R-MDMA CRYSTAL FORMS

Abstract

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

Description

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to compositions and methods for making crystal forms of R-MDMA.

2. Background Art

3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive drug that alters mood and perception, and is investigated as an adjunct in psychotherapy for posttraumatic 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 later also be studied and used for a range of other medical conditions. Such conditions where MDMA or related substances may be useful include, but are not limited to, substance-use disorder, depression, anxiety disorder (including social anxiety), anxiety with life-threatening disease, personality disorder including narcistic and antisocial disorder, autism and other developmental disorders and obsessive-compulsive disorder. MDMA or related substances can also be used to enhance individual or couple therapy.

There are several side effects and safety concerns regarding MDMA. Abuse of MDMA can produce hyperpyrexia, neurocognitive defects, and increased rates of depression. MDMA can also be neurotoxic which limits its ability to be used chronically with repeat administration. Use of MDMA often impairs declarative memory, prospective memory, and higher cognitive skills. Neurocognitive deficits are associated with reduced serotonin transporter (SERT) in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown localized reductions in brain activity during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skill, tremor, neurohormonal activity, and psychiatric status, have also been demonstrated. These effects are seen more with higher doses or longer use. (Parrott, Neuroscience & Biobehavioral Reviews, Volume 37, Issue 8, 2013, Pages 1466-1484).

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). It is believed that the neurotoxicity of racemic MDMA is caused by the S(+) enantiomer, not the R(−) enantiomer due to the low efficacy of the R(−) enantiomer as a releaser of dopamine. The R(−) enantiomer also does not produce hyperthermia. The R(−) enantiomer may have a lower risk of abuse. (Pitts, et al. Psychopharmacology (2018) 235:377-392). It has been shown that the enantiomers have different effects. R-MDMA and S-MDMA were evaluated for their effects in a parkinsonian animal model (Huot, et al., The Journal of Neuroscience, 2011, 31 (19):7190-7198), and it was found that R- MDMA, which is a selective compound for 5-HT2A receptors, decreased severity of peak-dose dyskinesia and increased duration of good ON-time, S-MDMA, which exhibits high affinity for SERT and moderate affinity for DAT, extended total duration of ON-time but exacerbated dyskinesia. This showed that racemic MDMA exerts simultaneous effects, reducing dyskinesia and extending ON-time, by 5-HT2A antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively. Therefore, it can be advantageous to use R-MDMA in treatments.

R-MDMA free base is an oil. Stabilization as a crystalline salt is needed to facilitate handling, enable long term storage, and drug product manufacture. 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, these preparations of R-MDMA HCl provided no or few details and/or are not suitable for large scale manufacture. The solid-state properties also have not been reported.

Therefore, there remains a need for compositions of R-MDMA that can be produced on an appropriate scale for use in treatments.

SUMMARY OF THE INVENTION

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

The present invention provides for a pharmaceutical composition of a crystalline form salt or polymorph of R-MDMA and pharmaceutically acceptable excipients.

The present invention provides for a method of treating an individual for a medical condition, by administering an effective amount of a composition of a crystalline form salt or polymorph of R-MDMA and treating the individual.

DESCRIPTION OF THE DRAWINGS

Other advantages of the present invention are readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:

FIG. 1 is an XRPD Diffractogram of R-MDMA HCl Pattern A;

FIG. 2 is a ¹H NMR spectrum of R-MDMA HCl Pattern A;

FIG. 3 is a DSC and TGA thermograph of R-MDMA HCl Pattern A;

FIG. 4 is a DVS profile of R-MDMA HCl Pattern A;

FIG. 5 is XRPD Diffractograms of R-MDMA HCl Pattern A at ambient conditions (middle) and at 0% relative humidity (top) and 90% relative humidity (bottom);

FIG. 6A is an XRPD Diffractogram of R-MDMA HBr Pattern A, FIG. 6B is a ¹H NMR spectrum of R-MDMA HBr Pattern A, and FIG. 6C is a DSC and TGA thermograph of R-MDMA HBr Pattern A;

FIG. 7 is a DVS profile of R-MDMA HBr Pattern A;

FIG. 8 is XRPD Diffractograms of R-MDMA HBr Pattern A at ambient conditions (bottom) and at 0% relative humidity (top) and 90% relative humidity (middle);

FIG. 9A is an XRPD Diffractogram of R-MDMA Phosphate Pattern C, FIG. 9B is a ¹H NMR spectrum of R-MDMA Phosphate Pattern C, and FIG. 9C is a DSC and TGA thermograph of R-MDMA Phosphate Pattern C;

FIG. 10A is a DVS profile of R-MDMA Phosphate Pattern C, and FIG. 10B is XRPD Diffractograms of R-MDMA Phosphate Pattern C at ambient conditions (middle) and at 0% relative humidity (bottom) and 90% relative humidity (top);

FIG. 11A is an XRPD Diffractogram of R-MDMA D-Tartrate Pattern C, FIG. 11B is a ¹H NMR spectrum of R-MDMA D-Tartrate Pattern C, and FIG. 11C a DSC and TGA thermograph of R-MDMA D-Tartrate Pattern C;

FIG. 12A is a DVS profile of R-MDMA Tartrate D-Pattern C, and FIG. 12B is XRPD Diffractograms of R-MDMA D-Tartrate Pattern C at ambient conditions (middle) and at 0% relative humidity (top) and 90% relative humidity (bottom);

FIG. 13A is an XRPD Diffractogram of R-MDMA hemi fumarate Pattern A, FIG. 13B is a ¹H NMR spectrum of R-MDMA hemi fumarate Pattern A, and FIG. 13C is a DSC and TGA thermograph of R-MDMA hemi fumarate Pattern A;

FIG. 14A is a DVS profile of R-MDMA hemi fumarate Pattern A, and FIG. 14B is an overlay of XRPD Diffractograms of R-MDMA hemi fumarate Pattern A at ambient conditions (middle) and at 0% relative humidity (bottom) and 90% relative humidity (top);

FIG. 15 is an XRPD Diffractogram of R-MDMA hemi oxalate Pattern A/A′;

FIG. 16 is a ¹H NMR spectrum of R-MDMA hemi oxalate Pattern A/A′;

FIG. 17 a DSC and TGA thermograph of R-MDMA hemi oxalate Pattern A/A′;

