Psilocin Crystal Form

Abstract

The present invention relates to crystalline forms of psilocin (4-hydroxy-N,N-dimethyltryptamine) salts or co-crystals, as well as compositions, methods of preparation, and methods of use thereof. The present invention also relates to said crystalline forms having improved physical properties, such as aqueous solubility and stability, wherein said crystalline forms and compositions thereof are suitable for oral, subcutaneous, intravenous, or intramuscular administration.

Description

[Technical Field]

[0001] Technical Field The present invention relates to a crystalline form of psilocin. Specifically, the present invention relates to a crystalline form of psilocin having improved physical properties such as aqueous solubility and stability.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 375,305, filed September 12, 2022, which is incorporated by reference in its entirety. [Background technology]

[0003] Background of the Invention

[0003] Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a naturally occurring psychoactive compound that can be isolated from psilocybin mushrooms. In vivo, psilocybin is rapidly dephosphorylated to the psychoactive compound psilocin. Research into the therapeutic benefits of psilocybin and its active metabolite, psilocin, has led to the use of these psychoactive substances for the treatment of a variety of conditions, including drug addiction, anxiety, depression, PTSD and eating disorders, and chronic pain.

[0004]

[0004] Both psilocin and psilocybin have limited stability in aqueous solutions, and such solutions degrade rapidly when exposed to light. Furthermore, the active agent, psilocin, has relatively low solubility in aqueous media, which limits its ability to be used in dosage forms suitable for, for example, intravenous or subcutaneous injection.

[0005]

[0005] Due to the potentially variable effects of psilocin on each individual and the variability of absorption after oral administration, it is difficult to provide a precise dose with predictable effects. Furthermore, the onset of therapeutic effect after oral administration is typically slow, beginning up to about 40 minutes after administration, and often not achieving a peak effect within several hours after administration. An intravenous formulation of psilocin is desirable because it has the potential to standardize interindividual variability in plasma concentrations and provide a more rapid onset of action. IV administration can also control the duration of the hallucinogenic experience.

[0006]

[0006] Furthermore, the increasing popularity and research into "microdosing" (i.e., administering psilocin or psilocybin in amounts significantly lower than typical therapeutic or recreational doses) means that there is a need to produce psilocin formulations that can be reliably used to accurately administer low doses, e.g., maintenance doses.

[0007]

[0007] Pharmaceutically active agents in crystalline or amorphous solid form can exist as single-component and multi-component solids. Single-component solids consist essentially of the agent in the absence of other substances. Single-component crystalline materials can exist as different polymorphs with different three-dimensional arrangements of the constituent components. Importantly, different polymorphs can have different properties, such as differences in stability, solubility, melting point, reactivity, and other processability.

[0008]

[0008] Multi-component solids containing two or more ionic species are called salts. Pharmaceutically active agents or their salts may also exist in forms such as hydrates, solvates, or co-crystals. Multi-component crystalline forms may also exhibit polymorphism if the components exist in two or more three-dimensional crystalline arrangements, each of which potentially exhibits different physical properties.

[0009]

[0009] Cocrystals are crystalline molecular complexes of two or more compounds held together in a crystal lattice by non-ionic interactions. Pharmaceutical cocrystals are cocrystals of an active drug with one or more compounds called coformers. Typical coformers include non-toxic, pharmaceutically acceptable substances such as food additives, preservatives, pharmaceutical excipients, or other active agents. Summary of the Invention [Problem to be solved by the invention]

[0010]

[0010] For at least the reasons stated above, there is a need to produce salt or co-crystal forms of psilocin that have improved aqueous solubility and / or stability. [Means for solving the problem]

[0011] overview According to a first aspect, the present invention provides a crystalline form of a pharmaceutically acceptable salt of psilocin (4-hydroxy-N,N-dimethyltryptamine), or a co-crystal of psilocin (4-hydroxy-N,N-dimethyltryptamine) with a coformer. In one embodiment, the pharmaceutically acceptable salt is an acid.

[0012]

[0012] The acid or coformer may be selected from one or more of acetic acid, aconitic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, erythorbic acid, fumaric acid, gentisic acid, glutamic acid, glycolic acid, hydrochloric acid, maleic acid, phosphoric acid, pyroglutamic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, arginine, lysine, methylparaben, nicotinamide, and ethyl acetate.

[0013]

[0013] In one embodiment, the acid is benzenesulfonic acid. The crystalline form can be besylate Form A.

[0014] Besylate Form A exhibits XRPD (X-ray powder diffraction) peaks at about 15.44° 2θ ± 0.20, 18.33° 2θ ± 0.20, and 25.41° 2θ ± 0.20, or peaks at about 14.73° 2θ ± 0.20, 15.44° 2θ ± 0.20, 18.33° 2θ ± 0.20, 22.59° 2θ ± 0.20, and 25.41° 2θ ± 0.20; or peaks at about 11.72° 2θ ± 0.20, 12.47° 2θ ± 0.20, 13.49° 2θ ± 0.20, 14.73° 2θ ± 0.20, 15.44° 2θ ± 0.20, 18.33° 2θ±0.20, 20.62° 2θ±0.20, 20.99° 2θ±0.20, 21.77° 2θ±0.20, 22.25° 2θ±0.20, 22.59° 2θ±0.20, 23.22° 2θ±0.20, 23.71° 2θ±0.20, 24.10° 2θ±0.20, and 25.41° 2θ±0.20.

[0015] In one embodiment, besylate Form A has a viscosity of about 7.69° 2θ ± 0.20, 10.26° 2θ ± 0.20, 10.96° 2θ ± 0.20, 11.72° 2θ ± 0.20, 12.47° 2θ ± 0.20, 12.84° 2θ ± 0.20, 13.49° 2θ ± 0.20, 14.73° 2θ ± 0.20, 15.44° 2θ ± 0.20, 16.18° 2θ ± 0.20, 18.33° 2θ ± 0.20, 19.04° 2θ ± 0.20, 19.68° 2θ ± 0.20, 20.62° 2θ ± 0.20, 20.99° 2θ±0.20, 21.77° 2θ±0.20, 22.25° 2θ±0.20, 22.59° 2θ±0.20, 23.22° 2θ±0.20, 23.71° 2θ±0.20, 24.10° 2θ±0.20, 25.15° 2θ±0.20, 25.41° 2θ±0.20, 25.65° 2θ±0.20, 26.29° 2θ±0.20, 26.76° 2θ±0.20, 27.72° 2θ±0.20, 27.99° 2θ±0.20, 28.67° 2θ±0.20, 28.93° 2θ±0.20, 29.63° 2θ±0.20, 30.43° 2θ±0.20, 30.76° 2θ±0.20, 31.15° 2θ±0.20, 31.77° 2θ±0.20, 32.13° 2θ±0.20, 32.94° 2θ±0.20, 33.65° 2θ±0.20, 34.94° 2θ±0.20, 35.69° 2θ±0.20, and 36.49° 2θ±0.20.

[0016] In another embodiment, besylate Form A is characterized by an X-ray powder diffraction spectrum substantially as depicted in FIG.

[0017]

[0017] In another embodiment, the acid is butyric acid. The crystalline form can be butyrate form A.

[0018] Butyrate Salt Form A may exhibit XRPD (X-ray powder diffraction) peaks at about 13.24° 2θ ± 0.20, 15.34° 2θ ± 0.20, and 15.88° 2θ ± 0.20; or may exhibit peaks at about 13.24° 2θ ± 0.20, 15.34° 2θ ± 0.20, 15.88° 2θ ± 0.20, 16.28° 2θ ± 0.20, 20.95° 2θ ± 0.20, and 27.79° 2θ ± 0.20; or may exhibit peaks at about 9.33° 2θ ± 0.20, 9.96° 2θ ± 0.20, 10.66° 2θ ± 0.20, 13.24° 2θ ± 0.20, 15.34° 2θ±0.20, 15.88° 2θ±0.20, 16.28° 2θ±0.20, 17.80° 2θ±0.20, 20.95° 2θ±0.20, 21.98° 2θ±0.20, 22.32° 2θ±0.20, 23.31° 2θ±0.20, 24.61° 2θ±0.20, and 27.79° 2θ±0.20.

[0019] In one embodiment, butyrate Form A has a symmetry of about 9.33° 2θ ± 0.20, 9.96° 2θ ± 0.20, 10.66° 2θ ± 0.20, 12.96° 2θ ± 0.20, 13.24° 2θ ± 0.20, 14.36° 2θ ± 0.20, 15.34° 2θ ± 0.20, 15.88° 2θ ± 0.20, 16.28° 2θ ± 0.20, 17.80° 2θ ± 0.20, 18.36° 2θ ± 0.20, 18.75° 2θ ± 0.20, 18.97° 2θ ± 0.20, 19.63° 2θ ± 0.20, 20.01° 2θ ± 0.20, 20.35° 2θ±0.20, 20.95° 2θ±0.20, 21.44° 2θ±0.20, 21.98° 2θ±0.20, 22.32° 2θ±0.20, 22.80° 2θ±0.20, 23.31° 2θ±0.20, 23.77° 2θ±0.20, 24.41° 2θ±0.20, 24.61° 2θ±0.20, 25.46° 2θ±0.20, 25.60° 2θ±0.20, 26.22° 2θ±0.20, 26.67° 2θ±0.20, 27.79° 2θ±0.20, and 29.07° 2θ±0.20.

[0020] In another embodiment, the butyrate salt Form A is characterized by an X-ray powder diffraction spectrum substantially as depicted in FIG.

[0021]

[0021] In another embodiment, the acid is gentisic acid. The crystalline form is gentisate Form A.

[0022] Gentisate Form A may exhibit XRPD peaks at about 15.80° 2θ ± 0.20, 16.51° 2θ ± 0.20, and 23.98° 2θ ± 0.20; or may exhibit XRPD peaks at about 15.52° 2θ ± 0.20, 15.80° 2θ ± 0.20, 16.51° 2θ ± 0.20, 23.98° 2θ ± 0.20, and 24.74° 2θ ± 0.20; or at about 12.77° 2θ ± 0.20, 14.08° 2θ ± 0.20, 15.52° 2θ ± 0.20, 15.80° 2θ ± 0.20, 15.98±0.20, 16.51° 2θ±0.20, 17.30° 2θ±0.20, 18.58° 2θ±0.20, 20.95° 2θ±0.20, 21.64° 2θ±0.20, 23.38° 2θ±0.20, 23.98° 2θ±0.20, 24.74° 2θ±0.20, 25.19° 2θ±0.20, 27.81° 2θ±0.20, 28.41° 2θ±0.20, and 28.80° 2θ±0.20.

