Crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide

Abstract

The present invention relates to the crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and its hydrates, solvates and polymorphs. The present invention further relates to pharmaceutical compositions comprising this compound and the use of this compound in the treatment and prevention of medical diseases, disorders and conditions, most particularly through NLRP3 inhibition.

Description

[Technical field]

[0001] The present invention relates to the crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and its hydrates, solvates and polymorphs. The present invention further relates to pharmaceutical compositions comprising this compound and the use of this compound in the treatment and prevention of medical diseases, disorders and conditions, most particularly through NLRP3 inhibition. [Background technology]

[0002] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits IL-1β production at micromolar concentrations in response to activation of NLRP3, but not NLRC4 or NLRP1. Other weak NLRP3 inhibitors characterized to date include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), but these agents have limited potency and are nonspecific.

[0003] Certain sulfonylurea-containing compounds have also been disclosed as inhibitors of NLRP3 (see, e.g., Baldwin et al., J. Med. Chem., 59(5), pp. 1691-1710, 2016; and WO2016 / 131098A1). WO2019 / 008025A1 discloses the amorphous potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide.

[0004] There is a need to provide compounds which have improved pharmacological and / or physiological and / or physicochemical properties and / or which offer useful alternatives to known compounds. Summary of the Invention

[0005] A first aspect of the present invention provides a crystalline form of the potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, or a hydrate or solvate thereof.

[0006] A second aspect of the invention provides a crystalline polymorph of the monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, or a hydrate or solvate thereof. Preferred examples of such polymorphs include the polymorphs designated herein as Form A, Form D, and Form B. Other examples of such polymorphs include the polymorphs designated herein as Form C, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, and Form N.

[0007] A third aspect of the invention provides a pharmaceutical composition comprising the crystalline form of the first aspect of the invention or the polymorph of the second aspect of the invention and a pharma- ceutically acceptable excipient.

[0008] Further aspects of the present invention provide medical uses and methods of treatment or prevention of diseases, disorders or conditions, most particularly by NLRP3 inhibition. [Brief description of the drawings]

[0009] [Figure 1A] 1 shows an XRPD analysis of polymorph A. [Figure 1B] 1 shows an XRPD analysis of polymorph A. [Diagram 2] 1 shows the TGA analysis of polymorph A. [Diagram 3] 1 shows the DSC analysis of polymorph A. [Figure 4A] 1 shows an XRPD analysis of polymorph D. [Figure 4B] 1 shows an XRPD analysis of polymorph D. [Diagram 5] 1 shows the TGA analysis of polymorph D. [Figure 6] 1 shows the DSC analysis of polymorph D. [Figure 7A] 1 shows an XRPD analysis of polymorph B. [Figure 7B] 1 shows an XRPD analysis of polymorph B. [Figure 8] 1 shows the TGA analysis of polymorph B. [Figure 9] 1 shows the DSC analysis of polymorph B. [Figure 10] 1 shows an XRPD analysis of pre-milling of Polymorph A (lower diffractogram) and overlaid post-milling of Polymorph A (upper diffractogram) as described in Evaluation Example 2. [Figure 11] 1 shows an XRPD analysis of the amorphous product from Comparative Example 1. [Figure 12] 1 shows an XRPD analysis of polymorph C. [Figure 13] 1 shows an XRPD analysis of polymorph E. [Figure 14] 1 shows an XRPD analysis of polymorph F. [Figure 15] 1 shows an XRPD analysis of polymorph G. [Figure 16] 1 shows an XRPD analysis of polymorph H. [Figure 17] 1 shows an XRPD analysis of polymorph I. [Figure 18] 1 shows an XRPD analysis of polymorph J. [Figure 19] 1 shows an XRPD analysis of polymorph K. [Figure 20] 1 shows an XRPD analysis of polymorph L. [Figure 21] 1 shows an XRPD analysis of polymorph M. [Figure 22] 1 shows an XRPD analysis of polymorph N. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Differences between solid forms of an active pharmaceutical compound can have significant effects on the properties of the compound, such as differences in crystallinity, solubility, intrinsic dissolution rate, bioavailability, stability to mechanical crushing, storage stability, and stability in aqueous and other media of a polymorph of the compound compared to amorphous and other polymorphs of the same compound.

[0011] The present invention provides a crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a hydrate or solvate thereof, which has certain advantages over the amorphous form. The present invention also provides a polymorph of the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a hydrate or solvate thereof, which has certain advantages over other polymorphs and amorphous forms.

[0012] A first aspect of the present invention provides a crystalline form of the potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, or a hydrate or solvate thereof. 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (also referred to as the free acid) has the formula: [ka]

[0013] The crystalline forms of the first aspect of the invention include salts having any ratio of the conjugate base of the free acid to potassium ion, such as monopotassium salts, dipotassium salts, and hemipotassium salts. In one embodiment, the crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide is the monopotassium salt.

[0014] The crystalline form of the first aspect of the present invention may be in the form of anhydrous or hydrate (e.g., hemihydrate, monohydrate, dihydrate, trihydrate or non-stoichiometric hydrate) or other solvate. Such solvates can be formed using common organic solvents, including but not limited to alcoholic solvents such as methanol, ethanol or isopropanol. In one embodiment, the crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide is anhydrous. In one embodiment, the crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide is a hydrate.

[0015] The crystalline form of the first aspect of the invention preferably has a crystallinity of 50% or more (e.g., 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 99% or more). As used herein, the crystalline form of the first aspect of the invention is typically referred to as crystalline when it has a crystallinity of 90% or more (e.g., 95% or more, or 99% or more). As used herein, crystallinity is the weight percentage of the crystalline form of the first aspect of the invention that is one or more polymorphs, expressed as a percentage of the total weight of the salt. Typically, crystallinity is determined by XRPD or DSC, preferably by XRPD.

[0016] The crystalline form of the first aspect of the present invention preferably has a chemical purity as measured by HPLC of at least 95 wt%, more preferably at least 97 wt%, more preferably at least 98 wt%, more preferably at least 99 wt%, more preferably at least 99.5 wt%, even more preferably at least 99.8 wt%, and most preferably at least 99.9 wt%.

[0017] The crystalline form of the first aspect of the present invention is 1The chemical purity as measured by H NMR is preferably at least 95 wt%, more preferably at least 97 wt%, more preferably at least 98 wt%, more preferably at least 99 wt%, and more preferably at least 99.5 wt%.

[0018] In one embodiment, the crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide is the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide anhydrate.

[0019] In one embodiment, the crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide is a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide hydrate (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or non-stoichiometric hydrate).

[0020] The crystalline form of the first aspect of the present invention may exist in one or more polymorphs. Polymorphism refers to the ability of a solid substance to exist in one or more different crystal structures (i.e., one or more different molecular arrangements relative to each other within a crystal lattice). Different polymorphs of a substance can have different physical properties, such as bioavailability, solubility, intrinsic dissolution rate, and calorimetric behavior (e.g., melting point). Different polymorphs may also show differences in stability (e.g., differences in stability with respect to conversion to other crystalline or amorphous forms, or differences in stability with respect to grinding). The physical properties of an active pharmaceutical ingredient may affect the safety performance and efficacy of a pharmaceutical product. Therefore, it is advantageous to identify polymorphs of a drug substance that have pharmaceutically acceptable properties.

[0021] Thus, a second aspect of the present invention provides a crystalline polymorph of the monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, or a hydrate or solvate thereof.

[0022] The crystalline form of the first aspect of the present invention and the polymorph of the second aspect of the present invention are 12 C. 13 C. 1 H, 2 H(D), 14 N, 15 N, 16 O. 17 O. 18 O. 19 F and 127 any stable isotope, including but not limited to I, and 11 C. 14 C. 3 H(T), 13 N, 15 O. 18 F, 123 I, 124 I, 125 I and 131 It may contain any radioisotope, including but not limited to I.

[0023] The polymorph of the second aspect of the invention preferably comprises more than 80%, preferably more than 90%, more preferably more than 95%, even more preferably more than 98%, and most preferably more than 99% of a single crystalline polymorph of the compound as measured by XRPD or DSC, preferably as measured by XRPD.

[0024] In certain embodiments, the polymorph of the second aspect is a polymorph of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt.

[0025] Preferred examples of polymorphs of the second aspect include the polymorphs designated herein as Form A, Form D, and Form B. Other examples of such polymorphs include the polymorphs designated herein as Form C, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, and Form N.

[0026] The polymorphs, Form A through Form N, can be characterized by techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and / or thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TGA-FTIR).

[0027] As used herein, XRPD data is typically data that can be obtained using CuKal radiation at 20°C. As used herein, the terms "approximately" or "nearly" used in relation to the positions of XRPD peaks typically refer to the stated positions ±0.2°2θ, preferably ±0.15°2θ. As used herein, DSC, TGA, and TGA-FTIR data are typically data that can be obtained using heating rates of 10 K / min, 5 K / min, and 10 K / min, respectively.

[0028] Form A polymorphism Form A polymorph is the first particularly preferred polymorph. It was the only anhydrous crystalline form identified. It has good solubility and was found to be thermodynamically stable as well as stable to prolonged grinding conditions. Thus, Form A polymorph is suitable for development as a pharmaceutical.

