R-MDMA crystalline forms

Abstract

A composition of a crystalline form salt or polymorph of R-MDMA. A pharmaceutical composition of a crystalline salt or polymorphic substance of R-MDMA and a pharmaceutically acceptable excipient. A method of treating a medical condition in a subject by administering to the subject an effective amount of a composition of a crystalline form salt or polymorph of R-MDMA and treating the subject.

Description

Background of the Invention 1. Technical Field

[0002] The present invention relates to compositions and methods for preparing R-MDMA crystalline forms. 2. Background technology

[0003] 3,4-Methylenedioxymethamphetamine (MDMA) is a mood- and perception-altering psychoactive drug that has been investigated as an adjunct to psychotherapy for post-traumatic stress disorder (PTSD), social anxiety, autism (Danforth, 2016; Danforth et al., 2018; Danforth et al., 2016; Mithoefer et al., 2019; Mithoefer et al., 2010; Oehen et al., 2013), and may also be investigated and used for a range of other medical conditions. Such conditions for which MDMA or related substances may be useful include, but are not limited to, substance use disorders, depression, anxiety disorders (including social anxiety disorder), anxiety disorders with life-threatening illness, personality disorders (including narcissistic and antisocial disorders), autism and other developmental disorders, and obsessive-compulsive disorder. MDMA or related substances may also be used to enhance individual or couples therapy.

[0004] MDMA has several side effects and safety issues. Abuse of MDMA can lead to hyperthermia, neurocognitive deficits and increased incidence of depression. MDMA may also be neurotoxic, which limits its ability to be administered repeatedly over a long period of time. The use of MDMA often impairs declarative memory, prospective memory and advanced cognitive skills. Neurocognitive deficits are associated with a reduction in serotonin transporters (SERT) in the hippocampus, parietal cortex and prefrontal cortex. EEG and ERP studies have shown that brain activity is locally reduced during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skills, tremors, neurohormonal activity and mental state have also been confirmed. These effects are more pronounced when used at higher doses or for longer periods of time. (Parrott, Neuroscience & Biobehavioral Reviews, Vol. 37, No. 8, 2013, pp. 1466-1484).

[0005] MDMA has two enantiomers, S(+)-MDMA and R(-)-MDMA. The R enantiomer is considered to be more active (Nichols et al., J. Med. Chem. 1986, 29, 2009-2015). It is believed that the neurotoxicity of racemic MDMA is caused by the S(+) enantiomer rather than the R(-) enantiomer, due to the lower efficacy of the R(-) enantiomer as a dopamine releaser. The R(-) enantiomer also does not produce high fever. The R(-) enantiomer may have a lower risk of abuse. (Pitts et al., Psychopharmacology (2018) 235: 377-392). It has been shown that enantiomers have different effects. The effects of R-MDMA and S-MDMA were evaluated in animal models of Parkinson's disease (Huot et al., The Journal of Neuroscience, 2011, 31(19):7190–7198), and it was found that R-MDMA, a selective compound for the 5-HT2A receptor, reduced the severity of peak dose dyskinesias and prolonged the duration of good ON time, while S-MDMA, which exhibited high affinity for SERT and moderate affinity for DAT, prolonged the total duration of ON time but exacerbated dyskinesias. This suggests that racemic MDMA produces both dyskinesia-reducing and ON-time-prolonging effects through 5-HT2A antagonism and SERT-selective mixed monoamine uptake inhibition, which are derived from its R and S enantiomers, respectively. Therefore, the use of R-MDMA in treatment may be advantageous.

[0006] R-MDMA free alkali is an oil. It needs to be stabilized as a crystalline salt for ease of handling, long-term storage and drug product manufacturing. R-MDMA HCl salt (CAS 69558-31-2) has been reported in the literature (S. Llabrés et al., European Journal of Medicinal Chemistry 81 (2014) 35-46, The Journal of Neuroscience, May 11, 2011, 31 (19): 7190–7198, J. Med. Chem. 1986, 29, 2009-2015). However, the preparation of these R-MDMAHCl does not provide detailed information or provides very little information, and / or is not suitable for large-scale production. Solid-state properties are not reported either.

[0007] Therefore, there remains a need for R-MDMA compositions that can be produced on an appropriate scale for use in therapy. Summary of the invention

[0008] The present invention provides a composition of a crystalline salt or polymorph of R-MDMA.

[0009] The present invention provides a pharmaceutical composition of a crystalline salt or polymorph of R-MDMA and a pharmaceutically acceptable excipient.

[0010] The present invention provides a method of treating a medical condition in a subject by administering an effective amount of a crystalline salt or polymorphic composition of R-MDMA and treating the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Other advantages of the present invention may be better understood with reference to the following detailed description in conjunction with the accompanying drawings, in which:

[0012] Figure 1 is the XRPD diffraction pattern of R-MDMA HCl mode A;

[0013] Figure 2 It is R-MDMA HCl mode A 1 H NMR spectrum;

[0014] Figure 3 is the DSC and TGA thermograms of R-MDMA HCl mode A;

[0015] Figure 4 is the DVS curve of R-MDMA HCl mode A;

[0016] Figure 5 is the XRPD diffraction pattern of R-MDMA HCl pattern A under ambient conditions (middle) and at 0% relative humidity (top) and 90% relative humidity (bottom);

[0017] Fig. 6A is the XRPD diffraction pattern of R-MDMA HBr mode A, Figure 6B It is R-MDMA HBr mode A 1 H NMR spectrum, and Figure 6C is the DSC and TGA heat map of R-MDMA HBr mode A;

[0018] Figure 7 is the DVS curve of R-MDMA HBr mode A;

[0019] Figure 8 is the XRPD diffraction pattern of R-MDMA HBr mode A under ambient conditions (bottom) and at 0% relative humidity (top) and 90% relative humidity (middle);

[0020] Fig.9A is the XRPD diffraction pattern of R-MDMA phosphate mode C, Fig. 9B It is R-MDMA phosphate mode C 1 H NMR spectrum, and Fig. 9Cis the DSC and TGA thermogram of R-MDMA phosphate mode C;

[0021] Fig. 10A is the DVS curve of R-MDMA phosphate mode C, and Fig. 10B is the XRPD diffraction pattern of R-MDMA phosphate pattern C under ambient conditions (middle) and at 0% relative humidity (bottom) and 90% relative humidity (top);

