Co-crystals of nitroxyl donating compounds

Abstract

The disclosed subject matter provides co-crystals of N-hydroxysulfonamide compounds, pharmaceutical compositions and kits comprising such co-crystals, and methods of using such co-crystals or pharmaceutical compositions comprising them. In particular, the disclosed subject matter provides methods of using such co-crystals or pharmaceutical compositions for treating heart failure.

Description

[0001] CO-CRYSTALS OF NITROXYL DONATING COMPOUNDS 1. BACKGROUND Nitroxyl (HNO) has been shown to have positive cardiovascular effects in in vitro and in vivo models of failing hearts. However, at physiological pH, nitroxyl dimerizes to hyponitrous acid, which subsequently dehydrates to nitrous oxide. Due to this metastability, nitroxyl for therapeutic use must be generated in situ from donor compounds. A variety of compounds capable of donating nitroxyl have been described and proposed for use in treating disorders known or suspected to be responsive to nitroxyl. See, e.g., U.S. Patent nos.6,936,639; 7,696,373; 8,030,356; 8,268,890; 8,227,639; 8,318,705; 8,987,326 and 9,464,061; and U.S. pre-grant publication nos.2009 / 0281067; 2009 / 0298795; 2011 / 0136827; 2011 / 0144067; 2015 / 36697; and 2015 / 0344437. U.S. Patent 8,987,326 describes nitroxyl donating compounds that are highly efficacious in treating cardiovascular diseases (e.g., heart failure) and have suitable toxicological profiles. One such nitroxyl donor, N-hydroxy-5-methylfuran-2-sulfonamide, has been evaluated in preclinical models and in Phase I / IIa studies. In these studies, N-hydroxy-5-methylfuran-2-sulfonamide demonstrated peripheral vasodilation and increased inotropy and improved lusitropy. Cowart D. et al., J Am Coll Cardiol 201565 A876; and European Heart Failure 2016 Congress in Florence, Italy, May 21–24, 2016. Formulating nitroxyl donating compounds has proven to be a considerable challenge. Many of the current nitroxyl donating compounds are insoluble in aqueous solutions and / or are insufficiently stable in solution and as crystalline solids. Instability of nitroxyl donating compounds makes their large-scale production particularly challenging. Nitroxyl donating compounds can be a challenge to formulate as a stable crystalline product. Appropriate stability is a critical attribute of any pharmaceutical, with the identification of stable storage conditions being required to ensure that it can be successfully delivered to patients with appropriate quality. Solubility and stability problems often preclude the use of such compounds in pharmaceutical compositions for parenteral and / or oral administration. Accordingly, there is a need to develop new solid forms of nitroxyl donating compounds that are sufficiently stable in solution and in the solid state. U.S. Patent 10,245,249 describes enhancing stability and / or solubility of nitroxyl donating compounds with a cyclodextrin. Nitroxyl donating compounds gradually release nitroxyl and at least one byproduct in the pharmaceutical composition, which can compromise the efficacy and safety of the composition. The presence of cyclodextrin can mitigate or eliminate the release of nitroxyl and byproducts in the pharmaceutical composition during storage, prior to administration to a patient. Pharmaceutical co-crystals have emerged over the past two decades as a new solid form. A pharmaceutical co-crystal is a crystalline solid composed of at least two co-formers, in which one of the co-formers is an active pharmaceutical ingredient (API) and the other is a pharmaceutically acceptable compound found in the generally regarded as safe (GRAS) list. Duggirala, N. K et al., Chem. Commun.2016, 52 (4), 640−655. Individual co-formers are present in a stoichiometric ratio and interact via non-covalent interactions (hydrogen bonding, π- π stacking, and van der Waals interactions). No proton transfer takes place between the co-formers. Co-crystals have the advantage of forming stable crystalline form as compared to amorphous solids. There is no need to make or break covalent bonds and there is theoretical capability of all types of API molecules (weakly ionizable / non-ionizable) to form co-crystals. The major advantage of co- crystals over salts is that co-crystals can be used for those drugs that are non-ionizable or weakly ionizable in nature. There are numerous potential co-formers (food additives, preservatives, pharmaceutical excipients, and other APIs) that can form co-crystals with the API via weak interactions. Yadav, A. V. et al., Indian Journal of Pharmaceutical Sciences 2009, 71 (4), 359-370. Using a suitable co-former, the properties of an API, including melting point (Aakeroy CB, et al., J Am Chem Soc 2009, 131, 17048-9; Batisai E et al., CrystEngComm 2014, 16, 9992-8; Fleischman SG et al., Cryst Growth Des 2003, 3, 909-19; and Stanton MK, Cryst Growth Des 2008, 8, 3856-62), solubility (Bethune SJ, et al., Cryst Growth Des 2011, 11, 2817-23; Chen Y, et al., Cryst Growth Des 2016, 16, 2923-30; Martin FA, et al., Cryst Growth Des 2013, 13, 4295-304; McNamara DP, et al., Pharm Res 2006, 23(8), 1888-97; and Wang JR, et al., Bioorg Med Chem Lett 2015, 25, 1036-9), stability (McNamara DP, et al., Pharm Res 2006, 23(8), 1888-97; Oswald IDH, et al., Acta Crystallogr B Struct Sci Cryst Eng Mater 2002, 58, 1057-66; and Variankaval N, et al., Cryst Growth Des 2006, 6, 690-700), manufacturability, tabletability (Krishna GR, et al., Cryst Growth Des 2015, 15 (1827-32); Maeno Y, F. T. et al., Int J Pharm 2014, 473, 179-86; and Zhou Z, L. W., et al., Int J Pharm 2016, 509, 391-9), permeability (Dai XL, et al., Cryst Growth Des 2016, 16, 4430-8), and bioavailability (Cheney ML, et al., J Pharm Sci 2011, 100, 2172-81; and Huang Y, Z. B., et al., J Pharm Sci 2014, 103, 2330-7) can be optimized. Thus, co-crystals offer the unique advantages of potentially retaining the pharmacological properties of the API and simultaneously benefiting from the physicochemical properties of the co- former. However, it is difficult to predict successful crystallization, and the properties, of the resulting co-crystals. Further, suitable pharmaceutical co-crystals are largely developed by a trial-and-error approach in which co-formers, the ratio of the two in the co-crystal, and the method for making them are varied. Another approach for developing pharmaceutical co-crystals is based on crystallography tools that rank potential co-formers to form co-crystals with an API. Citation of any reference in Section 1 of this application is not to be construed as an admission that such reference is prior art to the present application. 2. SUMMARY OF THE DISCLOSURE The present disclosure relates to the discovery of co-crystals of nitroxyl donating compounds, such as N-hydroxylsulfonamide compounds, that are highly stable as compared to their free form(s) and to formulations with a cyclodextrin. The co-crystals described herein are IV compatible (both physically and biologically). The co-crystals described herein also provide manufacturing advantages relative to their free form(s). The co-crystal approach, when used in manufacturing, avoids the step of isolating the neat form of the nitroxyl donating compound, which is thermally unstable. The co- crystals described herein are stable to 25 °C storage conditions, unlike their cyclodextrin lyophiles, which need to be stored frozen or refrigerated. In a particular embodiment, a co-crystal of the disclosure comprises a compound of the formula (1): and a co-crystal former selected group alanine, and proline. In another embodiment, the present disclosure provides a pharmaceutical composition comprising a co-crystal described above; and at least one pharmaceutically acceptable excipient. In another embodiment, the present disclosure provides a method of making a co-crystal of a nitroxyl donating compound and a co-crystal former. In one embodiment, the method comprises: (a) contacting a solution comprising the nitroxyl donating compound with a co-crystal former under crystallization conditions so as to form the co-crystal in solid phase; and optionally (b) isolating the co- crystal formed in step (a). The co-crystals and compositions of the disclosure can be used in treating a variety of conditions that are responsive to nitroxyl therapy. For instance, the co-crystals or compositions of the disclosure can be used to treat or prevent the occurrence of cardiovascular diseases. In certain embodiments, the co-crystals or compositions of the disclosure can be used to treat cardiovascular disease, ischemia / reperfusion injury, pulmonary hypertension or another condition responsive to nitroxyl therapy. In particular embodiments, the co-crystals or compositions of the disclosure can be used to treat heart failure. In a particular embodiment, the co-crystals or compositions of the disclosure can be used to treat decompensated heart failure (e.g., acute decompensated heart failure). In certain embodiments, the co-crystals or compositions of the disclosure can be used to treat systolic heart failure. In particular embodiments, the co-crystals or compositions of the disclosure can be used to treat diastolic heart failure. 3. BRIEF DESCRIPTION OF FIGURES FIG.1 shows the crystal structure of Co-Crystal 10 (a co-crystal of Compound 1 and alanine). FIG.2 shows the crystal structure of Co-Crystal 11 (a co-crystal of Compound 1 and glycine). FIG.3 shows the crystal structure of Co-Crystal 12 Form B (a co-crystal of Compound 1 and proline). FIG.4 shows the crystal structure of Co-Crystal 12 Form C (a co-crystal of Compound 1 and proline). FIG.5 shows the crystal structure of Co-Crystal 13 (a co-crystal of Compound 2 and proline). FIG.6 shows the crystal structure of Co-Crystal 14 (a co-crystal of Compound 3 and proline). FIG.7 shows the crystal structure of Co-Crystal 15 (a co-crystal of Compound 4 and proline). FIG.8 shows the crystal structure of Co-Crystal 16 (a co-crystal of Compound 5 and proline). FIG.9 shows the crystal structure of Co-Crystal 17 (a co-crystal of Compound 6 and proline). FIG.10 shows the crystal structure of Co-Crystal 18 (a co-crystal of Compound 7 and proline). FIG.11 shows the crystal structure of Co-Crystal 19 (a co-crystal of Compound 8 and proline). FIG.12 shows PXRD data for Compound 1 (Form A). FIG.13 shows PXRD data for Co-Crystal 12 Form B / C. FIG.14 shows the experimental PXRD patterns for Compound 1 (Form A), L-proline and Co-Crystal 12 Form B / C, together with simulated patters for Co-Crystal 12 Forms B and C. FIG.15 shows DSC data for Compound 1 (Form A). FIG.16 shows DSC data for Co-Crystal 12 Form B / C. FIG.17 shows TGA data for Compound 1 (Form A). FIG.18 shows TGA data for Co-Crystal 12 Form B / C. FIG.19 shows Moisture-Sorption Isotherms for Form B / C. FIG.20 shows PXRD data for Compound 2. FIG.21 shows PXRD data for Co-Crystal 13 (a co-crystal of Compound 2 and proline). FIG.22 shows PXRD data for Compound 3. FIG.23 shows PXRD data for Co-Crystal 14 (a co-crystal of Compound 3 and proline). FIG.24 shows PXRD data for Compound 4. FIG.25 shows PXRD data for Co-Crystal 15 (a co-crystal of Compound 4 and proline). FIG.26 shows PXRD data for Compound 6. FIG.27 shows PXRD data for Co-Crystal 17 (a co-crystal of Compound 6 and proline). FIG.28 shows PXRD data for Compound 7. FIG.29 shows PXRD data for Co-Crystal 18 (a co-crystal of Compound 7 and proline). FIG.30 shows PXRD data for Compound 8. FIG.31 shows PXRD data for Co-Crystal 19 (a co-crystal of Compound 8 and proline). FIG.32 shows a melting point analysis or decomposition temperature of neat form API (left), L- proline (right) and the corresponding co-crystal (middle). 