Sulcardine salts

Abstract

To provide a solid form of sulcardine salts other than sulfuric acid salts of sulcardine.SOLUTION: There is provided a solid form comprising an acid salt of sulcardine, wherein the acid is ethane-1,2-disulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2- sulfonic acid, hydrochloric acid, or hydrobromic acid.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 798,467, filed January 29, 2019, and U.S. Provisional Application No. 62 / 959,687, filed January 10, 2020, the entire contents of which are incorporated herein by reference.

[0002] Technical Field Provided herein are sulcardine salts, including crystalline sulcardine salts, but excluding sulfate salts of sulcardine. Also provided are pharmaceutical compositions containing the sulcardine salts and methods for treating arrhythmias, comprising administering an effective amount of the sulcardine salt. [Background technology]

[0003] 4-Methoxy-N-(3,5-bis-(1-pyrrolidinylmethyl)-4-hydroxybenzyl)benzenesulfonamide (or N-(4-hydroxy-3,5-bis(pyrrolidin-1-ylmethyl)benzyl)-4-methoxybenzenesulfonamide), also known as sarcardin, and its salts, such as sarcardin sulfate, constitute a group of compounds with potent antiarrhythmic activity. Sarcardin has similar in vitro potency in human atrial cardiomyocytes. Na-Peak , I Na-Late , I Ca,L , and I Kr (and I to and I Kur Sarcardin sulfate is a multi-ion channel blocker that specifically inhibits sarcardin sulfate (and to a lesser extent sarcardin sulfate) and may represent the only example of the antiarrhythmic substituted sulfonamide class. Sarcardin sulfate can be administered intravenously or orally to treat arrhythmias, including supraventricular tachyarrhythmias, premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, and atrial fibrillation. See, e.g., U.S. Patent Nos. 8,541,464 and 8,637,566. The preparation of sarcardin sulfate is reported in U.S. Patent No. 6,605,635.

[0004] Additionally, evidence to date suggests that one advantage of sarcardin and its salts is that they have little significant proarrhythmic potential, as demonstrated in rigorous preclinical safety models, including a conscious post-MI sudden death canine model and a validated ventricular occlusion rabbit model. Furthermore, sarcardin and its salts have been shown to neither significantly elevate the defibrillation threshold nor increase the risk of defibrillation failure in a post-MI canine model, as observed with flecainide. These data suggest that sarcardin and its salts, due to their very low apparent proarrhythmic potential, may be candidates for use in the presence of organic heart disease, prolonged QR syndrome, and ventricular arrhythmias, including premature ventricular contractions (PVCs), ventricular tachycardia (VT), and ventricular fibrillation (VF), or for treating acute and recurrent atrial fibrillation in acute or chronic administration settings, due to their availability for formulation into intravenous and oral administration. Summary of the Invention

[0005] In some embodiments, crystalline salts of salcardin and salt formers other than sulfuric acid are provided. A "salt former" is a compound (e.g., an acid counterion) that can be used to form a salt with salcardin, for example.

[0006] In some embodiments, provided herein is a solid form comprising an acid salt of sarcardin, wherein the acid is ethane-1,2-disulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2-sulfonic acid, hydrochloric acid, or hydrobromic acid. In some embodiments, the solid form is crystalline. In some embodiments, the solid form is amorphous.

[0007] In a further embodiment, a crystalline salt of salcardin and a halide salt former is provided.

[0008] In an additional embodiment, a crystalline salt of salcardin and a sulfonate former is provided.

[0009] In another embodiment, a salt of salcardin and a mononaphthalene salt forming agent is provided.

[0010] In a further embodiment, there are provided salts of sarcardin with naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2-sulfonic acid, hydrochloric acid, or hydrobromic acid.

[0011] In additional embodiments, there are provided crystalline salts of salcardin with naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2-sulfonic acid, hydrochloric acid, or hydrobromic acid.

[0012] In additional embodiments, Forms I and II of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid are provided.

[0013] In a further embodiment, Form I and Form II of the crystalline salt of salcardin and hydrochloric acid are provided.

[0014] In additional embodiments, a monoedisylate salt of sarcardin (mono-ethane-1,2-disulfonic acid salt) is provided. In some embodiments, the monoedisylate salt of sarcardin is a hydrate.

[0015] In other embodiments, a crystalline monoedisylate salt of sarcardin is provided. In additional embodiments, an amorphous monoedisylate salt of sarcardin is provided.

[0016] In yet a further embodiment, Form I and Form II of the crystalline salt of sulcardine monoedisylate are provided.

[0017] In an additional embodiment, a pharmaceutical composition is provided comprising a salcardin salt provided herein, including a crystalline salt, and one or more pharmaceutically acceptable excipients.

[0018] In some embodiments, provided herein are pharmaceutical compositions comprising a solid form provided herein and one or more pharmaceutically acceptable excipients.

[0019] In yet a further embodiment, there is provided a method of treating arrhythmia with the crystalline sarcardin provided herein, comprising a crystalline sarcardin salt, the method comprising administering such a salt to a patient.

[0020] In some embodiments, provided herein are methods of treating arrhythmia, the methods comprising administering to a subject a therapeutically effective amount of a solid form provided herein or a pharmaceutical composition provided herein, in some embodiments, the arrhythmia is atrial fibrillation, supraventricular tachyarrhythmia, ventricular extrasystole, ventricular tachycardia, or ventricular fibrillation. [Brief explanation of the drawings]

[0021] [Figure 1] 1 is a representative XRPD pattern of the crystalline salt of salcardin and naphthalene-1,5-disulfonic acid. [Figure 2] 1 is a representative TG / DTA thermogram of the crystalline salt of salcardin and naphthalene-1,5-disulfonic acid. [Figure 3] 1 is a representative 1H-NMR spectrum of the crystalline salt of salcardin with naphthalene-1,5-disulfonic acid. [Figure 4] 1 is a representative XRPD pattern of amorphous salcardin free base. [Figure 5] 1 is a typical XRPD pattern of naphthalene-1,5-disulfonic acid. [Figure 6] 1 is a representative XRPD pattern of Form I of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid. [Figure 7] 1 is a representative TG / DTA thermogram of Form I of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid. [Figure 8]1 is a representative 1H-NMR spectrum of Form I of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid. [Figure 9] 1 is a representative XRPD pattern of Form II of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid. [Figure 10] 1 is a representative TG / DTA thermogram of Form II of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid. [Figure 11] 1 is a representative 1H-NMR spectrum of Form II of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid. [Figure 12] 1 is a representative XRPD pattern of 1-hydroxy-2-naphthoic acid. [Figure 13] 1 is a representative XRPD pattern of the crystalline salt of salcardin and naphthalene-2-sulfonic acid. [Figure 14] 1 is a representative TG / DTA thermogram of the crystalline salt of salcardin and naphthalene-2-sulfonic acid. [Figure 15] 1 is a representative 1H-NMR spectrum of the crystalline salt of salcardin and naphthalene-2-sulfonic acid. [Figure 16] 1 is a typical XRPD pattern of naphthalene-2-sulfonic acid. [Figure 17] 1 is a representative XRPD pattern of Form I of the crystalline salt of salcardin with hydrochloric acid. [Figure 17A] 1 is a representative XRPD pattern of Form II of the crystalline salt of salcardin with hydrochloric acid. [Figure 18] 1 is a representative TG / DTA thermogram of Form I of the crystalline salt of salcardin with hydrochloric acid. [Figure 18A] 1 is a representative 1H-NMR spectrum of Form I of the crystalline salt of salcardin with hydrochloric acid. [Figure 19] 1 is a representative XRPD pattern of the crystalline salt of salcardin and ethane-1,2-disulfonic acid. [Figure 20]1 is a representative TG / DTA thermogram of the crystalline salt of salcardin with ethane-1,2-disulfonic acid. [Figure 21] 1 is a representative 1H-NMR spectrum of the crystalline salt of salcardin with ethane-1,2-disulfonic acid. [Figure 22] 1 is a typical XRPD pattern of ethane-1,2-disulfonic acid. [Figure 23] 1 is a representative XRPD pattern of the crystalline salt of salcardin with hydrobromic acid. [Figure 24] 1 is a representative TG / DTA thermogram of the crystalline salt of salcardin with hydrobromic acid. [Figure 25] 1 is a representative 1H-NMR spectrum of the crystalline salt of salcardin with hydrobromic acid. [Figure 26] 1 is a representative XRPD pattern of Form I of the monoedisylate salt of sarcardin. [Figure 27] 1 is a representative TG / DTA thermogram of Form I of the monoedisylate salt of sarcardin. [Figure 28] 1 is a representative XRPD pattern of Form II of the monoedisylate salt of sarcardin. [Figure 29] 1 is a representative TG / DTA thermogram of Form II of the monoedisylate salt of sarcardin. [Figure 30] 1 is a representative 1H-NMR spectrum of Form I of the monoedisylate salt of sarcardin. [Figure 31] 1 is a representative 1H-NMR spectrum of Form II of the monoedisylate salt of sarcardin. [Figure 32] 1 is an XRPD stack plot from Example 17. [Figure 33] 1 is an XRPD stack plot from Example 17. [Figure 34] 1 is an XRPD stack plot from Example 18. [Figure 35] 1 is an XRPD stack plot from Example 18. [Figure 36]A schematic representation of sarcardin 1-hydroxy-2-naphthoate is superimposed on the asymmetric unit encompassing one complete sarcardin 1-hydroxy-2-naphthoate formula unit. All non-hydrogen atoms are shown as thermal displacement ellipsoids set at a probability level of 50%. [Figure 37A] 1 is a representative FT-IR spectrum of Form I of the monoedisylate salt of sarcardin. [Figure 37B] 1 is a representative FT-IR spectrum of Form II of the monoedisylate salt of sarcardin. [Figure 37C] 1 shows a representative FT-IR spectrum overlay of both Form I and Form II of the monoedisylate salt of sarcardin. [Figure 38A] 1 shows plasma salcardin concentrations after a single oral dose of salcardin sulfate. [Figure 38B] 1 shows plasma sarcardin concentrations after a single oral dose of sarcardin monoedisylate. DETAILED DESCRIPTION OF THE INVENTION

[0022] The chemical name of sarcardin is 4-methoxy-N-(3,5-bis-(1-pyrrolidinylmethyl)-4-hydroxybenzyl)benzenesulfonamide (or N-(4-hydroxy-3,5-bis(pyrrolidin-1-ylmethyl)benzyl)-4-methoxybenzenesulfonamide) and has the following structure:

[0023] [ka]

[0024] Salcardin sulfate has the following structure:

[0025] [ka]

[0026] Salcardin sulfate can exist in hydrated forms. One such form is the trihydrate.

[0027] As used herein, unless otherwise specified, the term "crystalline form" and related terms refer to a solid form that is crystalline. In certain embodiments, a sample containing a salcardin solid form, such as the crystalline forms provided herein, may be substantially free of other solid forms, such as amorphous forms and / or other crystalline forms. In certain embodiments, a sample containing such a crystalline form of a salcardin salt provided herein may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of one or more other solid forms of the salcardin salt, such as amorphous forms and / or other crystalline forms. In certain embodiments, the crystalline forms of the salcardin salt provided herein may be physically and / or chemically pure. In certain embodiments, the crystalline forms of the salcardin salts provided herein may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure.

[0028] As used herein, unless otherwise specified, the terms "amorphous," "amorphous form," and related terms herein mean that the subject material, component, or product is substantially free of crystallinity as determined by X-ray diffraction. Such X-ray diffraction patterns often exhibit what is referred to as an "amorphous halo," as seen, for example, in Figure 4.

[0029] In some embodiments, the present disclosure provides salts formed from salcardin free base and an acid. These acids may be organic or inorganic. Some salts formed from salcardin and the acid are polymorphic. Various techniques can be used to demonstrate the formation of a salt of salcardin and an acid. For example, the salt solid can be analyzed by x-ray powder diffraction; if the pattern differs from the x-ray powder diffraction pattern for the component materials, a new composition has been formed. The pKa values ​​of the acid counterions listed below are greater than three units of the pKa value of the most strongly basic free base salcardin. Table 1 shows the pKa values ​​of free base salcardin for the salts identified in this disclosure.

[0030] [Table 1]

[0031] In each of the salt procedures, the free base of salcardin was used to make the corresponding salt. The free base of salcardin is amorphous, and a representative pattern can be seen in Figure 4. The x-ray powder diffraction patterns of the corresponding free acids have crystalline patterns, and the XRPD patterns of the salts all differ from the sum of the corresponding free acids and amorphous salcardin. Thus, the solids reported herein are not physical mixtures of amorphous salcardin and the corresponding acids. Indeed, the XRPD and pKa data indicate that the resulting solids are the salts detailed herein.

[0032] A screen was conducted to identify crystalline salts of salcardin. More than 25 potential salt formers were analyzed in numerous solvents and solvent systems. In most cases, crystalline salts were not formed, or the crystalline salts were unstable under storage conditions, such as 40°C and 75% RH. In contrast, salts made from the salt formers in Table 1 formed crystalline salts and were stable under the conditions provided herein, such as 40°C and 75% RH. A "salt former" is a compound that can be used to form a salt, for example, with salcardin. In many embodiments, the salt former is an acid. In addition to the salt screen, a polymorph screen was conducted on some of the identified salts.

[0033] For crystalline salts, a technique commonly used to characterize such crystalline salts is x-ray powder diffraction ("XRPD"). An XRPD pattern is an xy graph, with °2Θ (diffraction angle) on the x-axis and intensity on the y-axis. This pattern contains peaks that can be used to characterize the salt or other solid form. The peaks are typically represented and referenced by their position on the x-axis rather than their intensity on the y-axis, as peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is not typically used by those skilled in the art to characterize crystalline salts or other solid forms.

[0034] The XRPD pattern output from a diffractometer may be used to characterize a crystalline salt. However, a smaller subset of such data may also be, and generally is, appropriate for characterizing a crystalline salt. For example, a set of one or more peaks from such a pattern may be used to characterize a crystalline salt. In fact, a single XRPD peak may be used to characterize a crystalline salt. When a crystalline salt herein is characterized by "one or more peaks" in an XRPD pattern, and such peaks are listed, this means that any combination of the listed peaks can be used to characterize the crystalline salt. Furthermore, the presence of other peaks in an XRPD pattern does not negate or otherwise limit the characterization.

[0035] Other data may be used to characterize crystalline salts, either alone or in combination with XRPD data. For example, melting point is often used to characterize crystalline salts. In some embodiments, differential thermal analysis (DTA) is used to identify the melting onset behavior of some crystalline salts. Such onset may be characteristic of a particular crystalline salt. In some cases, melting is not observed below the temperature at which decomposition occurs. In some embodiments, infrared spectral (IR) data may be used to characterize crystalline salts, either alone or in combination with other solid state data, such as XRPD data.

