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WO2024057193A1 - Formes cristallines de psilocine - Google Patents

Formes cristallines de psilocine Download PDF

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Publication number
WO2024057193A1
WO2024057193A1 PCT/IB2023/059011 IB2023059011W WO2024057193A1 WO 2024057193 A1 WO2024057193 A1 WO 2024057193A1 IB 2023059011 W IB2023059011 W IB 2023059011W WO 2024057193 A1 WO2024057193 A1 WO 2024057193A1
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Prior art keywords
crystalline form
acid
psilocin
crystalline
peaks
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PCT/IB2023/059011
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English (en)
Inventor
Jim GILLIGAN
Peter Guzzo
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Tryp Therapeutics Inc
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Tryp Therapeutics Inc
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Publication date
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Priority to CA3267523A priority Critical patent/CA3267523A1/fr
Priority to AU2023343417A priority patent/AU2023343417A1/en
Priority to EP23864880.2A priority patent/EP4587426A1/fr
Priority to JP2025514085A priority patent/JP2025530158A/ja
Priority to IL319227A priority patent/IL319227A/en
Publication of WO2024057193A1 publication Critical patent/WO2024057193A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/124—Acids containing four carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to psilocin crystalline forms.
  • the present invention relates to psilocin crystalline forms having improved physical properties such as aqueous solubility and stability.
  • Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a psychoactive compound which is naturally- occurring, and may be isolated from psilocybin mushrooms. In vivo psilocybin is rapidly dephosphorylated to psilocin which is the psychoactive compound. Research into the therapeutic benefits of psilocybin and its active metabolite psilocin has led to the use of these psychoactives for the treatment of a variety of conditions including drug dependence, anxiety, depression, PTSD and eating disorders and chronic pain.
  • Both psilocin and psilocybin have limited stability in aqueous solutions and such solutions rapidly degrade on exposure to light.
  • the active agent psilocin has a relatively low solubility in aqueous media, which limits its ability to be used in, for example a dosage form suitable for intravenous or subcutaneous injection.
  • microdosing i.e., administering psilocin or psilocybin in quantities much lower than typical therapeutic or recreational doses
  • microdosing i.e., administering psilocin or psilocybin in quantities much lower than typical therapeutic or recreational doses
  • psilocin formulations which can reliably be used to accurately administer low doses, for example maintenance doses.
  • Crystalline or amorphous solid forms of a pharmaceutically active agents can exist as singlecomponent and multiple-component solids.
  • Single-component solids consist essentially of the agent in the absence of other substances.
  • Single-component crystalline materials may exist as different polymorphs, which have different three-dimensional arrangements of the component.
  • different polymorphs may have differing properties such as stability, solubility, melting point, reactivity, and other processability variations.
  • Multiple-component solids comprising two or more ionic species are referred to as salts.
  • a pharmaceutical active or its salt may also exist in forms such as hydrates, solvates or cocrystals.
  • Multiple- component crystal forms may also exhibit polymorphism if the components exist in more than one three- dimensional crystalline arrangement, with each form exhibiting potentially different physical properties.
  • Cocrystals are crystalline molecular complexes of two or more compounds bound together in a crystal lattice by non-ionic interactions.
  • Pharmaceutical cocrystals are cocrystals of an active agent and one or more compounds referred to as coformers.
  • Typical coformers include non-toxic pharmaceutically acceptable substances, such as a food additives, preservatives, pharmaceutical excipients, or other active agents.
  • the invention provides a crystalline form of a pharmaceutically acceptable salt of psilocin (4-hydroxy-N,N-dimethyltryptamine), or a cocrystal of psilocin (4-hydroxy-N,N- dimethyltryptamine) and a coformer.
  • the pharmaceutically acceptable salt is an acid.
  • 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, methyl paraben, nicotinamide and ethyl acetate.
  • the acid is benzenesulfonic acid.
  • the crystalline form may be Besylate Form A.
  • the besylate Form A may exhibits XRPD (X-ray power diffraction) peaks at about 15.44° 20 + 0.20, 18.33° 20 + 0.20, and 25.41° 20 + 0.20. or exhibit peaks at about 14.73° 20 + 0.20, 15.44° 20 + 0.20, 18.33° 20 + 0.20, 22.59° 20 + 0.20, and 25.41° 20 + 0.20; or exhibit peaks at about 11 .72° 20 + 0.20, 12.47° 20 + 0.20, 13.49° 20 + 0.20, 14.73° 20 + 0.20, 15.44° 20 + 0.20, 18.33° 20 + 0.20, 20.62° 20 + 0.20, 20.99° 20 + 0.20, 21 .77° 20 + 0.20, 22.25° 20 + 0.20, 22.59° 20 + 0.20, 23.22° 20 + 0.20, 23.71° 20 + 0.20, 24.10° 20 + 0.20, and 25.41° 20 + 0.20.
  • XRPD X-ray power d
  • the Besylate Form A may exhibit XRPD peaks at about 7.69° 20 + 0.20, 10.26° 20 + 0.20, 10.96° 20 + 0.20, 11 .72° 20 + 0.20, 12.47° 20 + 0.20, 12.84° 20 + 0.20, 13.49° 20 + 0.20, 14.73° 20 + 0.20, 15.44° 20 + 0.20, 16.18° 20 + 0.20, 18.33° 20 + 0.20, 19.04° 20 + 0.20, 19.68° 20 + 0.20, 20.62° 20 + 0.20, 20.99° 20 + 0.20, 21 .77° 20 + 0.20, 22.25° 20 + 0.20, 22.59° 20 + 0.20, 23.22° 20 + 0.20, 23.71° 20 + 0.20, 24.10° 20 + 0.20, 25.15° 20 + 0.20, 25.41° 20 + 0.20, 25.65° 20 + 0.20, 26.29° 20 + 0.20, 26.76° 20 + 0.20, 27.72° 20 + 0.20
  • Besylate Form A is characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 4.