FIG. 18 is a DVS profile of R-MDMA hemi oxalate Pattern A/A′;

FIG. 19 is an overlay of XRPD Diffractograms of R-MDMA hemi oxalate Pattern A/A′ at ambient conditions (middle) and at 0% relative humidity (top) and 90% relative humidity (bottom);

FIGS. 20A-20D are optical micrographs of R-MDMA HCl Pattern A, FIG. 20A is at 4× without oil, FIG. 20B is at 10× objective without oil, FIG. 20C is at 4× objective with oil, and FIG. 20D is at 10× objective with oil;

FIG. 21 is a representation of the asymmetric unit of the R-MDMA hydrochloride structure as determined by single crystal x-ray diffraction;

FIG. 22 is a representation of the crystal packing of the R-MDMA hydrochloride as determined by single crystal x-ray diffraction;

FIG. 23 is an overlay of the XRPD Diffractograms of R-MDMA maleate isolated from IPA (top, low crystallinity), an attempted hemi-salt from ethanol (middle, Pattern A), and a mono salt isolated from THF (bottom, Pattern A);

FIG. 24 is an overlay of the XRPD Diffractograms of R-MDMA maleate Pattern A isolated from THF (top, lower crystallinity), IPA (middle), and DCM (bottom);

FIG. 25 is an overlay of the XRPD Diffractograms of R-MDMA hemi-meso tartrate isolated from THF (top, mix of Patterns A and C), DCM (middle, Pattern A), and THF (bottom, Pattern B);

FIG. 26 is an XRPD Diffractogram of R-MDMA citrate;

FIG. 27 is an overlay of the XRPD Diffractograms of R-MDMA phosphate isolated from THF (top, Pattern C), IPA (middle, Pattern A), and DCM (bottom, Pattern B),

FIG. 28 is an overlay of the XRPD Diffractograms of R-MDMA hemi-naphthylene-1,5-disulphonate isolated from THF (top), IPA (middle), and DCM (bottom);

FIG. 29 is an overlay of the XRPD Diffractograms of R-MDMA sulfate Pattern B (top) and Pattern A (bottom) both isolated from DCM;

FIG. 30 is an overlay of the XRPD Diffractograms of R-MDMA mesylate isolated from THF (top) and DCM (bottom);

FIG. 31 is an overlay of the XRPD Diffractograms of R-MDMA acetate isolated from THF (top) and DCM (bottom);

FIG. 32 is an overlay of the XRPD Diffractograms of R-MDMA oxalate isolated from IPA (top), THF (middle), and DCM (bottom);

FIG. 33 is an XPRD Diffractogram of R-MDMA HBr pattern B;

FIG. 34 is an XPRD Diffractogram of R-MDMA phosphate pattern A;

FIG. 35 is an XPRD Diffractogram of R-MDMA phosphate pattern B;

FIG. 36 is an XPRD Diffractogram of R-MDMA tartrate pattern A;

FIG. 37 is an XPRD Diffractogram of R-MDMA tartrate pattern B;

FIG. 38 is an XPRD Diffractogram of R-MDMA maleate pattern A;

FIG. 39 is an XPRD Diffractogram of R-MDMA L-maleate pattern A;

FIG. 40 is an XPRD Diffractogram of R-MDMA hemi-napthylene-1,5-disulfonate pattern A;

FIG. 41 is an XPRD Diffractogram of R-MDMA hemi-fumarate pattern A;

FIG. 42 is an XPRD Diffractogram of R-MDMA oxalate pattern A;

FIG. 43 is an XPRD Diffractogram of R-MDMA sulfate pattern A;

FIG. 44 is an XPRD Diffractogram of R-MDMA sulfate pattern B;

FIG. 45 is an XPRD Diffractogram of R-MDMA mesylate pattern A; and

FIG. 46 is an XPRD Diffractogram of R-MDMA acetate pattern A.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for salts and polymorphs of R-MDMA, which can be used to prepare a stable crystalline form of R-MDMA for an appropriate scale for manufacture and to use in treatments.

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, hemi-naphthylene-1,5-disulphonate, hemi-fumarate, sulfate, mesylate, acetate, hemi-oxalate, or oxalate. More specifically, the salt can be in a particular 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, 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, hemi naptheylene-1,5-disulfonate pattern A, hemi naptheylene-1,5-disulfonate pattern B, hemi-oxalate pattern A, hemi-oxalate pattern A′, hemi-fumarate pattern A, hemi-fumarate pattern A′, mesylate pattern A, acetate pattern A, citrate pattern A, fumarate pattern A, or oxalate pattern A.

As further detailed below, when the acid is hydrochloric acid, the crystalline form can be 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. When the acid is hydrobromic acid, the crystalline form pattern A can be 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. When the acid is phosphoric acid, the crystalline form pattern C can be 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. 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 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 hemi-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 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 hemi-salt.

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 expressed 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 expressed 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 expressed 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 napthylene-1,5-disulfonic acid, the crystalline form can be 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. The salt can also be a hem i-salt. When the acid is oxalic acid, the crystalline form can be 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. When the acid is sulfuric acid, the crystalline form pattern A can be 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. 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.

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

The composition can also include prodrugs of salts or polymorphs of R-MDMA. A “prodrug” as used herein, refers to a compound that includes a moiety attached to an active drug substance that is metabolized after administration to an individual and the compound is converted into the active drug substance. Using a prodrug allows for improving how the active drug is absorbed, distributed, metabolized, and excreted. Prodrugs can be used to prevent release of the active drug in the gastrointestinal tract upon administration so that the drug can be released more favorably elsewhere in the body.

The prodrug compound includes a chemical modification to salt or polymorph of R-MDMA, such as an amino acid covalently attached thereto. The addition of the amino acid makes the active compound inactive mainly by preventing interaction with monoamine transporter, which is the site of action but also affecting bioavailability/rate of absorption. The amino acid can be lysine or any other amino acid 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 typically attached to the amine (N)-group of R-MDMA and hence reducing pharmacological activity at the primary site of action (cell-membrane monoamine transporters including serotonin, dopamine and norepinephrine transporter), and also altering extent and rate of absorption and mainly releasing active substance in the circulation after absorption of the inactive compound. The amino acid can be any other natural or synthetic amino acid. Any other chemical modification can also be used.