[0036] Like any data measurement, x-ray powder diffraction exhibits variability. In addition to variability in peak intensity, there is also variability in peak position along the x-axis. However, this variability can generally be addressed when reporting peak positions for characterization purposes. Such variability in peak position along the x-axis derives from a variety of sources. One arises from sample preparation. Samples of the same crystalline material prepared under different conditions may result in slightly different diffractograms. Factors such as particle size, water content, solvent content, and orientation can all affect how a sample diffracts x-rays. Another source of variability comes from instrument parameters. Different x-ray machines operate using different parameters, which can result in slightly different diffraction patterns from the same crystalline morphology. Similarly, different software packages process x-ray data in different ways, which also introduces variability. These and other sources of variability are known to those skilled in the pharmaceutical arts. Due to these sources of variation, it is common to list x-ray diffraction peaks using "about," "approximately," or other similar terms before the peak value in °2Θ, where data are presented within 0.1 or 0.2 °2Θ of the stated peak value, as appropriate. Unless otherwise specified, x-ray powder diffraction peaks provided herein are reported to have a variation of about ±0.2 degrees °2Θ, and are intended to be reported with such variation with or without the presence of "about," "approximately," or other similar terms. Variation also exists in thermal measurements, such as DTA, and may be indicative of sample purity. For DTA, typical measurement variation is about ±1°C.

[0037] For IR data, unless otherwise stated, IR peaks provided herein are approximately ±2 cm -1 and are intended to be reported with a variation of about, approximately, or other similar terminology.

[0038] Characterization data that "match" data for a reference solid form will be understood by those skilled in the art to correspond to the same solid form as the reference solid form. In analyzing whether data "match," those skilled in the art will understand that specific characterization data points may vary to a reasonable extent while describing a given solid form due, for example, to experimental error and routine sample-to-sample analysis.

[0039] In various embodiments, salts of salcardin and a mononaphthalene salt former are provided. A mononaphthalene salt former is one in which the former includes a single naphthalene moiety as a substituent. In some of these embodiments, the mononaphthalene salt former includes one or more sulfonic acid moieties, for example, one or two sulfonic acid moieties. When two sulfonic acid moieties are present, they may be on the same ring or different rings of the naphthalene group.

[0040] The mononaphthalene salt forming agent may be an organic acid, such as a carboxylic acid, which may be further substituted, for example, on the naphthalene group. Examples of substituents include hydroxyl groups. In some embodiments, the hydroxyl is ortho to the organic acid group when substituted with a hydroxyl group.

[0041] In some embodiments, crystalline salts of salcardin are provided. For example, crystalline salts of salcardin with a salt former other than sulfuric acid are provided. In other embodiments, crystalline salts of salcardin with an organic sulfonic acid are provided. Such sulfonic acids may be aromatic or aliphatic, each of which may be substituted or unsubstituted. An example of a substituent is hydroxyl. In other embodiments, crystalline salts of inorganic acids other than sulfuric acid are provided. For example, the present disclosure includes crystalline salts of salcardin with halides.

[0042] In another embodiment, there is provided a crystalline salt of sarcardin and an aromatic carboxylic acid. The aromatic moiety may be a naphthyl moiety, which may be further substituted with, for example, a hydroxyl group.

[0043] In some embodiments, a solid form is provided comprising an acid salt of salcardin, wherein the acid includes a single naphthalene moiety and one or more sulfonic acid moieties, carboxylic acid moieties, halogen acids, or ethane-1,2-disulfonic acid.

[0044] In some embodiments, the acid is an acid that includes a single naphthalene moiety and one or more sulfonic or carboxylic acid moieties. In some embodiments, the acid includes a single naphthalene moiety and one or more (e.g., one or two) sulfonic acid moieties. In some embodiments, the acid includes a single naphthalene moiety and one or more (e.g., one or two) carboxylic acid moieties. In some embodiments, the naphthalene moiety is directly substituted with a sulfonic or carboxylic acid moiety. In some embodiments, the naphthalene moiety is further substituted. In some embodiments, the naphthalene moiety is further substituted with a hydroxyl. In some embodiments, the acid is naphthalene-1,5-disulfonic acid. In some embodiments, the acid is 1-hydroxy-2-naphthoic acid. In some embodiments, the acid is naphthalene-2-sulfonic acid.

[0045] In some embodiments, the acid is a halide, in some embodiments, the acid is hydrochloric acid, in some embodiments, the acid is hydrobromic acid.

[0046] In some embodiments, the acid is ethane-1,2-disulfonic acid, also referred to herein as 1,2-ethanedisulfonic acid, which, when combined with sarcardin, can be referred to as an edisylate salt, such as a monoedisylate or hemiedisylate salt of sarcardin.

[0047] 1. Salcardin naphthalene-1,5-disulfonate In one embodiment, provided herein is a naphthalene-1,5-disulfonic acid salt of sarcardin. In some embodiments, the salt is crystalline.

[0048] In some embodiments, the molar ratio of salcardin to naphthalene-1,5-disulfonic acid in the salt is about 1: 1. In some embodiments, the salt is a mono-naphthalene-1,5-disulfonic acid salt of salcardin.

[0049] A representative XRPD pattern of the naphthalene-1,5-disulfonate salt of salcardin is shown in FIG.

[0050] In some embodiments, provided herein is a solid form comprising a naphthalene-1,5-disulfonate salt of salcardin, characterized in that one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or all of the peaks are at approximately 4.9, 9.0, 10.4, 11.3, 11.7, 12.3, 12.6, 14.1, 14.9, 15.9, 16.4, 18.0, 18.5, 19.0, 20.1, 21.0, 21.5, 22.8, 23.6, 24.8, and 26.3°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by seven peaks. In some embodiments, the solid form is characterized by 9 peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0051] In some embodiments, provided herein is a solid form comprising the naphthalene-1,5-disulfonate salt of salcardin, characterized by an XRPD pattern comprising peaks at about 14.9, 15.9, and 23.6 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 4.9 and 10.4 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 11.3, 12.3, and 19.0 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 4.9, 9.0, 10.4, 11.3, 11.7, 12.3, 14.1, 14.9, 15.9, 18.0, 19.0, 22.8, and 23.6 °2Θ.

[0052] In some embodiments, provided herein is a solid form comprising the naphthalene-1,5-disulfonic acid salt of salcardin, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0053] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0054] A representative TG / DTA thermogram for a naphthalene-1,5-disulfonate salt of salcardin is shown in Figure 2. In some embodiments, provided herein is a solid form comprising a naphthalene-1,5-disulfonate salt of salcardin, the solid form exhibiting a weight loss of about 0.6% upon heating from about 25°C to about 200°C. In some embodiments, provided herein is a solid form comprising a naphthalene-1,5-disulfonate salt of salcardin, characterized by a TG thermogram that matches the TG thermogram presented in Figure 2.

[0055] In some embodiments, provided herein is a solid form comprising a naphthalene-1,5-disulfonate salt of salcardin, the solid form exhibiting a thermal event as characterized by DTA with an onset temperature of about 244°C. In some embodiments, further, the peak temperature of the thermal event is about 249°C. In some embodiments, the thermal event corresponds to melting of the solid form, without being bound by any particular theory. In some embodiments, provided herein is a solid form comprising a naphthalene-1,5-disulfonate salt of salcardin, characterized by a DTA thermogram consistent with the DTA thermogram presented in Figure 2.

[0056] In some embodiments, provided herein is a solid form comprising a naphthalene-1,5-disulfonate salt of salcardin, the solid form exhibiting a mass increase of about 3.3% when the relative humidity (RH) is increased from about 5% to about 95%.

[0057] In some embodiments, the naphthalene-1,5-disulfonate salt of salcardin is prepared by combining salcardin and naphthalene-1,5-disulfonate (e.g., in about a 1:1 molar ratio) in a solvent (e.g., acetone) and subjecting the mixture to a temperature cycle (e.g., from about 5°C to about 25°C) for a period of time (e.g., about 72 hours). In other embodiments, the temperature cycle is from ambient temperature to about 40°C.

[0058] In some embodiments, a crystalline salt of salcardin and naphthalene-1,5-disulfonic acid is provided. Preparation of the crystalline salt of salcardin and naphthalene-1,5-disulfonic acid is shown in Example 4, and its large-scale preparation is described in Example 5. The crystalline salt of salcardin and naphthalene-1,5-disulfonic acid may be characterized by an XRPD pattern including a peak at about 4.9°2Θ. Additionally, the crystalline salt of salcardin and naphthalene-1,5-disulfonic acid may be characterized by an XRPD pattern including one or more peaks selected from about 4.9°2Θ, about 10.4°2Θ, about 11.7°2Θ, about 12.3°2Θ, and about 15.9°2Θ. Furthermore, an XRPD pattern substantially similar to FIG. 1 (obtained from Example 5) may be used to characterize the crystalline salt of salcardin and naphthalene-1,5-disulfonic acid. A peak list corresponding to many of the peaks in Figure 1 is shown in Table 2.

[0059] [Table 2]

[0060] Many embodiments of the crystalline salt of salcardin and naphthalene-1,5-disulfonic acid are characterized by an onset melting point of about 244° C. ( FIG. 2 ). This melting point can be used alone or in combination with XRPD data to characterize the aforementioned crystalline salt of salcardin and naphthalene-1,5-disulfonic acid. Thus, in some embodiments, the crystalline salt of salcardin and naphthalene-1,5-disulfonic acid may be characterized by an onset melting point of about 244° C., as well as (a) an XRPD pattern including a peak at about 4.9° 2Θ, (b) an XRPD pattern including one or more peaks selected from about 4.9° 2Θ, about 10.4° 2Θ, about 11.7° 2Θ, about 12.3° 2Θ, and about 15.9° 2Θ, or (c) an XRPD pattern substantially similar to FIG. 1.

[0061] Dynamic vapor sorption ("DVS") experiments showed that the salt prepared according to Example 5 took up approximately 3.3% water at 90% relative humidity ("RH"). The crystalline morphology of the salt was the same before and after the DVS experiment, although at 60% RH, there may have been a morphological change that, if any, reversed at the end of the DVS experiment. Under stability conditions of 40°C and 5% RH exposure for one week, the salt remained unchanged by XRPD. Furthermore, it remained unchanged after one week at 80°C and ambient RH, nor after one week under ambient light conditions by XRPD. HPLC measurements performed after these stability experiments showed that purity remained unchanged under these conditions (99% before and 99% after the one-week stability study). However, a decrease in crystallinity was observed upon exposure to ambient light. Without being bound by theory, it is believed that the observed decrease in crystallinity was due to insufficient sample in the XRPD plate of the XRPD instrument, and not a true loss of crystallinity in the sample.

[0062] For all stability studies under 40°C and 75% RH conditions provided herein, samples were placed in unsealed vials and stored in a stability chamber set at 40°C / 75% RH. For studies at 80°C, samples were placed in sealed vials and placed in an oven set at 80°C. For studies in ambient light, samples were placed in sealed vials and placed on a laboratory windowsill, exposed to ambient natural and artificial light.

[0063] The solubilities of the crystalline salts of naphthalene-1,5-disulfonic acid of Example 5 are shown below in Table 3 and were measured according to the procedure of Example 3. In this table, it can be seen that the solubility is low at acidic pH but increases as the pH becomes more basic than neutral.

[0064] [Table 3]

[0065] The XRPD pattern of the crystalline salt of salcardin and naphthalene-1,5-disulfonic acid is not a linear combination of the XRPD patterns of salcardin free base and the starting material naphthalene-1,5-disulfonic acid. For example, the peak at approximately 10.4°2Θ in the salt is absent in the XRPD pattern of naphthalene-1,5-disulfonic acid, as seen in Figure 5, and the XRPD pattern of salcardin free base is also absent. Therefore, the XRPD pattern in Figure 1 is not a linear combination of the starting materials of the salt.

[0066] Furthermore, the unique XRPD diffractogram and DTA melting event confirmed the formation of a new solid form. 1 The H-NMR spectrum showed the presence of counterion stoichiometry and possible peak shifts when compared to the free base, confirming that the material was a salt and not a new polymorph or solvate / hydrate of the individual components.

[0067] All combinations of the above embodiments are encompassed by this application.

[0068] 2. 1-Hydroxy-2-naphthoate Form I of Salcardin In one embodiment, provided herein is Form I of the 1-hydroxy-2-naphthoic acid salt of sarcardin. In some embodiments, the salt is crystalline.

[0069] In some embodiments, the molar ratio of salcardin to 1-hydroxy-2-naphthoic acid in the salt is about 1: 1. In some embodiments, the salt is salcardin mono-1-hydroxy-2-naphthoic acid salt.

[0070] A representative XRPD pattern of Form I of the 1-hydroxy-2-naphthoic acid salt of sarcardin is shown in FIG.

[0071] In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoate salt of sarcardin, characterized in that 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all of the peaks are at approximately 3.4, 6.7, 6.9, 10.0, 10.1, 13.8, 15.4, 15.9, 16.8, 17.3, 18.0, 18.6, 18.9, 19.8, 20.0, 20.3, 20.8, 21.8, and 23.5°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by seven peaks. In some embodiments, the solid form is characterized by nine peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0072] In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoate salt of salcardin, characterized by an XRPD pattern comprising peaks at about 16.8, 18.6, and 18.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 6.7 and 6.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 13.8, 20.3, and 20.8 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 3.4, 6.7, 6.9, 13.8, 15.4, 16.8, 17.3, 18.0, 18.6, 18.9, 20.3, 20.8, and 23.5 °2Θ.

[0073] In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoate salt of salcardin, characterized by an XRPD pattern comprising peaks at about 6.7, 6.9, and 16.8°2Θ. In some embodiments, the XRPD pattern further comprises a peak at about 18.9°2Θ.

[0074] In some embodiments, provided herein is a solid form comprising the 1-hydroxy-2-naphthoate salt of salcardin, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0075] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0076] A representative TG / DTA thermogram for Form I of 1-hydroxy-2-naphthoic acid salt of salcardin is shown in Figure 7. In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoic acid salt of salcardin, the solid form exhibiting a weight loss of about 3.5% upon heating from about 25°C to about 150°C. In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoic acid salt of salcardin, characterized by a TG thermogram that matches the TG thermogram presented in Figure 7.

[0077] In some embodiments, provided herein is a solid form comprising a 1-hydroxy-2-naphthoate salt of salcardin, the solid form exhibiting a thermal event with an onset temperature of about 161°C as characterized by DTA. In some embodiments, further, the peak temperature of the thermal event is about 163°C. In some embodiments, the thermal event corresponds to melting of the solid form, without being bound by any particular theory. In some embodiments, provided herein is a solid form comprising a 1-hydroxy-2-naphthoate salt of salcardin, characterized by a DTA thermogram consistent with the DTA thermogram presented in Figure 7.

[0078] In some embodiments, Form I of the 1-hydroxy-2-naphthoic acid salt of salcardin is prepared by combining salcardin and 1-hydroxy-2-naphthoic acid (e.g., in a molar ratio of about 1:1) in a solvent (e.g., ethyl acetate) and subjecting the mixture to temperature cycling (e.g., between ambient temperature and 40°C) for a period of time (e.g., about 72 hours).

