Solid forms of complement factor B inhibitors

Abstract

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

Description

[0001] Priority Claim

[0002] This application claims priority to U.S. Patent Application Serial No. 63 / 425,206, filed on November 14, 2022, the entire content of which (including any figures) is hereby incorporated by reference. Technical Field

[0003] 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 Art

[0004] The complement system is a key component of the innate immune system and has two major functions: host defense against microbial pathogens and clearance of apoptotic cells. Since its first discovery by Jules Bordet and Paul Ehrlich in the 1890s, more than a century of research on complement has revealed its diverse roles in immune responses, surveillance, homeostasis, and metabolism (Hajishengallis, Nat Immunol [Nature Immunology] 2017 18:1288-1298; Sim, Immunobiology [Immunobiology] 2016 221(10):1037-1045; Ricklin, Nat Immunol [Nature Immunology] 2010 11(9):785-797). The complement system consists of a large number of soluble proteins that are found in circulation and tissues as inactive zymogens that are activated upon cleavage by serine proteases. The activation of complement is tightly regulated by plasma and membrane-bound regulators. Dysregulation of complement activity due to genetic mutations, autoantibodies, or chronic inflammation has been found to cause tissue damage in a variety of pathological conditions, including autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and a wide range of kidney diseases (Zipfel, Nat Rev Immunol [Nature Reviews Immunology] 2009 9:729-749; Holers, Annu Rev Immunol [Annual Review of Immunology] 2014 32:433-459).

[0005] 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 bacteria (e.g., mannose-binding lectin (MBL)) (Garred, Immunol Rev 2016 274(1):74-97). Compared with the other two pathways that require specific stimuli for activation, the AP maintains a low level of activation in plasma through a spontaneous hydrolysis process called "tickover" and can also be secondarily activated by the other two complement pathways (Lachmann, Adv Immunol 2009 104:115-149). The AP forms a rapid self-amplifying loop unless inactivated by factor H and factor I. These three activation pathways generate protease complexes called "C3 convertases" (C3bBb and C4b2a) to cleave C3 and form C3bBbC3b as the C5 convertase. The terminal complement pathway assembles C5b with other complement proteins to form the C5b-9 membrane attack complex (MAC), which mediates the lysis of pathogens or apoptotic cells (Bhakdi, Immunol Today 1991 12:318-320). Two soluble fragments of the C3 and C5 cleavage products, C3a and C5a, also known as "anaphylatoxins", are potent chemoattractants that trigger pro-inflammatory responses through their receptors (Klos, Mol Immunol 2009 46(14):2753-2766).

[0006] Complement overactivation and renal deposition have been observed in multiple chronic kidney diseases (CKDs) including the following: 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 [Seminars in Immunopathology] 2018 40(1):125-140; Willows, Clin Med [Clinical Medicine] 2020 20(2):156-160). Preclinical and clinical evidence supports the role of complement (especially AP) in disease onset and progression. Genetic defects in complement genes (such as CFH, CFI, CFHRs, CFB, C3, and MCP / CD46) are directly associated with aHUS and C3G (Bu, J Am Soc Nephrol [Journal of the American Society of Nephrology] 2014 25(1):55-64; Marinozzi, J Am Soc Nephrol [Journal of the American Society of Nephrology] 2015 25:2053-2065; Xiao, Semin Thromb Hemost [Seminars in Thrombosis and Hemostasis] 2014 40(4):465-471). Activation of complement by autoantibodies and immune complexes in the kidney leads to kidney injury and contributes to disease progression in multiple glomerular diseases (Corvillo, Front Immunol [Frontiers in Immunology] 2019 10:886; Marinozzi, J Am Soc Nephrol [Journal of the American Society of Nephrology] 2017 28(5):1603-1613; Seikrit, N Engl J Med [The New England Journal of Medicine] 2018 379(25):2479-2481). Recent studies have provided evidence for the local production and activation of complement proteins in CKDs such as IgAN and diabetic kidney disease (Mühlig, Front Immunol [Frontiers in Immunology] 2020 11:1833; Zhou, Clin J Am Soc Nephrol [Clinical Journal of the American Society of Nephrology] 2021 16(2):213-224; Kelly Am J Nephrol [American Journal of Nephrology] 2015 41:48-56). It is believed that the local production of complement and the unique microenvironment in the kidney render this organ more vulnerable to complement overactivation (Thurman, Clin J Am Soc Nephrol [Clinical Journal of the American Society of Nephrology] 2020 11:1856).

[0007] Considerable efforts have been invested in the development of complement-targeted therapies. Eculizumab, a C5 monoclonal antibody, has been approved for the treatment of aHUS. However, when tested in C3G, only a subset of patients with high levels of C5b-9 (MAC) showed disease improvement. This may be due to the role of the activation fragments of C3 levels upstream of the terminal pathway (Vivarelli, Semin Thromb Hemost [Seminars in Thrombosis and Hemostasis] 2014 40(4):472-477). A variety of therapeutic agents targeting different complement pathways are currently under development, each with its own advantages and limitations (Zipfel, Front Immunol [Frontiers in Immunology] 2019 10:2166; Thurman, Kidney Int [Kidney International] 2016 90(4):746-752). Nevertheless, there remains a need for potent therapeutic compounds that block C3 and C5 levels of the complement system.

[0008] As a key enzyme of the alternative pathway (AP), complement factor B (CFB) provides an ideal target for blocking the central amplification loop and the terminal complement pathway. CFB knockout has been shown to be protective in the following rodent models: C3 glomerulopathy (C3G) (Pickering, Nat Genet 2002 31(4):424-428), membranous nephropathy (MN) (Luo, Front Immunol 2018 9:1433), ANCA-associated vasculitis (Xiao, Am J Pathol 2007 170(1):52-64), lupus nephritis (LN) (Watanabe, J Immunol 2000 164(2):786-794), and multiple kidney 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, prevention of kidney injury, and extended 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 of C3G, iptacopan demonstrated encouraging efficacy in reducing proteinuria after 12 weeks of treatment (Wong, J Am Soc Nephrol 2020 31:55A).

[0009] However, variability in complement activity and patient response has also been observed, suggesting that highly effective compounds with stronger and more persistent complement inhibition in vivo could provide greater therapeutic benefits to patients with C3G and a large spectrum of CKD. Accordingly, there is a desire to provide compounds that inhibit complement factor B.

[0010] Disclosed in PCT / US2022 / 032042, filed on June 3, 2022 and titled "SUBSTITUTED INDOLE COMPOUNDS AND METHODS OF USE THEREOF" (incorporated herein by reference in its entirety) is (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid having Formula I.

[0011]

[0012] The solid forms of the active pharmaceutical ingredient (API) of a particular drug are often important determinants of the ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo of the drug. Salt formation is a technique for optimizing the aforementioned properties of ionizable candidate drugs. Whether or not a counterion is present, where the same substance composition crystallizes in different lattice arrangements, crystalline forms appear, resulting in different thermodynamic properties and stabilities specific to a particular crystalline form. Crystalline forms can also include different hydrates or solvates of the same compound. When determining which form is preferred, many properties of the forms are compared and the preferred form is selected based on many physical property variables. It is entirely possible that in some cases, where certain aspects such as ease of preparation, stability, etc. are considered crucial, one form may be preferred. In other cases, for a greater dissolution rate and / or superior bioavailability, a different form may be preferred. It is not yet possible to predict whether a particular compound or a salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in a therapeutic composition, or which polymorph will exhibit such desired properties. SUMMARY OF THE INVENTION

[0013] 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.

[0014] In some embodiments, the crystalline form is Form A as described herein.

[0015] In some embodiments, Form A is prepared by a method comprising:

[0016] (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 is added to isopropanol with stirring at about 40 °C to about 50 °C to form a solution having a molar concentration of about 0.44;

[0017] (b) The solution is cooled to about 20 °C and stirred for about 72 hours to form a suspension;

[0018] (c) The suspension is filtered to obtain a solid;

[0019] (d) The solid is washed with isopropanol; and

[0020] (e) The solid is dried to provide Form A.

[0021] The present disclosure provides crystalline forms of the tosylate 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.

[0022] In some embodiments, the crystalline form is Form B as described herein.

[0023] In some embodiments, Form B is prepared by a method comprising:

[0024] (a) Ethanol is added 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 (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid;

[0025] (b) The suspension is heated to about 50 °C and stirred for about 15 minutes to form a solution;

[0026] (c) The solution is cooled to about 25 °C over about 15 minutes, then about 2.5 volumes of ethyl acetate are added;

[0027] (d) About 7.5 volumes of ethyl acetate are added over 2 hours at about 25 °C to form a slurry, and then the slurry is allowed to stand at about 25 °C for about 1 hour;

[0028] (e) The slurry is filtered to obtain a solid;

[0029] (f) The solid is washed with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3 by volume;

[0030] (g) Dry the solid to provide the solid form;

[0031] (h) Add the solid form to a binary mixture of isopropanol and water in a volume ratio of about 9:1, and then heat at about 50 °C for about 16 hours to form a slurry;

[0032] (i) Cool the slurry to about 25 °C and filter to obtain a solid; and

[0033] (j) Dry the solid at about 50 °C to provide Form B.

[0034] In some embodiments, the crystalline form is Form C as described herein.

[0035] In some embodiments, Form C is prepared by a method comprising:

[0036] (a) Add 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 (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid;

[0037] (b) Heat the suspension to about 50 °C and stir for about 15 minutes to form a solution;

[0038] (c) Cool the solution to about 25 °C within about 15 minutes, and then add about 2.5 volumes of ethyl acetate;

[0039] (d) Add about 7.5 volumes of ethyl acetate within 2 hours at about 25 °C to form a slurry, and then let the slurry stand at about 25 °C for about 1 hour;

[0040] (e) Filter the slurry to obtain a solid;

[0041] (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; and

[0042] (g) Dry the solid to provide Form C.

[0043] The hydrochloride 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 are disclosed herein.

[0044] In some embodiments, the crystalline form is Form D as described herein.

[0045] In some embodiments, Form D is prepared by a method comprising:

[0046] (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;

[0047] (b) adding about 0.55 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate;

[0048] (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;

[0049] (d) adding about 1.65 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate to form a slurry;

[0050] (e) stirring the slurry at about 24 °C for about 16 hours;

[0051] (f) filtering the slurry to obtain a solid;

[0052] (g) washing the solid with ethyl acetate; and

[0053] (h) drying the solid to provide Form D.

[0054] Some embodiments provide a pharmaceutical composition comprising one of Form A, Form B, Form C, or Form D, and a pharmaceutically acceptable carrier.

[0055] Some embodiments provide a pharmaceutical composition comprising Form A, and a pharmaceutically acceptable carrier.

[0056] Some embodiments provide a pharmaceutical composition comprising Form B, Form C, or Form D, and a pharmaceutically acceptable carrier.

[0057] Disclosed herein are methods of treating a disease or disorder associated with complement factor B (CFB), the method comprising administering to a subject having such a 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.

[0058] Disclosed herein are methods of treating a disease or disorder associated with complement factor B (CFB), the methods comprising administering to a subject having such a 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.

[0059] Some embodiments provide methods 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 kidney disease, the methods comprising administering to a subject having such a 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.

[0060] Some embodiments provide methods 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 kidney disease, the methods comprising administering to a subject having such a 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.

[0061] As used herein, when used to refer to a modified numerical value, the term “about” encompasses a range of numerical uncertainty of from 0% to 10% of the numerical value.

[0062] The terms “polymorph” and “polymorphic form” refer to different crystalline forms of a single compound. That is, polymorphs are different solids having the same molecular formula, but each polymorph can have different solid-state physical properties. Thus, a single compound can give rise to multiple polymorphic forms, each form having different solid-state physical properties, such as different solubility curves, dissolution rates, melting point temperatures, flowabilities, and / or different X-ray diffraction peaks.

[0063] The term “amorphous” means a solid in a non-crystalline state. An amorphous solid is a disordered arrangement of molecules and thus has no distinguishable lattice or unit cell and thus no definable long-range order. The solid-state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction (“XRPD”), differential scanning calorimetry (“DSC”), or other standard techniques known to those of skill in the art.

[0064] As used herein, a compound is "substantially pure" if it contains minor amounts of other components. Such components can include, for example, starting materials, residual solvents, other polymorphic or crystalline forms, opposite enantiomers, other salt forms, other solvates, or any other impurities that can result from the preparation, isolation, and / or recrystallization of the compounds provided herein. In some embodiments, the other components can include, for example, starting materials, residual solvents, other polymorphic or crystalline forms, opposite enantiomers, other salt forms, or any other impurities that can result from the preparation, isolation, and / or recrystallization of the compounds provided herein. 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 (e.g., a particular crystalline form or salt) is "substantially pure" if it 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 it constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the solid form.

[0065] The terms "effective amount" and "therapeutically effective amount" are used interchangeably herein and refer to the amount of an active compound or agent that elicits a biological or pharmacological response (including alleviation of the symptoms of the disease or disorder being treated) in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician. In particular, when administered to a subject in need of such treatment, an effective amount is sufficient to (i) treat or prevent a particular disease, condition, or disorder that can be treated with a CFB inhibitor, (ii) alleviate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the crystalline form corresponding to such a therapeutically effective amount will depend on factors such as the disease state and its severity, the identity of the mammal in need of treatment (e.g., body weight), and the like.

[0066] The term "free form" refers to a compound in a non-salt form.

[0067] The term "hydrate" means a compound or its salt that further includes water, either stoichiometric or non-stoichiometric, bound by non-covalent intermolecular forces. The term "anhydrate" means a compound or its salt that does not include water bound by non-covalent intermolecular forces, either stoichiometric or non-stoichiometric.

[0068] As used herein, the term "pharmaceutical composition" is intended to cover a product containing one or more active ingredients and one or more inert ingredients that make up the carrier, as well as any product directly or indirectly produced by the combination, compounding, or aggregation of any two or more of these ingredients, or by the dissociation of one or more of these ingredients, or by other types of reactions or interactions of one or more of these ingredients. Thus, the pharmaceutical compositions of the present disclosure cover any composition made by mixing a compound of the present disclosure or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

[0069] The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that can be administered to a patient together with a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and that, when administered in a dose sufficient to deliver a therapeutically effective amount of the compound, does not destroy its pharmacological activity and is non-toxic.

[0070] The term "subject" refers to an animal, including but not limited to primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, with respect to mammalian subjects such as humans.

[0071] In the context of treating a disease or disorder, the terms "treat", "treating", and "treatment" mean including alleviating 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 of its symptoms.

[0072] Details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 is the X-ray powder diffraction pattern 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.

[0074] Figure 2 is the X-ray powder diffraction pattern of Form A.

[0075] Figure 3 is the thermogravimetric analysis thermogram of Form A.

[0076] Figure 4 is the differential scanning calorimetry plot of Form A.

[0077] Figure 5is the X-ray powder diffraction pattern of Form A (alternative preparation).

[0078] Figure 6 is the differential scanning calorimetry pattern of Form A (alternative preparation).

[0079] Figure 7 is the thermogravimetric analysis thermogram of Form A (alternative preparation).

[0080] Figure 8 is of Form A (alternative preparation) 1 1H NMR spectrum.

[0081] Figure 9 is the scanning electron microscope image of Form A (alternative preparation).

[0082] Figure 10 is the intrinsic dissolution rate curve of Form A (alternative preparation) in pH 2.0 HCl buffer.

[0083] Figure 11 is the intrinsic dissolution rate curve of Form A (alternative preparation) in pH 6.5 phosphate buffer.

[0084] Figure 12 is the X-ray powder diffraction pattern of Form B.

[0085] Figure 13 is the thermogravimetric analysis thermogram of Form B.

[0086] Figure 14 shows the differential scanning calorimetry pattern of Form B.

[0087] Figure 15 is the X-ray powder diffraction pattern of Form B (alternative preparation).