[0029] The Form A polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.14° 2θ, 16.30° 2θ, and 20.66° 2θ. More typically, the Form A polymorph has an XRPD diffractogram that includes peaks at approximately 5.14° 2θ, 16.30° 2θ, 20.00° 2θ, and 20.66° 2θ. More typically, the Form A polymorph has an XRPD diffractogram that includes peaks at approximately 5.14° 2θ, 16.30° 2θ, 20.66° 2θ, and 22.54° 2θ. More typically, the Form A polymorph has an XRPD diffractogram that includes peaks at approximately 5.14° 2θ, 16.30° 2θ, 17.86° 2θ, 20.00° 2θ, and 20.66° 2θ. Even more typically, the Form A polymorph has an XRPD diffractogram that includes peaks at approximately 5.14°2θ, 16.30°2θ, 17.86°2θ, 18.60°2θ, 20.00°2θ, 20.66°2θ, and 22.54°2θ.Even more typically, the Form A polymorph has an XRPD diffractogram that includes peaks at approximately 5.14°2θ, 12.60°2θ, 16.30°2θ, 17.86°2θ, 18.60°2θ, 20.00°2θ, 20.66°2θ, 22.54°2θ, 25.36°2θ, and 25.90°2θ. Even more typically, the Form A polymorph has an XRPD diffractogram including peaks at approximately 5.14°2θ, 12.60°2θ, 16.30°2θ, 17.86°2θ, 18.60°2θ, 20.00°2θ, 20.66°2θ, 22.54°2θ, 23.70°2θ, 25.36°2θ, 25.90°2θ, 32.50°2θ, and 36.56°2θ. Even more typically, the Form A polymorph has an XRPD diffractogram including peaks at approximately 5.14°2θ, 8.90°2θ, 12.60°2θ, 16.30°2θ, 17.86°2θ, 18.60°2θ, 20.00°2θ, 20.66°2θ, 22.54°2θ, 23.70°2θ, 24.26°2θ, 25.36°2θ, 25.90°2θ, 28.90°2θ, 30.30°2θ, 32.50°2θ, 32.92°2θ, 35.40°2θ, and 36.56°2θ.

[0030] The Form A polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.14°2θ, 8.90°2θ, 12.60°2θ, 16.30°2θ, 17.86°2θ, 18.60°2θ, 20.00°2θ, 20.66°2θ, 22.54°2θ, 23.70°2θ, 24.26°2θ, 25.36°2θ, 25.90°2θ, 28.90°2θ, 30.30°2θ, 32.50°2θ, 32.92°2θ, 35.40°2θ, and 36.56°2θ. More typically, the Form A polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.14°2θ, 12.60°2θ, 16.30°2θ, 17.86°2θ, 18.60°2θ, 20.00°2θ, 20.66°2θ, 22.54°2θ, 23.70°2θ, 25.36°2θ, 25.90°2θ, 32.50°2θ, and 36.56°2θ. Even more typically, the Form A polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.14°2θ, 12.60°2θ, 16.30°2θ, 17.86°2θ, 18.60°2θ, 20.00°2θ, 20.66°2θ, 22.54°2θ, 25.36°2θ, and 25.90°2θ.

[0031] The Form A polymorph may have an XRPD diffractogram approximately as shown in Table 1 below: [Table 1]

[0032] The Form A polymorph may have an XRPD diffractogram approximately as shown in Figure 1A or 1B.

[0033] Polymorph Form A is an anhydrous polymorph. Polymorph Form A was the only anhydrous crystalline form identified.

[0034] Additionally, the Form A polymorph is hygroscopic and may contain varying amounts of non-assimilated water (i.e., not water of hydration). The amount of non-assimilated water varies depending on the preparation and storage conditions used. Amounts of non-assimilated water up to about 3% have been observed in the Form A polymorph. When stored at ambient conditions (about 20-40% RH (typically about 30% RH) and about 20-25°C), the Form A polymorph typically contains about 1% to about 1.5% non-assimilated water.

[0035] The Form A polymorph typically has a TGA profile that includes a weight loss of up to about 3% (typically up to about 2.5%, typically up to about 2%) between 25°C and 210°C.

[0036] The Form A polymorph may have a TGA profile approximately as shown in FIG.

[0037] The Form A polymorph typically has a DSC profile that includes a single endothermic event, and is believed to melt with decomposition. The endothermic event of the Form A polymorph typically has an onset at a temperature in the range of about 227°C to about 247°C (e.g., a temperature in the range of about 232°C to about 242°C, a temperature in the range of about 233°C to about 241°C, or a temperature of about 237°C). The endothermic event of the Form A polymorph typically has a peak at a temperature in the range of about 233°C to about 253°C (e.g., a temperature in the range of about 238°C to about 248°C, a temperature in the range of about 239°C to about 247°C, or a temperature of about 243°C).

[0038] The Form A polymorph may have a DSC profile approximately as shown in FIG.

[0039] The form A polymorph is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt in a solvent system to form a suspension; and (b) obtaining from the suspension a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form A polymorph.

[0040] In a preferred embodiment, the solvent system used in step (a) comprises a solvent selected from acetone, methyl ethyl ketone, acetonitrile, propionitrile, tert-butyl methyl ether, methyl acetate, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, nitromethane, toluene, anisole, chlorobenzene, and mixtures thereof. In a preferred embodiment, the solvent system used in step (a) consists of a solvent selected from acetone, methyl ethyl ketone, acetonitrile, propionitrile, tert-butyl methyl ether, methyl acetate, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, nitromethane, toluene, anisole, chlorobenzene, and mixtures thereof. In a preferred embodiment, the solvent system used in step (a) comprises a solvent selected from acetone, acetonitrile, and mixtures thereof. In a preferred embodiment, the solvent system used in step (a) consists of a solvent selected from acetone, acetonitrile, and mixtures thereof. In a preferred embodiment, the solvent system consists of acetone or acetonitrile.

[0041] In some embodiments, step (a) is carried out at a temperature in the range of 5°C to 60°C, or in the range of 10°C to 30°C, or in the range of 15°C to 25°C.

[0042] Form D polymorphism The Form D polymorph is a second particularly preferred polymorph. The Form D polymorph has good solubility and has been found to be stable in the presence of water, either as a solvent or co-solvent, or in the presence of humidity (such as >30% RH at 25° C.). Thus, the Form D polymorph is suitable for development as a pharmaceutical.

[0043] The Form D polymorph typically has an XRPD diffractogram that includes peaks at approximately 4.86°2θ, 9.74°2θ, 16.08°2θ, and 19.16°2θ. More typically, the Form D polymorph has an XRPD diffractogram that includes peaks at approximately 4.86°2θ, 8.42°2θ, 9.74°2θ, 16.08°2θ, and 19.16°2θ. More typically, the Form D polymorph has an XRPD diffractogram that includes peaks at approximately 4.86°2θ, 9.74°2θ, 16.08°2θ, 16.94°2θ, and 19.16°2θ. More typically, the Form D polymorph has an XRPD diffractogram that includes peaks at approximately 4.86°2θ, 9.74°2θ, 14.64°2θ, 16.08°2θ, 19.16°2θ, and 19.46°2θ. Even more typically, the Form D polymorph has an XRPD diffractogram that includes peaks at approximately 4.86°2θ, 9.74°2θ, 14.64°2θ, 16.08°2θ, 16.94°2θ, 17.62°2θ, 19.16°2θ, 19.46°2θ, and 20.98°2θ. Even more typically, the form D polymorph has an XRPD diffractogram including peaks at approximately 4.86°2θ, 8.42°2θ, 9.74°2θ, 12.76°2θ, 14.64°2θ, 16.08°2θ, 16.94°2θ, 17.62°2θ, 19.16°2θ, 19.46°2θ, 20.06°2θ, and 20.98°2θ.

[0044] The Form D polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.86°2θ, 8.42°2θ, 9.74°2θ, 12.76°2θ, 14.64°2θ, 16.08°2θ, 16.94°2θ, 17.62°2θ, 19.16°2θ, 19.46°2θ, 20.06°2θ, 20.98°2θ, 24.52°2θ, and 29.56°2θ. More typically, the Form D polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.86°2θ, 8.42°2θ, 9.74°2θ, 12.76°2θ, 14.64°2θ, 16.08°2θ, 16.94°2θ, 17.62°2θ, 19.16°2θ, 19.46°2θ, 20.06°2θ, and 20.98°2θ. Even more typically, the Form D polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.86°2θ, 9.74°2θ, 14.64°2θ, 16.08°2θ, 16.94°2θ, 17.62°2θ, 19.16°2θ, 19.46°2θ, 20.06°2θ, and 20.98°2θ.

[0045] The Form D polymorph may have an XRPD diffractogram approximately as shown in Table 2 below: [Table 2]

[0046] The Form D polymorph may have an XRPD diffractogram approximately as shown in Figure 4A or 4B.

[0047] The Form D polymorph is a hydrate. The Form D polymorph contains between about 4% and about 8% water. When stored at ambient conditions (about 20-40% RH (typically about 30% RH) and about 20-25° C.), the Form D polymorph typically contains about 6% to about 7% water (about 1.5 mol to about 1.8 mol per mol of monopotassium 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide).

[0048] The Form D polymorph typically has a TGA profile that includes about 4.3% to about 8.3% weight loss (e.g., about 5.3% to about 7.3% weight loss, about 5.8% to about 6.8% weight loss, about 6.1% to about 6.5% weight loss, or about 6.3% weight loss) between 25° C. and 160° C.

