Solid forms of an NLRP3 inhibitor and uses thereof

Abstract

The present disclosure relates to crystalline forms of Compound 1 freebase. The present disclosure also relates to processes for the preparation of the crystalline forms, compositions comprising the crystalline forms, and uses thereof, e.g., in the treatment and prevention of disorders in which NLRP3 activity is implicated.

Description

SOLID FORMS OF AN NLRP3 INHIBITOR AND USES THEREOFRELATED APPLICATION

[0001] This application claims priority to, and the benefit of, International Application PCT / CN2023 / 118568, filed September 13, 2023, the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] Innate immune responses are mediated by different types of receptors termed patternrecognition receptors (PRRs). PRRs recognize the presence of pathogen -associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once engaged these receptors trigger the activation of downstream inflammatory pathways that will help resolve injury. However, in many instances this activation can be uncontrolled and leads to disease.

[0003] The inflammasomes represent a class of PRRs that are crucial components of the innate immune response. Activation of the inflammasomes trigger a cascade of events that releases IL- 1 (3, IL- 18, and promotes an inflammatory form of cell death called pyroptosis induced by the activation of Gasdermin. Pyroptosis is a unique form of inflammatory cell death that leads to the release of not only cytokines but also other intracellular components that promote a broader immune response both of the innate and acquired immune system. Thus, inflammasome activation is a major regulatory of the inflammatory cascade.

[0004] NLRP3 is the most characterized inflammasome and has been shown to be critical in innate immunity and inflammatory responses. While several other NLR complexes, such as NLRC4, are activated under very specific circumstances, NLRP3 can be activated by numerous stimuli and should be seen as a sensor of intracellular homeostatic imbalance. Therefore, its precise functioning is essential. In addition to playing a role in host immune defense, dysregulation of NLRP3 has been linked to the pathogenesis of many inflammatory disorders. These include genetic diseases such as cryopyrin-associated periodic syndromes (CAPS) which is caused by gain-of-fimction mutations in the NLRP3 gene, as well as many prevalent neurologic and systemic diseases. Importantly, NLRP3 hyperactivation has been demonstrated pre-clinically to play a critical role in a plethora of inflammatory and degenerative diseases including, Non-Alcoholic Steatohepatitis (NASH), atherosclerosis and other cardiovascular diseases, Alzheimer’s disease, Parkinson’s disease, diabetes, gout, and numerous other autoinflammatory diseases. See, e.g., Li et al., European Journal of Pharmacology (2022) 928: 175091; Nguyen et al., Journal of Parkinson ’s Disease (2022) 72:2117- 2133; Su et al., Current Medicinal Chemistry (2021) 25:569-582; Zahid et al., Frontiers in Immunology (2019) 10:2538.SUMMARY

[0005] The present disclosure provides crystalline forms of Compound 1 freebase.

[0006] “Compound 1” is (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin- l-yl)-5 -methylphenol, also referred to herein as 5-methyl-2-[4-[[(3R)-5,5-dimethyltetrahydrofuran-3- yl]amino]pyrido[3,4-d]pyridazin-l-yl]phenol, having the structure:Compound 1

[0007] Compound 1 is an orally bioavailable, central nervous system (CNS) penetrant, potent and reversible small molecule inhibitor of NLRP3 being developed to treat neuroinflammatory and neurodegenerative diseases. Compound 1 is described in U.S. 11,618,751 and International Application No. PCT / US2023 / 064967, published as WO 2023 / 183943.

[0008] In some embodiments, the crystalline form of Compound 1 freebase is crystalline Form I freebase.

[0009] In some embodiments, the crystalline form of Compound 1 freebase is crystalline Form II freebase.

[0010] In some embodiments, the crystalline form of Compound 1 freebase is crystalline Form III freebase.

[0011] In some embodiments, provided is a composition comprising a mixture of Compound 1 freebase forms, wherein 75% (w / w%) of the mixture is crystalline Form I freebase. In some embodiments, the composition is a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0012] In some aspects, the present disclosure provides a pharmaceutical composition comprising a crystalline form of Compound 1 freebase, as described herein, and one or more pharmaceutically acceptable carriers.

[0013] In other aspects, provided is a method of treating or preventing a disease or disorder, the method comprising administering to a subject a form as described herein, or a composition as described herein.

[0014] In yet other aspect, the present disclosure provides a method of preparing a crystalline form of Compound 1 freebase.BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1A depicts (i) XRPD of Form I / II Freebase mixture, (ii) converting to Form I after post- competitive slurry experiments, and (iii) converting to Form I post-DVS.

[0016] FIG. IB depicts the identification of Form II Freebase by XRPD peak picks in the Form I / II Freebase mixture.

[0017] FIG. 1C depicts the TGA and DSC of Form I / II Freebase mixture.

[0018] FIG. 2A depicts the XRPD of Form I Freebase.

[0019] FIG. 2B depicts the TGA of Form I Freebase.

[0020] FIG. 2C depicts the DSC of Form I Freebase.

[0021] FIG. 2D depicts the PLM Image of Single Crystals of Form I Freebase.

[0022] FIG. 2E depicts the Experimental versus Simulated XRPD of Form I Freebase.

[0023] FIG. 2F depicts the Crystalline Packing of Form I Freebase (as viewed down the a axis).

[0024] FIG. 2G depicts the Crystalline Packing of Form I Freebase (as viewed down the b axis).

[0025] FIG. 2H depicts the Crystalline Packing of Form I Freebase (as viewed down the c axis).

[0026] FIG. 3A depicts the XRPD of Form III Freebase.

[0027] FIG. 3B depicts the DSC of Form III Freebase.DEFINITIONS

[0028] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0029] Terms of degree such as “about,” “substantially similar,” and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0030] “Morphic purity level” refers to a determination by solid-state NMR (ssNMR), vibrational (Raman) spectroscopy and / or X-ray Powder Diffraction (XRPD) of a given form’s purity percentage level (w / w%) relative to other known solid-state forms (e.g., crystalline forms, amorphous forms) of the same compound. See, for example, Mingyue et al., TrAC Trends in Analytical Chemistry (2021) 135: 116152 (ss NMR); Griffen et al., Journal of Pharmaceutical and Biomedical Analysis, (2016) 128:35-45 (Raman); and Dobelin, Powder Diffraction (2020) 35(4), 262-275 (XRPD), for methods describing determining purity levels. A “morphic purity level” of 95% or greater is considered “substantially free” of other known solid state forms of the same compound.

[0031] ‘ ‘Pure-phase” refers to a qualitative assessment by XRPD of a given form, using Cu K alpha radiation when measured at 25 °C, wherein characteristic non-overlapping signals associated with the other crystalline forms of that same compound are not observed by XRPD. A “morphic purity level” of 100% of a given form as determined by XRPD, using Cu K alpha radiation when measured at 25 °C, and “pure-phase” form of that given form are used interchangeably herein.

[0032] The term “stable” refers to a given form that maintains its form over a period of time, e.g., at least 3 months under long term and / or accelerated stability study conditions.

[0033] A “patient” or “subject” is used interchangeably herein, and refers to a mammal, e.g., ahuman, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. In some embodiments, the patient or subject is human.

[0034] ‘ ‘Effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a crystalline form of Compound 1 freebase sufficient to provide a therapeutic benefit in the treatment of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder in a subject in need thereof. An effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent. The effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0035] ‘ ‘Disease” or “disorder” are used interchangeably herein.

[0036] “Treating,” “treat,” or “treatment” describes the management and care of a subject in need thereof, for the purpose of combating a disease or disorder in the subject, and includes the administration of a crystalline form of Compound 1 freebase, as described herein, to alleviate the symptoms or complications of a disease or disorder, or to eliminate the disease or disorder. The term “treat” can also include treatment of a cell in vitro or treatment of an animal model (in vivo). It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a disease or disorder in a subject in need thereof, and therefore includes: (1) delaying the appearance of at least one clinical or subclinical symptom of the disease or disorder developing in a subject that is afflicted with the disease or disorder, (2) arresting, reducing or delaying the continued development of the disease or a relapse thereof in a subject (e.g. , in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease in a subject, z.e., causing regression of the disease or disorder or at least one of its clinical or subclinical symptoms.

[0037] As used herein, the term “preventing,” “prevent,” or “protecting against” describes the management and care of a subject in need thereof that may have or has a predisposition for the disease or disorder but has not yet experienced or displayed clinical or subclinical symptoms of the disease or disorder, for the purpose of preventing the appearance of at least one clinical or subclinical symptom of the disease or disorder in the subject, and includes the administration of a crystalline form of Compound 1 freebase, as described herein.

[0038] ‘ ‘Inhibition,” “inhibiting,” “inhibit,” and “inhibitor”, and the like, refer to the ability of a crystalline form of Compound 1 freebase, to reduce, slow, halt or prevent activity of a particular biological process (e.g., NLRP3 activity) in a cell relative to vehicle.

[0039] The phrase “at least one” refers to one instance or more than one instance.

[0040] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article.

[0041] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0042] The term “freebase” of Compound 1 refers to a neutral non-ionized form of the compound. It is understood that a freebase is not a salt.

[0043] The term “solvate” of Compound 1 refers to a crystalline form with at least one stoichiometric or non-stoichiometric amount of a solvent (non-water molecule) as a part of the unit cell within the crystalline lattice. Being “not-solvated” and being not a “solvate” are used interchangeably herein.

[0044] “Slightly hygroscopic” means an increase in mass wt.% from > 0.2 to < 2 wt.%, and “hygroscopic” means an increase in mass wt.% of > 2 wt.% to < 15%, each related to an increase in water content as determined by Dynamic Vapor Sorption (DVS). “Deliquescent” means sufficient water is absorbed to form a liquid. A mass wt.% of < 0.2 is considered “non -hygroscopic.”DETAILED DESCRIPTION OF SOME EMBODIMENTS(i) Compound 1 Freebase

[0045] “Compound 1” refers to a compound with the structure shown below:(Compound 1), also referred to herein as (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin- l-yl)-5 -methylphenol or 5-methyl-2-[4-[[(3R)-5,5-dimethyltetrahydrofuran-3-yl]amino]pyrido[3,4- d]pyridazin-l-yl]phenol. Compound 1 is described in U.S. 11,618,751 and International Application No. PCT / US2023 / 064967, published as WO 2023 / 183943.

[0046] The present disclosure provides crystalline forms of Compound 1 freebase.

[0047] In some embodiments, the crystalline form of Compound 1 freebase is crystalline Form I freebase.

[0048] In some embodiments, the crystalline form of Compound 1 freebase is crystalline Form II freebase.

[0049] In some embodiments, the crystalline form of Compound 1 freebase is crystalline Form III freebase.

[0050] In some embodiments, the crystalline form is isolated as a stable form.

[0051] In some embodiments, the crystalline form is isolated as a pure-phase crystalline form. a. X-Ray Powder Diffraction (XRPD) Characterizations

[0052] In some embodiments, the crystalline form of Compound 1 freebase is characterized by anXRPD pattern comprising a signal at 22.9±0.2 °20, using Cu K alpha radiation when measured at 25

[0053] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising a signal at 8.6±0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0054] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 17.3±0.5, and 22.9±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, and 22.9±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, and 22.9±0.1 °20 (e.g., 8.6, 17.3, and 22.9 °20))), using Cu K alpha radiation when measured at 25 °C.

[0055] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 17.3±0.5, 19.1±0.5, and 22.9±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, 19.H0.2, and 22.9±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, 19.1±0.1, and 22.9±0.1 °20 (e.g., 8.6, 17.3, 19.1, and 22.9 °20))), using Cu K alpha radiation when measured at 25 °C.

[0056] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 17.3±0.5, 19.1±0.5, 22.9±0.5, and 23.7±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, 19.1±0.2, 22.9±0.2, and 23.7±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, and 23.7±0.1 °20 (e.g., 8.6, 17.3, 19.1, 22.9, and 23.7 °20))), using Cu K alpha radiation when measured at 25 °C.

[0057] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 16.7±0.5, 17.3±0.5, 19.1±0.5, 22.9±0.5, and 23.7±0.5 °20 (e.g., 8.6±0.2, 16.7±0.2, 17.3±0.2, 19.1±0.2, 22.9±0.2, and 23.7±0.2 °20 (e.g., 8.6±0.1, 16.7±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, and 23.7±0.1 °20 (e.g., 8.6, 16.7, 17.3, 19.1, 22.9, and 23.7 °20))), using Cu K alpha radiation when measured at 25 °C.

[0058] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 16.7±0.5, 17.3±0.5, 19.1±0.5, 22.9±0.5, 23.7±0.5, and 27.3±0.5 °20 (e.g., 8.6±0.2, 16.7±0.2, 17.3±0.2, 19.1±0.2, 22.9±0.2, 23.7±0.2, and 27.3±0.2 °20 (e.g., 8.6±0.1, 16.7±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, 23.7±0.1, and 27.3±0.1 °20 (e.g., 8.6, 16.7, 17.3, 19.1, 22.9, 23.7, and 27.3 °20))), using Cu K alpha radiation when measured at 25 °C.