4. DETAILED DESCRIPTION The invention includes the following: (1.) A co-crystal comprising a nitroxyl donating compound and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glycine, alanine and proline. (2.) The co-crystal of the above (1.), wherein the nitroxyl donating compound is an N- hydroxysulfonamide compound. (3.) The co-crystal of the above (2.), wherein the N-hydroxysulfonamide compound is a compound listed in Table 1. (4.) The co-crystal of the above (1.), wherein the co-crystal former is proline. (5.) A co-crystal comprising a compound of formula (1): and a co-crystal former, wherein from the group consisting of glycine, alanine and proline. (6.) The co-crystal of the above (5.), wherein the co-crystal former is glycine. (7.) The co-crystal of the above (5.), wherein the co-crystal former is alanine. (8.) The co-crystal of the above (5.), wherein the co-crystal former is proline. (9.) A 1:1 co-crystal comprising a compound of formula (1):H3C SO2NHOHand glycine. (10.) A 2:1 co-crystal comprising a compound of formula (1): and alanine. (11.) A 1:1 co-crystal comprising a compound of formula (1): and proline. (12.) A pharmaceutical composition comprising the co-crystal of any one of the above (1.) to (11.) and at least one pharmaceutically acceptable excipient. (13.) The pharmaceutical composition of the above (12.), wherein the co-crystal former is glycine. (14.) The pharmaceutical composition of the above (12.), wherein the co-crystal former is alanine. (15.) The pharmaceutical composition of the above (12.), wherein the co-crystal former is proline. (16.) A method of making a co-crystal comprising: mixing a nitroxyl donating compound with a co-crystal former in a solvent under crystallization conditions so as to form the co-crystal in solid phase, wherein the co-crystal former is selected from the group consisting of glycine, alanine and proline. (17.) The method of the above (16.), wherein the nitroxyl donating compound is an N- hydroxysulfonamide compound. (18.) The method of the above (16.), wherein the N-hydroxysulfonamide compound is a compound listed in Table 1. (19.) The method of any one of above (16.) to (18.), wherein the co-crystal former is proline. (20.) The method of any one of the above (16.) to (19.), wherein the nitroxyl donating compound is a compound of formula (1): . (21.) The method of any one of the above (16.) to (20.), further comprising isolating the co- crystal. (22.) The method of any one of the above (16.) to (21.), wherein the solvent is methanol. (23.) A method of treating a cardiovascular disease responsive to nitroxyl therapy, comprising administering an effective amount of a co-crystal of any one of the above (1.) to (11.) or the pharmaceutical composition of any one of the above (12.) to (15.) to a patient in need thereof. (24.) The method of the above (23.), wherein the cardiovascular disease is heart failure. (25.) The method of the above (23.) or the above (24.), wherein the cardiovascular disease is acute decompensated heart failure. (26.) The method of any one of the above (23.) through (25.), wherein the co-crystal or pharmaceutical composition is administered intravenously. (27.) A kit comprising a co-crystal of any one of the above (1.) to (11.) in dry form or the pharmaceutical composition of any one of the above (12.) to (15.) in dry form; and a pharmaceutically acceptable liquid diluent. (28.) Use of the co-crystal of any one of the above (1.) to (11.) or use of the pharmaceutical composition of any one of the above (12.) to (15.) for the manufacture of a medicament useful for treating a cardiovascular disease. (29.) Use of the co-crystal of any one of the above (1.) to (11.) or use of the pharmaceutical composition of any one of the above (12.) to (15.) for the manufacture of a medicament useful for treating heart failure. (30.) Use of the co-crystal of any one of the above (1.) to (11.) or use of the pharmaceutical composition of any one of the above (12.) to (15.) for the manufacture of a medicament useful for treating acute decompensated heart failure. (31.) The co-crystal of any one of the above (1.) to (11.) or the pharmaceutical composition of any one of the above (12.) to (15.) for use in the treatment of a cardiovascular disease. (32.) The co-crystal of any one of the above (1.) to (11.) or the pharmaceutical composition of any one of the above (12.) through (15.) for use in the treatment of heart failure. (33.) The co-crystal of any of the above (1.) to (11.) or the pharmaceutical composition of any one of the above (12.) through (15.) for use in the treatment of acute decompensated heart failure. 4.1 Definitions Unless clearly indicated otherwise, the following terms as used herein have the meanings indicated below. The abbreviation “API” refers to active pharmaceutical ingredient. A “co-crystal former” refers to a molecule in a co-crystal other than an API. An “IV compatible co-crystal former” refers to a co-former that does not on its own have biological activity or present any toxicology issues when administered intravenously. A “co-crystal” refers to a crystalline solid composed of at least two co-formers. Co-crystals are different from salts, solvates, and hydrates. A “pharmaceutical co-crystal “ refers to a co-crystal, in which one of the co-formers is an active pharmaceutical ingredient (API) and the other is a pharmaceutically acceptable compound. An “IV compatible co-crystal” refers to a co-crystal that is compatible with intravenous administration. An X-ray powder patten is “substantially to that in [a particular] Figure” refers to an X-ray powder patten in which at least 90% of the signals in the two patterns overlap, at least 95% of the signals in the two patterns overlap, at least 98% of the signals in the two patterns overlap, or at least 99% of the signals in the two patterns overlap. A DSC plot is “substantially to that in [a particular] Figure” refers to a DSC plot in which at least 90% of the features in the two plots overlap, at least 95% of the features in the two plots overlap, at least 98% of the features in the two plots overlap, or at least 99% of the features in the two plots overlap. A TGA plot is “substantially to that in [a particular] Figure” refers to a TGA plot in which at least 90% of the features in the two plots overlap, at least 95% of the features in the two plots overlap, at least 98% of the features in the two plots overlap, or at least 99% of the features in the two plots overlap. “Pharmaceutically acceptable excipient” refers to any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, binder, and / or vehicle for delivery of a therapeutic agent to a patient, or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a compound or pharmaceutical composition into a unit dosage form for administration. Pharmaceutically acceptable excipients are known in the pharmaceutical arts and are disclosed, for example, in Gennaro, Ed., Remington: The Science and Practice of Pharmacy, 20thEd. (Lippincott Williams & Wilkins, Baltimore, MD, 2000) and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, D.C., (e.g., 1st, 2ndand 3rdEds., 1986, 1994 and 2000, respectively). As will be known to those in the art, pharmaceutically acceptable excipients can provide a variety of functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners. Examples of pharmaceutically acceptable excipients include without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropylmethylcellulose, and hydroxypropylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. “Unit dosage form” refers to a physically discrete unit suitable as a unitary dosage for a human or an animal. Each unit dosage form can contain a predetermined amount of a therapeutic agent calculated to produce a desired effect. Unless clearly indicated otherwise, a “patient” refers to an animal, such as a mammal, including but not limited to, a human. Hence, the methods disclosed herein can be useful in human therapy and veterinary applications. In particular embodiments, the patient is a mammal. In certain embodiments, the patient is a human. “Effective amount” refers to such amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, which in combination with its parameters of efficacy and potential for toxicity, as well as based on the knowledge of the practicing specialist, should be effective in a given therapeutic form. As is understood in the art, an effective amount can be administered in one or more doses. “Treatment”, “treating” and the like is an approach for obtaining a beneficial or desired result, including clinical results. For purposes of this disclosure, beneficial or desired results include but are not limited to inhibiting and / or suppressing the onset and / or development of a condition or reducing the severity of such condition, such as reducing the number and / or severity of symptoms associated with the condition, increasing the quality of life of those suffering from the condition, decreasing the dose of other medications required to treat the condition, enhancing the effect of another medication a patient is taking for the condition, and / or prolonging survival of patients having the condition. “Prevent”, “preventing” and the like refers to reducing the probability of developing a condition in a patient who does not have but is at risk of developing a condition. A patient “at risk” may or may not have a detectable condition and may or may not have displayed a detectable condition prior to the treatment methods disclosed herein. “At risk” denotes that a patient has one or more so- called risk factors, which are measurable parameters that correlate with development of a condition and are known in the art. A patient having one or more of these risk factors has a higher probability of developing the condition than a patient without such risk factor(s). “Positive inotrope” refers to an agent that causes an increase in myocardial contractile function. Exemplary positive inotropes are a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, and calcium-sensitizers. Beta-adrenergic receptor agonists include, among others, dopamine, dobutamine, terbutaline, and isoproterenol. Analogs and derivatives of such compounds are also intended. For example, U.S. Pat. No.4,663,351 discloses a dobutamine prodrug that can be administered orally. A condition that is “responsive to nitroxyl therapy” includes any condition in which administration of a compound that donates an effective amount of nitroxyl under physiological conditions treats and / or prevents the condition, as those terms are defined herein. A condition whose symptoms are suppressed or diminished upon administration of nitroxyl donor is a condition responsive to nitroxyl therapy. “Pulmonary hypertension” or “PH” refers to a condition in which the pulmonary arterial pressure is elevated. The current hemodynamic definition of PH is a mean pulmonary arterial pressure (MPAP) at rest of greater than or equal to 25 mmHg. Badesch et al., J. Amer. Coll. Cardiol. 54(Suppl.):S55-S66 (2009). “N / A” means not assessed. 4.2 Co-Crystals Of Nitroxyl Donating Compounds Nitroxyl donating compounds, such as N-hydroxysulfonamides, are considered prodrugs and are designed to release nitroxyl (HNO) in vivo. In general, the structure of the core of N- hydroxysulfonamide will determine the compound’s half-life at physiological pH and temperature. All N-hydroxysulfonamides have a pH dependent first-order decomposition to form HNO. An example of an N-hydroxysulfonamide nitroxyl donating compound is a compound of the formula (1):H3C SO2NHOHCompound 1 decomposes to O O O - S OH pKa ~8.5 S O + S OH the compound will be both in solution and as an isolated solid. For example, Compound 1, which has a pKa of ~ 8.5, is relatively unstable in solution (~60 min half-life) and as a crystalline solid. Because HNO is so reactive, there is a secondary degradation in the solid state that results in a non-linear and catastrophic decomposition of the API at standard temperature storage conditions. The present disclosure provides novel co-crystals of nitroxyl donating compounds. The co- crystals of the disclosure have a combination of properties that are desirable for formulating the nitroxyl donating compounds for clinical use. In particular, the co-crystals of the disclosure are highly stable, IV compatible, and easily manufactured. Importantly, the co-crystals of the disclosure have no impact on the half-life of the API. The co-crystals of the disclosure possess desirable properties and are thus suitable for therapeutic administration to humans. Table 1 provides eight specific N-hydroxysulfonamide nitroxyl donating compounds that can be used as the API in a co-crystal of the disclosure.