[0049] The Form D polymorph may have a TGA profile approximately as shown in FIG.

[0050] The Form D polymorph typically has a DSC profile that includes a first endothermic event (believed to be the loss of water of hydration), an exothermic event (believed to be a phase transition to the Form A polymorph), and a second endothermic event (believed to be melting accompanied by decomposition).

[0051] The first endotherm of the Form D polymorph is a broad range endotherm occurring between about 25°C and about 138°C.

[0052] The exotherm of the Form D polymorph typically has a first onset at a temperature in the range of about 137° C. to about 157° C. (e.g., a temperature in the range of about 142° C. to about 152° C., a temperature in the range of about 143° C. to about 151° C., or a temperature of about 147° C.) and a second onset at a temperature in the range of about 141° C. to about 161° C. (e.g., a temperature in the range of about 146° C. to about 156° C., a temperature in the range of about 147° C. to about 155° C., or a temperature of about 151° C.). The exothermic phenomenon of the Form D polymorph typically has a first peak at a temperature in the range of about 140°C to about 160°C (e.g., a temperature in the range of about 145°C to about 155°C, a temperature in the range of about 146°C to about 154°C, or a temperature of about 150°C) and a second peak at a temperature in the range of about 152°C to about 172°C (e.g., a temperature in the range of about 157°C to about 167°C, a temperature in the range of about 158°C to about 166°C, or a temperature of about 162°C).

[0053] The second endothermic event of the Form D polymorph typically has an onset at a temperature in the range of about 223° C. to about 243° C. (e.g., a temperature in the range of about 228° C. to about 238° C., a temperature in the range of about 229° C. to about 237° C., or a temperature of about 233° C.). The second endothermic event of the Form D polymorph typically has a peak at a temperature in the range of about 229° C. to about 249° C. (e.g., a temperature in the range of about 234° C. to about 244° C., a temperature in the range of about 235° C. to about 243° C., or a temperature of about 239° C.).

[0054] The Form D polymorph may have a DSC profile approximately as shown in FIG.

[0055] The form D polymorph is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt in a solvent system comprising methyl ethyl ketone, tetrahydrofuran, acetone, or a mixture thereof to form a suspension; (b) adding water to the suspension to dissolve the 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt to form a solution; and (c) obtaining from solution the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form D polymorph.

[0056] In a preferred embodiment, the solvent system used in step (a) comprises methyl ethyl ketone. In a preferred embodiment, the solvent system used in step (a) consists of methyl ethyl ketone.

[0057] In a preferred embodiment, the volume ratio of the solvent system in step (a) to water in step (b) is from 100:1 to 1:1 (eg, from 40:1 to 1:1, or about 12.5:1).

[0058] In a preferred embodiment, in step (b), the suspension is heated to form a solution, and in step (c), the solution is cooled (e.g., to room temperature or about 20-25° C.) to obtain the Form D polymorph from the solution.

[0059] Form B polymorphism The form B polymorph typically has an XRPD diffractogram that includes peaks at approximately 4.90° 2θ, 6.60° 2θ, and 7.06° 2θ. More typically, the form B polymorph has an XRPD diffractogram that includes peaks at approximately 4.90° 2θ, 6.60° 2θ, 7.06° 2θ, and 13.28° 2θ. More typically, the form B polymorph has an XRPD diffractogram that includes peaks at approximately 4.90° 2θ, 6.60° 2θ, 7.06° 2θ, and 18.58° 2θ. More typically, the form B polymorph has an XRPD diffractogram that includes peaks at approximately 4.90° 2θ, 6.60° 2θ, 7.06° 2θ, 13.06° 2θ, 13.28° 2θ, and 18.58° 2θ. Even more typically, the Form B polymorph has an XRPD diffractogram that includes peaks at approximately 4.90°2θ, 6.60°2θ, 7.06°2θ, 11.64°2θ, 13.06°2θ, 13.28°2θ, 18.58°2θ, 20.36°2θ, and 21.36°2θ.Even more typically, the Form B polymorph has an XRPD diffractogram that includes peaks at approximately 4.58°2θ, 4.90°2θ, 6.60°2θ, 7.06°2θ, 11.64°2θ, 13.06°2θ, 13.28°2θ, 17.98°2θ, 18.58°2θ, 18.74°2θ, 20.36°2θ, and 21.36°2θ. Even more typically, the form B polymorph has an XRPD diffractogram including peaks at approximately 4.58°2θ, 4.90°2θ, 6.60°2θ, 7.06°2θ, 9.26°2θ, 9.84°2θ, 11.64°2θ, 13.06°2θ, 13.28°2θ, 14.16°2θ, 16.32°2θ, 17.24°2θ, 17.98°2θ, 18.58°2θ, 18.74°2θ, 19.78°2θ, 20.36°2θ, and 21.36°2θ.

[0060] The Form B polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.58°2θ, 4.90°2θ, 6.60°2θ, 7.06°2θ, 9.26°2θ, 9.84°2θ, 11.64°2θ, 13.06°2θ, 13.28°2θ, 14.16°2θ, 16.32°2θ, 17.24°2θ, 17.98°2θ, 18.58°2θ, 18.74°2θ, 19.78°2θ, 20.36°2θ, and 21.36°2θ. More typically, the Form B polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximately 2θ values ​​selected from the following: 4.58°2θ, 4.90°2θ, 6.60°2θ, 7.06°2θ, 11.64°2θ, 13.06°2θ, 13.28°2θ, 17.98°2θ, 18.58°2θ, 18.74°2θ, 20.36°2θ, and 21.36°2θ. Even more typically, the Form B polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.58°2θ, 4.90°2θ, 6.60°2θ, 7.06°2θ, 11.64°2θ, 13.06°2θ, 13.28°2θ, 18.58°2θ, 20.36°2θ, and 21.36°2θ.

[0061] The Form B polymorph may have an XRPD diffractogram approximately as shown in Table 3 below: [Table 3]

[0062] The Form B polymorph may have an XRPD diffractogram approximately as shown in Figure 7A or 7B.

[0063] The Form B polymorph is a hydrate.

[0064] The Form B polymorph typically has a TGA profile comprising about 8.9% to about 12.9% weight loss (e.g., about 9.9% to about 11.9% weight loss, about 10.4% to about 11.4% weight loss, about 10.7% to about 11.1% weight loss, or about 10.9% weight loss) between 25° C. and 150° C.

[0065] The Form B polymorph may have a TGA profile approximately as shown in FIG.

[0066] The Form B polymorph typically has a DSC profile that includes a triple endothermic event (believed to be water release), followed by a weak exothermic event, followed by a weak endothermic event, followed by a broad endothermic event.

[0067] The Form B polymorph may have a DSC profile approximately as shown in FIG.

[0068] The form B polymorph is (a) providing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt in methanol to form a mixture; and (b) obtaining from the mixture a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form B polymorph.

[0069] In a preferred embodiment, in step (b), the mixture is maintained under ambient conditions (about 20-40% RH (typically about 30% RH) and about 20-25° C.) with stirring until the solvent evaporates and the Form B polymorph is obtained from the mixture.

[0070] Form C polymorphism The Form C polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.1°2θ, 8.9°2θ, 9.1°2θ, 15.2°2θ, and 22.7°2θ. More typically, the Form C polymorph has an XRPD diffractogram that includes peaks at approximately 5.1°2θ, 8.2°2θ, 8.9°2θ, 9.1°2θ, 13.3°2θ, 15.2°2θ, 17.2°2θ, 21.4°2θ, 22.7°2θ, and 23.1°2θ. Even more typically, the Form C polymorph has an XRPD diffractogram including peaks at approximately 5.1 °2θ, 8.2 °2θ, 8.9 °2θ, 9.1 °2θ, 11.8 °2θ, 12.3 °2θ, 12.4 °2θ, 13.3 °2θ, 15.1 °2θ, 15.2 °2θ, 16.4 °2θ, 17.2 °2θ, 20.9 °2θ, 21.2 °2θ, 21.4 °2θ, 22.2 °2θ, 22.7 °2θ, 23.1 °2θ, 25.5 °2θ, and 27.7 °2θ.

[0071] The Form C polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.1 °2θ, 8.2 °2θ, 8.9 °2θ, 9.1 °2θ, 11.8 °2θ, 12.3 °2θ, 12.4 °2θ, 13.3 °2θ, 15.1 °2θ, 15.2 °2θ, 16.4 °2θ, 17.2 °2θ, 20.9 °2θ, 21.2 °2θ, 21.4 °2θ, 22.2 °2θ, 22.7 °2θ, 23.1 °2θ, 25.5 °2θ, and 27.7 °2θ. More typically, the Form C polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.1 °2θ, 8.2 °2θ, 8.9 °2θ, 9.1 °2θ, 13.3 °2θ, 15.2 °2θ, 17.2 °2θ, 21.4 °2θ, 22.7 °2θ, and 23.1 °2θ.

[0072] The Form C polymorph may have an XRPD diffractogram approximately as shown in Table 4 below: [Table 4]

[0073] The Form C polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0074] The Form C polymorph is a hydrate.

[0075] The form C polymorph is (a) maintaining Form A of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt in a closed container over water at about 100% RH; and (b) obtaining a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form C polymorph.