[0059] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 16.7±0.5, 17.3±0.5, 19.1±0.5, 22.9±0.5, 23.7±0.5, 27.3±0.5, and 30.8±0.5 °20 (e.g., 8.6±0.2, 16.7±0.2, 17.3±0.2, 19.1±0.2, 22.9±0.2, 23.7±0.2, 27.3±0.2, and 30.8±0.2 °20 (e.g., 8.6±0.1, 16.7±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, 23.7±0.1, 27.3±0.1, and 30.8±0.1 °20 (e.g., 8.6, 16.7, 17.3, 19.1, 22.9, 23.7, 27.3, and 30.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0060] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 16.7±0.5, 17.3±0.5, 19.1±0.5, 21.9±0.5, 22.9±0.5, 23.7±0.5, 27.3±0.5, and 30.8±0.5 °20 (e.g., 8.6±0.2, 16.7±0.2, 17.3±0.2, 19.U0.2, 21.9±0.2, 22.9±0.2, 23.7±0.2, 27.3±0.2, and 30.8±0.2 °20 (e.g., 8.6±0.1, 16.7±0.1, 17.3±0.1, 19.1±0.1, 21.9±0.1, 22.9±0.1, 23.7±0.1, 27.3±0.1, and 30.8±0.1 °20 (e.g., 8.6, 16.7, 17.3, 19.1, 21.9, 22.9, 23.7,27.3, and 30.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0061] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 17.3±0.5, 19.1±0.5, 22.9±0.5, 23.7±0.5, and 27.3±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, 19.1±0.2, 22.9±0.2, 23.7±0.2, and 27.3±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, 23.7±0.1, and 27.3±0.1 °20 (e.g, 8.6, 17.3, 19.1, 22.9, 23.7, and 27.3 °20))), using Cu K alpha radiation when measured at 25 °C.

[0062] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 17.3±0.5, 19.1±0.5, 22.9±0.5, 23.7±0.5, 27.3±0.5, and 30.8±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, 19.1±0.2, 22.9±0.2, 23.7±0.2, 27.3±0.2, and 30.8±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, 23.7±0.1, 27.3±0.1, and 30.8±0.1 °20 (e.g., 8.6, 17.3, 19.1, 22.9, 23.7, 27.3, and 30.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0063] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 17.3±0.5, 19.1±0.5, 21.9±0.5, 22.9±0.5, 23.7±0.5, 27.3±0.5, and 30.8±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, 19.1±0.2, 21.9±0.2, 22.9±0.2, 23.7±0.2, 27.3±0.2, and 30.8±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, 19.1±0.1, 21.9±0.1, 22.9±0.1, 23.7±0.1, 27.3±0.1, and 30.8±0.1 °20 (e.g., 8.6, 17.3, 19.1, 21.9, 22.9, 23.7, 27.3, and 30.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0064] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern comprising signals at 8.6±0.5, 16.7±0.5, 17.3±0.5, 19.1±0.5, 21.9±0.5, 22.9±0.5, 23.7±0.5, 27.3±0.5, and 30.8±0.5 °20 (e.g., 8.6±0.2, 16.7±0.2, 17.3±0.2, 19.U0.2, 21.9±0.2, 22.9±0.2, 23.7±0.2, 27.3±0.2, and 30.8±0.2 °20 (e.g., 8.6±0.1, 16.7±0.1, 17.3±0.1, 19.1±0.1, 21.9±0.1, 22.9±0.1, 23.7±0.1, 27.3±0.1, and 30.8±0.1 °20 (e.g., 8.6, 16.7, 17.3, 19.1, 21.9, 22.9, 23.7, 27.3, and 30.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0065] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern having at least one signal selected from 8.6±0.5, 17.3±0.5, and 22.9±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, and 22.9±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, and 22.9±0.1 °20 (e.g., 8.6, 17.3, and 22.9 °20))), using Cu K alpha radiation when measured at 25 °C.

[0066] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern having at least two signal selected from 8.6±0.5, 17.3±0.5, and 22.9±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, and 22.9±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, and 22.9±0.1 °20 (e.g., 8.6, 17.3, and 22.9 °20))), using Cu K alpha radiation when measured at 25 °C.

[0067] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern having at least three signals selected from 8.6±0.5, 17.3±0.5, 19.1±0.5 , and 22.9±0.5 °20 (e.g., 8.6±0.2, 17.3±0.2, 19.1±0.2, and 22.9±0.2 °20 (e.g., 8.6±0.1, 17.3±0.1, 19.1±0.1, and 22.9±0.1 °20 (e.g., 8.6, 17.3, 19.1, and 22.9 °20))), using Cu K alpha radiation when measured at 25 °C.

[0068] In some embodiments, the crystalline form of Compound 1 freebase is characterized by anXRPD patern having at least four signals selected from 8.6±0.5, 17.3±0.5, 19.1 ±0.5, 22.9±0.5, and 23.7±0.5 °29 (e.g., 8.6±0.2, 17.3±0.2, 19. l±0.2, 22.9±0.2, and 23.7±0.2 °29 (e.g., 8.6±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, and 23.7±0.1 °29 (e.g., 8.6, 17.3, 19.1, 22.9, and 23.7 °29))), using Cu K alpha radiation when measured at 25 °C.

[0069] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern having at least five signals selected from 8.6±0.5, 16.7±0.5, 17.3±0.5, 19. l±0.5, 22.9±0.5, and 23.7±0.5 °29 (e.g., 8.6±0.2, 16.7±0.2, 17.3±0.2, 19. l±0.2, 22.9±0.2, and 23.7±0.2 °29 (e.g., 8.6±0.1, 16.7±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, and 23.7±0.1 °29 (e.g., 8.6, 16.7, 17.3, 19.1, 22.9, and 23.7 °29))), using Cu K alpha radiation when measured at 25 °C.

[0070] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern having at least five signals selected from 8.6±0.5, 17.3±0.5, 19. l±0.5, 22.9±0.5, 23.7±0.5, and 27.3±0.5 °29 (e.g., 8.6±0.2, 17.3±0.2, 19. l±0.2, 22.9±0.2, 23.7±0.2, and 27.3±0.2 °29 (e.g., 8.6±0.1, 17.3±0.1, 19.1±0.1, 22.9±0.1, 23.7±0.1, and 27.3±0.1 °29 (e.g., 8.6, 17.3, 19.1, 22.9, 23.7, and 27.3 °29))), using Cu K alpha radiation when measured at 25 °C.

[0071] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern having at least one X-ray powder diffraction signal at 11.4 ± 0.5, 11.8 ± 0.5, 12.2 ± 0.2,14.7 ± 0.5, 16.2 ± 0.5, 16.4 ± 0.5, 18.1 ± 0.5, 18.3 ± 0.5, 18.6 ± 0.5, 20.3 ± 0.5, 24.4 ± 0.5, 24.7 ± 0.5,25.1 ± 0.5, 25.9 ± 0.5, 26.1 ± 0.5, 26.4 ± 0.5, 28.6 ± 0.5, 28.9 ± 0.5, 29.3 ± 0.5, 29.5 ± 0.5, 30.0 ± 0.5,31.6 ± 0.5, 32.6 ± 0.5, 32.8 ± 0.5, 33.3 ± 0.5, 33.8 ± 0.5, 34.0 ± 0.5, 34.8 ± 0.5, 35.2 ± 0.5, 36.2 ± 0.5,36.7 ± 0.2, 37.3 ± 0.5, 38.1 ± 0.2, 38.7 ± 0.5, or 39.4 ± 0.5, using Cu K alpha radiation when measured at 25 °C.

[0072] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern having at least one X-ray powder diffraction signal at 11.4 ± 0.2, 11.8 ± 0.2, 12.2 ± 0.2,14.7 ± 0.2, 16.2 ± 0.2, 16.4 ± 0.2, 18.1 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 20.3 ± 0.2, 24.4 ± 0.2, 24.7 ± 0.2,25.1 ± 0.2, 25.9 ± 0.2, 26.1 ± 0.2, 26.4 ± 0.2, 28.6 ± 0.2, 28.9 ± 0.2, 29.3 ± 0.2, 29.5 ± 0.2, 30.0 ± 0.2,31.6 ± 0.2, 32.6 ± 0.2, 32.8 ± 0.2, 33.3 ± 0.2, 33.8 ± 0.2, 34.0 ± 0.2, 34.8 ± 0.2, 35.2 ± 0.2, 36.2 ± 0.2,36.7 ± 0.2, 37.3 ± 0.2, 38.1 ± 0.2, 38.7 ± 0.2, or 39.4 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0073] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern that does not have an X-ray powder diffraction signal at 6.6±0.5 °29 (e.g., 6.6±0.2 °29 (e.g., 6.6±0.1 °29 (e.g., 6.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0074] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern that does not have an X-ray powder diffraction signal at 13.9±0.5 °29 (e.g., 13.9±0.2 °29 (e.g., 13 ,9±0.1 °29 (e.g., 13.9 °29))), using Cu K alpha radiation when measured at 25 °C.

[0075] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern comprising one or more signals as described in Table 1 below.

[0076] In some embodiments, the crystalline form of Compound 1 freebase is characterized by anXRPD patern comprising two or more signals as described in Table 1 below.

[0077] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern comprising three or more signals as described in Table 1 below.

[0078] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern comprising four or more signals as described in Table 1 below.*The values shown in the above table are approximate value and subject to instrument differentiation and standard error.

[0079] In some embodiments, the crystalline Compound 1 freebase is characterized by the XRPD signals 1-44 as set forth in Table 1. In some embodiments, the crystalline form of Compound 1 so characterized is crystalline Form I freebase.

[0080] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD patern substantially similar to that set forth in FIG. 2A. In some embodiments, the crystalline form of Compound 1 so characterized is Form I freebase.

[0081] In some embodiments, Form I freebase is pure-phase Form I freebase.

[0082] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD patern comprising a signal at 6.6±0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0083] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 6.6±0.5, 8.3±0.5, and 12.3±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, and 12.3±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, and 12.3±0.1 °20 (e.g., 6.6, 8.3, and 12.3 °20))), using Cu K alpha radiation when measured at 25 °C.

[0084] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 6.6±0.5, 8.3±0.5, 12.3±0.5, and 21.8±0.5 °20 (e.g, 6.6±0.2, 8.3±0.2, 12.3±0.2, and 21.8±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, and 21.8±0.1 °20 (e.g., 6.6, 8.3, 12.3, and 21.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0085] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 6.6±0.5, 8.3±0.5, 12.3±0.5, 20.9±0.5, and 21.8±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, 12.3±0.2, 20.9±0.2, and 21.8±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, 20.9±0.1, and 21.8±0.1 °20 (e.g., 6.6, 8.3, 12.3, 20.9, and 21.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0086] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 6.6±0.5, 8.3±0.5, 12.3±0.5, and 18.7±0.5 °20 (e.g, 6.6±0.2, 8.3±0.2, 12.3±0.2, and 18.7±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, and 18.7±0.1 °20 (e.g., 6.6, 8.3, 12.3, and 18.7 °20))), using Cu K alpha radiation when measured at 25 °C.

[0087] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 6.6±0.5, 8.3±0.5, 12.3±0.5, 18.7±0.5, and 21.8±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, 12.3±0.2, 18.7±0.2, and 21.8±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, 18.7±0.1, and 21.8±0.1 °20 (e.g., 6.6, 8.3, 12.3, 18.7, and 21.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0088] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 6.6±0.5, 8.3±0.5, 12.3±0.5, 18.7±0.5, 20.9±0.5, and 21.8±0.5 °20 (e.g, 6.6±0.2, 8.3±0.2, 12.3±0.2, 18.7±0.2, 20.9±0.2, and 21.8±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, 18.7±0.1, 20.9±0.1, and 21.8±0.1 °20 (e.g., 6.6, 8.3, 12.3, 18.7, 20.9, and 21.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0089] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one signal selected from 6.6±0.5, 8.3±0.5, and 12.3±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, and 12.3±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, and 12.3±0.1 °20 (e.g., 6.6, 8.3, and 12.3 °20))), using Cu K alpha radiation when measured at 25 °C.

[0090] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least two signal selected from 6.6±0.5, 8.3±0.5, and 12.3±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, and 12.3±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, and 12.3±0.1 °20 (e.g., 6.6, 8.3, and 12.3 °20))), using Cu K alpha radiation when measured at 25 °C.

[0091] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least three signals selected from 6.6±0.5, 8.3±0.5, 12.3±0.5, and 21.8±0.5 °20 (e.g.,6.6±0.2, 8.3±0.2, 12.3±0.2, and 21.8±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, and 21.8±0.1 °20 (e.g., 6.6, 8.3, 12.3, and 21.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0092] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least four signals selected from 6.6±0.5, 8.3±0.5, 12.3±0.5, 20.9±0.5, and 21.8±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, 12.3±0.2, 20.9±0.2, and 21.8±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, 20.9±0.1, and 21.8±0.1 °20 (e.g., 6.6, 8.3, 12.3, 20.9, and 21.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0093] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least three signals selected from 6.6±0.5, 8.3±0.5, 12.3±0.5, and 18.7±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, 12.3±0.2, and 18.7±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, and 18.7±0.1 °20 (e.g., 6.6, 8.3, 12.3, and 18.7 °20))), using Cu K alpha radiation when measured at 25 °C.

[0094] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least four signals selected from 6.6±0.5, 8.3±0.5, 12.3±0.5, 18.7±0.5, and 21.8±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, 12.3±0.2, 18.7±0.2, and 21.8±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, 18.7±0.1, and 21.8±0.1 °20 (e.g., 6.6, 8.3, 12.3, 18.7, and 21.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0095] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least five signals selected from 6.6±0.5, 8.3±0.5, 12.3±0.5, 18.7±0.5, 20.9±0.5, and 21.8±0.5 °20 (e.g., 6.6±0.2, 8.3±0.2, 12.3±0.2, 18.7±0.2, 20.9±0.2, and 21.8±0.2 °20 (e.g., 6.6±0.1, 8.3±0.1, 12.3±0.1, 18.7±0.1, 20.9±0.1, and 21.8±0.1 °20 (e.g., 6.6, 8.3, 12.3, 18.7, 20.9, and 21.8 °20))), using Cu K alpha radiation when measured at 25 °C.