[0022] Fig.11A is the XRPD diffraction pattern of R-MDMA D-tartrate pattern C, Fig. 11B It is R-MDMA D-tartrate model C 1 H NMR spectrum, and Fig. 11C is the DSC and TGA thermogram of R-MDMA D-tartrate mode C;

[0023] Fig. 12A is the DVS curve of R-MDMA tartrate D-mode C, and Fig. 12B is the XRPD diffraction pattern of R-MDMA tartrate pattern C under ambient conditions (middle) and at 0% relative humidity (top) and 90% relative humidity (bottom);

[0024] Fig.13A is the XRPD diffraction pattern of R-MDMA hemifumarate mode A, Fig. 13B It is R-MDMA hemifumarate mode A 1 H NMR spectrum, and Fig. 13C is the DSC and TGA thermogram of R-MDMA hemifumarate mode A;

[0025] Fig.14A is the DVS curve of R-MDMA hemi-fumarate mode A, and Fig. 14B is an overlay of XRPD diffraction patterns of R-MDMA hemi-fumarate pattern A at ambient conditions (middle) and at 0% relative humidity (bottom) and 90% relative humidity (top);

[0026] Fig.15 is the XRPD diffraction pattern of R-MDMA hemioxalate pattern A / A';

[0027] Fig.16 It is R-MDMA hemioxalate model A / A' 1 H NMR spectrum;

[0028] Fig.17 is the DSC and TGA thermograms of R-MDMA hemioxalate mode A / A';

[0029] Fig.18is the DVS curve of R-MDMA hemioxalate mode A / A';

[0030] Fig.19 is an overlay of XRPD diffraction patterns of R-MDMA hemioxalate pattern A / A' at ambient conditions (middle) and at 0% relative humidity (top) and 90% relative humidity (bottom);

[0031] FIG. 20A to FIG. 20D This is an optical micrograph of R-MDMA HCl pattern A. Fig. 20A It is under the oil-free 4x objective lens. Fig. 20B It is under the oil-free 10x objective lens. Fig. 20C is under a 4x objective with oil, and Fig.20D It was under a 10x objective lens with oil;

[0032] Fig.21 is a diagrammatic representation of the asymmetric unit of the structure of R-MDMA hydrochloride determined by single crystal x-ray diffraction;

[0033] Fig. 22 is a graphic representation of the crystal packing of R-MDMA hydrochloride determined by single crystal x-ray diffraction;

[0034] Fig.23 Overlay of XRPD diffraction patterns of R-MDMA maleate salt isolated from IPA (top, low crystallinity), half salt prepared from ethanol (middle, pattern A), and mono salt isolated from THF (bottom, pattern A);

[0035] Fig.24 is an overlay of XRPD diffractograms of R-MDMA maleate pattern A isolated from THF (top, lower crystallinity), IPA (middle), and DCM (bottom);

[0036] Fig.25 is an overlay of XRPD diffraction patterns of R-MDMA hemi-meso-tartrate isolated from THF (top, mixture of patterns A and C), DCM (middle, pattern A), and THF (bottom, pattern B);

[0037] Fig.26 is the XRPD diffraction pattern of R-MDMA citrate;

[0038] Fig. 27 is an overlay of the XRPD diffraction patterns of R-MDMA phosphate isolated from THF (top, pattern C), IPA (middle, pattern A), and DCM (bottom, pattern B).

[0039] Fig.28is an overlay of XRPD diffraction patterns of R-MDMA hemi-naphthalene-1,5-disulfonate isolated from THF (top), IPA (middle), and DCM (bottom);

[0040] Fig.29 is an overlay of XRPD diffraction patterns of pattern B (top) and pattern A (bottom) of R-MDMA sulfate isolated from DCM;

[0041] Fig.30 is an overlay of the XRPD diffraction patterns of R-MDMA mesylate isolated from THF (top) and DCM (bottom);

[0042] Fig.31 is an overlay of the XRPD diffraction patterns of R-MDMA acetate isolated from THF (top) and DCM (bottom);

[0043] Fig.32 is an overlay of XRPD diffraction patterns of R-MDMA oxalate isolated from IPA (top), THF (middle), and DCM (bottom);

[0044] Fig.33 is the XPRD diffraction pattern of R-MDMA HBr mode B;

[0045] Fig.34 is the XPRD diffraction pattern of R-MDMA phosphate mode A;

[0046] Fig.35 is the XPRD diffraction pattern of R-MDMA phosphate mode B;

[0047] Fig.36 is the XPRD diffraction pattern of R-MDMA tartrate mode A;

[0048] Fig.37 is the XPRD diffraction pattern of R-MDMA tartrate pattern B;

[0049] Fig.38 is the XPRD diffraction pattern of R-MDMA maleate mode A;

[0050] Fig.39 is the XPRD diffraction pattern of R-MDMA L-maleate mode A;

[0051] Fig.40 is the XPRD diffraction pattern of R-MDMA hemi-naphthalene-1,5-disulfonate pattern A;

[0052] Fig.41 is the XPRD diffraction pattern of R-MDMA hemifumarate mode A;

[0053] Fig.42is the XPRD diffraction pattern of R-MDMA oxalate mode A;

[0054] Fig.43 is the XPRD diffraction pattern of R-MDMA sulfate mode A;

[0055] Fig.44 is the XPRD diffraction pattern of R-MDMA sulfate mode B;

[0056] Fig.45 is the XPRD diffraction pattern of R-MDMA mesylate, pattern A; and

[0057] Fig.46 is the XPRD diffraction pattern of R-MDMA acetate mode A. DETAILED DESCRIPTION

[0058] The present invention provides salts and polymorphs of R-MDMA which can be used to prepare stable crystalline forms of R-MDMA for manufacture on an appropriate scale and for use in therapy.

[0059] The salt can be, but is not limited to, hydrochloride (HCl), hydrobromide (HBr), maleate, L-malate, D-tartrate, semi-meso-tartrate, semi-L-tartrate, citrate, phosphate, semi-naphthalene-1,5-disulfonate, semi-fumarate, sulfate, methanesulfonate, acetate, hemi-oxalate or oxalate. More specifically, the salt can be a specific pattern, such as, but not limited to, hydrochloride pattern A, phosphate pattern A, phosphate pattern B, phosphate pattern C, HBr pattern A, HBr pattern B, HBr pattern C, semi-L-tartrate pattern A, semi-meso-tartrate pattern B, semi-meso-tartrate pattern C, meso-tartrate pattern A, meso-tartrate pattern B, sulfate pattern A, sulfate pattern B, D-tartrate pattern A, D-tartrate pattern B, D-tartrate pattern C, D-tartrate pattern D, D-tartrate pattern E, L-maleate pattern A, maleate pattern A, maleate pattern B, heminaphthalene-1,5-disulfonate pattern A, heminaphthalene-1,5-disulfonate pattern B, hemioxalate pattern A, hemioxalate pattern A', hemifumarate pattern A, hemifumarate pattern A', methanesulfonate pattern A, acetate pattern A, citrate pattern A, fumarate pattern A or oxalate pattern A.