Using a salt or polymorph of R-MDMA allows for daily use. The compositions are particularly useful in continual slow-release formulations, such as transdermal patches, that can provide a low dose over a long period of time. The compositions can also be administered in an intranasal spray. The composition can also be in a liquid dosage form such as, but not limited to, suspensions, solutions, emulsions, elixirs, tinctures, sprays, syrups, gels, magmas, liniments, lotions, ointments, pastes, drops, or inhalants. The composition can be in a solid dosage form such as, but not limited to, capsules, films, lozenge, patch, powder, tablets, pellets, pills, or troches.

The compound of the present invention is administered and dosed in accordance with good medical practice, considering the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners. The pharmaceutically “effective amount” for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.

In the method of the present invention, the compound of the present invention can be administered in various ways. It should be noted that it can be administered as the compound and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles. The compounds can be administered orally, subcutaneously, or parenterally including sublingual, buccal, inhalation, intravenous, intramuscular, and intranasal administration. Implants of the compounds are also useful. The patient being treated is a warm-blooded animal and, in particular, mammals including man. The 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 material not reacting with the active ingredients of the invention.

The doses can be single doses or multiple doses over a period of several days, weeks or months. The treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated.

When administering the compound of the present invention orally, it will generally be formulated in an immediate release capsule, immediate release tablet, modified release capsule or tablet (including enteric coatings), solution or suspension. When administering the compound of the present invention parenterally, it will generally be formulated in a sublingual or buccal orally dissolving tablet, dissolving film, intranasal powder, intranasal solution, inhaled powder, inhaled solution, transdermal patch, transdermal patch with microneedles or other permeation enhancers, or as a unit dosage injectable form (solution, suspension, emulsion). The 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 a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Nonaqueous vehicles such a cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions. Additionally, various additives which enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it will be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.

Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.

A pharmacological formulation of the present invention can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include: U.S. Pat. Nos. 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.

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

Specifically, the compositions can be used in treating medical disorders or conditions including post-traumatic stress disorder, social anxiety, autism spectrum disorder, substance use disorder, depression, anxiety disorder, anxiety with life-threatening disease, personality disorder including narcistic or antisocial personality disorder, schizophrenia, obsessive compulsive disorder, couple therapy, enhancement of any psychotherapy by inducing feelings of well-being connectivity, trust, love, empathy, openness, and pro-sociality, and enhancing therapeutic bond in any psychotherapy of patients or neurotic/healthy subjects.

The invention is further described in detail by reference to the following experimental examples. These examples are provided for the purpose of illustration only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass all variations which become evident as a result of the teaching provided herein.

EXAMPLE 1

General Procedure for the Preparation of Salts of R-MDMA

A salt screen was conducted using stock solutions of each acid prepared as indicated in Table 1. A stock solution of R-MDMA free base (1 g) in IPA (10 ml) was prepared at ambient temperature. Aliquots (0.4 ml, ˜30 mg) of the solution were charged to crystallization tubes. The solutions were heated to 50° C. and the relevant acid charged (1 equivalent) in one single aliquot. The solutions were equilibrated at 50° C. for 1 hour and then cooled to ambient temperature and equilibrated for 24 hours. Where suspensions were obtained, solids were isolated by filtration and dried in vacuo at 45° C. Where solutions persisted, further manipulation was required to obtain an isolable solid. The following methods were used primarily to induce crystallization and/or obtain a solid:

Reduction of solvent volume to ˜50% under a steady stream of nitrogen

Cooling to 0° C. and sub 0° C.

Addition of anti-solvent (MTBE) at ambient temperature followed by equilibration

Removal of solvent by a steady stream of nitrogen

Repeat scratching and trituration of resulting residue with MTBE followed by equilibration of solids where a suspension was obtained.

TABLE 1
Acid	Solvents(s)	Molarity	Result
Hydrochloric	IPA, DCM, THF	1M	Successful Salt Formation
Methane sulfonic	DCM, THF	1M	Successful Salt Formation
Maleic	IPA, THF	1M	Successful Salt Formation
(−)-(L)-Malic	IPA, DCM, THF	1M	Successful Salt Formation
L-Tartaric	IPA, DCM, THF	0.5M	Unsuccessful
D-Tartaric	IPA, DCM, THF	0.5M	Successful Salt Formation
Meso-Tartaric	THF	0.5M	Successful Salt Formation
Citric	IPA	0.5M	Successful Salt Formation
Succinic	IPA, DCM, THF	1M	Unsuccessful
Acetic	DCM, THF	1M	Successful Salt Formation
p-Toluenesulfonic	IPA, DCM, THF	1M	Unsuccessful
Sulfuric	DCM	1M	Successful Salt Formation
Phosphoric	IPA, DCM, THF	1M	Successful Salt Formation
Benzenesulfonic	IPA, THF	1M	Unsuccessful
Xinafoic	IPA, DCM, THF	0.5M	Unsuccessful
Hydrobromic	IPA, DCM, THF	1M	Successful Salt Formation
Oxalic	IPA, DCM, THF	1M	Successful Salt Formation
L-Aspartic	IPA, DCM, THF	Added as solid	Unsuccessful
Naphthylene-	IPA, DCM, THF	1M	Successful Salt Formation
1,5-disulfonic
L-Glutamic	IPA, DCM, THF	Added as solid	Unsuccessful
Malonic	IPA, DCM, THF	1M	Unsuccessful
Fumaric	IPA, DCM, THF	0.25M	Successful Salt Formation
D-glucuronic	IPA, DCM, THF	Added as solid	Unsuccessful
Benzoic	IPA, DCM, THF	1M	Unsuccessful
Gentisic	IPA, DCM, THF	1M	Unsuccessful

XRPD patterns for R-MDMA Maleate, R-MDMA L-Malate, R-MDMA Hemi Meso-tartrate, R-MDMA Citrate, R-MDMA Phosphate, R-MDMA Hemi Naphthylene-1,5-disulfonic, R-MDMA Sulfate, R-MDMA Mesylate, R-MDMA acetate, and R-MDMA Oxalate are shown in FIGS. 23-32.