  • the acid is butyric acid.
  • the crystalline form may be Butyrate Form A.
  • the Butyrate Form A may exhibit XRPD (X-ray power diffraction) peaks at about 13.24° 20 + 0.20, 15.34° 20 + 0.20, and 15.88° 20 + 0.20; or may exhibit peaks at about 13.24° 20 + 0.20, 15.34° 20 + 0.20, 15.88° 20 + 0.20, 16.28° 20 + 0.20, 20.95° 20 + 0.20, and 27.79° 20 + 0.20; or may exhibit XRPD (X-ray power diffraction) peaks at about 9.33° 20 + 0.20, 9.96° 20 + 0.20, 10.66° 20 + 0.20, 13.24° 20 + 0.20, 15.34° 20 + 0.20, 15.88° 20 + 0.20, 16.28° 20 + 0.20, 17.80° 20 + 0.20, 20.95° 20 + 0.20, 21 .98° 20 + 0.20, 22.32° 20 + 0.20, 23.
  • the Butyrate Form A may exhibit XRPD peaks at about 9.33° 20 + 0.20, 9.96° 20 + 0.20, 10.66° 20 + 0.20, 12.96° 20 + 0.20, 13.24° 20 + 0.20, 14.36° 20 + 0.20, 15.34° 20 + 0.20, 15.88° 20 + 0.20, 16.28° 20 + 0.20, 17.80° 20 + 0.20, 18.36° 20 + 0.20, 18.75° 20 + 0.20, 18.97° 20 + 0.20, 19.63° 20 + 0.20, 20.01° 20 + 0.20, 20.35° 20 + 0.20, 20.95° 20 + 0.20, 21 .44° 20 + 0.20, 21 .98° 20 + 0.20, 22.32° 20 + 0.20, 22.80° 20 + 0.20, 23.31° 20 + 0.20, 23.77° 20 + 0.20, 24.41° 20 + 0.20, 24.61° 20 + 0.20, 25.46° 20 + 0.20, 25.60° 20 + 0.20, 26
  • butyrate Form A may be characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 7.
  • the acid is gentisic acid.
  • the crystalline form is Gentisate Form A.
  • the Gentisate Form A may exhibits XRPD peaks at about 15.80° 20 + 0.20, 16.51 ° 20 + 0.20, and 23.98° 20 + 0.20;, or may exhibits XRPD peaks at about 15.52° 20 + 0.20, 15.80° 20 + 0.20, 16.51 ° 20 + 0.20, 23.98° 20 + 0.20, and 24.74° 20 + 0.20; or may exhibit XRPD peaks at about 12.77° 20 + 0.20, 14.08° 20 + 0.20, 15.52° 20 + 0.20, 15.80° 20 + 0.20, 15.98 + 0.20, 16.51 ° 20 + 0.20, 17.30° 20 + 0.20, 18.58° 20 + 0.20, 20.95° 20 + 0.20, 21 .64° 20 + 0.20, 23.38° 20 + 0.20, 23.98° 20 + 0.20, 24.74° 20 + 0.20, 25.19° 20 + 0.20, 27.81 ° 20 + 0.20, 28.41 ° 20 + 0.20, and
  • the Gentisate Form A may be characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 10.
  • the acid is benzoic acid.
  • the crystalline form is Benzoate Form A, for example as characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 16.
  • the acid is fumaric acid.
  • the crystalline form is Fumarate Form A, for example as characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 19.
  • the acid is tartaric acid.
  • the crystalline form is Tartrate Form A, for example as characterized by an X-ray powder diffraction spectrum substantially as depicted in Figure 23.
  • the crystalline form may be stable after storage at 25°C, 40°C, or 70°C for one day, one week, two weeks, one month, two months, three months, four months, five months, 6 months or at least one year.
  • the crystalline form may be more stable in water or saline compared to psilocin base in water or saline.
  • the crystalline form is stable for one day, one week, two weeks, one month, two months, three months, four months, five months, six months or at least one year during storage at 25°C, 40°C, or 70°C.
  • the solubility of the crystalline form may be at least about 0.25 mg/mL to at least about 10mg/mL in water or saline.
  • a method of producing the crystalline form comprising the steps of: a) reacting psilocin with the acid in a solvent; and b) drying the resultant product of step a).
  • 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.
  • 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.
  • a fifth aspect there is provided use of the crystalline form f the first aspect or the pharmaceutical composition of the third aspect in the manufacture of a medicament for treating or preventing a disease or condition.
  • a crystalline form of the first aspect or the pharmaceutical composition of the third aspect for use in treating or preventing a disease or condition in a subject.
  • Figure 1 shows an XRPD pattern of psilocin free base.
  • Figure 2 shows an indexing solution for psilocin free base with the following characteristics:
  • Figure 3 shows an 1 H NMR spectrum of psilocin free base.
  • Figure 4 shows an XRPD pattern of psilocin besylate Form A.
  • Figure 5 shows an indexing solution for psilocin besylate Form A with the following characteristics:
  • Figure 6 shows an 1 H NMR spectra of psilocin besylate Form A (middle), including reference spectra for psilocin free base (top) and benzenesulfonic acid (bottom).
  • Figure 7 shows an XRPD pattern of psilocin butyrate Form A.
  • Figure 8 shows an indexing solution for psilocin butyrate Form A with the following characteristics:
  • Figure 9 shows an 1 H NMR spectra of psilocin butyrate Form A (bottom), including reference spectrum for psilocin free base (top).
  • Figure 10 shows an XRPD overlay of psilocin gentisate Form A, including Gentisate Form A, RR (Reaction Ratio) 2:1 mol/mol, from EtOAc/2-8 °C (top); Gentisate Form A, post-dried, vacuum/RT/1 d (middle); and Gentisate Form A, preparation for additional materials (bottom).