[0096] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.2 ± 0.5, 7. 1 ± 0.5, 7.8 ± 0.5, 8.6 ± 0.5, 9.9 ± 0.5, 10.1 ± 0.5, 11.1 ± 0.5, 11.6 ± 0.5, 11.8 ± 0.5, 12.7 ± 0.5, 13.2 ± 0.5, 13.5 ± 0.5, 13.8 ± 0.5, 14.1 ± 0.5, 14.4 ± 0.5, 14.7 ± 0.5, 15.3 ± 0.5, 15.5 ± 0.5, 16.2 ± 0.5, 16.7 ± 0.5, 17.0 ± 0.5, 17.3 ± 0.5,17.7 ± 0.5, 17.9 ± 0.5, 18.1 ± 0.5, 18.7 ± 0.5, 19.1 ± 0.5, 19.5 ± 0.5, 19.8 ± 0.5, 20.2 ± 0.5, 20.9 ± 0.5,21.8 ± 0.5, 22.3 ± 0.5, 22.6 ± 0.5, 23.3 ± 0.5, 23.8 ± 0.5, 24.0 ± 0.5, 24.4 ± 0.5, 24.7 ± 0.5, 25.2 ± 0.5,25.8 ± 0.5, 26.5 ± 0.5, 26.9 ± 0.5, 27.0 ± 0.5, 28.0 ± 0.5, 28.5 ± 0.5, 28.8 ± 0.5, 29.7 ± 0.5, 30.5 ± 0.5,30.8 ± 0.5, 31.1 ± 0.5, 35.0 ± 0.5, 36.2 ± 0.5, 37.4 ± 0.5, 37.6 ± 0.5, 38.1 ± 0.5, 39.2 ± 0.5, or 39.5 ± 0.5, using Cu K alpha radiation when measured at 25 °C.

[0097] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.2 ± 0.2, 7. 1 ± 0.2, 7.8 ± 0.2, 8.6 ± 0.2, 9.9 ± 0.2, 10.1 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 11.8 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 13.5 ± 0.2, 13.8 ± 0.2, 14.1 ± 0.2, 14.4 ± 0.2, 14.7 ± 0.2, 15.3 ± 0.2, 15.5 ± 0.2, 16.2 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 17.3 ± 0.2,17.7 ± 0.2, 17.9 ± 0.2, 18.1 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.2 ± 0.2, 20.9 ± 0.2,21.8 ± 0.2, 22.3 ± 0.2, 22.6 ± 0.2, 23.3 ± 0.2, 23.8 ± 0.2, 24.0 ± 0.2, 24.4 ± 0.2, 24.7 ± 0.2, 25.2 ± 0.2,25.8 ± 0.2, 26.5 ± 0.2, 26.9 ± 0.2, 27.0 ± 0.2, 28.0 ± 0.2, 28.5 ± 0.2, 28.8 ± 0.2, 29.7 ± 0.2, 30.5 ± 0.2,30.8 ± 0.2, 31.1 ± 0.2, 35.0 ± 0.2, 36.2 ± 0.2, 37.4 ± 0.2, 37.6 ± 0.2, 38.1 ± 0.2, 39.2 ± 0.2, or 39.5 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0098] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.2 ± 0.5, 7. 1 ± 0.5, 7.8 ± 0.5, 8.6 ± 0.5, 9.9 ± 0.5, 10.1 ± 0.5, 11.1 ± 0.5, 11.6 ± 0.5, 11.8 ± 0.5, 12.7 ± 0.5, 13.2 ± 0.5, 13.5 ± 0.5, 13.9 ± 0.5, 14.1 ± 0.5, 14.4 ± 0.5, 14.7 ± 0.5, 15.3 ± 0.5, 15.5 ± 0.5, 16.2 ± 0.5, 16.7 ± 0.5, 17.0 ± 0.5, 17.3 ± 0.5,17.7 ± 0.5, 17.9 ± 0.5, 18.1 ± 0.5, 18.7 ± 0.5, 19.1 ± 0.5, 19.5 ± 0.5, 19.8 ± 0.5, 20.2 ± 0.5, 20.9 ± 0.5,21.8 ± 0.5, 22.3 ± 0.5, 22.6 ± 0.5, 23.3 ± 0.5, 23.8 ± 0.5, 24.0 ± 0.5, 24.4 ± 0.5, 24.7 ± 0.5, 25.2 ± 0.5,25.8 ± 0.5, 26.5 ± 0.5, 26.9 ± 0.5, 27.0 ± 0.5, 28.0 ± 0.5, 28.5 ± 0.5, 28.8 ± 0.5, 29.7 ± 0.5, 30.5 ± 0.5,30.8 ± 0.5, 31.1 ± 0.5, 35.0 ± 0.5, 36.2 ± 0.5, 37.4 ± 0.5, 37.6 ± 0.5, 38.1 ± 0.5, 39.2 ± 0.5, or 39.5 ± 0.5, using Cu K alpha radiation when measured at 25 °C.

[0099] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.2 ± 0.2, 7. 1 ± 0.2, 7.8 ± 0.2, 8.6 ± 0.2, 9.9 ± 0.2, 10.1 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 11.8 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 13.5 ± 0.2, 13.9 ± 0.2, 14.1 ± 0.2, 14.4 ± 0.2, 14.7 ± 0.2, 15.3 ± 0.2, 15.5 ± 0.2, 16.2 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 17.3 ± 0.2,17.7 ± 0.2, 17.9 ± 0.2, 18.1 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.2 ± 0.2, 20.9 ± 0.2,21.8 ± 0.2, 22.3 ± 0.2, 22.6 ± 0.2, 23.3 ± 0.2, 23.8 ± 0.2, 24.0 ± 0.2, 24.4 ± 0.2, 24.7 ± 0.2, 25.2 ± 0.2,25.8 ± 0.2, 26.5 ± 0.2, 26.9 ± 0.2, 27.0 ± 0.2, 28.0 ± 0.2, 28.5 ± 0.2, 28.8 ± 0.2, 29.7 ± 0.2, 30.5 ± 0.2,30.8 ± 0.2, 31.1 ± 0.2, 35.0 ± 0.2, 36.2 ± 0.2, 37.4 ± 0.2, 37.6 ± 0.2, 38.1 ± 0.2, 39.2 ± 0.2, or 39.5 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0100] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern that does not have an X-ray powder diffraction signal at 22.9±0.2 °20 (e.g., 22.9±0. 1 °20 (e.g., 22.9 °20))), using Cu K alpha radiation when measured at 25 °C.

[0101] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern that does not have an X-ray powder diffraction signal at 13.9 °20, using Cu K alpha radiation when measured at 25 °C.

[0102] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern that does not have an X-ray powder diffraction signal at 15 ,7±0.1 °20 (e.g., 15.7 °20), using Cu K alpha radiation when measured at 25 °C.

[0103] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising one or more signals as described in Table 2 below.

[0104] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising two or more signals as described in Table 2 below.

[0105] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising three or more signals as described in Table 2 below.

[0106] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising four or more signals as described in Table 2 below.*The values shown in the above table are approximate value and subject to instrument differentiation and standard error.

[0107] In some embodiments, the crystalline Compound 1 freebase is characterized by the XRPD signals 1-61 as set forth in Table 2. In some embodiments, the crystalline form of Compound 1 so characterized is crystalline Form III freebase.

[0108] In some embodiments, the crystalline Compound 1 freebase is Form III, which is characterized by an XRPD pattern substantially similar to that set forth in FIG. 3A. In some embodiments, the crystalline form of Compound 1 so characterized is Form III freebase.

[0109] In some embodiments, the Form III freebase is pure-phase Form III freebase.

[0110] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising a signal at 6.6±0.2 °20, using Cu K alpha radiation when measured at 25 °C.[oni] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising a signal at 7.2±0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0112] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 7.2±0.5, 13.9±0.5, and 15.7±0.5 °20 (e.g., 7.2±0.2, 13.9±0.2, and 15.7±0.2 °20 (e.g., 7.2±0.1, 13.9±0.1, and 15.7±0.1 °20 (e.g., 7.2, 13.9, and 15.7 °20))), using Cu K alpha radiation when measured at 25 °C.

[0113] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 7.2±0.5, 13.9±0.5, 15.7±0.5, and 19.6±0.5 °20 (e.g., 7.2±0.2, 13.9±0.2, 15.7±0.2, and 19.6±0.2 °20 (e.g., 7.2±0.1, 13.9±0.1, 15.7±0.1, and 19.6±0.1 °20 (e.g., 7.2, 13.9, 15.7, and 19.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0114] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 7.2±0.5, 10.3±0.5, 13.9±0.5, 15.7±0.5, and 19.6±0.5 °20 (e.g., 7.2±0.2, 10.3±0.2, 13.9±0.2, 15.7±0.2, and 19.6±0.2 °20 (e.g., 7.2±0.1, 10.3±0.1, 13.9±0.1, 15.7±0.1, and 19.6±0.1 °20 (e.g., 7.2, 10.3, 13.9, 15.7, and 19.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0115] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 7.2±0.5, 10.3±0.5, 13.9±0.5, 15.5±0.5, 15.7±0.5, and 19.6±0.5 °20 (e.g., 7.2±0.2, 10.3±0.2, 13.9±0.2, 15.5±0.2, 15.7±0.2, and 19.6±0.2 °20 (e.g., 7.2±0.1, 10.3±0.1, 13.9±0.1, 15.5±0.1, 15.7±0.1, and 19.6±0.1 °20 (e.g., 7.2, 10.3, 13.9, 15.5, 15.7, and 19.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0116] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising signals at 7.2±0.5, 7.8±0.5, 10.3±0.5, 13.9±0.5, 15.7±0.5, and 19.6±0.5 °20 (e.g, 7.2±0.2, 7.8±0.2, 10.3±0.2, 13.9±0.2, 15.7±0.2, and 19.6±0.2 °20 (e.g., 7.2±0.1, 7.8±0.1, 10.3±0.1, 13.9±0.1, 15.7±0.1, and 19.6±0.1 °20 (e.g., 7.2, 7.8, 10.3, 13.9, 15.7, and 19.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0117] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one signal selected from 7.2±0.5, 13.9±0.5, and 15.7±0.5 °20 (e.g., 7.2±0.2, 13.9±0.2, and 15.7±0.2 °20 (e.g., 7.2±0.1, 13.9±0.1, and 15.7±0.1 °20 (e.g., 7.2, 13.9, and 15.7 °20))), using Cu K alpha radiation when measured at 25 °C.

[0118] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least two signal selected from 7.2±0.5, 13.9±0.5, and 15.7±0.5 °20 (e.g., 7.2±0.2, 13.9±0.2, and 15.7±0.2 °20 (e.g., 7.2±0.1, 13.9±0.1, and 15.7±0.1 °20 (e.g., 12, 13.9, and 15.7 °20))), using Cu K alpha radiation when measured at 25 °C.

[0119] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least three signals selected from 7.2±0.5, 13.9±0.5, 15.7±0.5 , and 19.6±0.5 °20(e.g., 7.2±0.2, I3.9±0.2, 15.7±0.2, and 19.6±0.2 °20 (e.g., 7.2±0.1, 13.9±0.1, 15.7±0.1, and 19.6±0.1 °20 (e.g., 7.2, 13.9, 15.7, and 19.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0120] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least four signals selected from 7.2±0.5, 10.3±0.5, 13.9±0.5, 15.7±0.5, and 19.6±0.5 °20 (e.g., 7.2±0.2, 10.3±0.2, 13.9±0.2, 15.7±0.2, and 19.6±0.2 °20 (e.g., 7.2±0.1, 10.3±0.1, 13.9±0.1, 15.7±0.1, and 19.6±0.1 °20 (e.g., 7.2, 10.3, 13.9, 15.7, and 19.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0121] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least five signals selected from 7.2±0.5, 10.3±0.5, 13.9±0.5, 15.5±0.5, 15.7±0.5, and 19.6±0.5 °20 (e.g., 7.2±0.2, 10.3±0.2, 13.9±0.2, 15.5±0.2, 15.7±0.2, and 19.6±0.2 °20 (e.g., 7.2±0.1, 10.3±0.1, 13.9±0.1, 15.5±0.1, 15.7±0.1, and 19.6±0.1 °20 (e.g., 7.2, 10.3, 13.9, 15.5, 15.7, and 19.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0122] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least five signals selected from 7.2±0.5, 7.8±0.5, 10.3±0.5, 13.9±0.5, 15.7±0.5, and 19.6±0.5 °20 (e.g., 7.2±0.2, 7.8±0.2, 10.3±0.2, 13.9±0.2, 15.7±0.2, and 19.6±0.2 °20 (e.g., 7.2±0.1, 7.8±0.1, 10.3±0.1, 13.9±0.1, 15.7±0.1, and 19.6±0.1 °20 (e.g., 7.2, 7.8, 10.3, 13.9, 15.7, and 19.6 °20))), using Cu K alpha radiation when measured at 25 °C.

[0123] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.6 ± 0.5, 10.7 ± 0.5, 13.0 ± 0.5, 15.5 ± 0.5, 20.7 ± 0.5, 28.3 ± 0.5, or 31.3 ± 0.5 °20, using Cu K alpha radiation when measured at 25 °C.

