US20190100512A1 - Solid forms comprising (1e, 4e)-2-amino-n,n-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3h-benzo[b]azepine-4-carboxamide, compositions thereof, and uses thereof - Google Patents

Solid forms comprising (1e, 4e)-2-amino-n,n-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3h-benzo[b]azepine-4-carboxamide, compositions thereof, and uses thereof Download PDF

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US20190100512A1
US20190100512A1 US15/537,331 US201515537331A US2019100512A1 US 20190100512 A1 US20190100512 A1 US 20190100512A1 US 201515537331 A US201515537331 A US 201515537331A US 2019100512 A1 US2019100512 A1 US 2019100512A1
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compound
crystalline form
formula
xrpd pattern
peaks
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Hon-Wah Man
Timothy D. Fitzpatrick
Anthony FRANK
Ying Li
Xiaoling Lu
Marie G. Beauchamps
Antonio C. Ferretti
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Celgene Corp
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Celgene Corp
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Assigned to VENTIRX PHARMACEUTICALS, INC. reassignment VENTIRX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FITZPATRICK, TIMOTHY D.
Assigned to CELGENE CORPORATION reassignment CELGENE CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VENTIRX PHARMACEUTICALS, INC.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • compositions of the crystalline forms of (1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b] azepine-4-carboxamide (“Compound A”), methods of making the crystalline forms, and methods of using the crystalline forms for the treatment of diseases, including, for example, cancer.
  • cancers There is an enormous variety of cancers which are described in detail in the medical literature. Examples include cancers of the lung, colon, liver, kidneys, bladder, ovaries, prostate, breast, head and neck, brain, blood and intestine. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. To that end, there is a need in the art for additional molecular targets for effective anti-cancer therapies.
  • TLRs Toll-like receptors
  • NFKB NFKB
  • compositions including the crystalline forms of the compound of formula (I) described herein, methods of making the crystalline forms, and methods of using the crystalline forms for the treatment of diseases, including, for example, cancer.
  • the method includes agonizing a Toll-like receptor (TLR8) by contacting TLR8 with an effective amount of a crystalline form of the compound formula (I) described herein, wherein the effective amount agonizes the TLR8.
  • TLR8 Toll-like receptor
  • the method includes treating cancer by administering a therapeutically effective amount of a crystalline form of the compound formula (I) described herein to a subject in need thereof, thereby treating the cancer.
  • the crystalline forms of the compound of formula (I) and pharmaceutical compositions comprising the same can be used for methods of treating cancer.
  • FIG. 1 Illustrates the structure of Compound A
  • FIG. 2 Illustrates the 1 H NMR spectrum of assay determination of starting material.
  • the internal standard is hydrochinone dimethylether (HQDE).
  • FIG. 3 Illustrates the microscopy picture of Starting material.
  • the bar indicates 250 ⁇ m.
  • FIG. 4 Illustrates the overlay of 7 forms tested by HPLC with Compound A at 5.78 min. From bottom to top: blank, C2_1, A1_10, C3_1, C3 2, A1_5, A1_6 and A2_1 (corresponding to Experiment Nos. of Table 1-3).
  • FIG. SA. illlustrates one microscopy picture of different screening samples of form A.
  • FIG. 5B illlustrates another microscopy picture of different screening samples of form A.
  • FIG. 5C illlustrates another microscopy picture of different screening samples of form A.
  • FIG. 5D illlustrates another microscopy picture of different screening samples of form A. All pictures taken with crossed polarized filters. The bar indicates approximately 250 ⁇ m.
  • FIG. 6 Illustrates the 1 H NMR of Form A.
  • FIG. 7 Illustrates the DSC of crude sample (Form A) with two melting endotherms: 202° C. (peak, Form A) and 212° C. (peak, likely Form G).
  • FIG. 8 Illustrates the TGA with SDTA curve of Form A showing a weight loss of approximately 0.28% w/w up to the first melting endotherm.
  • FIG. 9A illustrates a microscopy picture of Form B (Table 1 experiment A1_10) taken with crossed polarization filters.
  • FIG. 9B illustrates a microscopy picture of Form B taken without polarization. The bar indicates approximately 250 ⁇ m.
  • FIG. 10 Illustrates the 1 H NMR of form B (Table 1 experiment A1_10) showing at 3.7 ppm 2 protons from compound and 8 protons from dioxane.
  • FIG. 11 Illustrates the DSC of form B (Table 1 experiment A1_10) with two endotherms. The endotherm of about 100° C. likely corresponds to dioxane release.
  • FIG. 12 Illustrates the TGA with SDTA curve of form B (Table 1 experiment A1_10) showing a weight loss of about 10% w/w around 100° C. and steady weight loss after this first step.
  • FIG. 13 Illustrates the 1 H NMR overlay of material after ACN slurry (bottom, ca. 0.9 eq) and after drying off ACN (bottom) and crude 3 (top).
  • FIG. 14 Illustrates the overlay of isolated material: top: completely dried (form C, crude 3#1), middle: gently dried (crude 2#1) and wet cake (bottom, crude 1#1).
  • FIG. 15 Illustrates the DSC of form C/J mixture (crude 2#1) containing approximately 0.9 eq ACN which causes an endotherm at about 100° C.
  • FIG. 16 Illustrates the DSC of form C (pure).
  • FIG. 17A illustrates the microscopy picture of form D (Table 2 experiment B1_1) showing hedgehog-like crystal agglomerates using crossed polarization filters.
  • FIG. 17B illustrates the microscopy picture of form D (Table 2 experiment B1_1) showing hedgehog-like crystal agglomerates without using polarization. The bar indicates approximately 250 ⁇ m.
  • FIG. 18 Illustrates the 1 H NMR of Form D.
  • FIG. 19 Illustrates the DSC of form D (Table 3 experiment C3 2) with two endotherm/exotherm combinations at about 140° C. and about 160° C. (both not integrated) and a melting endotherm at about 209° C. (peak).
  • FIG. 20 Illustrates the TGA with SDTA curve of form D (Table 3 experiment C3 2) showing a weight loss up to 150° C. of about 13% w/w (mono solvate would correspond to approximately 16% w/w).
  • FIG. 21A illustrates the microscopy picture of form E (Table 1 experiment A1_5) showing needle-like crystals using crossed polarization filters.
  • FIG. 21B illustrates the microscopy picture of form E (Table 1 experiment A1_5) showing needle-like crystals without polarization. The bar indicates approximately 250 ⁇ m.
  • FIG. 22A illustrates the microscopy picture of form F (Table 1 experiment A1_6) showing the border of the solidified oil with crossed polarization filters.
  • FIG. 22B illustrates the microscopy picture of form F (Table 1 experiment A1_6) showing the border of the solidified oil without polarization. The bar indicates approximately 250 ⁇ m.
  • FIG. 23 Illustrates the 1 H NMR of form F.
  • FIG. 24 Illustrates the DSC of form F (Table 1 experiment A1_6) with an endotherm/exotherm combination at about 100° C. (not integrated) and a melting endotherm at about 209° C. (peak).
  • FIG. 25 Illustrates the TGA with SDTA curve of form F (Table 1 experiment A1_6) showing a weight loss up to 160° C. of about 14% w/w (mono solvate would correspond to approximately 18% w/w).
  • FIG. 26A illustrates the microscopy pictures of form G (Table 1 experiment A2_1, A2_10) showing hedgehog-like crystal agglomerates with crossed polarization filters.
  • FIG. 26B illustrates the microscopy pictures of form G showing the needle forming form G with crossed polarization filters.
  • FIG. 26C illustrates the microscopy pictures of form G showing hedgehog-like crystal agglomerates without polarization. The red bar indicates about 250 ⁇ m.
  • FIG. 26D illustrates the microscopy pictures of form G showing the needle forming form G without polarization.
  • FIG. 27 Illustrates the 1 H NMR of form G.
  • FIG. 28 Illustrates the DSC of form G (Table 1 experiment A2_1) with a melting endotherm at around 209.5° C. (peak).
  • FIG. 29 Illustrates the TGA with SDTA curve of form G (Table 1 experiment A2_1) showing a weight loss up to 120° C. (18 min) of about 3.7% w/w which corresponds about the expected amount of isopropanol in the sample.
  • FIG. 30A illustrates the microscopy picture of form H (Table 2 experiment B2 2) showing crystals with bipyramidal habit with crossed polarization filters.
  • FIG. 30B illustrates the microscopy picture of form H (Table 2 experiment B2_2) showing crystals with bipyramidal habit without polarization. The bar indicates about 250 ⁇ m.
  • FIG. 31 Illustrates the 1 H NMR of form G.
  • FIG. 32A illustrates the microscopy picture of form I showing crystals without defined habit (after breaking the block) with crossed polarization filters.
  • FIG. 32B illustrates the microscopy picture of form I showing crystals without defined habit (after breaking the block) with crossed polarization filters without polarization. The bar indicates about 250 ⁇ m.
  • FIG. 33 Illustrates the 1 H NMR of form I.
  • FIG. 34 Illustrates the DSC with SDTA curve of form I with an endotherm at around 110° C. corresponding to a weight loss of 19.8% w/w.
  • FIG. 35 Illustrates the XRPD of form J.
  • FIG. 36 Illustrates the DSC of form J. An exotherm form conversion around 130° C. and a melting point at 212° C. (peak) which likely represents form G.
  • FIG. 37 Illustrates the form diagram of the 4 identified crystalline forms. Conversions in italics indicate unverified pathways.
  • FIG. 38 Illustrates the XRPD pattern of evaporation series (Ax_y-experiments). 9 digit number corresponds to the LIMS-Sample/ ID given in Table 1.
  • FIG. 39 Illustrates the XRPD pattern of cooling/precipitation series (Bx_y-experiments). 9 digit number corresponds to the LIMS-Sample/ID given in Table 2.
  • FIG. 40 Illustrates the XRPD pattern of slurry series (Cx_y-experiments, part 1). 9 digit number corresponds to the LIMS-Sample/ID given in Table 3.
  • FIG. 41 Illustrates the XRPD pattern of slurry series (Cx_y-experiments, part 1). 9 digit number corresponds to the LIMS-Sample/ID given in Table 3.
  • FIG. 42 Illustrates the XRPD of form A
  • FIG. 43 Illustrates the XRPD of form B.
  • FIG. 44 Illustrates the XRPD of form C.
  • FIG. 45 Illustrates the XRPD of form D.
  • FIG. 46 Illustrates the XRPD of form E.
  • FIG. 47 Illustrates the XRPD of form F.
  • FIG. 48 Illustrates the XRPD of form G.
  • FIG. 49 Illustrates the XRPD of form H.
  • FIG. 50 Illustrates the XRPD of form I.
  • crystalline and related terms used herein, when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, mean that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).
  • crystal forms As used herein and unless otherwise specified, the term “crystal forms,” “crystalline forms” and related terms herein refer to solid forms that are crystalline. Crystal forms include single-component crystal forms and multiple-component crystal forms, and include, but are not limited to, polymorphs, solvates, hydrates, and/or other molecular complexes. In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms.
  • a crystal form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more amorphous forms and/or other crystal forms on a weight basis.
  • a crystal form of a substance may be physically and/or chemically pure.
  • a crystal form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/or chemically pure.
  • polymorphs refer to two or more crystal forms that consist essentially of the same molecule, molecules, and/or ions. Like different crystal forms, different polymorphs may have different physical properties such as, e.g., melting temperature, heat of fusion, solubility, dissolution properties and/or vibrational spectra, as a result of the arrangement or conformation of the molecules and/or ions in the crystal lattice. The differences in physical properties may 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 including one polymorph than when including 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).
  • solubility/dissolution differences some solid-state transitions may result in lack of potency or, at the other extreme, toxicity.
  • the physical properties may be important in processing (e.g. one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities, and particle shape and size distribution might be different between polymorphs).
  • solvate and “solvated,” refer to a crystal form of a substance formed from the association of one or more solvent molecules to a compound provided herein.
  • solvate includes “hydrates” (e.g., a mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like, compound described herein where the solvent includes water).
  • a hydrate includes a compound provided herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • Polymorphs of solvates refers to the existence of more than one crystal form for a particular solvate composition.
  • polymorphs of hydrates refers to the existence of more than one crystal form for a particular hydrate composition.
  • desolvated solvate refers to a crystal form of a substance which may be prepared by removing the solvent from a solvate.
  • amorphous As used herein and unless otherwise specified, the terms “amorphous,” and “amorphous form,” and related terms used herein, refer that the substance, component or product in question is not substantially crystalline as determined by X-ray diffraction.
  • amorphous form describes a disordered solid form, i.e., a solid form lacking long range crystalline order.
  • an amorphous form of a substance may be substantially free of other amorphous forms and/or crystal forms.
  • an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more other amorphous forms and/or crystal forms on a weight basis.
  • an amorphous form of a substance may be physically and/or chemically pure.
  • an amorphous form of a substance is about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/or chemically pure.
  • Techniques for characterizing crystal forms and amorphous forms include those known and described in the art, such as, but not limited to, thermal gravimetric analysis (TGA), 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, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis and Karl Fischer analysis.
  • TGA thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • XRPD X-ray powder diffractometry
  • IR infrared
  • Raman spectroscopy solid-state and solution nuclear magnetic resonance (NMR) spectroscopy
  • optical microscopy hot stage optical
  • Characteristic unit cell parameters may be determined using one or more techniques such as, but not limited to, X-ray diffraction and neutron diffraction, including single-crystal diffraction and powder diffraction.
  • Techniques useful for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which may be used, e.g., to analyze diffraction peaks associated with a single phase in a sample including more than one solid phase.
  • Other methods useful for analyzing powder diffraction data include unit cell indexing, which allows one of skill in the art to determine unit cell parameters from a sample including crystalline powder.
  • pharmaceutically acceptable salts is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochlor
  • a “pharmaceutically acceptable excipient,” comprises a substance that aids the administration of an active agent to a subject or modifies the absorption by a subject upon administration.
  • a pharmaceutically acceptable excipient typically has no significant adverse toxicological effect on the patient.
  • pharmaceutically acceptable excipients include, but are not limited to, water, NaCl (including salt solutions), normal saline solutions, sucrose, glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • pharmaceutical excipients known in the art are useful in the present invention.
  • administer refers to the act of physically delivering a substance as it exists outside the body into a patient.
  • Administration includes all forms known in the art for delivering therapeutic agents, including but not limited to oral, topical, mucosal, injections, intradermal, intravenous, intramuscular delivery or other method of physical delivery described herein or known in the art (e.g., implantation of a slow-release device, such as a mini-osmotic pump to a subject; liposomal formulations; buccal; sublingual; palatal; gingival; nasal; vaginal; rectal; intra-arteriole; intraperitoneal; intraventricular; intracranial; or transdermal).
  • a slow-release device such as a mini-osmotic pump
  • administration of the substance typically occurs after the onset of disease, disorder or condition or symptoms thereof
  • administration of the substance typically occurs before the onset of the disease, disorder or condition or symptoms thereof.
  • treat contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity or symptoms of the disease or disorder, or retards or slows the progression or symptoms of the disease or disorder.
  • patient refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a composition described herein.
  • organisms include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • cancer is used in accordance with its plain ordinary meaning and refers to all types of neoplasms and malignant or benign tumors found in mammals. “Cancer” as used herein refers to leukemia, carcinomas and sarcomas. Exemplary cancers include acute myeloid leukemia (“AML”), chronic myelogenous leukemia (“CML”), and cancer of the brain, breast, pancreas, colon, liver, kidney, lung, non-small cell lung, melanoma, ovary, sarcoma, and prostate.
  • AML acute myeloid leukemia
  • CML chronic myelogenous leukemia
  • cancer of the brain breast, pancreas, colon, liver, kidney, lung, non-small cell lung, melanoma, ovary, sarcoma, and prostate.
  • cervix cancers stomach cancers, head & neck cancers, uterus cancers, mesothelioma, metastatic bone cancer, Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, and neoplasms of the endocrine and exocrine pancreas.
  • the cancer is colon carcinoma, ovarian cancer, breast cancer, head and neck cancer, renal cancer
  • Anti-cancer agent is used in accordance with its plain and ordinary meaning and refers to a composition (e.g., a chemotherapeutic agent) that inhibits the growth or proliferation of cells.
  • An anti-cancer agent may be an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer.
  • an “effective amount” is an amount sufficient to accomplish a stated purpose (e.g., achieve the effect for which it is administered, treat, manage, or prevent a disease, reduce enzyme activity, increase enzyme activity, or reduce one or more symptoms of a disease or condition).
  • the term “therapeutically effective amount” of a compound refers to the amount of the compound that, when administered, is sufficient to treat, manage or prevent one or more of the symptoms of a disease, disorder, or condition being treated.
  • the term also refers to the amount of the compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • the term encompasses an amount of the compound that improves overall therapy, reduces, or avoids symptoms or causes of a disease, disorder, or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • the crystalline form can be an unsolvated crystalline form (e.g., a crystal form substantially without solvent) or a solvated crystalline form.
  • the crystalline form of the compound of formula (I) can be obtained using techniques known in the art, including but not limited to, evaporative screening, cooling and precipitation screening, or slurry screening. Crystals of the crystalline forms of the compound of formula (I) can be obtained from solvents and techniques set forth in, for example, Table 1, Table 2, or Table 3.
  • the crystalline form can be an unsolvated crystalline form.
  • the crystalline form can be a solvated form.
  • the crystalline form can include a form described herein within the Examples set forth below (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J).
  • the crystalline form described herein can be referred to by its present solvation state (i.e., solvated or unsolvated), by its alphanumeric Form name, or a combination thereof
  • the crystalline form can, in embodiments, be an unsolvated crystalline form corresponding to Form A, Form C, Form G, or Form H.
  • the crystalline form can, in embodiments, be a solvated crystalline form corresponding to Form B, Form D, Form E, Form F, or Form I.
  • the crystalline form of the compound of formula (I) can be characterized by X-ray powder diffraction (XRPD).
  • XRPD X-ray powder diffraction
  • the crystalline form of the compound of formula (I) can be characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.9 ⁇ 0.3, 16.4 ⁇ 0.3, 18.5 ⁇ 0.3, 20.9 ⁇ 0.3, 21.2 ⁇ 0.3, 21.6 ⁇ 0.3, 23.0 ⁇ 0.3, 23.5 ⁇ 0.3, 24.2 ⁇ 0.3, and 27.4 ⁇ 0.3.