  • Gentisate Form A including Gentisate Form A, RR (Reaction Ratio) 2:1 mol/mol, from EtOAc/2-8 °C (top); Gentisate Form A, post-dried, vacuum/RT/1 d (middle); and Gentisate Form A, preparation for additional materials (bottom).
  • Figure 11 shows an indexing solution for psilocin gentisate Form A with the following characteristics:
  • Figure 12 shows an 1 H NMR spectra of psilocin gentisate Form A before drying (top middle) and after drying (bottom middle), including reference spectra for psilocin free base (top) and gentisic acid (bottom).
  • Figure 13 shows an XRPD pattern of psilocin acetate Form A.
  • Figure 14 shows an indexing solution for psilocin acetate Form A with the following characteristics:
  • Figure 15 shows an 1 H NMR spectrum of psilocin acetate Form A (middle), including reference spectra for psilocin free base (top) and acetic acid (bottom).
  • Figure 16 shows an XRPD overlay of psilocin benzoate Form A.
  • Figure 17 shows an indexing solution for psilocin benzoate Form A with the following characteristics:
  • Figure 18 shows an 1 H NMR spectra of psilocin benzoate Form A before drying (top middle) and after drying (bottom middle), including reference spectra for psilocin free base (top) and benzoic acid (bottom).
  • Figure 19 shows an XRPD overlay of psilocin fumarates Form A and Form B, including psilocin fumarate Form A, RR 1 :1 mol/mol, from acetone/2-8 °C (top); psilocin fumarate Form B + 2nd phase(s), from drying psilocin fumarate Form A (middle) and psilocin fumarate Form B, RR 1 :1 mol/mol, from IPA and drying (bottom).
  • Figure 20 shows an indexing solution for psilocin fumarate Form A with the following characteristics:
  • Figure 21 shows an indexing solution for psilocin fumarate Form B with the following characteristics:
  • Figure 22 shows an 1 H NMR spectra of psilocin fumarate Form A and psilocin fumarate Form B, including reference spectrum for psilocin free base (top); psilocin fumarate Form A (top middle); psilocin fumarate Form B (w/ minor 2nd phase) (bottom middle); and reference spectrum for fumaric acid (bottom).
  • Figure 23 shows an XRPD pattern of psilocin tartrate Form A.
  • Figure 24 shows an indexing solution for psilocin tartrate Form A with the following characteristics:
  • Figure 25 shows an 1 H NMR spectrum of psilocin tartrate Form A (middle), including reference spectra for psilocin free base (top) and tartaric acid (bottom).
  • Figure 26 shows the stability overtime of psilocin besylate, psilocin butyrate and psilocin gentisate compared to psilocin in saline solution. This graph is based on psilocin peak area over time [0064]
  • Figure 27 shows the stability overtime of psilocin besylate, psilocin butyrate and psilocin gentisate compared to psilocin in saline solution. This graph shows psilocin peak area as a percentage overtime.
  • a and “an” are used to refer to one or more than one (i.e., at least one) of the grammatical object of the article.
  • an element means one element, or more than one element.
  • pharmaceutically acceptable salt refers to those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are 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 on 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 compounds of the invention are known to one of skill in the art.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, fumaric, maleic, pyruvic, alkyl sulfonic, arylsulfonic, aspartic, glutamic, benzoic, anthranilic, mesylic, methanesulfonic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, ambonic, pamoic, pantothenic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, p-hydroxybutyric, galactaric, fumaric and galacturonic acids.
  • Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine.
  • 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), procaine, ammonium salts, quaternary salts such as tetramethylammonium salt, amino acid addition salts such as salts with glycine and arginine.
  • inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • treating encompasses curing, ameliorating or tempering the severity of a medical condition or one or more of its associated symptoms.
  • terapéuticaally 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 the subject being treated.
  • the terms are synonymous and are intended to qualify the amount of each agent that will achieve the goal of improvement in disease severity and/or the frequency of incidence over treatment of each agent by itself while preferably avoiding or minimising adverse side effects, including side effects typically associated with other therapies.
  • Those skilled in the art can determine an effective dose using information and routine methods known in the art.
  • a "pharmaceutical carrier, diluent or excipient” includes, but is not limited to, any physiological buffered (i.e. , about pH 6.0 to 7.4) medium comprising a suitable water-soluble organic carrier, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.
  • suitable water-soluble organic carriers include, but are not limited to, saline, dextrose, corn oil, dimethylsulfoxide, and gelatin capsules.
  • lactose lactose
  • mannitol corn starch
  • potato starch binders such as microcrystalline cellulose, cellulose derivatives such as hydroxypropylmethylcellulose, acacia, gelatins, disintegrators such as sodium carboxymethylcellulose, and lubricants such as talc or magnesium stearate.
  • binders such as microcrystalline cellulose, cellulose derivatives such as hydroxypropylmethylcellulose, acacia, gelatins, disintegrators such as sodium carboxymethylcellulose, and lubricants such as talc or magnesium stearate.
  • Subject includes any human or non-human mammal.
  • the compounds of the present invention may also be useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
  • the subject is a human.
  • administering and variations of that term including “administer” and “administration”, includes contacting, applying, delivering or providing a compound or composition of the invention to a subject by any appropriate means.
  • HPLC refers to High-performance liquid chromatography
  • NMR Nuclear magnetic resonance spectroscopy
  • PLM Polarized laser microscopy
  • XRPD refers to X-ray powder diffraction
  • FE refers to Fast evaporation
  • ACN refers to Acetonitrile
  • DMSO Dimethyl sulfoxide
  • EtOAc refers to Ethyl acetate
  • GRAS refers to Generally Regarded as Safe
  • HCI Hydrochloric acid
  • H3PO4 refers to Phosphoric acid
  • IPA refers to Isopropyl alcohol
  • MTBE refers to Methyl tert-butyl ether
  • THF Tetrahydrofuran
  • agg refers to aggregates/agglomerates
  • B/E refers to birefringence/extinction
  • IV refers to intravenous
  • LIMS refers to laboratory information management system
  • min refers to minute(s)
  • N2 refers to nitrogen
  • RT refers to room temperature
  • API Material X refers to material confirmed to contain the API but of unknown crystalline form.