[0124] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.6 ± 0.2, 10.7 ± 0.2, 13.0 ± 0.2, 15.5 ± 0.2, 20.7 ± 0.2, 28.3 ± 0.2, or 31.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0125] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.6 ± 0.5, 10.7 ± 0.5, 13.0 ± 0.5, 15.5 ± 0.5, 20.2 ± 0.5, 28.3 ± 0.5, or 31.3 ± 0.5 °20, using Cu K alpha radiation when measured at 25 °C.

[0126] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.6 ± 0.2, 10.7 ± 0.2, 13.0 ± 0.2, 15.5 ± 0.2, 20.2 ± 0.2, 28.3 ± 0.2, or 31.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0127] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.6 ± 0.5, 7.8± 0.5, 10.7 ± 0.5, 13.0 ± 0.5, 20.7 ± 0.5, 28.3 ± 0.5, or 31.3 ± 0.5 °20, using Cu K alpha radiation when measured at 25 °C.

[0128] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.6 ± 0.2, 7.8± 0.2, 10.7 ± 0.2, 13.0 ± 0.2, 20.7 ± 0.2, 28.3 ± 0.2, or 31.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0129] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern that does not have an X-ray powder diffraction signal at 22.9±0.5 °20 (e.g., 22.9±0.2°20 (e.g., 22.9±0.1 °20 (e.g., 22.9 °20))), using Cu K alpha radiation when measured at 25 °C.

[0130] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an XRPD pattern that does not have an X-ray powder diffraction signal at 8.3±0.2 °20 (e.g., 8.3±0.1 °20 (e.g., 8.3 °20)), using Cu K alpha radiation when measured at 25 °C. In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising one or more signals as described in Table 3 below.

[0131] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising two or more signals as described in Table 3 below.

[0132] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising three or more signals as described in Table 3 below.

[0133] In some embodiments, the crystalline Compound 1 freebase is characterized by an XRPD pattern comprising four or more signals as described in Table 3 below.*The values shown in the above table are approximate value and subject to instrument differentiation and standard error.

[0134] In some embodiments, the crystalline Compound 1 freebase is characterized by the XRPD signals 1-13 as set forth in Table 3. In some embodiments, the crystalline form of Compound 1 so characterized is crystalline Form II freebase. b. Differential Scanning Calorimetry (DSC) Characterizations

[0135] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an endothermic event between about 205 °C to about 208 °C, as measured by DSC.

[0136] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an endothermic event at 205±20 °C, 205±15 °C, 205±10 °C, or 205±5 °C (e.g., at about 205 °C), as measured by DSC. In some embodiments, the crystalline form of Compound 1 freebase is characterized by an endothermic event at 208±20 °C, 208±15 °C, 208±10 °C, or 208±5 °C (e.g., at about 208 °C), as measured by DSC. In some embodiments, the crystalline form of Compound 1 so characterized is Form I freebase.

[0137] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an endothermic event substantially similar to that set forth in FIG. 2C. In some embodiments, the crystalline form of Compound 1 so characterized is Form I freebase.

[0138] In some embodiments, the Form I freebase is pure-phase Form I freebase.

[0139] In some embodiments, the crystalline Compound 1 freebase is characterized by an endothermic event between about 200 °C to about 204 °C, as measured by DSC. In some embodiments, the crystalline Compound 1 freebase is characterized by an endothermic event at 200±20 °C, 200±15 °C, 200±10 °C, or 200±5 °C (e.g., at about 200 °C), as measured by DSC. In some embodiments, the crystalline Compound 1 freebase is characterized by an endothermic event at 204±20 °C, 204±15 °C, 204±10 °C, or 204±5 °C (e.g., at about 204 °C), as measured by DSC. In some embodiments, the crystalline form of Compound 1 so characterized is Form III freebase.

[0140] In some embodiments, the crystalline form of Compound 1 freebase is characterized by an endothermic event substantially similar to that set forth in FIG. 3B. In some embodiments, the crystalline form of Compound 1 so characterized is Form III freebase.

[0141] In some embodiments, the Form III freebase is pure-phase Form III freebase. c. Thermal Gravimetric Analysis (TGA) Characterization

[0142] In some embodiments, the crystalline form of Compound 1 freebase is characterized by a degradation event between about 270 °C to about 271 °C.

[0143] In some embodiments, the crystalline form of Compound 1 freebase is characterized by a degradation event at 270±40 °C, 270±30 °C, 270±20 °C, 270±15 °C, 270±10 °C, or 270±5 °C (e.g., at about 270 °C), as measured by TGA. In some embodiments, the crystalline form of Compound 1 freebase is characterized by a degradation event at 271±40 °C, 271±30 °C, 271±20 °C, 271±15 °C, 271±10 °C, or 271±5 °C (e.g., at about 271 °C), as measured by TGA. In some embodiments, the crystalline form of Compound 1 freebase is characterized by a degradation event at 270.5±40 °C, 270.5±30 °C, 270.5±20 °C, 270.5±15 °C, 270.5±10 °C, or 270.5±5 °C (e.g., at about 270.5 °C), as measured by TGA.

[0144] In some embodiments, the crystalline form of Compound 1 so characterized is Form I freebase.

[0145] In some embodiments, the crystalline form of Compound 1 freebase is characterized by a degradation event substantially similar to that set forth in FIG. 2B. In some embodiments, the crystalline form of Compound 1 so characterized is Form I freebase.

[0146] In some embodiments, the Form I freebase is pure-phase Form I freebase. d. Other Characterizations

[0147] In some embodiments, the crystalline form of Compound 1 freebase is reversibly hygroscopic and not solvated.

[0148] In some embodiments, the crystalline form of Compound 1 freebase is characterized by a water uptake of about 1-5% weight gain (e.g., 2.5% weight gain) between 0-80% relative humidity (RH) by Dynamic Vapor Sorption (DVS).

[0149] In some embodiments, the crystalline form of Compound 1 freebase has a less than 1% weight gain (e.g., no measurable weight gain, or between 0.2-0.9% weight gain) between 30-60% RH by Dynamic Vapor Sorption (DVS).

[0150] In some embodiments, the crystalline form of Compound 1 freebase is a mixture of Form I and Form II. In some embodiments, the mixture of Form I and Form II is characterized by an about l%-5% weight loss (e.g., 1.7% weight loss), followed by an about 2-6% weight loss (e.g., 3.5% weight loss) and decomposition at about 275 °C. In some embodiments, the first weight loss is attributed to residual ethanol (EtOH) solvent. In some embodiments, the second weight loss is attributed to loss of trapped solvent, e.g., trapped within in the crystalline lattice (e.g., trapped EtOH). In some embodiments, the mixture of Form I and Form II is characterized by an endothermic event with onset between about 115 °C and about 117 °C. In some embodiments, the mixture of Form I and Form II is characterized with a second endothermic event with onset between about 201 °C and 204 °C.

[0151] In some embodiments, Form II converts to Form I. In some embodiments, the second endothermic event correlates to the conversion of Form II freebase into Form I freebase.

[0152] In some embodiments, the mixture of Form I and Form II is characterized by a water uptake of about 3%-6% (e.g., 4.3%) between 0-80% relative humidity (RH) by Dynamic Vapor Sorption (DVS).

[0153] In some embodiments, the crystalline form of Compound 1 freebase is a mixture of Form I and Form III. In some embodiments, Form III converts to Form I.

[0154] In some embodiments, the crystalline Compound 1 freebase has a morphic purity level of about 75% Form I, 80% Form I, 85% Form I, 90% Form I, 91% Form I, 92% Form I, 93% Form I, 94% Form I, 95% Form I, 96% Form I, 97% Form I, 98% Form I, or 99% Form I (w / w%).

[0155] In some embodiments, the crystalline Compound 1 freebase is isolated as pure-phase Form I, i.e., having a morphic purity level of about 100% Form I. In some embodiments, crystalline Compound 1 freebase is isolated as pure-phase Form I, in which Form II and Form III are not observed by XRPD using Cu K alpha radiation when measured at 25 °C.

[0156] In some embodiments, the crystalline Compound 1 freebase has a particle size distribution diameter D10 to D90 range of about 9 microns to about 142 microns. In some embodiments, the crystalline Compound 1 freebase has a particle size distribution diameter D10 value of about 9 microns. In some embodiments, the crystalline Compound 1 freebase has a particle size distribution diameter D90 of about 142 microns. In some embodiments, the crystalline Compound 1 freebase has a particle size distribution mean D50 value of about 2 microns. In some embodiments, the crystalline form of Compound 1 so characterized is Form I freebase.

[0157] In some embodiments, the crystalline Compound 1 freebase is stable over time, e.g., at least 3 months under long term and / or accelerated stability study conditions. In some embodiments, the crystalline Compound 1 freebase is stable over time, e.g., at least 3 months under long term stability study conditions. In some embodiments, the crystalline Compound 1 freebase is stable overtime, e.g., at least 3 months under accelerated stability study conditions. In some embodiments, the crystalline form of Compound 1 so characterized is Form I freebase.

[0158] In some embodiments, the crystalline Compound 1 freebase has a morphic purity level of about 75% Form III, 80% Form III, 85% Form III, 90% Form III, 91% Form III, 92% Form III, 93% Form III, 94% Form III, 95% Form III, 96% Form III, 97% Form III, 98% Form III, or 99% Form III (w / w%).

[0159] In some embodiments, the crystalline Compound 1 freebase is isolated as pure-phase Form III, i.e., having a morphic purity level of about 100% Form III.(ii) Compositions

[0160] Compositions, including pharmaceutical compositions, comprising crystalline Compound 1 freebase are further contemplated herein.

[0161] In some embodiments, provided is a composition comprising a mixture of Compound 1 freebase forms, wherein 75% (w / w%) of the mixture is crystalline Form I.

[0162] In some embodiments, provided is a composition comprising a mixture of Compound 1 freebase forms, wherein 75% (w / w%) of the mixture is crystalline Form III.

[0163] In some embodiments, the composition is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers.

[0164] In some embodiments, provided is a pharmaceutical composition comprising a mixture of Compound 1 freebase forms, wherein 75% (w / w%) of the mixture is crystalline Form I.

[0165] In some embodiments, provided is a pharmaceutical composition comprising a mixture of Compound 1 freebase forms, wherein 75% (w / w%) of the mixture is crystalline Form III.

[0166] In some embodiments, the mixture of Compound 1 freebase forms is about 75% (w / w%) Form I of Compound 1.

[0167] In some embodiments, the mixture of Compound 1 freebase forms is about 80% (w / w%) Form I of Compound 1.

[0168] In some embodiments, the mixture of Compound 1 freebase forms is about 85% (w / w%) Form I of Compound 1.

[0169] In some embodiments, the mixture of Compound 1 freebase forms is about 90% (w / w%) Form I of Compound 1.

[0170] In some embodiments, the mixture of Compound 1 freebase forms is about 91% (w / w%) Form I of Compound 1.

[0171] In some embodiments, the mixture of Compound 1 freebase forms is about 92% (w / w%)Form I of Compound 1.

[0172] In some embodiments, the mixture of Compound 1 freebase forms is about 93% (w / w%) Form I of Compound 1.

[0173] In some embodiments, the mixture of Compound 1 freebase forms is about 94% (w / w%) Form I of Compound 1.

[0174] In some embodiments, the mixture of Compound 1 freebase forms is about 95% (w / w%) Form I of Compound 1.

[0175] In some embodiments, the mixture of Compound 1 freebase forms is about 96% (w / w%) Form I of Compound 1.

[0176] In some embodiments, the mixture of Compound 1 freebase forms is about 97% (w / w%) Form I of Compound 1.

[0177] In some embodiments, the mixture of Compound 1 freebase forms is about 98% (w / w%) Form I of Compound 1.

[0178] In some embodiments, the mixture of Compound 1 freebase forms is about 99% (w / w%) Form I of Compound 1.

[0179] In some embodiments, provided is a composition comprising Compound 1 freebase, wherein 100% of Compound 1 freebase is crystalline pure-phase Form I, i.e., 100% of Form I.

[0180] In some embodiments, the mixture of Compound 1 freebase forms is about 75% (w / w%) Form III of Compound 1.

[0181] In some embodiments, the mixture of Compound 1 freebase forms is about 80% (w / w%)Form III of Compound 1.

[0182] In some embodiments, the mixture of Compound 1 freebase forms is about 85% (w / w%)Form III of Compound 1.

[0183] In some embodiments, the mixture of Compound 1 freebase forms is about 90% (w / w%)Form III of Compound 1.

[0184] In some embodiments, the mixture of Compound 1 freebase forms is about 91% (w / w%)Form III of Compound 1.

[0185] In some embodiments, the mixture of Compound 1 freebase forms is about 92% (w / w%)Form III of Compound 1.

[0186] In some embodiments, the mixture of Compound 1 freebase forms is about 93% (w / w%)Form III of Compound 1.

[0187] In some embodiments, the mixture of Compound 1 freebase forms is about 94% (w / w%)Form III of Compound 1.

[0188] In some embodiments, the mixture of Compound 1 freebase forms is about 95% (w / w%)Form III of Compound 1.

[0189] In some embodiments, the mixture of Compound 1 freebase forms is about 96% (w / w%) Form III of Compound 1.

[0190] In some embodiments, the mixture of Compound 1 freebase forms is about 97% (w / w%) Form III of Compound 1.

[0191] In some embodiments, the mixture of Compound 1 freebase forms is about 98% (w / w%) Form III of Compound 1.