  • angle 2 ⁇ peaks set forth herein e.g., angle 2 ⁇ values for Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J
  • angle 2 ⁇ values described herein should be understood to include variances associated with X-ray diffraction spectroscopy.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 8.7 ⁇ 0.3, 9.2 ⁇ 0.3, 10.8 ⁇ 0.3, 14.8 ⁇ 0.3, 15.5 ⁇ 0.3, 17.7 ⁇ 0.3, 19.9 ⁇ 0.3, 20.4 ⁇ 0.3, 22.0 ⁇ 0.3, 22.4 ⁇ 0.3, 25.9 ⁇ 0.3, 26.3 ⁇ 0.3, 26.8 ⁇ 0.3, 27.0 ⁇ 0.3, 28.0 ⁇ 0.3, 28.9 ⁇ 0.3, and 29.8 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 8.7 ⁇ 0.3, 9.2 ⁇ 0.3, 10.8 ⁇ 0.3, 11.9 ⁇ 0.3, 14.8 ⁇ 0.3, 15.5 ⁇ 0.3, 16.4 ⁇ 0.3, 17.7 ⁇ 0.3, 18.5 ⁇ 0.3, 19.9 ⁇ 0.3, 20.4 ⁇ 0.3, 20.9 ⁇ 0.3, 21.2 ⁇ 0.3, 21.6 ⁇ 0.3, 22.0 ⁇ 0.3, 22.4 ⁇ 0.3, 23.0 ⁇ 0.3, 23.5 ⁇ 0.3, 24.2 ⁇ 0.3, 25.9 ⁇ 0.3, 26.3 ⁇ 0.3, 26.8 ⁇ 0.3, 27.0 ⁇ 0.3, 27.4 ⁇ 0.3, 28.0 ⁇ 0.3, 28.9 ⁇ 0.3, and 29.8 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.9 ⁇ 0.2, 16.4 ⁇ 0.2, 18.5 ⁇ 0.2, 20.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.6 ⁇ 0.2, 23.0 ⁇ 0.2, 23.5 ⁇ 0.2, 24.2 ⁇ 0.2, and 27.4 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 8.7 ⁇ 0.2, 9.2 ⁇ 0.2, 10.8 ⁇ 0.2, 14.8 ⁇ 0.2, 15.5 ⁇ 0.2, 17.7 ⁇ 0.2, 19.9 ⁇ 0.2, 20.4 ⁇ 0.2, 22.0 ⁇ 0.2, 22.4 ⁇ 0.2, 25.9 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.0 ⁇ 0.2, 28.0 ⁇ 0.2, 28.9 ⁇ 0.2, and 29.8 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 8.7 ⁇ 0.2, 9.2 ⁇ 0.2, 10.8 ⁇ 0.2, 11.9 ⁇ 0.2, 14.8 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.7 ⁇ 0.2, 18.5 ⁇ 0.2, 19.9 ⁇ 0.2, 20.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.6 ⁇ 0.2, 22.0 ⁇ 0.2, 22.4 ⁇ 0.2, 23.0 ⁇ 0.2, 23.5 ⁇ 0.2, 24.2 ⁇ 0.2, 25.9 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.0 ⁇ 0.2, 27.4 ⁇ 0.2, 28.0 ⁇ 0.2, 28.9 ⁇ 0.2, and 29.8 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.9 ⁇ 0.1, 16.4 ⁇ 0.1, 18.5 ⁇ 0.1, 20.9 ⁇ 0.1, 21.2 ⁇ 0.1, 21.6 ⁇ 0.1, 23.0 ⁇ 0.1, 23.5 ⁇ 0.1, 24.2 ⁇ 0.1, and 27.4 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 8.7 ⁇ 0.1, 9.2 ⁇ 0.1, 10.8 ⁇ 0.1, 14.8 ⁇ 0.1, 15.5 ⁇ 0.1, 17.7 ⁇ 0.1, 19.9 ⁇ 0.1, 20.4 ⁇ 0.1, 22.0 ⁇ 0.1, 22.4 ⁇ 0.1, 25.9 ⁇ 0.1, 26.3 ⁇ 0.1, 26.8 ⁇ 0.1, 27.0 ⁇ 0.1, 28.0 ⁇ 0.1, 28.9 ⁇ 0.1, and 29.8 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 8.7 ⁇ 0.1, 9.2 ⁇ 0.1, 10.8 ⁇ 0.1,11.9 ⁇ 0.1,14.8 ⁇ 0.1,15.5 ⁇ 0.1,16.4 ⁇ 0.1,17.7 ⁇ 0.1,18.5 ⁇ 0.1, 19.9 ⁇ 0.1, 20.4 ⁇ 0.1, 20.9 ⁇ 0.1, 21.2 ⁇ 0.1, 21.6 ⁇ 0.1, 22.0 ⁇ 0.1, 22.4 ⁇ 0.1, 23.0 ⁇ 0.1, 23.5 ⁇ 0.1, 24.2 ⁇ 0.1, 25.9 ⁇ 0.1, 26.3 ⁇ 0.1, 26.8 ⁇ 0.1, 27.0 ⁇ 0.1, 27.4 ⁇ 0.1, 28.0 ⁇ 0.1, 28.9 ⁇ 0.1, and 29.8 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.9, 16.4, 18.5, 20.9, 21.2, 21.6, 23.0, 23.5, 24.2, and 27.4.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 8.7, 9.2, 10.8, 14.8, 15.5, 17.7, 19.9, 20.4, 22.0, 22.4, 25.9, 26.3, 26.8, 27.0, 28.0, 28.9, and 29.8.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 8.7, 9.2, 10.8, 11.9, 14.8, 15.5, 16.4, 17.7, 18.5, 19.9, 20.4, 20.9, 21.2, 21.6, 22.0, 22.4, 23.0, 23.5, 24.2, 25.9, 26.3, 26.8, 27.0, 27.4, 28.0, 28.9, and 29.8.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 42 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.40 ⁇ 0.3, 5.40 ⁇ 0.3, 4.78 ⁇ 0.3, 4.24 ⁇ 0.3, 4.17 ⁇ 0.3, 4.09 ⁇ 0.3, 3.86 ⁇ 0.3, 3.77 ⁇ 0.3, 3.68 ⁇ 0.3, 3.25 ⁇ 0.3.
  • the d spacing values described herein should be understood to include variances associated with X-ray diffraction spectroscopy. All values for d spacings set forth herein (e.g., d spacings for Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J) are obtained by using a Cu K ⁇ radiation source (1.54 ⁇ ).
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include d spacings at about 10.20 ⁇ 0.3, 9.58 ⁇ 0.3, 8.18 ⁇ 0.3, 5.98 ⁇ 0.3, 5.70 ⁇ 0.3, 5.01 ⁇ 0.3, 4.45 ⁇ 0.3, 4.34 ⁇ 0.3, 4.02 ⁇ 0.3, 3.97 ⁇ 0.3, 3.43 ⁇ 0.3, 3.38 ⁇ 0.3, 3.32 ⁇ 0.3, 3.29 ⁇ 0.3, 3.17 ⁇ 0.3, 3.08 ⁇ 0.3, and 2.99 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 10.20 ⁇ 0.3, 7.40 ⁇ 0.3, 9.58 ⁇ 0.3, 8.18 ⁇ 0.3, 5.98 ⁇ 0.3, 5.70 ⁇ 0.3, 5.40 ⁇ 0.3, 5.01 ⁇ 0.3, 4.78 ⁇ 0.3, 4.45 ⁇ 0.3, 4.34 ⁇ 0.3, 4.24 ⁇ 0.3, 4.17 ⁇ 0.3, 4.09 ⁇ 0.3, 4.02 ⁇ 0.3, 3.97 ⁇ 0.3, 3.86 ⁇ 0.3, 3.77 ⁇ 0.3, 3.68 ⁇ 0.3, 3.43 ⁇ 0.3, 3.38 ⁇ 0.3, 3.32 ⁇ 0.3, 3.29 ⁇ 0.3, 3.25 ⁇ 0.3, 3.17 ⁇ 0.3, 3.08 ⁇ 0.3, and 2.99 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.40 ⁇ 0.2, 5.40 ⁇ 0.2, 4.78 ⁇ 0.2, 4.24 ⁇ 0.2, 4.17 ⁇ 0.2, 4.09 ⁇ 0.2, 3.86 ⁇ 0.2, 3.77 ⁇ 0.2, 3.68 ⁇ 0.2, 3.25 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include d spacings at about 10.20 ⁇ 0.2, 9.58 ⁇ 0.2, 8.18 ⁇ 0.2, 5.98 ⁇ 0.2, 5.70 ⁇ 0.2, 5.01 ⁇ 0.2, 4.45 ⁇ 0.2, 4.34 ⁇ 0.2, 4.02 ⁇ 0.2, 3.97 ⁇ 0.2, 3.43 ⁇ 0.2, 3.38 ⁇ 0.2, 3.32 ⁇ 0.2, 3.29 ⁇ 0.2, 3.17 ⁇ 0.2, 3.08 ⁇ 0.2, and 2.99 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 10.20 ⁇ 0.2, 7.40 ⁇ 0.2, 9.58 ⁇ 0.2, 8.18 ⁇ 0.2, 5.98 ⁇ 0.2, 5.70 ⁇ 0.2, 5.40 ⁇ 0.2, 5.01 ⁇ 0.2, 4.78 ⁇ 0.2, 4.45 ⁇ 0.2, 4.34 ⁇ 0.2, 4.24 ⁇ 0.2, 4.17 ⁇ 0.2, 4.09 ⁇ 0.2, 4.02 ⁇ 0.2, 3.97 ⁇ 0.2, 3.86 ⁇ 0.2, 3.77 ⁇ 0.2, 3.68 ⁇ 0.2, 3.43 ⁇ 0.2, 3.38 ⁇ 0.2, 3.32 ⁇ 0.2, 3.29 ⁇ 0.2, 3.25 ⁇ 0.2, 3.17 ⁇ 0.2, 3.08 ⁇ 0.2, and 2.99 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.40 ⁇ 0.1, 5.40 ⁇ 0.1, 4.78 ⁇ 0.1, 4.24 ⁇ 0.1, 4.17 ⁇ 0.1, 4.09 ⁇ 0.1, 3.86 ⁇ 0.1, 3.77 ⁇ 0.1, 3.68 ⁇ 0.1, 3.25 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further included spacings at about 10.20 ⁇ 0.1, 9.58 ⁇ 0.1, 8.18 ⁇ 0.1, 5.98 ⁇ 0.1, 5.70 ⁇ 0.1, 5.01 ⁇ 0.1, 4.45 ⁇ 0.1, 4.34 ⁇ 0.1, 4.02 ⁇ 0.1, 3.97 ⁇ 0.1, 3.43 ⁇ 0.1, 3.38 ⁇ 0.1, 3.32 ⁇ 0.1, 3.29 ⁇ 0.1, 3.17 ⁇ 0.1, 3.08 ⁇ 0.1, and 2.99 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 10.20 ⁇ 0.1, 7.40 ⁇ 0.1, 9.58 ⁇ 0.1, 8.18 ⁇ 0.1, 5.98 ⁇ 0.1, 5.70 ⁇ 0.1, 5.40 ⁇ 0.1, 5.01 ⁇ 0.1, 4.78 ⁇ 0.1, 4.45 ⁇ 0.1, 4.34 ⁇ 0.1, 4.24 ⁇ 0.1, 4.17 ⁇ 0.1, 4.09 ⁇ 0.1, 4.02 ⁇ 0.1, 3.97 ⁇ 0.1, 3.86 ⁇ 0.1, 3.77 ⁇ 0.1, 3.68 ⁇ 0.1, 3.43 ⁇ 0.1, 3.38 ⁇ 0.1, 3.32 ⁇ 0.1, 3.29 ⁇ 0.1, 3.25 ⁇ 0.1, 3.17 ⁇ 0.1, 3.08 ⁇ 0.1, and 2.99 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.40, 5.40, 4.78, 4.24, 4.17, 4.09, 3.86, 3.77, 3.68, 3.25.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further included spacings at about 10.20, 9.58, 8.18, 5.98, 5.70, 5.01, 4.45, 4.34, 4.02, 3.97, 3.43, 3.38, 3.32, 3.29, 3.17, 3.08, and 2.99.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 10.20, 7.40, 9.58, 8.18, 5.98, 5.70, 5.40, 5.01, 4.78, 4.45, 4.34, 4.24, 4.17, 4.09, 4.02, 3.97, 3.86, 3.77, 3.68, 3.43, 3.38, 3.32, 3.29, 3.25, 3.17, 3.08, and 2.99.
  • the crystalline form of the compound of formula (I) can be Form A, where Form A is characterized by the XRPD pattern described above or by a XRPD pattern corresponding substantially to FIG. 42 .
  • Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 200° C. to about 215° C. Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 200° C. to about 210° C. Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 200° C. to about 205° C. Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 200° C. to about 204° C. Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 200° C.
  • Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 200° C. to about 202° C. Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 202° C. to about 215° C. Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 202° C. to about 210° C. Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 202° C. to about 205° C. Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 205° C. to about 215° C.
  • Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 205° C. to about 210° C.
  • the Crystalline forms described herein of the compound of formula (I) can be can have a melting point of about 208° C. to about 212° C.
  • the crystalline form of the compound of formula (I) can include an endothermic event with an onset temperature of about 199° C. and about 211° C. as measured by differential scanning calorimetry (DSC).
  • the crystalline form of the compound of formula (I) (e.g., Form A) can be characterized by a DSC plot set forth in FIG. 7 .
  • the crystalline form of the compound of formula (I) can have a melting point of about 202° C.
  • the crystalline form of the compound of formula (I) can be Form A, where Form A has a melting point of about 202° C.
  • the crystalline forms of the compound of formula (I) described herein can be further characterized by TGA as described herein.
  • the crystalline form of the compound of formula (I) e.g., Form A
  • the crystalline form of the compound of formula (I) can be stable between about 0° C. to about 60° C.
  • Form A can be stable between about 0° C. to about 60° C.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 10.7 ⁇ 0.3, 15.2 ⁇ 0.3, 15.5 ⁇ 0.3, 17.5 ⁇ 0.3, 18.6 ⁇ 0.3, 19.7 ⁇ 0.3, 20.9 ⁇ 0.3, 21.8 ⁇ 0.3, 24.2 ⁇ 0.3, 24.7 ⁇ 0.3, and 26.4 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.3 ⁇ 0.3, 12.5 ⁇ 0.3, 15.9 ⁇ 0.3, 16.6 ⁇ 0.3, 18.2 ⁇ 0.3, 18.9 ⁇ 0.3, 22.3 ⁇ 0.3, 22.7 ⁇ 0.3, 23.1 ⁇ 0.3, 24.9 ⁇ 0.3, 25.3 ⁇ 0.3, 26.0 ⁇ 0.3, 27.2 ⁇ 0.3, 29.4 ⁇ 0.3, 30.0 ⁇ 0.3, 30.9 ⁇ 0.3, 31.8 ⁇ 0.3, and 35.4 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.3 ⁇ 0.3, 10.7 ⁇ 0.3, 15.2 ⁇ 0.3, 15.5 ⁇ 0.3, 12.5 ⁇ 0.3, 15.9 ⁇ 0.3, 16.6 ⁇ 0.3, 17.5 ⁇ 0.3, 18.2 ⁇ 0.3, 18.6 ⁇ 0.3, 18.9 ⁇ 0.3, 19.7 ⁇ 0.3, 20.9 ⁇ 0.3, 21.8 ⁇ 0.3, 22.3 ⁇ 0.3, 22.7 ⁇ 0.3, 23.1 ⁇ 0.3, 24.2 ⁇ 0.3, 24.7 ⁇ 0.3, 24.9 ⁇ 0.3, 25.3 ⁇ 0.3, 26.0 ⁇ 0.3, 26.4 ⁇ 0.3, 27.2 ⁇ 0.3, 29.4 ⁇ 0.3, 30.0 ⁇ 0.3, 30.9 ⁇ 0.3, 31.8 ⁇ 0.3, and 35.4 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 10.7 ⁇ 0.2, 15.2 ⁇ 0.2, 15.5 ⁇ 0.2, 17.5 ⁇ 0.2, 18.6 ⁇ 0.2, 19.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.8 ⁇ 0.2, 24.2 ⁇ 0.2, 24.7 ⁇ 0.2, and 26.4 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.3 ⁇ 0.2, 12.5 ⁇ 0.2, 15.9 ⁇ 0.2, 16.6 ⁇ 0.2, 18.2 ⁇ 0.2, 18.9 ⁇ 0.2, 22.3 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 24.9 ⁇ 0.2, 25.3 ⁇ 0.2, 26.0 ⁇ 0.2, 27.2 ⁇ 0.2, 29.4 ⁇ 0.2, 30.0 ⁇ 0.2, 30.9 ⁇ 0.2, 31.8 ⁇ 0.2, and 35.4 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.3 ⁇ 0.2, 10.7 ⁇ 0.2, 15.2 ⁇ 0.2, 15.5 ⁇ 0.2, 12.5 ⁇ 0.2, 15.9 ⁇ 0.2, 16.6 ⁇ 0.2, 17.5 ⁇ 0.2, 18.2 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 19.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.8 ⁇ 0.2, 22.3 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 24.2 ⁇ 0.2, 24.7 ⁇ 0.2, 24.9 ⁇ 0.2, 25.3 ⁇ 0.2, 26.0 ⁇ 0.2, 26.4 ⁇ 0.2, 27.2 ⁇ 0.2, 29.4 ⁇ 0.2, 30.0 ⁇ 0.2, 30.9 ⁇ 0.2, 31.8 ⁇ 0.2, and 35.4 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 10.7 ⁇ 0.1, 15.2 ⁇ 0.1, 15.5 ⁇ 0.1, 17.5 ⁇ 0.1, 18.6 ⁇ 0.1, 19.7 ⁇ 0.1, 20.9 ⁇ 0.1, 21.8 ⁇ 0.1, 24.2 ⁇ 0.1, 24.7 ⁇ 0.1, and 26.4 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.3 ⁇ 0.1, 12.5 ⁇ 0.1, 15.9 ⁇ 0.1, 16.6 ⁇ 0.1, 18.2 ⁇ 0.1, 18.9 ⁇ 0.1, 22.3 ⁇ 0.1, 22.7 ⁇ 0.1, 23.1 ⁇ 0.1, 24.9 ⁇ 0.1, 25.3 ⁇ 0.1, 26.0 ⁇ 0.1, 27.2 ⁇ 0.1, 29.4 ⁇ 0.1, 30.0 ⁇ 0.1, 30.9 ⁇ 0.1, 31.8 ⁇ 0.1, and 35.4 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.3 ⁇ 0.1, 10.7 ⁇ 0.1, 15.2 ⁇ 0.1,15.5 ⁇ 0.1,12.5 ⁇ 0.1,15.9 ⁇ 0.1,16.6 ⁇ 0.1,17.5 ⁇ 0.1,18.2 ⁇ 0.1, 18.6 ⁇ 0.1, 18.9 ⁇ 0.1, 19.7 ⁇ 0.1, 20.9 ⁇ 0.1, 21.8 ⁇ 0.1, 22.3 ⁇ 0.1, 22.7 ⁇ 0.1, 23.1 ⁇ 0.1, 24.2 ⁇ 0.1, 24.7 ⁇ 0.1, 24.9 ⁇ 0.1, 25.3 ⁇ 0.1, 26.0 ⁇ 0.1, 26.4 ⁇ 0.1, 27.2 ⁇ 0.1, 29.4 ⁇ 0.1, 30.0 ⁇ 0.1, 30.9 ⁇ 0.1, 31.8 ⁇ 0.1, and 35.4 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 10.7, 15.2, 15.5, 17.5, 18.6, 19.7, 20.9, 21.8, 24.2, 24.7, and 26.4.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.3, 12.5, 15.9, 16.6, 18.2, 18.9, 22.3, 22.7, 23.1, 24.9, 25.3, 26.0, 27.2, 29.4, 30.0, 30.9, 31.8, and 35.4.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.3, 10.7, 15.2, 15.5, 12.5, 15.9, 16.6, 17.5, 18.2, 18.6, 18.9, 19.7, 20.9, 21.8, 22.3, 22.7, 23.1, 24.2, 24.7, 24.9, 25.3, 26.0, 26.4, 27.2, 29.4, 30.0, 30.9, 31.8, and 35.4.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 43 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.23 ⁇ 0.3, 5.80 ⁇ 0.3, 5.70 ⁇ 0.3, 5.06 ⁇ 0.3, 4.77 ⁇ 0.3, 4.50 ⁇ 0.3, 4.24 ⁇ 0.3, 4.10 ⁇ 0.3, 3.67 ⁇ 0.3, 3.59 ⁇ 0.3, and 3.37 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 14.10 ⁇ 0.3, 7.05 ⁇ 0.3, 5.58 ⁇ 0.3, 5.34 ⁇ 0.3, 4.88 ⁇ 0.3, 4.69 ⁇ 0.3, 3.99 ⁇ 0.3, 3.91 ⁇ 0.3, 3.85 ⁇ 0.3, 3.57 ⁇ 0.3, 3.51 ⁇ 0.3, 3.42 ⁇ 0.3, 3.27 ⁇ 0.3, 3.03 ⁇ 0.3, 2.97 ⁇ 0.3, 2.89 ⁇ 0.3, 2.80 ⁇ 0.3, and 2.53 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 14.10 ⁇ 0.3, 8.23 ⁇ 0.3, 7.05 ⁇ 0.3, 5.80 ⁇ 0.3, 5.70 ⁇ 0.3, 5.58 ⁇ 0.3, 5.34 ⁇ 0.3, 5.06 ⁇ 0.3, 4.88 ⁇ 0.3, 4.77 ⁇ 0.3, 4.69 ⁇ 0.3, 4.50 ⁇ 0.3, 4.24 ⁇ 0.3, 4.10 ⁇ 0.3, 3.99 ⁇ 0.3, 3.91 ⁇ 0.3, 3.85 ⁇ 0.3, 3.67 ⁇ 0.3, 3.59 ⁇ 0.3, 3.57 ⁇ 0.3, 3.51 ⁇ 0.3, 3.42 ⁇ 0.3, 3.37 ⁇ 0.3, 3.27 ⁇ 0.3, 3.03 ⁇ 0.3, 2.97 ⁇ 0.3, 2.89 ⁇ 0.3, 2.80 ⁇ 0.3, and 2.53 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.23 ⁇ 0.2, 5.80 ⁇ 0.2, 5.70 ⁇ 0.2, 5.06 ⁇ 0.2, 4.77 ⁇ 0.2, 4.50 ⁇ 0.2, 4.24 ⁇ 0.2, 4.10 ⁇ 0.2, 3.67 ⁇ 0.2, 3.59 ⁇ 0.2, and 3.37 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 14.10 ⁇ 0.2, 7.05 ⁇ 0.2, 5.58 ⁇ 0.2, 5.34 ⁇ 0.2, 4.88 ⁇ 0.2, 4.69 ⁇ 0.2, 3.99 ⁇ 0.2, 3.91 ⁇ 0.2, 3.85 ⁇ 0.2, 3.57 ⁇ 0.2, 3.51 ⁇ 0.2, 3.42 ⁇ 0.2, 3.27 ⁇ 0.2, 3.03 ⁇ 0.2, 2.97 ⁇ 0.2, 2.89 ⁇ 0.2, 2.80 ⁇ 0.2, and 2.53 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 14.10 ⁇ 0.2, 8.23 ⁇ 0.2, 7.05 ⁇ 0.2, 5.80 ⁇ 0.2, 5.70 ⁇ 0.2, 5.58 ⁇ 0.2, 5.34 ⁇ 0.2, 5.06 ⁇ 0.2, 4.88 ⁇ 0.2, 4.77 ⁇ 0.2, 4.69 ⁇ 0.2, 4.50 ⁇ 0.2, 4.24 ⁇ 0.2, 4.10 ⁇ 0.2, 3.99 ⁇ 0.2, 3.91 ⁇ 0.2, 3.85 ⁇ 0.2, 3.67 ⁇ 0.2, 3.59 ⁇ 0.2, 3.57 ⁇ 0.2, 3.51 ⁇ 0.2, 3.42 ⁇ 0.2, 3.37 ⁇ 0.2, 3.27 ⁇ 0.2, 3.03 ⁇ 0.2, 2.97 ⁇ 0.2, 2.89 ⁇ 0.2, 2.80 ⁇ 0.2, and 2.53 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.23 ⁇ 0.1, 5.80 ⁇ 0.1, 5.70 ⁇ 0.1, 5.06 ⁇ 0.1, 4.77 ⁇ 0.1, 4.50 ⁇ 0.1, 4.24 ⁇ 0.1, 4.10 ⁇ 0.1, 3.67 ⁇ 0.1, 3.59 ⁇ 0.1, and 3.37 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 14.10 ⁇ 0.1, 7.05 ⁇ 0.1, 5.58 ⁇ 0.1, 5.34 ⁇ 0.1, 4.88 ⁇ 0.1, 4.69 ⁇ 0.1, 3.99 ⁇ 0.1, 3.91 ⁇ 0.1, 3.85 ⁇ 0.1, 3.57 ⁇ 0.1, 3.51 ⁇ 0.1, 3.42 ⁇ 0.1, 3.27 ⁇ 0.1, 3.03 ⁇ 0.1, 2.97 ⁇ 0.1, 2.89 ⁇ 0.1, 2.80 ⁇ 0.1, and 2.53 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 14.10 ⁇ 0.1, 8.23 ⁇ 0.1, 7.05 ⁇ 0.1, 5.80 ⁇ 0.1, 5.70 ⁇ 0.1, 5.58 ⁇ 0.1, 5.34 ⁇ 0.1, 5.06 ⁇ 0.1, 4.88 ⁇ 0.1, 4.77 ⁇ 0.1, 4.69 ⁇ 0.1, 4.50 ⁇ 0.1, 4.24 ⁇ 0.1, 4.10 ⁇ 0.1, 3.99 ⁇ 0.1, 3.91 ⁇ 0.1, 3.85 ⁇ 0.1, 3.67 ⁇ 0.1, 3.59 ⁇ 0.1, 3.57 ⁇ 0.1, 3.51 ⁇ 0.1, 3.42 ⁇ 0.1, 3.37 ⁇ 0.1, 3.27 ⁇ 0.1, 3.03 ⁇ 0.1, 2.97 ⁇ 0.1, 2.89 ⁇ 0.1, 2.80 ⁇ 0.1, and 2.53 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.23, 5.80, 5.70, 5.06, 4.77, 4.50, 4.24, 4.10, 3.67, 3.59, and 3.37.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 14.10, 7.05, 5.58, 5.34, 4.88, 4.69, 3.99, 3.91, 3.85, 3.57, 3.51, 3.42, 3.27, 3.03, 2.97, 2.89, 2.80, and 2.53.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 14.10, 8.23, 7.05, 5.80, 5.70, 5.58, 5.34, 5.06, 4.88, 4.77, 4.69, 4.50, 4.24, 4.10, 3.99, 3.91, 3.85, 3.67, 3.59, 3.57, 3.51, 3.42, 3.37, 3.27, 3.03, 2.97, 2.89, 2.80, and 2.53.
