Composition containing 5-methoxy-N,N-dimethyltryptamine benzoate

Abstract

The present invention provides compositions for treating conditions caused by dysfunction of the central nervous system and conditions caused by dysfunction of the peripheral nervous system. [Solution] A composition containing a pharmaceutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5MeODMT) benzoate that is pharmaceutically acceptable.

Description

[Technical Field]

[0001] This invention relates to pharmaceutically acceptable salts of 5-methoxy-N,N-dimethyltryptamine. In particular, but not exclusively, the invention relates to pharmaceutical formulations and their use. [Background technology]

[0002] 5-Methoxy-N,N-dimethyltryptamine (5MeODMT) is a pharmacologically active compound of the tryptamine class, with the chemical formula:

[0003] [ka]

[0004] It has. 5MeODMT is a naturally occurring psychoactive / psychedelic substance that is thought to act primarily through serotonin receptors. It is also associated with 5-HT2 and 5-HT2. 1A It is thought to have a high affinity for the subtype and / or inhibit the reuptake of monoamines.

[0005] However, 5MeODMT is not well understood, and its use has not been thoroughly explored. Furthermore, 5MeODMT is not easy to handle, and there are challenges in formulating it for effective delivery in pharmaceutically useful compositions.

[0006] In this technical field, there is still a need for improved formulations and uses of 5MeODMT. [Overview of the project]

[0007] A composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable salt of 5-methoxy-N,N-dimethyltryptamine (5MeODMT) is provided, as disclosed herein. In an embodiment, the anion of the salt is an aryl carboxylic acid. In an embodiment, the aryl carboxylic acid is substituted with 1 to 3 R groups. [[ID=​​​​​​​​​​​​​​​​​In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 0.05 mg to 100 mg. In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 0.1 mg to 50 mg.

[0012] In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 0.5 mg to 25 mg. In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 0.5 mg to 10 mg.

[0013] In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 1 mg to 10 mg. In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 1 mg to 8 mg. In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 3 mg to 15 mg.

[0014] In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 0.005 mg to 100 mg. In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 0.001 mg to 100 mg.

[0015] In an embodiment, the composition comprises a dosage of 5MeODMT in the range of 0.0005 mg to 100 mg. The level of the active agent can be adjusted as needed, for example, to suit a particular patient group (such as the elderly) or the condition being treated.

[0016] In an embodiment, the composition is formulated into a dosage form selected from oral, transdermal, inhalable, intravenous, or rectal dosage forms. For example, it is advantageous that the active agent can be delivered in different forms to suit a particular patient group (such as the elderly) or the condition being treated.

[0017] In the embodiment, the composition is formulated into a dosage form selected from tablets, capsules, granules, powders, free-flowing powders, inhalable powders, aerosols, sprays, vaping, buccal, sublingual, sublabial, injectable, or suppositories.

[0018] In this embodiment, the powder is suitable for administration by inhalation via a pharmaceutical dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-measured multi-dose dry powder inhaler, a nasal inhaler, or a pressurized metered-dose inhaler.

[0019] In the embodiment, the powder contains particles, the particles having a median diameter of 2000 μm, 1000 μm, 500 μm, 250 μm, 100 μm, 50 μm, or less than 1 μm. In the embodiment, the powder contains particles, the particles having a median diameter of 500 μm, 250 μm, 100 μm, 50 μm, 1 μm, or greater than 0.5 μm.

[0020] In this embodiment, the powder contains particles and has a particle size distribution of d10 = 20 to 60 μm and / or d50 = 80 to 120 μm and / or d90 = 130 to 300 μm.

[0021] The properties of the powder can be adjusted to suit the needs. For example, when made for nasal inhalation, the particles may be finer than when the powder is formulated into gelatin capsules, or they may be adjusted in a different way when compressed into tablets.

[0022] In the embodiment, the 5MeODMT salt is amorphous or crystalline. In the embodiment, the 5MeODMT salt is in a polymorphic crystalline form, and if necessary, the 5MeODMT salt is polymorph A.

[0023] In embodiments, the 5MeODMT salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, and optionally the salt is a chloride, benzoate, or fumarate.

[0024] In the embodiment, the 5MeODMT salt is formulated into a composition for mucosal delivery. In the embodiment, the 5MeODMT salt is a benzoate. In this embodiment, 5MeODMT benzoate matches pattern A, characterized by the XRPD diffractogram.

[0025] In the embodiment, 5MeODMT benzoate is characterized by peaks at 17.5, 17.7, and 21.0°2θ±0.1°2θ in the XRPD diffractogram, which is measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0026] In this embodiment, 5MeODMT benzoate is characterized by a peak in the XRPD diffractogram substantially shown in Figure 6 or Figure 7. In this embodiment, 5MeODMT benzoate is characterized by bands at approximately 3130, 1540, 1460, 1160, and 690 cm⁻¹ in the Fourier transform infrared spectroscopy (FTIR) spectrum.

[0027] In this embodiment, 5MeODMT benzoate is characterized by the FTIR spectrum for lot FP2 substantially shown in Figure 93. In this embodiment, 5MeODMT benzoate matches pattern B according to XRPD.

[0028] In this embodiment, 5MeODMT benzoate matches pattern B, characterized by a peak between 18.5 and 20°2θ ± 0.1°2θ in the XRPD diffractogram.

[0029] In this embodiment, 5MeODMT benzoate conforms to pattern B, substantially shown by the XRPD diffractograms for lots P1, R1, and Q1, substantially shown in Figure 24.

[0030] In this embodiment, 5MeODMT benzoate corresponds to pattern B, substantially shown by the XRPD diffractogram for lot R2, substantially shown in Figure 28. In this embodiment, 5MeODMT benzoate conforms to pattern B, substantially shown by the XRPD diffractograms for lots A1 and B1, substantially shown in Figure 38 or 39.

[0031] In this embodiment, 5MeODMT benzoate corresponds to pattern B morphology characterized by the FTIR spectrum for lot C2 substantially shown in Figure 93. In this embodiment, 5MeODMT benzoate corresponds to pattern C, characterized by a smaller, broader endothermic effect with a peak temperature of 108°C on a DSC thermograph.

[0032] In this embodiment, 5MeODMT benzoate corresponds to pattern C, characterized by the DSC thermograph substantially shown in Figure 65. In this embodiment, 5MeODMT benzoate corresponds to pattern C morphology as characterized by the DSC thermograph substantially shown in Figure 66.

[0033] In this embodiment, 5MeODMT benzoate matches pattern C according to XRPD. In this embodiment, 5MeODMT benzoate matches pattern C, characterized by a peak at 10.3°2θ ± 0.1°2θ in the XRPD diffractogram.

