[go: up one dir, main page]

WO2025245656A1 - Formes solides cristallines de bloqueurs des canaux sodiques - Google Patents

Formes solides cristallines de bloqueurs des canaux sodiques

Info

Publication number
WO2025245656A1
WO2025245656A1 PCT/CN2024/095465 CN2024095465W WO2025245656A1 WO 2025245656 A1 WO2025245656 A1 WO 2025245656A1 CN 2024095465 W CN2024095465 W CN 2024095465W WO 2025245656 A1 WO2025245656 A1 WO 2025245656A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
solvent
crystalline solid
temperature
solid form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/095465
Other languages
English (en)
Inventor
Juan HU
Silvina Garcia-Rubio
Baibai FAN
Shuimei SHEN
Youfa Jiang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Libertas Bio Inc
Original Assignee
Libertas Bio Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Libertas Bio Inc filed Critical Libertas Bio Inc
Priority to PCT/CN2024/095465 priority Critical patent/WO2025245656A1/fr
Priority to PCT/US2025/030962 priority patent/WO2025250498A1/fr
Publication of WO2025245656A1 publication Critical patent/WO2025245656A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Sodium channel blockers are useful in the treatment of dermatological conditions such as inflammation, pruritus and/or pain.
  • sodium channel blockers such as lidocaine suffer from the drawback of undesired blockade of motor function. This is because these sodium channel blockers fail to discriminate between sodium channel activity required for normal ongoing sensation and similar activity involved in nociceptor signaling. There remains a need for sodium channel blockers that are useful in treating various conditions such as inflammation, pruritus and/or pain while minimizing impairment of motor function.
  • Compound 1 One compound that is being evaluated for use in treating dermatological diseases and conditions, including those that may cause inflammation, pruritus and/or pain is (R) -1, 1-dimethyl-2- [2- ( (indan-2-yl) (2-methylphenyl) amino) ethyl] piperidinium bromide (referred to herein as “Compound 1” ) , and having a structure of:
  • Compound 1 is described in WO2012/112969, wherein Compound 1 is reported at Example 43, and certain formulations of Compound 1 are described in WO2020/113050, each of which is incorporated herein by reference in its entirety. There remains, however, a need for identifying crystalline, anhydrate, hydrate and/or solvate forms of Compound 1 useful for various therapeutic applications and a need for efficient methods of preparing certain crystalline solid forms of Compound 1.
  • the present disclosure provides, among other things, solid forms, e.g., crystalline, anhydrate, hydrate, and/or solvate forms of Compound 1.
  • the present disclosure provides methods of preparing said solid forms of Compound 1.
  • the present disclosure reports particular characteristics associated with the described solid forms that demonstrate their improved properties, e.g., improved solubility, stability, and the like, relative to other forms of Compound 1.
  • polymorph screening experiments identified certain solid forms that exhibited suitable stability for further development. Initial screens of various solid forms of Compound 1 resulted in several forms of Compound 1 that were metastable or unstable.
  • Identifying methods for the efficient preparation of crystalline solid forms of Compound 1 is useful for clinical studies and drug product manufacturing. As described herein, Applicant discovered that many solvent systems were not suitable for preparing solid crystalline forms of Compound 1 through crystallization due to, e.g., Compound 1’s poor solubility in certain solvent systems. Certain methods of preparing crystalline solid forms of Compound 1 suffered from low yield due to, e.g., significant loss of materials in the mother liquid. Moreover, certain methods of preparing solid crystalline solid form of Compound 1 suffered from low purity due to, e.g., degradation during the process.
  • the present disclosure provides a solution to the problems identified above and provides crystalline solid forms of Compound 1 that, in some embodiments, exhibit desirable characteristics such as improved stability, hygroscopicity, flow properties, ease of processing, consistency in manufacturing, particle size distribution, bulk density, and ease of formulation.
  • the present disclosure provides a crystalline solid form of Compound 1:
  • a crystalline solid form of Compound 1 is an anhydrate. In some embodiments, a crystalline solid form of Compound 1 is Form A, as described herein.
  • a crystalline solid form of Compound 1 is a hydrate. In some embodiments, a crystalline solid form of Compound 1 is Form B, as described herein.
  • a crystalline solid form of Compound 1 is metastable and is prone to convert to other solid forms of Compound 1.
  • a metastable solid form of Compound 1 refers to a solid form that is not stable when stored for extended periods of time under certain conditions, e.g., drying under atmosphere at room temperature for 3 days.
  • a crystalline solid form of Compound 1 is Form C, as described herein. In some embodiments, a crystalline solid form of Compound 1 is Form D, as described herein. In some embodiments, a crystalline solid form of Compound 1 is Form E, as described herein.
  • a crystalline solid form of Compound 1 is substantially stable and/or pure when stored for extended periods of time under certain conditions, e.g., drying under atmosphere at 35 °C for about 5 days.
  • the present disclosure provides methods of preparing crystalline solid forms of Compound 1 through crystallization. In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 1 comprising crystallizing Compound 1 in a solvent system. In some embodiments, the present disclosure provides suitable solvent systems that can be utilized in the methods of preparing crystalline solid forms of Compound 1. In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 1 with improved yield and/or purity. In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 1 that are suitable for commercial production, e.g., large scale preparation. In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 1 that tolerate rapid cooling and antisolvent addition rates. In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 1 in which the level of residual solvents does not exceed ICH guidelines.
  • FIG. 1A is an X-ray powder diffraction (XRPD) pattern of Compound 1 Form A.
  • FIG. 1B is a differential scanning calorimetric (DSC) and thermal gravimetric analysis (TGA) plot of Compound 1 Form A.
  • FIG. 1C is a 1 H NMR spectrum of Compound 1 Form A.
  • FIG. 2A is an XRPD pattern of Compound 1 Form B.
  • FIG. 2B is an overlay of XRPD patterns of Compound 1 Form A and Form B.
  • FIG. 2C is a DSC and TGA plot of Compound 1 Form B.
  • FIG. 2D is a 1 H NMR spectrum of Compound 1 Form B.
  • FIG. 3A is an XRPD pattern of Compound 1 Form C.
  • FIG. 3B is an overlay of XRPD patterns of Compound 1 Form B and Form C.
  • FIG. 4A is an XRPD pattern of Compound 1 Form D.
  • FIG. 4B is an overlay of XRPD patterns of Compound 1 Form B and Form D.
  • FIG. 5A is an XRPD pattern of Compound 1 Form E.
  • FIG. 5B is an overlay of XRPD patterns of Compound 1 Form B, Form C, Form D, and Form E.
  • FIG. 6 is an overlay of various crystalline solid forms of Compound 1.
  • FIG. 7 is a dynamic vapor sorption (DVS) plot of Compound 1 Form A.
  • FIG. 8 is a diagram illustrating different methods of converting various crystalline solid forms of Compound 1.
  • FIG. 9A is an overlay of XRPD patterns of final solids in critical water activity study at room temperature.
  • FIG. 9B is an overlay of XRPD patterns of final solids in critical water activity study at room temperature.
  • Compound 1 is being evaluated in the treatment of dermatological diseases and conditions, including those that may cause inflammation, pruritus and/or pain.
  • the present disclosure provides various crystalline solid forms of Compound 1.
  • the present disclosure recognizes the surprising discovery that Compound 1 is capable of forming crystalline solid forms, and further, that those forms exhibit improved stability and other beneficial properties relative to a corresponding amorphous form or other crystalline forms.
  • the present disclosure provides crystalline solid forms of Compound 1, represented by the structure below:
  • the present disclosure provides methods of preparing crystalline solid forms of Compound 1 that demonstrate improved yield, improved purity, improved efficiency, toleration to rapid cooling rate and antisolvent addition rate, and suitability for commercial production.
  • the present disclosure provides methods of preparing crystalline solid forms of Compound 1 in which the level of residual solvents does not exceed ICH guidelines.
  • the present disclosure provides methods of preparing crystalline solid forms of Compound 1 through crystallization.
  • provided methods comprise crystallizing Compound 1 in a solvent system.
  • the present disclosure provides particular pharmaceutical formulations (e.g., gels, creams, lotions, ointment, etc. ) of Compound 1 that are suitable for topical administration.
  • pharmaceutical formulations e.g., gels, creams, lotions, ointment, etc.
  • a disease, disorder, or condition in a subject in need thereof, comprising a step of administering to the subject a crystalline solid form of Compound 1 or a pharmaceutical formulation of Compound 1.
  • a disease, disorder, or condition comprises signs and symptoms of, for example, inflammation, pruritus and/or pain.
  • a disease, disorder, or condition is pruritus.
  • the term "approximately” or “about” may encompass a range of values that are within (i.e., ⁇ ) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.
  • Antagonist generally refers to an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level) .
  • an antagonist is one whose presence or level correlates with a target level or activity that is comparable to or less than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known antagonist, e.g., a positive control) .
  • an antagonist may be a direct antagonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an antagonist may be an indirect antagonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
  • carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • carriers are or include one or more solid components.
  • composition may be used to refer to a discrete physical entity that comprises one or more specified components.
  • a composition may be of any form-e.g., gas, gel, liquid, solid, etc.
  • Dosage form or unit dosage form may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject.
  • an active agent e.g., a therapeutic or diagnostic agent
  • each such unit contains a predetermined quantity of active agent.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen) .
  • Dosing regimen or therapeutic regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen) .
  • Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.
  • suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • modulator refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein) .
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator.
  • a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein.
  • a modulator is an agonist.
  • a modulator is an antagonist.
  • a patient refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans) . In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or
  • composition and pharmaceutical formulation refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions or pharmaceutical formulations may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) , tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) .
  • Prevent or prevention when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