  • the crystalline form of the compound of formula (I) can be Form B, where Form B is characterized by the XRPD pattern described above or by FIG. 43 .
  • the crystalline form of the compound of formula (I) can include an endothermic event with an onset temperature of about 94° C. and about 193° C. as determined by DSC.
  • the crystalline form of the compound of formula (I) (e.g., Form B) can be characterized by a DSC plot set forth in FIG. 11 .
  • the crystalline form of the compound of formula (I) can have a melting point of about 204° C.
  • the crystalline form of the compound of formula (I) can be Form B, where Form B has a melting point of about 204° C.
  • Form B can have a mass loss of about 12% when heated from about 80° C. to about 140° C.
  • Form B can be a solvated crystalline form, where Form B is a 1,4-dioxane solvate.
  • the crystalline form of the compound of formula (I) includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.0 ⁇ 0.3, 14.9 ⁇ 0.3, 18.0 ⁇ 0.3, 19.1 ⁇ 0.3, 21.0 ⁇ 0.3, and 22.8 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 5.6 ⁇ 0.3, 8.9 ⁇ 0.3, 9.6 ⁇ 0.3, 10.6 ⁇ 0.3, 13.5 ⁇ 0.3, 14.4 ⁇ 0.3, 15.3 ⁇ 0.3, 16.1 ⁇ 0.3, 16.9 ⁇ 0.3, 17.2 ⁇ 0.3, 20.3 ⁇ 0.3, 21.7 ⁇ 0.3, 22.1 ⁇ 0.3, 23.5 ⁇ 0.3, 23.9 ⁇ 0.3, 24.7 ⁇ 0.3, 26.8 ⁇ 0.3, 27.3 ⁇ 0.3, and 29.1 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 5.6 ⁇ 0.3, 8.9 ⁇ 0.3, 9.6 ⁇ 0.3, 10.6 ⁇ 0.3, 11.0 ⁇ 0.3, 13.5 ⁇ 0.3, 14.4 ⁇ 0.3, 14.9 ⁇ 0.3, 15.3 ⁇ 0.3, 16.1 ⁇ 0.3, 16.9 ⁇ 0.3, 17.2 ⁇ 0.3, 18.0 ⁇ 0.3, 19.1 ⁇ 0.3, 20.3 ⁇ 0.3, 21.0 ⁇ 0.321.7 ⁇ 0.3, 22.1 ⁇ 0.3, 22.8 ⁇ 0.3, 23.5 ⁇ 0.3, 23.9 ⁇ 0.3, 24.7 ⁇ 0.3, 26.8 ⁇ 0.3, 27.3 ⁇ 0.3, and 29.1 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.0 ⁇ 0.2, 14.9 ⁇ 0.2, 18.0 ⁇ 0.2, 19.1 ⁇ 0.2, 21.0 ⁇ 0.2, and 22.8 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 5.6 ⁇ 0.2, 8.9 ⁇ 0.2, 9.6 ⁇ 0.2, 10.6 ⁇ 0.2, 13.5 ⁇ 0.2, 14.4 ⁇ 0.2, 15.3 ⁇ 0.2, 16.1 ⁇ 0.2, 16.9 ⁇ 0.2, 17.2 ⁇ 0.2, 20.3 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 23.5 ⁇ 0.2, 23.9 ⁇ 0.2, 24.7 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, and 29.1 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 5.6 ⁇ 0.2, 8.9 ⁇ 0.2, 9.6 ⁇ 0.2, 10.6 ⁇ 0.2, 11.0 ⁇ 0.2, 13.5 ⁇ 0.2, 14.4 ⁇ 0.2, 14.9 ⁇ 0.2, 15.3 ⁇ 0.2, 16.1 ⁇ 0.2, 16.9 ⁇ 0.2, 17.2 ⁇ 0.2, 18.0 ⁇ 0.2, 19.1 ⁇ 0.2, 20.3 ⁇ 0.2, 21.0 ⁇ 0.221.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 23.9 ⁇ 0.2, 24.7 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, and 29.1 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.0 ⁇ 0.1, 14.9 ⁇ 0.1, 18.0 ⁇ 0.1, 19.1 ⁇ 0.1, 21.0 ⁇ 0.1, and 22.8 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 5.6 ⁇ 0.1, 8.9 ⁇ 0.1, 9.6 ⁇ 0.1,10.6 ⁇ 0.1,13.5 ⁇ 0.1,14.4 ⁇ 0.1,15.3 ⁇ 0.1,16.1 ⁇ 0.1,16.9 ⁇ 0.1, 17.2 ⁇ 0.1, 20.3 ⁇ 0.1, 21.7 ⁇ 0.1, 22.1 ⁇ 0.1, 23.5 ⁇ 0.1, 23.9 ⁇ 0.1, 24.7 ⁇ 0.1, 26.8 ⁇ 0.1, 27.3 ⁇ 0.1, and 29.1 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 5.6 ⁇ 0.1, 8.9 ⁇ 0.1, 9.6 ⁇ 0.1, 10.6 ⁇ 0.1, 11.0 ⁇ 0.1, 13.5 ⁇ 0.1, 14.4 ⁇ 0.1, 14.9 ⁇ 0.1, 15.3 ⁇ 0.1, 16.1 ⁇ 0.1, 16.9 ⁇ 0.1, 17.2 ⁇ 0.1, 18.0 ⁇ 0.1, 19.1 ⁇ 0.1, 20.3 ⁇ 0.1, 21.0 ⁇ 0.1, 21.7 ⁇ 0.1, 22.1 ⁇ 0.1, 22.8 ⁇ 0.1, 23.5 ⁇ 0.1, 23.9 ⁇ 0.1, 24.7 ⁇ 0.1, 26.8 ⁇ 0.1, 27.3 ⁇ 0.1, and 29.1 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.0, 14.9, 18.0, 19.1, 21.0, and 22.8.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 5.6, 8.9, 9.6, 10.6, 13.5, 14.4, 15.3, 16.1, 16.9, 17.2, 20.3, 21.7, 22.1, 23.5, 23.9, 24.7, 26.8, 27.3, and 29.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 5.6, 8.9, 9.6, 10.6, 11.0, 13.5, 14.4, 14.9, 15.3, 16.1, 16.9, 17.2, 18.0, 19.1, 20.3, 21.0, 21.7, 22.1, 22.8, 23.5, 23.9, 24.7, 26.8, 27.3, and 29.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 44 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.05 ⁇ 0.3, 5.94 ⁇ 0.3, 4.91 ⁇ 0.3, 4.63 ⁇ 0.3, 4.22 ⁇ 0.3, and 3.89 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 15.71 ⁇ 0.3, 9.97 ⁇ 0.3, 9.22 ⁇ 0.3, 8.33 ⁇ 0.3, 6.55 ⁇ 0.3, 6.16 ⁇ 0.3, 5.77 ⁇ 0.3, 5.50 ⁇ 0.3, 5.25 ⁇ 0.3, 5.15 ⁇ 0.3, 4.36 ⁇ 0.3, 4.09 ⁇ 0.3, 4.01 ⁇ 0.3, 3.78 ⁇ 0.3, 3.71 ⁇ 0.3, 3.60 ⁇ 0.3, 3.32 ⁇ 0.3, 3.26 ⁇ 0.3, and 3.07 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 15.71 ⁇ 0.3, 9.97 ⁇ 0.3, 9.22 ⁇ 0.3, 8.33 ⁇ 0.3, 8.05 ⁇ 0.3, 6.55 ⁇ 0.3, 6.16 ⁇ 0.3, 5.94 ⁇ 0.3, 5.77 ⁇ 0.3, 5.50 ⁇ 0.3, 5.25 ⁇ 0.3, 5.15 ⁇ 0.3, 4.91 ⁇ 0.3, 4.63 ⁇ 0.3, 4.36 ⁇ 0.3, 4.22 ⁇ 0.3, 4.09 ⁇ 0.3, 4.01 ⁇ 0.3, 3.89 ⁇ 0.3, 3.78 ⁇ 0.3, 3.71 ⁇ 0.3, 3.60 ⁇ 0.3, 3.32 ⁇ 0.3, 3.26 ⁇ 0.3, and 3.07 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.05 ⁇ 0.2, 5.94 ⁇ 0.2, 4.91 ⁇ 0.2, 4.63 ⁇ 0.2, 4.22 ⁇ 0.2, and 3.89 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 15.71 ⁇ 0.2, 9.97 ⁇ 0.2, 9.22 ⁇ 0.2, 8.33 ⁇ 0.2, 6.55 ⁇ 0.2, 6.16 ⁇ 0.2, 5.77 ⁇ 0.2, 5.50 ⁇ 0.2, 5.25 ⁇ 0.2, 5.15 ⁇ 0.2, 4.36 ⁇ 0.2, 4.09 ⁇ 0.2, 4.01 ⁇ 0.2, 3.78 ⁇ 0.2, 3.71 ⁇ 0.2, 3.60 ⁇ 0.2, 3.32 ⁇ 0.2, 3.26 ⁇ 0.2, and 3.07 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 15.71 ⁇ 0.2, 9.97 ⁇ 0.2, 9.22 ⁇ 0.2, 8.33 ⁇ 0.2, 8.05 ⁇ 0.2, 6.55 ⁇ 0.2, 6.16 ⁇ 0.2, 5.94 ⁇ 0.2, 5.77 ⁇ 0.2, 5.50 ⁇ 0.2, 5.25 ⁇ 0.2, 5.15 ⁇ 0.2, 4.91 ⁇ 0.2, 4.63 ⁇ 0.2, 4.36 ⁇ 0.2, 4.22 ⁇ 0.2, 4.09 ⁇ 0.2, 4.01 ⁇ 0.2, 3.89 ⁇ 0.2, 3.78 ⁇ 0.2, 3.71 ⁇ 0.2, 3.60 ⁇ 0.2, 3.32 ⁇ 0.2, 3.26 ⁇ 0.2, and 3.07 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.05 ⁇ 0.1, 5.94 ⁇ 0.1, 4.91 ⁇ 0.1, 4.63 ⁇ 0.1, 4.22 ⁇ 0.1, and 3.89 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 15.71 ⁇ 0.1, 9.97 ⁇ 0.1, 9.22 ⁇ 0.1, 8.33 ⁇ 0.1, 6.55 ⁇ 0.1, 6.16 ⁇ 0.1, 5.77 ⁇ 0.1, 5.50 ⁇ 0.1, 5.25 ⁇ 0.1, 5.15 ⁇ 0.1, 4.36 ⁇ 0.1, 4.09 ⁇ 0.1, 4.01 ⁇ 0.1, 3.78 ⁇ 0.1, 3.71 ⁇ 0.1, 3.60 ⁇ 0.1, 3.32 ⁇ 0.1, 3.26 ⁇ 0.1, and 3.07 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 15.71 ⁇ 0.1, 9.97 ⁇ 0.1, 9.22 ⁇ 0.1, 8.33 ⁇ 0.1, 8.05 ⁇ 0.1, 6.55 ⁇ 0.1, 6.16 ⁇ 0.1, 5.94 ⁇ 0.1, 5.77 ⁇ 0.1, 5.50 ⁇ 0.1, 5.25 ⁇ 0.1, 5.15 ⁇ 0.1, 4.91 ⁇ 0.1, 4.63 ⁇ 0.1, 4.36 ⁇ 0.1, 4.22 ⁇ 0.1, 4.09 ⁇ 0.1, 4.01 ⁇ 0.1, 3.89 ⁇ 0.1, 3.78 ⁇ 0.1, 3.71 ⁇ 0.1, 3.60 ⁇ 0.1, 3.32 ⁇ 0.1, 3.26 ⁇ 0.1, and 3.07 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.05, 5.94, 4.91, 4.63, 4.22, and 3.89.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 15.71, 9.97, 9.22, 8.33, 6.55, 6.16, 5.77, 5.50, 5.25, 5.15, 4.36, 4.09, 4.01, 3.78, 3.71, 3.60, 3.32, 3.26, and 3.07.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 15.71 ⁇ 0.2, 9.97 ⁇ 0.2, 9.22 ⁇ 0.2, 8.33 ⁇ 0.2, 8.05 ⁇ 0.2, 6.55 ⁇ 0.2, 6.16 ⁇ 0.2, 5.94 ⁇ 0.2, 5.77 ⁇ 0.2, 5.50 ⁇ 0.2, 5.25 ⁇ 0.2, 5.15 ⁇ 0.2, 4.91 ⁇ 0.2, 4.63 ⁇ 0.2, 4.36 ⁇ 0.2, 4.22 ⁇ 0.2, 4.09 ⁇ 0.2, 4.01 ⁇ 0.2, 3.89 ⁇ 0.2, 3.78 ⁇ 0.2, 3.71 ⁇ 0.2, 3.60 ⁇ 0.2, 3.32 ⁇ 0.2, 3.26 ⁇ 0.2, and 3.07 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) can be Form C, where Form C is characterized by the XRPD pattern described above or by FIG. 44 .
  • the crystalline form of the compound of formula (I) can include an endothermic event et temperature of about 211° C. as determined by DSC.
  • the crystalline form of the compound of formula (I) (e.g., Form C) can be characterized by a DSC plot set forth in FIG. 16 .
  • the crystalline form of the compound of formula (I) can have a melting point of about 213° C.