[0076] In a preferred embodiment, in step (a), 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt is maintained at a temperature of about 15 to 25° C. (preferably about 23° C.) for about 5 to 20 days (preferably about 13 days).

[0077] Form E polymorphism The Form E polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.6°2θ, 6.2°2θ, 10.7°2θ, 11.3°2θ, and 21.7°2θ. More typically, the Form E polymorph has an XRPD diffractogram that includes peaks at approximately 5.6°2θ, 6.2°2θ, 8.7°2θ, 10.7°2θ, 11.3°2θ, 14.4°2θ, 20.8°2θ, 21.5°2θ, 21.7°2θ, and 21.9°2θ. Even more typically, the Form E polymorph has an XRPD diffractogram including peaks at approximately 5.6 °2θ, 6.2 °2θ, 8.7 °2θ, 9.1 °2θ, 10.7 °2θ, 11.3 °2θ, 11.5 °2θ, 11.7 °2θ, 12.4 °2θ, 13.1 °2θ, 13.4 °2θ, 14.4 °2θ, 15.6 °2θ, 16.6 °2θ, 18.7 °2θ, 19.0 °2θ, 20.8 °2θ, 21.5 °2θ, 21.7 °2θ, and 21.9 °2θ.

[0078] The Form E polymorph typically has an XRPD diffractogram including 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.6 °2θ, 6.2 °2θ, 8.7 °2θ, 9.1 °2θ, 10.7 °2θ, 11.3 °2θ, 11.5 °2θ, 11.7 °2θ, 12.4 °2θ, 13.1 °2θ, 13.4 °2θ, 14.4 °2θ, 15.6 °2θ, 16.6 °2θ, 18.7 °2θ, 19.0 °2θ, 20.8 °2θ, 21.5 °2θ, 21.7 °2θ, and 21.9 °2θ. More typically, the Form E polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.6 °2θ, 6.2 °2θ, 8.7 °2θ, 10.7 °2θ, 11.3 °2θ, 14.4 °2θ, 20.8 °2θ, 21.5 °2θ, 21.7 °2θ, and 21.9 °2θ.

[0079] The Form E polymorph may have an XRPD diffractogram approximately as shown in Table 5 below: [Table 5]

[0080] The Form E polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0081] The Form E polymorph is a hydrate.

[0082] The form E polymorph is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in a mixture of acetonitrile / water in a ratio of about 5 / 95 (v / v) to form a suspension; and (b) obtaining from the suspension a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form E polymorph.

[0083] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 23° C.) for about 1-20 days (preferably about 6 days).

[0084] Form F polymorphism The Form F polymorph typically has an XRPD diffractogram that includes peaks at approximately 4.9°2θ, 9.8°2θ, 19.1°2θ, 20.5°2θ, and 22.2°2θ. More typically, the Form F polymorph has an XRPD diffractogram that includes peaks at approximately 4.9°2θ, 9.8°2θ, 15.6°2θ, 17.0°2θ, 19.1°2θ, 19.4°2θ, 19.9°2θ, 20.5°2θ, 21.7°2θ, and 22.2°2θ. Even more typically, the form F polymorph has an XRPD diffractogram including peaks at approximately 4.9°2θ, 6.5°2θ, 9.8°2θ, 12.9°2θ, 13.9°2θ, 14.7°2θ, 15.6°2θ, 15.9°2θ, 16.4°2θ, 17.0°2θ, 17.6°2θ, 19.1°2θ, 19.4°2θ, 19.9°2θ, 20.1°2θ, 20.5°2θ, 20.9°2θ, 21.2°2θ, 21.7°2θ, and 22.2°2θ.

[0085] The Form F polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.9 °2θ, 6.5 °2θ, 9.8 °2θ, 12.9 °2θ, 13.9 °2θ, 14.7 °2θ, 15.6 °2θ, 15.9 °2θ, 16.4 °2θ, 17.0 °2θ, 17.6 °2θ, 19.1 °2θ, 19.4 °2θ, 19.9 °2θ, 20.1 °2θ, 20.5 °2θ, 20.9 °2θ, 21.2 °2θ, 21.7 °2θ, and 22.2 °2θ. More typically, the Form F polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.9°2θ, 9.8°2θ, 15.6°2θ, 17.0°2θ, 19.1°2θ, 19.4°2θ, 19.9°2θ, 20.5°2θ, 21.7°2θ, and 22.2°2θ.

[0086] The Form F polymorph may have an XRPD diffractogram approximately as shown in Table 6 below: [Table 6]

[0087] The Form F polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0088] The Form F polymorph is a hydrate.

[0089] The form F polymorph is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in a mixture of acetonitrile / water in a ratio of about 95 / 5 (w / w) to form a suspension; and (b) obtaining from the suspension the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form F polymorph.

[0090] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 21° C.) for about 1-20 days (preferably about 3 days).

[0091] Form G polymorphism The Form G polymorph typically has an XRPD diffractogram that includes peaks at approximately 4.8°2θ, 8.7°2θ, 9.0°2θ, 16.4°2θ, and 18.0°2θ. More typically, the Form G polymorph has an XRPD diffractogram that includes peaks at approximately 4.8°2θ, 8.7°2θ, 9.0°2θ, 10.5°2θ, 14.5°2θ, 15.8°2θ, 16.4°2θ, 18.0°2θ, 20.3°2θ, and 22.7°2θ. Even more typically, the form G polymorph has an XRPD diffractogram including peaks at approximately 4.8°2θ, 8.7°2θ, 9.0°2θ, 9.6°2θ, 10.1°2θ, 10.5°2θ, 13.5°2θ, 14.5°2θ, 15.8°2θ, 16.4°2θ, 18.0°2θ, 19.8°2θ, 20.3°2θ, 21.8°2θ, 22.7°2θ, 23.4°2θ, 23.7°2θ, 24.9°2θ, 27.2°2θ, and 29.2°2θ.

[0092] The Form G polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.8 °2θ, 8.7 °2θ, 9.0 °2θ, 9.6 °2θ, 10.1 °2θ, 10.5 °2θ, 13.5 °2θ, 14.5 °2θ, 15.8 °2θ, 16.4 °2θ, 18.0 °2θ, 19.8 °2θ, 20.3 °2θ, 21.8 °2θ, 22.7 °2θ, 23.4 °2θ, 23.7 °2θ, 24.9 °2θ, 27.2 °2θ, and 29.2 °2θ. More typically, the Form G polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.8°2θ, 8.7°2θ, 9.0°2θ, 10.5°2θ, 14.5°2θ, 15.8°2θ, 16.4°2θ, 18.0°2θ, 20.3°2θ, and 22.7°2θ.

[0093] The Form G polymorph may have an XRPD diffractogram approximately as shown in Table 7 below: [Table 7]

[0094] The Form G polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0095] The Form G polymorph is a hydrate.

[0096] The form G polymorph is (a) drying 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt Form C at about 0% RH; and (b) obtaining a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form G polymorph.

[0097] In a preferred embodiment, in step (a), 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt is dried at a temperature of about 15 to 25° C. (preferably about 23° C.) for about 1 to 10 days (preferably about 5 days).

[0098] Form H polymorphism The Form H polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.1°2θ, 5.6°2θ, 6.5°2θ, 14.9°2θ, and 21.4°2θ. More typically, the Form H polymorph has an XRPD diffractogram that includes peaks at approximately 5.1°2θ, 5.6°2θ, 6.5°2θ, 13.1°2θ, 14.9°2θ, 15.2°2θ, 17.7°2θ, 17.9°2θ, 21.4°2θ, and 22.3°2θ. Even more typically, the Form H polymorph has an XRPD diffractogram including peaks at approximately 5.1 °2θ, 5.6 °2θ, 6.5 °2θ, 8.6 °2θ, 10.2 °2θ, 11.3 °2θ, 11.6 °2θ, 12.9 °2θ, 13.1 °2θ, 13.3 °2θ, 14.2 °2θ, 14.9 °2θ, 15.2 °2θ, 15.3 °2θ, 15.6 °2θ, 17.7 °2θ, 17.9 °2θ, 19.6 °2θ, 21.4 °2θ, and 22.3 °2θ.

[0099] The Form H polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.1 °2θ, 5.6 °2θ, 6.5 °2θ, 8.6 °2θ, 10.2 °2θ, 11.3 °2θ, 11.6 °2θ, 12.9 °2θ, 13.1 °2θ, 13.3 °2θ, 14.2 °2θ, 14.9 °2θ, 15.2 °2θ, 15.3 °2θ, 15.6 °2θ, 17.7 °2θ, 17.9 °2θ, 19.6 °2θ, 21.4 °2θ, and 22.3 °2θ. More typically, the Form H polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.1 °2θ, 5.6 °2θ, 6.5 °2θ, 13.1 °2θ, 14.9 °2θ, 15.2 °2θ, 17.7 °2θ, 17.9 °2θ, 21.4 °2θ, and 22.3 °2θ.

[0100] The Form H polymorph may have an XRPD diffractogram approximately as shown in Table 8 below: [Table 8]

[0101] The Form H polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0102] The Form H polymorph is a hydrate.

[0103] The form H polymorph is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in a mixture of acetonitrile / water in a ratio of about 85 / 15 (v / v) to form a suspension; and (b) obtaining from the suspension a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form H polymorph.

[0104] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 23° C.) for about 1-20 days (preferably about 13 days).

