EP4448488A2 - Benzoatsalz von 5-methoxy-n,n-dimethyltryptamin - Google Patents

Benzoatsalz von 5-methoxy-n,n-dimethyltryptamin

Info

Publication number
EP4448488A2
EP4448488A2 EP22830588.4A EP22830588A EP4448488A2 EP 4448488 A2 EP4448488 A2 EP 4448488A2 EP 22830588 A EP22830588 A EP 22830588A EP 4448488 A2 EP4448488 A2 EP 4448488A2
Authority
EP
European Patent Office
Prior art keywords
meo
dmt
benzoate
treatment
pattern
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22830588.4A
Other languages
English (en)
French (fr)
Inventor
Cosmo FEILDING-MELLEN
Jason Gray
Timothy Mason
Cosima Agnes RUDD GRETTON
Frank Wiegand
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beckley Psytech Ltd
Original Assignee
Beckley Psytech Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB2118011.2A external-priority patent/GB202118011D0/en
Priority claimed from GBGB2118005.4A external-priority patent/GB202118005D0/en
Priority claimed from GBGB2118007.0A external-priority patent/GB202118007D0/en
Priority claimed from GBGB2118008.8A external-priority patent/GB202118008D0/en
Priority claimed from GBGB2118006.2A external-priority patent/GB202118006D0/en
Priority claimed from GBGB2118099.7A external-priority patent/GB202118099D0/en
Priority claimed from GBGB2118095.5A external-priority patent/GB202118095D0/en
Priority claimed from GBGB2118156.5A external-priority patent/GB202118156D0/en
Priority claimed from GBGB2212113.1A external-priority patent/GB202212113D0/en
Priority claimed from GBGB2212117.2A external-priority patent/GB202212117D0/en
Application filed by Beckley Psytech Ltd filed Critical Beckley Psytech Ltd
Publication of EP4448488A2 publication Critical patent/EP4448488A2/de
Pending legal-status Critical Current

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Classifications

    • 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

Definitions

  • This invention relates to the benzoate salt of 5-methoxy-N,N-dimethyltryptamine, methods of synthesis, formulations, applications, and uses of the same.
  • 5-MeO-DMT benzoate is the benzoate salt of the pharmacologically active compound of the tryptamine class, 5-MeO-DMT, and has the following chemical structure:
  • 5-MeO-DMT is a psychoactive/psychedelic substance found in nature and is believed to act mainly through serotonin receptors. It is also believed to have a high affinity for the 5-HT2 and 5-HTIA subtypes, and/or inhibits monoamine reuptake.
  • a method of synthesizing the benzoate salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with a base, prior to the addition of benzoic acid.
  • making the benzoate salt via the HCI salt improves the quality of the benzoate salt, for example as compared to making the benzoate salt directly from the free base. Base washing the salt improves the quality of the resultant benzoate salt.
  • the benzoate salt is crystalline. In an embodiment, the benzoate salt is crystalline, as described subsequently herein below. In an embodiment, the benzoate salt is crystalline and conforms to Pattern A, B, C, D, E, F, G or H. In an embodiment, the benzoate salt is crystalline Pattern A.
  • the method comprises the step of suspending the hydrochloride salt in a suspending organic solvent; wherein optionally the suspending organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
  • the benzoic acid is in solution in an organic solvent; wherein optionally the organic solvent is an alcohol, ester, an acetate and/or an acetate ester. In an embodiment, the benzoic acid and the hydrochloride salt precursor (or resultant free base) are present in substantially equal molar amounts.
  • the reaction with the benzoic acid takes place at an elevated temperature, optionally at a temperature between 40-65, 45-60, 50-55°C, or at/near the boiling point of the resultant reaction mixture.
  • the reaction with the benzoic acid takes place at an elevated temperature, and the resultant reaction mixture is allowed to cool to room temperature or lower, is allowed to cool to below 10°C, is allowed to cool to below 5°C, or is allowed to cool to between 5 and 0°C.
  • the benzoate salt is filtered from the resultant reaction mixture.
  • the filtered benzoate salt is washed with a washing organic solvent; wherein optionally the washing organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
  • the benzoate salt is washed with cooled washing organic solvent, optionally the washing organic solvent is cooled to below room temperature, is cooled to below 10°C, is cooled to below 5°C, or cooled to between 5 and 0°C.
  • the filtered benzoate salt is dried under vacuum.
  • the hydrochloride salt is base-treated with an aqueous basic solution, prior to the addition of benzoic acid.
  • the hydrochloride salt is base-treated prior to the reaction with benzoic acid, optionally the hydrochloride salt is base- treated with an aqueous basic solution.
  • the hydrochloride salt is not isolated prior to the base washing.
  • the basic solution comprises an alkoxide, optionally the basic solution comprises sodium hydroxide, further optionally the basic solution is 5% aqueous sodium hydroxide.
  • the hydrochloride salt is suspended in the suspending organic solvent prior to being base-treated, wherein optionally the suspending organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
  • the resultant based-treated reaction is partitioned with an extracting organic solvent to give an extract comprising the base-conditioned hydrochloride salt; wherein optionally the extracting organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
  • the suspending organic solvent is is isopropyl acetate (IPAc).
  • the organic solvent is IPAc.
  • the washing organic solvent is IPAc.
  • the extracting organic solvent is IPAc.
  • the organic phase is washed with water.
  • the extract is reduced under vacuum to give a concentrate, optionally the extract is concentrated to approximately 8 volumes.
  • the extract is azeotropically dried with one or more batches of fresh extracting organic solvent, optionally the extracting organic solvent is IPAc.
  • the method comprises the steps of: combining 5-MeO-DMT hydrochloride salt and an organic solvent; optionally the organic solvent is IPAc adding a basic solution to the combined 5-MeO-DMT hydrochloride salt and organic solvent; optionally the basic solution is aqueous 5% NaOH;
  • Partitioning washing the resulting organic phase with water; drying the solvent; optionally azeotropically with IPAc concentrating under vacuum; adjusting the solvent temperature to between about 50-55°C; adding a solution of benzoic acid in further organic solvent; optionally the further organic solvent is IPAc adjusting the temperature to between about 0-5°C; filtering and washing with cold solvent; optionally the cold solvent is IPAc drying under vacuum to obtain the 5-MeO-DMT benzoate salt as a crystalline solid.
  • the crystalline 5-MeO-DMT benzoate produced is characterised by one or more of: peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20; and/or endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C.; and/or enthalpy in a DSC thermograph of between -130 and -140J/g; and/or onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
  • the method of synthesis is a method of large scale synthesis. In an embodiment, the method of synthesis is a method of synthesis of >100g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of synthesis of >200g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of synthesis of >300g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of synthesis of >400g of 5-MeO-DMT benzoate.
  • the method of synthesis is a method of synthesis of >500g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >100g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >200g of 5-MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >300g of 5- MeO-DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >400g of 5-MeO- DMT benzoate. In an embodiment, the method of synthesis is a method of recrystallization of >500g of 5-MeO-DMT benzoate.
  • the method of synthesis is a method of synthesis of an amorphous dry powder of 5-MeO-DMT benzoate.
  • an amorphous dry powder of 5-MeO-DMT benzoate there is provided an amorphous dry powder of 5-MeO-DMT benzoate.
  • a method of synthesis of 5-MeO-DMT benzoate wherein the 5-MeO-DMT benzoate is synthesised by reacting 5-MeO-DMT hydrochloride with a suitable solvent and benzoic acid.
  • Use of 5-MeO-DMT benzoate salt produced by any of the methods described herein, in a method of medical treatment.
  • a method of synthesizing an organic acid salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with the corresponding organic acid.
  • a method of synthesizing an organic acid salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with the corresponding organic acid in an organic solvent.
  • a method of synthesizing an organic acid salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with the corresponding organic acid in an organic solvent, wherein the resultant organic acid salt of 5-MeO-DMT is less soluble than the HCI salt of 5-MeO-DMT in the organic solvent.
  • a method of synthesizing an organic acid salt of 5-MeO-DMT comprising the step of treating the hydrochloride salt of 5-MeO-DMT with the corresponding organic acid in an organic solvent, wherein the HCI salt is placed in the organic solvent and the resultant organic acid salt of 5-MeO-DMT is less soluble in the organic solvent than the HCI salt of 5-MeO-DMT, and wherein the organic acid salt of 5-MeO-DMT remains in solution when the organic solvent is at elevated temperature, but falls out of solution when the reaction mixture is cooled.
  • an organic acid salt of 5-MeO-DMT wherein the HCI salt is base-treated prior to the reaction with the organic acid, optionally the hydrochloride salt is basetreated with an aqueous basic solution, further optionally base-treated with aqueous NaOH (e.g. 5% NaOH).
  • the organic acid is selected from any of the known organic acids.
  • the organic acid is selected from: lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, benzoic acid or tartaric acid.
  • the organic acid is benzoic acid.
  • a method of recrystallising the benzoate salt of 5-MeO-DMT from an organic solvent wherein the solvent is selected from one or more of an alcohol, ester, an acetate and/or an acetate alcohol, ester, and optionally IPAc or IPA.
  • a method of purifying the HCI salt of 5-MeO-DMT comprising the step of basetreating the HCI salt, optionally the hydrochloride salt is base-treated with an aqueous basic solution, further optionally base-treated with aqueous NaOH (e.g. 5% NaOH).
  • the 5-MeO-DMT salt contains no more than 1% of the hydroxyl impurity, shown below:
  • the 5-MeO-DMT salt contains no more than 2% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT salt contains no more than 3% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT salt contains no more than 4% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT salt contains no more than 5% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 1% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 2% of the hydroxyl impurity.
  • the 5-MeO-DMT HCI salt contains no more than 3% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 4% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT HCI salt contains no more than 5% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 1% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 2% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 3% of the hydroxyl impurity.
  • the 5-MeO-DMT benzoate salt contains no more than 4% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 5% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 1% of any impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 2% of any impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 3% of any impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 4% of any impurity. In an embodiment, the 5-MeO-DMT benzoate salt contains no more than 5% of any impurity.
  • the 5-MeO-DMT benzoate synthesised by the methods of the invention is substantially free of the hydroxyl impurity.
  • the 5-MeO-DMT benzoate synthesised by the methods of the invention contain no more than 1%, no more than 2%, no more than 3%, no more than 4% and/or no more than 5% of the hydroxyl impurity.
  • purity of the 5-MeO-DMT is determined by HPLC or RP-HPLC.
  • the 5-MeO-DMT has chemical purity of greater than 95, 96, 97, 98, 99 or 99.5% by HPLC.
  • the 5-MeO-DMT has chemical purity of greater than 95, 96, 97, 98, 99 or 99.5% by RP-HPLC. In an embodiment, there is no single impurity of greater than 1% by HPLC or RP-HPLC.
  • the resultant counter ion is fluoride, chloride, bromide, iodide, fumarate, succinate, oxalate, acetate, citrate, triflate, phosphate, tartrate, benzenesulfonate, tosylate, adipate, glycolate, ketoglutarate, malate, saccharinate).
  • composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable salt of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).
  • the salt anion is an aryl carboxylate.
  • the aryl carboxylate is substituted with one to three R groups.
  • the one or more R groups are independently selected from: alkynyl, carbonyl, aldehyde, haloformyl, alkyl, halide, hydroxy, alkoxy, carbonate ester, carboxylate, carboxyl, carboalkoxy, methoxy, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxylic anhydride, carboxamide, secondary, tertiary or quaternary amine, primary or secondary ketimine, primary or secondary aldimine, imide, azide, azo, cyanate, isocyanate, nitrate, nitrile, isonitrile, nitrosooxy, nitro, nitroso, oxime, pyridyl, carbamate, sulfhydryl, sulfide, disulfide, sulfinyl, sul
  • the one or more R groups are independently selected from: Ci - Cs alkyl, Ci - Cs alkoxy, Ci - Ce alkenyl or Ci - Ce alkynyl, and where each of these may be optionally substituted with one to three R groups as previously described.
  • composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine.
  • the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.05mg to lOOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of O.lmg to 50mg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5mg to 25mg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5mg to lOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of lmg to lOmg.
  • the composition comprises a dosage amount of 5-MeO-DMT in the range of lmg to 8mg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 3mg to 15mg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.005mg to lOOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of O.OOlmg to lOOmg. In an embodiment, the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.0005mg to lOOmg.
  • the level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
  • the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • the nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.
  • the 5-MeO-DMT salt is amorphous or crystalline.
  • the 5-MeO-DMT salt is a benzoate, fumarate, citrate, acetate, succinate, halide, phosphate, tartrate, benzenesulfonate, tosylate, adipate, glycolate, ketoglutarate, malate, saccharinate, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt.
  • the 5-MeO-DMT salt is formulated into a composition for mucosal delivery.
  • the 5-MeO-DMT salt is a benzoate salt.
  • the 5-MeO-DMT benzoate conforms to Pattern A as characterised by an XRPD diffractogram.
  • the 5-MeO-DMT benzoate is characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • 5-MeO-DMT benzoate is characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 6 or Figure 7.
  • the 5-MeO-DMT benzoate is characterised by bands at ca. 3130, 1540, 1460, 1160 and 690 cm-1 in a fourier-transform infrared spectroscopy (FTIR) spectra.
  • FTIR Fourier-transform infrared spectroscopy
  • the 5-MeO-DMT benzoate is characterised by a FTIR spectra for lot FP2 as substantially illustrated in Figure 93.
  • the 5-MeO-DMT benzoate conforms to Pattern B by XRPD.
  • the 5-MeO-DMT benzoate conforms to Pattern B as characterised by peaks in an XRPD diffractogram between 18.5 and 20° 20 ⁇ O.1°20. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern B as substantially illustrated by the XRPD diffractogram for lots Pl, R1 and QI as substantially illustrated in Figure 24.
  • the 5-MeO-DMT benzoate conforms to Pattern B as substantially illustrated by the XRPD diffractogram for lot R2 as substantially illustrated in Figure 28. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern B as substantially illustrated by the XRPD diffractogram for lots Al and Bl as substantially illustrated in Figures 38 or 39. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern B form as characterised by FTIR spectra for lot C2 as substantially illustrated in Figure 93. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern C form as characterised by a minor broad endotherm with a peak temperature of 108°C in a DSC thermograph.
  • the 5-MeO-DMT benzoate corresponds to Pattern C as characterised by a DSC thermograph as substantially illustrated in Figure 65. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern C form as characterised by a DSC thermograph as substantially illustrated in Figure 66. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern C by XRPD. In an embodiment, the 5- MeO-DMT benzoate conforms to Pattern C as characterised by a peak in an XRPD diffractogram at 10.3° 20 ⁇ O.1°20.
  • the 5-MeO-DMT benzoate conforms to Pattern C as substantially illustrated by the XRPD diffractogram for lot Al as substantially illustrated in Figure 68. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern C form as characterised by FTIR spectra for lot Cl as substantially illustrated in Figure 93. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern D by XRPD. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern D as substantially illustrated by the XRPD diffractogram in Figure 73 or Figure 74.
  • the 5-MeO-DMT benzoate corresponds to Pattern D as characterised by an endothermic event in a DSC thermograph at 118°C. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern D form as characterised by an endothermic event in a DSC thermograph at 118.58°C.
  • the 5-MeO-DMT benzoate conforms to Pattern E by XRPD. In an embodiment, the 5-MeO-DMT benzoate corresponds to Pattern E as substantially illustrated by the XRPD diffractogram for lot D in Figure 77 or Figure 78. In an embodiment, the 5-MeO-DMT corresponds to the Pattern E form as characterised by a major bimodal endothermic event with peak temperatures of 110.31°C and 113.13°C in a DSC thermograph. In an embodiment, the 5-MeO-DMT corresponds to Pattern E as characterised by a minor endothermic event with a peak temperature of 119.09°C in a DSC thermograph. In an embodiment, the 5-MeO-DMT corresponds to the Pattern E form as characterised by a DSC thermograph as substantially illustrated in Figure 79.
  • the 5-MeO-DMT benzoate corresponds to Pattern E as substantially illustrated by the XRPD diffractogram in Figure 80. In an embodiment, the 5-MeO-DMT benzoate corresponds to Pattern F by XRPD. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern F as characterised by an XRPD diffractogram for lot F (rerun) as substantially illustrated in Figure 84. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern F as characterised by an XRPD diffractogram for lot F (rerun) as substantially illustrated in Figure 85.
  • the 5-MeO-DMT benzoate conforms to Pattern F as characterised by an XRPD diffractogram for lot F (rerun) as substantially illustrated in Figure 89.
  • the 5-MeO-DMT benzoate corresponds to the Pattern F form as characterised by endothermic events at 90°C, 106°C and 180°C in a DSC thermograph.
  • the 5-MeO-DMT benzoate corresponds to the Pattern F form as characterised by endothermic events at 90.50°C, 106.65°C and 180.35°C in a DSC thermograph.
  • the 5-MeO-DMT benzoate conforms to Pattern G by XRPD. In an embodiment, the 5-MeO-DMT benzoate conforms to Pattern G, as characterised by an XRPD diffractogram for lot K as substantially illustrated in Figure 87. In an embodiment, the 5-MeO-DMT benzoate corresponds to the Pattern G form, as characterised by an endothermic event in a DSC thermograph of 119.61°C. In an embodiment, the composition comprises 5-MeO-DMT benzoate which conforms to a mixture of two or more of Patterns A to G by XRPD.
  • the dosage amount is the equivalent amount of the free base delivered when the salt is taken.
  • So lOOmg dosage amount of 5-MeO-DMT corresponds to 117mg of the hydrochloride salt (i.e. both providing the same molar amount of the active substance).
  • the greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt (i.e. 218.3 g/mol for the free base as compared to 254.8 g/mol for the salt).
  • a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
  • the composition comprises one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
  • the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N- trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl
  • TMC
  • the composition disclosed herein is for use as a medicament. In an embodiment, the composition disclosed herein is for use in a method of treatment of a human or animal subject by therapy.
  • the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, treatment resistant depression anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
  • sleep regulation such as insomnia
  • analgesics such as chronic pain
  • migraines migraines
  • trigeminal autonomic cephalgias such as short-lasting
  • Treatment of the above conditions may be beneficially improved by taking the invention.
  • the method of treatment is a method of treatment of alcohol-related diseases and disorders, eating disorders, impulse control disorders, nicotine-related disorders, tobacco-related disorders, methamphetamine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, benzodiazepine abuse or dependence related disorders, and/or opioid-related disorders.
  • the method of treatment is a method of treatment of tobacco addiction.
  • the method is a method of reducing tobacco use.
  • the method of treatment is a method of treatment of nicotine addiction.
  • the method is a method of reducing nicotine use.
  • the method of treatment is a method of treating alcohol abuse and/or addiction. In an embodiment, the method of treatment is a method of reducing alcohol use.
  • the method of treatment is a method of treating or preventing heavy drug use.
  • the method of treatment is a method of treating or preventing heavy drug use, including, but not limited to, alcohol, tobacco, nicotine, cocaine, methamphetamine, other stimulants, phencyclidine, other hallucinogens, marijuana, sedatives, tranquilizers, hypnotics, and opiates. It will be appreciated by one of ordinary skill in the art that heavy use or abuse of a substance does not necessarily mean the subject is dependent on the substance.
  • the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.
  • the composition is administered one or more times a year. In an embodiment, the composition is administered one or more times a month. In an embodiment, the composition is administered one or more times a week. In an embodiment, the composition is administered one or more times a day. In an embodiment, the composition is administered at such a frequency as to avoid tachyphylaxis.
  • the composition is administered together with a complementary treatment and/or with a further active agent. In an embodiment, the further active agent is a psychedelic compound, optionally a tryptamine.