[0060] As further described below, when the acid is hydrochloric acid, the crystalline form can be characterized by an x-ray powder diffraction pattern having peaks at about 15.8, about 17.5, about 19.7, about 24.8, and about 24.9, as indicated by 2θ. When the acid is hydrobromic acid, crystalline form pattern A can be characterized by an x-ray powder diffraction pattern having peaks at about 13.9, about 16.3, about 19.8, about 20.5, and about 24.0, as indicated by 2θ. When the acid is phosphoric acid, crystalline form pattern C can be characterized by an x-ray powder diffraction pattern having peaks at about 13.4, about 14.6, about 17.4, about 18.7, and about 22.1, as indicated by 2θ. When the acid is D-tartaric acid, the crystalline form pattern C can be characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 6.0, about 12.0, about 13.3, about 17.9, and about 24.1. When the acid is fumaric acid, the crystalline form can be characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Kα x-rays, the x-ray powder diffraction pattern having peaks expressed as 2θ at about 17.2, about 18.6, about 19.2, about 19.5, and about 21.8, and the salt can be a half salt. When the acid is oxalic acid, the crystalline form can be characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Kα x-rays, the x-ray powder diffraction pattern having peaks expressed as 2θ at about 15.2, about 16.4, about 16.8, about 19.3, and about 21.3, and the salt can be a half salt.

[0061] When the acid is hydrobromic acid, the crystalline form pattern B can be characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Kα x-rays, the x-ray powder diffraction pattern having peaks represented as 2θ at about 13.9, about 16.2, about 16.9, about 20.5 and about 24.1. When the acid is phosphoric acid, the crystalline form pattern A can be characterized by an x-ray powder diffraction pattern having peaks represented as 2θ at about 14.5, about 17.4, about 22.0, about 24.7 and about 24.9. When the acid is phosphoric acid, the crystalline form pattern B can be characterized by an x-ray powder diffraction pattern having peaks represented as 2θ at about 12.9, about 13.8, about 17.1, about 26.8 and about 27.8. When the acid is D-tartaric acid, the crystalline form pattern A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 5.6, about 11.3, about 15.4, about 17.2, and about 17.8. When the acid is D-tartaric acid, the crystalline form pattern B can be characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 5.1, about 16.3, about 19.3, about 20.4, and about 21.8. When the acid is maleic acid, the crystalline form can be characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 14.9, about 18.0, about 25.2, about 25.9, and about 27.9. When the acid is malic acid, the crystalline form can be characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 17.8, about 18.1, about 19.3, about 26.5, and about 27.3. When the acid is naphthalene-1,5-disulfonic acid, the crystalline form can be characterized by an x-ray powder diffraction pattern having peaks at about 14.6, about 15.2, about 15.8, about 16.8, and about 22.9, expressed as 2θ. The salt can also be a hemi-salt. When the acid is oxalic acid, the crystalline form can be characterized by an x-ray powder diffraction pattern having peaks at about 4.8, about 14.6, about 16.8, about 19.9, and about 21.0, expressed as 2θ. When the acid is sulfuric acid, the crystalline form pattern A can be characterized by an x-ray powder diffraction pattern having peaks at about 14.9, about 17.8, about 21.0, about 21.2, and about 23.8, expressed as 2θ. When the acid is sulfuric acid, the crystalline form pattern B can be characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 16.4, about 19.1, about 23.9, about 25.9, and about 27.8. When the acid is methanesulfonic acid, the crystalline form can be characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 16.2, about 17.9, about 18.5, about 21.2, and about 26.9. When the acid is acetic acid, the crystalline form can be characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 17.7, about 18.0, about 18.6, about 19.7, and about 20.3.

[0062] The salt or polymorph of R-MDMA can be administered at a dose of 10 mg to 1000 mg. MDMA is an agonist that releases monoamines (serotonin, norepinephrine or dopamine) primarily by interacting with membrane monoamine transporters (serotonin, norepinephrine and dopamine transporters) and may also release oxytocin (Hysek et al., 2014; Hysek et al., 2012b; Simmler et al., 2013; Verrico et al., 2007).

[0063] The composition may also include a prodrug of a salt or polymorph of R-MDMA. As used herein, "prodrug" refers to a compound that includes a portion attached to an active drug substance, which is metabolized after administration to an individual and the compound is converted to an active drug substance. The use of prodrugs can improve the absorption, distribution, metabolism and excretion patterns of the active drug. Prodrugs can be used to prevent the release of the active drug in the gastrointestinal tract after administration, so that the drug can be more advantageously released in other parts of the body.

[0064] Prodrug compounds include chemical modifications to salts or polymorphs of R-MDMA, such as amino acids covalently attached thereto. The addition of amino acids inactivates the active compound mainly by preventing interaction with monoamine transporters, which are sites of action, but also affect bioavailability / absorption rate. Amino acids can be lysine or any other amino acids, such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine, and are usually attached to the amine (N)-group of R-MDMA, thereby reducing the pharmacological activity of the main site of action (cell membrane monoamine transporters, including serotonin, dopamine and norepinephrine transporters), and also changing the degree and rate of absorption, and mainly releasing active substances in circulation after absorbing inactive compounds. Amino acids can be any other natural or synthetic amino acids. Any other chemical modification can also be used.

[0065] The use of salts or polymorphs of R-MDMA allows for daily use. The composition is particularly suitable for continuous sustained release formulations, such as transdermal patches, which can provide low doses over a long period of time. The composition can also be administered in the form of an intranasal spray. The composition can also be a liquid dosage form, such as but not limited to a suspension, solution, emulsion, elixir, tincture, spray, syrup, gel, serum, liniment, lotion, ointment, paste, drops or inhalant. The composition can be a solid dosage form, such as but not limited to a capsule, film, lozenge, patch, powder, tablet, granule, pill or lozenge.