[0023] In one embodiment, gentisate Form A has a molecular weight of about 7.74° 2θ ± 0.20, 9.01° 2θ ± 0.20, 11.01° 2θ ± 0.20, 12.29° 2θ ± 0.20, 12.77° 2θ ± 0.20, 13.15° 2θ ± 0.20, 13.80° 2θ ± 0.20, 14.08° 2θ ± 0.20, 15.52° 2θ ± 0.20, 15.80° 2θ ± 0.20, 15.98° 2θ ± 0.20, 16.11° 2θ ± 0.20, 16.51° 2θ ± 0.20, 17.30° 2θ ± 0.20, 18.07° 2θ±0.20, 18.58° 2θ±0.20, 19.13° 2θ±0.20, 19.39° 2θ±0.20, 19.56° 2θ±0.20, 20.95° 2θ±0.20, 21.64° 2θ±0.20, 22.18° 2θ±0.20, 22.45° 2θ±0.20, 23.03° 2θ±0.20, 23.38° 2θ±0.20, 23.98° 2θ±0.20, 24.74° 2θ±0.20, 24.95° 2θ±0.20, 25.19° 2θ±0.20, 25.71° 2θ±0.20, 26.08° 2θ±0.20, 26.47° 2θ±0.20, 27.28° 2θ±0.20, 27.81° 2θ±0.20, 28.41° 2θ±0.20, 28.80° 2θ±0.20, 30.13° 2θ±0.20, 30.66° 2θ±0.20, 31.90° 2θ±0.20, 32.16° 2θ±0.20, 32.57° 2θ±0.20, 33.37° 2θ±0.20, 33.75° 2θ±0.20, 34.77° 2θ±0.20, 35.29° 2θ±0.20, 36.25° 2θ±0.20, and 36.80° It exhibits XRPD peaks at 2θ±0.20.

[0024] In another embodiment, gentisate Form A is characterized by an X-ray powder diffraction spectrum substantially as depicted in FIG.

[0025]

[0025] In another embodiment, the acid is benzoic acid. The crystalline form is Benzoate Form A, characterized, for example, by an X-ray powder diffraction spectrum substantially as depicted in Figure 16.

[0026]

[0026] In another embodiment, the acid is fumaric acid. The crystalline form is fumarate Form A, characterized, for example, by an X-ray powder diffraction spectrum substantially as depicted in Figure 19.

[0027]

[0027] In another embodiment, the acid is tartaric acid. The crystalline form is tartrate salt Form A, characterized, for example, by an X-ray powder diffraction spectrum substantially as depicted in Figure 23.

[0028]

[0028] In some embodiments, the crystalline form may be stable after storage at 25°C, 40°C, or 70°C for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or at least 1 year.

[0029] The crystalline form may be more stable in water or saline compared to a psilocin standard in water or saline. For example, the crystalline form is stable during storage at 25°C, 40°C, or 70°C for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or at least 1 year.

[0030] In some embodiments, less than 10% of the crystalline form decomposes over a 36 hour period.

[0031] The solubility of the crystalline form can be from at least about 0.25 mg / mL to at least about 10 mg / mL in water or saline.

[0032] In a second aspect, there is provided a method of producing a crystalline form, comprising: a) reacting psilocin with an acid in a solvent; b) drying the resulting product of step a); A method is provided that includes:

[0033]

[0033] In a third aspect, there is provided a pharmaceutical composition comprising the crystalline form of the first aspect. The pharmaceutical composition may be formulated for oral, subcutaneous, intravenous, or intramuscular administration, intravenous administration.

[0034]

[0034] In a fourth aspect, there is provided a method of treating or preventing a disease or condition in a subject, comprising administering to the subject the crystalline form of the first aspect or the pharmaceutical composition of the third aspect.

[0035] In a fifth aspect, there is provided the use of a crystalline form of the first aspect or a pharmaceutical composition of the third aspect in the manufacture of a medicament for treating or preventing a disease or condition.

[0036] In a sixth aspect, there is provided a crystalline form of the first aspect or a pharmaceutical composition of the third aspect for use in treating or preventing a disease or condition in a subject. [Brief explanation of the drawings]

[0037] BRIEF DESCRIPTION OF THE DRAWINGS

[0037] [Figure 1]

[0038] 1 shows the XRPD pattern of psilocin free base. [Figure 2]

[0039] An indexing solution for psilocin free base with the following properties is shown:

[0038] [Table 1] [Figure 3]

[0040] 1 shows the 1H NMR spectrum of psilocin free base. [Figure 4]

[0041] 1 shows the XRPD pattern of psilocin besylate Form A. [Figure 5]

[0042] An indexing solution for psilocin besylate form A is shown, having the following properties:

[0039] [Table 2] [Figure 6]

[0043] 1H NMR spectrum of psilocin besylate Form A (middle panel) with reference spectra of psilocin free base (top panel) and benzenesulfonic acid (bottom panel). [Figure 7]

[0044] 1 shows the XRPD pattern of psilocin butyrate Form A. [Figure 8]

[0045] An indexing solution for psilocin butyrate form A is shown, having the following properties:

[0040] [Table 3] [Figure 9]

[0046] 1H NMR spectrum of psilocin butyrate Form A (bottom) with a reference spectrum of psilocin free base (top). [Figure 10]

[0047] XRPD overlays of gentisate psilocin Form A, including gentisate Form A from EtOAc / 2-8°C, RR (reaction ratio) 2:1 mol / mol (top); gentisate Form A, after drying, vacuum / RT / 1 d (middle); and gentisate Form A, prepared for additional material (bottom). [Figure 11]

[0048] An indexing solution for gentisic acid psilocin form A with the following properties is shown:

[0041] [Table 4] [Figure 12]

[0049] 1H NMR spectra of gentisic acid psilocin form A before (top center) and after drying (bottom center), including reference spectra of psilocin free base (top) and gentisic acid (bottom). [Figure 13]

[0050] 1 shows the XRPD pattern of psilocin acetate form A. [Figure 14]

[0051] An indexing solution for psilocin acetate form A is shown, having the following properties:

[0042] [Table 5] [Figure 15]

[0052] 1 shows the 1H NMR spectrum of psilocin acetate form A (middle) with reference spectra of psilocin free base (top) and acetic acid (bottom). [Figure 16]

[0053] 1 shows an XRPD overlay of psilocin benzoate Form A. [Figure 17]

[0054] An indexing solution for benzoic acid psilocin form A is shown, having the following properties:

[0043] [Table 6] [Figure 18]

[0055] 1H NMR spectra of psilocin benzoate form A before (top center) and after drying (bottom center), including reference spectra of psilocin free base (top) and benzoic acid (bottom). [Figure 19]

[0056] XRPD overlays of psilocin fumarate Form A and Form B from acetone / 2-8°C, RR 1:1 mol / mol (top); psilocin fumarate Form B + second phase from drying psilocin fumarate Form A (middle), and IPA, and psilocin fumarate Form B from drying, RR 1:1 mol / mol (bottom). [Figure 20]

[0057] An indexing solution for psilocin fumarate form A is shown, having the following properties:

[0044] [Table 7] [Figure 21]

[0058] An indexing solution for psilocin fumarate form B is shown, having the following properties:

[0045] [Table 8] [Figure 22]

[0059] 1H NMR spectra of psilocin fumarate Form A and psilocin fumarate Form B are shown, including a reference spectrum of psilocin free base (top row); psilocin fumarate Form A (top center); psilocin fumarate Form B (w / trace amount of second phase) (bottom center); and a reference spectrum of fumaric acid (bottom row). [Figure 23]

[0060] 1 shows the XRPD pattern of psilocin tartrate Form A. [Figure 24]

[0061] An indexing solution for psilocin tartrate form A with the following properties is shown:

[0046] [Table 9] [Figure 25]

[0062] 1 shows the 1H NMR spectrum of psilocin tartrate Form A (middle panel) with reference spectra of psilocin free base (top panel) and tartaric acid (bottom panel). [Figure 26]

[0063] 1 shows the stability over time of psilocin besylate, psilocin butyrate, and psilocin gentisate compared to psilocin in saline solution. The graph is based on psilocin peak area over time. [Figure 27]

[0064] 1 shows the stability over time of psilocin besylate, psilocin butyrate, and psilocin gentisate compared to psilocin in saline solution. The graph shows the psilocin peak area as a percentage over time. DETAILED DESCRIPTION OF THE INVENTION

[0047] definition

[0065] Throughout this specification, unless the context requires otherwise, the word "comprise", as well as variations such as "comprises" or "comprising", will be understood to mean the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps. The term "consisting of" means "consisting only of", i.e., including and limited to the stated elements, integers, or steps, and to the exclusion of any other elements, integers, or steps. The term "consisting essentially of" means the inclusion of the stated elements, integers, or steps, but may also include other elements, integers, or steps that do not materially alter or contribute to the mechanism of the invention.

[0048]

[0066] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention and is not to be construed as an admission that any or all of such matters form part of the prior art or were common general knowledge in the field relevant to the present invention as they existed prior to the priority date of each claim of this specification.

[0049]

[0067] Unless otherwise required by context or specifically stated otherwise, integers, steps, or elements of the technology recited herein as singular integers, steps, or elements explicitly encompass both the singular and plural forms of the recited integer, step, or element.

[0050]

[0068] In the context of this specification, the terms "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, a reference to "an" element means one element or more than one element.

[0051]

[0069] In the context of this specification, the term "about" means that reference to a number or value should not be considered an absolute number or value, but includes a range of tolerance for variation above or below that number or value consistent with what one of ordinary skill in the art would understand in accordance with the art, including within typical tolerances for error or instrumental limitations. In other words, the use of the term "about" will be understood to refer to a range or approximation that one of ordinary skill in the art would consider equivalent to the recited value in the context of achieving the same function or result.

