WO2023107931A1 - Salt and solid forms of indole analogs and methods of use thereof - Google Patents

Abstract

Disclosed herein are salts and solid forms of 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and norpsilocin. The solid form may be a salt and/or a crystalline form thereof, such as a polymorph or a salt thereof. Also disclosed are methods for making the solid forms and methods for administering the solid forms. The disclosed solid forms of 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and norpsilocin are useful for treating neurological disease and/or a psychiatric disorder in a subject.

Description

SALT AND SOLID FORMS OF INDOLE ANALOGS AND METHODS OF USE

THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to, and the benefit of, U.S. Provisional Patent Application Nos. 63/286,497, filed December 6, 2021; 63/286,694, filed December 7, 2021; 63/286,652, filed December 7, 2021; 63/288,899, filed December 13, 2021; 63/288,904, filed December 13, 2021; 63/289,773, filed December 15, 2021; 63/289,774, filed December 15, 2021; and 63/289,913, filed December 15, 2021, which are incorporated by reference in their entireties for all purposes.

SUMMARY

Disclosed herein are solid forms of 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and norpsilocin, including salts, solid forms of the compound and salts thereof, as well as polymorphs of solid forms.

Also disclosed are methods for making the solid forms and methods for using the solid forms of 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and norpsilocin. In some embodiments, the solid form of 5-MeO-DALT, 5- MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, or norpsilocin is a polymorph of the free base form of the compound. In other embodiments, the solid form of 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, norpsilocin is a salt, and maybe a polymorph of the salt. The salt may be formed from an acid selected from hydrochloric acid, fumaric acid, galactaric (mucic) acid, naphthalene- 1,5- disulfonic acid, citric acid, sulfuric acid, ^/-glucuronic acid, ethane-l,2-disulfonic acid, lactobionic acid, -toluenesulfonic acid, D-glucoheptonic acid, thiocyanic acid, (-)-Z- pyroglutamic acid, methanesulfonic acid, /.-malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, D-gluconic acid, benzenesulfonic acid, // A-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, Z-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, xinafoic acid, or a combination thereof. In any embodiments, a stoichiometric ratio of acid to 5-MeO- DALT is from about 0.4 to about 2.2, such as from about 0.5 to about 2, or from about 0.5, 1 or 2. In any embodiments, the solid form may be a crystalline solid, a hydrate, or a combination thereof. The crystalline solid may be substantially a single form, such as a polymorph form. And the polymorph may be selected to have one or more desired properties, particularly improved properties, such as physical properties, chemical properties, pharmacokinetic properties, or a combination thereof. The one or more desired properties may comprise melting point, glass transition temperature, flowability, thermal stability, mechanical stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

Also disclosed herein are embodiments, of a pharmaceutical composition, comprising a solid form of a disclosed compound, and a pharmaceutically acceptable excipient.

A method for administering the salts or solid forms described herein (e.g. 5-MeO- DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and/or norpsilocin). In some embodiments, the method comprises administering to a subject an effective amount of a salts or solid forms described herein (e.g. 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and/or norpsilocin), or a pharmaceutical composition thereof. In some embodiments, the subject is suffering from a neurological disease or a psychiatric disorder, or both, such as a neurodegenerative disorder. The neurological disorder or psychiatric disorder, or both, may comprise depression, addiction, anxiety, or a post-traumatic stress disorder, and/or the neurological disorder or psychiatric disorder, or both, may comprise treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

The method may comprise further comprising administering an effective amount of an empathogenic agent and/or a 5-HT2A antagonist to the subject. The 5-HT2A antagonist may be selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL- 100,907, pimavanserin, nelotanserin and lorcaserin.

In any embodiments, administering the solid form of the compound comprises oral, parenteral, or topical administration. In certain embodiments, oral administration is used, but in other particular embodiments, administration is by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION

Definitions

The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms “a,” “an,” and “the” refer to one or more than one, unless the context clearly dictates otherwise. The term “or” refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, “comprises” means “includes.” Thus, “comprising A or B,” means “including A, B, or A and B,” without excluding additional elements. All references, including patents and patent applications cited herein, are incorporated by reference in their entirety, unless otherwise specified.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims, are to be understood as being modified by the term “about.” Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and/or limits of detection under standard test conditions/methods. When directly and explicitly distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word “about” is expressly recited.

Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

“Administering” refers to any suitable mode of administration, including, oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini -osmotic pump, to the subject.

“Subject” refers to an animal, such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human subject.

“Therapeutically effective amount” or “therapeutically sufficient amount” or “effective or sufficient amount” refers to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.

“Neuronal plasticity” refers to the ability of the brain to change its structure and/or function continuously throughout a subject’s life. Examples of the changes to the brain include, but are not limited to, the ability to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses.

“Brain disorder” refers to a neurological disorder which affects the brain’s structure and function. Brain disorders can include, but are not limited to, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, treatment resistant depression, addiction, anxiety, post-traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and substance use disorder.

“Combination therapy” refers to a method of treating a disease or disorder, wherein two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents. For example, the compounds of the invention can be used in combination with other pharmaceutically active compounds. The compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

“Neurotrophic factors” refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons. “Modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., a positive allosteric modulator) of a G protein-coupled receptor (e.g., 5HT2A) are modulators of the receptor.

“Agonism” refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.

“Agonist” refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, “5HT2A agonist” can be used to refer to a compound that exhibits an ECso with respect to 5HT2A activity of no more than about 100 mM. In some embodiments, the term “agonist” includes full agonists or partial agonists. “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor. “Partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.

“Positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.

“Antagonism” refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur.

“Antagonist” or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.

“Composition” refers to a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation.

“Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. 5-MeO-DALT

‘W,7V-diallyl-5-methoxytryptamine” refers to the compound N- [2-(5 -methoxy- 1H- indol-3-yl)ethyl]-7V-prop-2-enylprop-2-en-l-amine. The compound may also be referred to as 5-methoxy-N,N-diallyl-lH-indole-3-ethanamine, 5-methoxy DALT, or 5-MeO-DALT.

5-MeO-DALT

Disclosed herein are solid forms of 7V,7V-diallyl-5-methoxytryptamine (5-MeO-DALT) that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms of 5-MeO-DALT and method of administering the solid forms of 5-MeO-DALT.

In some embodiments, the solid form of the compound is a crystalline form of 5- MeO-DALT. In some embodiments, the solid form of the compound is a salt of the compound. In some embodiments, the solid form of 5-MeO-DALT is a polymorph of 5- MeO-DALT, such as a polymorph of the free base compound or a polymorph of the salt. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.

A) Salts

In some embodiments, the solid form of 5-MeO-DALT comprises a salt of 5-MeO- DALT. Suitable salts include a pharmaceutically acceptable salt of 5-MeO-DALT. In some embodiments, the salt is not a hydrochloride salt of 5-MeO-DALT. In some embodiments, the salt of 5-MeO-DALT may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, /?-toluenesulfonic acid, salicylic acid, xinafoic acid and the like. In other embodiments, the salt of 5-MeO-DALT may be formed from a suitable pharmaceutically acceptable base, including, without limitation, inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tri s(hydroxymethyl)aminom ethane (Tris), ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference. In some embodiments, the salt may be formed using an acid from the table below.

In some embodiments, the acid is not hydrochloric acid.

The acid salts of 5-MeO-DALT disclosed herein can have any suitable stoichiometric ratio of acid to 5-MeO-DALT. In one embodiment, the molar ratio of acid to 5-MeO-DALT is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to 5-MeO-DALT of from about 0.5 to about 2, such as about 0.5, about 1 or about 2.

B) Solid forms

Embodiments of 5-MeO-DALT of the present disclosure are in a solid form. The solid form may be a crystalline form or an amorphous form. In some embodiments, the solid form is a crystalline form, such as a polymorph. In some embodiments, the solid form of 5- MeO-DALT is a salt. And in certain embodiments, the solid form is a crystalline salt form of the compound. A person of ordinary skill in the art understands that solid forms of 5-MeO- DALT such as crystalline forms including salt and non-salt crystalline forms of 5-MeO- DALT, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compounds are particular polymorphs of 5-MeO-DALT or 5-MeO-DALT salts.

In some embodiments, the solid form of 5-MeO-DALT disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of 5-MeO-DALT that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of 5-MeO-DALT. The 5-MeO-DALT may be a salt or free base compound. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.

The desired polymorph may be produced by techniques known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent.

Techniques to identify a particular solid form of 5-MeO-DALT are known to persons of ordinary skill in the art, and include, but are not limited to, X-ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and/or melting point.

5-MeO-DMT

“5-MeO-DMT” refers to the compound 2-(5-methoxy-U/-indol-3-yl)-A,A- dimethylethanamine. The compound may also be referred to as 5-methoxy dimethyl tryptamine, A,7V-dimethyl-5-methoxytryptamine, 5-methoxy-A,A-dimethyltryptamine, or 3- (2-(7V,A-dimethylamino)ethyl)-5-methoxyindole.

5-MeO-DMT

Disclosed herein are solid forms of 5-MeO-DMT that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms of 5-MeO-DMT and method of administering the solid forms of 5-MeO-DMT.

In some embodiments, the solid form of the compound is a crystalline form of 5- MeO-DMT. In some embodiments, the solid form of the compound is a salt of the compound. In some embodiments, the solid form of 5-MeO-DMT is a polymorph of 5-MeO- DMT, such as a polymorph of the free base compound or a polymorph of the salt. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.

A) Salts

In some embodiments, the solid form of 5-MeO-DMT comprises a salt of 5-MeO- DMT. Suitable salts include a pharmaceutically acceptable salt of 5-MeO-DMT. In some embodiments, the salt is not a hydrochloride salt of 5-MeO-DMT. In other embodiments, the salt is not an oleate salt of 5-MeO-DMT. In some embodiments, the salt of 5-MeO-DMT may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, - toluenesulfonic acid, salicylic acid, xinafoic acid and the like.

In other embodiments, the salt of 5-MeO-DMT may be formed from a suitable pharmaceutically acceptable base, including, without limitation, inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tri s(hydroxymethyl)aminom ethane (Tris), ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference.

In some embodiments, the salt may be formed using an acid from the table below.

In some embodiments, the acid is not hydrochloric acid.

In other embodiments, the acid is not oleic acid.

The acid salts of 5-MeO-DMT disclosed herein can have any suitable stoichiometric ratio of acid to 5-MeO-DMT. In one embodiment, the molar ratio of acid to 5-MeO-DMT is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to 5-MeO-DMT of from about 0.5 to about 2, such as about 0.5, about 1 or about 2. B) Solid forms

Embodiments of 5-MeO-DMT of the present disclosure are in a solid form. The solid form may be a crystalline form or an amorphous form. In some embodiments, the solid form is a crystalline form, such as a polymorph. In some embodiments, the solid form of 5-MeO- DMT is a salt. And in certain embodiments, the solid form is a crystalline salt form of the compound. A person of ordinary skill in the art understands that solid forms of 5-MeO-DMT such as crystalline forms including salt and non-salt crystalline forms of 5-MeO-DMT, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compounds are particular polymorphs of 5-MeO-DMT or 5-MeO-DMT salts.

In some embodiments, the solid form of 5-MeO-DMT disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of 5-MeO-DMT that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of 5-MeO-DMT. The 5-MeO-DMT may be a salt or free base compound. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.

The desired polymorph may be produced by techniques known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent.

Techniques to identify a particular solid form of 5-MeO-DMT are known to persons of ordinary skill in the art, and include, but are not limited to, X-ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and/or melting point. Aeruginascin

“Aeruginascin” refers to the compound [3-[2-(trimethylazaniumyl)ethyl]-l/7-indol-4- yl] hydrogen phosphate.

Aeruginascin

Disclosed herein are solid forms of aeruginascin that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms of aeruginascin and method of administering the solid forms of aeruginascin.

In some embodiments, the solid form of the compound is a crystalline form of aeruginascin. In some embodiments, the solid form of the compound is a salt of the compound. In some embodiments, the solid form of aeruginascin is a polymorph of aeruginascin, such as a polymorph of the free base compound (zwitterionic) or a polymorph of the salt. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.