  • the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof.
  • the further active agent is an antidepressant compound.
  • the further active agent is selected from an SSRI, SNRI, TCA or other antidepressant compounds.
  • the further active agent is selected from Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Am
  • the further active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline).
  • the complementary treatment is psychotherapy.
  • a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5- MeO-DMT for use in a method of treatment of treatment resistant depression (TRD).
  • TRD treatment resistant depression
  • a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-MeO-DMT for use in a method of treatment of depression.
  • a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5- MeO-DMT for use in a method of treatment of PTSD.
  • a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-MeO-DMT for use in a method of treatment of addiction/substance misuse disorders.
  • a nasal inhalation composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-MeO-DMT for use in a method of treatment of treatment resistant depression.
  • 'Pattern various forms of the 5-MeO- DMT benzoate salt may be referred to herein below as 'Pattern wherein the # refers to the corresponding XRPD pattern obtained for that form.
  • 'Pattern A' may be used as an abbreviation to refer to the form of 5- MeO-DMT benzoate salt giving rise to the Pattern A by XRPD.
  • 'Pattern B' may be used as an abbreviation to refer to the form of 5-MeO-DMT benzoate salt giving rise to the Pattern B by XRPD, and so on.
  • Figure 1 is a schematic route for the synthesis of 5-MeO-DMT.
  • Figure 2 is a further schematic route for the synthesis of 5-MeO-DMT.
  • Figure 3 is a schematic route for the preparation of a powder form of 5-MeO-DMT.
  • FIG. 4 is an overview of the slug mucosal irritation (SMI) test.
  • A First 15 minute contact period between slug and test item.
  • B Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour.
  • C Second 15 minute contact period between slug and test item.
  • D Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour.
  • E Third 15 minute contact period between slug and test item.
  • Figure 5 is a graph showing that the benzoate salt of 5-MeO-DMT has higher permeation compared with the hydrochloride salt, as per the experiment detailed in Example 9.
  • Figure 6 shows an XRPD diffractogram of 5-MeO-DMT benzoate prior to particle size reduction.
  • Figure 7 shows an XRPD diffractogram of 5-MeO-DMT benzoate following particle size reduction.
  • Figure 8 shows the XRPD diffractograms of Figures 6 and 7 overlaid on one another.
  • Figure 9 shows a DSC thermograph of 5-MeO-DMT benzoate.
  • Figure 10 shows a TGA thermograph of 5-MeO-DMT benzoate.
  • Figure 11 shows a combined TGA/DSC thermograph of 5-MeO-DMT benzoate.
  • Figure 12 shows a DVS isotherm of 5-MeO-DMT benzoate.
  • Figure 12 shows a Dynamic Vapour Sorption (DVS) isotherm for 5-MeO-DMT benzoate.
  • Figure 13 shows an optical micrograph of 5-MeO-DMT benzoate salt (A) and dark field (B) at x4 magnification.
  • Figure 14 shows two further optical micrographs of 5-MeO-DMT benzoate salt (A) and (B) at x4 magnification.
  • Figure 15 shows optical micrographs of 5-MeO-DMT benzoate salt (A) and (B) at xlO magnification.
  • Figure 16 shows further optical micrographs of 5-MeO-DMT benzoate salt (A) and (B) at lOx magnification.
  • Figure 17 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/20/126-FP).
  • Figure 18 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/45/006-FP).
  • Figure 19 shows XRPD pattern comparison of two different lots of 5-MeO-DMT benzoate.
  • Figure 20 shows a DSC thermograph of another lot of 5-MeO-DMT benzoate.
  • Figure 21 shows additional XRPD characterisation of multiple lots of 5-MeO-DMT benzoate.
  • Figure 22 shows DSC thermograph results for 5-MeO-DMT benzoate lots Cl, DI and El.
  • Figure 23 shows TGA thermograph results for 5-MeO-DMT benzoate lots Cl, DI and El at 10°C.min 1 .
  • Figure 24 shows XRPD pattern comparison of 5-MeO-DMT benzoate Pl (Toluene), QI (Chlorobenzene), and R1 (Anisole) against the XRPD pattern of Pattern A.
  • Figure 25 shows DSC thermographs of 5-MeO-DMT lots Pl, QI and R1 at 10°C.min -1 .
  • Figure 26 shows DSC thermograph expansions of 5-MeO-DMT lots Pl, QI and R1 at 10°C.min -1 .
  • Figure 27 shows TGA thermographs of 5-MeO-DMT lots Pl, QI and R1 at 10°C.min 1 .
  • Figure 28 shows XRPD pattern comparison of 5-MeO-DMT benzoate lots R1 and R2 (thermally cycled suspensions) compared with a reference Pattern A XRPD diffractogram.
  • Figure 29 shows DSC thermographs of 5-MeO-DMT benzoate lots P2, Q2 and R2 at 10°C.min -1 .
  • Figure 30 shows DSC thermograph expansions of 5-MeO-DMT benzoate lots P2, Q2 and R2 at 10°C.min -1 .
  • Figure 31 shows TGA thermographs of 5-MeO-DMT benzoate lots P2, Q2 and R2 at 10°C.min -1 .
  • Figure 32 shows XRPD pattern overlay of samples isolated via anti-solvent mediated crystallisation 5-MeO-DMT benzoate.
  • Figure 33 shows XRPD pattern overlay of 5-MeO-DMT benzoate lot Fl and a reference Pattern A form/material.
  • Figure 34 shows XRPD pattern overlay of 5-MeO-DMT benzoate samples isolated from cooling and a Pattern A reference.
  • Figure 35 shows XRPD pattern overlay of 5-MeO-DMT benzoate samples isolated from cooling post-particle size reduction and Pattern A reference.
  • Figure 36 shows XRPD pattern comparison for all samples from the reverse addition anti-solvent driven crystallisation of 5-MeO-DMT benzoate except for Al and Bl.
  • Figure 37 shows XRPD pattern comparison for 5-MeO-DMT benzoate F3 with a known Pattern A reference.
  • Figure 38 shows XRPD pattern comparison of 5-MeO-DMT benzoate Al and Bl.
  • Figure 39 shows XRPD patterns for 5-MeO-DMT benzoate Al, QI and a reference Pattern A pattern.
  • Figure 40 shows XRPD patterns for 5-MeO-DMT benzoate Bl, QI and a reference Pattern A pattern.
  • Figure 41 shows a DSC thermograph of 5-MeO-DMT benzoate sample Al at 10°C.min 1 isolated from methanol and toluene.
  • Figure 42 shows a DSC thermograph of 5-MeO-DMT benzoate Bl at 10°C.min-l isolated from isopropanol and toluene.
  • Figure 43 shows a DSC thermograph expansion of 5-MeO-DMT benzoate. Bl at 10°C.min-l isolated from isopropanol and toluene.
  • Figure 44 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 A, E; E Particle size reduced and Pattern A reference.
  • Figure 45 shows XRPD of 5-MeO-DMT benzoate lot 21-01-051 B, obtained from quenching the melt.
  • Figure 46 shows XRPD of 5-MeO-DMT benzoate lot 21-01-051 C, obtained by lyophilisation.
  • Figure 47 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 B after 20 hours, C after 20 hours, and Pattern A reference.
  • Figure 48 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 A, E; E particle size reduced, and Pattern A reference.
  • Figure 49 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-051 A, C, and D at lO’C.min -1 , isolated from acetone concentrate, 051 A, and lyophilisation, 051 C and 051 D.
  • Figure 50 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-051 C and C post 20 hours at 10’C.min 1 .
  • Figure 51 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-051 D, large scale lyophilised material, with temperature stamps corresponding to hot-stage microscopy images.
  • Figure 52 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 30.02°C.
  • Figure 53 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 54.21°C.
  • Figure 54 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 74.21°C.
  • Figure 55 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 114.23°C.
  • Figure 56 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 120.14°C.
  • Figure 57 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation.
  • Figure 58 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-054 M isolated from the equilibration of amorphous 5-MeO-DMT benzoate in a,a,a-trifluorotoluene with thermal modulation with lot 20-37-64 (Pattern A).
  • Figure 59 shows DSC thermograph comparison of a selection of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation classified as Pattern A.
  • Figure 60 shows DSC thermograph expansion comparison of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation classified as Pattern A, highlighting an event in lot 21-01-054 Q, solid isolated from anisole.
  • Figure 61 shows Expanded DSC thermograph expansion highlighting an event in lot 21-01-054 Q, isolated from anisole.
  • Figure 62 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al air dried 2 minutes, lot 21-01- 049 Bl, Pattern B, and lot 20-37-64, Pattern A.
  • Figure 63 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al-air dried 1 hour and lot 21-01- 060 Al-air dried 2 minutes.
  • Figure 64 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al-air dried 2 minutes, lot 21-01- 060 Al-air dried 1 hour, and lot 21-01-049 Bl, Pattern B.
  • Figure 65 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-060 Al, isolated immediately from IPA/toluene and air dried for 1 hour.
  • Figure 66 shows DSC thermograph expansion of 5-MeO-DMT benzoate lot 21-01-060 Al, isolated immediately from IPA/toluene and air dried for 1 hour.
  • Figure 67 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al air dried 20 hours, lot 21-01- 060 Al air dried 2 minutes, and lot 21-01-049 Bl, Pattern B reference.
  • Figure 68 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Bl, isolated after 3 hours equilibration then air dried for 2 mins and Al isolated immediately then air dried for 2 minutes.
  • Figure 69 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Bl, isolated after 3 hours equilibration then air dried for 20 hours and Bl isolated after 3 hours equilibration then air dried for 2 minutes, and lot 21-01-049 Bl, Pattern B.
  • Figure 70 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 solids isolated from amorphous 5-MeO-DMT benzoate exposed to solvent vapour.
  • Figure 71 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 K, isolated from amorphous 5- MeO-DMT benzoate exposed to solvent vapour, with lot 20-37-64, Pattern A.
  • Figure 72 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-058 B, lot 21-01-058 F, lot 21-01- 058 K, and lot 21-01-062 G.
  • Figure 73 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 20-37-64, Pattern A, lot 21- 01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours).
  • Figure 74 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours).
  • Figure 75 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours).
  • Figure 76 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-058 D, isolated from exposure of anisole vapour to amorphous form.
  • Figure 77 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-064 D, and 21-01-060 Bl (air dried 2 minutes).
  • Figure 78 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-064 D, and 21-01-060 Bl (air dried 2 minutes).
  • Figure 79 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 D at 10°C.min-l.
  • Figure 80 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-064 C, and 21-01-064 D.
  • Figure 81 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-064 C, and 21-01-064 D.
  • Figure 82 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 C at 10°C.min-l.
  • Figure 83 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 A, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
  • Figure 84 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 F and 21-01-073 F rerun.
  • Figure 85 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 F rerun, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
  • Figure 86 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-073 F rerun, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
  • Figure 87 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 K, 21-01-049 Bl, Pattern B, and 20-37-64.
  • Figure 88 shows XRPD of 5-MeO-DMT benzoate lot 21-01-078.
  • Figure 89 shows DVS isothermal plot of 5-MeO-DMT benzoate lot 21-01-078.
  • Figure 90 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-078 (post-DVS) and 20-37-64.
  • Figure 91 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl).
  • Figure 92 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl) at 450 to 2000 cm-1.
  • Figure 93 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl) at 450 to 2000 cm-1; spectra separated.
  • Figure 94 shows Forced Swim Test results, Time Immobile, for 5-MeO-DMT benzoate, vehicle and imipramine.
  • Figure 95 shows Forced Swim Test results, Latency to Immobility, for 5-MeO-DMT benzoate, vehicle and imipramine.
  • Figure 96 shows 5-MeO-DMT Group Mean Plasma Concentration (ng/mL) in Male Beagle Dogs - Group 2 (HCI salt) and Group 4 (benzoate salt) - Dose Level (0.4 mg/kg); wherein the Mean Plasma Concentration of Groups 2 and 4 are substantially the same with dose time.
  • Figure 97 shows an XRPD of Pattern H.
  • Figure 98 shows a DSC thermograph of Pattern H.
  • Figure 99 shows a DSC thermograph of Pattern H.
  • Figure 100 shows a DSC thermograph of Pattern H.
  • Figure 101 shows a FTIR spectra of Pattern H compared with Pattern A.
  • Figure 102 shows a FTIR spectra of Pattern H compared with Pattern A.
  • Figure 103 shows a FTIR spectra of Pattern H.
  • Figure 104 shows a FTIR spectra of Pattern A.
  • Figure 105 shows an XRPD diffractogram for 5-MeO-DMT hydrochloride lot 20/20/126-FP.
  • Figure 106 shows an XRPD diffractogram for 5-MeO-DMT hydrochloride lot 20/45/006-FP.
  • Figure 107 shows the XRPD diffractogram of Figures 105 and 106 overlaid on top of one another.
  • Figure 108 shows a DSC and TGA thermograph of 5-MeO-DMT Hydrochloride, lot 20/20/126-FP at 10°C/Min heating rate.
  • Figure 109 shows DSC thermographs of 5-MeO-DMT hydrochloride, lot 20/20/126-FP at 5°C/Min (Black), 10°C/Min (Red), 20°C/Min (Blue) and 40°C/Min (Green) heating rates.
  • Figure 110 shows a DSC and TGA thermograph of 5-MeO-DMT Hydrochloride, lot 20/45/006-FP at 10°C/Min heating rate.
  • Figure 111 shows DSC thermographs of 5-MeO-DMT hydrochloride, lot 20/45/06-FP at 5°C/Min (Black), 10°C/Min (Red), 20°C/Min (Blue) and 40°C/Min (Green) heating rates.
  • Figure 112 shows the DVS isotherm of 5-MeO-DMT Hydrochloride, lot 20/20/126-FP.
  • Figure 113 shows the DVS isotherm of 5-MeO-DMT Hydrochloride, lot 20/45/006-FP.
  • Figure 114 shows an optical micrograph of lot 20/20/126-FP of 5-MeO-DMT Hydrochloride at xlO magnification (A) and polarised (B).
  • Figure 115 shows optical micrographs of lot 20/20/126-FP of 5-MeO-DMT Hydrochloride at x50 magnification (A) and (B).
  • Figure 116 shows an optical micrograph of lot 20/45/006-FP of 5-MeO-DMT Hydrochloride at xlO magnification (A) and polarised (B).
  • Figure 117 shows an optical micrograph of lot 20/45/006-FP of 5-MeO-DMT Hydrochloride at x50 magnification (A) and (B).
  • Figure 122 shows a summary of the synthetic route to prepare MDMA from piperonal.
  • Figure 123 shows a summary of the synthetic route to prepare MDMA (and related analogues) from safrole.
  • Figure 124 shows a schematic outlining the preparation of HF-MAPs.
  • Figure 125 shows HF-MAPs prepared when viewed using a light microscope.
  • Figure 126 shows a comparison of percentage swelling over 240 minutes with 20% w/w Gantrez 8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCOa ('super swelling') and 20% w/w Gantrez 8 S-97+ 7.5% w/w PEG 10,000 ('normal swelling').
  • (B) shows a comparison of percentage swelling over 24 hours with 20% w/w Gantrez 8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCOa ('super swelling') and 20% w/w Gantrez 8 S-97+ 7.5% w/w PEG 10,000 ('normal swelling').
  • Figure 127 shows light microscope images of 20% w/w Gantrez 8 S-97, 7.5% w/w PEG 10,000 + 3% w/w NazCCh ('super swelling') before (A) and after (B) swelling in PBS.
  • Figure 130 shows a schematic representation of the Franz cells setup used for ex vivo permeation studies.
  • Figure 133 shows one embodiment of a microneedle array (1). Detailed description of the invention
  • Figure 1 shows a one-step synthesis of 5-MeO-DMT from the reaction of 4-methoxyphenylhydrazine hydrochloride with (N,N)-dimethylamino)butanal dimethyl acetal.
  • Figure 2 shows a three step synthesis of 5-MeO-DMT. The first step involves the reaction of 5-methoxyindole with oxalyl chloride. The resultant product is aminated with dimethylamine and then is reduced with lithium aluminium hydride.
  • Figure 3 shows the schematic route for the formation of a powder form of 5-MeO-DMT using a spray drying process. In an embodiment, it is a powder form of 5-MeO-DMT benzoate which is formed.
  • Step 1 Add methyl tert-butyl ether (MTBE) (15vol) into the reaction vessel and cool to -20 to -30°C, before adding oxalyl chloride (1.5 eq), maintaining the temperature at no more than -20°C. Add a solution of 5-methoxyindole (1.0 eq) in THF (lvol) to the reaction vessel, maintaining the temperature at no more than -20°C. Allow the reaction to warm to 0-5°C and stir for at least 1 hour, ensuring that no more than 2% of the starting material indole remains.
  • MTBE methyl tert-butyl ether
  • Step 2 Add the compound obtained in step 1 (1.0 eq) to a reaction vessel together with dimethylamine hydrochloride (3.0 eq) and methanol (2vol). Add 25% NaOMe in methanol (3.5 eq), to the reaction maintaining the temperature at no more than 30°C. Warm to and stir for no less than 5 hours, ensuring that no more than 0.5% of the starting material from step 1 remains. Adjust the temperature to 0-5°C over no less than 2 hours, then add water (5vol) over no less than 1 hour with stirring at 0-5°C for no less than 1 hour.
  • Step 3 Add the compound obtained in step 2 (1.0 eq) to a reaction vessel. Add IM LiAl H4 in THF (1.5 eq) in THF (8vol) to the reaction maintaining no more than 40°C. Heat at reflux for no less than 4 hours ensuring that no more than 2% of the starting material from step 2 remains.
  • 5-MeO-DMT hydrochloride salt also referred to herein as 5-MeO-DMT hydrochloride or the hydrochloride salt.
  • a purified form of 5-MeO-DMT hydrochloride obtained from a source of 5-MeO-DMT hydrochloride.
  • a purified mass of 5-MeO-DMT hydrochloride obtained from a source of 5-MeO-DMT hydrochloride.
  • 5-MeO-DMT hydrochloride is a commercially useful amount, for example not just a few crumbs of 5-MeO-DMT hydrochloride, or a few crystals, or a single crystal of 5-MeO-DMT hydrochloride.
  • the purified mass is greater than 0.5, 1, 2, 5, 10, 20, 50, 100, 250, 500 or 1000 grams. In an embodiment, the purified mass is a commercially useful amount of 5-MeO-DMT hydrochloride. In an embodiment, a useful amount of 5-MeO-DMT hydrochloride is sufficient to provide more than 20, 50, 100, 250, 500, 1,000, 5,000, 10,000, 25,000, 50,000 or 100,000 pharmaceutically effective treatment doses for human subjects in need thereof. In an embodiment, the purified mass is not a single crystal. In an embodiment, the purified mass is not a few crystals 5-MeO-DMT hydrochloride. In an embodiment, the purified mass is not a few crumbs of 5-MeO-DMT hydrochloride.
  • the purified mass is not sufficient to provide less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 treatment doses for human subjects in need thereof.
  • the source of 5-MeO-DMT hydrochloride contains impurities. In an embodiment, the source of 5-MeO-DMT hydrochloride is less pure than the purified mass of 5- MeO-DMT hydrochloride. In an embodiment, the purified mass of 5-MeO-DMT hydrochloride contains less/fewer impurities than the source of 5-MeO-DMT hydrochloride. In an embodiment, the source of 5-MeO-DMT hydrochloride contains more impurities than the purified mass of 5-MeO-DMT hydrochloride.
  • a purified mass of 5-MeO-DMT hydrochloride contains no more than 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4 or 5% of any impurity.
  • the phrase 'any impurity' can be understood to mean 'any one impurity'.
  • the term 'purified' is may be understood to be equivalent with the term 'pure'.