FIG. 23 shows an overlay of the XRPD Diffractograms of R-MDMA maleate isolated from IPA (top, low crystallinity), an attempted hemi-salt from ethanol (middle, Pattern A), and a mono salt isolated from THF (bottom, Pattern A). FIG. 24 shows an overlay of the XRPD Diffractograms of R-MDMA maleate Pattern A isolated from THF (top, lower crystallinity), IPA (middle), and DCM (bottom). FIG. 25 shows an overlay of the XRPD Diffractograms of R-MDMA hemi-meso tartrate isolated from THF (top, mix of Patterns A and C), DCM (middle, Pattern A), and THF (bottom, Pattern B). FIG. 26 shows an XRPD Diffractogram of R-MDMA citrate. FIG. 27 shows an overlay of the XRPD Diffractograms of R-MDMA phosphate isolated from THF (top, Pattern C), IPA (middle, Pattern A), and DCM (bottom, Pattern B). FIG. 28 shows an overlay of the XRPD Diffractograms of R-MDMA hemi-naphthylene-1,5-disulphonate isolated from THF (top), IPA (middle), and DCM (bottom). FIG. 29 shows an overlay of the XRPD Diffractograms of R-MDMA sulfate Pattern B (top) and Pattern A (bottom) both isolated from DCM. FIG. 30 shows an overlay of the XRPD Diffractograms of R-MDMA mesylate isolated from THF (top) and DCM (bottom). FIG. 31 shows an overlay of the XRPD Diffractograms of R-MDMA acetate isolated from THF (top) and DCM (bottom). FIG. 32 shows an overlay of the XRPD Diffractograms of R-MDMA oxalate isolated from IPA (top), THF (middle), and DCM (bottom).

EXAMPLE 2

R-MDMA HCl salt pattern A was prepared. An XRPD pattern is shown in FIG. 1. A ¹H NMR spectrum is shown in FIG. 2. A combined DSC/TGA thermograph is shown in FIG. 3. FIG. 4 shows a DVS profile and FIG. 5 shows XRPD patterns at ambient conditions, 0% relative humidity, and 90% relative humidity. TABLE 2 shows a XRPD peak list. Optical micrographs of R-MDMA HCl Pattern A are shown in FIGS. 20A-20D.

TABLE 2
Pos. [°2Theta]	Height [counts]	Rel. Int. [%]
5.5572*	291.82	4.27
7.8827	303.15	4.44
13.0575	86.93	1.27
14.1008	946.68	13.86
15.7291	860.20	12.59
15.8412	759.13	11.11
17.0695	560.49	8.20
17.4818	4848.55	70.97
19.7197	1722.78	25.22
20.7449	597.90	8.75
23.4371	657.45	9.62
24.7634	6831.40	100.00
24.9204	3673.06	53.77
26.0998	683.36	10.00
26.3478	467.14	6.84
26.8603	805.20	11.79
27.5765	227.72	3.33
28.4073	222.71	3.26
28.8410	216.13	3.16
29.1771	1023.13	14.98
29.4932	207.05	3.03
29.8012	106.04	1.55
30.7479	171.63	2.51
32.0077	28.83	0.42
32.7288	166.61	2.44
33.2899	149.29	2.19
34.4468	285.79	4.18
*The peak at 5.5572°2Theta is due the Kapton film used in the analysis and not related to R-MDMA HCl salt pattern A

EXAMPLE 3

R-MDMA HBr salt pattern A was prepared. An XRPD pattern is shown in FIG. 6A. A ¹H NMR spectrum is shown in FIG. 6B. A combined DSC/TGA thermograph is shown in FIG. 6C. FIG. 7 shows a DVS profile and FIG. 8 shows XRPD patterns at ambient conditions, 0% relative humidity, and 90% relative humidity. TABLE 3 shows a peak list.

TABLE 3
Pos. [°2Theta]	Height [counts]	Rel. Int. [%]
5.4037*	193.12	4.10
8.1368	478.42	10.16
12.6551	138.47	2.94
13.8761	1419.09	30.13
14.1061	265.63	5.64
15.0068	72.04	1.53
15.8255	673.12	14.29
16.2976	3244.46	68.89
16.9357	3894.80	82.70
17.4881	1321.50	28.06
19.8312	1577.27	33.49
20.5034	2006.71	42.61
20.7460	721.21	15.31
22.5278	159.84	3.39
23.7268	624.79	13.27
23.9884	4709.46	100.00
24.7697	987.25	20.96
24.9285	1036.96	22.02
25.4358	1019.65	21.65
25.9121	831.36	17.65
26.3210	992.66	21.08
26.8753	287.39	6.10
27.0681	227.78	4.84
27.9188	1034.56	21.97
28.4310	867.91	18.43
29.2394	577.73	12.27
31.2105	567.68	12.05
32.9325	447.82	9.51
33.2103	886.35	18.82
34.2108	582.02	12.36
34.8349	570.16	12.11
*The peak at 5.4037°2Theta is due the Kapton film used in the analysis and not related to R-MDMA HBr salt Pattern A

EXAMPLE 4

R-MDMA Phosphate salt pattern C was prepared. An XRPD pattern is shown in FIG. 9A. A ¹H NMR spectrum is shown in FIG. 9B. A combined DSC/TGA thermograph is shown in FIG. 9C. FIG. 10A shows a DVS profile and FIG. 10B shows XRPD patterns at ambient conditions, 0% relative humidity, and 90% relative humidity. TABLE 4 shows a peak list.