A) Salts

In some embodiments, the solid form of aeruginascin comprises a salt of aeruginascin. Suitable salts include a pharmaceutically acceptable salt of aeruginascin. In some embodiments, the salt is not a hydrochloride salt of aeruginascin. In some embodiments, the salt of aeruginascin may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, xinafoic acid and the like.

In other embodiments, the salt of aeruginascin may be formed from a suitable pharmaceutically acceptable base, including, without limitation, inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tri s(hydroxymethyl)aminom ethane (Tris), ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference. In some embodiments, the salt may be formed using an acid from the table below.

In some embodiments, the acid is not hydrochloric acid.

The acid salts of aeruginascin disclosed herein can have any suitable stoichiometric ratio of acid to aeruginascin. In one embodiment, the molar ratio of acid to aeruginascin is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to aeruginascin of from about 0.5 to about 2, such as about 0.5, about 1 or about 2.

B) Solid forms

Embodiments of aeruginascin of the present disclosure are in a solid form. The solid form may be a crystalline form or an amorphous form. In some embodiments, the solid form is a crystalline form, such as a polymorph. In some embodiments, the solid form of aeruginascin is a salt. And in certain embodiments, the solid form is a crystalline salt form of the compound. A person of ordinary skill in the art understands that solid forms of aeruginascin such as crystalline forms including salt and non-salt crystalline forms of aeruginascin, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compounds are particular polymorphs of aeruginascin or aeruginascin salts.

In some embodiments, the solid form of aeruginascin disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of aeruginascin that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of aeruginascin. The aeruginascin may be a salt or free base (zwitterionic) compound. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailabihty, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.

The desired polymorph may be produced by techniques known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent.

Techniques to identify a particular solid form of aeruginascin are known to persons of ordinary skill in the art, and include, but are not limited to, X-ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and/or melting point.

Baeocystin

“Baeocystin” refers to the compound [3-[2-(methylamino)ethyl]-U/-indol-4-yl] dihydrogen phosphate. The compound may also be referred to as 4-hydroxy-A- methyltryptamine 4-phosphate, beocystin, or A-desmethylpsilocybin.

Baeocystin

Disclosed herein are solid forms of baeocystin that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms of baeocystin and method of administering the solid forms of baeocystin.

In some embodiments, the solid form of the compound is a crystalline form of baeocystin. In some embodiments, the solid form of the compound is a salt of the compound. In some embodiments, the solid form of baeocystin is a polymorph of baeocystin, such as a polymorph of the free base compound or a polymorph of the salt. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.

A) Salts

In some embodiments, the solid form of baeocystin comprises a salt of baeocystin. Suitable salts include a pharmaceutically acceptable salt of baeocystin. In some embodiments, the salt is not a hydrochloride salt of baeocystin. In some embodiments, the salt of baeocystin may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, - toluenesulfonic acid, salicylic acid, xinafoic acid and the like.

In other embodiments, the salt of baeocystin may be formed from a suitable pharmaceutically acceptable base, including, without limitation, inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tri s(hydroxymethyl)aminom ethane (Tris), ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference.

In some embodiments, the salt may be formed using an acid from the table below.

In some embodiments, the acid is not hydrochloric acid.

The acid salts of baeocystin disclosed herein can have any suitable stoichiometric ratio of acid to baeocystin. In one embodiment, the molar ratio of acid to baeocystin is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to baeocystin of from about 0.5 to about 2, such as about 0.5, about 1 or about 2.

B) Solid forms

Embodiments of baeocystin of the present disclosure are in a solid form. The solid form may be a crystalline form or an amorphous form. In some embodiments, the solid form is a crystalline form, such as a polymorph. In some embodiments, the solid form of baeocystin is a salt. And in certain embodiments, the solid form is a crystalline salt form of the compound. A person of ordinary skill in the art understands that solid forms of baeocystin such as crystalline forms including salt and non-salt crystalline forms of baeocystin, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compounds are particular polymorphs of baeocystin or baeocystin salts.

In some embodiments, the solid form of baeocystin disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of baeocystin that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of baeocystin. The baeocystin may be a salt or free base compound. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.

The desired polymorph may be produced by techniques known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent.

Techniques to identify a particular solid form of baeocystin are known to persons of ordinary skill in the art, and include, but are not limited to, X-ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and/or melting point.

Dimethyl tryptamine (DMT)

“Dimethyl tryptamine” refers to the compound 2-(U/-indol-3-yl)-7V,7V- dimethylethanamine. The compound may also be referred to as /' ./' -dimethyl tryptamine, 2- (3-indolyl)ethyldimethylamine, 3-(2-dimethylaminoethyl)indole, or DMT.

Dimethyl tryptamine (DMT)

Disclosed herein are solid forms of dimethyl tryptamine (DMT) that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms of DMT and method of administering the solid forms of DMT.

In some embodiments, the solid form of the compound is a crystalline form of DMT. In some embodiments, the solid form of the compound is a salt of the compound. In some embodiments, the solid form of DMT is a polymorph of DMT, such as a polymorph of the free base compound or a polymorph of the salt. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.

A) Salts

In some embodiments, the solid form of DMT comprises a salt of DMT. Suitable salts include a pharmaceutically acceptable salt of DMT. In some embodiments, the salt is not a hydrochloride salt of DMT. In some embodiments, the salt of DMT may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, xinafoic acid and the like.

In other embodiments, the salt of DMT may be formed from a suitable pharmaceutically acceptable base, including, without limitation, inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tri s(hydroxymethyl)aminom ethane (Tris), ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference.

In some embodiments, the salt may be formed using an acid from the table below.

In some embodiments, the acid is not hydrochloric acid.

The acid salts of DMT disclosed herein can have any suitable stoichiometric ratio of acid to DMT. In one embodiment, the molar ratio of acid to DMT is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to DMT of from about 0.5 to about 2, such as about 0.5, about 1 or about 2.

B) Solid forms

Embodiments of DMT of the present disclosure are in a solid form. The solid form may be a crystalline form or an amorphous form. In some embodiments, the solid form is a crystalline form, such as a polymorph. In some embodiments, the solid form of DMT is a salt. And in certain embodiments, the solid form is a crystalline salt form of the compound. A person of ordinary skill in the art understands that solid forms of DMT such as crystalline forms including salt and non-salt crystalline forms of DMT, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compounds are particular polymorphs of DMT or DMT salts.

In some embodiments, the solid form of DMT disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of DMT that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of DMT. The DMT may be a salt or free base compound. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.

The desired polymorph may be produced by techniques known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent.

Techniques to identify a particular solid form of DMT are known to persons of ordinary skill in the art, and include, but are not limited to, X-ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and/or melting point.

Lisuride

“Lisuride” refers to the compound:

Lisuride which also may be referred to as “lysuride,” “mesorgydin,” or “methylergol carbamide.” “Subject” refers to an animal, such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human subject.

“Therapeutically effective amount” or “therapeutically sufficient amount” or “effective or sufficient amount” refers to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.

“Neuronal plasticity” refers to the ability of the brain to change its structure and/or function continuously throughout a subject’s life. Examples of the changes to the brain include, but are not limited to, the ability to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses. “Brain disorder” refers to a neurological disorder which affects the brain’s structure and function. Brain disorders can include, but are not limited to, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, treatment resistant depression, addiction, anxiety, post-traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and substance use disorder.

“Combination therapy” refers to a method of treating a disease or disorder, wherein two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents. For example, the compounds of the invention can be used in combination with other pharmaceutically active compounds. The compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

“Neurotrophic factors” refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.

“Modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., a positive allosteric modulator) of a G protein-coupled receptor (e.g., 5HT2A) are modulators of the receptor.

“Agonism” refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.

“Agonist” refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, “5HT2A agonist” can be used to refer to a compound that exhibits an ECso with respect to 5HT2A activity of no more than about 100 mM. In some embodiments, the term “agonist” includes full agonists or partial agonists. “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor. “Partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.

“Positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist. “Antagonism” refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur.

“Antagonist” or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.

“Composition” refers to a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation.

“Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

Disclosed herein are salts and solid forms of lisuride that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the salts and solid forms of lisuride and method of administering the salts and solid forms of the compound

In some embodiments, a solid form of the compound is a crystalline form of lisuride.

In some embodiments, the solid form of lisuride is a polymorph of lisuride, such as a polymorph of the free base compound or a polymorph of the salt. In some embodiments, the solid form of the compound is a salt of the compound. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.

A) Salts In some embodiments, the solid form of lisuride comprises a salt of lisuride. Suitable salts include pharmaceutically acceptable salts of lisuride. In some embodiments, the solid form of lisuride is not, and does not include, lisuride hydrogen maleate (also referred to as “LHM” or lisuride maleate).

In some embodiments, the salt of lisuride may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, xinafoic acid and the like.

In other embodiments, the salt of lisuride may be formed from a suitable pharmaceutically acceptable base, including, without limitation, inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tri s(hydroxymethyl)aminom ethane (Tris), ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, et al.. “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference.

In some embodiments, the salt may be formed using an acid from the table below.

But in certain embodiments, maleic acid is not used.

The acid salts of lisuride disclosed herein can have any suitable stoichiometric ratio of acid to lisuride. In one embodiment, the molar ratio of acid to lisuride is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to lisuride of from about 0.5 to about 2, such as about 0.5, about 1 or about 2.

A) Solid Forms

Embodiments of lisuride of the present disclosure are in a solid form. The solid form may be a crystalline form or an amorphous form. In some embodiments, the solid form is a crystalline form, such as a polymorph. In some embodiments, the solid form of lisuride is a salt. And in certain embodiments, the solid form is a crystalline salt form of the compound. A person of ordinary skill in the art understands that solid forms of lisuride, such as crystalline forms including salt and non-salt crystalline forms of lisuride, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compounds are particular polymorphs of lisuride or a lisuride salt.

In some embodiments, the solid form of lisuride disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of lisuride that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of lisuride. The lisuride may be a salt or free base compound. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.

The desired polymorph may be produced by techniques known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent.

Techniques to identify a particular solid form of lisuride are known to persons of ordinary skill in the art, and include, but are not limited to, X-ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and/or melting point.

Lisuride Maleate

“Lisuride Maleate,” also referred to as “Lisuride Hydrogen Maleate” (or “LHM”) refers to the maleic acid salt of lisuride

Disclosed herein are solid forms of lisuride maleate that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms and methods of administering the solid forms of the compounds.

With reference to the formula for lisuride, the maleic salt may be referred to herein as “lisuride hydrogen maleate” (or “LHM”) or lisuride maleate. In some embodiments, the solid form of the compound is a crystalline form of the compound. In some embodiments, the solid form of the compound is a polymorph of the compound, such as a novel polymorph that is not previously known in the art.

A) Solid Forms

A solid form of a salt may be a crystalline form or an amorphous form. A person of ordinary skill in the art understands that solid forms of compounds, such as crystalline forms of lisuride maleate, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compound is a novel polymorph of lisuride maleate.

In some embodiments, the solid form of lisuride maleate disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of lisuride maleate, that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of the molecule. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.

The desired polymorph may be produced by techniques as described herein and also are known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent. Techniques to identify a particular solid form of a compound are described herein and also are known to persons of ordinary skill in the art, and include, but are not limited to, X- ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and/or melting point.

Norpsilocin

“Norpsilocin” refers to the compound 3-[2-(methylamino)ethyl]-U/-indol-4-ol. The compound may also be referred to as 4-hydroxy-A-methyltryptamine, or 4-HO-NMT.

Norpsilocin

Disclosed herein are solid forms of norpsilocin that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms of norpsilocin and method of administering the solid forms of norpsilocin.

In some embodiments, the solid form of the compound is a crystalline form of norpsilocin. In some embodiments, the solid form of the compound is a salt of the compound. In some embodiments, the solid form of norpsilocin is a polymorph of norpsilocin, such as a polymorph of the free base compound or a polymorph of the salt. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.

A) Salts

In some embodiments, the solid form of norpsilocin comprises a salt of norpsilocin. Suitable salts include a pharmaceutically acceptable salt of norpsilocin. In some embodiments, the salt is not a hydrochloride salt of norpsilocin. In some embodiments, the salt of norpsilocin may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, /?-toluenesulfonic acid, salicylic acid, xinafoic acid and the like.

In other embodiments, the salt of norpsilocin may be formed from a suitable pharmaceutically acceptable base, including, without limitation, inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tri s(hydroxymethyl)aminom ethane (Tris), ethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference.