[0052]

[0070] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic reaction, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base group with a suitable organic acid. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from inorganic or organic acids. Examples of inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, heterocyclic carboxylic and sulfo classes of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucoronic acid, fumaric acid, maleic acid, pyruvic acid, alkylsulfonic acids, arylsulfonic acids, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid, pamoic acid, pantothenic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, algenic acid, β-hydroxybutyric acid, galactaric acid, fumaric acid, and galacturonic acid.Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metal salts made from lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc, and organic salts made from organic bases such as choline, diethanolamine, and morpholine. Alternatively, suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine; ammonium salts; quaternary salts such as tetramethylammonium salts; and amino acid addition salts such as salts with glycine and arginine. It will be understood by those skilled in the art that, for compounds that are solids, the compounds, agents, and salts of the present invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formulations.

[0053]

[0071] The terms "treating," "treatment," and "therapy" are used herein to refer to curative, prophylactic, palliative, and preventative therapy. Thus, in the context of this disclosure, the term "treating" encompasses curing, ameliorating, or reducing the severity of a medical condition or one or more of its associated symptoms.

[0054]

[0072] The terms "therapeutically effective amount" or "pharmacologically effective amount" or "effective amount" refer to an amount of an agent sufficient to produce a desired therapeutic or pharmacological effect in a treated subject. These terms are synonymous and are intended to limit the amount of each agent that will achieve the goal of improving disease severity and / or frequency of occurrence, preferably while avoiding or minimizing adverse side effects (including side effects typically associated with other therapies) relative to treatment with each agent alone. Those skilled in the art can determine effective dosages using information known in the art and routine methods.

[0055]

[0073] "Pharmaceutical carriers, diluents, or excipients" include, but are not limited to, suitable water-soluble organic carriers, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, and any physiologically buffered medium (i.e., about pH 6.0 to 7.4). Suitable water-soluble organic carriers include, but are not limited to, saline, dextrose, corn oil, dimethyl sulfoxide, and gelatin capsules. Other common additives include binders such as lactose, mannitol, corn starch, potato starch, and microcrystalline cellulose; cellulose derivatives such as hydroxypropylmethylcellulose; gum arabic, gelatin, disintegrating agents such as sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate.

[0056]

[0074] A "subject" includes any human or non-human mammal. Thus, in addition to being useful for human treatment, the compounds of the invention may also be useful for veterinary treatment of mammals, including companion and livestock animals such as, but not limited to, dogs, cats, horses, cattle, sheep, and pigs. In a preferred embodiment, the subject is a human.

[0057]

[0075] In the context of this specification, the term "administering" and variations of this term (including "administer" and "administration") include contacting, applying, delivering, or providing a compound or composition of the invention to a subject by any suitable means.

[0058] Abbreviations and Glossary

[0076] "HPLC" refers to high performance liquid chromatography.

[0059]

[0077] "NMR" refers to nuclear magnetic resonance spectroscopy.

[0060]

[0078] "PLM" refers to polarized laser microscopy.

[0061]

[0079] "XRPD" refers to X-ray powder diffraction.

[0062]

[0080] "FE" stands for fast evaporation.

[0063]

[0081] "ACN" refers to acetonitrile.

[0064]

[0082] "DMSO" refers to dimethyl sulfoxide.

[0065]

[0083] "EtOAc" refers to ethyl acetate.

[0066]

[0084] "EtOH" refers to ethanol.

[0067]

[0085] "GRAS" stands for Generally Regarded as Safe.

[0068]

[0086] "HCl" refers to hydrochloric acid.

[0069]

[0087] "H2O" refers to water.

[0070]

[0088] "H3PO4" refers to phosphoric acid.

[0071]

[0089] "IPA" refers to isopropyl alcohol.

[0072]

[0090] "MeOH" refers to methanol.

[0073]

[0091] "MTBE" refers to methyl tert-butyl ether.

[0074]

[0092] "THF" refers to tetrahydrofuran.

[0075]

[0093] "Agg." refers to aggregate / agglomerate.

[0076]

[0094] "B / E" refers to birefringence / extinction.

[0077]

[0095] "d" refers to the day.

[0078]

[0096] "h" refers to hours.

[0079]

[0097] "IV" refers to intravenous.

[0080]

[0098] "LIMS" refers to Laboratory Information Management System.

[0081]

[0099] "mol" refers to mole.

[0082]

[0100] "min" refers to minutes.

[0083]

[0101] "N2" refers to nitrogen.

[0084]

[0102] "RR" refers to response ratio.

[0085]

[0103] "RT" refers to room temperature.

[0086]

[0104] "w / " means "with."

[0087]

[0105] "API Material X" refers to a material that is in an unknown crystalline form but has been identified as containing the API.

[0088]

[0106] "API Form X" refers to a material that has been identified as containing the API and has been demonstrated to be composed of a single crystalline form.

[0089]

[0107] "API Salt / Co-crystal Material X" refers to a material that is of unknown crystalline form but has been identified as containing a salt or co-crystal of the API.

[0090]

[0108] "API Salt / Co-crystal Form X" refers to a material that has been identified as containing a salt or co-crystal of an API and has been demonstrated to be composed in a single crystalline form.

[0091]

[0109] "Crystalline" refers to a material that produces an XRPD pattern with sharp peaks (similar to instrumental peak widths) and weak diffuse scattering (relative to the peaks).

[0092]

[0110] "Disordered crystalline" refers to a material that produces an XRPD pattern with broad peaks (compared to the instrumental peak widths) and / or strong diffuse scattering (compared to the peaks). Disordered materials are: Microcrystals Crystals with a high defect density A mixture of crystalline and X-ray amorphous phases Or it could be a combination of the above. Additional analysis can distinguish between these options.

[0093]

[0111] "Insufficient signal" refers to the situation where insufficient signal above the expected background scattering is observed, which may indicate that the X-ray beam missed the sample and / or that the sample was of insufficient mass for analysis.

[0094]

[0112] "Particle statistical artifacts" refers to the situation where the particle size distribution contains a small number of large crystals, which can result in a sharp spike in the XRPD pattern.

[0095]

[0113] "Preferred orientation artifact" refers to the situation where particle morphology tends to non-random orientation in the sample holder, which can result in subtle and / or dramatic changes in relative peak intensities.

[0096]

[0114] "No peaks" refers to the situation where no Bragg peaks are observed in the XRPD pattern. The absence of peaks may be due to an X-ray amorphous sample and / or insufficient signal.

[0097]

[0115] "Single crystalline phase" refers to the situation where an XRPD pattern is determined to contain evidence of a single crystalline phase when all of the Bragg peaks can be indexed to a single unit cell.

[0098]

[0116] "X-ray amorphous" refers to the situation where there is diffuse scattering in the XRPD pattern, but no evidence of Bragg peaks. X-ray amorphous materials are: Nanocrystals Crystals with very high defect density Dynamically amorphous materials Thermodynamically amorphous materials Or it could be a combination of the above. Additional analysis can distinguish between these options.

[0099] Detailed Description

[0117] The invention will be described with reference to various specific and preferred embodiments and techniques, but it should be understood that many variations and modifications can be made without departing from the spirit and scope of the invention.

[0100]

[0118] In a preferred embodiment, the present invention relates to a crystalline form of a pharmaceutically acceptable salt of psilocin (4-hydroxy-N,N-dimethyltryptamine), or a co-crystal thereof (wherein the co-crystal includes a coformer). Preferably, the crystalline form is besylate Form A, butyrate Form A, or gentisate Form A.

[0101]

[0119] The crystalline forms described herein have numerous advantages over psilocin. These advantages may include one or more of the following: ·Improved solubility. -Stability improvements. -Reduction of inter-individual variability in plasma concentrations after administration Self-preserved formula. -Improved manufacturing methods. ·Improved bioavailability. · Improved side effect profile.

[0102]

[0120] In some embodiments, the crystalline forms described herein can provide enhanced physical properties, such as solubility, dissolution rate, bioavailability, physical stability, chemical stability, flowability, fractability, or compressibility. In some embodiments, a given API can form various co-crystals with one or more different corresponding molecules, and some of these co-crystals can exhibit enhanced solubility or stability.

[0103]

[0121] In one embodiment, the crystalline form of psilocin is in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt can be selected from any pharmaceutically acceptable salt known in the art. Preferably, the pharmaceutically acceptable salt is a base acid. The acid can be selected from the group consisting of acetic acid, aconitic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, erythorbic acid, fumaric acid, gentisic acid, glutamic acid, glycolic acid, hydrochloric acid, maleic acid, phosphoric acid, pyroglutamic acid, sorbic acid, succinic acid, sulfuric acid, and tartaric acid. Preferably, the acid is benzenesulfonic acid, butyric acid, gentisic acid, acetic acid, benzoic acid, fumaric acid, or tartaric acid. Even more preferably, the acid is benzenesulfonic acid, butyric acid, or gentisic acid.

[0104]

[0122] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of psilocin is a co-crystal with a coformer, which may be any pharmaceutically acceptable coformer known in the art. Preferably, the coformer is arginine, acetylsalicylic acid, glucose, nicotinic acid, aconitic acid, glutamic acid, oxalic acid, adipic acid, glutaric acid, proline, 4-aminosalicylic acid, glycine, propyl gallate, ascorbic acid, glycolic acid, pyroglutamic acid, benzoic acid, hippuric acid, saccharin, camphoric acid, 1-hydroxy-2-naphthoic acid, salicylic acid, capric acid, ketoglutaric acid, sebacic acid, cinnamic acid, lysine, sodium lauryl sulfate, citric acid, magnesium bromide, sorbic acid, cyclamic acid, maleic acid, succinic acid, ethyl maltol, malic acid, tartaric acid, ethylparaben, malonic acid, urea, fructose, maltol, vanillic acid, fumaric acid, mandelic acid, vanillin, gallic acid, methylparaben, zinc chloride, gentisic acid, nicotinamide, or ethyl acetate. Preferably, the coformer is selected from the group consisting of arginine, lysine, methylparaben, nicotinamide, and ethyl acetate. Preferably, the coformer is ethyl acetate.

[0105]

[0123] In one embodiment, the present invention can be a crystalline or amorphous form or a mixture thereof (e.g., a mixture of crystalline forms, or a mixture of crystalline and amorphous forms) comprising (a) psilocin, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and (b) a coformer.

[0106]

[0124] In one embodiment, provided herein is a crystalline form comprising: (a) psilocin, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer.

[0107]

[0125] In one embodiment, provided herein is a cocrystal comprising (a) psilocin, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and (b) a coformer.

[0108]

[0126] In one embodiment, provided herein is an amorphous form comprising (a) psilocin, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and (b) a coformer.