[0079] In some embodiments, a crystalline salt of sarcardin and 1-hydroxy-2-naphthoic acid is provided. In some embodiments, Form I of crystalline sarcardin 1-hydroxy-2-naphthoic acid is provided. The preparation of Form I of sarcardin 1-hydroxy-2-naphthoic acid salt is described in Example 6. Form I of crystalline sarcardin 1-hydroxy-2-naphthoic acid salt may be characterized by an XRPD pattern including one or more x-ray powder diffraction peaks selected from about 3.4°2Θ, about 6.7°2Θ, about 6.9°2Θ, and about 15.4°2Θ. In other embodiments, Form I of crystalline sarcardin 1-hydroxy-2-naphthoic acid salt may be characterized by an XRPD pattern including peaks selected from about 3.4°2Θ, about 6.7°2Θ, and about 6.9°2Θ. An XRPD pattern including a peak at about 3.4°2Θ and two peaks between about 6.5°2Θ and 7.1°2Θ can be used to characterize Form I of crystalline 1-hydroxy-2-naphthoate of salcardin. An XRPD pattern including a peak at about 3.4°2Θ can be used to characterize Form I of crystalline 1-hydroxy-2-naphthoate of salcardin, because a peak at that angle is not present in Form II of crystalline 1-hydroxy-2-naphthoate of salcardin. Similarly, an XRPD pattern including any of peaks at about 6.7°2Θ, about 6.9°2Θ, and about 15.4°2Θ can be used to characterize Form I of crystalline 1-hydroxy-2-naphthoate of salcardin. Form I of crystalline 1-hydroxy-2-naphthoate of salcardin may be characterized by an XRPD pattern substantially similar to that shown in FIG. 6. A peak list corresponding to many of the peaks in Figure 6 is shown in Table 4.

[0080] [Table 4]

[0081] Form I of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid may be characterized by an onset melting temperature of about 161° C. This melting point can be used alone or in combination with XRPD data to characterize Form I of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid. Thus, Form I of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid may be characterized by an onset melting point of about 161°C, as well as (a) an XRPD pattern including one or more peaks selected from 3.4°2Θ, about 6.7°2Θ, about 6.9°2Θ, and 15.4°2Θ; (b) an XRPD pattern including one or more peaks selected from about 3.4°2Θ, about 6.7°2Θ, and about 6.9°2Θ; (c) an XRPD pattern including a peak at about 3.4°2Θ and two peaks between about 6.5°2Θ and about 7.1°2Θ; or (d) an XRPD pattern substantially similar to Figure 6.

[0082] All combinations of the above embodiments are encompassed by this application.

[0083] 3. 1-Hydroxy-2-naphthoate Form II of Salcardin In one embodiment, provided herein is Form II of the 1-hydroxy-2-naphthoic acid salt of sarcardin. In some embodiments, the salt is crystalline.

[0084] In some embodiments, the molar ratio of salcardin to 1-hydroxy-2-naphthoic acid in the salt is about 1: 1. In some embodiments, the salt is salcardin mono-1-hydroxy-2-naphthoic acid salt.

[0085] A representative XRPD pattern of Form II of the 1-hydroxy-2-naphthoic acid salt of sarcardin is shown in FIG.

[0086] In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoate salt of sarcardin, characterized in that 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or all of the peaks are at approximately 5.8, 8.8, 10.1, 10.6, 12.1, 12.4, 13.8, 14.3, 14.6, 17.6, 17.8, 18.0, 18.6, 19.5, 19.9, 20.6, 21.4, 22.2, 25.3, 26.0, 27.6, and 28.2°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by 7 peaks. In some embodiments, the solid form is characterized by 9 peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0087] In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoate salt of salcardin, characterized by an XRPD pattern comprising peaks at about 5.8, 18.6, and 19.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 10.6, 17.8, and 21.4 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 20.6 and 25.3 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 5.8, 8.8, 10.6, 17.6, 17.8, 18.0, 18.6, 19.9, 20.6, 21.4, 25.3, and 28.2 °2Θ.

[0088] In some embodiments, provided herein is a solid form comprising the 1-hydroxy-2-naphthoate salt of salcardin, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0089] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0090] A representative TG / DTA thermogram for Form II of 1-hydroxy-2-naphthoic acid salt of salcardin is shown in Figure 10. In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoic acid salt of salcardin, the solid form exhibiting a weight loss of about 0.1% upon heating from about 25°C to about 150°C. In some embodiments, provided herein is a solid form comprising 1-hydroxy-2-naphthoic acid salt of salcardin, characterized by a TG thermogram that matches the TG thermogram presented in Figure 10.

[0091] In some embodiments, provided herein is a solid form comprising a 1-hydroxy-2-naphthoate salt of salcardin, the solid form exhibiting a thermal event with an onset temperature of about 168°C as characterized by DTA. In some embodiments, further, the peak temperature of the thermal event is about 170°C. In some embodiments, the thermal event corresponds to melting of the solid form, without being bound by any particular theory. In some embodiments, provided herein is a solid form comprising a 1-hydroxy-2-naphthoate salt of salcardin, characterized by a DTA thermogram consistent with the DTA thermogram presented in Figure 10.

[0092] In some embodiments, provided herein is a solid form comprising a 1-hydroxy-2-naphthoate salt of salcardin, the solid form exhibiting a mass increase of about 0.7% when the relative humidity (RH) is increased from about 10% to about 90%.

[0093] In some embodiments, Form II of 1-hydroxy-2-naphthoic acid salt of sarcardin has unit cell dimensions of approximately a=10.2 Å, b=29.9 Å, c=10.8 Å, α=90°, β=103.4°, and γ=90°. In some embodiments, Form II of 1-hydroxy-2-naphthoic acid salt of sarcardin has unit cell dimensions of approximately a=10.2 Å, b=29.92 Å, c=10.84 Å, α=90°, β=103.38°, and γ=90°. In some embodiments, Form II of 1-hydroxy-2-naphthoic acid salt of sarcardin has unit cell dimensions of approximately a=10.244 Å, b=29.917 Å, c=10.841 Å, α=90°, β=103.375°, and γ=90°. In some embodiments, Form II of 1-hydroxy-2-naphthoic acid salt of sarcardin has unit cell dimensions of approximately a=10.2443 Å, b=29.9171 Å, c=10.8406 Å, α=90°, β=103.375°, and γ=90°. In some embodiments, Form II of 1-hydroxy-2-naphthoic acid salt of sarcardin has a unit cell of the P21 / n space group. In some embodiments, Form II of 1-hydroxy-2-naphthoic acid salt of sarcardin has a unit cell of approximately 3232.31 Å. 3 / cell capacity. In some embodiments, Form II of the 1-hydroxy-2-naphthoate salt of sarcardin has a Z value of 4. In some embodiments, Form II of the 1-hydroxy-2-naphthoate salt of sarcardin has a Z' value of 1.

[0094] In some embodiments, Form II of the 1-hydroxy-2-naphthoic acid salt of sarcardin is prepared by subjecting a mixture of sarcardin and 1-hydroxy-2-naphthoic acid (e.g., in about a 1:1 molar ratio) in a solvent (e.g., toluene) to temperature cycling (e.g., between about 5°C and about 25°C) for a period of time (e.g., about 72 hours). In other embodiments, the temperature cycling is from ambient temperature to about 40°C.

[0095] In some embodiments, Form II of the crystalline salt of sarcardin and 1-hydroxy-2-naphthoic acid is prepared. The preparation of Form II of the crystalline salt of sarcardin and 1-hydroxy-2-naphthoic acid is described in Example 7, and a scaled-up example is provided in Example 8. Form II of the crystalline salt of sarcardin and 1-hydroxy-2-naphthoic acid may be characterized by an XRPD pattern including one or more peaks selected from about 5.8°2Θ and about 8.8°2Θ. None of these peaks are present in Form I of the crystalline salt of sarcardin and 1-hydroxy-2-naphthoic acid. Form II may further be characterized by an XRPD pattern including peaks at about 5.8°2Θ and 8.8°2Θ. Additionally, an XRPD pattern substantially similar to that shown in Figure 9 can be used to characterize Form II of the crystalline salt of sarcardin and 1-hydroxy-2-naphthoic acid. A peak list corresponding to many of the peaks in Figure 9 is provided in Table 5.

[0096] [Table 5]

[0097] Form II may be characterized by an onset melting temperature of about 168° C. (FIG. 10A). Form II may be further characterized by an onset melting temperature of about 168° C. along with (a) an XRPD pattern comprising one or more peaks selected from about 5.8° 2Θ and about 8.8° 2Θ, or (b) an XRPD pattern substantially similar to FIG. 9.

[0098] DVS experiments showed that the salt prepared according to Example 9 picked up approximately 0.7% water at 90% RH. The crystalline morphology of the salt was the same before and after the DVS experiments. Under stability conditions of 40°C and 75% RH for one week, the salt remained unchanged by XRPD. Furthermore, after one week at 80°C and ambient humidity, it remained unchanged under ambient light conditions by XRPD. HPLC measurements performed after these stability experiments showed that the purity remained unchanged under these conditions (99% before and 99% after the one-week stability study).

[0099] Table 6 shows a representative XRPD pattern of Form II of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid. The solubility decreases from 16.8 mg / mL to 0.2 mg / mL as the pH increases from 1.2 to 7.4. However, the material loses crystallinity at pH 1.2.

[0100] [Table 6]

[0101] The XRPD patterns of the various polymorphs of the crystalline salt of salcardin with 1-hydroxy-2-naphthoic acid are not linear combinations of the XRPD patterns of salcardin free base and 1-hydroxy-2-naphthoic acid. For example, Form I has a peak at approximately 6.9° 2Θ, and Form II has a peak at approximately 8.8° 2Θ. Such peaks are absent in the XRPD pattern of 1-hydroxy-2-naphthoic acid, as seen in Figure 12, and the XRPD pattern of salcardin free base is completely absent. Thus, the XRPD patterns in Figures 6 and 9 are not linear combinations of the starting salts.

[0102] Furthermore, the unique XRPD diffractogram and DTA melting event confirmed the formation of a new solid form. 1 The H-NMR spectrum showed the presence of counterion stoichiometry and possible peak shifts when compared to the free base, confirming that the material was a salt and not a new polymorph or solvate / hydrate of the individual components.

[0103] All combinations of the above embodiments are encompassed by this application.

[0104] 4. Salcardin Naphthalene-2-sulfonate In one embodiment, provided herein is a naphthalene-2-sulfonate salt of sarcardin. In some embodiments, the salt is crystalline.

[0105] In some embodiments, the molar ratio of salcardin to naphthalene-2-sulfonic acid in the salt is about 1: 1. In some embodiments, the salt is a mono-naphthalene-2-sulfonic acid salt of salcardin.

[0106] A representative XRPD pattern of the naphthalene-2-sulfonate salt of salcardin is shown in FIG.

[0107] In some embodiments, provided herein is a solid form comprising a naphthalene-2-sulfonate salt of salcardin, characterized in that one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of the peaks are at approximately 59.4, 10.6, 13.3, 13.5, 15.1, 16.6, 16.9, 17.2, 17.7, 17.8, 18.5, 18.9, 19.4, 19.7, 20.2, 21.3, 21.7, 22.8, 23.3, 24.8, 26.1, and 26.8°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by 7 peaks. In some embodiments, the solid form is characterized by 9 peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0108] In some embodiments, provided herein is a solid form comprising a naphthalene-2-sulfonate salt of salcardin, characterized by an XRPD pattern comprising peaks at about 17.2, 17.8, and 21.3 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 13.3, 13.5, 16.6, and 16.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 9.4 and 10.6 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 9.4, 10.6, 13.3, 13.5, 16.6, 16.9, 17.2, 17.7, 17.8, 19.7, 20.2, 21.3, and 24.8 °2Θ.

[0109] In some embodiments, provided herein is a solid form comprising the naphthalene-2-sulfonate salt of salcardin, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0110] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0111] A representative TG / DTA thermogram for a naphthalene-2-sulfonate salt of salcardin is shown in Figure 14. In some embodiments, provided herein is a solid form comprising a naphthalene-2-sulfonate salt of salcardin, the solid form exhibiting a weight loss of about 2.4% upon heating from about 25°C to about 60°C. In some embodiments, without being bound by theory, this weight loss corresponds to a loss of water. In some embodiments, provided herein is a solid form comprising a naphthalene-2-sulfonate salt of salcardin, characterized by a TG thermogram consistent with the TG thermogram presented in Figure 14.

[0112] In some embodiments, provided herein is a solid form comprising a naphthalene-2-sulfonate salt of salcardin, the solid form exhibiting a thermal event with an onset temperature of about 88°C as characterized by DTA. In some embodiments, further, the peak temperature of the thermal event is about 99°C. In some embodiments, the thermal event corresponds to melting of the solid form, without being bound by any particular theory. In some embodiments, provided herein is a solid form comprising a naphthalene-2-sulfonate salt of salcardin, characterized by a DTA thermogram consistent with the DTA thermogram presented in Figure 14.

[0113] In some embodiments, provided herein is a solid form comprising a naphthalene-2-sulfonate salt of salcardin, the solid form exhibiting a mass increase of about 0.8% when the relative humidity (RH) is increased from about 10% to about 90%.

[0114] In some embodiments, salcardin naphthalene-2-sulfonate is prepared by combining salcardin and naphthalene-2-sulfonate (e.g., in about a 1:1 molar ratio) in a solvent (e.g., ethyl acetate) and subjecting the mixture to a temperature cycle (e.g., from about 5°C to about 25°C) over a period of time (e.g., about 72 hours). In other embodiments, the temperature cycle is from ambient temperature to about 40°C.

[0115] In another embodiment, a crystalline salt of salcardin and naphthalene-2-sulfonic acid is provided. The preparation of the crystalline salt of salcardin and naphthalene-2-sulfonic acid is shown in Example 9, and its scaled-up preparation is shown in Example 10. This salt may be characterized by an XRPD pattern comprising one or more peaks selected from about 9.4°2Θ, about 10.6°2Θ, about 13.3°2Θ, about 13.5°2Θ, about 16.6°2Θ, about 16.9°2Θ, and about 17.2°2Θ. The salt may further be characterized by an XRPD pattern comprising peaks selected from about 9.4°2Θ, about 10.6°2Θ, and about 13.5°2Θ. Additionally, the salt may be further characterized by an XRPD pattern including two peaks between about 13.1°2Θ and about 13.7°2Θ, and three peaks between about 16.4°2Θ and about 17.4°2Θ. Figure 13 can be used to characterize the crystalline salt of salcardin and naphthalene-2-sulfonic acid. A peak list corresponding to many of the peaks in Figure 13 is provided in Table 7.

[0116] [Table 7]

[0117] The crystalline salt of salcardin and naphthalene-2-sulfonic acid may be characterized by an onset melting temperature of about 88°C (Figure 14). The crystalline salt may be characterized by an onset melting temperature of about 88°C, as well as (a) an XRPD pattern including one or more peaks selected from about 9.4°2Θ, about 10.6°2Θ, about 13.3°2Θ, about 13.5°2Θ, about 16.6°2Θ, about 16.9°2Θ, and 17.2°2Θ; (b) an XRPD pattern including peaks selected from about 9.4°2Θ, about 10.6°2Θ, and about 13.5°2Θ; (c) an XRPD pattern including two peaks between about 13.1°2Θ and about 13.7°2Θ and three peaks between about 16.4°2Θ and about 17.4°2Θ; or (d) an XRPD pattern substantially similar to Figure 13.

[0118] The TG / DTA experiment in Figure 14 showed a weight loss of 2.4%, corresponding to approximately 0.91 equivalents of water, which is consistent with hydrate formation. Thus, the crystalline salt prepared according to Example 10 forms a hydrate of the crystalline salt of, for example, salcardin and naphthalene-2-sulfonic acid.