In some embodiments, the salt may be formed using an acid from the table below.

In some embodiments, the acid is not hydrochloric acid.

The acid salts of norpsilocin disclosed herein can have any suitable stoichiometric ratio of acid to norpsilocin. In one embodiment, the molar ratio of acid to norpsilocin is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to norpsilocin of from about 0.5 to about 2, such as about 0.5, about 1 or about 2.

B) Solid forms

Embodiments of norpsilocin of the present disclosure are in a solid form. The solid form may be a crystalline form or an amorphous form. In some embodiments, the solid form is a crystalline form, such as a polymorph. In some embodiments, the solid form of norpsilocin is a salt. And in certain embodiments, the solid form is a crystalline salt form of the compound. A person of ordinary skill in the art understands that solid forms of norpsilocin such as crystalline forms including salt and non-salt crystalline forms of norpsilocin, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compounds are particular polymorphs of norpsilocin or norpsilocin salts.

In some embodiments, the solid form of norpsilocin disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of norpsilocin that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of norpsilocin. The norpsilocin may be a salt or free base compound. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.

The desired polymorph may be produced by techniques known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent.

Techniques to identify a particular solid form of norpsilocin are known to persons of ordinary skill in the art, and include, but are not limited to, X-ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and/or melting point.

Pharmaceutical Compositions and Formulations

In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more of the salts or solid forms described herein (e.g. 5-MeO-DALT, 5- MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and/or norpsilocin), illustrated above, and a pharmaceutically acceptable excipient. Such compositions are suitable for administration to a subject, such as a human subject.

The presently disclosed pharmaceutical compositions can be prepared in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, capsules, lozenges, cachets, slurries, suspensions, etc., suitable for ingestion by the patient. The compositions of the present disclosure can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the compositions of the present disclosure can be administered transdermally. The compositions of this disclosure can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin.

Pharmacol. 35: 1187-1193, 1995; Tjwa, ^/?/?. Allergy Asthma Immunol. 75: 107-111, 1995). Accordingly, the present disclosure also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and the salts or solid forms described herein (e.g. 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and/or norpsilocin).

For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington's").

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% to 70% or 10% to 70% of the compounds of the present disclosure.

Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from com, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen.

If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compounds of the present disclosure are dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include suspensions, for example, water or water/propylene glycol suspensions. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include suspensions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

Oil suspensions can be formulated by suspending the compound of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

The compositions of the present disclosure can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months.

In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution or suspension of the compositions of the present disclosure dissolved or suspended in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions or suspensions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pFI adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present disclosure in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3 -butanediol. In some embodiments, the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, for example, by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576-1587, 1989).

Administration

The compositions of the present disclosure can be administered by any suitable means, including oral, parenteral and topical methods. Transdermal administration methods, by a topical route, can be formulated as applicator sticks, suspensions, creams, ointments, pastes, jellies, paints, powders, and aerosols.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the compounds of the present invention. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The compound of the present invention can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, and the like as is known to those of ordinary skill in the art. Suitable dosage ranges for the compounds disclosed herein include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages for the compound of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg.

The compounds disclosed herein can be administered at any suitable frequency, interval and duration. For example, the compounds can be administered once an hour, or two, three or more times an hour, once a day, or two, three, or more times per day, or once every 2, 3, 4, 5, 6, or 7 days, so as to provide the preferred dosage level. When the compound of the present invention is administered more than once a day, representative intervals include 5, 10, 15, 20, 30, 45 and 60 minutes, as well as 1, 2, 4,

6, 8, 10, 12, 16, 20, and 24 hours. The compound of the present invention can be administered once, twice, or three or more times, for an hour, for 1 to 6 hours, for 1 to 12 hours, for 1 to 24 hours, for 6 to 12 hours, for 12 to 24 hours, for a single day, for 1 to 7 days, for a single week, for 1 to 4 weeks, for a month, for 1 to 12 months, for a year or more, or even indefinitely.

The composition can also contain other compatible therapeutic agents. The compounds described herein can be used in combination with one another, with other active agents known to be useful in modulating a glucocorticoid receptor, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

The compounds of the present disclosure can be co-administered with a second active agent. Co-administration includes administering the compound of the present disclosure and active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other. Coadministration also includes administering the compound of the present disclosure and active agent simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Moreover, the compound of the present disclosure and the active agent can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.

In some embodiments, co-administration can be accomplished by co-formulation, such as by preparing a single pharmaceutical composition including both the compound of the present disclosure and a second active agent. In other embodiments, the compound of the present disclosure and the second active agent can be formulated separately.

The disclosed compounds and the second active agent can be present in the compositions of the present disclosure in any suitable weight ratio, such as from about 1 : 100 to about 100: 1 (w/w), or about 1 :50 to about 50: 1, or about 1 :25 to about 25: 1, or about 1 : 10 to about 10: 1, or about 1 :5 to about 5: 1 (w/w). The compound of the present disclosure and the second active agent can be present in any suitable weight ratio, such as about 1 : 100 (w/w), 1 :50, 1 :25, 1 : 10, 1 :5, 1 :4, 1 :3, 1 :2, 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 25: 1, 50: 1 or 100: 1 (w/w). Other dosages and dosage ratios of the compound of the present disclosure and the active agent are suitable in the compositions and methods disclosed herein.

Methods of Treatment The salts or solid forms described herein (e.g. 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and/or norpsilocin) can be used for increasing neuronal plasticity. The compounds of the present disclosure can also be used to treat any brain disease. The compounds of the present disclosure can also be used for increasing at least one of translation, transcription or secretion of neurotrophic factors.

In some embodiments, a compound of the present disclosure is used to treat neurological diseases. In some embodiments, the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is a migraine, headaches (e.g., cluster headache), post- traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disease is a migraine or cluster headache. In some embodiments, the neurological disease is a neurodegenerative disorder, Alzheimer’s disease, or Parkinson’s disease. In some embodiments, the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia. In some embodiments, a compound of the present disclosure is used for increasing neuronal plasticity. In some embodiments, the compounds described herein are used for treating a brain disorder. In some embodiments, the compounds described herein are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors.

In some embodiments, the present disclosure provides a method of treating a disease, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the disease is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps. In some embodiments, the present invention provides a method of treating a disease of women’s reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.

In some embodiments, salts or solid forms described herein (e.g. 5-MeO-DALT, 5- MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and/or norpsilocin) have activity as 5-HT2A modulators. In some embodiments, the compounds of the present disclosure elicit a biological response by activating the 5-HT2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor). 5-HT2A agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018). 5-HT2A antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2A agonist activity, for example., DMT, LSD and DOI. In some embodiments, the compounds of the present disclosure are 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds of the present disclosure are selective 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.

In some embodiments, the 5-HT2A modulators (e.g., 5-HT2A agonists) are non- hallucinogenic. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used to treat neurological diseases, which modulators do not elicit dissociative side-effects. In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs. In some embodiments, the compounds described herein elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.

In some embodiments, serotonin receptor modulators, such as modulators of serotonin receptor 2A (5-HT2A modulators, e.g., 5-HT2A agonists), are used to treat a brain disorder. The presently disclosed compounds can function as 5-HT2A agonists alone, or in combination with a second therapeutic agent that also is a 5-HT2A modulator. In such cases the second therapeutic agent can be an agonist or an antagonist. In some instances, it may be helpful administer a 5-HT2A antagonist in combination with a compound of the present disclosure to mitigate undesirable effects of 5-HT2A agonism, such as potential hallucinogenic effects. Serotonin receptor modulators useful as second therapeutic agents for combination therapy as described herein are known to those of skill in the art and include, without limitation, ketanserin, volinanserin (MDL-100907), eplivanserin (SR-46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nelotanserin, blonanserin, mianserin, mirtazapine, roluperiodone (CYR-101, MIN-101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pruvanserin, AC-90179, AC-279, adatanserin, fananserin, HY10275, benanserin, butanserin, manserin, iferanserin, lidanserin, pelanserin, seganserin, tropanserin, lorcaserin, ICI-169369, methiothepin, methysergide, trazodone, cinitapride, cyproheptadine, brexpiprazole, cariprazine, agomelatine, setoperone, 1-(1- Naphthyl)piperazine, LY-367265, pirenperone, metergoline, deramciclane, amperozide, cinanserin, LY-86057, GSK-215083, cyamemazine, mesulergine, BF-1, LY-215840, sergolexole, spiramide, LY-53857, amesergide, LY-108742, pipamperone, LY-314228, 5-1- R91150, 5-MeO-NBpBrT, 9-Aminomethyl-9,10-dihydroanthracene, niaprazine, SB-215505, SB-204741 , SB-206553, SB-242084, LY-272015, SB-243213, SB-200646, RS-102221, zotepine, clozapine, chlorpromazine, sertindole, iloperidone, paliperidone, asenapine, amisulpride, aripiprazole, lurasidone, ziprasidone, lumateperone, perospirone, mosapramine, AMD A (9-Aminomethyl-9,10-dihydroanthracene), methiothepin, buspirone, an extended- release form of olanzapine (e.g., ZYPREXA RELPREVV), an extended-release form of quetiapine, an extended-release form of risperidone (e.g., Risperdal Consta), an extended- release form of paliperidone (e.g., Invega Sustenna and Invega Trinza), an extended-release form of fluphenazine decanoate including Prolixin Decanoate, an extended-release form of aripiprazole lauroxil including Aristada, an extended-release form of aripiprazole including Abilify Maintena, 3-(2-(4-(4-Fluorobenzoyl)piperazin-l-yl)ethyl)-5-methyl-5- phenylimidazolidine-2, 4-dione, 3-(2-(4-Benzhydrylpiperazin-l-yl)ethyl)-5-methyl-5-phe- nylimidazolidine-2, 4-dione, 3-(3-(4-(2-Fluorophenyl)piperazin-l-yl)propyl)-5-me- thyl-5-phenylimidazolidine-2, 4-dione, 3-(3-(4-(3-Fluorophenyl)piperazin-l-yl)propyl)-5-me- thyl-5-phenylimidazolidine-2, 4-dione, 3-(3-(4-(4-Fluorophenyl)piperazin-l-yl)propyl)-5-me- thyl-5-phenylimidazolidine-2, 4-dione, 3-(3-(4-(4-Fluorobenzoyl)piperazin-l-yl)propyl)-5- methyl-5-phenylimidazolidine-2, 4-dione, 3-(2-(4-(4-Fluorobenzoyl)piperazin-l-yl)ethyl)-8- phenyl- 1 ,3 -diazaspiro[4.5]decane-2, 4-dione, 3 -(2-(4-Benzhydrylpiperazin- 1 -yl)ethyl)-8- phenyl-l,3-diazaspiro[4.5]decane-2, 4-dione,

3 -(3 -(4-(2-Fluorophenyl)piperazin- 1 -yl)propyl)-8-phe- nyl-l,3-diazaspiro[4.5]decane-2, 4-dione,

3 -(3 -(4-(3 -Fluorophenyl)piperazin- 1 -yl)propyl)-8 -phe- nyl-l,3-diazaspiro[4.5]decane-2, 4-dione,

3 -(3 -(4-(4-Fluorophenyl)piperazin- 1 -yl)propyl)-8 -phe- nyl-l,3-diazaspiro[4.5]decane-2, 4-dione, and 3-(3-(4-(4-Fluorobenzoyl)piperazin-l- yl)propyl)-8-phenyl-l,3-diazaspiro[4.5]decane-2, 4-dione, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. . In some embodiments, the serotonin receptor modulator used as a second therapeutic is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the serotonin receptor modulator is administered prior to a compound disclosed herein, such as about three or about hours prior administration of a compound disclosed herein. In some embodiments, the serotonin receptor modulator is administered at most about one hour prior to the presently disclosed compound. Thus, in some embodiments of combination therapy with the presently disclosed compounds, the second therapeutic agent is a serotonin receptor modulator. In some embodiments the second therapeutic agent serotonin receptor modulator is provided at a dose of from about 10 mg to about 350 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 20 mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 10 mg to about 100 mg. In certain such embodiments, the compound of the present disclosure is provided at a dose of from about 10 mg to about 100 mg, or from about 20 mg to about 200 mg, or from about 15 mg to about 300 mg, and the serotonin receptor modulator is provided at a dose of about 10 mg to about 100 mg.