[0034] In this embodiment, 5MeODMT benzoate corresponds to pattern C, substantially shown by the XRPD diffractogram for lot A1, substantially shown in Figure 68. In this embodiment, 5MeODMT benzoate corresponds to pattern C morphology, characterized by the FTIR spectrum for lot C1 substantially shown in Figure 93.

[0035] In this embodiment, 5MeODMT benzoate matches pattern D according to XRPD. In this embodiment, 5MeODMT benzoate corresponds to pattern D, substantially shown by the XRPD diffractogram in Figure 73 or Figure 74.

[0036] In this embodiment, 5MeODMT benzoate corresponds to pattern D, characterized by an endothermic event at 118°C in a DSC thermograph. In this embodiment, 5MeODMT benzoate corresponds to pattern D, characterized by an endothermic event at 118.58°C in a DSC thermograph.

[0037] In this embodiment, 5MeODMT benzoate matches pattern E according to XRPD. In this embodiment, 5MeODMT benzoate corresponds substantially to pattern E, as shown by the XRPD diffractogram for lot D in Figure 77 or Figure 78.

[0038] In this embodiment, the 5MeODMT corresponds to pattern E, characterized by a major bimodal endothermic event with peak temperatures of 110.31°C and 113.13°C in the DSC thermograph.

[0039] In this embodiment, 5MeODMT corresponds to pattern E, characterized by the smaller endothermic event having a peak temperature of 119.09°C in the DSC thermograph. In this embodiment, the 5MeODMT corresponds to pattern E, characterized by the DSC thermograph substantially shown in Figure 79.

[0040] In this embodiment, 5MeODMT benzoate corresponds substantially to pattern E, as shown by the XRPD diffractogram in Figure 80. In this embodiment, 5MeODMT benzoate corresponds to pattern F according to XRPD.

[0041] In this embodiment, 5MeODMT benzoate matches pattern F, characterized by the XRPD diffractogram for lot F (rerun) substantially shown in Figure 84.

[0042] In this embodiment, 5MeODMT benzoate matches pattern F, characterized by the XRPD diffractogram for lot F (rerun) substantially shown in Figure 85.

[0043] In this embodiment, 5MeODMT benzoate matches pattern F, characterized by the XRPD diffractogram for lot F (rerun) substantially shown in Figure 89.

[0044] In this embodiment, 5MeODMT benzoate corresponds to pattern F, characterized by endothermic events at 90°C, 106°C, and 180°C in a DSC thermograph. In this embodiment, 5MeODMT benzoate corresponds to pattern F, characterized by endothermic events at 90.50°C, 106.65°C, and 180.35°C in a DSC thermograph.

[0045] In this embodiment, 5MeODMT benzoate matches pattern G by XRPD. In this embodiment, 5MeODMT benzoate matches pattern G, characterized by the XRPD diffractogram for lot K substantially shown in Figure 87.

[0046] In this embodiment, 5MeODMT benzoate corresponds to pattern G, characterized by an endothermic event at 119.61°C in a DSC thermograph. In the embodiment, the composition contains a 5MeODMT benzoate that matches a mixture of two or more patterns A to G according to XRPD.

[0047] In the case of salt, the dose is equivalent to the amount of free base delivered when the salt is ingested. Therefore, a 100 mg dose of 5MeODMT corresponds to 117 mg of hydrochloride (i.e., both deliver the same molar amount of active substance). The reason for the larger mass of salt required is the larger formula weight of the hydrochloride salt (i.e., 254.8 g / mol for the salt compared to 218.3 g / mol for the free base). Similarly, for deuterated or pulverized versions of 5MeODMT (which are also considered to be within the scope of this invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.

[0048] Amorphous and crystalline materials often exhibit different chemical / physical properties, such as improved solubility in solvents or enhanced thermal stability. Similarly, different polymorphs may exhibit different useful chemical / physical properties.

[0049] In the embodiment, the composition comprises one or more pharmaceutically acceptable carriers or excipients. In the embodiment, the composition comprises one or more of the following: a mucosal adhesion enhancer, a permeability enhancer, a cationic polymer, a cyclodextrin, a tight junction modifier, an enzyme inhibitor, a surfactant, a chelating agent, and a polysaccharide.

[0050] In the embodiment, the composition is chitosan, chitosan derivatives (N,N,N-trimethylchitosan (TMC), n-propyl-(quatopropyl (QuatPropyl)), n-butyl-(quatobutyl (QuatButyl)), and n-hexyl (quatohexyl ( This product contains one or more of the following: QuatHexyl))-N,N-dimethylchitosan (such as chitosan chloride), β-cyclodextrin, Clostridium perfringens enterotoxin, clostridium toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate, sodium lauryl sulfate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, sodium caprate, DHA, EPA, dipalmitoylphosphatidylcholine, soy lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.

[0051] In embodiments, the compositions disclosed herein are for use as pharmaceuticals. In embodiments, the compositions disclosed herein are for use in methods of treating human or animal subjects by therapy.

[0052] In this embodiment, the treatment method is: A condition caused by dysfunction of the central nervous system. A condition caused by dysfunction of the peripheral nervous system. Conditions that benefit from sleep regulation (such as insomnia), Conditions that benefit from painkillers (such as chronic pain), Migraine, Trigeminal autonomic cephalgia (including short-duration, persistent hemiglamic headache (SUNCT) with conjunctival congestion and lacrimation, and short-duration, persistent cephlamic headache (SUNA) with autonomic symptoms in the head), Conditions that benefit from neurogenesis (stroke, traumatic brain injury, Parkinson's dementia, etc.), A condition that benefits from anti-inflammatory treatment. Depression, Treatment-resistant depression, anxiety, Substance use disorder, Addiction disorder, Gambling disorder, Eating disorders, Obsessive-compulsive disorder, or This is a treatment method for body dysmorphic disorder. If necessary, the status is SUNCT and / or SUNA.

[0053] The above-mentioned conditions can be beneficially improved by ingesting the present invention. In the embodiment, the treatment method is a method for treating alcohol-related disorders and illnesses, eating disorders, impulse control disorders, nicotine-related disorders, tobacco-related disorders, methamphetamine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogenic drug use disorders, inhalant-related disorders, benzodiazepine abuse or dependence-related disorders, and / or opioid-related disorders.

[0054] In the embodiments, the treatment method is a method for treating tobacco addiction. In the embodiments, the method is a method for reducing tobacco use. In the embodiments, the treatment method is a method for treating nicotine addiction. In the embodiments, the method is a method for reducing nicotine use.

