 25° C.) for 2 to 3 hours. 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was isolated as a solid by filtration and rinsed with 2-propanol (2.36 kg).

After being dried under vacuum at 50° C. until the water content was less than 1.5% (˜16 hours), 1736.9 g 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4) was obtained as a brown solid (yield 86%). FIG. 77 depicts the 1H NMR spectrum of 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (4).

6.5.2 Preparation of 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine (5)

5-(3-fluorophenyl)-3-chloro-2-cyanopyridine (1.2 kg, 1.0 eq) and methanol (17.8 kg) were charged to a 30 L reactor equipped with an over-head agitator, condenser, thermocouple and nitrogen bubbler. 25% sodium methoxide in methanol (2.01 kg, 1.8 eq) was charged to the reactor and rinsed with methanol (1.2 kg). The reaction mixture was agitated at reflux (ca. 68° C.) for 12 to 24 hours until the reaction was determined to be complete.

The reaction mixture was distilled under vacuum to a volume of ca. 12 L with a maximum bath/jacket temperature of 50° C. After the mixture was cooled to 22° C. (19 to 25° C.), water (12 kg) was charged. After the mixture was agitated at 22° C. (19 to 25° C.) for 1 to 2 hours, crude 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine (5) was isolated as a solid by filtration. The filter cake was washed with methanol (0.95 kg) and pulled dry until no filtrate was observed.

The crude 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine (5) was transferred into an empty reactor with acetone (19.2 kg) and agitated at 22° C. (between 19 to 25° C.) until all solids dissolved (˜1 hour).

A celite pad (ca. 1″) was packed in a 3 L glass Buchner funnel and wetted with acetone. Activated carbon Darco G-60 (0.24 kg) was packed on the top of the celite pad. A second celite pad (ca 1″) was packed on the top of the carbon and wetted with acetone. The acetone solution was filtered through the carbon/celite pad and rinsed with acetone (4.8 kg).

The acetone solution was distilled under vacuum (bath temperature of 50° C.) to a volume of 4.8 L. Methanol (3.6 kg) was charged and the suspension and concentrated to 4.8 L. The acetone chasing was repeated twice. The slurry was agitated at 22° C. (19 to 25° C.) for 2 to 3 hours, 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine (5), filtered and washed with methanol (2.4 kg).

The isolated 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine (5) was dried under vacuum at 45° C. to give 992.3 g 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine (5) in 84% yield. FIG. 78 depicts the 1H NMR spectrum of 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine (5).

6.5.3 Preparation of 5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxylic acid (6)

5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine (1.35 kg, 1.0 eq) and 37% aqueous HCl (9.72 kg) were charged to a 30 L reactor with condenser, agitator, nitrogen line and scrubber containing ca. 20% aqueous sodium hydroxide. The reaction mixture was heated gradually to 70° C. (67 to 73° C.) over 2 hours.

After the mixture was agitated at 70° C. (67 to 73° C.) for 3 hours, water (8.1 kg) was charged. The reaction mixture was heated to reflux (108 to 110° C.) and agitated until the reaction was determined to be complete when the total AUC of 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine 5, 5-(3-fluorophenyl)-3-methoxypicolinamide (5′) (See 1H NMR in FIG. 81) and 5-(3-fluorophenyl)-3-methoxypicolinic acid (5″) (See 1H NMR in FIG. 81) was less than 1% as measured by HPLC (16 to 48 hr expected).

An alternative procedure after the water is charged comprises of: a) refluxing for ca. 16 hours; b) charging additional concentrated HCl (1.62 kg) to the reaction mixture; c) refluxing for 6 hours; d) charging another portion of concentrated HCl (1.62 kg) to the reaction mixture; and e) refluxing for 12 hours; and f) proceeding to HPLC analysis.

After the reaction mixture was cooled to 22° C. (19° C. to 25° C., water (4.05 kg), was charged and the reaction mixture agitated at 22° C. (19° C. to 25° C.) for ca. 3 to 4 hours. The solids were isolated by filtration, rinsed with water (6.75 kg) and dried.

The solid was transferred into a reactor with acetone (11.75 kg) and agitated at reflux (ca 58° C.) for 2 hours. The mixture was cooled to 22° C. (19° C. to 25° C.) and agitated at 22° C. for 2 hours. The solid was isolated by filtration and rinsed with water (2.13 kg).

The solid was dried under vacuum at 45 to 50° C. until the water content was less than 0.5% wt. 1200.3 g of 5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxylic acid (6) was obtained as an off-white solid in 84% yield. FIG. 79 depicts the 1H NMR spectrum of 5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxylic acid (6).