  • API Form X refers to material confirmed to contain an API and demonstrated to be constituted of a single crystalline form.
  • API salt/cocrystal Material X refers to material confirmed to contain a salt or cocrystal of the API but of unknown crystalline form.
  • API salt/cocrystal Form X refers to material confirmed to contain a salt or cocrystal of an API and demonstrated to be constituted of a single crystalline form.
  • Crystall refers to a substance that produces an XRPD pattern with sharp peaks (similar to instrumental peak widths) and weak diffuse scattering (relative to the peaks).
  • Disordered crystalline refers to a substance that produces an XRPD pattern with broad peaks (relative to instrumental peak widths) and/or strong diffuse scattering (relative to the peaks). Disordered materials may be:
  • Insufficient signal refers to circumstances where insufficient signal above the expected background scattering was observed. This may indicate that the X-ray beam missed the sample and/or that the sample was of insufficient mass for analysis.
  • particle statistics artifacts refers to the circumstances where particle size distribution contains a small number of large crystals which may lead to sharp spikes in the XRPD pattern.
  • Preferred orientation artifacts refers to circumstances where the particle morphology is prone to non-random orientation in the sample holder which may lead to subtle and/or dramatic changes in relative peak intensities.
  • No peaks refers to circumstances 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.
  • Single crystalline phase refers to circumstances where an XRPD pattern is judged to contain evidence of a single crystalline phase if all the Bragg peaks can be indexed with a single unit cell.
  • X-ray amorphous refers to circumstances where diffuse scatter is present, but no evidence for Bragg peaks in an XRPD pattern.
  • X-ray amorphous materials may be:
  • thermodynamic amorphous material • thermodynamic amorphous material or a combination of the above. Additional analysis may differentiate among these options.
  • the invention relates to a crystalline form of a pharmaceutically acceptable salt of psilocin (4-hydroxy-N,N-dimethyltryptamine), or a cocrystal thereof, wherein the cocrystal comprises a coformer.
  • the crystalline form is Besylate Form A, Butyrate Form A, or Gentisate Form A.
  • the crystalline forms described herein may provide enhanced physical properties, such as solubility, dissolution rate, bioavailability, physical stability, chemical stability, flowability, fractability, or compressibility.
  • a given API may form different cocrystals with one or more different counter-molecules, and some of these cocrystals may exhibit enhanced solubility or stability.
  • crystalline form of psilocin is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt may be selected from any pharmaceutically acceptable salt known in the art.
  • the pharmaceutically acceptable salt is a base form of an acid.
  • the acid may 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, pyrogluamic acid, sorbic acid, succinic acid, sulfuric acid and tartaric acid.
  • the acid is benzenesulfonic acid, butyric acid, gentisic acid, acetic acid, benzoic acid, fumaric acid, ortartaric acid. Even more preferably the acid is benzenesulfonic, butyric or gentisic acid.
  • the crystalline form of a pharmaceutically acceptable salt of psilocin is a cocrystal comprising a coformer.
  • the coformer may be any pharmaceutically acceptable coformer known in the art.
  • 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,
  • the coformer is selected from the group consisting of arginine, lysine, methyl paraben, nicotinamide and ethyl acetate.
  • the coformer is ethyl acetate.
  • the present invention may be a crystalline form or an amorphous form or mixtures thereof (e.g., mixtures of crystal forms, or mixtures of crystal and amorphous forms), which comprises (a) psilocin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof and (b) a coformer.
  • a crystal form comprising (a) psilocin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof and (b) a coformer.
  • a cocrystal comprising (a) psilocin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof and (b) a coformer.
  • an amorphous form comprising (a) psilocin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof and (b) a coformer.
  • a mixture comprising (i) a cocrystal comprising (a) psilocin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof and (b) a coformer; and (ii) a crystal form of psilocin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof.
  • a mixture comprising (i) a cocrystal 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.
  • the crystalline form is Besylate Form A.
  • the Besylate Form A has an XRPD (X-ray power diffraction) pattern having peaks at about 15.44° 20 + 0.20, 18.33° 20 + 0.20, and 25.41° 20 + 0.20.
  • the XRPD (X-ray power diffraction) pattern has peaks at about 14.73° 20 + 0.20, 15.44° 20 + 0.20, 18.33° 20 + 0.20, 22.59° 20 + 0.20, and 25.41° 20 + 0.20.
  • the XRPD X-ray power diffraction
  • the Besylate Form A has an XRPD (X-ray power diffraction) pattern having peaks at about 15.44° 20
  • the Besylate Form A has an XRPD pattern comprising peaks substantially or essentially the same as shown in Figures 4 or 5. In one embodiment, the Besylate Form A has an 1 H NMR spectrum comprising peaks substantially or essentially the same as shown in Figure 6.
  • the Besylate Form A may be solvated, hemi-solvated or unsolvated. In a preferred embodiment, the Besylate Form A is unsolvated.
  • the crystalline form is Butyrate Form A.
  • the Butyrate Form A has an XRPD pattern having peaks at about 13.24° 20 + 0.20, 15.34° 20 + 0.20, and 15.88° 20 + 0.20.
  • the Butyrate Form A has an XRPD pattern having peaks at about 13.24° 20 + 0.20, 15.34° 20 + 0.20, 15.88° 20 + 0.20, 16.28° 20 + 0.20, 20.95° 20 + 0.20, and 27.79° 20 + 0.20
  • the Butyrate Form A has an XRPD pattern having peaks at about 9.33° 20 + 0.20, 9.96° 20 + 0.20, 10.66° 20 + 0.20, 13.24° 20 + 0.20, 15.34° 20 + 0.20, 15.88° 20 + 0.20, 16.28° 20 + 0.20, 17.80° 20 + 0.20, 20.95° 20 + 0.20, 21 .98° 20 + 0.20, 22.32° 20 + 0.20, 23.31° 20 + 0.20, 24.61° 20 + 0.20, and 27.79° 20 + 0.20.