  • the purified mass is substantially free of the hydroxyl impurity shown below:
  • the purified mass contains no more than 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4 or 5% of the hydroxyl impurity.
  • the source of 5-MeO-DMT hydrochloride contains more hydroxyl impurity than the purified mass of 5-MeO-DMT hydrochloride.
  • the purified mass of 5-MeO-DMT hydrochloride contains less hydroxyl impurity than the source of 5-MeO-DMT hydrochloride.
  • the purified mass has a chemical purity of greater than 95, 96, 97, 98, 99 or 99.5% by HPLC or RP-HPLC.
  • the purified mass of 5-MeO-DMT hydrochloride is crystalline.
  • the purified mass is characterised by one or more of: peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5, 19.5, 23.9, 24.5, 25.1, 26.0, 26.9 and 28.3°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A; endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and/or a peak of between 142 and 148°C; enthalpy in a DSC thermograph of between 113J/g and -123J/g; onset of decomposition in a TGA thermograph of between 120 and 165°C.
  • the purified mass is characterised as described elsewhere in this document, such as in the Examples.
  • there is provided of obtaining a purified mass of 5-MeO-DMT hydrochloride wherein a source of 5-MeO-DMT hydrochloride is base-treated, optionally the source of 5-MeO-DMT hydrochloride is basetreated with an aqueous basic solution.
  • obtaining a purified mass of 5-MeO-DMT hydrochloride wherein 5-MeO-DMT hydrochloride is base-treated, optionally the source of 5-MeO-DMT hydrochloride is base-treated with an aqueous basic solution.
  • the basic solution comprises an alkoxide, optionally the basic solution comprises sodium hydroxide, further optionally the basic solution is 5% aqueous sodium hydroxide.
  • the source of 5-MeO-DMT hydrochloride is suspended in a suspending organic solvent prior to being base-treated, wherein optionally the suspending organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
  • the resultant base-treated reaction is partitioned with an extracting organic solvent to give an extract comprising the base-conditioned hydrochloride salt; wherein optionally the extracting organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
  • the extract is reduced under vacuum to give a concentrate of the purified mass of 5-MeO-DMT hydrochloride, optionally the extract is concentrated to approximately 8 volumes, or further optionally the solvent is removed to give the purified mass of 5-MeO-DMT hydrochloride in a solid form.
  • the extract or solid form of the purified mass of 5-MeO-DMT hydrochloride is azeotropically dried with one or more batches of fresh extracting organic solvent wherein optionally the extracting organic solvent is an alcohol, ester, an acetate and/or an acetate ester.
  • the purified mass of 5-MeO-DMT hydrochloride is obtained by filtration.
  • the filtered purified mass of 5-MeO-DMT hydrochloride is washed with a washing organic solvent.
  • the purified mass of 5-MeO-DMT hydrochloride is washed with cooled washing organic solvent, optionally the washing organic solvent is cooled to below room temperature, is cooled to below 10°C, is cooled to below 5°C, or cooled to between 5 and 0°C.
  • the purified mass of 5-MeO-DMT hydrochloride is dried under vacuum.
  • the suspending organic solvent, the washing organic solvent, and/or the extracting organic solvent is IPAc.
  • the purified mass of 5-MeO-DMT hydrochloride is isolated and subjected to a recrystallisation process.
  • the method comprises the steps of: combining the source of 5-MeO-DMT hydrochloride and an organic solvent; optionally the organic solvent is IPAc adding a basic solution to the combined 5-MeO-DMT hydrochloride salt and organic solvent; optionally the basic solution is aqueous 5% NaOH; partitioning; washing the resulting organic phase with water; drying the solvent; optionally azeotropically with IPAc; and concentrating under vacuum.
  • the method further comprises the steps of concentrating under vacuum to dryness.
  • the method further comprises the steps of: adjusting the solvent temperature to between about 50-55°C; adding one or more counter solvents in which the 5-MeO-DMT hydrochloride is substantially insoluble in; and/or adjusting the temperature to between about 0-5°C; filtering and washing with cold solvent; optionally the cold solvent is IPAc; and drying under vacuum to obtain the purified mass of 5-MeO-DMT hydrochloride in a solid form, optionally as a crystalline solid.
  • the purified mass of 5-MeO-DMT hydrochloride produced is characterised by one or more of: peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5, 19.5, 23.9, 24.5, 25.1, 26.0, 26.9 and 28.3°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A; endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C and/or a peak of between 142 and 148°C; enthalpy in a DSC thermograph of between 113J/g and -123J/g; onset of decomposition in a TGA thermograph of between 120 and 165°C.
  • a purified mass of 5-MeO-DMT hydrochloride obtained by the method described previously or subsequently.
  • an inorganic or organic acid salt of 5- MeO-DMT obtained by the step of treating the purified mass of 5-MeO-DMT hydrochloride as defined previously or subsequently, or obtained by the method previously or subsequently, with an inorganic acid or organic acid; wherein the resultant counter anion is the deprotonated form of the acid used, wherein optionally the resultant counter anion is a fluoride, bromide, iodide, fumarate, acetate, succinate, oxalate, acetate, citrate, triflate or benzoate anion; further optionally the anion is the benzoate.
  • 5-MeO-DMT hydrochloride which contains no more than 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4 or 5% of any impurity.
  • the 5-MeO-DMT hydrochloride is substantially free of the hydroxyl impurity shown below:
  • the 5-MeO-DMT hydrochloride contains no more than 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4 or 5% of the hydroxyl impurity. In an embodiment, the 5-MeO-DMT hydrochloride has a chemical purity of greater than 95, 96, 97, 98, 99 or 99.5%. In an embodiment, the 5-MeO-DMT hydrochloride has a chemical purity of greater than 95, 96, 97, 98, 99 or 99.5% by HPLC or RP-HPLC. In an embodiment, the 5-MeO-DMT hydrochloride is crystalline.
  • the crystalline 5-MeO-DMT hydrochloride is characterised as described elsewhere in this document, such as in the Examples. In an embodiment, there is provided pure 5-MeO-DMT hydrochloride. In an embodiment, this may be crystalline.
  • the source of 5-MeO-DMT hydrochloride is isolated as a solid or a solution or dispersed in a carrier medium e.g. a solvent. In an embodiment, the source of 5-MeO-DMT hydrochloride is obtained from the reaction of the free base of 5-MeO-DMT with hydrochloride.
  • the source of 5- MeO-DMT hydrochloride is obtained from the reaction of the free base of 5-MeO-DMT with hydrochloride wherein the reaction takes place in a solvent wherein the solvent may be one or more of toluene, IPA or IPAc.
  • the source of 5-MeO-DMT hydrochloride is obtained as described in the Examples.
  • the benzoate salt of 5-MeO-DMT has improved characteristics over the common hydrochloride salt, including reduced mucosal irritation, increased epithelial permeability and increased stability.
  • 5-MeO-DMT benzoate is a white to off white solid powder, soluble in water at >50mg/ml with a pH of 7-8 at 50mg/ml and a pKa of 9.71.
  • Example 4a An improved method of 5-MeO-DMT benzoate synthesis
  • a method for synthesising 5-MeO-DMT benzoate comprises the reduction of compound (1), this reaction requires refluxing in a large excess of lithium aluminium hydride and proceeds via a partially-reduced hydroxy impurity (2), see the reaction scheme below:
  • the above disclosed improved method allows for the provision of batches of 5-MeO-DMT benzoate in which the levels of the hydroxyl impurity are very low, 0.1% or lower, compared with 1.5% for the aforementioned method.
  • it is the hydrobromide salt which is produced by the above method, wherein HBr is added in place of benzoic acid.
  • it is any other herein described salt which is produced by the above method, wherein the benzoic acid is replaced by the corresponding acid, e.g. oxalate, oxalic acid.
  • the 5-MeO-DMT hydrochloride salt was taken up in 6 volumes of IPAc and then 1 equivalent of aqueous sodium hydroxide solution added. Following a pH check to confirm the solution was basic, layers were separated and the solution of 5-MeO-DMT free base in IPAc washed with water. After azeotropic distillation under reduced pressure to dry the batch the benzoate salt was formed by the addition of a solution of benzoic acid in IPAc at elevated temperature. Product was isolated by filtration following a cool-down and stir-out phase. As the salt formation is included as part of the process it was found that an increase in the overall volume of IPAc compared to that used for a standalone benzoate salt recrystallisation was beneficial.
  • 5-MeO-DMT benzoate salt was taken up in 15 volumes of toluene and then 1 equivalent of aqueous sodium hydroxide solution added. Following a pH check to confirm the solution was basic, layers were separated and the solution of 5-MeODMT free base in toluene washed with water. After azeotropic distillation under reduced pressure the hydrochloride salt was formed by the addition of a solution of hydrogen chloride in IPA at elevated temperature. Product was isolated by filtration following a cool-down and stir-out phase.
  • the hydrochloride salt was generated in 78% yield, It is of note that the intermediate hydroxy impurity present in the benzoate input material purged particularly well when isolating the hydrochloride salt, being present at a level of 0.1% compared to 0.7% present in the 5-MeODMT benzoate input material.
  • 5-MeO-DMT fumarate was successfully prepared from the HCI salt in good yield and good purity.
  • Use of the hydrochloride salt in this process has allowed the fumarate salt to be isolated with a low level of hydroxy impurity.
  • Production of 5-MeO-DMT fumarate by the method detailed in Example 5 resulted in a 70% yield with 93.91% purity and 5.07% of the hydroxy impurity present.
  • Spray drying a solution containing the substance(s) of interest (e.g. 5-MeO-DMT, or the salt, thereof inclusive of any excipients).
  • This can be done via an atomizing nozzle such as with rotary atomizers, pressure atomizers, twin fluid nozzles, ultrasonic atomizers, four-fluid nozzles. This is done so as to form droplets capable of generating co-formed particles in the desired particle size range.
  • a ProCepT spray dryer is used. In an embodiment, a ProCepT spray dryer with an ultrasonic nozzle is used. In an embodiment, there is dissolution of 5-MeO-DMT benzoate and HPMC in water to make input solution at a 50:50 ratio.
  • the Slug Mucosal Irritation (SMI) assay was initially developed at the Laboratory of Pharmaceutical Technology (UGent) to predict the mucosal irritation potency of pharmaceutical formulations and ingredients.
  • the test utilizes the terrestrial slug Arion lusitanicus.
  • the body wall of the slugs is a mucosal surface composed of different layers.
  • the outer single-layered columnar epithelium that contains cells with cilia, cells with micro-villi and mucus secreting cells covers the subepithelial connective tissue. Slugs that are placed on an irritating substance will produce mucus. Additionally tissue damage can be induced which results in the release of proteins and enzymes from the mucosal surface.
  • the test was validated using reference chemicals for eye irritation (ECETOC eye reference data bank).
  • ECETOC eye reference data bank reference chemicals for eye irritation
  • These studies have shown that the SMI assay can be used as an alternative to the in vivo eye irritation tests.
  • a multi-center prevalidation study with four participating laboratories showed that the SMI assay is a relevant, easily transferable and reproducible alternative to predict the eye irritation potency of chemicals.
  • the purpose of this assay was to assess the stinging, itching or burning potential of the test item(s) defined below. Using the objective values obtained for the mucus production the stinging, itching or burning potential of the test item(s) can be estimated by means of the prediction model that is composed of four categories (no, mild, moderate and severe).
  • Test System Slugs (Arion lusitanicus); 3 slugs per treatment group.
  • the parental slugs of Arion lusitanicus collected in local gardens along Gent and Aalter (Belgium) are bred in the laboratory in an acclimatized room (18-20°C).
  • the slugs are housed in plastic containers and fed with lettuce, cucumber, carrots and commercial dog food.
  • Test Design A single study was performed. Treatment time was 15 minutes three times on the same day.
  • Slugs weighing between 3 and 6 g were isolated from the cultures two days before the start of an experiment. The body wall was inspected carefully for evidence of macroscopic injuries. Only slugs with clear tubercles and with a foot surface that shows no evidence of injuries were used for testing purposes. The slugs were placed in a plastic box lined with paper towel moistened with PBS and were kept at 18 - 20°C. Daily the body wall of the slugs was wetted with 300 pl PBS using a micropipette.
  • the stinging, itching or burning potency of the test item(s), was evaluated by placing 3 slugs per treatment group 3 times a day on 100 pL of test item in a Petri dish for 15 ⁇ 1 min. After each 15-min contact period the slugs were transferred for 60 min into a fresh Petri dish on paper towel moistened with ImL PBS to prevent desiccation. An overview of this can be seen in Figure 4.
  • the amount of mucus produced during each contact period was measured by weighing the Petri dishes with the test item before and after each 15-min contact period.
  • the mucus production was expressed as % of the body weight.
  • the slugs were weighed before and after each 15-min contact.
  • test results were based upon the total amount of mucus production during 3 repeated contact periods with the test item.
  • the mucus production was expressed in % of the body weight by dividing the weight of the mucus produced during each contact period by the body weight of the slug before the start of that contact period.
  • the total mucus was calculated for each slug and then the mean per treatment group was calculated.
  • the classification prediction model shown in Table 1 was used to classify the compounds.
  • the negative control should be classified as causing no stinging, itching and burning (Total mucus production ⁇ 5.5%) the positive control item should be classified as causing severe stinging, itching and burning (Total mucus production > 17.5%)
  • NC negative control
  • PC positive control
  • BAC benzalkonium chloride
  • the average amount of mucus produced during each 15-min contact period and total mucus production (total MP) is presented in Table 2.
  • the negative control untreated slugs
  • the positive control on the other hand (DDWM/SLS 80/20) induced a high mucus production during each contact period (mean total MP > 17.5%) resulting in a classification as severe stinging, itching, and burning (SIB) reactions.
  • SIB severe stinging, itching, and burning
  • test items can be ranked according to increasing total mucus production: sodium acetate (10% w/v) ⁇ sodium citrate (10% w/v) ⁇ disodium fumarate (10% w/v) ⁇ sodium phosphate (10% w/v).
  • NC negative control
  • PC positive control
  • the total MP for a 60-min treatment (historical data) was compared with the total MP of the SIB protocol (3x 15- min treatment; current data).
  • a ranking is proposed from least SIB reactions to highest SIB reactions:
  • Sodium oxalate appears to be the most irritating salt since a 1% concentration results in 11.2% total MP after 1 hour of contact.
  • Sodium benzoate is the least irritating salt.
  • Example 8 Further slug mucosal irritation (SMI) testing
  • 5-MeO-DMT as a freebase compound is known to be highly irritating to the mucosal lining; therefore, it is commonly prepared as a salt for insufflation.
  • the hydrochloride (HCI) salt of 5-MeO-DMT is most commonly used due to ease of crystallisation. However, it is known that the HCI salt of 5-MeO-DMT is still quite irritating to the mucosal lining.
  • the 5-MeO-DMT benzoate produced 'mild' irritation compared to the 5-MeO-DMT HCI which scored as 'moderate' on testing.
  • ovine nasal epithelium to study nasal drug absorption is a technique which is well known to the person skilled in the art.
  • the benzoate salt has higher permeation across the epithelium.
  • BPL-5MEO refers to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).
  • test and control/vehicle items were administered by single dose intranasal administration to both nostrils, as shown in Table 7.
  • Table 7 Experimental Design of Study 15951 a The observers performing the FOB were not aware of the specific treatment administered to the animals. b Control animals were administered 0.1% hydroxypropyl methyl cellulose (HPMC) in water, c Dose volume did not exceed 25 pL/nostril for all animals regardless of their bodyweight.
  • HPMC hydroxypropyl methyl cellulose
  • FOB was performed at 4 stages: when the animals were in their home cage, while handling the animals, when the animals were freely moving in an open-field, and when they received diverse stimuli for reactivity evaluation.
  • the body temperature and neuromuscular strength were also measured on each of the occasions detailed above.
  • the FOB examinations were grouped according to functional domains of the nervous system as shown in Table 8.
  • Phase 1 assessed the onset and steady-state inhibition of hERG at a selected concentration of 30pm 5-MeO-DMT; Phase 2 assessed the concentration response if the results from Phase 1 showed inhibition of 20% or more.
  • the initial concentration of 30pm was selected based on the results of an exploratory dose-range finding study in dogs, where intranasal administration of 2.5mg/kg BPL-5MEO resulted in a mean Cmax of 803 ng/mL (3.67 pM) 5-MeO-DMT.
  • a solution of 30 pM used in Phase 1 provided an 8-fold margin over this concentration.
  • Phase 2 5- MeO-DMT inhibited hERG potassium ion channel current in a concentration-dependent manner as presented in Table 9.
  • Table 9 Mean Percent Inhibition of hERG Potassium ion Channel Current by 5-MeO-DMT (in protein free perfusate)
  • the calculated IC50 of 5-MeO-DMT for hERG potassium channel current was 8.69pm (95% confidence limits 5.78- 13.06pm) compared to 12.8 nM (95% confidence limits 6.8-24.3 nM) for the positive control, terfenadine.
  • the highest dose level was selected based on the results from an intranasal maximum tolerated dose (MTD) toxicity study in dogs (Study 62958) where repeated daily dosing 2.5mg/kg/day of BPL-MEO once daily for 5 consecutive days was marginally tolerable and associated with transient clinical observations of moderate to severe incoordination, vocalization, salivation, shaking, circling, sneezing, decreased activity, and labored respiration that resolved within 60 minutes post dosing. Therefore, the highest dose selected for this study was 1.2mg/kg/day. The lowest dose of 0.4mg/kg/day was based on consideration of a maximum clinical dose of 14mg/day, with the middose of 0.8mg/kg/day selected to provide a dose-response assessment.
  • MTD intranasal maximum tolerated dose
  • BPL-5MEO and control/vehicle were administered by intranasal instillation to both nostrils per session to a total of 4 dogs.
  • Each dog received 4 administrations (control/vehicle and 3 dose levels of BPL-5MEO) according to a Latin- square design, such that each dog received the various administrations in a unique sequence, as in Table 10.
  • a washout period of at least 2 days was allowed between each successive dose.
  • Table 10 Latin-square design for Dog Cardiovascular Study a Animal 1004A was replaced prior to dosing for Test Session 3 with animal 1104A due to low implant battery.
  • Low Dose, Mid Dose, High Dose were 0.4, 0.8, and 1.2mg/kg/day, respectively.
  • the nominal dose levels refer to the freebase of 5-MeO-DMT salt form.
  • the dose volume administered to each animal was 7 pL/kg/nostril. No animal exceeded a dose volume of 100 pL/nostril.
  • the Control/Vehicle was 0.1% hydroxypropyl methyl cellulose (HPMC) in water.
  • the telemetry signals for arterial blood pressure and pulse rate were recorded continuously over the telemetry recording period of at least 1.5 hours before the start of dosing and for at least 24 hours postdosing.
  • Systolic, diastolic and mean arterial blood pressures and pulse rate were obtained from transmitter catheter inserted into the femoral artery.
  • ECGs were obtained from the biopotential leads, from the telemetry transmitter, in a Lead II configuration.
  • Peak concentrations were reached within 3 to 14 minutes (Tmax), post dosing with apparent elimination half-lives ranging from 19 to 95 minutes. The values were not markedly different on Day l and Day 14. There was no apparent sex difference and no evidence of accumulation with repeated dosing.
  • the toxicology program completed with BPL-5MEO consisted of non-pivotal single/repeat dose intranasal studies to determine the MTD in order to help select the highest doses for the pivotal 14-day GLP intranasal toxicology studies in male and female Sprague Dawley rats and Beagle dogs.
  • the intranasal route of administration was used as this is the clinical route of administration.
  • the species selected were based upon information from the published literature, preliminary PK information, availability of historical control information from the testing laboratory, and their standard use and acceptance as appropriate surrogates for intranasal administration.