[0088] Figure 16 is the differential scanning calorimetry pattern of Form B (alternative preparation).

[0089] Figure 17 is the thermogravimetric analysis thermogram of Form B (alternative preparation).

[0090] Figure 18 is of Form B (alternative preparation) 1 1H NMR spectrum.

[0091] Figure 19 is the scanning electron microscope image of Form B (alternative preparation).

[0092] Figure 20 is the intrinsic dissolution rate of Form B in pH 2 buffer.

[0093] Figure 21is the intrinsic dissolution rate of Form B in pH 6.5 buffer.

[0094] Figure 22 is the dissolution profile of the capsule containing Form B.

[0095] Figure 23 is the X-ray powder diffraction pattern of Form C.

[0096] Figure 24 is the thermogravimetric analysis thermogram of Form C.

[0097] Figure 25 is the differential scanning calorimetry pattern of Form C.

[0098] Figure 26 is the X-ray powder diffraction pattern of Form D.

[0099] Figure 27 is the thermogravimetric analysis thermogram of Form D.

[0100] Figure 28 is the differential scanning calorimetry pattern of Form D. Detailed Description

[0101] The present disclosure features 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.

[0102]

[0103] The present disclosure also provides 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 that is substantially the same as that shown in Figure 1 and is shown in.

[0104] Form A

[0105] The present disclosure provides crystalline forms 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 (the compound of Formula I). In one embodiment, the free form is the anhydrous form. The crystalline form of the free form of the compound of Formula I (i.e., the anhydrous form) is referred to herein as Form A. Form A is described and characterized herein.

[0106] In some embodiments, the crystalline form is Form A and the XRPD pattern is substantially the same as that shown in Figure 2 the following.

[0107] In some embodiments, the crystalline form is Form A and the XRPD pattern is substantially the same as that shown in Figure 5 the following.

[0108] In some embodiments, the crystalline form is Form A and the XRPD pattern is represented by the peaks shown in the following table:

[0109]

[0110] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 10.7 ± 0.2 degrees 2θ. The X-ray powder diffraction pattern of Form A may further include one or more additional characteristic peaks.

[0111] In some embodiments, the X-ray powder diffraction pattern of Form A may further include one or more of the following additional characteristic peaks, which may also be used to identify Form A (e.g., in a sample).

[0112] For example, the XRPD pattern has a peak at 20.5 ± 0.2 degrees 2θ.

[0113] For example, the XRPD pattern has a peak at 18.8 ± 0.2 degrees 2θ.

[0114] For example, the XRPD pattern has a peak at 21.7 ± 0.2 degrees 2θ.

[0115] For example, the XRPD pattern has a peak at 19.6 ± 0.2 degrees 2θ.

[0116] For example, the XRPD pattern has a peak at 19.8 ± 0.2 degrees 2θ.

[0117] For example, the XRPD pattern has a peak at 12.5 ± 0.2 degrees 2θ.

[0118] For example, the XRPD pattern has a peak at 21.7 ± 0.2 degrees 2θ.

[0119] For example, the XRPD pattern has a peak at 23.3 ± 0.2 degrees 2θ.

[0120] For example, the XRPD pattern has a peak at 22.5 ± 0.2 degrees 2θ.

[0121] For example, the XRPD pattern has a peak at 27.3 ± 0.2 degrees 2θ.

[0122] For example, the XRPD pattern has a peak at 15.5 ± 0.2 degrees 2θ.

[0123] The X-ray powder diffraction pattern of Form A may further include one or more lower-intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0124] For example, the XRPD pattern has a peak at 5.3 ± 0.2 degrees 2θ.

[0125] For example, the XRPD pattern has a peak at 13.7 ± 0.2 degrees 2θ.

[0126] For example, the XRPD pattern has a peak at 16.5 ± 0.2 degrees 2θ.

[0127] For example, the XRPD pattern has a peak at 15.6 ± 0.2 degrees 2θ.

[0128] For example, the XRPD pattern has a peak at 23.5 ± 0.2 degrees 2θ.

[0129] For example, the XRPD pattern has a peak at 16.1 ± 0.2 degrees 2θ.

[0130] For example, the XRPD pattern has a peak at 28.9 ± 0.2 degrees 2θ.

[0131] For example, the XRPD pattern has a peak at 11.3 ± 0.2 degrees 2θ.

[0132] For example, the XRPD pattern has a peak at 26.7 ± 0.2 degrees 2θ.

[0133] For example, the XRPD pattern has a peak at 25.6 ± 0.2 degrees 2θ.

[0134] For example, the XRPD pattern has a peak at 29.2 ± 0.2 degrees 2θ.

[0135] 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).

[0136] 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).

[0137] 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).

[0138] 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, 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 (±0.2 degrees 2θ).

[0139] In some embodiments, the crystalline form is Form A, and the XRPD pattern has a peak at 10.7 (±0.2 degrees 2θ).

[0140] 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).

[0141] 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).

[0142] 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).

[0143] 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).

[0144] 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).

[0145] 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).

[0146] 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).

[0147] 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).

[0148] 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).

[0149] 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, and 16.3 (±0.2 degrees 2θ).

[0150] 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).

[0151] 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, 23.2, and 20.9 (±0.2 degrees 2θ).

[0152] 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, 23.2, 20.9, and 13.6 (±0.2 degrees 2θ).

[0153] 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, 23.2, 20.9, 13.6, and 5.3 (±0.2 degrees 2θ).

[0154] Those skilled in the art will recognize that the relative intensities of the peaks in an X-ray powder diffraction pattern can vary depending on sample preparation techniques, crystal size distribution, the various filters used, the sample mounting procedure, and the particular instrument employed. Thus, depending on the type of instrument and the settings (including filters) used, new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have negligible relative intensities (and thus may not be observable) in subsequently obtained patterns. As such, the absence of one or more of the lower relative intensity peaks described above does not, in itself, establish the absence of Form A (e.g., in a sample). However, the presence of the lower relative intensity peaks described above can generally be used to further establish the presence of Form A in a sample.

[0155] Form A may also have one or more of the following characteristics.

[0156] In 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 about 150 °C to about 220 °C (e.g., about 150 °C to about 190 °C, about 165 °C to about 205 °C, about 170 °C to about 220 °C, about 180 °C to about 200 °C, about 185 °C to about 195 °C, about 187 °C to about 191 °C, or about 189 °C). In some embodiments, the crystalline form is Form A having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2% at about 189 °C.

[0157] In some embodiments, the crystalline form 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%) at about 270 °C to about 330 °C (e.g., about 280 °C to about 320 °C, about 290 °C to about 310 °C, about 295 °C to about 305 °C, or about 300 °C). In some embodiments, the crystalline form is Form A having a TGA curve characterized by a weight loss of about 25% at about 300 °C.

[0158] In some embodiments, the crystalline form is Form A having a Figure 3 TGA curve substantially the same as that shown in

[0159] In some embodiments, the crystalline form is Form A having a Figure 7 TGA curve substantially the same as that shown in

[0160] In some embodiments, the crystalline form is Form A having a differential scanning calorimetry (DSC) curve characterized by a melting onset (endotherm) 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 about 201.9 °C. In some embodiments, the crystalline form is Form A having a differential scanning calorimetry (DSC) curve characterized by a melting onset (endotherm) at about 201.9 °C.

[0161] In some embodiments, the crystalline form is Form A having a DSC curve that is substantially the same as that shown in Figure 4 In some embodiments, the crystalline form is Form A having a DSC curve that is substantially the same as that shown in

[0162] In some embodiments, the crystalline form is Form A having a DSC curve that is substantially the same as that shown in Figure 6 In some embodiments, the crystalline form is Form A having a DSC curve that is substantially the same as that shown in

[0163] In some embodiments, the TGA plot of Form A shows a weight loss of about 0.51% at 150 °C when heated from 30 °C to 300 °C at 10 K / min.

[0164] In some embodiments, Form A absorbs up to 0.45% moisture by DVS at 25 °C, 95% RH.

[0165] In some embodiments, the crystalline form is Form A, which is characterized by a solubility of about 1.8 mg / mL to about 2.8 mg / mL (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 between these values) in fasted state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. 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) at about 37 °C after about 30 minutes. In some embodiments, Form A is characterized by a solubility of 2.2 mg / mL to 2.5 mg / mL in fasted state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, Form A is characterized by a solubility of about 2.3 mg / mL in fasted state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes.

[0166] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility 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, or greater than about 2.0 mg / mL, such as 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) after about 24 hours in fasted-state simulated gastric fluid (FaSSGF) at about 37°C. In some embodiments, Form A is characterized by having a solubility greater than about 1.8 mg / mL to greater than about 1.9 mg / mL after about 24 hours in fasted-state simulated gastric fluid (FaSSGF) at about 37°C. In some embodiments, Form A is characterized by having a solubility greater than about 1.9 mg / mL to greater than about 2 mg / mL after about 24 hours in fasted-state simulated gastric fluid (FaSSGF) at about 37°C. In some embodiments, Form A is characterized by having a solubility greater than about 2 mg / mL after about 24 hours in fasted-state simulated gastric fluid (FaSSGF) at about 37°C.

[0167] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility greater than 2 mg / mL after about 24 hours in fasted-state simulated gastric fluid (FaSSGF) with an initial pH of 1.6 at about 25°C.

[0168] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.26 mg / mL to about 0.36 mg / mL (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 between these values) after about 30 minutes in fed-state simulated intestinal fluid (FeSSIF) at about 37°C. In some embodiments, Form A is characterized by having a solubility of about 0.29 mg / mL to about 0.33 mg / mL after about 30 minutes in fed-state simulated intestinal fluid (FeSSIF) at about 37°C. In some embodiments, Form A is characterized by having a solubility of 0.30 mg / mL to 0.32 mg / mL after about 30 minutes in fed-state simulated intestinal fluid (FeSSIF) at about 37°C. In some embodiments, Form A is characterized by having a solubility of about 0.31 mg / mL after about 30 minutes in fed-state simulated intestinal fluid (FeSSIF) at about 37°C.

[0169] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.26 mg / mL to about 0.36 mg / mL (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 between these values) in fed-state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, Form A is characterized by having a solubility of about 0.30 mg / mL to about 0.32 mg / mL in fed-state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, Form A is characterized by having a solubility of 0.30 mg / mL to 0.32 mg / mL in fed-state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, Form A is characterized by having a solubility of about 0.31 mg / mL in fed-state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours.

[0170] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.18 mg / mL to about 0.28 mg / mL (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 between these values) in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, Form A is characterized by having a solubility of about 0.20 mg / mL to about 0.26 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, Form A is characterized by having a solubility of 0.23 mg / mL to 0.25 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.24 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes.

[0171] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of from about 0.13 mg / mL to about 0.23 mg / mL (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 between these values) after about 24 hours in fasted-state simulated intestinal fluid (FaSSIF) at about 37°C. In some embodiments, Form A is characterized by having a solubility of from about 0.15 mg / mL to about 0.20 mg / mL after about 24 hours in fasted-state simulated intestinal fluid (FaSSIF) at about 37°C. In some embodiments, Form A is characterized by having a solubility of from 0.17 mg / mL to 0.19 mg / mL after about 24 hours in fasted-state simulated intestinal fluid (FaSSIF) at about 37°C. In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.18 mg / mL after about 24 hours in fasted-state simulated intestinal fluid (FaSSIF) at about 37°C.

[0172] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.07 mg / mL after about 24 hours in fasted-state simulated intestinal fluid (FaSSIF) with an initial pH of 6.5 at about 25°C. In some embodiments, the fasted-state simulated intestinal fluid (FaSSIF) contains phosphate buffered saline (PBS).

[0173] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.07 mg / mL after about 24 hours in phosphate buffered saline (PBS) with an initial pH of 6.5 at about 25°C. In some embodiments, the phosphate buffered saline (PBS) contains sodium taurocholate (NaTC). In some embodiments, the phosphate buffered saline (PBS) contains 3 mM of sodium taurocholate (NaTC).

[0174] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility 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 between these values) in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, Form A is characterized by having a solubility of about 0.17 mg / mL to about 0.23 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, Form A is characterized by having a solubility of 0.20 mg / mL to 0.22 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.21 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes.

[0175] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility 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 between these values) in water having an initial pH of about 7.0 at about 37 °C after about 24 hours. In some embodiments, Form A is characterized by having a solubility of about 0.20 mg / mL to about 0.24 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, Form A is characterized by having a solubility of 0.20 mg / mL to 0.23 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.22 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 24 hours.

[0176] In some embodiments, the crystalline form is Form A, which is characterized by having a solubility of about 0.05 mg / mL in water having an initial pH of about 7.0 at about 25 °C after 24 hours.

[0177] In some embodiments, the crystalline form is Form A in a substantially pure form. In some embodiments, the crystalline form is Form A, wherein the 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, wherein the Form A is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 50 °C for 1 week. In some embodiments, the crystalline form is Form A, wherein the Form A is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 80 °C for 1 week. In some embodiments, the crystalline form is Form A, wherein the Form A is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 50 °C for 1 week. In some embodiments, the crystalline form is Form A, wherein the Form A is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 80 °C for 1 week.

[0178] Form B

[0179] 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 p-toluenesulfonate” 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-toluenesulfonic acid salt” are used interchangeably herein.

[0180]

[0181] 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 includes water, wherein the amount of water is from 0% to 2.7% w / w relative to the total weight of Form B. The water content may vary depending on the drying conditions and ambient humidity. In some embodiments, under ambient conditions, the amount of water is from 1.5% to 2.5% w / w. In some embodiments, under ambient conditions, the amount of water is from 1.5% to 2% w / w.

[0182] Form B is a highly crystalline form with a thick plate-like morphology. Form B may be a non-stoichiometric hydrate form, characterized as a channel hydrate, and exhibits reversible water adsorption and desorption behavior without hysteresis. The XRPD pattern of Form B does not change under a wide range of conditions including ambient humidity and temperature range.

[0183] In some embodiments, the crystalline form is Form B, and the XRPD pattern is substantially the same as that shown in Figure 12 as shown.

[0184] In some embodiments, the crystalline form is Form B, and the XRPD pattern is substantially the same as that shown in Figure 15 as shown.

[0185] In some embodiments, the crystalline form is Form B, and the XRPD pattern is represented by the peaks shown in the following table:

[0186]

[0187] In some embodiments, the crystalline form is characterized by an XRPD pattern having 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.

[0188] In some embodiments, the X-ray powder diffraction pattern of Form B may also include one or more of the following additional characteristic peaks, which may also be used to identify Form B (e.g., in a sample).

[0189] For example, the XRPD pattern has a peak at 9.3 ± 0.2 degrees 2θ.

[0190] For example, the XRPD pattern has a peak at 19.9 ± 0.2 degrees 2θ.

[0191] For example, the XRPD pattern has a peak at 22.9 ± 0.2 degrees 2θ.

[0192] For example, the XRPD pattern has a peak at 17.2 ± 0.2 degrees 2θ.

[0193] For example, the XRPD pattern has peaks at 10.2 ± 0.2 degrees 2θ.

[0194] For example, the XRPD pattern has peaks at 20.4 ± 0.2 degrees 2θ.

[0195] For example, the XRPD pattern has peaks at 21.3 ± 0.2 degrees 2θ.

[0196] For example, the XRPD pattern has peaks at 14.2 ± 0.2 degrees 2θ.

[0197] The X-ray powder diffraction pattern of Form B may also include one or more lower-intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0198] For example, the XRPD pattern has peaks at 18.2 ± 0.2 degrees 2θ.

[0199] For example, the XRPD pattern has peaks at 20.7 ± 0.2 degrees 2θ.

[0200] For example, the XRPD pattern has peaks at 15.4 ± 0.2 degrees 2θ.

[0201] For example, the XRPD pattern has peaks at 24.4 ± 0.2 degrees 2θ.