  • the Butyrate Form A has an XRPD pattern having peaks at about at about 9.33° 20 + 0.20, 9.96° 20 + 0.20, 10.66° 20 + 0.20, 12.96° 20 + 0.20, 13.24° 20 + 0.20, 14.36° 20 + 0.20, 15.34° 20 + 0.20, 15.88° 20 + 0.20, 16.28° 20 + 0.20, 17.80° 20 + 0.20, 18.36° 20 + 0.20, 18.75° 20 + 0.20, 18.97° 20 + 0.20, 19.63° 20 + 0.20, 20.01° 20 + 0.20, 20.35° 20 + 0.20, 20.95° 20 + 0.20, 21 .44° 20 + 0.20, 21 .98° 20 + 0.20, 22.32° 20 + 0.20, 22.80° 20 + 0.20, 23.31° 20 + 0.20, 23.77° 20 + 0.20, 24.41° 20 + 0.20, 24.61° 20 + 0.20, 25.46° 20 + 0.20, 25.60°
  • the Butyrate Form A has an XRPD pattern comprising peaks substantially or essentially the same as shown in Figures 7 or 8. In one embodiment, the Butyrate Form A has an 1 H NMR spectrum comprising peaks substantially or essentially the same as shown in Figure 9.
  • the Butyrate Form A may be solvated, hemi-solvated or unsolvated. Preferably, the Butyrate Form A is unsolvated.
  • the crystalline form is Gentisate Form A.
  • the Gentisate Form A has an XRPD pattern having peaks at about 15.80° 20 + 0.20, 16.51 ° 20 + 0.20, and 23.98° 20 + 0.20.
  • the Gentisate Form A has an XRPD pattern having peaks at about 15.52° 20 + 0.20, 15.80° 20 + 0.20, 16.51° 20 + 0.20, 23.98° 20 + 0.20, and 24.74° 20 + 0.20.
  • the Gentisate Form A has an XRPD pattern having peaks at about at about 12.77° 20 + 0.20, 14.08° 20 + 0.20, 15.52° 20 + 0.20, 15.80° 20 + 0.20, 15.98 + 0.20, 16.51 ° 20 + 0.20, 17.30° 20 + 0.20, 18.58° 20 + 0.20, 20.95° 20 + 0.20, 21 .64° 20 + 0.20, 23.38° 20 + 0.20, 23.98° 20 + 0.20, 24.74° 20 + 0.20, 25.19° 20 + 0.20, 27.81 ° 20 + 0.20, 28.41 ° 20 + 0.20, and 28.80° 20 + 0.20.
  • Gentisate Form A has an XRPD pattern having peaks at about 7.74° 20 + 0.20, 9.01 ° 20 + 0.20, 11.01 ° 20 + 0.20, 12.29° 20 + 0.20, 12.77° 20 + 0.20, 13.15° 20 + 0.20, 13.80° 20 + 0.20, 14.08° 20 + 0.20, 15.52° 20 + 0.20, 15.80° 20 + 0.20, 15.98° 20 + 0.20, 16.11 ° 20 + 0.20, 16.51 ° 20 + 0.20, 17.30° 20 + 0.20, 18.07° 20 + 0.20, 18.58° 20 + 0.20, 19.13° 20 + 0.20, 19.39° 20 + 0.20, 19.56° 20 + 0.20, 20.95° 20 + 0.20, 21 .64° 20 + 0.20, 22.18° 20 + 0.20, 22.45° 20 + 0.20, 23.03° 20 + 0.20, 23.38° 20 + 0.20, 23.98° 20 + 0.20, 24.74° 20 + 0.20, 24.
  • the Gentisate Form A has an XRPD pattern comprising peaks substantially or essentially the same as shown in Figures 10 or 11 .
  • the Gentisate Form A has an 1 H NMR spectrum comprising peaks substantially or essentially the same as shown in Figure 12.
  • the Gentisate Form A may be solvated, hemi-solvated or unsolvated.
  • the Gentisate Form A is hemi-solvated or unsolvated.
  • the crystalline form is Acetate Form A.
  • the Acetate Form A has an XRPD pattern having comprising peaks substantially or essentially the same as shown in Figures 13 or 14.
  • the Acetate Form A has an 1 H NMR spectrum comprising peaks substantially or essentially the same as shown in Figure 15.
  • the Acetate Form A may be solvated, hemi- solvated or unsolvated.
  • the crystalline form is Benzoate Form A.
  • the Benzoate Form A has an XRPD pattern comprising peaks substantially or essentially the same as shown in Figures 16 or 17.
  • the Benzoate Form A has an 1 H NMR spectrum comprising peaks substantially or essentially the same as shown in Figure 18.
  • the Benzoate Form A may be solvated, hemi-solvated or unsolvated.
  • the crystalline form is Fumarate Form A.
  • the Fumarate Form A has an XRPD pattern comprising peaks substantially or essentially the same as shown in Figures 19 or
  • the Fumarate Form A has an 1 H NMR spectrum comprising peaks substantially or essentially the same as shown in Figure 22.
  • the Fumarate Form A may be solvated, hemi-solvated or unsolvated.
  • the crystalline form is Fumarate Form B.
  • the Fumarate Form B has an XRPD pattern comprising peaks substantially or essentially the same as shown in Figures 19 or
  • the Fumarate Form B has an 1 H NMR spectrum comprising peaks substantially or essentially the same as shown in Figure 22.
  • the Fumarate Form B may be solvated, hemi-solvated or unsolvated.
  • the crystalline form is Tartrate Form A.
  • the Tartrate Form A has an XRPD pattern comprising peaks substantially or essentially the same as shown in Figures 23 or 24.
  • the Tartrate Form A has an 1 H NMR spectrum comprising peaks substantially or essentially the same as shown in Figure 25.
  • the Tartrate Form A may be solvated, hemi-solvated or unsolvated.
  • the present invention provides a pharmaceutical composition comprising the crystalline forms as described herein.
  • the compositions described herein may be formulated for oral, subcutaneous, intravenous, or intramuscular administration.
  • the pharmaceutical composition is formulated for intravenous administration.
  • the psilocin compositions described herein may comprise a pharmaceutically effective amount of psilocin, in association with one or more pharmaceutically acceptable excipients including carriers, vehicles and diluents.
  • excipient 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 properties or to permit or facilitate formation of a solution for oral, parenteral, intradermal, subcutaneous, or topical application.
  • Excipients can include, by way of illustration and not limitation, diluents, wetting agents, polymers, lubricants, stabilizers, and substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include (but are not limited to) stearic acid, magnesium stearate, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, dextrin, mannitol, sorbitol, lactose, sucrose, starches, gelatin, polymers such as polyvinyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycols, and other pharmaceutically acceptable materials.
  • excipients examples include Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000). The choice of excipient will to a large extent 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.
  • the crystalline forms provided herein have greater aqueous solubility (solubility in water or saline) than psilocin base.
  • the solubility of the crystal forms may 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.
  • the crystalline forms provided herein have improved stability either in solid form or in solution (water or saline) compared to psilocin base in solution.
  • the crystalline forms degrade at a much slower rate than psilocin in saline solution.
  • the crystalline forms when the crystalline forms are in an aqueous solution such as saline there is less than a 10% decrease in the amount of psilocin present overtime (e.g. 36 hours) compared to at least a 15% decrease for psilocin base.
  • the crystalline forms described herein are stable for one day, one week, two weeks, one month, two months, three months, four months, five months, six months or at least one year during storage under long term stability condition of 30° C, 65% relative humidity as well as at accelerated/stress condition of 40-45° C and 75% relative humidity.
  • the crystalline forms described herein are stable for at least two years under long term stability conditions of 30° C, 65% relative humidity as well as at accelerated/stress condition of 40-45° C and 75% relative humidity.
  • the stability can be further improved by formulating the crystalline forms with one or more excipients to reduce the effects of oxidation on the crystalline form, for example ascorbate, pyruvate, ascrorbyl palmitate, butylated hydroxytoluene, calcium stearate, citrate, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium thiosulfate, vitamin E, and sodium edetate.
  • excipients for example ascorbate, pyruvate, ascrorbyl palmitate, butylated hydroxytoluene, calcium stearate, citrate, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium thiosulfate, vitamin E, and sodium edetate.
  • the present invention provides a method of producing a stable crystalline form and /or a crystalline from with improved solubility, comprising the steps of: a) reacting psilocin with a pharmaceutically acceptable acid, as described herein, in a solvent; and b) drying the resultant product of step a).
  • 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.
  • the solvent may be selected from ethyl acetate or acetone.
  • the reaction between psilocin with the pharmaceutically acceptable acid is conducted at a lowered temperature, preferably from about 2-8 °C. In some embodiments, the drying is conducted under vacuum at ambient temperature.
  • the present invention provides a crystalline form or pharmaceutical composition, as described herein, useful for treating diseases and conditions such as psychological conditions, post-traumatic stress, attention deficit hyperactivity disorder, anxiety, addiction, depression, compulsion, IBS (irritable bowel syndrome), fibromyalgia, CRPS (complex regional pain syndrome), phantom limb, eating disorders, diabetes for example, diabetes associated with obesity and type 2 diabetes, neurological injuries, pain, for example nociplastic pain, and inflammatory conditions.
  • diseases and conditions such as psychological conditions, post-traumatic stress, attention deficit hyperactivity disorder, anxiety, addiction, depression, compulsion, IBS (irritable bowel syndrome), fibromyalgia, CRPS (complex regional pain syndrome), phantom limb, eating disorders, diabetes for example, diabetes associated with obesity and type 2 diabetes, neurological injuries, pain, for example nociplastic pain, and inflammatory conditions.
  • the present invention provides a method of treating or preventing a disease or condition in a subject comprising administering to the subject the crystalline form or the pharmaceutical composition, as described herein.
  • the present invention provides use of the crystalline form or pharmaceutical composition, as described herein, in the manufacture of a medicament for treating or preventing a disease or condition.
  • the present invention provides the crystalline form or the pharmaceutical composition, as described herein, for use in treating or preventing a disease or condition in a subject.
  • Example 1 Salt and cocrystal screens
  • Materials exhibiting unique crystalline XRPD patterns are assigned sequential alphabetical characters as the default designation, if no other character types already pertain to the compound. Each uniquely identified material is assigned a new designation, which includes the chemical name of the guest used. The designation is tentatively associated with the term "Material” until the phase purity and chemical composition is determined through further characterization. Presence of psilocin, composition determination, and verification of phase uniformity are necessary before the term "Form" is used.
  • Psilocin packaged in 36 pre-weighed vials was received as the starting materials. The initial characterization of the material is described below. The screening activities and characterization for the generated materials are discussed below.
  • the psilocin is a crystalline material, as shown in Figure 1 .
  • the XRPD pattern was successfully indexed, and the indexing solution is consistent with an unsolvated psilocin, as shown in Figure 3.
  • acids suitable for pharmaceutical salt development were selected, based on e.g., the calculated pKa (9.38, by ACD/pKa DB v11 .01) of psilocin, and the solubilities of psilocin (see Table 1) and acids. 4 coformers were included for screening. All acids and coformers used in this study are summarized below.
  • Besylate Form A was generated 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 indexing solution is consistent with an unsolvated mono-salt.
