EA043571B1 - SULCARDINE SALT - Google Patents

Description

Link to related applications

This application claims priority over the provisional patent application.

U.S. No. 62/798467, filed January 29, 2019, and No. 62/959687, filed January 10, 2020, the entire disclosure of which is incorporated herein by reference.

Field of technology to which the present invention relates

The present invention provides sulcardine salts other than sulcardine sulfuric acid salts, including crystalline sulcardine salts. In addition, pharmaceutical compositions containing such salts and methods for treating arrhythmias are also provided, the method comprising administering effective amounts of such salts.

BACKGROUND OF THE INVENTION

4-Methoxy-N-(3,5-bis(1-pyrrolidinylmethyl)-4-hydroxybenzyl)benzenesulfonamide (or N-(4hydroxy-3,5-bis(pyrrolidin-1-ylmethyl)benzyl)-4-methoxybenzenesulfonamide) , also known as sulcardine, and its salts such as sulcardine sulfate, constitute a group of compounds with high antiarrhythmic activity. Sulcardine is a multiple ion channel blocker that specifically inhibits I _Na-Peak , I _Na-Late , I _Ca , _L , and I _Kr with similar in vitro efficacies (and I _to and I _Kur to a lesser extent) in human atrial cardiomyocytes, and is a compound that may be the only example of the class of substituted sulfonamides of antiarrhythmic drugs. Sulcardine salts can be used as intravenously injected or oral doses for the treatment of arrhythmias, including supraventricular tachyarrhythmia, premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, and atrial fibrillation. See, for example, US Pat. No. 8,541,464 and US Pat. No. 8,637,566. The preparation of sulcardine sulfate salt is disclosed in US Pat. No. 6,605,635.

In addition, current evidence suggests that one of the advantages of sulcardine and its salts is that they do not have significant proarrhythmic activity, as demonstrated in highly robust preclinical safety study models, including the awake canine model of sudden death after myocardial infarction and a validated rabbit model of ventricular wedge pressure. In addition, they have not been shown to significantly increase the defibrillation threshold or increase the risk of failure to defibrillate in a canine model following myocardial infarction, as was observed for flecainide. Based on these data, sulcardine and salts, with their very low apparent proarrhythmic potential, have the potential to be used for the treatment of acute and recurrent atrial fibrillation in the presence of organic heart disease, long QR syndrome and ventricular arrhythmias, including premature ventricular contractions (PVC), ventricular tachycardia (VT). ) and ventricular fibrillation (VF), both with single and chronic administration, due to their ability to be included in intravenous and oral dosage formulations.

Summary of the present invention

In accordance with some embodiments, crystalline salts of sulcardine and salt formers other than sulfuric acid are provided. A salt former is a compound (eg, an acidic counterion) that can be used to form a salt with, for example, sulcardine.

In accordance with some embodiments, the present invention provides a solid form containing 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. In accordance with some embodiments, the solid form is crystalline. In accordance with some embodiments, the solid form is amorphous.

According to further embodiments, crystalline sulcardine salts and halide salt formers are provided.

According to additional embodiments, crystalline salts of sulcardine and a sulfonic acid as a salt former are provided.

In other embodiments, sulcardine salts and mononaphthalene salt formers are provided.

In further embodiments, salts of sulcardine are provided with naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2-sulfonic acid, hydrochloric acid or hydrobromic acid.

In further embodiments, crystalline salts of sulcardine and naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2-sulfonic acid, hydrochloric acid or hydrobromic acid are provided.

According to additional embodiments, Form I and Form II are crystalline salts of sulcardine and 1-hydroxy-2-naphthoic acid.

According to further embodiments, Form I and Form II are crystalline salts of sulcardine and hydrochloric acid.

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According to additional embodiments, monoedisylate salts (ie, ethane-1,2-disulfonic acid monosalts) of sulcardine are provided. In accordance with some embodiments, the sulcardine monoedisylate salts are hydrates.

In other embodiments, crystalline monoedisylate salts of sulcardine are provided. According to additional embodiments, amorphous monoedisylate salts of sulcardine are provided.

In yet further embodiments, Form I and Form II of crystalline salts of sulcardine monoedisylate are provided.

In accordance with additional embodiments, pharmaceutical compositions are provided containing the sulcardine salts provided herein, including crystalline salts and one or more pharmaceutically acceptable excipients.

In accordance with some embodiments, the present invention provides a pharmaceutical composition comprising a solid form provided herein and one or more pharmaceutically acceptable excipients.

In still further embodiments, methods are provided for treating arrhythmias with the sulcardine salts provided herein, including crystalline sulcardine salts, the method comprising administering such salts to a patient in need thereof.

In accordance with some embodiments, the present invention provides a method of treating an arrhythmia comprising administering to a subject in need thereof a therapeutically effective amount of a solid form as disclosed herein or a pharmaceutical composition as disclosed herein. In some embodiments, the arrhythmia is atrial fibrillation, supraventricular tachyarrhythmia, premature ventricular contraction, ventricular tachycardia, or ventricular fibrillation.

Brief description of drawings

In fig. Figure 1 shows a typical powder X-ray diffraction pattern of a crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid.

In fig. Figure 2 shows a typical TG/DTA thermogram of a crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid.

In fig. Figure 3 shows a typical ¹ H-NMR spectrum of a crystalline salt of sulcardine and naphthalene 1,5-disulfonic acid.

In fig. Figure 4 shows a typical powder X-ray diffraction pattern of amorphous sulcardine free base.

In fig. Figure 5 shows a typical powder X-ray diffraction pattern of naphthalene-1,5 disulfonic acid.

In fig. 6 shows a typical powder X-ray diffraction pattern of Form I of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

In fig. Figure 7 shows a typical TG/DTA thermogram of Form I of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

In fig. Figure 8 shows a typical ¹ H-NMR spectrum of Form I of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

In fig. 9 shows a typical powder X-ray diffraction pattern of Form II crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

In fig. 10 shows a typical TG/DTA thermogram of Form II crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

In fig. 11 shows a typical ¹ H-NMR spectrum of Form II of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

In fig. Figure 12 shows a typical powder X-ray diffraction pattern of 1-hydroxy-2naphthoic acid.

In fig. 13 shows a typical powder X-ray diffraction pattern of a crystalline salt of sulcardine and naphthalene-2-sulfonic acid.

In fig. Figure 14 shows a typical TG/DTA thermogram of a crystalline salt of sulcardine and naphthalene-2-sulfonic acid.

In fig. 15 shows a typical ¹ H-NMR spectrum of a crystalline salt of sulcardine and naphthalene-2sulfonic acid.

In fig. Figure 16 shows a typical powder X-ray diffraction pattern of naphthalene-2sulfonic acid.

In fig. 17 shows a typical powder X-ray diffraction pattern of Form I of a crystalline salt of sulcardine and hydrochloric acid.

In fig. 17A is a typical Form II powder X-ray diffraction pattern of a crystalline sulcardine hydrochloric acid salt.

In fig. Figure 18 shows a typical TG/DTA thermogram of Form I of a crystalline salt of sulcardine and hydrochloric acid.

In fig. 18A shows a typical 1H-NMR spectrum of Form I of a crystalline sulcardine hydrochloric acid salt.

In fig. Figure 19 shows a typical powder X-ray diffraction pattern of a crystalline salt of sulcardine and ethane-1,2-disulfonic acid.

In fig. Figure 20 shows a typical TG/DTA thermogram of a crystalline salt of sulcardine and ethane1,2-disulfonic acid.

In fig. Figure 21 shows a typical ¹ H-NMR spectrum of a crystalline salt of sulcardine and ethane-1,2 disulfonic acid.

In fig. Figure 22 shows a typical powder X-ray diffraction pattern of ethane-1,2 disulfonic acid.

In fig. Figure 23 shows a typical powder X-ray diffraction pattern of a crystalline salt of sulcardine and hydrobromic acid.

In fig. Figure 24 shows a typical TG/DTA thermogram of a crystalline salt of sulcardine and hydrobromic acid.

In fig. Figure 25 shows a typical Y-NMR spectrum of a crystalline salt of sulcardine and hydrobromic acid.

In fig. Figure 26 shows a typical powder X-ray diffraction pattern of Form I of the monoedisylate salt of sulcardine.

In fig. Figure 27 shows a typical TG/DTA thermogram of Form I of the monoedisylate salt of sulcardine.

In fig. 28 shows a typical powder X-ray diffraction pattern of Form II of sulcardine monoedisylate salt.

In fig. Figure 29 shows a typical TG/DTA thermogram of Form II of sulcardine monoedisylate salt.

In fig. 30 shows a typical Y-NMR spectrum of Form I of the monoedisylate salt of sulcardine.

In fig. 31 shows a typical Y-NMR spectrum of Form II of sulcardine monoedisylate salt.

In fig. 32 is a plot of the X-ray powder diffraction stack from Example 17.

In fig. 33 is a plot of the X-ray powder diffraction stack from Example 17.

In fig. 34 is an X-ray powder diffractometry stack plot from Example 18.

In fig. 35 is a plot of the X-ray powder diffraction stack from Example 18.

In fig. 36 shows the top layer of an asymmetric unit containing one complete form of the substance sulcardine 1-hydroxy-2-naphthoate and a schematic representation of sulcardine 1-hydroxy-2-naphthoate. All non-hydrogen atoms are shown with thermal strain ellipsoids set at the 50% probability level.

In fig. 37A shows a typical FT-IR spectrum of Form I of sulcardine monoedisylate salt; in fig. 37B shows a typical FT-IR spectrum of Form II of sulcardine monoedisylate salt; and in fig. Figure 37C shows the top layer of the FT-IR spectra of Form I and Form II of sulcardine monoedisylate salt.

In fig. 38A shows the plasma concentration of sulcardine after one oral administration of sulcardine sulfate salt; and in fig. 38B shows the plasma concentration of sulcardine after a single oral administration of sulcardine monoedisylate salt.

Detailed Description of the Present Invention

Sulcardine is characterized by the chemical name 4-methoxy-K-(3,5-bis-(1-pyrrolidinylmethyl)4-hydroxybenzyl)benzene sulfonamide (or K-(4-hydroxy-3,5-bis(pyrrolidin-1-ylmethyl)benzyl )-4methoxybenzenesulfonamide) and is characterized by the following structure:

Sulcardine sulfate is characterized by the following structure:

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Sulcardine sulfate can exist in hydrated form. One such form is the trihydrate.

As used herein and unless otherwise noted, the term crystalline forms and related terms refer to solid forms that are crystalline. In accordance with certain embodiments, a sample containing a solid form of sulcardine, such as the crystalline form provided in the present invention, may be substantially free of other solid forms, such as an amorphous form and/or other crystalline forms. In certain embodiments, such a sample containing the crystalline form of the sulcardine salt of the present invention may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9 %, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more other solid forms of sulcardine salt, such as an amorphous form and/or other crystalline forms of sulcardine salt mass. In accordance with certain embodiments, the crystalline form of the sulcardine salt provided in the present invention may be physically and/or chemically pure. In accordance with certain embodiments, the crystalline form of the sulcardine salt provided in the present invention may be approximately 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and/or chemically pure.

As used herein and unless otherwise noted, the term amorphous, amorphous form and related terms as used herein mean that the substance, component or product in question is not substantially crystalline as determined by x-ray diffraction.

Such X-ray diffraction patterns often show what is called an amorphous halogen, as seen, for example, in FIG. 4.

In accordance with some embodiments, the present invention provides salts formed by sulcardine free base and acids. Such acids may be organic or inorganic acids. Some of the salts obtained from sulcardine and these acids are polymorphic. Various techniques can be used to show that a sulcardine acid salt has been produced. For example, a solid, which may be a salt, can be analyzed by X-ray powder diffraction and, if the image differs from the X-ray powder diffraction of the constituent substances, then a new composition has been formed. The acid counterions shown below have pKa values greater than 3 units of the strongest basic pKa value of sulcardine free base. In table 1 shows the pKa of sulcardin free base relative to the salts defined in the present disclosure.

Table 1

pKa counterion data

Counterion (salt former) pK _a 1 2 3 Free comparator sulcardine bases 6.00 10.57 11.65 Hydrobromic acid -9.00 - - Hydrochloric acid -6.10 - - 1,5-Naphthalenedisulfonic acid -3.37 -2.64 - 1,2-Ethanesulfonic acid -2.06 -1.50 - Naphthalene-2-sulfonic acid 0.17 - - 1-Hydroxy-2-naphthoic acid 2.70 13.5 -

In each of the salt procedures, the free base of sulcardine was used to prepare the corresponding salts. The free base of sulcardin is amorphous and a representative image can be depicted in FIG. 4. X-ray powder diffraction patterns of the corresponding free acids are characterized by images that are crystalline, and all powder X-ray diffraction patterns of the salts are different from the sum of the corresponding free acids and amorphous sulcardine. Thus, the solids described in the present invention are not physical mixtures of amorphous sulcardine and the corresponding acid. In fact, the X-ray powder diffraction data and the pKa data indicate that the resulting solids are salts, as further described in the present invention.

Screening was carried out to identify crystalline salts of sulcardine. More than 25 possible salt formers were analyzed in many solvents and solvent systems. In most cases, either no crystalline salts were formed or the crystalline salts were not stable under storage conditions such as 40°C and 75% RH. Salts formed from salt formers in table. 1, by comparison, formed crystalline salts and were stable at 40°C and 75% RH under the conditions presented in the present invention. A salt former is a compound that can be used to form a salt with, for example, sulcardine. In accordance with many embodiments, the salt former is an acid. In addition to salt screening, polymorph screening was performed on several established salts.

For crystalline salts, a common technique for characterizing such crystalline salts is X-ray powder diffractometry (XRPD). A powder X-ray diffraction pattern is an x-y plot with °2θ (diffraction angle) on the x-axis and intensity on the y-axis. The image contains peaks that can be used to characterize salt or other salt forms. Peaks are usually represented and named by their x-axis position rather than their y-axis peak intensity, since 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 pharmaceutical field to characterize crystalline salts or other solid forms.

The X-ray powder diffraction pattern exiting the diffractometer can be used to characterize the crystalline salt. A smaller subset of such data, however, may also be and typically is suitable for characterizing a crystalline salt. For example, a collection of one or more peaks from such an image can be used to characterize a crystalline salt. In fact, a single peak in X-ray powder diffraction can be used to characterize a crystalline salt. If the crystalline salt herein is characterized by one or more X-ray powder diffraction peaks, and such peaks are listed, which means that any combination of the listed peaks can be used to characterize the crystalline salt. In addition, the fact that other peaks are present in the X-ray powder diffraction pattern does not invalidate or otherwise limit the characterization.

Other data may also be used to characterize the crystalline salt alone or in combination with X-ray powder diffraction data. For example, melting point has often been used to characterize crystalline salts. In accordance with some embodiments, differential thermal analysis (DTA) is used to determine the onset of melting symptoms of certain crystalline salts. Such initial moments may be a characteristic of specific crystalline salts. In some cases, no melting was observed below the temperature at which decomposition occurs. In accordance with some embodiments, infrared spectral (IR) data can be used to characterize crystalline salts either alone or in conjunction with other solid state data, such as X-ray powder diffractometry data.

As with any data measurement, there is variability in X-ray powder diffraction. In addition to variability in peak intensity, there is also variability in the position of the peaks on the x-axis. However, such variability can typically be taken into account when reporting peak positions for characterization purposes. This variability in peak positions along the x-axis comes from several sources. One comes from obtaining a sample. Samples of the same crystalline substance obtained under different conditions may give slightly different diffraction patterns. Factors such as particle size, moisture 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 and this may result in slightly different diffraction patterns from the same crystalline form. Likewise, different software packages process X-ray data and this also introduces variability. Such and other sources of variability are known to those skilled in the art in the pharmaceutical field. Because of such sources of variability, it is common to describe X-ray diffraction peaks by using the word about or about or another similar term before the peak value in °2θ, which represents data within 0.1 or 0.2°2θ of the specified peak value, as appropriate. Unless otherwise noted, the X-ray powder diffraction peaks provided herein are described with variability on the order of ±0.2°2θ and are intended to be described with such variability whether or not the word about or approximately or other similar term is present. . Variability also exists with thermal measurements such as DTA and can also indicate sample purity. For DTA, typical measurement variability is in the order of ±1°C.

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With respect to IR data, unless otherwise noted, the IR peaks presented in the present invention are described with variability on the order of ±2 cm ^-1 , and are intended to be described with such variability regardless of whether the word about or approximately or other similar term is present or No.

Characteristic data that matches the reference solid form, as understood by those skilled in the art, corresponds to the same solid form as the reference solid form. When considering whether the data are consistent, one skilled in the art will appreciate that specific performance data points may vary to a moderate extent while still describing the solid form represented, due to, for example, experimental error and routine sample-to-sample analysis.

In accordance with various embodiments, sulcardine salts and mononaphthalene salt formers are provided. A mononaphthalene former is one where the former contains one naphthalene moiety as a substituent. In accordance with some such embodiments, the mononaphthalene salt formers contain one or more sulfonic acid moieties, such as one or two sulfonic acid moieties. If two sulfonic acid moieties are present, they may be on the same ring or on different rings of the naphthalene group.

The mononaphthalene salt former may be an organic acid such as a carboxylic acid, and the salt former may be further substituted, for example, by a naphthalene group. An example of substituents includes a hydroxyl group. In some embodiments, when substituted with a hydroxyl group, the hydroxyl is ortho with respect to the organic acid group.