[0002] Table 1 Nitroxyl Donating Compounds (1) Br (2) ) ) ) The co-former is a compound selected from the group consisting of glycine, alanine, and proline. In a first embodiment, a co-crystal of the disclosure comprises a compound listed in Table 1 and the co-crystal former is glycine. In a second embodiment, a co-crystal of the disclosure comprises a compound listed in Table 1 and the co-crystal former is alanine. In a third embodiment, a co-crystal of the disclosure comprises a compound listed in Table 1 and the co-crystal former is proline. In a particular embodiment, a co-crystal of the disclosure comprises a compound of the formula (1): and the co-crystal former is the co-crystal is 1:1 Compound 1 and glycine. In another embodiment, a co-crystal of the disclosure comprises Compound 1 and the co- crystal former is alanine. In one aspect of this embodiment, the co-crystal is 2:1 Compound 1 and alanine. In another embodiment, a co-crystal of the disclosure comprises Compound 1 and the co- crystal former is proline. In one aspect of this embodiment, the co-crystal is 1:1 Compound 1 and proline. In another embodiment, the co-crystal comprises Compound 1 and proline and is characterized by an X-ray powder pattern substantially similar to that in FIG.13. In another embodiment, the co-crystal is characterized by an X-ray powder pattern substantially similar to that shown in FIG.14 for simulated and / or experimental patterns for Co-Crystal 12. In another embodiment, the co-crystal comprises Compound 1 and proline and is characterized by an X-ray powder pattern having peaks at one or more of 9.72, 11.7, and 12.9 (2-theta degrees) ±0.2. In another embodiment, the co-crystal comprises Compound 1 and proline and is characterized by an X-ray powder pattern having peaks at two or more of 9.72, 11.7, and 12.9 (2-theta degrees) ±0.2. In another aspect of this embodiment, the co-crystal comprises Compound 1 and proline and is characterized by a DSC plot substantially similar to that in FIG.16. In another aspect of this embodiment, the co-crystal comprises Compound 1 and proline and is characterized by a TGA plot substantially similar to that in FIG.18. In another embodiment, a co-crystal of the disclosure comprises Compound 2 and the co- crystal former is proline. In another embodiment, a co-crystal of the disclosure comprises Compound 3 and the co-crystal former is proline. In another embodiment, a co-crystal of the disclosure comprises Compound 4 and the co-crystal former is proline. In another embodiment, a co- crystal of the disclosure comprises Compound 5 and the co-crystal former is proline. In another embodiment, a co-crystal of the disclosure comprises Compound 6 and the co-crystal former is proline. In another embodiment, a co-crystal of the disclosure comprises Compound 7 and the co- crystal former is proline. In another embodiment, a co-crystal of the disclosure comprises Compound 8 and the co-crystal former is proline. In another embodiment, the co-crystal comprises Compound 2 and proline and is characterized by an X-ray powder pattern substantially similar to that in FIG.21. In another embodiment, the co-crystal comprises Compound 3 and proline and is characterized by an X-ray powder pattern substantially similar to that in FIG.23. In another embodiment, the co-crystal comprises Compound 4 and proline and is characterized by an X-ray powder pattern substantially similar to that in FIG.25. In another embodiment, the co-crystal comprises Compound 6 and proline and is characterized by an X-ray powder pattern substantially similar to that in FIG.27. In another embodiment, the co-crystal comprises Compound 7 and proline and is characterized by an X-ray powder pattern substantially similar to that in FIG.29. In another embodiment, the co-crystal comprises Compound 8 and proline and is characterized by an X-ray powder pattern substantially similar to that in FIG.31. In one embodiment, Compound 1 is characterized by an X-ray powder pattern substantially similar to that in FIG.12. In another embodiment, Compound 1 is characterized by an X-ray powder pattern having peaks at one or more of 12.9 or 18 (2-theta degrees) ±0.2. In another embodiment, Compound 1 is characterized by an X-ray powder pattern having peaks at two or more of 12.9 or 18 (2-theta degrees) ±0.2. 4.3 Methods of Making Co-Crystals In another embodiment, the present disclosure provides a method of making a co-crystal of a N-hydroxylsulfonamide compound and a co-former. In one embodiment, the method comprises: (a) contacting a solution comprising the N-hydroxylsulfonamide compound with a co-former under crystallization conditions so as to form the co-crystal in solid phase; and optionally (b) isolating the co- crystal formed in step (a). The N-hydroxylsulfonamide compound and co-former used in the methods of making co-crystals can be any disclosed herein. In some embodiments, step (a) comprises substep (i) adding a suitable amount of the N- hydroxylsulfonamide compound to a suitable solvent system to obtain a solution of N- hydroxylsulfonamide. The suitable solvent system comprises a solvent selected from the group consisting of methyl isobutyl ketone (MIBK), ethyl acetate, toluene, tetrahydrofuran, acetonitrile, methanol, isopropyl alcohol, cyclopentyl methyl ether (CPME), water, and mixtures thereof. In some aspects of this embodiment, substep (i) is performed at room temperature. In some embodiments, step (a) comprises substep (ii) adding a suitable amount of co-former to a suitable solvent system to obtain a solution of co-former. The suitable solvent system comprises a solvent selected from the group consisting of methyl isobutyl ketone (MIBK), ethyl acetate, toluene, tetrahydrofuran, acetonitrile, methanol, isopropyl alcohol, cyclopentyl methyl ether (CPME), water, and mixtures thereof. In some aspects of this embodiment, substep (ii) is performed at performed at room temperature. In some embodiments, step (a) comprises substep (iii) stirring the solution of the N- hydroxylsulfonamide compound and a co-former. Methods for isolating co-crystals are well-known in the art and include, filtration, rapid evaporation and wet grinding. 4.4 Pharmaceutical Compositions The disclosure also encompasses pharmaceutical compositions comprising a co-crystal of the disclosure and at least one pharmaceutically acceptable excipient. Examples of pharmaceutically acceptable excipients include those described above, such as carriers, surface active agents, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coatings, disintegrating agents, lubricants, sweeteners, preservatives, isotonic agents, and any combination thereof. The selection and use of pharmaceutically acceptable excipients is taught, e.g., in Troy, Ed., Remington: The Science and Practice of Pharmacy, 21stEd. (Lippincott Williams & Wilkins, Baltimore, MD, 2005). The pharmaceutical compositions can be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, as drenches (for example, aqueous or non-aqueous solutions or suspensions), tablets (for example, those targeted for buccal, sublingual and systemic absorption), caplets, boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, mouth sprays, troches, lozenges, pellets, syrups, suspensions, elixirs, liquids, emulsions and microemulsions; or (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension. The pharmaceutical compositions can be for immediate, sustained, or controlled release. In one particular embodiment, the pharmaceutical composition is formulated for intravenous administration. In another embodiment, the pharmaceutical composition is formulated for intravenous administration by continuous infusion. In another embodiment, the pharmaceutical composition is formulated for oral administration. Compounds for oral administration can be formulated as liquid or solid dosage forms. In particular embodiments where the co-crystals are formulated as oral liquid dosage forms, polyethylene glycol 300 (PEG300) can usefully serve as an excipient. The co-crystals and pharmaceutical compositions disclosed herein can be prepared as any appropriate unit dosage form, such as capsules, sachets, tablets, powder, granules, solution, suspension in an aqueous liquid, suspension in a non-aqueous liquid, oil-in-water liquid emulsion, water-in-oil liquid emulsion, liposomes, or bolus. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the therapeutic agent or agents in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can be optionally coated or scored and can be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as the therapeutic agents herein and other compounds known in the art, are known in the art and disclosed in issued U.S. patents, some of which include, but are not limited to, U.S. Pat. Nos.4,369,174, 4,842,866, and the references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Pat. Nos. 6,638,534, 5,217,720, 6,569,457, and the references cited therein). An artisan will recognize that in addition to tablets, other dosage forms can be formulated to provide slow or controlled release of the active ingredient. Such dosage forms include, but are not limited to, capsules, granulations and gel- caps. Pharmaceutical compositions suitable for topical administration include, without limitation, lozenges comprising the ingredients in a flavored basis, such as sucrose, acacia and tragacanth; and pastilles comprising the active ingredient in a flavored basis or in an inert basis, such as gelatin and glycerin. Various embodiments of pharmaceutical compositions suitable for parenteral administration include, without limitation, either aqueous sterile injection solutions or non-aqueous sterile injection solutions, each containing, for example, anti-oxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous sterile suspensions and non- aqueous sterile suspensions, each containing, for example, suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules or vials, and can be stored in a freeze dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water, immediately prior to use. Pharmaceutical compositions administered parenterally can be administered in an acidic, neutral, or basic solution. In one embodiment, pharmaceutical compositions of the disclosure can be formulated in an acidic solution having a pH of from about 4 to about 5, for instance, a pH of about 4, about 4.5, about 4.8, or about 5, including values there between. In another embodiment, pharmaceutical compositions of the disclosure can be formulated for parenteral use at a pH of from about 5 to about 6.2 (e.g., pH of about 5, about 5.5, about 5.8, about 6, or about 6,2, including values there between). 4.5 Methods of Using the Co-Crystals and Pharmaceutical Compositions of the Disclosure In one aspect, the disclosure provides a method of increasing in vivo nitroxyl levels, comprising administering to a patient in need thereof an effective amount of a co-crystal or a pharmaceutical composition as disclosed herein. In various embodiments, the patient has, is suspected of having, or is at risk of having or developing a condition that is responsive to nitroxyl therapy. In particular embodiments, the disclosure provides a method of treating, preventing or delaying the onset and / or development of a condition, comprising administering to a patient (including a patient identified as in need of such treatment, prevention or delay) an effective amount of a co-crystal or a pharmaceutical composition as disclosed herein. Identifying a patient in need thereof can be in the judgment of a physician, clinical staff, emergency response personnel or other health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). Particular conditions embraced by the methods disclosed herein include, without limitation, cardiovascular diseases, ischemia / reperfusion injury, and pulmonary hypertension (PH). 4.5.1 Cardiovascular Diseases In one embodiment, the disclosure provides a method of treating a cardiovascular disease, comprising administering an effective amount of a co-crystal or a pharmaceutical composition as disclosed herein to a patient in need thereof. Examples of cardiovascular diseases and symptoms that can usefully be treated with the co- crystals and compositions disclosed herein include cardiovascular diseases that are responsive to nitroxyl therapy, coronary obstructions, coronary artery disease (CAD), angina, heart attack, myocardial infarction, high blood pressure, ischemic cardiomyopathy and infarction, pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heart disease, pericardial disease, circulatory congestive states, peripheral edema, ascites, Chagas’ disease, ventricular hypertrophy, heart valve disease, heart failure, diastolic heart failure, systolic heart failure, congestive heart failure, acute congestive heart failure, acute decompensated heart failure, and cardiac hypertrophy. 4.5.1.1 Heart Failure The co-crystals and pharmaceutical compositions of the disclosure can be used to treat patients suffering from heart failure. The heart failure can be of any type or form, including any of the heart failures disclosed herein. Nonlimiting examples of heart failure include early-stage heart failure, Class I, II, III and IV heart failure, acute heart failure, congestive heart failure (CHF) and acute congestive heart failure. In one embodiment, the co-crystals and compositions of the disclosure can be used to treat acute decompensated heart failure. In embodiments where co-crystals and pharmaceutical compositions of the disclosure are used to treat patients suffering from heart failure, another active agent that treats heart failure can also be administered. In one such embodiment, the co-crystal or pharmaceutical composition can be administered in conjunction with a positive inotrope such as a beta-agonist. Examples of beta-agonists include, without limitation, dopamine, dobutamine, isoproterenol, analogs of such compounds and derivatives of such compounds. In another embodiment, the co-crystal or pharmaceutical composition can be administered in conjunction with a beta-adrenergic receptor antagonist (also referred to herein as beta-antagonist or beta-blocker). Examples of beta-antagonists include, without limitation, propranolol, metoprolol, bisoprolol, bucindolol, and carvedilol. 