  • Butyrate Material A was generated from a salt formation experiment in EtOAc using 1 :1 mol/mol psilocin and butyric acid, followed by drying.
  • the XRPD pattern ( Figure 7) was successfully indexed (figure 8).
  • the indexing solution suggests it can be an unsolvated mono-salt.
  • Gentisate Form A was generated from an experiment using 2:1 mol/mol psilocin and gensitic acid in EtOAc at 2-8 °C.
  • the XRPD pattern ( Figure 10) was successfully indexed ( Figure 11). Based on the indexing solution, Gentisate Form A may accommodate at least 1 mole of water or half mole of EtOAc, if it is a 1 :1 salt.
  • Tracrium® Atracurium Besylate
  • Cleviprex® Clevidipine Butyrate
  • 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).
  • Acetate Form A was generated from a reaction between psilocin and acetic acid (1 :1 mol/mol) in EtOAc. The solids were dried under vacuum at ambient temperature before analysis. The XRPD pattern ( Figure 13) was successfully indexed ( Figure 14). Based on the indexing solution, Acetate Form A can be an unsolvated material.
  • the 1 H NMR spectrum of Acetate Form A ( Figure 15) is consistent with psilocin chemical structure, containing 1 mole of acetic acid and 0.03 moles of EtOAc. Peak shifts were observed compared with the spectrum of psilocin free base, indicative of salt formation. Therefore Acetate Form A is likely an unsolvated mono-salt.
  • Fumarate Form A was generated 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 may accommodate 1 mole of acetone, if it is a hemi-fumarate.
  • the 1 H NMR spectrum of Fumarate Form A ( Figure 22) is generally consistent with that of psilocin, containing 0.5 moles of fumaric acid and 0.7 moles of acetone. Peak shifts are observed, compared with the spectrum of psilocin free base, indicative of salt formation.
  • Fumarate Form A was dried under vacuum at ambient temperature for 1 day, and the sample converted to a mixture of Fumarate Form B and minor unknown secondary phase(s). The 1 H NMR spectrum of this mixture is consistent with that of Fumarate Form A, containing 0.2 moles of acetone. From an additional salt experiment with fumaric acid in IPA, followed by drying under vacuum, a single phase of Fumarate Form B was generated. This XRPD pattern was successfully indexed and the indexing solution is consistent with an unsolvated hemi-fumarate.
  • Psilocin Tartrate Form A was generated from a reaction between psilocin and tartaric acid (1 :1 mol/mol) in acetone. The solids were dried under vacuum at ambient temperature before analysis. The XRPD pattern ( Figure 23) was successfully indexed ( Figure 24). Based on the indexing solution, Tartrate Form A can be unsolvated for a 1 :1 salt. The 1 H NMR spectrum of Tartrate Form A ( Figure 25) is consistent with psilocin chemical structure, containing 1 mole of tartaric acid and 0.1 moles of acetone. Peak shifts were observed compared with the spectrum of psilocin free base, indicative of salt formation.
  • Tartrate Form A is likely an unsolvated mono-salt.
  • Succinate Material A To complete the salt reaction and remove residual psilocin and acid, the mixture was re-slurried in EtOAc. In the re-slurried material, psilocin and succinic acid are not present. However an additional phase is observed. This mixture was not further analyzed.
  • XRPD patterns were collected with a PANalytical X’Pert PRO MPD or Empyrean diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source.
  • An elliptically graded multilayer mirror was used to focus Cu Kor X-ray radiation through the specimen and onto the detector.
  • a silicon specimen NIST SRM 640f was analyzed to verify the observed position of the Si (111) peak is consistent with the NIST-certified position.
  • a specimen of the sample was sandwiched between 3-pm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated 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) located 240 mm from the specimen and Data Collector software v. 5.5.
  • X’Celerator scanning position-sensitive detector
  • the XRPD data presented herein include x-ray diffraction patterns with labeled peaks and tables with peak lists.
  • the range of data collected is typically provided in the scientific report in which the data were initially reported, and is instrument dependent. Under most circumstances, peaks within the range of up to about 30° 20 were selected. Rounding algorithms were used to round each peak to the nearest 0.1° or 0.01° 20, depending upon the instrument used to collect the data and/or the inherent peak resolution. The location of the peaks along the x-axis (° 20) in both the figures and the tables were rounded to one or two significant figures after the decimal point based upon the above criteria.
  • Peak position variabilities are given to within +0.2° 20 based upon recommendations outlined in the USP discussion of variability in x- ray powder diffraction (USP-NF 2022, Issue 2, ⁇ 941 >, 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.].
  • XRPD X-Ray Powder Diffraction
  • GUID-14EBB55E-0D24-45A1- A84FFE4DCAAEE3E8_2_en-US official 01 May 2022.
  • the wavelength used to calculate d-spacings was 1 .5405929A, the Cu-Ka1 wavelength (Phys. Rev. A56(6) 4554-4568 (1997)). Variability associated with d-spacing estimates was calculated from the USP recommendation, at each d-spacing, and provided in the respective data tables.
  • variable hydrates and solvates may display peak variances greater than 0.2° 20 and therefore peak variances of 0.2° 20 are not applicable to these materials.
  • peak tables contain data identified only as "Prominent Peaks”. These peaks are a subset of the entire observed peak list. Prominent peaks are selected from observed peaks by identifying preferably non-overlapping, low-angle peaks, with strong intensity.
  • assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Reproducibility among XRPD patterns from multiple samples analyzed on a single diffractometer indicates that the particle statistics are adequate. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks”.
  • Example 4 Comparison of psilocin salt and psilocin free base solubility in saline
  • Psilocin besylate, psilocin butyrate, psilocin gentisate, and psilocin free base were prepared at 1 .0 mg/mL in saline. Psilocin free base was also prepared at 0.1 mg/mL. Solubility of material in solution was observed and pH was recorded (Table 13)
  • Example 5 Psilocin salt and psilocin free base stability 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 pm PTFE filter. Solutions were analyzed at various time points over 38 hours using the HPLC conditions set out in the tables 14 and 15. The psilocin salts are substantially more stable over time than psilocin (see Figures 26 and 27).