In accordance with some embodiments, crystalline salts of sulcardine are provided. For example, crystalline salts of sulcardine with salt formers other than sulfuric acid are presented. In other embodiments, crystalline salts of sulcardine with organic sulfonic acids are provided. Such sulfonic acids may be aromatic or aliphatic, and each 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 sulcardine and halides.

In other embodiments, crystalline salts of sulcardine and aromatic carboxylic acids are provided. Examples of aromatic moieties include naphthyl moieties. Naphthyl moieties may be further substituted, for example, by hydroxyl groups.

In accordance with some embodiments, the present invention provides a solid form containing a sulcardine acid salt, wherein the acid is an acid that contains one naphthalene moiety and one or more sulfonic or carboxylic acid, halide acid, or ethane-1,2-disulfonic acid moieties .

In accordance with some embodiments, the acid is an acid that contains one naphthalene moiety and one or more sulfonic or carboxylic acid moieties. In accordance with some embodiments, the acid contains one naphthalene moiety and one or more (eg, one or two) sulfonic acid moieties. In accordance with some embodiments, the acid contains one naphthalene moiety and one or more (eg, one or two) carboxylic acid moieties. In some embodiments, the naphthalene moiety is directly substituted with sulfonic or carboxylic acid moieties. In accordance with some embodiments, the naphthalene moiety is further substituted. In accordance with some embodiments, the naphthalene moiety is further replaced with 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.

In accordance with some embodiments, the acid is an acid halide. In accordance with some embodiments, the acid is hydrochloric acid. In accordance with some embodiments, the acid is hydrobromic acid.

In some embodiments, the acid is ethane-1,2-disulfonic acid, also referred to herein as 1,2-ethane-disulfonic acid. If the said acid is combined with sulcardine, it may be referred to as an edisylate salt, such as a monoedisylate salt or a hemi-edisylate salt of sulcardine.

1. Naphthalene-1,5-disulfonic acid salt of sulcardine.

In accordance with certain embodiments, the present invention provides a naphthalene-1,5-disulfonic acid salt of sulcardine. In accordance with some embodiments, the salt is crystalline.

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In some embodiments, the molar ratio of sulcardine to naphthalene-1,5-disulfonic acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is sulcardine naphthalene-1,5-disulfonic acid monosalt.

A typical powder X-ray diffraction pattern of the naphthalene-1,5-disulfonic acid salt of sulcardine is shown in FIG. 1.

In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-1,5-disulfonic acid salt of sulcardine, which is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20 or all peaks located at approximately the following positions: 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-1,5-disulfonic acid salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 14.9, 15.9 and 23.6° 2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 4.9 and 10.4° 2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 11.3, 12.3, and 19.0° 2θ. In accordance with some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-1,5-disulfonic acid salt of sulcardine, which has an X-ray powder diffraction pattern that matches the X-ray powder diffraction pattern shown in FIG. 1.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

Typical TG/DTA thermograms of the naphthalene-1,5-disulfonic acid salt of sulcardine are shown in FIG. 2. In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-1,5-disulfonic acid salt of sulcardine, which exhibits a weight loss of approximately 0.6% after heating from about 25°C to about 200°C. In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-1,5-disulfonic acid salt of sulcardine, which has a TG thermogram that is the same as the TG thermogram shown in FIG. 2.

In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-1,5-disulfonic acid salt of sulcardine, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of approximately 244°C. In accordance with some embodiments, the thermal event is also characterized by a peak temperature of approximately 249°C. In some embodiments, without limitation to any particular theory, the thermal phenomenon corresponds to the melting of a solid form. In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-1,5-disulfonic acid salt of sulcardine, which has a DTA thermogram that is the same as the DTA thermogram shown in FIG. 2.

In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-1,5-disulfonic acid salt of sulcardine, which exhibits a weight increase of approximately 3.3% when relative humidity (RH) increases from about 5% to about 95%.

In some embodiments, the naphthalene-1,5-disulfonic acid salt of sulcardine is prepared by subjecting a mixture of sulcardine and naphthalene-1,5-disulfonic acid (e.g., approximately 1:1 molar ratio) in a solvent (e.g., acetone) to a temperature cycle (e.g. , from about 5°C to about 25°C) over a period of time (eg, about 72 hours). In other embodiments, the temperature cycle is from ambient temperature to about 40°C.

In some embodiments, crystalline salts of sulcardine and naphthalene-1,5-disulfonic acid are provided. The preparation of the crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid is outlined in Example 4 and scaled up in Example 5. The crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid can be characterized by a powder X-ray diffraction pattern containing a peak of approximately 4 ,9°2θ. In addition, the crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid may be characterized by a powder x-ray diffraction pattern containing one or more peaks selected from about 4.9°2θ, about 10.4°2θ, about 11.7°2θ , approximately 12.3°2θ and approximately 15.9°2θ. In addition, the powder X-ray diffraction pattern is basically the same as in FIG. 1 (taken from Example 5) can be used to characterize the crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid. A list of peaks that corresponds to many of the peaks in Fig. 1, presented in table. 2.

table 2

Table of X-ray powder diffractometry peaks corresponding to Fig. 1

Position (°2θ) Interplanar distance d (A) Height (area) Relative intensity (%) 4.93 17.92 766.65 29.42 8.97 9.86 742.49 28.50 10.41 8.50 1199.68 46.04 11.34 7.80 1076.41 41.31 11.72 7.55 569.26 21.85 12.33 7.18 943.51 36.21 12.57 7.04 618.97 23.75 13.27 6.67 371.67 14.26 13.75 6.44 168.66 6.47 14.07 6.29 1114.30 42.76 14.24 6.22 310.84 11.93 14.85 5.96 2365.30 90.77 15.61 5.68 301.48 11.57 15.94 5.56 2605.69 100.00 16.21 5.47 419.81 16.11 16.43 5.40 861.99 33.08 16.92 5.24 148.02 5.68 17.81 4.98 333.96 12.82 18.03 4.92 1217.70 46.73 18.48 4.80 535.18 20.54 18.99 4.67 1613.33 61.92 19.79 4.49 377.24 14.48 20.14 4.41 805.76 30.92 21.04 4.22 1151.18 44.18 21.48 4.14 669.17 25.68 21.88 4.06 232.12 8.91

Crystalline salts of many varieties

Position (°2θ) Interplanar distance d (A) Height (area D) Relative intensity (%) 22.19 4.01 503.68 19.33 22.76 3.91 1515.94 58.18 23.41 3.80 676.80 25.97 23.60 3.77 1682.15 64.56 24.14 3.69 410.85 15.77 24.54 3.63 402.15 15.43 24.80 3.59 1250.18 47.98 25.10 3.55 568.12 21.80 25.22 3.53 650.94 24.98 25.51 3.49 205.46 7.89 25.88 3.44 239.93 9.21 26.28 3.39 933.43 35.82 26.85 3.32 335.28 12.87 27.16 3.28 380.80 14.61 27.86 3.20 230.45 8.84 28.39 3.14 285.83 10.97 28.93 3.09 327.73 12.58 29.61 3.02 189.91 7.29 30.15 2.96 350.83 13.46 31.17 2.87 174.26 6.69 31.60 2.83 207.20 7.95 32.20 2.78 223.79 8.59 32.69 2.74 305.52 11.73 33.21 2.70 362.52 13.91 33.80 2.65 150.63 5.78 34.20 2.62 157.52 6.05

implementation of sulcardine and naphthalene-1,5 disulfonic acid can be characterized by an initial melting point of approximately 244°C (Fig. 2). Melting point can be used alone or in combination with X-ray powder diffractometry data to characterize such crystalline salts of sulcardine and naphthalene-1,5-disulfonic acid. Thus, in accordance with some embodiments, the crystalline salts of sulcardine and naphthalene-1,5-disulfonic acid may have an initial melting point of approximately 244°C along with (a) a powder X-ray diffraction pattern containing a peak at approximately 4.9°2θ, or ( b) a powder X-ray diffraction pattern containing 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) powder

- 8 043571 X-ray diffraction pattern, basically the same as in FIG. 1.

A dynamic vapor sorption (DVS) experiment indicated that the salt prepared according to Example 5 absorbed approximately 3.3% water at 90% relative humidity (RH). The crystalline form of the salt before and after the DVS experiment was the same, although at 60% RH a change in shape was possible which, if it occurred, was converted at the end of the DVS experiment. Under stable exposure conditions for one week at 40°C and 75%RH, the salt remains unchanged by X-ray powder diffractometry. It was also unchanged at 80°C and ambient RH after one week and under natural light conditions, as determined by X-ray powder diffractometry, also after one week. HPLC measurements taken after these stability experiments indicated that purity did not change under these conditions (99% before the one week stability studies and 99% after). However, a decrease in crystallinity was observed upon exposure to ambient light. Without being bound by theory, it was believed that the observed decrease in crystallinity was caused by insufficient sample on the X-ray powder diffractometry plate of the X-ray powder diffractometry instrument rather than a true loss of sample crystallinity.

For all stability studies provided herein at 40°C/75%RH, samples were in an uncovered container and kept in a stability chamber set at 40°C/75%RH. For studies at 80°C, samples were kept in a sealed container and placed in an oven set at 80°C. For studies under natural light conditions, samples were kept in a sealed container placed on a window sill in the laboratory, which was exposed to ambient natural and artificial light.

The solubility of the crystalline salt of naphthalene-1,5-disulfonic acid of example 5 is shown in table. 3 below and was measured according to the procedures of Example 3. The table indicates that solubility is low for acidic pH values, but increases when the pH value becomes more basic than neutral.

Table 3

Solubility data for the crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid

Meaning rn buffer pH after addition pH after adjustment Temperature (°C) pH after 72 hours pH after adjustment Temperature (°C) Solubility -1 (mg-ml) 1.2 0.9 1.1 18.8 1.2 No data 18.7 1.6 3.0 2.7 3.0 18.8 3.0 No data 18.7 0.7 4.0 4.0 No data 18.8 4.0 No data 18.7 1.0

7.4 6.7 7.5 18.8 7.3 No data 18.7 6.9

The powder X-ray diffraction patterns of the crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid are not linear combinations of the powder X-ray diffraction patterns of the starting materials of sulcardine free base and naphthalene-1,5-disulfonic acid. For example, the peak at approximately 10.4°2θ in salt is not present in the powder X-ray diffraction pattern of naphthalene-1,5-disulfonic acid as seen in FIG. 5, and the free base of sulcardin does not contain any peaks in the powder X-ray diffraction pattern of sulcardin. Thus, the X-ray powder diffraction pattern in FIG. 1 are not a linear combination of salt starting materials.

In addition, using a specific X-ray powder diffraction pattern and DTA, melting events confirmed that a new solid form had been produced. ^{The 1} H-NMR spectrum showed the stoichiometric presence of the counterion and possible peak shifts compared to the free base, confirming that the substance was a salt and not a new polymorph or solvate/hydrate of the individual components.

All combinations of the above embodiments are covered by the present invention.

2. Form I of sulcardine 1-hydroxy-2-naphthoic acid salt.

In accordance with certain embodiments, the present invention provides Form I of sulcardine 1-hydroxy-2-naphthoic acid salt. According to some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to 1-hydroxy-2-naphthoic acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is sulcardine 1-hydroxy-2-naphthoic acid monosalt.

A typical powder X-ray diffraction pattern of sulcardine 1-hydroxy-2-naphthoic acid salt Form I is shown in FIG. 6.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18 or all peaks located approximately at the following positions: 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 16.8, 18.6 and 18.9°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 6.7 and 6.9°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 13.8, 20.3, and 20.8° 2θ. In accordance with some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 6.7, 6.9 and 16.8°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further comprises a peak at approximately 18.9°2θ.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that has an X-ray powder diffraction pattern that matches the X-ray powder diffraction pattern shown in FIG. 6.

In accordance with some embodiments, X-ray powder diffraction patterns are obtained using Cu Ka radiation.

Typical TG/DTA thermograms of sulcardine 1-hydroxy-2-naphthoic acid salt Form I are shown in FIG. 7. In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that exhibits a weight loss of approximately 3.5% after heating from about 25°C to about 150°C. In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that has a TG thermogram that is the same as the TG thermogram shown in FIG. 7.

In accordance with some embodiments, the present invention provides a solid form containing the 1-hydroxy-2-naphthoic acid salt of sulcardine, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of approximately 161°C. In accordance with some embodiments, the thermal event is also characterized by a peak temperature of approximately 163°C. In some embodiments, without limitation to any particular theory, the thermal phenomenon corresponds to the melting of a solid form. In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that has a DTA thermogram that is the same as the DTA thermogram shown in FIG. 7.

In some embodiments, sulcardine 1-hydroxy-2-naphthoic acid salt Form I is prepared by subjecting a mixture of sulcardine and 1-hydroxy-2-naphthoic acid (e.g., approximately 1:1 molar ratio) in a solvent (e.g., ethyl acetate) to temperature cycling (eg, from ambient temperature to about 40°C) over a period of time (eg, about 72 hours).

In some embodiments, crystalline salts of sulcardine and 1-hydroxy-2-naphthoic acid are provided. In accordance with some embodiments, Form I of the crystalline 1-hydroxy-2-naphthoic acid salt of sulcardine is provided. Get it

- 10 043571 Form I of the crystalline 1-hydroxy-2-naphthoic acid salt of sulcardine is described in Example 6. Form I of the crystalline salt of 1-hydroxy-2-naphthoic acid of sulcardine may be such that it is characterized by a powder x-ray diffraction pattern containing one or more peaks X-ray powder diffraction 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 the crystalline 1-hydroxy-2-naphthoic acid salt of sulcardine may be such that it is characterized by a powder x-ray diffraction pattern containing peaks selected from about 3.4°2θ, about 6.7°2θ, and about 6 ,9°2θ. An X-ray powder diffraction pattern containing a peak at approximately 3.4°2θ and two peaks from approximately 6.5°2θ to 7.1°2θ can be used to characterize Form I of the crystalline 1-hydroxy-2-naphthoic acid salt of sulcardine. An X-ray powder diffraction pattern containing a peak at approximately 3.4°2θ can be used to characterize Form I of the crystalline 1-hydroxy-2-naphthoic acid salt of sulcardine, since the peak at this angle is not present in Form II of the crystalline 1-hydroxy-2-naphthoic acid salt sulcardina. Likewise, a powder X-ray diffraction pattern containing any of the peaks at about 6.7°2θ, about 6.9°2θ, and about 15.4°2θ can be used to characterize Form I of the crystalline 1-hydroxy-2-naphthoic acid salt of sulcardine. Form I of the crystalline 1-hydroxy-2-naphthoic acid salt of sulcardine may be such that it exhibits a powder X-ray diffraction pattern substantially the same as in FIG. 6. List of peaks, corresponding to many peaks in Fig. 6, presented in table. 4.

Table 4

Table of X-ray powder diffractometry peaks corresponding to Fig. 6

Position (°20) Interplanar distance d(A) Height (area) Relative intensity (%) 3.36 26.29 464.50 20.94 6.42 13.77 227.16 10.24 6.73 13.14 977.62 44.07 6.88 12.84 1060.72 47.81 9.41 9.40 112.14 5.05 9.98 8.87 426.64 19.23 10.10 8.76 533.04 24.03 10.35 8.55 281.88 12.71 11.29 7.84 143.63 6.47 11.50 7.69 290.19 13.08 11.63 7.61 186.21 8.39 12.41 7.13 234.66 10.58 12.86 6.88 165.59 7.46 13.47 6.57 327.00 14.74 13.80 6.42 821.94 37.05 14.56 6.08 322.08 14.52 15.08 5.88 271.87 12.25 15.39 5.76 512.30 23.09

Position (°20) Interplanar distance d(A) Height (area) Relative intensity (%) 18.86 4.71 1174.78 52.95 19.61 4.53 294.20 13.26 19.83 4.48 428.02 19.29 20.03 4.43 572.68 25.81 20.27 4.38 956.28 43.10 20.77 4.28 958.02 43.18 21.05 4.22 287.54 12.96 21.79 4.08 398.48 17.96 22.13 4.02 120.13 5.41 22.89 3.88 178.98 8.07 23.13 3.85 223.35 10.07 23.52 3.78 745.83 33.62 24.43 3.64 244.31 11.01 24.69 3.61 315.40 14.22 25.21 3.53 238.50 10.75 25.43 3.50 269.23 12.14 25.85 3.45 175.35 7.90 26.54 3.36 305.89 13.79

- 11 043571

15.73 5.63 284.21 12.81 15.93 5.56 614.51 27.70 16.14 5.49 176.24 7.94 16.75 5.29 1215.12 54.77 17.28 5.13 739.59 33.34 17.96 4.94 737.11 33.23 18.58 4.78 2218.51 100.00

27.69 3.22 219.65 9.90 28.36 3.15 123.15 5.55 29.00 3.08 81.74 3.68 29.34 3.04 138.25 6.23 29.63 3.01 102.46 4.62 30.64 2.92 63.35 2.86 32.10 2.79 48.48 2.19 34.14 2.63 36.92 1.66

Form I of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid may have an initial melting point of approximately 161°C. Melting point can be used alone or in combination with X-ray powder diffractometry data to characterize Form I of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid. Thus, Form I of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid may be characterized by an initial melting point of approximately 161 °C together with (a) a powder X-ray diffraction pattern containing one or more peaks selected from 3.4°2θ, approximately 6.7°2θ, about 6.9°2θ, and about 15.4°2θ, or (b) a powder X-ray diffraction pattern containing one or more peaks selected from about 3.4°2θ, about 6.7°2θ, and approximately 6.9°2θ; or (c) an X-ray powder diffraction pattern containing a peak at approximately 3.4°2θ and two peaks from approximately 6.5°2θ to approximately 7.1°2θ; or (d) a powder X-ray diffraction pattern substantially the same as in FIG. 6.