[0109]

[0127] In one embodiment, provided herein is a mixture comprising: (i) a co-crystal comprising (a) psilocin, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and (b) a coformer; and (ii) a crystalline form of psilocin, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof.

[0110]

[0128] In one embodiment, provided herein is a mixture comprising: (i) a co-crystal comprising a) psilocin, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and (b) a coformer; and (ii) an amorphous form of psilocin, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof.

[0111]

[0129] In a preferred embodiment, the crystalline form is besylate Form A. Preferably, besylate Form A has an XRPD (X-ray powder diffraction) pattern with peaks at about 15.44° 2θ±0.20, 18.33° 2θ±0.20, and 25.41° 2θ±0.20. In another embodiment, the XRPD (X-ray powder diffraction) pattern has peaks at about 14.73° 2θ±0.20, 15.44° 2θ±0.20, 18.33° 2θ±0.20, 22.59° 2θ±0.20, and 25.41° 2θ±0.20. In another embodiment, the XRPD (X-ray powder diffraction) peaks at about 11.72° 2θ ± 0.20, 12.47° 2θ ± 0.20, 13.49° 2θ ± 0.20, 14.73° 2θ ± 0.20, 15.44° 2θ ± 0.20, 18.33° 2θ ± 0.20, 20.62° 2θ ± 0.20, 20.99° 2θ ± 0.20, 21.77° 2θ ± 0.20, 22.25° 2θ ± 0.20, 22.59° 2θ ± 0.20, 23.22° 2θ ± 0.20, 23.71° 2θ ± 0.20, 24.10° 2θ ± 0.20, and 25.41° 2θ ± 0.20.

[0112]

[0130] In one embodiment, besylate Form A has an XRPD (X-ray powder diffraction) pattern with a peak at about 15.44° 2θ. besylate Form A and having a viscosity of about 7.69° 2θ ± 0.20, 10.26° 2θ ± 0.20, 10.96° 2θ ± 0.20, 11.72° 2θ ± 0.20, 12.47° 2θ ± 0.20, 12.84° 2θ ± 0.20, 13.49° 2θ ± 0.20, 14.73° 2θ ± 0.20, 15.44° 2θ ± 0.20, 16.18° 2θ ± 0.20, 18.33° 2θ ± 0.20, 19.04° 2θ ± 0.20, 19.68° 2θ ± 0.20, 20.62° 2θ ± 0.20, 20.99° 2θ ± 0.20, 21.77° 2θ±0.20, 22.25° 2θ±0.20, 22.59° 2θ±0.20, 23.22° 2θ±0.20, 23.71° 2θ±0.20, 24.10° 2θ±0.20, 25.15° 2θ±0.20, 25.41° 2θ±0.20, 25.65° 2θ±0.20, 26.29° 2θ±0.20, 26.76° 2θ±0.20, 27.72° 2θ±0.20, 27.99° 2θ±0.20, 28.67° 2θ±0.20, 28.93° 2θ±0.20, 29.63° 2θ±0.20, 30.43° 5. The crystalline form of claim 4, exhibiting XRPD (X-ray powder diffraction) peaks at: 30.76° 2θ ± 0.20, 31.15° 2θ ± 0.20, 31.77° 2θ ± 0.20, 32.13° 2θ ± 0.20, 32.94° 2θ ± 0.20, 33.65° 2θ ± 0.20, 34.94° 2θ ± 0.20, 35.69° 2θ ± 0.20, and 36.49° 2θ ± 0.20.

[0113]

[0131] In one embodiment, besylate Form A has an XRPD pattern comprising peaks substantially or essentially the same as those shown in Figures 4 or 5. In one embodiment, besylate Form A comprises peaks substantially or essentially the same as those shown in Figure 6. 1 H NMR spectrum. Besylate Form A can be solvated, semi-solvated, or unsolvated. In a preferred embodiment, besylate Form A is unsolvated.

[0114]

[0132] In another preferred embodiment, the crystalline form is Butyrate Salt Form A. Preferably, Butyrate Salt Form A has an XRPD pattern with peaks at about 13.24° 2θ±0.20, 15.34° 2θ±0.20, and 15.88° 2θ±0.20.

[0115]

[0133] In another embodiment, butyrate salt Form A has an XRPD pattern with peaks at about 13.24° 2θ±0.20, 15.34° 2θ±0.20, 15.88° 2θ±0.20, 16.28° 2θ±0.20, 20.95° 2θ±0.20, and 27.79° 2θ±0.20.

[0116]

[0134] In another embodiment, butyrate salt Form A has an XRPD pattern with peaks at about 9.33° 2θ±0.20, 9.96° 2θ±0.20, 10.66° 2θ±0.20, 13.24° 2θ±0.20, 15.34° 2θ±0.20, 15.88° 2θ±0.20, 16.28° 2θ±0.20, 17.80° 2θ±0.20, 20.95° 2θ±0.20, 21.98° 2θ±0.20, 22.32° 2θ±0.20, 23.31° 2θ±0.20, 24.61° 2θ±0.20, and 27.79° 2θ±0.20.

[0117]

[0135] In a further embodiment, butyrate Form A has a viscosity of about 9.33° 2θ ± 0.20, 9.96° 2θ ± 0.20, 10.66° 2θ ± 0.20, 12.96° 2θ ± 0.20, 13.24° 2θ ± 0.20, 14.36° 2θ ± 0.20, 15.34° 2θ ± 0.20, 15.88° 2θ ± 0.20, 16.28° 2θ ± 0.20, 17.80° 2θ ± 0.20, 18.36° 2θ ± 0.20, 18.75° 2θ ± 0.20, 18.97° 2θ ± 0.20, 19.63° 2θ ± 0.20, 20.01° 2θ ± 0.20, 20.35° has an XRPD pattern with peaks at 2θ ± 0.20, 20.95° 2θ ± 0.20, 21.44° 2θ ± 0.20, 21.98° 2θ ± 0.20, 22.32° 2θ ± 0.20, 22.80° 2θ ± 0.20, 23.31° 2θ ± 0.20, 23.77° 2θ ± 0.20, 24.41° 2θ ± 0.20, 24.61° 2θ ± 0.20, 25.46° 2θ ± 0.20, 25.60° 2θ ± 0.20, 26.22° 2θ ± 0.20, 26.67° 2θ ± 0.20, 27.79° 2θ ± 0.20, and 29.07° 2θ ± 0.20.

[0118]

[0136] In one embodiment, butyrate salt Form A has an XRPD pattern comprising peaks substantially or essentially the same as those shown in Figures 7 or 8. In one embodiment, butyrate salt Form A comprises peaks substantially or essentially the same as those shown in Figure 9. 1 H NMR spectrum. Butyrate Form A may be solvated, semi-solvated, or unsolvated. Preferably, butyrate Form A is unsolvated.

[0119]

[0137] In another preferred embodiment, the crystalline form is gentisate Form A. Preferably, gentisate Form A has an XRPD pattern with peaks at about 15.80° 2θ±0.20, 16.51° 2θ±0.20, and 23.98° 2θ±0.20.

[0120]

[0138] In another embodiment, gentisate Form A has an XRPD pattern with peaks at about 15.52° 2θ±0.20, 15.80° 2θ±0.20, 16.51° 2θ±0.20, 23.98° 2θ±0.20, and 24.74° 2θ±0.20. In another embodiment, gentisate Form A has a viscosity of about 12.77° 2θ ± 0.20, 14.08° 2θ ± 0.20, 15.52° 2θ ± 0.20, 15.80° 2θ ± 0.20, 15.98±0.20, 16.51° 2θ ± 0.20, 17.30° 2θ ± 0.20, 18.58° 2θ ± 0.20, 20.95° 2θ ± 0.20, 21.64° 2θ ± 0.20, 23.38° 2θ ± 0.20, 23.98° 2θ ± 0.20, 24.74° 2θ ± 0.20, 25.19° 2θ ± 0.20, 27.81° 2θ ± 0.20, 28.41° It has an XRPD pattern with peaks at 28.80° 2θ±0.20 and 28.80° 2θ±0.20.

[0121]

[0139] In another embodiment, gentisate Form A has a saturation angle of about 7.74° 2θ ± 0.20, 9.01° 2θ ± 0.20, 11.01° 2θ ± 0.20, 12.29° 2θ ± 0.20, 12.77° 2θ ± 0.20, 13.15° 2θ ± 0.20, 13.80° 2θ ± 0.20, 14.08° 2θ ± 0.20, 15.52° 2θ ± 0.20, 15.80° 2θ ± 0.20, 15.98° 2θ ± 0.20, 16.11° 2θ ± 0.20, 16.51° 2θ ± 0.20, 17.30° 2θ ± 0.20, 18.07° 2θ ± 0.20, 18.58° 2θ±0.20, 19.13° 2θ±0.20, 19.39° 2θ±0.20, 19.56° 2θ±0.20, 20.95° 2θ±0.20, 21.64° 2θ±0.20, 22.18° 2θ±0.20, 22.45° 2θ±0.20, 23.03° 2θ±0.20, 23.38° 2θ±0.20, 23.98° 2θ±0.20, 24.74° 2θ±0.20, 24.95° 2θ±0.20, 25.19° 2θ±0.20, 25.71° 2θ±0.20, 26.08° 2θ±0.20, 26.47° 2θ±0.20, 27.28° 2θ±0.20, 27.81° 2θ±0.20, 28.41° 2θ±0.20, 28.80° 2θ±0.20, 30.13° 2θ±0.20, 30.66° 2θ±0.20, 31.90° 2θ±0.20, 32.16° 2θ±0.20, 32.57° 2θ±0.20, 33.37° 2θ±0.20, 33.75° 2θ±0.20, 34.77° 2θ±0.20, 35.29° 2θ±0.20, 36.25° 2θ±0.20, and 36.80° 2θ±0.20.

[0122]

[0140] In one embodiment, gentisate Form A has an XRPD pattern comprising peaks substantially or essentially the same as those shown in Figures 10 or 11. In one embodiment, gentisate Form A comprises peaks substantially or essentially the same as those shown in Figure 12. 1H NMR spectrum. Gentisate Form A can be solvated, semi-solvated, or unsolvated. Preferably, gentisate Form A is semi-solvated or unsolvated.