  • Example 6 Prophetic Example - Chemical stability
  • Solid-state stability may be assessed using a temperature/humidity control chamber.
  • a sample of each crystalline form is placed in the chamber and exposed to various temperatures and humidities, for example 25° C/60% RH, 40° C/75% RH, 70° C./75% RH, and/or irradiated with a Xenon lamp.
  • the crystalline form, thermal behavior, purity and/or weight change of the resultant sample after the exposure or irradiation may be evaluated by using one or more of XRPD, thermogravity/differential thermal analysis, differential scanning calorimetry, high performance liquid chromatography, or a microbalance.
  • each crystalline form will be stable.
  • the solid-state stability study after storage at 25° C/60% RH, or 40° C/75% RH, or 70° C./75% RH for one week, two weeks, one month, or two months the crystalline forms described herein will be chemically and physically stable
  • Example 7 Prophetic Example - Photostability
  • Example 8 Prophetic Example - Forced Degradation
  • a test will be carried out to assess the stability of the psilocin crystalline forms and free base psilocin to oxidative degradation. Forced degradation of the psilocin salts will be performed in H2O2, for example 0.3 % H202to test the oxidative stability of each crystalline form.
  • the appropriate volume of H2O2 will be added to a pre-weighed sample of the crystalline form in an amber vial (or other vial shieled from light) to give a maximum concentration of, for example 0.2 mg/mL of psilocin (free base equivalent).
  • the samples will be stored at 25°C and the purity of each sample was assessed periodically thereafter by HPLC. For example the samples may be assessed at 0, 1 , 6, and 24 hours using HPLC.

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Abstract

La présente invention concerne des formes cristallines de sels ou de co-cristaux de psilocine (4-hydroxy-N,N-diméthyltryptamine), ainsi que des compositions, des procédés de préparation et des procédés d'utilisation correspondants. La présente invention concerne également lesdites formes cristallines ayant des propriétés physiques améliorées telles que la solubilité aqueuse et la stabilité, les formes cristallines et leurs compositions étant appropriées pour une administration orale, sous-cutanée, intraveineuse ou intramusculaire.
PCT/IB2023/059011 2022-09-12 2023-09-12 Formes cristallines de psilocine Ceased WO2024057193A1 (fr)

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AU2023343417A AU2023343417A1 (en) 2022-09-12 2023-09-12 Psilocin crystalline forms
EP23864880.2A EP4587426A1 (fr) 2022-09-12 2023-09-12 Formes cristallines de psilocine
JP2025514085A JP2025530158A (ja) 2022-09-12 2023-09-12 サイロシン結晶形
IL319227A IL319227A (en) 2022-09-12 2023-09-12 Crystal forms of psilocin

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GB912715A (en) * 1958-02-21 1962-12-12 Sandoz Ltd 4-hydroxytryptamines
US20080293695A1 (en) * 2007-05-22 2008-11-27 David William Bristol Salts of physiologically active and psychoactive alkaloids and amines simultaneously exhibiting bioavailability and abuse resistance
WO2022173888A1 (fr) * 2021-02-10 2022-08-18 Eleusis Thereapeutics Us, Inc. Sels de psilocine de qualité pharmaceutique et leurs utilisations
WO2022251169A1 (fr) * 2021-05-24 2022-12-01 Canna-Chemistries Llc Sels cristallins de psilocine
WO2023078604A1 (fr) * 2021-11-05 2023-05-11 Cybin Irl Limited Formulations d'analogues de psilocybine et procédés d'utilisation
US11667607B1 (en) * 2022-06-30 2023-06-06 Zylorion Health Inc. Crystalline forms of compositions comprising psilocin and psilocybin
WO2023168023A1 (fr) * 2022-03-04 2023-09-07 Reset Pharmaceuticals, Inc. Co-cristaux ou sels comprenant de la psilocine

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GB912715A (en) * 1958-02-21 1962-12-12 Sandoz Ltd 4-hydroxytryptamines
US20080293695A1 (en) * 2007-05-22 2008-11-27 David William Bristol Salts of physiologically active and psychoactive alkaloids and amines simultaneously exhibiting bioavailability and abuse resistance
WO2022173888A1 (fr) * 2021-02-10 2022-08-18 Eleusis Thereapeutics Us, Inc. Sels de psilocine de qualité pharmaceutique et leurs utilisations
WO2022251169A1 (fr) * 2021-05-24 2022-12-01 Canna-Chemistries Llc Sels cristallins de psilocine
WO2023078604A1 (fr) * 2021-11-05 2023-05-11 Cybin Irl Limited Formulations d'analogues de psilocybine et procédés d'utilisation
WO2023168023A1 (fr) * 2022-03-04 2023-09-07 Reset Pharmaceuticals, Inc. Co-cristaux ou sels comprenant de la psilocine
US11667607B1 (en) * 2022-06-30 2023-06-06 Zylorion Health Inc. Crystalline forms of compositions comprising psilocin and psilocybin

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CASHMAN PAUL J, THORNTON ANDJOHN I, : "A Specific Microcrystalline Test for lndolamine Derivatives*", MICROCHEMICAL JOURNAL, vol. 20, no. 4, 1 January 1975 (1975-01-01), pages 511 - 518, XP093150374 *
RICHARD J. BASTIN, MICHAEL J. BOWKER, AND BRYAN J. SLATER: "Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 4, no. 5, 19 July 2000 (2000-07-19), US , pages 427 - 435, XP008154792, ISSN: 1083-6160, DOI: 10.1021/op000018u *

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IL319227A (en) 2025-04-01
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AU2023343417A1 (en) 2025-03-13
CA3267523A1 (fr) 2024-03-21

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