  • Treat As used herein, the terms “treat, ” “treatment, ” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • Compound 1 is being evaluated in the treatment of dermatological diseases and conditions, including those that may cause inflammation, pruritus and/or pain.
  • Compound 1 is represented by the structure of:
  • Compound 1 is described in WO2012/112969, wherein Compound 1 is reported at Example 43, and certain formulations of Compound 1 are described in WO2020/113050, each of which is incorporated herein by reference in its entirety.
  • Compound 1 can each exist in one or more polymorphic solid forms.
  • polymorph refers to the ability of a compound to exist in one or more different crystal structures.
  • one or more polymorphs may vary in pharmaceutically relevant physical properties between one form and another, e.g., solubility, stability, and/or hygroscopicity.
  • the present disclosure provides a crystalline solid form of Compound 1.
  • Compound 1 can occur in an amorphous solid form, in a crystalline solid form, or in mixtures of forms.
  • Crystalline solid forms of Compound 1 can exist in one or more unique solid forms, which can additionally comprise one or more molecules of water or solvent (i.e., hydrates or solvates, respectively) in the crystal lattice.
  • crystalline forms of Compound 1 each have distinct characteristic XRPD peaks that are not reported in previous disclosures of Compound 1.
  • a crystalline solid form of Compound 1 exists as an anhydrate.
  • a crystalline solid form that does not have any water incorporated into the crystalline structure is an “anhydrate. ”
  • a crystalline solid form of Compound 1 is an anhydrate.
  • a crystalline form of Compound 1 exists as a solvate and/or hydrate.
  • solvate refers to a solid form with a stoichiometric or non-stoichiometric amount of one or more solvents incorporated into the crystal structure.
  • a solvated or heterosolvated polymorph can comprise 0.05, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, etc. equivalents independently of one or more solvents incorporated into the crystal lattice.
  • hydrate refers to a solvate, wherein the solvent incorporated into the crystal structure is water.
  • provided forms are characterized by having peaks in its XRPD pattern selected from “substantially all” of a provided list, optionally within ⁇ 0.2 degrees 2-theta of the stated value.
  • an XRPD pattern having “substantially all” of a provided list of peaks refers to an XRPD pattern that comprises at least 80% (e.g., 80%, 85%, 90%, 95%, 99%or 100%) of the listed peaks.
  • an XRPD pattern comprises at least 90%of the listed peaks.
  • an XRPD pattern comprises all of the listed peaks.
  • an XRPD pattern comprises all but one of the listed peaks.
  • an XRPD pattern comprises all but two of the listed peaks.
  • an XRPD pattern comprises all but three of the listed peaks.
  • provided forms are characterized by having a pattern or spectrum that is “substantially similar” to a Figure provided herein.
  • a pattern or spectrum having “substantial similarity” to a Figure provided herein is one that comprises one or more features (e.g., position (degrees 2-theta) values, temperature values, %weight loss values, intensity, shape of curve, etc. ) of the provided Figure so as to enable identification of the form (e.g., solid and/or salt form) characterized by the pattern or spectrum as being the same as the form characterized in the Figure.
  • an XRPD pattern having substantial similarity to a provided Figure is one that comprises substantially all of the same peaks, optionally within ⁇ 0.2 degrees 2-theta of peaks in the reference Figure.
  • an XRPD pattern having substantial similarity to a provided Figure is one that comprises substantially all of the same peaks, optionally within ⁇ 0.2 degrees 2-theta of peaks in the reference Figure, with about the same intensities.
  • a crystalline solid form of Compound 1 is an anhydrate.
  • an anhydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta.
  • an anhydrate form of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta.
  • an anhydrate form of Compound 1 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta.
  • an anhydrate form of Compound 1 is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta. In some embodiments, an anhydrate form of Compound 1 is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta.
  • an anhydrate form of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern: 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta.
  • an anhydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from:
  • an anhydrate form of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm having a minima with a peak at about 224.0 °C.
  • DSC differential scanning calorimetry
  • an anhydrate form of Compound 1 is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 0.2%before 200 °C.
  • TGA thermogravimetric analysis
  • an anhydrate form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1A. In some embodiments, an anhydrate of Compound 1 is characterized by a DSC pattern substantially similar to FIG. 1B. In some embodiments, an anhydrate of Compound 1 is characterized by a TGA pattern substantially similar to FIG. 1B. In some embodiments, an anhydrate of Compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 1A; (b) a DSC pattern substantially similar to FIG. 1B; and (c) a TGA pattern substantially similar to FIG. 1B.
  • a crystalline solid form of Compound 1 is Form A.
  • a crystalline solid form of Compound 1 is a hydrate.
  • a hydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta. In some embodiments, a hydrate form of Compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta.
  • a hydrate form of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta. In some embodiments, a hydrate form of Compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta.
  • a hydrate form of Compound 1 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta. In some embodiments, a hydrate form of Compound 1 is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta.
  • a hydrate form of Compound 1 is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta. In some embodiments, a hydrate form of Compound 1 is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta.
  • a hydrate form of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern: 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta.
  • a hydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from:
  • a hydrate form of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm having two minor endotherms at 63.1 °C and 118.5 °C followed by a sharp melting at 223.6 °C (peaks) .
  • DSC differential scanning calorimetry
  • a hydrate form of Compound 1 is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 4.9%before 120 °C.
  • TGA thermogravimetric analysis
  • a hydrate form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 2A. In some embodiments, a hydrate of Compound 1 is characterized by a DSC pattern substantially similar to FIG. 2C. In some embodiments, a hydrate of Compound 1 is characterized by a TGA pattern substantially similar to FIG. 2C. In some embodiments, a hydrate of Compound 1 is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 2A; (b) a DSC pattern substantially similar to FIG. 2C; and (c) a TGA pattern substantially similar to FIG. 2C.
  • a crystalline solid form of Compound 1 is Form B.
  • a crystalline solid form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta. In some embodiments, a crystalline solid form of Compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta. In some embodiments, a crystalline solid form of Compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta. In some embodiments, a crystalline solid form of Compound 1 is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta. In some embodiments, a crystalline solid form of Compound 1 is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern: 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from:
  • a crystalline solid form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 3A.
  • a crystalline solid form of Compound 1 is Form C.
  • a crystalline solid form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 10.6, 14.6, 21.4, and 32.5 ⁇ 0.2 degrees 2-theta. In some embodiments, a crystalline solid form of Compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 10.6, 14.6, 21.4, and 32.5 ⁇ 0.2 degrees 2-theta. In some embodiments, a crystalline solid form of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 10.6, 14.6, 21.4, and 32.5 ⁇ 0.2 degrees 2-theta. In some embodiments, a crystalline solid form of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern: 10.6, 14.6, 21.4, and 32.5 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 4A.
  • a crystalline solid form of Compound 1 is Form D.
  • a crystalline solid form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern: 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a crystalline solid form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from:
  • a crystalline solid form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 5A.
  • a crystalline solid form of Compound 1 is Form E.
  • the present disclosure provides methods of preparing provided crystalline solid forms of Compound 1.
  • a provided method comprises crystallizing and/or re-crystallizing Compound 1 (amorphous, partially crystalline or crystalline) in a solvent system comprising one or more solvents.
  • a solvent system comprises a solvent and an antisolvent.
  • an “antisolvent” is a solvent in which Compound 1 is insoluble or substantially insoluble at room temperature.
  • a provided method comprises antisolvent addition to a solution of Compound 1, wherein a crystalline solid form of Compound 1 precipitates from a resulting solvent system comprising a solvent and an antisolvent.
  • a solvent system comprises one or more solvents independently selected from water, ethyl acetate (EtOAc) , dichloromethane (DCM) , chloroform, acetonitrile (MeCN or ACN) , methanol (MeOH) , ethanol (EtOH) , propyl alcohol (n-PrOH) , isopropyl alcohol (i-PrOH or IPA) , hexane, cyclohexane, heptane, pentane, cyclopentane, petroleum ether and a compound having a structure of R a -O-R b , wherein R a and R b are each independently selected from C 1 -C 6 aliphatic and C 3 -C 10 cycloaliphatic, or R a and R b are taken together to form a 3-10 membered ring having 0-2 additional heteroatoms independently selected from oxygen and nitrogen.
  • EtOAc ethyl
  • R a and R b are each independently selected from C 1 -C 6 alkyl and C 3 -C 10 cycloalkyl, or R a and R b are taken together to form a 3-6 membered ring having 0-1 additional heteroatom selected from oxygen and nitrogen.
  • R a -O-R b is diethyl ether, tetrahydrofuran (THF) , or methyl t-butyl ether (MTBE) .
  • a solvent system comprises a solvent selected from water, ethyl acetate (EtOAc) , dichloromethane (DCM) , chloroform, acetonitrile (MeCN) , methanol (MeOH) , ethanol (EtOH) , propyl alcohol (n-PrOH) , and isopropyl alcohol (i-PrOH) .
  • a solvent system comprises a solvent that is water.
  • a solvent system comprises a solvent that is EtOAc.
  • a solvent system comprises a solvent that is DCM.
  • a solvent system comprises a solvent that is chloroform and MeCN.
  • a solvent system comprises a solvent that is MeOH. In some embodiments, a solvent system comprises a solvent that is EtOH. In some embodiments, a solvent system comprises a solvent that is n-PrOH. In some embodiments, a solvent system comprises a solvent that is i-PrOH.
  • a solvent system comprises an antisolvent selected from hexane, cyclohexane, heptane, pentane, cyclopentane, petroleum ether and a compound having a structure of R a -O-R b , wherein R a and R b are each independently selected from C 1 -C 6 aliphatic and C 3 -C 10 cycloaliphatic, or R a and R b are taken together to form a 3-10 membered ring having 0-2 additional heteroatoms independently selected from oxygen and nitrogen.
