Solid forms of complement factor B inhibitors

Abstract

The present disclosure relates to crystalline forms of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid, and pharmaceutical compositions and uses thereof.

Description

[Technical Field]

[0001] Priority claims This application claims priority to U.S. Patent Application No. 63 / 425,206, filed November 14, 2022, the entire contents of which are incorporated herein by reference, including any drawings.

[0002] Disclosed herein are crystalline forms of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and the p-toluenesulfonate salt of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. [Background technology]

[0003] The complement system is a critical component of the innate immune system, with two primary functions: host defense against microbial pathogens and clearance of apoptotic cells. Since its initial discovery by Jules Bordet and Paul Ehrlich in the 1890s, over a century of research on complement has revealed its diverse roles in immune responses, surveillance, homeostasis, and metabolism (Hajishengallis, Nat Immunol 2017 18:1288-1298; Sim, Immunobiology 2016 221(10):1037-1045; Ricklin, Nat Immunol 2010 11(9):785-797). The complement system comprises a large number of soluble proteins found in the circulation and tissues as inactive zymogens that are activated upon serine protease cleavage. Complement activation is tightly regulated by both plasma and membrane-bound regulatory factors. Genetic mutations, autoantibodies, or dysregulation of complement activity during chronic inflammation have been found to cause tissue damage in a variety of pathological conditions, including autoimmunity, inflammation, and neurodegeneration, and in a wide range of renal diseases (Zipfel, Nat Rev Immunol 2009 9:729-749; Holers, Annu Rev Immunol 2014 32:433-459).

[0004] There are three activation pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP) (Merle, Front Immunol 2015 6:262). The CP is activated by immunoglobulins (IgG and IgM) and immune complexes through the binding of C1q to the Fc domain (Botto, Annu Rev Immunol 2002 205:395-406). The LP is activated by a group of proteins that bind to sugars on the surface of microorganisms, such as mannose-binding lectin (MBL) (Garred, Immunol Rev 2016 274(1):74-97). In contrast to the other two pathways, which require specific stimuli for activation, AP maintains a low level of activation in plasma through a spontaneous hydrolysis process called "tickover," and the other two complement pathways can also be activated secondarily (Lachmann, Adv Immunol 2009 104:115-149). AP rapidly forms a self-amplifying loop unless inactivated by factor H and factor I. The three activation pathways generate a protease complex (C3bBb and C4b2a) called the "C3 convertase" that cleaves C3 and forms C3bBbC3b as the C5 convertase. The terminal complement pathway combines C5b with other complement proteins to form the C5b-9 membrane attach complex (MAC), which mediates the lysis of pathogens or apoptotic cells (Bhakdi, Immunol Today 1991 12:318-320). Two soluble fragments of the cleavage products of C3 and C5, C3a and C5a, also called "anaphylatoxins," are potent chemoattractants that trigger proinflammatory responses through their receptors (Klos, Mol Immunol 2009 46(14):2753-2766).

[0005] Complement hyperactivation and renal deposition are observed in various chronic kidney diseases (CKD), including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), IgA nephropathy (IgAn), membranous nephropathy (MN), ANCA-associated vasculitis (AAV), focal segmental glomerulosclerosis (FSGS), and lupus nephritis (LN) (Harris, Semin Immunopathol 2018 40(1):125-140; Willows, Clin Med 2020 20(2):156-160). Preclinical and clinical evidence supports the role of complement, particularly AP, in disease initiation and progression. Genetic defects in complement genes, such as CFH, CFI, CFHR, CFB, C3, and MCP / CD46, are directly associated with aHUS and C3G (Bu, J Am Soc Nephrol 2014 25(1):55-64; Marinozzi, J Am Soc Nephrol 2015 25:2053-2065; Xiao, Semin Thromb Hemost 2014 40(4):465-471). Complement activation by autoantibodies and immune complexes in the kidneys causes renal injury and contributes to disease progression in multiple glomerular diseases (Corvillo, Front Immunol 2019 10:886; Marinozzi, J Am Soc Nephrol 2017 28(5):1603-1613; Seikrit, N Engl J Med 2018 379(25):2479-2481).Recent studies have provided evidence of local renal production and activity of complement proteins in CKD, including IgAN and diabetic kidney disease (Muehlig, Front Immunol 2020 11:1833; Zhou, Clin J Am Soc Nephrol 2021 16(2):213-224; Kelly Am J Nephrol 2015 41:48-56). Local production of complement in the kidney and its unique microenvironment make the organ more susceptible to complement overactivation (Thurman, Clin J Am Soc Nephrol 2020 11:1856).

[0006] Considerable effort has been directed toward the development of complement-targeted therapies. Eculizumab is a C5 monoclonal antibody approved for the treatment of aHUS. However, when tested with C3G, only a subset of patients with higher levels of C5b-9 (MAC) showed disease improvement. This is thought to be due to the contribution of activation fragments upstream of the C3 level in the terminal pathway (Vivarelli, Semin Thromb Hemost 2014 40(4):472-477). Multiple therapeutic agents targeting different complement pathways are currently in development, each with their own advantages and limitations (Zipfel, Front Immunol 2019 10:2166; Thurman, Kidney Int 2016 90(4):746-752). Nevertheless, there remains a need for potent therapeutic compounds that block both the C3 and C5 levels of the complement system.

[0007] As a key enzyme in the AP, CFB provides a highly desirable target for interrupting the central amplification loop and the terminal complement pathway. CFB knockout has been shown to be effective in rodent models of C3G (Pickering, Nat Genet 2002 31(4):424-428), MN (Luo, Front Immunol 2018 9:1433), ANCA-associated vasculitis (Xiao, Am J Pathol 2007 170(1):52-64), LN (Watanabe, J Immunol 2000 164(2):786-794), and multiple renal injury models (Thurman, Am J Physiol Renal Physiol 2012 302:F1529-F1536; Casiraghi, Am J Transplant 2017 17:2312-2325; Morigi, Sci Rep 2016). 6:8445). Genetic deficiency of CFB in these models results in reduced proteinuria, protection from renal damage, and prolonged survival. Like many complement proteins, CFB circulates in its native form at high plasma concentrations of 300–400 μg / mL. Recently, the selective CFB inhibitor iptacopan (LNP023) has been shown to bind to active CFB (Schubart Proc Natl Acad Sci U S A. 2019 116(16):7926–7931). In a phase II clinical trial in C3G, iptacopan demonstrated promising efficacy, reducing proteinuria after 12 weeks of treatment (Wong, J Am Soc Nephrol 2020 31:55A).

[0008] However, variability in complement activity and patient response has also been observed, indicating that highly potent compounds with stronger and more durable complement inhibition in vivo may offer greater therapeutic benefit to patients with C3G and widespread CKD. Therefore, it would be desirable to provide compounds that inhibit complement factor B.

[0009] (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid, of formula I below, is disclosed in PCT / US2022 / 032042, filed June 3, 2022, and entitled "SUBSTITUTED INDOLE COMPOUNDS AND METHODS OF USE THEREOF," the entire contents of which are incorporated herein by reference. [ka]

[0010] The solid-state form of a particular drug's active pharmaceutical ingredient (API) is often a key determinant of that drug's ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability. Salt formation is a technique for optimizing the above-mentioned properties of ionizable drug candidates. Crystal forms arise when substances of the same composition crystallize in different lattice arrangements, regardless of the presence of counterions, resulting in different thermodynamic properties and stability inherent to a particular crystalline form. Crystal forms may also include different hydrates or solvates of the same compound. When determining which form is preferred, multiple properties of the forms are compared, and the preferred form is selected based on many physical property variables. It is entirely possible that one form may be preferred in some situations where certain aspects, such as ease of preparation or stability, are important. In other situations, a different form may be preferred due to a higher dissolution rate and / or better bioavailability. It remains impossible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in therapeutic compositions, or whether any polymorphs will exhibit such desirable properties. Summary of the Invention

[0011] Disclosed herein is a crystalline form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0012] In some embodiments, the crystalline form is Form A as described herein.

[0013] In some embodiments, Form A is (a) adding (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid to isopropanol with stirring at about 40° C. to about 50° C. to form an approximately 0.44 molar solution; (b) cooling the solution to about 20°C and stirring for about 72 hours to form a suspension; (c) filtering the suspension to obtain a solid; (d) washing the solid with isopropanol; (e) drying the solid to provide Form A.

[0014] Disclosed herein is a crystalline p-toluenesulfonate salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0015] In some embodiments, the crystalline form is Form B as described herein.

[0016] In some embodiments, Form B is (a) adding ethanol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein the ethanol is about 3.5 volumes relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid; (b) heating the suspension to about 50°C and stirring for about 15 minutes to form a solution; (c) cooling the solution to about 25° C. over about 15 minutes, and then adding about 2.5 volumes of ethyl acetate; (d) adding about 7.5 volumes of ethyl acetate over 2 hours at about 25° C., then allowing the slurry to stand at about 25° C. for about 1 hour; (e) filtering the slurry to obtain a solid; (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) drying the solid to provide a solid form; (h) adding the solid form to a binary mixture of isopropanol and water in a volume ratio of about 9:1, and then heating at about 50° C. for about 16 hours to form a slurry; (i) cooling the slurry to about 25°C and filtering to obtain a solid; (j) drying the solid at about 50° C. to provide Form B.

[0017] In some embodiments, the crystalline form is Form C as described herein.

[0018] In some embodiments, Form C is (a) adding ethanol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein the ethanol is about 3.5 volumes relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid; (b) heating the suspension to about 50°C and stirring for about 15 minutes to form a solution; (c) cooling the solution to about 25° C. over about 15 minutes, and then adding about 2.5 volumes of ethyl acetate; (d) adding about 7.5 volumes of ethyl acetate over 2 hours at about 25° C., then allowing the slurry to stand at about 25° C. for about 1 hour; (e) filtering the slurry to obtain a solid; (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) drying the solid to provide Form C.

[0019] Disclosed herein is a crystalline hydrochloride salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0020] In some embodiments, the crystalline form is Form D as described herein.

[0021] In some embodiments, Form D is (a) preparing a solution of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in about 5.5 volumes of ethyl acetate; (b) adding about 0.55 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate; (c) adding a slurry of crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid hydrochloride in ethyl acetate to form a suspension; (d) adding about 1.65 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate to form a slurry; (e) stirring the slurry at about 24°C for about 16 hours; (f) filtering the slurry to obtain a solid; (g) washing the solid with ethyl acetate; (h) drying the solid to provide Form D.

[0022] Some embodiments provide a pharmaceutical composition comprising one of Form A, Form B, Form C, or Form D and a pharmaceutically acceptable carrier.

[0023] Some embodiments provide a pharmaceutical composition comprising Form A and a pharmaceutically acceptable carrier.

[0024] Some embodiments provide a pharmaceutical composition comprising Form B, Form C, or Form D and a pharmaceutically acceptable carrier.

[0025] Disclosed herein is a method of treating a disease or disorder associated with complement factor B (CFB), comprising administering to a subject having such disease or disorder a therapeutically effective amount of Form A, Form B, Form C, or Form D, or a pharmaceutical composition comprising Form A, Form B, Form C, or Form D and a pharmaceutically acceptable carrier.

[0026] Disclosed herein are methods for treating a disease or disorder associated with Complement Factor B (CFB), comprising administering to a subject having such disease or disorder a therapeutically effective amount of Form A, Form B, Form C, or Form D, or a pharmaceutical composition comprising Form B, Form C, or Form D and a pharmaceutically acceptable carrier.

[0027] Some embodiments provide a method of treating or preventing a disease or disorder selected from the group consisting of an autoimmune disease or disorder, an inflammatory disease or disorder, a metabolic disease or disorder, a neurological disease or disorder, a pulmonary disease, a respiratory disease or disorder, an ocular disease, a cardiovascular disease, and a renal disease, comprising administering to a subject having such disease or disorder a therapeutically effective amount of Form A, Form B, Form C, or Form D, or a pharmaceutical composition comprising Form A, Form B, Form C, or Form D and a pharmaceutically acceptable carrier.

[0028] Some embodiments provide a method of treating or preventing a disease or disorder selected from the group consisting of an autoimmune disease or disorder, an inflammatory disease or disorder, a metabolic disease or disorder, a neurological disease or disorder, a pulmonary disease, a respiratory disease or disorder, an ophthalmic disease, a cardiovascular disease, and a renal disease, comprising administering to a subject having such disease or disorder a therapeutically effective amount of Form A, Form B, Form C, or Form D, or a pharmaceutical composition comprising Form B, Form C, or Form D and a pharmaceutically acceptable carrier.

[0029] As used herein, when used to refer to modifying a numerical value, the term "about" encompasses a range of uncertainty for the numerical value, which is 0% to 10% of the numerical value.

[0030] The terms "polymorph" and "polymorphic form" refer to different crystalline forms of a single compound. That is, "polymorphs" are distinct solids that share the same molecular formula, but each polymorph may have distinct solid-state properties. Thus, a single compound can occur in a variety of polymorphic forms, each with different distinct solid-state physical properties, such as a different solubility profile, dissolution rate, melting point temperature, fluidity, and / or different X-ray diffraction peaks.

[0031] As used herein, the term "amorphous" refers to a solid in a solid state that is in a non-crystalline state. Amorphous solids are those of a disordered arrangement of molecules and therefore do not have a distinguishable crystal lattice or unit cell and, as a result, no indefinable long-range order. The solid-state form of a solid may be determined by polarized light microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art.

[0032] As used herein, a compound is "substantially pure" if the compound contains insignificant amounts of other components. Such components may include, for example, starting materials, residual solvents, other polymorphs or crystalline forms, other enantiomers, other salt forms, other solvates, or any other impurities that may be obtained by the preparation, isolation, and / or recrystallization of the compounds provided herein. In some embodiments, other components may include, for example, starting materials, residual solvents, other polymorphs or crystalline forms, other enantiomers, other salt forms, or any other impurities that may be obtained by the preparation, isolation, and / or recrystallization of the compounds provided herein. In some embodiments, a solid form (e.g., a particular crystalline form or salt) of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is "substantially pure" if the solid form consists of at least about 95% by weight of the solid form. In some embodiments, a solid form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is "substantially pure" if the solid form consists of at least about 97%, about 98%, about 99%, or about 99.5% by weight of the solid form.

[0033] The terms "effective amount" and "therapeutically effective amount" are used interchangeably herein and refer to an amount of an active compound or pharmaceutical agent that elicits a biological or medicinal response in an animal or human that is recognized by a tissue system, researcher, veterinarian, physician, or other clinician, including alleviation of the symptoms of the disease or disorder being treated. In particular, an effective amount, when administered to a subject in need of such treatment, is sufficient to (i) treat or prevent the particular disease, condition, or disorder treatable with an inhibitor of CFB, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of the crystalline forms described herein that corresponds to such a therapeutically effective amount will vary depending on factors such as the condition and its severity of the disease, and the identity (e.g., weight) of the mammal in need of treatment.

[0034] The term "free form" refers to the compound in its non-salt form.

[0035] The term "hydrate" refers to a compound or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The term "anhydrate" refers to a compound or a salt thereof that does not include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0036] The term "pharmaceutical composition" as used herein is intended to encompass a product containing an active ingredient and an inactive ingredient that constitutes a carrier, as well as any product resulting directly or indirectly from the combination, complex formation or aggregation of any two or more of the ingredients, or the dissociation of one or more of the ingredients, or any other type of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical composition of the present disclosure encompasses any composition made by mixing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

[0037] The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, which does not destroy its pharmacological activity and which is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

[0038] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as a human.

[0039] The terms "treat," "treating," and "treatment," in reference to the treatment of a disease or disorder, are meant to include reducing or eliminating the disorder, disease, or condition or one or more symptoms associated with the disorder, disease, or condition, or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0040] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0041] [Figure 1] FIG. 1 is an X-ray powder diffractogram of amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. [Figure 2] 1 is an X-ray powder diffractogram of Form A. [Figure 3] 1 is a thermogravimetric analysis thermogram of Form A. [Figure 4] 1 is a differential scanning calorimetry pattern of Form A. [Figure 5] 1 is an X-ray powder diffractogram of Form A (alternate preparation). [Figure 6] 1 is a differential scanning calorimetry pattern of Form A (alternative preparation). [Figure 7] 1 is a thermogravimetric analysis thermogram of Form A (alternative preparation). [Figure 8] 1H NMR spectrum of Form A (alternate preparation). [Figure 9] 1 is a scanning electron microscope image of Form A (alternative preparation). [Figure 10] 1 is an intrinsic dissolution rate curve for Form A (alternate preparation) in pH 2.0 HCl buffer. [Figure 11] 1 is an intrinsic dissolution rate curve for Form A (alternative preparation) in pH 6.5 phosphate buffer. [Figure 12-1] 1 is an X-ray powder diffractogram of Form B. [Figure 12-2] (As mentioned above.) [Figure 13] 1 is a thermogravimetric analysis thermogram of Form B. [Figure 14] 1 shows the differential scanning calorimetry pattern of Form B. [Figure 15] 1 is an X-ray powder diffractogram of Form B (alternate preparation). [Figure 16] 1 is a differential scanning calorimetry pattern of Form B (alternative preparation). [Figure 17] 1 is a thermogravimetric analysis thermogram of Form B (alternative formulation). [Figure 18] 1H NMR spectrum of Form B (alternate preparation). [Figure 19] 1 is a scanning electron microscope image of Form B (alternative preparation). [Figure 20] 1 is the intrinsic dissolution rate of Form B in pH 2 buffer. [Figure 21] 1 is the intrinsic dissolution rate of Form B in pH 6.5 buffer. [Figure 22] 1 is a dissolution profile of capsules containing Form B. [Figure 23] 1 is an X-ray powder diffractogram of Form C. [Figure 24] 1 is a thermogravimetric analysis thermogram of Form C. [Figure 25] 1 is a differential scanning calorimetry pattern of Form C. [Figure 26-1] 1 is an X-ray powder diffractogram of Form D. [Figure 26-2] (As mentioned above.) [Figure 27] 1 is a thermogravimetric analysis thermogram of Form D. [Figure 28] 1 is a differential scanning calorimetry pattern of Form D. DETAILED DESCRIPTION OF THE INVENTION

[0042] Featured herein are crystalline forms of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (Formula I below)) and salts thereof. [ka]

[0043] Also provided herein is amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. In some embodiments, the amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is characterized by an XRPD pattern substantially the same as that shown in FIG.

[0044] Form A The present disclosure provides a crystalline form of the free form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (compound of Formula I). ​​In one embodiment, the free form is an anhydrous form. The crystalline form of the free form of the compound of Formula I that is an anhydrous form is referred to herein as Form A. Form A is described and characterized herein.

[0045] In some embodiments, the crystalline form is Form A and the XRPD pattern is substantially the same as that shown in FIG.

[0046] In some embodiments, the crystalline form is Form A and the XRPD pattern is substantially the same as that shown in FIG.

[0047] In some embodiments, the crystalline form is Form A and the XRPD pattern is represented by the peaks shown in the table below.

[0048] [Table A]

[0049] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern with a peak at 10.7±0.2 degrees 2θ. The X-ray powder diffraction pattern of Form A can also include one or more additional characteristic peaks.