  • the crystalline form of the compound of formula (I) can be Form C, where Form C has a melting point of about 213° C.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 15.6 ⁇ 0.2, 22.0 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.6 ⁇ 0.2, 7.8 ⁇ 0.2, 9.0 ⁇ 0.2, 10.6 ⁇ 0.2, 13.7 ⁇ 0.2, 14.7 ⁇ 0.2, 16.3 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 18.2 ⁇ 0.2, 18.8 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 20.7 ⁇ 0.2, 21.2 ⁇ 0.2, 22.5 ⁇ 0.2, 25.0 ⁇ 0.2, 26.6 ⁇ 0.2, 27.6 ⁇ 0.2, and 28.7 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.6 ⁇ 0.2, 7.8 ⁇ 0.2, 9.0 ⁇ 0.2, 10.6 ⁇ 0.2, 13.7 ⁇ 0.2, 14.7 ⁇ 0.2, 15.6 ⁇ 0.2, 16.3 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 18.2 ⁇ 0.2, 18.8 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 20.7 ⁇ 0.2, 21.2 ⁇ 0.2, 22.0 ⁇ 0.2, 22.5 ⁇ 0.2, 23.7 ⁇ 0.2, 25.0 ⁇ 0.2, 26.6 ⁇ 0.2, 27.6 ⁇ 0.2, and 28.7 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 15.6 ⁇ 0.1, 22.0 ⁇ 0.1, and 23.7 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.6 ⁇ 0.1, 7.8 ⁇ 0.1, 9.0 ⁇ 0.1,10.6 ⁇ 0.1,13.7 ⁇ 0.1,14.7 ⁇ 0.1,16.3 ⁇ 0.1,17.1 ⁇ 0.1,18.1 ⁇ 0.1, 18.2 ⁇ 0.1, 18.8 ⁇ 0.1, 19.1 ⁇ 0.1, 19.7 ⁇ 0.1, 20.7 ⁇ 0.1, 21.2 ⁇ 0.1, 22.5 ⁇ 0.1, 25.0 ⁇ 0.1, 26.6 ⁇ 0.1, 27.6 ⁇ 0.1, and 28.7 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.6 ⁇ 0.1, 7.8 ⁇ 0.1, 9.0 ⁇ 0.1, 10.6 ⁇ 0.1, 13.7 ⁇ 0.1, 14.7 ⁇ 0.1, 15.6 ⁇ 0.1, 16.3 ⁇ 0.1, 17.1 ⁇ 0.1, 18.1 ⁇ 0.1, 18.2 ⁇ 0.1, 18.8 ⁇ 0.1, 19.1 ⁇ 0.1, 19.7 ⁇ 0.1, 20.7 ⁇ 0.1, 21.2 ⁇ 0.1, 22.0 ⁇ 0.1, 22.5 ⁇ 0.1, 23.7 ⁇ 0.1, 25.0 ⁇ 0.1, 26.6 ⁇ 0.1, 27.6 ⁇ 0.1, and 28.7 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 15.6, 22.0, and 23.7.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.6, 7.8, 9.0, 10.6, 13.7, 14.7, 16.3, 17.1, 18.1, 18.2, 18.8, 19.1, 19.7, 20.7, 21.2, 22.5, 25.0, 26.6, 27.6, and 28.7.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.6, 7.8, 9.0, 10.6, 13.7, 14.7, 15.6, 16.3, 17.1, 18.1, 18.2, 18.8, 19.1, 19.7, 20.7, 21.2, 22.0, 22.5, 23.7, 25.0, 26.6, 27.6, and 28.7.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 45 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 5.66 ⁇ 0.3, 4.02 ⁇ 0.3, and 3.75 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 13.46 ⁇ 0.3, 11.38 ⁇ 0.3, 9.79 ⁇ 0.3, 8.37 ⁇ 0.3, 6.43 ⁇ 0.3, 6.02 ⁇ 0.3, 5.44 ⁇ 0.3, 5.18 ⁇ 0.3, 4.90 ⁇ 0.3, 4.86 ⁇ 0.3, 4.72 ⁇ 0.3, 4.64 ⁇ 0.3, 4.50 ⁇ 0.3, 4.29 ⁇ 0.3, 4.19 ⁇ 0.3, 3.94 ⁇ 0.3, 3.55 ⁇ 0.3, 3.34 ⁇ 0.3, 3.22 ⁇ 0.3, and 3.10 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 13.46 ⁇ 0.3, 11.38 ⁇ 0.3, 9.79 ⁇ 0.3, 8.37 ⁇ 0.3, 6.43 ⁇ 0.3, 6.02 ⁇ 0.3, 5.66 ⁇ 0.3, 5.44 ⁇ 0.3, 5.18 ⁇ 0.3, 4.90 ⁇ 0.3, 4.86 ⁇ 0.3, 4.72 ⁇ 0.3, 4.64 ⁇ 0.3, 4.50 ⁇ 0.3, 4.29 ⁇ 0.3, 4.19 ⁇ 0.3, 4.02 ⁇ 0.3, 3.94 ⁇ 0.3, 3.75 ⁇ 0.3, 3.55 ⁇ 0.3, 3.34 ⁇ 0.3, 3.22 ⁇ 0.3, and 3.10 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 5.66 ⁇ 0.2, 4.02 ⁇ 0.2, and 3.75 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 13.46 ⁇ 0.2, 11.38 ⁇ 0.2, 9.79 ⁇ 0.2, 8.37 ⁇ 0.2, 6.43 ⁇ 0.2, 6.02 ⁇ 0.2, 5.44 ⁇ 0.2, 5.18 ⁇ 0.2, 4.90 ⁇ 0.2, 4.86 ⁇ 0.2, 4.72 ⁇ 0.2, 4.64 ⁇ 0.2, 4.50 ⁇ 0.2, 4.29 ⁇ 0.2, 4.19 ⁇ 0.2, 3.94 ⁇ 0.2, 3.55 ⁇ 0.2, 3.34 ⁇ 0.2, 3.22 ⁇ 0.2, and 3.10 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 13.46 ⁇ 0.2, 11.38 ⁇ 0.2, 9.79 ⁇ 0.2, 8.37 ⁇ 0.2, 6.43 ⁇ 0.2, 6.02 ⁇ 0.2, 5.66 ⁇ 0.2, 5.44 ⁇ 0.2, 5.18 ⁇ 0.2, 4.90 ⁇ 0.2, 4.86 ⁇ 0.2, 4.72 ⁇ 0.2, 4.64 ⁇ 0.2, 4.50 ⁇ 0.2, 4.29 ⁇ 0.2, 4.19 ⁇ 0.2, 4.02 ⁇ 0.2, 3.94 ⁇ 0.2, 3.75 ⁇ 0.2, 3.55 ⁇ 0.2, 3.34 ⁇ 0.2, 3.22 ⁇ 0.2, and 3.10 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 5.66 ⁇ 0.1, 4.02 ⁇ 0.1, and 3.75 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 13.46 ⁇ 0.1, 11.38 ⁇ 0.1, 9.79 ⁇ 0.1, 8.37 ⁇ 0.1, 6.43 ⁇ 0.1, 6.02 ⁇ 0.1, 5.44 ⁇ 0.1, 5.18 ⁇ 0.1, 4.90 ⁇ 0.1, 4.86 ⁇ 0.1, 4.72 ⁇ 0.1, 4.64 ⁇ 0.1, 4.50 ⁇ 0.1, 4.29 ⁇ 0.1, 4.19 ⁇ 0.1, 3.94 ⁇ 0.1, 3.55 ⁇ 0.1, 3.34 ⁇ 0.1, 3.22 ⁇ 0.1, and 3.10 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 13.46 ⁇ 0.1, 11.38 ⁇ 0.1, 9.79 ⁇ 0.1, 8.37 ⁇ 0.1, 6.43 ⁇ 0.1, 6.02 ⁇ 0.1, 5.66 ⁇ 0.1, 5.44 ⁇ 0.1, 5.18 ⁇ 0.1, 4.90 ⁇ 0.1, 4.86 ⁇ 0.1, 4.72 ⁇ 0.1, 4.64 ⁇ 0.1, 4.50 ⁇ 0.1, 4.29 ⁇ 0.1, 4.19 ⁇ 0.1, 4.02 ⁇ 0.1, 3.94 ⁇ 0.1, 3.75 ⁇ 0.1, 3.55 ⁇ 0.1, 3.34 ⁇ 0.1, 3.22 ⁇ 0.1, and 3.10 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 5.66, 4.02, and 3.75.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 13.46, 11.38, 9.79, 8.37, 6.43, 6.02, 5.44, 5.18, 4.90, 4.86, 4.72, 4.64, 4.50, 4.29, 4.19, 3.94, 3.55, 3.34, 3.22, and 3.10.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 13.46, 11.38, 9.79, 8.37, 6.43, 6.02, 5.66, 5.44, 5.18, 4.90, 4.86, 4.72, 4.64, 4.50, 4.29, 4.19, 4.02, 3.94, 3.75, 3.55, 3.34, 3.22, and 3.10.
  • the crystalline form of the compound of formula (I) can be Form D, where Form D is characterized by the XRPD pattern described above or by FIG. 45 .
  • the crystalline form of the compound of formula (I) (e.g., Form D) can include an endothermic event with an onset temperature of about 205° C. as determined by DSC.
  • the crystalline form of the compound of formula (I) can be characterized by a DSC plot set forth in FIG. 19 .
  • the crystalline form of the compound of formula (I) can have a melting point of about 209° C.
  • the crystalline form of the compound of formula (I) can be Form D, where Form D has a melting point of about 209° C.
  • the crystalline form of the compound of formula (I) (e.g., Form D) can have a mass loss of about 13% when heated from about 35° C. to about 153° C.
  • Form D can be a solvated crystalline form, where Form D is a dichloromethane solvate.
  • the crystalline form of the compound of formula (I) can be characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 8.8 ⁇ 0.3, 17.7 ⁇ 0.3, and 21.4 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 5.4 ⁇ 0.3, 9.3 ⁇ 0.3, 12.1 ⁇ 0.3, 13.4 ⁇ 0.3, 13.8 ⁇ 0.3, 18.0 ⁇ 0.3, 16.5 ⁇ 0.3, 18.3 ⁇ 0.3, 18.9 ⁇ 0.3, 19.5 ⁇ 0.3, 22.2 ⁇ 0.3, 22.6 ⁇ 0.3, 22.9 ⁇ 0.3, 23.3 ⁇ 0.3, 23.5 ⁇ 0.3, 24.4 ⁇ 0.3, 26.2 ⁇ 0.3, 26.8 ⁇ 0.3, 27.8 ⁇ 0.3, and 29.3 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 5.4 ⁇ 0.3, 8.8 ⁇ 0.3, 9.3 ⁇ 0.3, 12.1 ⁇ 0.3, 13.4 ⁇ 0.3, 13.8 ⁇ 0.3, 17.7 ⁇ 0.3, 18.0 ⁇ 0.3, 16.5 ⁇ 0.3, 18.3 ⁇ 0.3, 18.9 ⁇ 0.3, 19.5 ⁇ 0.3, 21.4 ⁇ 0.3, 22.2 ⁇ 0.3, 22.6 ⁇ 0.3, 22.9 ⁇ 0.3, 23.3 ⁇ 0.3, 23.5 ⁇ 0.3, 24.4 ⁇ 0.3, 26.2 ⁇ 0.3, 26.8 ⁇ 0.3, 27.8 ⁇ 0.3, and 29.3 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 8.8 ⁇ 0.2, 17.7 ⁇ 0.2, and 21.4 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 5.4 ⁇ 0.2, 9.3 ⁇ 0.2, 12.1 ⁇ 0.2, 13.4 ⁇ 0.2, 13.8 ⁇ 0.2, 18.0 ⁇ 0.2, 16.5 ⁇ 0.2, 18.3 ⁇ 0.2, 18.9 ⁇ 0.2, 19.5 ⁇ 0.2, 22.2 ⁇ 0.2, 22.6 ⁇ 0.2, 22.9 ⁇ 0.2, 23.3 ⁇ 0.2, 23.5 ⁇ 0.2, 24.4 ⁇ 0.2, 26.2 ⁇ 0.2, 26.8 ⁇ 0.2, 27.8 ⁇ 0.2, and 29.3 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 5.4 ⁇ 0.2, 8.8 ⁇ 0.2, 9.3 ⁇ 0.2, 12.1 ⁇ 0.2, 13.4 ⁇ 0.2, 13.8 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 16.5 ⁇ 0.2, 18.3 ⁇ 0.2, 18.9 ⁇ 0.2, 19.5 ⁇ 0.2, 21.4 ⁇ 0.2, 22.2 ⁇ 0.2, 22.6 ⁇ 0.2, 22.9 ⁇ 0.2, 23.3 ⁇ 0.2, 23.5 ⁇ 0.2, 24.4 ⁇ 0.2, 26.2 ⁇ 0.2, 26.8 ⁇ 0.2, 27.8 ⁇ 0.2, and 29.3 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 8.8 ⁇ 0.1, 17.7 ⁇ 0.1, and 21.4 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 5.4 ⁇ 0.1, 9.3 ⁇ 0.1, 12.1 ⁇ 0.1, 13.4 ⁇ 0.1, 13.8 ⁇ 0.1, 18.0 ⁇ 0.1, 16.5 ⁇ 0.1, 18.3 ⁇ 0.1, 18.9 ⁇ 0.1, 19.5 ⁇ 0.1, 22.2 ⁇ 0.1, 22.6 ⁇ 0.1, 22.9 ⁇ 0.1, 23.3 ⁇ 0.1, 23.5 ⁇ 0.1, 24.4 ⁇ 0.1, 26.2 ⁇ 0.1, 26.8 ⁇ 0.1, 27.8 ⁇ 0.1, and 29.3 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 5.4 ⁇ 0.1, 8.8 ⁇ 0.1, 9.3 ⁇ 0.1, 12.1 ⁇ 0.1, 13.4 ⁇ 0.1, 13.8 ⁇ 0.1, 17.7 ⁇ 0.1, 18.0 ⁇ 0.1, 16.5 ⁇ 0.1, 18.3 ⁇ 0.1, 18.9 ⁇ 0.1, 19.5 ⁇ 0.1, 21.4 ⁇ 0.1, 22.2 ⁇ 0.1, 22.6 ⁇ 0.1, 22.9 ⁇ 0.1, 23.3 ⁇ 0.1, 23.5 ⁇ 0.1, 24.4 ⁇ 0.1, 26.2 ⁇ 0.1, 26.8 ⁇ 0.1, 27.8 ⁇ 0.1, and 29.3 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 8.8, 17.7, and 21.4.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 5.4, 9.3, 12.1, 13.4, 13.8, 18.0, 16.5, 18.3, 18.9, 19.5, 22.2, 22.6, 22.9, 23.3, 23.5, 24.4, 26.2, 26.8, 27.8, and 29.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 5.4, 8.8, 9.3, 12.1, 13.4, 13.8, 17.7, 18.0, 16.5, 18.3, 18.9, 19.5, 21.4, 22.2, 22.6, 22.9, 23.3, 23.5, 24.4, 26.2, 26.8, 27.8, and 29.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 46 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 10.01 ⁇ 0.3, 4.99 ⁇ 0.3, and 4.14 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 16.41 ⁇ 0.3, 9.46 ⁇ 0.3, 7.30 ⁇ 0.3, 6.61 ⁇ 0.3, 6.40 ⁇ 0.3, 5.52 ⁇ 0.3, 5.38 ⁇ 0.3, 4.83 ⁇ 0.3, 4.67 ⁇ 0.3, 4.55 ⁇ 0.3, 3.99 ⁇ 0.3, 3.93, ⁇ 0.3 3.87 ⁇ 0.3, 3.81 ⁇ 0.3, 3.77 ⁇ 0.3, 3.64 ⁇ 0.3, 3.40 ⁇ 0.3, 3.32 ⁇ 0.3, and 3.04 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 16.41 ⁇ 0.3, 10.01 ⁇ 0.3, 9.46 ⁇ 0.3, 7.30 ⁇ 0.3, 6.61 ⁇ 0.3, 6.40 ⁇ 0.3, 5.52 ⁇ 0.3, 5.38 ⁇ 0.3, 4.99 ⁇ 0.3, 4.83 ⁇ 0.3, 4.67 ⁇ 0.3, 4.55 ⁇ 0.3, 4.14 ⁇ 0.3, 3.99 ⁇ 0.3, 3.93, ⁇ 0.3 3.87 ⁇ 0.3, 3.81 ⁇ 0.3, 3.77 ⁇ 0.3, 3.64 ⁇ 0.3, 3.40 ⁇ 0.3, 3.32 ⁇ 0.3, and 3.04 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 10.01 ⁇ 0.2, 4.99 ⁇ 0.2, and 4.14 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 16.41 ⁇ 0.2, 9.46 ⁇ 0.2, 7.30 ⁇ 0.2, 6.61 ⁇ 0.2, 6.40 ⁇ 0.2, 5.52 ⁇ 0.2, 5.38 ⁇ 0.2, 4.83 ⁇ 0.2, 4.67 ⁇ 0.2, 4.55 ⁇ 0.2, 3.99 ⁇ 0.2, 3.93, ⁇ 0.2 3.87 ⁇ 0.2, 3.81 ⁇ 0.2, 3.77 ⁇ 0.2, 3.64 ⁇ 0.2, 3.40 ⁇ 0.2, 3.32 ⁇ 0.2, and 3.04 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 16.41 ⁇ 0.2, 10.01 ⁇ 0.2, 9.46 ⁇ 0.2, 7.30 ⁇ 0.2, 6.61 ⁇ 0.2, 6.40 ⁇ 0.2, 5.52 ⁇ 0.2, 5.38 ⁇ 0.2, 4.99 ⁇ 0.2, 4.83 ⁇ 0.2, 4.67 ⁇ 0.2, 4.55 ⁇ 0.2, 4.14 ⁇ 0.2, 3.99 ⁇ 0.2, 3.93, ⁇ 0.2 3.87 ⁇ 0.2, 3.81 ⁇ 0.2, 3.77 ⁇ 0.2, 3.64 ⁇ 0.2, 3.40 ⁇ 0.2, 3.32 ⁇ 0.2, and 3.04 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 10.01 ⁇ 0.1, 4.99 ⁇ 0.1, and 4.14 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 16.41 ⁇ 0.1, 9.46 ⁇ 0.1, 7.30 ⁇ 0.1, 6.61 ⁇ 0.1, 6.40 ⁇ 0.1, 5.52 ⁇ 0.1, 5.38 ⁇ 0.1, 4.83 ⁇ 0.1, 4.67 ⁇ 0.1, 4.55 ⁇ 0.1, 3.99 ⁇ 0.1, 3.93, ⁇ 0.1 3.87 ⁇ 0.1, 3.81 ⁇ 0.1, 3.77 ⁇ 0.1, 3.64 ⁇ 0.1, 3.40 ⁇ 0.1, 3.32 ⁇ 0.1, and 3.04 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 10.01, 4.99, and 4.14.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 16.41, 9.46, 7.30, 6.61, 6.40, 5.52, 5.38, 4.83, 4.67, 4.55, 3.99, 3.93, 3.87, 3.81, 3.77, 3.64, 3.40, 3.32, and 3.04.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 16.41, 10.01, 9.46, 7.30, 6.61, 6.40, 5.52, 5.38, 4.99, 4.83, 4.67, 4.55, 4.14, 3.99, 3.93, 3.87, 3.81, 3.77, 3.64, 3.40, 3.32, and 3.04.
  • the crystalline form of the compound of formula (I) can be Form E, where Form E is characterized by the XRPD pattern described above or by FIG. 46 .