[0066] The administration and dosage of the compounds of the present invention should be consistent with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, the schedule of administration, the patient's age, sex, weight, and other factors known to medical practitioners. Therefore, the pharmaceutical "effective amount" for the purposes of this article is determined by considerations known in the art. The amount must be effective to achieve improvement, including but not limited to faster recovery, or improvement or elimination of symptoms, and other indicators selected by those skilled in the art as appropriate measures.

[0067] In the method of the present invention, the compound of the present invention can be used in a variety of ways. It should be noted that it can be used as a compound, and can be used alone or in combination with a pharmaceutically acceptable carrier, diluent, adjuvant and vehicle as an active ingredient. The compound can be administered orally, subcutaneously or parenterally, including sublingual, oral, inhaled, intravenous, intramuscular and intranasal administration. The implant of the compound is also applicable. The patient treated is a warm-blooded animal and particularly a mammal, including a human. Pharmaceutically acceptable carriers, diluents, adjuvants and vehicles and implant carriers generally refer to inert, nontoxic solid or liquid fillers, diluents or encapsulating materials that do not react with the active ingredient of the present invention.

[0068] Dosage can be a single dose or multiple doses over a period of days, weeks or months. The length of treatment is generally proportional to the length of the disease process and the effectiveness of the drug and the type of patient receiving treatment.

[0069] When the compound of the present invention is administered orally, it is usually formulated into quick-release capsules, quick-release tablets, modified-release capsules or tablets (including enteric coatings), solutions or suspensions. When the compound of the present invention is administered parenterally, it is usually formulated into sublingual or oral dissolving tablets, dissolving films, intranasal powders, intranasal solutions, inhalation powders, inhalation solutions, transdermal patches, transdermal patches with microneedles or other penetration enhancers, or formulated into unit dose injection forms (solutions, suspensions, emulsions). Pharmaceutical preparations suitable for injection include sterile aqueous solutions or dispersions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), their suitable mixtures and vegetable oils.

[0070] For example, suitable fluidity can be maintained by using coatings such as lecithin, by maintaining the required particle size and by using a surfactant in the case of dispersions. Non-aqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil or peanut oil and esters such as isopropyl myristate can also be used as the solvent system of the compound composition. In addition, various additives for enhancing the stability, sterility and isotonicity of the composition can be added, including antimicrobial preservatives, antioxidants, chelating agents and buffers. It can be ensured that microbial action is prevented by various antibacterial agents and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, etc.). In many cases, it is desirable to include isotonic agents, such as sugar, sodium chloride, etc. The absorption of injectable drug forms can be extended by using delayed absorption agents, such as aluminum monostearate and gelatin. However, according to the present invention, any vehicle, diluent or additive used must be compatible with the compound.

[0071] Sterile injectable solutions can be prepared by combining the compounds used to practice the invention with the appropriate solvent and various other ingredients in the required amount.

[0072] The pharmacological preparations of the present invention can be administered to a patient in the form of an injectable preparation containing any compatible carrier, such as various vehicles, adjuvants, additives and diluents; or the compounds used in the present invention can be administered to a patient parenterally in the form of a sustained-release subcutaneous implant or a targeted delivery system such as a monoclonal antibody, carrier delivery, iontophoresis, polymer matrix, liposomes and microspheres. Examples of delivery systems that can be used in the present invention include: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems and modules are well known to those skilled in the art.

[0073] The present invention provides a method of treating a medical disorder in an individual by administering to the individual an effective amount of a salt or polymorph composition of R-MDMA and treating the individual. The method may also include preventing or reducing the side effects of neurotoxicity, hyperthermia and dependence / addiction experienced with racemic MDMA. Any of the prodrugs listed above may also be used.

[0074] Specifically, the composition can be used to treat medical disorders or conditions, including post-traumatic stress disorder, social anxiety, autism spectrum disorder, substance use disorder, depression, anxiety disorders, anxiety associated with life-threatening illness, personality disorders (including narcissistic or antisocial personality disorder), schizophrenia, obsessive-compulsive disorder, couples therapy, to enhance any psychotherapy by inducing feelings of well-being, connection, trust, love, empathy, openness, and prosociality, and to enhance the therapeutic bond in any psychotherapy in patients or neurotic / healthy subjects.

[0075] The present invention is further described in detail by reference to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise stated. Therefore, the present invention should never be interpreted as being limited to the following examples, but should be interpreted as including all changes that become apparent due to the teachings provided herein.

[0076] Example 1.

[0077] General procedure for preparing salts of R-MDMA

[0078] Salt screening was performed using stock solutions of each acid prepared as shown in Table 1. A stock solution of R-MDMA free base (1 g) in IPA (10 ml) was prepared at ambient temperature. Aliquots of the solution (0.4 ml, ~30 mg) were loaded into crystallization tubes. The solution was heated to 50°C and the relevant acid (1 equivalent) was added in a single aliquot. The solution was balanced at 50°C for 1 hour, then cooled to ambient temperature and balanced for 24 hours. If a suspension was obtained, the solid was separated by filtration and dried in vacuo at 45°C. If the solution persisted, further manipulation was required to obtain a separable solid. The following methods were mainly used to induce crystallization and / or obtain solids:

[0079] Reduce the solvent volume to ~50% under a steady stream of nitrogen.

[0080] Cooling to 0℃ and below

[0081] Antisolvent (MTBE) was added at ambient temperature and then equilibrated

[0082] The solvent was removed by a steady stream of nitrogen

[0083] The resulting residue was repeatedly scraped and triturated with MTBE and the solid was then equilibrated to obtain a suspension.

[0084] Table 1

[0085]

[0086]

[0087] The XRPD patterns of R-MDMA maleate, R-MDMA L-malate, R-MDMA hemi-meso-tartrate, R-MDMA citrate, R-MDMA phosphate, R-MDMA heminaphthalene-1,5-disulfonate, R-MDMA sulfate, R-MDMA methanesulfonate, R-MDMA acetate, and R-MDMA oxalate are shown in Figures 23 to 32 middle.