All combinations of the above embodiments are covered by the present invention.

3. Form II of sulcardine 1-hydroxy-2-naphthoic acid salt.

In accordance with certain embodiments, the present invention provides Form II of sulcardine 1-hydroxy-2-naphthoic acid salt. In accordance with some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to 1-hydroxy-2-naphthoic acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is sulcardine 1-hydroxy-2-naphthoic acid monosalt.

A typical powder X-ray diffraction pattern of sulcardine 1-hydroxy-2-naphthoic acid salt Form II is shown in FIG. 9.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21 or all peaks located at approximately the following positions: 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 5.8, 18.6 and 19.9°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 10.6, 17.8, and 21.4°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 20.6 and 25.3°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that has an X-ray powder diffraction pattern that matches the X-ray powder diffraction pattern shown in FIG. 9.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

Typical TG/DTA thermograms of Form II sulcardine 1-hydroxy-2-naphthoic acid salt are shown in FIG. 10. According to some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that exhibits a weight loss of approximately 0.1% when heated from about 25° C. to about

150°C. In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that has a TG thermogram that is the same as the TG thermogram shown in FIG. 10.

In accordance with some embodiments, the present invention provides a solid form containing the 1-hydroxy-2-naphthoic acid salt of sulcardine, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of approximately 168°C. In accordance with some embodiments, the thermal event is also characterized by a peak temperature of approximately 170°C. In some embodiments, without limitation to any particular theory, the thermal phenomenon corresponds to the melting of a solid form. In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that has a DTA thermogram that is the same as the DTA thermogram shown in FIG. 10.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine 1-hydroxy-2-naphthoic acid salt that exhibits a weight increase of about 0.7% when subjected to an increase in relative humidity (RH) from about 10% to about 90% .

In some embodiments, Form II of sulcardine 1-hydroxy-2-naphthoic acid salt has the approximate unit cell dimensions of a=10.2 A, b=29.9 A, c=10.8 A, α=90°, β=103.4° and γ=90°. In some embodiments, Form II of sulcardine 1-hydroxy-2-naphthoic acid salt has the approximate unit cell dimensions of a=10.24 A, b=29.92 A, c=10.84 A, α=90°, β=103.38° and γ=90°. In some embodiments, Form II of sulcardine 1-hydroxy-2-naphthoic acid salt has the approximate unit cell dimensions of a=10.244 A, b=29.917 A, c=10.841 A, α=90°, β=103.375°, and γ =90°. In some embodiments, Form II of sulcardine 1-hydroxy-2-naphthoic acid salt has the approximate unit cell dimensions of: a=10.2443 A, b=29.9171 A, c=10.8406 A, α=90°, β= 103.375° and γ=90°. In some embodiments, Form II of sulcardine 1-hydroxy-2-naphthoic acid salt is characterized by a unit cell of the space group P2l/n. In accordance with some embodiments, Form II of sulcardine 1-hydroxy-2-naphthoic acid salt has a volume of approximately 3232.31 A ³ /cell. In accordance with some embodiments, Form II of sulcardine 1-hydroxy-2-naphthoic acid salt has a Z' value of 4. In accordance with some embodiments, Form II of sulcardine 1-hydroxy-2-naphthoic acid salt has a Z' value of 1.

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

In some embodiments, Form II is a crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid. The preparation of Form II of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid is described in Example 7 and with scaling in Example 8. Form II of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid may be such that it is characterized by a powder x-ray diffraction pattern, containing one or more peaks selected from approximately 5.8°2θ and approximately 8.8°2θ. None of these peaks are in Form I of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid. Form II may also be such that it is characterized by a powder X-ray diffraction pattern containing peaks at approximately 5.8°2θ and 8.8°2θ. In addition, the powder X-ray diffraction pattern is basically the same as in FIG. 9, and can be used to characterize Form II of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid. A list of peaks that corresponds to many of the peaks in Fig. 9, presented in table. 5.

- 13 043571

Table 5

Table of X-ray powder diffractometry peaks corresponding to Fig. 9

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 5.83 15.16 1547.63 98.74 8.77 10.08 313.32 19.99 9.26 9.55 73.46 4.69 10.13 8.73 489.19 31.21 10.56 8.38 1361.41 86.86 11.03 8.02 120.23 7.67 12.06 7.34 415.28 26.50 12.13 7.30 396.32 25.29 12.42 7.13 345.34 22.03 13.80 6.42 537.66 34.30 14.33 6.18 453.92 28.96 14.63 6.05 376.74 24.04 15.83 5.60 196.99 12.57 16.83 5.27 189.16 12.07 17.20 5.15 184.46 11.77 17.62 5.03 731.42 46.67 17.81 4.98 944.26 60.25 17.97 4.94 718.11 45.82 18.59 4.77 1391.57 88.79 18.80 4.72 301.13 19.21 19.12 4.64 316.24 20.18

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 19.45 4.56 381.14 24.32 19.86 4.47 1567.32 100.00 20.64 4.30 880.89 56.20 21.36 4.16 951.60 60.72 22.18 4.01 525.37 33.52 23.09 3.85 196.59 12.54 23.59 3.77 83.31 5.32 24.22 3.67 257.61 16.44 25.27 3.52 775.15 49.46 25.82 3.45 286.75 18.30 26.00 3.43 413.71 26.40 27.16 3.28 134.70 8.59 27.63 3.23 390.61 24.92 28.22 3.16 756.91 48.29 28.68 3.11 142.78 9.11 29.05 3.07 113.02 7.21 29.66 3.01 260.36 16.61 30.78 2.90 97.81 6.24 31.43 2.85 71.58 4.57 32.35 2.77 80.95 5.16 34.12 2.63 151.00 9.63

Form II may have an initial melting point of approximately 168° C. (FIG. 10). It may also be characterized by an initial melting point of approximately 168° C. together with (a) a powder X-ray diffraction pattern containing one or more peaks selected from approximately 5.8°2θ and approximately 8.8°2θ; or (b) a powder X-ray diffraction pattern substantially the same as in FIG. 9.

The DVS experiment indicated that the salt prepared according to Example 9 exhibited an absorption of 0.7% water at 90% RH. The crystalline form of the salt before and after the DVS experiment was the same. Under stable exposure conditions for one week at 40°C and 75% RH, the salt remained unchanged as determined by X-ray powder diffractometry. It was also unchanged at 80°C and ambient humidity after one week and under ambient light conditions by X-ray powder diffractometry. HPLC measurements made after such stability experiments indicated that purity did not change under these conditions (99% before the one week stability study and 99% after).

In table 6 shows the solubility of Form II crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid. The solubility increases from 16.8 mg/ml to 0.2 mg/ml as the pH value increases from 1.2 to 7.4. However, at a pH value of 1.2 the substance loses crystallinity.

- 14 043571

Table 6

Solubility data for Form II of sulcardine 1-hydroxy-2-naphthoic acid salt

Buffer pH value pH after added nya pH after adjusted Temperature (°C) pH in 72 hours pH after adjustment Temperature (°C) Solubility -1 (mg-ml) 1.2 1.9 1.2 18.8 3.4 1.2 18.5 16.8 3.0 4.3 3.0 18.8 4.0 2.9 18.5 4.2 4.0 4.4 4.0 18.8 4.5 4.1 18.5 6.1 7.4 7.3 No data 18.8 7.0 7.5 18.5 0.2

Powder X-ray diffraction patterns of various polymorphs of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid are not linear combinations of powder X-ray diffraction patterns of sulcardine free base and 1-hydroxy-2-naphthoic acid. For example, Form I has a peak of approximately 6.9°2θ, and Form II has a peak of approximately 8.8°2θ. Such peaks are absent in the X-ray powder diffraction pattern of 1-hydroxy2-naphthoic acid, as seen in FIG. 12, and the X-ray powder diffraction pattern of sulcardin free base does not contain any peaks. Thus, the powder X-ray diffraction patterns of Fig. 6 and fig. 9 are not a linear combination of salt starting materials.

In addition, using a specific X-ray powder diffraction pattern and DTA, melting events confirmed that a new solid form had been produced. ^{The 1} H-NMR spectrum showed the stoichiometric presence of the counterion and possible peak shifts compared to the free base, confirming that the substance was a salt and not a new polymorph or solvate/hydrate of the individual components.

All combinations of the above embodiments are covered by the present invention.

4. Naphthalene-2-sulfonic acid salt of sulcardine.

In accordance with certain embodiments, the present invention provides the naphthalene-2-sulfonic acid salt of sulcardine. In accordance with some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to naphthalene-2-sulfonic acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is sulcardine naphthalene-2-sulfonic acid monosalt.

A typical powder X-ray diffraction pattern of the naphthalene-2-sulfonic acid salt of sulcardine is shown in FIG. 13.

In accordance with some embodiments, the present invention provides a solid form containing a naphthalene-2-sulfonic acid salt of sulcardine, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21 or all peaks located at approximately the following positions: 9.4, 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-2-sulfonic acid salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 17.2, 17.8 and 21.3°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 13.3, 13.5, 16.6, and 16.9°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 9.4 and 10.6°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-2-sulfonic acid salt of sulcardine, which is characterized

- 15 043571 powder X-ray diffraction pattern, which coincides with the powder X-ray diffraction pattern shown in FIG. 13.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

Typical TG/DTA thermograms of the naphthalene-2-sulfonic acid salt of sulcardine are shown in FIG. 14. In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-2-sulfonic acid salt of sulcardine, which exhibits a weight loss of approximately 2.4% when heated from about 25°C to about 60°C. In some embodiments, without limitation to any particular theory, weight loss corresponds to water loss. In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-2-sulfonic acid salt of sulcardine, which has a TG thermogram that is the same as the TG thermogram presented in FIG. 14.

In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-2-sulfonic acid salt of sulcardine, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of approximately 88°C. In accordance with some embodiments, the thermal event is also characterized by a peak temperature of approximately 99°C. In some embodiments, without limitation to any particular theory, the thermal phenomenon corresponds to the melting of a solid form. In accordance with some embodiments, the present invention provides a solid form containing the naphthalene-2-sulfonic acid salt of sulcardine, which has a DTA thermogram that is the same as the DTA thermogram shown in FIG. 14.

In accordance with some embodiments, the present invention provides a solid form containing a naphthalene-2-sulfonic acid salt of sulcardine that exhibits a weight increase of approximately 0.8% when subjected to an increase in relative humidity (RH) from about 10% to about 90%.

In some embodiments, the naphthalene-2-sulfonic acid salt of sulcardine is prepared by subjecting a mixture of sulcardine and naphthalene-2-sulfonic acid (e.g., about 1:1 molar ratio) in a solvent (e.g., ethyl acetate) to a temperature cycle (e.g., from about 5 °C to approximately 25°C) over a period of time (eg approximately 72 hours). In other embodiments, the temperature cycle is from ambient temperature to about 40°C.

In other embodiments, a crystalline salt of sulcardine and naphthalene-2-sulfonic acid is provided. The preparation of the crystalline salt of sulcardine and naphthalene-2sulfonic acid is set forth in Example 9 and scaled up in Example 10. The salt may be such that it is characterized by a powder X-ray diffraction pattern containing one or more peaks selected from about 9.4°2θ, about 10.6 °2θ, approximately 13.3°2θ, approximately 13.5°2θ, approximately 16.6°2θ, approximately 16.9°2θ and approximately 17.2°2θ. It may also be characterized by a powder X-ray diffraction pattern containing peaks selected from about 9.4°2θ, about 10.6°2θ and about 13.5°2θ. In addition, it may further be characterized by a powder X-ray diffraction pattern containing two peaks from about 13.1°2θ to about 13.7°2θ and three peaks from about 16.4°2θ to about 17.4°2θ. Fig. 13 can be used to characterize the crystalline salt of sulcardine and naphthalene-2-sulfonic acid. A list of peaks that corresponds to many of the peaks in Fig. 13, presented in table. 7.

- 16 043571

Table 7

Table of X-ray powder diffractometry peaks corresponding to Fig. 13

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 7.07 12.51 176.92 5.50 22.81 3.90 604.94 18.82 9.44 9.37 513.36 15.97 23.25 3.83 506.64 15.76 9.95 8.89 203.06 6.32 23.48 3.79 363.82 11.32 10.56 8.38 770.75 23.97 24.13 3.69 241.26 7.50 10.80 8.19 360.51 11.21 24.34 3.66 359.42 11.18 12.00 7.38 184.87 5.75 24.80 3.59 1855.36 57.71 13.33 6.64 1251.95 38.94 25.23 3.53 221.07 6.88 13.53 6.54 1121.64 34.89 25.66 3.47 352.91 10.98 15.12 5.86 726.20 22.59 26.05 3.42 1106.51 34.41 15.31 5.79 301.11 9.37 26.83 3.32 517.54 16.10 16.56 5.35 1319.79 41.05 27.15 3.29 284.31 8.84 16.93 5.24 1180.83 36.73 27.95 3.19 386.04 12.01 17.20 5.16 2563.87 79.74 28.29 3.15 407.40 12.67 17.73 5.00 2168.94 67.46 28.52 3.13 261.41 8.13 17.82 4.98 2436.85 75.79 29.37 3.04 453.36 14.10 18.48 4.80 919.83 28.61 29.86 2.99 269.86 8.39 18.94 4.69 859.61 26.74 30.21 2.96 255.66 7.95 19.21 4.62 468.99 14.59 30.54 2.93 174.06 5.41 19.44 4.57 513.25 15.96 31.68 2.82 155.01 4.82 19.67 4.51 1153.36 35.87 32.06 2.79 183.12 5.70 20.22 4.39 2058.50 64.02 33.14 2.70 175.15 5.45 20.68 4.29 384.80 11.97 33.91 2.64 178.67 5.56 21.32 4.17 3215.20 100.00 34.48 2.60 115.50 3.59 21.74 4.09 1959.27 60.94

The crystalline salt of sulcardine and naphthalene-2-sulfonic acid may have an initial melting point of approximately 88° C. (FIG. 14). It may also be characterized by an initial melting point of approximately 88°C together with (a) a powder X-ray diffraction pattern containing one or more peaks selected from approximately 9.4°2θ, approximately 10.6°2θ, approximately 13.3°2θ, approximately 13.5°2θ, approximately 16.6°2θ, approximately 16.9°2θ and approximately 17.2°2θ; (b) a powder X-ray diffraction pattern containing peaks selected from about 9.4°2θ, about 10.6°2θ and about 13.5°2θ; (c) a powder X-ray diffraction pattern containing two peaks from about 13.1°2θ to about 13.7°2θ and three peaks from about 16.4°2θ to about 17.4°2θ; or (d) a powder X-ray diffraction pattern substantially the same as in FIG. 13.

In the TG/DTA experiment in FIG. 14 observed a weight loss of 2.4%, corresponding to approximately 0.91 water equivalents. This corresponds to a hydrate. Thus, a crystalline salt was prepared according to Example 10, for example, by preparing a hydrate of a crystalline salt of sulcardine and naphthalene-2sulfonic acid.

The DVS experiment indicated that the salt prepared according to Example 10 absorbed approximately 0.8% water at 10 to 90% RH, and that below 10% RH the substance appeared dehydrated. The crystalline form of the salt before and after the DVS experiment was the same. Under stable exposure conditions for one week at 40°C and 75% RH, the salt remained unchanged as determined by X-ray powder diffractometry. After one week at 80°C and ambient humidity the salt changed to an orange gel and under ambient light conditions after one week the substance was unchanged as determined by X-ray powder diffractometry but changed to a pale yellow color. HPLC measurements taken after these stability experiments showed that purity dropped from 99% to 98% after one week at 40°C and 75% RH, to 90% after one week at 80°C and to 97% after one week. under ambient light conditions.

Powder X-ray diffraction pattern of crystalline sulcardine salt and naphthalene-2sulfonic acid is not a linear combination of powder X-ray diffraction patterns

- 17 043571 free base of sulcardine and naphthalene-2-sulfonic acid. For example, naphthalene-2sulfonic acid has a peak at approximately 5°2θ, as seen in FIG. 16. Such peaks are absent in Fig. 13, and the X-ray powder diffraction pattern of sulcardin free base does not contain any peaks. Thus, the X-ray powder diffraction pattern of FIG. 13 is not a linear combination of salt starting materials.

In addition, using a specific X-ray powder diffraction pattern and DTA, melting events confirmed that a new solid form had been produced. ^{The 1} H-NMR spectrum showed the stoichiometric presence of the counterion and possible peak shifts compared to the free base, confirming that the substance was a salt and not a new polymorph or solvate/hydrate of the individual components.

The solubility of sulcardine salt and naphthalene-2-sulfonic acid is presented in table. 8 below and was prepared according to the procedures of Example 3.