  • Form E can be a solvated crystalline form, where Form E is a chlorobenzene solvate.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 4.6 ⁇ 0.3, 4.8 ⁇ 0.3, 15.3 ⁇ 0.3, 16.6 ⁇ 0.3, 18.1 ⁇ 0.3, and 22.9 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 7.3 ⁇ 0.3, 8.1 ⁇ 0.3, 9.7 ⁇ 0.3, 11.0 ⁇ 0.3, 12.2 ⁇ 0.3, 13.8 ⁇ 0.3, 14.8 ⁇ 0.3, 16.1 ⁇ 0.3, 17.5 ⁇ 0.3, 17.9 ⁇ 0.3, 18.5 ⁇ 0.3, 19.8 ⁇ 0.3, 20.2 ⁇ 0.3, 20.8 ⁇ 0.3, 21.5 ⁇ 0.3, 22.2 ⁇ 0.3, 23.4 ⁇ 0.3, 24.0 ⁇ 0.3, 24.8 ⁇ 0.3, 25.2 ⁇ 0.3, 25.8 ⁇ 0.3, 27.5 ⁇ 0.3, 27.9 ⁇ 0.3, and 31.9 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 4.6 ⁇ 0.3, 4.8 ⁇ 0.3, 7.3 ⁇ 0.3, 8.1 ⁇ 0.3, 9.7 ⁇ 0.3, 11.0 ⁇ 0.3, 12.2 ⁇ 0.3, 13.8 ⁇ 0.3, 14.8 ⁇ 0.3, 15.3 ⁇ 0.3, 16.1 ⁇ 0.3, 16.6 ⁇ 0.3, 17.5 ⁇ 0.3, 17.9 ⁇ 0.3, 18.1 ⁇ 0.3, 18.5 ⁇ 0.3, 19.8 ⁇ 0.3, 20.2 ⁇ 0.3, 20.8 ⁇ 0.3, 21.5 ⁇ 0.3, 22.2 ⁇ 0.3, 22.9 ⁇ 0.3, 23.4 ⁇ 0.3, 24.0 ⁇ 0.3, 24.8 ⁇ 0.3, 25.2 ⁇ 0.3, 25.8 ⁇ 0.3, 27.5 ⁇ 0.3, 27.9 ⁇ 0.3, and 31.9 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 4.6 ⁇ 0.2, 4.8 ⁇ 0.2, 15.3 ⁇ 0.2, 16.6 ⁇ 0.2, 18.1 ⁇ 0.2, and 22.9 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 7.3 ⁇ 0.2, 8.1 ⁇ 0.2, 9.7 ⁇ 0.2, 11.0 ⁇ 0.2, 12.2 ⁇ 0.2, 13.8 ⁇ 0.2, 14.8 ⁇ 0.2, 16.1 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.5 ⁇ 0.2, 19.8 ⁇ 0.2, 20.2 ⁇ 0.2, 20.8 ⁇ 0.2, 21.5 ⁇ 0.2, 22.2 ⁇ 0.2, 23.4 ⁇ 0.2, 24.0 ⁇ 0.2, 24.8 ⁇ 0.2, 25.2 ⁇ 0.2, 25.8 ⁇ 0.2, 27.5 ⁇ 0.2, 27.9 ⁇ 0.2, and 31.9 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 4.6 ⁇ 0.2, 4.8 ⁇ 0.2, 7.3 ⁇ 0.2, 8.1 ⁇ 0.2, 9.7 ⁇ 0.2, 11.0 ⁇ 0.2, 12.2 ⁇ 0.2, 13.8 ⁇ 0.2, 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, 16.1 ⁇ 0.2, 16.6 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.5 ⁇ 0.2, 19.8 ⁇ 0.2, 20.2 ⁇ 0.2, 20.8 ⁇ 0.2, 21.5 ⁇ 0.2, 22.2 ⁇ 0.2, 22.9 ⁇ 0.2, 23.4 ⁇ 0.2, 24.0 ⁇ 0.2, 24.8 ⁇ 0.2, 25.2 ⁇ 0.2, 25.8 ⁇ 0.2, 27.5 ⁇ 0.2, 27.9 ⁇ 0.2, and 31.9 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 4.6 ⁇ 0.1, 4.8 ⁇ 0.1, 15.3 ⁇ 0.1, 16.6 ⁇ 0.1, 18.1 ⁇ 0.1, and 22.9 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 7.3 ⁇ 0.1, 8.1 ⁇ 0.1, 9.7 ⁇ 0.1, 11.0 ⁇ 0.1, 12.2 ⁇ 0.1, 13.8 ⁇ 0.1, 14.8 ⁇ 0.1, 16.1 ⁇ 0.1, 17.5 ⁇ 0.1, 17.9 ⁇ 0.1, 18.5 ⁇ 0.1, 19.8 ⁇ 0.1, 20.2 ⁇ 0.1, 20.8 ⁇ 0.1, 21.5 ⁇ 0.1, 22.2 ⁇ 0.1, 23.4 ⁇ 0.1, 24.0 ⁇ 0.1, 24.8 ⁇ 0.1, 25.2 ⁇ 0.1, 25.8 ⁇ 0.1, 27.5 ⁇ 0.1, 27.9 ⁇ 0.1, and 31.9 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 4.6 ⁇ 0.1, 4.8 ⁇ 0.1, 7.3 ⁇ 0.1, 8.1 ⁇ 0.1, 9.7 ⁇ 0.1, 11.0 ⁇ 0.1, 12.2 ⁇ 0.1, 13.8 ⁇ 0.1, 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, 16.1 ⁇ 0.1, 16.6 ⁇ 0.1, 17.5 ⁇ 0.1, 17.9 ⁇ 0.1, 18.1 ⁇ 0.1, 18.5 ⁇ 0.1, 19.8 ⁇ 0.1, 20.2 ⁇ 0.1, 20.8 ⁇ 0.1, 21.5 ⁇ 0.1, 22.2 ⁇ 0.1, 22.9 ⁇ 0.1, 23.4 ⁇ 0.1, 24.0 ⁇ 0.1, 24.8 ⁇ 0.1, 25.2 ⁇ 0.1, 25.8 ⁇ 0.1, 27.5 ⁇ 0.1, 27.9 ⁇ 0.1, and 31.9 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 4.6, 4.8, 15.3, 16.6, 18.1, and 22.9.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 7.3, 8.1, 9.7, 11.0, 12.2, 13.8, 14.8, 16.1, 17.5, 17.9, 18.5, 19.8, 20.2, 20.8, 21.5, 22.2, 23.4, 24.0, 24.8, 25.2, 25.8, 27.5, 27.9, and 31.9.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 4.6 ⁇ 0.2, 4.8 ⁇ 0.2, 7.3 ⁇ 0.2, 8.1 ⁇ 0.2, 9.7 ⁇ 0.2, 11.0 ⁇ 0.2, 12.2 ⁇ 0.2, 13.8 ⁇ 0.2, 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, 16.1 ⁇ 0.2, 16.6 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.5 ⁇ 0.2, 19.8 ⁇ 0.2, 20.2 ⁇ 0.2, 20.8 ⁇ 0.2, 21.5 ⁇ 0.2, 22.2 ⁇ 0.2, 22.9 ⁇ 0.2, 23.4 ⁇ 0.2, 24.0 ⁇ 0.2, 24.8 ⁇ 0.2, 25.2 ⁇ 0.2, 25.8 ⁇ 0.2, 27.5 ⁇ 0.2, 27.9 ⁇ 0.2, and 31.9 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 47 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.27 ⁇ 0.3, 18.31 ⁇ 0.3, 5.77 ⁇ 0.3, 5.33 ⁇ 0.3, 4.65 ⁇ 0.3, and 3.88 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 12.06 ⁇ 0.3, 10.96 ⁇ 0.3, 9.11 ⁇ 0.3, 8.02 ⁇ 0.3, 7.22 ⁇ 0.3, 6.39 ⁇ 0.3, 5.98 ⁇ 0.3, 5.51 ⁇ 0.3, 5.07 ⁇ 0.3, 4.95 ⁇ 0.3, 4.78 ⁇ 0.3, 4.52 ⁇ 0.3, 4.39 ⁇ 0.3, 4.26 ⁇ 0.3, 4.12 ⁇ 0.3, 4.00 ⁇ 0.3, 3.80 ⁇ 0.3, 3.69 ⁇ 0.3, 3.61 ⁇ 0.3, 3.53 ⁇ 0.3, 3.45 ⁇ 0.3, 3.24 ⁇ 0.3, 3.19 ⁇ 0.3, and 2.80 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.27 ⁇ 0.3, 18.31 ⁇ 0.3, 12.06 ⁇ 0.3, 10.96 ⁇ 0.3, 9.11 ⁇ 0.3, 8.02 ⁇ 0.3, 7.22 ⁇ 0.3, 6.39 ⁇ 0.3, 5.98 ⁇ 0.3, 5.77 ⁇ 0.3, 5.51 ⁇ 0.3, 5.33 ⁇ 0.3, 5.07 ⁇ 0.3, 4.95 ⁇ 0.3, 4.78 ⁇ 0.3, 4.65 ⁇ 0.3, 4.52 ⁇ 0.3, 4.39 ⁇ 0.3, 4.26 ⁇ 0.3, 4.12 ⁇ 0.3, 4.00 ⁇ 0.3, 3.88 ⁇ 0.3, 3.80 ⁇ 0.3, 3.69 ⁇ 0.3, 3.61 ⁇ 0.3, 3.53 ⁇ 0.3, 3.45 ⁇ 0.3, 3.24 ⁇ 0.3, 3.19 ⁇ 0.3, and 2.80 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.27 ⁇ 0.2, 18.31 ⁇ 0.2, 5.77 ⁇ 0.2, 5.33 ⁇ 0.2, 4.65 ⁇ 0.2, and 3.88 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 12.06 ⁇ 0.2, 10.96 ⁇ 0.2, 9.11 ⁇ 0.2, 8.02 ⁇ 0.2, 7.22 ⁇ 0.2, 6.39 ⁇ 0.2, 5.98 ⁇ 0.2, 5.51 ⁇ 0.2, 5.07 ⁇ 0.2, 4.95 ⁇ 0.2, 4.78 ⁇ 0.2, 4.52 ⁇ 0.2, 4.39 ⁇ 0.2, 4.26 ⁇ 0.2, 4.12 ⁇ 0.2, 4.00 ⁇ 0.2, 3.80 ⁇ 0.2, 3.69 ⁇ 0.2, 3.61 ⁇ 0.2, 3.53 ⁇ 0.2, 3.45 ⁇ 0.2, 3.24 ⁇ 0.2, 3.19 ⁇ 0.2, and 2.80 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.27 ⁇ 0.2, 18.31 ⁇ 0.2, 12.06 ⁇ 0.2, 10.96 ⁇ 0.2, 9.11 ⁇ 0.2, 8.02 ⁇ 0.2, 7.22 ⁇ 0.2, 6.39 ⁇ 0.2, 5.98 ⁇ 0.2, 5.77 ⁇ 0.2, 5.51 ⁇ 0.2, 5.33 ⁇ 0.2, 5.07 ⁇ 0.2, 4.95 ⁇ 0.2, 4.78 ⁇ 0.2, 4.65 ⁇ 0.2, 4.52 ⁇ 0.2, 4.39 ⁇ 0.2, 4.26 ⁇ 0.2, 4.12 ⁇ 0.2, 4.00 ⁇ 0.2, 3.88 ⁇ 0.2, 3.80 ⁇ 0.2, 3.69 ⁇ 0.2, 3.61 ⁇ 0.2, 3.53 ⁇ 0.2, 3.45 ⁇ 0.2, 3.24 ⁇ 0.2, 3.19 ⁇ 0.2, and 2.80 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.27 ⁇ 0.1, 18.31 ⁇ 0.1, 5.77 ⁇ 0.1, 5.33 ⁇ 0.1, 4.65 ⁇ 0.1, and 3.88 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 12.06 ⁇ 0.1, 10.96 ⁇ 0.1, 9.11 ⁇ 0.1, 8.02 ⁇ 0.1, 7.22 ⁇ 0.1, 6.39 ⁇ 0.1, 5.98 ⁇ 0.1, 5.51 ⁇ 0.1, 5.07 ⁇ 0.1, 4.95 ⁇ 0.1, 4.78 ⁇ 0.1, 4.52 ⁇ 0.1, 4.39 ⁇ 0.1, 4.26 ⁇ 0.1, 4.12 ⁇ 0.1, 4.00 ⁇ 0.1, 3.80 ⁇ 0.1, 3.69 ⁇ 0.1, 3.61 ⁇ 0.1, 3.53 ⁇ 0.1, 3.45 ⁇ 0.1, 3.24 ⁇ 0.1, 3.19 ⁇ 0.1, and 2.80 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.27 ⁇ 0.1, 18.31 ⁇ 0.1, 12.06 ⁇ 0.1, 10.96 ⁇ 0.1, 9.11 ⁇ 0.1, 8.02 ⁇ 0.1, 7.22 ⁇ 0.1, 6.39 ⁇ 0.1, 5.98 ⁇ 0.1, 5.77 ⁇ 0.1, 5.51 ⁇ 0.1, 5.33 ⁇ 0.1, 5.07 ⁇ 0.1, 4.95 ⁇ 0.1, 4.78 ⁇ 0.1, 4.65 ⁇ 0.1, 4.52 ⁇ 0.1, 4.39 ⁇ 0.1, 4.26 ⁇ 0.1, 4.12 ⁇ 0.1, 4.00 ⁇ 0.1, 3.88 ⁇ 0.1, 3.80 ⁇ 0.1, 3.69 ⁇ 0.1, 3.61 ⁇ 0.1, 3.53 ⁇ 0.1, 3.45 ⁇ 0.1, 3.24 ⁇ 0.1, 3.19 ⁇ 0.1, and 2.80 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.27, 18.31, 5.77, 5.33, 4.65, and 3.88.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 12.06, 10.96, 9.11, 8.02, 7.22, 6.39, 5.98, 5.51, 5.07, 4.95, 4.78, 4.52, 4.39, 4.26, 4.12, 4.00, 3.80, 3.69, 3.61, 3.53, 3.45, 3.24, 3.19, and 2.80.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.27, 18.31, 12.06, 10.96, 9.11, 8.02, 7.22, 6.39, 5.98, 5.77, 5.51, 5.33, 5.07, 4.95, 4.78, 4.65, 4.52, 4.39, 4.26, 4.12, 4.00, 3.88, 3.80, 3.69, 3.61, 3.53, 3.45, 3.24, 3.19, and 2.80.
  • the crystalline form of the compound of formula (I) can be Form F, where Form F is characterized by the XRPD pattern described above or by FIG. 47 .
  • the crystalline form of the compound of formula (I) (e.g., Form F) can include an endothermic event with an onset temperature of about 206° C. as determined by DSC.
  • the crystalline form of the compound of formula (I) can be characterized by a DSC plot set forth in FIG. 24 .
  • the crystalline form of the compound of formula (I) can have a melting point of about 209° C.
  • the crystalline form of the compound of formula (I) can be Form F, where Form F has a melting point of about 209° C.
  • the crystalline form of the compound of formula (I) (e.g., Form F) can have a mass loss of about 14% when heated from about 40° C. to about 170° C.
  • Form F can be a solvated crystalline form, where Form F is a trifluoroethanol solvate.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 12.0 ⁇ 0.3, 13.4 ⁇ 0.3, 15.7 ⁇ 0.3, 16.4 ⁇ 0.3, 18.4 ⁇ 0.3, 19.5 ⁇ 0.3, 21.5 ⁇ 0.3, 22.4 ⁇ 0.3, 22.8 ⁇ 0.3, 23.5 ⁇ 0.3, and 24.2 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 9.4 ⁇ 0.3, 10.2 ⁇ 0.3, 11.3 ⁇ 0.3, 12.9 ⁇ 0.3, 14.7 ⁇ 0.3, 17.1 ⁇ 0.3, 17.7 ⁇ 0.3, 19.0 ⁇ 0.3, 20.1 ⁇ 0.3, 20.5 ⁇ 0.3, 21.8 ⁇ 0.3, 25.1 ⁇ 0.3, 25.9 ⁇ 0.3, 26.2 ⁇ 0.3, 28.7 ⁇ 0.3, 27.2 ⁇ 0.3, 28.5 ⁇ 0.3, 29.3 ⁇ 0.3, and 33.8 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 9.4 ⁇ 0.3, 10.2 ⁇ 0.3,11.3 ⁇ 0.3,12.0 ⁇ 0.3,12.9 ⁇ 0.3,13.4 ⁇ 0.3,14.7 ⁇ 0.3,15.7 ⁇ 0.3, 16.4 ⁇ 0.3, 17.1 ⁇ 0.3, 17.7 ⁇ 0.3, 18.4 ⁇ 0.3, 19.0 ⁇ 0.3, 19.5 ⁇ 0.3, 20.1 ⁇ 0.3, 20.5 ⁇ 0.3, 21.5 ⁇ 0.3, 21.8 ⁇ 0.3, 25.1 ⁇ 0.3, 22.4 ⁇ 0.3, 22.8 ⁇ 0.3, 23.5 ⁇ 0.3, 24.2 ⁇ 0.3, 25.9 ⁇ 0.3, 26.2 ⁇ 0.3, 28.7 ⁇ 0.3, 27.2 ⁇ 0.3, 28.5 ⁇ 0.3, 29.3 ⁇ 0.3, and 33.8 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 12.0 ⁇ 0.2, 13.4 ⁇ 0.2, 15.7 ⁇ 0.2, 16.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.5 ⁇ 0.2, 21.5 ⁇ 0.2, 22.4 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, and 24.2 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 9.4 ⁇ 0.2, 10.2 ⁇ 0.2, 11.3 ⁇ 0.2, 12.9 ⁇ 0.2, 14.7 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 19.0 ⁇ 0.2, 20.1 ⁇ 0.2, 20.5 ⁇ 0.2, 21.8 ⁇ 0.2, 25.1 ⁇ 0.2, 25.9 ⁇ 0.2, 26.2 ⁇ 0.2, 28.7 ⁇ 0.2, 27.2 ⁇ 0.2, 28.5 ⁇ 0.2, 29.3 ⁇ 0.2, and 33.8 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 9.4 ⁇ 0.2, 10.2 ⁇ 0.2, 11.3 ⁇ 0.2, 12.0 ⁇ 0.2, 12.9 ⁇ 0.2, 13.4 ⁇ 0.2, 14.7 ⁇ 0.2, 15.7 ⁇ 0.2, 16.4 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 18.4 ⁇ 0.2, 19.0 ⁇ 0.2, 19.5 ⁇ 0.2, 20.1 ⁇ 0.2, 20.5 ⁇ 0.2, 21.5 ⁇ 0.2, 21.8 ⁇ 0.2, 25.1 ⁇ 0.2, 22.4 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 24.2 ⁇ 0.2, 25.9 ⁇ 0.2, 26.2 ⁇ 0.2, 28.7 ⁇ 0.2, 27.2 ⁇ 0.2, 28.5 ⁇ 0.2, 29.3 ⁇ 0.2, and 33.8 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 12.0 ⁇ 0.1, 13.4 ⁇ 0.1, 15.7 ⁇ 0.1, 16.4 ⁇ 0.1, 18.4 ⁇ 0.1, 19.5 ⁇ 0.1, 21.5 ⁇ 0.1, 22.4 ⁇ 0.1, 22.8 ⁇ 0.1, 23.5 ⁇ 0.1, and 24.2 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 9.4 ⁇ 0.1, 10.2 ⁇ 0.1, 11.3 ⁇ 0.1, 12.9 ⁇ 0.1, 14.7 ⁇ 0.1, 17.1 ⁇ 0.1, 17.7 ⁇ 0.1, 19.0 ⁇ 0.1, 20.1 ⁇ 0.1, 20.5 ⁇ 0.1, 21.8 ⁇ 0.1, 25.1 ⁇ 0.1, 25.9 ⁇ 0.1, 26.2 ⁇ 0.1, 28.7 ⁇ 0.1, 27.2 ⁇ 0.1, 28.5 ⁇ 0.1, 29.3 ⁇ 0.1, and 33.8 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 9.4 ⁇ 0.1, 10.2 ⁇ 0.1, 11.3 ⁇ 0.1, 12.0 ⁇ 0.1, 12.9 ⁇ 0.1, 13.4 ⁇ 0.1, 14.7 ⁇ 0.1, 15.7 ⁇ 0.1, 16.4 ⁇ 0.1, 17.1 ⁇ 0.1, 17.7 ⁇ 0.1, 18.4 ⁇ 0.1, 19.0 ⁇ 0.1, 19.5 ⁇ 0.1, 20.1 ⁇ 0.1, 20.5 ⁇ 0.1, 21.5 ⁇ 0.1, 21.8 ⁇ 0.1, 25.1 ⁇ 0.1, 22.4 ⁇ 0.1, 22.8 ⁇ 0.1, 23.5 ⁇ 0.1, 24.2 ⁇ 0.1, 25.9 ⁇ 0.1, 26.2 ⁇ 0.1, 28.7 ⁇ 0.1, 27.2 ⁇ 0.1, 28.5 ⁇ 0.1, 29.3 ⁇ 0.1, and 33.8 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 12.0, 13.4, 15.7, 16.4, 18.4, 19.5, 21.5, 22.4, 22.8, 23.5, and 24.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 9.4, 10.2, 11.3, 12.9, 14.7, 17.1, 17.7, 19.0, 20.1, 20.5, 21.8, 25.1, 25.9, 26.2, 28.7, 27.2, 28.5, 29.3, and 33.8.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 9.4, 10.2, 11.3, 12.0, 12.9, 13.4, 14.7, 15.7, 16.4, 17.1, 17.7, 18.4, 19.0, 19.5, 20.1, 20.5, 21.5, 21.8, 25.1, 22.4, 22.8, 23.5, 24.2, 25.9, 26.2, 28.7, 27.2, 28.5, 29.3, and 33.8.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 48 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.35 ⁇ 0.3, 6.61 ⁇ 0.3, 5.62 ⁇ 0.3, 5.38 ⁇ 0.3, 4.82 ⁇ 0.3, 4.54 ⁇ 0.3, 4.13 ⁇ 0.3, 3.95 ⁇ 0.3, 3.89 ⁇ 0.3, 3.78 ⁇ 0.3, and 3.67 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 9.44 ⁇ 0.3, 8.63 ⁇ 0.3, 7.79 ⁇ 0.3, 6.84 ⁇ 0.3, 6.01 ⁇ 0.3, 5.16 ⁇ 0.3, 5.01 ⁇ 0.3, 4.66 ⁇ 0.3, 4.41 ⁇ 0.3, 4.32 ⁇ 0.3, 4.06 ⁇ 0.3, 3.53 ⁇ 0.3, 3.43 ⁇ 0.3, 3.39 ⁇ 0.3, 3.34 ⁇ 0.3, 3.27 ⁇ 0.3, 3.12 ⁇ 0.3, 3.04 ⁇ 0.3, and 2.64 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 9.44 ⁇ 0.3, 8.63 ⁇ 0.3, 7.79 ⁇ 0.3, 7.35 ⁇ 0.3, 6.84 ⁇ 0.3, 6.61 ⁇ 0.3, 6.01 ⁇ 0.3, 5.62 ⁇ 0.3, 5.38 ⁇ 0.3, 5.16 ⁇ 0.3, 5.01 ⁇ 0.3, 4.82 ⁇ 0.3, 4.66 ⁇ 0.3, 4.54 ⁇ 0.3, 4.41 ⁇ 0.3, 4.32 ⁇ 0.3, 4.13 ⁇ 0.3, 4.06 ⁇ 0.3, 3.95 ⁇ 0.3, 3.89 ⁇ 0.3, 3.78 ⁇ 0.3, 3.67 ⁇ 0.3, 3.53 ⁇ 0.3, 3.43 ⁇ 0.3, 3.39 ⁇ 0.3, 3.34 ⁇ 0.3, 3.27 ⁇ 0.3, 3.12 ⁇ 0.3, 3.04 ⁇ 0.3, and 2.64 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.35 ⁇ 0.2, 6.61 ⁇ 0.2, 5.62 ⁇ 0.2, 5.38 ⁇ 0.2, 4.82 ⁇ 0.2, 4.54 ⁇ 0.2, 4.13 ⁇ 0.2, 3.95 ⁇ 0.2, 3.89 ⁇ 0.2, 3.78 ⁇ 0.2, and 3.67 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 9.44 ⁇ 0.2, 8.63 ⁇ 0.2, 7.79 ⁇ 0.2, 6.84 ⁇ 0.2, 6.01 ⁇ 0.2, 5.16 ⁇ 0.2, 5.01 ⁇ 0.2, 4.66 ⁇ 0.2, 4.41 ⁇ 0.2, 4.32 ⁇ 0.2, 4.06 ⁇ 0.2, 3.53 ⁇ 0.2, 3.43 ⁇ 0.2, 3.39 ⁇ 0.2, 3.34 ⁇ 0.2, 3.27 ⁇ 0.2, 3.12 ⁇ 0.2, 3.04 ⁇ 0.2, and 2.64 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 9.44 ⁇ 0.2, 8.63 ⁇ 0.2, 7.79 ⁇ 0.2, 7.35 ⁇ 0.2, 6.84 ⁇ 0.2, 6.61 ⁇ 0.2, 6.01 ⁇ 0.2, 5.62 ⁇ 0.2, 5.38 ⁇ 0.2, 5.16 ⁇ 0.2, 5.01 ⁇ 0.2, 4.82 ⁇ 0.2, 4.66 ⁇ 0.2, 4.54 ⁇ 0.2, 4.41 ⁇ 0.2, 4.32 ⁇ 0.2, 4.13 ⁇ 0.2, 4.06 ⁇ 0.2, 3.95 ⁇ 0.2, 3.89 ⁇ 0.2, 3.78 ⁇ 0.2, 3.67 ⁇ 0.2, 3.53 ⁇ 0.2, 3.43 ⁇ 0.2, 3.39 ⁇ 0.2, 3.34 ⁇ 0.2, 3.27 ⁇ 0.2, 3.12 ⁇ 0.2, 3.04 ⁇ 0.2, and 2.64 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.35 ⁇ 0.1, 6.61 ⁇ 0.1, 5.62 ⁇ 0.1, 5.38 ⁇ 0.1, 4.82 ⁇ 0.1, 4.54 ⁇ 0.1, 4.13 ⁇ 0.1, 3.95 ⁇ 0.1, 3.89 ⁇ 0.1, 3.78 ⁇ 0.1, and 3.67 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 9.44 ⁇ 0.1, 8.63 ⁇ 0.1, 7.79 ⁇ 0.1, 6.84 ⁇ 0.1, 6.01 ⁇ 0.1, 5.16 ⁇ 0.1, 5.01 ⁇ 0.1, 4.66 ⁇ 0.1, 4.41 ⁇ 0.1, 4.32 ⁇ 0.1, 4.06 ⁇ 0.1, 3.53 ⁇ 0.1, 3.43 ⁇ 0.1, 3.39 ⁇ 0.1, 3.34 ⁇ 0.1, 3.27 ⁇ 0.1, 3.12 ⁇ 0.1, 3.04 ⁇ 0.1, and 2.64 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 9.44 ⁇ 0.1, 8.63 ⁇ 0.1, 7.79 ⁇ 0.1, 7.35 ⁇ 0.1, 6.84 ⁇ 0.1, 6.61 ⁇ 0.1, 6.01 ⁇ 0.1, 5.62 ⁇ 0.1, 5.38 ⁇ 0.1, 5.16 ⁇ 0.1, 5.01 ⁇ 0.1, 4.82 ⁇ 0.1, 4.66 ⁇ 0.1, 4.54 ⁇ 0.1, 4.41 ⁇ 0.1, 4.32 ⁇ 0.1, 4.13 ⁇ 0.1, 4.06 ⁇ 0.1, 3.95 ⁇ 0.1, 3.89 ⁇ 0.1, 3.78 ⁇ 0.1, 3.67 ⁇ 0.1, 3.53 ⁇ 0.1, 3.43 ⁇ 0.1, 3.39 ⁇ 0.1, 3.34 ⁇ 0.1, 3.27 ⁇ 0.1, 3.12 ⁇ 0.1, 3.04 ⁇ 0.1, and 2.64 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.35, 6.61, 5.62, 5.38, 4.82, 4.54, 4.13, 3.95, 3.89, 3.78, and 3.67.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 9.44, 8.63, 7.79, 6.84, 6.01, 5.16, 5.01, 4.66, 4.41, 4.32, 4.06, 3.53, 3.43, 3.39, 3.34, 3.27, 3.12, 3.04, and 2.64.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 9.44, 8.63, 7.79, 7.35, 6.84, 6.61, 6.01, 5.62, 5.38, 5.16, 5.01, 4.82, 4.66, 4.54, 4.41, 4.32, 4.13, 4.06, 3.95, 3.89, 3.78, 3.67, 3.53, 3.43, 3.39, 3.34, 3.27, 3.12, 3.04, and 2.64.
  • the crystalline form of the compound of formula (I) can be Form G, where Form G is characterized by the XRPD pattern described above or by FIG. 48 .
  • the crystalline form of the compound of formula (I) (e.g., Form G) can include an endothermic event with an onset temperature of about 206° C. as determined by DSC.
  • the crystalline form of the compound of formula (I) can be characterized by a DSC plot set forth in FIG. 28 .
  • the crystalline form of the compound of formula (I) can have a melting point of about 210° C.
  • the crystalline form of the compound of formula (I) can be Form G, where Form G has a melting point of about 210° C.
  • the crystalline form of the compound of formula (I) (e.g., Form G) can have a mass loss of about 3.7% heated from about 25° C. to about 115° C.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.0 ⁇ 0.3, 15.3 ⁇ 0.3, 15.6 ⁇ 0.3, 17.5 ⁇ 0.3, 18.9 ⁇ 0.3, 20.0 ⁇ 0.3, 21.1 ⁇ 0.3, 22.1 ⁇ 0.3, 24.6 ⁇ 0.3, 25.1 ⁇ 0.3, and 26.5 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.3 ⁇ 0.3, 12.7 ⁇ 0.3, 15.9 ⁇ 0.3, 18.2 ⁇ 0.3, 18.6 ⁇ 0.3, 22.6 ⁇ 0.3, 23.2 ⁇ 0.3, 24.2 ⁇ 0.3, 25.7 ⁇ 0.3, 27.0 ⁇ 0.3, 27.5 ⁇ 0.3, 29.5 ⁇ 0.3, 29.9 ⁇ 0.3, 30.5 ⁇ 0.3, 31.5 ⁇ 0.3, 32.2 ⁇ 0.3, 34.6 ⁇ 0.3, 35.1 ⁇ 0.3, and 35.6 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.3 ⁇ 0.3, 11.0 ⁇ 0.3, 12.7 ⁇ 0.3, 15.3 ⁇ 0.3, 15.6 ⁇ 0.3, 15.9 ⁇ 0.3, 17.5 ⁇ 0.3, 18.2 ⁇ 0.3, 18.6 ⁇ 0.3, 18.9 ⁇ 0.3, 20.0 ⁇ 0.3, 21.1 ⁇ 0.3, 22.1 ⁇ 0.3, 22.6 ⁇ 0.3, 23.2 ⁇ 0.3, 24.2 ⁇ 0.3, 24.6 ⁇ 0.3, 25.1 ⁇ 0.3, 25.7 ⁇ 0.3, 26.5 ⁇ 0.3, 27.0 ⁇ 0.3, 27.5 ⁇ 0.3, 29.5 ⁇ 0.3, 29.9 ⁇ 0.3, 30.5 ⁇ 0.3, 31.5 ⁇ 0.3, 32.2 ⁇ 0.3, 34.6 ⁇ 0.3, 35.1 ⁇ 0.3, and 35.6 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.0 ⁇ 0.2, 15.3 ⁇ 0.2, 15.6 ⁇ 0.2, 17.5 ⁇ 0.2, 18.9 ⁇ 0.2, 20.0 ⁇ 0.2, 21.1 ⁇ 0.2, 22.1 ⁇ 0.2, 24.6 ⁇ 0.2, 25.1 ⁇ 0.2, and 26.5 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.3 ⁇ 0.2, 12.7 ⁇ 0.2, 15.9 ⁇ 0.2, 18.2 ⁇ 0.2, 18.6 ⁇ 0.2, 22.6 ⁇ 0.2, 23.2 ⁇ 0.2, 24.2 ⁇ 0.2, 25.7 ⁇ 0.2, 27.0 ⁇ 0.2, 27.5 ⁇ 0.2, 29.5 ⁇ 0.2, 29.9 ⁇ 0.2, 30.5 ⁇ 0.2, 31.5 ⁇ 0.2, 32.2 ⁇ 0.2, 34.6 ⁇ 0.2, 35.1 ⁇ 0.2, and 35.6 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.3 ⁇ 0.2, 11.0 ⁇ 0.2, 12.7 ⁇ 0.2, 15.3 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 17.5 ⁇ 0.2, 18.2 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 20.0 ⁇ 0.2, 21.1 ⁇ 0.2, 22.1 ⁇ 0.2, 22.6 ⁇ 0.2, 23.2 ⁇ 0.2, 24.2 ⁇ 0.2, 24.6 ⁇ 0.2, 25.1 ⁇ 0.2, 25.7 ⁇ 0.2, 26.5 ⁇ 0.2, 27.0 ⁇ 0.2, 27.5 ⁇ 0.2, 29.5 ⁇ 0.2, 29.9 ⁇ 0.2, 30.5 ⁇ 0.2, 31.5 ⁇ 0.2, 32.2 ⁇ 0.2, 34.6 ⁇ 0.2, 35.1 ⁇ 0.2, and 35.6 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.0 ⁇ 0.1, 15.3 ⁇ 0.1, 15.6 ⁇ 0.1, 17.5 ⁇ 0.1, 18.9 ⁇ 0.1, 20.0 ⁇ 0.1, 21.1 ⁇ 0.1, 22.1 ⁇ 0.1, 24.6 ⁇ 0.1, 25.1 ⁇ 0.1, and 26.5 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.3 ⁇ 0.1, 12.7 ⁇ 0.1, 15.9 ⁇ 0.1, 18.2 ⁇ 0.1, 18.6 ⁇ 0.1, 22.6 ⁇ 0.1, 23.2 ⁇ 0.1, 24.2 ⁇ 0.1, 25.7 ⁇ 0.1, 27.0 ⁇ 0.1, 27.5 ⁇ 0.1, 29.5 ⁇ 0.1, 29.9 ⁇ 0.1, 30.5 ⁇ 0.1, 31.5 ⁇ 0.1, 32.2 ⁇ 0.1, 34.6 ⁇ 0.1, 35.1 ⁇ 0.1, and 35.6 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.3 ⁇ 0.1, 11.0 ⁇ 0.1, 12.7 ⁇ 0.1, 15.3 ⁇ 0.1, 15.6 ⁇ 0.1, 15.9 ⁇ 0.1, 17.5 ⁇ 0.1, 18.2 ⁇ 0.1, 18.6 ⁇ 0.1, 18.9 ⁇ 0.1, 20.0 ⁇ 0.1, 21.1 ⁇ 0.1, 22.1 ⁇ 0.1, 22.6 ⁇ 0.1, 23.2 ⁇ 0.1, 24.2 ⁇ 0.1, 24.6 ⁇ 0.1, 25.1 ⁇ 0.1, 25.7 ⁇ 0.1, 26.5 ⁇ 0.1, 27.0 ⁇ 0.1, 27.5 ⁇ 0.1, 29.5 ⁇ 0.1, 29.9 ⁇ 0.1, 30.5 ⁇ 0.1, 31.5 ⁇ 0.1, 32.2 ⁇ 0.1, 34.6 ⁇ 0.1, 35.1 ⁇ 0.1, and 35.6 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 11.0, 15.3, 15.6, 17.5, 18.9, 20.0, 21.1, 22.1, 24.6, 25.1, and 26.5.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 6.3, 12.7, 15.9, 18.2, 18.6, 22.6, 23.2, 24.2, 25.7, 27.0, 27.5, 29.5, 29.9, 30.5, 31.5, 32.2, 34.6, 35.1, and 35.6.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 6.3, 11.0, 12.7, 15.3, 15.6, 15.9, 17.5, 18.2, 18.6, 18.9, 20.0, 21.1, 22.1, 22.6, 23.2, 24.2, 24.6, 25.1, 25.7, 26.5, 27.0, 27.5, 29.5, 29.9, 30.5, 31.5, 32.2, 34.6, 35.1, and 35.6.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 49 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.03 ⁇ 0.3, 5.80 ⁇ 0.3, 5.69 ⁇ 0.3, 5.05 ⁇ 0.3, 4.69 ⁇ 0.3, 4.44 ⁇ 0.3, 4.21 ⁇ 0.3, 4.02 ⁇ 0.3, 3.61 ⁇ 0.3, 3.55 ⁇ 0.3, and 3.35 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 13.92 ⁇ 0.3, 6.96 ⁇ 0.3, 5.55 ⁇ 0.3, 4.87 ⁇ 0.3, 4.77 ⁇ 0.3, 3.93 ⁇ 0.3, 3.82 ⁇ 0.3, 3.67 ⁇ 0.3, 3.46 ⁇ 0.3, 3.29 ⁇ 0.3, 3.24 ⁇ 0.3, 3.02 ⁇ 0.3, 2.98 ⁇ 0.3, 2.92 ⁇ 0.3, 2.83 ⁇ 0.3, 2.77 ⁇ 0.3, 2.58 ⁇ 0.3, 2.55 ⁇ 0.3, and 2.52 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 13.92 ⁇ 0.3, 8.03 ⁇ 0.3, 6.96 ⁇ 0.3, 5.80 ⁇ 0.3, 5.69 ⁇ 0.3, 5.55 ⁇ 0.3, 5.05 ⁇ 0.3, 4.87 ⁇ 0.3, 4.77 ⁇ 0.3, 4.69 ⁇ 0.3, 4.44 ⁇ 0.3, 4.21 ⁇ 0.3, 4.02 ⁇ 0.3, 3.93 ⁇ 0.3, 3.82 ⁇ 0.3, 3.67 ⁇ 0.3, 3.61 ⁇ 0.3, 3.55 ⁇ 0.3, 3.46 ⁇ 0.3, 3.35 ⁇ 0.3, 3.29 ⁇ 0.3, 3.24 ⁇ 0.3, 3.02 ⁇ 0.3, 2.98 ⁇ 0.3, 2.92 ⁇ 0.3, 2.83 ⁇ 0.3, 2.77 ⁇ 0.3, 2.58 ⁇ 0.3, 2.55 ⁇ 0.3, and 2.52 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.03 ⁇ 0.2, 5.80 ⁇ 0.2, 5.69 ⁇ 0.2, 5.05 ⁇ 0.2, 4.69 ⁇ 0.2, 4.44 ⁇ 0.2, 4.21 ⁇ 0.2, 4.02 ⁇ 0.2, 3.61 ⁇ 0.2, 3.55 ⁇ 0.2, and 3.35 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 13.92 ⁇ 0.2, 6.96 ⁇ 0.2, 5.55 ⁇ 0.2, 4.87 ⁇ 0.2, 4.77 ⁇ 0.2, 3.93 ⁇ 0.2, 3.82 ⁇ 0.2, 3.67 ⁇ 0.2, 3.46 ⁇ 0.2, 3.29 ⁇ 0.2, 3.24 ⁇ 0.2, 3.02 ⁇ 0.2, 2.98 ⁇ 0.2, 2.92 ⁇ 0.2, 2.83 ⁇ 0.2, 2.77 ⁇ 0.2, 2.58 ⁇ 0.2, 2.55 ⁇ 0.2, and 2.52 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 13.92 ⁇ 0.2, 8.03 ⁇ 0.2, 6.96 ⁇ 0.2, 5.80 ⁇ 0.2, 5.69 ⁇ 0.2, 5.55 ⁇ 0.2, 5.05 ⁇ 0.2, 4.87 ⁇ 0.2, 4.77 ⁇ 0.2, 4.69 ⁇ 0.2, 4.44 ⁇ 0.2, 4.21 ⁇ 0.2, 4.02 ⁇ 0.2, 3.93 ⁇ 0.2, 3.82 ⁇ 0.2, 3.67 ⁇ 0.2, 3.61 ⁇ 0.2, 3.55 ⁇ 0.2, 3.46 ⁇ 0.2, 3.35 ⁇ 0.2, 3.29 ⁇ 0.2, 3.24 ⁇ 0.2, 3.02 ⁇ 0.2, 2.98 ⁇ 0.2, 2.92 ⁇ 0.2, 2.83 ⁇ 0.2, 2.77 ⁇ 0.2, 2.58 ⁇ 0.2, 2.55 ⁇ 0.2, and 2.52 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.03 ⁇ 0.1, 5.80 ⁇ 0.1, 5.69 ⁇ 0.1, 5.05 ⁇ 0.1, 4.69 ⁇ 0.1, 4.44 ⁇ 0.1, 4.21 ⁇ 0.1, 4.02 ⁇ 0.1, 3.61 ⁇ 0.1, 3.55 ⁇ 0.1, and 3.35 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 13.92 ⁇ 0.1, 6.96 ⁇ 0.1, 5.55 ⁇ 0.1, 4.87 ⁇ 0.1, 4.77 ⁇ 0.1, 3.93 ⁇ 0.1, 3.82 ⁇ 0.1, 3.67 ⁇ 0.1, 3.46 ⁇ 0.1, 3.29 ⁇ 0.1, 3.24 ⁇ 0.1, 3.02 ⁇ 0.1, 2.98 ⁇ 0.1, 2.92 ⁇ 0.1, 2.83 ⁇ 0.1, 2.77 ⁇ 0.1, 2.58 ⁇ 0.1, 2.55 ⁇ 0.1, and 2.52 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 13.92 ⁇ 0.1, 8.03 ⁇ 0.1, 6.96 ⁇ 0.1, 5.80 ⁇ 0.1, 5.69 ⁇ 0.1, 5.55 ⁇ 0.1, 5.05 ⁇ 0.1, 4.87 ⁇ 0.1, 4.77 ⁇ 0.1, 4.69 ⁇ 0.1, 4.44 ⁇ 0.1, 4.21 ⁇ 0.1, 4.02 ⁇ 0.1, 3.93 ⁇ 0.1, 3.82 ⁇ 0.1, 3.67 ⁇ 0.1, 3.61 ⁇ 0.1, 3.55 ⁇ 0.1, 3.46 ⁇ 0.1, 3.35 ⁇ 0.1, 3.29 ⁇ 0.1, 3.24 ⁇ 0.1, 3.02 ⁇ 0.1, 2.98 ⁇ 0.1, 2.92 ⁇ 0.1, 2.83 ⁇ 0.1, 2.77 ⁇ 0.1, 2.58 ⁇ 0.1, 2.55 ⁇ 0.1, and 2.52 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 8.03, 5.80, 5.69, 5.05, 4.69, 4.44, 4.21, 4.02, 3.61, 3.55, and 3.35.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 13.92, 6.96, 5.55, 4.87, 4.77, 3.93, 3.82, 3.67, 3.46, 3.29, 3.24, 3.02, 2.98, 2.92, 2.83, 2.77, 2.58, 2.55, and 2.52.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 13.92, 8.03, 6.96, 5.80, 5.69, 5.55, 5.05, 4.87, 4.77, 4.69, 4.44, 4.21, 4.02, 3.93, 3.82, 3.67, 3.61, 3.55, 3.46, 3.35, 3.29, 3.24, 3.02, 2.98, 2.92, 2.83, 2.77, 2.58, 2.55, and 2.52.