[0192] In some embodiments, the mixture of Compound 1 freebase forms is about 99% (w / w%) Form III of Compound 1.

[0193] In some embodiments, provided is a composition comprising Compound 1 freebase, wherein 100% of Compound 1 freebase is crystalline pure-phase Form III, i.e., 100% of Form III.

[0194] Exemplary pharmaceutical acceptable carriers may include diluents, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine .

[0195] The pharmaceutical compositions containing a crystalline Compound 1 freebase may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of crystalline Compound 1 freebase into preparations that can be used pharmaceutically. The appropriate formulation is dependent upon the route of administration chosen.

[0196] Administration of the composition to the subject can be accomplished via any mode of administration, for example, by oral administration, topical administration, or by injection. Depending on the intended mode of administration, the composition comprising crystalline Compound 1 freebase can be in solid, semi-solid or liquid dosage formulation.

[0197] A crystalline Compound 1 freebase may be administered alone in the pharmaceutical composition as the sole therapeutic agent, or may be administered in combination with another therapeutic agent. Combination treatment may be achieved by way of co-administration (e.g., the two agents being administered at the same time) or sequential administration (e.g., one agent being administered first, then the other). In the case of co-administration, the crystalline Compound 1 freebase may be administered in the same pharmaceutical composition as the other therapeutic agent, or may be administered in a separate pharmaceutical composition. The choice of the other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol.(iii) Methods of Treatment and Prevention

[0198] Crystalline Compound 1 freebase has been found useful as an inhibitor of NLRP3 activity.

[0199] In some aspects, provided is a method of treating or preventing a disease or disorder in asubject in need thereof, comprising administering to the subject an effective amount of a crystalline Compound 1 freebase, or a pharmaceutical composition thereof. In some aspects, provided is a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a crystalline Compound 1 freebase, or a pharmaceutical composition thereof.

[0200] In some aspects, provided is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline Compound 1 freebase, or a pharmaceutical composition thereof. In some aspects, provided is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a crystalline Compound 1 freebase, or a pharmaceutical composition thereof.

[0201] In some aspects, provided is a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of Form I of Compound 1 freebase, or a pharmaceutical composition thereof. In some aspects, provided is a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject Form I of Compound 1 freebase, or a pharmaceutical composition thereof.

[0202] In some aspects, provided is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of Form I of Compound 1 freebase, or a pharmaceutical composition thereof. In some aspects, provided is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject Form I of Compound 1 freebase, or a pharmaceutical composition thereof.

[0203] In some aspects, provided is a method of preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of Form I of Compound 1 freebase, or a pharmaceutical composition thereof. In some aspects, provided is a method of preventing a disease or disorder in a subject in need thereof, comprising administering to the subject Form I of Compound 1 freebase, or a pharmaceutical composition thereof.

[0204] In some aspects, provided is a crystalline form of Compound 1 freebase, or a pharmaceutical composition thereof, for use in treating or preventing a disease or disorder. In some aspects, provided is a crystalline form of Compound 1 freebase, or a pharmaceutical composition thereof, for use in treating a disease or disorder. In some aspects, provided is a crystalline form of Compound 1 freebase, or a pharmaceutical composition thereof, for use in preventing a disease or disorder.

[0205] In some aspects, provided is Form I of Compound 1 freebase, or a pharmaceutical composition thereof, for use in treating or preventing a disease or disorder. In some aspects, provided is Form I of Compound 1 freebase, or a pharmaceutical composition thereof, for use in treating a disease or disorder. In some aspects, provided is Form I of Compound 1 freebase, or a pharmaceutical composition thereof, for use in preventing a disease or disorder.

[0206] In some aspects, provided is the use of crystalline form of Compound 1 freebase, in themanufacture of a medicament, for the treatment or prevention of a disease or disorder. In some aspects, provided is the use of crystalline form of Compound 1 freebase, in the manufacture of a medicament, for the treatment of a disease or disorder. In some aspects, provided is the use of crystalline form of Compound 1 freebase, in the manufacture of a medicament, for the prevention of a disease or disorder.

[0207] In some aspects, provided is the use of Form I of Compound 1 freebase, in the manufacture of a medicament, for the treatment or prevention of a disease or disorder. In some aspects, provided is the use of Form I of Compound 1 freebase, in the manufacture of a medicament, for the treatment of a disease or disorder. In some aspects, provided is the use of Form I of Compound 1 freebase, in the manufacture of a medicament, for the prevention of a disease or disorder.

[0208] In some aspects, provided is the use of crystalline form of Compound 1 freebase for the treatment or prevention of a disease or disorder. In some aspects, provided is the use of crystalline form of Compound 1 freebase for the treatment of a disease or disorder. In some aspects, provided is the use of crystalline form of Compound 1 freebase for the prevention of a disease or disorder.

[0209] In some aspects, provided is the use of Form I of Compound 1 freebase for the treatment or prevention of a disease or disorder. In some aspects, provided is the use of Form I of Compound 1 freebase for the treatment of a disease or disorder. In some aspects, provided is the use of Form I of Compound 1 freebase for the prevention of a disease or disorder.

[0210] In some embodiments, the disease or disorder is associated with aberrant NLRP3 activity, and the method comprises inhibiting the aberrant NLRP3 activity such that the subject is treated.

[0211] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disease of the muscles, an inflammatory disorder, an autoimmune disorder, cancer, an infection, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, pain (including disorders related to pain management), an NLRP3-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3, or obesity (e.g., obesity related to neuroinflammation).

[0212] In some embodiments, the disease or disorder is a disease or disorder of central nervous system and / or peripheral nervous system (“PNS”), such as dementia, Alzheimer’s disease (“AD”) epilepsy (e.g., refractory epilepsy), traumatic brain injury (“TBI”), multiple sclerosis (“MS”), a developmental disturbance, acute disseminated encephalopathy, transverse myelitis, Parkinson’s disease (“PD”), amyotrophic lateral sclerosis (“ALS”), Huntington’s disease (“HD”), or spinal cord injury.

[0213] In some embodiments, the disease or disorder is a primary neurological disease of the muscle, such as a dystrophy or spinal muscular atrophy.

[0214] In some embodiments, the disease or disorder is an inflammatory disorder, such as gout oranemia of inflammation.

[0215] In some embodiments, the disease or disorder is an autoimmune disease, such as ulcerative colitis.

[0216] In some embodiments, the disease or disorder is cancer, such as skin cancer or colon cancer.

[0217] In some embodiments, the disease or disorder is an infection, such as a neuro-infection.

[0218] In some embodiments, the disease or disorder is a metabolic disease, such as diabetes, e.g., type 2 diabetes.

[0219] In some embodiments, the disease or disorder is obesity. In some embodiments, the obesity is related to neuroinflammation, e.g., hypothalamic inflammation and / or gliosis. In some embodiments, the obesity is related to a metabolic disorder.

[0220] In some embodiments, the disease or disorder is a cardiovascular disease, such as stroke, atherosclerosis or atherosclerotic cardiovascular disease (ASCVD) .

[0221] In some embodiments, the disease or disorder is a respiratory disease, such as asthma (e.g., steroid-resistant asthma, severe steroid-resistant asthma) or chronic obstructive pulmonary disease (“COPD”).

[0222] In some embodiments, the disease or disorder is a kidney disease, such as acute kidney disease, a chronic kidney disease, or a rare kidney disease.

[0223] In some embodiments, the disease or disorder is a liver disease, such as nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH, also known as MASH or metabolic dysfunction-associated steatohepatitis) .

[0224] In some embodiments, the disease or disorder is an ocular disease, such as optic neuritis or macular degeneration.

[0225] In some embodiments, the disease or disorder is a skin disease, such as psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0226] In some embodiments, the disease or disorder is a lymphatic disease.

[0227] In some embodiments, the disease or disorder is a rheumatic disease, such as osteoarthritis, dermatomyositis, Still’s disease, or juvenile idiopathic arthritis.

[0228] In some embodiments, the disease or disorder is a psychological disease, such as a neuropsychiatric condition, including depression, major depressive disorder, or refractory depression.

[0229] In some embodiments, the disease or disorder is a graft versus host disease.

[0230] In some embodiments, the disease or disorder is pain (including disorders related to pain management), such as headache pain, pain management addiction, osteoarthritis pain, or allodynia.

[0231] In some embodiments, the NLRP3 -related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome. In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory disease (NOMID).

[0232] In some embodiments, the disease or disorder is dementia, Alzheimer’s disease (“AD”), epilepsy (e.g., refractory epilepsy), traumatic brain injury (“TBI”), multiple sclerosis (“MS”), developmental disturbances, acute disseminated encephalopathy, transverse myelitis, Parkinson’s disease (“PD”), amyotrophic lateral sclerosis (“ALS”), spinal muscular atrophy, Huntington’s disease (“HD”), spinal cord injury, a dystrophy, a neuro-infection, pain (e.g., headache pain, osteoarthritis pain, or allodynia, pain management addiction), a neuropsychiatric condition (e.g. depression, major depressive disorder, refractory depression), neonatal onset multisystem inflammatory disease (“NOMID”), asthma, osteoarthritis, ulcerative colitis, gout, anemia of inflammation, Still’s disease, chronic obstructive pulmonary disease (“COPD”), osteoarthritis pain, or hidradenitis suppurativa or obesity (e.g., obesity related to neuroinflammation).(iv) Methods of Preparation

[0233] The crystalline Forms I, II, and III of Compound 1 freebase may be prepared by any suitable technique known in the art. In some aspects, the present disclosure provides crystalline Compound 1 freebase obtainable by, or obtained by, or directly obtained by a method for preparing as described in the Examples.

[0234] In some embodiments, the prepared crystalline form is a mixture of Form I and Form II. For example, in some embodiments, a mixture of Form I and Form II is prepared from crystallization in an organic alcohol, such as ethanol, followed by addition of a hydrocarbon, such as n-heptanes.

[0235] In some embodiments, Form II is converted to Form I. For example, in some embodiments, Form II is converted to Form I by treatment with (e.g., suspending in) an organic alcohol, such as methanol or ethanol. In some embodiments, Form II is converted to Form I upon drying.

[0236] In some embodiments, the prepared crystalline form is a mixture of Form I and Form III.

[0237] In some embodiments, Form III is converted to Form I. For example, in some embodiments, Form III is converted to Form I by treatment with (e.g., suspending in) an organic alcohol, such as methanol or ethanol.

[0238] In some embodiments, the prepared crystalline form of Compound 1 freebase has a morphic purity level of about 75% Form I, 80% Form I, 85% Form I, 90% Form I, 91% Form I, 92% Form I, 93% Form I, 94% Form I, 95% Form I, 96% Form I, 97% Form I, 98% Form I, or 99% Form I (w / w%).

[0239] In some embodiments, the prepared crystalline form is pure-phase Form I. For example, in some embodiments, pure-phase Form I is prepared from crystallization in an organic alcohol / water mixture, such as ethanol and water. In some embodiments, pure-phase Form I is prepared from crystallization in an organic alcohol / hydrocarbon mixture, such as ethanol and n-heptanes. In some embodiments, pure-phase Form I is prepared from crystallization in an organic alcohol / water mixture, followed by crystallization in an organic alcohol / hydrocarbon mixture. In some embodiments, pure- phase Form I is prepared from crystallization in an organic alcohol / hydrocarbon mixture, followed bycrystallization in an organic alcohol / water mixture.

[0240] In some embodiments, the prepared crystalline form of Compound 1 freebase has a morphic purity level of about 75% Form III, 80% Form III, 85% Form III, 90% Form III, 91% Form III, 92% Form III, 93% Form III, 94% Form III, 95% Form III, 96% Form III, 97% Form III, 98% Form III, or 99% Form III (w / w%).

[0241] In some embodiments, the prepared crystalline form is pure-phase Form III. For example, in some embodiments, pure-phase Form III is prepared from crystallization in a mixture of 2 or more organic alcohols, such as a methanol and butanol mixture.EXEMPLARY EMBODIMENTS - A

[0242] Exemplary Embodiment No. Al. A crystalline freebase form of Compound 1:

[0243] Exemplary Embodiment No. A2. The crystalline form of Exemplary Embodiment No. Al, having an X-ray powder diffraction signal at 8.6 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0244] Exemplary Embodiment No. A3. The crystalline form of Exemplary Embodiment Nos. Al or A2, having at least one additional signal at 17.3 ± 0.2 or 22.9 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0245] Exemplary Embodiment No. A4. The crystalline form of any one of the precedingExemplary Embodiments, having an X-ray powder diffraction signal at 8.6 ± 0.2, 17.3 ± 0.2, and 22.9 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0246] Exemplary Embodiment No. A5. The crystalline form of any one of the precedingExemplary Embodiments, having at least one additional X-ray powder diffraction signal at 19.1 ± 0.2 or 23.7 ± 0.2 °20 using Cu K alpha radiation when measured at 25 °C.

[0247] Exemplary Embodiment No. A6. The crystalline form of any one of the precedingExemplary Embodiments, having at least one additional X-ray powder diffraction signal at 16.7 ± 0.2, 21.9 ± 0.2, 27.3 ± 0.2, or 30.8 ± 0.2 using Cu K alpha radiation when measured at 25 °C.