[0123]

[0141] In another embodiment, the crystalline form is acetate salt Form A. Preferably, acetate salt Form A has an XRPD pattern including peaks substantially or essentially the same as those shown in Figures 13 or 14. In one embodiment, acetate salt Form A includes peaks substantially or essentially the same as those shown in Figure 15. 1 It has a H NMR spectrum. Acetate salt Form A may be solvated, semi-solvated, or unsolvated.

[0124]

[0142] In another embodiment, the crystalline form is benzoate Form A. Preferably, benzoate Form A has an XRPD pattern including peaks substantially or essentially the same as those shown in Figures 16 or 17. In one embodiment, benzoate Form A includes peaks substantially or essentially the same as those shown in Figure 18. 1 It has a H NMR spectrum. Benzoate Form A may be solvated, semi-solvated, or unsolvated.

[0125]

[0143] In another embodiment, the crystalline form is fumarate Form A. Preferably, fumarate Form A has an XRPD pattern comprising peaks substantially or essentially the same as those shown in Figures 19 or 20. In one embodiment, fumarate Form A comprises peaks substantially or essentially the same as those shown in Figure 22. 1 H NMR spectrum. Fumarate Form A may be solvated, semi-solvated, or unsolvated.

[0126]

[0144] In another embodiment, the crystalline form is fumarate Form B. Preferably, fumarate Form B has an XRPD pattern comprising peaks substantially or essentially the same as those shown in Figures 19 or 21. In one embodiment, fumarate Form B comprises peaks substantially or essentially the same as those shown in Figure 22. 1 H NMR spectrum. Fumarate Form B may be solvated, semi-solvated, or unsolvated.

[0127]

[0145] In another embodiment, the crystalline form is tartrate salt Form A. Preferably, tartrate salt Form A has an XRPD pattern comprising peaks substantially or essentially the same as those shown in Figures 23 or 24. In one embodiment, tartrate salt Form A comprises peaks substantially or essentially the same as those shown in Figure 25. 1 H NMR spectrum. Tartrate salt Form A may be solvated, semi-solvated, or unsolvated.

[0128]

[0146] In another embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form as described herein. The compositions described herein can be formulated for oral, subcutaneous, intravenous, or intramuscular administration. Preferably, the pharmaceutical composition can be formulated for intravenous administration.

[0129]

[0147] The psilocin compositions described herein can contain a pharmaceutically effective amount of psilocin in association with one or more pharmaceutically acceptable excipients, including carriers, vehicles, and diluents. The term "excipient," as used herein, means any substance, not itself a therapeutic agent, used as a diluent, adjuvant, or vehicle for delivery of a therapeutic agent to a subject, or added to a pharmaceutical composition to improve its handling or storage characteristics, or to enable or facilitate the formation of a solution for oral, parenteral, intradermal, subcutaneous, or topical application. Excipients can include, by way of illustration and not limitation, diluents, humectants, polymers, lubricants, stabilizers, and substances added to mask or counteract unpleasant tastes or odors, flavors, dyes, fragrances, and substances added to improve the appearance of the composition. Acceptable excipients include (but are not limited to) stearic acid, magnesium stearate, sodium and calcium phosphate and sulfate, magnesium carbonate, dextrin, mannitol, sorbitol, lactose, sucrose, starch, gelatin, polymers such as polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol, and other pharmaceutically acceptable materials. Examples of excipients and their uses are described in Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000). The choice of excipient will largely depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0130]

[0148] In some embodiments, the crystalline forms provided herein have aqueous solubility (solubility in water or saline) greater than that of baseline psilocin. For example, the solubility of the crystalline form can be at least about 0.25 mg / mL, 0.5 mg / mL, 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, or at least about 10 mg / mL.

[0131]

[0149] In some embodiments, the crystalline forms provided herein have improved stability in solid form or in solution (water or saline) compared to a psilocin standard in solution. For example, as demonstrated herein (see FIG. 27), the crystalline forms decompose at a significantly slower rate than psilocin in saline solution. In some embodiments, when the crystalline form is in an aqueous solution, such as saline, there is less than a 10% decrease in the amount of psilocin present over time (e.g., 36 hours), compared to at least a 15% decrease for the psilocin standard.

[0132]

[0150] In other embodiments, the crystalline forms described herein are stable for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or at least 1 year during storage under long-term stability conditions of 30°C and 65% relative humidity, as well as under accelerated / stress conditions of 40-45°C and 75% relative humidity.

[0133]

[0151] In some embodiments, the crystalline forms described herein are stable for at least 2 years under long-term stability conditions of 30°C and 65% relative humidity, as well as under accelerated / stress conditions of 40-45°C and 75% relative humidity.

[0134]

[0152] While the crystalline forms described herein have improved stability compared to the psilocin standard, it is believed that stability can be further enhanced by formulating the crystalline form with one or more excipients (e.g., ascorbate, pyruvate, ascorbyl palmitate, butylated hydroxytoluene, calcium stearate, citrate, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium thiosulfate, vitamin E, and sodium edetate) to reduce the effects of oxidation on the crystalline form.

[0135]

[0153] In another embodiment, the present invention provides a method for producing a stable crystalline form and / or a crystalline form with improved solubility, comprising: a) reacting psilocin with a pharmaceutically acceptable acid in a solvent as described herein; b) drying the resulting product of step a); A method is provided that includes:

[0136]

[0154] In some embodiments, the ratio of psilocin to acid is 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, or 5:1 mol / mol. In some embodiments, the solvent can be selected from ethyl acetate or acetone. In some embodiments, the reaction of psilocin with the pharmaceutically acceptable acid is carried out at reduced temperature, preferably about 2-8°C. In some embodiments, drying is carried out in vacuo at ambient temperature.

[0137]

[0155] In another embodiment, the present invention provides a crystalline form or pharmaceutical composition as described herein useful for treating a disease or condition such as a psychiatric condition, post-traumatic stress, attention deficit hyperactivity disorder, anxiety, addiction, depression, obsessive-compulsive disorder, IBS (irritable bowel syndrome), fibromyalgia, CRPS (complex regional pain syndrome), phantom limb, eating disorders, diabetes, e.g., diabetes associated with obesity and type 2 diabetes, nerve injury, pain, e.g., nociceptive pain, and inflammatory conditions.

[0138]

[0156] In some embodiments, the present invention provides a method of treating or preventing a disease or condition in a subject, comprising administering to the subject a crystalline form or pharmaceutical composition as described herein.

[0139]

[0157] In some embodiments, the present invention provides the use of a crystalline form or pharmaceutical composition as described herein in the manufacture of a medicament for treating or preventing a disease or condition.

[0140]

[0158] In some embodiments, the present invention provides a crystalline form or pharmaceutical composition as described herein for use in treating or preventing a disease or condition in a subject.

[0141]

[0159] It will be appreciated by those skilled in the art that numerous variations and / or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive.

[0142]

[0160] In order that the present technology may be more clearly understood, preferred embodiments will now be described with reference to the following examples. [Example]

[0143] Example

[0161] The present invention will now be illustrated by the following examples, which should not be construed as limiting the invention in any way, but are merely illustrative of the various embodiments described herein.

[0144] Example 1: Salt and co-crystal selection analysis

[0162] Materials exhibiting distinctive crystalline XRPD patterns are assigned consecutive alphabetical letters as a default name unless another letter type is already attached to the compound. Each uniquely identified material is assigned a new name that includes the chemical name of the guest used. This name is provisionally accompanied by the term "material" until phase purity and chemical composition are determined through further characterization. Verification of the presence, composition, and phase homogeneity of psilocin is required before the term "form" can be used.

[0145]

[0163] In this selection, an attempt was made to index the XRPD pattern. Indexing and structure refinement are computational studies. Successful indexing of the pattern indicates that the sample is composed primarily or exclusively of a single crystalline phase.

[0146] Characterization of psilocin

[0164] Sample psilocin packaged in 36 pre-weighed vials was obtained as starting material. Initial characterization of this material is described below. Screening activities and characterization of this produced material are discussed below.

[0147]

[0165] One of these samples (pre-weighed vials) was analyzed by XRPD, XRPD indexing, and 1 was used for H NMR analysis.

[0148]

[0166] By XRPD, psilocin is a crystalline material as shown in Figure 1. The XRPD pattern was successfully indexed and the indexed solution is consistent with unsolvated psilocin as shown in Figure 3.

[0149]

[0167] This psilocin 1 The 1 H NMR spectrum is consistent with the chemical structure of psilocin, as shown in Figure 4.

[0150]

[0168] The approximate solubility of psilocin was evaluated in several solvents as shown in Table 1 below.

[0151] [Table 10]

[0152]

[0169] Psilocin free base is poorly soluble in water and alcohol, but relatively soluble in other organic solvents (≥8 mg / mL). This solubility estimate was used to design experiments for salt selection. After 1 day of ambient temperature storage, samples placed in water showed a strong discoloration (black), while the other samples remained colorless.

[0153] Psilocin salt / cocrystal selection

[0170] For example, based on the calculated pKa of psilocin (9.38, according to ACD / pKa DB v11.01) and the solubility of psilocin (see Table 1) and the acid, 20 acids suitable for pharmaceutical salt development were selected. Four coformers were included in the screening. All acids and coformers used in this study are summarized below.

[0154] [Table 11]

[0155]

[0171] For salt / cocrystal formation experiments, solvent-based techniques were used, including evaporation, solvent-antisolvent addition, and slurry / trituration. Due to stability issues with psilocin, most of the experiments were performed at subambient conditions (2-8 °C) or under N2 flow. Materials isolated from these experiments were observed under PLM and, if birefringence was observed, analyzed by XRPD. Most samples were dried in vacuum at ambient temperature before XRPD analysis. XRPD patterns were compared with those of psilocin and acid / coformer reference patterns. Detailed experimental conditions, observations, and results of the screening experiments are summarized in Tables 3 and 4.

[0156] [Table 12]

[0157] [Table 13]

[0158] [Table 14]

[0159] [Table 15]

[0160] [Table 16]

[0161] [Table 17]

[0162] [Table 18]

[0163] [Table 19]

[0164] [Table 20]

[0165] [Table 21]

[0166] [Table 22]

[0167]

[0172] This selection produced several crystalline materials with distinctive XRPD patterns. 1 Further analysis by H NMR confirmed salt formation. XRPD indexing and 1 The 1 H NMR results are summarized in Table 5.