[0202] For example, the XRPD pattern has peaks at 20.2 ± 0.2 degrees 2θ.

[0203] For example, the XRPD pattern has peaks at 23.7 ± 0.2 degrees 2θ.

[0204] For example, the XRPD pattern has peaks at 15.3 ± 0.2 degrees 2θ.

[0205] For example, the XRPD pattern has peaks at 25.2 ± 0.2 degrees 2θ.

[0206] For example, the XRPD pattern has peaks at 18.7 ± 0.2 degrees 2θ.

[0207] For example, the XRPD pattern has peaks at 18.5 ± 0.2 degrees 2θ.

[0208] For example, the XRPD pattern has peaks at 16.9 ± 0.2 degrees 2θ.

[0209] For example, the XRPD pattern has peaks at 13.8 ± 0.2 degrees 2θ.

[0210] 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).

[0211] 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).

[0212] 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).

[0213] 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, 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 (±0.2 degrees 2θ).

[0214] In some embodiments, the crystalline form is Form B and the XRPD pattern has a peak at 11.7 (±0.2 degrees 2θ).

[0215] 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).

[0216] 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).

[0217] 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).

[0218] 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).

[0219] 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).

[0220] 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).

[0221] 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).

[0222] 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).

[0223] 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).

[0224] 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, 18.2, and 25.5 (±0.2 degrees 2θ).

[0225] 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, 18.2, 25.5, and 15.4 (±0.2 degrees 2θ).

[0226] 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, 18.2, 25.5, 15.4, and 20.7 (±0.2 degrees 2θ).

[0227] 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, 18.2, 25.5, 15.4, 20.7, and 27.6 (±0.2 degrees 2θ).

[0228] 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, 18.2, 25.5, 15.4, 20.7, 27.6, and 24.4 (±0.2 degrees 2θ).

[0229] 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, 18.2, 25.5, 15.4, 20.7, 27.6, and 24.4 (±0.2 degrees 2θ).

[0230] When the humidity was decreased from 30% RH to 0% RH and then back to 30% RH, the variable humidity XRPD of Form B showed reversible peak shifts. The XRPD patterns of Form B remained almost unchanged between 30% RH and 90% RH. When Form B was exposed to low humidity conditions, only minor differences in the XRPD patterns were observed, but these patterns could also be explained by the crystal structure (hta02a) of Form B. This indicates that the dehydrated form can be an isomorphous or polymorphic phase of Form B.

[0231] Those skilled in the art will recognize that the relative intensities of the peaks in an X-ray powder diffraction pattern can vary depending on sample preparation techniques, crystal size distribution, various filters used, sample mounting procedures, and the specific instrument employed. Thus, depending on the type of instrument and the settings (including filters) used, new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have negligible relative intensities (and thus may not be observable) in subsequently obtained patterns. As such, the absence of one or more of the lower relative intensity peaks described above does not, by itself, establish the absence of Form B (e.g., in a sample). However, the presence of the lower relative intensity peaks described above can generally be used to further confirm the presence of Form B in a sample.

[0232] Form B may also have one or more of the following characteristics.

[0233] 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% loss) at about 60 °C to about 100 °C. In some embodiments, the crystalline form is Form B having a TGA curve characterized by a weight loss of about 1% at about 60 °C to about 100 °C.

[0234] In some embodiments, the crystalline form is Form B having a TGA curve that is substantially the same as that shown in Figure 13 .

[0235] In some embodiments, the crystalline form is Form B having a TGA curve that is substantially the same as that shown in Figure 17 .

[0236] In some embodiments, the crystalline form is Form B having a DSC curve that is substantially the same as that shown in Figure 14 .

[0237] In some embodiments, the crystalline form is Form B having a DSC curve that is substantially the same as that shown in Figure 16 .

[0238] In some embodiments, Form B has a DSC thermogram characterized by broad endothermic peaks at T 起始 = 29.8 °C and T 峰 = 65 °C when heated from 30 °C to 300 °C at a rate of 10 K / min.

[0239] In some embodiments, Form B has a DSC thermogram showing broad endothermic peaks at T 起始 = 29.8 °C (enthalpy 41.9 J / g) and T 峰 = 65 °C when heated from 30 °C to 300 °C at a rate of 10 K / min.

[0240] In some embodiments, the TGA plot of Form B shows a weight loss of about 1.9% to 2.0% at 100 °C when heated from 30 °C to 300 °C at 10 K / min.

[0241] In some embodiments, Form B absorbs up to 2.7% moisture by DVS at 25 °C, 95% RH. In some embodiments, the crystalline form is Form B in substantially pure form. In some embodiments, the crystalline form is Form B, wherein the 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, wherein the Form B is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 50 °C for 1 week. In some embodiments, the crystalline form is Form B, wherein the Form B is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 80 °C for 1 week. In some embodiments, the crystalline form is Form B, wherein the Form B is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 50 °C for 1 week. In some embodiments, the crystalline form is Form B, wherein the Form B is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 80 °C for 1 week.

[0242] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.32 mg / mL to about 0.45 mg / mL (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 between these values) in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, Form B is characterized by having a solubility of about 0.36 mg / mL to about 0.42 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of 0.39 mg / mL to 0.41 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.40 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes.

[0243] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.49 mg / mL to about 0.59 mg / mL (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 between these values) in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, Form B is characterized by having a solubility of about 0.50 mg / mL to about 0.56 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of 0.53 mg / mL to 0.55 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.54 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours.

[0244] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.45 mg / mL to about 0.52 mg / mL (e.g., about 0.49 mg / mL) after about 24 hours in fasted-state simulated gastric fluid (FaSSGF) with an initial pH of 1.6 at about 25°C.

[0245] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility greater than about 1.5 mg / mL to greater than 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) after about 30 minutes in fed-state simulated intestinal fluid (FeSSIF) at about 37°C. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility greater than 1.9 mg / mL to greater than 2 1.9 mg / mL after about 30 minutes in fed-state simulated intestinal fluid (FeSSIF) at about 37°C. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility greater than about 2 mg / mL after about 30 minutes in fed-state simulated intestinal fluid (FeSSIF) at about 37°C.

[0246] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility greater than about 1.5 mg / mL to greater than 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) after about 24 hours in fed-state simulated intestinal fluid (FeSSIF) at about 37°C. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility greater than 1.9 mg / mL to greater than 2 mg / mL after about 24 hours in fed-state simulated intestinal fluid (FeSSIF) at about 37°C. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility greater than about 2 mg / mL after about 24 hours in fed-state simulated intestinal fluid (FeSSIF) at about 37°C.

[0247] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of greater than about 1.5 mg / mL to greater than about 2 mg / mL (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 fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, Form B is characterized by having a solubility of greater than 1.8 mg / mL to greater than 1.9 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, Form B is characterized by having a solubility of greater than about 2 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes.

[0248] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.48 mg / mL to about 0.58 mg / mL (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 between these values) in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, Form B is characterized by having a solubility of about 0.51 mg / mL to about 0.54 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, Form B is characterized by having a solubility of 0.52 mg / mL to 0.54 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.53 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours.

[0249] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of greater than 2 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) with an initial pH of 6.5 at about 25 °C after about 24 hours. In some embodiments, the fasted-state simulated intestinal fluid (FaSSIF) contains phosphate buffered saline (PBS).

[0250] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility greater than 2 mg / mL after about 24 hours in phosphate buffered saline (PBS) with an initial pH of 6.5 at about 25°C. In some embodiments, the phosphate buffered saline (PBS) contains sodium taurocholate (NaTC). In some embodiments, the phosphate buffered saline (PBS) contains 3 mM of sodium taurocholate (NaTC).

[0251] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility 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 between these values) after about 30 minutes in water with an initial pH of about 7.0 at about 37°C. In some embodiments, Form B is characterized by having a solubility of about 0.46 mg / mL to about 0.50 mg / mL after about 30 minutes in water with an initial pH of about 7.0 at about 37°C. In some embodiments, Form B is characterized by having a solubility of 0.47 mg / mL to 0.49 mg / mL after about 30 minutes in water with an initial pH of about 7.0 at about 37°C. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.48 mg / mL after about 30 minutes in water with an initial pH of about 7.0 at about 37°C.

[0252] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.51 mg / mL to about 0.61 mg / mL (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 between these values) after about 24 hours in water at about 37°C. In some embodiments, Form B is characterized by having a solubility of about 0.53 mg / mL to about 0.58 mg / mL after about 24 hours in water with an initial pH of about 7.0 at about 37°C. In some embodiments, Form B is characterized by having a solubility of 0.55 mg / mL to 0.57 mg / mL after about 24 hours in water with an initial pH of about 7.0 at about 37°C. In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.56 mg / mL after about 24 hours in water at about 37°C.

[0253] In some embodiments, the crystalline form is Form B, which is characterized by having a solubility of about 0.38 mg / mL to about 0.42 mg / mL (e.g., about 0.39 mg / mL) after 24 hours in water having an initial pH of about 7.0 at about 25°C.

[0254] In some embodiments, the crystalline form is Form B, which is characterized by having an intrinsic dissolution rate of about 0.15 mg / min / cm 2 to about 0.2 mg / min / cm 2 (e.g., 0.18 mg / min / cm 2 ) in a buffer at pH 6.5. In some embodiments, the buffer is a phosphate buffer.

[0255] Form C

[0256] Some embodiments provide a crystalline form of the p-toluenesulfonate 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 form of the p-toluenesulfonate 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 the anhydrous form. In some embodiments, the crystalline form is characterized by an XRPD pattern having a peak at 22.3 ± 0.2 degrees 2θ. For ease of explanation, the foregoing 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.

[0257] In some embodiments, the crystalline form is Form C, and the XRPD pattern is represented by the peaks shown in the following table:

[0258]

[0259]

[0260] In some embodiments, the crystalline form is Form C, and the XRPD pattern is substantially the same as that shown in Figure 23 .

[0261] In some embodiments, the X-ray powder diffraction pattern of Form C may also include one or more of the following additional characteristic peaks, which may also be used to identify Form C (e.g., in a sample).

[0262] For example, the XRPD pattern has a peak at 17.3 ± 0.2 degrees 2θ.

[0263] For example, the XRPD pattern has a peak at 17.5 ± 0.2 degrees 2θ.

[0264] For example, the XRPD pattern has a peak at 21.8 ± 0.2 degrees 2θ.

[0265] For example, the XRPD pattern has a peak at 11.5 ± 0.2 degrees 2θ.

[0266] For example, the XRPD pattern has a peak at 15.3 ± 0.2 degrees 2θ.

[0267] For example, the XRPD pattern has a peak at 10.2 ± 0.2 degrees 2θ.

[0268] For example, the XRPD pattern has a peak at 10.7 ± 0.2 degrees 2θ.

[0269] For example, the XRPD pattern has a peak at 26.6 ± 0.2 degrees 2θ.

[0270] The X-ray powder diffraction pattern of Form C may also include one or more lower intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0271] For example, the XRPD pattern has a peak at 19.8 ± 0.2 degrees 2θ.

[0272] For example, the XRPD pattern has a peak at 5.3 ± 0.2 degrees 2θ.

[0273] For example, the XRPD pattern has a peak at 11.3 ± 0.2 degrees 2θ.

[0274] For example, the XRPD pattern has a peak at 19.7 ± 0.2 degrees 2θ.

[0275] For example, the XRPD pattern has a peak at 18.6 ± 0.2 degrees 2θ.

[0276] For example, the XRPD pattern has a peak at 24.7 ± 0.2 degrees 2θ.

[0277] For example, the XRPD pattern has a peak at 24.1 ± 0.2 degrees 2θ.

[0278] For example, the XRPD pattern has a peak at 20.4 ± 0.2 degrees 2θ.

[0279] For example, the XRPD pattern has a peak at 18.2 ± 0.2 degrees 2θ.

[0280] For example, the XRPD pattern has a peak at 25.6 ± 0.2 degrees 2θ.

[0281] For example, the XRPD pattern has a peak at 21.5 ± 0.2 degrees 2θ.

[0282] For example, the XRPD pattern has peaks at 13.3 ± 0.2 degrees 2θ.

[0283] For example, the XRPD pattern has peaks at 19.1 ± 0.2 degrees 2θ.

[0284] For example, the XRPD pattern has peaks at 9.5 ± 0.2 degrees 2θ.

[0285] For example, the XRPD pattern has peaks at 13.6 ± 0.2 degrees 2θ.

[0286] For example, the XRPD pattern has peaks at 27.3 ± 0.2 degrees 2θ.

[0287] For example, the XRPD pattern has peaks at 19.4 ± 0.2 degrees 2θ.

[0288] For example, the XRPD pattern has peaks at 16.3 ± 0.2 degrees 2θ.

[0289] For example, the XRPD pattern has peaks at 37.9 ± 0.2 degrees 2θ.

[0290] For example, the XRPD pattern has peaks at 24.5 ± 0.2 degrees 2θ.

[0291] For example, the XRPD pattern has peaks at 22.6 ± 0.2 degrees 2θ.

[0292] For example, the XRPD pattern has peaks at 39.6 ± 0.2 degrees 2θ.

[0293] For example, the XRPD pattern has peaks at 23.2 ± 0.2 degrees 2θ.

[0294] For example, the XRPD pattern has peaks at 37.0 ± 0.2 degrees 2θ.

[0295] For example, the XRPD pattern has peaks at 28.8 ± 0.2 degrees 2θ.

[0296] For example, the XRPD pattern has peaks at 30.9 ± 0.2 degrees 2θ.

[0297] For example, the XRPD pattern has peaks at 29.3 ± 0.2 degrees 2θ.

[0298] 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).

[0299] 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).

[0300] 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).

[0301] 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, 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 (±0.2 degrees 2θ).

[0302] Those skilled in the art will recognize that the relative intensities of the X-ray powder diffraction pattern peaks can vary depending on sample preparation techniques, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument employed. Thus, depending on the type of instrument and the settings (including filters) used, new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have negligible relative intensities (and thus may not be observable) in subsequently obtained patterns. As such, the absence of one or more of the lower relative intensity peaks described above does not itself determine the absence of Form C (e.g., in a sample). However, the presence of the lower relative intensity peaks described above can generally be used to further confirm the presence of Form C in a sample.

[0303] Form C may also have one or more of the following characteristics.

[0304] 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%) at about 210°C to about 240°C. In some embodiments, the crystalline form is Form C having a TGA curve characterized by a weight loss of about 0.4% at about 210°C to about 240°C.

[0305] In some embodiments, the crystalline form is Form C having a TGA curve that is substantially the same as that shown in Figure 24 ...

[0306] In some embodiments, the crystalline form is Form C having a TGA curve that is substantially the same as that shown in Figure 25Form C of the substantially identical DSC curves shown in []. In some embodiments, the crystalline form is Form C having a DSC curve characterized by a melting onset of about 187 °C.

[0307] In some embodiments, the crystalline form is Form C in a substantially pure form. In some embodiments, the crystalline form is Form C, wherein 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, wherein Form C is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 50 °C for 1 week. In some embodiments, the crystalline form is Form C, wherein Form C is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 80 °C for 1 week. In some embodiments, the crystalline form is Form C, wherein Form C is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 50 °C for 1 week. In some embodiments, the crystalline form is Form C, wherein Form C is at least 99%, 99.3%, 99.5%, 99.7% or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 80 °C for 1 week.

[0308] In some embodiments, the TGA graph of Form C shows a weight loss of about 0.2% at 180 °C when heated from 30 °C to 300 °C at 10 K / min.

[0309] In some embodiments, Form C absorbs up to 0.4% moisture by DVS at 25 °C, 95% RH.