[0055] In the embodiment, the treatment method is a method for treating alcohol abuse and / or addiction. In the embodiment, the treatment method is a method for reducing alcohol use. In this embodiment, the treatment method is a method for treating or preventing the overuse of drugs.

[0056] In embodiments, the treatment method is a method for treating or preventing the heavy use of drugs, including but not limited to alcohol, tobacco, nicotine, cocaine, methamphetamine, other stimulants, phencyclidine, other hallucinogens, marijuana, sedatives, tranquilizers, sleeping pills, and opioids. Those skilled in the art will understand that heavy use or abuse of a substance does not necessarily mean that the subject is dependent on that substance.

[0057] In this embodiment, the treatment method is a treatment method for two or more of the above conditions, for example, the treatment method may be a treatment method for depression and anxiety. In this embodiment, the composition is administered once or multiple times a year.

[0058] In the embodiment, the composition is administered once or more times a month. In the embodiment, the composition is administered once or more times per week. In the embodiment, the composition is administered once or multiple times a day.

[0059] In the embodiment, the composition is administered at a frequency that avoids tachyphylaxis. In the embodiment, the composition is administered with supplemental treatments and / or additional activators.

[0060] In embodiments, further activators are psychedelic compounds, and optionally tryptamines. In embodiments, further activators include lysergic acid diethylamide (LSD), psilocybin, psilocine, or prodrugs thereof.

[0061] In some embodiments, a further activator is an antidepressant compound. In embodiments, further activators are selected from SSRIs, SNRIs, TCAs, or other antidepressant compounds.

[0062] In embodiments, further activators include citalopram (Celexa, Cipramil), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox, Faberin), paroxetine (Paxil, Seroxat), sertraline (Zoloft, Lustral), desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomirnacipran (Fetzima), and myrrh. Cipra (Ixel, Savella), venlafaxine (Effexor), bilazodone (Viibryd), vortioxetine (Trintellix), nefazodone (Dutonin, Nefadar, Serzone), trazodone (Desyrel), reboxetine (Edronax), teniroxazine (Lucelan, Metatone), biloxazine (Vivalan), bupropion (Wellbutrin), amitriptyline (Elavil, Endep), Amitriptyline oxide (Amioxid, Ambivalon, Equilibrin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dibenzepine (Noveril, Victoril), dimethacrine (Istonil), dosurepin (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Lomont, Gamanil), melitracene (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxyptylline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen / Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin), Maprotiline ( Ludiomil, Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Isocarboxazide (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caloxazone (Surodil, Timostenil), Metralindol (Inkazan), Moclobemide (Aurorix, Manerix), Pirazidol, Troxatone (Humoryl), Agomelatine (Valdoxan), Esketamine (Spravato), The following drugs are selected: ketamine (Ketalar), tandospirone (Sediel), thianeptine (Stablon, Coaxil), amisulpride (Solian), aripiprazole (Abilify), brexpiprazole (Rexulti), lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), trifluoperazine (Stelazine), buspirone (Buspar), lithium (Eskalith, Lithobid), modafinil (Provigil), thyroxine (T4), and triiodothyronine (T3).

[0063] In embodiments, further activators are selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (leboxetine), Viibryd (virazodone), Wellbutrin (bupropion), and Zoloft (sertraline).

[0064] In this embodiment, the supplementary treatment is psychotherapy. In one embodiment, a composition is provided comprising a pharmaceutically acceptable amount of 5MeODMT benzoate for use in a method for treating treatment-resistant depression.

[0065] In one embodiment, a composition is provided comprising a pharmaceutically acceptable amount of 5MeODMT benzoate for use in a method for treating depression. In one embodiment, a composition is provided comprising a pharmaceutically acceptable amount of 5MeODMT benzoate for use in a method for treating PTSD.

[0066] In one embodiment, a composition is provided comprising a pharmaceutically acceptable amount of 5MeODMT benzoate for use in a method of treating poisoning / substance misuse disorder. In one embodiment, a nasal inhalation composition is provided containing a pharmaceutically acceptable amount of 5MeODMT benzoate for use in a method for treating treatment-resistant depression.

[0067] The conditions described above may be beneficially improved by taking the present invention in conjunction with several supplementary treatments, and these treatments may occur with far less regularity than some other treatments that require daily treatment or even multiple treatments per day.

[0068] For the sake of brevity, various forms of 5MeODMT benzoate may be referred to as “Pattern #” below in this specification, where # refers to the corresponding XRPD pattern obtained for that form. For example, “Pattern A” may be used as an abbreviation to refer to the form of 5MeODMT benzoate that produces Pattern A by XRPD. Similarly, “Pattern B” may be used as an abbreviation to refer to the form of 5MeODMT benzoate that produces Pattern B by XRPD, etc.

[0069] Next, the present invention will be further described with reference to the following attached drawings. [Brief explanation of the drawing]

[0070] [Figure 1] This is a schematic diagram of the synthesis pathway of 5MeODMT. [Figure 2]This is a diagram illustrating a further schematic pathway for the synthesis of 5MeODMT. [Figure 3] This is a diagram illustrating the schematic pathway for preparing 5MeODMT in powder form. [Figure 4] This is a diagram illustrating the slug mucosal irritation (SMI) test. (A) First contact time between the slug and the test sample: 15 minutes. (B) The slug is moved to a wet paper towel in a new petri dish for 1 hour. (C) Second contact time between the slug and the test sample: 15 minutes. (D) The slug is moved to a wet paper towel in a new petri dish for 1 hour. (E) Third contact time between the slug and the test sample: 15 minutes. [Figure 5] This graph shows that the benzoate of 5MeODMT has higher permeability compared to the hydrochloride, as detailed in the experiment described in Example 9. [Figure 6] This figure shows the XRPD diffractogram of 5MeODMT benzoate before particle size reduction. [Figure 7] This figure shows the XRPD diffractogram of 5MeODMT benzoate after particle size reduction. [Figure 8] Figures 6 and 7 show the XRPD diffractograms superimposed on each other. [Figure 9] This is a DSC thermograph of 5MeODMT benzoate. [Figure 10] This is a TGA thermograph of 5MeODMT benzoate. [Figure 11] This figure shows a TGA / DSC thermograph of the combination of 5MeODMT benzoate. [Figure 12] This is a diagram showing the DVS isotherm of 5MeODMT benzoate.