[0119] In DVS experiments, the salt prepared according to Example 10 took up approximately 0.8% water between 10 and 90% RH, and the material is expected to dehydrate below 10% RH. The crystalline morphology of the salt was the same before and after the DVS experiment. Under stability conditions of one week of exposure at 40°C and 5% RH, the salt remained unchanged by XRPD. After one week at 80°C and ambient humidity, the salt transformed into an orange gel. After one week under ambient light conditions, the material remained unchanged by XRPD but turned pale yellow. HPLC analysis performed after these stability experiments showed a decrease in purity from 99% to 98% after one week at 40°C and 75% RH, a decrease to 90% after one week at 80°C, and a decrease to 97% after one week under ambient light conditions.

[0120] The XRPD pattern of the crystalline salt of salcardin and naphthalene-2-sulfonic acid is not a linear combination of the XRPD patterns of salcardin free base and naphthalene-2-sulfonic acid. For example, a peak for naphthalene-2-sulfonic acid at approximately 5°2Θ can be seen in Figure 16. No such peak is present in Figure 13, and is absent in the XRPD pattern of salcardin free base. Thus, the XRPD pattern in Figure 13 is not a linear combination of the starting salt materials.

[0121] Furthermore, the unique XRPD diffractogram and DTA melting event confirmed the formation of a new solid form. 1 The H-NMR spectrum showed the presence of counterion stoichiometry and possible peak shifts when compared to the free base, confirming that the material was a salt and not a new polymorph or solvate / hydrate of the individual components.

[0122] The solubilities of salts of salcardin and naphthalene-2-sulfonic acid are shown in Table 8 below and were prepared according to the procedure of Example 3.

[0123] [Table 8]

[0124] All combinations of the above embodiments are encompassed by this application.

[0125] 5. Sarcardin Hydrochloride Form I In one embodiment, provided herein is salcardin hydrochloride Form I. In some embodiments, the salt is crystalline.

[0126] In some embodiments, the molar ratio of salcardin to hydrochloric acid in the salt is about 1: 1. In some embodiments, the salt is the hydrochloride salt of salcardin.

[0127] A representative XRPD pattern of salcardin hydrochloride Form I is shown in FIG.

[0128] In some embodiments, provided herein is a solid form comprising the hydrochloride salt of sarcardin, characterized in that 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or all of the peaks are at approximately 11.4, 11.5, 12.3, 13.0, 13.9, 14.8, 16.1, 17.2, 17.4, 17.8, 18.1, 18.6, 19.2, 19.8, 20.0, 20.3, 21.9, 23.6, 23.9, 25.4, 25.5, 27.4, and 28.4°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by 7 peaks. In some embodiments, the solid form is characterized by 9 peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0129] In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, the solid form being characterized by an XRPD pattern comprising peaks at about 17.4, 17.8, and 23.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 13.9, 20.3, and 21.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 17.2 and 18.6 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 11.4, 12.3, 13.0, 13.9, 17.2, 17.4, 17.8, 18.1, 18.6, 19.8, 20.3, 21.9, and 23.9 °2Θ.

[0130] In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, the solid form characterized by an XRPD pattern comprising peaks at about 12.3, 13.0, and 17.8 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 13.9, 17.4, and 23.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 20.3 and 21.9 °2Θ.

[0131] In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0132] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0133] A representative TG / DTA thermogram for Form I of salcardin hydrochloride is shown in Figure 18. In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, which exhibits a weight loss of about 3.1% upon heating from about 25°C to about 90°C. In some embodiments, without being bound by theory, this weight loss corresponds to a loss of water. In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, characterized by a TG thermogram consistent with the TG thermogram presented in Figure 18.

[0134] In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, characterized by a DTA thermogram that matches the DTA thermogram presented in FIG.

[0135] In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, the solid form exhibiting a mass increase of about 2.2% when the relative humidity (RH) is increased from about 10% to about 90%.

[0136] In some embodiments, Form I of salcardin hydrochloride is prepared by combining salcardin and hydrochloric acid (e.g., in a molar ratio of about 1:1) in a solvent (e.g., THF) and subjecting the mixture to temperature cycling (e.g., from about 5°C to about 25°C) for a period of time (e.g., about 72 hours).

[0137] In additional embodiments, a crystalline salt of salcardin and hydrochloric acid (also referred to as salcardin hydrochloride) is provided. This hydrochloride salt is polymorphic. In Example 11, Form II of the crystalline salt of salcardin and hydrochloric acid was produced. Upon scale-up, Form I of the crystalline salt of salcardin and hydrochloric acid was produced. Form I may be characterized by an XRPD pattern including one or more peaks selected from about 12.3°2Θ and about 13.0°2Θ. In some embodiments, the XRPD pattern of Form I lacks peaks below about 9.5°2Θ. An XRPD pattern substantially similar to that shown in Figure 17 can also be used to characterize Form II of the crystalline salt of salcardin and hydrochloric acid. A peak list corresponding to many of the peaks in Figure 17 is provided in Table 9.

[0138] [Table 9]

[0139] The TG / DTA experiment in Figure 18 showed a weight loss of about 3.1%, corresponding to about 0.88 equivalents of water for Form I, which is consistent with hydrate. Thus, the crystalline salt (Form I) prepared according to Example 12 produces a hydrate of the crystalline salt of, for example, salcardin and hydrochloric acid.

[0140] DVS experiments showed that the salt (Form I) prepared according to Example 12 picked up approximately 2.2% water at 90% RH. The crystalline morphology of the salt was the same before and after the DVS experiments. Under stability conditions of one week of exposure at 40°C and 5% RH, the salt remained unchanged by XRPD. After one week at 80°C and ambient humidity, the salt turned into an orange gel, and after one week under ambient light conditions, the material remained unchanged by XRPD. HPLC measurements performed after these stability experiments showed a decrease in purity from 99% to 98% after one week at 40°C and 75% RH, a decrease to 90% after one week at 80°C, and no change (99%) after one week under ambient light conditions.

[0141] All combinations of the above embodiments are encompassed by this application.

[0142] 6. Sarcardin Hydrochloride Form II In one embodiment, provided herein is Form II of sarcardin hydrochloride. In some embodiments, the salt is crystalline.

[0143] In some embodiments, the molar ratio of salcardin to hydrochloric acid in the salt is about 1: 1. In some embodiments, the salt is the hydrochloride salt of salcardin.

[0144] A representative XRPD pattern of salcardin hydrochloride Form II is shown in Figure 17A.

[0145] In some embodiments, provided herein is a solid form comprising the hydrochloride salt of sarcardin, characterized in that one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or all of the peaks are at approximately 10.1, 11.8, 13.5, 15.9, 16.4, 17.5, 17.8, 18.2, 18.4, 19.4, 19.6, 20.3, 20.6, 22.5, 23.5, 24.5, 25.5, 26.5, 26.6, 27.0, and 33.2°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by seven peaks. In some embodiments, the solid form is characterized by 9 peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0146] In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, the solid form being characterized by an XRPD pattern comprising peaks at about 13.5, 19.6, and 20.6 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 10.1, 11.8, and 16.4 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 17.8, 19.4, and 25.5 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 10.1, 11.8, 13.5, 15.9, 16.4, 17.8, 19.4, 19.6, 20.6, 23.5, 25.5, 26.5, 26.6, and 27.0 °2Θ. In some embodiments, the XRPD pattern does not include the peak at about 12.3 °2Θ. In some embodiments, the XRPD pattern does not include a peak at about 13.0° 2Θ.

[0147] In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, the solid form being characterized by an XRPD pattern comprising peaks at about 11.8, 13.5, 19.6, and 20.6 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 17.8, 19.4, and 25.5 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 23.5 and 26.5 °2Θ. In some embodiments, the XRPD pattern does not include a peak at about 12.3 °2Θ. In some embodiments, the XRPD pattern does not include a peak at about 13.0 °2Θ.

[0148] In some embodiments, provided herein is a solid form comprising salcardin hydrochloride, characterized by an XRPD pattern that matches the XRPD pattern presented in Figure 17A.

[0149] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0150] In some embodiments, salcardin hydrochloride Form II is prepared by combining salcardin and hydrochloric acid (e.g., in about a 1:1 molar ratio) in a solvent (e.g., a mixture of 2-propanol and heptane) and subjecting the mixture to temperature cycling (e.g., from ambient temperature to about 40° C.) for a period of time (e.g., about 72 hours). In some embodiments, the solvent is a 2:1 v / v mixture of 2-propanol and heptane.

[0151] Form II may be characterized by an XRPD pattern comprising one or more peaks selected from about 10.1°2Θ, 11.8°2Θ, about 13.5°2Θ, and about 16.4°2Θ, but lacking peaks between about 10.1°2Θ and about 11.8°2Θ. In some embodiments, the XRPD pattern of Form II lacks peaks below about 9.5°2Θ. The XRPD pattern of Form II is shown in Figure 17A. Table 9A below is a peak table for certain peaks in Figure 17A.

[0152] [Table 10]

[0153] Because hydrochloric acid is a liquid under the experimental conditions used herein, the solid obtained is not a mixture of hydrochloric acid and amorphous salcardin free base, but rather a crystalline salt of salcardin and hydrochloric acid.

[0154] All combinations of the above embodiments are encompassed by this application.

[0155] 7. Salcardin Hemiedisylate In one embodiment, provided herein is an ethane-1,2-disulfonic acid salt of sarcardin. In some embodiments, the salt is crystalline.

[0156] In some embodiments, the molar ratio of salcardin to ethane-1,2-disulfonic acid in the salt is about 2: 1. In some embodiments, the salt is a hemi-ethane-1,2-disulfonic acid salt of salcardin.

[0157] A representative XRPD pattern of the ethane-1,2-disulfonic acid salt of salcardin is shown in FIG.

[0158] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized in that 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or all of the peaks are at approximately 5.6, 11.0, 13.0, 14.1, 14.9, 16.2, 16.8, 17.2, 17.5, 17.8, 18.8, 19.4, 19.6, 20.4, 21.7, 21.8, 22.2, 23.7, 25.1, 25.7, 25.8, and 27.2°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by 7 peaks. In some embodiments, the solid form is characterized by 9 peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0159] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an XRPD pattern comprising peaks at about 14.1, 17.8, and 23.7 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 5.6 and 14.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 11.0 and 13.0 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 5.6, 11.0, 13.0, 14.1, 14.9, 16.2, 17.2, 17.5, 17.8, 18.8, 19.6, 20.4, 21.8, and 23.7 °2Θ.

[0160] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0161] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0162] A representative TG / DTA thermogram for the hemiedisylate salt of salcardin is shown in Figure 20. In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, the solid form exhibiting a weight loss of about 0.4% upon heating from about 25°C to about 160°C. In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by a TG thermogram that matches the TG thermogram presented in Figure 20.

[0163] In some embodiments, provided herein is a solid form comprising an ethane-1,2-disulfonic acid salt of salcardin, the solid form exhibiting a thermal event with an onset temperature of about 211°C as characterized by DTA. In some embodiments, further, the peak temperature of the thermal event is about 213°C. In some embodiments, the thermal event corresponds to a melting of the solid form, without being bound by any particular theory. In some embodiments, provided herein is a solid form comprising an ethane-1,2-disulfonic acid salt of salcardin, characterized by a DTA thermogram consistent with the DTA thermogram presented in Figure 20.

[0164] In some embodiments, provided herein is a solid form comprising an ethane-1,2-disulfonic acid salt of salcardin, the solid form exhibiting a mass increase of about 0.5% when the relative humidity (RH) is increased from about 10% to about 90%.

[0165] In some embodiments, the hemi-ethane-1,2-disulfonic acid salt of sarcardin is prepared by combining sarcardin and ethane-1,2-disulfonic acid salt (e.g., in a molar ratio of about 2:1) in a solvent and subjecting the mixture to temperature cycling (e.g., from about 5°C to about 25°C) for a period of time (e.g., about 72 hours). In other embodiments, the temperature cycling is between ambient temperature and about 40°C. In some embodiments, the solvent is toluene. In some embodiments, the solvent is a mixture of toluene and heptane (e.g., 2:1 v / v).

[0166] In additional embodiments, provided herein are crystalline salts of salcardin and ethane-1,2-disulfonic acid. The preparation of the crystalline salt of salcardin and ethane-1,2-disulfonic acid is shown in Example 13, and its scaled-up preparation is shown in Example 14. Such crystalline salts may be characterized by an XRPD pattern including one or more peaks selected from about 5.6°2Θ, about 11.0°2Θ, about 13.0°2Θ, about 14.1°2Θ, and about 14.9°2Θ. An XRPD pattern substantially similar to that shown in Figure 19 may also be used to characterize the crystalline salt of salcardin and ethane-1,2-disulfonic acid. These crystalline salts may be characterized by an onset melting temperature of about 211°C, with or without characteristic XRPD data. Thus, for example, a crystalline salt of salcardin and ethane-1,2-disulfonic acid may be characterized by an onset melting temperature of about 211°C, as well as (a) an XRPD pattern including one or more peaks selected from about 5.6°2Θ, about 11.0°2Θ, about 13.0°2Θ, about 14.1°2Θ, and about 14.9°2Θ, or (b) an XRPD pattern substantially similar to Figure 19. A peak list corresponding to many of the peaks in Figure 19 is provided in Table 10. The solubility of the crystalline ethane-1,2-disulfonic acid salt of salcardin is provided in Table 11.

[0167] [Table 11]

[0168] The XRPD pattern of the crystalline salt of salcardin with ethane-1,2-disulfonic acid is not a linear combination of the XRPD patterns of the salcardin free base and ethane-1,2-disulfonic acid starting materials. For example, the salt has a peak at approximately 5.6° 2Θ. Such a peak is absent in the XRPD pattern of ethane-1,2-disulfonic acid, as seen in Figure 22, and the XRPD pattern of salcardin free base is completely absent. Thus, the XRPD pattern in Figure 19 is not a physical mixture of the salt starting materials. The solubilities of salcardin with ethane-1,2-disulfonic acid salts are shown below in Table 11 and were prepared according to the procedure of Example 3.

[0169] Furthermore, the unique XRPD diffractogram and DTA melting event confirmed the formation of a new solid form. 1 The H-NMR spectrum showed approximately 0.5 equivalents of counter ion and possible peak shifts compared to the free base, confirming that the material was a salt and not a new polymorph or solvate / hydrate of the individual components.

[0170] The salt of Example 14, 1 The H-NMR spectrum showed 0.5 equivalents of ethane-1,2-disulfonic acid. This is consistent with a hemi-salt, so for every two equivalents of salcardin free base in the salt, there is one equivalent of ethane-1,2-disulfonic acid. Ethane-1,2-disulfonic acid has two acidic groups that can form a salt with salcardin free base. Therefore, in this hemi-salt, two salcardin free base molecules form a salt with one free acid molecule.

[0171] DVS experiments showed that the salt prepared according to Example 14 picked up approximately 0.5% water at 90% RH. The crystalline morphology of the salt was the same before and after the DVS experiments. Under stability conditions of one week of exposure at 40°C and 75% RH, the salt remained unchanged by XRPD. After one week at 80°C and ambient humidity, the salt remained unchanged by XRPD, and after one week under ambient light conditions, the material remained unchanged by XRPD. HPLC measurements performed after these stability experiments showed a decrease in purity from 99% to 98% after one week at 40°C and 75% RH, a decrease to 97% after one week at 80°C, and a decrease to 97% after one week under ambient light conditions.