TABLE 4
Pos. [°2Theta]	Height [counts]	Rel. Int. [%]
5.5933*	314.26	3.71
6.7120	1463.62	17.29
11.0061	117.13	1.38
12.4581	214.70	2.54
13.4401	3376.34	39.89
14.5831	5178.19	61.18
15.8037	309.37	3.66
17.0318	752.37	8.89
17.4296	3585.24	42.36
17.6959	1623.41	19.18
17.9810	1155.77	13.66
18.2968	1122.82	13.27
18.6521	4274.66	50.50
19.2043	2262.49	26.73
19.8418	357.63	4.23
20.1207	858.15	10.14
20.6363	1402.11	16.57
21.3206	1336.33	15.79
22.0698	8463.94	100.00
22.5246	149.77	1.77
23.3717	880.78	10.41
24.1294	1822.51	21.53
24.7174	1023.53	12.09
25.2689	507.17	5.99
25.9310	219.42	2.59
26.7534	571.42	6.75
27.0313	2091.66	24.71
27.6391	430.88	5.09
27.8387	556.84	6.58
28.6081	494.50	5.84
29.3231	872.29	10.31
29.8311	107.90	1.27
31.0937	104.60	1.24
31.8357	229.89	2.72
32.3008	213.60	2.52
32.6420	534.16	6.31
33.0506	164.93	1.95
33.8005	112.81	1.33
34.6870	176.75	2.09
*The peak at 5.5933°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Phosphate salt Pattern C

EXAMPLE 5

R-MDMA D-Tartrate salt pattern C was prepared. An XRPD pattern is shown in FIG. 11A. A ¹H NMR spectrum is shown in FIG. 11B. A combined DSC/TGA thermograph is shown in FIG. 11C. FIG. 12A shows a DVS profile and FIG. 12B shows XRPD patterns at ambient conditions, 0% relative humidity, and 90% relative humidity. TABLE 5 shows a peak list.

TABLE 5
Pos. [°2Theta]	Height [counts]	Rel. Int. [%]
6.0212	2938.98	49.89
12.0299	5890.44	100.00
12.2883	1592.45	27.03
13.3191	5495.43	93.29
14.5373	498.48	8.46
14.9605	455.50	7.73
16.8415	1500.75	25.48
17.1210	1034.74	17.57
17.3873	382.61	6.50
17.8942	5184.48	88.02
18.0921	2151.93	36.53
18.6161	358.40	6.08
19.0778	2800.58	47.54
19.2726	2128.07	36.13
20.1050	87.26	1.48
20.7111	568.66	9.65
21.2597	123.10	2.09
21.6960	1240.97	21.07
21.9990	1304.87	22.15
22.6411	880.09	14.94
22.7879	919.72	15.61
23.3431	121.84	2.07
23.8329	618.92	10.51
24.1016	2992.56	50.80
24.7982	685.38	11.64
25.6629	1603.44	27.22
26.7730	1490.93	25.31
26.9182	2487.28	42.23
27.1711	1401.38	23.79
27.4342	2391.16	40.59
28.4098	978.38	16.61
29.4454	1002.79	17.02
29.8441	273.66	4.65
30.1732	416.26	7.07
30.8702	327.30	5.56
30.9955	482.52	8.19
32.2250	162.51	2.76
32.4730	216.94	3.68
34.1810	645.27	10.95
34.3229	648.62	11.01

EXAMPLE 6

R-MDMA Hemi Fumarate salt pattern A was prepared. An XRPD pattern is shown in FIG. 13A. A ¹H NMR spectrum is shown in FIG. 13B. A combined DSC/TGA thermograph is shown in FIG. 13C. FIG. 14A shows a DVS profile and FIG. 14B shows XRPD patterns at ambient conditions, 0% relative humidity, and 90% relative humidity. TABLE 6 shows a peak list.

TABLE 6
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
5.5483*	269.35	3.52
8.2947	418.13	5.46
10.8354	990.17	12.94
12.0372	135.26	1.77
13.1509	1529.52	19.98
13.6854	155.72	2.03
15.0461	104.18	1.36
16.4206	735.65	9.61
16.6360	2191.31	28.63
16.9358	118.80	1.55
17.2348	3012.02	39.35
17.7440	319.13	4.17
18.5506	7654.08	100.00
19.2196	2936.93	38.37
19.5403	2961.63	38.69
19.8161	766.34	10.01
20.2385	740.34	9.67
21.7576	7237.01	94.55
22.1034	901.37	11.78
22.5160	223.02	2.91
23.1352	136.99	1.79
23.6121	1698.78	22.19
24.8289	1172.82	15.32
25.1156	657.29	8.59
25.7098	2446.33	31.96
26.6211	842.48	11.01
27.5786	463.47	6.06
28.0091	792.27	10.35
28.4639	1794.27	23.44
28.9710	1111.17	14.52
29.3666	242.11	3.16
29.9828	172.98	2.26
30.3189	107.74	1.41
31.2008	216.96	2.83
31.8310	626.80	8.19
32.1818	155.46	2.03
32.5820	209.01	2.73
32.8981	277.16	3.62
33.6505	280.07	3.66
34.0118	217.23	2.84
*The peak at 5.5483°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Hemi Fumarate salt pattern A

EXAMPLE 7

R-MDMA Hemi Oxalate salt pattern A/A′ was prepared. An XRPD pattern is shown in FIG. 15. A ¹H NMR spectrum is shown in FIG. 16. A combined DSC/TGA thermograph is shown in FIG. 17. FIG. 18 shows a DVS profile and FIG. 19 shows XRPD patterns at ambient conditions, 0% relative humidity, and 90% relative humidity. TABLE 7 shows a peak list.

TABLE 7
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
5.6067*	286.38	23.80
10.5240	814.71	67.72
13.8857	217.12	18.05
15.0254	750.40	62.37
15.2341	1203.14	100.00
15.4706	262.50	21.82
16.3578	952.81	79.19
16.5902	461.18	38.33
16.7826	930.69	77.36
16.9482	889.44	73.93
17.1771	927.09	77.06
17.5576	230.64	19.17
18.3303	457.58	38.03
18.5269	659.50	54.81
19.1292	505.95	42.05
19.3374	1097.72	91.24
19.8244	405.47	33.70
19.9946	624.36	51.89
20.5402	572.37	47.57
20.8923	305.06	25.36
21.3494	969.08	80.55
21.6811	538.58	44.76
21.8436	440.02	36.57
22.2062	290.71	24.16
23.9886	896.22	74.49
24.9100	272.08	22.61
25.8815	306.79	25.50
26.1479	215.23	17.89
26.5164	174.95	14.54
26.9530	98.31	8.17
27.4310	146.16	12.15
27.9933	498.22	41.41
28.5682	298.73	24.83
29.2594	170.43	14.17
29.9849	78.87	6.56
31.6716	110.60	9.19
33.1333	108.36	9.01
34.2308	195.88	16.28
*The peak at 5.6067°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Hemi Oxalate salt pattern A/A′

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 heated to 40° C. The resulting solution was clarified via a 0.45 μm filter and allowed to age allowing for solvent egress. Once suitable crystal growth had occurred, the crystal structure of R-MDMA HCl Form 1 was determined from data measured at low temperature (100 K) and at a wavelength of 1.54180 Å. R-MDMA HCl crystallizes in the monoclinic space group P2₁. In the asymmetric unit, one monocationic (R)-MDMA and one chloride anion were found (overall ratio 1:1) as shown in FIG. 21 and crystal packing was found as shown in FIG. 22.