  • the experimental design of the pivotal 14-day studies included an assessment of systemic exposures (toxicokinetics) and a 14-day recovery period to assess reversibility of any adverse or delayed responses.
  • the once daily dosing for 14 consecutive days in the pivotal studies was intended to provide sufficient systemic exposure to characterize the toxicity potential for a drug substance with a very short half-life.
  • the objectives of this non-GLP study were to determine the maximum tolerated dose and the toxicity profile of BPL- 5MEO following intranasal instillation in the rat.
  • the study consisted of 2 parts.
  • the objective of the first part was to determine the MTD of BPL-5MEO following a single intranasal administration to Sprague- Dawley rats.
  • the doses used in part 1 were 15, 30, 50, 65, and 75mg/kg. Each subsequent dose was administered following at least 24 hours from the commencement of the previous dose. There were 2 males and 2 females in each dose group.
  • the objective of the second part was to determine the toxicity of BPL-5MEO at the MTD of 75mg/kg following once daily intranasal administration for 7 consecutive days to Sprague-Dawley rats.
  • necropsy consisted of an external examination, including reference to all clinically-recorded lesions, as well as a detailed internal examination.
  • necropsy During Phase 2, assessments of mortality, clinical signs and body weights were performed. Following dosing, all animals were euthanized and subjected to a necropsy examination on Day 8. The necropsy consisted of an external examination, including reference to all clinically-recorded lesions, as well as a detailed internal examination. Study plan specific tissues/organs were collected and retained, then trimmed and preserved promptly once the animal was euthanized but these were not further examined microscopically.
  • the objectives of this study were to determine the maximum tolerated dose and the toxicity of the test item, 5- MeO-DMT (as the hydrochloride salt), following intranasal instillation in the dogs. In support of these objectives, the study consisted of 2 individual phases.
  • the test item was administered once by intranasal instillation to one male and female dog for up to 5 dose levels until the highest tolerable dose (MTD) was determined as described in Table 11.
  • MTD tolerable dose
  • Table 11 Doses Administered in the Dose Escalation Phase in Study 62958 a Each subsequent dose was administered following a washout period of minimum 3 days between doses. b Dose levels refer to the freebase of BPL-5MEO salt form. c Targeted dose concentrations were calculated based on an estimated body weight of 10 kg. d These animals were dosed at higher dose level of 5mg/kg.
  • BPL-5MEO was administered at the MTD to one male and female dog once daily by intranasal instillation for 5 consecutive days and then twice daily on Days 6 and 7 (minimum 4 hours apart).
  • assessments of mortality, clinical signs, body weights and food consumption were performed.
  • a series of blood samples were collected on Days 1 and 7 for determination of plasma concentrations of 5-MeO-DMT using an LC/MS/MS method.
  • All animals were euthanized and subjected to a necropsy examination on Day 8.
  • the necropsy consisted of an external examination; including reference to all clinically-recorded lesions, as well as a detailed internal examination. Study plan specific tissues/organs were collected and preserved following necropsy but were not further examined microscopically.
  • BPL-5MEO plasma concentration (Cmax) ranged from 541 to 803 ng/mL and was reached (Tmax) within 2 to 15 minutes post dose in both sexes.
  • Dose normalized AUCs ranged from 2980 to 7320 min*kg*ng/mL/mg in both sexes.
  • Tmax BPL-5MEO plasma concentrations declined at an estimated ti/2from 19.1 to 34 minutes in both sexes. There were no sex differences in any of the measured toxicokinetic parameters on either occasion. Over the 7-day treatment period, BPL-5MEO did not accumulate when administered daily by intranasal instillation.
  • the objective of this GLP study was to determine the toxicity and toxicokinetic (TK) profile of BPL-5MEO following intranasal instillation in Sprague Dawley rats for 14 consecutive days and to assess the persistence, delayed onset, or reversibility of any changes following a 14-day recovery period.
  • TK toxicokinetic
  • BPL-5MEO and control/vehicle were administered to groups of rats once daily by intranasal instillation for 14 consecutive days as described in Table 12.
  • Table 12 Doses Administered in 14-Day Repeat Dose Study in Rats a Vehicle control animals were administered 0.1% Hydroxypropyl methyl cellulose (HPMC) in water, b Nominal dose levels refer to the freebase of 5-MeO-DMT salt form. c The dose volume administered to each animal was 75 pL/kg/nostril. d Dose volume was not to exceed 25 pL/nostril for all animals regardless of their bodyweight.
  • HPMC Hydroxypropyl methyl cellulose
  • the animals were monitored for mortality, clinical signs, respiratory measurements, body weights, food consumption, and body temperature. Ophthalmoscopic examinations and respiratory function tests were performed on all animals at scheduled timepoints. Clinical pathology assessments (hematology, coagulation, clinical chemistry, and urinalysis) were evaluated at termination. Blood samples were collected from the jugular vein from the TK animals on Days 1 and 14, for up to 8 hours after treatment for bioanalysis of 5-MeO-DMT concentrations in plasma and the subsequent calculation of toxicokinetic parameters. Following dosing, the Main animals were euthanized and subjected to a complete necropsy examination on Day 15. The Recovery animals were observed for an additional 14 days and then euthanized and subjected to a complete necropsy examination on Day 28.
  • TK animals were euthanized after the last blood collection and discarded without further examination. At terminal euthanasia, selected tissues/organs were weighed, and microscopic evaluations of a standard set of tissues including the nasal turbinates (4 sections) and brain (7 sections) were performed for all Main and Recovery study animals.
  • mice in the Main group were euthanized and subjected to a necropsy examination on Day 15.
  • the animals in the Recovery group were observed for 14 days and then euthanized and subjected to a necropsy examination on Day 28.
  • a series of 8 blood samples (approximately 0.5mL each) were collected from all rats in the Toxicokinetic group (3 rats/sex/timepoint) on Days 1 and 14 of the treatment period at 2, 5, 10, 15 and 30 minutes, and 1.0, 3.0 and 8 hours after treatment.
  • rats (3 rats/sex) in the Toxicokinetic group only 1 sample was collected at the 15 minutes post dosing timepoint on Days 1 and 14.
  • Toxicity was based on the following parameters monitored: mortality/morbidity, clinical observations, body weights/gains, food consumption, ophthalmoscopy, clinical pathology (hematology, coagulation, chemistry, and urinalysis), necropsy observations, selected organ weights, and microscopic examination of a complete set of standard tissues including 4 cross levels of the nasal cavity and 7 sections of the brain.
  • activated partial thromboplastin times were increased for both sexes in the mid (20mg/kg/day) and high (75mg/kg/day) dose groups. All the coagulation values on Day 28 were comparable to control group. All other changes in the coagulation parameters were not attributed to the administration of BPL-5MEO as they were minor (within the normal physiological range), comparable to control values, and/or not dose-related.
  • Table 13 Thymus Weights for Male Animals Compared to Control Group a
  • the organ weight in grams is reported, for other groups, the percentage compared to the control value is shown.
  • miceroscopic changes observed in rats dosed with 75mg/kg/day of BPL-5MEO included: respiratory epithelium, minimal to mild degeneration, hyperplasia, and squamous metaplasia, minimal mononuclear infiltrate and/or lumen exudate in nasal cavities 1, 2, 3, and/or 4; transitional epithelium, minimal hyperplasia in nasal cavity 1, and; olfactory epithelium, minimal to mild degeneration and/or minimal mononuclear infiltrate and erosion in nasal cavities 2, 3, and/or 4.
  • Minimal degeneration of the olfactory epithelium of the nasal cavities 2 and 3 was noted in male and/or female rats dosed with 5 and/or 20mg/kg/day of BPL-5MEO (Group 2 and 3).
  • Minimal degeneration of the respiratory epithelium of the nasal cavities 1 and 2 was noted in male and/or female rats dosed with 20mg/kg/day of BPL-5MEO (Group 3).
  • the sex ratios ranged between 0.4 and 6.2, but as the sex ratio randomly varied between dose groups and occasions, it was considered there was no sex-related difference.
  • AUCo-nast Area under the plasma drug concentration-time curve from the time of dosing to the last quantifiable concentration
  • AUCiNF_obs Area under the plasma drug concentration-time curve from the time of dosing extrapolated to infinity
  • Cmax The maximum plasma concentration
  • h hours
  • SE standard error of mean
  • ti/2 Terminal elimination half-life
  • Tmax Time to maximum plasma concentration.
  • the NOAEL was reported as the lowest dose of 5mg/kg. b. A 14-Day Repeat-Dose Intranasal Toxicity Study Followed by a 14-Day Recovery Period in Dogs (Study 62959)
  • the objective of this GLP study was to determine the toxicity and TK profile of BPL-5MEO following intranasal instillation in Beagle dogs for 14 consecutive days and to assess the persistence, delayed onset, or reversibility of any changes following a 14-day recovery period.
  • BPL-5MEO and control/vehicle were administered to groups of dogs once daily by intranasal instillation for 14 consecutive days as described in Table 15.
  • Table 15 Doses Administered in 14-Day Repeat Dose Study in Dogs a Vehicle control animals were administered 0.1% Hydroxypropyl methyl cellulose (HPMC) in water. b Dose levels refer to the freebase of 5-MeO-DMT salt form. c Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia and aggressiveness after dosing on Day 1 at the dose level of 2.5mg/kg. The dose level was subsequently decreased on Day 1 for the Replicates B and C to 1.5mg/kg. Replicate A received 1.5mg/kg on Days 2 to 14. d The dose volume administered to each animal was 10 pL/kg/nostril.
  • Dose volume was not to exceed 100 pL/nostril for all animals regardless of their bodyweight. Assessments of mortality, clinical signs, olfactory reflex, body weights, food consumption, ophthalmology, and electrocardiograms were performed. In addition, clinical pathology assessments (hematology, coagulation, clinical chemistry and urinalysis) were evaluated once pretreatment and at termination. Blood samples were collected from the jugular vein of all animals on Days 1 and 14, at up to 8 time points relative to treatment, for analysis of test item concentration in plasma and the subsequent calculation of toxicokinetic parameters. Following dosing, the Main animals were euthanized and subjected to a complete necropsy examination on Day 15.
  • a series of 8 blood samples were collected from the jugular vein from all treated animals on each of Days 1 and 14 of the treatment period at 2, 5, 10, 15, 30, and 60 minutes as well as 3 and 8 hours after treatment.
  • Group 1 only one sample was taken at 15 minutes post dosing on Days 1 and 14 in order to confirm the absence of BPL-5MEO in animals in the vehicle control group. Blood samples were analysed for the BPL-5MEO concentration in plasma and the subsequent calculation of TK parameters.
  • SD standard deviation a' for Control group, the control value is mentioned, for other groups, the percentage compared to the control value is shown.
  • b Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia and aggressiveness after dosing on Day 1 at the dose level of 2.5mg/kg. The dose level was subsequently decreased on Day 1 for the Replicates B and C to 1.5mg/kg. Replicate A received 1.5mg/kg on Days 2 to 14.
  • AUCo-nast Area under the plasma drug concentration-time curve from the time of dosing to the last quantifiable concentration
  • AUCiNF_obs Area under the plasma drug concentration-time curve from the time of dosing extrapolated to infinity
  • Cmax The maximum plasma concentration
  • h hours
  • ti/2 Terminal elimination half-life
  • Tmax Time to maximum plasma concentration.
  • a Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia and aggressiveness after dosing on Day 1 at the dose level of 2.5mg/kg. The dose level was subsequently decreased on Day 1 for the Replicates B and C to 1.5mg/kg. Replicate A received 1.5mg/kg on Days 2 to 14.
  • the reported NOAEL for BPL-5MEO when dosed for 14 consecutive days by intranasal administration, followed by a 14-day recovery period was considered to be 1.5mg/kg/day, corresponding of 213 (220) h*ng/mL (combined for both sexes).
  • HED Human Equivalent Dose (for a 60 kg human)
  • a NOAEL determined in the 14-day toxicology studies for both species.
  • the genotoxicity potential of 5-MeO-DMT was evaluated in silico (computational analysis) for structural alerts and in vitro in GLP assays to assess mutagenic and clastogenic potential following the ICH S2 ( Rl) Guidance.
  • 5-MeO-DMT its primary active metabolite, bufotenine, and an identified drug substance impurity, MW234, were evaluated for quantitative structural activity relationships for potential mutagenicity and/or carcinogenicity using two computation analytical methods, Arthur Nexus and the Leadscope Genetox Statistical Models. The evaluation from both analyses did not identify any structural alerts associated with 5-MeO-DMT or bufotenine, and a possible nor an identified drug substance impurity MW234.
  • the mutagenic potential of 5-MeO-DMT was evaluated in a GLP Bacterial Reverse Mutation Test (Ames test) for the ability to induce reverse mutations at selected loci of Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537 and the Escherichia coll tester strain WP2uvrA. These strains were treated with 5-MeO-DMT at concentrations of 1.6, 5, 16, 50, 160, 500, 1600 and 5000 pg per plate along with the vehicle/negative and appropriate positive controls. The assay was performed in triplicate using the pre-incubation method in the absence and presence of an exogenous metabolic activation system, phenobarbital/5,6-benzoflavone-induced rat liver 59 microsomal enzyme mix (59 mix)
  • the clastogenic potential of 5-MeO-DMT was evaluated in a GLP in vitro micronucleus test using Chinese hamster ovary (CHO)-Kl cells using flow cytometry. Exponentially growing cells were treated in duplicate with the 5-MeO- DMT at 9 concentrations up to the recommended upper limit of 1 mM (corresponding to approximately 300 pg/mL): 1.25, 2.5, 5.0, 10, 20, 40, 80, 150 and 300 pg/mL. The treatment with the vehicle/negative and positive controls was concurrently performed.
  • BPL-5MEO has been synthesised to Good Manufacturing Practice (GMP) standards and prefilled into the Aptar Unidose Intranasal Liquid Delivery System device.
  • the device allows a single fixed dose of BPL-5MEO to be administered intranasally.
  • the liquid is prefilled into and administered using a standard single unit dose nasal pump device.
  • Excipients used in the formulation are water, 0.1% hydroxypropyl methylcellulose (HPMC) and sodium hydroxyl (NaOH). Two concentrations of the formulation will be used, 70mg/mL (for dose levels below 7mg), and 140mg/mL (for dose levels above 7mg).
  • composition comprising 5-MeO-DMT hydrochloride, wherein the composition comprises: water;
  • HPMC hydroxypropyl methylcellulose
  • composition comprising 5-MeO-DMT benzoate, wherein the composition comprises: water;
  • HPMC hydroxypropyl methylcellulose
  • composition comprising 5-MeO-DMT hydrochloride, wherein the composition comprises: water;
  • HPMC hydroxypropyl methylcellulose
  • composition comprising 5-MeO-DMT benzoate, wherein the composition comprises: water;
  • HPMC hydroxypropyl methylcellulose
  • NaOH sodium hydroxyl
  • an intranasal composition comprising 5-MeO-DMT hydrochloride, wherein the composition comprises: water;
  • HPMC hydroxypropyl methylcellulose
  • an intranasal composition comprising 5-MeO-DMT benzoate, wherein the composition comprises: water;
  • HPMC hydroxypropyl methylcellulose
  • an intranasal composition comprising 5-MeO-DMT hydrochloride, wherein the composition comprises: water;
  • HPMC hydroxypropyl methylcellulose
  • an intranasal composition comprising 5-MeO-DMT benzoate, wherein the water;
  • HPMC hydroxypropyl methylcellulose
  • the composition comprises 25-400mg/mL; 25-300mg/mL; 25-200mg/mL; 25-100mg/mL; 25- 50mg/mL; 50-400mg/mL; 50-300mg/mL; 60-400mg/mL; 60-300mg/mL; 150-400mg/mL; 150-300mg/mL; 200- 300mg/mL; 200-400mg/mL; 30-100mg/mL; 300-400mg/mL; 300-500mg/mL; 45-75mg/mL; 50-70mg/mL; 55- 65mg/mL; or 50-60mg/mL 5-MeO-DMT.
  • an intranasal liquid delivery system comprising a composition of 5-MeO-DMT.
  • a single unit dose capsule of a composition of 5-MeO-DMT there is provided an intranasal composition comprising a dosage amount 50-150mg/ml 5-MeO-DMT in a liquid medium, wherein the 5-MeO-DMT is formulated as the benzoate salt of 5-MeO-DMT (5-MeO-DMT benzoate).
  • 5-MeO-DMT benzoate is present as a suspension or emulsion in the liquid medium.
  • an intranasal liquid delivery system comprising:
  • BPL-5MEO is administered to subjects by a trained member of the research team using a single unit dose pump spray.
  • the unit contains only 1 spray, so should not be tested before use. While sitting down the subject is asked to blow their nose to clear the nasal passages. Once the tip of the device is placed into the nostril the clinic staff will press the plunger to release the dose.
  • a method for the administration of 5-MeO-DMT comprising administering the 5-MeO-DMT as an intranasal spray to a human subject wherein the human subject has followed patient preparation parameters that include blowing their nose to clear their nasal passages immediately prior to administration.
  • the human subject is seated.
  • a method for the delivery of 5-MeO-DMT to the brain of a human subject comprising administering the 5-MeO-DMT as an intranasal spray to a human subject wherein the human subject has followed patient preparation parameters that include blowing their nose to clear their nasal passages immediately prior to administration.
  • the XRPD pattern of 5-MeO-DMT benzoate salt was acquired before and following particle size reduction with a mortar and pestle. This reduced the intensity of dominant diffractions and revealed that the XRPD pattern of the benzoate salt was prone to preferred orientation prior to particle size reduction, which is a function of the habit and particle size of the material.
  • XRPD patterns of the benzoate salt prior to and following particle size reduction can be seen in Figures 6 and 7 respectively.
  • the XRPD patterns of the benzoate salt prior to and following particle size reduction overlaid on one another can be seen in Figure 8.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.2°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.3°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.1°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.2°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.3°20.
  • crystalline 5- MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.1°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5,
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.3°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO- DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0,
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.2°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.3°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram as substantially illustrated in Figures 6, 7 or 8.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 6.
  • crystalline 5- MeO-DMT benzoate characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 7.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram as substantially illustrated in Figure 8.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of:
  • a DVS isotherm profile as previously or subsequently described; and A crystalline structure as previously or subsequently described.
  • the differential scanning calorimetry (DSC) thermograph of 5-MeO-DMT benzoate salt contained one endotherm with an onset of 123.34°C, peak of 124.47°C and an enthalpy of 134.72J/g. There were no other thermal events.
  • the DSC thermograph, acquired at 10°C/min, can be seen in Figure 9.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C as substantially illustrated in Figure 9.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C as substantially illustrated in Figure 9.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of 123°C.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of 123°C a substantially illustrated in Figure 9.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of 124°C.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of 124°C as substantially illustrated in Figure 9.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C and a peak of between 122 and 128°C.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C and a peak of between 122 and 128°C as substantially illustrated in Figure 9.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C and a peak of between 124 and 126°C.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C and a peak of between 124 and 126°C as substantially illustrated in Figure 9.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak of between 124 and 126°C and an enthalpy of between -130 and -140J/g.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak of between 124 and 126°C and an enthalpy of between -130 and -140J/g as substantially illustrated in Figure 9.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak of between 124 and 126°C and an enthalpy of between -130 and -135J/g.
  • crystalline 5-MeO-DMT benzoate characterised by an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak of between 124 and 126°C and an enthalpy of between -130 and -135J/g as substantially illustrated in Figure 9.
  • the thermogravimetric analysis (TGA) thermograph of 5-MeO-DMT benzoate salt revealed that the onset of decomposition was ca 131°C, which is past the melt at ca 125°C.
  • the TGA thermograph acquired at 10°C/min, can be seen in Figure 10.