[0310] In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of from about 0.82 mg / mL to about 0.91 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, or any value between these values) in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, Form C is characterized by having a solubility of from about 0.85 mg / mL to about 0.89 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, Form C is characterized by having a solubility of from 0.86 mg / mL to 0.88 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, Form C is characterized by having a solubility of about 0.87 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of from 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 between these values) in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, Form C is characterized by having a solubility of from about 0.83 mg / mL to about 0.88 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, Form C is characterized by having a solubility of from 0.84 mg / mL to 0.87 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of about 0.85 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours.In some embodiments, the crystalline form is Form C, characterized by having a solubility of from about 1.58 mg / mL to about 1.70 mg / mL (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 between these values) in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form C, characterized by having a solubility of from about 1.60 mg / mL to about 1.65 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form C, characterized by having a solubility of from 1.62 mg / mL to 1.64 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form C, characterized by having a solubility of about 1.63 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 30 minutes.

[0311] In some embodiments, the crystalline form is Form C, characterized by having a solubility of from about 1.64 mg / mL to about 1.74 mg / mL (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 between these values) in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, characterized by having a solubility of from about 1.67 mg / mL to about 1.71 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, characterized by having a solubility of from 1.68 mg / mL to 1.70 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, characterized by having a solubility of about 1.69 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours.

[0312] In some embodiments, the crystalline form is Form C, characterized by having a solubility of about 1.62 mg / mL to about 1.72 mg / mL (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 between these values) in simulated fasting state intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form C, characterized by having a solubility of about 1.66 mg / mL to about 1.70 mg / mL in simulated fasting state intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form C, characterized by having a solubility of 1.67 mg / mL to 1.69 mg / mL in simulated fasting state intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form C, characterized by having a solubility of about 1.68 mg / mL in simulated fasting state intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes.

[0313] In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of from about 0.08 mg / mL to about 0.18 mg / mL (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 between these values) in fasting state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of from about 0.11 mg / mL to about 0.15 mg / mL in fasting state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of from 0.12 mg / mL to 0.14 mg / mL in fasting state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of about 0.13 mg / mL in fasting state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of from 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 between these values) in water with an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, Form C is characterized by having a solubility of from about 0.86 mg / mL to about 0.90 mg / mL in water with an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, Form C is characterized by having a solubility of from 0.87 mg / mL to 0.89 mg / mL in water with an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of about 0.88 mg / mL in water with an initial pH of about 7.0 at about 37 °C after about 30 minutes.

[0314] In some embodiments, the crystalline form is Form C, which is characterized by having a solubility 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 between these values) in water having an initial pH of about 7.0 at about 37 °C after about 24 hours. In some embodiments, Form C is characterized by having a solubility of about 0.86 mg / mL to about 0.90 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 24 hours. In some embodiments, Form C is characterized by having a solubility of 1.10 mg / mL to 1.14 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form C, which is characterized by having a solubility of about 1.12 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 24 hours.

[0315] Form D

[0316] Some embodiments provide crystalline forms of the hydrochloride 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.

[0317] In some embodiments, the crystalline form is Form D, and the XRPD pattern is substantially the same as that shown in Figure 26 as shown.

[0318] In some embodiments, the crystalline form is characterized by an XRPD pattern that includes a peak at 13.1 ± 0.2 degrees 2θ. For ease of explanation, the foregoing 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.

[0319] The X-ray powder diffraction pattern of Form D may also include one or more lower intensity characteristic peaks. The relative intensity of these additional peaks is generally lower than the relative intensity associated with the characteristic peaks described above.

[0320] For example, the XRPD pattern has a peak at 16.4 ± 0.2 degrees 2θ.

[0321] For example, the XRPD pattern has a peak at 10.4 ± 0.2 degrees 2θ.

[0322] For example, the XRPD pattern has a peak at 16.6 ± 0.2 degrees 2θ.

[0323] For example, the XRPD pattern has a peak at 23.4 ± 0.2 degrees 2θ.

[0324] For example, the XRPD pattern has a peak at 18.2 ± 0.2 degrees 2θ.

[0325] For example, the XRPD pattern has a peak at 15.9 ± 0.2 degrees 2θ.

[0326] For example, the XRPD pattern has a peak at 24.9 ± 0.2 degrees 2θ.

[0327] For example, the XRPD pattern has a peak at 17.5 ± 0.2 degrees 2θ.

[0328] The X-ray powder diffraction pattern of Form D may also include one or more lower intensity characteristic peaks. The relative intensity of these additional peaks is generally lower than the relative intensity associated with the characteristic peaks described above.

[0329] For example, the XRPD pattern has a peak at 20.6 ± 0.2 degrees 2θ.

[0330] For example, the XRPD pattern has a peak at 24.1 ± 0.2 degrees 2θ.

[0331] For example, the XRPD pattern has a peak at 27.9 ± 0.2 degrees 2θ.

[0332] For example, the XRPD pattern has a peak at 22.4 ± 0.2 degrees 2θ.

[0333] For example, the XRPD pattern has a peak at 8.2 ± 0.2 degrees 2θ.

[0334] For example, the XRPD pattern has a peak at 19.9 ± 0.2 degrees 2θ.

[0335] For example, the XRPD pattern has a peak at 15.2 ± 0.2 degrees 2θ.

[0336] For example, the XRPD pattern has a peak at 27.3 ± 0.2 degrees 2θ.

[0337] For example, the XRPD pattern has a peak at 15.7 ± 0.2 degrees 2θ.

[0338] For example, the XRPD pattern has a peak at 26.8 ± 0.2 degrees 2θ.

[0339] For example, the XRPD pattern has a peak at 19.7 ± 0.2 degrees 2θ.

[0340] For example, the XRPD pattern has a peak at 22.6 ± 0.2 degrees 2θ.

[0341] For example, the XRPD pattern has a peak at 26.3 ± 0.2 degrees 2θ.

[0342] For example, the XRPD pattern has a peak at 25.4 ± 0.2 degrees 2θ.

[0343] For example, the XRPD pattern has a peak at 9.9 ± 0.2 degrees 2θ.

[0344] For example, the XRPD pattern has a peak at 9.6 ± 0.2 degrees 2θ.

[0345] For example, the XRPD pattern has a peak at 24.4 ± 0.2 degrees 2θ.

[0346] For example, the XRPD pattern has a peak at 12.4 ± 0.2 degrees 2θ.

[0347] For example, the XRPD pattern has a peak at 31.6 ± 0.2 degrees 2θ.

[0348] For example, the XRPD pattern has a peak at 20.9 ± 0.2 degrees 2θ.

[0349] For example, the XRPD pattern has a peak at 14.9 ± 0.2 degrees 2θ.

[0350] For example, the XRPD pattern has a peak at 11.0 ± 0.2 degrees 2θ.

[0351] For example, the XRPD pattern has a peak at 33.2 ± 0.2 degrees 2θ.

[0352] For example, the XRPD pattern has a peak at 30.3 ± 0.2 degrees 2θ.

[0353] For example, the XRPD pattern has a peak at 26.0 ± 0.2 degrees 2θ.

[0354] For example, the XRPD pattern has a peak at 11.2 ± 0.2 degrees 2θ.

[0355] For example, the XRPD pattern has a peak at 34.0 ± 0.2 degrees 2θ.

[0356] For example, the XRPD pattern has a peak at 32.5 ± 0.2 degrees 2θ.

[0357] For example, the XRPD pattern has a peak at 39.3 ± 0.2 degrees 2θ.

[0358] For example, the XRPD pattern has a peak at 35.3 ± 0.2 degrees 2θ.

[0359] For example, the XRPD pattern has a peak at 37.6 ± 0.2 degrees 2θ.

[0360] For example, the XRPD pattern has a peak at 35.5 ± 0.2 degrees 2θ.

[0361] For example, the XRPD pattern has a peak at 32.1 ± 0.2 degrees 2θ.

[0362] For example, the XRPD pattern has a peak at 29.8 ± 0.2 degrees 2θ.

[0363] 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).

[0364] 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).

[0365] 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).

[0366] 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, 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 (±0.2 degrees 2θ).

[0367] Those skilled in the art will recognize that the relative intensities of the X-ray powder diffraction pattern peaks can vary depending on sample preparation techniques, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument employed. Thus, depending on the type of instrument and the settings (including filters) used, new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have negligible relative intensities (and thus may not be observable) in subsequently obtained patterns. As such, the absence of one or more of the lower relative intensity peaks described above does not, in itself, establish the absence of Form D (e.g., in a sample). However, the presence of the lower relative intensity peaks described above can generally be used to further confirm the presence of Form D in a sample.

[0368] Form D may also have one or more of the following characteristics.

[0369] In some embodiments, the crystalline form is Form D, characterized by a TGA curve showing 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%) at about 210 °C to about 230 °C. In some embodiments, the crystalline form is Form D, characterized by a TGA curve showing a weight loss of about 0.7% at about 210 °C to about 230 °C.

[0370] In some embodiments, the crystalline form is Form D, characterized by being substantially the same as the Figure 27 TGA curve shown therein.

[0371] In some embodiments, the crystalline form is Form D, characterized by being substantially the same as the Figure 28 DSC curve shown therein.

[0372] In some embodiments, the crystalline form is Form D in a substantially pure form. In some embodiments, the crystalline form is Form D, wherein the 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, wherein the Form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 50 °C for 1 week. In some embodiments, the crystalline form is Form D, wherein the Form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 80 °C for 1 week. In some embodiments, the crystalline form is Form D, wherein the Form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 50 °C for 1 week. In some embodiments, the crystalline form is Form D, wherein the Form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 80 °C for 1 week.

[0373] In some embodiments, the crystalline form is Form D, which is characterized by having a solubility of from about 2.2 mg / mL to about 2.3 mg / mL (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 between these values) in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, Form D is characterized by having a solubility of from about 2.22 mg / mL to about 2.28 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, Form D is characterized by having a solubility of from 2.24 mg / mL to 2.26 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form D, which is characterized by having a solubility of about 2.25 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 30 minutes.

[0374] In some embodiments, the crystalline form is Form D, which is characterized by having a solubility greater than about 1.5 mg / mL to greater than 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-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, Form D is characterized by having a solubility greater than about 1.8 mg / mL to greater than about 2 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, Form D is characterized by having a solubility greater than 1.9 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form D, which is characterized by having a solubility greater than about 2 mg / mL in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours.

[0375] In some embodiments, the crystalline form is Form D, which is characterized by having a solubility of from about 1.95 mg / mL to about 2.25 (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 between these values) in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 30 minutes. In some embodiments, Form D is characterized by having a solubility of from about 2.16 mg / mL to about 2.22 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 30 minutes. In some embodiments, Form D is characterized by having a solubility of from 2.18 mg / mL to 2.20 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form D, which is characterized by having a solubility of about 2.19 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 30 minutes.

[0376] In some embodiments, the crystalline form is Form D, which is characterized by having a solubility of from about 2.28 mg / mL to about 2.38 (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 between these values) in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, Form D is characterized by having a solubility of from about 2.31 mg / mL to about 2.35 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, Form D is characterized by having a solubility of from 2.32 mg / mL to 2.34 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form D, which is characterized by having a solubility of about 2.33 mg / mL in fed state simulated intestinal fluid (FeSSIF) at about 37 °C after about 24 hours.

[0377] In some embodiments, the crystalline form is Form D, which is characterized by having a solubility of from about 2.14 mg / mL to about 2.24 mg / mL (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 between these values) in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, Form D is characterized by having a solubility of from about 2.16 mg / mL to about 2.22 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, Form D is characterized by having a solubility of from 2.18 mg / mL to 2.20 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form D, which is characterized by having a solubility of about 2.19 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 30 minutes.

[0378] In some embodiments, the crystalline form is Form D, which is characterized by having a solubility greater than about 1.5 mg / mL to greater than about 2 mg / mL (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 fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, Form D is characterized by having a solubility greater than about 1.8 mg / mL to greater than about 2 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, Form D is characterized by having a solubility greater than 1.9 mg / mL to greater than 2 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form D, which is characterized by having a solubility greater than about 2 mg / mL in fasted-state simulated intestinal fluid (FaSSIF) at about 37 °C after about 24 hours.

[0379] In some embodiments, the crystalline form is Form D, characterized by having a solubility of from 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 between these values) in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, Form D is characterized by having a solubility of from about 2.06 mg / mL to about 2.10 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, Form D is characterized by having a solubility of from 2.07 mg / mL to 2.09 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 30 minutes. In some embodiments, the crystalline form is Form D, characterized by having a solubility of about 2.08 mg / mL in water at about 37 °C after about 30 minutes.

[0380] In some embodiments, the crystalline form is Form D, characterized by having a solubility of greater than about 1.5 mg / mL to greater than about 2 mg / mL (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 water having an initial pH of about 7.0 at about 37 °C after about 24 hours. In some embodiments, Form D is characterized by having a solubility of greater than about 1.8 mg / mL to greater than about 2 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 24 hours. In some embodiments, Form D is characterized by having a solubility of greater than 1.9 mg / mL to 2 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 24 hours. In some embodiments, the crystalline form is Form D, characterized by having a solubility of greater than about 2 mg / mL in water having an initial pH of about 7.0 at about 37 °C after about 24 hours.

[0381] In some embodiments, the crystalline form or crystalline forms (e.g., Form A, Form B, Form C, or Form D) comprise from 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% to 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 solvate is an isopropanol solvate.

[0382] Methods for preparing Forms A, B, C, and D

[0383] As will be appreciated by those skilled in the art, additional methods for 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., the tosylate form and the hydrochloride form) will be apparent to those of ordinary skill in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize (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, methods described in the following references: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd 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 their subsequent editions.

[0384] Method for preparing Form A

[0385] In some embodiments, the crystalline form is Form A, which is prepared by a method comprising:

[0386] (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;

[0387] (b) cooling the solution to form a suspension;

[0388] (c) filtering the suspension to provide the crystalline form.

[0389] 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.

[0390] 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, 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 carried out 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 carried out 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 carried out 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, 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, for example, 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.

[0391] In some embodiments, cooling the solution comprises cooling the solution by at least about 5°C, for example, at least about 10°C or at least about 20°C. In some embodiments, cooling the solution comprises cooling the solution to about 15°C to about 25°C, for example, cooling to about 18°C to about 22°C. For example, cooling to about 20°C. In some embodiments, the solution is agitated (e.g., stirred) during and after cooling. In some embodiments, the agitation is carried out for at least about 1 hour, for example, at least about 6, 12, 18, 24, 36, 48, 60, or 72 hours. In some embodiments, the agitation is carried out 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.

[0392] In some embodiments, filtering the suspension to provide the crystalline form comprises filtering the suspension to form a solid, washing the solid with a solvent, and drying the solid to provide the 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.

[0393] In some embodiments, the crystalline form is Form A, which is prepared by a method comprising:

[0394] (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 a solution having a concentration of about 0.44 molar;

[0395] (b) cooling the solution to about 20°C and stirring for about 72 hours to form a suspension;

[0396] (c) filtering the suspension to obtain a solid;

[0397] (d) washing the solid with isopropanol; and

[0398] (e) drying the solid to provide the crystalline form.

[0399] Method for preparing Form B

[0400] In some embodiments, the crystalline form is Form B, which is prepared by a method comprising:

[0401] (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;

[0402] (b) heating the suspension to form a solution;

[0403] (c) cooling the solution and then adding ethyl acetate;

[0404] (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;

[0405] (e) adding ethyl acetate to form a slurry;

[0406] (f) filtering the slurry to form a solid;

[0407] (g) washing the solid with a solvent;

[0408] (h) drying the solid to provide the crystalline form;

[0409] (i) adding the solid form to a binary mixture of isopropanol and water and then heating to form a slurry;

[0410] (j) cooling and filtering the slurry to form a solid; and

[0411] (k) drying the solid to provide the crystalline form.

[0412] 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.

[0413] 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 relative 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 relative 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.

[0414] 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 agitating 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.