[0248] Exemplary Embodiment No. A7. The crystalline form of any one of the precedingExemplary Embodiments, having at least one additional X-ray powder diffraction signal at 1 1 .4 ± 0.2, 1 1.8 ± 0.2, 12.2 ± 0.2, 14.7 ± 0.2, 16.2 ± 0.2, 16.4 ± 0.2, 18.1 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 20.3 ± 0.2, 24.4 ± 0.2, 24.7 ± 0.2, 25.1 ± 0.2, 25.9 ± 0.2, 26.1 ± 0.2, 26.4 ± 0.2, 28.6 ± 0.2, 28.9 ± 0.2, 29.3 ± 0.2, 29.5 ± 0.2, 30.0 ± 0.2, 31.6 ± 0.2, 32.6 ± 0.2, 32.8 ± 0.2, 33.3 ± 0.2, 33.8 ± 0.2, 34.0 ± 0.2,34.8 ± 0.2, 35.2 ± 0.2, 36.2 ± 0.2, 36.7 ± 0.2, 37.3 ± 0.2, 38.1 ± 0.2, 38.7 ± 0.2, or 39.4 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0249] Exemplary Embodiment No. A8. The crystalline form of any one of the preceding Exemplary Embodiments, characterized by a single endothermic event between about 205 °C to about 208 °C, as measured by differential scanning calorimetry (DSC).

[0250] Exemplary Embodiment No. A9. The crystalline form of any one of the preceding Exemplary Embodiments, characterized by decomposition between about 270 °C to about 271 °C, as measured by thermogravimetric analysis (TGA).

[0251] Exemplary Embodiment No. A10. The crystalline form of any one of the preceding Exemplary Embodiments, wherein the form is reversibly hygroscopic and not solvated.

[0252] Exemplary Embodiment No. All. The crystalline form of any one of the preceding Exemplary Embodiments, wherein the form is stable for 3 months under long term and / or accelerated stability study conditions.

[0253] Exemplary Embodiment No. A12. The crystalline form of any one of the preceding Exemplary Embodiments, having a particle size distribution mean D50 value of about 2 microns.

[0254] Exemplary Embodiment No. A13. The crystalline form of any one of the preceding Exemplary Embodiments, characterized by having an X-ray powder diffraction pattern substantially similar to that as set forth in FIG. 2A.

[0255] Exemplary Embodiment No. A14. The crystalline form of Exemplary Embodiment No. Al, wherein the crystalline freebase form is pure -phase Form I.

[0256] Exemplary Embodiment No. A15. The crystalline form of Exemplary Embodiment No. Al, having an X-ray powder diffraction signal at 6.6 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0257] Exemplary Embodiment No. A16. The crystalline form of Exemplary Embodiment No. Al or Exemplary Embodiment No. A15, having at least one additional signal at 8.3 ± 0.2 or ± 12.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0258] Exemplary Embodiment No. A17. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A 15-Al 6, having an X-ray powder diffraction signal at 6.6 ± 0.2, 8.3 ± 0.2, and ± 12.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0259] Exemplary Embodiment No. A18. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A 15-Al 7, having at least one additional X-ray powder diffraction signal at 18.7 ± 0.2, 20.9 ± 0.2, and 21.8 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0260] Exemplary Embodiment No. A19. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A15-A18, having at least one additional X-ray powder diffraction signal at 6.2 ± 0.2, 7.1 ± 0.2, 7.8 ± 0.2, 8.6 ± 0.2, 9.9 ± 0.2, 10.1 ± 0.2, 11.1 ± 0.2, 11.6 ±0.2, 11.8 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 13.5 ± 0.2, 13.9 ± 0.2, 14.1 ± 0.2, 14.4 ± 0.2, 14.7 ± 0.2, 15.3 ± 0.2, 15.5 ± 0.2, 16.2 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 17.3 ± 0.2, 17.7 ± 0.2, 17.9 ± 0.2, 18.1 ± 0.2, 18.7 ±0.2, 19.1 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.2 ± 0.2, 20.9 ± 0.2, 21.8 ± 0.2, 22.3 ± 0.2, 22.6 ± 0.2, 23.3 ±0.2, 23.8 ± 0.2, 24.0 ± 0.2, 24.4 ± 0.2, 24.7 ± 0.2, 25.2 ± 0.2, 25.8 ± 0.2, 26.5 ± 0.2, 26.9 ± 0.2, 27.0 ±0.2, 28.0 ± 0.2, 28.5 ± 0.2, 28.8 ± 0.2, 29.7 ± 0.2, 30.5 ± 0.2, 30.8 ± 0.2, 31.1 ± 0.2, 35.0 ± 0.2, 36.2 ±0.2, 37.4 ± 0.2, 37.6 ± 0.2, 38.1 ± 0.2, 39.2 ± 0.2, or 39.5 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0261] Exemplary Embodiment No. A20. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A 15-Al 9, characterized by a single endothermic event between about 200 °C to about 204 °C, as measured by differential scanning calorimetry (DSC).

[0262] Exemplary Embodiment No. A21. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A15-A20, characterized by having an X-ray powder diffraction pattern substantially similar to that as set forth in FIG. 3A.

[0263] Exemplary Embodiment No. A22. The crystalline form of Exemplary Embodiment No. Al, wherein the crystalline freebase form is pure-phase Form III.

[0264] Exemplary Embodiment No. A23. The crystalline form of Exemplary Embodiment No. Al, having an X-ray powder diffraction signal at 7.2 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0265] Exemplary Embodiment No. A24. The crystalline form of Exemplary Embodiment No. Al or Exemplary Embodiment No. A23, having at least one additional signal at 13.9 ± 0.2 or 15.7 ± 0.2, °20, using Cu K alpha radiation when measured at 25 °C.

[0266] Exemplary Embodiment No. A25. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A23-A24, having an X-ray powder diffraction signal at 7.2 ± 0.2, 13.9 ± 0.2, and 15.7 ± 0.2, °20 using Cu K alpha radiation when measured at 25 °C.

[0267] Exemplary Embodiment No. A26. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A23-A25, having at least one additional X-ray powder diffraction signal at 7.8 ± 0.2, 10.3 ± 0.2, or 19.6 ± 0.2 °20 using Cu K alpha radiation when measured at 25 °C.

[0268] Exemplary Embodiment No. A27. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A23-A26, having at least one additional X-ray powder diffraction signal at 6.6± 0.2, 10.7 ± 0.2, 13.0 ± 0.2, 15.5 ± 0.2, 20.2 ± 0.2, 28.3 ± 0.2, or 31.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0269] Exemplary Embodiment No. A28. The crystalline form of Exemplary Embodiment No. Al or any one of Exemplary Embodiment Nos. A23-A27, characterized by having each of XRPD signals 1-13 as set forth in Table 3.

[0270] Exemplary Embodiment No. A29. A composition comprising a mixture of (R)-2-(4-((5,5- dimethyltetrahydrofuran-3 -yl)amino)pyrido [3 ,4-d]pyridazin- 1 -y 1) -5 -methylphenol (Compound 1)freebase forms, wherein 75% (w / w%) of the mixture is the crystalline form of any one of Exemplary Embodiment Nos. A2-A12.

[0271] Exemplary Embodiment No. A30. The composition of Exemplary Embodiment No. A29, wherein 95% (w / w%) of the mixture is the crystalline form of any one of Exemplary Embodiment Nos. A2-A12.

[0272] Exemplary Embodiment No. A31. The composition of Exemplary Embodiment Nos. A29 or A30, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0273] Exemplary Embodiment No. A32. A pharmaceutical composition comprising a form of any one of Exemplary Embodiment Nos. A1-A28, and one or more pharmaceutically acceptable carriers.

[0274] Exemplary Embodiment No. A33. A method of treating or preventing a disease or disorder, the method comprising administering to a subject a form of any one of Exemplary Embodiment Nos. A1-A28, or a composition of any one of Exemplary Embodiment Nos. A29-A32.

[0275] Exemplary Embodiment No. A34. The method of Exemplary Embodiment No. A33, wherein the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disease of the muscles, an inflammatory disorder, an autoimmune disorder, cancer, an infection, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, pain (including disorders related to pain management), or an NLRP3-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0276] Exemplary Embodiment No. A35. A method of preparing a crystalline form of Compound 1 freebase of any one of the preceding Exemplary Embodiments, as described herein and / or in the Examples.

[0277] Exemplary Embodiment No. A36. The method of Exemplary Embodiment No. A35, wherein the crystalline form is pure-phase Form I.

[0278] Exemplary Embodiment No. A37. The method of Exemplary Embodiment No. A36, wherein Form II is converted to Form I to provide pure-phase Form I.

[0279] Exemplary Embodiment No. A38. The method of Exemplary Embodiment No. A36, wherein Form III is converted to Form I to provide pure-phase Form I.

[0280] Exemplary Embodiment No. A39. The method of Exemplary Embodiment No. A35, wherein the crystalline form is pure-phase Form III.EXEMPLARY EMBODIMENTS - B

[0281] Exemplary Embodiment No. Bl. A crystalline freebase form of Compound 1:

[0282] Exemplary Embodiment No. B2. The crystalline form of Exemplary Embodiment No. Bl, having an X-ray powder diffraction signal at 8.6 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0283] Exemplary Embodiment No. B3. The crystalline form of Exemplary Embodiment No. Bl or Exemplary Embodiment No. B2, having an X-ray powder diffraction signal at 17.3 ± 0.2 or 22.9 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0284] Exemplary Embodiment No. B4. The crystalline form of any one of the preceding Exemplary Embodiments, having X-ray powder diffraction signals at 8.6 ± 0.2, 17.3 ± 0.2, and 22.9 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0285] Exemplary Embodiment No. B5. The crystalline form of any one of the precedingExemplary Embodiments, having at least one additional X-ray powder diffraction signal at 19.1 ± 0.2 or 23.7 ± 0.2 °20 using Cu K alpha radiation when measured at 25 °C.

[0286] Exemplary Embodiment No. B6. The crystalline form of any one of the precedingExemplary Embodiments, having at least one additional X-ray powder diffraction signal at 16.7 ± 0.2, 21.9 ± 0.2, 27.3 ± 0.2, or 30.8 ± 0.2 using Cu K alpha radiation when measured at 25 °C.

[0287] Exemplary Embodiment No. B7. The crystalline form of any one of the precedingExemplary Embodiments, having at least one additional X-ray powder diffraction signal at 11.4 ± 0.2, 11.8 ± 0.2, 12.2 ± 0.2, 14.7 ± 0.2, 16.2 ± 0.2, 16.4 ± 0.2, 18.1 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 20.3 ± 0.2,24.4 ± 0.2, 24.7 ± 0.2, 25.1 ± 0.2, 25.9 ± 0.2, 26.1 ± 0.2, 26.4 ± 0.2, 28.6 ± 0.2, 28.9 ± 0.2, 29.3 ± 0.2,29.5 ± 0.2, 30.0 ± 0.2, 31.6 ± 0.2, 32.6 ± 0.2, 32.8 ± 0.2, 33.3 ± 0.2, 33.8 ± 0.2, 34.0 ± 0.2, 34.8 ± 0.2,35.2 ± 0.2, 36.2 ± 0.2, 36.7 ± 0.2, 37.3 ± 0.2, 38.1 ± 0.2, 38.7 ± 0.2, or 39.4 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0288] Exemplary Embodiment No. B8. The crystalline form of any one of the precedingExemplary Embodiments, characterized by a single endothermic event between about 205 °C to about 208 °C, as measured by differential scanning calorimetry (DSC).

[0289] Exemplary Embodiment No. B9. The crystalline form of any one of the preceding Exemplary Embodiments, characterized by decomposition between about 270 °C to about 271 °C, as measured by thermogravimetric analysis (TGA).

[0290] Exemplary Embodiment No. B10. The crystalline form of any one of the preceding Exemplary Embodiments, wherein the form is reversibly hygroscopic and not solvated.

[0291] Exemplary Embodiment No. Bll. The crystalline form of any one of the preceding Exemplary Embodiments, wherein the form is stable for 3 months under long term and / or acceleratedstability study conditions.

[0292] Exemplary Embodiment No. B12. The crystalline form of any one of the preceding Exemplary Embodiments, having a particle size distribution mean D50 value of about 2 microns.

[0293] Exemplary Embodiment No. B13. The crystalline form of any one of the preceding Exemplary Embodiments, characterized by having an X-ray powder diffraction pattern substantially similar to that as set forth in FIG. 2A.

[0294] Exemplary Embodiment No. B14. The crystalline form of Exemplary Embodiment No. Bl, wherein the crystalline freebase form is pure-phase Form I.

[0295] Exemplary Embodiment No. B15. The crystalline form of Exemplary Embodiment No. Bl, having an X-ray powder diffraction signal at 6.6 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0296] Exemplary Embodiment No. B16. The crystalline form of Exemplary Embodiment No. Bl or Exemplary Embodiment No. B 15, having an X-ray powder diffraction signal at 8.3 ± 0.2 or ± 12.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0297] Exemplary Embodiment No. B17. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B15-B16, having X-ray powder diffraction signals at 6.6 ± 0.2, 8.3 ± 0.2, and ± 12.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0298] Exemplary Embodiment No. B18. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B15-B17, having at least one additional X-ray powder diffraction signal at 18.7 ± 0.2, 20.9 ± 0.2, or 21.8 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0299] Exemplary Embodiment No. B19. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B15-B18, having at least one additional X-ray powder diffraction signal at 6.2 ± 0.2, 7.1 ± 0.2, 7.8 ± 0.2, 8.6 ± 0.2, 9.9 ± 0.2, 10.1 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 11.8 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 13.5 ± 0.2, 13.8 ± 0.2, 14.1 ± 0.2, 14.4 ± 0.2, 14.7 ± 0.2, 15.3 ± 0.2, 15.5 ± 0.2, 16.2 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 17.3 ± 0.2, 17.7 ± 0.2, 17.9 ± 0.2, 18.1 ± 0.2, 19.1 ±0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.2 ± 0.2, 22.3 ± 0.2, 22.6 ± 0.2, 23.3 ± 0.2, 23.8 ± 0.2, 24.0 ± 0.2, 24.4 ±0.2, 24.7 ± 0.2, 25.2 ± 0.2, 25.8 ± 0.2, 26.5 ± 0.2, 26.9 ± 0.2, 27.0 ± 0.2, 28.0 ± 0.2, 28.5 ± 0.2, 28.8 ±0.2, 29.7 ± 0.2, 30.5 ± 0.2, 30.8 ± 0.2, 31.1 ± 0.2, 35.0 ± 0.2, 36.2 ± 0.2, 37.4 ± 0.2, 37.6 ± 0.2, 38.1 ±0.2, 39.2 ± 0.2, or 39.5 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0300] Exemplary Embodiment No. B20. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B15-B19, characterized by a single endothermic event between about 200 °C to about 204 °C, as measured by differential scanning calorimetry (DSC).