[0071] This figure shows the dynamic vapor adsorption (DVS) isotherm for 5MeODMT benzoate. [Figure 13] This figure shows optical microscope images (A) and dark-field (B) of 5MeODMT benzoate at 4x magnification. [Figure 14] The figure further shows two 4x magnification optical microscope images of 5MeODMT benzoate (A) and (B). [Figure 15] Figures (A) and (B) are optical microscope images of 5MeODMT benzoate at 10x magnification. [Figure 16] The figures (A) and (B) further show optical microscope images of 5MeODMT benzoate at 10x magnification. [Figure 17] This figure shows the DVS isotherm of 5MeODMT hydrochloride (lot 20 / 20 / 126-FP). [Figure 18] This figure shows the DVS isotherm of 5MeODMT hydrochloride (lot 20 / 45 / 006-FP). [Figure 19] This figure shows a comparison of the XRPD patterns of 5MeODMT benzoate from two different lots. [Figure 20] This figure shows a DSC thermograph of 5MeODMT benzoate from a different lot. [Figure 21] This figure additionally shows the XRPD characterization of multiple lots of 5MeODMT benzoate. [Figure 22] This figure shows the DSC thermograph results for 5MeODMT benzoate lots C1, D1, and E1. [Figure 23] This figure shows the TGA thermograph results for 5MeODMT benzoate lots C1, D1, and E1 at 10°C·min-1. [Figure 24] This figure shows a comparison of the XRPD patterns of 5MeODMT benzoates P1 (toluene), Q1 (chlorobenzene), and R1 (anisole) against the XRPD pattern of pattern A. [Figure 25] This figure shows DSC thermographs of 5MeODMT lots P1, Q1, and R1 at 10°C·min-1. [Figure 26] This figure shows an enlarged DSC thermograph of 5MeODMT lots P1, Q1, and R1 at 10°C·min-1. [Figure 27]This figure shows the TGA thermographs of 5MeODMT lots P1, Q1, and R1 at 10°C·min-1. [Figure 28] This figure shows a comparison of the XRPD patterns of 5MeODMT benzoate lots R1 and R2 (thermal-cycled suspensions) compared to the XRPD diffractogram of reference pattern A. [Figure 29] This figure shows DSC thermographs of 5MeODMT benzoate lots P2, Q2, and R2 at 10°C·min-1. [Figure 30] This figure shows an enlarged DSC thermograph of 5MeODMT benzoate lots P2, Q2, and R2 at 10°C·min-1. [Figure 31] This figure shows the TGA thermographs of 5MeODMT benzoate lots P2, Q2, and R2 at 10°C·min-1. [Figure 32] This figure shows the polymerization of XRPD patterns of samples isolated by crystallization mediated by the antisolvent of 5MeODMT benzoate. [Figure 33] This figure shows the polymerization of 5MeODMT benzoate lot F1 and standard pattern A form / material XRPD pattern. [Figure 34] This figure shows the polymerization of a 5MeODMT benzoate sample isolated from cooling and an XRPD pattern based on pattern A. [Figure 35] This figure shows the polymerization of 5MeODMT benzoate samples isolated after cooling following particle size reduction, and the XRPD pattern based on pattern A. [Figure 36] This figure shows a comparison of the XRPD patterns of all samples obtained from reverse addition anti-solvent driven crystallization of 5MeODMT benzoates, excluding A1 and B1. [Figure 37] This figure shows a comparison of the XRPD patterns of 5MeODMT benzoate F3 with the known pattern A criterion. [Figure 38] This figure shows a comparison of the XRPD patterns of 5MeODMT benzoates A1 and B1. [Figure 39] This figure shows the XRPD patterns of 5MeODMT benzoate A1, Q1, and the reference pattern A. [Figure 40] This figure shows the XRPD patterns of 5MeODMT benzoate B1, Q1, and reference pattern A. [Figure 41] This figure shows a DSC thermograph of sample A1 of 5MeODMT benzoate isolated from methanol and toluene at 10°C·min-1. [Figure 42] This figure shows a DSC thermograph of 5MeODMT benzoate B1 isolated from isopropanol and toluene at 10°C·min-1. [Figure 43] This figure shows a magnified DSC thermograph of 5MeODMT benzoate B1 isolated from isopropanol and toluene at 10°C·min-1. [Figure 44] This figure shows a comparison of XRPD values ​​for 5MeODMT benzoate lot 21-01-051 A, E, particle size reduction E, and pattern A. [Figure 45] This figure shows the XRPD of 5MeODMT benzoate lot 21-01-051 B obtained from rapid cooling of the molten material. [Figure 46] This figure shows the XRPD of 5MeODMT benzoate lot 21-01-051 C obtained by freeze-drying. [Figure 47] This figure shows a comparison of XRPD levels after 20 hours for 5MeODMT benzoate lot 21-01-051 B, lot C, and pattern A. [Figure 48] This figure shows a comparison of XRPDs based on 5MeODMT benzoate lot 21-01-051 A, E, particle size reduction E, and pattern A. [Figure 49] This figure shows a DSC thermographic comparison of 5MeODMT benzoate lots 21-01-051 A, C, and D isolated from acetone concentrate 051 A, lyophilized 051 C, and 051 D at 10°C·min-1. [Figure 50]This figure shows a comparison of DSC thermographs of 5MeODMT benzoate lot 21-01-051 at 10°C·min-1 after 20 hours. [Figure 51] This figure shows a DSC thermograph of lot 21-01-051 D of 5MeODMT benzoate, a large-scale freeze-dried material, with temperature markings corresponding to the hot stage microscope image. [Figure 52] This figure shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 30.02°C. [Figure 53] This figure shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 54.21°C. [Figure 54] This figure shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 74.21°C. [Figure 55] This figure shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 114.23°C. [Figure 56] This figure shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 120.14°C. [Figure 57] This figure shows a comparison of XRPD patterns of solid 5MeODMT benzoate lot 21-01-054 isolated from the equilibration of amorphous 5MeODMT benzoate with thermal control. [Figure 58] This figure shows a comparison of the XRPD patterns of lot 21-01-054 M of 5MeODMT benzoate, isolated from the equilibration of amorphous 5MeODMT benzoate in α,α,α-trifluorotoluene with thermal control, with lot 20-37-64 (pattern A). [Figure 59] This figure shows a DSC thermographic comparison of selected solids from lot 21-01-054 of 5MeODMT benzoate, classified as pattern A, isolated from the equilibration of amorphous 5MeODMT