In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used to treat neurological diseases. In some embodiments, the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.

In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used for increasing neuronal plasticity. In some embodiments, non-hallucinogenic 5- HT_2A modulators (e.g., 5-HT2A agonists) are used for treating a brain disorder. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-FIT2A agonists) are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors.

In some embodiments the presently disclosed compounds are given to patients in a low dose that is lower than would produce noticeable psychedelic effects but high enough to provide a therapeutic benefit. This dose range is predicted to be between 200 pg (micrograms) and 2 mg.

A) Methods for Increasing Neuronal Plasticity

Neuronal plasticity refers to the ability of the brain to change structure and/or function throughout a subject’s life. New neurons can be produced and integrated into the central nervous system throughout the subject’s life. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.

In some embodiments, increasing neuronal plasticity by treating a subject with one or more of the disclosed compound can treat neurodegenerative disorder, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.

In some embodiments, the present disclosure provides methods for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of the present disclosure. In some embodiments, increasing neuronal plasticity improves a brain disorder described herein.

In some embodiments, a compound of the present disclosure is used to increase neuronal plasticity. In some embodiments, the compounds used to increase neuronal plasticity have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, decreased neuronal plasticity is associated with a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.

In some embodiments, the experiment or assay to determine increased neuronal plasticity of any compound of the present disclosure is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentrationresponse experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2A binding assay, or a 5-HT2A blocking experiment (e.g., ketanserin blocking experiments). In some embodiments, the experiment or assay to determine the hallucinogenic potential of any compound of the present invention is a mouse head-twitch response (HTR) assay.

In some embodiments, the present disclosure provides a method for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound disclosed herein.

B) Methods of Treating a Brain Disorder

In some embodiments, the present disclosure provides a method of treating a disease, including administering to a subject in need thereof, a therapeutically effective amount of the salts or solid forms described herein (e.g. 5-MeO-DALT, 5-MeO-DMT, aeruginascin, baeocystin, DMT, lisuride, lisuride maleate, and/or norpsilocin). In some embodiments, the disease is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps. In some embodiments, the present disclosure provides a method of treating a disease of women’s reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause. In some embodiments, the present disclosure provides a method of treating a brain disorder, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the present disclosure provides a method of treating a brain disorder with combination therapy, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure and at least one additional therapeutic agent.

In some embodiments, 5-HT2A modulators (e.g., 5-HT2A agonists) are used to treat a brain disorder. In some embodiments, the brain disorders comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.

In some embodiments, a compound of the present disclosure is used to treat brain disorders. In some embodiments, the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the brain disorder is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, panic disorder, suicidality, schizophrenia, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.

In some embodiments, the present disclosure provides a method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein. In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.

In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer’s, or Parkinson’s disease. In some embodiments, the brain disorder is a psychological disorder, depression, addiction, anxiety, or a post-traumatic stress disorder. In some embodiments, the brain disorder is depression. In some embodiments, the brain disorder is addiction. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury or substance use disorder. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the brain disorder is stroke or traumatic brain injury. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder. In some embodiments, the brain disorder is schizophrenia. In some embodiments, the brain disorder is alcohol use disorder.

In some embodiments, the method further comprises administering one or more additional therapeutic agent that is lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).

In certain embodiments of the method for treating a brain disorder with a solid form disclosed herein, a second therapeutic agent that is an empathogenic agent is administered. Examples of suitable empathogenic agents for use in combination with the present solid forms include phenethylamines, such as 3,4-methylene- di oxymethamphetamine (MDMA), and analogs thereof. Other suitable empathogenic agents for use in combination with the presently disclosed compounds include, without limitation, N- Allyl-3,4-methylenedi oxy-amphetamine (MDAL)

A-Butyl -3, 4-methylenedi oxyamphetamine (MDBU)

A-Benzyl-3, 4-methylenedi oxyamphetamine (MDBZ)

A-Cy cl opropylmethyl-3, 4-methylenedi oxyamphetamine (MDCPM)

A, A-Dimethyl-3, 4-methylenedi oxyamphetamine (MDDM) A-Ethyl-3,4-methylenedioxyamphetamine (MDE; MDEA) A-(2-Hydroxyethyl)-3, 4-methylenedi oxy amphetamine (MDHOET) A-Isopropyl -3, 4-methylenedi oxyamphetamine (MDIP)

A-Methy 1 -3 , 4-ethy 1 enedi oxy amphetamine (MDMC)

A-Methoxy-3 , 4-methylenedi oxyamphetamine (MDMEO)

N-(2 -Methoxy ethyl)-3, 4-methylenedi oxyamphetamine (MDMEOET) alpha, alpha, A-Trimethyl-3, 4-methylenedi oxyphenethylamine (MDMP;

3.4-Methylenedioxy-A-methylphentermine)

A-Hydroxy-3, 4-methylenedi oxyamphetamine (MDOH)

3.4-Methy 1 enedi oxy phenethyl amine (MDPE A) alpha, alpha-Dimethyl-3, 4-methylenedi oxyphenethylamine (MDPH; 3,4- methylenedi oxyphentermine)

A-Propargyl-3, 4-methylenedi oxyamphetamine (MDPL)

Methylenedi oxy-2-aminoindane (MDAI)

1.3 -B enzodioxolyl -A-m ethyl butanam i ne MBDB

N-methyl -1,3 -benzodi oxolylbutanamine, MBDB ,

3.4-methylenedi oxy -A-methyl-a-ethylphenylethylamine

3.4-Methylenedioxyamphetamine MDA

Methylone (also known as "3, 4-methylenedi oxy -A-methylcathinone)

Ethylone, also known as 3,4-methylenedioxy-A-ethylcathinone GHB or Gamma Hydroxybutyrate or sodium oxybate A-Propyl-3,4-methylenedioxyamphetamine (MDPR), and the like.

In some embodiments, the compounds of the present disclosure are used in combination with the standard of care therapy for a neurological disease described herein. Non- limiting examples of the standard of care therapies, may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Nonlimiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. Additional examples of standard of care therapeutics are known to those of ordinary skill in the art.

C) Methods of increasing at least one of translation, transcription, or secretion of neurotrophic factors

Neurotrophic factors refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons. Increasing at least one of translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing at least one of translation, transcription, or secretion of neurotrophic factors can increasing neuronal plasticity. In some embodiments, increasing at least one of translation, transcription, or secretion of neurotrophic factors can promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and/or increasing dendritic spine density.

In some embodiments, 5-HT2A modulators (e.g., 5-HT2A agonists) are used to increase at least one of translation, transcription, or secretion of neurotrophic factors. In some embodiments, a compound of the present disclosure is used to increase at least one of translation, transcription, or secretion of neurotrophic factors. In some embodiments, increasing at least one of translation, transcription or secretion of neurotrophic factors treats a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).

In some embodiments, the experiment or assay used to determine increase translation of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry. In some embodiments, the experiment or assay used to determine increase transcription of neurotrophic factors includes gene expression assays, PCR, and microarrays. In some embodiments, the experiment or assay used to determine increase secretion of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.

In some embodiments, the present disclosure provides a method for increasing at least one of translation, transcription or secretion of neurotrophic factors, comprising contacting a neuronal cell with a compound disclosed herein.

EXAMPLES

5-MeO-DALT Examples

5-MeO-DALT Example Al Salt Screen

5-MeO-DALT is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table Al

The information obtained is used for designing the subsequent salt screen. The salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts. Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and/or 2 molar equivalents of the acid.

Table A2 - Exemplary Acids

In some embodiments, the acid is not hydrochloric acid.

Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:

• Free base and acid are dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• Free base and acid are dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled to a subambient temperature (between -78 °C to 15 °C). The cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are added to a solvent or mixture of solvents, where one or both components are not fully dissolved. The slurry is agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). The same experiment can be also performed in solvent systems where the solvents are not miscible.

• Free base and acid are milled together (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• Free base and acid are melted together, and cooled to various temperatures using various cooling rates.

• If an amorphous form of a salt is obtained, the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.

The stoichiometric ratio of acid to 5-MeO-DALT is confirmed by

NMR, HPLC, or both as is known to those of ordinary skill in the art.

The salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on salts that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present.

5-MeO-DALT Example A2

Polymorph Screen

The active pharmaceutical ingredient (API), which may be a free base or a salt, is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table A3

The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening: • API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried).

• API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

• API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried).

• API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the API. The final solids will be filtered and dried (air dried or vacuum dried).

• API is heated to a specific temperature and cooled (at ambient conditions or in a dry box). The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 'H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 J/g). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °C at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of 10°C/min.

The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.

X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku/MSC, The Woodlands, TX) from 5° to 45° 29 with steps of 0.1°, and the measuring time is 1.0 second/step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation (X = 1.54056A) at 30 kV and 15 mA.

Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni -filtered CuKai radiation ( = 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW 1120/00 generator fitted with a Huber long fine- focus tube PW2273/20 and a Huber Guinier Monochromator Series 611/15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kmin'¹ using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is exposed to X-rays and multiple scans were recorded. A 20- range of 4.00 - 100.0° is used with a step size of 0.005° 20.

In certain embodiments wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.

In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.

5-MeO-DMT Examples

5-MeO-DMT Example Bl Salt Screen

5-MeO-DMT is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment). Table Bl

The information obtained is used for designing the subsequent salt screen. The salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts. Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and/or 2 molar equivalents of the acid. Table B2 - Exemplary Acids

In some embodiments, the acid is not hydrochloric acid.

In other embodiments, the acid is not oleic acid. Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:

• Free base and acid are dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• Free base and acid are dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled to a subambient temperature (between -78 °C to 15 °C). The cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are added to a solvent or mixture of solvents, where one or both components are not fully dissolved. The slurry is agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). The same experiment can be also performed in solvent systems where the solvents are not miscible.

• Free base and acid are milled together (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• Free base and acid are melted together, and cooled to various temperatures using various cooling rates.

• If an amorphous form of a salt is obtained, the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.

The stoichiometric ratio of acid to 5-MeO-DMT is confirmed by NMR, HPLC, or both as is known to those of ordinary skill in the art.

The salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on salts that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present. 5-MeO-DMT Example B2

Polymorph Screen

The active pharmaceutical ingredient (API), which may be a free base or a salt, is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table B3

The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening:

• API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried).

• API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

• API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried). • API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the API. The final solids will be filtered and dried (air dried or vacuum dried).

• API is heated to a specific temperature and cooled (at ambient conditions or in a dry box).

The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by

NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 J/g). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °C at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of 10°C/min.

The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.

X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku/MSC, The Woodlands, TX) from 5° to 45° 29 with steps of 0.1°, and the measuring time is 1.0 second/step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation (X = 1.54056 ) at 30 kV and 15 mA.

Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni -filtered CuKai radiation ( = 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW 1120/00 generator fitted with a Huber long fine- focus tube PW2273/20 and a Huber Guinier Monochromator Series 611/15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kinin'¹ using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is exposed to X-rays and multiple scans were recorded. A 20- range of 4.00 - 100.0° is used with a step size of 0.005° 20.

In certain embodiments wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.

In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.

Aeruginascin Examples

Aeruginascin Example Cl Salt Screen

Aeruginascin is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table Cl

The information obtained is used for designing the subsequent salt screen. The salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts. Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and/or 2 molar equivalents of the acid.

Table C2 - Exemplary Acids

In some embodiments, the acid is not hydrochloric acid.

Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:

• Free base and acid are dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• Free base and acid are dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled to a subambient temperature (between -78 °C to 15 °C). The cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are added to a solvent or mixture of solvents, where one or both components are not fully dissolved. The slurry is agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). The same experiment can be also performed in solvent systems where the solvents are not miscible.

• Free base and acid are milled together (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent. • Free base and acid are melted together, and cooled to various temperatures using various cooling rates.

• If an amorphous form of a salt is obtained, the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.

The stoichiometric ratio of acid to aeruginascin is confirmed by 'H NMR, HPLC, or both as is known to those of ordinary skill in the art.

The salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on salts that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present.

Aeruginascin Example C2 Polymorph Screen

The active pharmaceutical ingredient (API), which may be a free base or a salt, is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table C3

The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening:

• API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated). • API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). • API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). • API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried).

• API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

• API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried).

• API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the API. The final solids will be filtered and dried (air dried or vacuum dried).