[0050] In some embodiments, the X-ray powder diffraction pattern of Form A may also include one or more additional characteristic peaks, which may also be used to identify Form A (e.g., in a sample).

[0051] For example, the XRPD pattern has a peak at 20.5±0.2 degrees 2θ.

[0052] For example, the XRPD pattern has a peak at 18.8±0.2 degrees 2θ.

[0053] For example, the XRPD pattern has a peak at 21.7±0.2 degrees 2θ.

[0054] For example, the XRPD pattern has a peak at 19.6±0.2 degrees 2θ.

[0055] For example, the XRPD pattern has a peak at 19.8±0.2 degrees 2θ.

[0056] For example, the XRPD pattern has a peak at 12.5±0.2 degrees 2θ.

[0057] For example, the XRPD pattern has a peak at 21.7±0.2 degrees 2θ.

[0058] For example, the XRPD pattern has a peak at 23.3±0.2 degrees 2θ.

[0059] For example, the XRPD pattern has a peak at 22.5±0.2 degrees 2θ.

[0060] For example, the XRPD pattern has a peak at 27.3±0.2 degrees 2θ.

[0061] For example, the XRPD pattern has a peak at 15.5±0.2 degrees 2θ.

[0062] The X-ray powder diffraction pattern of Form A may also include one or more low-intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0063] For example, the XRPD pattern has a peak at 5.3±0.2 degrees 2θ.

[0064] For example, the XRPD pattern has a peak at 13.7±0.2 degrees 2θ.

[0065] For example, the XRPD pattern has a peak at 16.5±0.2 degrees 2θ.

[0066] For example, the XRPD pattern has a peak at 15.6±0.2 degrees 2θ.

[0067] For example, the XRPD pattern has a peak at 23.5±0.2 degrees 2θ.

[0068] For example, the XRPD pattern has a peak at 16.1±0.2 degrees 2θ.

[0069] For example, the XRPD pattern has a peak at 28.9±0.2 degrees 2θ.

[0070] For example, the XRPD pattern has a peak at 11.3±0.2 degrees 2θ.

[0071] For example, the XRPD pattern has a peak at 26.7±0.2 degrees 2θ.

[0072] For example, the XRPD pattern has a peak at 25.6±0.2 degrees 2θ.

[0073] For example, the XRPD pattern has a peak at 29.2±0.2 degrees 2θ.

[0074] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, and 18.8 (±0.2 degrees 2θ).

[0075] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 18.8, and 21.7 (±0.2 degrees 2θ).

[0076] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 18.8, 21.7, 19.6, 19.8, 12.5, 21.1, 23.3, 22.5, 27.3, and 15.55 (±0.2 degrees 2θ).

[0077] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks (±0.2 degrees 2θ) at 10.7, 20.5, 18.8, 21.7, 19.6, 19.8, 12.5, 21.1, 23.3, 22.5, 27.3, 15.5, 5.3, 13.7, 16.5, 15.6, 23.5, 16.1, 28.7, 11.3, 26.7, 25.6, and 29.2.

[0078] In some embodiments, the crystalline form is Form A and the XRPD pattern has a peak at 10.7 (±0.2 degrees 2θ).

[0079] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7 and 20.5 (±0.2 degrees 2θ).

[0080] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, and 19.5 (±0.2 degrees 2θ).

[0081] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 19.5, and 21.6 (±0.2 degrees 2θ).

[0082] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 19.5, 21.6, and 18.8 (±0.2 degrees 2θ).

[0083] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, and 12.4 (±0.2 degrees 2θ).

[0084] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, and 22.5 (±0.2 degrees 2θ).

[0085] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, and 15.5 (±0.2 degrees 2θ).

[0086] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, and 21.2 (±0.2 degrees 2θ).

[0087] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, and 15.9 (±0.2 degrees 2θ).

[0088] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks (±0.2 degrees 2θ) at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, and 16.3.

[0089] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, 16.3, and 23.2 (±0.2 degrees 2θ).

[0090] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks (±0.2 degrees 2θ) at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, 16.3, 23.2, and 20.9.

[0091] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks (±0.2 degrees 2θ) at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, 16.3, 23.2, 20.9, and 13.6.

[0092] In some embodiments, the crystalline form is Form A and the XRPD pattern has peaks (±0.2 degrees 2θ) at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, 16.3, 23.2, 20.9, 13.6, and 5.3.

[0093] Those skilled in the art will recognize that the relative intensities of peaks in an X-ray powder diffraction pattern can vary depending on the sample preparation technique, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument used. Thus, depending on the type and settings (including filters) of the instrument used, new peaks may be observed in the subsequently obtained pattern, or peaks observed in the previously obtained pattern may have negligible relative intensities (and therefore not be observed) in the subsequently obtained pattern. Thus, the absence of one or more of the lower relative intensity peaks may not, in itself, prove the absence of Form A (e.g., in a sample). However, the presence of the lower relative intensity peaks can generally be used to further prove the presence of Form A in a sample.

[0094] Form A may also have one or more of the following characteristics:

[0095] In some embodiments, the crystalline form is about 150 o C ~ approx. 220 o C (e.g., about 150 o C ~ approx. 190 o C, about 165 o C ~ approx. 205 o C, about 170 o C ~ approx. 220 o C, about 180 o C ~ about 200 o C, about 185 o C ~ approx. 195 o C, about 187 o C ~ approx. 191 o C or about 189 oIn some embodiments, the crystalline form is Form A having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 4% (e.g., about 1% to about 3%, or about 2%) at 189°C. o C is Form A with a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2%.

[0096] In some embodiments, the crystalline form has a pH of about 270 to about 330 (e.g., about 280 o C ~ approx. 320 o C, about 290 o C ~ approx. 310 o C, about 295 o C ~ approx. 305 o C, or about 300 o C) is Form A having a TGA curve characterized by a weight loss of about 15% to about 35% (e.g., about 20% to about 27%, about 23% to about 35%, about 20% to about 30%, about 23% to about 25%). In some embodiments, the crystalline form is Form A having a TGA curve characterized by a weight loss of about 300%. o C is Form A with a TGA curve characterized by a weight loss of about 25%.

[0097] In some embodiments, the crystalline form is Form A, which has a TGA curve substantially the same as that shown in FIG.

[0098] In some embodiments, the crystalline form is Form A, which has a TGA curve substantially the same as that shown in FIG.

[0099] In some embodiments, the crystalline form is Form A having a differential scanning calorimetry (DSC) curve characterized by an onset of melting at about 185° C. to about 220° C., about 190° C. to about 215° C., about 195° C. to about 208° C., about 198° C. to about 207° C., about 200° C. to about 204° C., about 201° C. to about 203° C., or an end of about 201.9° C. In some embodiments, the crystalline form is Form A having a differential scanning calorimetry (DSC) curve characterized by an onset of melting at about 201.9° C.

[0100] In some embodiments, the crystalline form is Form A having a DSC curve substantially the same as that shown in FIG.

[0101] In some embodiments, the crystalline form is Form A having a DSC curve substantially the same as that shown in FIG.

[0102] In some embodiments, Form A has a TGA diagram when heated from 30°C to 300°C at 10 K / min, showing a weight loss of about 0.51% at 150°C.

[0103] In some embodiments, Form A absorbs up to 0.45% water at 25° C. and 95% RH via DVS.

[0104] In some embodiments, the crystalline form is Form A, characterized by a solubility of about 1.8 mg / mL to about 2.8 mg / mL in fasted state simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C., e.g., about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, or any value therebetween. In some embodiments, Form A is characterized by a solubility of about 2.2 mg / mL to about 2.5 mg / mL in fasted state simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, Form A is characterized by a solubility of 2.2 mg / mL to 2.5 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, Form A is characterized by a solubility of about 2.3 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C.

[0105] In some embodiments, the crystalline form is Form A, characterized by a solubility of greater than about 1.7 mg / mL to greater than about 2 mg / mL, e.g., greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, greater than about 2.0 mg / mL, e.g., about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, or about 3.0 mg / mL, or any value therebetween, in simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. under fasting conditions. In some embodiments, Form A is characterized by a solubility of greater than about 1.8 mg / mL to greater than about 1.9 mg / mL in simulated gastric fluid (FaSSGF) under fasting conditions after about 24 hours at about 37° C. In some embodiments, Form A is characterized by a solubility of greater than about 1.9 mg / mL to greater than about 2 mg / mL in artificial gastric fluid (FaSSGF) in the fasted state after about 24 hours at about 37° C. In some embodiments, Form A is characterized by a solubility of about 2 mg / mL in artificial gastric fluid (FaSSGF) in the fasted state after about 24 hours at about 37° C.

[0106] In some embodiments, the crystalline form is Form A, characterized by a solubility of greater than 2 mg / mL in fasted simulated gastric fluid (FaSSGF) at an initial pH of 1.6 at about 25° C. after about 24 hours.

[0107] In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.26 mg / mL to about 0.36 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C., e.g., about 0.26 mg / mL, about 0.27 mg / mL, about 0.28 mg / mL, about 0.29 mg / mL, about 0.30 mg / mL, about 0.31 mg / mL, about 0.32 mg / mL, about 0.33 mg / mL, about 0.34 mg / mL, about 0.35 mg / mL, about 0.36 mg / mL, or any value therebetween. In some embodiments, Form A is characterized by a solubility of about 0.29 mg / mL to about 0.33 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.30 mg / mL to about 0.32 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.31 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C.

[0108] In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.26 mg / mL to about 0.36 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C., e.g., about 0.26 mg / mL, about 0.27 mg / mL, about 0.28 mg / mL, about 0.29 mg / mL, about 0.30 mg / mL, about 0.31 mg / mL, about 0.32 mg / mL, about 0.33 mg / mL, about 0.34 mg / mL, about 0.35 mg / mL, about 0.36 mg / mL, or any value therebetween. In some embodiments, Form A is characterized by a solubility of about 0.30 mg / mL to about 0.32 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.30 mg / mL to about 0.32 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.31 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C.

[0109] In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.18 mg / mL to about 0.28 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C., e.g., about 0.18 mg / mL, about 0.19 mg / mL, about 0.20 mg / mL, about 0.21 mg / mL, about 0.22 mg / mL, about 0.23 mg / mL, about 0.24 mg / mL, about 0.25 mg / mL, about 0.26 mg / mL, about 0.27 mg / mL, about 0.28 mg / mL, or any value therebetween. In some embodiments, Form A is characterized by a solubility of about 0.20 mg / mL to about 0.26 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.23 mg / mL to about 0.25 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.24 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C.

[0110] In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.13 mg / mL to about 0.23 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C., e.g., about 0.13 mg / mL, about 0.14 mg / mL, about 0.15 mg / mL, about 0.16 mg / mL, about 0.17 mg / mL, about 0.18 mg / mL, about 0.19 mg / mL, about 0.20 mg / mL, about 0.21 mg / mL, about 0.22 mg / mL, about 0.23 mg / mL, or any value therebetween. In some embodiments, Form A is characterized by a solubility of about 0.15 mg / mL to about 0.20 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.17 mg / mL to about 0.19 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.18 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C.

[0111] In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.07 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at a starting pH of 6.5 and about 25° C. In some embodiments, the fasted simulated intestinal fluid (FaSSIF) comprises phosphate buffer saline (PBS).

[0112] In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.07 mg / mL in phosphate buffered saline (PBS) after about 24 hours at about 25° C. at a starting pH of 6.5. In some embodiments, the phosphate buffered saline (PBS) comprises sodium taurocholate (NaTC). In some embodiments, the phosphate buffered saline (PBS) comprises 3 mM sodium taurocholate (NaTC).

[0113] In some embodiments, the crystalline form is Form A, characterized by a solubility in water of about 0.16 mg / mL to about 0.26 mg / mL, e.g., about 0.16 mg / mL, about 0.17 mg / mL, about 0.18 mg / mL, about 0.19 mg / mL, about 0.20 mg / mL, about 0.21 mg / mL, about 0.22 mg / mL, about 0.23 mg / mL, about 0.24 mg / mL, about 0.25 mg / mL, about 0.26 mg / mL, or any value therebetween, after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.17 mg / mL to about 0.23 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.20 mg / mL to about 0.22 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.21 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C.

[0114] In some embodiments, the crystalline form is Form A, characterized by a solubility in water of about 0.17 mg / mL to about 0.27 mg / mL, e.g., about 0.17 mg / mL, about 0.18 mg / mL, about 0.19 mg / mL, about 0.20 mg / mL, about 0.21 mg / mL, about 0.22 mg / mL, about 0.23 mg / mL, about 0.24 mg / mL, about 0.25 mg / mL, about 0.26 mg / mL, about 0.27 mg / mL, or any value therebetween, after about 24 hours at a starting pH of about 7.0 and about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.20 mg / mL to about 0.24 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form A is characterized by a solubility of about 0.20 mg / mL to about 0.23 mg / mL in water after about 30 minutes at an initial pH of about 7.0 and about 37° C. In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.22 mg / mL in water after about 24 hours at an initial pH of about 7.0 and about 37° C.

[0115] In some embodiments, the crystalline form is Form A, characterized by a solubility of about 0.05 mg / mL in water at a starting pH of about 7.0 at about 25° C. after about 24 hours.

[0116] In some embodiments, the crystalline form is Form A, which is a substantially pure form. In some embodiments, the crystalline form is Form A, and Form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w). In some embodiments, the crystalline form is Form A, and Form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 50° C. and about 10% relative humidity for 1 week. In some embodiments, the crystalline form is Form A, and Form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 80° C. and about 10% relative humidity for 1 week. In some embodiments, the crystalline form is Form A, and Form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 50° C. and about 75% relative humidity for 1 week. In some embodiments, the crystalline form is Form A, and Form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 80° C. and about 75% relative humidity for 1 week.

[0117] Form B The present disclosure provides (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate (Formula II). The terms "(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid" and "(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate" are used interchangeably herein. [ka]

[0118] The present disclosure provides a crystalline form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate (referred to herein as Form B). In some embodiments, Form B comprises water, wherein the water is in an amount of 0 wt. % to 2.7 wt. % based on the total weight of Form B. The water content can vary according to drying conditions and ambient humidity. In some embodiments, the water is in an amount of 1.5 wt. % to 2.5 wt. % under ambient conditions. In some embodiments, the water is in an amount of 1.5 wt. % to 2 wt. % under ambient conditions.

[0119] Form B is a highly crystalline form with a thick plate-like morphology. Form B may be a non-stoichiometric hydrate form, characterized by channel hydrates and exhibiting reversible water sorption / desorption behavior without hysteresis. Form B does not exhibit changes in its XRPD pattern over a wide range of conditions, including ambient humidity and temperature ranges.

[0120] In some embodiments, the crystalline form is Form B and the XRPD pattern is substantially the same as that shown in FIG.

[0121] In some embodiments, the crystalline form is Form B and the XRPD pattern is substantially the same as that shown in FIG.

[0122] In some embodiments, the crystalline form is Form B and the XRPD pattern is represented by the peaks shown in the table below.

[0123] [Table B]

[0124] In some embodiments, the crystalline form is characterized by an XRPD pattern with a peak at 11.8±0.2 degrees 2θ. The X-ray powder diffraction pattern of Form B may also include one or more additional characteristic peaks.

[0125] In some embodiments, the X-ray powder diffraction pattern of Form B may also include one or more additional characteristic peaks, which may also be used to identify Form B (e.g., in a sample).

[0126] For example, the XRPD pattern has a peak at 9.3±0.2 degrees 2θ.

[0127] For example, the XRPD pattern has a peak at 19.9±0.2 degrees 2θ.

[0128] For example, the XRPD pattern has a peak at 22.9±0.2 degrees 2θ.

[0129] For example, the XRPD pattern has a peak at 17.2±0.2 degrees 2θ.

[0130] For example, the XRPD pattern has a peak at 10.2±0.2 degrees 2θ.

[0131] For example, the XRPD pattern has a peak at 20.4±0.2 degrees 2θ.

[0132] For example, the XRPD pattern has a peak at 21.3±0.2 degrees 2θ.

[0133] For example, the XRPD pattern has a peak at 14.2±0.2 degrees 2θ.

[0134] The X-ray powder diffraction pattern of Form B may also include one or more low-intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0135] For example, the XRPD pattern has a peak at 18.2±0.2 degrees 2θ.

[0136] For example, the XRPD pattern has a peak at 20.7±0.2 degrees 2θ.

[0137] For example, the XRPD pattern has a peak at 15.4±0.2 degrees 2θ.

[0138] For example, the XRPD pattern has a peak at 24.4±0.2 degrees 2θ.

[0139] For example, the XRPD pattern has a peak at 20.2±0.2 degrees 2θ.

[0140] For example, the XRPD pattern has a peak at 23.7±0.2 degrees 2θ.

[0141] For example, the XRPD pattern has a peak at 15.3±0.2 degrees 2θ.

[0142] For example, the XRPD pattern has a peak at 25.2±0.2 degrees 2θ.

[0143] For example, the XRPD pattern has a peak at 18.7±0.2 degrees 2θ.

[0144] For example, the XRPD pattern has a peak at 18.5±0.2 degrees 2θ.

[0145] For example, the XRPD pattern has a peak at 16.9±0.2 degrees 2θ.

[0146] For example, the XRPD pattern has a peak at 13.8±0.2 degrees 2θ.

[0147] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.8, 9.3, and 19.9 (±0.2 degrees 2θ).

[0148] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.8, 9.3, 19.9, and 22.9 (±0.2 degrees 2θ).

[0149] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.8, 9.3, 19.9, 22.9, 17.2, 10.2, 20.4, 21.3, and 14.2 (±0.2 degrees 2θ).

[0150] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks (±0.2 degrees 2θ) at 11.8, 9.3, 19.9, 22.9, 17.2, 10.2, 20.4, 21.3, 14.2, 18.2, 20.7, 15.4, 24.4, 20.2, 23.7, 15.3, 25.2, 18.7, 18.5, 16.9, and 13.8.

[0151] In some embodiments, the crystalline form is Form B and the XRPD pattern has a peak at 11.7 (±0.2 degrees 2θ).

[0152] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7 and 19.9 (±0.2 degrees 2θ).

[0153] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, and 9.3 (±0.2 degrees 2θ).

[0154] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, and 9.3 (±0.2 degrees 2θ).

[0155] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, 9.3, and 10.1 (±0.2 degrees 2θ).

[0156] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, 9.3, 10.1, and 22.9 (±0.2 degrees 2θ).

[0157] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, and 17.2 (±0.2 degrees 2θ).

[0158] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, and 20.4 (±0.2 degrees 2θ).

[0159] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, and 14.2 (±0.2 degrees 2θ).

[0160] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, and 21.3 (±0.2 degrees 2θ).

[0161] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, and 18.2 (±0.2 degrees 2θ).

[0162] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks (±0.2 degrees 2θ) at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, and 25.5.

[0163] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks (±0.2 degrees 2θ) at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, 25.5, and 15.4.

[0164] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks (±0.2 degrees 2θ) at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, 25.5, 15.4, and 20.7.

[0165] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks (±0.2 degrees 2θ) at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, 25.5, 15.4, 20.7, and 27.6.

[0166] In some embodiments, the crystalline form is Form B and the XRPD pattern has peaks (±0.2 degrees 2θ) at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, 25.5, 15.4, 20.7, 27.6, and 24.4.