[0301] Exemplary Embodiment No. B21. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B15-B20, characterized by having an X-ray powder diffraction pattern substantially similar to that as set forth in FIG. 3A.

[0302] Exemplary Embodiment No. B22. The crystalline form of Exemplary Embodiment No. Bl,wherein the crystalline freebase form is pure-phase Form III.

[0303] Exemplary Embodiment No. B23. The crystalline form of Exemplary Embodiment No. Bl, having an X-ray powder diffraction signal at 7.2 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

[0304] Exemplary Embodiment No. B24. The crystalline form of Exemplary Embodiment No. Bl or Exemplary Embodiment No. B23, having an X-ray powder diffraction signal at 13.9 ± 0.2 or 15.7 ± 0.2, °20, using Cu K alpha radiation when measured at 25 °C.

[0305] Exemplary Embodiment No. B25. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B23-B24, having X-ray powder diffraction signals at 7.2 ± 0.2, 13.9 ± 0.2, and 15.7 ± 0.2, °20 using Cu K alpha radiation when measured at 25 °C.

[0306] Exemplary Embodiment No. B26. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B23-B25, having at least one additional X-ray powder diffraction signal at 7.8 ± 0.2, 10.3 ± 0.2, or 19.6 ± 0.2 °20 using Cu K alpha radiation when measured at 25 °C.

[0307] Exemplary Embodiment No. B27. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B23-B26, having at least one additional X-ray powder diffraction signal at 6.6± 0.2, 10.7 ± 0.2, 13.0 ± 0.2, 15.5 ± 0.2, 20.7 ± 0.2, 28.3 ± 0.2, or 31.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

[0308] Exemplary Embodiment No. B28. The crystalline form of Exemplary Embodiment No. Bl or any one of Exemplary Embodiments Nos. B23-B27, characterized by having each of XRPD signals 1-13 as set forth in Table 3.

[0309] Exemplary Embodiment No. B29. A composition comprising a mixture of (R)-2-(4-((5,5- dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-l-yl)-5-methylphenol (Compound 1) freebase forms, wherein 75% (w / w%) of the mixture is the crystalline form of any one of Exemplary Embodiments Nos. B2-B14.

[0310] Exemplary Embodiment No. B30. The composition of Exemplary Embodiment No. B29, wherein 95% (w / w%) of the mixture is the crystalline form of any one of Exemplary Embodiments Nos. B2-B14.

[0311] Exemplary Embodiment No. B31. The composition of Exemplary Embodiments Nos. B29 or B30, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0312] Exemplary Embodiment No. B32. A pharmaceutical composition comprising the crystalline form of any one of Exemplary Embodiments Nos. Bl-28, and one or more pharmaceutically acceptable carriers.

[0313] Exemplary Embodiment No. B33. A method of treating or preventing a disease or disorder, the method comprising administering to a subject the crystalline form of any one of Exemplary Embodiments Nos. B1-B28, or the composition of any one of Exemplary Embodiments Nos. B29-

[0314] Exemplary Embodiment No. B34. The method of Exemplary Embodiment No. B33, wherein the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disease of the muscles, an inflammatory disorder, an autoimmune disorder, cancer, an infection, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, pain (including disorders related to pain management), an NLRP3-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3, or obesity.

[0315] Exemplary Embodiment No. B35. A method of preparing the crystalline form of Compound 1 freebase of any one of Exemplary Embodiments Nos. B1-B28, as described herein and / or in the Examples.

[0316] Exemplary Embodiment No. B36. The method of Exemplary Embodiment No. B35, wherein the crystalline form is pure-phase Form I.

[0317] Exemplary Embodiment No. B37. The method of Exemplary Embodiment No. B36, wherein Form II is converted to Form I to provide the pure-phase Form I.

[0318] Exemplary Embodiment No. B38. The method of Exemplary Embodiment No. B36, wherein Form III is converted to Form I to provide the pure-phase Form I.

[0319] Exemplary Embodiment No. B39. The method of Exemplary Embodiment No. B35, wherein the crystalline form is pure-phase Form III.EXEMPLIFICATION

[0320] In order that this disclosure may be more fully understood, the following Examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.Analytical MethodsX-Ray Powder Diffraction (XRPD)

[0321] X-ray powder diffraction data in the transmission mode was collected on a Bruker D8 Discover using Cu Ka radiation (40 kV, 40 mA), X-ray focusing Gobel mirror, 0 - 0 goniometer, divergence slit (1.0 mm), Collimator (6 x 1.5 mm) and the SSD 160-2 Detector with a 4.5 °20 to 5.0 °20 / opening without Nickel filter. The software used for data collection wasDIFFRAC. COMMANDER version 6.5.0.1 and the data was presented using DIFFRAC.EVA version 4.2.1.11. XRPD diffractograms were acquired under ambient conditions (25 °C) via transmission on a 96 well plate. The data collection range was 3.0 - 40.0 °20 (degrees 2-theta) with a step size of 0.020 °20 (degrees 2-theta) and a collection time of 0.20 seconds per step. Samples were prepared by placing the powder or slurry onto a 96 well plate.Single Crystal X-ray Diffraction (SXRD)

[0322] A suitable crystal was selected and mounted on a MITIGEN holder in perfluoroether oil. Data was collected on a Rigaku 007HF diffractometer with HF Varimax confocal mirrors, an UG2 goniometer, and HyPix 6000HE detector at 100(2) K using Cu-Ka radiation (1.54178 A), with the crystal kept at a steady T= 100(2) K during data collection.Polarized Light Microscopy

[0323] Optical microscopy was performed using the Nikon Eclipse LV100ND Optical Microscope equipped with 5, 10, 20, 50 and 100x objective lens. The microscope is coupled with a PROMICRA, PROMICAM 3-5CP digital camera. The camera is controlled by the QuickPHOTO MICRO 3.2 software. The camera software measurement tool is calibrated using a transmitted Illumination slide (76 x 26 mm, crossed scale - 20 mm divided into 0.1 mm divisions, 200 divisions of 0.1 mm (100 pm)). Samples were prepared by distributing a powder over a microscope slide.Differential Scanning Calorimetry (DSC)

[0324] DSC data was collected on a TA Instruments Q2000 DSC. A predefined amount of the sample, 2.0 to 10.0 mg, was placed in an aluminum pan and heated at 10 °C / minute from 40 °C to 300 °C or varied as experimentation dictated. A purge of dry nitrogen at 100 mb / minute was maintained over the sample. The instrument control and data acquisition are acquired using Q Advantage software release version 5.5.23. The data was processed and presented using the TA Universal Analysis 2000 software version 4.5A build 4.5.0.5.Dynamic Vapor Sorption (DVS)

[0325] Dynamic Vapor Sorption (DVS) was carried out using the TA Instruments Q5000 SA. A predefined amount of the sample, 2.0 to 10.0 mg, was placed in a platinum pan. The sample was allowed to equilibrate at 50 °C at 0% RH for a period of 60 minutes. The sample was then equilibrated at 25 °C before ramping the humidity from 0 to 95% RH at 5% increments every hour. A similar ramp profile was used for desorption cycle. XRPD analysis was also performed on post DVS samples. Mass change by DVS is related to hygroscopicity.Thermal Gravimetric Analysis (TGA)

[0326] TGA data was collected on a TA Instruments Q5000 TGA. A predefined amount of the sample, 2.0 to 10.0 mg, was placed in an aluminum pan and heated at 10 °C / minute from 40 °C to 300 °C, or varied as experimentation dictated. A purge of dry nitrogen at 25 mb / minute was maintained over the sample. The instrument control and data acquisition are acquired using Q Advantage software release version 5.5.23. The data was processed and presented using the TA Universal Analysis 2000 software version 4.5A build 4.5.0.5.HPLC Assay Method 1

[0327] Column: Poroshell 120 Phenyl-Hexyl, 150 x 4.6 mm, 2.7 pm; Flow Rate: 1.0 mL / min;Column Temperature: 40 °C; Mobile Phase A: Water + 0.1% (v / v) trifluoroacetic acid (TFA); Mobile Phase B: Acetonitrile + 0.05% (v / v) TFA; Run Time: 22 minutes; Injection Volume: 5 pL; Detection: UV at 262 nm. Gradient: see Table A.Karl Fisher Titration

[0328] KF titration for water determination was performed using a Mitsubishi Moisture meter Model CA-200. Aquamicron AX or CXU was used as the reagent. Samples of approximately 100 mg were weighed in a glass weighing boat (variable W). After transferring the sample into the KR titration cell, the empty glass weighing boat was weighed (variable w). Direct titration was performed in duplicate, and mean water content was reported in % w / w.

[0329] The water content in % w / w in the sample was calculated according to the following equation: Water content of sample (% w / w) = (M / W-w) x (100 / 1,000,000), where M = amount of water measured in the sample titration (ug); W = weight of the weighing boat and sample (g); w = weight of empty weighing boat after transferring sample to the KF titration cell (g); (W -w) = weight of material transferred (g); 1,000,000 = factor to convert ug to g; and 100 = factor to convert result to 0 / / o.Example 1. Crystalline Form I and II Freebases(i) Form I / II mixture

[0330] 40 g of Compound 1 free base was dissolved in 330 mb ethanol (EtOH), and the solution was separated by chiral HPLC with the following conditions: CHIRAL ART Amylose-SA, 7*25cm,10um; mobile phase A: hexanes, mobile phase B: ethanol (EtOH) with 0.1% 7M NH3in methanol(MeOH); isocratic 50% B in 15 min; detector: UV 220 nm. The purified Compound 1 was obtained as light-yellow solid after concentration, which was then suspended in 200 mL n-heptanes and treated by wet milling at 20-25 °C. The solid was filtered, washed with 40 mL n-heptanes, and dried at approximately 50 °C under vacuum.

[0331] The solid was determined to be a mixture of two crystalline Compound 1 freebase forms: designated Form I and Form II freebases by XRPD. Competitive slurry experiments were performedby stirring a saturated suspension of the Form I / II freebase mixture in either methanol (MeOH) or ethanol (EtOH) at 500 RPM at 25 °C for a period of time. For example, in one experiment, approximately 200 mg of the Form I / II freebase mixture was added to a 7 mb vial. An appropriate amount of MeOH was added to form a slurry and the vial was capped and stirred at 25 °C at 500 RPM for 24 hours. The solids were then filtered and analyzed by XRPD, confirming Form II freebase reverted to Form I freebase, thereby identifying Form I freebase as the more thermodynamically stable form of the two forms. See FIG. 1A, comparing the XRPD of the Form I / II freebase mixture to the XRPD after the slurry experiment; see FIG. 2A, providing the XRPD of pure-phase Form I freebase; and see FIG. IB, identifying the signals attributed to Form II freebase. See also Table B(it) Form I

[0332] Single crystals suitable for single crystal X-ray diffraction (SXRD) analysis were obtained from dissolving 40 mg of Compound 1 freebase in 20% v / v methanol / isopropyl acetate. The sample was temperature cycled between 0-50 °C at 5 °C / min heating rate and 0. 1 °C / min cooling rate and 20 minutes isotherm at 0 °C after each cycle. A total of 15 cycles were applied. Thin block like crystals approximately 50-190 pm in length were obtained and analyzed by polarized light microscopy (PLM). See FIG 2D. A comparison of a simulated XRPD of the single crystal to the experimental Form I freebase XRPD, confirming the single crystals are consistent with, and thus correspond to, Form I freebase. See FIG. 2E.

[0333] Table D provides the crystal structure data and structural refinement parameters from the SXRD analysis. The crystal structure was refined into the tetragonal space group P4;,2|2 (no. 96). The asymmetric unit comprises one molecule of Compound 1 freebase, with eight asymmetric units in the unit cell and with no solvent accessible voids. See FIGS. 2F-2H, providing the crystalline packing viewed down the a axis (FIG. 2F), b axis (FIG. 2G), and c axis (FIG. 2H).

[0334] Large-scale preparation of Form I from ethanol / water, followed by ethanol / n-heptanes, provided bulk crystalline material having a particle size distribution diameter DIO to D90 range of about 9 microns to about 142 microns, and having a particle size distribution mean D50 value of about 22 microns. See Table E. The large-scale preparation is as follows: (1) Charge Compound 1 freebase (5 kg) and water (15 V). (2) Slurry for at least 2 hours. (3) Filter, wash w / 2 V water. (4) Recharge water-wet cake to reactor. (5) Charge water (2.5 V minus water on cake), and ethanol (42.5 V). (6) Polishing fdtration. (7) Concentrate to 5.5 V at <50 °C. (8) Add ethanol (10 V) and concentrate to 5.5 V. (9) Add ethanol (5 V), concentrate to 5.5 V. (10) Target <2.5% wt / v water. (11) Charge n-heptanes (11 V). (12) Filter, wash with 2 V of 1:2 ethanol-n-heptanes twice. (13) Dry at 45 °C. and (14) Store at 15-25 °C.