[0172] [Table 12]

[0173] All combinations of the above embodiments are encompassed by this application.

[0174] 8. Mono-edisylate Form of Salcardin I In one embodiment, provided herein is an ethane-1,2-disulfonic acid salt of sarcardin. In some embodiments, the salt is crystalline.

[0175] In some embodiments, the molar ratio of sarcardin to ethane-1,2-disulfonic acid in the salt is about 1:1. In some embodiments, the salt is a mono-ethane-1,2-disulfonic acid salt of sarcardin. In some embodiments, provided herein is Form I of the monoedisylate salt of sarcardin. In some embodiments, Form I is a hydrate of the monoedisylate salt of sarcardin. In some embodiments, Form I is a monohydrate of the monoedisylate salt of sarcardin.

[0176] A representative XRPD pattern of Form I of the mono-ethane-1,2-disulfonate salt (mono-edisylate salt) of sarcardin is shown in FIG.

[0177] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of sarcardin, characterized in that one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, or all of the peaks are at approximately 9.2, 9.6, 10.4, 12.8, 13.8, 14.2, 14.9, 16.3, 18.8, 18.9, 20.2, 20.8, 21.2, 22.7, 23.3, 24.5, 24.8, and 26.2°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by seven peaks. In some embodiments, the solid form is characterized by nine peaks. In some embodiments, the solid form is characterized by eleven peaks. In some embodiments, the solid form is characterized by all peaks.

[0178] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an XRPD pattern comprising peaks at about 18.8, 20.2, and 21.2 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 9.2, 10.4, and 13.8 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 9.6, 14.2, and 14.9 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 9.2, 9.6, 10.4, 13.8, 14.2, 14.9, 18.8, 18.9, 20.2, 21.2, 22.7, and 24.8 °2Θ.

[0179] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0180] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0181] A representative TG / DTA thermogram for Form I of the monoedisylate salt of salcardin is shown in Figure 27. In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, which exhibits a weight loss of about 2.8% upon heating from about 25°C to about 150°C, and a weight loss of about 0.5% upon heating from about 150°C to about 200°C. In some embodiments, without being bound by any particular theory, the total weight loss corresponds to the loss of about 1 equivalent of water. In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by a TG thermogram consistent with the TG thermogram presented in Figure 27.

[0182] In some embodiments, provided herein is a solid form comprising an ethane-1,2-disulfonic acid salt of salcardin, the solid form exhibiting a thermal event with an onset temperature of about 244°C as characterized by DTA. In some embodiments, further, the peak temperature of the thermal event is about 273°C. In some embodiments, the thermal event corresponds to decomposition of the solid form, without being bound by any particular theory. In some embodiments, provided herein is a solid form comprising an ethane-1,2-disulfonic acid salt of salcardin, characterized by a DTA thermogram consistent with the DTA thermogram presented in Figure 27.

[0183] A representative FT-IR spectrum of Form I of the monoedisylate salt of sarcardin is shown in Figure 37A. -1 Provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an FT-IR spectrum comprising peaks at about 3556, 1206, and 814 cm. -1 In some embodiments, a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin is provided, characterized by one or more FT-IR spectra including a peak at about 3556 cm. -1In some embodiments, the FT-IR spectrum comprises a peak at about 1206 cm -1 In some embodiments, the FT-IR spectrum comprises a peak at about 814 cm -1 In some embodiments, the FT-IR spectrum comprises the following approximate peaks:

[0184] [Table 13]

[0185] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an FT-IR spectrum that matches the FT-IR spectrum presented in Figure 37A.

[0186] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by both the XRPD pattern and FT-IR spectrum provided in this section. For example, in some embodiments, the solid form is characterized by an XRPD pattern comprising peaks at about 18.8, 20.2, and 21.2°2Θ, and a peak at 3500 cm -1 It is characterized by an FT-IR spectrum containing peaks above 1000 kJ / cm.

[0187] In some embodiments, Form I of the monoedisylate salt of sarcardin is prepared by combining sarcardin and ethane-1,2-disulfonic acid salt (e.g., in about a 1:1 molar ratio) in a solvent and subjecting the mixture to temperature cycling (e.g., from ambient temperature to about 40° C.) for a period of time (e.g., about 48 hours). In some embodiments, the solvent is toluene.

[0188] In additional embodiments, provided herein is a monoedisylate salt of sarcardin. In such salts, there is one equivalent of ethane-1,2-disulfonic acid for every equivalent of sarcardin. Also provided herein are crystalline monoedisylate salts of sarcardin, such as crystalline monoedisylate salt Form I of sarcardin and crystalline monoedisylate salt Form II of sarcardin. Form I of crystalline monoedisylate salt of sarcardin is shown in Example 17, and Form II of crystalline monoedisylate salt of sarcardin is shown in Example 18. Also provided herein are hydrates of sarcardin monoedisylate. Such hydrates include monohydrates and dihydrates.

[0189] Form I of the crystalline monoedisylate salt of sarcardin is a monohydrate and may be characterized by an XRPD pattern with a peak at about 14.2°2Θ. Form I of the crystalline monoedisylate salt may be further characterized by an XRPD pattern with a peak at about 9.2°2Θ, with no peak at about 5.2°2Θ. Form I of the crystalline monoedisylate salt may be further characterized by an XRPD pattern with two peaks between about 9.0°2Θ and about 9.8°2Θ. Form I of the crystalline monoedisylate salt may be further characterized by an XRPD pattern with two peaks between about 9.0°2Θ and about 9.8°2Θ, with the difference between the two peaks being about 0.4°2Θ. In some embodiments, the difference between the two peaks is 0.4°2Θ±0.1°2Θ. Form I of the crystalline monoedisylate salt of salcardin may be further characterized by an XRPD pattern comprising one or more peaks selected from about 9.2°2Θ, about 9.6°2Θ, about 10.4°2Θ, about 13.8°2Θ, about 14.2°2Θ, and about 14.9°2Θ. An XPRD pattern substantially similar to Figure 26 can also be used to characterize Form I of the crystalline monoedisylate salt of salcardin. 1 Using H-NMR spectroscopy, it is possible to confirm that the stoichiometry of ethane-1,2-disulfonic acid and salcardin is 1:1 (see Figure 30).

[0190] Form I of the crystalline monoedisylate salt of sarcardin further exhibits an XRPD peak at about 14.2° 2Θ and an XRPD peak at about 3500 cm -1 Form I of the crystalline monoedisylate salt of sarcardin may be further characterized by an FT-IR spectrum comprising an XRPD peak at about 14.2° 2Θ with the absence of a peak at about 5.2° 2Θ, and a peak at about 3500 cm -1 It may be characterized by an FT-IR spectrum containing a peak greater than about 1206 cm -1 and approximately 814 cm -1 Form I of the crystalline monoedisylate salt of sarcardin further comprises one or more FT-IR peaks at about 3500 cm. Form I of the crystalline monoedisylate salt of sarcardin further comprises an XRPD pattern with two peaks between about 9.0° 2Θ and about 9.8° 2Θ, in some embodiments with a difference between the two peaks of about 0.4° 2Θ, and one or more FT-IR peaks at about 3500 cm. -1 It may be characterized by an FT-IR spectrum containing a peak greater than about 1206 cm -1 and approximately 814 cm -1 Form I of the crystalline monoedisylate salt of sarcardin further comprises an XRPD pattern comprising one or more peaks at about 9.2°2Θ, about 9.6°2Θ, about 10.4°2Θ, about 13.8°2Θ, about 14.2°2Θ, and about 14.9°2Θ, and one or more peaks at about 3500 cm -1 characterized by an FT-IR spectrum containing a peak greater than about 1206 cm -1 and approximately 814 cm -1 In some embodiments herein, the compound further comprises one or more FT-IR peaks at about 3500 cm -1 The peak of the super- -1 is.

[0191] The TG / DTA thermogram for Form I of the crystalline monoedisylate salt of sarcardin is shown in Figure 27. This figure reveals a mass loss of approximately 2.8% and approximately 0.5%, consistent with approximately 1 equivalent of water. Karl Fischer analysis of Form I revealed a water content of 3%, or approximately 1 equivalent of water. This is consistent with the TG data, which showed a mass loss of approximately 3.2%, corresponding to 1 equivalent of water. Form I is therefore a monohydrate. No melting was observed prior to decomposition at 244 °C. A peak list corresponding to many of the peaks in Figure 26 is provided below in Table 11A.

[0192] [Table 14]

[0193] The XRPD pattern of Form I of the crystalline monoedisylate salt of salcardin is not a linear combination of the XRPD patterns of the ethane-1,2-disulfonic acid salt and amorphous salcardin free base. For example, Form I of the crystalline monoedisylate salt of salcardin has a peak at about 9.2°2Θ that is not present in the ethane-1,2-disulfonic acid salt XRPD pattern of Figure 22, and is absent in amorphous salcardin. The XRPD pattern of Figure 26 is not a physical mixture of the salt starting materials.

[0194] In some embodiments, Form I of the monoedisylate salt of sarcardin converts to Form II of the monoedisylate salt of sarcardin under aqueous conditions. Form I of the monoedisylate salt of sarcardin was tested for its thermodynamic solubility and found to be highly soluble (>150 mg / mL) in all buffer systems evaluated (Table 11B). XRPD analysis revealed no solids. Due to the high solubility, HPLC analysis was not performed on the samples.

[0195] [Table 15]

[0196] All combinations of the above embodiments are encompassed by this application.

[0197] 9. Mono-edisylate Form II of Salcardin In one embodiment, provided herein is an ethane-1,2-disulfonic acid salt of sarcardin. In some embodiments, the salt is crystalline.

[0198] In some embodiments, the molar ratio of sarcardin to ethane-1,2-disulfonic acid in the salt is about 1:1. In some embodiments, the salt is a mono-ethane-1,2-disulfonic acid salt of sarcardin. In some embodiments, provided herein is Form II of the monoedisylate salt of sarcardin. In some embodiments, Form I is a hydrate of the monoedisylate salt of sarcardin. In some embodiments, Form II is a dihydrate of the monoedisylate salt of sarcardin.

[0199] A representative XRPD pattern of Form II of the mono-ethane-1,2-disulfonate salt (mono-edisylate salt) of sarcardin is shown in FIG.

[0200] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized in that 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or all of the peaks are at approximately 5.2, 9.1, 10.2, 10.8, 11.3, 11.9, 13.6, 14.8, 15.3, 15.7, 16.4, 16.9, 17.6, 18.2, 18.6, 19.2, 19.4, 20.4, 20.6, 20.7, 21.3, 21.9, 22.7, 23.6, and 25.7 °2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by 5 peaks. In some embodiments, the solid form is characterized by 7 peaks. In some embodiments, the solid form is characterized by 9 peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0201] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an XRPD pattern comprising peaks at about 15.7, 16.9, and 23.6 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 5.2, 9.1, and 11.3 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 17.6 and 19.2 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 5.2, 9.1, 10.2, 10.8, 11.3, 11.9, 13.6, 15.7, 16.9, 17.6, 18.6, 19.2, 20.7, 21.3, and 23.6 °2Θ.

[0202] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0203] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0204] A representative TG / DTA thermogram for Form II of the monoedisylate salt of salcardin is shown in Figure 29. In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, which exhibits a weight loss of about 4.9% upon heating from about 100°C to about 150°C. In some embodiments, without being bound by theory, this weight loss corresponds to a loss of about 2 equivalents of water. In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by a TG thermogram consistent with the TG thermogram presented in Figure 29.

[0205] In some embodiments, provided herein is a solid form comprising an ethane-1,2-disulfonic acid salt of salcardin, the solid form exhibiting a first thermal event with an onset temperature of about 103°C and a second thermal event with an onset temperature of about 242°C, as characterized by DTA. In some embodiments, the peak temperature of the first thermal event is also about 119°C, and the peak temperature of the second thermal event is also about 275°C. In some embodiments, without being bound by any particular theory, the first thermal event corresponds to dehydration of the solid form, and the second thermal event corresponds to decomposition of the solid form. In some embodiments, provided herein is a solid form comprising an ethane-1,2-disulfonic acid salt of salcardin, characterized by a DTA thermogram consistent with the DTA thermogram presented in Figure 29.

[0206] A representative FT-IR spectrum of Form II of the monoedisylate salt of sarcardin is shown in Figure 37B. -1 Provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an FT-IR spectrum that does not contain peaks above about 3374 and 826 cm. -1In some embodiments, a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin is provided, characterized by an FT-IR spectrum comprising one or more peaks greater than about 3374 cm. -1 In some embodiments, the FT-IR spectrum comprises a peak at about 826 cm -1 In some embodiments, the FT-IR spectrum comprises the following approximate peaks:

[0207] [Table 16]

[0208] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by an FT-IR spectrum that matches the FT-IR spectrum presented in Figure 37B.

[0209] In some embodiments, provided herein is a solid form comprising the ethane-1,2-disulfonic acid salt of salcardin, characterized by both the XRPD pattern and FT-IR spectrum provided in this section. For example, in some embodiments, the solid form is characterized by an XRPD pattern comprising peaks at about 15.7, 16.9, and 23.6°2Θ, and a peak at 3500 cm -1 The FT-IR spectrum is characterized by no peaks above 1000 kJ / cm.

[0210] In some embodiments, Form II of the monoedisylate salt of sarcardin is prepared by combining sarcardin and ethane-1,2-disulfonic acid salt (e.g., in a molar ratio of about 1:1) in a solvent and subjecting the mixture to temperature cycling (e.g., from ambient temperature to about 40° C.) for a period of time (e.g., about or at least 96 hours). In some embodiments, the solvent is toluene.

[0211] In some embodiments, Form II of the monoedisylate salt of sarcardin is prepared by slurrying Form I of the monoedisylate salt of sarcardin (including mixtures containing Form I of the monoedisylate salt of sarcardin) in a mixture of ethanol and water for a period of time (e.g., about 120 hours).

[0212] Crystalline sarcardin monoedisylate Form II is a more highly hydrated form than Form I and may be characterized by an XRPD pattern with a peak at about 5.2°2Θ. Crystalline sarcardin monoedisylate Form II may be further characterized by an XRPD pattern including one or more peaks at about 5.2°2Θ, about 9.1°2Θ, about 10.2°2Θ, about 10.8°2Θ, about 11.3°2Θ, about 13.6°2Θ, and about 15.7°2Θ. An XPRD pattern substantially similar to Figure 28 may also be used to characterize crystalline sarcardin monoedisylate Form II. 1 Using 1 H-NMR spectroscopy, it is possible to confirm that the stoichiometry of ethane-1,2-disulfonic acid and salcardin is 1:1 (see Figure 31).