benzoate with thermal control. [Figure 60]This figure shows a magnified comparison of DSC thermographs of lot 21-01-054 solid, classified as pattern A, isolated from the equilibration of amorphous 5MeODMT benzoate with thermal control, highlighting the event of lot 21-01-054 Q, a solid isolated from anisole. [Figure 61] This figure shows an enlarged DSC thermograph highlighting the event of lot 21-01-054 Q isolated from anisole. [Figure 62] This figure shows a comparison of XRPD patterns of 5MeODMT benzoate lot 21-01-060 A1, lot 21-01-049 B1, pattern B, and lot 20-37-64, pattern A, after air-drying for 2 minutes. [Figure 63] This figure shows a comparison of XRPD patterns of 5MeODMT benzoate lot 21-01-060 A1 after 1 hour of air drying and lot 21-01-060 A1 after 2 minutes of air drying. [Figure 64] This figure shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-060 A1 - air-dried for 2 minutes, lot 21-01-060 A1 - air-dried for 1 hour, and lot 21-01-049 B1, pattern B. [Figure 65] This figure shows a DSC thermograph of 5MeODMT benzoate lot 21-01-060 A1, immediately isolated from IPA / toluene and air-dried for 1 hour. [Figure 66] This is a magnified DSC thermograph of 5MeODMT benzoate lot 21-01-060 A1, immediately isolated from IPA / toluene and air-dried for 1 hour. [Figure 67] This figure shows a comparison of XRPD patterns based on pattern B for 5MeODMT benzoate lot 21-01-060 A1 air-dried for 20 hours, lot 21-01-060 A1 air-dried for 2 minutes, and lot 21-01-049 B1. [Figure 68]This figure shows a comparison of the XRPD patterns of 5MeODMT benzoate lot 21-01-060 B1, which was isolated after 3 hours of equilibration and then air-dried for 2 minutes, and A1, which was immediately isolated and then air-dried for 2 minutes. [Figure 69] This figure shows a comparison of the XRPD patterns of lot 21-01-049 B1 and lot 21-01-049 B1 of 5MeODMT benzoate, which were isolated after 3 hours of equilibration and then air-dried for 20 hours, and lot 21-01-060 B1. [Figure 70] This figure shows a comparison of XRPD patterns of solid 5MeODMT benzoate lot 21-01-058 isolated from amorphous 5MeODMT benzoate exposed to solvent vapor. [Figure 71] This figure shows an XRPD pattern comparison of lot 21-01-058 K of 5MeODMT benzoate isolated from amorphous 5MeODMT benzoate exposed to solvent vapor, with lot 20-37-64, pattern A. [Figure 72] This figure shows a comparison of DSC thermographs of 5MeODMT benzoate lots 21-01-058 B, 21-01-058 F, 21-01-058 K, and 21-01-062 G. [Figure 73] This figure shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-058 D, lot 20-37-64, pattern A; lot 21-01-049 B1, pattern B; and lot 21-01-060 B1, pattern C (air-dried for 20 hours). [Figure 74] This figure shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-058 D, lot 21-01-049 B1, pattern B, and lot 21-01-060 B1, pattern C (air-dried for 20 hours). [Figure 75] This figure shows a comparison of magnified XRPD patterns of 5MeODMT benzoate lot 21-01-058 D, lot 21-01-049 B1, pattern B, and lot 21-01-060 B1, pattern C (air-dried for 20 hours). [Figure 76] This figure shows a DSC thermograph of lot 21-01-058 D of 5MeODMT benzoate isolated from exposure to anisole vapor in an amorphous form. [Figure 77] This figure shows a comparison of the XRPD patterns of 5MeODMT benzoate lot 21-01-064 D and 21-01-060 B1 (air-dried for 2 minutes). [Figure 78] This figure shows a comparison of magnified XRPD patterns of 5MeODMT benzoate lot 21-01-064 D and 21-01-060 B1 (air-dried for 2 minutes). [Figure 79] This figure shows a DSC thermograph of 5MeODMT benzoate lot 21-01-064 D at 10°C·min-1. [Figure 80] This figure shows a comparison of the XRPD patterns of 5MeODMT benzoate lots 21-01-064 C and 21-01-064 D. [Figure 81] This figure shows a comparison of magnified XRPD patterns for 5MeODMT benzoate lots 21-01-064 C and 21-01-064 D. [Figure 82] This is a DSC thermograph of 5MeODMT benzoate lot 21-01-064 C at 10°C·min-1. [Figure 83] This figure shows a comparison of XRPD patterns for 5MeODMT benzoate lots 21-01-073 A, 21-01-049 B1, pattern B, and 20-37-64, pattern A. [Figure 84] This figure shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-073 F and 21-01-073 F rerun. [Figure 85] This figure shows an XRPD pattern comparison of 5MeODMT benzoate lot 21-01-073 F rerun, 21-01-049 B1, pattern B, and 20-37-64, pattern A. [Figure 86]This figure shows a comparison of enlarged XRPD patterns for 5MeODMT benzoate lot 21-01-073 F rerun, 21-01-049 B1, pattern B, and 20-37-64, pattern A. [Figure 87] This figure shows a comparison of XRPD patterns for 5MeODMT benzoate lots 21-01-073 K, 21-01-049 B1, pattern B, and 20-37-64. [Figure 88] This is a diagram showing the XRPD of 5MeODMT benzoate lot 21-01-078. [Figure 89] This figure shows the DVS isotherm plot for 5MeODMT benzoate lot 21-01-078. [Figure 90] This figure shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-078 (after DVS) and 20-37-64. [Figure 91] This figure shows the FTIR polymerization of 5MeODMT benzoate in pattern A (20-20-150FP2), pattern B (21-01-071 C2), and pattern C (21-010071 C1). [Figure 92] This figure shows the FTIR polymerization of 5MeODMT benzoate in patterns A (20-20-150FP2), B (21-01-071 C2), and C (21-010071 C1) at 450-2000 cm⁻¹. [Figure 93] This figure shows the FTIR polymerization of 5MeODMT benzoate in three patterns: Pattern A (20-20-150FP2), Pattern B (21-01-071 C2), and Pattern C (21-010071 C1), separated into spectra, at 450-2000 cm⁻¹. [Figure 94] This figure shows the results of a forced swimming test with 5MeODMT benzoate, vehicle, and imipramine, including immobility time. [Figure 95] This figure shows the results of forced swimming tests for 5MeODMT benzoate, vehicle, and imipramine, and the latency to immobility. [Figure 96]This figure shows the mean plasma concentration (ng / mL) of 5MeODMT in male beagle dogs, group 2 (HCl salt) and group 4 (benzoate), and the corresponding dose level (0.4 mg / kg). The mean plasma concentrations of groups 2 and 4 are substantially the same at the time of administration. [Modes for carrying out the invention]