  • R a and R b are each independently selected from C 1 -C 6 alkyl and C 3 -C 10 cycloalkyl, or R a and R b are taken together to form a 3-6 membered ring having 0-1 additional heteroatom selected from oxygen and nitrogen.
  • R a -O-R b is diethyl ether, tetrahydrofuran (THF) , or methyl t-butyl ether (MTBE) .
  • a solvent system comprises an antisolvent that is MTBE.
  • a solvent system comprises MeOH and MTBE. In some embodiments, a solvent system comprises EtOH and MTBE. In some embodiments, a solvent system comprises n-PrOH and MTBE.
  • a solvent system comprises a first solvent and a second solvent and the ratio of the first solvent: second solvent is about 1: 1 v/v to about 1: 1000 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 1000: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 1: 500 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 500: 1 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 1: 200 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 200: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 1: 100 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 100: 1 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 1: 50 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v to about 50: 1 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 2 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 3 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 4 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 5 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 6 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 7 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 8 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 9 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 10 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 20 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 50 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 100 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 200 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 500 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1: 1000 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 2: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 3: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 4: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 5: 1 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 6: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 7: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 8: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 9: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 10: 1 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 20: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 50: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 100: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 200: 1 v/v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 500: 1 v/v.
  • a solvent system comprises a first solvent and a second solvent and the ratio of first solvent: second solvent is about 1000: 1 v/v.
  • a first solvent is a solvent in which Compound 1 is soluble or substantially soluble and is as described herein.
  • a second solvent is an antisolvent in which Compound 1 is insoluble or substantially insoluble and is as described herein.
  • a first solvent is MeOH and a second solvent is MTBE.
  • the ratio of MeOH: MTBE is about 1: 9 v/v. In some embodiments, the ratio of MeOH: MTBE is 1: 1 v/v.
  • Compound 1 Form A is prepared by crystallizing and/or re-crystallizing Compound 1 (amorphous, partially crystalline or crystalline) in a solvent system as described herein. In some embodiments, Compound 1 Form A is prepared by crystallizing Compound 1 in a solvent system comprising MeOH and MTBE.
  • Compound 1 Form A is prepared through antisolvent addition using a solvent system as described herein. In some embodiments, Compound 1 Form A is prepared through antisolvent addition in a solvent system comprising MeOH and MTBE.
  • Compound 1 Form D is prepared through antisolvent addition using a solvent system as described herein. In some embodiments, Compound 1 Form D is prepared through antisolvent addition in a solvent system comprising H 2 O and THF.
  • a provided method comprises:
  • step (b) adding antisolvent to the solution resulted from step (a) at temperature B;
  • step (c) optionally adding a seed of Compound 1 to the resulting mixture from step (b) at temperature C;
  • step (d) optionally adding additional antisolvent to the resulting mixture from step (b) or step (c) at temperature D;
  • step (e) cooling the resulting mixture from step (b) , (c) , or (d) to temperature E.
  • a method of preparing Compound 1 Form A comprises:
  • step (b) adding antisolvent to the solution resulted from step (a) at temperature B;
  • step (c) optionally adding a seed of Compound 1 to the resulting mixture from step (b) at temperature C;
  • step (d) optionally adding additional antisolvent to the resulting mixture from step (b) or step (c) at temperature D;
  • step (e) cooling the resulting mixture from step (b) , (c) , or (d) to temperature E.
  • step (c) is absent. In some embodiments, step (d) is absent. In some embodiments, both steps (c) and (d) are absent.
  • a provided method comprises:
  • step (b) adding antisolvent to the solution resulted from step (a) at temperature B;
  • step (c) adding a seed of Compound 1 to the resulting mixture from step (b) at temperature C;
  • step (d) adding additional antisolvent to the resulting mixture from step (c) at temperature D;
  • step (e) cooling the resulting mixture from step (d) to temperature E.
  • a method of preparing Compound 1 Form A comprises:
  • step (b) adding antisolvent to the solution resulted from step (a) at temperature B;
  • step (c) adding a seed of Compound 1 to the resulting mixture from step (b) at temperature C;
  • step (d) adding additional antisolvent to the resulting mixture from step (c) at temperature D;
  • step (e) cooling the resulting mixture from step (d) to temperature E.
  • a solvent used in step (a) is MeOH. In some embodiments, a solvent used in step (a) is EtOH. In some embodiments, a solvent used in step (a) is n-PrOH. In some embodiments, a solvent used in step (a) is i-PrOH. In some embodiments, a solvent used in step (a) is water. In some embodiments, a solvent used in step (a) is EtOAc. In some embodiments, a solvent used in step (a) is water. In some embodiments, a solvent used in step (a) is DCM. In some embodiments, a solvent used in step (a) is cholorform. In some embodiments, a solvent used in step (a) is MeCN.
  • temperature A is about 10 °C to about 60 °C. In some embodiments, temperature A is about 10 °C to about 50 °C. In some embodiments, temperature A is about 10 °C to about 40 °C. In some embodiments, temperature A is about 10 °C to about 30 °C. In some embodiments, temperature A is about 10 °C to about 20 °C. In some embodiments, temperature A is about 10 °C to about 15 °C. In some embodiments, temperature A is about 15 °C to about 60 °C. In some embodiments, temperature A is about 15 °C to about 50 °C. In some embodiments, temperature A is about 15 °C to about 40 °C.
  • temperature A is about 15 °C to about 30 °C. In some embodiments, temperature A is about 15 °C to about 20 °C. In some embodiments, temperature A is about 20 °C to about 60 °C. In some embodiments, temperature A is about 20 °C to about 50 °C. In some embodiments, temperature A is about 20 °C to about 40 °C. In some embodiments, temperature A is about 20 °C to about 30 °C. In some embodiments, temperature A is about 30 °C to about 60 °C. In some embodiments, temperature A is about 30 °C to about 50 °C. In some embodiments, temperature A is about 30 °C to about 40 °C. In some embodiments, temperature A is about 40 °C to about 60 °C. In some embodiments, temperature A is about 40 °C to about 50 °C. In some embodiments, temperature A is about 50 °C to about 60 °C. In some embodiments, temperature A is about 40 °C to about 50 °C
  • temperature A is room temperature (e.g., about 20-25 °C) . In some embodiments, temperature A is about 30 °C. In some embodiments, temperature A is about 40 °C. In some embodiments, temperature A is about 50 °C. In some embodiments, temperature A is about 60 °C. In some embodiments, temperature A is about 25 °C. In some embodiments, temperature A is about 20 °C. In some embodiments, temperature A is about 15 °C. In some embodiments, temperature A is about 10 °C.
  • an antisolvent used in step (b) is MTBE. In some embodiments, an antisolvent used in step (b) is diethyl ether. In some embodiments, an antisolvent used in step (b) is THF. In some embodiments, an antisolvent used in step (b) is hexane. In some embodiments, an antisolvent used in step (b) is cyclohexane. In some embodiments, an antisolvent used in step (b) is heptane. In some embodiments, an antisolvent used in step (b) is pentane. In some embodiments, an antisolvent used in step (b) is cyclopentane.
  • an antisolvent used in step (b) is petroleum ether. In some embodiments, an antisolvent used in step (b) is a compound having a structure of R a -O-R b , wherein R a and R b are each independently as described herein.
  • temperature B is about 10 °C to about 70 °C. In some embodiments, temperature B is about 10 °C to about 60 °C. In some embodiments, temperature B is about 10 °C to about 50 °C. In some embodiments, temperature B is about 10 °C to about 45 °C. In some embodiments, temperature B is about 10 °C to about 40 °C. In some embodiments, temperature B is about 10 °C to about 30 °C. In some embodiments, temperature B is about 10 °C to about 20 °C. In some embodiments, temperature B is about 20 °C to about 70 °C. In some embodiments, temperature B is about 20 °C to about 60 °C.
  • temperature B is about 20 °C to about 50 °C. In some embodiments, temperature B is about 20 °C to about 45 °C. In some embodiments, temperature B is about 20 °C to about 40 °C. In some embodiments, temperature B is about 20 °C to about 30 °C. In some embodiments, temperature B is about 30 °C to about 70 °C. In some embodiments, temperature B is about 30 °C to about 60 °C. In some embodiments, temperature B is about 30 °C to about 50 °C. In some embodiments, temperature B is about 30 °C to about 45 °C. In some embodiments, temperature B is about 30 °C to about 40 °C.
  • temperature B is about 40 °C to about 70 °C. In some embodiments, temperature B is about 40 °C to about 60 °C. In some embodiments, temperature B is about 40 °C to about 50 °C. In some embodiments, temperature B is about 40 °C to about 45 °C. In some embodiments, temperature B is about 45 °C to about 70 °C. In some embodiments, temperature B is about 45 °C to about 60 °C. In some embodiments, temperature B is about 45 °C to about 50 °C. In some embodiments, temperature B is about 50 °C to about 70 °C. In some embodiments, temperature B is about 50 °C to about 60 °C. In some embodiments, temperature B is about 60 °C to about 70 °C.
  • temperature B is room temperature (e.g., about 20-25 °) . In some embodiments, temperature B is about 30 °C. In some embodiments, temperature B is about 40 °C. In some embodiments, temperature B is about 45 °C. In some embodiments, temperature B is about 50 °C. In some embodiments, temperature B is about 60 °C. In some embodiments, temperature B is about 70 °C. In some embodiments, temperature B is about 20 °C. In some embodiments, temperature B is about 15 °C. In some embodiments, temperature B is about 10 °C.
  • a seed of Compound 1 used in step (c) is at an amount of about 0.01%w/w to about 10%w/w, as calculated based on the amount of Compound 1 which applies throughout the present disclosure unless stated otherwise. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.01%w/w to about 5%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.05%w/w to about 5%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.1%w/w to about 3%w/w.