[0168] [Table 23]

[0169] [Table 24]

[0170] [Table 25]

[0171]

[0173] Besylate Form A Besylate Form A was produced from a salt formation experiment in EtOAc using 1:1 mol / mol psilocin and benzenesulfonic acid, followed by drying. The XRPD pattern (Figure 4) was successfully indexed (Figure 5). The indexed solution is consistent with an unsolvated monosalt.

[0172]

[0174] Besylate Form A 1 The H NMR spectrum (FIG. 6) is generally consistent with that of psilocin containing 1.0 M benzenesulfonic acid and 0.02 M EtOAc. Compared to the spectrum of psilocin free base, a peak shift is observed, suggesting salt formation.

[0173]

[0175] The observed and prominent peak positions from the XPRD pattern of psilocin besylate Form A (FIG. 4) are provided in Tables 6 and 7.

[0174] [Table 26]

[0175] [Table 27]

[0176] [Table 28]

[0177] Butyrate Form A Butyrate material A was produced from a salt formation experiment in EtOAc using 1:1 mol / mol psilocin and butyric acid, followed by drying. The XRPD pattern (FIG. 7) was successfully indexed (FIG. 8). The indexing solution suggests that this may be an unsolvated monosalt.

[0178] Butyrate Form A 1 The H NMR spectrum (FIG. 9) is generally consistent with that of psilocin containing 1.0 mole butyric acid and <0.01 mole EtOAc. Compared to the spectrum of psilocin free base, a peak shift is observed, suggesting salt formation.

[0179]

[0178] The observed and prominent peak positions from the XPRD pattern of psilocin butyrate Form A (Figure 7) are provided in Tables 8 and 9.

[0180] [Table 29]

[0181] [Table 30]

[0182] [Table 31]

[0183] Gentisate Form A Gentisate Form A was produced from an experiment using 2:1 mol / mol psilocin and gentisic acid in EtOAc at 2-8° C. The XRPD pattern (FIG. 10) was successfully indexed (FIG. 11). Based on the indexing solution, gentisate Form A can accommodate at least one mole of water or half a mole of EtOAc if it is a 1:1 salt.

[0184] Gentisate Form A 1 The H NMR spectrum (FIG. 12) is generally consistent with that of psilocin containing 1.0 mole of gentisic acid and 1.0 mole of EtOAc. Compared to the spectrum of psilocin free base, a peak shift is observed, suggesting salt formation.

[0185]

[0181] Gentisate Form A is dried in vacuum at ambient temperature for 1 day, and the sample maintains the same morphology after drying.

[0186]

[0182] Gentisate Form A after drying 1 The H NMR spectrum (FIG. 12) is consistent with that before drying, although containing 0.4 M EtOAc. Additional material of gentisate Form A was produced for further analysis.

[0187]

[0183] The observed and prominent peak positions from the XPRD pattern of gentisate Form A (Figure 10) are provided in Tables 10 and 11.

[0188] [Table 32]

[0189] [Table 33]

[0190] [Table 34]

[0191] Acid Use in FDA-Approved IV Medications

[0184] Benzene sulfonic acid, butyric acid, and gentisic acid have all been involved in the development of FDA-approved IV drugs, and therefore are considered potentially safe salt formers for IV administration.

[0192] Tracrium®, or atracurium besylate, is a medium-duration, non-depolarizing skeletal muscle relaxant for IV administration (https: / / www.rxlist.com / tracrium-drug.htm). Cleviprex®, or clevidipine butyrate, is an IV dihydropyridine calcium channel blocker (https: / / www.cleviprex.com). AZEDRA® (iobenguane I 131) injection for IV use contains sodium gentisate as an excipient (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 209607s000lbl.pdf).

[0193] Acetate Form A Acetate Form A was produced from the reaction of psilocin with acetic acid (1:1 mol / mol) in EtOAc. The solid was dried in vacuo at ambient temperature before analysis. The XRPD pattern (FIG. 13) was successfully indexed (FIG. 14). Based on the indexing solution, acetate Form A may be an unsolvated material. 1 The H NMR spectrum (FIG. 15) is consistent with the chemical structure of psilocin containing 1 mole of acetic acid and 0.03 moles of EtOAc. A peak shift was observed compared to the spectrum of psilocin free base, suggesting salt formation. Therefore, acetate Form A appears to be an unsolvated monosalt.

[0194] Benzoate Form A

[0187] Through experiments on the salt of psilocin with benzoic acid (1:1 mol / mol) at 2-8°C, a new crystalline material designated as benzoic acid psilocin Form A was obtained. Its XRPD pattern (Figure 16) was successfully indexed (Figure 17), and the indexing solution is consistent with the unsolvated 1:1 benzoic acid salt. Benzoic acid Form A 1The H NMR spectrum (FIG. 18) is generally consistent with that of psilocin containing 1.0 mole of benzoic acid and 2.1 moles of IPA. A peak shift is observed compared to the spectrum of psilocin free base, suggesting salt formation. Benzoate Form A is dried in a vacuum at ambient temperature for 1 day, and the dried sample maintains the same morphology (see Table 12 below).

[0195] [Table 35]

[0196]

[0188] Benzoate Form A after drying 1 The H NMR spectrum is consistent with the spectrum of the solution containing 0.04 moles of IPA before drying. These results indicate that benzoate Form A may be an unsolvated monobenzoate. The solubility of benzoate Form A in ACN is less than 0.25 mg / mL (see Table 6), significantly lower than the solubility of psilocin free base in ACN (9 mg / mL—see Table 2). The solubility of benzoate Form A in DMSO is greater than 12 mg / mL (see Table 13). Therefore, DMSO can be considered as a solvent for HPLC analysis for stability studies.

[0197] [Table 36]

[0198] Fumarate Form A Fumarate Form A was produced from an experiment using 1:1 mol / mol psilocin and fumaric acid in acetone at 2-8°C. The XRPD pattern of fumarate Form A (Figure 19) was successfully indexed (Figure 20). Based on the indexing solution, fumarate Form A can accommodate 1 mole of acetone if it is a hemifumarate salt. 1The H NMR spectrum (FIG. 22) is generally consistent with that of psilocin containing 0.5 moles of fumaric acid and 0.7 moles of acetone. A peak shift is observed compared to the spectrum of psilocin free base, suggesting salt formation. Fumarate Form A was dried in a vacuum at ambient temperature for one day, converting the sample to a mixture of fumarate Form B and a trace amount of an unknown second phase. 1 The H NMR spectrum is consistent with that of fumarate salt Form A containing 0.2 molar acetone. Additional salt experiments using fumaric acid in IPA, followed by drying in vacuo, produced single-phase fumarate salt Form B. This XRPD pattern was successfully indexed, and the indexing solution is consistent with the unsolvated hemifumarate salt.

[0199] Tartrate Form A Psilocin tartrate Form A was produced from the reaction of psilocin with tartaric acid (1:1 mol / mol) in acetone. The solid was dried in vacuo at ambient temperature before analysis. The XRPD pattern (Figure 23) was successfully indexed (Figure 24). Based on the indexing solution, tartrate Form A may not be solvated for the 1:1 salt. 1 The H NMR spectrum (FIG. 25) is consistent with the chemical structure of psilocin containing 1 mole of tartaric acid and 0.1 mole of acetone. Compared to the spectrum of psilocin free base, a peak shift was observed, suggesting salt formation. Therefore, tartrate salt Form A appears to be an unsolvated monosalt.

[0200] Succinate Material A Salt experiments using 1:1 mol / mol psilocin and succinic acid in EtOAc produced a mixture of novel material containing succinic acid and psilocin. This novel material is designated succinate material A. To drive the salt reaction to completion and remove residual psilocin and acid, the mixture was reslurried in EtOAc. No psilocin or succinic acid is present in the reslurried material; however, an additional phase is observed. This mixture was not further characterized.

[0201] Experiments with other acids / coformers

[0192] No new crystalline material was observed in experiments using aconitic acid, ascorbic acid, citric acid, erythorbic acid, glutamic acid, glycolic acid, hydrochloric acid, maleic acid, phosphoric acid, pyroglutamic acid, sorbic acid, sulfuric acid, arginine, lysine, methylparaben, and nicotinamide (see Tables 3 and 4).

[0202]

[0193] Experiments using psilocin and citric acid at 1:1 mol / mol yielded a sample that exhibited birefringence. However, by XRPD, this sample appeared to be X-ray amorphous. Visual observations showed that the sample deliquesced after XRPD, suggesting that the sample may be physically unstable at ambient temperatures. 1 The H NMR spectrum is generally consistent with that of psilocin containing 1.5 moles of ACN and nearly 1 mole of citric acid (estimated by peak overlap). A peak shift is observed compared to the spectrum of psilocin free base, suggesting salt formation.

[0203] Experiments using psilocin and maleic acid at 1:2 mol / mol at 2-8°C yielded a yellow suspension that exhibited birefringence. However, the solid gelled shortly after the sample was returned to ambient temperature. The sample was maintained at 2-8°C with further stirring, again yielding a yellow suspension. The solid was quickly isolated at ambient temperature and subsequently dried in vacuo at ambient temperature. By XRPD, the final sample appeared to be a mixture of amorphous material and a minor crystalline phase, not consistent with maleic acid or psilocin. This mixture was not studied further.

[0204] Example 2. Methods Approximate solubility

[0195] A weighed sample was treated with an aliquot of the specified solvent at ambient temperature. Complete dissolution of the test material was determined by visual inspection. Solubility was estimated based on the total solvent volume used to achieve complete dissolution. If complete dissolution was achieved by adding only a certain amount, the value was reported as "greater than"; if complete dissolution was not achieved, the value was reported as "less than". Due to the use of too large a solvent amount or a slow rate of dissolution, the actual solubility may exceed the calculated value.

[0205] Fast Evaporation (FE)

[0196] Solutions were prepared in the selected solvent and allowed to evaporate from uncapped vials at ambient temperature.

[0206] X-ray powder diffraction (XRPD) XRPD patterns were collected using a PANalytical X'Pert PRO MPD or Empyrean diffractometer with an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptically gradient multilayer mirror was used to focus the Cu Kα X-ray radiation through the specimen and onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the observed position of the Si(111) peak was consistent with that established by NIST. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and an anti-scatter knife edge were used to minimize background caused by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.5.5.