[0088] Fig.23 Shown are overlays of the XRPD diffractograms of the R-MDMA maleate salt isolated from IPA (top, low crystallinity), the hemi-salt prepared from ethanol (middle, pattern A), and the mono-salt isolated from THF (bottom, pattern A). Fig.24 Shown are overlays of XRPD diffractograms of R-MDMA maleate salt pattern A isolated from THF (top, lower crystallinity), IPA (middle), and DCM (bottom). Fig.25 Shown are overlays of XRPD diffractograms of R-MDMA hemi-meso-tartrate isolated from THF (top, mixture of patterns A and C), DCM (middle, pattern A), and THF (bottom, pattern B). Fig.26 Shown is the XRPD diffractogram of R-MDMA citrate. Fig. 27 Shown are overlays of XRPD diffraction patterns of R-MDMA phosphate isolated from THF (top, panel C), IPA (middle, panel A), and DCM (bottom, panel B). Fig.28 Shown are overlays of XRPD diffractograms of R-MDMA hemi-naphthalene-1,5-disulfonate isolated from THF (top), IPA (middle), and DCM (bottom).

[0089] Fig.29 Shown is an overlay of the XRPD diffraction patterns of Pattern B (top) and Pattern A (bottom) of R-MDMA sulfate isolated from DCM. Fig.30 Shown are overlays of XRPD diffractograms of R-MDMA mesylate isolated from THF (top) and DCM (bottom). Fig.31 Shown are overlays of the XRPD diffractograms of R-MDMA acetate isolated from THF (top) and DCM (bottom). Fig.32 Shown are overlays of XRPD diffractograms of R-MDMA oxalate isolated from IPA (top), THF (middle), and DCM (bottom).

[0090] Example 2

[0091] Preparation of R-MDMA HCl Salt Model A. Figure 1 An XRPD pattern is shown. Figure 2 Shows 1H NMR spectrum. Figure 3 Combined DSC / TGA thermograms are shown. Figure 4 shows the DVS curve, and Figure 5 XRPD patterns at ambient conditions, 0% relative humidity, and 90% relative humidity are shown. Table 2 shows the XRPD peak list. An optical micrograph of R-MDMA HCl pattern A is shown in FIG. 20A to FIG. 20D .

[0092] Table 2

[0093]

[0094]

[0095] *The peak at 5.5572° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MAHCl salt mode A

[0096] Example 3.

[0097] Preparation of R-MDMA HBr salt pattern A. Fig. 6A An XRPD pattern is shown. Figure 6B Shows 1 H NMR spectrum. Figure 6C Combined DSC / TGA thermograms are shown. Figure 7 shows the DVS curve, and Figure 8 XRPD patterns at ambient conditions, 0% relative humidity and 90% relative humidity are shown. Table 3 shows the peak list.

[0098] Table 3

[0099]

[0100]

[0101] *The peak at 5.4037° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA HBr salt mode A

[0102] Example 4.

[0103] Preparation of R-MDMA phosphate pattern C. Fig.9A An XRPD pattern is shown. Fig. 9B Shows 1 H NMR spectrum. Fig. 9C Combined DSC / TGA thermograms are shown. Fig. 10A shows the DVS curve, and Fig. 10B XRPD patterns at ambient conditions, 0% relative humidity and 90% relative humidity are shown. Table 4 shows the peak list.

[0104] Table 4

[0105]

[0106]

[0107] *The peak at 5.5933° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA phosphate mode C

[0108] Example 5.

[0109] Preparation of R-MDMA D-tartrate Model C. Fig.11A An XRPD pattern is shown. Fig. 11B Shows 1 H NMR spectrum. Fig. 11C Combined DSC / TGA thermograms are shown. Fig. 12A shows the DVS curve, and Fig. 12B XRPD patterns at ambient conditions, 0% relative humidity and 90% relative humidity are shown. Table 5 shows the peak list.

[0110] Table 5

[0111]

[0112]

[0113] Example 6.

[0114] Preparation of R-MDMA hemifumarate Model A. Fig.13A An XRPD pattern is shown. Fig. 13B Shows 1 H NMR spectrum. Fig. 13C Combined DSC / TGA thermograms are shown. Fig.14A shows the DVS curve, and Fig. 14B XRPD patterns at ambient conditions, 0% relative humidity and 90% relative humidity are shown. Table 6 shows the peak list.

[0115] Table 6

[0116]

[0117]

[0118] *The peak at 5.5483° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA hemi-fumarate mode A

[0119] Example 7.

[0120] Preparation of R-MDMA hemioxalate pattern A / A'. Fig.15 An XRPD pattern is shown. Fig.16 Shows 1 H NMR spectrum. Fig.17 Combined DSC / TGA thermograms are shown. Fig.18 shows the DVS curve, and Fig.19 XRPD patterns at ambient conditions, 0% relative humidity and 90% relative humidity are shown. Table 7 shows the peak list.

[0121] Table 7

[0122]

[0123]

[0124] *The peak at 5.6067° 2θ is due to the Kapton membrane used in the analysis and has nothing to do with the R-MD MA hemi-oxalate mode A / A'

[0125] Example 8.

[0126] Single crystal X-ray structure

[0127] R-MDMA HCl (25 mg) was weighed into a crystallization tube. Dichloromethane (20 vol) was added and the mixture was heated to 40°C. The resulting solution was clarified through a 0.45 μm filter and aged to allow the solvent to flow out. Once suitable crystal growth occurred, the reaction was continued according to the conditions at low temperature (100 K) and The data measured at 100 nm and 100 nm determined the crystal structure of R-MDMA HCl form 1. R-MDMA HCl crystallizes in the monoclinic space group P21. In the asymmetric unit, Fig.21 As shown, a monocation (R)-MDMA and a chloride anion were found (total ratio 1:1), and as Fig. 22 As shown, crystal stacking was found.

[0128] Example 9

[0129] Preparation of R-MDMA HBr salt pattern B. Table 8 shows the XPR D peak data for HBr pattern B. Fig.33 XPRD plots are shown.

[0130] Table 8

[0131] Position [°2θ] Height [Count] Relative strength [%] 5.6128* 277.76 11.09 8.0771 198.08 7.91 13.8548 948.75 37.87 16.1891 2505.58 100.00 16.9445 2433.61 97.13 19.7438 710.56 28.36 20.4682 1208.93 48.25 22.5868 112.60 4.49 23.6399 387.01 15.45 24.1138 2191.78 87.48 25.4482 692.94 27.66 25.9531 493.78 19.71 26.2274 515.76 20.58 26.9150 131.4 5.24 27.8992 662.87 26.46 28.4350 707.32 28.23 29.1067 195.83 7.82 31.0628 312.37 12.47 32.8741 199.15 7.95 33.2445 310.89 12.41 34.2551 383.92 15.32

[0132] *The peak at 5.6128° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA hydrobromide mode B

[0133] Example 10

[0134] R-MDMA phosphate pattern A was prepared. Table 9 shows the XPRD peak data for phosphate pattern A. Fig.34 XPRD data are shown.