[0072] Figure 1 shows the one-step synthesis of 5MeODMT from the reaction of 4-methoxyphenylhydrazine hydrochloride with (N,N)-dimethylamino)butanal dimethyl acetal. Figure 2 shows the three-step synthesis of 5MeODMT. The first step involves the reaction of 5-methoxyindole with oxalyl chloride. The resulting product is aminated with dimethylamine and then reduced with lithium aluminum hydride.

[0073] Figure 3 shows the schematic pathway for the formation of the powder form of 5MeODMT using a spray drying process. [Examples]

[0074] Example 1: Synthesis of 5MeODMT (free base) in one step (free base) A schematic diagram of this reaction is shown in Figure 1. Hydrazine (1.0 equivalent), diethyl acetal (1.2 equivalents), and aqueous sulfuric acid (0.1 equivalent) were heated together at 65-75°C for 18 hours. After adding MTBE (10 vol), the pH was adjusted to approximately 10 using 12% caustic (approximately 1.1 equivalents). The layers were separated, and the aqueous fraction was back-extracted with MTBE (10 vol). The combined organic fraction was washed twice with water (10 vol) and then evaporated to dryness under vacuum. Yield 100%.

[0075] Example 2: Synthesis of 5MeODMT (free base) in 3 steps A schematic diagram of this reaction is shown in Figure 2. Step 1 - Add methyl tert-butyl ether (MTBE) (15 vol) to the reaction vessel, cool to -20 to -30°C, then add oxalyl chloride (1.5 equivalents) and maintain the temperature below -20°C. While maintaining the temperature below -20°C, add the solution of 5-methoxyindole (1.0 equivalent) in THF (1 vol) to the reaction vessel. Warm the reaction to 0 to 5°C and stir for at least 1 hour, ensuring that no more than 2% of the starting material indole remains.

[0076] Cool the reaction to between -20 and -30°C, add the methanol (1 vol) and MTBE (1 vol) solutions, and maintain the temperature below -20°C. Warm the reaction to 0-5°C over 30 minutes or more, stirring for at least 1 hour.

[0077] Filter the solid and wash with MTBE cooled to 0-5°C. Add the washed filtered solid and methanol (20 vol) to the reaction vessel. Heat to 60-65°C and stir for 30 minutes or less. Cool to 0-5°C over 2 hours or more and stir for 2 hours or more. Filter the solid and wash with MTBE cooled to 0-5°C. Dry the obtained solid at 40°C or below for 12 hours or more. Yield 95%.

[0078] Step 2 - Add the compound obtained in Step 1 (1.0 equivalent) to the reaction vessel along with dimethylamine hydrochloride (3.0 equivalents) and methanol (2 vol). While maintaining the temperature below 30°C, add 25% NaOMe (3.5 equivalents) from the methanol to the reaction. Heat and stir for at least 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 at least 2 hours, then add water (5 vol) over at least 1 hour while stirring at 0-5°C for at least 1 hour.

[0079] The solid is filtered, washed with water cooled to 0-5°C, and the resulting solid is dried at 40°C or below for at least 12 hours. Yield: 85%. Step 3 - Add the compound obtained in Step 2 (1.0 equivalent) to the reaction vessel. While maintaining a temperature of 40°C or lower, add 1.5 equivalents of 1 M LiAlH4 in THF (8 vol) to the reaction. Heat under reflux for at least 4 hours, ensuring that no more than 2% of the starting material from Step 2 remains.

[0080] Adjust the temperature to 0-5°C, and add water (0.25 vol) in THF (0.75 vol) over 30 minutes or more, maintaining the temperature below 10°C. Then, while maintaining the temperature below 10°C, add 15% caustic (0.25 vol). While maintaining the temperature below 10°C, add water (0.65 vol). Add THF (0.25 vol) as a container rinsing solution and stir the contents at 0-5°C for 30 minutes or more. Add sodium sulfate (100 wt%) and stir the contents at 0-5°C for 30 minutes or more.

[0081] Filter the solid, wash with toluene (2 × 10 vol), and separate the liquid. Put the THF liquid back into a clean container and distill under vacuum with minimal stirring. Add the toluene and distill under vacuum to about 10 vol. Then add water (5 vol) and stir for at least 15 minutes. Stop, allow to settle, remove and discard the aqueous layer. Add 4% HCl (about 4 vol) to bring the pH between 1 and 2, and stir for at least 15 minutes. Stop, allow to settle, remove and discard the organic layer. Add MTBE (15 vol). Add 15% caustic (about 0.9 vol) to bring the pH between 11 and 13. Stir for at least 15 minutes. Stop, allow to settle, remove and discard the aqueous layer. Add water (5 vol). Stir for at least 15 minutes. Stop, allow to settle, remove and discard the aqueous layer.

[0082] Example 3: Synthesis of 5MeODMT hydrochloride Dissolve 5MeODMT (free base) in toluene (1.0-2.5 vol). Or Next, isopropyl alcohol (IPA) (2.5 vol) was added, followed by the addition of 1.25 M HCl (1.0 equivalent) from the IPA, and the temperature was adjusted to 0-5°C over 1 hour.

[0083] If no precipitate / crystals form, add toluene (6.25 vol) over 30 minutes. Then, stir the mixture at 0-5°C for 2 hours. Filter the resulting solid and wash with toluene (3.8 vol). Dry the solid under vacuum at ambient temperature. Yield 58%.

[0084] Example 4: Synthesis of 5MeODMT benzoate 5MeODMT (free base) was dissolved in toluene (1 equivalent), and benzoic acid (1 equivalent) in toluene (10 vol) was added over 20 minutes, while stirring at room temperature for 2 hours. The resulting precipitate / crystals were filtered, washed with toluene (2.5 vol), and dried under vacuum at room temperature.

[0085] Isopropyl acetate (IPAc) (15.8 vol) was added to the solid obtained above, and the temperature was raised to approximately 73°C until the solid dissolved. The solution was cooled to 0-5°C over 2 hours, and this temperature was maintained for 1 hour with stirring. The resulting benzoate was filtered and vacuum-dried at room temperature. Yield: 68%.

[0086] Example 5: Synthesis of 5MeODMT fumarate 5MeODMT (free base) was added to a solution of fumaric acid (0.5 equivalents) in IPA over 15 minutes at 40-45°C. The resulting solution was cooled to room temperature and stirred for 16 hours. Then, the solution was cooled to 0-5°C while stirring for 2 hours. The resulting precipitate / crystals were filtered and rinsed with toluene (2.5 vol). Yield 68%.