[0207] The XRPD data presented herein include X-ray diffraction patterns with labeled peaks and tables containing peak lists. The range of data collected is typically provided in the scientific publication in which the data was originally reported and is instrument-dependent. Under most circumstances, peaks within a range of up to approximately 30° 2θ were selected. A rounding algorithm was used to round each peak to the nearest 0.1° or 0.01° 2θ, depending on the instrument used to collect the data and / or the inherent peak resolution. In both figures and tables, peak positions along the x-axis (° 2θ) were rounded to one or two significant decimal places based on the criteria described above. Peak position variability is based on the USP discussion of variability in x-ray powder diffraction (USP-NF 2022, Issue 2, <941> The accuracy is within ±0.2° 2θ based on the recommendations outlined in [Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder Diffraction (XRPD)], GUID-14EBB55E-0D24-45A1-A84FFE4DCAAEE3E8_2_en-US, official 01 May 2022. The accuracy and precision of any specific measurements reported herein have not been determined. Furthermore, third-party measurements on independently prepared samples using different instruments may result in variations greater than ±0.2° 2θ. For the listing of d-spacings, the wavelength used to calculate the d-spacings was 1.5405929 Å, i.e., the Cu-Kα wavelength (Phys. Rev. A56(6)4554-4568(1997)). The variability associated with the d-spacing estimates was calculated from the USP recommendations for each d-spacing and is provided in the respective data tables.

[0208]

[0199] According to USP guidelines, varying hydrates and solvates may exhibit peak variations greater than 0.2° 2θ, and therefore the 0.2° 2θ peak variation is not applicable to these materials.

[0209] For samples with only one XRPD pattern, and where there is no other means to assess whether the sample provides a suitable approximation of the powder average, the peak table contains data identified only as "prominent peaks." These peaks are a subset of the entire observed peak list. Prominent peaks are preferably selected from the observed peaks by identifying non-overlapping, low-angle peaks with strong intensity.

[0210]

[0201] When multiple diffraction patterns are available, particle statistics (PS) and / or preferred orientation (PO) can be assessed. Reproducibility between XRPD patterns from multiple samples analyzed on a single diffractometer indicates adequate particle statistics. Consistency in relative intensities between XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern can be compared to a calculated XRPD pattern based on a single crystal structure, if available. Two-dimensional scattering patterns using an area detector can also be used to assess PS / PO. If the effects of both PS and PO are determined to be negligible, the XRPD pattern represents the powder average intensity of the sample, and prominent peaks can be identified as "representative peaks."

[0211] Proton solution nuclear magnetic resonance spectroscopy ( 1 H NMR)

[0202] Proton solution NMR spectra were acquired using a Bruker AVANCE 600 MHz Spectrometer using DMSO-d6, with specific acquisition parameters listed on the first full spectrum plot in the figure.

[0212] Polarized Light Microscopy (PLM) Optical microscopy was performed using a Leica MZ12.5 stereomicroscope. Samples were viewed using a 0.8-10x objective with crossed polarizers and a first-order red compensator. Samples were viewed in situ or in a small amount of mineral oil.

[0213] XRPD Indexing

[0204] In this study, high-resolution XRPD patterns were indexed using X'Pert High Score Plus 2.2a (2.2.1) or TRIADS (registered trademark). Indexing and structure refinement were computational studies. A match between the observed peaks and the accepted peak positions, marked with red bars, indicates a consistent unit cell determination. Successful indexing of a pattern indicates that the sample is composed primarily of a single crystalline phase. The assigned extinction signature, unit cell parameters, and space group consistent with the assembly quantities are entered in each of the following figures showing the tentative indexing solution. To confirm the tentative indexing solution, the molecular packing motif within the crystallographic unit cell must be determined. No molecular packing attempts were performed.

[0214] Example 4: Comparison of the solubility of psilocin salts and psilocin free base in saline Psilocin besylate, psilocin butyrate, psilocin gentisate, and psilocin free base were prepared in saline at 1.0 mg / mL. Psilocin free base was also prepared at 0.1 mg / mL. The solubility of the materials in the solution was monitored, and the pH was recorded (Table 13).

[0215] [Table 37]

[0216]

[0206] It is clear that psilocin salts are substantially more soluble in saline than psilocin free base.

[0217] Example 5: Stability of psilocin salts and psilocin free base in saline Psilocin besylate, psilocin butyrate, psilocin gentisate, and psilocin free base were prepared at 1.0 mg / mL in saline. Samples were filtered through a 0.2 μm PTFE filter. The solutions were analyzed at various time points over a 38-hour period using the HPLC conditions presented in Tables 14 and 15. Psilocin salts are substantially more stable over time than psilocin (see Figures 26 and 27).

[0218] [Table 38]

[0219] [Table 39]

[0220] Example 6: Hypothetical Example - Chemical Stability

[0208] Solid-state stability can be assessed using a temperature / humidity controlled chamber. Samples of each crystalline form are placed in the chamber and exposed to various temperatures and humidities, such as 25°C / 60%RH, 40°C / 75%RH, and 70°C / 75%RH, and / or irradiated with a xenon lamp. The resulting crystalline form, thermal behavior, purity, and / or weight change of the sample after exposure or irradiation can be assessed using one or more of XRPD, thermogravimetry / differential thermal analysis, differential scanning calorimetry, high-performance liquid chromatography, or a microbalance.

[0221] Each crystalline form is expected to be stable. For example, in solid-state stability studies after storage at 25°C / 60% RH, 40°C / 75% RH, or 70°C / 75% RH for 1 week, 2 weeks, 1 month, or 2 months, the crystalline forms described herein will be chemically and physically stable. Furthermore, fewer degradation products are expected to be found in the crystalline forms compared to psilocin. In this context, purity can be determined by HPLC measurement, and degradation products are expected to be less than 2%, 5%, 10%, or 15% of the total crystalline form after storage at 25°C / 60% RH, 40°C / 75% RH, or 70°C / 75% RH for 1 week, 2 weeks, 1 month, or 2 months.

[0222] Example 7: Hypothetical Example - Light Stability

[0210] Light stability experiments will be conducted on aqueous solutions of the solid psilocin crystalline form and 0.2 mg / mL of free base to a depth of approximately 3 mm. Prior to dissolution, the water will be purged with nitrogen for 30 minutes to prevent oxidative degradation. For each sample, duplicate vials will be prepared, with one exposed to light and the other serving as a control, wrapped in foil for the duration of the experiment. Samples will be exposed to an iridescence level equivalent to one week of bright sunlight, e.g., 500 W / m2 (300-800 nm). Observations will be made on the free base, psilocin salts, and each crystalline form before and after exposure. Purity analysis will be performed on all samples at 0.2 mg / mL of free base using HPLC after exposure. X-ray powder diffraction will be performed on the solid psilocin salt samples before and after exposure.

[0223]

[0211] Similar experiments can be performed to compare the photostability levels in clear and amber glass vials and to consider the presence or absence of nitrogen.

[0224]

[0212] It is expected that the purity and stability of the solid sample after light exposure will not change when compared to before exposure. It is also expected that XRPD analysis will reveal that the sample will not change crystalline form after the light stability experiment.

[0225] All of these crystalline forms are expected to exhibit greater stability in the presence of light compared to free base psilocin. While the purity of the free base in solution after exposure is known to decrease substantially (down to approximately 35%), these crystalline forms are expected to retain >75% or even >90% purity (by HPLC) after light exposure.

[0226] Example 8: Hypothetical Example - Forced Decomposition Tests will be conducted to evaluate the stability of psilocin crystalline forms and free base psilocin against oxidative degradation. To test the oxidative stability of each crystalline form, forced decomposition of the psilocin salt will be performed in H2O2, e.g., 0.3% H2O2. An appropriate volume of H2O2 will be added to a pre-weighed sample of the crystalline form in an amber vial (or other vial shielded from light) to provide a maximum concentration, e.g., 0.2 mg / mL psilocin (free base equivalent). The samples will be stored at 25°C, and the purity of each sample will be periodically evaluated by HPLC thereafter. For example, samples can be evaluated using HPLC at 0, 1, 6, and 24 hours.

[0227]

[0215] In H2O2, the rate of decomposition is predicted to be slower for the crystalline form compared to free base psilocin, demonstrating that the crystalline form will have superior shelf life stability and resistance to oxidative degradation.

Claims

1. A crystalline form of a pharmaceutically acceptable salt of psilocin (4-hydroxy-N,N-dimethyltryptamine), or a co-crystal of psilocin (4-hydroxy-N,N-dimethyltryptamine) with a coformer.

2. The crystalline form of claim 1 , wherein the pharmaceutically acceptable salt is an acid.

3. 3. The crystalline form of claim 2, wherein the acid or coformer is selected from one or more of acetic acid, aconitic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, erythorbic acid, fumaric acid, gentisic acid, glutamic acid, glycolic acid, hydrochloric acid, maleic acid, phosphoric acid, pyroglutamic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, arginine, lysine, methylparaben, nicotinamide, and ethyl acetate.

4. 4. The crystalline form of claim 3, wherein the acid is benzenesulfonic acid.

5. 5. The crystalline form of claim 4, wherein the crystalline form is besylate Form A and exhibits XRPD (X-ray powder diffraction) peaks at about 15.44° 2θ±0.20, 18.33° 2θ±0.20, and 25.41° 2θ±0.

20.

6. 5. The crystalline form of claim 4, wherein the crystalline form is besylate Form A and exhibits XRPD (X-ray powder diffraction) peaks at about 14.73° 2θ±0.20, 15.44° 2θ±0.20, 18.33° 2θ±0.20, 22.59° 2θ±0.20, and 25.41° 2θ±0.

20.

7. the crystalline form is besylate Form A and is soluble in water at approximately 11.72° 2θ ± 0.20, 12.47° 2θ ± 0.20, 13.49° 2θ ± 0.20, 14.73° 2θ ± 0.20, 15.44° 2θ ± 0.20, 18.33° 2θ ± 0.20, 20.62° 2θ ± 0.20, 20.99° 2θ ± 0.20, 21.77° 2θ ± 0.20, 22.25° 2θ ± 0.20, 22.59° 2θ ± 0.20, 23.22° 2θ ± 0.20, 23.71° 2θ ± 0.20, 24.10° 2θ ± 0.20, and 25.41° 2θ ± 0.

20.

5. The crystalline form of claim 4, exhibiting an XRPD (X-ray powder diffraction) peak at 2θ±0.

20.