4.5.1.2 Ischemia / Reperfusion Injury In another embodiment, the disclosure provides a method of treating, preventing or delaying the onset and / or development of ischemia / reperfusion injury, comprising administering an effective amount of a co-crystal or a pharmaceutical composition as disclosed herein to a subject in need thereof. In a particular embodiment, the method is for preventing ischemia / reperfusion injury. In a particular embodiment, a co-crystal or a pharmaceutical composition of the disclosure is administered prior to the onset of ischemia. In a particular embodiment, a co-crystal or a pharmaceutical composition of the disclosure is administered prior to procedures in which myocardial ischemia can occur, for example an angioplasty or surgery, such as a coronary artery bypass graft surgery. In a particular embodiment, a co-crystal or a pharmaceutical composition of the disclosure is administered after ischemia but before reperfusion. In a particular embodiment, a co-crystal or a pharmaceutical composition of the disclosure is administered after ischemia and reperfusion. In another embodiment, a co-crystal or a pharmaceutical composition of the disclosure can be administered to a patient who is at risk for an ischemic event. In a particular embodiment, a co-crystal or a pharmaceutical composition of the disclosure is administered to a patient at risk for a future ischemic event, but who has no present evidence of ischemia. The determination of whether a patient is at risk for an ischemic event can be performed by any method known in the art, such as by examining the patient or the patient’s medical history. In a particular embodiment, the patient has had a prior ischemic event. Thus, the patient can be at risk of a first or subsequent ischemic event. Examples of patients at risk for an ischemic event include patients with known hypercholesterolemia, EKG changes associated with ischemia (e.g., peaked or inverted T-waves or ST segment elevations or depression in an appropriate clinical context), abnormal EKG not associated with active ischemia, elevated CKMB, clinical evidence of ischemia (e.g., crushing sub-sternal chest pain or arm pain, shortness of breath and / or diaphoresis), prior history of myocardial infarction, elevated serum cholesterol, sedentary lifestyle, angiographic evidence of partial coronary artery obstruction, echocardiographic evidence of myocardial damage, or any other evidence of a risk for a future ischemic event. Examples of ischemic events include, without limitation, myocardial infarction (MI) and neurovascular ischemia, such as a cerebrovascular accident (CVA). In another embodiment, the subject of treatment is an organ that is to be transplanted. In a particular embodiment, a co-crystal or a pharmaceutical composition of the disclosure can be administered prior to reperfusion of the organ in a transplant recipient. In a particular embodiment, a co-crystal or a pharmaceutical composition of the disclosure can be administered prior to removal of the organ from the donor, for example through the perfusion cannulas used in the organ removal process. If the organ donor is a live donor, for example a kidney donor, the co-crystals or pharmaceutical compositions of the disclosure can be administered to the organ donor. In a particular embodiment, the co-crystals or pharmaceutical compositions of the disclosure are administered by storing the organ in a solution comprising the co-crystal or pharmaceutical composition. For example, a co-crystal or pharmaceutical composition of the disclosure can be included in the organ preservation solution, such as the University of Wisconsin “UW” solution, which is a solution comprising hydroxyethyl starch substantially free of ethylene glycol, ethylene chlorohydrin and acetone (see U.S. Pat. No.4,798,824). In a particular embodiment, a co-crystal or a pharmaceutical composition of the disclosure that is administered is such that ischemia / reperfusion injury to the tissues of the organ is reduced upon reperfusion in the recipient of transplanted organ. In a particular embodiment, the method reduces tissue necrosis (the size of infarct) in at-risk tissues. Ischemia / reperfusion injury can damage tissues other than those of the myocardium and the disclosed subject matter embraces methods of treating or preventing such damage. In various embodiments, the ischemia / reperfusion injury is non-myocardial. In particular embodiments, the method reduces injury from ischemia / reperfusion in the tissue of the brain, liver, gut, kidney, bowel, or any part of the body other than the myocardium. In another embodiment, the patient is at risk for such injury. Selecting a person at risk for non-myocardial ischemia could include a determination of the indicators used to assess risk for myocardial ischemia. However, other factors can indicate a risk for ischemia / reperfusion in other tissues. For example, surgery patients often experience surgery-related ischemia. Thus, patients scheduled for surgery could be considered at risk for an ischemic event. The following risk factors for stroke (or a subset of these risk factors) could demonstrate a patient’s risk for ischemia of brain tissue: hypertension, cigarette smoking, carotid artery stenosis, physical inactivity, diabetes mellitus, hyperlipidemia, transient ischemic attack, atrial fibrillation, coronary artery disease, congestive heart failure, past myocardial infarction, left ventricular dysfunction with mural thrombus, and mitral stenosis. Ingall, Postgrad. Med.107(6):34-50 (2000). Further, complications of untreated infectious diarrhea in the elderly can include myocardial, renal, cerebrovascular and intestinal ischemia. Slotwiner-Nie et al., Gastroenterol. Clin. N. Amer.30(3):625-635 (2001). Alternatively, patients could be selected based on risk factors for ischemic bowel, kidney and / or liver disease. For example, treatment would be initiated in elderly patients at risk of hypotensive episodes (such as surgical blood loss). Thus, patients presenting with such an indication would be considered at risk for an ischemic event. In another embodiment, the patient has any one or more of the conditions listed herein, such as diabetes mellitus and hypertension. Other conditions that can result in ischemia, such as cerebral arteriovenous malformation, could demonstrate a patient’s risk for an ischemic event. 4.5.2 Pulmonary Hypertension In another embodiment, a co-crystal or pharmaceutical composition of the disclosure can be used to prevent or delay the onset and / or development of pulmonary hypertension. In one such embodiment, a co-crystal or a pharmaceutical composition of the disclosure can be used to prevent or delay the onset and / or development of pulmonary arterial hypertension (PAH). In another embodiment, the disclosure provides a method of reducing mean pulmonary arterial pressure (MPAP), comprising administering an effective amount of a co-crystal or a pharmaceutical composition disclosed herein to a patient in need thereof. In another embodiment, the MPAP is reduced by up to about 50%. In another embodiment, the MPAP is reduced by up to about 25%. In another embodiment, the MPAP is reduced by up to about 20%. In another embodiment, the MPAP is reduced by up to about 15%. In another embodiment, the MPAP is reduced by up to 10%. In another embodiment, the MPAP is reduced by up to about 5%. In another embodiment, the MPAP is reduced to be from about 12 mmHg to about 16 mmHg. In another embodiment, the MPAP is reduced to be about 15 mmHg. 4.6 Administration Modes, Regimens, and Dose Levels The co-crystals and pharmaceutical compositions of the disclosure can be administered via parenteral (e.g., subcutaneous, intramuscular, intravenous or intradermal) administration. In certain embodiments, the co-crystal or pharmaceutical composition is administered by intravenous infusion. In other embodiments, the co-crystals and pharmaceutical compositions of the disclosure can be administered by oral administration. When a pharmaceutical composition of the disclosure is administered, dosages are expressed based on the amount of active pharmaceutical ingredient, i.e., the amount of co-crystal of the disclosure present in the pharmaceutical composition. For intravenous administration, the dose can usefully be expressed per unit time, either as a fixed amount per unit time or as a weight-based amount per unit time. In various embodiments, a co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount of at least about 0.1 μg / kg / min, at least about 0.2 μg / kg / min, at least about 0.3 μg / kg / min, at least about 0.4 μg / kg / min, at least about 0.5 μg / kg / min, at least about 1 μg / kg / min, at least about 2.5 μg / kg / min, at least about 5 μg / kg / min, at least about 7.5 μg / kg / min, at least about 10 μg / kg / min, at least about 11 μg / kg / min, at least about 12 μg / kg / min, at least about 13 μg / kg / min, at least about 14 μg / kg / min, at least about 15 μg / kg / min, at least about 16 μg / kg / min, at least about 17 μg / kg / min, at least about 18 μg / kg / min, at least about 19 μg / kg / min, at least about 20 μg / kg / min, at least about 21 μg / kg / min, at least about 22 μg / kg / min, at least about 23 μg / kg / min, at least about 24 μg / kg / min, at least about 25 μg / kg / min, at least about 26 μg / kg / min, at least about 27 μg / kg / min, at least about 28 μg / kg / min, at least about 29 μg / kg / min, at least about 30 μg / kg / min, at least about 31 μg / kg / min, at least about 32 μg / kg / min, at least about 33 μg / kg / min, at least about 34 μg / kg / min, at least about 35 μg / kg / min, at least about 36 μg / kg / min, at least about 37 μg / kg / min, at least about 38 μg / kg / min, at least about 39 μg / kg / min, or at least about 40 μg / kg / min. In various embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount of no more than about 100 μg / kg / min, no more than about 90 μg / kg / min, no more than about 80 μg / kg / min, no more than about 70 μg / kg / min, no more than about 60 μg / kg / min, no more than about 50 μg / kg / min, no more than about 49 μg / kg / min, no more than about 48 μg / kg / min, no more than about 47 μg / kg / min, no more than about 46 μg / kg / min, no more than about 45 μg / kg / min, no more than about 44 μg / kg / min, no more than about 43 μg / kg / min, no more than about 42 μg / kg / min, no more than about 41 μg / kg / min, no more than about 40 μg / kg / min, no more than about 39 μg / kg / min, no more than about 38 μg / kg / min, no more than about 37 μg / kg / min, no more than about 36 μg / kg / min, no more than about 35 μg / kg / min, no more than about 34 μg / kg / min, no more than about 33 μg / kg / min, no more than about 32 μg / kg / min, no more than about 31 μg / kg / min, or no more than about 30 μg / kg / min In some embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount ranging from about 0.1 μg / kg / min to about 100 μg / kg / min, about 1 μg / kg / min to about 100 μg / kg / min, about 2.5 μg / kg / min to about 100 μg / kg / min, about 5 μg / kg / min to about 100 μg / kg / min, about 10 μg / kg / min to about 100 μg / kg / min, about 1.0 μg / kg / min to about 80 μg / kg / min, from about 10.0 μg / kg / min to about 70 μg / kg / min, from about 20 μg / kg / min to about 60 μg / kg / min, from about 15 μg / kg / min to about 50 μg / kg / min, from about 0.01 μg / kg / min to about 1.0 μg / kg / min, from about 0.01 μg / kg / min to about 10 μg / kg / min, from about 0.1 μg / kg / min to about 1.0 μg / kg / min, from about 0.1 μg / kg / min to about 10 μg / kg / min, from about 1.0 μg / kg / min to about 5 μg / kg / min, from about 70 μg / kg / min to about 100 μg / kg / min, or from about 80 μg / kg / min to about 90 μg / kg / min. In particular embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount ranging from about 10 μg / kg / min to about 50 μg / kg / min, about 20 μg / kg / min to about 40 μg / kg / min, about 25 μg / kg / min to about 35 μg / kg / min, or about 30 μg / kg / min to about 40 μg / kg / min. In particular embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount of from about 20 μg / kg / min to about 30 μg / kg / min. In a variety of embodiments, including various oral administration embodiments, the co- crystals or pharmaceutical compositions of the disclosure are administered according to a weight-based daily dosing regimen, either as a single daily dose (QD) or in multiple divided doses administered, e.g., twice a day (BID), three times a day (TID), or four times a day (QID). In certain embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered in a dose of at least about 0.5 mg / kg / d, at least about 0.75 mg / kg / d, at least about 1.0 mg / kg / d, at least about 1.5 mg / kg / d, at least about 2 mg / kg / d, at least about 2.5 mg / kg / d, at least about 3 mg / kg / d, at least about 4 mg / kg / d, at least about 5 mg / kg / d, at least about 7.5 mg / kg / d, at least about 10 mg / kg / d, at least about 12.5 mg / kg / d, at least about 15 mg / kg / d, at least about 17.5 mg / kg / d, at least about 20 mg / kg / d, at least about 25 mg / kg / d, at least about 30 mg / kg / d, at least about 35 mg / kg / d, at least about 40 mg / kg / d, at least about 45 mg / kg / d, at least about 50 mg / kg / d, at least about 60 mg / kg / d, at least about 70 mg / kg / d, at least about 80 mg / kg / d, at least about 90 mg / kg / d, or at least about 100 mg / kg / d. In certain embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered at a dose of no more than about 100 mg / kg / d, no more than about 100 mg / kg / d, no more than about 90 mg / kg / d, no more than about 80 mg / kg / d, no more than about 80 mg / kg / d, no more than about 75 mg / kg / d, no more than about 70 mg / kg / d, no more than about 60 mg / kg / d, no more than about 50 mg / kg / d, no more than about 45 mg / kg / d, no more than about 