  • crystalline 5-MeO-DMT benzoate characterised by an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
  • crystalline 5-MeO-DMT benzoate characterised by an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10.
  • crystalline 5-MeO-DMT benzoate characterised by an onset of decomposition in a TGA thermograph of 131°C.
  • crystalline 5-MeO-DMT benzoate characterised by an onset of decomposition in a TGA thermograph of 131°C as substantially illustrated in Figure 10.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C; and an onset of decomposition in a TGA thermograph of 131°C.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C and a peak of between 124 and 126°C; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C and a peak of between 124 and 126°C as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, a peak of 124°C; and an onset of decomposition in a TGA thermograph of 131°C.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, a peak of 124°C as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of 131°C as substantially illustrated in Figure 10.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C, a peak of between 124 and 126°C and an enthalpy of between -130 and -140J/g; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C, a peak of between 124 and 126°C and an enthalpy of between -130 and -140J/g as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, a peak of 124°C and an enthalpy of -135°C; and an onset of decomposition in a TGA thermograph of 131°C.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, a peak of 124°C and an enthalpy of -135°C as substantially illustrated in Figure 9; and an onset of decomposition in a TGA thermograph of 131°C as substantially illustrated in Figure 10.
  • the DVS profile for 5-MeO-DMT benzoate salt revealed reversible water uptake/loss over the humidity range and no hysteresis.
  • the water uptake/loss from 0 to 90% was gradual and amounted to a maximum of ca 0.20% and was a consequence of wetting of the solid.
  • the DVS isotherm can be seen in Figure 12.
  • the DVS isotherm of a 5-MeO-DMT Hydrochloride, lot 20/20/126-FP (Figure 17) was found to undergo significant moisture uptake upon the first sorption cycle from 70%RH. Approximately 23% w / w uptake is observed between 70- 80%RH, whereas less than 0.3% w / w moisture uptake from 0-70%RH was observed. A further 20% w / w moisture uptake is observed up to and when held at 90%RH before commencement of the second desorption cycle. Subsequent sorption and desorption cycles follow a similar profile with some observed hysteresis between operations that do not match the original desorption step. These return to ca. 6-9% w / w above the minimum mass recorded at 0%RH, which indicates significant retention of moisture. Upon completion of the DVS cycle, the input material was noted to have completed deliquesced.
  • a modified DVS isotherm of lot 20/45/006-FP (the same crystalline version) was undertaken to examine material behaviour from 60%RH and above.
  • No significant moisture uptake/loss in first desorption-sorption profile between 0-70%RH was noted ( Figure 18) followed by a ca. 0.46%w/w increase from 70-75%RH.
  • a further ca. 7% uptake is observed from 75-80%RH, then ca. 40% from 80-85%w/w.
  • DVS provides a versatile and sensitive technique for evaluating the stability of pharmaceutical formulations.
  • the DVS profiles show that the stability of the benzoate salt of 5-MeO-DMT is significantly higher than that of the hydrochloride salt and is therefore a more promising salt for development as a pharmaceutical composition.
  • an increased stability composition of 5-MeO-DMT wherein the composition comprises the benzoate salt.
  • a composition of 5-MeO-DMT having an increased stability wherein the composition comprises the benzoate salt.
  • there pharmaceutical composition may be a nasal inhalation composition. It is advantageous that the 5-MeO-DMT benzoate salt retains a low/consistent moisture content over its shelf-life preserving its ability to be consistently formulated, and preserving its ability to be inhaled in a free flowing powder form.
  • crystalline 5-MeO-DMT benzoate characterised by a DVS isotherm profile as substantially illustrated in Figure 12.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, between 124 and 126°C, optionally a peak of between 124 and 126°C and optionally an enthalpy of between -130 and -140J/g as substantially illustrated in Figure 9; an onset of decomposition in a TGA thermograph of between 128 and 135°C, between 129 and 134°C, between 130 and 133°C or between 130 and 132°C as substantially illustrated in Figure 10; and a DVS isotherm profile as substantially illustrated in Figure 12.
  • crystalline 5-MeO-DMT benzoate characterised by one or more of: an endothermic event in a DSC thermograph having an onset temperature of 123°C, optionally a peak of 124°C and optionally an enthalpy of -135°C as substantially illustrated in Figure 9; an onset of decomposition in a TGA thermograph of 131°C as substantially illustrated in Figure 10; and a DVS isotherm profile as substantially illustrated in Figure 12.
  • any form of the 5-MeO-DMT salt is the hydrochloride salt where the hydrochloride is characterized by one or more of: peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5 and 19.5°20 ⁇ O.1°20; peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5, 19.5, 23.9, 24.5, 25.1, 26.0, 26.9 and 28.3°20 ⁇ O.1°20; peaks in an XRPD diffractogram at 9.2, 12.2, 13.7, 14.1, 15.0, 18.5, 19.0, 19.5, 21.2, 23.3, 23.9, 24.5, 25.1, 26.0, 26.9, 27.5, 28.3, 29.0, 30.9 and 31.1°20 ⁇ O.1°20 as measured by X-ray powder diffraction using an x- ray wavelength of 1.5406 A.; endothermic event in a DSC thermograph having an onset temperature of between 140 and 150°C
  • the peaks in an XRPD diffractogram may be at determined ⁇ O.l°20, ⁇ O.2°20 or ⁇ O.3°20. It is considered that within the scope of the invention/disclosure, any numbers expressed to two decimal places can be rounded to one decimal place or to whole numbers. The person skilled in the art will appreciate the defining characteristics of one of more of the previously or subsequently described embodiments may be interchanged with those of one or more other embodiments.
  • Optical microscopy examination was undertaken using an Olympus BX53M polarised light microscope and an Olympus SC50 digital video camera for image capture using imaging software Olympus Stream Basic, V2.4.
  • the image scale bar was verified against an external graticule, 1.5/0.6/0.01 mm DIV, on a monthly basis.
  • a small amount of each sample was placed onto a glass slide and dispersed using mineral dispersion oil if required.
  • the samples were viewed with appropriate magnification and various images recorded.
  • Optical micrographs of 5-MeO-DMT benzoate salt were acquired.
  • the material is composed of large rhombohedral/trigonal crystals, ranging from 400 to 1000 microns.
  • the propensity of 5-MeO-DMT benzoate to polymorphism was investigated and is considered low with solids isolated with two different XRPD patterns.
  • the equilibration of 5-MeO-DMT benzoate in solvents with thermal modulation induced a form or version change which are not considered to be solvates.
  • the anti-solvent mediated crystallisation investigation of 5-MeO-DMT benzoate did not afford any solids indicating form or version change.
  • the controlled cooling crystallisation investigation of 5-MeO-DMT benzoate did not afford any solids indicating form or version change.
  • the reverse anti-solvent mediated crystallisation investigation of 5-MeO-DMT benzoate did induce a form or version change.
  • Pattern A Two versions of 5-MeO-DMT benzoate have been identified, the Pattern A form (see Example 17, hereafter this form is referred to as Pattern A) version and a second, Pattern B form, believed to be meta-stable.
  • Pattern B Two versions of 5-MeO-DMT benzoate have been identified, the Pattern A form (see Example 17, hereafter this form is referred to as Pattern A) version and a second, Pattern B form, believed to be meta-stable.
  • the equilibration investigation of 5-MeO-DMT benzoate in a range of solvents with thermal modulation returned Pattern A by XRPD from most solvents.
  • the equilibration solvents toluene, chlorobenzene, and anisole induced a form or version change in the 5-MeO-DMT benzoate and is defined as Pattern B by XRPD.
  • Solvate formation can be excluded based upon TGA.
  • the anti-solvent mediated crystallisation investigation of 5-MeO-DMT benzoate afforded solids which were concordant Pattern A by XRPD indicating no form or version change.
  • the controlled cooling crystallisation investigation of 5-MeO-DMT benzoate afforded solids which were concordant Pattern A by XRPD indicating no form or version change.
  • the reverse anti-solvent mediated crystallisation investigation of 5-MeO-DMT benzoate returned Pattern A form from most mixtures.
  • the methanoktoluene and IPA:toluene mixtures produced material which is considered to be Pattern B form with improved characteristics compared to the Pattern B form solids isolated via solvent equilibration.
  • XRPD examination revealed a powder pattern of 5-MeO-DMT benzoate that was concordant with that found in previous XRPD examinations (see Example 17, Pattern A form).
  • DSC examination Figure 20
  • Figure 20 revealed one sharp endotherm with an onset of 122.95°C and a peak at 124.41°C which was a match with Pattern A form (see Example 18 wherein the onset is 123.34°C and the peak at 124.47°C). Additional XRPD examination of multiple lots of 5-MeO-DMT benzoate can be seen in Figure 21, matching Pattern A.
  • DSC revealed the minor endo-exotherm was smaller for sample Q2 with peak temperatures of 113.41 and 114.32°C but the major endotherm was unaffected with a peak temperature of 124.23°C ( Figures 29 - 31).
  • DSC examination of sample R2 revealed the endothermic event in the minor endo-exotherm had two peaks of 111.53 and 113.49°C followed by the exotherm with a peak temperature of 114.39°C, the minor events were much larger compared to R1 and the second minor endothermic event was not present (Figures 29 - 31).
  • TGA examination revealed a negligible weight loss for samples P2 and Q2. For sample R2 there was a weight reduction of 0.583% before decomposition. The increase in weight loss corresponds to the increase in the magnitude of the minor events revealed by DSC ( Figures 29 - 31).
  • 5- MeO-DMT benzoate 25 ⁇ 0.5mg was dissolved in the minimal volume of solvent at 50°C (detailed in the Table below). The solutions were clarified through a 0.45pm Teflon syringe filter into pre-heated crystallisation tubes and cooled from 50°C to -10°C over 60 hours (1°C Hr-1 cooling rate) and held at -10°C for 50 hours (no agitation).
  • crystallisations contained large off-white crystals on the base of the crystallisation tube (detailed in the Table below).
  • the crystals were directly transferred from the crystallisation tube to the XRPD sample holder and were left open to the atmosphere for ca. 1 hour prior to analysis.
  • the remaining mixtures were agitated at 400rpm at ambient temperature, open to the atmosphere to allow partial solvent evaporation, over 18 hours.
  • the first anti-solvent-driven crystallisation of 5-MeO-DMT benzoate revealed a selection of suitable solvent/anti- solvent mixtures.
  • suitable solvent/anti-solvent mixtures were re-examined with reverse addition of hot stock solution to cold anti-solvent to potentially rapidly precipitate a new and/or meta-stable solid form version of 5-MeO-DMT benzoate.
  • 5-MeO-DMT benzoate 165 ⁇ 0.5mg was charged to vials A to F and dissolved in the minimal amount of solvent at 50°C as detailed in the Table below.
  • Anti-solvent 1ml was charged to crystallisation tubes then cooled to -10°C and agitated at 400rpm. Aliquots of the stock solutions of 5-MeO-DMT benzoate, ca. 50mg, were charged directly to the anti-solvents. All crystallisation tubes afforded suspensions within 5 minutes of addition of the 5-MeO-DMT benzoate solution. Suspensions were isolated immediately in vacuo via isolute then transferred to vacuum oven and dried at 50°C for 18 hours.
  • the DSC thermograph of sample Al revealed an endothermic event with onset ca. 110°C and major peak at 113.98°C, followed by an exotherm with onset 114.72°C and peak at 116.42°C, followed by a second endotherm with an onset of 123.00°C and peak at 123.72°C.
  • DSC examination of sample Bl revealed a similar DSC thermograph to Al but the first endothermic event was larger, 108 J.g 1 compared 90 J.g 1 and only contained 2 peak temperatures of 109.00 and 110.32°C instead of the 3 present in Al.
  • the exothermic event that immediately followed was smaller, 17 J.g 1 compared to 41 J.g -1 .
  • the second main endotherm was also smaller for Bl at 38 J.g 1 compared to 80 J.g 1 for Al.
  • crystalline 5-MeO-DMT benzoate as described above.
  • crystalline 5-MeO-DMT salt characterised by an endothermic or exothermic event in a DSC thermograph as substantially illustrated in any one of the Figures.
  • a composition comprising 5-MeO-DMT benzoate Pattern A form.
  • 5-MeO-DMT benzoate 101.55mg, was dissolved in THF, 4mL and clarified into a lOOmL round bottom flask. The solution was concentrated in vacuo 40°C at 200rpm. The liquid evaporated from the flask, yielding a concentrated clear colourless liquid residue around the flask. The residue was dissolved in acetone, 4ml, concentrated in vacuo at 40°C at 200rpm. The liquid evaporated from the flask, yielding a concentrated clear colourless liquid residue around the flask. Small crystals were visible on the inside of the flask, these were isolated after 18 hours affording 21-01- 051 A. Quench of melt
  • 5-MeO-DMT benzoate was held at 125°C for 5 minutes by TGA then cooled to ambient over 3 minutes affording 21- 01-051 B. The sample was analysed immediately and after 20 hours held in a sealed container.
  • 5-MeO-DMT benzoate 200mg was dissolved in deionised water, 10ml, and clarified through a 0.45pm nylon filter into a 500mL round bottom flask, then frozen into a thin layer. The flask was transferred to a vacuum and equilibrated to ambient temperature affording a fluffy white solid, 21-01-051 C. The solid transformed into gum over ca. 1 hour. The sample was analysed immediately and after 20 hours held in a sealed container.
  • the XRPD patterns of 5-MeO-DMT benzoate 21-01-051 B and C were concordant with Pattern A, indicating that the amorphous form converts to Pattern A form in a sealed container at ambient temperature and pressure.
  • the XRPD pattern of 5- MeO-DMT benzoate 21-01-051 A the solid isolated by acetone concentration, was concordant with Pattern A form. Rapid in vacuo concentration did not produce the amorphous version.
  • the XRPD patterns revealed 5-MeO-DMT benzoate 21-01-051 B and C to have an amorphous 'halo', indicating quenching molten material and lyophilisation produced amorphous 5-MeO-DMT benzoate.
  • Figure 47 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01- 051 B after 20 hours, C after 20 hours, and Pattern A reference.
  • the XRPD pattern of 5-MeO-DMT benzoate 21-01- 051 E were concordant with Pattern A, indicating that the amorphous form converts to Pattern A form at 60°C for 10 minutes.
  • Figure 48 shows XRPD comparison of 5-MeO-DMT benzoate lot 21-01-051 A, E, E particle size reduced, and Pattern A reference.
  • FIG. 50 shows DSC thermograph comparison of 5-MeO-DMT benzoate lot 21-01-051 C and C post 20 hours at 10°C.min -1 .
  • Amorphous 5-MeO-DMT benzoate can be generated by lyophilisation of an aqueous solution and the quenched melt. The amorphous 5-MeO-DMT benzoate will convert to Pattern A form material on standing.
  • an amorphous 5-MeO-DMT benzoate there is provided an amorphous 5-MeO-DMT benzoate.
  • a composition comprising an amorphous 5-MeO-DMT benzoate.
  • Figure 51 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-051 D, large scale lyophilised material, with temperature stamps corresponding to hot-stage microscopy images.
  • Figure 52 shows Micrograph image of 5-MeO- DMT benzoate lot 21-01-051 D at 30.02°C.
  • Figure 53 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01- 051 D at 54.21°C.
  • Figure 54 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 74.21°C.
  • Figure 55 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 114.23°C.
  • Figure 56 shows Micrograph image of 5-MeO-DMT benzoate lot 21-01-051 D at 120.14°C.
  • Amorphous 5-MeO-DMT benzoate 21-01-51 D, 24x 25 ⁇ 2mg was transferred to crystallisation tubes and solvent, 0.125mL charged as detailed in the Table below. The mixtures were agitated at 300rpm at 25°C for 30 minutes. Solvent, 0.125mL, was charged to relevant mixtures and equilibrated for 18 hours.
  • Figure 57 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation.
  • Figure 58 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-054 M isolated from the equilibration of amorphous 5-MeO-DMT benzoate in a,a,a-trifluorotoluene with thermal modulation with lot 20-37-64 (Pattern A).
  • Figure 59 shows DSC thermograph comparison of a selection of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation classified as Pattern A form.
  • Figure 60 shows DSC thermograph expansion comparison of a selection of 5-MeO-DMT benzoate lot 21-01-054 solids isolated from the equilibration of amorphous 5-MeO-DMT benzoate with thermal modulation classified as Pattern A form, highlighting an event in lot 21-01-054 Q, solid isolated from anisole.
  • Figure 61 shows Expanded DSC thermograph expansion highlighting an event in lot 21-01-054 Q, isolated from anisole.
  • Figure 62 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al air dried 2 minutes, lot 21-01- 049 Bl, Pattern B, and lot 20-37-64, Pattern A.
  • Figure 63 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al-air dried 1 hour and lot 21-01-060 Al-air dried 2 minutes.
  • Figure 64 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al-air dried 2 minutes, lot 21-01-060 Al-air dried 1 hour, and lot 21-01-049 Bl, Pattern B.
  • the DSC thermograph of 5-MeO-DMT benzoate 21-01-060 Al (air dried 1 hour) Figure 65 and Figure 66) revealed a minor broad endotherm with a peak temperature of 108°C which is considered characteristic of Pattern C form solid.
  • FIG. 65 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-060 Al, isolated immediately from IPA/toluene and air dried for 1 hour.
  • Figure 66 shows DSC thermograph expansion of 5- MeO-DMT benzoate lot 21-01-060 Al, isolated immediately from IPA/toluene and air dried for 1 hour.
  • An XRPD pattern of 5-MeO-DMT benzoate lot 21-01-060 Al was acquired following a total of 20 hours air drying.
  • Figure 67 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Al air dried 20 hours, lot 21-01-060 Al air dried 2 minutes, and lot 21-01-049 Bl, Pattern B ref.
  • 5-MeO-DMT benzoate 21-01-060 Bl produced from reverse anti-solvent addition, equilibrated for 3 hours, then isolated and air drying at ambient temperature. Immediately following isolation, the solid was analysed by XRPD. This revealed a diffraction pattern concordant with 21-01-060 Al, Pattern C ( Figure 68). The XRPD pattern ( Figure 69) was reacquired following 20 hours air drying and revealed the solid was still Pattern C but contained diffractions at 17.2° and 19.5 20 indicative of Pattern B.
  • Figure 68 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Bl, isolated after 3 hours equilibration then air dried for 2 mins and Al isolated immediately then air dried for 2 minutes.
  • Figure 69 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-060 Bl, isolated after 3 hours equilibration then air dried for 20 hours and Bl isolated after 3 hours equilibration then air dried for 2 minutes, and lot 21-01-049 Bl, Pattern B.
  • Example 25 Investi ation of the impact of solvent vapour diffusion upon amorphous 5-MeO-DMT benzoate
  • amorphous solid to solvent vapour Subjecting an amorphous solid to solvent vapour is considered to be a low energy process for inducing form or version change of the solid in order to generate meta stable versions and/or solvates from the amorphous solid for comparison and evaluation.
  • 5-MeO-DMT benzoate 497.44mg, was dissolved in deionised water, lOmL, and clarified into a 500mL round bottom flask and lyophilised as detailed previously.
  • the fluffy white solid produced, 12x 25mg was charged to HPLC vials and placed in a sealed container with ca. 2mL of solvent.
  • the solvents employed and observations are detailed in the Table below. Following equilibration for 7 days, solids were transferred to XRPD sample holder directly and analysed by XRPD. DSC was collected for all notable samples by XRPD and a selection of Pattern A form solids.
  • Figure 70 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 solids isolated from amorphous 5-MeO-DMT benzoate exposed to solvent vapour.
  • Figure 71 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 K, isolated from amorphous 5-MeO-DMT benzoate exposed to solvent vapour, with lot 20-37-64, Pattern A.