[0213] Crystalline salcardin monoedisylate Form II has an XRPD pattern with a peak at about 5.2° 2Θ and a peak at about 3500 cm -1 characterized by an FT-IR spectrum that does not contain a peak above about 3374 cm -1 and approximately 826 cm -1 In some embodiments, crystalline sarcardin monoedisylate Form II further comprises one or more peaks at about 5.2°2Θ, about 9.1°2Θ, about 10.2°2Θ, about 10.8°2Θ, about 11.3°2Θ, about 13.6°2Θ, and about 15.7°2Θ, and a peak at about 3500 cm -1 characterized by an FT-IR spectrum that does not contain a peak above and optionally at about 3374 cm -1 and approximately 826 cm -1 Further, the peaks include one or more of:

[0214] The TG / DTA thermogram for Form II of the crystalline monoedisylate salt of salcardin is shown in Figure 29. From this figure, a mass loss of approximately 4.9% was observed between approximately 100°C and approximately 150°C, corresponding to approximately 2 equivalents of water. Karl Fischer analysis of Form II indicated a 5% water content, or approximately 2 equivalents of water. This is consistent with the TG data, which showed a mass loss of approximately 4.9%, corresponding to 2 equivalents of water. Therefore, Form II is a dihydrate. A peak list corresponding to many of the peaks in Figure 28 is provided in Table 11C.

[0215] [Table 17]

[0216] The XRPD pattern of Form II of the crystalline monoedisylate salt of salcardin is not a linear combination of the XRPD patterns of ethane-1,2-disulfonic acid and amorphous salcardin free base. For example, Form II of the crystalline monoedisylate salt of salcardin has a peak at about 5.2°2Θ that is not present in the free acid XRPD pattern of Figure 22 and is absent in amorphous salcardin. The XRPD pattern of Figure 28 is not a physical mixture of the salt starting materials.

[0217] Thermodynamic solubility data for Form II of the monoedisylate salt of sarcardin are shown in Table 14 of Example 25.

[0218] All combinations of the above embodiments are encompassed by this application.

[0219] 10. Sarcardin Hydrobromide In certain embodiments, provided herein is salcardin hydrobromide, hi some embodiments, the salt is crystalline.

[0220] In some embodiments, the molar ratio of salcardin to hydrobromic acid in the salt is about 1: 1. In some embodiments, the salt is the monohydrobromide salt of salcardin.

[0221] A representative XRPD pattern of salcardin hydrobromide is shown in FIG.

[0222] In some embodiments, provided herein is a solid form comprising salcardin hydrobromide, characterized in that one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of the peaks are at approximately 5.7, 13.0, 14.1, 14.9, 16.2, 17.1, 17.3, 17.9, 18.8, 19.1, 19.7, 20.5, 22.0, 22.4, 23.6, 24.0, 24.9, 25.1, 25.5, 27.5, 28.2, and 30.4°2Θ. In some embodiments, the solid form is characterized by three peaks. In some embodiments, the solid form is characterized by five peaks. In some embodiments, the solid form is characterized by seven peaks. In some embodiments, the solid form is characterized by 9 peaks. In some embodiments, the solid form is characterized by 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0223] In some embodiments, provided herein is a solid form comprising salcardin hydrobromide, the solid form characterized by an XRPD pattern comprising peaks at about 17.9, 19.7, and 24.0 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 14.1 and 14.9 °2Θ. In some embodiments, the XRPD pattern further comprises peaks at about 5.7, 13.0, and 16.2 °2Θ. In some embodiments, the XRPD pattern comprises peaks at about 5.7, 13.0, 14.1, 14.9, 16.2, 17.1, 17.3, 17.9, 18.8, 19.7, 20.5, and 24.0 °2Θ.

[0224] In some embodiments, provided herein is a solid form comprising salcardin hydrobromide, characterized by an XRPD pattern that matches the XRPD pattern presented in FIG.

[0225] In some embodiments, the XRPD pattern is obtained using Cu Kα radiation.

[0226] A representative TG / DTA thermogram for salcardin hydrobromide is shown in Figure 24. In some embodiments, provided herein is a solid form comprising salcardin hydrobromide, the solid form exhibiting a weight loss of about 4.3% upon heating from about 25°C to about 175°C. In some embodiments, provided herein is a solid form comprising salcardin hydrobromide, characterized by a TG thermogram that matches the TG thermogram presented in Figure 24.

[0227] In some embodiments, provided herein is a solid form comprising salcardin hydrobromide characterized by a DTA thermogram that matches the DTA thermogram presented in FIG.

[0228] In some embodiments, salcardin hydrobromide is prepared by combining salcardin and hydrobromic acid in a solvent (e.g., THF) (e.g., a mixture of 2-propanol and heptane) and subjecting the mixture to temperature cycling (e.g., ambient temperature to about 40° C.) for a period of time (e.g., about 72 hours). In some embodiments, the solvent is a 2:1 v / v mixture of 2-propanol and heptane.

[0229] In another embodiment, a crystalline salt of salcardin and hydrobromic acid is provided. Preparation of the crystalline salt of salcardin and hydrobromic acid is shown in Example 15. Such a crystalline salt may be characterized by an XRPD pattern including one or more peaks selected from about 5.7°2Θ, about 13.0°2Θ, about 14.1°2Θ, about 14.9°2Θ, and about 16.2°2Θ. An XRPD pattern substantially similar to that shown in Figure 23 can also be used to characterize the crystalline salt of salcardin and hydrobromic acid. A peak list corresponding to many of the peaks in Figure 23 is provided in Table 12.

[0230] Because hydrobromic acid is a liquid under the experimental conditions used herein, the solid obtained is not a mixture of hydrobromic acid and amorphous salcardin free base, but rather a crystalline salt of salcardin and hydrobromic acid.

[0231] [Table 18]

[0232] Also provided herein are pharmaceutical compositions containing salts of salcardin, including crystalline salts of salcardin. Such pharmaceutical compositions comprise one or more pharmaceutically acceptable excipients and a salt, such as the crystalline salts provided herein. Such pharmaceutical compositions can be administered orally or can be configured for delivery parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, etc., in any conventional effective dosage unit form, including immediate-release, sustained-release, and timed-release oral preparations.

[0233] Further provided herein are methods and uses for treating disorders, such as arrhythmias, in a human subject by administering to the human an effective amount of a salcardin salt, such as the crystalline salt provided herein, and / or a pharmaceutical composition comprising salcardin, such as the crystalline salt, wherein the arrhythmias include atrial fibrillation, premature ventricular contractions, ventricular tachycardia, and supraventricular tachyarrhythmias, such as ventricular fibrillation. In some embodiments, the disorder is atrial fibrillation.

[0234] As used herein, unless otherwise specified, "treat," "treatment," and "treating" refer to an approach for obtaining a beneficial or desired result, including, but not limited to, therapeutic benefit. In some embodiments, therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated. In some embodiments, a therapeutic effect is achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that the patient experiences improvement, even though the patient may still suffer from the underlying disease.

[0235] A "subject" of treatment is a prokaryotic or eukaryotic cell, tissue culture, tissue, or animal, e.g., a mammal, including a human. Non-human animals that may be treated include, for example, monkeys, mice, dogs, rabbits, farm animals, sport animals, and pets. As used herein, unless otherwise specified, a "patient" is a human subject.

[0236] The following numbered embodiments are contemplated, but are not limited to:

[0237] Item 1. Salt of salcardin and a mononaphthalene salt former.

[0238] Item 2. The salt of item 1, wherein the mononaphthalene salt former contains one or more sulfonic acid moieties.

[0239] Item 3. The salt of item 2, wherein the mononaphthalene salt former contains one sulfonic acid moiety.

[0240] Item 4. The salt of item 2, wherein the mononaphthalene salt former contains two sulfonic acid moieties.

[0241] Item 5. The salt of item 4, wherein the two sulfonic acid moieties are on the same aromatic ring.

[0242] Item 6. The salt according to item 1, wherein the former mononaphthalene salt forming agent is an organic acid.

[0243] Item 7. The salt of item 6, wherein the organic acid is a carboxylic acid.

[0244] Item 8. The salt of item 7, wherein the salt-forming agent is substituted.

[0245] Item 9. The salt of item 8, wherein the salt-forming agent is substituted with an —OH group.

[0246] Item 10. The salt of item 8 or 9, wherein the substitution is ortho to the organic acid group.

[0247] Item 11. The salt of item 4, wherein the two sulfonic acid moieties are on different rings of the naphthalene salt former.

[0248] Item 12. A crystalline salt of salcardin and a salt former, wherein the salt former is not sulfuric acid.

[0249] Item 13. Crystalline salt of salcardin and a sulfonate former.

[0250] Item 14. The crystalline salt of item 13, wherein the sulfonic acid is aromatic and contains one or more sulfonic acid moieties.

[0251] Item 15. The crystalline salt of item 14, wherein the aromatic sulfonic acid comprises a naphthyl moiety and one or two sulfonic acid moieties.

[0252] Item 16. The crystalline salt of item 15, wherein the naphthyl moiety is further substituted.

[0253] Item 17. The crystalline salt of item 16, wherein the substituent is hydroxyl.

[0254] Item 18. The crystalline salt of item 13, wherein the sulfonic acid is aliphatic and contains one or two sulfonic acid moieties.

[0255] Item 19. Crystalline salts of salcardin with inorganic acids other than sulfuric acid.

[0256] Item 20. The crystalline salt according to item 19, wherein the salt of salcardin is a halide.

[0257] Item 21 Salt of salcardin and naphthalene-1,5-disulfonic acid.

[0258] Item 22. Crystalline salt of salcardin and naphthalene-1,5-disulfonic acid.

[0259] Item 23. A crystalline salt of salcardin and naphthalene-1,5-disulfonic acid according to item 22, comprising an x-ray powder diffraction peak at about 4.6°2Θ.

[0260] Item 24: A crystalline salt of salcardin and naphthalene-1,5-disulfonic acid described in item 22 or 23, having an X-ray powder diffraction pattern including one or more peaks selected from about 4.9°2Θ, about 10.4°2Θ, about 11.7°2Θ, about 12.3°2Θ, and about 15.9°2Θ.

[0261] Item 25: A crystalline salt of salcardin and naphthalene-1,5-disulfonic acid according to any one of items 22 to 24, having an initial melting temperature of about 244°C.

[0262] Item 26. A crystalline salt of salcardin and naphthalene-1,5-disulfonic acid as described in item 22, having an x-ray powder diffraction pattern substantially identical to that shown in FIG.

[0263] Item 27. A crystalline salt of salcardin and naphthalene-1,5-disulfonic acid according to item 26, having an initial melting temperature of about 244°C.

[0264] Item 28. Form of crystalline salt of salcardin with hydrochloric acid II.

[0265] Item 29. Salt of salcardin and 1-hydroxy-2-naphthoic acid.

[0266] Item 30. Crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid.

[0267] Item 31. Form I of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid.

[0268] Item 32. A crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid described in item 31, having an X-ray powder diffraction pattern including one or more peaks selected from about 3.4°2Θ, about 6.7°2Θ, about 6.9°2Θ, and about 15.4°2Θ.

[0269] Item 33: A crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid described in item 31, having an X-ray powder diffraction pattern including one or more peaks selected from about 3.4°2Θ, about 6.7°2Θ, and about 6.9°2Θ.

[0270] Item 34: A crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid described in item 31, having an X-ray powder diffraction pattern including a peak selected from about 3.4°2Θ and two peaks between about 6.5°2Θ and about 7.1°2Θ.

[0271] Item 35: A crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid according to any one of items 31 to 34, having an initial melting temperature of about 161°C.

[0272] Item 36: A crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid according to item 29, 30, or 31, having an x-ray powder diffraction pattern substantially identical to that shown in Figure 6.

[0273] Item 37. Form II of the crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid.

[0274] Item 38. A crystalline salt according to paragraph 28, having an XRPD pattern substantially similar to Figure 17A.

[0275] Item 39: A crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid described in item 37, having an X-ray powder diffraction pattern including one or more peaks selected from about 5.8°2Θ and about 8.8°2Θ.

[0276] Item 40. Form of crystalline salt of salcardin with hydrochloric acid I.

[0277] Item 41. The crystalline salt of item 28, having an x-ray powder diffraction pattern including one or more peaks selected from about 10.1°2Θ, about 11.8°2Θ, about 13.5°2Θ, and about 16.4°2Θ.

[0278] Item 42. The crystalline salt of item 28, having an x-ray powder diffraction pattern with no peaks below about 9.5° 2Θ and no peaks between about 10.1° 2Θ and about 11.8° 2Θ.

[0279] Item 43: A crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid according to Item 37, having an initial melting temperature of about 168°C.

[0280] Item 44: A crystalline salt of salcardin and 1-hydroxy-2-naphthoic acid according to item 37 or 43, having an x-ray powder diffraction pattern substantially identical to that shown in Figure 9.

[0281] Item 45 Salt of salcardin and naphthalene-2-sulfonic acid.

[0282] Item 46. Crystalline salt of salcardin and naphthalene-2-sulfonic acid.

[0283] Item 47. A crystalline salt of salcardin and naphthalene-2-sulfonic acid described in item 46, having an X-ray powder diffraction pattern including one or more peaks selected from about 9.4°2Θ, about 10.6°2Θ, about 13.3°2Θ, about 13.5°2Θ, about 16.6°2Θ, about 16.9°2Θ, and about 17.2°2Θ.

[0284] Item 48: A crystalline salt of salcardin and naphthalene-2-sulfonic acid described in item 46, having an X-ray powder diffraction pattern including one or more peaks selected from about 9.4°2Θ, about 10.6°2Θ, about 13.3°2Θ, and about 13.5°2Θ.

[0285] Item 49: A crystalline salt of salcardin and naphthalene-2-sulfonic acid according to item 46, having an X-ray powder diffraction pattern including peaks selected from about 9.4°2Θ, about 10.6°2Θ, and about 13.5°2Θ.

[0286] Item 50: A crystalline salt of salcardin and naphthalene-2-sulfonic acid described in item 46, having an X-ray powder diffraction pattern including two peaks between about 13.1°2Θ and about 13.7°2Θ, and three peaks between about 16.4°2Θ and about 17.4°2Θ.

[0287] Item 51. A crystalline salt of salcardin and naphthalene-2-sulfonic acid according to any one of items 46 to 50, having an initial melting temperature of about 88°C.

[0288] Item 52: A crystalline salt of salcardin and naphthalene-2-sulfonic acid according to item 46 or 51, having an x-ray powder diffraction pattern substantially identical to that shown in FIG. 13.

[0289] Item 53. Salts of sarcardine and hydrochloride.

[0290] Item 54. Crystalline salt of salcardin and hydrochloride.

[0291] Item 55. A crystalline salt of salcardin hydrochloride according to item 40, having an x-ray powder diffraction pattern including one or more peaks selected from about 12.3° 2Θ and about 13.0° 2Θ.

[0292] Item 56. A crystalline salt of salcardin hydrochloride according to item 54 or 55, having an x-ray powder diffraction pattern substantially similar to that of FIG. 17.

[0293] Item 57 Salt of salcardin and ethane-1,2-disulfonic acid.

[0294] Item 58. Crystalline salt of salcardin and ethane-1,2-disulfonic acid.

[0295] Item 59: A crystalline salt of salcardin and ethane-1,2-disulfonic acid described in item 58, having an X-ray powder diffraction pattern including one or more peaks selected from about 5.6°2Θ, about 11.0°2Θ, about 13.0°2Θ, about 14.1°2Θ, and about 14.9°2Θ.

[0296] Item 60: A crystalline salt of salcardin and ethane-1,2-disulfonic acid as described in Item 58, having an x-ray powder diffraction pattern substantially identical to that of Figure 19.