40 mg / kg / d, no more than about 35 mg / kg / d, no more than about 30 mg / kg / d. In a variety of embodiments, the dose is from about 0.001 mg / kg / d to about 10,000 mg / kg / d. In certain embodiments, the dose is from about 0.01 mg / kg / d to about 1,000 mg / kg / d. In certain embodiments, the dose is from about 0.01 mg / kg / d to about 100 mg / kg / d. In certain embodiments, the dose is from about 0.01 mg / kg / d to about 10 mg / kg / d. In certain embodiments, the dose is from about 0.1 mg / kg / d to about 1 mg / kg / d. In certain embodiments, the dose is less than about 1 g / kg / d. In certain embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered in a dose range in which the low end of the range is any amount from about 0.1 mg / kg / day to about 90 mg / kg / day and the high end of the range is any amount from about 1 mg / kg / day to about 100 mg / kg / day (e.g., from about 0.5 mg / kg / day to about 2 mg / kg / day in one series of embodiments and from about 5 mg / kg / day to about 20 mg / kg / day in another series of embodiment). In particular embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered in a dose range of about 3 to about 30 mg / kg, administered from once a day (QD) to three times a day (TID). In certain embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered according to a flat (i.e., non-weight-based) dosing regimen, either as a single daily dose (QD) or in multiple divided doses administered, e.g., twice a day (BID), three times a day (TID), or four times a day (QID). In various embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered at a dose of at least about 0.01 grams / day (g / d), at least about 0.05 g / d, at least about 0.1 g / d, at least about 0.5 g / d, at least about 1 g / d, at least about 1.5 g / d, at least about 2.0 g / d, at least about 2.5 g / d, at least about 3.0 g / d, or at least about 3.5 g / d. In various embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered at a dose of no more than about 5 g / d, no more than about 4.5 g / d, no more than about 4 g / d, no more than about 3.5 g / d, no more than about 3 g / d, no more than about 2.5 g / d, or no more than about 2 g / d. In certain embodiments, the co-crystal or pharmaceutical composition of the disclosure is administered in a dose of about 0.01 grams per day to about 4.0 grams per day. In certain embodiments, the co-crystal or pharmaceutical composition of the disclosure can be administered at a dose in which the low end of the range is any amount from about 0.1 mg / day to about 400 mg / day and the high end of the range is any amount from about 1 mg / day to about 4000 mg / day. In certain embodiments, the co-crystal or pharmaceutical composition is administered in a dose of about 5 mg / day to about 100 mg / day. In various embodiments, the co-crystal or pharmaceutical composition is administered at a dose of from about 150 mg / day to about 500 mg / day. The dosing interval for parenteral or oral administration can be adjusted according to the needs of the patient. For longer intervals between administrations, extended release or depot formulations can be used. A co-crystal or pharmaceutical composition as disclosed herein can be administered prior to, at substantially the same time with, or after administration of an additional therapeutic agent. The administration regimen can include pretreatment and / or co-administration with the additional therapeutic agent. In such case, the compound or pharmaceutical composition and the additional therapeutic agent can be administered simultaneously, separately, or sequentially. Examples of administration regimens include without limitation: administration of each co- crystal, pharmaceutical composition or therapeutic agent in a sequential manner; and co-administration of each co-crystal, pharmaceutical composition or therapeutic agent in a substantially simultaneous manner (e.g., as in a single unit dosage form) or in multiple, separate unit dosage forms for each compound, pharmaceutical composition or therapeutic agent. It will be appreciated by those in the art that the “effective amount” or “dose” (“dose level”) will depend on various factors such as the particular administration mode, administration regimen, compound, and pharmaceutical composition selected, as well as the particular condition and patient being treated. For example, the appropriate dose level can vary depending upon the activity, rate of excretion and potential for toxicity of the specific compound or pharmaceutical composition employed; the age, body weight, general health, gender and diet of the patient being treated; the frequency of administration; the other therapeutic agent(s) being co-administered; and the type and severity of the condition. 4.7 Kits Comprising the Compounds or Pharmaceutical Compositions The disclosure provides kits comprising a co-crystal or a pharmaceutical composition disclosed herein. In a particular embodiment, the kit comprises a co-crystal or a pharmaceutical composition disclosed herein, each in dry form, and a pharmaceutically acceptable liquid diluent. In particular embodiments, either a co-crystal in dry form or a pharmaceutical composition in dry form contains about 2.0% or less water by weight, about 1.5% or less water by weight, about 1.0% or less water by weight, about 0.5% or less water by weight, about 0.3% or less water by weight, about 0.2% or less water by weight, about 0.1% or less water by weight, about 0.05% or less water by weight, about 0.03% or less water by weight, or about 0.01% or less water by weight. Pharmaceutically acceptable liquid diluents are known in the art and include but are not limited to sterile water, saline solutions, aqueous dextrose, glycerol, glycerol solutions, and the like. Other examples of suitable liquid diluents are disclosed by Nairn, "Solutions, Emulsions, Suspensions and Extracts," pp.721-752 in Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins, Baltimore, MD, 2000). In one embodiment, the kit further comprises instructions for using the co-crystal or pharmaceutical composition. The instructions can be in any appropriate form, such as written or electronic form. In another embodiment, the instructions can be written instructions. In another embodiment, the instructions are contained in an electronic storage medium (e.g., magnetic diskette or optical disk). In another embodiment, the instructions include information as to the compound or pharmaceutical composition and the manner of administering the compound or pharmaceutical composition to a patient. In another embodiment, the instructions relate to a method of use disclosed herein (e.g., treating, preventing and / or delaying onset and / or development of a condition selected from cardiovascular diseases, ischemia / reperfusion injury, pulmonary hypertension and other conditions responsive to nitroxyl therapy). In another embodiment, the kit further comprises suitable packaging. Where the kit comprises more than one co-crystal or pharmaceutical composition, the co-crystals or pharmaceutical compositions can be packaged patiently in separate containers or combined in one container when cross-reactivity and shelf-life permit. 5. EXAMPLES The following examples are presented for illustrative purposes and should not serve to limit the scope of the disclosed subject matter. Materials and Synthesis Compounds 1 – 8 were synthesized based on methods reported previously.1,2The co-formers used were glycine (Gly), Isoleucine (Iso), D-Alanine (Ala), Arginine (Arg), Valine (Val), Serine (Ser), Threonine (The) and L-proline (Pro). All co-formers were purchased from Sigma-Aldrich with purity of ≥98%. Example 1 - General Procedure for the Formation of Co-Crystals A concentrated solution of a co-former (e.g., L-Proline) was prepared using methanol or water. Separately, a concentrated solution of the N-hydroxysulfonamide compound was prepared. The two solutions were then combined with stirring. The resulting slurry of co-crystal was held at room temperature for several hours. The slurry was then filtered, washed with methanol, and dried in a vacuum oven to yield pure co-crystal. Example 1.1 - Co-Crystals of Compound 1 with Carboxylic Acid Co-Formers Carboxylic acids are common co-formers and traditionally used in biologics as buffers. Following the general procedure described in Example 1, unsuccessful attempts were made to crystallize Compound 1 with a variety of carboxylic acid co-formers and solvents. The unsuccessful co-formers include benzoic acid, citric acid, fumaric acid, L-maleic acid, succinic acid, L-tartaric acid, maleic acid, salicylic acid, L-arginine, L-valine, L-isoleucine, L-leucine hydrochloride, L-serine, L- threonine, monosodium succinate, EDTA, EDTA di-sodium salt, glutamic acid, glutamine, asparagine, valine, gluconic acid sodium salt, malic acid sodium salt, malic acid sodium salt, sodium citrate, sodium succinate, and sodium tartrate. The solvents used were methyl isobutyl ketone (MIBK), ethyl acetate, toluene, tetrahydrofuran, acetonitrile, methanol, cyclopentyl methyl ether (CPME), and 50% isopropyl alcohol / water. Example 1.2 - Co-Crystal 10 (Co-Crystal of Compound 1 and Alanine) To a round bottom flask was charged L-alanine (14g, 157 mmol) and water (60 mL). While stirring, the mixture was heated to 60°C to dissolve the majority of L-alanine. The thin slurry was cooled to 40°C and Compound 1 (13g, 73 mmol) was added. The solution was allowed to cool to room temperature while stirring. The slurry was then swept with nitrogen to slowly evaporate some of the water until a thick slurry of product had formed. The crystalline product was then isolated by vacuum filtration and washed with 5 mL of water. The solids were transferred to a glass dish and dried in a vacuum oven for 2 days at ambient temperature to yield a white, solid powder (15g, 55 mmol). The resulting Co-Crystal 10 was confirmed by SCXRD. Example 1.3 - Co-Crystal 11 (Co-Crystal of Compound 1 and Glycine) Compound 1 (13g, 73 mmol) was dissolved in ethanol and added to an aqueous solution of glycine (14g, 157 mmol). Upon rapid evaporation under nitrogen, co-crystals of Compound 1 and glycine monohydrate was isolated. The resulting Co-Crystal 11 was analyzed by means of PXRD and SCXRD. Example 1.4 - Co-Crystal 12 (Co-Crystal of Compound 1 and Proline) Form B: To a round bottom flask was charged Compound 1 (12g, 68 mmol) and water (100 mL). The mixture was stirred until a clear solution persisted. In a separate flask, L-proline (10g, 87 mmol) was mixed with water (30 mL) and heated until clear. The aqueous L-proline solution was then added in small portions to the aqueous Compound 1 solution over 1 hour while stirring. Crystallization occurred after approximately 25% of the proline solution was added. The resulting slurry was stirred for an additional 1 hour. The product was isolated via vacuum filtration and washed with 20 mL of water. The solids were transferred to a glass dish and dried in a vacuum oven for 2 days at ambient temperature to yield a white, solid powder (12g, 41 mmol). During the reaction, excess proline (4 eq) was used to drive equilibrium towards co-crystal formation and provide increased yield. Form C: A second polymorph of Compound 1-Pro was obtained by dissolving Compound 1 (12g, 68 mmol) in aqueous medium, water (100 mL) or water / alcohol mixture. The mixture was stirred until a clear solution persisted. In a separate flask, L-proline (10g, 87 mmol) was mixed with water (30 mL) and heated until clear. The aqueous L-proline solution was then added in small portions to the aqueous Compound 1 solution over 1 hour while stirring. The solution was slowly evaporated at ~40°C. During the reaction, excess proline (4 eq) was used to drive equilibrium towards co-crystal formation and provide increased yield. Example 1.5 - Co-Crystal 13 (Co-Crystal of Compound 2 and Proline) 1g of L-proline was dissolved in 5 mL of methanol.0.5 eq (~ 1g) of Compound 2 was dissolved separately in 5 mL of methanol. The two streams were combined, first passing through syringe filter to remove any solids. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 13 was confirmed by SCXRD. Example 1.6 - Co-Crystal 14 (Co-Crystal of Compound 3 and Proline) 1g of L-proline was dissolved in 5 mL of methanol.0.5 eq (~ 1g) of Compound 3 was dissolved separately in 5 mL of methanol. The two streams were combined, first passing through syringe filters to remove any solids. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 14 was confirmed by SCXRD. Example 1.7 - Co-Crystal 15 (Co-Crystal of Compound 4 and Proline) 1g of L-proline was dissolved in 5 mL of methanol.0.5 eq (~ 1g) of Compound 4 was dissolved separately in 5 mL of methanol. The two streams were combined, first passing through syringe filter to remove any solids. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 15 was confirmed by SCXRD. Example 1.8 - Co-Crystal 16 (Co-Crystal of Compound 5 and Proline) 25 mg of Compound 5 and 32mg of L-proline were almost completely dissolved in ~200uL of ethanol / AcN (1:1) at 50°C at ambient conditions. Full dissolution of the input solid was ultimately observed. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 16 was confirmed by SCXRD. Example 1.9 - Co-Crystal 17 (Co-Crystal of Compound 6 and Proline) 1g of proline was dissolved in 5 mL of methanol / water (1:1). 0.5 eq (~ 1g) of Compound 6 was dissolved separately in 5 mL of methanol / water (1:1). The two streams were combined, first passing through a syringe filter to remove any solids. The vial was returned to ambient conditions and loosely capped to allow for slow evaporation of the mother liquor. The resulting Compound 6-Pro co-crystal was confirmed by SCXRD. Example 1.10 - Co-Crystal 18 (Co-Crystal of Compound 7 and Proline) 17.8 mg of Compound 7 and 32mg of L-proline were fully dissolved in ~200μL of methanol at room temperature. The vial was loosely capped to allow for slow evaporation of the mother liquor. Co-Crystal 18 crystallized from these conditions and was used for SCXRD analysis. The resulting Co-Crystal 18 was confirmed by SCXRD. Example 1.11 - Co-Crystal 19 (Co-Crystal of Compound 8 and Proline) Three stoichiometries, 1:1 (19mg:13mg), 1:2(19mg:22mg) and 1:3(19mg:32mg), of Compound 8 and L-proline, respectively, were each ground in a drop of methanol solvent. After 20 seconds, the mixtures were dissolved in methanol solvent at room temperature. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 19 was confirmed by SCXRD. Example 2 – Crystallography Example 2.1 – Single-crystal X-ray Diffraction (SCXRD) To confirm the formation of a co-crystal, single-crystal X-ray Diffraction (SCXRD) experiments were performed. Single crystal X-ray data for all compounds were collected at room temperature, except for Co- Crystal 17 and Co-Crystal 14, which were collected at 273K on a Bruker SMART APEX CCD area detector diffractometer equipped with an APEX II CCD detector and IµS microfocus X-ray source of monochromatic Cu Kα radiation. The APEX3 software suite was used for data collection, cell refinement, andreduction.3,4Absorption corrections were performed by the multi-scan method implemented inSADABS.5Space group assignments were determined by examination of systematic absences, E- statistics, and successive refinement of the structures. Structure solutions were performed using intrinsic phasing methods implemented with ShelXT and structure refinements were performed by least-squares refinements against |F|2followed by difference Fourier synthesis using ShelXL,6-8implemented in the Olex2 software package.9All non- hydrogen atoms were refined with anisotropic displacement parameters. The hydrogen atoms on carbon atoms were placed in ideal positions and refined as riding atoms with relative isotropic displacement parameters for all structures. Hydrogen atoms on heteroatoms were located from residual electron density and freely refined for Co-Crystal 11, Co-Crystal 17, Co-Crystal 19, and Co-Crystal 16; in all other structures these hydrogen atoms were also refined with riding models. Table 2 provides selected crystal data and details on structure determinations from SCXRD analysis. Table 2. Co-Crystal Co-Crystal Co-Crystal 10 Co-Crystal Co-Crystal 13 12-A 12-B 11 F rm l C H NOS C H NO C H NOS CH NOS C H BrNOS ≤ 9 = 7 Table 2 (cont’d) Co-Crystal 17 Co-Crystal 19 Co-Crystal 18 Co-Crystal Co-Crystal Co-Crystal 16 14 15 Formula C H BrNO C H NOS C H NOS C H NO C H NO C H NO5 ic 11 ) 16 5) ) ≤ ≤ = 0 Co-Crystal 17 Co-Crystal 19 Co-Crystal 18 Co-Crystal Co-Crystal Co-Crystal 16 14 15 Final R indexes [all R1 = 00422 R1 = 00697 R1 = 00793 R1 = R1 = R1 = 2 n tota , crysta structures o a t e co-crysta s o t e ntroxy onatng compoun s were obtained (FIG.1 – FIG.11). Two unique crystal structures of Co-Crystal 12 (Compound 1-Pro) were obtained, Form B (FIG.3) and Form C (FIG.4). These forms were found to be polytypes, i.e., both structures contain identical layers, with differences arising from inter-layer relationships. For the purposes of additional discussion, Co-Crystal 12 (Compound 1-Pro) refers to Form B / C unless specified otherwise. Example 2.2 – Experimental Crystal Structure Analysis Example 2.2.1 – Descriptions of Hydrogen Bonding Networks Compound 1 neat form: The crystal structure of Compound 1 has been reported previously2. The neat form Compound 1 has two hydrogen-bond donors, the amine group (NH) and the hydroxyl group (OH). These combine to form a C22(7) motif along the crystallographic c-axis. Hydrogen bond interactions forms between the hydroxyl and sulfonyl group, OH…O=S, with a distance of 2.824(2) Å, with the amine forming another interaction with the sulfonyl, NH...O=S, with a distance of 2.971(2)Å. Additionally, the furan rings form a π -stacking arrangement along the a-axis with ring centroid distances of 3.5736(12) Å and 3.9244(12)Å alternating through the stack. Co-Crystal 10 (Compound 1-Ala co-crystal): The single-crystal structure of Co-Crystal 10 contains two molecules of alanine per one molecule of API. In this structure, the only heteromeric hydrogen bond is OH(API)… O=C(Ala). Additional stabilization of the structure comes from homomeric interactions between API:API and alanine:alanine. Co-Crystal 10 also exhibits hydrogen- bonding between the NH of Compound 1 and the sulfonyl oxygen, NH(API)…O=S(API), as is observed in the pure API itself as well as NH(Ala)…C=O(Ala) interaction in alanine. Co-Crystal 11 (Compound 1-Gly co-crystal): The single-crystal structure of Co-Crystal 11 contains one molecule of API, one molecule of glycine and one molecule of water per asymmetric unit. The structure is stabilized by heteromeric interactions between API:glycine via OH(API)…C=O(Gly), API:water via NH(API)…O(water), gly:water via OH(water)…C=O(Gly). Co-Crystal 12 (Compound 1-Pro co-crystal): Two crystal structures of Co-Crystal 12 were obtained, Form B and Form C. The asymmetric unit of both structures consists of two pairs of Compound 1-Pro units. There are two hydrogen-bond donors in the API, the secondary amine group and the hydroxyl group (OH). There are two hydrogen-bond donors in proline, the two protons of the primary amine. In both crystal structures, two heteromeric interactions, OH(API)…O=C(Pro) and NH(API)…O=C(Pro), are observed along with homomeric interactions between proline molecules NH(Pro)…O=C(Pro). The sulfonyl O atoms do not form hydrogen bonds. In the Co-Crystal 12 (Pro co-crystal), OH (API) behaves very similar to Co-Crystal 10 and Co-Crystal 11 (Ala and Gly co-crystals). However, NH(API) in this crystal structure also forms a heteromeric interaction with the Proline co-former. Because both OH and NH in the Co-Crystal 12 (Compound 1-Pro co-crystal) participate in heteromeric interactions with the proline coformer, this coformer was used for further experiments. Hydrogen bonding interactions are provided in Table 3. Table 3 - Hydrogen-bond interactions observed in the crystal structures of Compound 1 co- crystals. Co-Crystal 10 Co-Crystal 11Co-Crystal 12Co-Crystal 12 Form BForm C =2 When comparing the observed hydrogen-bonding interactions in the crystal structures of all the Co-Crystals, similarities were observed. In all crystal structures of the Co-Crystals 13-19, two conformations (boat and chair) of proline were observed as seen in Co-Crystal 12 (Compound 1-Pro). The intermolecular interactions observed in the series of co-crystals were remarkably consistent. In all eight cases (including Co-Crystal 12), the homomeric interaction OH(API) …S=O(HNO) is replaced with an even stronger heteromeric interaction between the API and L-proline via OH(API)…C=O(Pro). Overall, each crystal structure is stabilized by homomeric (pro…pro or API…API or both) and heteromeric interactions, leading to a final stable structure. Example 3 – Powder X-Ray Diffraction (PXRD) Powder X-ray Diffraction (PXRD) is a powerful and fundamental tool to identify solid forms of compounds or complexes by comparing their individual characteristic powder patterns. Simulated powder patterns from Form B and Form C calculated from SCXRD data can act as reference to ascertain the pure phases by comparing them with experimental patterns for Co-Crystal 12 Forms B / C. PXRD data of Compound 1 (Form A) were obtained using a Bruker C2 GADDS. The radiation was Cu Kα (40 KV, 40 mA). The sample-detector distance was 15 cm. Samples were placed in sealed glass capillaries with diameters of ≤ 1mm. The capillary was rotated during data collection. Data were collected for approximately 2≤2θ≤32° with a sample exposure time of at least 1000 seconds. The resulting two-dimensional diffraction arcs were integrated to create a traditional 1-dimensional PXRD pattern with a step size of 0.05 degrees 2θ in the approximate range of 2 to 32 degrees 2θ. PXRD patterns of Form B / C were recorded on an Empyrean (PANalytical) X-ray powder diffractometer with Cu Kα radiation. The diffractometer was equipped with a ceramic tube which was set at the power level of 45kV and 40mA, and a RTMS PIXcel ID detector. Incident optics consisted of a 0.02rad soller slit; 10mm beam mask; 1º antiscatter slit; and auto-divergence slit set to 10mm illuminated length. Diffracted optics consisted of a 0.02rad soller slit; auto-anti-scatter slit set to 10mm illuminated length; Ni-K-Beta filter, and detector window of ~2.9º. Data were collected in reflectance geometry, whilst spinning, over a 2θ range of 2-40°, with a step size of 0.033-040°, and counting time of 1 sec / step in continuous model. FIG.12 and FIG.13 show the PXRD data of Compound 1 (Form A) and Co-Crystal 12 Form B / C, respectively. Table 4 provides the characteristic PXRD peaks for Form A and Co- Crystal 12 Form B / C. Table 4. Characteristic PXRD Peaks (2-theta degrees) ±0.2 Form A Form B / C 129 972 . s ows t e exper menta patterns or ompoun , -pro ne, an o- Crystal 12 Form B / C, along with simulated patterns for Co-Crystal 12 Forms B and C. The PXRD patterns for Compound 1 and L-proline show significant differences from those of the co-crystal forms, thereby indicating the formation of new phases. The experimental patterns obtained here exhibit a good fit with the combination of the simulated patters of both crystal forms. Slight differences could be due to disorder or preferred orientation effects. Example 4 – Differential Scanning Calorimetry (DSC) Differential scanning calorimetry (DSC) experiments were performed on Compound 1 (Form A) and Co-Crystal 12 Form B / C using a TA Instrument - model Q2000 or Q1000. The sample (about 1-10 mg) was weighed in an aluminum pan and the weight recorded accurately to a hundredth of a milligram before transferring the sample to the DSC. The instrument was purged with nitrogen gas at 50mL / min. Data were collected between room temperature and 300 °C at a heating rate of 10 °C / min. DSC plots were generated such that the endothermic peaks pointed down. FIG.15 shows the DSC plot for Compound 1 (Form A) and FIG.16 shows the DSC plot for Co-Crystal 12 Form B / C. Compound 1 exhibited a melt endotherm onset at 103 °C ± 3 °C (results shown in FIG.32) and Co-Crystal 12 exhibited an exothermic peak at about 175 °C ± 3 °C. The ~70 °C increase in the melting temperature indicates that the introduction of L-proline improved the stability of Compound 1. Example 5 – Thermal Gravimetric Analysis (TGA) Thermal gravimetric analysis (TGA) experiments of Compound 1 (Form A) and Co-Crystal 12 Form B / C were performed using a TA Instrument - model Q5000 or Q500. The sample (about 10- 30 mg) was placed in a previously tarred platinum pan. The weight of the sample was measured accurately and recorded to a thousandth of a milligram by the instrument. The furnace was purged with nitrogen gas at 100 mL / min. Data were collected between room temperature and 300 °C at a heating rate of 10 °C / min. FIG.17 shows the TGA plot for Compound 1 (Form A) and FIG.18 shows the TGA plot for Co-Crystal 12 Form B / C. Compound 1 exhibited < 0.5% weight loss at 95 °C (results not shown). Example 6 – DSC and TGA Comparisons of Compounds 2 – 4 and 6 – 8 and their Co-Crystals Having achieved considerable structural consistency, it was subsequently examined whether the melting behavior of co-crystals formed could be correlated with the neat form API. Following the procedures in Example 4 and Example 5, DSC and TGA data were collected for Compounds 2 – 4 and 6 – 8 and their corresponding Co-Crystals (data not shown). FIG.32 shows that the melting points or decomposition temperature of the seven new crystalline solids (thermal data of Compound 5 was not obtained due to very limited sample size) have been improved upon co-crystallization. Specifically, the melting or decomposition temperature of all API-Pro co-crystals of the disclosure fall in-between that of the pure API and the L-proline co-crystal, indicating that formation of Pro co-crystal stabilizes these API as compared to the neat form (API alone). Example 7 –Moisture Sorption Isotherms Moisture sorption isotherms were collected in a VTI SGA-100 Symmetric Vapor Analyzer or TA Instrument VTI-SA+ Vapor Sorption Analyzer using approximately 10 mg of sample. The sample was dried at 60°C until the loss rate of 0.0005 wt % / min was obtained for 10 minutes. The sample was tested at 25°C and 4 or 5, 15, 25, 35, 45, 50, 65, 75, 85, and 95% RH. Equilibration at each RH was reached when the rate of 0.0003 wt% / min for 35 minutes was achieved or a maximum of 600 minutes. FIG.19 show moisture-sorption isotherms for Co-Crystal 12 Form B / C. Dynamic Vapor Sorption (DVS) measures how much and how soon water can be absorbed into or desorbed from a sample as a function of humidity. Co-Crystal 12 Form B / C exhibited a ~0.1% moisture uptake in the range of 5-85% relative humidity (RH). This indicates that the co-crystal was non-hygroscopic and stable at high humidity, in contrast to Compound 1, which was unstable in the solid state under standard temperature storage (results not shown). Example 8 - General Procedure for Determining Solid State Stability To understand long-term stability of the L-proline co-crystal, physical stability analyses (DSC, TGA, and PXRD) were performed on samples of Co-Crystal 12 (Compound 1-Pro) that had been held for 1, 3, 6, and 12 months at three different conditions (5 °C, 25°C / 60 RH open and 25 °C / 60 RH closed). The analyses showed no change in the form. PXRD showed the samples remained crystalline with no changes to the powder patterns. Additionally, the behavior observed in the DSC and TGA experiments was consistent with the t=0 sample, confirming that the material remains stable at the conditions tested. Upon visual inspection, Compound 1 was found to convert to a brown sticky mass upon exposure to 25 °C / 65% RH, whereas Co-Crystal 12 (Compound 1-Pro) remained stable at 25°C / 60 % RH for up to 12 months (Table 5). The chemical stability analysis by UPLC performed on the co-crystals, stored a different conditions of temperature and humidity shows excellent potency retention with no significant degradation of Co-Crystal 12. As indicated in Table 5, Compound 1-pro is stable at 25°C / 65 % RH until 12 months, whereas Compound 1 decomposes in ~ 2 weeks.