Table 8

Solubility data for sulcardine salt and naphthalene-2-sulfonic acid

Meaning rn buffer pH after addition pH after adjustment Temperature (°C) pH after 72 hours pH after adjustment Temperature (°C) Solubility -1 (mg-ml) 1.2 1.2 No data 18.7 4.8 1.3 18.7 23.6 3.0 5.4 3.0 18.7 6.0 3.0 18.5 10.3 4.0 4.7 4.0 18.7 4.7 3.9 18.5 18.9 7.4 7.9 7.5 18.7 8.0 7.4 18.5 5.9

All combinations of the above embodiments are covered by the present invention.

5. Form I of sulcardine hydrochloride salt.

In accordance with certain embodiments, the present invention provides Form I of the hydrochloride salt of sulcardine. In accordance with some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to hydrochloric acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is a monohydrochloride salt of sulcardine.

A typical powder X-ray diffraction pattern of Form I of the hydrochloride salt of sulcardine is shown in FIG. 17.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or all peaks located approximately at the following positions: 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 17.4, 17.8 and 23.9°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 13.9, 20.3, and 21.9° 2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 17.2 and 18.6°2θ. In some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 12.3, 13.0 and 17.8°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 13.9, 17.4, and 23.9°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 20.3 and 21.9°2θ.

- 18 043571

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine that has an X-ray powder diffraction pattern that matches the X-ray powder diffraction pattern shown in FIG. 17.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

Typical TG/DTA thermograms of Form I of sulcardine hydrochloride salt are shown in FIG. 18. In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine that exhibits a weight loss of approximately 3.1% when heated from about 25°C to about 90°C. In some embodiments, without limitation to any particular theory, weight loss corresponds to water loss. In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine that has a TG thermogram that is the same as the TG thermogram shown in FIG. 18.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine that has a DTA thermogram that is the same as the DTA thermogram shown in FIG. 18.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine that exhibits a weight increase of approximately 2.2% when subjected to an increase in relative humidity (RH) from about 10% to about 90%.

In some embodiments, the Form I hydrochloride salt of sulcardine is prepared by subjecting a mixture of sulcardine and hydrochloric acid (e.g., about 1:1 molar ratio) in a solvent (e.g., THF) to a temperature cycle (e.g., about 5° C. to about 25° C. ) over a period of time (eg approximately 72 hours).

According to further embodiments, crystalline salts of sulcardine and hydrochloric acid (also referred to as sulcardine hydrochloride) are provided. The hydrochloride salt is polymorphic. In Example 11, Form II of the crystalline salt of sulcardine and hydrochloric acid was prepared. Form I of the crystalline salt of sulcardine and hydrochloric acid was prepared on a large scale. Form I may be such that it is characterized by a powder x-ray diffraction pattern containing one or more peaks selected from about 12.3°2θ to about 13.0°2θ. In some embodiments, the X-ray powder diffraction pattern for Form I does not have a peak below about 9.5°2θ. Powder X-ray diffraction pattern is basically the same as in FIG. 17 can also be used to characterize Form I of the crystalline salt of sulcardine and hydrochloric acid. A list of peaks that corresponds to many of the peaks in Fig. 17 is presented in table. 9.

- 19 043571

Table 9

Table of X-ray powder diffractometry peaks corresponding to Fig. 17

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 10.22 8.66 300.67 11.38 22.68 3.92 190.64 7.22 11.36 7.79 675.81 25.58 23.38 3.80 284.59 10.77 11.46 7.72 424.83 16.08 23.61 3.77 405.95 15.37 12.33 7.18 488.93 18.51 23.85 3.73 2280.36 86.31 12.68 6.98 312.92 11.84 24.44 3.64 141.40 5.35 13.04 6.79 683.23 25.86 24.81 3.59 370.66 14.03 13.64 6.49 223.45 8.46 25.40 3.50 545.64 20.65 13.93 6.36 1401.98 53.07 25.51 3.49 497.09 18.82 14.80 5.99 519.94 19.68 25.95 3.43 185.92 7.04 16.13 5.50 449.22 17.00 26.85 3.32 189.34 7.17 16.33 5.43 176.44 6.68 27.36 3.26 571.69 21.64 17.20 5.16 867.18 32.82 27.79 3.21 283.01 10.71 17.36 5,N 1662.60 62.93 28.01 3.19 187.54 7.10 17.84 4.97 2641.96 100.00 28.37 3.15 472.36 17.88 18.06 4.91 726.55 27.50 28.86 3.09 334.24 12.65 18.56 4.78 1020.63 38.63 29.39 3.04 167.27 6.33 19.24 4.61 565.65 21.41 29.87 2.99 213.81 8.09 19.84 4.48 816.78 30.92 30.32 2.95 114.60 4.34 20.01 4.44 517.67 19.59 30.66 2.92 135.45 5.13 20.28 4.38 1252.88 47.42 31.03 2.88 111.04 4.20 20.52 4.33 256.72 9.72 31.93 2.80 160.34 6.07 20.74 4.28 137.55 5.21 32.46 2.76 266.62 10.09 21.94 4.05 1439.82 54.50 33.18 2.70 274.03 10.37 22.46 3.96 159.16 6.02 33.91 2.64 159.84 6.05

In the TG/DTA experiment in FIG. 18 observed a mass loss of approximately 3.1%, corresponding to approximately 0.88 water equivalents for Form I. This corresponds to a hydrate. Thus, the crystalline salt prepared according to Example 12 (Form I), for example, gives a hydrate of the crystalline salt of sulcardine and hydrochloric acid.

The DVS experiment indicated that the salt prepared according to Example 12 (Form I) absorbed approximately 2.2% water at 90% RH. The crystalline form of the salt before and after the DVS experiment was the same. Under stable exposure conditions for one week at 40°C and 75% RH, the salt remained unchanged as determined by X-ray powder diffractometry. After one week at 80°C and ambient humidity, the salt changed to an orange gel and under ambient light conditions after one week the substance was unchanged as determined by X-ray powder diffractometry. HPLC measurements taken after these stability experiments showed that purity dropped from 99% to 98% after one week at 40°C and 75% RH, to 90% after one week at 80°C and remained unchanged (99%) after one week under ambient light conditions.

All combinations of the above embodiments are covered by the present invention.

6. Form II of sulcardine hydrochloride salt.

In accordance with certain embodiments, the present invention provides Form II of sulcardine hydrochloride salt. In accordance with some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to hydrochloric acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is a monohydrochloride salt of sulcardine.

- 20 043571

A typical powder X-ray diffraction pattern of Form II of the hydrochloride salt of sulcardine is shown in FIG. 17A.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or all peaks located at approximately the following positions: 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 13.5, 19.6 and 20.6°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 10.1, 11.8, and 16.4°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 17.8, 19.4, and 25.5°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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 accordance with some embodiments, the X-ray powder diffraction pattern does not contain a peak at approximately 12.3° 2θ. In accordance with some embodiments, the X-ray powder diffraction pattern does not contain a peak at approximately 13.0°2θ.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 11.8, 13.5, 19.6 and 20.6°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 17.8, 19.4, and 25.5°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 23.5 and 26.5°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern does not contain a peak at approximately 12.3°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern does not contain a peak at approximately 13.0°2θ.

In accordance with some embodiments, the present invention provides a solid form containing a hydrochloride salt of sulcardine that has an X-ray powder diffraction pattern that matches the X-ray powder diffraction pattern shown in FIG. 17A.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

In some embodiments, Form II of sulcardine hydrochloride salt is prepared by subjecting a mixture of sulcardine and hydrochloric acid (e.g., approximately 1:1 molar ratio) in a solvent (e.g., a mixture of 2-propanol and heptane) to a temperature cycle (e.g., from ambient temperature to approximately 40°C) for a period of time (eg approximately 72 hours). In accordance with some embodiments, the solvent is a 2:1 v/v mixture. 2-propanol and heptane.

Form II may be such that it is characterized by a powder X-ray diffraction pattern containing one or more peaks selected from about 10.1°2θ, 11.8°2θ, about 13.5°2θ and about 16.4°2θ, and in which there is no peak between peaks from approximately 10.1°2θ to approximately 11.8°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern for Form II does not contain peaks below approximately 9.5°2θ. The X-ray powder diffraction pattern for Form II is described in FIG. 17A, and table. 9A below is a peak table for certain peaks in FIG. 17A.

- 21 043571

Table 9A

Table of X-ray powder diffractometry peaks corresponding to Fig. 17A

Position (°20) Interplanar distance d(A) Height (area) Relative intensity (%) 10.12 8.74 681.32 26.84 11.84 7.47 369.32 14.55 12.82 6.91 63.84 2.51 13.10 6.76 110.39 4.35 13.49 6.56 2538.87 100.00 15.87 5.58 524.69 20.67 16.43 5.40 591.14 23.28 17.47 5.08 398.30 15.69 17.77 4.99 1071.67 42.21 18.21 4.87 228.77 9.01 18.40 4.82 310.33 12.22 19.44 4.57 1544.92 60.85 19.64 4.52 2246.73 88.49 20.29 4.38 248.44 9.79 20.62 4.31 1593.00 62.74 20.89 4.25 194.17 7.65 21.50 4.13 197.47 7.78 22.45 3.96 393.25 15.49

Position (°20) Interplanar distance d(A) Height (area) Relative intensity (%) 22.94 3.88 84.83 3.34 23.53 3.78 714.86 28.16 24.19 3.68 56.04 2.21 24.54 3.63 227.53 8.96 25.47 3.50 1004.01 39.55 25.80 3.45 137.82 5.43 26.51 3.36 899.17 35.42 26.58 3.36 685.29 26.99 27.03 3.30 567.72 22.36 27.38 3.26 133.29 5.25 28.34 3.15 142.10 5.60 29.08 3.07 94.63 3.73 29.45 3.03 66.95 2.64 30.70 2.91 66.42 2.62 31.11 2.87 32.85 1.29 32.03 2.79 81.34 3.20 33.18 2.70 338.04 13.31 34.15 2.62 109.96 4.33

Since hydrochloric acid is liquid under the experimental conditions used in the present invention, the resulting solid is not a mixture of hydrochloric acid and the amorphous free base of sulcardine. The solid is a crystalline salt of sulcardine and hydrochloric acid.

All combinations of the above embodiments are covered by the present invention.

7. Hemi-edisylate salt of sulcardine.

In accordance with certain embodiments, the present invention provides the ethane-1,2-disulfonic acid salt of sulcardine. In accordance with some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to ethane1,2-disulfonic acid in the salt is approximately 2:1. In some embodiments, the salt is sulcardine ethane-1,2-disulfonic acid hemisol.

A typical powder X-ray diffraction pattern of the ethane-1,2-disulfonic acid salt of sulcardine is shown in FIG. 19.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21 or all peaks located at approximately the following positions: 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 14.1, 17.8 and 23.7°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 5.6 and 14.9°2θ. According to some options

- 22 043571 implementation, the powder X-ray diffraction pattern additionally contains peaks at approximately 11.0 and 13.0°2θ. In some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which has an X-ray powder diffraction pattern that matches the X-ray powder diffraction pattern shown in FIG. 19.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

Typical TG/DTA thermograms of the hemi-edisylate salt of sulcardine are shown in FIG. 20. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which exhibits a weight loss of approximately 0.4% when heated from about 25°C to about 160°C. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which has a TG thermogram that is the same as the TG thermogram shown in FIG. 20.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of approximately 211°C. In accordance with some embodiments, the thermal event is also characterized by a peak temperature of approximately 213°C. In some embodiments, without limitation to any particular theory, the thermal phenomenon corresponds to the melting of a solid form. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which has a DTA thermogram that is the same as the DTA thermogram shown in FIG. 20.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine that exhibits a weight increase of about 0.5% when subjected to an increase in relative humidity (RH) from about 10% to about 90% .

In some embodiments, sulcardine ethane-1,2-disulfonic acid hemisol is prepared by subjecting a mixture of sulcardine and ethane-1,2-disulfonic acid (e.g., about 2:1 molar ratio) in a solvent to a temperature cycle (for example, from about 5° C to about 25°C) over a period of time (eg, about 72 hours). In other embodiments, the temperature cycle is from ambient temperature to about 40°C. In accordance with some embodiments, the solvent is toluene. In some embodiments, the solvent is a mixture of toluene and heptane (eg, 2:1 v/v).

In accordance with additional embodiments, the present invention provides crystalline salts of sulcardine and ethane-1,2-disulfonic acid. The preparation of the crystalline salt of sulcardine and ethane-1,2-disulfonic acid was carried out in Example 13 and scaled up in Example 14. Such crystalline salts may be such that they are characterized by a powder X-ray diffraction pattern containing one or more peaks selected from approximately 5.6° 2θ, approximately 11.0°2θ, approximately 13.0°2θ, approximately 14.1°2θ and approximately 14.9°2θ. Powder X-ray diffraction pattern, which is basically the same as in FIG. 19 can also be used to characterize the crystalline salt of sulcardine and ethane1,2-disulfonic acid. Such crystalline salts may have an initial melting point of approximately 211°C with or without characteristic X-ray powder diffraction data. Thus, for example, crystalline salts of sulcardine and ethane-1,2-disulfonic acid may be characterized by an initial melting point of approximately 211°C and (a) a powder X-ray diffraction pattern containing one or more peaks selected from approximately 5.6°2θ, approximately 11.0°2θ, approximately 13.0°2θ, approximately 14.1°2θ and approximately 14.9°2θ or (b) a powder X-ray diffraction pattern substantially the same as in FIG. 19. List of peaks, corresponding to many of the peaks in Fig. 19, is presented in table 10. The solubility of the crystalline salt of ethane-1,2-disulfonic acid sulcardine is presented in table. eleven.

- 23 043571

Table 10

Table of X-ray powder diffractometry peaks corresponding to Fig. 19

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 5.57 15.86 540.23 23.02 10.30 8.59 58.41 2.49 11.04 8.02 362.80 15.46 13.01 6.80 293.26 12.50 14.08 6.29 1596.56 68.04 14.91 5.94 800.37 34.11 16.17 5.48 769.99 32.81 16.81 5.28 566.17 24.13 17.19 5.16 752.16 32.05 17.51 5.07 836.58 35.65 17.80 4.98 2346.65 100.00 18.78 4.72 1215.08 51.78 19.39 4.58 629.39 26.82 19.56 4.54 1338.23 57.03 20.03 4.43 253.56 10.81 20.40 4.35 1052.82 44.86 20.72 4.29 216.99 9.25 21.70 4.09 1084.31 46.21 21.77 4.08 1509.90 64.34

Powder X-ray diffraction patterns

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 22.20 4.00 780.52 33.26 22.92 3.88 193.45 8.24 23.71 3.75 2285.76 97.40 24.46 3.64 330.10 14.07 25.06 3.55 617.83 26.33 25.74 3.46 436.99 18.62 25.78 3.46 437.79 18.66 26.44 3.37 135.81 5.79 27.16 3.28 367.43 15.66 27.50 3.24 285.44 12.16 28.65 3.12 229.50 9.78 29.15 3.06 208.61 8.89 29.65 3.01 131.08 5.59 30.09 2.97 241.51 10.29 31.59 2.83 134.52 5.73 32.47 2.76 150.91 6.43 33.52 2.67 136.46 5.82 33.98 2.64 186.80 7.96

crystalline salts of sulcardine and ethane-1,2-disulfonic acid are not linear combinations of powder X-ray diffraction patterns of the amorphous free base of sulcardine and ethane-1,2-disulfonic acid. For example, salt has a peak at approximately 5.6°2θ. There is no such peak in the X-ray powder diffraction pattern of the corresponding ethane-1,2-disulfonic acid, as seen in FIG. 22, and the X-ray powder diffraction pattern of sulcardin free base does not contain any peaks. Thus, the X-ray powder diffraction pattern in FIG. 19 is not a physical mixture of salt starting materials. The solubility of the ethane-1,2-disulfonic acid salt of sulcardine is presented in table. 11 below and was prepared according to the procedures of Example 3.

In addition, a specific X-ray powder diffraction pattern and DTA melting phenomenon confirmed that a new solid form had been obtained. ^{The 1} H-NMR spectrum showed the presence of approximately 0.5 equivalents of the counterion and possible peak shifts compared to the free base, confirming that the substance was a salt and not a new polymorph or solvate/hydrate of the individual components.

In ^{the 1} H NMR spectrum in FIG. 21, which is the salt of Example 14, 0.5 equivalents of ethane-1,2-disulfonic acid was observed. This corresponds to a hemisol such that there is 1 equivalent of ethane-1,2-disulfonic acid for every two equivalents of sulcardine free base in the salt. Ethane-1,2-disulfonic acid contains two acid groups that can form a salt with the free base sulcardine. Thus, in such a hemisol, two molecules of the free base of sulcardin form a salt with one molecule of the free acid.

The DVS experiment indicated that the salt prepared according to Example 14 absorbed approximately 0.5% water at 90% RH. The crystalline form of the salt before and after the DVS experiment was the same. Under stable exposure conditions for one week at 40°C and 75% RH, the salt remained unchanged as determined by X-ray powder diffractometry. The salt remained unchanged at 80°C and ambient humidity after one week, as determined by X-ray powder diffractometry, and under natural light conditions, the substance remained unchanged after one week, as determined by X-ray powder diffractometry. HPLC measurements carried out after these stability experiments showed that the purity dropped from 99% to 98% after one week at 40°C and 75% RH, to 97% after one week at

- 24 043571

80°C and up to 97% after one week under natural light conditions.