[0167] Variable humidity XRPD of Form B showed a reversible shift in peaks when humidity was decreased from 30% RH to 0% RH and then returned to 30% RH. The XRPD pattern of Form B remained nearly unchanged from 30% RH to 90% RH. Only minor differences in the XRPD pattern were observed when Form B was exposed to low humidity conditions, but these patterns can also be explained by the crystalline structure of Form B (hta02a). This suggests that the dehydrated form is likely an isostructural or isostructural phase of Form B.

[0168] Those skilled in the art will recognize that the relative intensities of peaks in an X-ray powder diffraction pattern can vary depending on the sample preparation technique, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument used. Thus, depending on the type and settings (including filters) of the instrument used, new peaks may be observed in the subsequently obtained pattern, or peaks observed in the previously obtained pattern may have negligible relative intensities (and therefore not be observed) in the subsequently obtained pattern. Thus, the absence of one or more of the lower relative intensity peaks may not, in itself, prove the absence of Form B (e.g., in the sample). However, the presence of the lower relative intensity peaks can generally be used to further prove the presence of Form B in the sample.

[0169] Form B may also have one or more of the following characteristics:

[0170] In some embodiments, the crystalline form is at about 60 o C~about 100 o In some embodiments, the crystalline form is Form B having a TGA curve characterized by a weight loss of about 0.5% to about 10% (e.g., about 0.5% to about 8%, about 0.5% to about 6%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1.5%, or about 1%) over a period of about 60 C. o C~about 100 o C is Form B having a TGA curve characterized by a weight loss of about 1% or more.

[0171] In some embodiments, the crystalline form is Form B, which has a TGA curve substantially the same as that shown in FIG.

[0172] In some embodiments, the crystalline form is Form B, which has a TGA curve substantially the same as that shown in FIG.

[0173] In some embodiments, the crystalline form is Form B having a DSC curve substantially the same as that shown in FIG.

[0174] In some embodiments, the crystalline form is Form B having a DSC curve substantially the same as that shown in FIG.

[0175] In some embodiments, Form B exhibits a T 開始 = 29.8℃ and T ピーク It has a DSC thermogram characterized by a broad endotherm at = 65°C.

[0176] In some embodiments, Form B has an enthalpy of 41.9 J / g. 開始 = 29.8℃ and T ピーク It has a DSC thermogram when heated from 30 to 300°C at a rate of 10 K / min, showing a broad endotherm at 65°C.

[0177] In some embodiments, Form B has a TGA diagram when heated from 30°C to 300°C at 10 K / min, showing a weight loss of about 1.9% to 2.0% at 100°C.

[0178] In some embodiments, Form B absorbs up to 2.7% water by DVS at 25°C and 95% RH. In some embodiments, the crystalline form is Form B, which is a substantially pure form. In some embodiments, the crystalline form is Form B, and Form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w). In some embodiments, the crystalline form is Form B, and Form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 50°C and about 10% relative humidity for 1 week. In some embodiments, the crystalline form is Form B, and Form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 80°C and about 10% relative humidity for 1 week. In some embodiments, the crystalline form is Form B, and Form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 50° C. and about 75% relative humidity for 1 week. In some embodiments, the crystalline form is Form B, and Form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 80° C. and about 75% relative humidity for 1 week.

[0179] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.32 mg / mL to about 0.45 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C., e.g., about 0.32 mg / mL, about 0.33 mg / mL, about 0.34 mg / mL, about 0.35 mg / mL, about 0.36 mg / mL, about 0.37 mg / mL, about 0.38 mg / mL, about 0.39 mg / mL, about 0.40 mg / mL, about 0.41 mg / mL, about 0.42 mg / mL, about 0.43 mg / mL, about 0.44 mg / mL, about 0.45 mg / mL, or any value therebetween. In some embodiments, Form B is characterized by a solubility of about 0.36 mg / mL to about 0.42 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form B, characterized by a solubility of 0.39 mg / mL to 0.41 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.40 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C.

[0180] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.49 mg / mL to about 0.59 mg / mL in simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. in the fasted state, e.g., about 0.49 mg / mL, about 0.50 mg / mL, about 0.51 mg / mL, about 0.52 mg / mL, about 0.53 mg / mL, about 0.54 mg / mL, about 0.55 mg / mL, about 0.56 mg / mL, about 0.57 mg / mL, about 0.58 mg / mL, about 0.59 mg / mL, or any value therebetween. In some embodiments, Form B is characterized by a solubility of about 0.50 mg / mL to about 0.56 mg / mL in simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. in the fasted state. In some embodiments, the crystalline form is Form B, characterized by a solubility of 0.53 mg / mL to 0.55 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.54 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C.

[0181] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.45 mg / mL to about 0.52 mg / mL, e.g., about 0.49 mg / mL, in simulated gastric fluid (FaSSGF) at a starting pH of 1.6 after about 24 hours at about 25°C in the fasted state.

[0182] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 1.5 mg / mL to about 2 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C., e.g., greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL. In some embodiments, the crystalline form is Form B, characterized by a solubility of greater than 1.9 mg / mL to greater than 21.9 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form B, characterized by a solubility of about 2 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C.

[0183] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 1.5 mg / mL to about 2 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C., e.g., greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL. In some embodiments, the crystalline form is Form B, characterized by a solubility of greater than 1.9 mg / mL to greater than 2 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form B, characterized by a solubility of greater than 2 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C.

[0184] In some embodiments, the crystalline form is Form B, characterized by a solubility of greater than about 1.5 mg / mL to greater than about 2 mg / mL in fasted simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C., e.g., greater than about 1.5 mg / mL, greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL. In some embodiments, Form B is characterized by a solubility of greater than 1.8 mg / mL to greater than about 1.9 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C. In some embodiments, Form B is characterized by a solubility of greater than about 2 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C.

[0185] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.48 mg / mL to about 0.58 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C., e.g., about 0.48 mg / mL, about 0.49 mg / mL, about 0.50 mg / mL, about 0.51 mg / mL, about 0.52 mg / mL, about 0.53 mg / mL, about 0.54 mg / mL, about 0.55 mg / mL, about 0.56 mg / mL, about 0.57 mg / mL, about 0.58 mg / mL, or any value therebetween. In some embodiments, Form B is characterized by a solubility of about 0.51 mg / mL to about 0.54 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, Form B is characterized by a solubility of about 0.52 mg / mL to about 0.54 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.53 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C.

[0186] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 2 mg / mL in fasting simulated intestinal fluid (FaSSIF) after about 24 hours at a starting pH of 6.5 at about 25° C. In some embodiments, the fasting simulated intestinal fluid (FaSSIF) comprises phosphate buffered saline (PBS).

[0187] In some embodiments, the crystalline form is Form B, characterized by a solubility of greater than about 2 mg / mL in phosphate buffered saline (PBS) after about 24 hours at about 25° C. at a starting pH of 6.5. In some embodiments, the phosphate buffered saline (PBS) comprises sodium taurocholate (NaTC). In some embodiments, the phosphate buffered saline (PBS) comprises 3 mM sodium taurocholate (NaTC).

[0188] In some embodiments, the crystalline form is Form B, characterized by a solubility in water of about 0.42 mg / mL to about 0.51 mg / mL, e.g., about 0.42 mg / mL, about 0.43 mg / mL, about 0.44 mg / mL, about 0.45 mg / mL, about 0.46 mg / mL, about 0.47 mg / mL, about 0.48 mg / mL, about 0.49 mg / mL, about 0.50 mg / mL, about 0.51 mg / mL, or any value therebetween, after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form B is characterized by a solubility of about 0.46 mg / mL to about 0.50 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form B is characterized by a solubility of about 0.47 mg / mL to about 0.49 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.48 mg / mL in water at a starting pH of about 7.0 and at about 37° C. after about 30 minutes.

[0189] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.51 mg / mL to about 0.61 mg / mL in water after about 24 hours at about 37° C., e.g., about 0.51 mg / mL, about 0.52 mg / mL, about 0.53 mg / mL, about 0.54 mg / mL, about 0.55 mg / mL, about 0.56 mg / mL, about 0.57 mg / mL, about 0.58 mg / mL, about 0.59 mg / mL, about 0.60 mg / mL, about 0.61 mg / mL, or any value therebetween. In some embodiments, Form B is characterized by a solubility of about 0.53 mg / mL to about 0.58 mg / mL in water after about 24 hours at about 37° C. at a starting pH of about 7.0. In some embodiments, Form B is characterized by a solubility of about 0.55 mg / mL to about 0.57 mg / mL in water after about 24 hours at about 37° C. at a starting pH of about 7.0. In some embodiments, the crystalline form is Form B, which is characterized by a solubility of about 0.56 mg / mL in water after about 24 hours at about 37°C.

[0190] In some embodiments, the crystalline form is Form B, characterized by a solubility of about 0.38 mg / mL to about 0.42 mg / mL, e.g., about 0.39 mg / mL, in water at a starting pH of about 7.0 and at about 25° C. after about 24 hours.

[0191] In some embodiments, the crystalline form exhibits a pH of 0.18 mg / min / cm in a pH 6.5 buffer. 2 etc., approximately 0.15 mg / min / cm 2 ~about 0.2mg / min / cm 2 In some embodiments, the buffer is a phosphate buffer.

[0192] Form C Some embodiments provide a crystalline p-toluenesulfonate salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. In some embodiments, the crystalline p-toluenesulfonate salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is an anhydrous form. In some embodiments, the crystalline form is characterized by an XRPD pattern with a peak at 22.3±0.2 degrees 2θ. For ease of description, the above-mentioned polymorph is referred to herein as "Form C." The X-ray powder diffraction pattern of Form C may also include one or more additional characteristic peaks.

[0193] In some embodiments, the crystalline form is Form C and the XRPD pattern is represented by the peaks shown in the table below.

[0194] [Table C]

[0195] In some embodiments, the crystalline form is Form C and the XRPD pattern is substantially the same as that shown in FIG.

[0196] In some embodiments, the X-ray powder diffraction pattern of Form C may also include one or more additional characteristic peaks, which may also be used to identify Form C (e.g., in a sample).

[0197] For example, the XRPD pattern has a peak at 17.3±0.2 degrees 2θ.

[0198] For example, the XRPD pattern has a peak at 17.5±0.2 degrees 2θ.

[0199] For example, the XRPD pattern has a peak at 21.8±0.2 degrees 2θ.

[0200] For example, the XRPD pattern has a peak at 11.5±0.2 degrees 2θ.

[0201] For example, the XRPD pattern has a peak at 15.3±0.2 degrees 2θ.

[0202] For example, the XRPD pattern has a peak at 10.2±0.2 degrees 2θ.

[0203] For example, the XRPD pattern has a peak at 10.7±0.2 degrees 2θ.

[0204] For example, the XRPD pattern has a peak at 26.6±0.2 degrees 2θ.

[0205] The X-ray powder diffraction pattern of Form C may also include one or more low-intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0206] For example, the XRPD pattern has a peak at 19.8±0.2 degrees 2θ.

[0207] For example, the XRPD pattern has a peak at 5.3±0.2 degrees 2θ.

[0208] For example, the XRPD pattern has a peak at 11.3±0.2 degrees 2θ.

[0209] For example, the XRPD pattern has a peak at 19.7±0.2 degrees 2θ.

[0210] For example, the XRPD pattern has a peak at 18.6±0.2 degrees 2θ.

[0211] For example, the XRPD pattern has a peak at 24.7±0.2 degrees 2θ.

[0212] For example, the XRPD pattern has a peak at 24.1±0.2 degrees 2θ.

[0213] For example, the XRPD pattern has a peak at 20.4±0.2 degrees 2θ.

[0214] For example, the XRPD pattern has a peak at 18.2±0.2 degrees 2θ.

[0215] For example, the XRPD pattern has a peak at 25.6±0.2 degrees 2θ.

[0216] For example, the XRPD pattern has a peak at 21.5±0.2 degrees 2θ.

[0217] For example, the XRPD pattern has a peak at 13.3±0.2 degrees 2θ.

[0218] For example, the XRPD pattern has a peak at 19.1±0.2 degrees 2θ.

[0219] For example, the XRPD pattern has a peak at 9.5±0.2 degrees 2θ.

[0220] For example, the XRPD pattern has a peak at 13.6±0.2 degrees 2θ.

[0221] For example, the XRPD pattern has a peak at 27.3±0.2 degrees 2θ.

[0222] For example, the XRPD pattern has a peak at 19.4±0.2 degrees 2θ.

[0223] For example, the XRPD pattern has a peak at 16.3±0.2 degrees 2θ.

[0224] For example, the XRPD pattern has a peak at 37.9±0.2 degrees 2θ.

[0225] For example, the XRPD pattern has a peak at 24.5±0.2 degrees 2θ.

[0226] For example, the XRPD pattern has a peak at 22.6±0.2 degrees 2θ.

[0227] For example, the XRPD pattern has a peak at 39.6±0.2 degrees 2θ.

[0228] For example, the XRPD pattern has a peak at 23.2±0.2 degrees 2θ.

[0229] For example, the XRPD pattern has a peak at 37.0±0.2 degrees 2θ.

[0230] For example, the XRPD pattern has a peak at 28.8±0.2 degrees 2θ.

[0231] For example, the XRPD pattern has a peak at 30.9±0.2 degrees 2θ.

[0232] For example, the XRPD pattern has a peak at 29.3±0.2 degrees 2θ.

[0233] In some embodiments, the crystalline form is Form C, and the XRPD pattern has peaks at 22.3, 17.3, and 17.5 (±0.2 degrees 2θ).

[0234] In some embodiments, the crystalline form is Form C, and the XRPD pattern has peaks at 22.3, 17.3, 17.5, and 21.8 (±0.2 degrees 2θ).

[0235] In some embodiments, the crystalline form is Form C and the XRPD pattern has peaks at 22.3, 17.3, 17.5, 21.8, 11.5, 15.3, 10.2, 10.7, and 26.6 (±0.2 degrees 2θ).

[0236] In some embodiments, the crystalline form is Form C, and the XRPD pattern has peaks (±0.2 degrees 2θ) at 22.3, 17.3, 17.5, 21.8, 11.5, 15.3, 10.2, 10.7, 26.6, 19.8, 5.3, 11.3, 19.7, 18.6, 24.7, 24.1, 20.4, 18.2, 25.6, 21.5, 13.3, 19.1, 9.5, 13.6, 27.3, 19.4, 16.3, 37.9, 24.5, 22.6, 39.6, 23.2, 37.0, 28.8, 30.9, and 29.3.

[0237] Those skilled in the art will recognize that the relative intensities of peaks in an X-ray powder diffraction pattern can vary depending on the sample preparation technique, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument used. Thus, depending on the type and settings (including filters) of the instrument used, new peaks may be observed in the subsequently obtained pattern, or peaks observed in the previously obtained pattern may have negligible relative intensities (and therefore not be observed) in the subsequently obtained pattern. Thus, the absence of one or more of the lower relative intensity peaks may not, in itself, establish the absence of Form C (e.g., in a sample). However, the presence of the lower relative intensity peaks can generally be used to further establish the presence of Form C in a sample.

[0238] Form C may also have one or more of the following characteristics:

[0239] In some embodiments, the crystalline form has a pH of about 210 to about 240 o In some embodiments, the crystalline form is Form C having a TGA curve characterized by a weight loss of about 0.1% to about 10% (e.g., about 0.1% to about 7%, about 0.1% to about 4%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.2% to about 0.6%, or about 0.4%) over a range of about 210 to about 240°C. o Form C having a TGA curve characterized by a weight loss of about 0.4% or more.

[0240] In some embodiments, the crystalline form is Form C, which has a TGA curve substantially the same as that shown in FIG.

[0241] In some embodiments, the crystalline form is Form C having a DSC curve substantially the same as that shown in Figure 25. In some embodiments, the crystalline form is Form C having a DSC curve characterized by an onset of melting of about 187°C.

[0242] In some embodiments, the crystalline form is Form C, which is a substantially pure form. In some embodiments, the crystalline form is Form C, and Form C is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w). In some embodiments, the crystalline form is Form C, and Form C is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 50° C. and about 10% relative humidity for 1 week. In some embodiments, the crystalline form is Form C, and Form C is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 80° C. and about 10% relative humidity for 1 week. In some embodiments, the crystalline form is Form C, which is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 50° C. and about 75% relative humidity for 1 week. In some embodiments, the crystalline form is Form C, which is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 80° C. and about 75% relative humidity for 1 week.

[0243] In some embodiments, Form C has a TGA diagram when heated from 30°C to 300°C at 10 K / min, showing a weight loss of about 0.2% at 180°C.

[0244] In some embodiments, Form C absorbs up to 0.4% water at 25° C. and 95% RH via DVS.

[0245] In some embodiments, the crystalline form is Form C, characterized by a solubility of about 0.82 mg / mL to about 0.91 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C., e.g., about 0.82 mg / mL, about 0.83 mg / mL, about 0.84 mg / mL, about 0.85 mg / mL, about 0.86 mg / mL, about 0.87 mg / mL, about 0.88 mg / mL, about 0.89 mg / mL, about 0.90 mg / mL, about 0.91 mg / mL, or any value therebetween. In some embodiments, Form C is characterized by a solubility of about 0.85 mg / mL to about 0.89 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, Form C is characterized by a solubility of 0.86 mg / mL to 0.88 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, Form C is characterized by a solubility of about 0.87 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 0.8 mg / mL to about 0.9 mg / mL, e.g., about 0.8 mg / mL, about 0.81 mg / mL, about 0.82 mg / mL, about 0.83 mg / mL, about 0.84 mg / mL, about 0.85 mg / mL, about 0.86 mg / mL, about 0.87 mg / mL, about 0.88 mg / mL, about 0.89 mg / mL, about 0.90 mg / mL, or any value therebetween, in simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. in the fasted state. In some embodiments, Form C is characterized by a solubility of about 0.83 mg / mL to about 0.88 mg / mL in simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. in the fasted state. In some embodiments, Form C is characterized by a solubility of 0.84 mg / mL to 0.87 mg / mL in simulated gastric fluid (FaSSGF) in the fasted state after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 0.85 mg / mL in simulated gastric fluid (FaSSGF) in the fasted state after about 24 hours at about 37° C.In some embodiments, the crystalline form is Form C, characterized by a solubility of about 1.58 mg / mL to about 1.70 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C., e.g., about 1.58 mg / mL, about 1.59 mg / mL, about 1.60 mg / mL, about 1.61 mg / mL, about 1.62 mg / mL, about 1.63 mg / mL, about 1.64 mg / mL, about 1.65 mg / mL, about 1.66 mg / mL, about 1.67 mg / mL, about 1.68 mg / mL, about 1.69 mg / mL, about 1.70 mg / mL, or any value therebetween. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 1.60 mg / mL to about 1.65 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of 1.62 mg / mL to 1.64 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of 1.63 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C.

[0246] In some embodiments, the crystalline form is Form C, characterized by a solubility of about 1.64 mg / mL to about 1.74 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C., e.g., about 1.64 mg / mL, about 1.65 mg / mL, about 1.66 mg / mL, about 1.67 mg / mL, about 1.68 mg / mL, about 1.69 mg / mL, about 1.70 mg / mL, about 1.71 mg / mL, about 1.72 mg / mL, about 1.73 mg / mL, about 1.74 mg / mL, or any value therebetween. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 1.67 mg / mL to about 1.71 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of 1.68 mg / mL to 1.70 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of 1.69 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C.