• API is heated to a specific temperature and cooled (at ambient conditions or in a dry box).

The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated,

NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 J/g). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °C at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of 10°C/min.

The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.

X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku/MSC, The Woodlands, TX) from 5° to 45° 29 with steps of 0.1°, and the measuring time is 1.0 second/step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation (X = 1.54056 ) at 30 kV and 15 mA.

Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni -filtered CuKai radiation ( = 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW 1120/00 generator fitted with a Huber long fine- focus tube PW2273/20 and a Huber Guinier Monochromator Series 611/15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kmin'¹ using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is exposed to X-rays and multiple scans were recorded. A 20- range of 4.00 - 100.0° is used with a step size of 0.005° 20.

In certain embodiments wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.

In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.

Baeocystin Examples

Baeocystin Example DI Salt Screen

Baeocystin is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table DI

The information obtained is used for designing the subsequent salt screen. The salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts. Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and/or 2 molar equivalents of the acid.

Table D2 - Exemplary Acids

In some embodiments, the acid is not hydrochloric acid.

Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:

• Free base and acid are dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• Free base and acid are dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled to a subambient temperature (between -78 °C to 15 °C). The cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are added to a solvent or mixture of solvents, where one or both components are not fully dissolved. The slurry is agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). The same experiment can be also performed in solvent systems where the solvents are not miscible.

• Free base and acid are milled together (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• Free base and acid are melted together, and cooled to various temperatures using various cooling rates.

• If an amorphous form of a salt is obtained, the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.

The stoichiometric ratio of acid to baeocystin is confirmed by NMR, HPLC, or both as is known to those of ordinary skill in the art.

The salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on salts that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present.

Baeocystin Example D2

Polymorph Screen

The active pharmaceutical ingredient (API), which may be a free base or a salt, is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table D3

The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening: • API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried).

• API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

• API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried).

• API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the API. The final solids will be filtered and dried (air dried or vacuum dried). API is heated to a specific temperature and cooled (at ambient conditions or in a dry box).

The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated,

NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 J/g). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °C at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of 10°C/min.

The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.

X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku/MSC, The Woodlands, TX) from 5° to 45° 29 with steps of 0.1°, and the measuring time is 1.0 second/step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation (X = 1.54056 ) at 30 kV and 15 mA.

Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni -filtered CuKai radiation ( = 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW 1120/00 generator fitted with a Huber long fine- focus tube PW2273/20 and a Huber Guinier Monochromator Series 611/15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kmin'¹ using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is exposed to X-rays and multiple scans were recorded. A 20- range of 4.00 - 100.0° is used with a step size of 0.005° 20.

In certain embodiments wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.

In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.

DMT Examples

DMT Example El Salt Screen

DMT is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table El

The information obtained is used for designing the subsequent salt screen. The salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts. Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and/or 2 molar equivalents of the acid.

Table E2 - Exemplary Acids

In some embodiments, the acid is not hydrochloric acid. Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:

• Free base and acid are dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• Free base and acid are dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled to a subambient temperature (between -78 °C to 15 °C). The cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are added to a solvent or mixture of solvents, where one or both components are not fully dissolved. The slurry is agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). The same experiment can be also performed in solvent systems where the solvents are not miscible.

• Free base and acid are milled together (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• Free base and acid are melted together, and cooled to various temperatures using various cooling rates.

• If an amorphous form of a salt is obtained, the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.

The stoichiometric ratio of acid to DMT is confirmed by NMR, HPLC, or both as is known to those of ordinary skill in the art.

The salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on salts that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present. DMT Example E2

Polymorph Screen

The active pharmaceutical ingredient (API), which may be a free base or a salt, is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table E3

The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening:

• API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried).

• API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

• API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried). • API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the API. The final solids will be filtered and dried (air dried or vacuum dried).

• API is heated to a specific temperature and cooled (at ambient conditions or in a dry box).

The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by

NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 J/g). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °C at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of 10°C/min.

The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.

X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku/MSC, The Woodlands, TX) from 5° to 45° 29 with steps of 0.1°, and the measuring time is 1.0 second/step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation (X = 1.54056 ) at 30 kV and 15 mA.

Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni -filtered CuKai radiation ( = 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW 1120/00 generator fitted with a Huber long fine- focus tube PW2273/20 and a Huber Guinier Monochromator Series 611/15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kinin'¹ using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is exposed to X-rays and multiple scans were recorded. A 20- range of 4.00 - 100.0° is used with a step size of 0.005° 20.

In certain embodiments wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.

In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.

Lisuride Examples Lisuride Example Fl Salt Screen

Lisuride is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

The information obtained is used for designing the subsequent salt screen. The salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts. Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and/or 2 molar equivalents of the acid.

In some embodiments, maleic acid is not used.

Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:

• Free base and acid are dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• Free base and acid are dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled to a subambient temperature (between -78 °C to 15 °C). The cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are added to a solvent or mixture of solvents, where one or both components are not fully dissolved. The slurry is agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). The same experiment can be also performed in solvent systems where the solvents are not miscible.

• Free base and acid are milled together (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent. • Free base and acid are melted together, and cooled to various temperatures using various cooling rates.

• If an amorphous form of a salt is obtained, the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.

The stoichiometric ratio of acid to lisuride is confirmed by NMR, HPLC, or both as is known to those of ordinary skill in the art.

The salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on salts that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present.

Lisuride Example F2 Polymorph Screen

The active pharmaceutical ingredient (API), which may be a free base or a salt, is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening:

• API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated). • API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling . The solids formed will be recovered by filtration and dried (air dried or vacuum dried). • API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). • API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried).

• API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

• API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried).

• API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the API. The final solids will be filtered and dried (air dried or vacuum dried).

• API is heated to a specific temperature and cooled (at ambient conditions or in a dry box).

The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by

NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 J/g). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °C at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of 10°C/min.

The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.

X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku/MSC, The Woodlands, TX) from 5° to 45° 29 with steps of 0.1°, and the measuring time is 1.0 second/step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation (X = 1.54056 ) at 30 kV and 15 mA.

Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni -filtered CuKai radiation ( = 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW 1120/00 generator fitted with a Huber long fine- focus tube PW2273/20 and a Huber Guinier Monochromator Series 611/15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kmin'¹ using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is exposed to X-rays and multiple scans are recorded. A 20- range of 4.00 - 100.0° is used with a step size of 0.005° 20.

In certain embodiments wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.

In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.

Lisuride Maleate Example Polymorph Production - Example G1

The active pharmaceutical ingredient (API), lisuride maleate, is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening:

• API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried). • API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

• API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried).

• API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the API. The final solids will be filtered and dried (air dried or vacuum dried).

• API is heated to a specific temperature and cooled (at ambient conditions or in a dry box).

The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by

NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 J/g). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °C at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of 10°C/min.

The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.

X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku/MSC, The Woodlands, TX) from 5° to 45° 29 with steps of 0.1°, and the measuring time is 1.0 second/step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation (X = 1.54056A) at 30 kV and 15 mA.

Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni -filtered CuKai radiation ( = 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW 1120/00 generator fitted with a Huber long fine- focus tube PW2273/20 and a Huber Guinier Monochromator Series 611/15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kmin'¹ using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is exposed to X-rays and multiple scans are recorded. A 20- range of 4.00 - 100.0° is used with a step size of 0.005° 20.

In certain embodiments wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.

In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well-defined crystal structure and a high degree of crystallinity.

Norpsilocin Examples

Norpsilocin Example Hl Salt Screen

Norpsilocin is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

Table Hl

The information obtained is used for designing the subsequent salt screen. The salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts. Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and/or 2 molar equivalents of the acid.

Table H2 - Exemplary Acids

In some embodiments, the acid is not hydrochloric acid.

Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:

• Free base and acid are dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• Free base and acid are dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled to a subambient temperature (between -78 °C to 15 °C). The cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). • Free base and acid are dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• Free base and acid are added to a solvent or mixture of solvents, where one or both components are not fully dissolved. The slurry is agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). The same experiment can be also performed in solvent systems where the solvents are not miscible.

• Free base and acid are milled together (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• Free base and acid are melted together, and cooled to various temperatures using various cooling rates.

• If an amorphous form of a salt is obtained, the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.

The stoichiometric ratio of acid to norpsilocin is confirmed by

HPLC, or both as is known to those of ordinary skill in the art.

The salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on salts that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present.

Norpsilocin Example H2 Polymorph Screen

The active pharmaceutical ingredient (API), which may be a free base or a salt, is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size/morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment). Table H3

The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening: • API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

• API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

• API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried).

• API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

• API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

• API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried).

• API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

• Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the API. The final solids will be filtered and dried (air dried or vacuum dried). API is heated to a specific temperature and cooled (at ambient conditions or in a dry box).

The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated,

NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 J/g). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °C at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of 10°C/min.

The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.

X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku/MSC, The Woodlands, TX) from 5° to 45° 29 with steps of 0.1°, and the measuring time is 1.0 second/step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation (X = 1.54056 ) at 30 kV and 15 mA.

Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni -filtered CuKai radiation ( = 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW 1120/00 generator fitted with a Huber long fine- focus tube PW2273/20 and a Huber Guinier Monochromator Series 611/15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kmin'¹ using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is exposed to X-rays and multiple scans were recorded. A 20- range of 4.00 - 100.0° is used with a step size of 0.005° 20.

In certain embodiments wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.

In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.

Biological Example 1

Evaluation of Metabolic Stability in Human Liver Microsomes

Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained. P- nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCh), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich.

Determination of Metabolic Stability: 7.5 mM stock preparations of test compounds of the disclosed compounds are prepared in a suitable solvent, such as DMSO. The 7.5 mM stock preparations are diluted to 12.5-50 pM in acetonitrile (ACN). The 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCh. The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A 10 pL aliquot of the 12.5-50 pM test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 4.0 mg/mL human liver microsomes, 0.25 pM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCh. The reaction mixtures are incubated at 37 °C, and 50 pL aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 pL of ice-cold ACN (acetonitrile) with internal standard to stop the reactions. The plates are stored at 4 °C for 20 minutes after which 100 pL of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied

Bio-systems API 4000 mass spectrometer. The same procedure is followed for the positive control, 7-ethoxy coumarin (1 pM). Testing is done in triplicate.

Data analysis: The in vitro T/₂s for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship. in vitro T/₂ = 0.693/k k = -[slope of linear regression of % parent remaining (In) vs incubation time] The apparent intrinsic clearance is calculated using the following equation:

CLint (mL/min/kg) = (0.693 / in vitro T) (Incubation Volume / mg of microsomes) (45 mg microsomes / gram of liver) (20 gm of liver / kg b.w.)

Data analysis is performed using Microsoft Excel Software.

In these experiments, values equal to or more than a 15% increase in half-life are considered to be a significant difference if the apparent intrinsic clearance ratio (norpsilocin salt or solid form/ comparator solid form) is >1.15 or <0.85, then there is considered to be significant differentiation.

Biological Example 2 Oral Bioavailability in Rats

Pharmacokinetics of test articles following a single intravenous or oral administration in rats: A pharmacokinetic (PK) study is performed in three male Sprague-Dawley (SD) rats following intravenous (IV) and oral (PO) administration of a compound disclosed herein. Test compounds are measured in plasma.

A detailed description of the in vivo methods:

Rat Strain Rats used in these studies are supplied by Charles River (Margate UK) and are specific pathogen free. The strain of rats is Sprague Dawley. Male rats are 175 - 225g on receipt and are allowed to acclimatise for 5-7 days. Animal Housing

Rats are group housed in sterilised individual ventilated cages that expose the animals at all times to HEPA filtered sterile air. Animals will have free access to food and water (sterile) and will have sterile aspen chip bedding (at least once weekly). The room temperature is 22°C +/- 1°C, with a relative humidity of 60% and maximum background noise of 56dB. Rats are exposed to 12 hour light/dark cycles. Treatment

The test articles are administered in a suitable dose volume for intravenous (IV) or (PO) for oral routes of administration.

Single IV/PO dose pharmacokinetics study in rats

Each test article is administered as a single IV bolus (via a lateral tail-vein) or a single oral gavage in cohorts of 3 rats per route. Following dose administrations, a lOOpL whole blood sample (EDTA) is collected via the tail-vein at various time-points. The blood is centrifuged to separate plasma. Approximately 40pL of plasma is dispensed per time-point, per rat, in a 96 well plate and frozen until analysis. Bioanalysis is carried out on plasma samples.