[0297] Item 61: A crystalline salt of salcardin and ethane-1,2-disulfonic acid according to any one of items 58 to 60, having an initial melting temperature of about 211°C.

[0298] Item 62. Salt of salcardin with hydrobromic acid.

[0299] Item 63. Crystalline salt of salcardin and hydrobromic acid.

[0300] Item 64. A crystalline salt of salcardin and hydrobromic acid described in Item 63, having an X-ray powder diffraction pattern including one or more peaks selected from about 5.7°2Θ, about 13.0°2Θ, about 14.1°2Θ, about 14.9°2Θ, and about 16.2°2Θ.

[0301] Item 65. A crystalline salt of salcardin and hydrobromic acid as described in Item 63, having an x-ray powder diffraction pattern substantially similar to that of Figure 23.

[0302] Item 66. A salt of sarcardine with a salt former selected from naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2-sulfonic acid, hydrochloric acid, ethane-1,2-disulfonic acid, or hydrobromic acid.

[0303] Item 67. A crystalline salt of sarcardine with a salt former selected from naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2-sulfonic acid, hydrochloric acid, or hydrobromic acid.

[0304] Paragraph 68: A pharmaceutical composition comprising the salcardin salt composition of any one of paragraphs 1 to 67 or 72 to 88 and one or more pharmaceutically acceptable excipients.

[0305] Clause 69. A method of treating arrhythmia with a pharmaceutically effective amount of the pharmaceutical composition of clause 68, comprising administering the composition to a patient.

[0306] Clause 70. A method of treating arrhythmia with a pharmaceutically effective amount of a salcardin salt of any one of clauses 1 through 67 or 72 through 88, comprising administering the salt to a patient.

[0307] Clause 71. The method of clause 69 or clause 70, wherein the arrhythmia is atrial fibrillation, supraventricular tachyarrhythmia, ventricular extrasystole, ventricular tachycardia, or ventricular fibrillation.

[0308] Item 72. The salt of any one of items 45 to 52, wherein the salt is a hydrate.

[0309] Item 73. Crystalline salt Form I according to item 54, wherein there are no peaks below about 9.5° 2Θ.

[0310] Item 74. The salt of any one of items 53 to 56, wherein the salt is a hydrate.

[0311] Item 75. A crystalline salt according to item 31, having an x-ray powder diffraction pattern including a peak at about 3.4°2Θ.

[0312] Item 76. Monoedisylate salt of sarcardin.

[0313] Item 77. A crystalline sarcardin salt according to item 76.

[0314] Item 78. Crystalline monoedisylate salt form I of sarcardin.

[0315] Item 79. Crystalline monoedisylate monohydrate of sarcardin.

[0316] Item 80: A crystalline monoedisylate salt of sarcardin according to any one of items 76 to 79, having an X-ray powder diffraction pattern including a peak at about 14.2°2Θ.

[0317] Item 81. The crystalline monoedisylate salt of any one of items 76 to 79, comprising one or more peaks selected from about 9.2°2Θ, about 9.6°2Θ, about 10.4°2Θ, about 13.8°2Θ, about 14.2°2Θ, and about 14.9°2Θ.

[0318] Item 82. Crystalline monoedisylate salt form II of sarcardin.

[0319] Item 83. Hydrate of crystalline monoedisylate salt of sarcardin.

[0320] Item 84. Crystalline monoedisylate dihydrate of sarcardin.

[0321] Item 85: A crystalline monoedisylate salt of sarcardin according to any one of items 82 to 84, having an X-ray powder diffraction pattern including a peak at about 5.2°2Θ.

[0322] Item 86: The crystalline monoedisylate salt of sarcardin according to any one of items 82 to 84, comprising one or more peaks selected from about 9.1°2Θ, about 10.2°2Θ, about 10.8°2Θ, about 11.3°2Θ, and about 13.6°2Θ.

[0323] Item 87. A hydrate according to item 76.

[0324] Item 88. A hydrate according to item 87, having a molar hydration greater than 1. [Example]

[0325] Analysis method XRPD analysis was performed on a PANalytical X'pert Pro equipped with a Pixcel detector (128 channels), scanning samples from 3 to 35° 2°Θ. Materials were mounted on a multiwell plate with a Mylar polymer film to support the samples. The multiwell plate was then placed in the diffractometer and analyzed using Cu K radiation (αλ = 1.54060 Å, αλ = 1.54443 Å, β = 1.39225 Å, α:α ratio = 0.5), operated in transmission mode (step size 0.0130° 2°Θ, step time 18.87 s) using a generator setting of 40 kV / 40 mA. Data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0326] Approximately 5 mg of material was weighed into an open aluminum pan and placed in a simultaneous thermogravimetry / differential thermal analyzer (TG / DTA) and held at room temperature. The sample was then heated from 20 to 400 °C at a rate of 10 °C / min, during which the change in sample weight was recorded along with any differential thermal events (DTA). 3 Nitrogen was used as the purge gas at a flow rate of 1 / min.

[0327] For protons, a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz was used. 1 H NMR experiments were performed in deuterated DMSO, with each sample prepared at a concentration of approximately 10 mM. The pH of the solutions was measured using a Hanna H12210 pH meter equipped with a microelectrode operating between pH -2 and 16.

[0328] HPLC analysis was performed on a Dionex Ultimate 3000 instrument with the following parameters:

[0329] [Table 19] [Example]

[0330] Free base preparation and screening Salcardin sulfate trihydrate was dissolved in ethyl acetate (16 vol.) and saturated sodium bicarbonate solution (16 vol.). The biphasic solution was transferred to a separatory funnel, and the layers were separated. The organic layer was dried over sodium sulfate, and the solvent was then removed by rotary evaporation. The resulting oil was dried under vacuum at ambient temperature for approximately 3 hours. Figure 4 shows the XRPD pattern of the resulting amorphous salcardin free base. For all cases, an initial screening procedure, detailed below, was performed on 10 mg of salcardin free base. Comparing all XRPD diffractograms to salcardin sulfate trihydrate, salcardin free base, and the associated counterions, clearly indicated differences. [Example]

[0331] solubility 20 mM buffers were prepared at pH 1.2 (HCl / KCl), pH 3.0 (HCl / glycine), pH 4.0 (citric acid / sodium citrate), and pH 7.4 (monobasic potassium phosphate / NaOH). 0.5 mL of each buffer was added with the appropriate salt to form a slurry. The pH of the slurry was measured and adjusted to 0.2 M buffer components (e.g., 0.2 M HCl) as needed. (aq) ) was used to restore the desired pH (initial pH of the buffer). The sample was slurried at ambient temperature for approximately 72 hours.

[0332] After this time, if solids remained, the pH was again brought back to the desired pH with 0.2 M buffer components as needed. If no solids remained, additional solids were added to reform the slurry, and then the pH was again brought back to the desired pH with 0.2 M buffer components as needed. All samples were then slurried for an additional 2 hours before being analyzed for concentration by HPLC. [Example]

[0333] Naphthalene-1,5-disulfonate To the salcardin free base was added naphthalene-1,5-disulfonic acid (1.05 eq.) and acetone (20 vol.). The sample was temperature cycled between ambient and 40°C in 4-hour periods over approximately 72 hours, leaving a white and orange solid.

[0334] The material was crystalline by XRPD. A mass loss of 2.9% was observed in TG before decomposition occurred, and a melting event was observed in DTA with an onset temperature of 243°C. Naphthalene-1,5-disulfonic acid (1.0 eq.) was added. 1 H-NMR showed no significant solvent. The solubility was 1.6 mg in a pH 1.2 buffer solution. · mL -1 , 0.7 mg in pH 3.0 buffer solution · mL -1 , 1.0 mg in pH 4.0 buffer solution · mL -1 , and 6.9 mg in pH 7.4 buffer. · mL -1 (Table 3). [Example]

[0335] Scale-up of naphthalene-1,5-disulfonate To 200 mg of salcardin free base was added 2 mL of acetone and 169.8 mg (1.05 eq.) of naphthalene-1,5-disulfonic acid. This sample was subjected to temperature cycling according to Example 16. The resulting solid was filtered through a Buchner funnel and the filter was allowed to dry for approximately 15 minutes. Figure 1 shows the XRPD pattern for this example. Figure 1 shows the XRPD pattern of this salt, indicating that the salt is crystalline. A peak table is provided in Table 2. There was no weight loss in the TG until decomposition occurred, and a melting event was observed in the DTA with an onset temperature of 244°C (Figure 2). Naphthalene-1,5-disulfonic acid 1 H-NMR showed a 1:1 ratio, but no significant solvent was observed (Figure 3). Solubility was measured at 1.6 mg in a pH 1.2 buffer solution. · mL -1 , 0.7 mg in pH 3.0 buffer solution · mL -1, 1.0 mg in pH 4.0 buffer solution · mL -1 , and 6.9 mg in pH 7.4 buffer. · mL -1 (Table 3). [Example]

[0336] 1-Hydroxy-2-naphthoate Form I A 1 M stock solution of 1-hydroxy-2-naphthoic acid in THF (1.05 eq.) and ethyl acetate (20 vol.) was added to salcardin free base. The sample was temperature cycled between ambient and 40°C in 4-hour cycles over approximately 72 hours, then placed in a refrigerator for approximately 24 hours, leaving a brown solid.

[0337] This material was crystalline by XRPD (Figure 6) with peaks at the positions detailed in Table 4. A 3.5% mass loss (1.3 eq. water) was observed in the TG before decomposition occurred, and one melting event was observed in the DTA with an onset temperature of 161 °C. 1-Hydroxy-2-naphthoic acid (1.0 eq.) was added. 1 1 H-NMR showed no significant solvent (Figure 8). [Example]

[0338] 1-Hydroxy-2-naphthoate Form II A 1 M stock solution of 1-hydroxy-2-naphthoic acid in THF (1.05 eq.) and toluene (20 vol.) was added to the salcardin free base. The sample was temperature cycled between ambient and 40°C in 4-hour periods over approximately 72 hours, then placed in a refrigerator for approximately 24 hours. The vial containing the sample was opened, and the solvent was allowed to evaporate, leaving a white and brown solid.

[0339] The material was crystalline by XRPD. A 1.1% mass loss was observed in TG before decomposition occurred, and one melting event was observed in DTA with an onset temperature of 166°C. 1-Hydroxy-2-naphthoic acid (1.0 eq.) was added. 1 1 H-NMR showed no significant solvent. [Example]

[0340] Scale-up of 1-hydroxy-2-naphthoic acid salt Form II 2 mL of toluene and 457 μL of a 1 M solution of 1-hydroxy-2-naphthoic acid in THF were added to 200 mg of salcardin free base. The sample was temperature cycled according to Example 16. The solid was filtered through a Buchner funnel and the filter was allowed to dry for approximately 15 minutes.

[0341] This material was crystalline by XRPD (Figure 9) with peaks at the positions detailed in Table 5. There was no mass loss in TG until decomposition occurred, and one melting event was observed in DTA with an onset temperature of 168°C (Figure 10). 1-Hydroxy-2-naphthoic acid (1.0 eq.) was added. 1 H-NMR showed no significant solvent (Figure 11). Solubility was measured and found to be 16.8 mg in a pH 1.2 buffer solution. · mL -1 , 4.2 mg in pH 3.0 buffer solution · mL -1 , 6.1 mg in pH 4.0 buffer solution · mL -1 , and 0.2 mg in pH 7.4 buffer. · mL -1 (Table 6). [Example]

[0342] Naphthalene-2-sulfonate A 1 M stock solution of naphthalene-2-sulfonic acid in THF (1.05 eq.) and ethyl acetate (20 vol.) was added to the salcardin free base. The sample was temperature cycled between ambient and 40°C in 4-hour periods over approximately 72 hours. Heptane (10 vol.) was added, and the sample was placed in a freezer for approximately 24 hours. The vial containing the sample was opened, and the solvent was evaporated, leaving a white and orange solid.

[0343] The material was crystalline by XRPD. A 2.6% mass loss (1.0 eq. water) was observed in TG before decomposition occurred, and one melting event was observed in DTA with an onset temperature of 95°C. Naphthalene-2-sulfonic acid (1.0 eq.) was added. 1 1 H-NMR showed no significant solvent. [Example]

[0344] Scale-up of naphthalene-2-sulfonate 2 mL of toluene and 457 μL of a 1 M solution of naphthalene-2-sulfonic acid in THF were added to 200 mg of salcardin free base. The sample was temperature cycled according to Example 16. The solid was filtered through a Buchner funnel and the filter was dried to give a white solid.

[0345] The material was crystalline by XRPD (Figure 13) with peaks at the positions detailed in Table 7. A 2.4% mass loss (1.0 eq. water) was observed in the TG before decomposition occurred, and one melting event was observed in the DTA with an onset temperature of 88°C (Figure 14). Naphthalene-2-sulfonic acid (1.0 eq.) was added. 1 H-NMR showed no significant solvent (Figure 15). Solubility was measured and found to be 23.6 mg in a pH 1.2 buffer solution. · mL -1 , 1.2 mg in pH 3.0 buffer solution · mL -1 , 18.9 mg in pH 4.0 buffer solution · mL -1 , and 5.9 mg in pH 7.4 buffer. · mL -1 (Table 8). [Example]

[0346] Hydrochloride (Form II) A 1 M HCl stock solution in THF (1.05 eq.), 2-propanol (20 vol.), and heptane (10 vol.) was added to salcardin free base. The sample was temperature cycled between ambient and 40°C in 4-hour periods over approximately 72 hours. Additional heptane (20 vol.) was added and the sample was placed in a freezer for approximately 24 hours, leaving a white solid. The material was crystalline by XRPD (Figure 17A). [Example]

[0347] Scale-up of the hydrochloride salt (Form I) 200 mg of salcardin free base was added to 2 mL of THF and 457 μL of 1 M hydrochloric acid solution in THF. The sample was temperature cycled according to Example 16. The solid was filtered through a Buchner funnel and the filter was dried to give a white solid.

[0348] The material was crystalline by XRPD (Figure 17) with peaks at the positions detailed in Table 9. There was a 3.1% mass loss in TG, which equates to approximately 0.88 equivalents of water (Figure 18). 1 This was not observed by H-NMR (Figure 18A). [Example]

[0349] Ethane-1,2-disulfonic acid salt A 1 M stock solution of ethane-1,2-disulfonic acid in THF (1.05 eq.), toluene (20 vol.), and heptane (10 vol.) was added to salcardin free base. The sample was temperature cycled between ambient and 40°C in 4-hour periods over approximately 72 hours. Additional heptane (20 vol.) was added, and the sample was placed in a freezer for approximately 24 hours, leaving a white solid.

[0350] The material was crystalline by XRPD. A 1.4% mass loss was observed in TG before decomposition occurred, and one melting event was observed in DTA with an onset temperature of 201 °C. Ethane-1,2-disulfonic acid (0.6 eq.) was added. 11 H-NMR showed no significant solvent. [Example]

[0351] Scale-up of ethane-1,2-disulfonate To 200 mg of salcardin free base was added 2 mL of toluene and 218 μL of a 1 M solution of ethane-1,2-disulfonic acid in THF (0.55 eq.). The sample was subjected to temperature cycling according to Example 16. The solid was filtered through a Buchner funnel and dried to give a white solid.