[0247] In some embodiments, the crystalline form is Form C, characterized by a solubility of about 1.62 mg / mL to about 1.72 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C., e.g., about 1.62 mg / mL, about 1.63 mg / mL, about 1.64 mg / mL, about 1.65 mg / mL, about 1.66 mg / mL, about 1.67 mg / mL, about 1.68 mg / mL, about 1.69 mg / mL, about 1.70 mg / mL, about 1.71 mg / mL, or any value therebetween. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 1.66 mg / mL to about 1.70 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 1.67 mg / mL to about 1.69 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 1.68 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C.

[0248] In some embodiments, the crystalline form is Form C, characterized by a solubility of about 0.08 mg / mL to about 0.18 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C., e.g., about 0.08 mg / mL, about 0.09 mg / mL, about 0.10 mg / mL, about 0.11 mg / mL, about 0.12 mg / mL, about 0.13 mg / mL, about 0.14 mg / mL, about 0.15 mg / mL, about 0.16 mg / mL, about 0.17 mg / mL, about 0.18 mg / mL, or any value therebetween. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 0.11 mg / mL to about 0.15 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 0.12 mg / mL to about 0.14 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility of about 0.13 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form C, characterized by a solubility in water of about 0.82 mg / mL to about 0.92 mg / mL, e.g., about 0.82 mg / mL, about 0.83 mg / mL, about 0.84 mg / mL, about 0.85 mg / mL, about 0.86 mg / mL, about 0.87 mg / mL, about 0.88 mg / mL, about 0.89 mg / mL, about 0.90 mg / mL, about 0.91 mg / mL, about 0.92 mg / mL, or any value therebetween, after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form C is characterized by a solubility of about 0.86 mg / mL to about 0.90 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form C is characterized by having a solubility of 0.87 mg / mL to 0.89 mg / mL in water after about 30 minutes at an initial pH of about 7.0 and about 37° C. In some embodiments, the crystalline form is Form C, characterized by having a solubility of about 0.88 mg / mL in water after about 30 minutes at an initial pH of about 7.0 and about 37° C.

[0249] In some embodiments, the crystalline form is Form C, characterized by a solubility in water of about 0.8 mg / mL to about 1.4 mg / mL, e.g., about 0.8 mg / mL, about 0.85 mg / mL, about 0.9 mg / mL, about 0.95 mg / mL, about 1.0 mg / mL, about 1.05 mg / mL, about 1.1 mg / mL, about 1.15 mg / mL, about 1.2 mg / mL, about 1.25 mg / mL, about 1.3 mg / mL, about 1.35 mg / mL, about 1.4 mg / mL, or any value therebetween, after about 24 hours at a starting pH of about 7.0 and about 37° C. In some embodiments, Form C is characterized by a solubility of about 0.86 mg / mL to about 0.90 mg / mL in water after about 24 hours at a starting pH of about 7.0 and about 37° C. In some embodiments, Form C is characterized by having a solubility of about 1.10 mg / mL to about 1.14 mg / mL in water after about 24 hours at an initial pH of about 7.0 and about 37° C. In some embodiments, the crystalline form is Form C, characterized by having a solubility of about 1.12 mg / mL in water after about 24 hours at an initial pH of about 7.0 and about 37° C.

[0250] Form D Some embodiments provide a crystalline hydrochloride salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0251] In some embodiments, the crystalline form is Form D and the XRPD pattern is substantially the same as that shown in FIG.

[0252] In some embodiments, the crystalline form is characterized by an XRPD pattern with a peak at 13.1±0.2 degrees 2θ. For ease of description, the above-mentioned polymorph is referred to herein as "Form D." The X-ray powder diffraction pattern of Form D may also include one or more additional characteristic peaks.

[0253] The X-ray powder diffraction pattern of Form D may also include one or more low-intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0254] For example, the XRPD pattern has a peak at 16.4±0.2 degrees 2θ.

[0255] For example, the XRPD pattern has a peak at 10.4±0.2 degrees 2θ.

[0256] For example, the XRPD pattern has a peak at 16.6±0.2 degrees 2θ.

[0257] For example, the XRPD pattern has a peak at 23.4±0.2 degrees 2θ.

[0258] For example, the XRPD pattern has a peak at 18.2±0.2 degrees 2θ.

[0259] For example, the XRPD pattern has a peak at 15.9±0.2 degrees 2θ.

[0260] For example, the XRPD pattern has a peak at 24.9±0.2 degrees 2θ.

[0261] For example, the XRPD pattern has a peak at 17.5±0.2 degrees 2θ.

[0262] The X-ray powder diffraction pattern of Form C may also include one or more low-intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0263] For example, the XRPD pattern has a peak at 20.6±0.2 degrees 2θ.

[0264] For example, the XRPD pattern has a peak at 24.1±0.2 degrees 2θ.

[0265] For example, the XRPD pattern has a peak at 27.9±0.2 degrees 2θ.

[0266] For example, the XRPD pattern has a peak at 22.4±0.2 degrees 2θ.

[0267] For example, the XRPD pattern has a peak at 8.2±0.2 degrees 2θ.

[0268] For example, the XRPD pattern has a peak at 19.9±0.2 degrees 2θ.

[0269] For example, the XRPD pattern has a peak at 15.2±0.2 degrees 2θ.

[0270] For example, the XRPD pattern has a peak at 27.3±0.2 degrees 2θ.

[0271] For example, the XRPD pattern has a peak at 15.7±0.2 degrees 2θ.

[0272] For example, the XRPD pattern has a peak at 26.8±0.2 degrees 2θ.

[0273] For example, the XRPD pattern has a peak at 19.7±0.2 degrees 2θ.

[0274] For example, the XRPD pattern has a peak at 22.6±0.2 degrees 2θ.

[0275] For example, the XRPD pattern has a peak at 26.3±0.2 degrees 2θ.

[0276] For example, the XRPD pattern has a peak at 25.4±0.2 degrees 2θ.

[0277] For example, the XRPD pattern has a peak at 9.9±0.2 degrees 2θ.

[0278] For example, the XRPD pattern has a peak at 9.6±0.2 degrees 2θ.

[0279] For example, the XRPD pattern has a peak at 24.4±0.2 degrees 2θ.

[0280] For example, the XRPD pattern has a peak at 12.4±0.2 degrees 2θ.

[0281] For example, the XRPD pattern has a peak at 31.6±0.2 degrees 2θ.

[0282] For example, the XRPD pattern has a peak at 20.9±0.2 degrees 2θ.

[0283] For example, the XRPD pattern has a peak at 14.9±0.2 degrees 2θ.

[0284] For example, the XRPD pattern has a peak at 11.0±0.2 degrees 2θ.

[0285] For example, the XRPD pattern has a peak at 33.2±0.2 degrees 2θ.

[0286] For example, the XRPD pattern has a peak at 30.3±0.2 degrees 2θ.

[0287] For example, the XRPD pattern has a peak at 26.0±0.2 degrees 2θ.

[0288] For example, the XRPD pattern has a peak at 11.2±0.2 degrees 2θ.

[0289] For example, the XRPD pattern has a peak at 34.0±0.2 degrees 2θ.

[0290] For example, the XRPD pattern has a peak at 32.5±0.2 degrees 2θ.

[0291] For example, the XRPD pattern has a peak at 39.3±0.2 degrees 2θ.

[0292] For example, the XRPD pattern has a peak at 35.3±0.2 degrees 2θ.

[0293] For example, the XRPD pattern has a peak at 37.6±0.2 degrees 2θ.

[0294] For example, the XRPD pattern has a peak at 35.5±0.2 degrees 2θ.

[0295] For example, the XRPD pattern has a peak at 32.1±0.2 degrees 2θ.

[0296] For example, the XRPD pattern has a peak at 29.8±0.2 degrees 2θ.

[0297] In some embodiments, the crystalline form is Form D, and the XRPD pattern has peaks at 13.1, 16.4, and 10.4 (±0.2 degrees 2θ).

[0298] In some embodiments, the crystalline form is Form D, and the XRPD pattern has peaks at 13.1, 16.4, 10.4, 16.6, and 23.4 (±0.2 degrees 2θ).

[0299] In some embodiments, the crystalline form is Form D and the XRPD pattern has peaks at 13.1, 16.4, 10.4, 16.6, 23.4, 18.2, 15.9, 24.9, and 17.5 (±0.2 degrees 2θ).

[0300] In some embodiments, the crystalline form is Form D and the XRPD pattern has peaks (±0.2 degrees 2θ) at 13.1, 16.4, 10.4, 16.6, 23.4, 18.2, 15.9, 24.9, 17.5, 20.6, 24.1, 27.91, 22.4, 8.2, 19.9, 15.2, 27.3, 15.7, 26.8, 19.7, 22.6, 26.3, 25.4, 9.9, 9.6, 24.4, 12.4, 31.6, 20.9, 14.9, 11.0, 33.2, 30.3, 26.0, 11.2, 34.0, 32.5, 39.3, 35.3, 37.6, 35.5, 32.1, and 29.8.

[0301] Those skilled in the art will recognize that the relative intensities of peaks in an X-ray powder diffraction pattern can vary depending on the sample preparation technique, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument used. Thus, depending on the type and settings (including filters) of the instrument used, new peaks may be observed in the subsequently obtained pattern, or peaks observed in the previously obtained pattern may have negligible relative intensities (and therefore not be observed) in the subsequently obtained pattern. Thus, the absence of one or more of the lower relative intensity peaks may not, in itself, establish the absence of Form D (e.g., in a sample). However, the presence of the lower relative intensity peaks can generally be used to further establish the presence of Form D in a sample.

[0302] Form D may also have one or more of the following characteristics:

[0303] In some embodiments, the crystalline form has a pH of about 210 to about 230 o In some embodiments, the crystalline form is Form D having a TGA curve characterized by a weight loss of about 0.1% to about 10% (e.g., about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1.3%, about 0.4% to about 1%, about 0.6% to about 0.8%, or about 0.7%) over a range of 100 to 1200°C. o C is Form D having a TGA curve characterized by a weight loss of about 0.7% or more.

[0304] In some embodiments, the crystalline form is Form D, characterized by a TGA curve substantially the same as that shown in FIG.

[0305] In some embodiments, the crystalline form is Form D, characterized by a DSC curve substantially the same as that shown in FIG.

[0306] In some embodiments, the crystalline form is Form D, which is a substantially pure form. In some embodiments, the crystalline form is Form D, and Form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w). In some embodiments, the crystalline form is Form D, and Form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 50° C. and about 10% relative humidity for 1 week. In some embodiments, the crystalline form is Form D, and Form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 80° C. and about 10% relative humidity for 1 week. In some embodiments, the crystalline form is Form D, which is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 50° C. and about 75% relative humidity for 1 week. In some embodiments, the crystalline form is Form D, which is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 80° C. and about 75% relative humidity for 1 week.

[0307] In some embodiments, the crystalline form is Form D, characterized by a solubility of about 2.2 mg / mL to about 2.3 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C., e.g., about 2.2 mg / mL, about 2.22 mg / mL, about 2.24 mg / mL, about 2.26 mg / mL, about 2.28 mg / mL, about 2.30 mg / mL, or any value therebetween. In some embodiments, Form D is characterized by a solubility of about 2.22 mg / mL to about 2.28 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, Form D is characterized by a solubility of 2.24 mg / mL to 2.26 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form D, characterized by a solubility of about 2.25 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37°C.

[0308] In some embodiments, the crystalline form is Form D, characterized by a solubility of about 1.5 mg / mL to about 2 mg / mL, e.g., greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL, in fasted simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. In some embodiments, Form D is characterized by a solubility of about 1.8 mg / mL to about 2 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. In some embodiments, Form D is characterized by a solubility of about 1.9 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form D, characterized by a solubility of about 2 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 24 hours at about 37° C.

[0309] In some embodiments, the crystalline form is Form D, characterized by a solubility of about 1.95 mg / mL to about 2.25 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C., e.g., about 1.95 mg / mL, about 2.0 mg / mL, about 2.05 mg / mL, about 2.10 mg / mL, about 2.15 mg / mL, about 2.2 mg / mL, about 2.25 mg / mL, or any value therebetween. In some embodiments, Form D is characterized by a solubility of about 2.16 mg / mL to about 2.22 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C. In some embodiments, Form D is characterized by a solubility of about 2.18 mg / mL to about 2.20 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form D, characterized by a solubility of 2.19 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 30 minutes at about 37°C.

[0310] In some embodiments, the crystalline form is Form D, characterized by a solubility of about 2.28 mg / mL to about 2.38 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C., e.g., about 2.28 mg / mL, about 2.29 mg / mL, about 2.30 mg / mL, about 2.31 mg / mL, about 2.32 mg / mL, about 2.33 mg / mL, about 2.34 mg / mL, about 2.35 mg / mL, about 2.36 mg / mL, about 2.37 mg / mL, about 2.38 mg / mL, or any value therebetween. In some embodiments, Form D is characterized by a solubility of about 2.31 mg / mL to about 2.35 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C. In some embodiments, Form D is characterized by a solubility of about 2.32 mg / mL to about 2.34 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form D, characterized by a solubility of about 2.33 mg / mL in fed state simulated intestinal fluid (FeSSIF) after about 24 hours at about 37° C.

[0311] In some embodiments, the crystalline form is Form D, characterized by a solubility of about 2.14 mg / mL to about 2.24 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C., e.g., about 2.14 mg / mL, about 2.15 mg / mL, about 2.16 mg / mL, about 2.17 mg / mL, about 2.18 mg / mL, about 2.19 mg / mL, about 2.20 mg / mL, about 2.21 mg / mL, about 2.22 mg / mL, about 2.23 mg / mL, about 2.24 mg / mL, or any value therebetween. In some embodiments, Form D is characterized by a solubility of about 2.16 mg / mL to about 2.22 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C. In some embodiments, Form D is characterized by a solubility of about 2.18 mg / mL to about 2.20 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C. In some embodiments, the crystalline form is Form D, characterized by a solubility of about 2.19 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37° C.

[0312] In some embodiments, the crystalline form is Form D, characterized by a solubility of greater than about 1.5 mg / mL to greater than about 2 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C., e.g., greater than about 1.5 mg / mL, greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL. In some embodiments, Form D is characterized by a solubility of greater than about 1.8 mg / mL to greater than about 2 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, Form D is characterized by a solubility of greater than 1.9 mg / mL to greater than about 2 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37° C. In some embodiments, the crystalline form is Form D, characterized by a solubility of greater than about 2 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37°C.

[0313] In some embodiments, the crystalline form is Form D, characterized by a solubility in water of about 2.03 mg / mL to about 2.13 mg / mL, e.g., about 2.03 mg / mL, about 2.04 mg / mL, about 2.05 mg / mL, about 2.06 mg / mL, about 2.07 mg / mL, about 2.08 mg / mL, about 2.09 mg / mL, about 2.10 mg / mL, about 2.11 mg / mL, about 2.12 mg / mL, about 2.13 mg / mL, or any value therebetween, after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form D is characterized by a solubility of about 2.06 mg / mL to about 2.10 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, Form D is characterized by having a solubility of 2.07 mg / mL to 2.09 mg / mL in water after about 30 minutes at a starting pH of about 7.0 and about 37° C. In some embodiments, the crystalline form is Form D, characterized by having a solubility of about 2.08 mg / mL in water after about 30 minutes at about 37° C.

[0314] In some embodiments, the crystalline form is Form D, characterized by a solubility of greater than about 1.5 mg / mL to greater than about 2 mg / mL in water at about 37° C. after about 24 hours at an initial pH of about 7.0 in the fasted state, e.g., greater than about 1.5 mg / mL, greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL. In some embodiments, Form D is characterized by a solubility of greater than about 1.8 mg / mL to greater than about 2 mg / mL in water at about 37° C. after about 24 hours at an initial pH of about 7.0. In some embodiments, Form D is characterized by a solubility of 1.9 mg / mL to 2 mg / mL in water at about 37° C. after about 24 hours at an initial pH of about 7.0. In some embodiments, the crystalline form is Form D, characterized by a solubility of about 2 mg / mL in water at about 37° C. after about 24 hours.

[0315] In some embodiments, a crystalline form or forms (eg, Form A, Form B, Form C, or Form D) comprises about 1% to about 99% of the corresponding solvate. For example, about 1% to about 5%, about 6% to about 10%, about 10% to about 15%, about 15% to about 20%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, about 95% to about 99%, about 1% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 99%, about 1% to about 30%, about 30% to about 60%, about 60% to about 99%, about 1%, about 2%, about 3%, about 5%, about 10%, about 12%, about 15%, about 17%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% of the crystalline form comprises the corresponding solvate. In some embodiments, the solvate is a methanol solvate, an ethyl acetate solvate, an ethanol solvate, an isopropanol solvate, a tetrahydrofuran solvate, an acetonitrile solvate, or a diethyl ether solvate. In some embodiments, the solvent is an isopropanol solvate.

[0316] Methods for preparing Form A, Form B, Form C and Form D As can be appreciated by one of ordinary skill in the art, additional methods of synthesizing (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid, its crystalline forms, and crystalline forms (e.g., tosylate and hydrochloride salt forms) will be apparent to one of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0317] Method for preparing Form A In some embodiments, the crystalline form is (a) adding (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid to an alcohol to form a solution; (b) cooling the solution to form a suspension; (c) filtering the suspension to provide a crystalline form.

[0318] In some embodiments, the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in step (a) is amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0319] In some embodiments, the alcohol comprises methanol, ethanol, and / or isopropanol. For example, the alcohol comprises isopropanol. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. For example, the alcohol is isopropanol. In some embodiments, the adding of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid to the alcohol to form a solution is performed with agitation. In some embodiments, the agitation comprises stirring. In some embodiments, the agitation is stirring. In some embodiments, adding (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid to the alcohol to form a solution is performed at a temperature of about 25° C. to about 70° C. In some embodiments, adding (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid to the alcohol to form a solution is performed at a temperature of about 25° C. to about 50° C., 50° C. to about 70° C., 30° C. to about 60° C., 35° C. to about 55° C., 40° C. to about 50° C., 40° C. to about 45° C., or 45° C. to about 50° C. In some embodiments, the concentration of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in the solution is about 0.05 M to about 0.8 M, e.g., about 0.05 M to about 0.4 M, about 0.4 M to about 0.8 M, about 0.2 M to about 0.6 M, about 0.4 M to about 0.5 M, about 0.42 M to about 0.46 M, or about 0.44 M. For example, the concentration of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in the solution is about 0.44 M.

[0320] In some embodiments, cooling the solution comprises cooling the solution for at least about 5 minutes. o C, e.g., at least about 10 o C or at least about 20 o In some embodiments, cooling the solution comprises cooling the solution by about 15°C. o C ~ approx. 25 o C, e.g., about 18 o C ~ approx. 22 o This involves cooling the solution to, for example, about 20°C. o C. In some embodiments, the solution is agitated (e.g., stirred) during and after cooling. In some embodiments, the stirring is for at least about 1 hour, e.g., at least about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours. In some embodiments, the stirring is for about 1 hour to about 96 hours, about 1 hour to about 24 hours, about 24 hours to about 48 hours, about 48 hours to about 72 hours, about 72 hours to about 96 hours, about 48 hours to about 96 hours, about 54 hours to about 90 hours, about 60 hours to about 84 hours, about 66 hours to about 78 hours, about 70 hours to about 74 hours, or about 72 hours. In some embodiments, the solution becomes a suspension after cooling.