8. the crystalline form is besylate Form A and has molecular weights of about 7.69° 2θ ± 0.20, 10.26° 2θ ± 0.20, 10.96° 2θ ± 0.20, 11.72° 2θ ± 0.20, 12.47° 2θ ± 0.20, 12.84° 2θ ± 0.20, 13.49° 2θ ± 0.20, 14.73° 2θ ± 0.20, 15.44° 2θ ± 0.20, 16.18° 2θ ± 0.20, 18.33° 2θ ± 0.20, 19.04° 2θ ± 0.20, 19.68° 2θ ± 0.20, 20.62° 2θ ± 0.20, 20.99° 2θ ± 0.20, 21.77° 2θ ± 0.20 2θ±0.20, 22.25° 2θ±0.20, 22.59° 2θ±0.20, 23.22° 2θ±0.20, 23.71° 2θ±0.20, 24.10° 2θ±0.20, 25.15° 2θ±0.20, 25.41° 2θ±0.20, 25.65° 2θ±0.20, 26.29° 2θ±0.20, 26.76° 2θ±0.20, 27.72° 2θ±0.20, 27.99° 2θ±0.20, 28.67° 2θ±0.20, 28.93° 2θ±0.20, 29.63° 2θ±0.20, 30.43° 5. The crystalline form of claim 4, exhibiting XRPD (X-ray powder diffraction) peaks at: 30.76° 2θ ± 0.20, 31.15° 2θ ± 0.20, 31.77° 2θ ± 0.20, 32.13° 2θ ± 0.20, 32.94° 2θ ± 0.20, 33.65° 2θ ± 0.20, 34.94° 2θ ± 0.20, 35.69° 2θ ± 0.20, and 36.49° 2θ ± 0.

20.

9. 9. The crystalline form of any one of claims 4 to 8, which is besylate Form A characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 4.

10. The crystalline form of claim 3, wherein the acid is butyric acid.

11. 11. The crystalline form of claim 10, wherein the crystalline form is butyrate salt Form A and exhibits XRPD (X-ray powder diffraction) peaks at about 13.24° 2θ±0.20, 15.34° 2θ±0.20, and 15.88° 2θ±0.

20.

12. 11. The crystalline form of claim 10, wherein the crystalline form is butyrate salt Form A and exhibits XRPD (X-ray powder diffraction) peaks at about 13.24° 2θ ± 0.20, 15.34° 2θ ± 0.20, 15.88° 2θ ± 0.20, 16.28° 2θ ± 0.20, 20.95° 2θ ± 0.20, and 27.79° 2θ ± 0.

20.

13. 11. The crystalline form of claim 10, wherein the crystalline form is butyrate salt Form A and exhibits XRPD (X-ray powder diffraction) peaks at about 9.33° 2θ ± 0.20, 9.96° 2θ ± 0.20, 10.66° 2θ ± 0.20, 13.24° 2θ ± 0.20, 15.34° 2θ ± 0.20, 15.88° 2θ ± 0.20, 16.28° 2θ ± 0.20, 17.80° 2θ ± 0.20, 20.95° 2θ ± 0.20, 21.98° 2θ ± 0.20, 22.32° 2θ ± 0.20, 23.31° 2θ ± 0.20, 24.61° 2θ ± 0.20, and 27.79° 2θ ± 0.

20.

14. the crystalline form is butyrate Form A and has optical resolutions of about 9.33° 2θ ± 0.20, 9.96° 2θ ± 0.20, 10.66° 2θ ± 0.20, 12.96° 2θ ± 0.20, 13.24° 2θ ± 0.20, 14.36° 2θ ± 0.20, 15.34° 2θ ± 0.20, 15.88° 2θ ± 0.20, 16.28° 2θ ± 0.20, 17.80° 2θ ± 0.20, 18.36° 2θ ± 0.20, 18.75° 2θ ± 0.20, 18.97° 2θ ± 0.20, 19.63° 2θ ± 0.20, 20.01° 2θ ± 0.20, 20.35° 2θ±0.20, 20.95° 2θ±0.20, 21.44° 2θ±0.20, 21.98° 2θ±0.20, 22.32° 2θ±0.20, 22.80° 2θ±0.20, 23.31° 2θ±0.20, 23.77° 2θ±0.20, 24.41° 2θ±0.20, 24.61° 2θ±0.20, 25.46° 2θ±0.20, 25.60° 2θ±0.20, 26.22° 2θ±0.20, 26.67° 2θ±0.20, 27.79° 2θ±0.20, and 29.07° 11. The crystalline form of claim 10, exhibiting an XRPD (X-ray powder diffraction) peak at 2θ±0.

20.

15. 11. The crystalline form of any one of claims 8 to 10, which is butyrate salt Form A characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 7.

16. The crystalline form of claim 3, wherein the acid is gentisic acid.

17. 17. The crystalline form of claim 16, wherein the crystalline form is gentisate Form A and exhibits XRPD (X-ray powder diffraction) peaks at about 15.80° 2θ±0.20, 16.51° 2θ±0.20, and 23.98° 2θ±0.

20.

18. 17. The crystalline form of claim 16, wherein the crystalline form is gentisate Form A and exhibits XRPD (X-ray powder diffraction) peaks at about 15.52° 2θ ± 0.20, 15.80° 2θ ± 0.20, 16.51° 2θ ± 0.20, 23.98° 2θ ± 0.20, and 24.74° 2θ ± 0.

20.

19. the crystalline form is gentisate Form A and has a molecular weight of about 12.77° 2θ ± 0.20, 14.08° 2θ ± 0.20, 15.52° 2θ ± 0.20, 15.80° 2θ ± 0.20, 15.98 ± 0.20, 16.51° 2θ ± 0.20, 17.30° 2θ ± 0.20, 18.58° 2θ ± 0.20, 20.95° 2θ ± 0.20, 21.64° 2θ ± 0.20, 23.38° 2θ ± 0.20, 23.98° 2θ ± 0.20, 24.74° 2θ ± 0.20, 25.19° 2θ ± 0.20, 27.81° 2θ ± 0.20, 28.41° 17. The crystalline form of claim 16, exhibiting XRPD (X-ray powder diffraction) peaks at 2θ±0.20 and 28.80° 2θ±0.

20.

20. the crystalline form is gentisate Form A and has molecular weights of about 7.74° 2θ ± 0.20, 9.01° 2θ ± 0.20, 11.01° 2θ ± 0.20, 12.29° 2θ ± 0.20, 12.77° 2θ ± 0.20, 13.15° 2θ ± 0.20, 13.80° 2θ ± 0.20, 14.08° 2θ ± 0.20, 15.52° 2θ ± 0.20, 15.80° 2θ ± 0.20, 15.98° 2θ ± 0.20, 16.11° 2θ ± 0.20, 16.51° 2θ ± 0.20, 17.30° 2θ ± 0.20, 18.07° 2θ ± 0.20, 18.58° 2θ±0.20, 19.13° 2θ±0.20, 19.39° 2θ±0.20, 19.56° 2θ±0.20, 20.95° 2θ±0.20, 21.64° 2θ±0.20, 22.18° 2θ±0.20, 22.45° 2θ±0.20, 23.03° 2θ±0.20, 23.38° 2θ±0.20, 23.98° 2θ±0.20, 24.74° 2θ±0.20, 24.95° 2θ±0.20, 25.19° 2θ±0.20, 25.71° 2θ±0.20, 26.08° 2θ±0.20, 26.47° 2θ±0.20, 27.28° 2θ±0.20, 27.81° 2θ±0.20, 28.41° 2θ±0.20, 28.80° 2θ±0.20, 30.13° 2θ±0.20, 30.66° 2θ±0.20, 31.90° 2θ±0.20, 32.16° 2θ±0.20, 32.57° 2θ±0.20, 33.37° 2θ±0.20, 33.75° 2θ±0.20, 34.77° 2θ±0.20, 35.29° 2θ±0.20, 36.25° 2θ±0.20, and 36.80° 17. The crystalline form of claim 16, exhibiting an XRPD (X-ray powder diffraction) peak at 2θ±0.

20.

21. 21. The crystalline form of any one of claims 16 to 20, which is gentisate Form A characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 10.

22. The crystalline form of claim 3, wherein the acid is benzoic acid.

23. 19. The crystalline form of any one of claims 16 to 18, which is Benzoate Form A characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 16.

24. The crystalline form of claim 3, wherein the acid is fumaric acid.

25. 23. The crystalline form of any one of claims 20 to 22, which is fumarate salt Form A characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 19.

26. The crystalline form of claim 3, wherein the acid is tartaric acid.

27. 23. The crystalline form of any one of claims 20 to 22, which is tartrate salt Form A characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 23.

28. 28. The crystalline form of any one of claims 1 to 27, which is stable after storage at 25°C, 40°C, or 70°C for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or at least 1 year.

29. 29. The crystalline form of any one of claims 1 to 28, which is more stable in water or saline compared to a psilocin standard in water or saline.

30. 30. The crystalline form of claim 29, which is stable during storage at 25°C, 40°C, or 70°C for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or at least 1 year.

31. 31. The crystalline form of claim 29 or 30, wherein less than 10% of the crystalline form decomposes over 36 hours.

32. 32. The crystalline form of any one of claims 1 to 31, wherein the solubility of the crystalline form is from at least about 0.25 mg / mL to at least about 10 mg / mL in water or saline.

33. a) reacting psilocin with the acid in a solvent; b) drying the resulting product of step a); 33. A method for producing the crystalline form of any one of claims 2 to 32, comprising:

34. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 32.

35. 35. The pharmaceutical composition of claim 34, formulated for oral, subcutaneous, intravenous, or intramuscular administration.

36. 36. The pharmaceutical composition of claim 35, formulated for intravenous administration.

37. 37. A method of treating or preventing a disease or condition in a subject, comprising administering to the subject a crystalline form of any one of claims 1 to 32 or a pharmaceutical composition of any one of claims 34 to 36.

38. Use of a crystalline form according to any one of claims 1 to 32 or a pharmaceutical composition according to any one of claims 34 to 36 in the manufacture of a medicament for treating or preventing a disease or condition.

39. A crystalline form according to any one of claims 1 to 32 or a pharmaceutical composition according to any one of claims 34 to 36 for use in treating or preventing a disease or condition in a subject.

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