  • a seed of Compound 1 used in step (c) is at an amount of about 0.5%w/w to about 3%w/w. In some embodiments, a seed of Compound 1 used in step (c) is no more than about 3%w/w. In some embodiments, a seed of Compound 1 used in step (c) is no more than about 2.5%w/w. In some embodiments, a seed of Compound 1 used in step (c) is no more than about 2%w/w. In some embodiments, a seed of Compound 1 used in step (c) is no more than about 1.5%w/w. In some embodiments, a seed of Compound 1 used in step (c) is no more than about 1%w/w. In some embodiments, a seed of Compound 1 used in step (c) is no more than about 0.5%w/w. In some embodiments, a seed of Compound 1 used in step (c) is no more than about 0.1%w/w.
  • a seed of Compound 1 used in step (c) is at an amount of about 0.1%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.2%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.3%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.4%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.5%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.6%w/w.
  • a seed of Compound 1 used in step (c) is at an amount of about 0.7%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.8%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 0.9%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 1%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 1.5%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 2%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 2.5%w/w. In some embodiments, a seed of Compound 1 used in step (c) is at an amount of about 3%w/w.
  • temperature C is about 10 °C to about 70 °C. In some embodiments, temperature C is about 10 °C to about 60 °C. In some embodiments, temperature C is about 10 °C to about 50 °C. In some embodiments, temperature C is about 10 °C to about 45 °C. In some embodiments, temperature C is about 10 °C to about 40 °C. In some embodiments, temperature C is about 10 °C to about 30 °C. In some embodiments, temperature C is about 10 °C to about 20 °C. In some embodiments, temperature C is about 20 °C to about 70 °C. In some embodiments, temperature C is about 20 °C to about 60 °C.
  • temperature C is about 20 °C to about 50 °C. In some embodiments, temperature C is about 20 °C to about 45 °C. In some embodiments, temperature C is about 20 °C to about 40 °C. In some embodiments, temperature C is about 20 °C to about 30 °C. In some embodiments, temperature C is about 30 °C to about 70 °C. In some embodiments, temperature C is about 30 °C to about 60 °C. In some embodiments, temperature C is about 30 °C to about 50 °C. In some embodiments, temperature C is about 30 °C to about 45 °C. In some embodiments, temperature C is about 30 °C to about 40 °C.
  • temperature C is about 40 °C to about 70 °C. In some embodiments, temperature C is about 40 °C to about 60 °C. In some embodiments, temperature C is about 40 °C to about 50 °C. In some embodiments, temperature C is about 40 °C to about 45 °C. In some embodiments, temperature C is about 45 °C to about 70 °C. In some embodiments, temperature C is about 45 °C to about 60 °C. In some embodiments, temperature C is about 45 °C to about 50 °C. In some embodiments, temperature C is about 50 °C to about 70 °C. In some embodiments, temperature C is about 50 °C to about 60 °C. In some embodiments, temperature C is about 60 °C to about 70 °C.
  • temperature C is room temperature (e.g., about 20-25 °C) . In some embodiments, temperature C is about 30 °C. In some embodiments, temperature C is about 40 °C. In some embodiments, temperature C is about 45 °C. In some embodiments, temperature C is about 50 °C. In some embodiments, temperature C is about 60 °C. In some embodiments, temperature C is about 70 °C. In some embodiments, temperature C is about 20 °C. In some embodiments, temperature C is about 15 °C. In some embodiments, temperature C is about 10 °C.
  • an antisolvent used in step (d) is the same antisolvent used in step (b) . In some embodiments, an antisolvent used in step (d) is different from an antisolvent used in step (b) . In some embodiments, an antisolvent used in step (d) is MTBE. In some embodiments, an antisolvent used in step (d) is diethyl ether. In some embodiments, an antisolvent used in step (d) is THF. In some embodiments, an antisolvent used in step (d) is hexane. In some embodiments, an antisolvent used in step (d) is cyclohexane. In some embodiments, an antisolvent used in step (d) is heptane.
  • an antisolvent used in step (d) is pentane. In some embodiments, an antisolvent used in step (b) is cyclopentane. In some embodiments, an antisolvent used in step (d) is petroleum ether. In some embodiments, an antisolvent used in step (d) is a compound having a structure of R a -O-R b , wherein R a and R b are each independently as described herein.
  • temperature D is about 10 °C to about 70 °C. In some embodiments, temperature D is about 10 °C to about 60 °C. In some embodiments, temperature D is about 10 °C to about 50 °C. In some embodiments, temperature D is about 10 °C to about 45 °C. In some embodiments, temperature D is about 10 °C to about 40 °C. In some embodiments, temperature D is about 10 °C to about 30 °C. In some embodiments, temperature D is about 10 °C to about 20 °C. In some embodiments, temperature D is about 20 °C to about 70 °C. In some embodiments, temperature D is about 20 °C to about 60 °C.
  • temperature D is about 20 °C to about 50 °C. In some embodiments, temperature D is about 20 °C to about 45 °C. In some embodiments, temperature D is about 20 °C to about 40 °C. In some embodiments, temperature D is about 20 °C to about 30 °C. In some embodiments, temperature D is about 30 °C to about 70 °C. In some embodiments, temperature D is about 30 °C to about 60 °C. In some embodiments, temperature D is about 30 °C to about 50 °C. In some embodiments, temperature D is about 30 °C to about 45 °C. In some embodiments, temperature D is about 30 °C to about 40 °C.
  • temperature D is about 40 °C to about 60 °C. In some embodiments, temperature D is about 40 °C to about 50 °C. In some embodiments, temperature D is about 40 °C to about 45 °C. In some embodiments, temperature D is about 40 °C to about 70 °C. In some embodiments, temperature D is about 45 °C to about 60 °C. In some embodiments, temperature D is about 45 °C to about 50 °C. In some embodiments, temperature D is about 50 °C to about 70 °C. In some embodiments, temperature D is about 50 °C to about 60 °C. In some embodiments, temperature D is about 60 °C to about 70 °C.
  • temperature D is room temperature (e.g., about 20-25 °C) . In some embodiments, temperature D is about 30 °C. In some embodiments, temperature D is about 40 °C. In some embodiments, temperature D is about 45 °C. In some embodiments, temperature D is about 50 °C. In some embodiments, temperature D is about 60 °C. In some embodiments, temperature D is about 70 °C. In some embodiments, temperature D is about 20 °C. In some embodiments, temperature D is about 15 °C. In some embodiments, temperature D is about 10 °C.
  • cooling in step (e) is carried out during a course of about 48 hours. In some embodiments, cooling in step (e) is carried out during a course of about 24 hours. In some embodiments, cooling in step (e) is carried out during a course of about 12 hours. In some embodiments, cooling in step (e) is carried out during a course of about 6 hours. In some embodiments, cooling in step (e) is carried out during a course of about 5 hours. In some embodiments, cooling in step (e) is carried out during a course of about 4.5 hours. In some embodiments, cooling in step (e) is carried out during a course of about 4 hours. In some embodiments, cooling in step (e) is carried out during a course of about 3.5 hours.
  • cooling in step (e) is carried out during a course of about 3 hours. In some embodiments, cooling in step (e) is carried out during a course of about 2.5 hours. In some embodiments, cooling in step (e) is carried out during a course of about 2 hours. In some embodiments, cooling in step (e) is carried out during a course of about 1.5 hours. In some embodiments, cooling in step (e) is carried out during a course of about 1 hours. In some embodiments, cooling in step (e) is carried out during a course of about 0.5 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 24 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 18 hours.
  • cooling in step (e) is carried out during a course of less than about 12 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 6 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 5 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 4 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 3 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 2 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 1.5 hours. In some embodiments, cooling in step (e) is carried out during a course of less than about 0.5 hours.
  • temperature E is about -20 °C to about 40 °C. In some embodiments, temperature E is about -15 °C to about 40 °C. In some embodiments, temperature E is about -10 °C to about 40 °C. In some embodiments, temperature E is about -5 °C to about 40 °C. In some embodiments, temperature E is about 0 °C to about 40 °C. In some embodiments, temperature E is about 5 °C to about 40 °C. In some embodiments, temperature E is about 10 °C to about 40 °C. In some embodiments, temperature E is about 15 °C to about 40 °C. In some embodiments, temperature E is about 20 °C to about 40 °C.
  • temperature E is about 30 °C to about 40 °C. In some embodiments, temperature E is about -20 °C to about 30 °C. In some embodiments, temperature E is about -15 °C to about 30 °C. In some embodiments, temperature E is about -10 °C to about 30 °C. In some embodiments, temperature E is about -5 °C to about 30 °C. In some embodiments, temperature E is about 0 °Cto about 30 °C. In some embodiments, temperature E is about 5 °C to about 30 °C. In some embodiments, temperature E is about 10 °C to about 30 °C. In some embodiments, temperature E is about 15 °C to about 30 °C.
  • temperature E is about 20 °C to about 30 °C. In some embodiments, temperature E is about -20 °C to about 20 °C. In some embodiments, temperature E is about -15 °C to about 20 °C. In some embodiments, temperature E is about -10 °C to about 20 °C. In some embodiments, temperature E is about -5 °C to about 20 °C. In some embodiments, temperature E is about 0 °C to about 20 °C. In some embodiments, temperature E is about 5 °C to about 20 °C. In some embodiments, temperature E is about 10 °C to about 20 °C. In some embodiments, temperature E is about 15 °C to about 20 °C.
  • temperature E is about -20 °C to about 15 °C. In some embodiments, temperature E is about -15 °C to about 15 °C. In some embodiments, temperature E is about -10 °C to about 15 °C. In some embodiments, temperature E is about -5 °C to about 15 °C. In some embodiments, temperature E is about 0 °C to about 15 °C. In some embodiments, temperature E is about 5 °C to about 15 °C. In some embodiments, temperature E is about 10 °C to about 15 °C. In some embodiments, temperature E is about -20 °C to about 10 °C. In some embodiments, temperature E is about -15 °C to about 10 °C.
  • temperature E is about -10 °C to about 10 °C. In some embodiments, temperature E is about -5 °C to about 10 °C. In some embodiments, temperature E is about 0 °C to about 10 °C. In some embodiments, temperature E is about 5 °C to about 10 °C. In some embodiments, temperature E is about -20 °C to about 5 °C. In some embodiments, temperature E is about -15 °C to about 5 °C. In some embodiments, temperature E is about -10 °C to about 5 °C. In some embodiments, temperature E is about -5 °Cto about 5 °C. In some embodiments, temperature E is about 0 °C to about 5 °C.
  • temperature E is about -20 °C to about 0 °C. In some embodiments, temperature E is about -15 °C to about 0 °C. In some embodiments, temperature E is about -10 °C to about 0 °C. In some embodiments, temperature E is about -5 °C to about 0 °C. In some embodiments, temperature E is about -20 °C to about -5 °C. In some embodiments, temperature E is about -15 °C to about -5 °C. In some embodiments, temperature E is about -10 °C to about -5 °C. In some embodiments, temperature E is about -20 °C to about -10 °C. In some embodiments, temperature E is about -15 °C to about -10 °C. In some embodiments, temperature E is about -20 °C to about -15 °C.
  • temperature E is room temperature (e.g., about 20-25 °C) . In some embodiments, temperature E is about 30 °C. In some embodiments, temperature E is about 40 °C. In some embodiments, temperature E is about 20 °C. In some embodiments, temperature E is about 15 °C. In some embodiments, temperature E is about 10 °C. In some embodiments, temperature E is about 5 °C. In some embodiments, temperature E is about 0 °C. In some embodiments, temperature E is about -5 °C. In some embodiments, temperature E is about -10 °C. In some embodiments, temperature E is about -15 °C. In some embodiments, temperature E is about -20 °C.
  • temperature A is about 20 °C to about 40 °C
  • temperature B is about 40 °C to about 50 °C
  • temperature C is about 40 °C to about 50 °C
  • temperature D is about 40 °C to about 50 °C
  • temperature E is about -5 °C to about 10 °C.
  • temperature A is about 30 °C
  • temperature B is about 45 °C
  • temperature C is about 45 °C
  • temperature D is about 45 °C
  • temperature E is about 0 °C.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 1: 1000 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 1: 500 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 1: 200 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 1: 100 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 1: 50 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 1: 10 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 1000: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 500: 1 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 200: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 100: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 50: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 10: 1 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 1: 9 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v to about 9: 1 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 2 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 3 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 4 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 5 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 6 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 7 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 8 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 9 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 10 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 20 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 50 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 100 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 200 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 500 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1: 1000 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 2: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 3: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 4: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 5: 1 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 6: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 7: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 8: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 9: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 10: 1 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 20: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 50: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 100: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 200: 1 v/v. In some embodiments, a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 200: 1 v/v.
  • a ratio of solvent: antisolvent in the resulting solvent system of step (e) is about 1000: 1 v/v.
  • a solvent is MeOH and an antisolvent is MTBE in the resulting solvent system of step (e) .
  • a ratio of MeOH: MTBE in the resulting solvent system of step (e) is about 1: 9 v/v.
  • a ratio of MeOH: MTBE in the resulting solvent system of step (e) is about 9: 1 v/v.
  • a ratio of MeOH: MTBE in the resulting solvent system of step (e) is about 1: 9 v/v.
  • a ratio of MeOH: MTBE in the resulting solvent system of step (e) is about 1: 1 v/v.
  • a ratio of MeOH: MTBE in the resulting solvent system of step (e) is about 1: 1 v/v.
  • Compound 1 Form A is obtained from step (e) as described herein.
  • a provided method comprises:
  • step (b) adding MTBE to the solution resulted from step (a) at about 45 °C;
  • step (c) optionally adding a seed of Compound 1 to the resulting mixture from step (b) at about 45 °C;
  • step (d) adding additional MTBE to the resulting mixture from step (c) at temperature 45 °C;
  • step (e) cooling the resulting mixture from step (d) to temperature 0 °C.
  • a provided method comprises:
  • step (b) adding MTBE to the solution resulted from step (a) at about 45 °C;
  • step (c) optionally adding a seed of Compound 1 to the resulting mixture from step (b) at about 45 °C;
  • step (d) adding additional MTBE to the resulting mixture from step (c) at temperature 45 °C;
  • step (e) cooling the resulting mixture from step (d) to temperature 0 °C.
  • a method of preparing Compound 1 Form A comprises:
  • step (b) adding MTBE to the solution resulted from step (a) at about 45 °C;
  • step (c) optionally adding a seed of Compound 1 to the resulting mixture from step (b) at about 45 °C;
  • step (d) adding additional MTBE to the resulting mixture from step (c) at temperature 45 °C;
  • step (e) cooling the resulting mixture from step (d) to temperature 0 °C.
  • a method of preparing Compound 1 Form A comprises:
  • step (b) adding MTBE to the solution resulted from step (a) at about 45 °C;
  • step (c) optionally adding a seed of Compound 1 to the resulting mixture from step (b) at about 45 °C;
  • step (d) adding additional MTBE to the resulting mixture from step (c) at temperature 45 °C;
  • step (e) cooling the resulting mixture from step (d) to temperature 0 °C.
  • a provided method comprises solid vapor diffusion wherein solid Compound 1 is brought into contact with vapor of a volatile solvent to yield a crystalline solid form of Compound 1.
  • a volatile solvent is n-PrOH.
  • a volatile solvent is acetone.
  • a volatile solvent is methyl ethyl ketone (MEK) .
  • a volatile solvent is EtOAc.
  • a volatile solvent is MTBE.
  • a volatile solvent is H 2 O.
  • a volatile solvent is chloroform.
  • a volatile solvent is MeCN.
  • a volatile solvent is N, N-dimethylacetamide.
  • a volatile solvent is 2-methyltetrahydrofuran.
  • Compound 1 Form A is prepared by solid vapor diffusion using a volatile solvent as described herein.
  • a provided method comprises liquid vapor diffusion wherein Compound 1 is dissolved in a solvent and its solution is brought into contact with vapor of an antisolvent as described herein.
  • a solvent is i-PrOH.
  • a solvent is dimethylsulfoxide (DMSO) .
  • a solvent is MeCN.
  • an antisolvent is MTBE.
  • an antisolvent is n-hexane.
  • an antisolvent is isobutyl acetate.
  • an antisolvent is 2-methyltetrahydrofuran.
  • an antisolvent is acetone.
  • an antisolvent is MTBE.
  • Compound 1 Form A is prepared by liquid vapor diffusion using i-PrOH as a solvent and MTBE as antisolvent. In some embodiments, Compound 1 Form A is prepared by liquid vapor diffusion using i-PrOH as a solvent and n-hexane as antisolvent. In some embodiments, Compound 1 Form A is prepared by liquid vapor diffusion using DMSO as a solvent and isobutyl acetate as antisolvent. In some embodiments, Compound 1 Form A is prepared by liquid vapor diffusion using DMSO as a solvent and 2-methyltetrahydrofuran as antisolvent. In some embodiments, Compound 1 Form A is prepared by liquid vapor diffusion using MeCN as a solvent and acetone as antisolvent. In some embodiments, Compound 1 Form A is prepared by liquid vapor diffusion using MeCN as a solvent and MTBE as antisolvent.
  • a provided method comprises slow evaporation wherein Compound 1 is dissolved in a solvent system which is then allowed to evaporate to yield a crystalline solid form of Compound 1.
  • a solvent system comprises MeOH/cyclopentyl methyl ether (CPME) .
  • CPME cyclopentyl methyl ether
  • a solvent system comprises i-PrOH.
  • a solvent system comprises acetone/DCM.
  • a solvent system comprises chloroform/toluene.
  • Compound 1 Form A is prepared by slow evaporation in i-PrOH. In some embodiments, Compound 1 Form A is prepared by slow evaporation in acetone/DCM. In some embodiments, Compound 1 Form A is prepared by slow evaporation in chloroform/toluene.
  • Compound 1 Form B is prepared by slow evaporation in MeOH/cyclopentyl methyl ether.
  • a provided method comprises polymer-induced crystallization wherein Compound 1 is dissolved in a solvent system, to which a polymer mixture of PVC and PVP is added, and the solvent system is allowed to evaporate to yield a crystalline solid form of Compound 1.
  • a solvent system comprises EtOH/methyl isobutyl ketone (MIBK) .
  • MIBK isobutyl ketone
  • a solvent system comprises 2-methyltetrahydrofuran/DCM.
  • a solvent system comprises MeCN/isopropyl acetate (IPAc) .
  • Compound 1 Form A is prepared by polymer-induced crystallization in a solvent system comprising EtOH/methyl isobutyl ketone. In some embodiments, Compound 1 Form A is prepared by polymer-induced crystallization in a solvent system comprising 2-methyltetrahydrofuran/DCM.
  • Compound 1 Form B is prepared by polymer-induced crystallization in a solvent system comprising MeCN/isopropyl acetate.
  • a provided method comprises slurrying Compound 1 in a solvent system at room temperature.
  • a solvent system comprises MeOH/CPME.
  • a solvent system comprises EtOH/n-heptane.
  • a solvent system comprises IPA/toluene.
  • a solvent system comprises acetone.
  • a solvent system comprises MEK.
  • a solvent system comprises 2-MeTHF.
  • a solvent system comprises 1, 4-Dioxane/H 2 O.
  • a solvent system comprises MeOH/CPME.
  • a solvent system comprises toluene.
  • a solvent system comprises ACN/IPAc. In some embodiments, a solvent system comprises DCM/n-heptane. In some embodiments, a solvent system comprises DMSO/anisole. In some embodiments, a solvent system comprises n-methyl-2-pyrrolidone (NMP) /MIBK. In some embodiments, a solvent system comprises acetone/H 2 O. In some embodiments, a solvent system comprises THF. In some embodiments, a solvent system comprises H 2 O. In some embodiments, a solvent system comprises THF/H 2 O.
  • Compound 1 Form A is prepared by slurrying Compound 1 in a solvent system as described at room temperature.
  • a provided method comprises slurrying Compound 1 in a solvent system at 50 °C.
  • a solvent system comprises MeOH/MEK.
  • a solvent system comprises IPA/n-heptane.
  • a solvent system comprises 2-butanol/EtOAc.
  • a solvent system comprises acetone.
  • a solvent system comprises MIBK.
  • a solvent system comprises IPAc.
  • a solvent system comprises CPME.
  • a solvent system comprises 2-MeTHF.
  • a solvent system comprises 1, 4-dioxane.
  • a solvent system comprises toluene.
  • a solvent system comprises anisole. In some embodiments, a solvent system comprises ACN/MTBE. In some embodiments, a solvent system comprises CHCl 3 /n-Heptane. In some embodiments, a solvent system comprises DMF/toluene. In some embodiments, a solvent system comprises THF/H 2 O. In some embodiments, a solvent system comprises acetone/H 2 O.
  • Compound 1 Form A is prepared by slurrying Compound 1 in a solvent system as described in at 50 °C.
  • a provided method comprises slowly cooling a solution of Compound 1 in a solvent system to a lower temperature.
  • a solvent system comprises 2-butanol.
  • a solvent system comprises acetone.
  • a solvent system comprises EtOAc/EtOH.
  • a solvent system comprises THF/H 2 O.
  • a solvent system comprises ACN/MEK.
  • a solvent system comprises CHCl 3 /n-heptane.
  • a solvent system comprises DMF/toluene.
  • a solvent system comprises EtOH/MTBE.
  • Compound 1 Form A is prepared by slowly cooling Compound 1 in a solvent system comprising acetone. In some embodiments, Compound 1 Form A is prepared by slowly cooling Compound 1 in a solvent system comprising EtOAc/EtOH. In some embodiments, Compound 1 Form A is prepared by slowly cooling Compound 1 in a solvent system comprising EtOH/MTBE.
  • Compound 1 Form B is prepared by slowly cooling Compound 1 in a solvent system comprising THF/H 2 O.
  • Compound 1 Form A is prepared by slowly cooling Compound 1 in a solvent system comprising CHCl 3 /n-heptane.
  • Compound 1 Form C is prepared by slowly cooling Compound 1 in a solvent system comprising 2-butanol.
  • a provided method comprising grinding Compound 1, optionally with addition of a solvent system.
  • a solvent system comprises EtOH.
  • a solvent system comprises H 2 O.
  • Compound 1 Form A is prepared by grinding Compound 1 in a solvent system as described herein.
  • the present disclosure provides compositions comprising a crystalline solid form of Compound 1.
  • a provided composition comprises a crystalline solid form of Compound 1 that is substantially free of impurities.
  • the term “substantially free of impurities” means that the composition contains no significant amount of extraneous matter. Such extraneous matter may include starting materials, alternative crystalline forms, residual solvents, or any other impurities that may result from the preparation of and/or isolation of a crystalline solid form.
  • the composition comprises at least about 90%by weight of a solid crystalline form of Compound 1.
  • a provided composition comprising a crystalline solid form of Compound 1 is substantially pure (e.g., comprises at least about 95%, 97%, 97.5%, 98%98.5%, 99%, 99.5%, or 99.8%by weight of the provided crystalline solid form based on the total weight of the composition) .
  • a composition comprising a crystalline solid form of Compound 1 comprises no more than about 5.0 percent of total organic impurities.
  • a composition comprising a crystalline solid form of Compound 1 comprises no more than about 3.0 percent of total organic impurities.
  • a composition comprising a crystalline solid form of Compound 1 comprises no more than about 1.5 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 comprises no more than about 1.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form of Compound 1 comprises no more than about 0.5 percent of total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.
  • a provided composition comprising a crystalline solid form of Compound 1 comprises 95%or greater by weight of a crystalline solid form of Compound 1.
  • a composition comprises 96%or greater by weight of a crystalline solid form of Compound 1.
  • a composition comprises 97%or greater by weight of a crystalline solid form of Compound 1.
  • a composition comprises 98%or greater by weight of a crystalline solid form of Compound 1.
  • a composition comprises 99%or greater by weight of a crystalline solid form of Compound 1.
  • a composition comprises 99.9%or greater by weight of a crystalline solid form of Compound 1.
  • a level of residual solvents in a provided crystalline solid form of Compound 1 does not exceed ICH guidelines. In some embodiments, a level of residual solvents in a provided crystalline solid form of Compound 1 is lower than ICH guidelines. In some embodiments, a level of residual solvents in a provided crystalline solid form of Compound 1 is about 20%lower than ICH guidelines. In some embodiments, a level of residual solvents in a provided crystalline solid form of Compound 1 is about 50%lower than ICH guidelines. In some embodiments, a level of residual solvents in a provided crystalline solid form of Compound 1 is about 80%lower than ICH guidelines.
  • a level of residual solvents in a provided crystalline solid form of Compound 1 is about 90%lower than ICH guidelines. In some embodiments, a level of residual solvents in a provided crystalline solid form of Compound 1 is about 95%lower than ICH guidelines. In some embodiments, a level of residual solvents in a provided crystalline solid form of Compound 1 is about 99%lower than ICH guidelines.
  • a crystalline solid form of the present disclosure is stable or substantially stable when subject to predetermined conditions for predetermined times.
  • the term “stable” or “substantially stable” means a crystalline solid form remains substantially free of impurities when subject to predetermined conditions for predetermined times.
  • a crystalline solid form of the present disclosure remains stable when subject to predetermined conditions for predetermined times.
  • a crystalline solid form of the present disclosure can be stored and remain stable or substantially stable at various predetermined temperatures and relative humidities for defined or predetermined time periods, for example in an open or closed container.
  • a crystalline solid form of the present disclosure is stable or substantially stable upon storage at about 5, 25, 30, 37 or 40 °C and about 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%or 100%relative humidity for a period of at least about 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 20, 25, 30, 35, 40, 45, 48, 50, 51, 52, 53, 55 or 60 h, 1 week, 2 weeks, 3 weeks or 4 week; 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months.
  • Compound 1 Form A is stable after drying under atmospheric pressure at 35 °C for about 5 days and remains substantially stable.
  • the present disclosure provides a pharmaceutical formulation comprising a crystalline solid form of Compound 1 and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical formulation is one described in WO2020/113050, which is incorporated herein by reference in its entirety.
  • compounds and crystalline solid forms provided herein can be administered alone or can be coadministered to the subject.
  • Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (e.g., with more than one compound) .
  • compounds and crystalline solid forms provided herein can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms.
  • compounds and crystalline solid forms provided herein is formulated as a topical pharmaceutical formulation.
  • a topical pharmaceutical formulation is a cream.
  • a topical pharmaceutical formulation is a gel.
  • a topical pharmaceutical formulation is an ointment.
  • a topical pharmaceutical formulation is an emulsion.
  • a topical pharmaceutical formulation is a solution.
  • a pharmaceutical formulation is administered topically. In some embodiments, a pharmaceutical formulation is administered transdermally.
  • formulations can include pharmaceutically acceptable excipients, which can be either solid or liquid.
  • a crystalline solid form described herein is incorporated into a pharmaceutical formulation suitable for topical administration.
  • a pharmaceutical formulation described herein comprises one or more suitable excipients selected from magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, purified water, cetareth-20, glyceryl stearate, PEG-100 stearate, beeswax, mineral oil, glyceryl monostearate, propylene glycol, Tween 80, cetyl alcohol, transcutol-P, and the like.
  • a pharmaceutical formulation comprises one or more of purified water, cetareth-20, glyceryl stearate, PEG-100 stearate, beeswax, mineral oil, glyceryl monostearate, propylene glycol, Tween 80, cetyl alcohol, and transcutol-P.
  • Quantity of active ingredient in a unit dose preparation may be varied or adjusted according to the particular application and the potency of the active ingredient.
  • a pharmaceutical formulation described herein can, if desired, also contain other compatible therapeutic agents.
  • crystalline solid forms and compositions and formulations comprising said crystalline solid forms are useful in the treatment of a variety of diseases and disorders.
  • a provided crystalline solid form is useful for treating a disease, disorder, or condition that is mediated by sodium ion channel.
  • the present disclosure provides a method of treating a disease, disorder or condition, comprising administering to a subject in need thereof a crystalline solid form of Compound 1.
  • a disease, disorder, or condition comprises signs and symptoms including inflammation, pruritus and/or pain.
  • a disease, disorder, or condition is atopic dermatitis, hand and foot eczema, postherpetic itch, dermatitis herpetiformis, postherpetic neuralgia, HIV-associated distal sensory polyneuropathy, prurigo nodularis, pemphigus vulgaris, hypertrophic scar, chronic prurigo, uremic pruritus or notalgia paresthetica.
  • a disease, disorder, or condition comprises signs and symptoms of inflammation.
  • a disease, disorder, or condition comprises signs and symptoms of pruritus.
  • a disease, disorder, or condition comprises signs and symptoms of pain.
  • a disease, disorder, or condition is atopic dermatitis.
  • a disease, disorder, or condition is hand and foot eczema.
  • a disease, disorder, or condition is postherpetic itch.
  • a disease, disorder, or condition is dermatitis herpetiformis.
  • a disease, disorder, or condition is postherpetic neuralgia.
  • a disease, disorder, or condition is HIV-associated distal sensory polyneuropathy.
  • a disease, disorder, or condition is prurigo nodularis.
  • a disease, disorder, or condition is pemphigus vulgaris. In some embodiments, a disease, disorder, or condition is hypertrophic scar. In some embodiments, a disease, disorder, or condition is chronic prurigo. In some embodiments, a disease, disorder, or condition is uremic pruritus. In some embodiments, a disease, disorder, or condition is notalgia paresthetica.
  • a disease, disorder, or condition is alopecia areata, chronic hand eczema, hidradenitis suppurativa, pemphigus vulgaris, psoriasis, cutaneous lupus, vitiligo, inflammatory bowel disease, rheumatoid arthritis, asthma, allergic rhinitis, systemic lupus erythematosus, psoriatic arthritis, multiple sclerosis, acute myeloid leukemia, graft versus host disease, myelofibrosis, warm hemolytic anemia, idiopathic thrombocytopenic purpura, immunoglobulin A nephropathy, scleroderma, idiopathic pulmonary fibrosis, uveitis, eosinophilic esophagitis, or lupus nephritis.
  • a disease, disorder, or condition is alopecia areata. In some embodiments, a disease, disorder, or condition is chronic hand eczema. In some embodiments, a disease, disorder, or condition is hidradenitis suppurativa. In some embodiments, a disease, disorder, or condition is pemphigus vulgaris. In some embodiments, a disease, disorder, or condition is psoriasis, cutaneous lupus. In some embodiments, a disease, disorder, or condition is vitiligo. In some embodiments, a disease, disorder, or condition is inflammatory bowel disease. In some embodiments, a disease, disorder, or condition is rheumatoid arthritis.
  • a disease, disorder, or condition is asthma. In some embodiments, a disease, disorder, or condition is allergic rhinitis. In some embodiments, a disease, disorder, or condition is systemic lupus erythematosus. In some embodiments, a disease, disorder, or condition is psoriatic arthritis. In some embodiments, a disease, disorder, or condition is multiple sclerosis. In some embodiments, a disease, disorder, or condition is acute myeloid leukemia. In some embodiments, a disease, disorder, or condition is graft versus host disease. In some embodiments, a disease, disorder, or condition is myelofibrosis. In some embodiments, a disease, disorder, or condition is warm hemolytic anemia.
  • a disease, disorder, or condition is idiopathic thrombocytopenic purpura. In some embodiments, a disease, disorder, or condition is immunoglobulin A nephropathy. In some embodiments, a disease, disorder, or condition is scleroderma. In some embodiments, a disease, disorder, or condition is idiopathic pulmonary fibrosis. In some embodiments, a disease, disorder, or condition is uveitis. In some embodiments, a disease, disorder, or condition is eosinophilic esophagitis. In some embodiments, a disease, disorder, or condition is and lupus nephritis.
  • the crystalline solid form is an anhydrate and is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.4, 9.4, 13.0, 17.7, 18.9, 19.6, 20.8, 24.7, and 27.5 ⁇ 0.2 degrees 2-theta.
  • TGA Thermal Gravimetric Analysis
  • DSC Differential Scanning Calorimetric Analysis
  • the crystalline solid form is a hydrate and is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.6, 13.0, 17.4, 18.0, 19.6, 20.1, 20.7, 21.2, and 21.8 ⁇ 0.2 degrees 2-theta.
  • TGA Thermal Gravimetric Analysis
  • DSC Differential Scanning Calorimetric Analysis
  • the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.0, 8.7, 12.2, 13.7, 18.4, 19.8, 22.5, 24.7, and 25.5 ⁇ 0.2 degrees 2-theta.
  • the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 10.6, 14.6, 21.4, and 32.5 ⁇ 0.2 degrees 2-theta.
  • the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.5, 11.9, 14.8, 15.8, 18.0, 20.8, 21.3, and 22.9 ⁇ 0.2 degrees 2-theta.
  • a sample comprising the crystalline solid form of any one of embodiments 1-22, wherein the sample comprises about 90%by weight of the crystalline solid form.
  • a sample comprising the crystalline solid form of any one of embodiments 1-22, wherein the sample comprises about 95%by weight of the crystalline solid form.
  • a sample comprising the crystalline solid form of any one of embodiments 1-22, wherein the sample comprises about 98%by weight of the crystalline solid form.
  • a sample comprising the crystalline solid form of any one of embodiments 1-22, wherein the sample comprises about 99%by weight of the crystalline solid form.
  • a sample comprising the crystalline solid form of any one of embodiments 1-22, wherein the sample is substantially free of impurities.
  • the disease, disorder, or condition for which the signs and symptoms include inflammation, pruritus and/or pain is selected from the group consisting of atopic dermatitis, hand and foot eczema, postherpetic itch, dermatitis herpetiformis, postherpetic neuralgia, HIV-associated distal sensory polyneuropathy, prurigo nodularis, pemphigus vulgaris, hypertrophic scar, chronic prurigo, uremic pruritus and notalgia paresthetica.
  • embodiment 31 or 32 wherein the disease, disorder, or condition comprises signs and symptoms of inflammation, pruritus and/or pain is selected from atopic dermatitis, alopecia areata, hand and foot eczema, chronic hand eczema, hidradenitis suppurativa, pemphigus vulgaris, psoriasis, cutaneous lupus, vitiligo, inflammatory bowel disease, rheumatoid arthritis, asthma, allergic rhinitis, systemic lupus erythematosus, psoriatic arthritis, multiple sclerosis, acute myeloid leukemia, graft versus host disease, myelofibrosis, warm hemolytic anemia, idiopathic thrombocytopenic purpura, immunoglobulin A nephropathy, scleroderma, idiopathic pulmonary fibrosis, uveitis, eosinophilic e
  • the solvent system comprises MeOH and MTBE.
  • X-ray powder diffraction data were collected under ambient conditions on a Bruker D2 PHASER diffractometer. A ⁇ 2 mg sample was flattened on a silicon sample holder and compacted by a glass slide with the protection of a piece of weighing paper. An X-ray generator of 300 W was employed at 30 kV and 10 mA and was equipped with an X-ray tube of Cu (K ⁇ ) , with the K ⁇ 2/K ⁇ 1 intensity ratio of 0.50 The divergence slit was 0.6 mm and soller slit was 4°. Data was collected at a speed of 0.15 s/step with step size of 0.02° (2 ⁇ ) and a total step of 1837.
  • X-ray powder diffraction data were collected under ambient conditions on a Malvern Panalytical Aeris diffractometer. A few milligrams of sample were flattened on a silicon sample holder and compacted by a glass slide with the protection of a piece of weighing paper. An X-ray generator of 300 W was employed at 40 kV and 7.5 mA and was equipped with an X-ray tube of Cu (K ⁇ ) , with the K ⁇ 2/K ⁇ 1 intensity ratio of 0.50 Data were collected from 3° to 40° (2 ⁇ ) at a speed of 0.14 s/step.
  • Thermogravimetric analysis data were collected with a TA Discovery series 550. A few milligrams of material were placed into a Tzero aluminum pan and the sample was heated from room temperature to target temperature with a heating rate of 10 °C per minute under nitrogen protection (flow rate: 60 mL/min) .
  • Thermogravimetric analysis data were collected with a TA Discovery series TGA5500. A few milligrams of material were placed into a Tzero aluminum pan and the sample was heated from room temperature to target temperature with a heating rate of 10 °C per minute under nitrogen protection (flow rate: 25 mL/min) .
  • Differential scanning calorimetry was performed with a TA Discovery 2500 series DSC. A few milligrams of material were placed into a Tzero aluminum pan and seal it with a Tzero hermetic lid. Samples were analyzed from room temperature to target temperature with a heating rate of 10 °C per minute under 50 mL per minute of nitrogen flow.
  • Heating experiment was performed with a TA Discovery 2500 series DSC using the same nitrogen flow rate. An appropriate amount of material was placed into a Tzero aluminum pan for analysis, with the procedures of 1) heating to target temperature with a heating rate of 10 °C per minute, 2) keeping isothermal at target temperature for ⁇ 6 min, and 3) cooling down to room temperature.
  • Dynamic vapor sorption was performed with an Intrinsic series DVS at 25 °C under nitrogen blow. Approximately 30 milligrams of material were used. Samples were analyzed using methods below: 0%RH to 95%RH at 10%RH (5%from 90 to 95%RH) , 95%RH to 0%RH at 10%RH (5%from 95 to 90%RH) .
  • the solid samples were examined using Phenom pure.
  • the samples were sprayed in an ion sputtering apparatus for 60 s.
  • the resulting solid was put into a scanning electron microscope and the electron scanning mode was turned on.
  • the crystal morphology and microstructure were obtained by adjusting the different magnification times.
  • HPLC of with PDA detector was employed to determine purity.
  • Photomicrographs were taken using a Nikon ECLIPSE Ci-POL polarized light microscope at room temperature equipped with eyepieces of 10x and objective of 20x magnification. Sample ( ⁇ 1 mg) was dispersed with a drop of oil on a glass slide and photomicrograph was taken.
  • Form A was obtained after stirring at RT for 3 ⁇ 4 days. Then 1 ⁇ 2 mg Form B (D394-20230425-01-E0008-A4) was added and stirred for another ⁇ 3 days, and Form A was finally obtained.
  • Form A was further investigated under a series of water activities (a w of 0 ⁇ 1) in acetone/H 2 O at RT.
  • Compound 1 Form A was suspended in 0.3 ⁇ 0.5 mL of corresponding solvent systems. After equilibrium for ⁇ 2 h, samples were centrifuged (1000 rpm, 3 min) and supernatant was added to the HPLC vials containing Compound 1 Form A and Compound 1 Form B with equivalent mass ratio (3.5 mg for each) . After stirring magnetically at RT for ⁇ 3 days, solid was collected by centrifugation for XRPD analysis.
  • Compound 1 Form A was prepared as described in the examples above.
  • FIG. 1A An XRPD spectrum of Compound 1 Form A is provided in FIG. 1A.
  • TGA/DSC analysis of Compound 1 Form A is provided in FIG. 1B
  • 1 H NMR analysis of Compound 1 Form A is provided in FIG. 1C. Based on the TGA results, Compound 1 Form A was assigned as an anhydrate.
  • TGA result showed a weight loss of 0.2%before 200 °C, and DSC data (FIB. 1B) exhibited an endotherm at 224.0 °C (peak) , possibly attributed to melting.
  • Compound 1 Form B was prepared as described in the examples above.
  • FIG. 2A An XRPD spectrum of Compound 1 Form B is provided in FIG. 2A.
  • TGA/DSC analysis of Compound 1 Form B is provided in FIG. 2C
  • 1 H NMR analysis of Compound 1 Form B is provided in FIG. 2D. Based on the TGA results, Compound 1 Form B was assigned as a hydrate.
  • FIG. 3A An XRPD spectrum of Compound 1 Form C is provided in FIG. 3A.
  • XRPD overlay of Compound 1 Form B and Form C (FIG. 3B) showed that Form C converted to Form B gradually during drying under atmosphere at room temperature (26 ⁇ 28 °C, 48 ⁇ 58%RH) within 1 ⁇ 3 days, indicating that Form C was a metastable form.
  • Compound 1 Form D was prepared as described in the examples above.
  • FIG. 4A An XRPD spectrum of Compound 1 Form D is provided in FIG. 4A.
  • XRPD overlay of Compound 1 Form B and Form D (FIG. 4B) showed that Form D converted to Form B after drying under atmosphere at RT (27 ⁇ 31 °C, 53 ⁇ 61%RH) for another 3 days. Re-preparation trials were conducted in duplicate and only gel was obtained. The results indicated that Form D was a metastable form.
  • Compound 1 Form E was obtained in the re-preparation of Compound 1 Form C. Limited solids were obtained after slow cooling to 5 °C from 2-butanol and more solids precipitate after being kept at -20 °C for ⁇ 3 days. The wet cake showed new crystal form by XRPD, named as Compound 1 Form E. After being kept at -20 °C for another ⁇ 9 days, XRPD results showed that sample was converted to Form C. The sample were converted to Form A after drying under atmosphere at room temperature (29 ⁇ 31 °C, 50 ⁇ 60%RH) overnight. The results indicated that Compound 1 Form E was a metastable form.
  • FIG. 5A An XRPD spectrum of Compound 1 Form E is provided in FIG. 5A.
  • XRPD overlay of Compound 1 Form B, Form C, Form D, and Form E (FIG. 5B) showed that D394-20230425-01-E0014-B1-01 batch was partially converted to Form C, and D394-20230425-01-E0014-B2-01 batch was fully converted to Form C.
  • the batches were converted to Form A after drying under atmosphere at RT (29 ⁇ 31 °C, 50 ⁇ 60%RH) overnight. The results indicated that Form E was possibly a metastable form.
  • FIG. 8 A diagram demonstrating the conversion between various crystalline solid forms of Compound 1 is shown in FIG. 8.
  • solubility of Compound 1 was estimated in common-used solvent systems at various temperatures, e.g., room temperature, 50 °C, etc. Approximately 20 mg Compound 1 was added into a HPLC glass vial. Solvents were then added stepwise into the vials until the solids were dissolved or a total volume of 2.0 mL was reached. Results indicated that:
  • the present Example demonstrated a 5g scale-up preparation of Compound 1 Form A through crystallization as described herein.
  • the present Example demonstrated that, among other things, Compound 1 Form A prepared by a method described herein showed high chemical purity, chiral purity, and low residual solvents. Furthermore, the present Example demonstrated low mother liquid loss. Still further, the present Example demonstrated that provided methods are suitable for commercial production, e.g., large scale preparation.
  • seed loading is beneficial to controllable and smooth precipitation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des formes solides cristallines du composé 1.
PCT/CN2024/095465 2024-05-27 2024-05-27 Formes solides cristallines de bloqueurs des canaux sodiques Pending WO2025245656A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2024/095465 WO2025245656A1 (fr) 2024-05-27 2024-05-27 Formes solides cristallines de bloqueurs des canaux sodiques
PCT/US2025/030962 WO2025250498A1 (fr) 2024-05-27 2025-05-27 Formes solides cristallines d'inhibiteurs des canaux sodiques

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2024/095465 WO2025245656A1 (fr) 2024-05-27 2024-05-27 Formes solides cristallines de bloqueurs des canaux sodiques

Publications (1)

Publication Number Publication Date
WO2025245656A1 true WO2025245656A1 (fr) 2025-12-04

Family

ID=96346203

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2024/095465 Pending WO2025245656A1 (fr) 2024-05-27 2024-05-27 Formes solides cristallines de bloqueurs des canaux sodiques
PCT/US2025/030962 Pending WO2025250498A1 (fr) 2024-05-27 2025-05-27 Formes solides cristallines d'inhibiteurs des canaux sodiques

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2025/030962 Pending WO2025250498A1 (fr) 2024-05-27 2025-05-27 Formes solides cristallines d'inhibiteurs des canaux sodiques

Country Status (1)

Country Link
WO (2) WO2025245656A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103547566A (zh) * 2011-02-18 2014-01-29 恩多制药公司 氨基茚满化合物及其治疗疼痛的用途
WO2014028675A1 (fr) * 2012-08-15 2014-02-20 Endo Pharmaceuticals Inc. Utilisation de composés d'aminoindane dans le traitement d'une vessie hyperactive et d'une cystopathie interstitielle sous-muqueuse

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3886827A4 (fr) 2018-11-30 2022-08-31 Asana BioSciences, LLC Formulations, méthodes, kit et formes posologiques permettant une stabilité améliorée d'un principe actif pharmaceutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103547566A (zh) * 2011-02-18 2014-01-29 恩多制药公司 氨基茚满化合物及其治疗疼痛的用途
WO2014028675A1 (fr) * 2012-08-15 2014-02-20 Endo Pharmaceuticals Inc. Utilisation de composés d'aminoindane dans le traitement d'une vessie hyperactive et d'une cystopathie interstitielle sous-muqueuse

Also Published As

Publication number Publication date
WO2025250498A1 (fr) 2025-12-04

Similar Documents

Publication Publication Date Title
US20250188054A1 (en) Crystalline forms of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2 (trifluoromethyl)isonicotinamide as raf inhibitors for the treatment of cancer
CN107400134B (zh) 嘌呤衍生物的结晶形式
KR102522895B1 (ko) Jak 키나아제 억제제 바이설페이트의 결정형 및 이의 제조방법
CN103313985A (zh) 嘧啶并[6,1-a]异喹啉-4-酮化合物的结晶型
WO2012123325A1 (fr) Nouvelles formes cristallines du sel de trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7] oxépino[4,5-c]pyrrole avec l'acide maléique
WO2021218948A1 (fr) Formes cristallines d'un composé de sulfonamide et leur procédé de préparation
EP3565819B1 (fr) Nouvelles formes solides de [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tétrahydrofuran-2-yl]propyl]acétate
CN110944979B (zh) Odm-201晶型及其制备方法和药物组合物
WO2025245656A1 (fr) Formes solides cristallines de bloqueurs des canaux sodiques
CN119053609A (zh) 一种卢比替定的晶型及其制备方法
EP4222148A1 (fr) Forme cristalline de tegavivint, son procédé de préparation et son utilisation
AU2016236659B2 (en) AHU377 crystal form, preparation method and use thereof
WO2025020171A1 (fr) Formes cristallines d'un inhibiteur de jak/syk
US20250179056A1 (en) Novel sulfate salt forms of isochroman-imidazole structured alpha-2a adrenoceptor agonist
CN103819469A (zh) 一种达沙替尼的晶型及其制备方法
US20060194833A1 (en) Crystalline 1H-imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1H-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses
CN120265614A (zh) 5-[(2,4-二硝基苯氧基)甲基]-1-甲基-2-硝基-1h-咪唑的结晶形式
JP2025186242A (ja) ６－クロロ－７－（４－（４－クロロベンジル）ピペラジン－１－イル）－２－（１，３－ジメチル－１Ｈ－ピラゾール－４－イル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジンの塩及び多形体
CN115515954A (zh) 6-氯-7-(4-(4-氯苄基)哌嗪-1-基)-2-(1,3-二甲基-1h-吡唑-4-基)-3h-咪唑并[4,5-b]吡啶的盐和多晶型形式
WO2025130951A1 (fr) Polymorphes de ad-35, leurs procédés de préparation et leur utilisation
TW202321205A (zh) Sco-101的熱力穩定形式
CN118632851A (zh) (S)-5-苄基-N-(5-甲基-4-氧代-2,3,4,5-四氢吡啶并[3,2-b][1,4]氧氮杂卓-3-基)-4H-1,2,4-三唑-3-甲酰胺的晶型
WO2023137035A1 (fr) Formes cristallines de ((s)-5-benzyl-n-(5-méthyl-4-oxo-2, 3,4,5- tétrahydropyrido [3,2-b] [l,4]oxazépin-3-yl)-4h-l,2,4-triazole-3-carboxamide
WO2023280272A1 (fr) Formes cristallines d'évobrutinib et son sel, procédé de préparation correspondant et utilisation associée
KR20210122140A (ko) (-)-시벤졸린 숙신산염의 결정다형