[0415] 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 agitating the solution. For example, step (c) comprises stirring the solution. In some embodiments, step (c) comprises cooling the solution 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 (c) comprises cooling the solution for about 15 minutes. In some embodiments, the volume of ethyl acetate added to the solution relative to the volume of the suspension 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. In some embodiments, the volume of ethyl acetate added to the solution relative to the volume of the suspension is about 2.5 volumes.

[0416] In some embodiments, (d) is not performed. In some embodiments, (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 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 the binary mixture in step (d) is carried out at about 25°C.

[0417] In some embodiments, the addition of ethyl acetate in step (d) is carried out within about 15 minutes to about 4 hours (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 within about 2 hours. 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 are 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).

[0418] 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 the 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 the solvent relative to the volume of the solid.

[0419] 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, the heating is carried out 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, the heating is carried out at about 50 °C. In some embodiments, after adding the solid form to the binary mixture of isopropanol, the 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, the heating is carried out for about 16 hours.

[0420] In some embodiments, the cooling of the slurry in step (j) is carried out at about 0 °C to about 35 °C (e.g., about 0 °C to about 30 °C, about 5 °C to about 30 °C, about 10 °C to about 30 °C, about 15 °C to about 30 °C, about 20 °C to about 30 °C, about 22 °C to about 28 °C, or about 25 °C). In some embodiments, the cooling of the slurry in step (j) is carried out at about 25 °C.

[0421] In some embodiments, the drying of the solid in step (k) is carried out at about 30 °C to about 70 °C (e.g., about 35 °C to about 65 °C, about 40 °C to about 60 °C, about 45 °C to about 55 °C, or about 50 °C). In some embodiments, the drying of the solid in step (k) is carried out at about 50 °C.

[0422] In some embodiments, the crystalline form is Form B, which is prepared by a method comprising:

[0423] (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 (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid;

[0424] (b) heating the suspension to about 50 °C and stirring for about 15 minutes to form a solution;

[0425] (c) cooling the solution to about 25 °C within about 15 minutes, and then adding about 2.5 volumes of ethyl acetate;

[0426] (d) adding about 7.5 volumes of ethyl acetate over 2 hours at about 25 °C to form a slurry, and then allowing the slurry to stand at about 25 °C for about 1 hour;

[0427] (e) filtering the slurry to obtain a solid;

[0428] (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3;

[0429] (g) drying the solid to provide a solid form;

[0430] (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;

[0431] (i) cooling the slurry to about 25 °C and filtering to obtain a solid; and

[0432] (j) drying the solid at about 50 °C to provide the crystalline form.

[0433] In some embodiments, the crystalline form is Form B, which is prepared by a method comprising:

[0434] (a) Water and acetone are added 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;

[0435] (b) The suspension is heated to about 50 °C and stirred to form a solution, and then the solution is cooled to room temperature;

[0436] (c) Seed crystals of Form B are added to the solution to form a suspension;

[0437] (d) About 2.2 volumes of water are added to the suspension in step (c) over several hours to form a suspension;

[0438] (e) The suspension in step (d) is cooled and maintained at a temperature below room temperature for several hours, and it is filtered to obtain a solid; and

[0439] (f) The solid is dried at about 40 °C to 50 °C to provide a crystalline form.

[0440] Method for preparing Form C

[0441] In some embodiments, the crystalline form is Form C, which is prepared by a method comprising:

[0442] (a) An alcohol is added 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;

[0443] (b) The suspension is heated to form a solution;

[0444] (c) The solution is cooled, and then ethyl acetate is added;

[0445] (d) Optionally, 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 is added to form a mixture;

[0446] (e) Ethyl acetate is added to form a slurry;

[0447] (f) The slurry is filtered to form a solid;

[0448] (g) The solid is washed with a solvent; and

[0449] (h) The solid is dried to provide a crystalline form.

[0450] 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.

[0451] 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 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. In some embodiments, step (a) comprises adding about 3.5 volumes of alcohol 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.

[0452] 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 agitating 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.

[0453] In some embodiments, step (c) includes 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) includes cooling the solution to about 25°C. In some embodiments, step (c) includes agitating the suspension. For example, step (c) includes stirring the solution. In some embodiments, step (c) includes cooling the solution 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 (c) includes cooling the solution for about 15 minutes. In some embodiments, the 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 ethyl acetate added to the solution is about 2.5 volumes relative to the volume of the solution.

[0454] In some embodiments, (d) is not performed. In some embodiments, (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 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 the binary mixture in step (d) is carried out at about 25°C.

[0455] In some embodiments, the addition of ethyl acetate in step (d) is carried out over a period of about 15 minutes to about 4 hours (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 over a period of about 2 hours. In some embodiments, the addition of ethyl acetate in step (d) is carried out at a temperature of 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 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). In some embodiments, about 7.5 volumes of ethyl acetate are added relative to the volume of the mixture before the addition of ethyl acetate.

[0456] 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 volume of the solid.

[0457] In some embodiments, the crystalline form is Form C, which is prepared by a method comprising:

[0458] (a) Ethanol is added 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 (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid;

[0459] (b) The suspension is heated to about 50 °C and stirred for about 15 minutes to form a solution;

[0460] (c) The solution is cooled to about 25 °C within about 15 minutes, and then ethyl acetate is added;

[0461] (d) Ethyl acetate is added over 2 hours at about 25 °C to form a slurry, and then the slurry is allowed to stand at about 25 °C for about 1 hour;

[0462] (e) The slurry is filtered to obtain a solid;

[0463] (f) The solid is washed with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; and

[0464] (g) The solid is dried to provide a crystalline form.

[0465] In some embodiments, the crystalline form is Form C, which is prepared by a method comprising:

[0466] (a) Ethanol is added 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 (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid;

[0467] (b) The suspension is heated to about 50 °C and stirred for about 15 minutes to form a solution;

[0468] (c) The solution is cooled to about 25 °C within about 15 minutes, and then ethyl acetate is added;

[0469] (d) Ethyl acetate is added over 2 hours at about 25 °C to form a slurry, and then the slurry is allowed to stand at about 25 °C for about 1 hour;

[0470] (e) The slurry is filtered to form a solid;

[0471] (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; and

[0472] (g) Dry the solid to provide the crystalline form.

[0473] Method for preparing Form D

[0474] In some embodiments, the crystalline form is Form D, which is prepared by a method comprising:

[0475] (a) Prepare 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;

[0476] (b) Add a solution of hydrogen chloride in ethyl acetate or diethyl ether;

[0477] (c) Add 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;

[0478] (d) Add a solution of hydrogen chloride in ethyl acetate or diethyl ether to form a slurry;

[0479] (e) Age the slurry;

[0480] (f) Filter the slurry to form a solid;

[0481] (g) Wash the solid with a solvent; and

[0482] (h) Dry the solid to provide the crystalline form.

[0483] 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.

[0484] 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 the 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 the solvent is about 5.5 volumes relative to the volume of the starting material.

[0485] In some embodiments, the solution of hydrogen chloride in ethyl acetate or diethyl ether is the solution of hydrogen chloride 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.

[0486] In some embodiments, the amount of hydrogen chloride added in step (b) 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 relative to the amount 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 amount of hydrogen chloride added in step (b) is about 0.55 equivalents relative to the amount 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.

[0487] 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 solution of 1M 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, the 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, the solution of 1M 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.

[0488] In some embodiments, the amount of hydrogen chloride added in step (d) relative to the amount 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 from about 0.1 to about 2.2 (e.g., from about 0.2 to about 2.2, from about 0.8 to about 2, from about 1 to about 2, from about 1.3 to about 2, from 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 amount 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 about 1.65 equivalents.

[0489] In some embodiments, aging the slurry in step (e) includes agitating the slurry. In some embodiments, agitating the slurry in step (e) includes 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 at about 0 °C to about 35 °C (e.g., about 0 °C to about 30 °C, about 5 °C to about 30 °C, about 10 °C to about 30 °C, about 15 °C to about 30 °C, about 20 °C to about 30 °C, about 22 °C to about 28 °C, or about 24 °C). In some embodiments, the slurry is aged at about 24 °C.

[0490] 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.

[0491] In some embodiments, the crystalline form is Form D, which is prepared by a method comprising:

[0492] (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;

[0493] (b) adding about 0.55 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate;

[0494] (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;

[0495] (d) adding about 1.65 equivalents of a 1 molar solution of hydrogen chloride in ethyl acetate to form a slurry;

[0496] (e) stirring the slurry at about 24 °C for about 16 hours;

[0497] (f) filtering the slurry to obtain a solid;

[0498] (g) washing the solid with ethyl acetate; and

[0499] (h) drying the solid to provide the crystalline form.

[0500] Formulation

[0501] In another aspect, the present invention provides 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 any combination of Form A, Form B, Form C, and Form D, and a pharmaceutically acceptable carrier.

[0502] For example, the pharmaceutical composition comprises Form A and Form B and a pharmaceutically acceptable carrier.

[0503] For example, the pharmaceutical composition comprises Form A and Form C and a pharmaceutically acceptable carrier.

[0504] For example, the pharmaceutical composition comprises Form A and Form D and a pharmaceutically acceptable carrier.

[0505] For example, the pharmaceutical composition comprises Form B and Form C and a pharmaceutically acceptable carrier.

[0506] For example, the pharmaceutical composition comprises Form B and Form D and a pharmaceutically acceptable carrier.

[0507] For example, the pharmaceutical composition comprises Form C and Form D and a pharmaceutically acceptable carrier.

[0508] For example, the pharmaceutical composition comprises Form A, Form B, Form C, and a pharmaceutically acceptable carrier.

[0509] For example, the pharmaceutical composition comprises Form A, Form B, Form D, and a pharmaceutically acceptable carrier.

[0510] For example, the pharmaceutical composition comprises Form B, Form C, Form D, and a pharmaceutically acceptable carrier.

[0511] For example, the pharmaceutical composition comprises Form A, Form C, Form D, and a pharmaceutically acceptable carrier.

[0512] For example, the pharmaceutical composition comprises Form A, Form B, Form C, Form D, and a pharmaceutically acceptable carrier.

[0513] 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 combination of two, three, or four of crystalline Forms A, B, C, or D).

[0514] Some embodiments provide a composition (e.g., a pharmaceutical composition or formulation) comprising one or more (e.g., 1 or 2, e.g., 1) active ingredient(s), wherein the active ingredient (or at least one active ingredient):

[0515] (i) is Form A, Form B, Form C, or Form D, or any combination thereof (e.g., any combination of two, three, or four of Forms A, B, C, or D); or

[0516] (ii) comprises one or more (e.g., 1 or 2, e.g., 1) of 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 Form A, Form B, Form C, Form D, or any combination thereof (e.g., any combination of two, three, or four of crystalline Forms A, B, C, or D).

[0517] The composition may comprise one or more of the following features.

[0518] The composition may comprise one or more pharmaceutically acceptable carriers.

[0519] Solid dosage forms of the pharmaceutical compositions of the invention 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 the following substances: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution blockers, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets, and pills, the dosage form may also contain buffering agents. Excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycol may also be used, and solid pharmaceutical compositions of a similar type may be used as fillers in soft and hard gelatin capsules.

[0520] Solid dosage forms of the pharmaceutical compositions of the invention, such as tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shells (such as enteric coatings and other pharmaceutical coatings). The solid dosage forms may optionally contain opacifying agents and may also be formulated such that they release one or more active ingredients only in or preferably in a delayed manner in a certain part of the intestine. Examples of available embedded pharmaceutical compositions include polymeric substances and waxes.

[0521] The active compound may also be in microencapsulated form and, if appropriate, may contain one or more of the above excipients.

[0522] Liquid dosage forms of the pharmaceutical compositions of the invention for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0523] In addition to the active compound, the suspension of the compounds of the present invention may also contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan (e.g., polyoxyethylene (20) sorbitan monooleate, i.e., polysorbate 80 or "Tween 80"), microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0524] The pharmaceutical compositions disclosed herein for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders that are reconstituted into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Adequate fluidity can be maintained, for example, by the use of coating materials (e.g., 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., methyl cellulose (e.g., methocel) and hydroxypropyl methyl cellulose).

[0525] In some embodiments, the pH of the liquid (e.g., injectable) composition is from 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 from about 8.5 to about 10.

[0526] In addition to the inert diluent, these pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, sweetening agents, flavoring agents, and fragrances. The action of microorganisms can be prevented by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Extended absorption of injectable drug forms can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin). The compounds can be incorporated into sustained-release or targeted delivery systems (e.g., polymer matrices, liposomes, and microspheres). Such formulations can provide more effective compound distribution.

[0527] The pharmaceutical compositions as injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of a sterilizing agent in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable media immediately before use.

[0528] Dosage forms for local administration of the compounds or pharmaceutical compositions of the present disclosure include powders, patches, sprays, ointments, and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0529] 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, in a dosage range of from about 0.01 milligrams per kilogram (mg / kg) to about 1000 mg / kg per 4 to 120 hours (e.g., from about 0.01 to about 100 mg / kg, from about 0.1 to about 100 mg / kg), or as required according to the particular drug, dosage form, and / or route of administration. Other routes of administration include enteral, intraarterial, intraperitoneal, and intrathecal administration. Freireich et al., Cancer Chemother. Rep. [Cancer Chemotherapy Reports] 50, 219-244 (1966) describe the dose relationships in animals and humans (based on milligrams per square meter of body surface). The body surface area can be approximately determined from the patient's height and weight. See, for example, Scientific Tables [Scientific Tables], Geigy Pharmaceuticals [Geigy Pharmaceuticals], Ardsley, N.Y., 537 (1970).

[0530] 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.

[0531] 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.

[0532] In some embodiments, the particle size (D of the crystalline form (e.g., Form A, Form B, Form C, or Form D) 50) is from about 1 μm to about 100 μm, for example, 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. In some embodiments, the particle size (D 50 ) of the crystalline form (e.g., Form A, Form B, Form C, or Form D) is from about 1 μm to about 50 μm. In some embodiments, the particle size (D 50 ) of the crystalline form (e.g., Form A, Form B, Form C, or Form D) is from about 1 μm to about 25 μm. In some embodiments, the particle size (D 50 ) of the crystalline form (e.g., Form A, Form B, Form C, or Form D) is from about 1 μm to about 5 μm.

[0533] Method of use

[0534] Provided herein are methods of using the crystalline forms disclosed herein, or pharmaceutical compositions thereof, for treating, preventing, or ameliorating a disease or disorder mediated by the alternative complement pathway or a disease or disorder otherwise affected via the alternative complement pathway. In certain further embodiments, provided herein are methods of using the crystalline forms disclosed herein, or pharmaceutical compositions thereof, for treating, preventing, or ameliorating a disease or disorder mediated by complement factor B (CFB) or a disease or disorder otherwise affected via complement factor B (CFB). In certain further embodiments, provided herein are methods of using the crystalline forms disclosed herein, or pharmaceutical compositions thereof, for treating, preventing, or ameliorating a disease or disorder mediated by inhibition of the alternative complement pathway or a disease or disorder otherwise affected via inhibition of the alternative complement pathway. In certain further embodiments, provided herein are methods of using the crystalline forms disclosed herein, or pharmaceutical compositions thereof, for treating, preventing, or ameliorating a disease or disorder mediated by inhibition of complement factor B or a disease or disorder otherwise affected via inhibition of complement factor B.

[0535] 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.

[0536] Some embodiments provide methods of treating or preventing a disease or disorder as described herein (e.g., a complement-related disease or disorder) in a subject in need thereof, the method 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.

[0537] Examples of known complement-related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, conditions of inappropriate or undesired complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, inflammatory disorders, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, post-pump syndromes in balloon angioplasty, cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and nerve regeneration. Additionally, other known complement-related diseases are pulmonary diseases and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumoconiosis, inert dusts and minerals (e.g., silica, coal dust, beryllium and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals such as chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia and hydrochloric acid), smoke injury, thermal injury (e.g., burns, frostbite), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation; eye diseases including age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, and uveitis associated with retinal vein occlusion (including Behcet's disease and other subtypes of uveitis), antiphospholipid syndrome.

[0538] In some embodiments, the disease or disorder is selected from the group consisting of: age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, pemphigus ophthalmicus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / familial dominant drusen (Malattia leventinese), Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus flavimaculatus, corneal inflammation, neurological disorders such as multiple sclerosis, 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, conditions of inappropriate or undesired complement activation (e.g., hemodialysis complications, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory conditions, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), 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 coli hemolytic uremic syndrome), periodontitis, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases (e.g., Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schönlein purpura or HSP), hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion conditions, myocardial infarction, post-pump syndrome during balloon angioplasty, cardiopulmonary bypass, or renal bypass, atherosclerosis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis);COVID-19, immune complex diseases and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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 infarction, pneumonia, fibrotic pneumoconiosis, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microscopic immune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, Graves' disease and hidradenitis suppurativa.;

[0539] In some embodiments, the disease or disorder is selected from the group consisting of: multiple sclerosis, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, pemphigus ophthalmicus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion condition, myocardial infarction, stroke, pump syndrome after balloon angioplasty, cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders 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, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic disease, Goodpasture's syndrome, pulmonary vasculitis, microscopic immunotype vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, metabolic syndrome, and hidradenitis suppurativa.

[0540] In some embodiments, the disease or disorder is immune complex membranoproliferative glomerulonephritis (IC-MPGN).

[0541] In some embodiments, the disease or disorder is neuromyelitis optica (NMO).

[0542] In some embodiments, the disease or disorder is hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA).

[0543] Some embodiments provide methods of treating or preventing kidney diseases or disorders selected from the group consisting of: chronic kidney disease, diabetic nephropathy, glomerular kidney disease, complement C3 glomerulopathy (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), the method comprising administering to a subject having such a 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.

[0544] In some embodiments, the kidney disease is selected from the group consisting of: chronic kidney disease, diabetic nephropathy, glomerular kidney disease, complement C3 glomerulopathy (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, polycystic kidney disease (PKD), and immune complex membranoproliferative glomerulonephritis (IC-MPGN).

[0545] In some embodiments, the kidney disease is chronic kidney disease.

[0546] In some embodiments, the kidney disease is diabetic nephropathy.

[0547] In some embodiments, the kidney disease is glomerular kidney disease.

[0548] In some embodiments, the kidney disease is complement C3 glomerulopathy (C3G).

[0549] In some embodiments, the kidney disease is IgA nephropathy (IgAN).

[0550] In some embodiments, the kidney disease is membranous nephropathy (MN).

[0551] In some embodiments, the kidney disease is focal segmental glomerulosclerosis (FSGS).

[0552] In some embodiments, the kidney disease is atypical hemolytic uremic syndrome (aHUS).

[0553] In some embodiments, the kidney disease is dense deposit disease (DDD).

[0554] In some embodiments, the kidney disease is minimal change disease (MCD).

[0555] In some embodiments, the kidney disease is paroxysmal nocturnal hemoglobinuria (PNH).

[0556] In some embodiments, the kidney disease is ANCA-associated vasculitis.

[0557] In some embodiments, the kidney disease is lupus nephritis.

[0558] In some embodiments, the kidney disease is polycystic kidney disease (PKD).

[0559] In some embodiments, the kidney disease is immune complex membranoproliferative glomerulonephritis (IC-MPGN).

[0560] The present disclosure will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present disclosure in any way.

[0561] Additional embodiments

[0562] 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.

[0563] 2. The crystalline form according to Example 1, wherein the crystalline form is Form A, characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 10.7 ± 0.2 degrees 2θ.

[0564] 3. The crystalline form according to Example 2, wherein the XRPD pattern has a peak at 20.5 ± 0.2 degrees 2θ.

[0565] 4. The crystalline form according to any one of Examples 2-3, wherein the XRPD pattern has a peak at 18.8 ± 0.2 degrees 2θ.

[0566] 5. The crystalline form according to any one of Examples 2-4, wherein the XRPD pattern has a peak at 21.7 ± 0.2 degrees 2θ.

[0567] 6. The crystalline form according to any one of Examples 2-5, wherein the XRPD pattern has a peak at 19.6 ± 0.2 degrees 2θ.

[0568] 7. The crystalline form according to any one of Examples 2-6, wherein the XRPD pattern has a peak at 19.8 ± 0.2 degrees 2θ.

[0569] 8. The crystalline form according to any one of Examples 2-7, wherein the XRPD pattern has a peak at 12.5 ± 0.2 degrees 2θ.

[0570] 9. The crystalline form according to any one of Examples 2-8, wherein the XRPD pattern has a peak at 21.1 ± 0.2 degrees 2θ.

[0571] 10. The crystalline form according to any one of Examples 2-9, wherein the XRPD pattern has a peak at 23.3 ± 0.2 degrees 2θ.

[0572] 11. The crystalline form according to any one of Examples 2-10, wherein the XRPD pattern has a peak at 22.6 ± 0.2 degrees 2θ.

[0573] 12. The crystalline form according to any one of Examples 2-11, wherein the XRPD pattern has a peak at 27.3 ± 0.2 degrees 2θ.

[0574] 13. The crystalline form according to any one of Examples 2-12, wherein the XRPD pattern has a peak at 15.6 ± 0.2 degrees 2θ.

[0575] 14. The crystalline form according to Example 1, wherein the crystalline form is Form A, and wherein the XRPD pattern has peaks at 10.7, 20.5, and 18.8 (±0.2 degrees 2θ).

[0576] 15. The crystalline form according to Example 1, wherein the crystalline form is Form A, and wherein the XRPD pattern has peaks at 10.7, 20.5, 18.8, and 21.7 (±0.2 degrees 2θ).

[0577] 16. The crystalline form according to Example 1, wherein the crystalline form is Form A, and wherein the XRPD pattern peaks are 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 (±0.2 degrees 2θ).

[0578] 17. The crystalline form according to Example 1, wherein the crystalline form is 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 is in free form, and further wherein the free form is the anhydrous form.

[0579] 18. The crystalline form according to Example 1, wherein the crystalline form is Form A, and wherein the XRPD pattern is substantially the same as that shown in Figure 2 as shown.

[0580] 19. The crystalline form according to any one of embodiments 1-18, wherein the crystalline form is Form A having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2% at about 189 °C.

[0581] 20. The crystalline form according to any one of embodiments 1-19, wherein the crystalline form is Form A having a TGA curve characterized by a weight loss of about 25% at about 300 °C.

[0582] 21. The crystalline form according to any one of embodiments 1-20, wherein the crystalline form is Form A having a TGA curve Figure 3 substantially the same as that shown in

[0583] 22. The crystalline form according to any one of embodiments 1-21, wherein the crystalline form is Form A having a differential scanning calorimetry (DSC) curve characterized by a melting onset (endotherm) at about 201.9 °C.

[0584] 23. The crystalline form according to any one of embodiments 1-22, wherein the crystalline form is Form A having a DSC curve Figure 4 substantially the same as that shown in

[0585] 24. The crystalline form according to any one of embodiments 1-23, wherein the crystalline form is Form A, characterized by having a solubility of about 2.3 mg / mL after about 30 minutes in fasted state simulated gastric fluid (FaSSGF) at about 37 °C.

[0586] 25. The crystalline form according to any one of embodiments 1-24, wherein the crystalline form is Form A, characterized by having a solubility of about 0.31 mg / mL after about 24 hours in fed state simulated intestinal fluid (FeSSIF) at about 37 °C.

[0587] 26. The crystalline form according to any one of embodiments 1-25, wherein the crystalline form is Form A, characterized by having a solubility of about 0.18 mg / mL after about 24 hours in fasted state simulated intestinal fluid (FaSSIF) at about 37 °C.

[0588] 27. The crystalline form according to any one of embodiments 1-26, wherein the crystalline form is Form A, characterized by having a solubility of about 0.22 mg / mL after about 24 hours in water at about 37 °C.

[0589] 28. The crystalline form according to any one of embodiments 1-27, wherein the crystalline form is Form A, which is prepared by a method comprising:

[0590] (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 was added to isopropanol with stirring at about 40 °C to about 50 °C to form a solution having a concentration of about 0.44 molar;

[0591] (b) The solution was cooled to about 20 °C and stirred for about 72 hours to form a suspension;

[0592] (c) The suspension was filtered to obtain a solid;

[0593] (d) The solid was washed with isopropanol; and

[0594] (e) The solid was dried to provide a crystalline form.

[0595] 29. A crystalline form of the p-toluenesulfonate 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.

[0596] 30. The crystalline form according to Example 29, wherein the crystalline form is Form B, characterized by an XRPD pattern having a peak at 11.8 ± 0.2 degrees 2θ.

[0597] 31. The crystalline form according to Example 30, wherein the XRPD pattern has a peak at 9.3 ± 0.2 degrees 2θ.

[0598] 32. The crystalline form according to any one of Examples 29 - 31, wherein the XRPD pattern has a peak at 19.9 ± 0.2 degrees 2θ.

[0599] 33. The crystalline form according to any one of Examples 29 - 32, wherein the XRPD pattern has a peak at 22.9 ± 0.2 degrees 2θ.

[0600] 34. The crystalline form according to any one of Examples 29 - 33, wherein the XRPD pattern has a peak at 17.2 ± 0.2 degrees 2θ.

[0601] 35. The crystalline form according to any one of Examples 29 - 34, wherein the XRPD pattern has a peak at 10.2 ± 0.2 degrees 2θ.

[0602] 36. The crystalline form according to any one of Examples 29 - 35, wherein the XRPD pattern has a peak at 20.4 ± 0.2 degrees 2θ.

[0603] 37. The crystalline form according to any one of Examples 29 - 36, wherein the XRPD pattern has a peak at 21.3 ± 0.2 degrees 2θ.

[0604] 38. A crystalline form as described in any one of Examples 29 - 37, wherein the XRPD pattern has a peak at 14.2 ± 0.2 degrees 2θ.

[0605] 39. A crystalline form as described in Example 29, wherein the crystalline form is Form B and wherein the XRPD pattern has peaks at 11.80, 9.30 and 19.9 (±0.2 degrees 2θ).

[0606] 40. A crystalline form as described in Example 29, wherein the crystalline form is Form B and wherein the XRPD pattern has peaks at 11.8, 9.3, 19.9 and 22.9 (±0.2 degrees 2θ).

[0607] 41. A crystalline form as described in Example 29, wherein the crystalline form is Form B and wherein 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).

[0608] 42. A crystalline form as described in Example 29, wherein the crystalline form is Form B and wherein the XRPD pattern is substantially the same as that shown in Figure 12 or Figure 15 as shown.

[0609] 43. A crystalline form as described in any one of Examples 29 - 42, wherein the crystalline form is Form B having a TGA curve characterized by a weight loss of about 1% at about 60 °C to about 100 °C.

[0610] 44. A crystalline form as described in any one of Examples 29 - 43, wherein the crystalline form is Form B having a TGA curve substantially the same as that shown in Figure 13 or Figure 17 as shown.

[0611] 45. A crystalline form as described in any one of Examples 29 - 44, wherein the crystalline form is Form B having a DSC curve substantially the same as that shown in Figure 14 or Figure 16 as shown.

[0612] 46. A crystalline form as described in any one of Examples 29 - 45, wherein the crystalline form is Form B, characterized by having a solubility of about 0.54 mg / mL in fasted state simulated gastric fluid (FaSSGF) at about 37 °C after about 24 hours.

[0613] 47. The crystalline form according to any one of Examples 29 - 46, wherein the crystalline form is Form B, characterized in that it has a solubility greater than about 2 mg / mL after about 24 hours in simulated intestinal fluid (FeSSIF) in the fed state at about 37 °C.

[0614] 48. The crystalline form according to any one of Examples 29 - 47, wherein the crystalline form is Form B, characterized in that it has a solubility of about 0.53 mg / mL after about 24 hours in simulated intestinal fluid (FaSSIF) in the fasted state at about 37 °C.

[0615] 49. The crystalline form according to any one of Examples 29 - 48, wherein the crystalline form is Form B, characterized in that it has a solubility of about 0.56 mg / mL after about 24 hours in water at about 37 °C.

[0616] 50. The crystalline form according to any one of Examples 29 - 49, wherein the crystalline form is Form B, which is prepared by a method comprising:

[0617] (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 (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid;

[0618] (b) heating the suspension to about 50 °C and stirring for about 15 minutes to form a solution;

[0619] (c) cooling the solution to about 25 °C within about 15 minutes, and then adding about 2.5 volumes of ethyl acetate;

[0620] (d) adding about 7.5 volumes of ethyl acetate within 2 hours at about 25 °C to form a slurry, and then allowing the slurry to stand at about 25 °C for about 1 hour;

[0621] (e) filtering the slurry to obtain a solid;

[0622] (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3;

[0623] (g) drying the solid to provide a solid form;

[0624] (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;

[0625] (i) Cool the slurry to about 25 °C and filter to obtain solids; and

[0626] (j) Dry the solids at about 50 °C to provide a crystalline form.

[0627] 51. The crystalline form according to Example 29, wherein the crystalline form is Form C, characterized by an XRPD pattern having peaks at 22.3 ± 0.2 degrees 2θ.

[0628] 52. The crystalline form according to Example 51, wherein the XRPD pattern has a peak at 17.3 ± 0.2 degrees 2θ.

[0629] 53. The crystalline form according to any one of Examples 51 - 52, wherein the XRPD pattern has a peak at 17.5 ± 0.2 degrees 2θ.

[0630] 54. The crystalline form according to any one of Examples 51 - 53, wherein the XRPD pattern has a peak at 21.8 ± 0.2 degrees 2θ.

[0631] 55. The crystalline form according to any one of Examples 51 - 54, wherein the XRPD pattern has a peak at 11.5 ± 0.2 degrees 2θ.

[0632] 56. The crystalline form according to any one of Examples 51 - 55, wherein the XRPD pattern has a peak at 15.3 ± 0.2 degrees 2θ.

[0633] 57. The crystalline form according to any one of Examples 51 - 56, wherein the XRPD pattern has a peak at 10.2 ± 0.2 degrees 2θ.

[0634] 58. The crystalline form according to any one of Examples 51 - 57, wherein the XRPD pattern has a peak at 10.7 ± 0.2 degrees 2θ.

[0635] 59. The crystalline form according to any one of Examples 51 - 58, wherein the XRPD pattern has a peak at 26.6 ± 0.2 degrees 2θ.

[0636] 60. The crystalline form according to any one of Examples 29 - 59, wherein Form B includes water, wherein the amount of water is 0 to 2.7% w / w relative to the total weight of Form B.

[0637] 61. The crystalline form according to Example 29, wherein the crystalline form is Form C, and wherein the XRPD pattern has peaks at 22.3, 17.3 and 17.5 (± 0.2 degrees 2θ).

[0638] 62. The crystalline form as described in Example 29, wherein the crystalline form is Form C and wherein the XRPD pattern has peaks at 22.3, 17.3, 17.5 and 21.8 (±0.2 degrees 2θ).

[0639] 63. The crystalline form as described in Example 29, wherein the crystalline form is Form C and wherein 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).

[0640] 64. The crystalline form as described in Example 29, wherein the crystalline form is Form C and wherein the XRPD pattern is substantially the same as that shown in Figure 23 as shown.

[0641] 65. The crystalline form as described in Example 29, wherein the p-toluenesulfonate 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 in the anhydrous form.

[0642] 66. The crystalline form as described in any one of Examples 29 and 61-65, wherein the crystalline form is Form C having a TGA curve characterized by a weight loss of about 0.4% at about 210 °C to about 240 °C.

[0643] 67. The crystalline form as described in any one of Examples 29 and 61-66, wherein the crystalline form is Form C having a TGA curve substantially the same as that shown in Figure 24 as shown.