[0135] Table 9

[0136] Position [°2θ] Height [cts] Relative strength [%] 5.5661* 268.91 24.32 13.3505 97.94 8.86 14.0295 95.08 8.60 14.5108 350.8 31.73 15.7641 102.62 9.28 17.4001 1105.56 100.00 17.9146 295.74 26.75 18.2251 132.89 12.02 18.5732 264.62 23.94 19.1536 106.52 9.64 20.6353 162.37 14.69 21.9954 611.68 55.33 23.2998 192.73 17.43 24.6975 1066.32 96.45 24.8545 637.45 57.66 26.0326 100.04 9.05 26.8020 294.85 26.67 28.5395 68.87 6.23 29.0512 144.92 13.11 34.3710 68.32 6.18

[0137] *The peak at 5.5661° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA phosphate mode A

[0138] Embodiment 11

[0139] Preparation of R-MDMA Phosphate Pattern B. Table 10 shows the XP RD peak data for Phosphate Pattern B. Fig.35 XPRD data are shown.

[0140] Table 10

[0141] Position [°2θ] Height [cts] Relative strength [%] 5.6096* 241.62 12.9 12.9201 530.82 28.34 13.8398 1408.66 75.2 14.4737 67.56 3.61 17.1453 1474.05 78.69 17.4568 192.62 10.28 18.0352 126.78 6.77 19.2568 325.93 17.4 19.8713 100.1 5.34 20.9476 148.48 7.93 21.5796 78.41 4.19 23.3679 104.17 5.56 24.7430 273.21 14.58 26.7586 490.38 26.18 27.8429 1873.25 100 29.2104 407.13 21.73 32.7550 200.23 10.69

[0142] *The peak at 5.6096° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA Phosphate Mode B

[0143] Example 12

[0144] Preparation of R-MDMA tartrate salt pattern A. Table 11 shows the XPRD peak data for tartrate salt pattern A. Fig.36 XPRD data are shown.

[0145] Table 11

[0146]

[0147]

[0148] Embodiment 13

[0149] Preparation of R-MDMA tartrate salt pattern B. Table 12 shows the XPRD peak data for tartrate salt pattern B. Fig.37 XPRD data are shown.

[0150] Table 12

[0151]

[0152]

[0153] Embodiment 14

[0154] Preparation of R-MDMA maleate salt pattern A. Table 13 shows the XPRD peak data for maleate salt pattern A. Fig.38 XPRD data are shown.

[0155] Table 13

[0156]

[0157]

[0158] *The peak at 5.5552° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA maleate mode A

[0159] Embodiment 15

[0160] Preparation of R-MDMA L-malate salt Pattern A. Table 14 shows the XPRD peak data for Pattern A of the L-maleate salt. Fig.39 XPRD data are shown.

[0161] Table 14

[0162]

[0163]

[0164] *The peak at 5.5662° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA L-malate Mode A

[0165] Example 16

[0166] Preparation of R-MDMA hemi-naphthalene-1,5-disulfonate salt pattern A. Table 15 shows the XPRD peak data for hemi-naphthalene-1,5-disulfonate salt pattern A. Fig.40 XPRD data are shown.

[0167] Table 15

[0168]

[0169]

[0170] *The peak at 5.6688° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA hemi-naphthalene-1,5-disulfonate mode A

[0171] Embodiment 17

[0172] Preparation of R-MDMA hemi-fumarate pattern A. Table 16 shows the XPRD peak data for hemi-fumarate pattern A. Fig.41 The data are shown.

[0173] Table 16

[0174]

[0175]

[0176] *The peak at 5.6776° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA hemi-fumarate mode A

[0177] Embodiment 18

[0178] Preparation of R-MDMA oxalate pattern A. Table 17 shows the XPRD peak data for oxalate pattern A. Fig.42 The data are shown.

[0179] Table 17

[0180] Position [°2θ] Height [cts] Relative strength [%] 4.7803 2417.01 100.00 5.6800* 301.49 12.47 9.5688 466.34 19.29 14.3615 461.24 19.08 14.5524 1323.96 54.78 16.7644 1323.05 54.74 18.6813 255.38 10.57 19.9255 1654.73 68.46 21.0140 1991.20 82.38 21.4829 494.49 20.46 21.6477 856.19 35.42 22.9982 160.71 6.65 23.2578 847.49 35.06 23.6747 603.85 24.98 24.7315 78.83 3.26 25.2086 150.68 6.23 25.7177 377.44 15.62 27.6607 502.72 20.80 28.0826 799.42 33.07 29.3331 331.69 13.72 32.0277 157.76 6.53 32.4106 450.15 18.62 33.4686 123.06 5.09

[0181] *The peak at 5.6800° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA oxalate mode A

[0182] Embodiment 19

[0183] Preparation of R-MDMA Sulfate Salt Pattern A. Table 18 shows the X PRD peak data for Sulfate Salt Pattern A. Fig.43 The data are shown.

[0184] Table 18

[0185]

[0186]

[0187] *The peak at 5.6758° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA Sulfate Mode A

[0188] Embodiment 20

[0189] Preparation of R-MDMA Sulfate Salt Pattern B. Table 19 shows the XP RD peak data for Sulfate Salt Pattern B. Fig.44 The data are shown.

[0190] Table 19

[0191]

[0192]

[0193] *The peak at 5.6459° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA Sulfate Mode B

[0194] Embodiment 21

[0195] Preparation of R-MDMA mesylate salt pattern A. Table 20 shows the XPRD peak data for mesylate salt pattern A. Fig.45 The data are shown.