[0105] Form I polymorphism The Form I polymorph typically has an XRPD diffractogram that includes peaks at approximately 4.7°2θ, 5.0°2θ, 6.2°2θ, 6.7°2θ, and 15.6°2θ. More typically, the Form I polymorph has an XRPD diffractogram that includes peaks at approximately 3.7°2θ, 4.7°2θ, 5.0°2θ, 6.2°2θ, 6.7°2θ, 10.2°2θ, 12.3°2θ, 12.9°2θ, 14.6°2θ, and 15.6°2θ. Even more typically, the Form I polymorph has an XRPD diffractogram including peaks at approximately 3.7°2θ, 4.7°2θ, 5.0°2θ, 6.2°2θ, 6.7°2θ, 7.0°2θ, 7.1°2θ, 7.7°2θ, 9.5°2θ, 9.8°2θ, 10.2°2θ, 10.4°2θ, 10.8°2θ, 11.0°2θ, 11.3°2θ, 12.3°2θ, 12.9°2θ, 14.6°2θ, 14.9°2θ, and 15.6°2θ.

[0106] The Form I polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 3.7 °2θ, 4.7 °2θ, 5.0 °2θ, 6.2 °2θ, 6.7 °2θ, 7.0 °2θ, 7.1 °2θ, 7.7 °2θ, 9.5 °2θ, 9.8 °2θ, 10.2 °2θ, 10.4 °2θ, 10.8 °2θ, 11.0 °2θ, 11.3 °2θ, 12.3 °2θ, 12.9 °2θ, 14.6 °2θ, 14.9 °2θ, and 15.6 °2θ. More typically, the Form I polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 3.7°2θ, 4.7°2θ, 5.0°2θ, 6.2°2θ, 6.7°2θ, 10.2°2θ, 12.3°2θ, 12.9°2θ, 14.6°2θ, and 15.6°2θ.

[0107] The Form I polymorph may have an XRPD diffractogram approximately as shown in Table 9 below: [Table 9]

[0108] The Form I polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0109] The Form I polymorph is believed to be an n-propanol solvate.

[0110] The Form I polymorph is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in n-propanol to form a suspension (preferably in a closed container); and (b) obtaining from the suspension the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form I polymorph.

[0111] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 23° C.) for about 1-24 hours (preferably about 2 hours).

[0112] Form J polymorphism The form J polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.2°2θ, 5.7°2θ, 19.2°2θ, 21.6°2θ, and 22.9°2θ. More typically, the form J polymorph has an XRPD diffractogram that includes peaks at approximately 5.2°2θ, 5.7°2θ, 19.2°2θ, 19.7°2θ, 20.6°2θ, 21.2°2θ, 21.6°2θ, 21.9°2θ, 22.9°2θ, and 23.6°2θ. Even more typically, the form J polymorph has an XRPD diffractogram including peaks at approximately 5.2 °2θ, 5.7 °2θ, 6.6 °2θ, 17.0 °2θ, 19.2 °2θ, 19.7 °2θ, 20.3 °2θ, 20.4 °2θ, 20.6 °2θ, 20.7 °2θ, 21.0 °2θ, 21.2 °2θ, 21.6 °2θ, 21.8 °2θ, 21.9 °2θ, 22.0 °2θ, 22.9 °2θ, 23.6 °2θ, 24.4 °2θ, and 24.5 °2θ.

[0113] The Form J polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.2 °2θ, 5.7 °2θ, 6.6 °2θ, 17.0 °2θ, 19.2 °2θ, 19.7 °2θ, 20.3 °2θ, 20.4 °2θ, 20.6 °2θ, 20.7 °2θ, 21.0 °2θ, 21.2 °2θ, 21.6 °2θ, 21.8 °2θ, 21.9 °2θ, 22.0 °2θ, 22.9 °2θ, 23.6 °2θ, 24.4 °2θ, and 24.5 °2θ. More typically, the Form J polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.2° 2θ, 5.7° 2θ, 19.2° 2θ, 19.7° 2θ, 20.6° 2θ, 21.2° 2θ, 21.6° 2θ, 21.9° 2θ, 22.9° 2θ, and 23.6° 2θ.

[0114] The Form J polymorph may have an XRPD diffractogram approximately as shown in Table 10 below: [Table 10]

[0115] The Form J polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0116] The Form J polymorph is believed to be an ethanol solvate.

[0117] The form J polymorphism is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in ethanol to form a suspension (preferably in a closed container); and (b) obtaining from the suspension a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form J polymorph.

[0118] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 23° C.) for about 1-24 hours (preferably about 2 hours).

[0119] Form K polymorphism The form K polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.1°2θ, 6.1°2θ, 18.2°2θ, 19.3°2θ, and 20.6°2θ. More typically, the form K polymorph has an XRPD diffractogram that includes peaks at approximately 5.1°2θ, 5.8°2θ, 6.1°2θ, 11.7°2θ, 16.2°2θ, 18.2°2θ, 18.5°2θ, 19.3°2θ, 20.6°2θ, and 21.7°2θ. Even more typically, the form K polymorph has an XRPD diffractogram including peaks at approximately 5.1 °2θ, 5.8 °2θ, 6.1 °2θ, 9.1 °2θ, 10.1 °2θ, 11.7 °2θ, 12.2 °2θ, 13.5 °2θ, 15.2 °2θ, 15.6 °2θ, 16.2 °2θ, 17.2 °2θ, 18.2 °2θ, 18.5 °2θ, 19.0 °2θ, 19.3 °2θ, 19.5 °2θ, 20.3 °2θ, 20.6 °2θ, and 21.7 °2θ.

[0120] The form K polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.1 °2θ, 5.8 °2θ, 6.1 °2θ, 9.1 °2θ, 10.1 °2θ, 11.7 °2θ, 12.2 °2θ, 13.5 °2θ, 15.2 °2θ, 15.6 °2θ, 16.2 °2θ, 17.2 °2θ, 18.2 °2θ, 18.5 °2θ, 19.0 °2θ, 19.3 °2θ, 19.5 °2θ, 20.3 °2θ, 20.6 °2θ, and 21.7 °2θ. More typically, the form K polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.1 °2θ, 5.8 °2θ, 6.1 °2θ, 11.7 °2θ, 16.2 °2θ, 18.2 °2θ, 18.5 °2θ, 19.3 °2θ, 20.6 °2θ, and 21.7 °2θ.

[0121] The form K polymorph may have an XRPD diffractogram approximately as shown in Table 11 below: [Table 11]

[0122] The form K polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0123] The form K polymorph is believed to be an n-methyl-2-pyrrolidone (NMP) solvate.

[0124] The form K polymorph is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in n-methyl-2-pyrrolidone (NMP) to form a suspension (preferably in a closed container); and (b) obtaining from the suspension a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form K polymorph.

[0125] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 23° C.) for about 1-24 hours (preferably about 2 hours).

[0126] Form L polymorphism The Form L polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.0°2θ, 10.0°2θ, 11.6°2θ, 18.1°2θ, and 18.5°2θ. More typically, the Form L polymorph has an XRPD diffractogram that includes peaks at approximately 5.0°2θ, 5.9°2θ, 10.0°2θ, 11.6°2θ, 18.1°2θ, 18.3°2θ, 18.5°2θ, 19.3°2θ, 20.2°2θ, and 20.8°2θ. Even more typically, the form L polymorph has an XRPD diffractogram including peaks at approximately 5.0 °2θ, 5.9 °2θ, 10.0 °2θ, 11.6 °2θ, 17.4 °2θ, 18.1 °2θ, 18.3 °2θ, 18.5 °2θ, 18.9 °2θ, 19.1 °2θ, 19.3 °2θ, 20.2 °2θ, 20.8 °2θ, 21.5 °2θ, 23.6 °2θ, 24.6 °2θ, 25.1 °2θ, 27.8 °2θ, 28.8 °2θ, and 30.3 °2θ.

[0127] The Form L polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.0 °2θ, 5.9 °2θ, 10.0 °2θ, 11.6 °2θ, 17.4 °2θ, 18.1 °2θ, 18.3 °2θ, 18.5 °2θ, 18.9 °2θ, 19.1 °2θ, 19.3 °2θ, 20.2 °2θ, 20.8 °2θ, 21.5 °2θ, 23.6 °2θ, 24.6 °2θ, 25.1 °2θ, 27.8 °2θ, 28.8 °2θ, and 30.3 °2θ. More typically, the form L polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.0°2θ, 5.9°2θ, 10.0°2θ, 11.6°2θ, 18.1°2θ, 18.3°2θ, 18.5°2θ, 19.3°2θ, 20.2°2θ, and 20.8°2θ.

[0128] The Form L polymorph may have an XRPD diffractogram approximately as shown in Table 12 below: [Table 12]

[0129] The form L polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0130] The Form L polymorph is believed to be a methanol solvate.

[0131] The form L polymorph is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in methanol to form a suspension (preferably in a closed container); and (b) obtaining from the suspension the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form L polymorph.

[0132] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 23° C.) for about 1-24 hours (preferably about 2 hours).

[0133] Form M polymorphism The Form M polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.5°2θ, 5.7°2θ, 6.4°2θ, 19.3°2θ, and 19.8°2θ. More typically, the Form M polymorph has an XRPD diffractogram that includes peaks at approximately 4.6°2θ, 5.5°2θ, 5.7°2θ, 6.4°2θ, 19.3°2θ, 19.8°2θ, 19.9°2θ, 20.2°2θ, 21.0°2θ, and 21.1°2θ. Even more typically, the form M polymorph has an XRPD diffractogram including peaks at approximately 4.6°2θ, 5.5°2θ, 5.7°2θ, 6.4°2θ, 12.8°2θ, 14.7°2θ, 15.6°2θ, 16.2°2θ, 17.3°2θ, 17.5°2θ, 19.3°2θ, 19.8°2θ, 19.9°2θ, 20.2°2θ, 20.4°2θ, 21.0°2θ, 21.1°2θ, 23.0°2θ, 24.0°2θ, and 24.5°2θ.

[0134] The Form M polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.6 °2θ, 5.5 °2θ, 5.7 °2θ, 6.4 °2θ, 12.8 °2θ, 14.7 °2θ, 15.6 °2θ, 16.2 °2θ, 17.3 °2θ, 17.5 °2θ, 19.3 °2θ, 19.8 °2θ, 19.9 °2θ, 20.2 °2θ, 20.4 °2θ, 21.0 °2θ, 21.1 °2θ, 23.0 °2θ, 24.0 °2θ, and 24.5 °2θ. More typically, the Form M polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 4.6° 2θ, 5.5° 2θ, 5.7° 2θ, 6.4° 2θ, 19.3° 2θ, 19.8° 2θ, 19.9° 2θ, 20.2° 2θ, 21.0° 2θ, and 21.1° 2θ.

[0135] The Form M polymorph may have an XRPD diffractogram approximately as shown in Table 13 below: [Table 13]

[0136] The Form M polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0137] The Form M polymorph is believed to be a dimethylformamide (DMF) solvate.

[0138] The form M polymorphism is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in dimethylformamide (DMF) to form a suspension (preferably in a closed container); and (b) obtaining from the suspension a crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form M polymorph.

[0139] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 23° C.) for about 1-15 days (preferably about 9 days).

[0140] Form N polymorphism The Form N polymorph typically has an XRPD diffractogram that includes peaks at approximately 5.0°2θ, 5.8°2θ, 17.7°2θ, 20.2°2θ, and 22.7°2θ. More typically, the Form N polymorph has an XRPD diffractogram that includes peaks at approximately 5.0°2θ, 5.4°2θ, 5.8°2θ, 11.3°2θ, 17.7°2θ, 19.0°2θ, 20.2°2θ, 21.1°2θ, 21.6°2θ, and 22.7°2θ. Even more typically, the Form N polymorph has an XRPD diffractogram including peaks at approximately 5.0 °2θ, 5.4 °2θ, 5.8 °2θ, 6.3 °2θ, 7.3 °2θ, 10.7 °2θ, 11.3 °2θ, 12.4 °2θ, 13.7 °2θ, 14.6 °2θ, 15.2 °2θ, 17.7 °2θ, 19.0 °2θ, 20.2 °2θ, 20.9 °2θ, 21.1 °2θ, 21.6 °2θ, 22.7 °2θ, 23.3 °2θ, and 25.4 °2θ.

[0141] The Form N polymorph typically has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.0 °2θ, 5.4 °2θ, 5.8 °2θ, 6.3 °2θ, 7.3 °2θ, 10.7 °2θ, 11.3 °2θ, 12.4 °2θ, 13.7 °2θ, 14.6 °2θ, 15.2 °2θ, 17.7 °2θ, 19.0 °2θ, 20.2 °2θ, 20.9 °2θ, 21.1 °2θ, 21.6 °2θ, 22.7 °2θ, 23.3 °2θ, and 25.4 °2θ. More typically, the Form N polymorph has an XRPD diffractogram that includes 5 or more (e.g., 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks, with the 10 most intense peaks having approximate 2θ values ​​selected from the following: 5.0°2θ, 5.4°2θ, 5.8°2θ, 11.3°2θ, 17.7°2θ, 19.0°2θ, 20.2°2θ, 21.1°2θ, 21.6°2θ, and 22.7°2θ.

[0142] The Form N polymorph may have an XRPD diffractogram approximately as shown in Table 14 below: [Table 14]

[0143] The Form N polymorph may have an XRPD diffractogram approximately as shown in FIG.

[0144] The Form N polymorph is believed to be a dimethylsulfoxide (DMSO) solvate.

[0145] Form N polymorphism is (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt (preferably Form A) in dimethylsulfoxide (DMSO) to form a suspension (preferably in a closed container); and (b) obtaining from the suspension the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as the Form N polymorph.

[0146] In a preferred embodiment, in step (a), the suspension is maintained, preferably in a sealed container, at a temperature of about 15-25° C. (preferably about 23° C.) for about 1-15 days (preferably about 9 days).

[0147] A third aspect of the invention provides a pharmaceutical composition comprising the crystalline form of the first aspect of the invention or the polymorph of the second aspect of the invention and a pharma- ceutically acceptable excipient.

[0148] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Aulton's Pharmaceutics - The Design and Manufacture of Medicines", MEAulton and KMG Taylor, Churchill Livingstone Elsevier, 4th Edition, 2013. Pharmaceutically acceptable excipients, including adjuvants, diluents or carriers, that may be used in the pharmaceutical composition of the present invention are those conventionally used in the field of pharmaceutical formulations.

[0149] A fourth aspect of the invention provides a crystalline form of the first aspect of the invention, a polymorph of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention for use in medicine and / or in the treatment or prevention of a disease, disorder or condition.

[0150] A fifth aspect of the invention provides the use of a crystalline form of the first aspect of the invention, a polymorph of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.

[0151] A sixth aspect of the invention provides a method of treating or preventing a disease, disorder or condition, the method comprising administering an effective amount of a crystalline form of the first aspect of the invention, a polymorph of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, thereby treating or preventing the disease, disorder or condition.

[0152] Typically, when the crystalline form of the first aspect of the invention, the polymorph of the second aspect of the invention, or the pharmaceutical composition of the third aspect of the invention is used for the treatment or prevention of diseases, disorders and conditions, the crystalline form of the first aspect of the invention or the polymorph of the second aspect of the invention acts as an NLRP3 inhibitor.

[0153] In one embodiment, the disease, disorder or condition to be treated or prevented is selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) status of the lymphatic system; (xiv) mental disorder; (xv) pain; and (xvi) A disease in which an individual is determined to carry a germline or somatic non-silent mutation in NLRP3.

[0154] Typically, the treatment or prevention of a disease, disorder or condition involves administration of a crystalline form of the first aspect of the invention, a polymorph of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention to a subject.

[0155] A seventh aspect of the invention provides a method of inhibiting NLRP3, comprising use of a crystalline form of the first aspect of the invention, a polymorph of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention to inhibit NLRP3. In one embodiment of the seventh aspect of the invention, the method is carried out ex vivo or in vitro.

[0156] Unless otherwise specified, in any of the fourth to seventh aspects of the present invention, the subject may be a human or other animal. Typically, the subject is a mammal, more typically, a human or a domesticated mammal such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse, etc. Most typically, the subject is a human.

[0157] Any of the medicaments used in the present invention may be administered by oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), respiratory (aerosol), rectal, vaginal or topical (including transdermal, buccal, mucosal and sublingual) administration.

[0158] Typically, the mode of administration selected will be that most suitable for the disorder, disease, or condition being treated or prevented.

[0159] For the avoidance of doubt, it is to be understood that, to the extent practicable, any embodiment of a given aspect of the invention may be implemented in combination with any other embodiment of the same aspect of the invention. Further, to the extent practicable, a preferred, exemplary or optional embodiment of any aspect of the invention is also to be considered as a preferred, exemplary or optional embodiment of the other aspects of the invention. EXAMPLES

[0160] All solvents, reagents and compounds were purchased and used without further purification unless otherwise noted.

[0161] RH means relative humidity.

[0162] The X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TGA-FTIR), and differential scanning calorimetry (DSC) techniques mentioned in the examples were carried out under the following conditions:

[0163] High-resolution X-ray powder diffraction (XRPD) High-resolution X-ray powder diffraction patterns were recorded in transmission geometry. X-ray diffraction patterns were recorded on a STOES TADIP diffractometer using CuKa1 radiation (1.5406 Å) and a Mythen position sensitive detector at 20 °C. Samples (approximately 10-50 mg) were prepared between thin polymer films and typically analyzed without further processing of the material (e.g., grinding or sieving).

[0164] Forms E, F, H, I, J, K, L, M and N were measured between two Kapton® films giving rise to a typical broad reflection between 4.7° 2θ and 6.1° 2θ.

[0165] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed on a Mettler-Toledo thermogravimetric analyzer TGA / DSC1, TGA / DSC3+. For thermogravimetric analysis, approximately 5-15 mg of sample was placed in an aluminum pan, accurately weighed, and sealed with a perforated lid. Prior to the measurement, the perforated lid was automatically pierced, resulting in an approximately 0.5 mm pinhole. The sample was then heated under a nitrogen flow of approximately 50 mL / min, applying a heating rate of 5 K / min, typically up to a maximum temperature of 350 °C.

[0166] Thermogravimetric analysis combined with Fourier transform infrared spectroscopy (TGA-FTIR) Thermogravimetric analysis was performed on a Netzsch TG209F1 Libra connected to a Bruker Vertex70IR spectrometer to analyze the gas stream evolving at the TGA outlet. For thermogravimetric analysis, approximately 5-15 mg of sample was placed in an aluminum pan, accurately weighed, and sealed with a perforated lid. Prior to the measurement, the perforated lid was automatically pierced, resulting in an approximately 0.5 mm pinhole. The sample was then heated to a maximum temperature of typically 200 °C, applying a heating rate of 10 K / min under a nitrogen flow of approximately 20 mL / min.

[0167] Differential Scanning Calorimetry (DSC) DSC thermograms were recorded using a Mettler-Toledo differential scanning calorimeter DSC2. For the measurements, about 2-6 mg of sample was placed in an aluminum pan, accurately weighed and sealed with a perforated lid. Prior to the measurement, the perforated lid was pierced, resulting in an approximately 0.5 mm pinhole. A sealed lid can also be used to measure the sample under pressure. The sample was then heated under a nitrogen flow of about 100 mL / min, typically applying a heating rate of 1-20 K / min, usually 10 K / min, up to a maximum temperature of typically 180-350 °C (depending on the decomposition temperature).

[0168] Comparative Example 1: Amorphous 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium can be prepared as described in WO2019 / 008025 (Example 6).

[0169] The procedure described in WO2019 / 008025 for the preparation of monopotassium 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (Example 6) was repeated as described therein. Specifically, to a cooled (0° C.) solution of 1-ethylpiperidine-4-sulfonamide in THF was added potassium tert-butoxide. The ice bath was removed and the reaction mixture was allowed to warm to room temperature over 40 minutes with stirring. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene in THF was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and water was added. The suspension was filtered through cotton wool and subsequently purified by automated reverse phase column chromatography (water for 5 min followed by a gradual change to 30:70 water:MeOH over 25 min) to give monopotassium 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as a white solid which was analyzed by XRPD and found to be amorphous. The XRPD of the amorphous form is shown in FIG. 11.

[0170] Example 1: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A A portion of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium (50 mg, 1 wt.) and the appropriate solvent listed in Table 15 (1000 μl, 20 volumes) were charged into separate vessels and stirred at 20° C. for 7 days. After this time, the product was isolated by filtration, washed with recycled maturation solvent, dried under reduced pressure at 40° C., and analyzed by XRPD. [Table 15]

[0171] The XRPD, TGA and DSC spectra of Form A are shown in Figures 1-3, respectively. Form A is anhydrous by DSC.

[0172] Example 2: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium was charged to a reaction vessel. Methanol (116.4 kg) was charged to the vessel, the temperature was adjusted to 15-25°C as necessary, and stirred for 10-20 minutes (until a homogeneous cloudy solution was formed with no solid clumps present). The solution was filtered through a 1 μm filter at 15-25°C. The filter was washed with methanol (11.3 kg) at 15-25°C. The solution was concentrated to approximately 44 L at 25-35°C. Acetonitrile (116.6 kg) was charged to the mixture and the solution was concentrated to approximately 74 L at 25-35°C. Acetonitrile (58.7 kg) was added to the mixture and the mixture was concentrated to approximately 74 L at ≦35°C. The mixture was filtered through a 1 μm filter at 15-25°C. The filter was washed with methanol (11.3 kg) at 15-25°C. The solution was concentrated to approximately 44 L at 25-35°C. Acetonitrile (116.6 kg) was charged to the mixture and the solution was concentrated to approximately 74 L at 25-35°C. Acetonitrile (58.7 kg) was added to the mixture and the mixture was concentrated to approximately 74 L at ≦35°C. 1 Analyzed for residual methanol content by 1 H NMR. Pass criteria: ≦3.0% w / w methanol.

[0173] Acetonitrile (58.8 kg) was charged to the vessel and the temperature was adjusted to 15-25° C. The slurry was aged at 15-25° C. for at least 1 hour (target 1-2 hours) and then filtered through a 20 μm cloth at 15-25° C. The filter cake was washed twice with acetonitrile (23.9 kg, 23.6 kg) at 15-25° C.

[0174] The wet filter cake was analyzed for residual phenol by HPLC. Pass criteria: ≦0.20% phenol by area. The solids were dried under a nitrogen stream at a maximum of 50° C. for at least 2 hours and analyzed for residual moisture content using KF. Pass criteria: ≦2.0% w / w water. Drying was continued while the sample was analyzed.

[0175] The solid, 1 The solid was analyzed for residual acetonitrile by H NMR. Acceptance criteria: ≦0.2% w / w MeCN. 1 Analyzed for residual DMSO by H NMR. Pass criteria: ≦0.4% w / w DMSO. The solid was analyzed for residual solvent levels by GC. Pass criteria: ≦3750 ppm DMSO, ≦2250 ppm MeOH, and ≦308 ppm MeCN.

[0176] The product 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A was obtained by: Emission: 14.42kg Yield: 98% HPLC purity: 99.5% XRPD, TGA, and DSC spectra similar to those in Figures 1-3 were observed.

[0177] Example 3: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form D 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium was charged to a vial and methyl ethyl ketone was added (750 μl, 10 volumes). The suspension was heated on a hot plate set at 85° C. and water co-solvent (60 μl) was added until complete dissolution was achieved. The solution was cooled and allowed to stand for 24 hours. The product 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form D was isolated by centrifugation and the pellet was oven dried under vacuum at 40° C. for 20 hours, removed and analyzed by XRPD. Yield 56%.

[0178] The XRPD, TGA and DSC spectra of Form D are shown in Figures 4-6, respectively. Form D is a hydrate by DSC.

[0179] Example 4: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form D 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium was charged to a vial and acetone was added (750 μl, 10 volumes). The suspension was heated on a hot plate set at 85° C. and water co-solvent (100 μl) was added until complete dissolution was achieved. The solution was cooled and allowed to stand for 24 hours. The product 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form D was isolated by centrifugation and the pellet was oven dried under vacuum at 40° C. for 20 hours, removed and analyzed by XRPD. Yield 46%.

[0180] Similar XRPD, TGA, and DSC spectra to those in Figures 4-6 were observed.

[0181] Example 5: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form B 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium (501.6 mg) was dissolved in methanol (4 mL) at ambient conditions. The resulting cloudy solution was filtered through a 0.22 μm PVDF syringe filter and evaporated under stirring (100 rpm) at ambient conditions (approximately 30% RH, 22° C.) until the solvent evaporated to obtain 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form B.

[0182] The XRPD, TGA and DSC spectra of Form B are shown in Figures 7-9, respectively. Form B is a hydrate by TGA-FTIR.

[0183] Example 6: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form C 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (50 mg) was stored in a sealed container over pure water at 100% relative humidity for 13 days at 23° C. The resulting white solid was removed from high humidity storage and immediately analyzed by XRPD as 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form C.

[0184] The XRPD of Form C is shown in FIG.

[0185] Example 7: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form E 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (500 mg) was suspended in acetonitrile / water 5 / 95 (v / v) (3 mL) in a closed vessel at 23° C. for 6 days. The white slurry was filtered and the resulting 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form E was analyzed immediately by XRPD without further drying.

[0186] The XRPD of Form E is shown in FIG.

[0187] Example 8: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form F 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (200 mg) was suspended in acetonitrile / water 95 / 5 (w / w) (2.6 g) in a closed container at 21° C. for 3 days. An aliquot of the white homogeneous suspension was placed on filter paper and the liquid phase was removed. The resulting 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form F was analyzed immediately by XRPD without further drying.

[0188] The XRPD of Form F is shown in FIG.

[0189] Example 9: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form G 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form G was obtained by drying for 5 days at 23° C. and 0% RH. The resulting white solid material was removed from the dry atmosphere and immediately analyzed by XRPD as 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form G.

[0190] The XRPD of Form G is shown in FIG.

[0191] Example 10: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form H 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (124 mg) was suspended in acetonitrile / water 85 / 15 (v / v) (0.5 mL) in a closed vessel at 23° C. for 13 days. The white slurry was filtered and the resulting 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form H was analyzed immediately by XRPD without further drying.

[0192] The XRPD of Form H is shown in FIG.

[0193] Example 11: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form I 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (100 mg) was suspended in n-propanol (1 mL) in a closed vessel for 2 hours at 23° C. The white slurry was filtered and the resulting 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form I was analyzed immediately by XRPD without further drying.

[0194] The XRPD of Form I is shown in FIG.

[0195] Example 12: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form J 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (100 mg) was suspended in ethanol (1 mL) in a closed vessel for 2 hours at 23° C. The white slurry was filtered and the resulting 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form J was analyzed immediately by XRPD without further drying.

[0196] The XRPD of form J is shown in FIG.

[0197] Example 13: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form K 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (50 mg) was suspended in n-methyl-2-pyrrolidone (NMP) (0.1 mL) in a sealed container for 2 hours at 23° C. The white slurry was filtered and the resulting 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form K was analyzed immediately by XRPD without further drying.

[0198] The XRPD of form K is shown in FIG.

[0199] Example 14: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form L 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (50 mg) was suspended in methanol (0.1 mL) in a closed vessel for 2 hours at 23° C. The white slurry was filtered and the resulting 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form L was analyzed immediately by XRPD without further drying.

[0200] The XRPD of form L is shown in FIG.