Table 11

Solubility data for sulcardine ethane-1,2-disulfonic acid hemisol

Meaning rn buffer pH after addition pH after regulation Temperature (°C) pH after 72 hours pH after adjustment Temperature (°C) Dissolve -1 MOSTE (mg-ml) 1.2 1.7 1.2 18.8 1.2 No data 18.7 41.1 3.0 6.7 3.0 18.8 4.3 3.0 18.7 46.3 4.0 5.8 4.0 18.8 4.1 4.1 18.5 36.1 7.4 7.8 7.3 18.7 7.5 No data 18.5 18.9

All combinations of the above embodiments are covered by the present invention.

8. Form I of sulcardine monoedisylate salt.

In accordance with certain embodiments, the present invention provides the ethane-1,2-disulfonic acid salt of sulcardine. In accordance with some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to ethane1,2-disulfonic acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is ethane-1,2-disulfonic acid sulcardine monosalt. In accordance with some embodiments, the present invention provides Form I of the sulcardine monoedisylate salt. In some embodiments, Form I is sulcardine monoedisylate salt hydrate. In some embodiments, Form I is sulcardine monoedisylate salt monohydrate.

A typical powder X-ray diffraction pattern of sulcardine ethane-1,2-disulfonic acid monosalt Form I (monoedisylate salt) is shown in FIG. 26.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, or all peaks located approximately at the following positions: 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 18.8, 20.2 and 21.2°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 9.2, 10.4, and 13.8°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 9.6, 14.2, and 14.9°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which has an X-ray powder diffraction pattern that matches the X-ray powder diffraction pattern shown in FIG. 26.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

Typical TG/DTA thermograms of Form I of sulcardine monoedisylate salt are shown in FIG. 27. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which exhibits a weight loss of approximately 2.8% when heated from about 25°C to about 150°C and loss weight of approximately 0.5% when heated from approximately 150°C to approximately 200°C. In accordance with some embodiments, without limitation to any particular theory, the general

- 25 043571 weight loss corresponds to a loss of approximately 1 equivalent of water. In accordance with some embodiments, the present invention provides a solid form containing the ethane1,2-disulfonic acid salt of sulcardine, which has a TG thermogram that matches

TG thermogram shown in Fig. 27.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of approximately 244°C. In accordance with some embodiments, the thermal event is also characterized by a peak temperature of approximately 273°C. In some embodiments, without limitation to any particular theory, the thermal phenomenon corresponds to the disintegration of a solid form. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which has a DTA thermogram that is the same as the DTA thermogram shown in FIG. 27.

A typical FT-IR spectrum of Form I of sulcardine monoedisylate salt is shown in FIG. 37A. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by an FT-IR spectrum containing a peak above about 3500 cm ^-1 . In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2 disulfonic acid salt of sulcardine, which is characterized by an FT-IR spectrum containing one or more peaks at approximately 3556, 1206 and 814 cm ^-1 . In accordance with some embodiments, the FT-IR spectrum contains a peak at approximately 3556 cm ^-1 . In accordance with some embodiments, the FT-IR spectrum contains a peak at approximately 1206 cm ^-1 . In accordance with some embodiments, the FT-IR spectrum contains a peak at approximately 814 cm ^-1 . In accordance with some embodiments, the FT-IR spectrum contains the following approximate peaks:

- 26 043571

Peak shift (cm ¹ ) Relative intensity 3556 122.47 3483 123.71 3259 3302.59 3017 252.73 2767 91.18 2631 33.02 1639 17.86 1593 14.70 1576 60.59 1497 13.11 1447 40.31 1435 45.66 1330 14.39 1304 10.36 1260 2208.13 1232 5.80 1206 15.59 1146 72.43 1115 66.80 1093 9.28 1069 10.60 1054 50.84 1023 24.78 946 12.70 922 46.33 898 8.59 845 22.97 814 6.66 800 5.68 767 26.59 666 20.65 621 18.06 548 47.25 521 8.68 486 12.29

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine that has an FTIR spectrum that matches the FT-IR spectrum shown in FIG. 37A.

In accordance with some embodiments, the present invention provides

- 27 043571 solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by both a powder X-ray diffraction pattern and an FT-IR spectrum presented in this section. For example, in accordance with some embodiments, the solid form is such that it is characterized by a powder x-ray diffraction pattern containing peaks of approximately 18.8,

20.2 and 21.2°2θ, and is characterized by an FT-IR spectrum containing a peak above 3500 cm ^-1 .

In some embodiments, Form I of the sulcardine monoedisylate salt is prepared by subjecting a mixture of sulcardine and ethane-1,2-disulfonic acid (e.g., about 1:1 molar ratio) in a solvent to a temperature cycle (e.g., from about ambient temperature to about 40° C) over a period of time (eg, approximately 48 hours). In accordance with some embodiments, the solvent is toluene.

In accordance with additional embodiments, the present invention provides a monoedisylate salt of sulcardine. This salt contains one equivalent of ethane-1,2 disulfonic acid for every one equivalent of sulcardine. In addition, the present invention provides crystalline monoedisylate salts of sulcardine, such as Form I crystalline sulcardine monoedisylate salt and Form II crystalline sulcardine monoedisylate salt. Form I crystalline sulcardine monoedisylate salt is presented in Example 17 and Form II crystalline sulcardine monoedisylate salt is presented in Example 18. Additionally, the present invention provides hydrates of sulcardine monoedisylate. Such hydrates include monohydrates and dihydrates.

Form I of the crystalline monoedisylate salt of sulcardine is a monohydrate and may be such that it is characterized by a powder x-ray diffraction pattern containing a peak at approximately 14.2°2θ. Form I of the crystalline monoedisylate salt may also be characterized by a powder x-ray diffraction pattern containing a peak at approximately 9.2°2θ and no peak at approximately 5.2°2θ. Form I of the crystalline monoedisylate salt may also be characterized by a powder x-ray diffraction pattern containing two peaks from about 9.0°2θ to about 9.8°2θ. Form I of the crystalline monoedisylate salt may also be characterized by a powder x-ray diffraction pattern containing two peaks from about 9.0°2θ to about 9.8°2θ, where the differences between the two peaks are approximately 0.4°2θ. In some embodiments, the difference between the two peaks is 0.4°2θ ±0.1°2θ. Form I of the crystalline sulcardine monoedisylate salt may also be characterized by a powder x-ray diffraction pattern containing 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 approximately 14.9°2θ. An XPRD image which is basically the same as in FIG. 26 can also be used to characterize Form I of the crystalline monoedisylate salt of sulcardine. ¹ H-NMR spectroscopy can be used to confirm the 1:1 stereochemistry of ethane-1,2-disulfonic acid to sulcardine (see Fig. 30).

Form I of the crystalline sulcardine monoedisylate salt may also have an X-ray powder diffraction peak at approximately 14.2°2θ and an FT-IR spectrum containing a peak above approximately 3500 cm ^-1 . Form I of the crystalline sulcardine monoedisylate salt may also be characterized by an X-ray powder diffraction peak of approximately 14.2°2θ with no peak at approximately 5.2°2θ and an FT-IR spectrum containing a peak above approximately 3500 cm ^-1 , and additionally optionally containing one or more FT-IR peaks at approximately 1206 cm ^-1 and approximately 814 cm ^-1 . Form I of the crystalline sulcardine monoedisylate salt may also be characterized by a powder x-ray diffraction pattern containing two peaks at approximately 9.0°2θ and approximately 9.8°2θ, and wherein, in some embodiments, the difference between the two peaks is approximately 0.4°2θ, and F.T. -IR spectrum containing a peak above about 3500 cm ^-1 and additionally optionally containing one or more FT-IR peaks at about 1206 cm ^-1 and about 814 cm ^-1 . Form I of the crystalline sulcardine monoedisylate salt may also be characterized by a powder x-ray diffraction pattern containing one or more peaks at approximately 9.2°2θ, approximately 9.6°2θ, approximately 10.4°2θ, approximately 13.8°2θ, approximately 14.2 °2θ and about 14.9°2θ, and an FT-IR spectrum containing a peak above about 3500 cm ^-1 and additionally optionally containing one or more FT-IR peaks about 1206 cm ^-1 and about 814 cm ^-1 . In some embodiments provided herein, the peak above about 3500 cm ^-1 is located at about 3556 cm ^-1 .

The TG/DTA thermogram of Form I crystalline sulcardine monoedisylate salt is shown in FIG. 27. This figure shows a mass loss of approximately 2.8% and also approximately 0.5%, which corresponds to approximately 1 equivalent of water. Using the Karl-Fischer Form I assay, a water content of 3% or approximately 1 water equivalent was observed. This coincides with the TG data, which showed a mass loss of approximately 3.2%, which is equal to 1 equivalent of water. Thus,

- 28 043571 form I is a monohydrate. No melting was observed before disintegration at 244°C. A list of peaks that corresponds to many of the peaks in Fig. 26, presented in table. 11A below.

Table 11A

Table of X-ray powder diffractometry peaks corresponding to Fig. 26

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 9.24 9.57 1201.01 39.54 9.64 9.18 834.18 27.46 10.43 8.48 1171.61 38.57 10.95 8.08 123.70 4.07 11.69 7.57 234.65 7.72 11.90 7.44 143.27 4.72 12.13 7.29 356.05 11.72 12.79 6.92 521.37 17.16 13.78 6.43 1830.88 60.27 14.17 6.25 702.56 23.13 14.90 5.95 689.32 22.69 15.82 5.60 319.52 10.52 16.26 5.45 604.12 19.89 16.61 5.34 246.29 8.11 16.91 5.24 275.56 9.07 17.57 5.05 281.78 9.28 18.31 4.84 340.47 11.21 18.75 4.73 2126.07 69.99 18.91 4.69 1760.45 57.95 19.36 4.59 369.21 12.15 20.16 4.41 3037.68 100.00 20.84 4.26 729.02 24.00 21.22 4.19 2157.40 71.02 21.97 4.05 189.19 6.23

Powder X-ray diffraction pattern

Position (°2θ) Interplanar distance 4(A) Height (area) Relative intensity (%) 22.66 3.92 1004.82 33.08 22.94 3.88 339.16 11.17 23.27 3.82 463.64 15.26 23.52 3.78 375.21 12.35 24.08 3.70 412.11 13.57 24.49 3.63 1003.15 33.02 24.78 3.59 1218.59 40.12 25.75 3.46 311.13 10.24 26.19 3.40 861.54 28.36 26.47 3.37 408.66 13.45 27.08 3.29 213.95 7.04 27.87 3.20 113.08 3.72 28.54 3.13 148.42 4.89 29.50 3.03 139.71 4.60 29.89 2.99 111.32 3.66 30.49 2.93 405.51 13.35 30.83 2.90 134.88 4.44 31.32 2.86 95.18 3.13 31.82 2.81 189.90 6.25 32.39 2.76 124.64 4.10 33.38 2.68 115.93 3.82 33.69 2.66 157.79 5.19 34.23 2.62 138.31 4.55 34.65 2.59 121.38 4.00

Form I of the crystalline monoedisylate salt of sulcardine is not a linear combination of powder X-ray diffraction patterns of ethane-1,2 disulfonic acid and the amorphous free base of sulcardine. For example, Form I of the crystalline sulcardine monoedisylate salt has a peak at approximately 9.2°2θ, which is absent in the powder X-ray diffraction pattern of ethane-1,2-disulfonic acid of FIG. 22 and amorphous sulcardine is not characterized by peaks. Powder X-ray diffraction pattern of Fig. 26 is not a physical mixture of salt starting materials.

In accordance with some embodiments, Form I of the sulcardine monoedisylate salt is converted to Form II of the sulcardine monoedisylate salt under aqueous conditions. When Form I of the sulcardine monoedisylate salt was tested for its thermodynamic solubility, higher solubility (>150 mg/mL) was observed in all buffer systems identified (Table 11B). No solids were observed by X-ray powder diffractometry analysis. HPLC analysis was not performed on the samples due to high solubility.

- 29 043571

Table 11B

Observations and results of thermodynamic solubility of form I of sulcardine monoedisylate salt in 20 mM buffers

Buffer In 4 hours In 16 hours Conc. (mg/ml) Nab l. pH Adjusted pH Nab l. pH Adjusted pH pH1.2HC1/ KS1 Transparent colorless solution 1.06 1.24 Transparent colorless solution 0.55 1.20 >150 рНЗ,0НС1/ glycine Transparent colorless solution 2.46 3.02 Transparent colorless solution 1.21 2.96 >150 pH 4.0, citrate Transparent colorless solution 3.16 4.05 Transparent colorless solution 1.31 3.95 >150 pH 6.8, phosphate Transparent colorless solution 5.25 6.81 Transparent colorless solution 1.35 6.74 >150 pH 7.4, phosphate Transparent colorless solution 5.86 7.26 Transparent colorless solution 0.99 7.54 >150 pH 8.0, phosphate Transparent colorless solution 6.07 8.01 Transparent colorless solution 1.1 7.93 >150 FaSSGF Transparent colorless solution 1.17 No data Transparent colorless solution 1.15 No data >150

All combinations of the above embodiments are covered by the present invention.

9. Form II of sulcardine monoedisylate salt.

In accordance with certain embodiments, the present invention provides the ethane-1,2-disulfonic acid salt of sulcardine. In accordance with some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to ethane1,2-disulfonic acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is ethane-1,2-disulfonic acid sulcardine monosalt. In accordance with some embodiments, the present invention provides Form II of sulcardine monoedisylate salt. In some embodiments, Form I is sulcardine monoedisylate salt hydrate. In some embodiments, Form II is sulcardine monoedisylate salt dihydrate.

A typical powder X-ray diffraction pattern of Form II ethane-1,2-disulfonic acid monosalt (monoedisylate salt) of sulcardine is shown in FIG. 28.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by 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 peaks located at approximately the following positions: 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 accordance with some embodiments, the solid form is characterized by 3 of the peaks. In accordance with some embodiments, the solid form is characterized by 5 of the peaks. In accordance with some embodiments, the solid form is characterized by 7 of the peaks. In accordance with some embodiments, the solid form is characterized by 9 of the peaks. In accordance with some embodiments, the solid form has 11 of the peaks. In accordance with some embodiments, the solid form has all peaks.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 15.7, 16.9 and 23.6°2θ. IN

- 30 043571 According to some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 5.2, 9.1 and 11.3°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 17.6 and 19.2°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which has an X-ray powder diffraction pattern that matches the X-ray powder diffraction pattern shown in FIG. 28.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

Typical TG/DTA thermograms of Form II sulcardine monoedisylate salt are shown in FIG. 29. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which exhibits a weight loss of approximately 4.9% when heated from about 100°C to about 150°C. In some embodiments, without limitation to any particular theory, weight loss corresponds to a loss of approximately 2 water equivalents. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2 disulfonic acid salt of sulcardine, which has a TG thermogram that is the same as the TG thermogram shown in FIG. 29.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which exhibits, as characterized by DTA, a first thermal event with an initial temperature of approximately 103° C. and a second thermal event with an initial temperature of approximately 242°C. In accordance with some embodiments, the first thermal event also has a peak temperature of approximately 119°C, and the second thermal event also has a peak temperature of approximately 275°C. According to some embodiments, without limiting any particular theory, the first thermal event corresponds to dehydration and the second thermal event corresponds to dehydration of the solid form. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which has a DTA thermogram that is the same as the DTA thermogram shown in FIG. 29.

A typical FT-IR spectrum of Form II of sulcardine monoedisylate salt is shown in FIG. 37B. In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, which is characterized by an FT-IR spectrum containing no peak above about 3500 cm ^-1 . In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2 disulfonic acid salt of sulcardine, which is characterized by an FT-IR spectrum containing one or more peaks at approximately 3374 and 826 cm ^-1 . In accordance with some embodiments, the FTIR spectrum contains a peak at approximately 3374 cm ^-1 . In accordance with some embodiments, the FT-IR spectrum contains a peak at approximately 826 cm ^-1 . In accordance with some embodiments, the FT-IR spectrum contains the following approximate peaks.

- 31 043571

1495 1453 1423 1323 1298 1259 1226 1181 1149 1107 1094 1080 1056 1027 920 894 881 850 826 799 767 715 666 604 541 527 489 409

12.76 49.22 313.08 17.45 160.55 11.46 10.72 19.42 74.56 24.63 79.44 92.85 205.98 33.93 9.90 2273.93 23.72 9.73 13.48 887.71 14.45 428.00 11.35 310.95 87.23 34.14 282.63 16.33

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine that has an FTIR spectrum that matches the FT-IR spectrum shown in FIG. 37B.

In accordance with some embodiments, the present invention provides a solid form containing the ethane-1,2-disulfonic acid salt of sulcardine, as characterized by both the powder X-ray diffraction pattern and the FT-IR spectrum presented in this section. For example, in accordance with some embodiments, the solid form is such that it is characterized by a powder X-ray diffraction pattern containing peaks at approximately 15.7, 16.9 and 23.6°2θ, and is characterized by an FT-IR spectrum containing no peaks above 3500 cm ^-1 .