[0321] In some embodiments, filtering the suspension to provide a crystalline form comprises filtering the suspension to form a solid, washing the solid with a solvent, and drying the solid to provide a crystalline form. In some embodiments, the solvent comprises ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or a combination thereof. In some embodiments, the solvent is ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or a combination thereof. In some embodiments, the solvent comprises methanol, ethanol, and / or isopropanol. For example, the solvent comprises isopropanol. In some embodiments, the solvent is methanol, ethanol, or isopropanol. For example, the solvent is isopropanol.

[0322] In some embodiments, the crystalline form is (a) adding (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid to isopropanol with stirring at about 40° C. to about 50° C. to form an approximately 0.44 molar solution; (b) cooling the solution to about 20°C and stirring for about 72 hours to form a suspension; (c) filtering the suspension to obtain a solid; (d) washing the solid with isopropanol; (e) drying the solid to provide a crystalline form.

[0323] Method for preparing Form B In some embodiments, the crystalline form is (a) adding an alcohol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension; (b) cooling the solution to form a suspension; (c) cooling the solution and then adding ethyl acetate; (d) optionally adding a suspension of crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate in a binary mixture of ethanol and ethyl acetate to form a mixture; (e) adding ethyl acetate to form a slurry; (f) filtering the slurry to form a solid; (g) washing the solid with a solvent; (h) drying the solid to provide a crystalline form; (i) adding the solid form to a binary mixture of isopropanol and water, followed by heating to form a slurry; (j) cooling and filtering the slurry to form a solid; (k) drying the solid to provide a crystalline form.

[0324] In some embodiments, the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in step (a) is amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0325] In some embodiments, the alcohol comprises methanol, ethanol, and / or isopropanol. For example, the alcohol comprises ethanol. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. For example, the alcohol is ethanol. In some embodiments, step (a) comprises adding about 1 to about 6 (e.g., about 2 to about 5, about 3 to about 4, or about 3.5) volumes of alcohol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. In some embodiments, step (a) comprises adding about 3.5 volumes of alcohol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0326] In some embodiments, step (b) comprises heating the suspension to about 30°C to about 70°C (e.g., about 40°C to about 60°C, about 45°C, about 50°C, or about 55°C). In some embodiments, step (b) comprises stirring the suspension. For example, step (b) comprises stirring the suspension. In some embodiments, step (b) comprises heating the suspension for about 1 minute to about 2 hours (e.g., about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 12 minutes to about 17 minutes, or about 15 minutes). For example, step (b) comprises heating the suspension for about 15 minutes.

[0327] In some embodiments, step (c) comprises cooling the solution to about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, step (c) comprises cooling the solution to about 25°C. In some embodiments, step (c) comprises stirring the solution. For example, step (c) comprises stirring the solution. In some embodiments, step (c) comprises cooling the solution over about 1 minute to about 2 hours (e.g., about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 12 minutes to about 17 minutes, or about 15 minutes). For example, step (c) comprises cooling the solution over about 15 minutes. In some embodiments, the amount of ethyl acetate added to the solution is about 1 to about 4 (e.g., about 1 to about 3, about 2 to about 4, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, or about 4) volumes relative to the volume of the suspension. In some embodiments, the amount of ethyl acetate added to the solution is about 2.5 volumes relative to the volume of the suspension.

[0328] In some embodiments, step (d) is not performed. In some embodiments, step (d) is performed. In some embodiments, the ratio of ethanol to ethyl acetate in the binary mixture in step (d) is about 3:1 to about 1:4 by volume (e.g., about 2:1 to about 1:4, about 1:1 to about 1:4, about 1:2 to about 1:4, or about 1:3). For example, the ratio of ethanol to ethyl acetate in the binary mixture in step (d) is about 1:3 by volume. In some embodiments, the addition of the binary mixture in step (d) is performed at about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the addition of the binary mixture in step (d) is performed at about 25°C.

[0329] In some embodiments, the addition of ethyl acetate in step (d) is carried out for about 15 minutes to about 4 hours or more (e.g., about 15 minutes to about 3 hours, about 1 hour to about 2.5 hours, about 1.5 hours to about 2.5 hours, about 1.75 hours to about 2.25 hours, or about 2 hours). For example, the addition of ethyl acetate in step (d) is carried out for about 2 hours or more. In some embodiments, the addition of ethyl acetate in step (d) is carried out at about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the addition of ethyl acetate in step (d) is carried out at about 25°C. In some embodiments, about 1 to about 12 volumes (e.g., about 2 to about 10, about 4 to about 9, about 5 to about 9, about 7 to about 8, or about 7.5 volumes) of ethyl acetate is added relative to the volume of the mixture before the addition of ethyl acetate. In some embodiments, about 7.5 volumes of ethyl acetate are added relative to the volume of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid used in step (a).

[0330] In some embodiments, the solvent in step (g) comprises ethanol, ethyl acetate, or both. In some embodiments, the solvent in step (g) comprises ethanol. In some embodiments, the solvent in step (g) comprises ethyl acetate. In some embodiments, the solvent in step (g) is a binary mixture of ethanol and ethyl acetate. In some embodiments, the ratio of ethanol to ethyl acetate in the binary mixture is about 3:1 to about 1:4 by volume (e.g., about 2:1 to about 1:4, about 1:1 to about 1:4, about 1:2 to about 1:4, or about 1:3). For example, the ratio of ethanol to ethyl acetate in the binary mixture is about 1:3 by volume. In some embodiments, the solid is washed with about 1 to about 4 volumes (e.g., about 1 to about 3, about 1.5 to about 2.5, or about 2 volumes) of solvent relative to the volume of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid used in step (a). In some embodiments, the solid is washed with about 2 volumes of solvent relative to the solvent on the solid.

[0331] In some embodiments, the ratio of isopropanol to water in the binary mixture in step (i) is about 1:1 to about 20:1 by volume (e.g., about 2:1 to about 20:1, about 5:1 to about 20:1, or about 9:1). In some embodiments, the ratio of isopropanol to water in the binary mixture in step (i) is about 9:1 by volume. In some embodiments, after adding the solid form to the binary mixture of isopropanol, heating is performed at about 30°C to about 70°C (e.g., about 40°C to about 60°C, about 45°C, about 50°C, or about 55°C). In some embodiments, after adding the solid form to the binary mixture of isopropanol, heating is performed at about 50°C. In some embodiments, after adding the solid form to the binary mixture of isopropanol, heating is carried out for about 1 hour to about 48 hours (e.g., about 5 hours to about 36 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, about 15 hours to about 17 hours, or about 16 hours). In some embodiments, after adding the solid form to the binary mixture of isopropanol, heating is carried out for about 16 hours.

[0332] In some embodiments, cooling the slurry in step (j) comprises cooling the slurry to a temperature of about 0 o C ~ approx. 35 o C (e.g., about 0 o C ~ about 30 o C, about 5 o C ~ about 30 o C, about 10 o C ~ about 30 o C, about 15 o C ~ about 30 o C, about 20 o C ~ about 30 o C, about 22 o C ~ approx. 28 o C or about 25 o In some embodiments, cooling the slurry in step (j) is carried out over a period of about 25 minutes. o It is performed in C.

[0333] In some embodiments, drying the solid in step (k) is performed for about 30 minutes. o C ~ about 70 o C (e.g., about 35o C~about 65 o C, about 40 o C~about 60 o C, about 45 o C ~ approx. 55 o C or about 50 o In some embodiments, drying the solid in step (k) is carried out for about 50 minutes. o It is performed in C.

[0334] In some embodiments, the crystalline form is (a) adding ethanol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein the ethanol is about 3.5 volumes relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid; (b) heating the suspension to about 50°C and stirring for about 15 minutes to form a solution; (c) cooling the solution to about 25° C. over about 15 minutes, and then adding about 2.5 volumes of ethyl acetate; (d) adding about 7.5 volumes of ethyl acetate over 2 hours at about 25° C., then allowing the slurry to stand at about 25° C. for about 1 hour; (e) filtering the slurry to obtain a solid; (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) drying the solid to provide a solid form; (h) adding the solid form to a binary mixture of isopropanol and water in a volume ratio of about 9:1, and then heating at about 50° C. for about 16 hours to form a slurry; (i) cooling the slurry to about 25°C and filtering to obtain a solid; (j) drying the solid at about 50° C. to provide a crystalline form.

[0335] In some embodiments, the crystalline form is (a) adding water and acetone to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension; (b) heating the suspension to about 50°C and stirring to form a solution, followed by cooling the solution to room temperature; (c) adding seed Form B crystals to the solution to form a suspension; (d) adding about 2.2 volumes of water to the suspension in step (c) over a period of several hours to form a suspension; (e) cooling the suspension in step (b) and maintaining it below room temperature for several hours and filtering to obtain a solid; (f) Add about 40g of solids o C~50 o and drying with C to provide a crystalline form.

[0336] Method for preparing Form C In some embodiments, the crystalline form is (a) adding an alcohol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension; (b) cooling the solution to form a suspension; (c) cooling the solution and then adding ethyl acetate; (d) optionally adding a suspension of crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate in a binary mixture of ethanol and ethyl acetate to form a mixture; (e) adding ethyl acetate to form a slurry; (f) filtering the slurry to form a solid; (g) washing the solid with a solvent; (h) drying the solid to provide a crystalline form.

[0337] In some embodiments, the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in step (a) is amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0338] In some embodiments, the alcohol comprises methanol, ethanol, and / or isopropanol. For example, the alcohol comprises ethanol. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. For example, the alcohol is ethanol. In some embodiments, step (a) comprises adding about 1 to about 6 (e.g., about 2 to about 5, about 3 to about 4, or about 3.5) volumes of alcohol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. In some embodiments, step (a) comprises adding about 3.5 volumes of alcohol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0339] In some embodiments, step (b) comprises heating the suspension to about 30°C to about 70°C (e.g., about 40°C to about 60°C, about 45°C, about 50°C, or about 55°C). In some embodiments, step (b) comprises stirring the suspension. For example, step (b) comprises stirring the suspension. In some embodiments, step (b) comprises heating the suspension for about 1 minute to about 2 hours (e.g., about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 12 minutes to about 17 minutes, or about 15 minutes). For example, step (b) comprises heating the suspension for about 15 minutes.

[0340] In some embodiments, step (c) comprises cooling the solution to about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, step (c) comprises cooling the solution to about 25°C. In some embodiments, step (c) comprises stirring the suspension. For example, step (c) comprises stirring the solution. In some embodiments, step (c) comprises cooling the solution over about 1 minute to about 2 hours (e.g., about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 12 minutes to about 17 minutes, or about 15 minutes). For example, step (c) comprises cooling the solution over about 15 minutes. In some embodiments, the amount of ethyl acetate added to the solution is about 1 to about 4 (e.g., about 1 to about 3, about 2 to about 4, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, or about 4) volumes relative to the volume of the solution. In some embodiments, the amount of ethyl acetate added to the solution is about 2.5 volumes relative to the volume of the solution.

[0341] In some embodiments, step (d) is not performed. In some embodiments, step (d) is performed. In some embodiments, the ratio of ethanol to ethyl acetate in the binary mixture in step (d) is about 3:1 to about 1:4 by volume (e.g., about 2:1 to about 1:4, about 1:1 to about 1:4, about 1:2 to about 1:4, or about 1:3). For example, the ratio of ethanol to ethyl acetate in the binary mixture in step (d) is about 1:3 by volume. In some embodiments, the addition of the binary mixture in step (d) is performed at about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the addition of the binary mixture in step (d) is performed at about 25°C.

[0342] In some embodiments, the addition of ethyl acetate in step (d) is carried out for about 15 minutes to about 4 hours or more (e.g., about 15 minutes to about 3 hours, about 1 hour to about 2.5 hours, about 1.5 hours to about 2.5 hours, about 1.75 hours to about 2.25 hours, or about 2 hours). For example, the addition of ethyl acetate in step (d) is carried out for about 2 hours or more. In some embodiments, the addition of ethyl acetate in step (d) is carried out at about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the addition of ethyl acetate in step (e) is carried out at about 25°C. In some embodiments, about 1 to about 12 volumes (e.g., about 2 to about 10, about 4 to about 9, about 5 to about 9, about 7 to about 8, or about 7.5 volumes) of ethyl acetate is added relative to the volume of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid used in step (a). In some embodiments, about 7.5 volumes of ethyl acetate is added relative to the volume of the mixture before the addition of ethyl acetate.

[0343] In some embodiments, the solvent in step (g) comprises ethanol, ethyl acetate, or both. In some embodiments, the solvent in step (g) comprises ethanol. In some embodiments, the solvent in step (g) comprises ethyl acetate. In some embodiments, the solvent in step (g) is a binary mixture of ethanol and ethyl acetate. In some embodiments, the ratio of ethanol to ethyl acetate in the binary mixture is about 3:1 to about 1:4 by volume (e.g., about 2:1 to about 1:4, about 1:1 to about 1:4, about 1:2 to about 1:4, or about 1:3). For example, the ratio of ethanol to ethyl acetate in the binary mixture is about 1:3 by volume. In some embodiments, the solid is washed with about 1 to about 4 volumes (e.g., about 1 to about 3, about 1.5 to about 2.5, or about 2 volumes) of solvent relative to the volume of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid used in step (a). In some embodiments, the solid is washed with about 2 volumes of solvent relative to the solvent on the solid.

[0344] In some embodiments, the crystalline form is (a) adding ethanol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein the ethanol is about 3.5 volumes relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid; (b) heating the suspension to about 50°C and stirring for about 15 minutes to form a solution; (c) cooling the solution to about 25° C. over about 15 minutes, and then adding about 2.5 volumes of ethyl acetate; (d) adding ethyl acetate over 2 hours at about 25° C., then allowing the slurry to stand at about 25° C. for about 1 hour; (e) filtering the slurry to obtain a solid; (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) drying the solid to provide a crystalline form.

[0345] In some embodiments, the crystalline form is (a) adding ethanol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein the ethanol is about 3.5 volumes relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid; (b) heating the suspension to about 50°C and stirring for about 15 minutes to form a solution; (c) cooling the solution to about 25° C. over about 15 minutes, and then adding ethyl acetate; (d) adding ethyl acetate over 2 hours at about 25° C., then allowing the slurry to stand at about 25° C. for about 1 hour; (e) filtering the slurry to form a solid; (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) drying the solid to provide a crystalline form.

[0346] Method for preparing Form D In some embodiments, the crystalline form is (a) preparing a solution of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in a solvent; (b) adding a solution of hydrogen chloride in ethyl acetate or diethyl ether; (c) adding a slurry of crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid hydrochloride in a solvent to form a suspension; (b) adding approximately hydrogen chloride in ethyl acetate or diethyl ether to the slurry; (e) aging the slurry; (f) filtering the slurry to form a solid; (g) washing the solid with a solvent; (h) drying the solid to provide a crystalline form.

[0347] In some embodiments, the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in step (a) is amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0348] In some embodiments, the solvent in step (a) comprises ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or a combination thereof. In some embodiments, the solvent in step (a) comprises ethyl acetate. In some embodiments, the solvent in step (a) is ethyl acetate. In some embodiments, the amount of solvent is about 2 to about 11 (e.g., about 3 to about 10, about 4 to about 7, about 5 to about 6, or about 5.5) volumes relative to the volume of the starting material. In some embodiments, the amount of solvent is about 5.5 volumes relative to the volume of the starting material.

[0349] In some embodiments, the hydrogen chloride solution in ethyl acetate or diethyl ether is a hydrogen chloride solution in ethyl acetate. In some embodiments, the concentration of the hydrogen chloride solution is about 0.5 M to about 2 M (e.g., about 0.5 to about 1.5 M, about 0.7 M to about 2 M, about 0.8 M to about 1.2 M, or about 1 M). In some embodiments, the concentration of the hydrogen chloride solution is about 1 M.

[0350] In some embodiments, the amount of hydrogen chloride added in step (b) relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is about 0.1 to about 2.2 (e.g., about 0.2 to about 2, about 0.4 to about 1.2, about 0.4 to about 0.7, or about 0.55) equivalents. In some embodiments, the amount of hydrogen chloride added in step (b) relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is about 0.55 equivalents.

[0351] In some embodiments, the crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid hydrochloride used to form the suspension in step (c) is formed by combining a solution of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in ethyl acetate with a 1 M solution of hydrogen chloride in ethyl acetate to form a precipitate, and then filtering the precipitate to provide crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid hydrochloride. In some embodiments, a solution of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in ethyl acetate contains less than 1% by weight (e.g., less than 0.1%, less than 0.01%, less than 0.001%, less than 0.0001%, less than 0.00001%, or less than 0.000001%) of water. In some embodiments, a 1 M solution of hydrogen chloride in ethyl acetate contains less than 1% by weight (e.g., less than 0.1%, less than 0.01%, less than 0.001%, less than 0.0001%, less than 0.00001%, or less than 0.000001%) of water. In some embodiments, the solvent in step (c) comprises ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or a combination thereof. In some embodiments, the solvent in step (c) comprises ethyl acetate. In some embodiments, the solvent in step (c) is ethyl acetate.

[0352] In some embodiments, the amount of hydrogen chloride added in step (d) relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is about 0.1 to about 2.2 (e.g., about 0.2 to about 2.2, about 0.8 to about 2, about 1 to about 2, about 1.3 to about 2, about 1.5 to about 1.8, or about 1.65) equivalents. In some embodiments, the amount of hydrogen chloride added in step (b) relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is about 1.65 equivalents.

[0353] In some embodiments, step (e) includes aging the slurry and agitating the slurry. In some embodiments, step (e) includes agitating the slurry and stirring the slurry. In some embodiments, the slurry is aged for about 1 hour to about 48 hours (e.g., about 5 hours to about 36 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, about 15 hours to about 17 hours, or about 16 hours). In some embodiments, the slurry is aged for about 16 hours. In some embodiments, the slurry is aged for about 0. o C ~ approx. 35 o C (e.g., about 0 o C ~ about 30 o C, about 5 o C ~ about 30 o C, about 10 o C ~ about 30 o C, about 15 o C ~ about 30 o C, about 20 o C ~ about 30 o C, about 22 o C ~ approx. 28 o C, or about 24 o C). In some embodiments, the slurry is aged for about 24 o It is aged over C.

[0354] In some embodiments, the solvent in step (g) comprises ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or a combination thereof. In some embodiments, the solvent in step (g) comprises ethyl acetate. In some embodiments, the solvent in step (g) is ethyl acetate.

[0355] In some embodiments, the crystalline form is (a) preparing a solution of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in about 5.5 volumes of ethyl acetate; (b) adding about 0.55 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate; (c) adding a slurry of crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in ethyl acetate hydrochloride to form a suspension; (d) adding about 1.65 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate to form a slurry; (e) stirring the slurry at about 24°C for about 16 hours; (f) filtering the slurry to obtain a solid; (g) washing the solid with ethyl acetate; (h) drying the solid to provide Form D.