6.5.4 Preparation of N-carboxymethyl-5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxamide (1)

5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxylic acid (1.8 kg), THF (7.2 kg) and N,N-diisopropylethylamine (2.2 kg) were charged to a 30 L reactor with stirrer, addition funnel, condenser, and nitrogen bubbler. The mixture was cooled to 3° C. (0 to 6° C.).

Trimethylacetyl chloride (2.05 kg, 2.2 eq) was added via an addition funnel to the reaction mixture while keeping the temperature around 3° C. (0 to 6° C.). The reaction mixture was agitated at 3° C. (0 to 6° C.) until the reaction was determined to be complete by HPLC (1 to 3 hours).

Glycine methyl ester HCl salt (1.21 kg, 1.25 eq.) was added to the reaction mixture followed by N,N-diisopropylethylamine (1.31 kg, 1.30 eq.) while keeping the temperature below 22° C.

The reaction mixture was agitated at 22° C. (19 to 25° C.) until deemed complete by HPLC (4 to 12 hours expected).

Ethanol (4.32 kg) was added and the reaction mixture and agitated for 15 to 30 minutes. The reaction mixture was distilled under reduce pressure at a maximum temperature of 45° C. to ca. 5 volumes. The solvent switch was repeated twice

Ethanol (4.32 kg) and water (9.0 kg) were added to the reaction mixture and agitated at 22° C. (19 to 25° C.) for 3 hours. The solid was isolated by filtration, rinsed with a mixture of water (1.8 kg) and ethanol (1.42 kg), followed by rinsing with water (1.8 kg). The solid was dried on the filter for ca. 2 hours. The resulting solid was white to off-white and contained 3 to 5% of methyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetate (8) (See 1H NMR in FIG. 83) and 94 to 97% 5-(3-fluorophenyl)-2-(2-methoxy-2-oxoethylcarbamoyl)pyridin-3-yl pivalate (9) (See 1H NMR in FIG. 82).

The methyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetate (8) and 5-(3-fluorophenyl)-2-(2-methoxy-2-oxoethylcarbamoyl)pyridin-3-yl pivalate (9) mixture, and THF (11.16 kg) were charged to a 30 L reactor with stirrer, addition funnel, thermocouple and nitrogen line. The mixture was agitated at 22° C. (19 to 25° C.) until all solids dissolved, followed by the addition of water (9.0 kg). A solution of 50% NaOH (1.85 kg) in water (1.8 kg) was added to the reaction mixture while keeping the temperature around 3° C. (0 to 5° C.). The reaction mixture was warmed to 22° C. (19 to 25° C.) and agitated until the reaction was deemed to be complete.

The reaction mixture was adjusted to ˜pH 2, by adding concentrated HCl (ca. 2.36 kg, 3.1 eq.) while keeping the temperature below 25° C. The reaction mixture was agitated at 22° C. (19 to 25° C.) for ca. 30 minutes to 1 hour. The organic phase was separated and filtered through a one μm filter.

The solution was distilled under reduced pressure at not more than 45° C. to ca. 3 volumes. Acetone (5.65 kg) was charged, followed by distillation under vacuum to ca. 3 volumes. After the solvent chase was twice repeated, water (10.8 kg) was charged to the slurry, followed by agitation at 22° C. (19 to 25° C.) for at least 2 hours. The solid was isolated by filtration, washed with a mixture of acetone (1.42 kg) and water (1.8 kg).

The solid was dried under vacuum at 50° C. to give 1818.4 g N-carboxymethyl-5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxamide (1) as a white to off white solid in 81% yield. FIG. 80 depicts the 1H NMR spectrum of N-carboxymethyl-5-(3-fluorophenyl)-3-hydroxypyridine-2-carboxamide (1).

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Patents Cited in This Cited by
Title Current Assignee Application Date Publication Date
三環式ヘテロアリール誘導体 YAMANOUCHI PHARMACEUT CO LTD 05 August 1999 20 February 2001
過剰増殖障害および血管新生に関連する疾患の処置に有用なヘテロアリール置換ピラゾール誘導体 バイエル·インテレクチュアル·プロパティ·ゲゼルシャフト·ミット·ベシュレンクテル·ハフツング,BAYER INTELLECTUAL PROPERTY GMBH 08 May 2008 12 August 2010
Substituted heterocyclic carboxylic acid amide esters, their preparation and their us as medicaments HOECHST AKTIENGESELLSCHAFT 27 October 1994 03 May 1995
3-alkoxypyridine-2-carboxylic acid amide esters, their preparation and their use as drugs HOECHST AKTIENGESELLSCHAFT 30 April 1996 06 November 1997
Pharmaceuticals and methods for treating hypoxia and screening methods therefor DANA FARBER CANCER INSTITUTE 19 March 2002 19 December 2002
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US10150734 Solid forms 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, 1 US10150734 Solid forms 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, 2 US10150734 Solid forms 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, 3