  • the DSC thermograph comparison of a selection of Pattern A form solids revealed an endothermic event with peak temperatures between 123.69°C and 124.14°C which is indicative of Pattern A form and corroborates the XRPD data.
  • the DSC thermograph of lot 21-01-058 G (not Pattern A form, by XRPD) demonstrates a minor endothermic event prior to the main endotherm and is elaborated on below.
  • Figure 72 shows DSC thermograph comparison of 5-MeO- DMT benzoate lot 21-01-058 B, lot 21-01-058 F, lot 21-01-058 K, and lot 21-01-062 G.
  • 5-MeO-DMT benzoate 21-01-058 D solid isolated from exposure of amorphous 5-MeO-DMT benzoate to anisole vapour for 7 days
  • Figure 74 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours).
  • Figure 75 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-058 D, lot 21-01-049 Bl, Pattern B, and lot 21-01-060 Bl, Pattern C (air dried 20 hours).
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01-058 D Figure 76), isolated from amorphous 5-MeO-DMT benzoate exposed to anisole vapour revealed an endothermic event with a peak temperature of 118.58°C. This corroborates the XRPD data, confirming a new version has been isolated.
  • Figure 76 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-058 D, isolated from exposure of anisole vapour to amorphous form.
  • the XRPD pattern of Pattern D form is similar to Pattern C, the toluene hemi-solvate, but with variance in peak position.
  • Amorphous 5-MeO-DMT benzoate exposed to all other solvent vapours returned exclusively Pattern A by XRPD and DSC.
  • Pattern C form was isolated via reverse anti-solvent addition of isopropanol solution of 5- MeO-DMT benzoate to toluene, this solid is believed to be a hemi-solvate which when desolvated afforded Pattern B form.
  • Pattern B form has been accessed by equilibration of 5-MeO-DMT benzoate in anisole and chlorobenzene.
  • Pattern B form may be accessed from anisole and chlorobenzene hemi-solvates, consequently reverse anti-solvent addition to chlorobenzene and anisole is believed to afford a hemi-solvate as with toluene.
  • 5-MeO-DMT benzoate 20/20/150FP2, 650mg was charged to sample vial with IPA, 13ml, and heated to 50°C. The clear solution was clarified through a 0.45pm nylon syringe filter. Anti-solvent, 4ml, was charged to crystallisation tubes and cooled to -10°C with agitation via stirrer bead at 750rpm as detailed in the Table below. IPA stock solution at 50°C, 2ml, was charged to cold anti-solvent, 4ml, at -10°C. Observations are detailed in the Table below, with B, D, and F isolated immediately. Tubes A, C, and E were equilibrated for 3 hours then isolated. Suspensions were transferred to isolute cartridge and dried in vacuo for NMT 60 seconds and analysed immediately, following 4 hours, and 44 hours open to atmosphere. 5-MeO-DMT benzoate 21-01-064 E was damp after air drying for 60 seconds.
  • 5-MeO-DMT benzoate 21-01-064 D was isolated immediately following the formation of the suspension afforded by the addition of concentrated IPA solution to chlorobenzene at -10°C.
  • the XRPD revealed the diffraction pattern of 5-MeO-DMT benzoate lot 21-01-064 D was similar to 21-01-060 Bl (air dried 2 minutes), Pattern C ( Figure 77).
  • Several diffractions including 19 and 20° 20 are slightly higher and lower compared to Pattern C which are not consequences of the sample presentation ( Figure 78).
  • 5-MeO-DMT benzoate lot 21-01-064 D is a new diffraction pattern, and defined herein as Pattern E.
  • Figure 77 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-064 D, and 21-01-060 Bl (air dried 2 minutes).
  • Figure 78 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-064 D, and 21-01-060 Bl (air dried 2 minutes).
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 D revealed a major bimodal endothermic event with peak temperatures of 110.31°C and 113.13°C ( Figure 79), followed by a minor endothermic event with a peak temperature of 119.09°C.
  • Figure 79 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 D at 10°C.min-l.
  • Figure 80 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-064 C, and 21-01-064 D.
  • Figure 81 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-064 C, and 21-01-064 D.
  • the DSC thermograph of 21-01-064 C is similar to that of the thermograph of 21-01-064 D.
  • Figure 82 shows DSC thermograph of 5-MeO-DMT benzoate lot 21-01-064 C at 10°C.min-l.
  • the 1H NMR spectrum of 5-MeO-DMT benzoate lot 21-01-064 C isolated following a 3 hour equilibration revealed the stoichiometry of the salt to be 1:1 and also revealed a salt to solvent ratio for chlorobenzene of 1:0.506 and a salt to solvent ratio for IPA of 1:0.004.
  • the isolated salt is a chlorobenzene hemi- solvate.
  • the XRPD of 5-MeO-DMT benzoate lot 21-01-064 F revealed a diffraction pattern concordant with 21-01-058 D, Pattern D from the vapour diffusion investigation of amorphous 5-MeO-DMT benzoate in anisole, but more crystalline and does not contain minor diffractions characteristic of Pattern A.
  • the XRPD of 5-MeO-DMT benzoate 21-01-064 E revealed a diffraction pattern concordant with 21-01-064 F, Pattern D.
  • the XRPD of 5-MeO-DMT benzoate 21-01-064 E (air dried 4 hours) revealed a diffraction pattern concordant with 21-01-064 E, Pattern D.
  • the XRPD of 5-MeO-DMT benzoate 21-01-064 E (air dried 44 hours) revealed a diffraction pattern concordant with 21-01-064 E, Pattern D but with an additional diffraction at 18.3° 20, which is believed to be an indication of Pattern B.
  • 5-MeO-DMT benzoate lot 21-01-060 A2 was produced by the same methodology as 049 Bl except on a larger scale and afforded an identical product by XRPD and DSC but contained residual IPA by 1H NMR.
  • 5-MeO-DMT benzoate lot 21-01-049 Al was produced by the same methodology as 049 Bl except it was initially dissolved in methanol, XRPD revealed a powder pattern concordant with Pattern B with some Pattern C. 1H NMR revealed a salt to toluene ratio of 1:0.03. DSC examination revealed a similar thermograph to 049 Bl but the first endothermic event at 110°C was larger and the subsequent endothermic melt of Pattern B form is bimodal and peaks at a lower temperature. Following the melt of Pattern B form, Pattern A form crystallises, and melts as expected. 5-MeO-DMT benzoate lot 21-01-060 B2 was produced by the same methodology as 060 A2 but equilibrated for 3 hours before isolation and drying in vacuo. XRPD revealed a mixture of Pattern B with some Pattern
  • 5-MeO-DMT benzoate lot 21-01-060 Al (air dried 20 hours) was produced by the same methodology as 060 A2 but was air dried instead of at 50°C in vacuo.
  • XRPD revealed a mixture of Pattern B and C.
  • 1H NMR revealed a salt to toluene ratio of 1:0.04.
  • 060 Al contained a significant amount more IPA than other samples (1:0.2 instead of 1:0.05). This may have modified the endothermic events during the DSC examination of the sample, but the Pattern A form melt endothermic event is present.
  • 5-MeO-DMT benzoate lot 21-01-047 J was produced by crystallisation from chlorobenzene at 50°C and dried in vacuo at 50°C.
  • XRPD revealed the sample to be a mixture of Pattern B and some Pattern A.
  • DSC examination revealed an endothermic event similar to the endothermic event considered to be loss of toluene, which is believed to indicate the loss of chlorobenzene.
  • the melting endotherm of Pattern B form occurs earlier than for 049 Bl but the crystallisation of Pattern A form is very exothermic and is accompanied by a melt of Pattern A form.
  • Pattern B form material contains a characteristic endo-exothermic event as it melts then crystallises as Pattern A form, Pattern B form is produced by the desolvation of hemi-solvates, therefore an endothermic event characteristic of the residual hemi-solvate is present in all samples isolated.
  • the thermal characteristics will be modified by the loss of toluene.
  • 5-MeO-DMT benzoate lot 21-01-064 B was produced by reverse anti-solvent addition of an IPA solution to toluene.
  • XRPD revealed Pattern C which was supported by a ratio of 1:0.5 of salt to toluene by 1H NMR indicating a toluene hemi-solvate.
  • DSC examination revealed a bimodal endothermic event with peak temperatures of 111.3°C and 112.1°C, this indicates the endothermic event at 111°C in the Pattern B mixtures was a result of residual Pattern C. There were endothermic events indicative of Pattern B form, which suggested transformation to Pattern B form then Pattern A form.
  • 5-MeO-DMT benzoate lot 21-01-064 A was produced by the same methodology as 064 B but was equilibrated for 3 hours before isolation.
  • XRPD and 1H NMR revealed identical characteristics as 064 B.
  • DSC examination revealed a different major multi-modal endothermic event with a peak temperature of 115.0°C.
  • XRPD revealed a mixture of Pattern C and Pattern B for both
  • 1H NMR revealed less toluene in 060 Bl than for 064 A, which is believed to be a result of air drying which supports the presence of Pattern B form in the sample by XRPD.
  • DSC examination revealed an endothermic event with a peak temperature of 111.3°C for both, followed by multiple unique endothermic events.
  • XRPD revealed a mixture of Pattern C with some Pattern B.
  • DSC examination revealed a broad exothermic event between 105 and 113°C followed by a weak endothermic event indicative of Pattern C form and endothermic events indicative of Pattern B form.
  • the change to the heating rate is the cause of the change to thermal behaviour, as the DSC thermograph of 21-01-064 A (44 hour air dried) sample is similar to 21-01-064 A the transformation of Pattern C form occurred in situ during the examination.
  • 5-MeO-DMT benzoate 21-01-060 Al air dried 1 hour was produced by the same methodology as 064 A but isolated immediately.
  • XRPD revealed a mixture of Pattern C and some Pattern B.
  • DSC examination revealed a thermograph indicative of Pattern B form with a minor exothermic event at ca 109°C.
  • 5-MeO-DMT benzoate Pattern C form is a toluene hemi-solvate it has no characteristic endothermic event except for a melt between 110°C and 115°C.
  • the XRPD pattern of the toluene hemi-solvate of 5-MeO-DMT benzoate is distinct to 5-MeO-DMT benzoate. Desolvation may occur under ambient conditions and it is considered that Pattern B form is produced. The thermal characteristics will be influenced by the loss of toluene during DSC examination.
  • 5-MeO-DMT benzoate lot 21-01-064 E was produced by reverse anti-solvent addition of an IPA solution to anisole, then equilibrated for 3 hours before isolation.
  • XRPD revealed Pattern D but this was not supported by 1H NMR which revealed a ratio of salt to anisole of 1:1.04, the isolated solid was damp after isolation.
  • DSC examination revealed very poorly defined broad endothermic events with peak temperatures of 113.51°C and 161.93°C, the endothermic event at 113.51°C is believed to be a result of the melting of the hemi-solvate present by XRPD followed by evaporation of anisole.
  • the DSC thermograph is not considered representative of Pattern D form due to the solvent content.
  • 5-MeO-DMT benzoate lot 21-01-058 D was produced by exposure of the amorphous form to anisole vapour.
  • XRPD revealed a mixture of Pattern D and some Pattern A diffractions which was supported by 1H NMR which revealed a ratio of salt to anisole of 1:0.47 indicating an anisole hemi-solvate.
  • DSC examination revealed an endothermic event with a peak temperature of 118.6°C, which is concordant with the data collected from 064 F.
  • the melt of Pattern A form is not revealed in the DSC thermograph, this could be modified by the liberated anisole solvent present in the sample.
  • 5-MeO-DMT benzoate lot 21-01-064 E air dried 4 hours was produced by air drying 064 E for 4 hours.
  • DSC examination was performed at 2.5°C.min-l with the aim to resolve the bimodal endothermic event observed in the thermograph of 064 E.
  • DSC examination revealed a minor endothermic event with a peak temperature of 111.24°C, this endothermic event is concordant with the broad endothermic event observed in 064 E. The better resolution of this endothermic is believed to be a result of the slower heating rate, or due to removal of residual anisole by air drying.
  • Pattern D form is an anisole hemi- solvate and has been produced directly from exposure of the amorphous form to anisole vapour as well as reverse anti-solvent addition from an IPA solution to cold anisole. No characteristic thermal behaviour has been identified although, endothermic events near 118°C are common and the lack of recrystallisation to Pattern B or A forms is believed to be due to the presence of residual anisole.
  • the Table below is a summary of predominantly Pattern E form compositional and crystallographic characteristics.
  • the table below is a summary of predominantly Pattern E form thermal characteristics, the endothermic event at 123.7°C is characteristic of Pattern A.
  • 5-MeO-DMT benzoate lot 21-01-064 D was produced by reverse anti-solvent addition of an IPA solution to chlorobenzene.
  • XRPD revealed Pattern E, this was supported by 1H N MR which revealed a ratio of salt to chlorobenzene of 1:0.506 indicating a chlorobenzene hemi-solvate.
  • DSC examination revealed a bimodal endothermic event with peak temperatures of 111.3°C and 113.1°C, followed by a minor endothermic event with a peak temperature of 119.1°C.
  • 5-MeO-DMT benzoate lot 21-01-064 C was produced by reverse anti-solvent addition of an IPA solution to cold chlorobenzene, then equilibrated for 3 hours before isolation.
  • 5-MeO-DMT benzoate lot 21-01-064 C air dried 44 hours was produced by air drying 064 C (air dried 4 hours) for a further 40 hours.
  • XPRD revealed Pattern E DSC examination revealed a bimodal endothermic event with peak temperatures of 115.1°C and 115.8°C. The endothermic event of 064 C (air dried 44 hours) is similar to 064 C but peaks at a slightly higher temperature.
  • 5-MeO-DMT benzoate Pattern E form is a chlorobenzene hemi-solvate with no defined thermal characteristics except for a multi-modal endothermic event between 110 and 117°C. Similarly, to the anisole hemi-solvate, Pattern A and B forms do not recrystallise from the melt. Chlorobenzene hemi-solvate appears to not desolvate when open to ambient conditions and did not desolvate over 44 hours.
  • the DSC thermograph of the hemi-solvates were similar to those isolated from IPA/antisolvent but with minor differences which are considered to be a consequence of how they were prepared. Drying 5-MeO-DMT benzoate toluene hemi-solvate and chlorobenzene hemi-solvate in vacuo at 50°C for 67 hours afforded Pattern A form, but the anisole hemi-solvate afforded predominantly Pattern B form. Addition of 5-MeO-DMT benzoate/IPA solution to toluene at -10°C then air dried for 5 minutes afforded the toluene hemi-solvate when performed on a lg input.
  • 5-MeO-DMT benzoate methyl benzoate hemi-solvate (Pattern F form) has been isolated from controlled cooling of a clarified 5-MeO-DMT benzoate methyl benzoate solution from 50°C to -10°C.
  • 5-MeO-DMT benzoate 2- chlorotoluene hemi-solvate (Pattern G form) has been isolated from controlled cooling of a clarified 5-MeO-DMT benzoate 2-chlorotoluene solution from 80°C to -10°C. Equilibration in a,a,a-trifluorotoluene did not afford a hemi- solvate as anticipated from a monosubstituted aromatic solvent.
  • Pattern B form which indicated a cumene hemi-solvate.
  • DVS examination of amorphous 5-MeO-DMT benzoate revealed a weight loss of ca. 2% indicating the elimination of a component and confirming that a stable hydrate of 5-MeO-DMT benzoate was not isolated.
  • Pattern A form is the most stable version of 5-MeO-DMT benzoate and is the thermodynamically favoured product except when isolated from a small selection of solvents, which afforded the respective hemi-solvate.
  • Stability studies revealed conversion of all patterns to Pattern A form when dried in vacuo at 50°C. However, Pattern B form has been shown to be stable when open to atmosphere at ca. 20°C for up to 12 days.
  • Pattern C form underwent partial conversion to Pattern B form within 24 hours when open to atmosphere at ca. 20°C, but failed to convert any further from a Pattern B/C mixed version over an additional 11 days.
  • FTIR spectra for Patterns A, B and C were overall similar though there were some unique bands in Pattern A form and absent bands that were otherwise present and shared by Patterns B and C forms. Controlled cooling crystallisation investigation with an expanded solvent selection
  • Sample F isolated from methyl benzoate was a thick white paste after air drying for 5 minutes and was left to air dry on the XRPD sample holder for a further 30 minutes which then afforded a dry powder.
  • 5-MeO-DMT benzoate lots 21-01-073 B, C, D, E, G, H, and L were isolated from n-propyl acetate, isopropyl acetate, iso-butyl acetate, ethyl formate, methyl propionate, 4-methyl-2-pentanone, and a,a,a-trifluorotoluene respectively.
  • the XRPD of these samples revealed powder patterns concordant with 5-MeO-DMT benzoate lot 20-37-64, Pattern A.
  • the DSC thermograph of a selection of pattern A material revealed a common endothermic event with a peak temperature ranging from 123.07°C to 124.17°C with an enthalpy of ca.
  • Figure 83 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 A, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01-073 A revealed an endothermic event with a peak temperature of 123.58°C, this is characteristic of Pattern A form.
  • the 1H NMR spectrum of 5-MeO-DMT benzoate lots 21-01-073 A isolated following controlled cooling, then air dried for 5 minutes revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio of methyl acetate of 1:0.033.
  • 5-MeO- DMT benzoate lot 21-01-073 F was isolated from controlled cooling of a methyl benzoate solution from 50°C to - 10°C, then air dried for 5 minutes. After air drying for 5 minutes the sample was a paste, air drying further for 30 minutes afforded a damp powder.
  • the XRPD of 5-MeO-DMT benzoate lot 21-01-073 F revealed an XRPD pattern with an amorphous halo ( Figure 84). The sample was re-run after further air drying.
  • the XRPD of 5-MeO-DMT benzoate 21-01-073 F (re-run) revealed a diffraction pattern concordant with the initial measurement but with a reduced amorphous halo ( Figure 85).
  • Pattern F form The diffraction pattern demonstrated some similarities with both Pattern A and B ( Figure 86) but the presence of unique diffractions and absence of characteristic Pattern A and Pattern B diffractions indicate this material to be a unique solid form version, identified herein as Pattern F form.
  • Figure 84 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 F and 21-01-073 F rerun.
  • Figure 85 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 F rerun, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
  • Figure 86 shows XRPD pattern expansion comparison of 5-MeO-DMT benzoate lot 21-01-073 F rerun, 21-01-049 Bl, Pattern B, and 20-37-64, Pattern A.
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01- 073 F revealed a broad endothermic event with a peak temperature of 90.50°C, this was followed by a small endothermic event with a peak temperature of 106.65°C. This was followed by a broad and shallow endothermic event with a peak temperature of 180.35°C. DSC examination was repeated after the sample was stored in a sealed container for 24 hours.
  • the DSC thermograph revealed a major endothermic event with a peak temperature of 95.33°C, followed by an exothermic event with a peak temperature of 102.70°C. This was followed by an endothermic event with a peak temperature of 113.77°C.
  • 5-MeO-DMT benzoate lot 21-01-073 I was isolated from controlled cooling of a 5-MeO-DMT benzoate cumene solution from 50°C to -10°C, then air dried for 5 minutes.
  • the XRPD of 5-MeO-DMT benzoate lot 21-01-073 I revealed the diffraction pattern was concordant with SPS552021-01-049 Bl, Pattern B.
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01-073 I revealed an endothermic event with a peak temperature of 109.24°C with a broad shoulder at ca. 100°C.
  • 5-MeO-DMT benzoate lots 21-01-073 I isolated following controlled cooling, then air dried for 5 minutes revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio of 1:0.035.
  • 5- MeO-DMT benzoate lot 21-01-073 J was isolated from controlled cooling of an 5-MeO-DMT benzoate toluene solution from 50°C to -10°C, then air dried for 5 minutes.