[0087] Example 6: 5MeODMT powder Figure 3 shows a schematic route for preparing 5MeODMT (or its salt) in powder form. The three main steps in the process are: 1. Spray drying of a solution of the target substance (e.g., 5MeODMT, or its salts, including any excipients). This can be done via atomizing nozzles such as rotary atomizers, pressure atomizers, twin-fluid nozzles, ultrasonic atomizers, or quad-fluid nozzles. This is done to form droplets that can produce simultaneously formed particles within a desired particle size range. 2. Drying of the atomized droplets (e.g., using nitrogen gas at high temperature if necessary). 3. Separation and recovery of dry particles from the gas stream (e.g., using a cyclone separator to capture the required size fraction).

[0088] Example 7 Slug mucosal irritation assay The slug mucosal irritation (SMI) assay was initially developed at the Laboratory of Pharmaceutical Technology (UGent) to predict the mucosal irritation potential of pharmaceutical formulations and components. The test utilizes the terrestrial slug, Arion lusitanicus. The slug's body wall is a mucosal surface composed of various layers. The outer simple columnar epithelium, containing ciliated cells, microvilli, and mucus-secreting cells, covers the subepithelial connective tissue. Slugs placed on an irritant produce mucus. Furthermore, tissue damage may be induced, leading to the release of proteins and enzymes from the mucosal surface. Several studies have shown that the SMI assay is a useful tool for evaluating the local tolerability of pharmaceutical formulations and components. Classification predictive models have been developed to distinguish between irritation (mucus production) and tissue damage (release of proteins and enzymes). In addition, several studies on ophthalmic preparations have shown that increased mucus production is associated with an increased incidence of stinging, itching, and burning sensations. In 2010, a clinical trial was conducted to evaluate the stinging and burning sensations of multiple diluted shampoos. Participants were instilled with a 5% diluted shampoo solution or artificial tears into their eyes, and scored their discomfort on a 5-point scale at multiple time points up to 30 minutes after instillation. The same shampoo was tested with an SMI assay using a stinging, itching, and burning (SIB) protocol. This study showed that increased mucus production was associated with an increased incidence of stinging and burning in human eye irritation tests. The validity of assays for reliably predicting nasal irritation, as well as stinging and burning, was demonstrated using multiple over-the-counter (OTC) nasal formulations, isotonic and hypertonic salines.

[0089] Furthermore, the tests were validated using a reference chemical for eye irritation (ECETOC Ocular Reference Databank). These studies demonstrate that the SMI assay can be used as an alternative to in vivo eye irritation testing. In addition, a multicenter prevalidation study by four participating laboratories showed that the SMI assay is a valid, readily transferable, and reproducible alternative for predicting the eye irritation potential of chemicals.

[0090] The purpose of this assay was to assess the likelihood of stinging, itching, and burning sensations from the test samples, as defined below. Using objective values ​​obtained for mucus production, a predictive model consisting of four categories (none, mild, moderate, and severe) could be used to estimate the likelihood of stinging, itching, or burning sensations from the test samples. Comparison item: • Negative control - Name: Phosphate-buffered saline (PBS) • Positive control - Name: 1% (w / v) benzalkonium chloride in PBS Test sample: compound 1 Name: 10% (w / v) disodium fumarate in PBS CASRN:17013-01-3 Batch: KBSJ-P0 Description: Colorless solution Storage conditions: Room temperature (formulated on the day of the experiment) compound 2 Name: 10% (w / v) monosodium phosphate in PBS CASRN:7558-80-7 Batch: 2A / 220991 Description: Colorless solution Storage conditions: Room temperature (formulated on the day of the experiment) compound 3 Name: 10% (w / v) sodium acetate in PBS CASRN:127-09-3 Batch: 5A / 233258 Description: Colorless solution Storage conditions: Room temperature (formulated on the day of the experiment) compound 4 Name: 10% (w / v) sodium citrate in PBS CASRN:68-04-2 Vial batch: 5A / 241516 Description: Colorless solution Storage conditions: Room temperature (formulated on the day of the experiment) Test subjects: Slugs (Arion lucitanicus), 3 slugs per treatment group. Adult Arion lucitanicus slugs collected from local gardens along Gent and Aalter (Belgium) were bred in a laboratory acclimatization room (18-20°C). The slugs were kept in plastic containers and fed lettuce, cucumber, carrots, and commercial dog food.

[0091] Test design: A single test was performed. The processing time was 15 minutes, and it was performed three times on the same day. Preparing for slugs: Slugs weighing 3-6 g were isolated from the culture two days before the start of the experiment. The body walls were carefully examined for signs of macroscopic injury. Only slugs with clear granular scales and leg surfaces that showed no signs of injury were used for the test. The slugs were placed in a plastic box lined with paper towels moistened with PBS and maintained at 18-20°C. The slugs' body walls were moistened daily with 300 μl of PBS using a micropipette. Test procedure: The potential for stinging, itching, or burning sensations from the test samples was evaluated by placing three slugs per treatment group in 100 μL of test sample in a Petri dish for 15 ± 1 minutes, three times a day. After each 15-minute contact period, the slugs were transferred to a paper towel moistened with 1 mL of PBS in a new Petri dish for 60 minutes to prevent drying. A summary of this can be seen in Figure 4. Mucus production: The amount of mucus produced during each 15-minute contact period was measured by weighing the petri dish containing the test sample before and after each contact period. Mucus production was expressed as a percentage of body weight. Slugs were weighed before and after each 15-minute contact period. Classification prediction model Based on the endpoints of the SMI assay, a classification predictive model was used to estimate the likelihood of stinging, itching, or burning from the test product.

[0092] The evaluation of the test results was based on the total amount of mucus produced during three repeated contact periods with the test sample. For each slug, mucus production was expressed as a percentage of body weight by dividing the weight of mucus produced during each contact period by the slug's body weight before the start of that contact period. The total mucus for each slug was calculated, and the average per treatment group was determined. The compounds were classified using the classification prediction model shown in Table 1.

[0093] [Table 1]

[0094] Acceptance Criteria For the test to be considered valid, it must meet the following criteria: - Negative controls should be classified as those that do not produce stinging, itching, or burning sensations (total mucus production < 5.5%). - Positive control samples should be classified as causing severe stinging, itching, and burning sensations (total mucus production ≥ 17.5%). Irritation potential

[0095] [Table 2]

[0096] Table 2 shows the average amount of mucus produced and total mucus production (total MP) during each 15-minute contact period. According to the classification predictive model of the SMI test, no reaction was induced in the negative control (untreated slugs) (mean total MP < 5.5%). On the other hand, the positive control (DDWM / SLS 80 / 20) induced high mucus production during each contact period (mean total MP ≥ 17.5%) and was classified as a severe stinging, itching, and burning (SIB) reaction. Acceptance criteria were met, and the experiment was considered valid.