Dose formulation Samples

Dose formulation samples were diluted in two steps with 50:50 (v/v) methanol/water to an appropriate concentration, then diluted 10:90 (v/v) with control matrix to match to the calibration standard in plasma.

Sample Extraction procedure

Calibration and QC standards, incurred samples, blank matrix and dose formulation samples were extracted by protein precipitation, via the addition of a bespoke acetonitrile (ACN)-based Internal Standard (IS) solution, containing several compounds and including Metoprolol and Rosuvastatin, both of which were monitored for during analysis. Following centrifugation, a 40 pL aliquot of supernatant was diluted by the addition of 80 pL water. The prepared sample extracts were analysed by LC-MS/MS. In one embodiment, the oral bioavailability of a disclosed crystalline solid form is superior to an amorphous or known crystalline form. Biological assays and methods

Head-Twitch Response (HTR). The head-twitch response assay is performed as is known to those of skill in the art using both male and female C57BL/6J mice (2 per treatment). The mice are obtained and were approximately 8 weeks old at the time of the experiments. Compounds were administered via intraperitoneal injection (5 mL/kg) using 0.9% saline as the vehicle. As a positive control, 5-MeO-DMT fumarate (2: 1 amine/acid) was utilized. Behavior was videotaped, later scored by two blinded observers, and the results were averaged (Pearson correlation coefficient = 0.93).

Serotonin and Opioid Receptor Functional Assays. Functional assay screens at 5- HT and opioid receptors are performed in parallel using the same compound dilutions and 384-well format high-throughput assay platforms. Assays assess activity at all human isoforms of the receptors, except where noted for the mouse 5-HT2A receptor. Receptor constructs in pcDNA vectors were generated from the Presto-Tango GPCR library with minor modifications. All compounds were serially diluted in drug buffer (HBSS, 20 mM HEPES, pH 7.4 supplemented with 0.1% bovine serum albumin and 0.01% ascorbic acid) and dispensed into 384-well assay plates using a FLIPR ^{E I RA} (Molecular Devices). Every plate included a positive control such as 5-HT (for all 5-HT receptors), DADLE (DOR), salvinorin A (KOR), and DAMGO (MOR). For measurements of 5-HT2A, 5-HT2B, and 5- HT2C Gq-mediated calcium flux function, HEK Flp-In 293 T-Rex stable cell lines (Invitrogen) were loaded with Fluo-4 dye for one hour, stimulated with compounds and read for baseline (0-10 seconds) and peak fold-over-basal fluorescence (5 minutes) at 25°C on the FLIPR^TETRA. For measurement of 5-HT6 and 5-HT7a functional assays, Gs-mediated cAMP accumulation was detected using the split-luciferase GloSensor assay in HEKT cells measuring luminescence on a Microbeta Trilux (Perkin Elmer) with a 15 min drug incubation at 25°C. For 5-HT1 A, 5-HT1B, 5-HT1F, MOR, KOR, and DOR functional assays, Gi/o- mediated cAMP inhibition was measured using the split-luciferase GloSensor assay in HEKT cells, conducted similarly as above, but in combination with either 0.3 pM isoproterenol (5- HT1A, 5-HT1B, 5-HT1F) or 1 pM forskolin (MOR, KOR, and DOR) to stimulate endogenous cAMP accumulation. For measurement of 5-HT1D, 5-HT1E, 5-HT4, and 5- HT5A functional assays, P-arrestin2 recruitment was measured by the Tango assay utilizing HTLA cells expressing TEV fused-P-arrestin2, as described previously with minor modifications. Data for all assays were plotted and non-linear regression was performed using “log(agonist) vs. response” in Graphpad Prism to yield Emax and ECso parameter estimates.

5HT2A Sensor Assays. HEK293T (ATCC) 5HT2A sensor stable line (sLightl.3s) is generated via lentiviral transduction of HIV-EFla-sLightl.3 and propagated from a single colony. Lentivirus is produced using 2^nd generation lentiviral plasmids pHIV-EFla - sLightl.3, pHCMV-G, and pCMV-deltaR8.2.

For the screening of the compounds, sLightl.3s cells are plated in 96-well plates at a density of 40000 24-hours prior to imaging. On the day of imaging, compounds in DMSO are diluted from the 100 mM stock preparations to working concentrations of 1 mM, 100 mM and 1 pM with a DMSO concentration of 1%. Immediately prior to imaging, cells growing in DMEM (Gibco) are washed 2x with HBSS (Gibco) and in agonist mode 180pL of HBSS or in antagonist mode 160pL of HBSS is added to each well after the final wash. For agonist mode, images are taken before and after the addition of the 20pL compound working preparation into the wells containing 180pL HBSS. This produces final compound concentrations of 100 mM, 10 mM and 100 nM with a DMSO concentration of 0.1%. For antagonist mode, images are taken before and after addition of 20pL of 900nM 5-HT and again after 20pL of the compound working preparation to produce final concentrations of lOOnM for 5HT and lOOmM, lOmM and lOOnM for the compounds with a DMSO concentration of 0.1%. Each compound is tested in triplicate (3 wells) for each concentration (lOOmM, lOmM and lOOnM). Additionally, within each plate, lOOnM 5HT and 0.1% DMSO controls are also imaged.

Imaging is performed using the Leica DMi8 inverted microscope with a 40x objective using the FITC preset with an excitation of 460nm and emission of 512-542nm. For each well, the cellular membrane where the 5HT2A sensor is targeted is autofocused using the adaptive focus controls and 5 images from different regions within the well were taken with each image processed from a 2x2 binning.

For data processing, the membranes from each image are segmented and analyzed using a custom algorithm written in MATFAB producing a single raw fluorescence intensity value. For each well the 5 raw fluorescence intensity values generated from the 5 images are averaged and the change in fluorescence intensity (dFF) is calculated as: dFF — (Fsat ^_ Fapo)/ Fapo

For both agonist and antagonist modes, the fluorescence intensity values before compound addition in FIBSS only are used as the F_apo values while the fluorescence intensity values after compound addition are used as the F_sat values. For agonist mode, data are as percent activation relative to 5HT, where 0 is the average of the DMSO wells and 100 is the average of the 100 pM 5HT wells. For antagonist mode, the inactivation score is calculated as:

Inactivation score = (dFFF(Compound+5HT) - dFF(5HT))/dFF(5HT)

Plasticity Effects: Treatment of rat embryonic cortical neurons with compounds disclosed herein is evaluated for increased dendritic arbor complexity at 6 days in vitro (DIV6) as measured by Sholl analysis. The effect of the present compounds on dendritic growth can be determined to be 5-HT2A-dependent, if pretreatment with ketanserin — a 5- HT2A antagonist — inhibits their effects.

In addition to promoting dendritic growth, the present compounds also are evaluated for increased dendritic spine density to a comparable extent as ibogaine in mature cortical cultures (DIV20). The effects of the compounds on cortical dendritic spine dynamics in vivo using transcranial 2-photon imaging is assessed. First, spines are imaged on specific dendritic loci defined by their relation to blood vessel and dendritic architectures. Next, the animals are systemically administered vehicle, a compound of the present invention, or a positive control compound. After 24 h, the same dendritic segments are re-imaged, and the number of spines gained or lost is quantified. Examples of the presently disclosed compounds increase spine formation in mouse primary sensory cortex, suggesting that the present compounds support neuronal plasticity.

As increased cortical structural plasticity in the anterior parts of the brain mediates the sustained (>24 h) antidepressant- like effects of ketamine and play a role in the therapeutic effects of 5-HT2A agonists, the impact of the present compounds on forced swim test (FST) behavior is evaluated. First, a pretest is used to induce a depressive phenotype. Compounds are administered 24 h after the pre-test, and the FST is performed 24 h and 7 d post compound administration. Effective compounds of the invention, like ketamine, significantly reduced immobility 24 h after administration.

Dendritogenesis Assays. Compounds disclosed herein are evaluated for their ability to increase dendritic arbor complexity in cultures of cortical neurons using a phenotypic assay. Following treatment, neurons are fixed and visualized using an antibody against MAP2 — a cytoskeletal protein localized to the somatodendritic compartment of neurons. Sholl analysis is then performed, and the maximum number of crossings (Nmax) was used as a quantitative metric of dendritic arbor complexity. For statistical comparisons between specific compounds, the raw Nmax values are compared. Percent efficacies are determined by setting the Nmax values for the vehicle (DMSO) and positive (ketamine) controls equal to 0% and 100%, respectively.

Animals. For the dendritogenesis experiments, timed pregnant Sprague Dawley rats are obtained. For the head-twitch response assay, male and female C57BL/6J mice are obtained.

Dendritogenesis - Sholl Analysis. Dendritogenesis experiments are performed following a previously published methods with slight modifications. Neurons are plated in 96-well format (200 pL of media per well) at a density of approximately 15,000 cells/well in Neurobasal (Life Technologies) containing 1% penicillin-streptomycin, 10% heat-inactivated fetal bovine serum, and 0.5 mM glutamine. After 24 h, the medium is replaced with Neurobasal containing lx B27 supplement (Life Technologies), 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 pM glutamate. After 3 days in vitro (DIV3), the cells are treated with compounds. All compounds tested in the dendritogenesis assays are treated at 10 pM. Stock preparations of the compounds in DMSO are first diluted 100-fold in Neurobasal before an additional 10-fold dilution into each well (total dilution = 1 : 1000; 0.1% DMSO concentration). Treatments are randomized. After 1 h, the media is removed and replaced with new Neurobasal media containing lx B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 mM glutamate. The cells are allowed to grow for an additional 71 h. At that time, neurons are fixed by removing 80% of the media and replacing it with a volume of 4% aqueous paraformaldehyde (Alfa Aesar) equal to 50% of the working volume of the well. Then, the cells are incubated at room temperature for 20 min before the fixative is aspirated and each well washed twice with DPBS. Cells are permeabilized using 0.2% Triton X-100 (ThermoFisher) in DPBS for 20 minutes at room temperature without shaking. Plates are blocked with antibody diluting buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS for 1 h at room temperature. Then, plates are incubated overnight at 4°C with gentle shaking in ADB containing a chicken anti-MAP2 antibody (1 : 10,000; EnCor, CPCA-MAP2). The next day, plates are washed three times with DPBS and once with 2% ADB in DPBS. Plates are incubated for 1 h at room temperature in ADB containing an antichicken IgG secondary antibody conjugated to Alexa Fluor 488 (Life Technologies, 1 : 500) and washed five times with DPBS. After the final wash, 100 pL of DPBS is added per well and imaged on an ImageXpress Micro XL High-Content Screening System (Molecular Devices, Sunnyvale, CA) with a 20x objective. Images are analyzed using ImageJ Fiji (version 1.51 W). First, images corresponding to each treatment are sorted into individual folders that are then blinded for data analysis. Plate controls (both positive and negative) are used to ensure that the assay is working properly as well as to visually determine appropriate numerical values for brightness/contrast and thresholding to be applied universally to the remainder of the randomized images. Next, the brightness/contrast settings are applied, and approximately 1-2 individual pyramidal-like neurons per image (i.e., no bipolar neurons) are selected using the rectangular selection tool and saved as separate files. Neurons are selected that do not overlap extensively with other cells or extend far beyond the field of view.

In Vivo Spine Dynamics. Male and female Thyl- GFP-M line mice (n = 5 per condition) are purchased from The Jackson Laboratory (J AX #007788) and maintained. In vivo transcranial two-photon imaging and data analysis are performed as previously described. Briefly, mice are anesthetized with an intraperitoneal (i.p.) injection of a mixture of ketamine (87 mg/kg) and xylazine (8.7 mg/kg). A small region of the exposed skull is manually thinned down to 20-30 pm for optical access. Spines on apical dendrites in mouse primary sensory cortices are imaged using a Bruker Ultima IV two-photon microscope equipped with an Olympus water-immersion objective (40x, NA = 0.8) and a Ti: Sapphire laser (Spectra-Physics Mai-Tai, excitation wavelength 920 nm). Images are taken at a zoom of 4.0 (pixel size 0.143 x 0.143 pm) and Z-step size of 0.7 pm. The mice receive an i.p. injection (injection volume = 5 mL/kg) of a disclosed compound immediately after they recover from anesthesia given prior to the first imaging session. The animals are re-imaged 24 h after drug administration. Dendritic spine dynamics were analyzed using ImageJ. Spine formation and elimination were quantified as percentages of spine number on day 0.