[0644] 68. The crystalline form as described in any one of Examples 29 and 61-67, wherein the crystalline form is Form C having a DSC curve characterized by a melting onset of about 187 °C.

[0645] 69. The crystalline form as described in any one of Examples 29 and 61-68, wherein the crystalline form is Form C having a DSC curve substantially the same as that shown in Figure 25 as shown.

[0646] 70. The crystalline form as described in any one of Examples 29 and 61-69, wherein the crystalline form is Form C, characterized by having a solubility of about 0.85 mg / mL after about 24 hours in fasted-state simulated gastric fluid (FaSSGF) at about 37 °C.

[0647] 71. The crystalline form according to any one of Examples 29 and 61 - 70, wherein the crystalline form is Form C, characterized in that it has a solubility of about 1.69 mg / mL in simulated intestinal fluid in the fed state (FeSSIF) at about 37 °C after about 24 hours.

[0648] 72. The crystalline form according to any one of Examples 29 and 61 - 71, wherein the crystalline form is Form C, characterized in that it has a solubility of about 0.13 mg / mL in simulated intestinal fluid in the fasting state (FaSSIF) at about 37 °C after about 24 hours.

[0649] 73. The crystalline form according to any one of Examples 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 at about 37 °C after about 24 hours.

[0650] 74. The crystalline form according to any one of Examples 29 and 61 - 73, wherein the crystalline form is Form C, which is prepared by a method comprising:

[0651] (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 (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid;

[0652] (b) heating the suspension to about 50 °C and stirring for about 15 minutes to form a solution;

[0653] (c) cooling the solution to about 25 °C within about 15 minutes, and then adding about 2.5 volumes of ethyl acetate;

[0654] (d) adding about 7.5 volumes of ethyl acetate within 2 hours at about 25 °C to form a slurry, and then allowing the slurry to stand at about 25 °C for about 1 hour;

[0655] (e) filtering the slurry to obtain a solid;

[0656] (f) washing the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; and

[0657] (g) drying the solid to provide the crystalline form.

[0658] 75. Crystalline form of the hydrochloride 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.

[0659] 76. The crystalline form according to Example 75, wherein the crystalline form is Form D, characterized by an XRPD pattern comprising a peak at 13.1 ± 0.2 degrees 2θ.

[0660] 77. The crystalline form according to Example 75, wherein the XRPD pattern has a peak at 16.4 ± 0.2 degrees 2θ.

[0661] 78. The crystalline form according to any one of Examples 75-77, wherein the XRPD pattern has a peak at 10.4 ± 0.2 degrees 2θ.

[0662] 79. The crystalline form according to any one of Examples 75-78, wherein the XRPD pattern has a peak at 16.6 ± 0.2 degrees 2θ.

[0663] 80. The crystalline form according to any one of Examples 75-79, wherein the XRPD pattern has a peak at 23.4 ± 0.2 degrees 2θ.

[0664] 81. The crystalline form according to any one of Examples 75-80, wherein the XRPD pattern has a peak at 18.2 ± 0.2 degrees 2θ.

[0665] 82. The crystalline form according to any one of Examples 75-81, wherein the XRPD pattern has a peak at 15.9 ± 0.2 degrees 2θ.

[0666] 83. The crystalline form according to any one of Examples 75-82, wherein the XRPD pattern has a peak at 24.9 ± 0.2 degrees 2θ.

[0667] 84. The crystalline form according to any one of Examples 75-83, wherein the XRPD pattern has a peak at 17.5 ± 0.2 degrees 2θ.

[0668] 85. The crystalline form according to Example 75, wherein the crystalline form is Form D, and wherein the XRPD pattern has peaks at 13.1, 16.4, and 10.4 (± 0.2 degrees 2θ).

[0669] 86. The crystalline form according to Example 75, wherein the crystalline form is Form D, and wherein the XRPD pattern has peaks at 13.1, 16.4, 10.4, 16.6, and 23.4 (± 0.2 degrees 2θ).

[0670] 87. The crystalline form as described in Example 75, wherein the crystalline form is Form D, and wherein 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).

[0671] 88. The crystalline form as described in Example 75, wherein the crystalline form is Form D, and wherein the XRPD pattern is substantially the same as that shown in Figure 26 the same.

[0672] 89. The crystalline form as described in any one of Examples 75 - 88, wherein the crystalline form is Form D, characterized by a TGA curve showing a weight loss of about 0.7% at about 210 °C to about 230 °C.

[0673] 90. The crystalline form as described in any one of Examples 75 - 89, wherein the crystalline form is Form D, characterized by a TGA curve substantially the same as that shown in Figure 27 the same.

[0674] 91. The crystalline form as described in any one of Examples 75 - 90, wherein the crystalline form is Form D, characterized by a DSC curve substantially the same as that shown in Figure 28 the same.

[0675] 92. The crystalline form as described in any one of Examples 75 - 91, wherein the crystalline form is Form D, characterized by having a solubility of about 2.25 mg / mL after about 30 minutes in fasted state simulated gastric fluid (FaSSGF) at about 37 °C.

[0676] 93. The crystalline form as described in any one of Examples 75 - 92, wherein the crystalline form is Form D, characterized by having a solubility of about 2.33 mg / mL after about 24 hours in fed state simulated intestinal fluid (FeSSIF) at about 37 °C.

[0677] 94. The crystalline form as described in any one of Examples 75 - 93, wherein the crystalline form is Form D, characterized by having a solubility of about 2.19 mg / mL after about 30 minutes in fasted state simulated intestinal fluid (FaSSIF) at about 37 °C.

[0678] 95. The crystalline form as described in any one of Examples 75 - 94, wherein the crystalline form is Form D, characterized by having a solubility of about 2.08 mg / mL after about 30 minutes in water at about 37 °C.

[0679] 96. The crystalline form as described in any one of Examples 75 - 95, wherein the crystalline form is Form D, which is prepared by a method comprising:

[0680] (a) Prepare 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;

[0681] (b) Add a solution of about 0.55 equivalents of 1 molar hydrochloric acid in ethyl acetate;

[0682] (c) Add 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;

[0683] (d) Add a solution of about 1.65 equivalents of 1 molar hydrochloric acid in ethyl acetate to form a slurry;

[0684] (e) Stir the slurry at about 24 °C for about 16 hours;

[0685] (f) Filter the slurry to obtain a solid;

[0686] (g) Wash the solid with ethyl acetate; and

[0687] (h) Dry the solid to provide the crystalline form.

[0688] 97. A pharmaceutical composition comprising the crystalline form as described in any one of Examples 1-96, and a pharmaceutically acceptable carrier.

[0689] 98. A method of treating a disease or disorder associated with complement factor B (CFB), the method comprising administering to a subject suffering from such a disease or disorder a therapeutically effective amount of the crystalline form as described in any one of Examples 1-96, or the pharmaceutical composition as described in Example 94.

[0690] 99. A method of treating or preventing a disease or disorder selected from: autoimmune diseases or disorders, inflammatory diseases or disorders, metabolic diseases or disorders, nervous system diseases or disorders, lung diseases, respiratory diseases or disorders, ophthalmic diseases, cardiovascular diseases, and kidney diseases, the method comprising administering to a subject suffering from such a disease or disorder a therapeutically effective amount of the crystalline form as described in any one of Examples 1-96, or the pharmaceutical composition as described in Example 97.

[0691] 100. A method of treating or preventing a disease or disorder selected from the group consisting of: multiple sclerosis, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, pemphigus ophthalmicus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, hemodialysis complications, hyperacute allogeneic graft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion condition, myocardial infarction, stroke, pump syndrome after balloon angioplasty, cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders 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, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microscopic polyangiitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, metabolic syndrome and hidradenitis suppurativa, the method comprising administering to a subject suffering from such a disease or disorder a therapeutically effective amount of a crystalline form as described in any one of Examples 1-96, or a pharmaceutical composition as described in Example 97.

[0692] 101. A method of treating or preventing a disease or disorder selected from the group consisting of: kidney disease, chronic kidney disease, diabetic nephropathy, glomerular kidney disease, complement C3 glomerulopathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD), minimal change nephropathy (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis and polycystic kidney disease (PKD), the method comprising administering to a subject suffering from such a disease or disorder a therapeutically effective amount of a crystalline form as described in any one of Examples 1-96, or a pharmaceutical composition as described in Example 97.

[0693] 102. The crystalline form according to any one of Examples 1-96, or the pharmaceutical composition according to Example 97, for use in the treatment of the disease or disorder of Example 99 or 100 in a subject in need of such treatment.

[0694] Examples

[0695] Materials and Methods

[0696] X-ray powder diffraction (XRPD)

[0697] XRPD analysis was performed on a Bruker D8-Advance X-ray diffractometer in Bragg-Brentano configuration using copper Kα1 and Kα2 radiation, a nickel filter, and a LynxEye silicon strip detector (40 kV, 40 mA) at . The slits were set to 0.6 mm divergence, 8 mm anti-scatter, 2.5° Soller, and XRPD was obtained from 1 to 60 2θ degrees.

[0698] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0699] TGA and DSC were performed simultaneously on the same sample using a Mettler Toledo TGA / DSC 3+ . The protective gas and purge gas were nitrogen with flow rates of 20 - 30 mL / min and 50 - 100 mL / min, respectively. The required amount of sample (5 - 10 mg) was directly weighed in a sealed aluminum pan with a pinhole and analyzed according to the following parameters:

[0700]

[0701] Alternative TGA and DSC methods

[0702]

[0703]

[0704] Solubility studies

[0705] At room temperature (RT, 20 °C - 24 °C), solubility was measured by the addition method and the gravimetric method.

[0706] For the addition method, approximately 20 mg of the solid was added to a 2 mL vial, and then the corresponding solvent was slowly added until complete dissolution was observed.

[0707] For the gravimetric method, approximately 30 mg of solid was added to a 2 mL vial, and then 0.75 mL of solvent was added. The slurry was stirred for two days at a constant temperature. 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 on a hot plate under an atmosphere of 50 °C, and then placed under vacuum at 50 °C at approximately -29 inHg for 3 hours, and then finally weighed.

[0708] PBS-V1 + 3 mM NaTC

[0709] Sodium taurocholate (NaTC) was purchased from a supplier. Describe the assay. Add an amount equivalent to 3 mM to PBS V1. Stir until dissolved. Equilibrate at 25 °C or 37 °C for 1 h before use. Discard after 48 h.

[0710] PBS-V1 + FaSSIF-V2 (fasting state simulated intestinal fluid)

[0711] FaSSIF-V2 was purchased from a supplier (biorelevant.com). Determine the amount to be added to PBS-V1 according to Table 1. Stir until dissolved. Equilibrate at 25 °C or 37 °C for 1 h before use. Discard after 48 h.

[0712] PBS-V1 + 0.3 FeSSIF-V2 (fed state simulated intestinal fluid)

[0713] FeSSIF-V2 was purchased from a supplier (biorelevant.com). Determine the amount to be added to PBS-V1 according to Table 1. Stir until dissolved. Equilibrate at 25 °C or 37 °C for 1 h before use. Discard after 48 h.

[0714] PBS-V1 + FeSSIF-V2 (fed state simulated intestinal fluid)

[0715] FeSSIF-V2 was purchased from a supplier (biorelevant.com). Determine the amount to be added to PBS-V1 according to Table 1. Stir until dissolved. Equilibrate at 25 °C or 37 °C for 1 h before use. Discard after 48 h.

[0716] PBS-V1 + 2 FeSSIF-V2 (fed state simulated intestinal fluid)

[0717] FeSSIF-V2 was purchased from a supplier (biorelevant.com). Determine the amount to be added to PBS-V1 according to Table 1. Stir until dissolved. Equilibrate at 25 °C or 37 °C for 1 h before use. Discard after 48 h.

[0718] Table 1 Summary of the composition of biorelevant media

[0719]

[0720] Abbreviations

[0721] ACN: Acetonitrile

[0722] THF: Tetrahydrofuran

[0723] MeOH: Methanol

[0724] EtOH: Ethanol

[0725] EA or EtOAc: Ethyl acetate

[0726] DMSO: Dimethyl sulfoxide

[0727] IPAc: Isopropyl acetate

[0728] MEK: Methyl ethyl ketone

[0729] MTBE: Methyl tert-butyl ether

[0730] 2-MeTHF: 2-Methyltetrahydrofuran

[0731] MIBK: Methyl isobutyl ketone

[0732] NaTC: Sodium taurocholate

[0733] NMP: N-Methyl-2-pyrrolidone

[0734] DCM: Dichloromethane

[0735] XRPD: X-ray powder diffraction

[0736] TSA: p-Toluenesulfonic acid

[0737] Tosylate: p-Toluenesulfonate

[0738] FaSSGF: Fasted-state simulated gastric fluid

[0739] FeSSIF: Fed-state simulated intestinal fluid

[0740] FaSSIF: Fasted-state simulated intestinal fluid

[0741] Kleptose: Hydroxypropyl β-cyclodextrin

[0742] K value: Vapor-liquid equilibrium ratio

[0743] Methocel: Hydroxypropyl methylcellulose

[0744] D 50 : Average particle size diameter determined from the particle size distribution

[0745] Experimental procedures and characterization data

[0746] Form A

[0747] 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

[0748]

[0749] To a solution of (S)-tert-butyl 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 1 M aqueous LiOH (5.0 equiv). The mixture was heated to 45 °C with stirring for 16 h. The resulting reaction mixture was diluted with water (to 0.1 M), concentrated to one volume under reduced pressure, and then acidified to pH 6 with citric acid (5% aqueous). The resulting suspension was filtered, washed with one volume of water, and then dried to afford an off-white solid as the amorphous compound (87% yield). Figure 1 is the X-ray powder diffraction pattern 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.

[0750] At 40 °C - 50 °C, the amorphous solid was added to a stirred solution of isopropanol (to 0.44 M). After 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 one volume of isopropanol, and then dried to afford an off-white crystalline solid (94% yield). 1H-NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.25 (t, J = 2.9 Hz, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 3.70 (s, 3H), 3.53 (d, J = 11.8 Hz, 1H), 3.23 (s, 1H), 3.16 (d, J = 11.9 Hz, 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 diffraction pattern of the obtained crystalline Form A 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 depicted in Figure 2 and.

[0751] Table 2. List of XRPD peaks of Form A.

[0752]

[0753] The thermogravimetric analysis thermogram is depicted in Figure 3 and. The differential scanning calorimetry plot is shown in Figure 4 and. Alternative preparation of crystalline Form A 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

[0754] Approximately 3.0 g of amorphous (S)-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was weighed into a 50 mL EasyMax reactor, and then 20 mL of MeOH was added. The suspension was heated to 50 °C, stirred at a stirring speed of 500 rpm for 20 min, and then seeded with pre-prepared Form A crystals. After maintaining at 50 °C for 3 h, the suspension was cooled to 25 °C within 250 min, and then heated to 50 °C within 30 min. After aging at 50 °C for another 3 h, 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%. The molecular formula of the anhydrous free form is C 26 H28 F2N2O3 (454.52 g / mol). The 1 1H NMR (400 MHz, DMSO-d6) is depicted in Figure 8 .

[0755] The X-ray powder diffraction pattern of Form A (alternative preparation) is depicted in Figure 5 .

[0756] The differential scanning calorimetry graph of Form A (alternative preparation) is shown in Figure 6 . The thermogravimetric analysis thermogram of Form A (alternative preparation) is depicted in Figure 7 .

[0757] Form A exhibits a plate-like morphology as in Figure 9 .