[0003] Table 5 - Chemical stability of Compound 1 (Form A) vs Co-Crystal 12 Form B / C. Data is color coded based on the stability results with light gray as poor stability, medium gray as intermediate and dark gray indicating good stability. Compound 1 Co-Crystal 12 Condition Time Total color Appearance Total color Appearance ts The examples described herein show that co-crystals with L-proline as a co-former provide a dramatic increase in chemical stability through strong heteromeric hydrogen-bonded interactions between the API and L-proline. The N-hydroxy proton in Compound 1 binds to the strong C=O acceptor group of L-proline, as compared to the neat form of the API, where it interacts with the sulfoxide acceptors. Co-crystallization of Compound 1 with L-proline provided a straightforward, inexpensive, and commercially viable approach to improve the melting point, solid state stability, and no-hygroscopicity of the neat API. Comparable improvements in decomposition temperatures were seen in Co-Crystals 13 - 19. Proline co-crystal forms of N-hydroxysulfonamides clearly demonstrate better chemical and physical stability over neat forms. REFERENCES The following references are hereby incorporated by reference in their entireties: 1. Aizawa, K.; Nakagawa, H.; Matsuo, K.; Kawai, K.; Ieda, N.; Suzuki, T.; Miyata, N., Piloty’s acid derivative with improved nitroxyl-releasing characteristics. Bioorganic & Medicinal Chemistry Letters 2013, 23 (8), 2340-2343. 2. Sandhu, B.; Savage, S. A.; Park, H.; Ilott, A.; Albrecht, J.; Yin, S.; Sarjeant, A. A., Using In Silico Tools To Map the Structural Landscape of Nitroxyl (HNO Donor) Compounds. Crystal Growth & Design 2022. 3. Bruker (2016). APEX3 (Version 2015.9). Bruker AXS Inc., Madison, Wisconsin, USA. 4. Bruker (2016) SAINT V8.35A. Data Reduction Software. 5. Sheldrick, G. M. (1996). SADABS. Program for Empirical Absorption Correction. 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Taylor, Journal of Chemical Information and Modeling, 2018, 58, 615-629. 20. L. Fábián, Crystal Growth & Design, 2009, 9, 1436-1443. 21. I. J. Bruno, J. C. Cole, P. R. Edgington, M. Kessler, C. F. Macrae, P. McCabe, J. Pearson and R. Taylor, Acta Crystallogr B, 2002, 58, 389-397. 22. N. K. Duggirala, M. L. Perry, Ö. Almarsson and M. J. Zaworotko, Chem Commun (Camb), 2016, 52, 640-655. 23. B. Sandhu, S. A. Savage, H. Park, A. Ilott, J. Albrecht, S. Yin and A. A. Sarjeant, Crystal Growth & Design, 2022, 22, 4105-4114. 24. N. Issa, P. G. Karamertzanis, G. W. A. Welch and S. L. Price, Crystal Growth & Design, 2009, 9, 442-453. 25. C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P. McCabe, E. Pidcock, L. Rodriguez- Monge, R. Taylor, J. van de Streek and P. A. Wood, Journal of Applied Crystallography, 2008, 41, 466- 470. 26. M. A. Mohammad, A. Alhalaweh and S. P. Velaga, Int J Pharm, 2011, 407, 63-71. 27. M. Khalaji, M. J. Potrzebowski and M. K. Dudek, Crystal Growth & Design, 2021, 21, 2301-2314. 28. R. Taylor and P. A. Wood, Chemical Reviews, 2019, 119, 9427-9477. 29. P. A. Wood, N. Feeder, M. Furlow, P. T. A. Galek, C. R. Groom and E. Pidcock, CrystEngComm, 2014, 16, 5839-5848. It will be apparent to those in the art that specific embodiments of the disclosed subject matter may be directed to one or more of the above- and below-indicated embodiments in any combination. While the invention has been disclosed in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. Therefore, the description and examples should not be construed as limiting the scope of the invention. All references, publications, patents, and patent applications disclosed herein are hereby incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A co-crystal comprising a nitroxyl donating compound and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glycine, alanine and proline.