EXAMPLE 9

R-MDMA HBr salt pattern B was prepared. TABLE 8 shows XPRD peak data for HBr pattern B. FIG. 33 shows the XPRD pattern.

TABLE 8
Pos. [°2Theta]	Height [counts]	Rel. Int. [%]
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
*The peak at 5.6128°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Hydrobromide salt Pattern B

EXAMPLE 10

R-MDMA phosphate salt pattern A was prepared. TABLE 9 shows XPRD peak data for phosphate pattern A. FIG. 34 shows the XPRD data.

TABLE 9
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
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
*The peak at 5.5661°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Phosphate salt Pattern A

EXAMPLE 11

R-MDMA phosphate salt pattern B was prepared. TABLE 10 shows XPRD peak data for phosphate pattern B. FIG. 35 shows the XPRD data.

TABLE 10
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
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
*The peak at 5.6096°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Phosphate salt Pattern B

EXAMPLE 12

R-MDMA tartrate salt pattern A was prepared. TABLE 11 shows XPRD peak data for tartrate pattern A. FIG. 36 shows the XPRD data.

TABLE 11
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
3.2852	180.25	6.37
5.6552	2830.79	100.00
11.3164	1860.27	65.72
11.5095	384.03	13.57
13.2902	817.14	28.87
14.0055	117.25	4.14
15.4044	1631.13	57.62
16.8794	352.65	12.46
17.2467	1375.03	48.57
17.8497	938.46	33.15
18.4594	310.23	10.96
19.0778	138.72	4.90
21.3487	925.62	32.70
21.7886	105.41	3.72
22.7414	396.37	14.00
23.5663	91.55	3.23
25.7552	327.96	11.59
26.3722	751.63	26.55
27.5549	83.66	2.96
28.0300	147.14	5.20
28.6545	118.65	4.19
29.7989	95.18	3.36
30.9490	142.05	5.02
32.8387	79.81	2.82
33.7321	88.26	3.12
34.4586	84.37	2.98

EXAMPLE 13

R-MDMA tartrate salt pattern B was prepared. TABLE 12 shows XPRD peak data for tartrate pattern B. FIG. 37 shows the XPRD data.

TABLE 12
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
5.1154	3836.59	39.19
10.2367	452.95	4.63
13.3392	165.32	1.69
14.4193	1284.46	13.12
14.8706	875.43	8.94
15.2430	1009.91	10.32
15.3823	997.71	10.19
16.3008	1600.39	16.35
16.9403	200.64	2.05
17.3228	305.39	3.12
18.4550	411.49	4.20
19.2838	9790.36	100.00
20.3663	4552.07	46.5
20.7318	1112.48	11.36
21.0086	956.01	9.76
21.3581	927.69	9.48
21.7890	5956.64	60.84
22.0242	1250.14	12.77
22.2842	1441.90	14.73
22.8432	143.22	1.46
23.4631	290.74	2.97
24.1102	705.71	7.21
24.6539	71.37	0.73
25.1504	525.50	5.37
25.6056	80.56	0.82
26.2284	516.33	5.27
26.9493	317.97	3.25
27.2705	795.07	8.12
27.7912	73.29	0.75
28.4469	39.49	0.40
29.6258	363.6	3.71
31.0092	233.51	2.39
31.9570	251.63	2.57
32.4271	510.96	5.22
32.6872	508.76	5.20
33.1162	267.26	2.73
33.3847	360.55	3.68
34.1111	573.99	5.86
34.5103	412.42	4.21

EXAMPLE 14

R-MDMA maleate salt pattern A was prepared. TABLE 13 shows XPRD peak data for maleate pattern A. FIG. 38 shows the XPRD data.

TABLE 13
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
5.5552*	273.38	8.75
10.0668	692.83	22.17
13.2926	129.00	4.13
14.9329	3124.99	100.00
15.2652	759.40	24.30
18.0407	1852.08	59.27
20.0928	64.96	2.08
20.8947	241.03	7.71
21.5717	150.79	4.83
24.1232	114.63	3.67
24.7935	578.76	18.52
25.2140	956.81	30.62
25.9166	1320.52	42.26
26.8599	760.13	24.32
27.9146	1394.9	44.64
29.0481	606.03	19.39
29.9241	56.38	1.80
30.5025	95.43	3.05
30.8645	260.87	8.35
31.4425	61.83	1.98
31.8066	172.01	5.5
32.0353	258.38	8.27
33.0096	146.53	4.69
34.1256	54.76	1.75
*The peak at 5.5552°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Maleate salt Pattern A

EXAMPLE 15

R-MDMA L-malate salt pattern A was prepared. TABLE 14 shows XPRD peak data for L-maleate pattern A. FIG. 39 shows the XPRD data.

TABLE 14
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
5.5662*	292.17	32.94
11.8203	89.59	10.10
13.0800	267.20	30.13
13.8024	250.56	28.25
14.6599	118.72	13.39
17.1997	448.66	50.59
17.8007	488.07	55.03
18.0922	753.52	84.97
18.8774	156.25	17.62
19.2735	886.85	100.00
20.8354	459.27	51.79
22.6889	117.28	13.22
23.4077	392.35	44.24
24.1732	315.49	35.57
25.2252	248.48	28.02
26.5473	505.03	56.95
27.2672	563.85	63.58
27.8003	66.12	7.46
28.0832	103.59	11.68
29.1725	132.38	14.93
29.4901	100.28	11.31
29.8761	69.89	7.88
30.5450	162.99	18.38
32.1611	355.32	40.07
32.7232	145.17	16.37
34.0007	37.84	4.27
*The peak at 5.5662°2Theta is due the Kapton film used in the analysis and not related to R-MDMA L-Malate salt Pattern A

EXAMPLE 16

R-MDMA hemi-napthylene-1,5-disulfonate salt pattern A was prepared. TABLE 15 shows XPRD peak data for hemi-napthylene-1,5-disulfonate pattern A. FIG. 40 shows the XPRD data.

TABLE 15
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
3.4561	419.96	21.00
4.0704	949.76	47.5
5.6688*	513.72	25.69
8.1471	280.45	14.03
10.8199	335.14	16.76
12.2179	527.28	26.37
12.9164	470.99	23.56
14.6460	1342.90	67.17
15.2155	1383.32	69.19
15.5027	337.18	16.86
15.8180	1195.41	59.79
16.0875	882.96	44.16
16.8031	1999.40	100.00
17.9332	330.84	16.55
18.5420	202.07	10.11
19.0754	620.78	31.05
19.6194	436.41	21.83
20.1116	881.05	44.07
20.4433	463.25	23.17
21.3968	463.79	23.2
21.9571	471.27	23.57
22.8863	1155.37	57.79
23.3282	365.48	18.28
23.5957	580.06	29.01
24.2285	630.66	31.54
24.5715	307.64	15.39
25.0337	380.22	19.02
25.3534	590.37	29.53
26.0402	510.36	25.53
26.6543	294.38	14.72
27.0299	183.06	9.16
27.5965	112.22	5.61
28.7697	261.99	13.10
29.1905	191.75	9.59
29.5317	597.13	29.87
29.8224	326.38	16.32
30.6671	128.02	6.40
31.2694	53.00	2.65
32.0042	120.94	6.05
32.4960	121.27	6.07
33.4625	55.65	2.78
*The peak at 5.6688°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Hemi-napthylene-1,5-disulfonate salt Pattern A

EXAMPLE 17

R-MDMA hemi-fumarate salt pattern A was prepared. TABLE 16 shows XPRD peak data for hemi-fumarate pattern A. FIG. 41 shows the data.

TABLE 16
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
5.6776*	292.45	10.66
8.2781	130.39	4.75
10.8097	318.67	11.61
13.1373	489.36	17.83
14.8913	236.12	8.61
16.6141	892.35	32.52
17.2125	958.49	34.93
17.7134	382.08	13.92
18.5047	2743.94	100.00
19.2044	916.14	33.39
19.5173	145.41	5.30
20.1977	233.44	8.51
20.9529	330.48	12.04
21.7168	2519.34	91.81
22.0799	316.38	11.53
22.8318	102.23	3.73
23.5645	511.81	18.65
24.1374	108.44	3.95
24.7768	392.14	14.29
25.0545	210.88	7.69
25.6702	893.91	32.58
26.5823	270.95	9.87
27.5938	114.09	4.16
27.9523	314.15	11.45
28.4305	528.14	19.25
28.9354	333.05	12.14
29.346	65.45	2.39
29.8385	102.76	3.75
31.1497	41.65	1.52
31.7937	281.98	10.28
32.514	85.19	3.10
32.8481	106.13	3.87
33.5784	119.65	4.36
34.0279	79.15	2.88
*The peak at 5.6776°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Hemi-fumarate salt Pattern A

EXAMPLE 18

R-MDMA oxalate salt pattern A was prepared. TABLE 17 shows XPRD peak data for oxalate salt pattern A. FIG. 42 shows the data.

TABLE 17
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
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
*The peak at 5.6800°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Oxalate salt Pattern A

EXAMPLE 19

R-MDMA sulfate salt pattern A was prepared. TABLE 18 shows XPRD peak data for sulfate pattern A. FIG. 43 shows the data.

TABLE 18
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
5.6758*	245.26	23.88
14.9463	600.95	58.50
17.7631	1027.23	100.00
18.0436	405.51	39.48
18.2903	423.73	41.25
21.0072	950.85	92.56
21.2257	579.52	56.42
22.0438	98.43	9.58
22.5929	214.51	20.88
23.2614	78.60	7.65
23.8432	572.53	55.74
24.1647	189.39	18.44
27.8586	61.45	5.98
30.1519	223.72	21.78
31.0970	60.78	5.92
31.8386	64.94	6.32
*The peak at 5.6758°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Sulfate salt Pattern A

EXAMPLE 20

R-MDMA sulfate salt pattern B was prepared. TABLE 19 shows XPRD peak data for sulfate pattern B. FIG. 44 shows the data.

TABLE 19
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
5.6459*	312.53	4.91
7.7484	1117.07	17.56
7.9744	1907.59	30.00
8.1187	1775.86	27.92
11.4236	670.82	10.55
12.9016	147.98	2.33
14.7607	1643.5	25.84
15.5820	1795.78	28.24
16.3703	2304.95	36.24
16.8435	1357.73	21.35
17.2234	1612.83	25.36
17.3999	996.25	15.67
17.5729	569.62	8.96
17.8540	292.85	4.6
18.5197	1650.96	25.96
19.1489	3573.65	56.19
20.0420	384.33	6.04
20.3879	1245.65	19.59
21.2722	284.38	4.47
21.8271	1209.53	19.02
22.5176	934.77	14.70
23.1398	132.61	2.09
23.8579	3730.92	58.67
24.2268	190.38	2.99
24.6091	167.57	2.63
24.8039	367.95	5.79
25.6585	1630.84	25.64
25.9377	6359.64	100.00
26.4666	1409.84	22.17
26.8953	433.68	6.82
27.2082	986.72	15.52
27.5481	570.12	8.96
27.8372	4908.13	77.18
28.4267	362.82	5.71
28.8986	408.14	6.42
29.7543	795.98	12.52
30.2410	1484	23.33
30.4810	637.72	10.03
31.4228	187.52	2.95
32.1925	86.40	1.36
33.0050	131.52	2.07
33.2811	104.29	1.64
34.0216	249.87	3.93
*The peak at 5.6459°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Sulfate salt Pattern B

EXAMPLE 21

R-MDMA mesylate salt pattern A was prepared. TABLE 20 shows XPRD peak data for mesylate pattern A. FIG. 45 shows the data.

TABLE 20
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
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
*The peak at 5.5246°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Mesylate salt Pattern A

EXAMPLE 22

R-MDMA acetate salt pattern A was prepared. TABLE 21 shows XPRD peak data for acetate pattern A. FIG. 46 shows the data.

TABLE 21
Pos. [°2Th.]	Height [cts]	Rel. Int. [%]
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
*The peak at 5.5678°2Theta is due the Kapton film used in the analysis and not related to R-MDMA Acetate salt Pattern A

Throughout this application, various publications, including United States patents, are referenced by author and year and patents by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

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.

Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention can be practiced otherwise than as specifically described.

Claims

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

2. The composition of claim 1, wherein said salt is chosen from the group consisting of hydrochloride, hydrobromide, maleate, L-malate, D-tartrate, hemi-meso-tartrate, hemi-L-tartrate, citrate, phosphate, hemi-naphthylene-1,5-disulphonate, hemi-fumarate, sulfate, mesylate, acetate, hemi-oxalate, and oxalate.

3. The composition of claim 1, wherein said salt is chosen 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 B, D-tartrate pattern C, D-tartrate pattern D, D-tartrate pattern E, L-maleate pattern A, maleate pattern A, maleate pattern B, hemi naptheylene-1,5-disulfonate pattern A, hemi naptheylene-1,5-disulfonate pattern B, hemi-oxalate pattern A, hemi-oxalate pattern A′, hemi-fumarate pattern A, hemi-fumarate pattern A′, mesylate pattern A, acetate pattern A, citrate pattern A, fumarate pattern A, and oxalate pattern A.

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

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

6. The composition of claim 5, wherein said amino acid is chosen 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 form salt or polymorph of R-MDMA and pharmaceutically acceptable excipients.

8. The pharmaceutical composition of claim 7, wherein said salt is chosen from the group consisting of hydrochloride, hydrobromide, maleate, L-malate, D-tartrate, hemi-meso-tartrate, hemi-L-tartrate, citrate, phosphate, hemi-naphthylene-1,5-disulphonate, hemi-fumarate, sulfate, mesylate, acetate, hemi-oxalate, and oxalate.

9. The pharmaceutical composition of claim 7, wherein said salt is chosen 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 B, D-tartrate pattern C, D-tartrate pattern D, D-tartrate pattern E, L-maleate pattern A, maleate pattern A, maleate pattern B, hemi naptheylene-1,5-disulfonate pattern A, hemi naptheylene-1,5-disulfonate pattern B, hemi-oxalate pattern A, hemi-oxalate pattern A′, hemi-fumarate pattern A, hemi-fumarate pattern A′, mesylate pattern A, acetate pattern A, citrate pattern A, fumarate pattern A, and oxalate pattern A.

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

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

12. The pharmaceutical composition of claim 11, wherein said amino acid is chosen 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 said composition is formulated in a continual slow-release formulation.

14. The pharmaceutical composition of claim 13, wherein said composition is formulated in a transdermal patch.

15. The pharmaceutical composition of claim 7, wherein said composition is formulated in an intranasal spray.

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

17. The pharmaceutical composition of claim 7, wherein said composition is formulated in a solid dosage form chosen from the group consisting of capsules, films, lozenge, patch, powder, tablets, pellets, pills, and troches.

18. A method of treating an individual for a medical condition, including the steps of: administering an effective amount of a composition of a crystalline form salt or polymorph of R-MDMA to the individual; andtreating the individual.

19. The method of claim 18, further including the step of preventing or reducing side effects of neurotoxicity, hyperthermia and dependence/addiction experienced with racemic MDMA.

20. The method of claim 18, wherein the medical condition is chosen from the group consisting of post-traumatic stress disorder, social anxiety, autism spectrum disorder, substance use disorder, depression, anxiety disorder, anxiety with life-threatening disease, personality disorder, schizophrenia, obsessive compulsive disorder, couple therapy, enhancement of any psychotherapy by inducing feelings of well-being connectivity, trust, love, empathy, openness, and pro-sociality, and enhancing therapeutic bond in any psychotherapy of patients or neurotic/healthy subjects.

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

22. The method of claim 18, wherein the salt is chosen 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 B, D-tartrate pattern C, D-tartrate pattern D, D-tartrate pattern E, L-maleate pattern A, maleate pattern A, maleate pattern B, hemi naptheylene-1,5-disulfonate pattern A, hemi naptheylene-1,5-disulfonate pattern B, hemi-oxalate pattern A, hemi-oxalate pattern A′, hemi-fumarate pattern A, hemi-fumarate pattern A′, mesylate 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 in a dose of 10-1000 mg.

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

25. The method of claim 18, wherein the composition is formulated in a continual slow-release formulation.

26. The method of claim 25, wherein said composition is formulated in a transdermal patch.

27. The method of claim 18, wherein said composition is formulated in an intranasal spray.

28. The method of claim 18, wherein said composition is formulated in a liquid dosage form chosen from the group consisting of suspensions, solutions, emulsions, elixirs, tinctures, sprays, syrups, gels, magmas, liniments, lotions, ointments, pastes, drops, and inhalants.

29. The method of claim 18, wherein said composition is formulated in a solid dosage form chosen from the group consisting of capsules, films, lozenge, patch, powder, tablets, pellets, pills, and troches.

30. The composition of claim 1, wherein said acid is hydrochloric acid, and said 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 said acid is hydrobromic acid, and said 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 said acid is phosphoric acid, and said 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 said acid is D-tartaric acid, and said 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 said acid is fumaric acid, and said crystalline form is characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Kα x-rays 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 said salt is a hemi-salt.

36. The composition of claim 1, wherein said acid is oxalic acid, and said crystalline form is characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Kα x-rays having peaks expressed as 2θ at about 15.2, about 16.4, about 16.8, about 19.3, and about 21.3.

37. The corn position of claim 33, wherein said salt is a hemi-salt.

38. The composition of claim 1, wherein said acid is hydrobromic acid, and said crystalline form is characterized by an x-ray powder diffraction pattern obtained by irradiation with Cu Kα x-rays 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 said acid is phosphoric acid, and said 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 said acid is phosphoric acid, and said 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 said acid is D-tartaric acid, and said 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 said acid is D-tartaric acid, and said 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 said acid is maleic acid, and said 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 said acid is malic acid, and said crystalline form is 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.

45. The composition of claim 1, wherein said acid is napthylene-1,5-disulfonic acid, and said 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 said salt is a hemi-salt.

47. The composition of claim 1, wherein said acid is oxalic acid, and said 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 said acid is sulfuric acid, and said 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 said acid is methanesulfonic acid, and said 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 said acid is acetic acid, and said 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.