In some embodiments, Form II sulcardine monoedisylate salt is prepared by subjecting a mixture of sulcardine and ethane-1,2-disulfonic acid (e.g., about 1:1 molar ratio) in a solvent to a temperature cycle (e.g., from about ambient temperature to about 40° C) over a period of time (eg, approximately 96 hours or at least 96 hours). In accordance with some embodiments, the solvent is toluene.

In some embodiments, Form II sulcardine monoedisylate salt is prepared by suspending Form I sulcardine monoedisylate salt (including a mixture including Form I sulcardine monoedisylate salt) in a mixture of ethanol and water over a period of time (e.g., approximately 120 hours).

Form II of crystalline sulcardine monoedisylate is a more highly active hydrate than Form I and may be characterized by a powder X-ray diffraction pattern containing a peak at approximately 5.2°2θ. Form II of crystalline monoedisylate sulcardine

- 32 043571 may also be such that it is characterized by a powder x-ray diffraction pattern containing one or more peaks of approximately 5.2°2θ, approximately 9.1°2θ, approximately 10.2°2θ, approximately 10.8°2θ, approximately 11, 3°2θ, approximately 13.6°2θ and approximately 15.7°2θ. The XPRD image is basically the same as in FIG. 28 can also be used to characterize Form II crystalline sulcardine monoedisylate. ¹ H-NMR spectroscopy can be used to confirm the 1:1 stereochemistry of ethane-1,2-disulfonic acid to sulcardine (see Fig. 31).

Form II of crystalline sulcardine monoedisylate may be such that it is characterized by a powder x-ray diffraction pattern containing a peak at approximately 5.2°2θ and an FT-IR spectrum containing no peak above about 3500 cm ^-1 and additionally optionally containing one or more peaks at approximately 3374 cm ^-1 and approximately 826 cm ^-1 . In accordance with some embodiments, Form II of crystalline sulcardine monoedisylate may be such that it is characterized by a powder x-ray diffraction pattern containing 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 an FT-IR spectrum containing no peak above about 3500 cm ^-1 and additionally optionally containing one or more peaks at about 3374 cm ^-1 and approximately 826 cm ^-1 .

The TG/DTA thermogram of Form II crystalline sulcardine monoedisylate salt is shown in FIG. 29. This figure shows a mass loss of approximately 4.9% from about 100°C to about 150°C, which corresponds to approximately 2 equivalents of water. Using the Karl Fischer assay, Form II showed a water content of 5% or approximately 2 water equivalents. This corresponds to the TG data, which shows a weight loss of approximately 4.9%, which is equal to 2 water equivalents. Thus, Form II is a dihydrate. A list of peaks that corresponds to many of the peaks in Fig. 28, presented in table. 11C below.

Table 11C

Table of X-ray powder diffractometry peaks corresponding to Fig. 28

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 5.22 16.92 626.89 51.50 9.06 9.76 681.27 55.97 10.20 8.67 109.66 9.01 10.81 8.19 324.50 26.66 11.27 7.85 572.37 47.03 11.55 7.66 27.19 2.23 11.93 7.42 200.22 16.45 12.86 6.89 68.38 5.62 13.63 6.50 334.09 27.45 14.80 5.99 213.77 17.56 15.25 5.81 282.83 23.24 15.72 5.64 1157.68 95.11 16.03 5.53 82.77 6.80 16.43 5.40 294.20 24.17 16.90 5.25 1169.96 96.12 17.65 5.03 862.29 70.84 18.17 4.88 226.04 18.57 18.63 4.76 954.64 78.43 19.19 4.63 1071.81 88.06

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 21.85 4.07 327.62 26.92 22.37 3.97 132.49 10.88 22.75 3.91 567.46 46.62 23.57 3.77 1217.17 100.00 23.98 3.71 227.83 18.72 24.47 3.64 165.02 13.56 25.14 3.54 262.59 21.57 25.41 3.51 200.31 16.46 25.67 3.47 594.26 48.82 26.20 3.40 266.78 21.92 26.64 3.35 29.00 2.38 27.14 3.29 350.89 28.83 27.42 3.25 100.31 8.24 28.30 3.15 224.81 18.47 29.26 3.05 172.82 14.20 29.86 2.99 105.40 8.66 30.30 2.95 156.11 12.83 30.82 2.90 55.74 4.58 31.33 2.85 136.59 11.22

19.41 4.57 631.85 51.91 20.37 4.36 569.13 46.76 20.55 4.32 834.23 68.54 20.72 4.29 901.63 74.08 21.02 4.23 218.90 17.98 21.29 4.17 866.71 71.21

31.95 2.80 93.08 7.65 32.63 2.74 117.42 9.65 33.30 2.69 38.69 3.18 33.92 2.64 56.32 4.63 34.34 2.61 35.17 2.89 34.56 2.59 40.07 3.29

- 33 043571

The powder X-ray diffraction pattern of Form II of the crystalline sulcardine monoedisylate salt is not a linear combination of the powder X-ray diffraction patterns of ethane-1,2disulfonic acid and the amorphous sulcardine free base. For example, Form II of the crystalline sulcardine monoedisylate salt has a peak at approximately 5.2°2θ, which is not present in the free acid powder X-ray diffraction pattern of FIG. 22 and amorphous sulcardine does not contain peaks. Powder X-ray diffraction pattern of Fig. 28 is not a physical mixture of salt starting materials.

Data on the thermodynamic solubility of form II of the monoedisylate salt of sulcardine are presented in table. 14 examples 25.

All combinations of the above embodiments are covered by the present invention.

10. Hydrobromic salt of sulcardine.

In accordance with certain embodiments, the present invention provides the hydrobromic salt of sulcardine. In accordance with some embodiments, the salt is crystalline.

In some embodiments, the molar ratio of sulcardine to hydrobromic acid in the salt is approximately 1:1. In accordance with some embodiments, the salt is a monohydrogen bromide salt of sulcardine.

A typical powder X-ray diffraction pattern of the hydrobromide salt of sulcardine is shown in FIG. 23.

In accordance with some embodiments, the present invention provides a solid form containing a hydrobromic salt of sulcardine, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or all peaks located approximately at the following positions: 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 accordance with some embodiments, the solid shape is characterized by 3 shape is characterized by shape is characterized by shape is characterized by shape is characterized from from from from peaks. peaks In peaks. In peaks. IN

In accordance with some embodiments, the implementation of the solid corresponds to the correspondence of the peaks. In accordance with some some some embodiments, embodiments, implementation of solid solid solid certain embodiments of the solid form is characterized by all peaks.

In accordance with some embodiments, the present invention provides a solid form containing the hydrobromic salt of sulcardine, which is characterized by a powder X-ray diffraction pattern containing peaks at approximately 17.9, 19.7 and 24.0°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 14.1 and 14.9°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern further contains peaks at approximately 5.7, 13.0, and 16.2°2θ. In accordance with some embodiments, the X-ray powder diffraction pattern contains peaks at approximately 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.

In accordance with some embodiments, the present invention provides a solid form containing the hydrobromic salt of sulcardine, which is characterized by a powder x-ray diffraction pattern that matches the powder x-ray diffraction pattern presented in FIG. 23.

In accordance with some embodiments, X-ray powder diffraction patterns were obtained using Cu Ka radiation.

Typical TG/DTA thermograms of sulcardine hydrobromide salt are shown in FIG. 24. In accordance with some embodiments, the present invention provides a solid form containing sulcardine hydrobromide salt that exhibits a weight loss of approximately 4.3% when heated from about 25°C to about 175°C. In accordance with some embodiments, the present invention provides a solid form containing the hydrobromic salt of sulcardine that has a TG thermogram that is the same as the TG thermogram shown in FIG. 24.

In accordance with some embodiments, the present invention provides a solid form containing sulcardine hydrobromic salt that has a DTA thermogram that matches the DTA thermogram shown in FIG. 24.

In some embodiments, the hydrobromic salt of sulcardine is prepared by subjecting a mixture of sulcardine and hydrobromic acid (e.g., a mixture of 2-propanol and heptane) in a solvent (e.g., THF) to a temperature cycle (e.g., from ambient temperature to about 40° C.) for period of time (eg approximately 72 hours). In accordance with some embodiments, the solvent is a 2:1 v/v mixture. 2-propanol and heptane.

In other embodiments, a crystalline salt of sulcardine and hydrobromic acid is provided. The preparation of a crystalline salt of sulcardine and hydrobromic acid is described in Example 15. Such crystalline salts may be those characterized by a powder X-ray diffraction pattern containing one or more peaks selected from about 5.7°2θ, about 13.0°2θ, about 14, 1°2θ, approximately 14.9°2θ and approximately 16.2°2θ. Powder X-ray diffraction pattern, which is basically the same as in FIG. 23 can also be used to characterize the crystalline salt of sulcardine and hydrobromic acid. A list of peaks that corresponds to many of the peaks in Fig. 23, presented in table. 12.

Since hydrobromic acid is a liquid under the experimental conditions used in the present invention, the resulting solid is not a mixture of hydrobromic acid and the amorphous free base of sulcardine. The solid is a crystalline salt of sulcardine and hydrobromic acid.

Table 12

Table of X-ray powder diffractometry peaks corresponding to Fig. 23

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 5.67 15.59 202.55 7.95 10.19 8.68 75.28 2.96 11.15 7.94 203.88 8.00 11.35 7.80 175.10 6.87 13.00 6.81 381.66 14.98 14.06 6.30 1205.09 47.31 14.91 5.94 992.41 38.96 16.18 5.48 601.35 23.61 17.10 5.18 725.41 28.48 17.31 5.12 936.93 36.78 17.90 4.96 2547.34 100.00 18.84 4.71 697.93 27.40 19.13 4.64 390.40 15.33 19.49 4.56 302.05 11.86 19.73 4.50 1485.49 58.32 20.50 4.33 1381.71 54.24 21.59 4.12 153.90 6.04

Position (°2θ) Interplanar distance d(A) Height (area) Relative intensity (%) 22.03 4.04 344.89 13.54 22.41 3.97 764.97 30.03 23.56 3.78 598.26 23.49 24.03 3.70 2322.47 91.17 24.92 3.57 524.02 20.57 25.14 3.54 894.69 35.12 25.49 3.49 312.98 12.29 25.80 3.45 167.45 6.57 26.45 3.37 185.80 7.29 26.99 3.30 215.09 8.44 27.47 3.25 858.15 33.69 28.22 3.16 529.54 20.79 28.70 3.11 169.95 6.67 29.12 3.07 268.04 10.52 30.43 2.94 494.06 19.40 31.50 2.84 67.06 2.63 32.17 2.78 167.35 6.57 33.26 2.69 183.14 7.19 33.76 2.65 198.30 7.78 34.24 2.62 131.07 5.15

The present invention also relates to pharmaceutical compositions containing sulcardine salts, including crystalline sulcardine salts. Such pharmaceutical compositions contain one or more pharmaceutically acceptable excipients and a salt, such as a crystalline salt disclosed herein. Such pharmaceutical compositions may be administered orally or formulated for delivery in any effective conventional dosage unit form, including immediate-release, slow-release, sustained-release oral, parenteral, topical, nasal, ophthalmic, ophthalmic, sublingual, rectal, vaginal, and the like.

In addition, the present invention relates to methods and uses for treating diseases in humans, such as arrhythmias, including supraventricular tachyarrhythmias, such as atrial fibrillation, premature ventricular contractions, ventricular tachycardia and ventricular fibrillation, by administering to a person effective amounts of sulcardine salt, including crystalline salts , and/or pharmaceutical compositions containing sulcardine salts, including the crystalline salts disclosed herein. In accordance with some embodiments, the disease is atrial fibrillation.

As used herein and unless otherwise noted, the terms treat, treatment and

- 35 043571 processing refers to an approach to obtain beneficial or desired results, including, without limitation, a therapeutic effect. In some embodiments, a therapeutic effect means eliminating or alleviating the underlying disease being treated. In some embodiments, the therapeutic effect is achieved by eliminating or alleviating one or more physiological symptoms associated with the underlying disease such that the patient experiences improvement even though the patient still suffers from the underlying disease.

The subject of treatment is a prokaryotic or eukaryotic cell, tissue culture, tissue or animal, such as a mammal, including a human. Non-human animals to be treated include, for example, monkey, mouse, canine, Leporidae such as rabbit, livestock, sporting animals and pets. As used herein and unless otherwise noted, the patient is a human subject.

The following numbered embodiments have been considered and are not intended to be limiting.

Item 1. Salt of sulcardine and mononaphthalene salt former.

Point 2. The salt according to point 1, where the mononaphthalene salt former contains one or more sulfonic acid moieties.

Point 3. Salt according to point 2, where the mononaphthalene salt former contains one sulfonic acid fragment.

Point 4. Salt according to point 2, where the mononaphthalene salt former contains two sulfonic acid fragments.

Item 5. The salt of item 4, where two sulfonic acid moieties are on the same aromatic ring.

Point 6. Salt according to point 1, where the mononaphthalene salt former is an organic acid.

Item 7. The salt of item 6, where the organic acid is a carboxylic acid.

Point 8. Salt according to point 7, where the salt former is substituted.

Item 9. Salt according to item 8, where the salt former is replaced by an -OH group.

Item 10. Salt according to items 8 or 9, where the substitution is ortho with respect to the organic acid group.

Item 11. Salt according to item 4, where two sulfonic acid fragments are located on different rings of the naphthalene salt former.

Item 12. Crystalline salt of sulcardine and a salt-forming agent, where the salt-forming agent is not sulfuric acid.

Item 13. Crystalline salt of sulcardine and sulfonic acid salt former.

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

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

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

Item 17. Crystalline salt according to item 16, where the substituent is hydroxyl.

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

Item 19. Crystalline salt of sulcardine and inorganic acid other than sulfuric.

Item 20. The crystalline salt of item 19, wherein the sulcardine salt is a halide.

Item 21. Salt of sulcardine and naphthalene-1,5-disulfonic acid.

Item 22. Crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid.

Item 23. The crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid according to item 22, containing an X-ray powder diffractometry peak at approximately 4.6°2θ.

Item 24. The crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid of items 22 or 23, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 4.9°2θ, about 10.4°2θ, about 11.7°2θ, approximately 12.3°2θ and approximately 15.9°2θ.

Item 25. The crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid according to any one of items 22-24, characterized by an initial melting point of approximately 244°C.

Item 26. The crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid of item 22 containing an X-ray powder diffractometry image is basically the same as in FIG. 1.

Item 27. The crystalline salt of sulcardine and naphthalene-1,5-disulfonic acid according to item 26, characterized by an initial melting point of approximately 244°C.

- 36 043571

Item 28. Form II of crystalline salt of sulcardine and hydrochloric acid.

Item 29. Salt of sulcardine and 1-hydroxy-2-naphthoic acid.

Item 30. Crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

Item 31. Form I of the crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

Item 32. The crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid of item 31, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 3.4°2θ, about 6.7°2θ, about 6, 9°2θ and approximately 15.4°2θ.

Item 33. The crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid of item 31, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 3.4°2θ, about 6.7°2θ and about 6, 9°2θ.

Item 34. The crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid of item 31, characterized by an X-ray powder diffraction image containing peaks selected from about 3.4°2θ and two peaks from about 6.5°2θ to about 7 ,1°2θ.

Item 35. The crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid according to any one of items 31-34, characterized by an initial melting point of approximately 161°C.

Item 36. The crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid according to items 29, 30 or 31, characterized by an X-ray powder diffractometry image substantially the same as in FIG. 6.

Item 37. Form II of crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid.

Item 38. The crystalline salt of item 28, characterized by substantially the same powder X-ray diffraction pattern as in FIG. 17A.

Item 39. The crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid of item 37, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 5.8°2θ and about 8.8°2θ.

Item 40. Form I of the crystalline salt of sulcardine and hydrochloric acid.

Item 41. The crystalline salt of item 28, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 10.1°2θ, about 11.8°2θ, about 13.5°2θ, and about 16.4°2θ .

Item 42. The crystalline salt of item 28, characterized by an X-ray powder diffractometry image where there is no peak below about 9.5°2θ and no peaks between peaks about 10.1°2θ and about 11.8°2θ.

Item 43. Crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid according to item 37, characterized by an initial melting point of approximately 168°C.

Item 44. The crystalline salt of sulcardine and 1-hydroxy-2-naphthoic acid according to items 37 or 43, characterized by an X-ray powder diffractometry image substantially the same as in FIG. 9.

Item 45. Salt of sulcardine and naphthalene-2-sulfonic acid.

Item 46. Crystalline salt of sulcardine and naphthalene-2-sulfonic acid.

Item 47. The crystalline salt of sulcardine and naphthalene-2-sulfonic acid of item 46, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 9.4°2θ, about 10.6°2θ, about 13.3° 2θ, approximately 13.5°2θ, approximately 16.6°2θ, approximately 16.9°2θ and approximately 17.2°2θ.

Item 48. The crystalline salt of sulcardine and naphthalene-2-sulfonic acid of item 46, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 9.4°2θ, about 10.6°2θ, about 13.3° 2θ and approximately 13.5°2θ.

Item 49. The crystalline salt of sulcardine and naphthalene-2-sulfonic acid of item 46, characterized by an X-ray powder diffraction image containing peaks selected from about 9.4°2θ, about 10.6°2θ, and about 13.5°2θ.

Item 50. The crystalline salt of sulcardine and naphthalene-2-sulfonic acid of item 46, characterized by an X-ray powder diffraction image containing two peaks from about 13.1°2θ to about 13.7°2θ and three peaks from about 16.4°2θ to approximately 17.4°2θ.