  • the crystalline form of the compound of formula (I) can be Form H, where Form H is characterized by the XRPD pattern described above or by FIG. 49 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 12.3 ⁇ 0.3, 14.8 ⁇ 0.3, 16.4 ⁇ 0.3, 18.5 ⁇ 0.3, 19.3 ⁇ 0.3, 19.6 ⁇ 0.3, 20.3 ⁇ 0.3, 21.1 ⁇ 0.3, 22.1 ⁇ 0.3, 22.5 ⁇ 0.3, 23.2 ⁇ 0.3, 24.1 ⁇ 0.3, 25.4 ⁇ 0.3, and 28.2 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 4.6 ⁇ 0.3, 8.7 ⁇ 0.3, 8.3 ⁇ 0.3, 9.1 ⁇ 0.3, 10.3 ⁇ 0.3, 11.0 ⁇ 0.3, 13.5 ⁇ 0.3, 14.0 ⁇ 0.3, 15.4 ⁇ 0.3, 17.1 ⁇ 0.3, 24.8 ⁇ 0.3, 27.2 ⁇ 0.3, 27.7 ⁇ 0.3, 29.4 ⁇ 0.3, 30.2 ⁇ 0.3, and 37.2 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 4.6 ⁇ 0.3, 8.7 ⁇ 0.3, 8.3 ⁇ 0.3, 9.1 ⁇ 0.3, 10.3 ⁇ 0.3, 11.0 ⁇ 0.3, 12.3 ⁇ 0.3, 13.5 ⁇ 0.3, 14.0 ⁇ 0.3, 14.8 ⁇ 0.3, 15.4 ⁇ 0.3, 16.4 ⁇ 0.3, 17.1 ⁇ 0.3, 18.5 ⁇ 0.3, 19.3 ⁇ 0.3, 19.6 ⁇ 0.3, 20.3 ⁇ 0.3, 21.1 ⁇ 0.3, 22.1 ⁇ 0.3, 22.5 ⁇ 0.3, 23.2 ⁇ 0.3, 24.1 ⁇ 0.3, 24.8 ⁇ 0.3, 25.4 ⁇ 0.3, 27.2 ⁇ 0.3, 27.7 ⁇ 0.3, 28.2 ⁇ 0.3, 29.4 ⁇ 0.3, 30.2 ⁇ 0.3, and 37.2 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 12.3 ⁇ 0.2, 14.8 ⁇ 0.2, 16.4 ⁇ 0.2, 18.5 ⁇ 0.2, 19.3 ⁇ 0.2, 19.6 ⁇ 0.2, 20.3 ⁇ 0.2, 21.1 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, 23.2 ⁇ 0.2, 24.1 ⁇ 0.2, 25.4 ⁇ 0.2, and 28.2 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 4.6 ⁇ 0.2, 8.7 ⁇ 0.2, 8.3 ⁇ 0.2, 9.1 ⁇ 0.2, 10.3 ⁇ 0.2, 11.0 ⁇ 0.2, 13.5 ⁇ 0.2, 14.0 ⁇ 0.2, 15.4 ⁇ 0.2, 17.1 ⁇ 0.2, 24.8 ⁇ 0.2, 27.2 ⁇ 0.2, 27.7 ⁇ 0.2, 29.4 ⁇ 0.2, 30.2 ⁇ 0.2, and 37.2 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 4.6 ⁇ 0.2, 8.7 ⁇ 0.2, 8.3 ⁇ 0.2, 9.1 ⁇ 0.2, 10.3 ⁇ 0.2, 11.0 ⁇ 0.2, 12.3 ⁇ 0.2, 13.5 ⁇ 0.2, 14.0 ⁇ 0.2, 14.8 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 17.1 ⁇ 0.2, 18.5 ⁇ 0.2, 19.3 ⁇ 0.2, 19.6 ⁇ 0.2, 20.3 ⁇ 0.2, 21.1 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, 23.2 ⁇ 0.2, 24.1 ⁇ 0.2, 24.8 ⁇ 0.2, 25.4 ⁇ 0.2, 27.2 ⁇ 0.2, 27.7 ⁇ 0.2, 28.2 ⁇ 0.2, 29.4 ⁇ 0.2, 30.2 ⁇ 0.2, and 37.2 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 12.3 ⁇ 0.1, 14.8 ⁇ 0.1, 16.4 ⁇ 0.1, 18.5 ⁇ 0.1, 19.3 ⁇ 0.1, 19.6 ⁇ 0.1, 20.3 ⁇ 0.1, 21.1 ⁇ 0.1, 22.1 ⁇ 0.1, 22.5 ⁇ 0.1, 23.2 ⁇ 0.1, 24.1 ⁇ 0.1, 25.4 ⁇ 0.1, and 28.2 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 4.6 ⁇ 0.1, 8.7 ⁇ 0.1, 8.3 ⁇ 0.1, 9.1 ⁇ 0.1, 10.3 ⁇ 0.1, 11.0 ⁇ 0.1, 13.5 ⁇ 0.1, 14.0 ⁇ 0.1, 15.4 ⁇ 0.1, 17.1 ⁇ 0.1, 24.8 ⁇ 0.1, 27.2 ⁇ 0.1, 27.7 ⁇ 0.1, 29.4 ⁇ 0.1, 30.2 ⁇ 0.1, and 37.2 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 4.6 ⁇ 0.1, 8.7 ⁇ 0.1, 8.3 ⁇ 0.1, 9.1 ⁇ 0.1, 10.3 ⁇ 0.1, 11.0 ⁇ 0.1, 12.3 ⁇ 0.1, 13.5 ⁇ 0.1, 14.0 ⁇ 0.1, 14.8 ⁇ 0.1, 15.4 ⁇ 0.1, 16.4 ⁇ 0.1, 17.1 ⁇ 0.1, 18.5 ⁇ 0.1, 19.3 ⁇ 0.1, 19.6 ⁇ 0.1, 20.3 ⁇ 0.1, 21.1 ⁇ 0.1, 22.1 ⁇ 0.1, 22.5 ⁇ 0.1, 23.2 ⁇ 0.1, 24.1 ⁇ 0.1, 24.8 ⁇ 0.1, 25.4 ⁇ 0.1, 27.2 ⁇ 0.1, 27.7 ⁇ 0.1, 28.2 ⁇ 0.1, 29.4 ⁇ 0.1, 30.2 ⁇ 0.1, and 37.2 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks (i.e., degrees 2 ⁇ ) at about 12.3, 14.8, 16.4, 18.5, 19.3, 19.6, 20.3, 21.1, 22.1, 22.5, 23.2, 24.1, 25.4, and 28.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can further include angle 2 ⁇ peaks at about 4.6, 8.7, 8.3, 9.1, 10.3, 11.0, 13.5, 14.0, 15.4, 17.1, 24.8, 27.2, 27.7, 29.4, 30.2, and 37.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes angle 2 ⁇ peaks at about 4.6, 8.7, 8.3, 9.1, 10.3, 11.0, 12.3, 13.5, 14.0, 14.8, 15.4, 16.4, 17.1, 18.5, 19.3, 19.6, 20.3, 21.1, 22.1, 22.5, 23.2, 24.1, 24.8, 25.4, 27.2, 27.7, 28.2, 29.4, 30.2, and 37.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern corresponding substantially to FIG. 50 .
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.17 ⁇ 0.3, 5.96 ⁇ 0.3, 5.41 ⁇ 0.3, 4.79 ⁇ 0.3, 4.59 ⁇ 0.3, 4.51 ⁇ 0.3, 4.37 ⁇ 0.3, 4.21 ⁇ 0.3, 4.01 ⁇ 0.3, 3.95 ⁇ 0.3, 3.83 ⁇ 0.3, 3.68 ⁇ 0.3, 3.50 ⁇ 0.3, and 3.15 ⁇ 0.3.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 19.19 ⁇ 0.3, 13.10 ⁇ 0.3, 10.69 ⁇ 0.3, 9.71 ⁇ 0.3, 8.54 ⁇ 0.3, 8.02 ⁇ 0.3, 6.54 ⁇ 0.3, 6.33 ⁇ 0.3, 5.75 ⁇ 0.3, 5.18 ⁇ 0.3, 3.58 ⁇ 0.3, 3.28 ⁇ 0.3, 3.22 ⁇ 0.3, 3.03 ⁇ 0.3, 2.95 ⁇ 0.3, and 2.41 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.19 ⁇ 0.3, 13.10 ⁇ 0.3, 10.69 ⁇ 0.3, 9.71 ⁇ 0.3, 8.54 ⁇ 0.3, 8.02 ⁇ 0.3, 7.17 ⁇ 0.3, 6.54 ⁇ 0.3, 6.33 ⁇ 0.3, 5.96 ⁇ 0.3, 5.75 ⁇ 0.3, 5.41 ⁇ 0.3, 5.18 ⁇ 0.3, 4.79 ⁇ 0.3, 4.59 ⁇ 0.3, 4.51 ⁇ 0.3, 4.37 ⁇ 0.3, 4.21 ⁇ 0.3, 4.01 ⁇ 0.3, 3.95 ⁇ 0.3, 3.83 ⁇ 0.3, 3.68 ⁇ 0.3, 3.58 ⁇ 0.3, 3.50 ⁇ 0.3, 3.28 ⁇ 0.3, 3.22 ⁇ 0.3, 3.15 ⁇ 0.3, 3.03 ⁇ 0.3, 2.95 ⁇ 0.3, 2.41 ⁇ 0.3.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.17 ⁇ 0.2, 5.96 ⁇ 0.2, 5.41 ⁇ 0.2, 4.79 ⁇ 0.2, 4.59 ⁇ 0.2, 4.51 ⁇ 0.2, 4.37 ⁇ 0.2, 4.21 ⁇ 0.2, 4.01 ⁇ 0.2, 3.95 ⁇ 0.2, 3.83 ⁇ 0.2, 3.68 ⁇ 0.2, 3.50 ⁇ 0.2, and 3.15 ⁇ 0.2.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 19.19 ⁇ 0.2, 13.10 ⁇ 0.2, 10.69 ⁇ 0.2, 9.71 ⁇ 0.2, 8.54 ⁇ 0.2, 8.02 ⁇ 0.2, 6.54 ⁇ 0.2, 6.33 ⁇ 0.2, 5.75 ⁇ 0.2, 5.18 ⁇ 0.2, 3.58 ⁇ 0.2, 3.28 ⁇ 0.2, 3.22 ⁇ 0.2, 3.03 ⁇ 0.2, 2.95 ⁇ 0.2, and 2.41 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.19 ⁇ 0.2, 13.10 ⁇ 0.2, 10.69 ⁇ 0.2, 9.71 ⁇ 0.2, 8.54 ⁇ 0.2, 8.02 ⁇ 0.2, 7.17 ⁇ 0.2, 6.54 ⁇ 0.2, 6.33 ⁇ 0.2, 5.96 ⁇ 0.2, 5.75 ⁇ 0.2, 5.41 ⁇ 0.2, 5.18 ⁇ 0.2, 4.79 ⁇ 0.2, 4.59 ⁇ 0.2, 4.51 ⁇ 0.2, 4.37 ⁇ 0.2, 4.21 ⁇ 0.2, 4.01 ⁇ 0.2, 3.95 ⁇ 0.2, 3.83 ⁇ 0.2, 3.68 ⁇ 0.2, 3.58 ⁇ 0.2, 3.50 ⁇ 0.2, 3.28 ⁇ 0.2, 3.22 ⁇ 0.2, 3.15 ⁇ 0.2, 3.03 ⁇ 0.2, 2.95 ⁇ 0.2, 2.41 ⁇ 0.2.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.17 ⁇ 0.1, 5.96 ⁇ 0.1, 5.41 ⁇ 0.1, 4.79 ⁇ 0.1, 4.59 ⁇ 0.1, 4.51 ⁇ 0.1, 4.37 ⁇ 0.1, 4.21 ⁇ 0.1, 4.01 ⁇ 0.1, 3.95 ⁇ 0.1, 3.83 ⁇ 0.1, 3.68 ⁇ 0.1, 3.50 ⁇ 0.1, and 3.15 ⁇ 0.1.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 19.19 ⁇ 0.1, 13.10 ⁇ 0.1, 10.69 ⁇ 0.1, 9.71 ⁇ 0.1, 8.54 ⁇ 0.1, 8.02 ⁇ 0.1, 6.54 ⁇ 0.1, 6.33 ⁇ 0.1, 5.75 ⁇ 0.1, 5.18 ⁇ 0.1, 3.58 ⁇ 0.1, 3.28 ⁇ 0.1, 3.22 ⁇ 0.1, 3.03 ⁇ 0.1, 2.95 ⁇ 0.1, and 2.41 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.19 ⁇ 0.1, 13.10 ⁇ 0.1, 10.69 ⁇ 0.1, 9.71 ⁇ 0.1, 8.54 ⁇ 0.1, 8.02 ⁇ 0.1, 7.17 ⁇ 0.1, 6.54 ⁇ 0.1, 6.33 ⁇ 0.1, 5.96 ⁇ 0.1, 5.75 ⁇ 0.1, 5.41 ⁇ 0.1, 5.18 ⁇ 0.1, 4.79 ⁇ 0.1, 4.59 ⁇ 0.1, 4.51 ⁇ 0.1, 4.37 ⁇ 0.1, 4.21 ⁇ 0.1, 4.01 ⁇ 0.1, 3.95 ⁇ 0.1, 3.83 ⁇ 0.1, 3.68 ⁇ 0.1, 3.58 ⁇ 0.1, 3.50 ⁇ 0.1, 3.28 ⁇ 0.1, 3.22 ⁇ 0.1, 3.15 ⁇ 0.1, 3.03 ⁇ 0.1, 2.95 ⁇ 0.1, 2.41 ⁇ 0.1.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 7.17, 5.96, 5.41, 4.79, 4.59, 4.51, 4.37, 4.21, 4.01, 3.95, 3.83, 3.68, 3.50, and 3.15.
  • the XRPD pattern of the crystalline form of the compound of formula (I) can be further characterized by d spacings at about 19.19, 13.10, 10.69, 9.71, 8.54, 8.02, 6.54, 6.33, 5.75, 5.18, 3.58, 3.28, 3.22, 3.03, 2.95, and 2.41.
  • the crystalline form of the compound of formula (I) is characterized by a XRPD pattern that includes d spacings at about 19.19, 13.10, 10.69, 9.71, 8.54, 8.02, 7.17, 6.54, 6.33, 5.96, 5.75, 5.41, 5.18, 4.79, 4.59, 4.51, 4.37, 4.21, 4.01, 3.95, 3.83, 3.68, 3.58, 3.50, 3.28, 3.22, 3.15, 3.03, 2.95, 2.41.
  • the crystalline form of the compound of formula (I) can be Form I, where Form I is characterized by the XRPD pattern described above or by FIG. 50 .
  • the crystalline form of the compound of formula (I) can include an endothermic event with an onset temperature of about 110° C. as determined by DSC.
  • the crystalline form of the compound of formula (I) (e.g., Form I) can be characterized by a DSC plot set forth in FIG. 34 .
  • the crystalline form of the compound of formula (I) (e.g., Form I) can have a mass loss of 20% when heated from about 25° C. to about 180° C.
  • Form I can be a solvated crystalline form, where Form I is a trifluoroethanol solvate.
  • the crystalline form of the compound of formula (I) (e.g., Form J) can include an exothermic event with an onset temperature of about 130° C. as determined by DSC.
  • the crystalline form of the compound of formula (I) (e.g., Form I) can be characterized by a DSC plot set forth in FIG. 36 .
  • the crystalline form of the compound of formula (I) can have a loss of about 19.8% when heated from about 25° C. to about 180° C.
  • the crystalline form of the compound of formula (I) can be Form J, where Form J has a loss of about 19.8% when heated from about 25° C. to about 180° C.
  • the crystalline form of the compound of formula (I) can be Form J, where Form J is characterized by the XRPD pattern described above or by FIG. 35 .
  • the crystalline forms of the compound of formula (I), including those described herein can interconvert.
  • a crystalline form of the compound of formula (I) as described herein converts to Form A, where Form A is as described herein.
  • the crystalline forms can interconvert as set forth in FIG. 37 .
  • the TLR can be Toll-like receptor 8 (TLR8).
  • TLR8 Toll-like receptor 8
  • the TLR can be in a cell where the cell is an immune response cell.
  • the cell can be a myeloid dendritic cell, a monocyte cell, or a natural killer cell.
  • the cell can be a myeloid dendritic cell.
  • the cell can be a monocyte cell.
  • the cell can be a natural killer cell.
  • the cell can be part of an organism (e.g., a mammal).
  • the organism can be a human.
  • the crystalline form can be in solution as part of a dose, for example, by administration through intravenous administration.
  • the method includes contacting the protein (e.g. TLR) with an effective amount of a compound, or pharmaceutically acceptable salt thereof, as described herein.
  • a protein e.g. TLR
  • the method includes treating cancer by administering a therapeutically effective amount of a crystalline form of the compound of formula (I) described herein to a subject in need thereof, thereby treating the cancer.
  • the cancer can be a solid tumor cancer or lymphoma as described herein.
  • the cancer can be colon carcinoma, ovarian cancer, breast cancer, head and neck cancer, renal cancer, bladder cancer, hepatocellular cancer, or lymphoma.
  • the cancer can be colon carcinoma.
  • the cancer can be ovarian cancer.
  • the cancer can be breast cancer.
  • the cancer can be head and neck cancer.
  • the cancer can be renal cancer.
  • the cancer can be bladder cancer.
  • the cancer can be hepatocellular cancer.
  • the cancer can be lymphoma.
  • the cancer can be treated by agonizing a TLR (e.g., TLR8) as described herein.
  • the method of treating cancer can further include co-administering an anti-cancer agent described herein.
  • a compound described herein e.g., Compound A or a pharmaceutically acceptable salt thereof, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant
  • inhalation nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • Compounds described herein e.g., Compound A or a pharmaceutically acceptable salt thereof, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles described herein and for which are appropriate for the desired route of administration.
  • a compound described herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • the pharmaceutical composition is prepared for intravenous administrations.
  • the pharmaceutical composition includes a pharmaceutically acceptable excipient described herein and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
  • compositions can be administered to the patient in a single dosage comprising a therapeutically effective amount of a compound described herein.
  • the compound can be a crystalline compound having form A as described herein.
  • compositions can be administered to the patient in multiple doses that include a therapeutically effective amount of a compound described herein, e.g., Compound A or a pharmaceutically acceptable salt thereof
  • compositions can be administered to the patient in a single, daily dosage form, once per day. In other embodiments, the compositions can be administered to the patient two or more (i.e., two, three, four or more) times per day, or as needed according to the particular treatment regimen designed by the patient's physician.
  • the amount of the compositions administered each time throughout the treatment period can be the same.
  • the amount administered each time during the treatment period can vary (e.g., the amount administered at a given time can be more or less than the amount administered previously).
  • doses given later in therapy can be lower than those administered during the acute phase (i.e., earlier stages) of treatment. Appropriate dosing schedules depending on the specific circumstances will be apparent to persons of ordinary skill in the art.
  • the doses administered during the entirety of the treatment are all equal (i.e., the same concentration of compound is administered in each dose).
  • the doses administered during the treatment are not all the same amount (e.g., the amount can increase or decrease during treatment).
  • the doses increase over time.
  • the doses decrease over time. Increasing dose over the course of treatment can, in embodiments, mitigate undesired side effects.
  • dose, dose frequency, and duration are adjusted to result in a therapeutically effective concentration of the compounds described herein in a subject.
  • the plasma concentration is maintained above the minimal effective concentration (MEC).
  • compounds described herein e.g., in a pharmaceutical composition
  • a dosage regimen i.e., a combination of doses designed to achieve one or more desired effects designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time.
  • dose, dose frequency, and duration of the induction phase may be selected to achieve a desired effect, e.g., a therapeutic effect, within a specified time period. In certain embodiments, it is desirable to achieve a desired effect as quickly as possible. In such embodiments, early intervention by administration of high dose and/or high dose frequency of compounds described herein may be desirable.
  • early intervention by administration of a low dose and/or low dose frequency and/or long duration may be desirable.
  • early intervention by administration with a low dose and/or low dose frequency and/or long duration mitigates undesired side effects.
  • early intervention by administration with relatively low doses may result in better tolerance of the pharmaceutical agent.
  • Such embodiments may include gradual increases of dose over time.
  • doses, dose frequency, and duration of the induction phase may be selected to achieve an acceptable safety profile.
  • such variables may be selected to mitigate toxicity of the pharmaceutical composition.
  • doses increase over time.
  • the treatment includes administration of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more than twenty doses.
  • subjects are monitored for effects (therapeutic and/or toxic effects) and doses, dose frequency, and/or duration of treatment may be adjusted based on the results of such monitoring. It will be recognized by one of ordinary skill in the art that doses, dose frequency, and duration of treatment may be manipulated independently to achieve a desired effect.
  • One or more additional therapies such as additional active ingredients (e.g., compounds described herein or pharmaceutically acceptable salts thereof, or anti-cancer agents), can be used in combination.
  • additional active ingredients e.g., compounds described herein or pharmaceutically acceptable salts thereof, or anti-cancer agents
  • one or more additional anti-cancer agents described herein are used in combination with compounds described herein, e.g., Compound A or a pharmaceutically acceptable salt thereof
  • Anti-cancer agents include, but are not limited to: abraxane; ace-11; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amrubicin; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol;
  • anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
  • Specific additional active agents include, but are not limited to, oblimersen (GENASENSE®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (DECADRON®), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, ARISA®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetax
  • the additional active agent is a taxol, gemcitabine, or cisplatin (including cisplatin derivatives such as, for example, carboplatin or oxaliplatin).
  • the additional active agent is etoposide, tamoxifen, taxotere, or cytarabine.
  • the additional active agent is pacilitaxel, tamoxifen, or taxol.
  • the additional active agent is daunorubicin, prdisone, doxorubicin, or adriamycin.
  • the terms “in combination” and “co-administration” are used interchangeably and include the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the terms does not restrict the order in which therapies (e.g., compounds described herein and anti-cancer agents) are administered to a patient with a disease or disorder.