  • the XRPD of 5-MeO-DMT benzoate lot 21-01-073 J revealed the diffraction pattern was concordant with 5-MeO-DMT benzoate lot 21-01-064 A, Pattern C.
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01-073 J revealed an endothermic event with peak temperatures of 110.00°C, 115.03°C, and 120.60°C.
  • the DSC thermograph is similar to 5-MeO-DMT benzoate lot 21-01-071 Cl, previously isolated Pattern C form material, although the minor peaks are different which is believed to be a consequence of sample preparation.
  • the 1H NMR spectrum of 5-MeO-DMT benzoate lots 21-01-073 J isolated following controlled cooling, then air dried for 5 minutes revealed the stoichiometry of the salts to be 1:1 and also revealed a salt to solvent ratio of 1:0.473, confirming the isolation of the Pattern C form toluene hemi-solvate.
  • 5-MeO-DMT benzoate lot 21-01-073 K was isolated from controlled cooling of an 5-MeO-DMT benzoate 2- chlorotoluene solution from 50°C to -10°C, then air dried for 5 minutes.
  • the XRPD of 5-MeO-DMT benzoate lot 21- 01-073 K revealed a diffraction pattern that was unique ( Figure 87) and is herein identified as Pattern G.
  • Figure 87 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-073 K, 21-01-049 Bl, Pattern B, and 20-37-64.
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01-073 K revealed an endothermic event with peak temperatures of 111.28°C and 119.61°C.
  • Example 31 DVS examination of amorphous 5-MeO-DMT benzoate produced via lyophilisation
  • 5-MeO-DMT benzoate 20/20/150FP2, 150mg was dissolved in deionised (DI) water, 5ml affording a clear solution.
  • DI deionised
  • the solution was clarified into a 500ml round bottom flask, the round bottom flask was rotated in an acetone/dry ice bath to freeze the solution in a thin layer around the flask. The ice was sublimed in vacuo at ambient temperature affording a fluffy white solid. The solid was removed from the round bottom flask and transferred to the DVS instrument. During this transfer, the solid collapsed to a sticky gum.
  • the sample was examined by DVS from 40% RH and cycled between 0%RH and 90%RH twice.
  • XRPD was collected on a portion of the sample post-lyophoilisation and post-DVS examination.
  • the XRPD of 5-MeO-DMT benzoate before DVS analysis revealed an amorphous diffraction pattern which was expected ( Figure 88).
  • Figure 88 shows XRPD of 5-MeO-DMT benzoate lot 21-01-078.
  • the DVS examination demonstrates an initial weight reduction of ca. 1.4% from the start of the investigation during the first desorption cycle (Figure 89) which was much lower than the 5 wt% required for a 5-MeO-DMT benzoate monohydrate.
  • Weight reduction continues despite the RH increasing to 70 %RH during the first sorption. At 80 and 90 %RH on the first sorption cycle, there is a small increase in weight. Following this there is a weight reduction to the minimum on the second desorption cycle, on the subsequent sorption cycle there is no change in weight until 50 %RH, between 50 %RH and 90 %RH there is a weight increase of 0.2%.
  • Figure 89 shows DVS isothermal plot of 5-MeO-DMT benzoate lot 21-01-078.
  • Figure 90 shows XRPD pattern comparison of 5-MeO-DMT benzoate lot 21-01-078 (post-DVS) and 20-37-64.
  • Amorphous 5-MeO-DMT benzoate is unstable and undergoes transformation to Pattern A form under all conditions studied. Under ambient conditions it is believed that the amorphous version uptakes moisture from the atmosphere which is eliminated from the sample following conversion to Pattern A form.
  • Example 32 FTIR spectroscopy of 5-MeO-DMT benzoate Patterns A, B and C
  • Figure 91 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl).
  • Figure 92 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20- 20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl) at 450 to 2000 cm-1.
  • Figure 93 shows FTIR overlay of 5-MeO-DMT benzoate Pattern A form (20-20-150FP2), Pattern B form (21-01-071 C2) and Pattern C form (21-010071 Cl) at 450 to 2000 cm-1; spectra separated.
  • Pattern A form demonstrates a number of bands of significantly different intensity compared to Patterns B form and C form. Such notable bands were observed at ca. 3130, 1540, 1460, 1160 and 690 cm-1, whilst key absent (or significantly reduced intensity) bands present in Patterns B and C included those observed at ca. 3230 and 1640 cm-1. Patterns B and C forms demonstrated far fewer differences in their FTIRs to one another, as when compared to the FTIR of the Pattern A form.
  • Pattern C form hemi-solvate desolvates somewhat readily to afford the Pattern B form, resulting in a relatively small change to the crystal lattice compared to the energy required (i.e.; drying in vacuo at elevated temperature) to induce conversion of Pattern B form to Pattern A form, restructuring the crystal lattice to a greater extent than facile desolvation.
  • Pattern C form in vacuo at 50°C for 24 hours historically often afforded Pattern B form and Pattern B form is known to transform to Pattern A form at 90°C as observed by hot stage microscopy.
  • the stability of Pattern A form and Pattern B form under both atmospheric conditions and in vacuo at 50°C was investigated to determine the relationship between the forms.
  • Example 34 Competitive equilibration of5-MeO-DMT benzoate Pattern A, B, and C forms in solvents
  • Pattern A, B, and C forms The relationship between 5-MeO-DMT benzoate Pattern A, B, and C forms was investigated to determine the thermodynamically stable version and hierarchy.
  • Competitive equilibration was conducted between Pattern A and B forms, and Pattern A and C forms in a variety of solvents including IPA and toluene.
  • Pattern A form was expected to be the most stable form given its melting point of 124°C and prevalence during most investigations performed.
  • 5-MeO-DMT benzoate 20/20/150FP2 Pattern A form, 15mg, was charged to all crystallisation tubes.
  • 5-MeO-DMT benzoate lot 21-01-071 C2 Pattern B form, 30mg, was charged to AB crystallisation tubes.
  • Solvent, 0.5ml was charged to crystallisation tubes as detailed in the Table below.
  • Suspensions were agitated at lOOrpm at 20 ⁇ 2°C for 24 hours.
  • Suspensions were isolated via isolute cartridge and air dried for 5 minutes and characterised by XRPD and DSC. The XRPD of all samples revealed the majority gave Pattern A.
  • Sample AC5 isolated from MEK revealed an additional diffraction at 8.8 °20 however this was considered to be caused by the splitting of the diffraction at 9 °20 due to better resolution between diffractions of this sample.
  • the DSC thermograph of most Pattern A form samples revealed an endothermic event with peak temperatures ranging from 123.74°C to 124.22°C which is indicative of Pattern A form.
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01-079 AB2 revealed a bimodal endothermic event with peak temperatures of 114.96°C and 121.92°C.
  • the thermal characteristics are similar to previously isolated pattern C samples, including 5-MeO-DMT benzoate lot 21-01-073 J.
  • the DSC thermograph of 5-MeO-DMT benzoate lot 21-01-079 AC2 revealed a minor endothermic event with a peak temperature of 110.11°C, followed by overlapping endothermic and exothermic events between 110.73°C and 113.23°C. This was followed by an endothermic event with a peak temperature of 122.82°C, this endothermic event is comparable to the melt of Pattern A form when recrystallised from Pattern B form.
  • the physical surroundings of the participant/patient/subject are of high importance in the character of many psychedelic experiences.
  • the space should be private, meaning that there should be no chance of intrusion by others. Ideally, sound from outside (e.g. the hallway, the street, etc.) will be minimal.
  • the dosing sessions should take place in rooms that feel like a living room or den rather than a clinical setting. Artwork, plants, flowers, soft furniture, soft lighting, and related decor should be employed in creating a cozy and relaxing aesthetic. Artwork with any specific religious iconography, ideological connotation, or tendency to evoke negative emotions should be avoided.
  • the dosing room may also provide comfortable furniture for the participant and the therapists, who may sit on either side of the participant.
  • the room should shield the participant from sights and sounds of the world beyond the room, and the participant should not have any cause for concern of observation or interruption by anyone other than the therapists.
  • the space may also contain:
  • Audio and video-recording equipment If allowed in the study protocol the participant will have already consented to being recorded, and should be made aware of the equipment, but it should be placed to be as unobtrusive as possible. Participants may request the cessation of recording at any time. Physical Space
  • the space may be large enough to accommodate chairs for two therapists, the stereo equipment and cabinet for storage of the participant's belongings and any extra supplies the therapists may need during the day.
  • the space may accommodate a bed or couch on which the participant can either sit up or lie down with a comfortable surroundings of pillows.
  • the space may be at least 100 2 feet or 10 2 meters so that participants do not feel cramped or too physically close to therapists. Participants should have room to explore a variety of positions including sitting on the floor or stretch their bodies without restriction. A bathroom should be either accessible directly from the session room or nearby.
  • 5-MeO-DMT sessions may use a pre-set playlist of nature sounds for creating a calm atmosphere. These nature sounds are considered to be a background element, helping drown out any noise from outside the room, and keep the participant focused on their experience. Participants are not instructed to listen to the sounds in any particular way, but may be asked to focus on it as a way of grounding their senses and relaxing before or after session.
  • Medication discontinuation can be challenging for participants. Participants are to have discontinued all contraindicated medications and completed washout periods prior to Prep-1 with the therapist.
  • the study team members, including the therapist, may provide supportive check-in calls with the participant prior to this, as-needed during the washout period, but should not start Prep-1 until washout is complete and the participant confirms intention to continue with the therapy.
  • This treatment model includes three, 60-90 minute preparatory sessions with the therapist. These take place 7 days, 4 days, and 1 day before the 5-MeO-DMT session. Preparatory sessions are designed to take place via telemedicine, but can be in-person if possible.
  • the therapist will spend some of the preparation session time getting to know the participant.
  • the therapist may ask open-ended questions about:
  • the therapist should be listening for how the participant talks about themselves and their relationship to their depression, how they relate to the therapist and study environment, and stay attuned to establishing a sense of trust and rapport with the participant. Clinical impressions of difficulty forming a trusting relationship with the therapist or any other clinical factors that could interfere with the participants' ability to engage in the treatment should be noted and discussed with the study team. Although in the preparatory session stage, the therapist may learn more of the participant that could be reasons for study exclusion.
  • the therapist should explain the therapeutic model used in this research study to the participant in the first preparation session.
  • the explanation should include:
  • That the therapy is:
  • the therapist establishes the environment of physical, emotional, and psychological safety.
  • the therapist explains the safety of 5-MeO-DMT and the safety procedures relevant to the participant's physical health for the session.
  • emotional safety the therapist states that all emotional experiences are welcomed, that there is no area of experience that the participant is not welcome to share.
  • Safety can also be established through the calm reassuring presence of the therapist, which does not always require the use of language.
  • Psychological/relational safety is established by assuring the participant that their wishes will be respected with regards to the use of touch. Also, the participant is to be reassured that if they choose not to participate in the 5MDE experience they may do so at any point up until drug administration and that this will be respected, and that the therapy sessions will still be available to them if they make that choice.
  • the therapist can use the following techniques to establish safety with the participant:
  • Non-ordinary state of consciousness was often associated with experienced engendered by psychedelic compounds. However, alterations of consciousness are experienced on a daily basis, as moods or feelings shift, or when people shift from awake alertness to feeling tired and drowsy. "Non-ordinary state of consciousness” emphasizes the quality of an experience that is not ordinarily had on a daily occurrence, but can still be within human experience.
  • the therapist may begin this conversation by asking the participant about their existing knowledge of 5-MeO-DMT effects, and listen for specific expectation or ideas about it.
  • the therapist is to encourage an attitude of openness toward the experience, encouraging participants to explore what kinds/ideas they may have and be open to the possibility that it will not be possible to imagine what this will be like. Participants may have specific expectations based on the media, prior experience with 5-MeO-DMT or other psychedelics, or other kinds of non-ordinary states of consciousness. It is important for therapists to provide a balanced description of what the participant may experience.
  • Participant's social support may be assessed during preparation sessions and be determined by the therapist to be adequate to support the patient through the process of change, especially in the event of either disappointment or dramatic symptom reduction.
  • the study therapist may, with the participant's permission, have a phone call with the participants therapist to describe the nature of the study and therapeutic approach and answer any questions the therapist may have.
  • the study therapist may also educate any friends or family members who are close to the participant and have questions regarding the nature of the study, the 5-MeO-DMT experience, and what to expect.
  • the therapist should discuss social support with the participant including preparing the participant for the variety of reactions their friends and family may have.
  • Therapists may advise participants to take caution around posting about their experience on social media so as not to elicit excessive public commentary. Inadequate social support or use of social media in a way that may be disruptive to the therapeutic process may be discussed and resolved prior to 5-MeO-DMT administration.
  • the therapist should explain that on the day of the session that a member of the research team will enter the room briefly to administer the study drug.
  • the therapist should explain the participant positioning, e.g. they will be in a seated position on the bed or couch, that the research team member will insert the nasal spray device in one nostril, and that they will be asked to allow the therapist to assist them in lying down on the bed or couch immediately afterward.
  • Session procedures including boundaries, use of touch, safety, etc.
  • the therapist will explain the process of the session.
  • the session is contained by the timing of the dosing and the physical environment of the dosing room. It begins when the participant enters the room and engages with the therapist in the Session Opening. Session Opening is a formal moment in which the participant and therapist sit together in the room, all preparations having been made, and playlist started. The therapist may lead a breathing exercise of the participant's choice, if the participant is open to engaging in one, and ask the participant to reflect on the values they choose in the preparation session, or any other value or intention that is important to them. Once the participant signals that they are ready, a member of the research team will administer the nasal spray to the participant.
  • Trust and safety are not only communicated verbally, but also this may be nonverbally through how a therapist holds themselves in the presence of the participant. If a therapist is overly anxious, or fearful, this may be felt by the participant. It is important that the therapist is centered throughout the dosing session, particularly at times when a participant is expressing intense affect, unusual somatic expressions, or is asking for support.
  • Some participants may experience an intensified awareness of their body such as feeling their heart rate more strongly or physical sensations in their temple. Other participants may be aware of a tingling in their body, changes or perceived difficulty breathing, or other unusual physiological experiences. It is important for the therapist to communicate that these changes in perception are normal and should not be a focus of preoccupation or fear. If these sensations arise, the participant should be encouraged to communicate these to the therapist, if they so desire. The therapist should reassure the participant that these sensations are expected and are normal to have. The therapist can inform and remind the participant that naturally occurring 5-MeO-DMT has been consumed in other settings for hundreds of years with no indication that it is physically harmful, and that these changes are expected and will resolve shortly.
  • Expectations can be defined as mental representations and beliefs of how something in the future will be. Sometimes expectations can be explicitly identified, and sometimes they are subperceptual, taken for granted. Both kinds of expectations may be important to treatment.
  • the therapist should ask about explicit expectations and encourage the participant to acknowledge and set these aside such that they do not engage in comparing their experience to expectations.
  • the therapist is also listening for subperceptual expectations that may come into awareness through the therapy.
  • Intentions are ways of relating to a behaviour or experience.
  • the 5-MeO-DMT treatment it can be important for the therapist to elicit and understand the participant's intentions as these can vary greatly and may be taken for granted.
  • Therapists are to engage participants in a process of identifying and setting their intentions such that these are explicit and can be referenced later in integration. The purpose of the intention is for it to be identified and then let go of, with the knowledge that it can be part of the 5MED.
  • Therapeutic touch is touch that is intended to connect with, sooth, or otherwise communicate with the participant for therapeutic aims. It is always fully consensual, non- sexual, and the participant is encouraged to decline or cease therapeutic touch at any time.
  • Touch for safety reasons can include supporting a participant who is having trouble walking by offering an arm to hold, or blocking a patient back from leaving the room while under acute drug effects. This touch is agreed to in advance, is always non-sexual, and limited to specific safety concerns. Therapists should discuss both of these and establish boundaries with participants ahead of session.
  • Participants should be encouraged to take some time to rest and integrate their experience after their session day. Study therapists should ask participants to plan for time off after their session, at least the full day of the session and the day after the session. Therapists should explain that after the acute effects of the 5-MeO-DMT have worn off they will stay together in the room for a while. This period of time will be for the participant to readjust to their experience after the acute effects. They will be asked to share what they can recall about their experience and any reactions they have. They will not be asked to share anything they don't want to share, and are welcome to keep their experience private. They may choose to write or draw about their experience, art supplies and writing supplies will be available.
  • Breathing practices include: Balancing Breath, Diaphragmatic Breath and Counted Breath.
  • the therapeutic protocol may use a customized Personal Values Card Sort to assist with the therapeutic focus on shift in sense of self. This is done by asking about how people relate to their chosen values before the session, and how they relate to them afterward, drawing attention to shifts, changes, and using these as a guide for the kind of changes the participant may desire to make. It is used as a way to elicit conversation about the participant's sense of self, beliefs about self, and changes in those senses/beliefs throughout the therapy. Therapists may engage participants in the card sort exercise in the third preparation session such that it occurs 1-2 days before the dosing session.
  • the session may be conducted by the therapist with an assistant therapist such that a second person is available to assist in case of any adverse event or physical complication in the participant's safety.
  • the assistant who will be present for the session should be introduced in Prep Session 3 and included in a conversation such that they get to know the participant.
  • the therapist is present with the participant during the session — including pre-experience and post-experience times. This is the only session that must be conducted in-person.
  • the site and therapist should schedule about 3 hours for the session, including pre-experience and post-experience time. This does not include the time allotted to engage in baseline measures and enrolment confirmation prior to the session.
  • Local regulatory approvals will determine the minimum length of time a participant must be under observation following 5-MeO-DMT administration.
  • the Therapist, Assistant Therapist, and participant together in the room review all aspects of the room and safety procedures.
  • the therapist should introduce the participant to the team member administering the 5- MeO-DMT, to create a sense of familiarity.
  • Therapist introduces any Assistant Therapist and reviews safety features of the room and the equipment present.
  • Participant has time to ask any questions. The therapist will ask about any responses to the situation and how the participant is feeling about their session. The participant should not be rushed into the dosing by the therapists. The therapist will ask the participant to engage in a period of relaxation prior to dosing.
  • Participant will be asked to lie down, close their eyes, listen to the music, and, if willing, engage in at least one of the breathing exercises with the therapist's guidance. When the participant is settled and comfortable, the therapist will initiate the Session Opening. This practice helps contain and emphasize the specialness of the experience. Therapists will contact the member of the research team to come to the room and administer the 5-MeO-DMT. The team member should be aware not to disrupt the peaceful atmosphere of the room. The participant should be in a seated position when insufflating the 5-MeO-DMT, as the effects may be felt quickly, the participant should be transitioned to a prone position and remain prone for the duration of the effect of the 5-MeO-DMT.
  • This may be in the form of slow intentional inhaling and exhaling, or any other activity that helps the therapist ground and self-regulate. This is both for the therapist's benefit, as well as the participants', because a participant in a heightened non-ordinary state may be particularly attune to or pick up on their therapist's anxiety. It is optimal for the therapist to follow the participant's lead when choosing to verbally engage as the 5- MeO-DMT experience appears to be subsiding. Therapists may be eager to ask the participant about their experience, but it is preferable to wait until the participant is ready to share on their own. A participant may wish to remain in a period of silence, even after the apparent acute 5-MeO-DMT effect is gone. It is appropriate for therapists to greet participants with a friendly smile and welcoming nonverbal behaviour, and allow participants to take the lead on sharing when they feel ready.
  • the Therapist will encourage the participant to stay with their experience for a period of time of at least one hour after the acute effects of the 5-MeO-DMT have worn off and the participant is once again aware of their surroundings and situation in the treatment room.