[0356] formulation In another aspect, provided herein are pharmaceutical compositions comprising the crystalline forms as described herein. In some embodiments, the pharmaceutical composition comprises Form A and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises Form B and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises Form C and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises Form D and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises Form A, Form B, Form C, and Form D and a pharmaceutically acceptable carrier.

[0357] For example, the pharmaceutical composition comprises Form A and Form B and a pharmaceutically acceptable carrier.

[0358] For example, the pharmaceutical composition comprises Form A and Form C and a pharmaceutically acceptable carrier.

[0359] For example, the pharmaceutical composition comprises Form A and Form D and a pharmaceutically acceptable carrier.

[0360] For example, the pharmaceutical composition comprises Form B and Form C and a pharmaceutically acceptable carrier.

[0361] For example, the pharmaceutical composition comprises Form B and Form D and a pharmaceutically acceptable carrier.

[0362] For example, the pharmaceutical composition comprises Form C and Form D and a pharmaceutically acceptable carrier.

[0363] For example, the pharmaceutical composition comprises Form A, Form B, Form C and a pharmaceutically acceptable carrier.

[0364] For example, the pharmaceutical composition comprises Form A, Form B, Form D and a pharmaceutically acceptable carrier.

[0365] For example, the pharmaceutical composition comprises Form B, Form C, Form D and a pharmaceutically acceptable carrier.

[0366] For example, the pharmaceutical composition comprises Form A, Form C, Form D and a pharmaceutically acceptable carrier.

[0367] For example, the pharmaceutical composition comprises Form A, Form B, Form C, Form D and a pharmaceutically acceptable carrier.

[0368] In some embodiments, the pharmaceutical composition comprises at least about 0.5 weight percent (e.g., at least about 1 weight percent, at least about 2 weight percent, 5 weight percent, at least about 10 weight percent, at least about 20 weight percent, at least about 30 weight percent, at least about 40 weight percent, at least about 50 weight percent, at least about 60 weight percent, at least about 70 weight percent, at least about 80 weight percent, at least about 90 weight percent, at least about 95 weight percent, at least about 99 weight percent) of Form A, Form B, Form C, or Form D, or any combination thereof (e.g., any two, three, or four of crystalline Forms A, B, C, or D in combination).

[0369] Some embodiments provide a composition (e.g., a pharmaceutical composition or pharmaceutical formulation) comprising one or more (e.g., one or two, e.g., one) active ingredients, wherein the active ingredient (or at least one active ingredient) is: (i) Form A, Form B, Form C, or Form D, or any combination thereof (e.g., any two, three, or four of Forms A, B, C, or D in combination); or (ii) comprises at least about 0.5 weight percent (e.g., at least about 1 weight percent, at least about 2 weight percent, at least about 5 weight percent, at least about 10 weight percent, at least about 20 weight percent, at least about 30 weight percent, at least about 40 weight percent, at least about 50 weight percent, at least about 60 weight percent, at least about 70 weight percent, at least about 80 weight percent, at least about 90 weight percent, at least about 95 weight percent, at least about 99 weight percent) of one or more (e.g., one or two, e.g., one) of Form A, Form B, Form C, or Form D, or any combination thereof (e.g., any two, three, or four of crystalline Forms A, B, C, or D in combination).

[0370] The composition may include one or more of the following features.

[0371] The composition may include one or more pharmaceutically acceptable carriers.

[0372] Solid dosage forms of the pharmaceutical composition for oral administration include capsules, tablets, pills, powders, and granules. In one embodiment, the solid dosage form is a capsule. In one embodiment, the solid dosage form is a capsule filled with pure Form A, Form B, Form C, Form D, or any combination thereof. In some embodiments, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0373] The solid dosage forms of the pharmaceutical composition, such as tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shells, such as enteric coatings and other pharmaceutical coatings. They may also optionally contain opacifying agents and may be formulated to release the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedded pharmaceutical compositions that can be used include polymeric substances and waxes.

[0374] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

[0375] The liquid dosage form of the pharmaceutical composition for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.In addition to active compounds, the liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, etc., and mixtures thereof.

[0376] The compound suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters (e.g., polyoxyethylene (20) sorbitan monooleate, i.e., Polysorbate 80 or "Tween 80"), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0377] The pharmaceutical compositions of the present disclosure for injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Other excipients or carriers include, for example, kleptose (hydroxypropyl β-cyclodextrin) and water-soluble polymers derived from cellulose (e.g., methylcellulose (e.g., Methocel) and hydroxypropyl methylcellulose).

[0378] In some embodiments, the pH of the liquid (e.g., injectable) composition is about 5 to about 12 (e.g., about 6 to about 11, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7.5 to about 8.0, about 8 to about 10.5, about 8.5 to about 10, about 8.5, about 9, about 9.5, or about 10). For example, the pH of the liquid composition is about 8.5 to about 10.

[0379] In addition to inert diluents, these pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersing agents, sweeteners, flavorings, and perfuming agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, for example, aluminum monostearate and gelatin. The compounds can be incorporated into sustained-release or targeted delivery systems, such as polymer matrices, liposomes, and microspheres. Such formulations can provide more effective distribution of the compounds.

[0380] Pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0381] Dosage forms for topical administration of the compounds or pharmaceutical compositions of the present disclosure include powders, patches, sprays, ointments, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0382] The compounds and compositions described herein can be administered, for example, orally, parenterally (e.g., subcutaneously, intradermally, intravenously, or intramuscularly), topically, rectally, nasally, sublingually, or buccally, at dosages ranging from about 0.01 milligrams per kilogram (mg / kg) to about 1000 mg / kg (e.g., about 0.01 to about 100 mg / kg, about 0.1 to about 100 mg / kg) every 4 to 120 hours, or according to the requirements of the particular drug, dosage form, and / or route of administration. Other routes of administration include enteral, intraarterial, intraperitoneal, and intrathecal administration. The correlation of dosages for animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep. 50, 219-244 (1966). Body surface area can be largely determined from the patient's height and weight. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 537 (1970).

[0383] In some embodiments, the composition comprises Form A, Form B, Form C, or Form D, hydroxypropyl β-cyclodextrin, and water. In some embodiments, the composition comprises Form A, hydroxypropyl β-cyclodextrin, and water. In some embodiments, the composition comprises Form B, hydroxypropyl β-cyclodextrin, and water. In some embodiments, the composition comprises Form C, hydroxypropyl β-cyclodextrin, and water. In some embodiments, the composition comprises Form D, hydroxypropyl β-cyclodextrin, and water.

[0384] In some embodiments, the composition comprises Form A, Form B, Form C or Form D, methocel, tween 80, and water. In some embodiments, the composition comprises Form A, methocel, tween 80, and water. In some embodiments, the composition comprises Form B, methocel, tween 80, and water. In some embodiments, the composition comprises Form C, methocel, tween 80, and water. In some embodiments, the composition comprises Form D, methocel, tween 80, and water.

[0385] In some embodiments, the crystalline form (e.g., Form A, Form B, Form C, or Form D) has a particle size (D) of about 1 μm to about 100 μm, e.g., about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, or about 100 μm. 50 In some embodiments, the crystalline form (e.g., Form A, Form B, Form C, or Form D) has a particle size (D) of about 1 μm to about 50 μm. 50 In some embodiments, the crystalline form (e.g., Form A, Form B, Form C, or Form D) has a particle size (D) of about 1 μm to about 25 μm. 50 In some embodiments, the crystalline form (e.g., Form A, Form B, Form C, or Form D) has a particle size (D) of about 1 μm to about 5 μm. 50 )

[0386] How to use Provided herein are methods of using the crystalline forms disclosed herein, or pharmaceutical compositions thereof, for the treatment, prevention, or amelioration of diseases or disorders mediated by or otherwise affected through the alternative complement pathway. In more specific embodiments, provided herein are methods of using the crystalline forms disclosed herein, or pharmaceutical compositions thereof, for the treatment, prevention, or amelioration of diseases or disorders mediated by or otherwise affected through complement factor B (CFB). In even more specific embodiments, provided herein are methods of using the crystalline forms disclosed herein, or pharmaceutical compositions thereof, for the treatment, prevention, or amelioration of diseases or disorders mediated by or otherwise affected through the alternative complement pathway or via inhibition of the alternative complement pathway. In even more specific embodiments, provided herein are methods of using the crystalline forms disclosed herein, or pharmaceutical compositions thereof, for the treatment, prevention, or amelioration of diseases or disorders mediated by or otherwise affected through inhibition of complement factor B (CFB).

[0387] In some embodiments, the crystalline form is Form A. In some embodiments, the crystalline form is Form B. In some embodiments, the crystalline form is Form C. In some embodiments, the crystalline form is Form D.

[0388] Some embodiments provide a method of treating or preventing a disease or disorder as described herein (e.g., a complement-associated disease or disorder) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form A, Form B, Form C, or Form D, or a pharmaceutical composition comprising Form A, Form B, Form C, or Form D and a pharmaceutically acceptable carrier.

[0389] Examples of known complement-associated diseases or disorders include neurological diseases, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, disorders due to inappropriate or undesired activation of the complement system, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injuries including burns and frostbite, myocarditis, post-ischemic reperfusion states, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, arteriosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex diseases and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, and nerve regeneration. In addition, other known complement-related diseases include dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrochloric acid), smoke injury, thermal injury (e.g., burns, frostbite), asthma, allergies, bronchial congestion, and the like. These include lung diseases and disorders such as pulmonary atrophy, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, oligoimmune vasculitis, immune complex-associated inflammation, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, uveitis due to Behçet's disease, multifocal choroiditis, Vogt-Koyanagi-Harada disease, intermediate uveitis, birdshot chorioretinitis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigus, non-arteritic anterior ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, uveitis (including Behçet's disease and other subtypes), and antiphospholipid syndrome.

[0390] In some embodiments, the disease or disorder is age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada disease, intermediate uveitis, birdshot choroiditis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia-Leventinese, Sorsby's fundus dystrophy, late onset macular dystrophy, North Carolina macular dystrophy, Stargardt's disease, keratitis, multiple sclerosis Neurological disorders such as stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity, disorders due to inappropriate or undesired activation of the complement system (e.g., hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy), inflammatory diseases, paroxysmal nocturnal hemoglobinuria, C3 nephritis (including dense deposition disease and C3 nephritis), immune complex membranoproliferative glomerulonephritis (Immunoproliferative glomerulonephritis), and inflammatory disorders. complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy (including idiopathic membranous nephropathy), diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, CD55 deficiency with excessive activation of the complement system, vascular thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica,NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), hematopoietic stem cell transplantation-associated thrombotic microangiopathy microangiopathy, HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass and renal bypass, arteriosclerosis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, COVID-19, immune complex and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic kidney disease The present invention relates to a method for treating chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust rash, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, oligoimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's disease, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity, immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, Graves' disease, and hidradenitis suppurativa.

[0391] In some embodiments, the disease or disorder is multiple sclerosis, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis due to Behcet's disease, multifocal choroiditis, Vogt-Koyanagi-Harada disease, intermediate uveitis, birdshot choroiditis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigoid, non-arteritic anterior ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, stroke, balloon angioplasty, cardiopulmonary bypass or post-pump syndrome in renal bypass, arteriosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex disease and autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and pulmonary infarction, pneumonia, fibrosing dust borne diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, oligoimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, metabolic syndrome, and hidradenitis suppurativa.

[0392] In some embodiments, the disease or disorder is immune complex membranoproliferative glomerulonephritis (IC-MPGN).

[0393] In some embodiments, the disease or disorder is neuromyelitis optica (NMO).

[0394] In some embodiments, the disease or disorder is hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA).

[0395] Some embodiments provide a method of treating or preventing a renal disease or disorder selected from the group consisting of chronic kidney disease, diabetic nephropathy, glomerular kidney disease, complement C3 nephropathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis, and polycystic kidney disease (PKD), comprising administering to a subject having such disease or disorder a therapeutically effective amount of Form A, Form B, Form C, or Form D, or a pharmaceutical composition comprising Form A, Form B, Form C, or Form D and a pharmaceutically acceptable carrier.

[0396] In some embodiments, the kidney disease is selected from the group consisting of chronic kidney disease, diabetic nephropathy, glomerular kidney disease, complement C3 nephropathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis, and polycystic kidney disease (PKD) and immune complex membranoproliferative glomerulonephritis (IC-MPGN).

[0397] In some embodiments, the kidney disease is chronic kidney disease.

[0398] In some embodiments, the kidney disease is diabetic nephropathy.

[0399] In some embodiments, the kidney disease is a glomerular kidney disease.

[0400] In some embodiments, the kidney disease is complement C3 nephropathy (C3G).

[0401] In some embodiments, the kidney disease is IgA nephropathy (IgAN).

[0402] In some embodiments, the kidney disease is membranous nephropathy (MN).

[0403] In some embodiments, the kidney disease is focal segmental glomerulosclerosis (FSGS).

[0404] In some embodiments, the kidney disease is atypical hemolytic uremic syndrome (aHUS).

[0405] In some embodiments, the kidney disease is dense deposit disease (DDD).

[0406] In some embodiments, the renal disease is minimal change disease (MCD).

[0407] In some embodiments, the renal disease is paroxysmal nocturnal hemoglobinuria (PNH).

[0408] In some embodiments, the renal disease is ANCA-associated vasculitis.

[0409] In some embodiments, the kidney disease is lupus nephritis.

[0410] In some embodiments, the kidney disease is polycystic kidney disease (PKD).

[0411] In some embodiments, the kidney disease is immune complex membranoproliferative glomerulonephritis (IC-MPGN).

[0412] The present disclosure is further described in the following examples, which should be understood as being for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0413] Further embodiments 1. Crystalline form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. 2. The crystalline form of embodiment 1, wherein the crystalline form is Form A, characterized by an X-ray powder diffraction (XRPD) pattern with a peak at 10.7±0.2 degrees 2θ. 3. The crystalline form of embodiment 2, wherein the XRPD pattern has a peak at 20.5±0.2 degrees 2θ. 4. The crystalline form of any one of embodiments 2-3, wherein the XRPD pattern has a peak at 18.8±0.2 degrees 2θ. 5. The crystalline form of any one of embodiments 2-4, wherein the XRPD pattern has 21.7± peaks (±0.2 degrees 2θ). 6. The crystalline form of any one of embodiments 2-5, wherein the XRPD pattern has a peak at 19.6±0.2 degrees 2θ. 7. The crystalline form of any one of embodiments 2-6, wherein the XRPD pattern has a peak at 19.8±0.2 degrees 2θ. 8. The crystalline form of any one of embodiments 2-7, wherein the XRPD pattern has a peak at 12.5±0.2 degrees 2θ. 9. The crystalline form of any one of embodiments 2-8, wherein the XRPD pattern has a peak at 21.1±0.2 degrees 2θ. 10. The crystalline form of any one of embodiments 2-9, wherein the XRPD pattern has a peak at 23.3±0.2 degrees 2θ. 11. The crystalline form of any one of embodiments 2-10, wherein the XRPD pattern has a peak at 22.6±0.2 degrees 2θ. 12. The crystalline form of any one of embodiments 2-11, wherein the XRPD pattern has a peak at 27.3±0.2 degrees 2θ. 13. The crystalline form of any one of embodiments 2-12, wherein the XRPD pattern has a peak at 15.6±0.2 degrees 2θ. 14. The crystalline form of embodiment 1, wherein the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, and 18.8 (±0.2 degrees 2θ). 15. The crystalline form of embodiment 1, wherein the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 18.8, and 21.7 (±0.2 degrees 2θ). 16. The crystalline form of embodiment 1, wherein the crystalline form is Form A and the XRPD pattern has peaks (±0.2 degrees 2θ) at 10.7, 20.5, 18.8, 21.7, 19.6, 19.8, 12.5, 21.1, 23.3, 22.5, 27.3, and 15.5. 17. The crystalline form of embodiment 1, wherein the crystalline form is Form A and wherein (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is in the free form, and further wherein the free form is in the anhydrous form. 18. The crystalline form of embodiment 1, wherein the crystalline form is Form A and the XRPD pattern is substantially the same as that shown in Figure 2. 19. The crystalline form is approximately 189 o 19. The crystalline form of any one of embodiments 1-18, which is Form A having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2% at C. 20. The crystalline form is ca. o 20. The crystalline form of any one of embodiments 1-19, which is Form A having a TGA curve characterized by a weight loss of about 25% at C. 21. The crystalline form of any one of embodiments 1-20, wherein the crystalline form is Form A having a TGA curve substantially the same as that shown in Figure 3. 22. The crystalline form of any one of embodiments 1-21, wherein the crystalline form is Form A having a differential scanning calorimetry (DSC) curve characterized by an onset of melting at about 201.9°C (end). 23. The crystalline form of any one of embodiments 1-22, wherein the crystalline form is Form A having a DSC curve substantially the same as that shown in Figure 4. 24. The crystalline form of any one of embodiments 1-23, wherein the crystalline form is Form A, characterized by a solubility of about 2.3 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37°C. 25. The crystalline form of any one of embodiments 1-24, wherein the crystalline form is Form A, characterized by a solubility of about 0.31 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 24 hours at about 37°C. 26. The crystalline form of any one of embodiments 1-25, wherein the crystalline form is Form A, characterized by a solubility of about 0.18 mg / mL in fasted simulated intestinal fluid (FaSSIF) after about 24 hours at about 37°C. 27. The crystalline form of any one of embodiments 1-26, wherein the crystalline form is Form A, characterized by a solubility of about 0.22 mg / mL in water after about 24 hours at about 37°C. 28. The crystalline form is (a) adding (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid to isopropanol with stirring at about 40° C. to about 50° C. to form an approximately 0.44 molar solution; (b) cooling the solution to about 20°C and stirring for about 72 hours to form a suspension; (c) filtering the suspension to obtain a solid; (d) washing the solid with isopropanol; 28. The crystalline form of any one of embodiments 1-27, wherein the crystalline form is Form A prepared by a process comprising: (e) drying the solid to provide the crystalline form. 29. Crystalline p-toluenesulfonate salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. 30. The crystalline form of embodiment 29, wherein the crystalline form is form B, characterized by an XRPD pattern with a peak at 11.8±0.2 degrees 2θ. 31. The crystalline form of embodiment 30, wherein the XRPD pattern has a peak at 9.3±0.2 degrees 2θ. 32. The crystalline form of any one of embodiments 29-31, wherein the XRPD pattern has a peak at 19.9±0.2 degrees 2θ. 33. The crystalline form of any one of embodiments 29-32, wherein the XRPD pattern has a peak at 22.9±0.2 degrees 2θ. 34. The crystalline form of any one of embodiments 29-33, wherein the XRPD pattern has a peak at 17.2±0.2 degrees 2θ. 35. The crystalline form of any one of embodiments 29-34, wherein the XRPD pattern has a peak at 10.2±0.2 degrees 2θ. 36. The crystalline form of any one of embodiments 29-35, wherein the XRPD pattern has a peak at 20.4±0.2 degrees 2θ. 37. The crystalline form of any one of embodiments 29-36, wherein the XRPD pattern has a peak at 21.3±0.2 degrees 2θ. 38. The crystalline form of any one of embodiments 29-37, wherein the XRPD pattern has a peak at 14.2±0.2 degrees 2θ. 39. The crystalline form of embodiment 29, wherein the crystalline form is form B and the XRPD pattern has peaks at 11.80, 9.30, and 19.9 (±0.2 degrees 2θ). 40. The crystalline form of embodiment 29, wherein the crystalline form is form B and the XRPD pattern has peaks at 11.8, 9.3, 19.9, and 22.9 (±0.2 degrees 2θ). 41. The crystalline form of embodiment 29, wherein the crystalline form is form B and the XRPD pattern has peaks at 11.8, 9.3, 19.9, 22.9, 17.2, 10.2, 20.4, 21.3, and 14.2 (±0.2 degrees 2θ). 42. The crystalline form of embodiment 29, wherein the crystalline form is form B and the XRPD pattern is substantially the same as that shown in Figure 12 or 15. 43. The crystalline form is ca. o C~about 100 o The crystalline form of any one of embodiments 29-42, which is form B having a TGA curve characterized by a weight loss of about 1% at C. 44. The crystalline form of any one of embodiments 29-43, wherein the crystalline form is form B having a TGA curve substantially the same as that shown in FIG. 13 or FIG. 17. 45. The crystalline form of any one of embodiments 29-44, wherein the crystalline form is form B having a DSC curve substantially the same as that shown in FIG. 14 or FIG. 16. 46. ​​The crystalline form of any one of embodiments 29-45, wherein the crystalline form is Form B, characterized by a solubility of about 0.54 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 24 hours at about 37°C. 47. The crystalline form of any one of embodiments 29-46, wherein the crystalline form is Form B, characterized in that it has a solubility of about 2 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 24 hours at about 37°C. 48. The crystalline form of any one of embodiments 29-47, wherein the crystalline form is Form B, characterized by a solubility of about 0.53 mg / mL in fasting simulated intestinal fluid (FaSSIF) after about 24 hours at about 37°C. 49. The crystalline form of any one of embodiments 29-48, wherein the crystalline form is Form B, characterized in that it has a solubility of about 0.56 mg / mL in water after about 24 hours at about 37°C. 50. The crystalline form is (a) adding ethanol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein the ethanol is about 3.5 volumes relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid; (b) heating the suspension to about 50°C and stirring for about 15 minutes to form a solution; (c) cooling the solution to about 25° C. over about 15 minutes, and then adding about 2.5 volumes of ethyl acetate; (d) adding about 7.5 volumes of ethyl acetate over 2 hours at about 25° C., then allowing the slurry to stand at about 25° C. for about 1 hour; (e) filtering the slurry to obtain a solid; (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) drying the solid to provide a solid form; (h) adding the solid form to a binary mixture of isopropanol and water in a volume ratio of about 9:1, followed by about 50 ℃ for about 16 hours to form a slurry; (i) cooling the slurry to about 25°C and filtering to obtain a solid; (j) Add about 50g of solids ℃ 50. The crystalline form of any one of embodiments 29-49, which is Form B prepared by a process comprising: 51. The crystalline form of embodiment 29, wherein the crystalline form is form C, characterized by an XRPD pattern with a peak at 22.3±0.2 degrees 2θ. 52. The crystalline form of embodiment 51, wherein the XRPD pattern has a peak at 17.3±0.2 degrees 2θ. 53. The crystalline form of any one of embodiments 51-52, wherein the XRPD pattern has a peak at 17.5±0.2 degrees 2θ. 54. The crystalline form of any one of embodiments 51-53, wherein the XRPD pattern has a peak at 21.8±0.2 degrees 2θ. 55. The crystalline form of any one of embodiments 51-54, wherein the XRPD pattern has a peak at 11.5±0.2 degrees 2θ. 56. The crystalline form of any one of embodiments 51-55, wherein the XRPD pattern has a peak at 15.3±0.2 degrees 2θ. 57. The crystalline form of any one of embodiments 51-56, wherein the XRPD pattern has a peak at 10.2±0.2 degrees 2θ. 58. The crystalline form of any one of embodiments 51-57, wherein the XRPD pattern has a peak at 10.7±0.2 degrees 2θ. 59. The crystalline form of any one of embodiments 51-58, wherein the XRPD pattern has a peak at 26.6±0.2 degrees 2θ. 60. The crystalline form according to any one of embodiments 29-59, wherein form B comprises water, wherein the water is in an amount of 0 w / w% to about 2.7 w / w%, based on the total weight of form B. 61. The crystalline form of embodiment 29, wherein the crystalline form is Form C and the XRPD pattern has peaks at 22.3, 17.3, and 17.5 (±0.2 degrees 2θ). 62. The crystalline form of embodiment 29, wherein the crystalline form is Form C and the XRPD pattern has peaks at 22.3, 17.3, 17.5, and 21.8 (±0.2 degrees 2θ). 63. The crystalline form of embodiment 29, wherein the crystalline form is Form C and the XRPD pattern has peaks at 22.3, 17.3, 17.5, 21.8, 11.5, 15.3, 10.2, 10.7, and 26.6 (±0.2 degrees 2θ). 64. The crystalline form of embodiment 29, wherein the crystalline form is form C and the XRPD pattern is substantially the same as that shown in Figure 23. 65. The crystalline form of embodiment 29, wherein the p-toluenesulfonate salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is an anhydrous form. 66. The crystalline form is about 210 to about 240 o 66. The crystalline form of any one of embodiments 29 and 61-65, which is form C having a TGA curve characterized by a weight loss of about 0.4% at C. 67. The crystalline form of any one of embodiments 29 and 61-66, wherein the crystalline form is form C having a TGA curve substantially the same as that shown in Figure 24. 68. The crystalline form of any one of embodiments 29 and 61-67, wherein the crystalline form is form C having a DSC curve characterized by an onset of melting at about 187°C. 69. The crystalline form of any one of embodiments 29 and 61-68, wherein the crystalline form is form C having a DSC curve substantially the same as that shown in Figure 25. 70. The crystalline form of any one of embodiments 29 and 61-69, wherein the crystalline form is Form C, characterized by a solubility of about 0.85 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 24 hours at about 37°C. 71. The crystalline form of any one of embodiments 29 and 61-70, wherein the crystalline form is Form C, characterized by a solubility of about 1.69 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 24 hours at about 37°C. 72. The crystalline form of any one of embodiments 29 and 61-71, wherein the crystalline form is Form C, characterized by a solubility of about 0.13 mg / mL in fasting simulated intestinal fluid (FaSSIF) after about 24 hours at about 37°C. 73. The crystalline form of any one of embodiments 29 and 61-72, wherein the crystalline form is Form C, characterized in that it has a solubility of about 1.12 mg / mL in water after about 24 hours at about 37°C. 74. The crystalline form can be prepared by (a) adding ethanol to (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein the ethanol is about 3.5 volumes relative to the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid; (b) heating the suspension to about 50°C and stirring for about 15 minutes to form a solution; (c) cooling the solution to about 25° C. over about 15 minutes, and then adding about 2.5 volumes of ethyl acetate; (d) adding about 7.5 volumes of ethyl acetate over 2 hours at about 25° C., then allowing the slurry to stand at about 25° C. for about 1 hour; (e) filtering the slurry to obtain a solid; (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; The embodiment of any one of embodiments 29 and 61-73, wherein the crystalline form is Form C prepared by a process comprising: (g) drying the solid to provide the crystalline form. 75. Crystalline hydrochloride salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid. 76. The crystalline form of embodiment 75, wherein the crystalline form is form D, characterized by an XRPD pattern with a peak at 13.1±0.2 degrees 2θ. 77. The crystalline form of embodiment 75, wherein the XRPD pattern has a peak at 16.4±0.2 degrees 2θ. 78. The crystalline form of any one of embodiments 75-77, wherein the XRPD pattern has a peak at 10.4±0.2 degrees 2θ. 79. The crystalline form of any one of embodiments 75-78, wherein the XRPD pattern has a peak at 16.6±0.2 degrees 2θ. 80. The crystalline form of any one of embodiments 75-79, wherein the XRPD pattern has a peak at 23.4±0.2 degrees 2θ. 81. The crystalline form of any one of embodiments 75-80, wherein the XRPD pattern has a peak at 18.2±0.2 degrees 2θ. 82. The crystalline form of any one of embodiments 75-81, wherein the XRPD pattern has a peak at 15.9±0.2 degrees 2θ. 83. The crystalline form of any one of embodiments 75-82, wherein the XRPD pattern has a peak at 24.9±0.2 degrees 2θ. 84. The crystalline form of any one of embodiments 75-83, wherein the XRPD pattern has a peak at 17.5±0.2 degrees 2θ. 85. The crystalline form of embodiment 75, wherein the crystalline form is form D and the XRPD pattern has peaks at 13.1, 16.4, and 10.4 (±0.2 degrees 2θ). 86. The crystalline form of embodiment 75, wherein the crystalline form is form D and the XRPD pattern has peaks at 13.1, 16.4, 10.4, 16.6, and 23.4 (±0.2 degrees 2θ). 87. The crystalline form of embodiment 75, wherein the crystalline form is form D and the XRPD pattern has peaks at 13.1, 16.4, 10.4, 16.6, 23.4, 18.2, 15.9, 24.9, and 17.5 (±0.2 degrees 2θ). 88. The crystalline form of embodiment 75, wherein the crystalline form is form D and the XRPD pattern is substantially the same as that shown in Figure 26. 89. The crystalline form is about 210 to about 230 o The crystalline form of any one of embodiments 75-88, which is form D having a TGA curve characterized by a weight loss of about 0.7% at C. 90. The crystalline form of any one of embodiments 75-89, wherein the crystalline form is form D having a TGA curve substantially the same as that shown in Figure 27. 91. The crystalline form of any one of embodiments 75-90, wherein the crystalline form is form D having a DSC curve substantially the same as that shown in Figure 28. 92. The crystalline form of any one of embodiments 75-91, wherein the crystalline form is Form D, characterized by a solubility of about 2.25 mg / mL in fasted simulated gastric fluid (FaSSGF) after about 30 minutes at about 37°C. 93. The crystalline form of any one of embodiments 75-92, wherein the crystalline form is Form D, characterized in that it has a solubility of about 2.33 mg / mL in fed simulated intestinal fluid (FeSSIF) after about 24 hours at about 37°C. 94. The crystalline form of any one of embodiments 75-93, wherein the crystalline form is Form D, characterized by a solubility of about 2.19 mg / mL in fasting simulated intestinal fluid (FaSSIF) after about 30 minutes at about 37°C. 95. The crystalline form of any one of embodiments 75-94, wherein the crystalline form is form D, characterized in that it has a solubility of about 2.08 mg / mL in water after about 30 minutes at about 37°C. 96. The crystalline form can be prepared by (a) preparing a solution of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in about 5.5 volumes of ethyl acetate; (b) adding about 0.55 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate; (c) adding a slurry of crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid hydrochloride in ethyl acetate to form a suspension; (d) adding about 1.65 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate to form a slurry; (e) stirring the slurry at about 24°C for about 16 hours; (f) filtering the slurry to obtain a solid; (g) washing the solid with ethyl acetate; (h) drying the solid to provide the crystalline form. 97. A pharmaceutical composition comprising the crystalline form of any one of embodiments 1-96 and a pharmaceutically acceptable carrier. 98. A method for treating a disease or disorder associated with complement factor B (CFB), comprising administering to a subject having such disease or disorder a therapeutically effective amount of the crystalline form of any one of embodiments 1-96, or the pharmaceutical composition of embodiment 94. 99. A method for treating or preventing a disease or disorder selected from the group consisting of an autoimmune disease or disorder, an inflammatory disease or disorder, a metabolic disease or disorder, a neurological disease or disorder, a pulmonary disease, a respiratory disease or disorder, an ophthalmic disease, a cardiovascular disease, and a renal disease, comprising administering to a subject having such disease or disorder a therapeutically effective amount of a crystalline form of any one of embodiments 1-96, or the pharmaceutical composition of embodiment 97. 100. Multiple sclerosis, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis due to Behcet's disease, multifocal choroiditis, Vogt-Koyanagi-Harada disease, intermediate uveitis, birdshot chorioretinitis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigus, non-arteritic anterior ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion , hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion state, myocardial infarction, stroke, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass and renal bypass, arteriosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or inflammation 97. A method for treating or preventing a disease or disorder selected from: hemoglobinemia, immune complex and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust mitosis, pulmonary fibrosis, asthma, allergies, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, oligoimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, metabolic syndrome, hidradenitis suppurativa, the method comprising administering to a subject having such disease or disorder a therapeutically effective amount of a crystalline form of any one of embodiments 1-96, or the pharmaceutical composition of embodiment 97. 101. A method for treating or preventing a kidney disease or disorder selected from chronic kidney disease, diabetic nephropathy, glomerular kidney disease, complement C3 nephropathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis, and polycystic kidney disease (PKD), comprising administering to a subject having such disease or disorder a therapeutically effective amount of the crystalline form of any one of embodiments 1 to 96, or the pharmaceutical composition of embodiment 97. 102. The crystalline form of any one of embodiments 1 to 96, or the pharmaceutical composition of embodiment 97, for use in treating a disease or disorder of embodiment 99 or 100 in a subject in need of such treatment. [Example]

[0414] Materials and Methods X-ray powder diffraction (XRPD) XRPD analysis was performed on a D8-Advance X-ray diffractometer in Bragg-Brentano configuration using copper Kα1 & Kα2 radiation at 1.5418 Å, a nickel filter, and a LynxEye silicon strip detector (40 kV, 40 mA). The slits were set to 0.6 mm divergence, 8 mm anti-scatter, and a 2.5° solar, and XRPD was acquired from 1 to 60 degrees 2θ.

[0415] Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) TGA and DSC were measured using a Mettler Toledo TGA / DSC 3+ The protective and purge gases were nitrogen at flow rates of 20-30 mL / min and 50-100 mL / min, respectively. The desired amount of sample (5-10 mg) was weighed directly into a sealed aluminum pan with a pinhole and analyzed according to the following parameters:

[0416] [Table D]

[0417] [Table E]

[0418] [Table F]

[0419] Solubility Test The solubility was measured by addition and gravimetric methods at room temperature (RT, 20-24°C).

[0420] For the addition method, approximately 20 mg of solid was added to a 2 mL vial, followed by slow addition of the respective solvent until complete dissolution was observed.

[0421] For the gravimetric method, approximately 30 mg of solid was added to a 2 mL vial, followed by 0.75 mL of solvent. The slurry was stirred at a constant temperature for two days. After stirring for two days, the slurry was syringe filtered and the supernatant was transferred to a tared vial. The supernatant solution was evaporated to dryness at 50°C in air on a hot plate and then placed under vacuum at 50°C for three hours at approximately -29 inHg before final weighing.

[0422] PBS-V1+3mM NaTC Purchase sodium taurocholate (NaTC) from a supplier. Assay description: Add equivalent to 3 mM to PBS V1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 hour before use. Discard after 48 hours.

[0423] PBS-V1 + FaSSIF-V2 (artificial intestinal fluid in the fasting state) Purchase FaSSIF-V2 from a supplier (biorelevant.com). Amount added to PBS-V1 as per Table 1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 hour before use. Discard after 48 hours.

[0424] PBS-V1 + 0.3FeSSIF-V2 (artificial intestinal fluid during feeding) Purchase FeSSIF-V2 from a supplier (biorelevant.com). Amount added to PBS-V1 as per Table 1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 hour before use. Discard after 48 hours.

[0425] PBS-V1 + FeSSIF-V2 (artificial intestinal fluid during feeding) Purchase FeSSIF-V2 from a supplier (biorelevant.com). Amount added to PBS-V1 as per Table 1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 hour before use. Discard after 48 hours.

[0426] PBS-V1 + 2FeSSIF-V2 (artificial intestinal fluid during feeding) Purchase FeSSIF-V2 from a supplier (biorelevant.com). Amount added to PBS-V1 as per Table 1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 hour before use. Discard after 48 hours.

[0427] [Table 1]

[0428] Abbreviation ACN: acetonitrile THF: tetrahydrofuran MeOH: Methanol EtOH: ethanol EA or EtOAc: ethyl acetate DMSO: dimethyl sulfoxide IPAc: Isopropyl acetate MEK: Methyl ethyl ketone MTBE: tert-butyl methyl ether 2-MeTHF: 2-methyltetrahydrofuran MIBK: Methyl isobutyl ketone NaTC: sodium taurocholate NMP: N-methyl-2-pyrrolidone DCM: dichloromethane XRPD: X-ray powder diffraction TSA: p-toluenesulfonic acid Tosylate: p-toluenesulfonate FaSSGF: Artificial gastric juice in the fasting state FeSSIF: artificial intestinal fluid during feeding FaSSIF: Fasting artificial intestinal fluid Kleptose: Hydroxypropyl β-cyclodextrin K value: Vapor-liquid equilibrium ratio Methocel: Hydroxypropyl methylcellulose D 50 : Average particle size determined from particle size distribution

[0429] Experimental procedures and characterization data Form A Preparation of amorphous and Form A crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid [ka] tert-Butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.0 equiv.) in 1:1 v / v THF / MeOH (0.09 M) was added to 1 M aqueous LiOH solution (5.0 equiv.). The mixture was heated to 45° C. with stirring for 16 hours. The resulting reaction mixture was diluted with water (to 0.1 M), concentrated to 1 volume under reduced pressure, and then acidified to pH 6 with citric acid (5% aqueous solution). The resulting suspension was filtered, washed with 1 volume of water, and then dried to give an off-white solid (87% yield) as an amorphous compound. FIG. 1 is an X-ray powder diffractogram of amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

[0430] The amorphous solid was added to a stirred solution of isopropanol (to 0.44 M) at 40-50°C. After the addition was complete, the solution was cooled to 20°C and the resulting suspension was stirred for 72 h. The suspension was filtered, washed with 1 volume of isopropanol, and then dried to give an off-white crystalline solid (94% yield). 1H-NMR(400MHz,DMSO-d6):δ 10.82(s,1H),7.97(d,J=7.9Hz,2H),7.68(d,J=7.8Hz,2H),7.25(t,J=2.9Hz,1H),6.65( s,1H),6.45(s,1H),3.70(s,3H),3.53(d,J=11.8Hz,1H),3.23(s,1H),3.16(d,J=11.9Hz , 1H), 2.67 (d, J = 12.4 Hz, 1H), 2.59 (d, J = 13.1 Hz, 1H), 2.46 (s, 1H), 2.43 (s, 3H), 2.29 (t, J = 13.3 Hz, 2H), 1.98 (s, 1H), 1.70 (d, J = 9.0 Hz, 2H), 1.53 (d, J = 9.5 Hz, 2H). LCMS (ESI) m / z 455 (M+1). The X-ray powder diffractogram of the obtained Form A crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is shown in Figure 2.

[0431] [Table 2]

[0432] The thermogravimetric analysis thermogram is shown in Figure 3. The differential scanning calorimetry pattern is shown in Figure 4.