[0196] Table 20

[0197] Position [°2θ] Height [cts] Relative strength [%] 5.5246* 308.75 7.87 8.5544 890.95 22.71 10.9603 373.51 9.52 13.6810 547.78 13.97 14.0813 227.27 5.79 15.8062 370.07 9.43 16.1599 1815.73 46.29 17.4746 1138.46 29.02 17.9244 3500.9 89.25 18.4882 2681.18 68.36 19.1923 1611.76 41.09 19.8760 559.39 14.26 20.7120 211.15 5.38 21.2153 3922.40 100.00 22.3234 1089.78 27.78 22.6119 155.68 3.97 23.2038 872.94 22.26 23.4404 196.27 5 24.0694 847.93 21.62 24.7619 1077.11 27.46 25.1591 635.58 16.20 26.2361 404.18 10.30 26.9048 1908.51 48.66 27.5418 264.59 6.75 27.9032 187.77 4.79 28.8917 396.43 10.11 29.1362 222.28 5.67 29.9252 321.78 8.20 30.7305 250.76 6.39 31.0839 125.67 3.20 32.0562 122.81 3.13 32.6099 91.73 2.34 33.4459 225.43 5.75 34.0844 60.22 1.54

[0198] *The peak at 5.5246° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA mesylate mode A

[0199] Embodiment 22

[0200] Preparation of R-MDMA acetate pattern A. Table 21 shows the X PRD peak data for acetate pattern A. Fig.46 The data are shown.

[0201] Table 21

[0202] Position [°2θ] Height [cts] Relative strength [%] 5.5678* 287.37 12.19 7.4482 325.60 13.81 10.9336 183.68 7.79 12.3386 265.46 11.26 14.8665 237.00 10.05 16.4549 720.48 30.57 17.0256 216.59 9.19 17.7496 1175.31 49.86 17.9574 967.20 41.03 18.5827 868.02 36.83 19.7005 2357.05 100.00 20.2921 873.47 37.06 21.4221 238.37 10.11 21.9194 88.32 3.75 22.5404 254.49 10.8 23.155 294.93 12.51 23.6578 393.98 16.71 23.9598 253.17 10.74 24.1429 208.33 8.84 24.7590 66.15 2.81 25.1835 119.82 5.08 25.5008 598.96 25.41 25.8655 116.53 4.94 27.0594 440.07 18.67 27.8674 145.03 6.15 28.9870 165.14 7.01 30.3487 165.25 7.01 30.8472 185.74 7.88 31.2993 260.10 11.04 31.7746 105.32 4.47 32.1819 116.80 4.96 32.9273 130.61 5.54 34.4031 78.06 3.31

[0203] *The peak at 5.5678° 2θ is due to the Kapton membrane used in the analysis and is not related to R-MD MA acetate mode A

[0204] Throughout this application, various publications, including U.S. patents, are cited by author and year, and patents are cited by number. The full citations of these publications are listed below. The disclosures of these publications and patents are hereby incorporated by reference in their entirety into this application in order to more fully describe the state of the art to which the present invention relates.

[0205] The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation.

[0206] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings and it is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

Claims

1. A composition of a crystalline salt or polymorph of R-MDMA.

2. The composition of claim 1, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, maleate, L-malate, D-tartrate, hemi-meso-tartrate, hemi-L-tartrate, citrate, phosphate, hemi-naphthalene-1,5-disulfonate, hemi-fumarate, sulfate, methanesulfonate, acetate, hemi-oxalate and oxalate.

3. The composition of claim 1, wherein the salt is selected from the group consisting of: hydrochloride pattern A, phosphate pattern A, phosphate pattern B, phosphate pattern C, HBr pattern A, HBr pattern B, HBr pattern C, semi-L-tartrate pattern A, semi-meso-tartrate pattern B, semi-meso-tartrate pattern C, meso-tartrate pattern A, meso-tartrate pattern B, sulfate pattern A, sulfate pattern B, D-tartrate pattern A, D-tartrate pattern Tartrate pattern B, D-tartrate pattern C, D-tartrate pattern D, D-tartrate pattern E, L-maleate pattern A, maleate pattern A, maleate pattern B, hemi-naphthalene-1,5-disulfonate pattern A, hemi-naphthalene-1,5-disulfonate pattern B, hemi-oxalate pattern A, hemi-oxalate pattern A', hemi-fumarate pattern A, hemi-fumarate pattern A', methanesulfonate pattern A, acetate pattern A, citrate pattern A, fumarate pattern A, and oxalate pattern A.

4. The composition of claim 1, wherein the composition is in the form of a prodrug.

5. The composition of claim 4, wherein the prodrug is an amino acid covalently attached to a crystalline form salt or polymorph of R-MDMA.

6. The composition of claim 5, wherein the amino acid is selected from the group consisting of lysine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

7. A pharmaceutical composition comprising a crystalline salt or polymorph of R-MDMA and a pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 7, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, maleate, L-malate, D-tartrate, hemi-meso-tartrate, hemi-L-tartrate, citrate, phosphate, hemi-naphthalene-1,5-disulfonate, hemi-fumarate, sulfate, methanesulfonate, acetate, hemi-oxalate, and oxalate.

9. The pharmaceutical composition of claim 7, wherein the salt is selected from the group consisting of: hydrochloride pattern A, phosphate pattern A, phosphate pattern B, phosphate pattern C, HBr pattern A, HBr pattern B, HBr pattern C, semi-L-tartrate pattern A, semi-meso-tartrate pattern B, semi-meso-tartrate pattern C, meso-tartrate pattern A, meso-tartrate pattern B, sulfate pattern A, sulfate pattern B, D-tartrate pattern A, D-tartrate pattern C, Tartarate pattern B, D-tartrate pattern C, D-tartrate pattern D, D-tartrate pattern E, L-maleate pattern A, maleate pattern A, maleate pattern B, hemi-naphthalene-1,5-disulfonate pattern A, hemi-naphthalene-1,5-disulfonate pattern B, hemi-oxalate pattern A, hemi-oxalate pattern A', hemi-fumarate pattern A, hemi-fumarate pattern A', methanesulfonate pattern A, acetate pattern A, citrate pattern A, fumarate pattern A and oxalate pattern A.

10. The pharmaceutical composition of claim 7, wherein the composition is in the form of a prodrug.

11. The composition of claim 10, wherein the prodrug is an amino acid covalently attached to a crystalline form salt or polymorph of the R-MDMA.

12. The pharmaceutical composition of claim 11, wherein the amino acid is selected from the group consisting of lysine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

13. The pharmaceutical composition of claim 7, wherein the composition is formulated as a continuous sustained release preparation.

14. The pharmaceutical composition of claim 13, wherein the composition is formulated as a transdermal patch.

15. The pharmaceutical composition of claim 7, wherein the composition is formulated as an intranasal spray.

16. The pharmaceutical composition of claim 7, wherein the composition is formulated into a liquid dosage form selected from the group consisting of suspensions, solutions, emulsions, elixirs, tinctures, sprays, syrups, gels, serums, liniments, lotions, ointments, pastes, drops, and inhalants.