[0335] Thermogravimetric Analysis (TGA) of Form I shows a decomposition temperature of270.5 °C. No significant weight loss was observed between 20-150 °C, corroborating Form I freebase is anhydrous and not solvated. See FIG. 2B.

[0336] Differential Scanning Calorimetry (DSC) of Form I shows no endothermic events observed in the DSC scan between 30-170 °C, further corroborating Form I is anhydrous and not solvated. The endothermic melt was observed at 205.8 °C (onset), with a peak at 207.2 °C, and a heat of fusion of 123.8 J / g. See FIG. 2C.

[0337] Dynamic Vapor Sorption (DVS) indicated Form I had water uptake of 2.5% weight gain between 0-80% relative humidity (RH), with <1% weight gain between 30-60% RH, but that all the adsorbed water was lost during the drying cycle, indicating Form I is reversibly hygroscopic. XRPD of the material after the DVS analysis showed that the Form I crystalline phase was unchanged,supporting the position that Form I is a stable crystalline form.

[0338] Long term stability studies (at 25 °C ± 2 °C / 60% ± 5% relative humidity (RH)) and accelerated stability studies (at 40 °C ± 2 °C / 75% ± 5% RH) were also conducted on Form I freebase. See Tables F and G, respectively. Assay (% w / w) and purity levels (% area) were determined following HPLC Assay Method 1, and water content determined by Karl Fisher titration. As shown, the Form I freebase form is maintained over a period of 3 months under both low and high stress conditions, confirming Form I freebase is stable and exhibits low water absorption.(iii) Form II

[0339] 'H NMR analysis confirmed that the crystalline Form I / II freebase mixture contained approximately 0.3 molar equivalents of ethanol (EtOH). Data not shown. Taken together with the above analysis of Form I freebase, the NMR result suggests Form II freebase is an EtOH solvate, containing EtOH trapped in the Form II freebase crystalline lattice.

[0340] Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) of the Form I / II freebase mixture further supports the suggestion that Form II freebase is an EtOH solvate.

[0341] For example, TGA of the Form I / II mixture demonstrated approximately 1.7% weight loss attributed to residual EtOH solvent loss and another 3.5% step weight loss attributed to loss of approximately 0.3 equivalents of bound EtOH (trapped solvent), followed by onset of thermal decomposition at 275 °C. See FIG. 1C, lower scan.

[0342] DSC of the Form I / II freebase mixture demonstrated a broad endothermic event with onset temperature at 115 °C and peak at 117 °C, and the high temperature at which this event occurred suggested solvent loss, and that the solvent was strongly bound within the crystalline lattice. This endothermic event was followed by a second endothermic melt with onset at 201 °C and peak at 204 °C, with a heat of fusion of 96.08 J / g. See FIG. 1C, upper scan. This second endothermic melt is alsoconsistent with conversion of Form II freebase into Form I freebase, as Form I freebase exhibited a similar endothermic melt. Compare the upper scan, second endothermic event of FIG. 1C to the single endothermic event observed in the DSC of pure Form I provided in FIG. 2C.

[0343] Form I / II freebase mixture experienced approximately 4.3% water uptake between 0-80% relative humidity (RH) by Dynamic Vapor Sorption (DVS), demonstrating the mixture is hygroscopic, a result which is also consistent with the DVS analysis of pure Form I freebase, finding Form I freebase to be reversibly hygroscopic. The XRPD post-DVS analysis also confirmed Form II freebase had fully desolvated to Form I freebase. See Form I / II freebase post-DVS XRPD in FIG. 1A.Example 2. Crystalline Form III

[0344] Approximately 150 mg of a mixture of Form I / II freebase was added to a 14 mL vial. 11 mL of 27.3% v / v methanol (MeOH) / 2 -butanol were added to fully dissolve solids. The vial was then uncapped and left to fast evaporate at 50 °C under N2 flow until all solvents were evaporated. The crystalline solid was collected and analyzed by XRPD to confirm a new freebase form of Compound 1, referred to herein as Form III freebase. See FIG. 3A for the XRPD of Form III freebase. See also Table H, providing the XRPD signals for Form III freebase.

[0345] Differential scanning calorimetry (DSC) of Form III freebase showed a single endothermic event at 200 °C (onset), suggesting Form III freebase is anhydrous and non-solvated, with a peak at 204 °C, and heat of fusion of 123.7 J / g, See FIG. 3B forthe DSC scan of Form III freebase.

[0346] Competitive slurry experiments were performed with a mixture of Form I / III freebase at 5 °C, 25 °C and 50 °C in methanol (MeOH). All solids isolated after 24 hours had fully converted to Form I freebase, as determined by XRPD, thereby identifying Form I freebase as the more thermodynamically stable form of the two forms.OTHER EMBODIMENTS

[0347] It should be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure also consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are understood to be included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0348] This application refers to various patents and publications, each of which is incorporated herein by reference. If there is a conflict between any of the incorporated references and the present disclosure, the present disclosure shall control.

[0349] The foregoing has been described of non-limiting embodiments of the present disclosure. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

AMENDED CLAIMS received by the International Bureau on 07 February 2025 (07.02.2025)1.

2. The crystalline form of claim 1, having an X-ray powder diffraction signal at 8.6 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

3. The crystalline form of claim 1 or claim 2, having an X-ray powder diffraction signal at 17.3 ± 0.2 or 22.9 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

4. The crystalline form of any one of the preceding claims, having X-ray powder diffraction signals at 8.6 ± 0.2, 17.3 ± 0.2, and 22.9 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

5. The crystalline form of any one of the preceding claims, having at least one additional X-ray powder diffraction signal at 19. 1 ± 0.2 or 23.7 ± 0.2 °20 using Cu K alpha radiation when measured at 25 °C.

6. The crystalline form of any one of the preceding claims, having at least one additional X-ray powder diffraction signal at 16.7 ± 0.2, 21.9 ± 0.2, 27.3 ± 0.2, or 30.8 ± 0.2 using Cu K alpha radiation when measured at 25 °C.

7. The crystalline form of any one of the preceding claims, having at least one additional X-ray powder diffraction signal at 11.4 ± 0.2, 11.8 ± 0.2, 12.2 ± 0.2, 14.7 ± 0.2, 16.2 ± 0.2, 16.4 ± 0.2, 18.1 ±0.2, 18.3 ± 0.2, 18.6 ± 0.2, 20.3 ± 0.2, 24.4 ± 0.2, 24.7 ± 0.2, 25.1 ± 0.2, 25.9 ± 0.2, 26.1 ± 0.2, 26.4 ±0.2, 28.6 ± 0.2, 28.9 ± 0.2, 29.3 ± 0.2, 29.5 ± 0.2, 30.0 ± 0.2, 31.6 ± 0.2, 32.6 ± 0.2, 32.8 ± 0.2, 33.3 ±0.2, 33.8 ± 0.2, 34.0 ± 0.2, 34.8 ± 0.2, 35.2 ± 0.2, 36.2 ± 0.2, 36.7 ± 0.2, 37.3 ± 0.2, 38.1 ± 0.2, 38.7 ±0.2, or 39.4 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

8. The crystalline form of any one of the preceding claims, characterized by a single endothermic event between about 205 °C to about 208 °C, as measured by differential scanning calorimetry (DSC).

9. The crystalline form of any one of the preceding claims, characterized by decomposition between about 270 °C to about 271 °C, as measured by thermogravimetric analysis (TGA).

10. The crystalline form of any one of the preceding claims, wherein the form is reversibly hygroscopic and not solvated.

11. The crystalline form of any one of the preceding claims, wherein the form is stable for 3 months under long term and / or accelerated stability study conditions.

12. The crystalline form of any one of the preceding claims, having a particle size distribution mean D50 value of about 22 microns.

13. The crystalline form of any one of the preceding claims, characterized by having an X-ray powder diffraction pattern substantially similar to that as set forth in FIG. 2A.

14. The crystalline form of claim 1, wherein the crystalline freebase form is pure-phase Form I.

15. The crystalline form of claim 1, having an X-ray powder diffraction signal at 6.6 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

16. The crystalline form of claim 1 or claim 15, having an X-ray powder diffraction signal at 8.3 ± 0.2 or ± 12.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

17. The crystalline form of claim 1 or any one of claims 15-16, having X-ray powder diffraction signals at 6.6 ± 0.2, 8.3 ± 0.2, and ± 12.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

18. The crystalline form of claim 1 or any one of claims 15-17, having at least one additional X- ray powder diffraction signal at 18.7 ± 0.2, 20.9 ± 0.2, or 21.8 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

19. The crystalline form of claim 1 or any one of claims 15-18, having at least one additional X- ray powder diffraction signal at 6.2 ± 0.2, 7.1 ± 0.2, 7.8 ± 0.2, 8.6 ± 0.2, 9.9 ± 0.2, 10.1 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 11.8 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 13.5 ± 0.2, 13.8 ± 0.2, 14.1 ± 0.2, 14.4 ± 0.2, 14.7 ±0.2, 15.3 ± 0.2, 15.5 ± 0.2, 16.2 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 17.3 ± 0.2, 17.7 ± 0.2, 17.9 ± 0.2, 18.1 ±0.2, 19.1 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.2 ± 0.2, 22.3 ± 0.2, 22.6 ± 0.2, 23.3 ± 0.2, 23.8 ± 0.2, 24.0 ±0.2, 24.4 ± 0.2, 24.7 ± 0.2, 25.2 ± 0.2, 25.8 ± 0.2, 26.5 ± 0.2, 26.9 ± 0.2, 27.0 ± 0.2, 28.0 ± 0.2, 28.5 ±0.2, 28.8 ± 0.2, 29.7 ± 0.2, 30.5 ± 0.2, 30.8 ± 0.2, 31.1 ± 0.2, 35.0 ± 0.2, 36.2 ± 0.2, 37.4 ± 0.2, 37.6 ±0.2, 38. 1 ± 0.2, 39.2 ± 0.2, or 39.5 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

20. The crystalline form of claim 1 or any one of claims 15-19, characterized by a single endothermic event between about 200 °C to about 204 °C, as measured by differential scanning calorimetry (DSC).

21. The crystalline form of claim 1 or any one of claims 15-20, characterized by having an X-ray powder diffraction pattern substantially similar to that as set forth in FIG. 3A.

22. The crystalline form of claim 1, wherein the crystalline freebase form is pure-phase Form III.

23. The crystalline form of claim 1, having an X-ray powder diffraction signal at 7.2 ± 0.2, using Cu K alpha radiation when measured at 25 °C.

24. The crystalline form of claim 1 or claim 23, having an X-ray powder diffraction signal at 13.9 ± 0.2 or 15.7 ± 0.2, °20, using Cu K alpha radiation when measured at 25 °C.

25. The crystalline form of claim 1 or any one of claims 23-24, having X-ray powder diffraction signals at 7.2 ± 0.2, 13.9 ± 0.2, and 15.7 ± 0.2, °20 using Cu K alpha radiation when measured at 25 °C.

26. The crystalline form of claim 1 or any one of claims 23-25, having at least one additional X- ray powder diffraction signal at 7.8 ± 0.2, 10.3 ± 0.2, or 19.6 ± 0.2 °20 using Cu K alpha radiation when measured at 25 °C.

27. The crystalline form of claim 1 or any one of claims 23-26, having at least one additional X- ray powder diffraction signal at 6.6± 0.2, 10.7 ± 0.2, 13.0 ± 0.2, 15.5 ± 0.2, 20.7 ± 0.2, 28.3 ± 0.2, or 31.3 ± 0.2 °20, using Cu K alpha radiation when measured at 25 °C.

28. The crystalline form of claim 1 or any one of claims 23-27, characterized by having each of XRPD signals 1-13 as set forth in Table 3.

29. A composition comprising aa mmiixxttuurree of (R)-2-(4-((5,5-dimethyltetrahydrofuran-3- yl)amino)pyrido[3,4-d]pyridazin-l-yl)-5-methylphenol (Compound 1) freebase forms, wherein 75% (w / w%) of the mixture is the crystalline form of any one of claims 2-14.

30. The composition of claim 29, wherein 95% (w / w%) of the mixture is the crystalline form of any one of claims 2-14.

31. The composition of claims 29 or 30, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

32. A pharmaceutical composition comprising the crystalline form of any one of claims 1-28, and one or more pharmaceutically acceptable carriers.

33. A method of treating or preventing a disease or disorder, the method comprising administering to a subject the crystalline form of any one of claims 1-28, or the composition of any one of claims 29- 32.

34. The method of claim 33, wherein the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disease of the muscles, an inflammatory disorder, an autoimmune disorder, cancer, an infection, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, pain (including disorders related to pain management), an NLRP3- related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3, or obesity.

35. A method of preparing the crystalline form of Compound 1 freebase of any one of claims 1- 28, as described herein and / or in the Examples.

36. The method of claim 35, wherein the crystalline form is pure-phase Form I.

37. The method of claim 36, wherein Form II is converted to Form I to provide the pure-phase Form I.

38. The method of claim 36, wherein Form III is converted to Form I to provide the pure-phase Form I.

39. The method of claim 35, wherein the crystalline form is pure-phase Form III.

Images