[0433] Alternative preparation of Form A crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid Approximately 3.0 g of amorphous tert-butyl (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was weighed into a 50 mL EasyMax reactor, followed by 20 mL of MeOH. The suspension was heated to 50° C. and stirred at a stirring speed of 500 rpm for 20 minutes, then seeded with pre-made Form A crystals. After maintaining at 50° C. for 3 hours, the suspension was cooled to 25° C. for 250 minutes, followed by heating at 50° C. for 30 minutes. After aging at 50° C. for another 3 hours, the suspension was cooled to 5° C. and stirred overnight. The suspension was filtered, and the filter cake was dried under vacuum at 50° C. overnight. 2.4 g of dry solid was obtained, with a yield of 80%. Molecular formula of the anhydrous free form: C 26 H 28 F2N2O3 (454.52 g / mol). Solid 1 The H NMR (400 MHz, DMSO-d6) is shown in Figure 8.

[0434] The X-ray powder diffractogram of Form A (alternate preparation) is shown in FIG.

[0435] The differential scanning calorimetry pattern of Form A (alternate preparation) is shown in Figure 6. The thermogravimetric analysis thermogram of Form A (alternate preparation) is shown in Figure 7.

[0436] Form A shows a plate-like form as shown in FIG.

[0437] Form B Preparation of Form B (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate Amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (5 g) was charged to a 100 mL EasyMax vessel, followed by p-toluene p-toluenesulfonic acid monohydrate (TSA·HO) (2.30 g, 1.1 equiv.). Ethanol (EtOH) (17.5 mL, 3.5 vol) was then added, and the resulting suspension was stirred (240 rpm), heated to 50° C. for 15 minutes, and then cooled to 25° C. over 15 minutes to give a clear, dark brown solution. Ethyl acetate (12.5 mL, 2.5 vol) was added, followed by standing at 25° C. for 30 minutes. Ethyl acetate (37.5 mL, 7.5 vol) was then charged to the reactor via a dosing pump over 2 hours. After the anti-solvent addition was complete, the purple slurry was allowed to stand at 25° C. for 1 hour.

[0438] The final slurry was filtered, washed twice with 2 volumes of EtOH:EtOAc (26:74 v / v), and dried until a mobile powder was obtained. Filtration was successful, with a K value of 10.4 cm / (min bar).

[0439] The solid was transferred to a tared bottle and dried in a vacuum oven at 50° C. for 16 hours (approximately −29 in Hg). The solid was isolated in 79 mole % yield.

[0440] Form B was prepared by heating the tosylate salt (300 mg) in IPA:water (9:1 by volume, 1.5 mL) at 50° C. for 16 hours. The resulting slurry was sampled for XPRD, then cooled to room temperature and filtered. The resulting wet cake solid was dried under active vacuum in a vacuum oven at 50° C. The yield was 237 mg (79 w / w%).

[0441] The X-ray powder diffractogram for Form B is shown in Figure 12. The XRPD peak table is shown below.

[0442] [Table 3]

[0443] The thermogravimetric analysis thermogram is shown in Figure 13. The differential scanning calorimetry pattern is shown in Figure 14.

[0444] Alternative Preparation I of Form B (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate Approximately 10 g of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and 1.05 equivalents of p-TsOH monohydrate (about 4.45 g) were weighed into a 400 mL EasyMax reactor. 10 mL of water and 90 mL of acetone were added to the reactor, and the solution was heated to 50° C. The solution was stirred at 300 rpm for 20 minutes and then cooled to 25° C. The solution was seeded with 50 mg of previously prepared Form B crystals. The temperature was maintained for 1 hour, and then 220 mL of water was charged within 5 hours. After maintaining for 2 hours, the reaction was cooled to 5° C. in 2 hours and stirred overnight. The suspension was filtered and the filter cake was dried at 40° C. under vacuum for 24 hours to give 11.59 g of Form B(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate (80%). 1 H-NMR(400MHz,DMSO-d6):δ 11.19(s,1H),8.14(d,2H),7.84(d,1H),7.49(m,3H),7.11(d,2H),6.77(s,1H),6.39(t,1H),4.63(m,1H),4.23(m,1H),4.08(d,1H),3.6 9(s,3H),3.41(m,2H),2.67-2.82(m,2H),2.48(s,3H),2.45(m,2H),2.28(s,3H),1.98-2.23(m,2H),1.79(d,2H)(FIG.18).Molecular formula of tosylate anhydride C 26 H 28F2N2O3C7H8O3S(626.72g / mOl).

[0445] The X-ray powder diffractogram of Form B (alternate preparation) is shown in FIG.

[0446] [Table 4]

[0447] The thermogravimetric analysis thermogram is shown in Figure 17. The differential scanning calorimetry pattern is shown in Figure 16. Form B exhibits a plate-like morphology as shown in Figure 19.

[0448] Form B Alternative Preparation II of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate 2.0 g of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid and 0.89 g of p-toluenesulfonic acid were weighed into a 100 mL reactor. 16.2 g of acetone / water (9 / 1, v / v) was added, and the solution was stirred at 25°C and 250 rpm. 10 mL of water was added, followed by 5 mg of seeds, and this was maintained for 2 hours. An additional 30 mL of water was added over 4 hours, and the solution was then cooled to 5°C in 2 hours. After maintaining at 5°C overnight, the suspension was filtered, and the filter cake was dried under vacuum at 50°C overnight. 2.2 g of dry solid was obtained, with a yield of 80%.

[0449] Water content in Form A and Form B Form B contained a water content of 2.3 w / w% based on the total weight of the tosylate salt, compared to 0.15 w / w% in Form A based on the total weight of the free form, by Karl Fischer titration under ambient conditions.

[0450] The mass changes from the DVS isotherm (2 cycles 40-0-95-0-40%RH) are shown in the table below. Mass changes are based on the dry weight of each.

[0451] [Table 5]

[0452] The XRPD profile did not change after the DVS experiment.

[0453] The maximum water absorption of Form B is 2.67% in DVS at 25°C and 95% RH.

[0454] [Table 6]

[0455] Stability of Form A and Form B In bulk, Form A is chemically stable when stored at 11% or 75% RH and 50°C for 1 week. When stored at 11% or 75% RH and 80°C, approximately 0.1% to approximately 0.3% disintegration and slight to moderate discoloration were observed. Form A is chemically and physically stable when stored in HPMC and HGC capsules at 11% and 75% RH and 50°C for 2 weeks. When exposed to a light stress of 1200 kLux, approximately 0.9% disintegration occurred. The polymorphic form remained unchanged under the stress conditions.

[0456] In bulk, Form B is chemically stable when stored at 50°C, 50°C / 75% RH, and 80°C / 11% RH for 1 week. However, when stored at 75% RH and 80°C, approximately 0.1% disintegration and slight to slight discoloration were observed. Form B is chemically and physically stable when stored in HPMC and HGC capsules at 50°C and 11% and 75% RH for 2 weeks. When exposed to a light stress of 1200 kLux, approximately 0.2% disintegration and slight discoloration were observed. The form remained unchanged under the stress conditions.

[0457] There was no change in Form A or Form B by XPRD when exposed to 80% or 92% RH for 24 hours.

[0458] Solubility of Form A and Form B The solubility of Forms A and B in water and biorelevant buffer at 25°C was collected at 24 hours. Form B showed significantly increased solubility at 24 hours in all media compared to Form A.

[0459] [Table 7]

[0460] Intrinsic dissolution of Form A and Form B The intrinsic dissolution rate of Form A at pH 2.0, 0.01M HCl is 0.081 mg / min / cm 2 (Figure 10) and 0.015 mg / min / cm in the same medium. 2 In PBS-V1 (pH 6.5), the intrinsic dissolution rate of Form A is 0.0028 mg / min / cm 2 (Figure 11), whereas Form B had a kinetic energy of 0.18 mg / min / cm 2 shows a much higher dissolution rate of (Figure 21).

[0461] [Table G]

[0462] Compression stability of Form A and Form B When Form A or Form B was subjected to 4 ton compression for 5 minutes, there was no morphological change by XPRD.

[0463] Method: Approximately 100 mg of drug substance is compressed (tablet diameter 8 mm) using a hydraulic press at 4 t for 5 minutes. Samples are then characterized by XRPD to detect any changes in the solid state.

[0464] Milling and wet granulation of Form A and Form B Dry milling (2 min and 5 min) and wet granulation (water and ethanol) did not result in any morphological changes in Form A and Form B. However, a decrease in crystallinity was observed from the XRPD patterns after milling.

[0465] Method: The granules are obtained in solid form. The granulation solvent is added dropwise until the solid is fully wetted. The wet solid is milled for approximately 2 minutes. The wet cake is dried under vacuum or at atmospheric pressure. The solid form and crystallinity are assessed, for example, by XRPD and / or DSC.

[0466] Flow characteristics of Form B Form B had good flow properties and good bulk density suitable for both precision drug processing filler configurations (ultrasonic and vibration modules). See U.S. Patent No. 11,642,315.

[0467] Dissolution of Form B in capsules Capsules containing Form B showed 100% dissolution in 40 minutes in FaSSGF and FeSSIF (Figure 22). The particle size of the material used was characterized as 53.2 μm (x50). The test conditions were as follows: -Dose / strength, 25 mg (calculated as free form) -HGC capsules, 3# -450mL FaSSGF(pH1.6)+450mL FaSSIF(2x, pH7.5) -Temperature 37℃ - Peddle, 75 rpm -Spiral sinker FaSSIF (2x, pH 7.5) added at -30 min -Repeat testing

[0468] Overview of Form A and Form B Forms A and B exhibited desirable properties in all respects, except that Form B offered improved solubility and dissolution profile, as well as flow properties suitable for a capsule formulation approach.

[0469] The use of methanol, ethanol, or any other alcohol during the manufacture of drug substances or drug products must be carefully avoided to prevent the possible formation of toluenesulfonate esters, which are known to have genotoxic effects.

[0470] Form C Preparation of Form C(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate Amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (5 g) and p-toluenesulfonic acid monohydrate (TSA·HO) (2.30 g, 1.1 equiv.) were charged to a 100 mL EasyMax vessel. Ethanol (17.5 mL, 3.5 vol) was then added, and the resulting suspension was heated to 50°C with stirring (240 rpm) for 15 minutes, then cooled to 25°C over 15 minutes. To the resulting clear, dark brown solution was added EtOAc (12.5 mL, 2.5 vol) and then allowed to stand at 25°C for 30 minutes. EtOAc (37.5 mL, 7.5 vol) was then added to the reactor over 2 hours using a dosing pump. After the anti-solvent addition was complete, the purple slurry was then aged for 1 hour at 25° C. The final slurry was filtered, washed twice with 2 volumes of EtOH:EtOAc (26:74 by volume), and dried until a mobile powder was obtained.

[0471] Figure 23 is an X-ray powder diffractogram of Form C and the XRPD peak table is shown below.

[0472] [Table 8-1]

[0473] [Table 8-2]

[0474] The thermogravimetric analysis thermogram is shown in Figure 24. The differential scanning calorimetry pattern is shown in Figure 25.

[0475] Alternative preparation of Form C(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate 1 g of Form B was dissolved in 3 mL of MeOH, and then the solution was added to 15 mL of EA. After several hours, the suspension was filtered and the filter cake was dried in vacuo at 40° C. overnight to give approximately 650 mg of Form C (65%).

[0476] The X-ray powder diffractogram of Form C is consistent with FIG.

[0477] polymorphic stability The competitive equilibrium between Form B and Form C indicated that Form B was the stable polymorphic form in all tested solvents or solvent mixtures.

[0478] Form D Preparation of Form D of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid hydrochloride salt To a solution of amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid in EtOAc (5.5 volumes) was added a portion of 1 M HCl in EtOAc (0.55 equivalents), followed by the seed slurry, to give a gray suspension. The remaining 1 M HCl in EtOAc (1.65 equivalents) was then added in one portion to give a viscous gray slurry. The resulting viscous slurry was stirred at 24° C. and aged for 16 hours. The resulting slurry was filtered and the top washed with 2×1.5 volumes of EtOAc. The filter cake was dried under vacuum to give an off-white solid (71% yield). The X-ray powder diffractogram of Form D is shown in Figure 26. A thermogravimetric analysis thermogram is shown in Figure 27. The differential scanning calorimetry pattern is shown in FIG.

[0479] [Table 9-1]

[0480] [Table 9-2]

[0481] Solubility Test Form A (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid, Form B (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid p-toluenesulfonate in simulated fluid at 37°C. Solubility Data for Form C (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic Acid p-Toluenesulfonate and Form D (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic Acid Hydrochloride

[0482] [Table 10]

[0483] Pharmacokinetic studies The pharmacokinetic profile of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid was evaluated in rats, dogs, or non-human primates (NHPs) as the amorphous compound, as a 20% kleptose solution in water, and as a suspension of Form A in 0.5% methocel plus 0.1% tween 80 in water.

[0484] Preparation of amorphous solution formulations Amorphous (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid was weighed into a glass vial equipped with a magnetic stir bar to obtain formulations at dose concentrations ranging from 0.1 to 1000 mg / kg. Approximately one-third of the final volume of a 20% aqueous solution of kleptose (hydroxypropyl β-cyclodextrin, Aldrich, catalog number 128446-35-5) was added to the vial (to yield either a 5 mL / kg or 10 mL / kg dose volume, depending on the species). The mixture was basified to a pH of 8.5 to 10 using dropwise addition of 2 to 5 M aqueous NaOH while monitoring the pH. The suspension was stirred, vortexed, and sonicated for 15 to 20 minutes to obtain a homogeneous mixture. The remaining ⅓ of the final volume of 20% kleptose was added to the vial, followed by further stirring, vortexing, and sonication for 15-20 minutes to obtain a homogeneous mixture. The pH was monitored and further adjusted to pH 8.5-10 as needed. The final ⅓ of the final volume of 20% kleptose was added to the vial, followed by further stirring, vortexing, and sonication for 15-20 minutes to obtain a homogeneous solution. With gentle stirring, the pH was adjusted to 7.5-8.0 by dropwise addition of 1.0 M aqueous HCl. The formulation should remain in solution.

[0485] Table 10 describes the pharmacokinetic properties of the amorphous solution formulations after oral administration.

[0486] [Table 11]

[0487] Preparation of Form A suspension formulation Form A crystalline (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid was weighed into a glass vial equipped with a magnetic stir bar to obtain formulations at dosage concentrations of 0.1-1000 mg / kg. The crystalline material preferably has a D of less than 50 μm. 50and preferably has a particle size having a D of less than 5 μM 50 The desired volume of 0.5% methocel (viscosity 400 cP, Aldrich, catalog number 9004-67-5) / 0.1% tween 80 (Aldrich, catalog number 9005-65-6) was added (to obtain a dose volume of 5 mL / kg). The contents of the vial were stirred at 400-500 rpm on a stir plate. Gentle vortexing or bath sonication can be applied to break up any large clumps. The vial must be thoroughly mixed to ensure homogeneity immediately prior to administration to the animals.

[0488] Table 12 describes the pharmacokinetic properties of the crystal suspension formulation after oral administration.

[0489] [Table 12]

[0490] Form A has a higher C than the amorphous form. max , AUC 0~24時間 and C 24時間 exhibiting a smaller particle size and resulting in higher overall exposure due to the higher surface area resulting from the smaller particle size.

[0491] A number of embodiments of the present disclosure have been described. Nevertheless, it will be understood that various modifications can be made without departing from the spirit and scope of the disclosure. Accordingly, other embodiments reside within the scope of the following claims.

Claims

1. A crystalline form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

2. 2. The crystalline form of claim 1, wherein the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, and 18.8 (±0.2 degrees 2θ).

3. 2. The crystalline form of claim 1, wherein the crystalline form is Form A and the XRPD pattern has peaks at 10.7, 20.5, 18.8, and 21.7 (±0.2 degrees 2θ).

4. 2. The crystalline form of claim 1, wherein the crystalline form is Form A and the XRPD pattern has peaks (±0.2 degrees 2θ) at 10.7, 20.5, 18.8, 21.7, 19.6, 19.8, 12.5, 21.1, 23.3, 22.5, 27.3, and 15.

5.

5. 5. The crystalline form of any one of claims 1 to 4, wherein the crystalline form is Form A having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.51% at 150°C when heated from 30°C to 300°C at 10 K / min.

6. 2. The crystalline form of claim 1, wherein the (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid is in free form, and further wherein the free form is an anhydrous form.

7. Crystalline p-toluenesulfonate salt form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid.

8. 8. The crystalline form of claim 7, wherein the crystalline form is Form B and the XRPD pattern has peaks at 11.80, 9.30, and 19.9 (±0.2 degrees 2θ).

9. 8. The crystalline form of claim 7, wherein the crystalline form is Form B and the XRPD pattern has peaks at 11.8, 9.3, 19.9, and 22.9 (±0.2 degrees 2θ).

10. 8. The crystalline form of claim 7, wherein the crystalline form is Form B and the XRPD pattern has peaks (±0.2 degrees 2θ) at 11.8, 9.3, 19.9, 22.9, 17.2, 10.2, 20.4, 21.3, and 14.

2.

11. 8. The crystalline form of claim 7, wherein the crystalline form is Form B, and Form B contains water in an amount of 0 w / w% to 2.7 w / w%.

12. 12. The crystalline form of any one of claims 7 to 11, wherein the crystalline form is Form B having a TGA curve characterized by a weight loss of about 1.9% to about 2.0% at 100°C when heated from 30°C to 300°C at 10 K / min.

13. The crystalline form exhibits a T 開始 = 29.8 ° C and T ピーク 12. The crystalline form of any one of claims 7 to 11, which is form B having a DSC thermogram characterized by a broad endotherm at = 65°C.

14. 12. The crystalline form of any one of claims 7 to 11, wherein the crystalline form is Form B that absorbs a maximum of 2.7% water at 25°C and 95% RH by dynamic vapor sorption (DVS).

15. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 14 and a pharmaceutically acceptable carrier.

16. 16. A method of treating a disease or disorder associated with Complement Factor B (CFB), comprising administering to a subject having such disease or disorder a therapeutically effective amount of the crystalline form of any one of claims 1 to 14, or the pharmaceutical composition of claim 15.

17. The disease or disorder associated with complement factor B (CFB) is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis due to Behcet's disease, multifocal choroiditis, Vogt-Koyanagi-Harada disease, intermediate uveitis, birdshot chorioretinitis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia-Leventinese, Sorsby's fundus dystrophy, tardive macular dystrophy, North Carolina macular dystrophy, Stargardt's disease, keratitis, multiple sclerosis, stroke, Guillain-Barré syndrome, spinal cord injury, and traumatic brain injury. injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, inflammatory diseases, paroxysmal nocturnal hemoglobinuria, C3 nephritis (including dense deposit disease and C3 nephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy (including idiopathic membranous nephropathy), diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia colicoli-induced hemolytic uremic syndrome), periodontitis, CD55 deficiency with complement system hyperactivation, vascular thrombosis, protein-losing enteropathy (CHAPLE syndrome), Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion state, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass and renal bypass, arteriosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, COVID-19, rheumatoid arthritis, osteoarthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis , liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and pulmonary infarction, pneumonia, fibrosing dust rash, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, oligoimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) , Buerger's disease, cryoglobulinemia, Kawasaki disease, Takayasu's arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity, immune thrombocytopenia, cold agglutinin disease, warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, Graves' disease and hidradenitis suppurativa.

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