[0352] The material was crystalline by XRPD (Figure 19) with peaks at the positions detailed in Table 10. There was no mass loss in TG until decomposition occurred, and one melting event was observed in DTA with an onset temperature of 211°C (Figure 20). Ethane-1,2-sulfonic acid (0.5 eq.) was added. 1 H-NMR showed no significant solvent (Figure 21). Solubility was measured and found to be 41.1 mg in a pH 1.2 buffer solution. · mL -1 , 46.3 mg in pH 3.0 buffer solution · mL -1 , 36.1 mg in pH 4.0 buffer solution · mL -1 , and 18.9 mg in pH 7.4 buffer solution. · mL -1 (Table 11). [Example]

[0353] Hydrobromide A 1 M HBr stock solution in THF (1.05 eq.), 2-propanol (20 vol.), and heptane (10 vol.) was added to salcardin free base. The sample was temperature cycled between ambient temperature and 40°C in 4-hour periods over approximately 72 hours. Additional heptane (20 vol.) was added, and the sample was placed in a freezer for approximately 24 hours. The vial containing the sample was opened, and the solvent was evaporated, leaving an orange solid.

[0354] The material was crystalline by XRPD (Figure 23) with peaks at the positions detailed in Table 12. TG showed a 4.3% mass loss before decomposition occurred, but DTA showed no melting events (Figure 24). 1 This was not observed by H-NMR (Figure 25). [Example]

[0355] Temperature cycling of Examples 5, 8, 10, 12, and 14 Temperature cycling was performed with stirring using the following method. 1. Keep at 25℃ for 1 hour 2. Cool to 5°C at 0.1°C / min 3. Keep at 5℃ for 1 hour 4. Heat to 25°C at 0.1°C / min 5. Repeat the above for a total of 72 hours, then remove the sample at 5°C. [Example]

[0356] Preparation of Form I of the crystalline monoedisylate salt of sarcardin. To a solution containing approximately 3 g of salcardin free base was added 45 mL of toluene to form a solution. Approximately 6.85 mL (1.05 eq.) of a 1 M ethane-1,2-disulfonic acid stock solution (ethane-1,2-disulfonic acid dihydrate in THF) was added to this solution, forming a gummy solid. This solution was temperature cycled between ambient temperature and 40°C for approximately 24 hours in 4-hour cycles. After 24 hours, a small amount of free-flowing white solid was observed in the flask, and large clumps of gummy white material were observed in the flask. Both materials appeared primarily amorphous by XRPD (diffraction patterns LNB15318-53-1-Slurry and LNB15318-53-1-Bulk in Figure 32). This material was then temperature cycled for an additional 24 hours. After 48 hours, a mixture of free-flowing off-white powder and off-white solid aggregates was observed in the flask. An aliquot of the free-flowing material was collected for XRPD analysis, the pattern of which can be seen in Figure 33 (diffraction pattern LNB15318-53-1-48h). The material was filtered by Buchner filtration and dried under vacuum at ambient temperature for approximately 24 hours. The dried material was collected, weighed, and analyzed by XRPD (diffraction pattern LNB15318-53-1-Dry in Figures 26 and 33). This diffraction pattern, LNB15318-53-1-Dry, was used to generate a peak list for Form I.

[0357] Amorphous monoedisylate salt of sarcardin: During polymorph screening of the monoedisylate salt, several lots of material were freeze-dried prior to experimentation. After freeze-drying, the material appeared as a clear, colorless gum rather than a solid. 1 H NMR analysis confirmed that the material was still the monoedisylate salt. [Example]

[0358] Preparation of Form II of the crystalline monoedisylate salt of sarcardin. To a solution containing approximately 4 g of salcardin free base, 60 mL of toluene was added to form a solution. To this solution, 9.34 mL (1.05 eq.) of a 1 M ethane-1,2-disulfonic acid stock solution (ethane-1,2-disulfonic acid dihydrate in THF) was added, forming a gummy solid. The sample was temperature cycled between ambient temperature and 40°C with stirring for approximately 96 hours in 4-hour cycles. A free-flowing off-white powder was observed. A wet solid sample was analyzed by XRPD. This material appeared as a mixture of Form I of the monoedisylate salt and what is herein designated Form II (diffraction pattern LNB1919-44-1 in Figure 34). The solid was isolated by Buchner filtration and dried under vacuum at ambient temperature overnight. The dried material was collected and transferred to a 100 mL Duran flask. 40 mL of EtOH / water (0.4 aw) was added to form a mobile slurry. The slurry was then stirred with a stir bar at ambient temperature for approximately 120 hours. An aliquot of the material was removed and analyzed by XRPD (diffraction pattern LNB1919-44-3 in Figures 28 and 35). This material was identified as monoedisylate Form II. The bulk material was isolated by Buchner filtration and dried under vacuum at ambient temperature for approximately 24 hours. The dried material was analyzed by XRPD (diffraction pattern LNB1919-44-3-Dry in Figure 35), which confirmed that this material was Form II. This diffraction pattern LNB1919-44-3-Dry was used to generate a peak list for Form II. [Example]

[0359] Comparative Pattern Preparation - Form I of the Crystalline Monoedisylate Salt of Salcardin Approximately 100 mg of salcardin free base was dissolved in 2 mL of toluene. To this was added 229 μL of a 1 M ethane-1,2-disulfonic acid stock solution (ethane-1,2-disulfonic acid dihydrate in THF). The sample was temperature cycled between ambient and 40°C for 4 hour cycles. An aliquot of this material was collected after approximately 24 hours and temperature cycled for an additional 24 hours. An aliquot of the material was removed and analyzed by XRPD. A unique crystalline pattern was observed. This pattern is LNB15318-51-1 48 hours in Figure 32 and is designated Form I of the monoedisylate salt. [Example]

[0360] Comparative pattern preparation - Form II of the crystalline monoedisylate salt of sarcardin Form II was first observed during GVS characterization of Form I. Material collected after GVS analysis of Form I was analyzed by XRPD. A new pattern (Form II) was observed, indicating the formation of a higher hydrate. The XRPD control is "LNB15318-53-1-PostGVS" in Figure 34. [Example]

[0361] GVS (Gravimetric Vapor Sorption) of Example 20 Approximately 26 mg of Form I was placed on a mesh vapor sorption pan and loaded into a Hiden Analytical IGASorp Moisture Sorption Analyzer balance. The sample was subjected to a ramping profile from 40 to 90% relative humidity (RH) in 10% increments, maintaining the sample at each step until a stable weight was achieved at 25 °C (98% step completion, minimum step time 30 minutes, maximum step time 60 minutes). After the sorption cycle was completed, the sample was dried to 0% RH using the same procedure and finally returned to the starting point of 40% RH. Two cycles were performed. The weight change during the sorption / desorption cycle was plotted to determine the hygroscopicity of the sample. Material collected after GVS analysis was analyzed by XRPD. [Example]

[0362] KF analysis Approximately 30 mg of material for KF analysis was weighed into a pre-weighed glass vial. This material was then added to the titration cell of a KF coulometer containing the hydranal solution. The empty vial was back-weighed after the addition of the solid to determine the mass of material added to the cell. The sample was then titrated. Analysis was performed in duplicate, and the results were averaged. [Example]

[0363] Single-crystal X-ray analysis of Form II of the 1-hydroxy-2-naphthoate salt of sarcardin. Single-crystal X-ray analysis of Form II of the 1-hydroxy-2-naphthoate salt of sarcardin was performed at 120 K using closed-tube generated Mo Kα radiation (λ = 0.71073 Å) on an Agilent Supernova single-crystal X-ray diffractometer. The monoclinic space group is P21 / n (a = 10.2443(2) Å, b = 29.9171(6) Å, c = 10.8406(3) Å, β = 103.375(2)°, volume = 3232.31(13) Å). 3 All data were scaled, solved, and refined for a 2Θ (Z = 4, Z' = 1) model. A final model was constructed using 123,397 (11,798 unique) reflections in the 2Θ range from 5.622 to 65.972°, returning an R1 (I > (2σI)) value of 5.79%, confirming the predicted structure of salcardin. The asymmetric unit (Figure 36) was found to encompass one complete salcardin molecule with one associated 1-hydroxy-2-naphthoic acid counterion (1:1 salcardin:counterion ratio). A characteristic experimental XRPD 2Θ diffractogram was calculated using data collected at 120 K, which was consistent with salt form II. Crystallographic data are shown in Table 13.

[0364] [Table 20] [Example]

[0365] Infrared spectroscopic analysis of Form I and Form II of the monoedisylate salt of sarcardin. Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed in the center of the spectrometer plate and a spectrum was obtained using the following parameters: Resolution: 4cm -1 Background scan time: 16 scans Sample scan time: 16 scans Data collection: 4000~400cm -1 Result spectrum: transmittance Software: OPUS version 6

[0366] The FT-IR spectra are shown in Figure 37A (Form I), Figure 37B (Form II) and Figure 37C (overlap). [Example]

[0367] Evaluation of thermodynamic solubility of selected salt forms The thermodynamic solubilities of salcardin sulfate trihydrate, naphthoate Form II (1-hydroxy-2-naphthoate Form II), and monoedisylate Form II were determined in a medium consisting of 0.9% sodium chloride solution and 5% dextrose in water.

[0368] Procedure: Approximately 10 mg aliquots of the appropriate salt were added to 1 mL of the selected medium to form a mobile slurry. The observed slurry was stirred at ambient temperature for approximately 16 hours. A sample was collected and the pH recorded. Additional solids were added to the sample, and a clear solution was observed. The sample was stirred for an additional 8 hours at ambient temperature. The pH of the sample was recorded after 24 hours. The sample was filtered by centrifugation, and the observed solids were analyzed by XRPD. The mother liquor was submitted for HPLC analysis.

[0369] The thermodynamic solubility results are listed in Table 14.

[0370] [Table 21] [Example]

[0371] PK analysis of salcardin salt

[0372] Materials and Methods The pharmacokinetic objective of this study was to evaluate exposure to sarcardin after oral capsule administration or intravenous (IV) infusion of sarcardin sulfate, sarcardin naphthoate, or sarcardin monoedisylate (Form II) in male dogs during a pharmacokinetic study.

[0373] Naive beagle dogs were fasted. The dosage formulations (oral [PO] capsules and intravenous [IV] infusion) were prepared the day before dosing. The IV formulation was made with 10 mM glycine (adjusted to pH 3.0 ± 0.1), 3% mannitol (qs) in sterile water for injection, USP, filtered through a 0.22 μm PVDF filter, and stirred for at least 30 minutes before administration. The capsule dose was filled into the appropriate number of size 12 gelatin capsules as a powder of the active pharmaceutical ingredient the day before dosing.

[0374] Oral dosing was by oral capsule once on day 1, and IV dosing was by IV infusion over approximately 45 minutes (±2 minutes) once on day 1.

[0375] Blood samples from orally dosed animals were collected at 0.5, 1, 2, 3, 5, 8, 12, 18, 24, and 36 hours post-dose. Blood samples from IV dosed animals were collected approximately 0.33, 0.75 (end of infusion), 1.5, 3, 6, 9, 12, 18, and 24 hours after the start of the infusion.

[0376] Blood samples were centrifuged at 3,200 RPM for 10 minutes under refrigerated (2°C–8°C) conditions, and the resulting plasma was divided into two aliquots (150 μl and the remainder), frozen, and shipped for bioanalysis. Plasma samples were analyzed for salcardin concentrations by Citoxlab North America, Laval, Quebec, Canada.

[0377] Individual sarcardin plasma concentration-time profiles for animals treated with sarcardin sulfate, sarcardin monoedisylate, or sarcardin naphthoate were analyzed using a model-independent method (Gibaldi M, Perrier D. Pharmacokinetics. 2 nd ed. New York: Marcel Dekker, Inc., 1982:409-17). Pharmacokinetic parameters were obtained / calculated from each animal on day 1.

[0378] Results - Plasma concentration The Cmax values ​​after a single oral dose of salcardin were 2820 ng / mL for the sulfate formulation (Figure 38A) and 4570 ng / mL for the monoedisylate formulation (Figure 38B). Data from all animals in each group were used to calculate mean pharmacokinetic parameters. The oral monoedisylate value includes animal 2001 (Figure 38B), which is considered an outlier and may reflect a dosing error. Without the data from animal 2001, the Cmax value for the monoedisylate formulation would likely be higher than 4570 ng / mL. The median peak plasma concentrations of salcardin were observed 2 hours after administration (Tmax 2 hr) for the salcardin sulfate formulation and 0.5 hours after administration (Tmax 0.5 hr) for the monoedisylate formulation.

[0379] This faster Tmax and higher Cmax profile observed with oral administration of the monoedisylate salt compared to the sulfate salt (possibly due to the increased solubility of the edisylate form) may offer the advantage of an immediate-release formulation, which could provide for the more rapid treatment of acute atrial fibrillation.

[0380] As reported in Mason et al., Circulation 140:A11495 (2019) and described in U.S. Patent Application No. 16 / 712,677 (both of which are incorporated herein by reference in their entireties), plasma concentrations of salcardin and changes in certain ECG parameters (e.g., I) related to its ion channel blocking mechanism have been shown to be correlated with the efficacy of salcardin. Na-PeakQRS augmentation consistent with I block, and I Na-Peak and I Ca,L Based on human clinical trial data, which demonstrate a linear concentration-effect relationship with the number of steroid hormones (an increase in the PR interval consistent with inhibition of both), as well as supporting animal model data, the monoedisylate salt is predicted to elicit significantly greater pharmacodynamic effects (ECG changes) than the sulfate salt at T=0.5 hr after oral administration. This is further predicted to transition to a faster efficacy for the monoedisylate salt form compared to the sulfate form.

[0381] The foregoing detailed description is provided to aid those skilled in the art in practicing the invention. However, the invention described and claimed herein is not limited in scope by the specific embodiments disclosed herein, since these embodiments are intended to be illustrative of various aspects of the invention. Any equivalent embodiments are intended to be within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description without departing from the spirit or scope of the inventive discovery. Such modifications are further intended to be within the scope of the appended claims.

[0382] All publications, patents, patent applications, and other references cited in this application are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. The citation of any reference herein shall not be construed as an admission that it is prior art to the present invention.

Claims

1. A dihydrate of the monoedisylate salt of salcardin, having an X-ray powder diffraction pattern obtained using CuKα radiation, including peaks at approximately 5.2°2Θ, 9.1°2Θ, and 11.3°2Θ.

2. A dihydrate of the monoedisylate salt of salcardin as described in claim 1, having an X-ray powder diffraction pattern obtained using CuKα radiation, further including one or more peaks at approximately 10.2°2Θ, approximately 10.8°2Θ, approximately 13.6°2Θ, and approximately 15.7°2Θ.

3. A dihydrate of the monoedisylate salt of salcardin as described in claim 1, having an X-ray powder diffraction pattern obtained using CuKα radiation, further including peaks at about 15.7°2Θ, about 16.9°2Θ, and about 23.6°2Θ.

4. A dihydrate of the monoedisylate salt of salcardin as described in claim 1, wherein the salt provides an in vivo plasma profile comprising a median Cmax greater than about 4570 ng / ml when orally administered to a subject, with a Tmax that is within about 0.5 hours after administration.

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