Forced Swim Test (FST). Male C57/BL6J mice (9-10 weeks old at time of experiment) are obtained. After 1 week in the vivarium each mouse is handled for approximately 1 minute by the experimenter for 3 consecutive days leading up to the first FST. All experiments are carried out by the same experimenter who performs handling. During the FST, mice undergo a 6 min swim session in a clear Plexiglas cylinder 40 cm tall, 20 cm in diameter, and filled with 30 cm of 24 ± 1°C water. Fresh water is used for every mouse. After handling and habituation to the experimenter, drug-naive mice first undergo a pretest swim to more reliably induce a depressive phenotype in the subsequent FST sessions. Immobility scores for all mice are determined after the pre-test and mice are randomly assigned to treatment groups to generate groups with similar average immobility scores to be used for the following two FST sessions. The next day, the animals receive intraperitoneal injections of experimental compounds (20 mg/kg), a positive control (ketamine, 3 mg/kg), or vehicle (saline). The animals were subjected to the FST 30 mins after injection and then returned to their home cages. All FSTs are performed between the hours of 8 am and 1 pm. Experiments are video-recorded and manually scored offline. Immobility time — defined as passive floating or remaining motionless with no activity other than that needed to keep the mouse’s head above water — is scored for the last 4 min of the 6 min trial.

Statistical analysis. Treatments are randomized, and data are analyzed by experimenters blinded to treatment conditions. Statistical analyses are performed using GraphPad Prism (version 8.1.2). The specific tests are F-statistics and degrees of freedom. All comparisons are planned prior to performing each experiment. For dendritogenesis experiments a one way ANOVA with Dunnett’s post hoc test is deemed most appropriate. Ketamine was included as a positive control to ensure that the assay is working properly.

Alcohol Use Disorder Model: To assess the anti -addictive potential of the present compounds, an alcohol drinking paradigm that models heavy alcohol use and binge drinking behavior in humans is employed. Using a 2-bottle choice setup (20% ethanol (v/v), EtOH vs. water, H2O), mice are subjected to repeated cycles of binge drinking and withdrawal over the course of 7 weeks.

This schedule results in heavy EtOH consumption, binge drinking-like behavior, and generates blood alcohol content equivalent to that of human subjects suffering from alcohol use disorder (AUD). Next, compounds of the disclosure are administered via intraperitoneal injection 3 h prior to a drinking session, and EtOH and H2O consumption is monitored. Effective compounds of the disclosure robustly reduce binge drinking during the first 4 h, decreasing EtOH consumption. With exemplary compounds, consumption of ethanol is lower for at least two days following administration with no effect on water intake. Efficacy in this assay suggests the present compounds are useful for the treatment of AUD.

In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims. 5-MEO-DALT EMBODIMENTS

1. A solid form of 5-MeO-DALT having at least one improved property compared to previously known solid forms of 5-MeO-DALT.

2. The solid form of embodiment 1, wherein the compound is a salt.

3. The solid form of embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-l,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane- 1,2-disulfonic acid, lactobionic acid, -toluenesulfonic acid, Z>-glucoheptonic acid, thiocyanic acid, (-)-Z-pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, Z>-gluconic acid, benzenesulfonic acid, Z>,Z-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, /.-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, hydrochloric acid, fumaric acid, xinafoic acid, or a combination thereof.

4. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to 5- MeO-DALT is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.

5. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to 5- MeO-DALT is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.

6. The solid from of embodiment 3, wherein the stoichiometric ratio of acid to 5- MeO-DALT is selected from about 0.5, 1 and 2 molar equivalents of the acid.

7 The solid form of embodiment 1, wherein the solid form is a free base form of 5-MeO-DALT.

8. The solid form of any one of embodiments 1 - 7, wherein the solid form is a crystalline solid. 9. The solid form of embodiment 8, wherein the crystalline solid is a substantially single polymorph.

10. The solid form of any of embodiments 1 - 9, wherein the solid form is a hydrate.

11. The solid form of any one of embodiments 1-10, wherein the at least one improved property is selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

12. The solid form of embodiment 11, wherein the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

13. A pharmaceutical composition, comprising a solid form of a compound according to any one of embodiments 1 - 12, and a pharmaceutically acceptable excipient.

14. A method, comprising administering to a subject an effective amount of a solid form of a compound according to any one of embodiments 1 - 14, or a pharmaceutical composition according to embodiment 13.

15. The method of embodiment 14, wherein the subject has a neurological disease or a psychiatric disorder, or both.

16. The method of embodiment 15, wherein the neurological disorder is a neurodegen erative disorder.

17. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder. 18. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

19. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

20. The method of any one of embodiments 14 - 19, wherein administering comprises oral, parenteral, or topical administration.

21. The method of any one of embodiments 14 - 19, wherein administering comprises oral administration.

22. The method of embodiment 20, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

23. The method of embodiment 15, further comprising administering to the subject an effective amount of an empathogenic agent.

24. The method of embodiment 23, wherein the empathogenic agent is MDMA.

25. The method of embodiment 15, further comprising administering a 5-HT2A antagonist to the subject.

26. The method of embodiment 25, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin. 5-MEO-DMT EMBODIMENTS

1. A solid form of 5-MeO-DMT having at least one improved property compared to previously known solid forms of 5-MeO-DMT.

2. The solid form of embodiment 1, wherein the compound is a salt.

3. The solid form of embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-l,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane- 1,2-disulfonic acid, lactobionic acid, -toluenesulfonic acid, Z>-glucoheptonic acid, thiocyanic acid, (-)-Z-pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, Z>-gluconic acid, benzenesulfonic acid, Z>,Z-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, /.-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, hydrochloric acid, fumaric acid, xinafoic acid, or a combination thereof.

4. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to 5- MeO-DMT is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.

5. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to 5- MeO-DMT is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.

6. The solid from of embodiment 3, wherein the stoichiometric ratio of acid to 5- MeO-DMT is selected from about 0.5, 1 and 2 molar equivalents of the acid.

7 The solid form of embodiment 1, wherein the solid form is a free base form of 5-MeO-DMT.

8. The solid form of any one of embodiments 1 - 7, wherein the solid form is a crystalline solid. 9. The solid form of embodiment 8, wherein the crystalline solid is a substantially single polymorph.

10. The solid form of any of embodiments 1 - 9, wherein the solid form is a hydrate.

11. The solid form of any one of embodiments 1-10, wherein the at least one improved property is selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

12. The solid form of embodiment 11, wherein the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

13. A pharmaceutical composition, comprising a solid form of a compound according to any one of embodiments 1 - 12, and a pharmaceutically acceptable excipient.

14. A method, comprising administering to a subject an effective amount of a solid form of a compound according to any one of embodiments 1 - 14, or a pharmaceutical composition according to embodiment 13.

15. The method of embodiment 14, wherein the subject has a neurological disease or a psychiatric disorder, or both.

16. The method of embodiment 15, wherein the neurological disorder is a neurodegen erative disorder.

17. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder. 18. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

19. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

20. The method of any one of embodiments 14 - 19, wherein administering comprises oral, parenteral, or topical administration.

21. The method of any one of embodiments 14 - 19, wherein administering comprises oral administration.

22. The method of embodiment 20, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

23. The method of embodiment 15, further comprising administering to the subject an effective amount of an empathogenic agent.

24. The method of embodiment 23, wherein the empathogenic agent is MDMA.

25. The method of embodiment 15, further comprising administering a 5-HT2A antagonist to the subject.

26. The method of embodiment 25, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin. AERUGINASCIN EMBODIMENTS

1. A solid form of aeruginascin having at least one improved property compared to previously known solid forms of aeruginascin.

2. The solid form of embodiment 1, wherein the compound is a salt.

3. The solid form of embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-l,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane- 1,2-disulfonic acid, lactobionic acid, -toluenesulfonic acid, £>-glucoheptonic acid, thiocyanic acid, (-)-Z-pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, £>-gluconic acid, benzenesulfonic acid, £>,Z-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, /.-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, hydrochloric acid, fumaric acid, xinafoic acid, or a combination thereof.

4. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to aeruginascin is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.

5. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to aeruginascin is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.

6. The solid from of embodiment 3, wherein the stoichiometric ratio of acid to aeruginascin is selected from about 0.5, 1 and 2 molar equivalents of the acid.

7 The solid form of embodiment 1, wherein the solid form is a free base form of aeruginascin.

8. The solid form of any one of embodiments 1 - 7, wherein the solid form is a crystalline solid. 9. The solid form of embodiment 8, wherein the crystalline solid is a substantially single polymorph.

10. The solid form of any of embodiments 1 - 9, wherein the solid form is a hydrate.

11. The solid form of any one of embodiments 1-10, wherein the at least one improved property is selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

12. The solid form of embodiment 11, wherein the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

13. A pharmaceutical composition, comprising a solid form of a compound according to any one of embodiments 1 - 12, and a pharmaceutically acceptable excipient.

14. A method, comprising administering to a subject an effective amount of a solid form of a compound according to any one of embodiments 1 - 14, or a pharmaceutical composition according to embodiment 13.

15. The method of embodiment 14, wherein the subject has a neurological disease or a psychiatric disorder, or both.

16. The method of embodiment 15, wherein the neurological disorder is a neurodegen erative disorder.

17. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder. 18. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

19. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

20. The method of any one of embodiments 14 - 19, wherein administering comprises oral, parenteral, or topical administration.

21. The method of any one of embodiments 14 - 19, wherein administering comprises oral administration.

22. The method of embodiment 20, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

23. The method of embodiment 15, further comprising administering to the subject an effective amount of an empathogenic agent.

24. The method of embodiment 23, wherein the empathogenic agent is MDMA.

25. The method of embodiment 15, further comprising administering a 5-HT2A antagonist to the subject.

26. The method of embodiment 25, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin. BAEOCYSTIN EMBODIMENTS

1. A solid form of baeocystin having at least one improved property compared to previously known solid forms of baeocystin.

2. The solid form of embodiment 1, wherein the compound is a salt.

3. The solid form of embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-l,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane- 1,2-disulfonic acid, lactobionic acid, -toluenesulfonic acid, Z>-glucoheptonic acid, thiocyanic acid, (-)-Z-pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, Z>-gluconic acid, benzenesulfonic acid, Z>,Z-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, /.-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, hydrochloric acid, fumaric acid, xinafoic acid, or a combination thereof.

4. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to baeocystin is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.

5. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to baeocystin is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.

6. The solid from of embodiment 3, wherein the stoichiometric ratio of acid to baeocystin is selected from about 0.5, 1 and 2 molar equivalents of the acid.

7 The solid form of embodiment 1, wherein the solid form is a free base form of baeocystin.

8. The solid form of any one of embodiments 1 - 7, wherein the solid form is a crystalline solid. 9. The solid form of embodiment 8, wherein the crystalline solid is a substantially single polymorph.

10. The solid form of any of embodiments 1 - 9, wherein the solid form is a hydrate.

11. The solid form of any one of embodiments 1-10, wherein the at least one improved property is selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

12. The solid form of embodiment 11, wherein the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

13. A pharmaceutical composition, comprising a solid form of a compound according to any one of embodiments 1 - 12, and a pharmaceutically acceptable excipient.

14. A method, comprising administering to a subject an effective amount of a solid form of a compound according to any one of embodiments 1 - 14, or a pharmaceutical composition according to embodiment 13.

15. The method of embodiment 14, wherein the subject has a neurological disease or a psychiatric disorder, or both.

16. The method of embodiment 15, wherein the neurological disorder is a neurodegen erative disorder.

17. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder. 18. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

19. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

20. The method of any one of embodiments 14 - 19, wherein administering comprises oral, parenteral, or topical administration.

21. The method of any one of embodiments 14 - 19, wherein administering comprises oral administration.

22. The method of embodiment 20, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

23. The method of embodiment 15, further comprising administering to the subject an effective amount of an empathogenic agent.