Item 51. The crystalline salt of sulcardine and naphthalene-2-sulfonic acid according to any one of items 46-50, characterized by an initial melting point of approximately 88°C.

Item 52. The crystalline salt of sulcardine and naphthalene-2-sulfonic acid according to items 46 or 51, characterized by an X-ray powder diffractometry image substantially the same as in FIG. 13.

Item 53. Salt of sulcardine and hydrochloride.

- 37 043571

Item 54. Crystalline salt of sulcardine and hydrochloride.

Item 55. The crystalline salt of sulcardine hydrochloride of item 40, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 12.3°2θ and about 13.0°2θ.

Item 56. The crystalline salt of sulcardine hydrochloride according to item 54 or 55, characterized by substantially the same X-ray powder diffractometry image as in FIG. 17.

Item 57. Salt of sulcardine and ethane-1,2-disulfonic acid.

Item 58. Crystalline salt of sulcardine and ethane-1,2-disulfonic acid.

Item 59. The crystalline salt of sulcardine and ethane-1,2-disulfonic acid of item 58, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 5.6°2θ, about 11.0°2θ, about 13, 0°2θ, approximately 14.1°2θ and approximately 14.9°2θ.

Item 60. The crystalline salt of sulcardine and ethane-1,2-disulfonic acid of item 58, characterized by substantially the same X-ray powder diffractometry image as in FIG. 19.

Item 61. The crystalline salt of sulcardine and ethane-1,2-disulfonic acid according to any one of items 58-60, characterized by an initial melting point of approximately 211°C.

Item 62. Salt of sulcardine and hydrobromic acid.

Item 63. Crystalline salt of sulcardine and hydrobromic acid.

Item 64. The crystalline salt of sulcardine and hydrobromic acid of item 63, characterized by an X-ray powder diffraction image containing one or more peaks selected from about 5.7°2θ, about 13.0°2θ, about 14.1°2θ, about 14 .9°2θ and approximately 16.2°2θ.

Item 65. The crystalline salt of sulcardine and hydrobromic acid of item 63, characterized by substantially the same X-ray powder diffractometry image as in FIG. 23.

Item 66. A salt of sulcardine and 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.

Item 67. A crystalline salt of sulcardine and a salt former selected from naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, naphthalene-2-sulfonic acid, hydrochloric acid or hydrobromic acid.

Clause 68. A pharmaceutical composition containing the sulcardine salt composition according to any one of clauses 1-67 or 72-88 and one or more pharmaceutically acceptable excipients.

Clause 69. A method of treating arrhythmia with a pharmaceutically effective amount of the pharmaceutical composition of claim 68, the method comprising administering such composition to a patient in need thereof.

Clause 70. A method of treating arrhythmia with a pharmaceutically effective amount of sulcardine salt according to any one of claims 1-67 or 72-88, the method comprising administering such salt to a patient in need thereof.

Clause 71. The method of claim 69 or 70, wherein the arrhythmia is selected from supraventricular tachyarrhythmia, premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation.

Clause 72. The salt of any one of clauses 45-52, wherein the salt is a hydrate.

Item 73. Form I of the crystalline salt of item 54 where there is no peak below approximately 9.5°2θ.

Clause 74. The salt of any one of clauses 53-56, wherein the salt is a hydrate.

Item 75. The crystalline salt of item 31, characterized by an X-ray powder diffraction image containing a peak of approximately 3.4°2θ.

Item 76. Sulcardine monoedisylate salt.

Item 77. Crystalline salt of sulcardine according to item 76.

Item 78. Form I of crystalline monoedisylate salt of sulcardine.

Item 79. Monohydrate of crystalline monoedisylate salt of sulcardine.

Item 80. The crystalline sulcardine monoedisylate salt of any one of items 76 to 79, characterized by an X-ray powder diffractometry image containing a peak at approximately 14.2°2θ.

Claim 81. The crystalline monoedisylate of any one of clauses 76-79, 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 approximately 14.9°2θ.

Item 82. Form II of crystalline monoedisylate salt of sulcardine.

Item 83. Hydrate of crystalline monoedisylate salt of sulcardine.

- 38 043571

Item 84. Dihydrate of crystalline monoedisylate salt of sulcardine.

Item 85. The crystalline sulcardine monoedisylate salt of any one of items 82 to 84, characterized by an X-ray powder diffractometry image containing a peak of approximately 5.2°2θ.

Claim 86. The crystalline monoedisylate salt of sulcardine according to any one of clauses 82-84, containing one or more peaks selected from about 5.2°2θ, about 9.1°2θ, about 10.2°2θ, about 10.8°2θ , approximately 11.3°2θ and approximately 13.6°2θ.

Clause 87. Hydrate according to clause 76.

Clause 88. Hydrate according to clause 87, where the molar hydration is more than 1.

Examples

Example 1. Methods of analysis.

X-ray powder diffractometry (XRPD) analysis was performed on a PANalytical X'pert pro with a PIXcel detector (128 channels), scanning samples from 3 to 35°2θ. The substance was loaded onto a multiwell plate with Mylar polymer film to support the sample. Then the multiwell plate was placed in a diffractometer and analyzed using Cu K radiation (α1 λ=1.54060 A; _α2 =1.54443 A; β=1.39225 A; α1: _α2 ratio =0.5) in transmission mode (step size 0.0130°2θ, step time 18.87 s) with generator parameters 40 kV/40 mA. Data were visualized and images were created using the computer application HighScore Plus 4.7 (PANalytical, 2017).

Approximately 5 mg of the substance was weighed in an open aluminum pan and loaded into a synchronous thermogravimetric/differential thermal analyzer (TG/DTA) and kept at room temperature. The sample was then heated at a rate of 10°C/min from 20°C to 400°C and during this time the change in sample mass was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas at a flow rate of 300 cm ³ /min.

1H-NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. Experiments were performed in deuterated DMSO, and each sample was prepared at approximately 10 mM concentration. The pH value of solutions was measured using a Hanna H12210 pH meter with a microelectrode operating in the pH range from -2 to 16.

HPLC analysis was performed on a Dionex Ultimate 3000 device with the following parameters:

Column: Phenomenex Luna C18, 150x4.6 mm, 5 microns Column temperature: 30°C Mobile phase A: 0.2% phosphoric acid Mobile phase B: methanol Diluent: 50:50 MeOH:H ₂ O Passage time: 12 minutes Flow rate: 1.0 ml/min Injection volume: 5 µl Detection: 237 nm Gradient:

Example 2 Free base preparation and screening.

Sulcardine sulfate trihydrate was dissolved in ethyl acetate (16 vol.) and saturated sodium bicarbonate solution (16 vol.). The two-phase solution was transferred to a separatory funnel and the layers were separated. The organic layer was dried over sodium sulfate, then the solvent was removed by rotary evaporation and the resulting oil was dried under vacuum at ambient temperature for approximately 3 hours. FIG. Figure 4 shows a powder X-ray diffraction pattern of the obtained amorphous free base of sulcardine. In all cases, the initial screening, detailed below, was performed on 10 mg of sulcardine free base. All X-ray powder diffraction patterns were compared with sulcardine sulfate trighydrate, sulcardine free base, and

- 39 043571 relevant counteriones and found that they were different.

Example 3: Solubility.

20 mM buffers were prepared with 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). The appropriate salt was added to 0.5 ml of each buffer to form a suspension. The pH of the suspension was measured and adjusted again to the desired pH (ie, the initial pH of the buffer), if necessary, using 0.2 M buffer components (eg, 0.2 M HC1( _aq )). Samples were suspended at ambient temperature for approximately 72 h.

After this time, if solid remained, the pH was adjusted again to the desired pH, if necessary, using the components of the 0.2 M buffer. If no solid remained, additional solid was added to re-suspension before the pH was adjusted again to the desired pH, if necessary, using the components of the 0.2 M buffer. All samples were then suspended for an additional 2 h before analysis by HPLC to determine concentration.

Example 4. Naphthalene-1,5-disulfonic acid salt.

Naphthalene-1,5-disulfonic acid (1.05 eq) and acetone (20 vol) were added to sulcardine free base. The sample was temperature cycled from ambient temperature to 40°C in 4 hour cycles for approximately 72 hours to produce a white and orange solid.

The substance was crystalline as determined by X-ray powder diffractometry. A mass loss of 2.9% was observed at TG until decomposition and a melting event at DTA with a decomposition onset temperature of 243°C. Naphthalene-1,5-disulfonic acid (1.0 eq.) was observed in ¹ H-NMR, but the solvent was not observed to a significant extent. Solubility was 1.6 mghml ^-1 in pH 1.2 buffer, 0.7 mghml ^-1 in pH 3.0 buffer, 1.0 mghml ^-1 in pH 4.0 buffer and 6.9 mghml ^-1 in buffer with pH 7.4 (Table 3).

Example 5: Scaling of naphthalene-1,5-disulfonic acid salt.

To sulcardine free base (200 mg) were added 2 ml of acetone and 169.8 mg of naphthalene-1,5 disulfonic acid (1.05 eq.). The sample was subjected to a temperature cycle in accordance with Example 16. The resulting solid was filtered using a Buchner funnel and the filtrate was dried for approximately 15 minutes, FIG. 1 shows the X-ray powder diffraction pattern for this example, FIG. Figure 1 shows a powder X-ray diffraction pattern of this salt, which indicates a crystalline substance. The table of peaks is shown in Table 2. No mass loss was observed at TG until decomposition and a melting event at DTA with an onset temperature of 244°C was observed (Fig. 2). Naphthalene-1,5-disulfonic acid was observed in ¹ H-NMR at 1:1, and the solvent was not observed to a significant extent (Figure 3). The measured solubility was 1.6 mgxml ^-1 in pH 1.2 buffer, 0.7 mgxml ^-1 in pH 3.0 buffer, 1.0 mgxml ^-1 in pH 4.0 buffer and 6.9 mgxml ^{- 1} in buffer with pH 7.4 (Table 3).

Example 6 Form I of 1-hydroxy-2-naphthoic acid salt.

A 1 M stock solution of 1-hydroxy-2-naphthoic acid in THF (1.05 eq) and ethyl acetate (20 vol) was added to sulcardine free base. The sample was temperature cycled from ambient to 40°C in 4 hour cycles over approximately 72 hours and then refrigerated for approximately 24 hours to produce a brown solid.

The substance was crystalline, as determined by X-ray powder diffractometry (Fig. 6), and had peaks at the positions indicated in the table. 4. A mass loss of 3.5% was observed at TG until decomposition (1.3 equiv. water) and a single melting event at DTA with an onset temperature of decomposition of 161°C (Fig. 7). 1-Hydroxy-2-naphthoic acid (1.0 eq.) was observed in ¹ H-NMR, and the solvent was not observed to a significant extent (Fig. 8).

Example 7 Form II of 1-hydroxy-2-naphthoic acid salt.

A 1 M stock solution of 1-hydroxy-2-naphthoic acid in THF (1.05 eq) and toluene (20 vol) was added to sulcardine free base. The sample was temperature cycled from ambient temperature to 40°C in 4 hour cycles over approximately 72 hours and then placed in a refrigerator for approximately 24 hours. The container containing the sample was opened and the solvent was allowed to evaporate to leave a white and Brown color.

The substance was crystalline as determined by X-ray powder diffractometry. A mass loss of 1.1% was observed at TG until decomposition and a single melting event at DTA with an onset temperature of 166°C. 1-Hydroxy-2-naphthoic acid (1.0 eq.) was observed in ¹ H-NMR, but the solvent was not observed to a significant extent.

Example 8: Scaling of 1-hydroxy-2-naphthoic acid salt for Form II.

To 200 mg of sulcardine free base were added 2 ml of toluene and 457 microliters of a 1 M solution of 1-hydroxy-2-naphthoic acid in THF. The sample was subjected to a temperature cycle in accordance with Example 16. The solid was filtered using a Buchner funnel and the filtrate was dried

- 40 043571 for approximately 15 minutes.

The substance was crystalline, as determined by X-ray powder diffractometry (Fig. 9), and had peaks at the positions shown in the table. 5. No mass loss was observed at TG until decomposition and a single melting event at DTA with a decomposition onset temperature of approximately 168°C (FIG. 10). 1-Hydroxy-2-naphthoic acid (1.0 eq.) was observed in Ή-NMR, but the solvent was not observed to a significant extent (Fig. 11). The measured solubility was 16.8 mgxml ^-1 in pH 1.2 buffer, 4.2 mgxml ^-1 in pH 3.0 buffer, ^6.1 mgxml'1 in pH 4.0 buffer, and 0.2 mgxml' ¹ in buffer with pH 7.4 (Table 6).

Example 9. Naphthalene-2-sulfonic acid salt.

A 1 M stock solution of naphthalene-2-sulfonic acid in THF (1.05 eq) and ethyl acetate (20 vol) was added to sulcardine free base. The sample was temperature cycled from ambient temperature to 40°C in 4 hour cycles for approximately 72 hours. Heptane (10 vol) was added and the sample was placed in a refrigerator for approximately 24 hours. The container containing the sample was opened and the solvent was allowed to evaporate to produce a white and orange solid.

The substance was crystalline as determined by X-ray powder diffractometry. We observed a mass loss of 2.6% at TG until decomposition (1.0 equiv. water) and a single melting event at DTA with an onset temperature of 95°C. Naphthalene-2-sulfonic acid (1.0 eq.) was observed in 1H-NMR, but the solvent was not observed to a significant extent.

Example 10 Scale-up of naphthalene-2-sulfonic acid salt To 200 mg of sulcardin free base was added 2 ml of toluene and 457 microliters of a 1 M solution of naphthalene-2-sulfonic acid in THF. The sample was subjected to a temperature cycle in accordance with Example 16. The solid was filtered using a Buchner funnel and the filtrate was dried to obtain a white solid.

The substance was crystalline, as determined by X-ray powder diffractometry (Fig. 13), and had peaks at the positions indicated in the table. 7. We observed a mass loss of 2.4% at TG until decomposition (approximately 1.0 equiv. water) and a single endothermic event at DTA with an onset temperature of decomposition of 88°C (Fig. 14). Naphthalene-2-sulfonic acid (1.0 eq.) was observed in 1H-NMR, but the solvent was not observed to a significant extent (Fig. 15). The measured solubility was 23.6 mghml ^-1 in pH 1.2 buffer, 10.3 mghml ^-1 in pH 3.0 buffer, 18.9 mghml ^-1 in pH 4.0 buffer and 5.9 mghml ^{- 1} in buffer with pH 7.4 (Table 8).

Example 11 Hydrochloric Acid Salt (Form II) A 1M stock solution of HCl in THF (1.05 eq), 2-propanol (20 vol) and heptane (10 vol) was added to sulcardine free base. The sample was temperature cycled from ambient to 40° C. in 4 hour cycles over approximately 72 hours. More heptane (20 vol) was added and the sample was refrigerated for approximately 24 hours to produce a white solid. The material was crystalline as determined by X-ray powder diffractometry (FIG. 17A).

Example 12: Scale-up of Hydrochloric Acid Salt (Form I) To 200 mg of sulcardine free base was added 2 ml of THF and 457 microliters of a 1 M solution of hydrochloric acid in THF. The sample was subjected to a temperature cycle in accordance with Example 16. The solid was filtered using a Buchner funnel and the filtrate was dried to obtain a white solid.

The substance was crystalline, as determined by X-ray powder diffractometry (Fig. 17), and had peaks at the positions indicated in the table. 9. A mass loss of 3.1% was observed at TG, equivalent to approximately 0.88 equivalents of water (Fig. 18). No solvent peaks were observed in 1H-NMR (Fig. 18A).

Example 13. 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 sulcardine free base. The sample was temperature cycled from ambient to 40° C. in 4 hour cycles over approximately 72 hours. More heptane (20 vol) was added and the sample was refrigerated for approximately 24 hours to produce a white solid.

The substance was crystalline as determined by X-ray powder diffractometry. We observed a mass loss of 1.4% at TG until decomposition and a single melting event at DTA with an onset temperature of 201 °C. Ethane-1,2-disulfonic acid (0.6 eq.) was observed by 1H-NMR, but the solvent was not observed to a significant extent.

Example 14: Scaling of ethane-1,2-disulfonic acid salt.

To 200 mg of sulcardine free base was added 2 ml of toluene and 218 μl of a 1 M solution of ethane1,2-disulfonic acid in THF (0.55 equiv.). The sample was subjected to a temperature cycle in accordance with Example 16. The solid was filtered using a Buchner funnel and the filtrate was dried to obtain a white solid.

The substance was crystalline as determined by X-ray powder diffraction

- 41 043571 meters (Fig. 19), and had peaks at the positions indicated in Table 10. No mass loss was observed at TG until decomposition and a single melting event at DTA with an onset temperature of 211° C. (Fig. 20). Ethane-1,2-disulfonic acid (0.5 eq.) was observed in ¹ H-NMR, and the solvent was not observed to a significant extent (Fig. 21). The measured solubility was 41.1 mghml ^-1 in pH 1.2 buffer, 46.3 mghml ^-1 in pH 3.0 buffer, 36.1 mghml ^-1 in pH 4.0 buffer and 18.9 mghml ^{- 1} in buffer with pH 7.4 (Table 11).

Example 15. Hydrobromic acid salt.