  • To stay with the experience means to continue directing attention toward it in whatever way feels most appropriate to the participant, without turning to engagement in distractions, entertainment, or the concerns of daily life.
  • the therapist will invite the participant to describe their experience, if they choose to, and respect the choice not to if the participant is unready. If the participant does describe their experience the therapist is to listen and encourage the participant to express whatever they would like to share without interpretation or attempts to make meaning. The therapist practices simply listening, encouraging the participant to describe what they can about the experience.
  • the therapist also offers the participant the option of resting and listening to the music, or to write about or draw any aspects of the experience they desire. At the end of this time period, the therapist will verify with the participant that they feel ready to close the session, will engage in the Session Closing, and contact the study team for exit assessment.
  • the key principle of integration sessions is to help the participant focus on shifts in their perception of themselves and the implications of these as they relate to their depression.
  • Self for the purpose of this study, is broadly defined as the narrative or historical self, the sense of a coherent "I" that moves through experiences, and the self-identities one may use. It is key to remember that the sense of self, or the "I,” is reflected in both the experiencer's selfexperience and experience of the object of experience, therefore descriptions may, on the surface, be of changes in the perception of the external world, but reflect shifts in the internal processes. To this end, the following therapeutic tasks will guide the integration sessions.
  • the sessions are less structured than preparatory sessions to accommodate variations in participant responses. There are three tasks: The first should occur at all sessions, the second and third may be introduced and engaged in if and when the participant is ready and willing. The tasks are:
  • Therapists ask open-ended questions about the participant's experience and listen with non-judgmental curiosity to the participant's descriptions. Therapists ask only that participants focus on the 5MDE and related material, such that their time together is focused on the treatment. Therapists should focus inquiry on the participant's experience, asking them to tune into any aspect of the three types of sense of self they can identify.
  • the therapist will reintroduce the values identified in the Values Card Sort from preparation and bring discussion back to them if and when appropriate in the integration sessions. There is by no means a requirement to engage in the structured discussion of the values, but it serves as a framework where needed to direct the focus of sessions toward participants' shift in sense of self.
  • the therapist may ask for example, to reintroduce the values:
  • the therapist can for example continue to focus on shifts in how the participant is relating to his value of "Family" by enquiring about what he is noticing in this area. Create ways the participant can act to enhance their relationship to their chosen values; identify value-oriented action in their life as an integration practice. Integration can be understood as a process of embodying or living out the insights one has. In at least one of the integration sessions, the earliest the therapist feels the participant can engage in this stage, the therapist should introduce the idea of identifying value-oriented actions they can take in their lives as integration practices.
  • the therapist can invite the participant to recall the values they identified (or any other that is important to them), recall the insights or experiences of their 5-MeO- DMT session, and think creatively about things they might try intentionally doing differently in order to implement positive change in their relationship to the values based on those insights and experiences
  • a method of administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient who is diagnosed with depression comprising:
  • the forced swim test is a model of behavioural despair and is sensitive to detection of various classes of antidepressant drugs.
  • CCAC Canadian Council on Animal Care
  • mice Male CD-I mice from Charles River Laboratories (St. Constant, Quebec, Canada) served as test subjects in this study. Animals generally weighed 25-30 g at the time of testing.
  • mice received the appropriate dose of vehicle, test article, or positive control (treatments summarized above). Following the appropriate pre-treatment time, animals were gently placed into tall glass cylinders filled with water (20-25°C). After a period of vigorous activity, each mouse adopted a characteristic immobile posture which is readily identifiable. The swim test involves scoring the duration of immobility. Over a 6-minute test session, the latency to first immobility is recorded (in seconds). The duration of immobility (in seconds) during the last 4 minutes of the test is also measured. Activity or inactivity from 0-2 minutes is not recorded.
  • Latency to immobility vehicle: 95.5 ⁇ 4.6 seconds - 5-MeO-DMT benzoate 121.8 ⁇ 22.0 seconds (0.5 mg/kg), 120.9 ⁇ 13.3 seconds (1.5 mg/kg), 85.0 ⁇ 9.5 seconds (5 mg/kg), imipramine 268.6 ⁇ 30.3 second, Figure 95).
  • the objective of this toxicokinetic study was to assess and compare the toxicokinetic profile of the test items, 5- MeO-DMT-HCI (in a vehicle of 0.1% metolose, Group 2) and 5-MeO-DMT-benzoate (in a vehicle of 0.2% metolose + 0.01% BZK, Group 4).
  • the vehicle or active test item formulations were administered to male Beagle dogs intranasally, at a dose level of 0.4mg/kg in the active groups (corresponding to freebase).
  • a series of blood samples was collected from each dog at the following time points: pre-dose (0), 2, 5, 8, 10, 15, 30 and 60 minutes, and 2- and 8-hours post-dose. Plasma samples were analysed for quantification of concentration of 5-MeO-DMT in each sample using a validated method.
  • a polymorph of 5-MeO-DMT benzoate as characterised by an XRPD pattern as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a polymorph of 5-MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a polymorph of 5-MeO-DMT benzoate as characterised by one or more endothermic events in a DSC thermograph as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a polymorph of 5-MeO-DMT benzoate as characterised by TGA thermograph as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a polymorph of 5-MeO-DMT benzoate as characterised by a DVS isotherm profile as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a polymorph of 5-MeO-DMT benzoate as characterised by a crystalline appearance as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a polymorph of 5-MeO-DMT benzoate as characterised by a particle size distribution as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a polymorph of 5-MeO-DMT benzoate as characterised by a FITR spectra as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a polymorph of 5-MeO-DMT benzoate produced as previously or subsequently described.
  • a method of producing a polymorph of 5-MeO-DMT benzoate as previously or subsequently described is provided.
  • composition comprising a polymorph of 5-MeO-DMT benzoate as previously or subsequently described.
  • a 5-MeO-DMT benzoate solvate as characterised as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • a 5-MeO-DMT benzoate hemi-solvate as characterised as substantially illustrated in any one of the Figures or as previously or subsequently described.
  • compositions as herein described for the manufacture of a medicament for the treatment of any one of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, treatment resistant depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders.
  • sleep regulation such as insomnia
  • analgesics such as chronic pain
  • migraines migraines
  • trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform
  • sleep regulation such as insomnia
  • analgesics such as chronic pain
  • migraines migraines
  • trigeminal autonomic cephalgias such as short-lasting unilateral neuralg
  • Pattern H is demonstrated to be metastable and to undergo conversion to Pattern A via solvent equilibration.
  • Pattern B and Pattern H samples (ca. 20 mg of each) were also amassed in the same set of solvents (400 pl, 10 volumes) to assess the proposition that there might be an enantiotropic relationship between Pattern B and Pattern H.
  • Pattern H is characterised by an XRPD as substantially illustrated in Figure 97.
  • lots 8006740000 and 8006740000 PSR are Pattern H
  • 5520-5-2 and 5520-5-2 PSR are Pattern A
  • 19-29-115 A is Pattern H but 19-29-115 A
  • PSR is a mixture of Pattern H and Pattern A and 19-29-118A and 19-29- 118A PSR are Pattern H.
  • Pattern H is characterised by a succinct melt-endo-exo crystallisation event from Pattern H to Pattern A at a l°C/Min heating rate.
  • Pattern H is characterised by a DSC thermograph as substantially illustrated in Figure 98.
  • Pattern H is characterised by a DSC thermograph as substantially illustrated in Figure 99. In an embodiment, Pattern H is characterised by a DSC thermograph as substantially illustrated in Figure 100. In an embodiment, Pattern A is characterised by FTIR spectra as substantially illustrated in Figure 104. In an embodiment, Pattern H is characterised by FTIR spectra as substantially illustrated in any one of Figures 101,102 and 103. In an embodiment, Pattern H is characterised by highly coloured large crystals >200 microns. In an embodiment, Pattern H is characterised by irregularly shaped blue coloured small crystals ca.20-100 microns. In an embodiment, Pattern A is characterised by rhombic shaped non birefringent large crystals ca. 400 microns. In an embodiment, Pattern H is obtained following manufacture of 5- MeO-DMT benzoate in isopropyl acetate.
  • a sub-lingual formulation comprising 5-MeO-DMT benzoate.
  • the sub-lingual formulation is a fast-dissolve sub-lingual formulation.
  • the sub-lingual formulation is produced by freeze-drying/lyophilisation.
  • the sub-lingual formulation is produced by:
  • passing said blisters through a cryogenic freezing process controls the size of ice crystals.
  • the sub-lingual formulation disintegrates in less than 30 seconds from coming into contact with saliva. In an embodiment, the sub-lingual formulation disintegrates in 3-10 seconds.
  • an orally disintegrating tablet (ODT) comprising 5-MeO-DMT benzoate.
  • the ODT is a fast-dissolve sub-lingual formulation.
  • the ODT is produced by freeze-drying/lyophilisation.
  • the ODT is produced by:
  • passing said blisters through a cryogenic freezing process controls the size of ice crystals.
  • the ODT disintegrates in less than 30 seconds from coming into contact with saliva. In an embodiment, the ODT disintegrates in 3-10 seconds.
  • a nasal formulation of 5-MeO-DMT benzoate there is provided a nasal formulation of 5-MeO-DMT benzoate. In an embodiment, there is provided a spray-dried nasal formulation of 5-MeO-DMT benzoate. In an embodiment, there is provided a spray- dried amorphous particulate powder formulation of 5-MeO-DMT benzoate. In an embodiment, there is provided a spray-dried amorphous particulate powder formulation of 5-MeO-DMT benzoate, wherein the formulation has been co-sprayed with hydroxypropyl methylcellulose (HPMC). In an embodiment, the nasal formulation has a median particle size of 10 to 100 micron, 20 to 90 micron, 30 to 80 micron, 40 to 70 micron, 30 to 60 micron or 40 to 50 micron.
  • the nasal formulation has a median particle size of 20 to 40 micron.
  • a microneedle array for use in administration of the 5-MeO-DMT wherein said array comprises a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable composition.
  • a microneedle array for use in administration of the 5-MeO-DMT wherein said array comprises a base element and a plurality of microneedles which project from said base element, wherein the microneedles are composed of a swellable hydrogel forming polymer composition. Any hydrogel polymer composition which can penetrate the stratum corneum of skin and which swells in the presence of liquid may be used.
  • the microneedles are fabricated from one or more hydrogel-forming polymers containing one or more hydrophilic functional groups.
  • suitable polymers include, but are not necessarily limited to, polyvinylalcohol), amylopectin, carboxymethylcellulose (CMC)chitosan, poly(hydroxyethylmethacrylate) (polyHEMA), poly(acrylic acid), and poly(caprolactone), or a Gantrez ® -type polymer.
  • Gantrez ® -type polymers include poly(methylvinylether/maleic acid), esters thereof and similar, related, polymers (eg poly(methyl/vinyl ether/maleic anhydride).
  • the hydrogel-forming polymer is a Gantrez ® -type polymer such as poly(methyl/vinyl ether/maleic acid) (PMVEMA), an ester thereof or poly(methyl/vinyl ether/maleic anhydride) (PMVEMAH).
  • Crosslinking of polymers may be used to further vary the strength and swelling characteristics of microneedles as well as the release characteristics of the microneedles.
  • a lightly-crosslinked hydrogel microneedle could rapidly deliver a drug bolus where one dose only is required e.g. for vaccine delivery.
  • a moderately-crosslinked hydrogel microneedle could be used to allow prolonged drug delivery, thus facilitating a constant drug plasma level.
  • moderately-crosslinked hydrogel microneedles could keep puncture holes in the SC open.
  • moderately-crosslinked hydrogel microneedles might optionally widen the puncture holes as a result of absorption of moisture from tissue, and swelling of the microneedles.
  • the polymer composition of the microneedles and/or the base element may be cross-linked using any suitable technique known in the art.
  • the crosslinking may be physical or chemical or a combination of both.
  • Suitable crosslinking agents include polyhydric alcohols (eg glycerol, propylene glycol (poly(ethylene glycol) or a polyamino compound which can form amides with reactive groups of a polymer.
  • the hydrogel-forming polymer is a Gantrez ® type polymer cross-linked using a polyhydric alcohol.
  • the microneedles of the microneedle arrays of the invention may be of any size and shape such that they can penetrate the stratum corneum of mammalian skin without breaking upon their insertion into the skin.
  • the microneedles of the microneedle arrays of the invention are 1 - 3000 pm in height.
  • the microneedles have a width (or, in the case of microneedles with substantially circular cross sections, a diameter) of 50 - 500 pm.
  • the base element and microneedles may be comprised of the same or different materials. Typically the base element will be composed of the same polymer composition as the microneedles.
  • the mechanical strength and rate of swelling of the microneedles of the microneedle arrays of the invention will be determined by a number of factors including the shape of the microneedles and the polymer(s) of which the microneedles are composed.
  • a transdermal delivery device comprising a microneedle array as previously or subsequently described.
  • the 5-MeO-DMT (optionally the benzoate salt) may be comprised within a reservoir or matrix with which the microneedle array is in communication.
  • the 5-MeO-DMT (optionally the benzoate salt) moves from the reservoir or matrix through the microneedles to the skin.
  • the 5-MeO-DMT (optionally the benzoate salt) may be comprised within the polymer composition of the microneedle array.
  • 5-MeO-DMT (optionally the benzoate salt) can be chemically bonded to the polymer(s) making up the microneedles and/or base elements.
  • the 5-MeO-DMT (optionally the benzoate salt) can be released upon insertion into the skin by; dissolution of the microneedles, hydrolysis, enzymatic or spontaneous non-catalysed breakage of the bonds holding it to the polymer(s). The rate of drug release can thus be determined by the rate of reaction/bond breakage.
  • movement of 5-MeO-DMT (optionally the benzoate salt) from the microneedle array into the skin may occur passively.
  • movement may be controlled externally, for example iontophoretically.
  • an iontophoretic device comprising a microneedle array as previously or subsequently described.
  • a method of delivering 5-MeO-DMT (optionally the benzoate salt) through or into the skin comprising providing a microneedle array or a transdermal therapeutic device, either of which may be as previously or subsequently described, wherein the microneedle array or transdermal therapeutic device comprises 5- MeO-DMT (optionally the benzoate salt), applying the microneedle array to the skin such that the microneedles protrude through or into the stratum corneum, allowing the microneedles to swell, allowing the 5-MeO-DMT (optionally the benzoate salt) to flow through the microprotusions into the skin.
  • Transdermal delivery devices can be affixed to the skin or other tissue to deliver 5-MeO-DMT (optionally the benzoate salt) continuously or intermittently, for example for durations ranging from a few seconds to several hours or days.
  • the microneedle arrays of the invention may be used to deliver more than one active agent from the same transdermal therapeutic device.
  • a first active agent could be comprised within the polymer of which the microneedles are composed with a second active agent stored in a reservoir.
  • the microneedles On positioning on the skin and puncturing of the stratum corneum, the microneedles will swell and the active agent will be released from the microneedles. Subsequently, the second active agent may be released from the reservoir and enter the skin via the microneedles.
  • microneedles Drug contained in the microneedles themselves will be rapidly released upon swelling, initially as a burst release due to drug at the surface of the microneedles. The subsequent extent of release will be determined by crosslink density and the physicochemical properties of the drug. Release of drug from the drug reservoir will occur more slowly at first as a result of the time required to swell the microneedles up as far as the drug reservoir, subsequent partitioning of the drug into the swolleneedles and diffusion of the drug through the swollen matrix.
  • the microarrays may thus be adapted to deliver two active agents in succession, with the composition adapted, e.g. by crosslinking of the composition of the microneedles, to vary delivery times of one or both active agents.
  • a microneedle array for use in the administration of 5-MeO-DMT (optionally the benzoate salt), wherein said array comprises a plurality of microneedles composed of a swellable polymer composition which in its dry state is hard and brittle to penetrate the stratum corneum of a patients skin, wherein the microneedles are fabricated from at least one polymer selected from poly(methylvinylether/maleic acid), esters thereof and poly (methyl/vinyl ether/maleic anhydride), wherein the polymer is a cross-linked polymer, and using a cross-linker at a polymer-crosslinker ratio of 2:1.
  • a transdermal delivery device capable of the administration of two different active agents with different release profiles.
  • the first active agent is delivered rapidly over less than 5, less than 10 or less than 15 minutes.
  • the second active agent is delivered only after the rapid delivery of the first active agent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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EP22830588.4A 2021-12-13 2022-12-13 Benzoatsalz von 5-methoxy-n,n-dimethyltryptamin Pending EP4448488A2 (de)

Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
GBGB2118005.4A GB202118005D0 (en) 2021-12-13 2021-12-13 Methods of synthesis
GBGB2118007.0A GB202118007D0 (en) 2021-12-13 2021-12-13 Methods of treatment
GBGB2118008.8A GB202118008D0 (en) 2021-12-13 2021-12-13 Combination Pharmaceutical composition
GBGB2118006.2A GB202118006D0 (en) 2021-12-13 2021-12-13 Methods of treatment
GBGB2118011.2A GB202118011D0 (en) 2021-12-13 2021-12-13 Methods of treatment
GBGB2118099.7A GB202118099D0 (en) 2021-12-14 2021-12-14 Methods of synthesis
GBGB2118095.5A GB202118095D0 (en) 2021-12-14 2021-12-14 Combination pharmaceutical composition
GBGB2118156.5A GB202118156D0 (en) 2021-12-15 2021-12-15 Methods of synthesis
GB202118293 2021-12-16
GB202118305 2021-12-16
GB202118309 2021-12-16
GB202118295 2021-12-16
GBGB2212113.1A GB202212113D0 (en) 2022-08-19 2022-08-19 Method of synthesis
GBGB2212117.2A GB202212117D0 (en) 2022-08-19 2022-08-19 Method of synthesis
PCT/GB2022/053208 WO2023111544A2 (en) 2021-12-13 2022-12-13 Benzoate salt of 5-methoxy-n,n-dimethyltryptamine

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US11759452B2 (en) 2020-05-08 2023-09-19 Psilera Inc. Compositions of matter and pharmaceutical compositions
JP2024521747A (ja) 2021-05-25 2024-06-04 アタイ セラピューティクス， インコーポレイテッド 新しいｎ，ｎ－ジメチルトリプタミン塩および結晶塩形態
AU2023246548A1 (en) * 2022-03-27 2024-11-07 GH Research Ireland Limited 5-methoxy-n.n-dimethyltryptamine for the treatment of psychomotor retardation
US12264131B2 (en) 2022-08-19 2025-04-01 Beckley Psytech Limited Pharmaceutically acceptable salts and compositions thereof
EP4618946A1 (de) * 2022-11-14 2025-09-24 Beckley Psytech Limited Formulierungen von 5-meo-dmt
US12246005B2 (en) 2023-06-13 2025-03-11 Beckley Psytech Limited 5-methoxy-n,n-dimethyltryptamine (5-MeO-DMT) formulations
WO2025054397A1 (en) * 2023-09-08 2025-03-13 Atai Therapeutics, Inc. Parenteral formulations for n,n-dimethyltryptamine (dmt) and dmt analogs, methods of making, and methods of use thereof
WO2025076151A1 (en) * 2023-10-02 2025-04-10 Atai Therapeutics, Inc. N-n-dimethyltryptamine (dmt) and dmt analog oral transmucosal film compositions, methods of making, and methods of use thereof

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BR112022021831A2 (pt) * 2020-05-01 2022-12-13 Emergex Usa Corp Dispositivos de liberação transdérmica de fármacos tendo micro projeções revestidas com psilocibina, dietilamida do ácido lisérgico ou 3,4-metilenodioximetanfetamina
KR20230024378A (ko) * 2020-06-12 2023-02-20 벡클리 싸이테크 리미티드 5-메톡시-n, n-디메틸트립타민의 벤조에이트 염을 포함하는 조성물

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