24. The method of embodiment 23, wherein the empathogenic agent is MDMA.

25. The method of embodiment 15, further comprising administering a 5-HT2A antagonist to the subject.

26. The method of embodiment 25, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin.

DMT EMBODIMENTS 1. A solid form of DMT having at least one improved property compared to previously known solid forms of DMT.

2. The solid form of embodiment 1, wherein the compound is a salt.

3. The solid form of embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-l,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane- 1,2-di sulfonic acid, lactobionic acid, -toluenesulfonic acid, Z>-glucoheptonic acid, thiocyanic acid, (-)-Z-pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, Z>-gluconic acid, benzenesulfonic acid, Z>,Z-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, /.-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, hydrochloric acid, fumaric acid, xinafoic acid, or a combination thereof.

4. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to DMT is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.

5. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to DMT is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.

6. The solid from of embodiment 3, wherein the stoichiometric ratio of acid to DMT is selected from about 0.5, 1 and 2 molar equivalents of the acid.

7 The solid form of embodiment 1, wherein the solid form is a free base form of DMT.

8. The solid form of any one of embodiments 1 - 7, wherein the solid form is a crystalline solid.

9. The solid form of embodiment 8, wherein the crystalline solid is a substantially single polymorph. 10. The solid form of any of embodiments 1 - 9, wherein the solid form is a hydrate.

11. The solid form of any one of embodiments 1-10, wherein the at least one improved property is selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

12. The solid form of embodiment 11, wherein the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

13. A pharmaceutical composition, comprising a solid form of a compound according to any one of embodiments 1 - 12, and a pharmaceutically acceptable excipient.

14. A method, comprising administering to a subject an effective amount of a solid form of a compound according to any one of embodiments 1 - 14, or a pharmaceutical composition according to embodiment 13.

15. The method of embodiment 14, wherein the subject has a neurological disease or a psychiatric disorder, or both.

16. The method of embodiment 15, wherein the neurological disorder is a neurodegen erative disorder.

17. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder.

18. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. 19. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

20. The method of any one of embodiments 14 - 19, wherein administering comprises oral, parenteral, or topical administration.

21. The method of any one of embodiments 14 - 19, wherein administering comprises oral administration.

22. The method of embodiment 20, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

23. The method of embodiment 15, further comprising administering to the subject an effective amount of an empathogenic agent.

24. The method of embodiment 23, wherein the empathogenic agent is MDMA.

25. The method of embodiment 15, further comprising administering a 5-HT2A antagonist to the subject.

26. The method of embodiment 25, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin.

LISURIDE EMBODIMENTS

1. A solid form of lisuride.

2. The solid form of embodiment 1, wherein the compound is a salt. 3. The solid form of embodiment 2, wherein the salt is an acid addition salt.

4. The solid form of embodiment 2, wherein the salt is not a maleate salt.

5. The solid form of embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-l,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane- 1,2-disulfonic acid, lactobionic acid, -toluenesulfonic acid, Z>-glucoheptonic acid, thiocyanic acid, (-)-Z-pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, Z>-gluconic acid, benzenesulfonic acid, Z>,Z-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, /.-aspartic acid, cinnamic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, fumaric acid, or a combination thereof.

6. The solid form of embodiment 3, wherein a stoichiometric ratio of acid to lisuride is from about 0.4 to about 2.2.

7. The solid form of embodiment 3, wherein a stoichiometric ratio of acid to lisuride is from about 0.5 to about 2.

8. The solid from of embodiment 3 wherein a stoichiometric ratio of acid to lisuride is selected from about 0.5, 1, or 2.

9. The solid form of embodiment 1, wherein the solid form is a free base form of lisuride.

10. The solid form of any of embodiments 1 - 9, wherein the solid form is a hydrate.

11. The solid form of any one of embodiments 1 - 10, wherein the solid form is a crystalline solid.

12. The solid form of embodiment 11, wherein the crystalline solid is a substantially single polymorph. 13. The solid form of embodiment 12, wherein the polymorph is selected to have one or more desired properties.

14. The solid form of embodiment 13, wherein the one or more desired properties are selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

15. The solid form of embodiment 13 or embodiment 14, wherein the one or more desired properties comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

16. A pharmaceutical composition, comprising a solid form of a compound according to any one of embodiments 1 - 15, and a pharmaceutically acceptable excipient.

17. A method, comprising administering to a subject an effective amount of a solid form of a compound according to any one of embodiments 1 - 15, or a pharmaceutical composition according to embodiment 16.

18. The method of embodiment 17, wherein the subject has a neurological disease, a psychiatric disorder, or both.

19. The method of embodiment 18, wherein the neurological disorder is a neurodegenerative disorder.

20. The method of embodiment 18, wherein the neurological disorder, psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder. 21. The method of embodiment 18, wherein the neurological disorder, psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

22. The method of embodiment 18, wherein the neurological disorder, psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

23. The method of any one of embodiments 18 - 22, wherein administering comprises oral, parenteral, or topical administration.

24. The method of any one of embodiments 18 - 22, wherein administering comprises oral administration.

25. The method of embodiment 17, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

26. The method of embodiment 18, further comprising administering to the subject an effective amount of an empathogenic agent.

27. The method of embodiment 26, wherein the empathogenic agent is MDMA.

28. The method of embodiment 18, further comprising administering a 5-HT2A antagonist to the subject.

29. The method of embodiment 28, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin.

LISURIDE MALEATE EMBODIMENTS

1. A solid form of lisuride maleate having at least one improved property. 2. A solid form of lisuride maleate made by the method described in Example 1.

3. The solid form of lisuride maleate according to embodiment 2 having at least one improved property compared to amorphous lisuride maleate.

4. The solid form of lisuride maleate according to any one of embodiments 1 - 3, wherein the at least one improved property comprises a physical property, chemical property, pharmacokinetic property, or a combination thereof.

5. The solid form of lisuride maleate of any one of embodiments 1 - 4, wherein the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

6. The solid form of lisuride maleate according to any one of embodiments 1 - 5, wherein the solid form of lisuride maleate is a hydrate.

7. A pharmaceutical composition, comprising a solid form of lisuride maleate according to any one of embodiments 1 - 6, and a pharmaceutically acceptable excipient.

8. A method, comprising administering to a subject an effective amount of a solid form of lisuride maleate according to any one of embodiments 1 - 6, or a pharmaceutical composition according to embodiment 7.

9. The method of embodiment 8, wherein the subject has a neurological disease or a psychiatric disorder, or both.

10. The method of embodiment 9, wherein the neurological disorder is a neurodegen erative disorder. 11. The method of embodiment 9, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder.

12. The method of embodiment 9, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

13. The method of embodiment 9, wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

14. The method of any one of embodiments 8 - 13, wherein administering comprises oral, parenteral, or topical administration.

15. The method of any one of embodiments 8 - 13, wherein administering comprises oral administration.

16. The method of embodiment 14, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

17. The method of embodiment 9, further comprising administering to the subject an effective amount of an empathogenic agent.

18. The method of embodiment 17, wherein the empathogenic agent is MDMA.

19. The method of embodiment 9, further comprising administering a 5-HT2A antagonist to the subject.

20. The method of embodiment 19, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin. NORPSILOCIN EMBODIMENTS

1. A solid form of norpsilocin having at least one improved property compared to previously known solid forms of norpsilocin.

2. The solid form of embodiment 1, wherein the compound is a salt.

3. The solid form of embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-l,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane- 1,2-disulfonic acid, lactobionic acid, -toluenesulfonic acid, Z>-glucoheptonic acid, thiocyanic acid, (-)-Z-pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, Z>-gluconic acid, benzenesulfonic acid, Z>,Z-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, /.-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, hydrochloric acid, fumaric acid, xinafoic acid, or a combination thereof.

4. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to norpsilocin is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.

5. The solid form of embodiment 3, wherein the stoichiometric ratio of acid to norpsilocin is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.

6. The solid from of embodiment 3, wherein the stoichiometric ratio of acid to norpsilocin is selected from about 0.5, 1 and 2 molar equivalents of the acid.

7 The solid form of embodiment 1, wherein the solid form is a free base form of norpsilocin.

8. The solid form of any one of embodiments 1 - 7, wherein the solid form is a crystalline solid.

9. The solid form of embodiment 8, wherein the crystalline solid is a substantially single polymorph. 10. The solid form of any of embodiments 1 - 9, wherein the solid form is a hydrate.

11. The solid form of any one of embodiments 1-10, wherein the at least one improved property is selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

12. The solid form of embodiment 11, wherein the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

13. A pharmaceutical composition, comprising a solid form of a compound according to any one of embodiments 1 - 12, and a pharmaceutically acceptable excipient.

14. A method, comprising administering to a subject an effective amount of a solid form of a compound according to any one of embodiments 1 - 14, or a pharmaceutical composition according to embodiment 13.

15. The method of embodiment 14, wherein the subject has a neurological disease or a psychiatric disorder, or both.

16. The method of embodiment 15, wherein the neurological disorder is a neurodegen erative disorder.

17. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder. 18. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

19. The method of embodiment 15, wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

20. The method of any one of embodiments 14 - 19, wherein administering comprises oral, parenteral, or topical administration.

21. The method of any one of embodiments 14 - 19, wherein administering comprises oral administration.

22. The method of embodiment 20, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

23. The method of embodiment 15, further comprising administering to the subject an effective amount of an empathogenic agent.

24. The method of embodiment 23, wherein the empathogenic agent is MDMA.

25. The method of embodiment 15, further comprising administering a 5-HT2A antagonist to the subject.

26. The method of embodiment 25, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin.

Claims

CLAIMS What is claimed is:

1. A solid form of lisuride.

2. The solid form of claim 1, wherein the compound is a salt.

3. The solid form of claim 2, wherein the salt is an acid addition salt.

4. The solid form of claim 2, wherein the salt is not a maleate salt.

5. The solid form of claim 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthal ene-l,5-disulfonic acid, citric acid, sulfuric acid, d- glucuronic acid, ethane- 1,2-disulfonic acid, lactobionic acid, -toluenesulfonic acid, D- glucoheptonic acid, thiocyanic acid, (-)-Z-pyroglutamic acid, methanesulfonic acid, /.-malic acid, dodecyl sulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, Z>-gluconic acid, benzenesulfonic acid, Z>,Z-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, /.-aspartic acid, cinnamic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, fumaric acid, or a combination thereof.

6. The solid form of claim 3, wherein a stoichiometric ratio of acid to lisuride is from about 0.4 to about 2.2.

7. The solid form of claim 3, wherein a stoichiometric ratio of acid to lisuride is from about 0.5 to about 2.

8. The solid from of claim 3 wherein a stoichiometric ratio of acid to lisuride is selected from about 0.5, 1, or 2.

9. The solid form of claim 1, wherein the solid form is a free base form of lisuride.

10. The solid form of any of claims 1 - 9, wherein the solid form is a hydrate.

11. The solid form of any one of claims 1 - 10, wherein the solid form is a crystalline solid.

12. The solid form of claim 11, wherein the crystalline solid is a substantially single polymorph.

13. The solid form of claim 12, wherein the polymorph is selected to have one or more desired properties.

14. The solid form of claim 13, wherein the one or more desired properties are selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

15. The solid form of claim 13 or claim 14, wherein the one or more desired properties comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

16. A pharmaceutical composition, comprising a solid form of a compound according to any one of claims 1 - 15, and a pharmaceutically acceptable excipient.

17. A method, comprising administering to a subject an effective amount of a solid form of a compound according to any one of claims 1 - 15, or a pharmaceutical composition according to claim 16.

18. The method of claim 17, wherein the subject has a neurological disease, a psychiatric disorder, or both.

19. The method of claim 18, wherein the neurological disorder is a neurodegen erative disorder.

20. The method of claim 18, wherein the neurological disorder, psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder.

21. The method of claim 18, wherein the neurological disorder, psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

22. The method of claim 18, wherein the neurological disorder, psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

23. The method of any one of claims 18 - 22, wherein administering comprises oral, parenteral, or topical administration.

24. The method of any one of claims 18 - 22, wherein administering comprises oral administration.

25. The method of claim 17, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

26. The method of claim 18, further comprising administering to the subject an effective amount of an empathogenic agent.

27. The method of claim 26, wherein the empathogenic agent is MDMA.

28. The method of claim 18, further comprising administering a 5-HT2A antagonist to the subject.

29. The method of claim 28, wherein the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin.