R-MDMA Crystal Form

Abstract

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

Description

Technical Field

[0001] The present invention relates to compositions and methods for producing crystalline forms of R-MDMA.

Background Art

[0002] 3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive drug that alters mood and perception and has been studied 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 be studied and utilized in the future for various other medical conditions. Such conditions in which MDMA or related substances may be useful include, but are not limited to, substance use disorders, depression, anxiety disorders (including social anxiety), anxiety associated with life-threatening illnesses, personality disorders (including narcissistic and antisocial disorders), autism and other developmental disorders, and obsessive-compulsive disorder. MDMA or related substances can also be used to enhance individual or couples therapy.

[0003] Regarding MDMA, there are several side effects and safety concerns. The abuse of MDMA can result in hyperthermia, neurocognitive impairment, and an increase in depression. MDMA may also have neurotoxicity that limits the ability to be used long-term with repeated dosing. The use of MDMA often impairs declarative memory, prospective memory, and higher cognitive abilities. Neurocognitive deficits are associated with a reduction in the serotonin transporter (SERT) in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown a local reduction in brain activity during neurocognitive performance. Disorders in sleep, mood, vision, pain, psychomotor ability, tremor, neurohormonal activity, and mental state have also been demonstrated. These effects are more seen with high doses or long-term use. (Parrott, Neuroscience & Biobehavioral Reviews, Volume 37, Issue 8, 2013, Pages 1466 - 1484).

[0004] MDMA has two enantiomers (S(+)-MDMA and R(-)-MDMA). The R enantiomer is thought to be more active (Nichols, et al. J. Med. Chem. 1986, 29, 2009-2015). The neurotoxicity of racemic MDMA is thought to be caused by the S(+) enantiomer rather than the R(-) enantiomer because of the low efficacy of the R(-) enantiomer as a dopamine releaser. The R(-) enantiomer does not cause hyperthermia. The R(-) enantiomer may have a low abuse risk. (Pitts, et al. Psychopharmacology (2018) 235:377-392). Enantiomers have been shown to have different effects. R-MDMA and S-MDMA were evaluated for their effects in a Parkinson's disease animal model (Huot, et al., The Journal of Neuroscience, 2011, 31(19):7190-7198). R-MDMA, a compound selective for the 5-HT2A receptor, decreased the severity of peak-dose dyskinesia, increased the duration of good on-time, showed high affinity for SERT, and showed moderate affinity for DAT. S-MDMA, which showed high affinity for SERT and moderate affinity for DAT, extended the total duration of on-time but worsened dyskinesia. This indicates that racemic MDMA exerts a simultaneous effect of reducing dyskinesia and extending on-time due to 5-HT2A antagonism and inhibition of SERT-selective mixed monoamine uptake caused by the R and S enantiomers, respectively. Therefore, it may be advantageous to use R-MDMA for treatment.

[0005] The R-MDMA free base is an oil. Stabilization as a crystalline salt is required to facilitate handling, long-term storage, and pharmaceutical manufacture. The R-MDMA HCl salt (CAS 69558-31-2) has been reported in the literature (S. Llabres 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-MDMA HCls provides little or no detail and / or is not suitable for scale-up manufacture. Solid properties have also not been reported.

[0006] Accordingly, there remains a need for compositions of R-MDMA that can be produced on a suitable scale for use in treatment. SUMMARY OF THE INVENTION

[0007] The present invention provides a composition of a crystalline form salt or polymorph of R-MDMA.

[0008] The present invention provides a pharmaceutical composition comprising a crystalline form salt or polymorph of R-MDMA and a pharmaceutically acceptable excipient.

[0009] The present invention provides a method of treating a medical condition of an individual by administering an effective amount of a composition of a crystalline form salt or polymorph of R-MDMA to the individual. The present invention will be better understood, and other advantages of the present invention will be readily appreciated, when considered in conjunction with the accompanying drawings and the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0010]

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DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention provides salts and polymorphs of R-MDMA that can be used to prepare R-MDMA in a crystalline form that is stable at scales suitable for manufacture and use in treatment.

[0012] The salt can be, but is not limited to, hydrochloride (HCl), hydrobromide (HBr), maleate, L - malate, D - tartrate, hemi - meso - tartrate, hemi - L - tartrate, citrate, phosphate, heminaphthylene - 1,5 - disulfonate, hemifumarate, sulfate, mesylate, acetate, hemioxalate, or oxalate. More specifically, the salt can be of a specific pattern (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 B, D - tartrate pattern C, D - tartrate pattern D, D - tartrate pattern E, L - maleate pattern A, maleate pattern A, maleate pattern B, heminaphthylene - 1,5 - disulfonate pattern A, heminaphthylene - 1,5 - disulfonate pattern B, hemioxalate pattern A, hemioxalate pattern A’, hemifumarate pattern A, hemifumarate pattern A’, mesylate pattern A, acetate pattern A, citrate pattern A, fumarate pattern A, or oxalate pattern A).

[0013] As will be described in further detail below, when the acid is hydrochloric acid, the crystalline form may be characterized by an X-ray powder diffraction pattern having peaks represented as about 15.8, about 17.5, about 19.7, about 24.8, and about 24.9 as 2θ. When the acid is hydrobromic acid, the crystalline form pattern A may be characterized by an X-ray powder diffraction pattern having peaks represented as about 13.9, about 16.3, about 19.8, about 20.5, and about 24.0 as 2θ. When the acid is phosphoric acid, the crystalline form pattern C may be characterized by an X-ray powder diffraction pattern having peaks represented as about 13.4, about 14.6, about 17.4, about 18.7, and about 22.1 as 2θ. When the acid is D-tartaric acid, the crystalline form pattern C may be characterized by an X-ray powder diffraction pattern having peaks represented as about 6.0, about 12.0, about 13.3, about 17.9, and about 24.1 as 2θ. When the acid is fumaric acid, the crystalline form may be characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as about 17.2, about 18.6, about 19.2, about 19.5, and about 21.8 as 2θ, and the salt may be a hemisalt. When the acid is oxalic acid, the crystalline form may be characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as about 15.2, about 16.4, about 16.8, about 19.3, and about 21.3 as 2θ, and the salt may be a hemisalt.

[0014] 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 having peaks represented as about 13.9, about 16.2, about 16.9, about 20.5, and about 24.1 as 2θ. 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 about 14.5, about 17.4, about 22.0, about 24.7, and about 24.9 as 2θ. 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 about 12.9, about 13.8, about 17.1, about 26.8, and about 27.8 as 2θ. When the acid is D-tartaric acid, the crystalline form pattern A can be characterized by an X-ray powder diffraction pattern having peaks represented as about 5.6, about 11.3, about 15.4, about 17.2, and about 17.8 as 2θ. When the acid is D-tartaric acid, the crystalline form pattern B can be characterized by an X-ray powder diffraction pattern having peaks represented as about 5.1, about 16.3, about 19.3, about 20.4, and about 21.8 as 2θ. When the acid is maleic acid, the crystalline form can be characterized by an X-ray powder diffraction pattern having peaks represented as about 14.9, about 18.0, about 25.2, about 25.9, and about 27.9 as 2θ. When the acid is malic acid, the crystalline form can be characterized by an X-ray powder diffraction pattern having peaks represented as about 17.8, about 18.1, about 19.3, about 26.5, and about 27.3 as 2θ. When the acid is naphthalene-1,5-disulfonic acid, the crystalline form can be characterized by an X-ray powder diffraction pattern having peaks represented as about 14.6, about 15.2, about 15.8, about 16.8, and about 22.9 as 2θ. The salt can also be a hemisalt. When the acid is oxalic acid, the crystalline form can be characterized by an X-ray powder diffraction pattern having peaks represented as about 4.8, about 14.6, about 16.8, about 19.9, and about 21.0 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 represented as about 14.9, about 17.8, about 21.0, about 21.2, and about 23.8 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 represented as about 16.4, about 19.1, about 23.9, about 25.9, and about 27.8 as 2θ.When the acid is methanesulfonic acid, the crystalline form may be characterized by an X-ray powder diffraction pattern having peaks represented as about 16.2, about 17.9, about 18.5, about 21.2, and about 26.9 as 2θ. When the acid is acetic acid, the crystalline form may be characterized by an X-ray powder diffraction pattern having peaks represented as about 17.7, about 18.0, about 18.6, about 19.7, and about 20.3 as 2θ.

[0015] The salts or polymorphs of R-MDMA can be administered in doses of 10 to 1000 mg. MDMA is typically an agonist that interacts with membrane monoamine transporters (serotonin, norepinephrine, or dopamine transporters) to release primarily monoamines (serotonin, norepinephrine, and dopamine), and in some cases, oxytocin as well (Hysek et al., 2014; Hysek et al., 2012b; Simmler et al., 2013; Verrico et al., 2007).

[0016] The composition may also include a prodrug of a salt or polymorph of R-MDMA. As used herein, "prodrug" refers to a compound that contains a moiety linked to an active drug substance that is metabolized after administration to an individual and converted to the active drug substance. The use of prodrugs improves the absorption, distribution, metabolism, and excretion of the active ingredient. Prodrugs can be used to prevent the active ingredient from being released in the gastrointestinal tract upon administration so that the drug is released more favorably at other sites in the body.

[0017] Prodrug compounds include chemical modifications to the salt or polymorph of R-MDMA, e.g., an amino acid covalently attached thereto. By adding an amino acid, the active compound is inactivated mainly by preventing its interaction with the monoamine transporters (which are the sites of action and also affect bioavailability / absorption rate). The amino acid can be lysine or any other amino acid (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine), and usually binds to the amine (N) group of R-MDMA, thereby reducing the pharmacological activity at the main sites of action (cell membrane monoamine transporters, e.g., serotonin, dopamine, and norepinephrine transporters), changing the degree and rate of absorption, and being able to release the active substance mainly into the circulation after absorption of the inactive compound. The amino acid can be other natural or synthetic amino acids. Any other chemical modification can also be used.

[0018] Using the salt or polymorph of R-MDMA allows for daily use. The composition is particularly useful for sustained-release formulations (e.g., transdermal patches) that can provide low doses over a long period. The composition can also be administered as a nasal spray. The composition can also be present in liquid dosage forms (e.g., but not limited to, suspensions, solutions, emulsions, elixirs, tinctures, sprays, syrups, gels, magmas, coatings, lotions, ointments, pastes, drops, or inhalants). The composition can be present in solid dosage forms (e.g., but not limited to, capsules, films, lozenges, patches, powders, tablets, pellets, pills, or troches).

[0019] The compounds of the present invention are administered and dosed in accordance with good medical practice, taking into account the clinical state of the individual patient, the site and method of administration, the dosing schedule, the age, sex, weight of the patient, and other factors known to the medical practitioner. Thus, a pharmaceutically "effective amount" as used herein is determined with regard to the considerations known in the art. The amount must be effective to achieve improvement (including, but not limited to, more rapid recovery, or improvement or disappearance of symptoms and other markers that those skilled in the art would select as appropriate measures).

[0020] In the methods of the present invention, the compounds of the present invention can be administered in a variety of ways. It should be noted that it can be administered as a compound, either alone or as an active ingredient in combination with a pharmaceutically acceptable carrier, diluent, adjuvant, and vehicle. The compound can be administered by oral, subcutaneous, or parenteral (e.g., sublingual, buccal, inhalation, intravenous, intramuscular, and intranasal) administration. Implants of the compound are also useful. The patient to be treated is a warm-blooded animal, particularly a mammal including humans. Pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles, as well as implant carriers, generally refer to inert, non-toxic solid or liquid fillers, diluents, or encapsulating materials that generally do not react with the active ingredients of the present invention.

[0021] Administration can be a single administration, or multiple administrations over several days, weeks, or months. The length of treatment generally is proportional to the length of the progression of the disease and the effectiveness of the drug and the length of the patient being treated.

[0022] When the compounds of the present invention are administered orally, they will typically be formulated as immediate release capsules, immediate release tablets, modified release capsules or tablets (including enteric coatings), solutions, or suspensions. When the compounds of the present invention are administered parenterally, they will generally be formulated as tablets that dissolve sublingually or in the buccal mucosa, dissolving films, intranasal powders, intranasal solutions, inhalation powders, inhalation solutions, transdermal patches, micro needles or transdermal patches containing other penetration enhancers, or unit dose injectables (solutions, suspensions, emulsions). Pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils.

[0023] Proper fluidity can be maintained, for example, by the use of coatings (such as lecithin), maintenance of the required particle size in the case of dispersions, and the use of surfactants. 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 composite composition. Furthermore, various additives (including antibacterial and preservative agents, antioxidants, chelating agents, and buffering agents) can be added to enhance the stability, sterility, and isotonicity of the composition. Prevention of the action of microorganisms can be ensured with various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, etc.). In many cases, it is desirable for it to contain isotonic agents (such as sugars, sodium chloride, etc.). The use of agents that delay absorption (such as aluminum monostearate and gelatin) can cause sustained absorption of the injectable pharmaceutical form. However, in accordance with the present invention, the vehicle, diluent, or additive used must be compatible with the compound.

[0024] The sterile injectable solutions can be prepared by admixing the compounds utilized in the practice of the invention in the required amounts in a suitable solvent as desired, with various other ingredients.

[0025] The pharmacological formulations of the present invention can be administered to a patient as injectable formulations containing a compatible carrier (e.g., various vehicles, adjuvants, additives, and diluents), or the compounds utilized in the present invention can be administered parenterally to a patient in the form of a sustained release subcutaneous implant or a targeted delivery system (e.g., monoclonal antibodies, vector delivery, iontophoresis, polymeric matrix, liposomes, and microspheres). Examples of delivery systems useful 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.

[0026] The present invention provides a method of treating a medical disorder in an individual by administering to the individual an effective amount of a composition of a salt or polymorph of R-MDMA and treating the individual. The method can further include preventing or reducing the neurotoxicity, hyperthermia, and dependence / abuse side effects experienced with racemic MDMA. Any of the above prodrugs can be used.

[0027] Specifically, the composition can be used for the treatment of a medical disorder or condition (post-traumatic stress disorder, social anxiety, autism spectrum disorder, substance use disorder, depression, anxiety disorder, anxiety associated with life-threatening diseases, personality disorder (including narcissistic personality disorder or antisocial personality disorder), schizophrenia, obsessive-compulsive disorder), couples therapy, enhancement of any psychotherapy (by inducing well-being, connectedness, trust, love, empathy, openness, and prosociality, and by strengthening the therapeutic bond in any psychotherapy of a patient or neurotic / healthy subject).

[0028] The present invention will be further described in detail by referring to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting, unless otherwise specified. Accordingly, the present invention should not be construed as being limited to the following examples, but rather should be interpreted as encompassing all variations that become apparent as a result of the teachings provided herein.

[0029] Example 1. General procedure for the preparation of salts of R-MDMA Salt screening was carried out using the 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. An aliquot of the solution (0.4 ml, approximately 30 mg) was charged into a crystallization tube. The solution was heated to 50 °C and the relevant acid (1 equivalent) was added to one aliquot. The solution was equilibrated at 50 °C for 1 hour and then cooled to ambient temperature and equilibrated for 24 hours. When a suspension was obtained, the solid was separated by filtration and dried in vacuo at 45 °C. When a solution remained, further operations were required to obtain a separable solid. Primarily, the following methods were used to induce crystallization and / or obtain a solid: Reducing the solvent volume to approximately 50% under a steady flow of nitrogen Cooling to 0 °C and below Adding an anti-solvent (TBME) at ambient temperature and then equilibrating Removing the solvent by a steady flow of nitrogen Repeatedly scraping and pulverizing the obtained residue with TBME and then equilibrating the solid to obtain a suspension. [Table 1]

[0030] The XRPD patterns of R-MDMA maleate, R-MDMA L-malate, R-MDMA hemi-meso tartrate, R-MDMA citrate, R-MDMA phosphate, R-MDMA heminaaphthylene-1,5-disulfonate, R-MDMA sulfate, R-MDMA mesylate, R-MDMA acetate, and R-MDMA oxalate are shown in Figures 23 to 32.

[0031] Figure 23 shows an overlay of the XRPD diffraction patterns of R-MDMA maleate isolated from IPA (upper, low crystallinity), the attempted hemisalt from ethanol (center, Pattern A), and the monosalt isolated from THF (lower, Pattern A). Figure 24 shows an overlay of the XRPD diffraction patterns of Pattern A of R-MDMA maleate isolated from THF (upper, low crystallinity), IPA (center), and DCM (lower). Figure 25 shows an overlay of the XRPD diffraction patterns of R-MDMA hemi-meso tartrate isolated from THF (upper, mixture of Pattern A and C), DCM (center, Pattern A), and THF (lower, Pattern B). Figure 26 shows the XRPD diffraction pattern of R-MDMA citrate. Figure 27 shows an overlay of the XRPD diffraction patterns of R-MDMA phosphate isolated from THF (upper, Pattern C), IPA (center, Pattern A), and DCM (lower, Pattern B). Figure 28 shows an overlay of the XRPD diffraction patterns of R-MDMA heminaaphthylene-1,5-disulfonate isolated from THF (upper), IPA (center), and DCM (lower). Figure 29 shows an overlay of the XRPD diffraction patterns of Pattern B (upper) and Pattern A (lower) of R-MDMA sulfate separated from DCM. Figure 30 shows an overlay of the XRPD diffraction patterns of R-MDMA mesylate isolated from THF (upper) and DCM (lower). Figure 31 shows an overlay of the XRPD diffraction patterns of R-MDMA acetate isolated from THF (upper) and DCM (lower). Figure 32 shows an overlay of the XRPD diffraction patterns of R-MDMA oxalate isolated from IPA (upper), THF (center), and DCM (lower).

[0032] Example 2 The R-MDMA HCl salt Pattern A was prepared. The XRPD pattern is shown in Figure 1. 1 The 1H NMR spectrum is shown in Figure 2. The combination of DSC / TGA thermographs is shown in Figure 3. Figure 4 shows the DVS profile, and Figure 5 shows the XRPD patterns under ambient conditions, 0% relative humidity, and 90% relative humidity. Table 2 shows the XRPD peak list. The optical micrographs of R-MDMA HCl Pattern A are shown in Figures 20A - 20D.

Table 2

[0033] Example 3. The R-MDMA HBr salt Pattern A was prepared. The XRPD pattern is shown in Figure 6A. 1 The 1H NMR spectrum is shown in Figure 6B. The combination of DSC / TGA thermographs is shown in Figure 6C. Figure 7 shows the DVS profile, and Figure 8 shows the XRPD patterns under ambient conditions, 0% relative humidity, and 90% relative humidity. Table 3 shows the peak list.

Table 3-1

Table 3-2

[0034] Example 4. The R-MDMA phosphate Pattern C was prepared. The XRPD pattern is shown in Figure 9A. 1 The 1H NMR spectrum is shown in Figure 9B. The combination of DSC / TGA thermographs is shown in Figure 9C. Figure 10A shows the DVS profile, and Figure 10B shows the XRPD patterns under ambient conditions, 0% relative humidity, and 90% relative humidity. Table 4 shows the peak list.

Table 4-1

Table 4-2

[0035] Example 5. The R-MDMA D-tartrate Pattern C was prepared. The XRPD pattern is shown in Figure 11A. 1 The 1H NMR spectrum is shown in Figure 11B. The combination of DSC / TGA thermographs is shown in Figure 11C. Figure 12A shows the DVS profile, and Figure 12B shows the XRPD patterns under ambient conditions, relative humidity 0%, and relative humidity 90%. Table 5 shows the peak list. [Table 5-1] [Table 5-2]

[0036] Example 6. The R-MDMA hemifumarate Pattern A was prepared. The XRPD pattern is shown in Figure 13A. 1 The 1H NMR spectrum is shown in Figure 13B. The combination of DSC / TGA thermographs is shown in Figure 13C. Figure 14A shows the DVS profile, and Figure 14B shows the XRPD patterns under ambient conditions, relative humidity 0%, and relative humidity 90%. Table 6 shows the peak list. [Table 6-1] [Table 6-2]

[0037] Example 7. The R-MDMA hemisuccinate Pattern A / A’ was prepared. The XRPD pattern is shown in Figure 15. 1 The 1H NMR spectrum is shown in Figure 16. The combination of DSC / TGA thermographs is shown in Figure 17. Figure 18 shows the DVS profile, and Figure 19 shows the XRPD patterns under ambient conditions, relative humidity 0% and relative humidity 90%. Table 7 shows the peak list.

Table 7-1

Table 7-2

[0038] Example 8. Single crystal X-ray structure 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 with a 0.45 μm filter and aged to allow solvent drainage. When appropriate crystal growth occurred, the crystal structure of R-MDMA HCl Form 1 was determined from data measured at low temperature (100 K) and a wavelength of 1.54180 Å. R-MDMA HCl crystallizes in the monoclinic space group P21. In the asymmetric unit, one monocation (R)-MDMA and one chloride anion (total ratio 1:1) as shown in Figure 21 were detected, and crystal packing as shown in Figure 22 was detected.

[0039] Example 9 The R-MDMA HBr salt Pattern B was prepared. Table 8 shows the XPRD peak data of the HBr Pattern B. Figure 33 shows the XPRD pattern.

Table 8

[0040] Example 10 The R-MDMA phosphate Pattern A was prepared. Table 9 shows the XPRD peak data of the phosphate Pattern A. Figure 34 shows the XPRD data.

Table 9

[0041] Example 11 The R-MDMA phosphate Pattern B was prepared. Table 10 shows the XPRD peak data of the phosphate Pattern B. Figure 35 shows the XPRD data.

Table 10

[0042] Example 12 R-MDMA tartrate pattern A was prepared. Table 11 shows the XPRD peak data of tartrate pattern A. Figure 36 shows the XPRD data.

Table 11

[0043] Example 13 R-MDMA tartrate pattern B was prepared. Table 12 shows the XPRD peak data of tartrate pattern B. Figure 37 shows the XPRD data.

Table 12-1

Table 12-2

[0044] Example 14 R-MDMA maleate pattern A was prepared. Table 13 shows the XPRD peak data of maleate pattern A. Figure 38 shows the XPRD data.

Table 13

[0045] Example 15 R-MDMA L-malate pattern A was prepared. Table 14 shows the XPRD peak data of L-malate pattern A. Figure 39 shows the XPRD data.

Table 14

[0046] Example 16 R-MDMA heminaftylene-1,5-disulfonate pattern A was prepared. Table 15 shows the XPRD peak data of heminaftylene-1,5-disulfonate pattern A. Figure 40 shows the XPRD data.

Table 15-1

Table 15-2

[0047] Example 17 R-MDMA hemifumarate pattern A was prepared. Table 16 shows the XPRD peak data of hemifumarate pattern A. Figure 41 shows the data.

Table 16-1

Table 16-2

[0048] Example 18 R-MDMA oxalate pattern A was prepared. Table 17 shows the XPRD peak data of oxalate pattern A. Figure 42 shows the data.

Table 17

[0049] Example 19 R-MDMA sulfate pattern A was prepared. Table 18 shows the XPRD peak data of sulfate pattern A. Figure 43 shows the data.

Table 18

[0050] Example 20 R-MDMA sulfate pattern B was prepared. Table 19 shows the XPRD peak data of sulfate pattern B. Figure 44 shows the data.

Table 19-1

Table 19-2

[0051] Example 21 R-MDMA mesylate pattern A was prepared. Table 20 shows the XPRD peak data of mesylate pattern A. Figure 45 shows the data.

Table 20-1

Table 20-2

[0052] Example 22 R-MDMA acetate pattern A was prepared. Table 21 shows the XPRD peak data of acetate pattern A. Figure 46 shows the data.

Table 21-1

Table 21-2

[0053] Throughout this application, various publications, including U.S. patents, are referenced by author and year, and patents are referenced by number. The full citations of the publications are listed below. The disclosures of these publications and patents are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.

[0054] The present invention has been described by way of example, and it should be understood that the terms used are not intended to be limiting but rather as words of description.

[0055] Of course, in light of the above teachings, many modifications and variations are possible to the present invention. Therefore, within the scope of the appended claims, the present invention should be understood to be practiced otherwise than as specifically described herein.

Claims

1. R-MDMA is R-MDMA HBr having X-ray powder diffraction (XRPD) peaks represented by 2θ approximately 13.9, 16.2, 16.9, 20.5, and 24.1; R-MDMA HBr having XRPD peaks represented by 2θ approximately 13.9, 16.3, 19.8, 20.5, and 24.0; R-MDMA phosphate having XRPD peaks represented by 2θ at approximately 13.4, 14.6, 17.4, 18.7, and 22.1; R-MDMA phosphate having XRPD peaks represented by 2θ at approximately 14.5, 17.4, 22.0, 24.7, and 24.9; R-MDMA phosphate having XRPD peaks represented by 2θ approximately 12.9, 13.8, 17.1, 26.8, and 27.8; R-MDMA D-tartrate having XRPD peaks represented by approximately 5.6, 11.3, 15.4, 17.2, and 17.8 as 2θ; R-MDMA D-tartrate having XRPD peaks represented by 2θ at approximately 5.1, 16.3, 19.3, 20.4, and 21.8; R-MDMA D-tartrate having XRPD peaks represented by 2θ at approximately 6.0, 12.0, 13.3, 17.9, and 24.1; R-MDMA hemisulfate having XRPD peaks represented by 2θ at approximately 15.2, 16.4, 16.8, 19.3, and 21.3; R-MDMA naphthylene-1,5-disulfonate having XRPD peaks represented by 2θ at approximately 14.6, 15.2, 15.8, 16.8, and 22.9; R-MDMA oxalate having XRPD peaks represented by 2θ at approximately 4.8, 14.6, 16.8, 19.9, and 21.0; R-MDMA sulfate having XRPD peaks represented by 2θ at approximately 14.9, 17.8, 21.0, 21.2, and 23.8; R-MDMA mesylate having XRPD peaks represented by 2θ at approximately 16.2, 17.9, 18.5, 21.2, and 26.9; R-MDMA acetate having XRPD peaks represented by 2θ at approximately 17.7, 18.0, 18.6, 19.7, and 20.3; R-MDMA maleate having XRPD peaks represented by approximately 14.9, 18.0, 25.2, 25.9, and 27.9 as 2θ; or R-MDMA L-malate has XRPD peaks represented by 2θ at approximately 17.8, 18.1, 19.3, 26.5, and 27.

3. This is the crystalline form of R-MDMA.

2. The crystal morphology according to claim 1, wherein the crystal morphology is R-MDMA HBr having peaks represented by 2θ of about 13.9, about 16.2, about 16.9, about 20.5, and about 24.

1.

3. The crystal morphology according to claim 2, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 33.

4. The crystal morphology according to claim 1, wherein the crystal morphology is R-MDMA HBr having peaks represented by 2θ of about 13.9, about 16.3, about 19.8, about 20.5, and about 24.

0.

5. The crystal morphology according to claim 4, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 8.

6. The crystal morphology according to claim 1, wherein the crystal morphology is an R-MDMA phosphate having peaks represented by 2θ of about 13.4, about 14.6, about 17.4, about 18.7, and about 22.

1.

7. The crystal morphology according to claim 6, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 9A.

8. The crystal morphology according to claim 6, wherein the crystal morphology has a thermogravimetric analysis (TG) substantially shown in Figure 9C.

9. The crystal morphology according to claim 6, wherein the crystal morphology exhibits an endothermic phenomenon characterized by DSC and has an onset temperature of about 184.01°C and / or a peak temperature of about 185.49°C.

10. The crystal morphology according to claim 6, wherein the crystal morphology has dynamic vapor adsorption (DVS) substantially shown in Figure 10A.

11. The crystal morphology according to claim 1, wherein the crystal morphology is an R-MDMA phosphate having peaks represented by 2θ of about 14.5, about 17.4, about 22.0, about 24.7, and about 24.

9.

12. The crystal morphology according to claim 11, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 34.

13. The crystal morphology according to claim 1, wherein the crystal morphology is an R-MDMA phosphate having peaks represented by 2θ of about 12.9, about 13.8, about 17.1, about 26.8, and about 27.

8.

14. The crystal morphology according to claim 13, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 35.

15. The crystal morphology according to claim 1, wherein the crystal morphology is R-MDMA D-tartrate having peaks represented by 2θ of about 5.6, about 11.3, about 15.4, about 17.2, and about 17.

8.

16. The crystal morphology according to claim 15, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 36.

17. The crystal morphology according to claim 1, wherein the crystal morphology is R-MDMA D-tartrate having peaks represented by 2θ of about 5.1, about 16.3, about 19.3, about 20.4, and about 21.

8.

18. The crystal morphology according to claim 17, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 37.

19. The crystal morphology according to claim 1, wherein the crystal morphology is R-MDMA D-tartrate having peaks represented by 2θ of about 6.0, about 12.0, about 13.3, about 17.9, and about 24.

1.

20. The crystal morphology according to claim 19, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 12B.

21. The crystal morphology according to claim 1, wherein the crystal morphology is an R-MDMA hemioxalate having peaks represented by 2θ of about 15.2, about 16.4, about 16.8, about 19.3, and about 21.

3.

22. The crystal morphology according to claim 21, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 15.

23. The crystal morphology according to claim 1, wherein the crystal morphology is R-MDMA naphthylene-1,5-disulfonate having peaks represented by 2θ of about 14.6, about 15.2, about 15.8, about 16.8, and about 22.

9.

24. The crystal morphology according to claim 23, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 40.

25. The crystal morphology according to claim 1, wherein the crystal morphology is R-MDMA oxalate having peaks represented by 2θ of about 4.8, about 14.6, about 16.8, about 19.9, and about 21.

0.

26. The crystal morphology according to claim 25, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 42.

27. ​​The crystal morphology according to claim 1, wherein the crystal morphology is an R-MDMA sulfate having peaks represented by 2θ of about 14.9, about 17.8, about 21.0, about 21.2, and about 23.

8.

28. The crystal morphology according to claim 27, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 43.

29. The crystal morphology according to claim 1, wherein the crystal morphology is an R-MDMA mesylate having peaks represented by 2θ of about 16.2, about 17.9, about 18.5, about 21.2, and about 26.

9.

30. The crystal morphology according to claim 29, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 45.

31. The crystal morphology according to claim 1, wherein the crystal morphology is an R-MDMA acetate having peaks represented by 2θ of about 17.7, about 18.0, about 18.6, about 19.7, and about 20.

3.

32. The crystal morphology according to claim 31, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 46.

33. The crystal morphology according to claim 1, wherein the crystal morphology is an R-MDMA maleate having peaks represented by 2θ of about 14.9, about 18.0, about 25.2, about 25.9, and about 27.

9.

34. The crystal morphology according to claim 33, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 38.

35. The crystal morphology according to claim 1, wherein the crystal morphology is R-MDMA L-malate having peaks represented by 2θ of about 17.8, about 18.1, about 19.3, about 26.5, and about 27.

3.

36. The crystal morphology according to claim 35, wherein the crystal morphology has an X-ray powder diffraction pattern substantially shown in Figure 39.

37. A pharmaceutical composition comprising the crystalline form described in Claim 1 and a pharmaceutically acceptable excipient.

38. The pharmaceutical composition according to claim 37, wherein the composition is incorporated into a sustained-release formulation.

39. The pharmaceutical composition according to claim 38, wherein the composition is incorporated into a transdermal patch.

40. The pharmaceutical composition according to claim 37, wherein the composition is incorporated into an intranasal spray.

41. The pharmaceutical composition according to claim 37, wherein the composition is formulated into a liquid dosage form selected from the group consisting of suspensions, liquids, emulsions, elixirs, tinctures, sprays, syrups, gels, magmas, topical agents, lotions, ointments, pastes, intravenous agents, and inhalants.

42. The pharmaceutical composition according to claim 37, wherein the composition is formulated into a solid dosage form selected from the group consisting of capsules, films, lozenges, patches, powders, tablets, pellets, pills, and lozenges.

43. A pharmaceutical composition for treating a medical condition, comprising the crystalline form described in Claim 1.

44. The pharmaceutical composition according to claim 43, which prevents or reduces the side effects of neurotoxicity, hyperthermia, or dependence / toxicity experienced with racemic MDMA.

45. The pharmaceutical composition according to claim 43, wherein the aforementioned 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; and enhancement of any psychotherapy by inducing feelings of happiness, connection, trust, love, empathy, openness, and prosociality, and by strengthening therapeutic bonds in any psychotherapy for patients or neurotic / healthy subjects.

46. The pharmaceutical composition according to claim 43, wherein the composition is administered in a dose of 10 to 1000 mg.

47. The pharmaceutical composition according to claim 43, wherein the composition is administered daily.

48. The pharmaceutical composition according to claim 43, wherein the composition is incorporated into a sustained-release formulation.

49. The pharmaceutical composition according to claim 43, wherein the composition is incorporated into a transdermal patch.

50. The pharmaceutical composition according to claim 43, wherein the composition is incorporated into an intranasal spray.

51. The pharmaceutical composition according to claim 43, wherein the composition is formulated into a liquid dosage form selected from the group consisting of suspensions, liquids, emulsions, elixirs, tinctures, sprays, syrups, gels, magmas, topical agents, lotions, ointments, pastes, intravenous agents, and inhalants.

52. The pharmaceutical composition according to claim 43, wherein the composition is formulated into a solid dosage form selected from the group consisting of capsules, films, lozenges, patches, powders, tablets, pellets, pills, and lozenges.

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