  • therapies e.g., compounds described herein and anti-cancer agents
  • a first therapy (e.g., a compound described herein, including pharmaceutically acceptable salts thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., an anti-cancer agent) to the subject.
  • a second therapy e.g., an anti-cancer agent
  • Triple therapy is also contemplated herein (e.g., a compound described herein and two anti-cancer
  • Anti-cancer agents can be administered prior to, concurrently with, or subsequent to the administration of compounds described herein, e.g., Compound A or a pharmaceutically acceptable salt thereof.
  • Administration of one or more of the compounds provided herein and one or more second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration.
  • the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the cancer being treated.
  • the route of administration of the compounds provided herein can be independent of the route of administration of a second therapy.
  • the compounds provided herein are administered orally.
  • the compounds provided herein are administered intravenously.
  • the compounds provided herein can be administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • a compound provided herein and a second therapy are administered by the same mode of administration, e.g., orally or by IV.
  • a compound provided herein is administered by one mode of administration, e.g., by IV, whereas the second agent (e.g., an anticancer agent) is administered by another mode of administration, e.g., orally.
  • the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg.
  • the specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount of the first active agent, and any optional additional active agents concurrently administered to the patient.
  • the second active agent is oblimersen (GENASENSE®), GM-CSF, G-CSF, SCF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof
  • GM-CSF, G-CSF, SCF or EPO is administered subcutaneously during about five days in a four or six week cycle in an amount ranging from about 1 to about 750 mg/m2/day, from about 25 to about 500 mg/m2/day, from about 50 to about 250 mg/m2/day, or from about 50 to about 200 mg/m2/day.
  • GM-CSF may be administered in an amount of from about 60 to about 500 mcg/m2 intravenously over 2 hours or from about 5 to about 12 mcg/m2/day subcutaneously.
  • G-CSF may be administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted depending on rise of total granulocyte counts.
  • the maintenance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 mcg subcutaneously.
  • EPO may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, estrogen receptor antagonists, and/or PLX3397 (Plexxikon) to patients with metastatic breast cancer.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered to patients with colon cancer in combination with ARISA®, avastatin, taxol, and/or taxotere.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered with capecitabine and/or PLX4032 (Plexxikon) to patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt, thereof, is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes C & D colorectal cancer or to patients who have been previously treated for metastatic colorectal cancer.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered to patients with refractory colorectal cancer in combination with capecitabine, xeloda, and/or CPT-11.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal carcinoma.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered alone or in combination with interferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa to patients with primary or metastatic liver cancer.
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered in combination with ABT-737 (Abbott Laboratories) and/or obatoclax (GX15-070) to patients with lymphoma and other blood cancers.
  • ABT-737 Abbott Laboratories
  • GX15-070 obatoclax
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt, thereof, is administered alone or in combination with a second active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma.
  • a second active ingredient such as vinblastine or fludarabine
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered to patients with various types or stages of ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered to patients with various types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof
  • a compound provided herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered to patients with various types or stages of solid tumors in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
  • the compound described herein e.g., Compound A or a pharmaceutically acceptable salt thereof, is administered intravenously.
  • Also encompassed herein is a method of increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a patient, which includes administering to the patient (e.g., a human) a compound provided herein, or a pharmaceutically acceptable salts thereof.
  • Patients that can benefit by this method are those likely to suffer from an adverse effect associated with anti-cancer drugs for treating a specific cancer of the breast.
  • the administration of a compound provided herein, or pharmaceutically acceptable salt thereof in embodiments, alleviates or reduces adverse effects which are of such severity that it would otherwise limit the amount of anti-cancer drug.
  • a compound provided herein, or pharmaceutically acceptable salt thereof is administered orally and daily in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 50 mg, or from about 2 to about 25 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient. In one embodiment, a compound provided herein, or pharmaceutically acceptable salt thereof is administered orally and daily in an amount ranging from about 0.1 to about 50 mg, or from about 2 to about 50 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient.
  • a compound provided herein, or pharmaceutically acceptable salt thereof is administered orally and daily in an amount ranging from about 1 to about 50 mg, or from about 2 to about 50 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient. In one embodiment, a compound provided herein, or pharmaceutically acceptable salt thereof is administered orally and daily in an amount ranging from about 0.1 to about 25 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient.
  • a compound provided herein, or pharmaceutically acceptable salt thereof is administered orally and daily in an amount ranging about 1 to about 25 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient.
  • one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof are administered in combination with specific agents such as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.
  • encompassed herein is a method of treating, preventing and/or managing cancer, by administering one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof, in conjunction with (e.g. before, during, or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer.
  • conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer.
  • a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
  • Compounds provided herein, or pharmaceutically acceptable salts thereof and other active ingredient can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with conventional therapy.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid, or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
  • one or more of the compounds provided herein are administered daily in a single or divided doses in, for example, a four to six week cycle with a rest period of about a week or two weeks.
  • the cycling method further allows the frequency, number, and length of dosing cycles to be increased.
  • a compound provided herein or pharmaceutically acceptable salts thereof for more cycles than are typical when it is administered alone.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are administered for a greater number of cycles that would typically cause dose-limiting toxicity in a patient to whom a second active ingredient is not also being administered.
  • the compounds provided herein are administered daily and continuously for about three or four weeks at a dose of from about 0.1 to about 150 mg/d followed by a break of one or two weeks. In one embodiment, the compounds provided herein are administered daily and continuously for about three or four weeks at a dose of from about 1 to about 150 mg/d followed by a break of one or two weeks. In one embodiment, the compounds provided herein are administered daily and continuously for about three or four weeks at a dose of from about 0.1 to about 50 mg/d followed by a break of one or two weeks. In one embodiment, the compounds provided herein are administered daily and continuously for about three or four weeks at a dose of from about 1 to about 50 mg/d followed by a break of one or two weeks.
  • a compound provided herein and a second active ingredient are administered orally, with administration of the compound provided herein occurring 30 to 60 minutes prior to a second active ingredient, during a cycle of four to six weeks.
  • the combination of the compound provided herein and a second active ingredient is administered by intravenous infusion over about 90 minutes every cycle.
  • one cycle comprises the administration from about 0.1 to about 150 mg/day of the compound provided herein and from about 50 to about 200 mg/m2/day of a second active ingredient daily for three to four weeks and then one or two weeks of rest.
  • the number of cycles during which the combinatorial treatment is administered to a patient is ranging from about one to about 24 cycles, from about two to about 16 cycles, or from about four to about three cycles.
  • Single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal, or transcutaneous administration to a patient.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
  • topical e.g., eye drops or other ophthalmic preparations
  • transdermal e.g., transcutaneous administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water e
  • compositions, shape, and type of dosage forms provided herein may vary depending on their use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients than an oral dosage form used to treat the same disease. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
  • a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form provided herein depends on a variety of factors, including, but not limited to, the route of administration.
  • 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.
  • the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, encompassed herein are pharmaceutical compositions and dosage forms that contain little, if any, lactose.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions provided herein can comprise excipients that are listed, for example, in the U.S. Pharmacopeia (USP) 25 NF20 (2002).
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • 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.
  • the dosage forms provided herein comprise one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof, in an amount ranging from about 0.10 to about 1000 mg, from about 0.10 to about 500 mg, from about 0.10 to about 200 mg, from about 0.10 to about 150 mg, from about 0.10 to about 100 mg, or from about 0.10 to about 50 mg.
  • the dosage forms provided herein comprise one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof, in an amount of about 0.1, about 1, about 2, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, about 25, about 50, about 100, about 150, or about 200 mg.
  • compositions provided herein that are suitable for oral administration are formulated as discrete dosage forms, examples of which include, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients and may be prepared by some known methods of pharmacy. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
  • the 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.
  • 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.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by some known methods of pharmacy. In certain embodiments, 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.
  • a tablet is prepared by compression or molding.
  • compressed tablets are be prepared by compressing in a suitable machine the active ingredients in a free-flowing form, e.g., powder or granules, optionally mixed with an excipient.
  • molded tablets are made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.
  • 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 provided herein 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, AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof.
  • An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., AVICEL RC-581).
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions provided herein is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants are used in the compositions provided herein to provide tablets the ability to 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 should be used to form solid oral dosage forms provided herein. The amount of disintegrant used varies based upon the type of formulation. In certain embodiments, the pharmaceutical compositions provided herein comprise from about 0.5 to about 15 weight percent or from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof
  • Lubricants that are suitable for use in pharmaceutical compositions and dosage forms provided herein 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 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 lubricants include, but are not limited to, a syloid silica gel (AEROSIL200, W.R. Grace Co., Baltimore, Md.), a coagulated aerosol of synthetic silica (Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide, Cabot Co. of Boston, Mass.), and mixtures thereof.
  • a syloid silica gel AEROSIL200, W.R. Grace Co., Baltimore, Md.
  • a coagulated aerosol of synthetic silica Degussa Co. of Plano, Tex.
  • CAB-O-SIL a pyrogenic silicon dioxide, Cabot Co. of Boston, Mass.
  • lubricants are used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • a solid oral dosage form comprising one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
  • a solid oral dosage form comprising one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof; and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
  • the active ingredients provided herein are administered by controlled release means or by delivery devices.
  • controlled release means include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference in its entirety.
  • such dosage forms are be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • active ingredients for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • single unit dosage forms suitable for oral administration including, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the drug In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms provided herein include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as,
  • Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • excipients e.g., carriers and diluents
  • other materials that can be used to provide topical and mucosal dosage forms encompassed herein depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • the excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Additional examples of such ingredients can be found, for example, in Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990).
  • TGA Volatile Components Thermogravimetry was performed using a TGA 851e apparatus that included an oven, oven temperature sensor and sample temperature sensor/aluminum oxide pan/analytical micro balance. An empty aluminum oxide pan was used to collect the background curve, after which an accurately weighed amount of sample (10 mg) was placed in a clean and dry pan. The measurement was done as described above.
  • HPLC For purity estimation and determination of the solubility in solution a generic in-house HPLC method was used. HPLC was performed using a Phenomenex Luna 3 pm C18 (50 ⁇ 4.6 mm) column and detected with a DAD detector, recording at 214 nm.
  • the polymorphism screening was performed using an approach to find kinetically preferred polymorphs as well as thermodynamically preferred or in other words more stable polymorphs.
  • the kinetically preferred polymorphs were examined using evaporation and cooling crystallizations.
  • Thermodynamically preferred polymorphs were examined using slurry type experiments.
  • the forms described herein are assigned to sequential capital letters (e.g., A, B, C . . . ).
  • the starting material used for screening was a pale yellow to beige solid.
  • NMR assay of the material was found to be 95.6% w/w and HPLC indicated 99.07% a/a.
  • the material appeared crystalline by microscopy ( FIG. 3 ) as well as by XRPD which showed a mixture of Forms A and G.
  • DSC indicated a melting point of around 202° C. with a second melting event around 211° C.
  • TGA with SDTA curve indicated a weight loss of around 0.2% w/w up to the endothermic events as well as further weight loss during melting/form conversion which probably is due to beginning degradation.
  • the suspensions were dried using a nitrogen stream.
  • the evaporated solvent provides a small amount of solid compared to the material suspended (i.e., the slurry form still should be dominant).
  • Form A was present in the starting material used for the screening and occurred in nearly all screening experiments. Form A was the most often obtained form and Form A is likely the thermodynamically most stable form from 0 to 60° C.
  • the crystal habit of Form A appeared to vary widely ( FIG. 5A, 5B, 5C, and 5D ) from agglomerates of fine needles (brushlike), undefined forms (stone knife form), rod-like needles or almost cubic crystals.
  • XRPD FIG. 42
  • the 1 H NMR FIG. 6
  • TGA ( FIG. 8 ) with SDTA curve shows a similar curve as DSC with two endotherms and only 0.28% w/w weight loss up to the first melting endotherm. The increasing weight loss around melting points indicated thermal degradation.
  • Form B was obtained from tested screening experiments and from slurry in 1,4-dioxane and evaporation from 1,4-dioxane.
  • Form B is a 1,4-dioxane solvate as confirmed by NMR ( FIG. 10 ), which shows 1 eq of 1,4-dioxane.
  • Form B was nicely crystalline under the microscope ( FIG. 9A and 9B ) but does not appear to have a clear crystal habit.
  • XRPD of Form B ( FIG. 43 ) shows good intensity of reflexes which can be at least partially come from nicely crystalline material.
  • NMR showed approximately one equivalent of dioxane in the solid isolated from the evaporation experiment (Table 1, A1_10).
  • DSC ( FIG. 11 ) showed an endotherm around 100° C. that corresponds to dioxane evaporation. The corresponding weight drop can be observed in TGA ( FIG. 12 ).
  • the second endotherm in DSC around does not appear to correspond to an event in TGA.
  • the weight loss necessary for 1 eq of dioxane (about 16% w/w) was only reached around 180° C. but the SDTA curve does not show the lower nor the higher endotherm observed in DSC.
  • the second endotherm may correspond to remaining solvent released during melt of the partially desolvated solid.
  • Form C Initially Form C was found present in experiment C3_1—likely in a pure form. After drying-out acetonitrile ( FIG. 13 : ACN at 2.02 ppm, confirmed by spiking ACN as signal was expected at 2.10 ppm) from material showing this pattern a new pattern could be observed where many reflexes almost vanished (the reflexes present in Form J).
  • the material from the screening as well as the scale-up experiment contained ACN in the solid ( FIG. 13 ) but could be dried under vacuum at ambient temperature.
  • the wet cake (paste: crude 1#1), the gently dried cake (crude 2#1) and the completely dried cake (crude 3#1) were also checked by XRPD ( FIG. 14 ):
  • the reflexes of Form J are vanishing (see e.g., at 7.5 2theta).
  • the screening sample A3_1 (evaporation from acetonitrile) converted to Form A during drying.
  • Form C 200 mg starting material (Form A/G mixture) was suspended in ACN and intensively stirred for 15 days. The suspension was filtered and the solid dried in vacuum (max. vacuum, ambient temperature) to give Form C.
  • Form D Form D was isolated from the screening experiments, using dichloromethane as solvent. The slurry and quick cooling experiment but not the evaporation experiment led to Form D. Thus Form D was likely a (weak) solvate as weak vacuum during drying led to complete desolvation.
  • XRPD FIG. 45
  • Form D is not well resolved with relatively broad reflexes. Additionally either an amorphous halo appears to be present or due to low sample amount the measurement does show high background noise.
  • NMR NMR ( FIG. 18 ) showed one equivalent of dichloromethane at 5.3 ppm.
  • DSC ( FIG. 19 ) and TGA ( FIG. 20 ) correspond when it comes to weight loss and the related endothermicity. Although not integrated in DSC prior to the first endothermic event a steady endotherm can be observed. After a first endotherm/exotherm a second smaller one can be observed leading to a melting point likely corresponding to Form G.
  • Form E was observed from evaporation from chlorobenzene.
  • the scale-up experiments evaporation from chlorobenzene leading to Form G, slurry in chlorobenzene led to Form A (even wet solid).
  • a seeded crystallization in chlorobenzene led to Form G with only traces of Form E.
  • Form E is a chlorobenzene solvate.
  • Form F was obtained from evaporation from trifluoroethanol. The material formed a solidified oil and no crystal habit could be determined ( FIG. 22A and 22B ). NMR ( FIG. 23 ) revealed about 0.95 eq of trifluoroethanol (3.95 ppm) and XRPD ( FIG. 47 ) showed a crystalline material with not well resolved reflexes. Without being bound by any particular theory, this may arise from non-ideal crystallization out of an oil/resin with residual amorphous/resin-like residue in the material.
  • TGA DSC ( FIG. 24 ) and TGA ( FIG. 25 ) confirmed that Form F contained a large amount of trifluoroethanol.
  • TGA indicated that less than 1 eq (about 0.8 eq) trifluoroethanol was released, without being bound by any particular theory, this could be because of the sample desolvating partially before starting the measurement or because the solvent is not completely released from the melt.
  • Form F is likely a mono trifluoroethanol solvate. Evaporation of a trifluoroethanol solution also yields Form I.
  • Form G was present in the starting material used for the screening. It occurred in many experiments during the screening phase. The conversion to Form A in the slurry screening in most solvents showed that Form G was less stable at 25° C. in comparison to Form A. Remaining Form A/G mixes indicated that a certain level of solubility appeared necessary to improve form conversion. Form G has a needle-like habit ( FIG. 26A, 26B, 26C, and 26D ) with a high tendency to form agglomerates.
  • Form G showed only one melting point (peak: 209.5° C.) in DSC ( FIG. 28 ) but no clear corresponding solvent loss in TGA ( FIG. 29 ).
  • Form G was obtained by evaporating a solution in chlorobenzene at ambient temperature. Evaporation, in some instances, afforded a mixture of Form G and Form E.
  • On 270 mg scale a solution in isopropanol afforded Form A after evaporation.
  • Form H was observed in cooling experiments, including THF and isopropanol as solvents.
  • the crystal habit of Form F appears to be bipyramidal ( FIG. 30A and 30B ).
  • Form H can be obtained as a mixture with Form A in a seeded scale-up experiment from THF. Drying off the remaining THF at ambient temperature led to pure Form A. Although this could also have been a solid transformation of a non-solvated form into another form, Form A is more stable than Form H.
  • the drying of the Form A/H mixture was performed 5 days after the scale-up run which would correspond to a quick form transition in case not the drying would have caused form transition.
  • Form H was available in small amounts from the THF screening experiment (B2_2). Collected NMR data ( FIG. 31 ) indicated a THF content of approximately 2.4 equivalents. Form H cannot be a THF solvate because it was obtained from isopropanol as well. The detected THF either showed wet solid or that form H is a channel solvate also possible with isopropanol.
  • a mixture of Form A and Form H was tested by XRPD after drying off residual THF and only Form A was visible. Without being bound by any particular theory, this may occur by a desolvation effect of a potential channel solvate or by form conversion of a kinetic form to the stable Form A.
  • Form I is likely a mono trifluoroethanol solvate as indicated by NMR ( FIG. 33 ) showing about 1.1 eq trifluoroethanol and by TGA ( FIG. 34 ). Insufficient material hindered additional analytics.
  • Form J The exotherm event in DSC ( FIG. 36 ) indicated a monotropic correlation to Form G which itself has an enantiotropic relation to Form A. Hence Form J is less stable than Form A.
  • Solubility data for Forms A and G was collected to determine the most stable form from 0 to 60° C.
  • the screening results confirmed Form A to be more stable than Form G at 20° C.
  • Form J Forms J and C were identified as potential non-solvates and their stability was investigated. Form J could be eliminated as stable form because, in part, the DSC ( FIG. 36 ) indicated an exothermic form conversion around 140° C. This leads to a form melting at 210° C., which likely represents Form G and therefore represents a monotropic relation.
  • Form C Form C was obtained by drying a Form C/J mixture.
  • the XRPD pattern appeared to contain traces of reflexes of Form J.
  • Slurries of Form C seeded with Form A (15% w/w) in ethanol and acetone were performed during 18 h.
  • the resulting solid was pure Form A.
  • Solubility of Form A To develop a Form A crystallization, a series of solubility data points was collected (Table 5). An amount of up to 15 mg was suspended in 150 ⁇ L and the mixture stirred for 2 days. Solubility was then determined by HPLC or by calculation if a solution was observed.
  • Form A is the most stable form from 0° C. to 60° C.
  • Form G is an enantiotropic form of Form A (higher melting point than Form A but at least above melting point of Form A more stable than Form A) but the transition temperature is not known.
  • Form C and J are less stable than Forms A and G and are in a monotropic correlation to Forms A and G.

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US15/537,331 2014-12-16 2015-12-15 Solid forms comprising (1e, 4e)-2-amino-n,n-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3h-benzo[b]azepine-4-carboxamide, compositions thereof, and uses thereof Abandoned US20190100512A1 (en)

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US10604510B2 (en) 2014-12-16 2020-03-31 Celgene Corporation Solid forms comprising (1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[B]azepine-4-carboxami compositions thereof, and uses thereof

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AU2015362720B2 (en) 2019-11-21
JP2017537962A (ja) 2017-12-21
EP3233088A2 (fr) 2017-10-25
WO2016100302A2 (fr) 2016-06-23
CA2970358A1 (fr) 2016-06-23
IL252744A0 (en) 2017-08-31
EA201791346A1 (ru) 2018-01-31
US20200002316A1 (en) 2020-01-02
JP2020079261A (ja) 2020-05-28
SG11201704791WA (en) 2017-07-28
EP3233088A4 (fr) 2018-09-19
MX2017007955A (es) 2018-02-19
JP6707088B2 (ja) 2020-06-10
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