17. The pharmaceutical composition of claim 7, wherein the composition is formulated into a solid dosage form selected from the group consisting of capsules, films, lozenges, patches, powders, tablets, granules, pills, and lozenges.

18. A method of treating a medical condition in an individual comprising the steps of: administering to the individual an effective amount of a crystalline salt or polymorphic composition of R-MDMA; as well as Treating the individual.

19. The method of claim 18, further comprising the step of preventing or reducing the neurotoxic, hyperthermic and dependence / addiction side effects experienced with the use of racemic MDMA.

20. The method of claim 18, wherein the medical condition is selected from the group consisting of post-traumatic stress disorder, social anxiety, autism spectrum disorder, substance use disorder, depression, anxiety disorder, anxiety associated with life-threatening illness, personality disorder, schizophrenia, obsessive compulsive disorder, couples therapy, any psychotherapy to enhance the therapeutic bond in patients or neurotic / healthy subjects by inducing feelings of well-being, connection, trust, love, empathy, openness, and prosociality.

21. The method of claim 18, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, maleate, L-malate, D-tartrate, hemi-meso-tartrate, hemi-L-tartrate, citrate, phosphate, hemi-naphthalene-1,5-disulfonate, hemi-fumarate, sulfate, methanesulfonate, acetate, hemi-oxalate, and oxalate.

22. The method of claim 18, wherein the salt is selected from the group consisting of: hydrochloride pattern A, phosphate pattern A, phosphate pattern B, phosphate pattern C, HBr pattern A, HBr pattern B, HBr pattern C, hemi-L-tartrate pattern A, hemi-meso-tartrate pattern B, hemi-meso-tartrate pattern C, meso-tartrate pattern A, meso-tartrate pattern B, sulfate pattern A, sulfate pattern B, D-tartrate pattern A, D-tartrate pattern C, Tartrate pattern B, D-tartrate pattern C, D-tartrate pattern D, D-tartrate pattern E, L-maleate pattern A, maleate pattern A, maleate pattern B, hemi-naphthalene-1,5-disulfonate pattern A, hemi-naphthalene-1,5-disulfonate pattern B, hemi-oxalate pattern A, hemi-oxalate pattern A', hemi-fumarate pattern A, hemi-fumarate pattern A', methanesulfonate pattern A, acetate pattern A, citrate pattern A, fumarate pattern A, and oxalate pattern A.

23. The method of claim 18, wherein the composition is administered at a dose of 10 mg to 1000 mg.

24. The method of claim 18, wherein the composition is administered daily.

25. The method of claim 18, wherein the composition is formulated as a continuous sustained release formulation.

26. The method of claim 25, wherein the composition is formulated as a transdermal patch.

27. The method of claim 18, wherein the composition is formulated as an intranasal spray.

28. The method of claim 18, wherein the composition is formulated into a liquid dosage form selected from the group consisting of a suspension, a solution, an emulsion, an elixir, a tincture, a spray, a syrup, a gel, a serum, a liniment, a lotion, an ointment, a paste, drops, and an inhalant.

29. The method of claim 18, wherein the composition is formulated into a solid dosage form selected from the group consisting of capsules, films, lozenges, patches, powders, tablets, granules, pills, and lozenges.

30. The composition of claim 1, wherein the acid is hydrochloric acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 15.8, about 17.5, about 19.7, about 24.8, and about 24.

9.

31. The composition of claim 1, wherein the acid is hydrobromic acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 13.9, about 16.3, about 19.8, about 20.5, and about 24.

0.

32. The composition of claim 1, wherein the acid is phosphoric acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 13.4, about 14.6, about 17.4, about 18.7, and about 22.

1.

33. The composition of claim 1, wherein the acid is D-tartaric acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 6.0, about 12.0, about 13.3, about 17.9, and about 24.

1.

34. The composition of claim 1, wherein the acid is fumaric acid and the crystalline form is characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Kα x-rays, the x-ray powder diffraction pattern having peaks expressed as 2θ at about 17.2, about 18.6, about 19.2, about 19.5, and about 21.

8.

35. The composition of claim 34, wherein the salt is a hemi-salt.

36. The composition of claim 1, wherein the acid is oxalic acid and the crystalline form is characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Ka x-rays, the x-ray powder diffraction pattern having peaks expressed as 2θ at about 15.2, about 16.4, about 16.8, about 19.3, and about 21.

3.

37. The composition of claim 33, wherein the salt is a hemi-salt.

38. The composition of claim 1, wherein the acid is hydrobromic acid and the crystalline form is characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Kα x-rays, the x-ray powder diffraction pattern having peaks expressed as 2θ at about 13.9, about 16.2, about 16.9, about 20.5, and about 24.

1.

39. The composition of claim 1, wherein the acid is phosphoric acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 14.5, about 17.4, about 22.0, about 24.7, and about 24.

9.

40. The composition of claim 1, wherein the acid is phosphoric acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 12.9, about 13.8, about 17.1, about 26.8, and about 27.

8.

41. The composition of claim 1, wherein the acid is D-tartaric acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 5.6, about 11.3, about 15.4, about 17.2, and about 17.

8.

42. The composition of claim 1, wherein the acid is D-tartaric acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 5.1, about 16.3, about 19.3, about 20.4, and about 21.

8.

43. The composition of claim 1, wherein the acid is maleic acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 14.9, about 18.0, about 25.2, about 25.9, and about 27.

9.

44. The composition of claim 1, wherein the acid is malic acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2-theta at about 17.8, about 18.1, about 19.3, about 26.5, and about 27.

3.

45. The composition of claim 1, wherein the acid is naphthalene-1,5-disulfonic acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 14.6, about 15.2, about 15.8, about 16.8, and about 22.

9.

46. ​​The composition of claim 45, wherein the salt is a hemi-salt.

47. The composition of claim 1, wherein the acid is oxalic acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 4.8, about 14.6, about 16.8, about 19.9, and about 21.

0.

48. The composition of claim 1, wherein the acid is sulfuric acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 14.9, about 17.8, about 21.0, about 21.2, and about 23.

8.

49. The composition of claim 1, wherein the acid is methanesulfonic acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 16.2, about 17.9, about 18.5, about 21.2, and about 26.

9.

50. The composition of claim 1, wherein the acid is acetic acid and the crystalline form is characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 17.7, about 18.0, about 18.6, about 19.7, and about 20.3.

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