[0201] Example 15: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form M 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (100 mg) was suspended in dimethylformamide (DMF) (0.5 mL) in a closed vessel at 23° C. for 9 days. The initial white slurry turned into a solid block of colorless crystals that could not be stirred. The resulting 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form M was not further dried and the wet solid was immediately analyzed by XRPD.

[0202] The XRPD of Form M is shown in FIG.

[0203] Example 16: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form N 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form A (50 mg) was suspended in dimethylsulfoxide (DMSO) (0.1 mL) in a closed vessel at 23° C. for 9 days. The initial white slurry turned into a solid block of colorless crystals that was not stirrable. The resulting 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium Form N was analyzed immediately by XRPD without further drying.

[0204] The XRPD of Form N is shown in FIG.

[0205] Evaluation Example 1: Equilibration of Competitive Suspensions Form A (50 mg, 1 wt.) and Form D (amounts see Table 16) were charged into vials and anhydrous acetonitrile (1000 μl, 20 vol) was added. The vials were stirred at 20° C. or 40° C. for 96 hours. [Table 16]

[0206] Upon stirring at 20° C. or 40° C. (see Table 16), complete conversion to the single form, Form A, was observed after 96 hours. This study indicates that under these conditions, Form A is the thermodynamically more stable polymorph.

[0207] Evaluation Example 2: Mechanical Grinding of Form A Form A (50.4 mg) was milled for 24 hours. The product was collected and analyzed by XRPD to determine if a phase change had occurred.

[0208] Figure 10 shows the XRPD of pre-milling (lower diffractogram) and overlaid post-milling (upper diffractogram) of Form A. As shown in Figure 10, no significant change in polymorphism was observed. This experiment indicates that Form A is physically stable to extended milling conditions.

[0209] Evaluation Example 3: Solubility Determination Crystalline 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide salt (50 mg, 1 wt.) or crystalline 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide free acid (as a control) (50 mg, 1 wt.) was stirred in purified water (1000 μl, 20 volumes) at 20° C. The limiting solubility (mg / ml) was determined after 48 hours at 20° C. using the Q 1 Determined by 1 H NMR (measured against an internal standard, 2,3,5,6-tetrachloronitrobenzene). [Table 17]

[0210] This study indicates that the crystalline potassium salt exhibits the greatest solubility and the least hydrolysis under these conditions.

[0211] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined solely by the claims.

Claims

1. The crystalline potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, or a hydrate or solvate thereof.

2. The salt according to claim 1, which is a monopotassium salt.

3. A polymorphic crystal of the salt according to claim 2, having an XRPD diffractogram containing peaks at approximately 5.14° 2θ, 16.30° 2θ, and 20.66° 2θ.

4. A polymorphic crystal of the salt according to claim 2, having an XRPD diffractogram containing five or more peaks having approximate 2θ values selected from the following: 5.14° 2θ, 8.90° 2θ, 12.60° 2θ, 16.30° 2θ, 17.86° 2θ, 18.60° 2θ, 20.00° 2θ, 20.66° 2θ, 22.54° 2θ, 23.70° 2θ, 24.26° 2θ, 25.36° 2θ, 25.90° 2θ, 28.90° 2θ, 30.30° 2θ, 32.50° 2θ, 32.92° 2θ, 35.40° 2θ, and 36.56° 2θ.

5. A polymorphic crystal according to claim 3, having a TGA profile including a maximum weight loss of approximately 3% between 25°C and 210°C.

6. A polymorphic crystal according to claim 3, having a DSC profile including a single endothermic phenomenon with onset in the temperature range of approximately 233°C to approximately 241°C.

7. A method for preparing a polymorphic crystal according to any one of claims 3 to 6, comprising: (a) suspending the monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide in a solvent system to form a suspension; and (b) obtaining the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide as a polymorphic crystal according to any one of claims 3 to 6 from the suspension.

8. The production method according to claim 7, wherein the solvent system used in step (a) contains a solvent selected from acetone, methyl ethyl ketone, acetonitrile, propionitrile, tert-butyl methyl ether, methyl acetate, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, nitromethane, toluene, anisole, chlorobenzene, and mixtures thereof.

9. The polymorphic crystal of the salt according to claim 2, having an XRPD diffractogram containing peaks at approximately 4.86° 2θ, 9.74° 2θ, 16.08° 2θ, and 19.16° 2θ.

10. The polymorphic crystal of the salt according to claim 2, having an XRPD diffractogram containing five or more peaks having approximate 2θ values selected from the following: 4.86° 2θ, 8.42° 2θ, 9.74° 2θ, 12.76° 2θ, 14.64° 2θ, 16.08° 2θ, 16.94° 2θ, 17.62° 2θ, 19.16° 2θ, 19.46° 2θ, 20.06° 2θ, 20.98° 2θ, 24.52° 2θ, and 29.56° 2θ.

11. The polymorphic crystal according to claim 9, having a TGA profile including a weight loss of approximately 5.3% to approximately 7.3% between 25°C and 160°C.

12. The polymorphic crystal according to claim 9, having a DSC profile including a first broad endothermic phenomenon, a first onset at a temperature in the range of approximately 143°C to approximately 151°C, an exothermic phenomenon with a second onset at a temperature in the range of approximately 147°C to approximately 155°C, and a second endothermic phenomenon with an onset at a temperature in the range of approximately 229°C to approximately 237°C.

13. A method for preparing the polymorphic crystal according to any one of claims 9 to 12, comprising: (a) suspending 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt in a solvent system containing methyl ethyl ketone, tetrahydrofuran, acetone, or a mixture thereof to form a suspension; (b) adding water to the suspension to dissolve 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide monopotassium salt to form a solution; and (c) Obtaining the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide from the solution as a polymorphic crystal according to any one of claims 9 to 12, A method comprising.

14. A polymorphic crystal of the salt according to claim 2, having an XRPD diffractogram containing peaks at approximately 4.90° 2θ, 6.60° 2θ, and 7.06° 2θ.

15. A polymorphic crystal of the salt according to claim 2, having an XRPD diffractogram containing five or more peaks having approximate 2θ values selected from the following for the ten strongest peaks: 4.58° 2θ, 4.90° 2θ, 6.60° 2θ, 7.06° 2θ, 9.26° 2θ, 9.84° 2θ, 11.64° 2θ, 13.06° 2θ, 13.28° 2θ, 14.16° 2θ, 16.32° 2θ, 17.24° 2θ, 17.98° 2θ, 18.58° 2θ, 18.74° 2θ, 19.78° 2θ, 20.36° 2θ, and 21.36° 2θ.

16. A polymorphic crystal according to claim 14, having a TGA profile containing a weight loss of about 9.9% to about 11.9% between 25°C and 150°C.

17. A polymorphic crystal according to claim 14, having a DSC profile containing a triple endothermic phenomenon, followed by a weak exothermic phenomenon, followed by a weak endothermic phenomenon, followed by an extensive endothermic phenomenon.

18. A method for preparing a polymorphic crystal according to any one of claims 14 to 17, (a) Providing a monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide in methanol to form a mixture; and (b) Obtaining the crystalline monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide from the mixture as a polymorphic crystal according to any one of claims 14 to 17, A method comprising.

19. A pharmaceutical composition comprising the crystalline salt according to claim 1 or 2, or a polymorphic crystal according to any one of claims 3 to 6, 9 to 12, and 14 to 17.

20. The crystalline salt according to claim 1 or 2, or the polymorphic crystal according to any one of claims 3 to 6, 9 to 12 and 14 to 17, for use in medicine.

21. The crystalline salt according to claim 1 or 2, or the polymorphic crystal according to any one of claims 3 to 6, 9 to 12 and 14 to 17, for use in the treatment or prevention of a disease, disorder or condition wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

22. The crystalline salt according to claim 1 or 2, or the polymorphic crystal according to any one of claims 3 to 6, 9 to 12 and 14 to 17, for use in the treatment or prevention of a disease, disorder or condition selected from the following: (i) Inflammation; (ii) Autoimmune disease; (iii) Cancer; (iv) Infectious disease; (v) Central nervous system disease; (vi) Metabolic disease; (vii) Cardiovascular disease; (viii) Respiratory disease; (ix) Liver disease; (x) Kidney disease; (xi) Eye disease; (xii) Skin disease; (xiii) Lymphatic condition; (xiv) Mental disorder; (xv) Pain; and (xvi) Any disease in which an individual is determined to carry a germline or somatic non-silent mutation in NLRP3.

23. The pharmaceutical composition according to claim 19, for use in the treatment or prevention of a disease, disorder or condition wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

24. The pharmaceutical composition according to claim 19, for use in the treatment or prevention of a disease, disorder or condition selected from the following: (i) Inflammation; (ii) Autoimmune disease; (iii) Cancer; (iv) Infectious disease; (v) Central nervous system disease; (vi) Metabolic disease; (vii) Cardiovascular disease; (viii) Respiratory disease; (ix) Liver disease; (x) Kidney disease; (xi) Eye disease; (xii) Skin disease; (xiii) Lymphatic condition; (xiv) Mental disorder; (xv) Pain; and (xvi) Any disease in which an individual is determined to carry a germline or somatic non-silent mutation in NLRP3.

25. The crystalline salt according to claim 1 or 2, or the polymorphic crystal according to any one of claims 3 to 6, 9 to 12 and 14 to 17, for inhibiting NLRP3.

26. The pharmaceutical composition according to claim 19, for inhibiting NLRP3.

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