A 1 M stock solution of HBr in THF (1.05 eq.), 2-propanol (20 vol.) and heptane (10 vol.) was added to sulcardine free base. The sample was temperature cycled from ambient temperature to 40°C in 4 hour cycles for approximately 72 hours. More heptane (20 vol) was added and the sample was placed in a refrigerator for approximately 24 hours. The container containing the sample was opened and the solvent allowed to evaporate to give an orange solid.

The material was crystalline as determined by X-ray powder diffractometry (FIG. 23) and had peaks at the positions shown in Table 1. 12. We observed a mass loss of 4.3% at TG until decomposition and no melting event at DTA (Fig. 24). No solvent was observed to be present to a significant extent in ¹ H-NMR (Fig. 25).

Example 16. Temperature cycle according to examples 5, 8, 10, 12 and 14.

Temperatures were cycled with stirring using the following method.

1. Holding at 25°C for 1 hour.

2. Cooling to 5°C at 0.1°C/min.

3. Holding at 5°C for 1 hour.

4. Heating to 25°C at 0.1°C/min.

5. Repeat for a total of 72 hours, removing samples at 5°C.

Example 17. Preparation of Form I of crystalline monoedisylate salt of sulcardine.

To a solution containing approximately 3 g of sulcardine free base was added 45 ml of toluene to form a solution. To this solution was added approximately 6.85 mL (1.05 eq.) of 1 M ethane-1,2-disulfonic acid stock solution (ethane-1,2-disulfonic acid dihydrate was used in THF) to obtain a gummy solid. The solution was temperature cycled from ambient temperature to 40° C. in cycles of 4 hours over approximately 24 hours. After 24 hours, a small amount of a free-flowing white solid was observed in the flask and a large amount of a white gummy substance was observed in the flask. Both substances were found to be predominantly amorphous according to X-ray powder diffractometry (diffraction patterns of LNB15318-53-1-suspension and LNB15318-53-1-bulk in Fig. 32). The 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 agglomerates was observed in the flask. An aliquot of the free-flowing material was collected for X-ray powder diffraction analysis and the pattern can be seen in FIG. 33 (diffraction pattern LNB15318-53-1-484). The material was filtered using Buchner filtration and dried under vacuum at ambient temperature for approximately 24 hours. The dried material was collected, weighed and analyzed by X-ray powder diffractometry (diffraction pattern of LNB15318-53-1-cyxoe in FIGS. 26 and 33). Peak lists for Form I were obtained using the diffraction pattern of LNB15318-53-1-cyxoe.

Amorphous monoedisylate salt of sulcardin: During the polymorphic screening of the monoedisylate salt, batches of the substance were lyophilized before performing experiments. After lyophilization, the substance appeared more like a clear, colorless gum than a solid. 1H NMR analysis was carried out on the gum, which confirmed that the substance was still a monoedisylate salt.

Example 18. Preparation of Form II crystalline monoedisylate salt of sulcardine.

To a solution containing approximately 4 g of sulcardine free base was added 60 ml of toluene to form a solution. To this solution was added 9.34 ml (1.05 eq.) of 1 M ethane-1,2-disulfonic acid stock solution (ethane-1,2-disulfonic acid dihydrate was used in THF) to form a gummy solid. The sample was subjected to temperature cycling from ambient temperature to 40°C in 4 hour cycles over approximately 96 hours with agitation. A loose, off-white powder was observed. The wet solid sample was analyzed by X-ray powder diffractometry. The substance appeared to be a mixture of monoedisylate form I and a new substance called form II (diffraction pattern LNB1919-44-1 in Fig. 34). The solid was isolated on a Buchner filter funnel and dried under vacuum at ambient temperature overnight. The dried material was collected and transferred to a 100 ml Duran flask. 40 ml EtOH/water (0.4 water activity) was added to form a mobile suspension. The slurry was then stirred at ambient temperature using a stirrer for approximately 120 hours. An aliquot of the material was removed and analyzed by X-ray powder diffractometry (diffraction pattern LNB1919-44-3 in FIG. 28 and FIG. 35). The substance was identified as form II monoedisylate. The bulk substance was isolated on a Buchner filtration funnel and dried in vacuum at ambient temperature for approximately 24 hours. The dried substance was analyzed by X-ray powder diffractometry (diffraction pattern

LNB1919-44-3-dry in fig. 35), which is shown as Form II. The peak list for Form II was generated using the diffraction pattern of LNB1919-44-3-dry.

Example 19. Preparation of a reference sample - form I of the crystalline monoedisylade salt of sulcardine.

Approximately 100 mg of sulcardin free base was dissolved in 2 ml of toluene. 229 μl of a stock solution of 1 M ethane-1,2-disulfonic acid (ethane-1,2-disulfonic acid dihydrate was used in THF) was added thereto. The sample was subjected to temperature cycles from ambient temperature to 40°C in 4-hour cycles. An aliquot of the substance was withdrawn after approximately 24 hours and further subjected to temperature cycling for 24 hours. An aliquot of the substance was collected and analyzed by X-ray powder diffractometry. A particular crystalline pattern was observed. Sample, LNB15318-51-1 48 h in Fig. 32 was designated as monoedisylate form I.

Example 20. Preparation of a reference sample - form II of the crystalline monoedisylade salt of sulcardine.

Form II was first observed during GVS characterization of Form I.

The material collected after GVS analysis of Form I was analyzed by X-ray powder diffractometry. A new sample (designated Form II) was observed and the formation of a highly active hydrate was observed. The XRD reference is LNB15318-53-1-after GVS in FIG. 34.

Example 21. GVS (Gravimetric Vapor Sorption) for Example 20.

Approximately 26 mg of Form I was placed on the mesh pan of a moisture absorption balance and placed on an IGASorp moisture absorption balance from Hiden Analytical. The sample was processed according to the protective drying program with a change in relative humidity (RH) from 40 to 90% with an increase of 10%, maintaining the sample at each step until it reached a suitable weight (step completion 98%, minimum step duration 30 min, maximum step duration 60 min) at 25°C. After completion of the sorption cycle, the sample was dried using the same procedure to 0% RH and finally returned to the starting point of 40% RH. Two cycles were carried out. The change in mass during the sorption/desorption cycles was plotted, which made it possible to determine the hygroscopic nature of the sample. The material collected after GVS analysis was analyzed by X-ray powder diffractometry.

Example 22. KF analysis.

Approximately 30 mg of material for KF analysis was weighed into a pre-weighed glass vessel. The substance was then added to the titration cell of a KF coulometer containing Hydranal solution. The empty vessel was weighed again after adding the solid to determine the mass of the substance added to the cell. They were then sampled. The analysis was performed twice and the average results were calculated.

Example 23. Single-crystal X-ray diffraction analysis of Form II of sulcardine 1-hydroxy-2-naphthoic acid salt.

Single crystal X-ray diffraction analysis of Form II of sulcardine 1-hydroxy-2-naphthoic acid salt was carried out at 120 K using Mo Κα radiation (λ=0.71073 A) formed by a sealed tube using an Agilent Supernova single crystal X-ray diffractometer. All data were combined, determined and improved in the monoclinic spatial group P2l/n (a=10.2443(2) A, b=29.9171(6) A, c=10.8406(3) A; β=103.375(2 )°, volume=3232.31(13) A ³ , Z=4, Z'=1). The final model was constructed using 123,397 (11,798 unique) reflections across the 2θ range from 5.622 to 65.972° returning an R1 (I>(2σI)) value of 5.79%, confirming the expected structure of sulcardin. The asymmetric unit (FIG. 36) was shown to contain one complete sulcardine molecule with one bound 1-hydroxy-2-naphthoic acid counterion (1:1 ratio, sulcardine:counterion). A typical experimental 2Θ powder X-ray diffraction pattern was calculated using data collected at 120 K, which was the same as the form II salt. Crystal data are shown in table. 13.

- 43 043571

Table 13

Crystallographic parameters and indicators of purification of form II of 1-hydroxy-2-naphthoic acid salt of sulcardine

Form II sulcardine 1-hydroxy-2-naphthoic acid salt Empirical formula C ₃₅ H ₄ iN ₃ O7S Molecular weight according to the formula 647.77 Temperature/K 120(1) Crystal system Monoclinic Space group P21/i a/A 10.2443(2) b/a 29.9171(6) s/A 10.8406(3) a/° 90 β/° 103.375(2) γ/° 90 Volume/A ³ 3232.31(13) Ζ,Ζ 4, 1

Peale g/cm ³ 1.331 μ/mm' ¹ 0.154 F(000) 1376.0 Crystal size/mm ³ 0.367 x 0.258 x 0.136 Radiation/A ΜοΚα (λ = 0.71073) 2Θ data acquisition range/ ⁰ 5,622 - 65,972 Index ranges -15 <h< 15, -45 <k<45, -16 <1 < 16 Collected Reflections 123397 Independent reflections 11798 [Rint = 0.0414, R^a = 0.0255] Data/Limitations/Options 11798/0/422 X 1.145 Final R indices [F ¹ > 2σ (F ² )] Ri = 0.0579, wR ₂ = 0.1316 Final R indices [all data] Ri = 0.0673, wR ₂ = 0.1357 Apmax, Apmin/e A' ³ 0.85/-0.39 Ri = (Σ \F ₀ \ - \F _C \ )/Σ F _o ); wR ₂ = {Σ [w(F ₀ ² - Fc ² ) ² ] / Σ [w(F0 ² ) ² ]} ^1/2 ; A = {Σ [^(Fo ¹ - Ff ) ² ] / (n-r)'/ ¹

Example 24 Infrared spectroscopy analysis of Form I and Form II of sulcardine monoedisylate salt.

Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. A sufficient amount of substance was placed at the center of the spectrometer plate and spectra were obtained using the following parameters.

Cleavage: 4 cm ^-1 .

Background scan time: 16 scans.

Sample scanning time: 16 scans.

Data acquisition: 4000 to 400 cm ^-1 .

Spectrum result: transparency.

Software: OPUS, version 6.

The FT-IR spectrum is shown in Fig. 37A (Form I), FIG. 37B (Form II) and FIG. 37C (top layer).

Example 25. Evaluation of the thermodynamic solubility of selected salt forms.

The thermodynamic solubility of sulcardine sulfate trihydrate, Form II naphthoate (i.e. Form II salt of 1-hydroxy-2-naphthoic acid) and Form II monoedisylate salt was determined to be

- 44 043571 the following medium: 0.9% sodium chloride solution and 5% dextrose in water.

Procedure: To 1 ml of the selected medium, the appropriate salt was added at approx. 10 mg aliquots to form a mobile suspension. The observed suspensions were stirred at ambient temperature for approx. 16 hours. Samples were collected and the pH value was recorded. Additional solid was added to samples in which clear solutions were observed. Samples were shaken at ambient conditions for an additional 8 hours. The pH value of the samples was recorded after 24 hours. Samples were filtered by centrifugation and the observed solids were analyzed by X-ray powder diffractometry. The stock solutions were subjected to HPLC analysis.

The results of thermodynamic solubility are presented in table. 14.

Table 14

Thermodynamic solubility results

Salt form Wednesday Results with X-ray powder diffractometry of residual solids substances Purity (%) Concentration (mg/ml) Sulfate trihydrate 0.9% sodium chloride Sulfate trihydrate >99.9 88.5 5% dextrose in water Sulfate trihydrate >99.9 61.2 Form II naphthoate 0.9% sodium chloride Form II naphthoate 96.3 0.6 5% dextrose in water Form II naphthoate 95.7 0.4 Form II monoedisylate 0.9% sodium chloride Form II monoedisylate (mostly amorphous) 99.5 303.4 5% dextrose in water Form II monoedisylate (slightly crystalline) 99.4 295.4

Example 26. Pharmacokinetic analysis of sulcardine salts.

Materials and methods.

The pharmacokinetic objective of this study was to evaluate the effects of sulcardine in male dogs in a pharmacokinetic study following oral capsule administration or intravenous (IV) infusion of sulcardine sulfate salt, sulcardine naphthoate salt, or sulcardine monoedisylate salt (Form II).

The Beagle dogs used earlier in experiments to develop the skill were in a state of hunger. Dosing formulations (oral [PO] capsule and intravenous [IV] infusion) were received the day before dosing. Formulations for intravenous administration were prepared in 10 mM glycine (pH adjusted to 3.0 ± 0.1), 3% mannitol, sufficient in sterile water for injection, USP filtered through a 0.22 μm PVDF filter and mixed for at least at least 30 minutes before dosing. Capsule doses were encapsulated as active pharmaceutical ingredient powder into an appropriate number of size 12 gelatin capsules the day before dosing.

Oral dosing was administered once on day 1 via oral capsule administration, and intravenous dosing was administered once on day 1 via intravenous infusion over approximately 45 minutes (±2 minutes).

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

Blood samples were centrifuged under refrigerated conditions (2°C-8°C) at 3200 rpm for 10 minutes, and the resulting plasma was divided into two aliquots (150 μl and the remaining), then frozen and sent for bioanalysis. Plasma samples were analyzed for sulcardine concentrations using Citoxlab North America, Laval, Quebec, Canada.

Individual plasma sulcardine concentration-time profiles in animals receiving sulcardine sulfate, sulcardine monoedisylate, or sulcardine naphthoate were analyzed using non-model methods (Gibaldi M, Perrier D. Pharmacokinetics. ^2nd ed. New York: Marcel Dekker, Inc. ., 1982:409-17). Pharmacokinetic parameters were obtained/calculated for each animal on day 1.

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Claims (10)

Results. Plasma levels. After a single oral administration of sulcardine, _Cmax values were 2820 ng/ml for the group receiving the sulfate salt formulation (Figure 38A) and 4570 ng/ml for the group receiving the monoedisylate salt formulation (Figure 38B). Average pharmacokinetic parameters were calculated using data from all animals in each group. The values for the oral monoedisylate group included the value for animal 2001 (FIG. 38B), which appears to be an outlier and may reflect a dosing error. Without animal 2001 data, the _Cmax value for the monoedisylate salt formulation group is likely to be greater than 4570 ng/mL. Mean peak plasma concentrations of sulcardine were observed at 2 hours post-dose for the group receiving the sulcardine sulfate salt formulation ( _Tmax 2 hours) and at 0.5 hours post-dose ( _Tmax 0.5 hours) for the group receiving the sulcardine sulfate salt formulation receiving a composition based on monoedisylate salt. This profile of faster T _max and higher C _max observed with oral dosing of monoedisylate compared to the sulfate salt (likely due to the increased solubility of the edisylate salt form) may provide advantages for an immediate release formulation, allowing faster treatment acute atrial fibrillation. Based on data from human clinical studies demonstrating a linear concentration-response relationship between sulcardine plasma levels and a number of changes in specific ECG parameters associated with its ion channel blocking mechanism (eg, an increase in QRS consistent with blocking I _Na . _Pea k, and an increase in PR interval, consistent with inhibition of both _INa - _Peak and _ICa , _L ), as disclosed in Mason et al., Circulation 140:A11495 (2019) and as described in US application No. 16/712677 (both documents included in this document by reference in its entirety), as well as supporting data obtained in animal models, monoedisylate can be expected to produce significantly greater pharmacodynamic effects (ECG changes) than the sulfate salt at T=0.5 hours after oral administration doses. In addition, it is expected that this will result in a faster onset of effect when using the monoedisylate form compared to the sulfate form. The detailed description set forth above is provided to assist those skilled in the art in practicing the present invention. However, the scope of the present invention as described and claimed herein should not be limited to the specific embodiments disclosed herein, as these embodiments are intended to illustrate several aspects of the invention. Any equivalent embodiments are considered to be within the scope of the present invention. Indeed, various modifications of the present invention, which do not depart from the spirit or scope of the present invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are also considered to be within the scope of the appended claims. All publications, patents, patent applications and other references cited in the present invention are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other the referenced source has been specifically and individually indicated as being incorporated by reference in its entirety for all purposes. The citation of a reference source herein should not be construed as an admission that it relates to the prior art of the present invention. CLAIM 1. Sulcardine ethane-1,2-disulfonic acid salt hydrate. 2. The hydrate according to claim 1, wherein the hydrated ethane-1,2-disulfonic acid salt of sulcardine is crystalline. 3. The hydrate according to claim 2, wherein the hydrated ethane-1,2-disulfonic acid salt of sulcardine is a dihydrate. 4. The hydrate according to claim 2, wherein the crystalline salt is a monoedisylate salt of sulcardine. 5. The hydrate according to claim 4, wherein the salt is a dihydrate. 6. The hydrate according to claim 4, wherein the salt is characterized by a powder X-ray diffraction pattern containing a peak at 5.2°2θ. 7. The hydrate according to claim 6, wherein the salt is characterized by a powder X-ray diffraction pattern further containing one or more peaks at 9.1°2θ, 10.2°2θ, 10.8°2θ, 11.3°2θ, 13.6° 2θ and 15.7°2θ. 8. The hydrate according to claim 6, wherein the salt is characterized by a powder X-ray diffraction pattern additionally containing peaks at 15.7°2θ, 16.9°2θ and 23.6°2θ. 9. The hydrate according to claim 6, wherein the salt is characterized by a powder X-ray diffraction pattern additionally containing peaks at 9.1°2θ and 11.3°2θ. 10. Hydrate according to claim 4, wherein the salt is characterized by a powder X-ray diffraction pattern, -