[0758] Form B

[0759] 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 4-methylbenzenesulfonate

[0760] 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 added to a 100 mL EasyMax vessel, and then 4-methylbenzenesulfonic acid monohydrate (TSA·H2O) (2.30 g, 1.1 equivalents) was added. Then ethanol (EtOH) (17.5 mL, 3.5 vol.) was added, and the resulting suspension was agitated (240 rpm) and heated to 50 °C for 15 min, then cooled to 25 °C over 15 min to produce a clear dark brown solution. Ethyl acetate (12.5 mL, 2.5 vol.) was added, and then it was allowed to stand at 25 °C for 30 min. Then ethyl acetate (37.5 mL, 7.5 vol.) was added to the reactor over 2 h via a feed pump. After the anti-solvent addition was complete, the purple slurry was then allowed to stand at 25 °C for 1 h.

[0761] The final slurry was filtered, washed twice with 2 volumes of EtOH:EtOAc (26:74 v / v), and pulled dry until a transferable powder was obtained. Filtration was carried out advantageously with a K value of 10.4 cm2 / (min·bar).

[0762] The solid was transferred to a tared bottle and dried in a 50 °C vacuum oven (approx. -29 in Hg) for 16 h. The solid was isolated in 79 mol% yield.

[0763] Form B was prepared by heating the starting tosylate (300 mg) in IPA: water (9:1 vol., 1.5 mL) at 50 °C for 16 h. The resulting slurry was sampled for XRPD, then cooled to room temperature and filtered. The resulting wet filter cake solid was dried in a 50 °C vacuum oven under active vacuum. The yield was 237 mg (79% w / w).

[0764] The X-ray powder diffraction pattern of Form B is shown in Figure 12 and the following shows the XRPD peak table.

[0765] Table 3. XRPD Peak List of Form B

[0766]

[0767]

[0768] The thermogravimetric analysis thermogram is depicted in Figure 13 and the differential scanning calorimetry plot is shown in Figure 14

[0769] Alternative Preparation I 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, Form B

[0770] 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 eq of p-TsOH monohydrate (ca. 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 min and then cooled to 25 °C. The solution was seeded with 50 mg of pre-prepared Form B crystals. The temperature was held for 1 h and then 220 mL of water was added over 5 h. After holding for 2 h, the reaction was cooled to 5 °C over 2 h and stirred overnight. The suspension was filtered and the filter cake was dried under vacuum at 40 °C for 24 h to yield 11.59 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 p-toluenesulfonate, Form B (80%). 1 ​1H-NMR (400 MHz, 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), 3.69 (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)( Figure 18 ). The molecular formula of the anhydrous p-toluenesulfonate is C 26 H 28 F2N2O3·C7H8O3S (626.72 g / mol).

[0771] The X-ray powder diffraction pattern of the obtained Form B (Alternative Preparation) is depicted in Figure 15 .

[0772] Table 4. List of XRPD Peaks of Form B (Alternative Preparation I)

[0773]

[0774] The thermogravimetric analysis thermogram is depicted in Figure 17 . The differential scanning calorimetry graph is shown in Figure 16 . Form B shows a plate-like morphology as in Figure 19 .

[0775] 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, Form B

[0776] Weigh 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 into a 100 mL reactor. Add 16.2 g of acetone / water (9 / 1, v / v), and stir the solution at a stirring speed of 250 rpm at 25 °C. Add 10 mL of water, then add 5 mg of seeds and maintain for 2 hours. Add another 30 mL of water within 4 h, and then cool the solution to 5 °C within 2 h. After maintaining at 5 °C overnight, filter the suspension, and dry the filter cake under vacuum at 50 °C overnight. 2.2 g of dry solid is obtained with a yield of 80%.

[0777] Water Content in Forms A and B

[0778] Under ambient conditions, by Karl Fischer titration, Form B contains 2.3 % w / w water content relative to the total weight of the tosylate, while Form A contains 0.15 % w / w water content relative to the total weight of the free form.

[0779] The mass changes measured by DVS isotherm (2 cycles, 40 - 0 - 95 - 0 - 40 % RH) are shown in the table below. The mass changes are based on the dry weight of each.

[0780] Table 5 Mass changes of Forms A and B measured by DVS at 25 °C

[0781]

[0782] After the above DVS experiment, the XRPD curve did not change.

[0783] In DVS, at 95 % RH and 25 °C, the maximum water absorption of Form B is 2.67 %.

[0784] Table 6 Mass changes of Form B measured by DVS at 25 °C and 40 °C

[0785]

[0786]

[0787] Stability of Forms A and B

[0788] In the bulk state, Form A is chemically stable when stored at 50 °C and 11 % RH or 75 % RH for 1 week. When stored at 80 °C and 11 % RH or 75 % RH, there is about 0.1 % to 0.3 % degradation and slight to moderate discoloration is observed. Form A 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 1200 kLux light stress, there is about 0.9 % degradation. Under stress conditions, the polymorphic form remains unchanged.

[0789] In the bulk state, Form B is chemically stable when stored at 50 °C and 11% RH, 50 °C / 75% RH, and 80 °C / 11% RH for 1 week. However, when stored at 80 °C and 75% RH, there is approximately 0.1% degradation and slight discoloration is 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 1200 kLux of light stress, there is approximately 0.2% degradation and slight discoloration is observed. Under stress conditions, the form remains unchanged.

[0790] When exposed to 80% or 92% RH for 24 hours, no change in Form A or B is shown by XRPD.

[0791] Solubility of Forms A and B

[0792] The solubility of Forms A and B in water and biorelevant buffers at 25 °C was collected at 24 h. Form B showed a significantly increased solubility compared to Form A at 24 h in all media.

[0793] Table 7 Solubility (mg / mL) in water and biorelevant buffers at 25 °C

[0794]

[0795] “ / / ”: Not tested due to clear solution or limited residual material

[0796] “-”: No form change

[0797] Intrinsic dissolution of Forms A and B

[0798] The intrinsic dissolution rate of Form A in 0.01 M HCl at pH 2.0 is 0.081 mg / min / cm 2 ( Figure 10 ), which is higher than the intrinsic dissolution rate of Form B in the same medium of 0.015 mg / min / cm 2 ( Figure 20 ). In PBS-V1 (pH 6.5), the intrinsic dissolution rate of Form A is 0.0028 mg / min / cm 2 ( Figure 11 ), while Form B shows a much higher dissolution rate (0.18 mg / min / cm 2 )( Figure 21 ).

[0799]

[0800] Compression stability of Forms A and B

[0801] When Form A or B is compressed at 4 tons for 5 minutes, there is no change in form in XRPD.

[0802] Method: Use a hydraulic press to compress approximately 100 mg of the active pharmaceutical ingredient at 4 t for 5 minutes (tablet diameter 8 mm). Then, characterize the sample by XRPD to detect any changes in the solid state.

[0803] Grinding and wet granulation of Forms A and B

[0804] Dry grinding (2 min and 5 min) and wet granulation (with water and ethanol) do not cause any form changes in Forms A and B. However, after grinding, a decrease in crystallinity was observed from the XRPD pattern.

[0805] Method: Obtain granules in solid form. Add the granulation solvent dropwise until the solid is sufficiently wetted. Grind the wet solid for approximately 2 min. Dry the wet filter cake under vacuum or at atmospheric pressure. Evaluate the solid form and crystallinity by, for example, XRPD and / or DSC.

[0806] Flow properties of Form B

[0807] Form B has good flowability and good bulk density, both of which are suitable for precision pharmaceutical processing filler configurations (sonication and vibration modules). See U.S. Patent No. 11,642,315.

[0808] Dissolution of Form B in capsules

[0809] Capsules containing Form B showed 100% dissolution in FaSSGF and FeSSIF within 40 min ( Figure 22 ). The particle size of the material used was characterized as 53.2 μm (x50). The test conditions were as follows:

[0810] - Dose / specification, 25 mg (calculated as the free form)

[0811] - HGC capsule, size 3

[0812] - 450 mL FaSSGF (pH 1.6) + 450 mL FaSSIF (2x, pH 7.5)

[0813] - Temperature 37 °C

[0814] - Paddle method, 75 rpm

[0815] - Helical settling tablet

[0816] - Add FaSSIF (2x, pH 7.5) at 30 min

[0817] - Repeat the test

[0818] Summary of Forms A and B

[0819] Forms A and B exhibit desirable properties in all respects. However, Form B offers improved solubility and dissolution profiles, as well as flow properties suitable for capsule formulation methods.

[0820] To prevent the possible formation of toluenesulfonates, which are known to have genotoxic effects, care should be taken to avoid the use of methanol, ethanol, or any other alcohol during the manufacture of the active pharmaceutical ingredient or the drug product.

[0821] Form C

[0822] Preparation 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, Form C

[0823] 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·H2O) (2.30 g, 1.1 eq) were added to a 100 mL EasyMax vessel. Then ethanol (17.5 mL, 3.5 vol.) was added, and the resulting suspension was heated to 50 °C with agitation (240 rpm) for 15 min and then cooled to 25 °C within 15 min. EtOAc (12.5 mL, 2.5 vol.) was added to the resulting clear dark brown solution, and then it was allowed to stand at 25 °C for 30 min. Then EtOAc (37.5 mL, 7.5 vol.) was added to the reactor over 2 h using a feed pump. After the antisolvent addition was complete, the purple slurry was aged at 25 °C for 1 h. The final slurry was filtered, washed twice with 2 volumes of EtOH:EtOAc (26:74 v / v), and pulled dry until a transferable powder was obtained.

[0824] Figure 23 is the X-ray powder diffraction pattern of Form C, and the following shows the XRPD peak table.

[0825] Table 8. XRPD peak list 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, Form C.

[0826]

[0827]

[0828] The thermogravimetric analysis thermogram is depicted in Figure 24In. The differential scanning calorimetry plot shows in Figure 25 In.

[0829] 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

[0830] Dissolve 1 g of form B in 3 mL of MeOH, then add the solution to 15 mL of EA. Filter the suspension after a few hours and dry the filter cake under vacuum at 40 °C overnight to yield approximately 650 mg of form C (65%).

[0831] The X-ray powder diffraction pattern of form C is consistent with Figure 23 In agreement.

[0832] Polymorph stability

[0833] The competitive equilibrium between form B and form C shows that form B is the stable polymorphic form in all tested solvents or solvent mixtures.

[0834] Form D

[0835] Preparation of 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

[0836] Add a portion (0.55 equivalent) of 1 M HCl in EtOAc 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 vol.), then add the seed slurry to produce a gray suspension. Then add the remaining 1 M HCl in EtOAc (1.65 equivalents) in one portion to produce a thick gray slurry. Stir and age the resulting thick slurry at 24 °C for 16 h. Filter the resulting slurry and wash the top with 1.5 volumes of EtOAc twice. Dry the filter cake under vacuum to obtain an off-white solid (71% yield). The X-ray powder diffraction pattern of form D shows in Figure 26 In. The thermogravimetric analysis thermogram is depicted in Figure 27 In. The differential scanning calorimetry plot shows in Figure 28 In.

[0837] Table 9. List of XRPD peaks of form D.

[0838]

[0839]

[0840] Solubility study

[0841] Solubility data of 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, 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 in simulated fluid at 37 °C

[0842] Table 10

[0843]

[0844] Pharmacokinetic study

[0845] The pharmacokinetic profiles 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 were evaluated in rats, dogs or non-human primates (NHP) as an amorphous compound as a 20% solution of kleptose in water and as a suspension of form A in 0.5% methocel + 0.1% tween 80 in water.

[0846] Preparation of amorphous solution formulations

[0847] 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 with a magnetic stir bar to give a formulation at a dose concentration of 0.1 - 1000 mg / kg. Approximately one-third of the final volume of 20% kleptose (hydroxypropyl β-cyclodextrin, Aldrich, CAS No. 128446-35-5) in water was added to the vial (to give a dose volume of 5 mL / kg or 10 mL / kg depending on the species). The mixture was basified to a pH of 8.5 to 10 using dropwise addition of 2 - 5 M aqueous NaOH, and the pH was monitored. The suspension was stirred, vortexed, and sonicated for 15 - 20 minutes to obtain a homogeneous mixture. A second one-third of the final volume of 20% kleptose was added to the vial, and further stirred, vortexed, and sonicated for 15 - 20 minutes to obtain a homogeneous mixture. The pH was monitored, and if necessary, the pH could be further adjusted to pH 8.5 to 10. The final one-third of the final volume of 20% kleptose was added to the vial, and further stirred, vortexed, and sonicated for 15 - 20 minutes to obtain a homogeneous solution. The pH of the solution was adjusted to a pH of 7.5 to 8.0 by dropwise addition of 1.0 M aqueous HCl with gentle stirring. The formulation should remain in solution.

[0848] Table 10 describes the pharmacokinetic properties of the amorphous solution formulation after oral administration.

[0849] Table 11. Pharmacokinetic properties 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.

[0850]

[0851]

[0852] Preparation of Form A suspension formulations

[0853] Crystalline 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 was weighed into a glass vial with a magnetic stir bar to give a formulation at a dose concentration of 0.1 - 1000 mg / kg. The particle size of the crystalline material should preferably be D 50 less than 50 μm, and ideally D 50Less than 5 μm. Add the required volume of 0.5% methocel (viscosity 400 cP, Aldrich, CAS No. 9004-67-5) / 0.1% tween-80 (Aldrich, CAS No. 9005-65-6) (to obtain a 5 mL / kg dose volume). Stir the contents of the vial on a magnetic stirrer at 400 - 500 rpm. Gentle vortexing or bath sonication can be applied to break up any large agglomerates. The vial should be well mixed to ensure uniformity prior to animal dosing.

[0854] Table 12 describes the pharmacokinetic properties of the crystalline suspension formulation after oral administration.

[0855] Table 12. Pharmacokinetic properties of crystalline 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.

[0856]

[0857] 1. Particle size D 50 = 5.1 μm. 2. Particle size D 50 = 101 μm.

[0858] Form A exhibits higher C max , AUC 0-24h and C 24h , resulting in higher overall exposure and smaller particle size. This is because the smaller the particle size, the larger the surface area.

[0859] Numerous embodiments of the present disclosure have been described. However, it should be understood that various modifications can be made without departing from the spirit and scope of the present disclosure. Accordingly, other embodiments are within the 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. The crystalline form according to claim 1, wherein the crystalline form is Form A, and wherein the XRPD pattern has peaks at 10.7, 20.5 and 18.8 (±0.2 degrees 2θ).

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

4. The crystalline form according to claim 1, wherein the crystalline form is Form A, and wherein 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 15.5 (±0.2 degrees 2θ).

5. The crystalline form according to any one of claims 1-4, 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. The crystalline form according to 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 the anhydrous form.

7. A p-toluenesulfonate 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.

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

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

10. The crystalline form according to claim 7, wherein the crystalline form is Form B, and wherein 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).

11. The crystalline form according to claim 7, wherein the crystalline form is Form B, and wherein Form B contains from 0% to 2.7% w / w of water.

12. The crystalline form according to any one of claims 7-11, 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 according to any one of claims 7-11, wherein the crystalline form is Form B having a DSC thermogram characterized by broad endothermic peaks at T 起始 = 29.8 °C and T 峰 = 65 °C when heated from 30 °C to 300 °C at a rate of 10 K / min.

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

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

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

17. The method according to claim 16, wherein 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, Behçet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multifocal honeycomb retinal dystrophy / familial dominant drusen, Sorsby fundus dystrophy, late-onset retinal macular dystrophy, North Carolina macular dystrophy, fundus flavimaculatus, corneal inflammation, multiple sclerosis, 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, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), 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 coli hemolytic uremic syndrome), periodontitis, CD55 deficiency with complement overactivation, 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 transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion condition, myocardial infarction, post-pump syndrome during balloon angioplasty, cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, COVID-19, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, 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 infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic disease, Goodpasture's syndrome, pulmonary vasculitis, microscopic immune-type vasculitis,Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's disease, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis and obesity, immune thrombocytopenia, cold agglutinin disease, warm antibody autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, Graves' disease and hidradenitis suppurativa.

Images