2. The co-crystal of claim 1, wherein the nitroxyl donating compound is an N- hydroxysulfonamide compound.

3. The co-crystal of claim 2, wherein the N-hydroxysulfonamide compound is a compound listed in Table 1.

4. The co-crystal of claim 1, wherein the co-crystal former is proline.

5. A co-crystal comprising a compound of formula (1): and a co-crystal former, whereinfrom the group consisting of glycine, alanine and proline.

6. The co-crystal of claim 5, wherein the co-crystal former is glycine. The co-crystal of claim 5, wherein the co-crystal former is alanine. The co-crystal of claim 5, wherein the co-crystal former is proline.

9. A 1:1 co-crystal comprising a compound of formula (1):and glycine.

10. A 2:1 co-crystal comprising a compound of formula (1): H3C SO2NHOHand alanine.

11. A 1:1 co-crystal comprising a compound of formula (1): and proline.

12. A pharmaceutical composition comprising the co-crystal of any one of claims 1 to 11 and at least one pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12, wherein the co-crystal former is glycine.

14. The pharmaceutical composition of claim 12, wherein the co-crystal former is alanine.

15. The pharmaceutical composition of claim 12, wherein the co-crystal former is proline.

16. A method of making a co-crystal comprising: mixing a nitroxyl donating compound with a co-crystal former in a solvent under crystallization conditions so as to form the co-crystal in solid phase, wherein the co-crystal former is selected from the group consisting of glycine, alanine and proline.

17. The method of claim 16, wherein the nitroxyl donating compound is an N- hydroxysulfonamide compound.

18. The method of claim 16, wherein the N-hydroxysulfonamide compound is a compound listed in Table 1.

19. The method of any one of claims 16 to 18, wherein the co-crystal former is proline.

20. The method of any one of claims 16 to 19, wherein the nitroxyl donating compound is a compound of formula (1): SO2NHOH21. The method of any one of claims 16 to 20, further comprising isolating the co-crystal.

22. The method of any one of claims 16 to 20, wherein the solvent is methanol.

23. A method of treating a cardiovascular disease responsive to nitroxyl therapy, comprising administering an effective amount of a co-crystal of any one of claims 1 to 11 or the pharmaceutical composition of any one of claims 12 to 15 to a patient in need thereof.

24. The method of claim 23, wherein the cardiovascular disease is heart failure.

25. The method of claim 23 or claim 24, wherein the cardiovascular disease is acute decompensated heart failure.

26. The method of any one of claims 23 to 25, wherein the co-crystal or pharmaceutical composition is administered intravenously.

27. A kit comprising a co-crystal of any one of claims 1 to 11 in dry form or the pharmaceutical composition of any one of claims 12 to 15 in dry form; and a pharmaceutically acceptable liquid diluent.

28. Use of the co-crystal of any one of claims 1 to 11 or use of the pharmaceutical composition of any one of claims 12 to 15 for the manufacture of a medicament useful for treating a cardiovascular disease.

29. Use of the co-crystal of any one of claims 1 to 11 or use of the pharmaceutical composition of any one of claims 12 to 15 for the manufacture of a medicament useful for treating heart failure.

30. Use of the co-crystal of any one of claims 1 to 11 or use of the pharmaceutical composition of any one of claims 12 to 15 for the manufacture of a medicament useful for treating acute decompensated heart failure.

31. The co-crystal of any one of claims 1 to 11 or the pharmaceutical composition of any one of claims 12 to 15 for use in the treatment of a cardiovascular disease.

32. The co-crystal of any one of claims 1 to 11 or the pharmaceutical composition of any one of claims 12 to 15 for use in the treatment of heart failure.

33. The co-crystal of any one of claims 1 to 11 or the pharmaceutical composition of any one of claims 12 to 15 for use in the treatment of acute decompensated heart failure.

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