[0097] A total of four different solutions were tested. The amount of mucus produced during each 15-minute contact period ranged from 10% to 17.5%, indicating a moderate SIB reaction. The test samples can be ranked according to the increase in total mucus production: sodium acetate (10% w / v) < sodium citrate (10% w / v) < disodium fumarate (10% w / v) < sodium phosphate (10% w / v). Numerical data

[0098] [Table 3]

[0099] [Table 4]

[0100] [Table 5]

[0101] [Table 6]

[0102] [Table 7]

[0103] result The total MP (past data) for a 60-minute treatment was compared to the total MP of the SIB protocol (3 × 15-minute treatment; current data). The table below shows the ranking from the lowest to the highest SIB reaction.

[0104] [Table 8]

[0105] Sodium oxalate appears to be the most irritating salt, as it produces 11.2% total MP after 1 hour of contact at a 1% concentration. Sodium benzoate is the least irritating salt.

[0106] Example 8 Further slug mucosal irritation (SMI) testing 5MeODMT as a free base compound is known to be highly irritating to the mucosal lining, and is therefore generally prepared as a salt for inhalation. Hydrochloric acid (HCl) salt of 5MeODMT is most commonly used due to its ease of crystallization. However, HCl salt of 5MeODMT is still known to be extremely irritating to the mucosal lining.

[0107] Following the results above, which showed that sodium benzoate was the least irritating salt among those tested, further SMI tests were performed with 5MeODMT benzoate and common 5MeODMT HCl salts according to the method described above (Example 7). The results are shown below.

[0108] [Table 9]

[0109] 5MeODMT benzoate produced a "mild" irritation compared to 5MeODMT HCl, which was scored as "moderate" in the test. Example 9 Penetration data The use of sheep nasal epithelium for studying nasal drug absorption is a well-known technique to those skilled in the art.

[0110] The penetration of 5MeODMT benzoate and 5MeODMT HCl has been tested by the applicants. A drug solution equivalent to a 1.25% concentration was prepared in water and applied to the nasal epithelium of sheep. The average cumulative penetration amount (μg / cm³) of benzoate and hydrochloride was measured. 2 The results are shown in the table below (mean ± SD, n=5).

[0111] [Table 10]

[0112] Figure 5 shows the cumulative amounts of 5MeODMT benzoate and 5MeODMT hydrochloride that penetrated the sheep nasal epithelium per unit area following the application of a 1.25% drug solution prepared in water (mean ± SD, n=5).

[0113] As can be clearly seen, benzoates exhibit higher penetration through the epithelium. The data obtained from the above tests indicate that 5MeODMT benzoate provides higher penetration and less mucosal irritation than commonly used HCl salts; therefore, this combination of properties makes benzoates an ideal candidate for mucosal delivery. For example, less 5MeODMT benzoate may be required for inhalation to provide the same benefits as HCl salts, and the lower irritation of benzoates provides a synergistic benefit. Furthermore, a smaller amount of the compound makes inhalation easier to achieve.

[0114] Example 10 Effects on central nervous system function In the following examples, BPL-5MEO is 5-methoxy-N,N-dimethyltryptamine This refers to n (5 MeODMT).

[0115] In the following examples, 5MeODMT hydrochloride was used. The following examples (10-14) summarize applicant-initiated safety pharmacology studies to evaluate the effects of BPL-5MEO on CNS, cardiovascular, and respiratory function. The study design was conducted in compliance with GLP regulations, based on the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S7A / B guidance.

[0116] The pharmacological effects of BPL-5MEO on CNS function were evaluated using the Functional Observational Balance (FOB) method in male Sprague-Dawley rats following a single intranasal administration (ITR study 15951).

[0117] The test and control / vehicle products were administered by single-dose intranasal administration into both nostrils, as shown in Table 7.

[0118] [Table 11]

[0119] The parameters monitored included mortality and clinical signs. General behavioral changes were assessed using FOB at six time points: before medication and at 15 minutes, 1, 2, 4, and 24 hours after medication. In each case, FOB was performed in four stages: when the animals were in their home cages, when the animals were being handled, when the animals were moving freely in the open field, and when the animals received various stimuli for responsiveness assessment. Body temperature and neuromuscular strength were also measured in each of the scenarios detailed above.

[0120] The FOB tests were grouped according to the functional area of ​​the nervous system, as shown in Table 8.

[0121] [Table 12]

[0122] There were no deaths or illnesses related to the procedure. Transient clinical signs associated with BPL-5MEO were observed immediately after administration, mainly consisting of decreased activity, lying on the cage floor, shallow / increased respiration, and dilated pupils in all dose groups. Tremors, salivation, and gasping were observed in some animals at 3 and 10 mg / kg doses, and spasms were observed in one animal at 10 mg / kg.

[0123] In the behavioral domain of FOB animals, single intranasal administration of BPL-5MEO at doses of 1.5, 3, and 10 mg / kg resulted in transient activity reduction, decreased lying on the cage floor, and reduced standing up 15 minutes after administration. All behavioral parameters were comparable to those of control animals 1 hour after administration.

[0124] In the neuro(sensorymotor) / neuromuscular regions of FOB, single intranasal administration of BPL-5MEO at 1, 5, and 10 mg / kg resulted in transient gait changes (difficulty moving) at all dose levels. All neuro(sensorymotor) / neuromuscular parameters were comparable to those of control animals one hour after administration.

[0125] In the autonomic nervous system area, single intranasal administration of BPL-5MEO at doses of 1, 5, and 10 mg / kg is used. These changes were associated with increased salivation, piloerection, respiration, pupil dilation, and body temperature changes observed across all dose levels. All autonomic parameters were comparable to those of control animals 2 hours post-administration.

[0126] In conclusion, single intranasal administration of BPL-5MEO at doses of 1.5, 3, and 10 mg / kg resulted in transient clinical signs consistent with observable changes in behavioral, neuro(sensorymotor) / neuromuscular, and autonomic parameters, which resolved completely within 1 or 2 hours post-administration.

[0127] Example 11 Effects on cardiovascular function in vitro test In stably transfected human embryonic kidney (HEK-293) cells expressing the hERG gene, the rapidly activated delayed-rectifying cardiac potassium current, the hERG potassium channel current (I Kr The in vitro effect of 5MeODMT on ) was evaluated using the patch-clamp method (CRL test 1020-5458). This assay is employed as a screening tool to assess the potential risk of QT interval prolongation.

[0128] The study was conducted in two phases: Phase 1 evaluated the onset and steady-state inhibition of hERG at selected concentrations of 30 μm 5MeODMT, and Phase 2 evaluated the concentration response if the results of Phase 1 showed inhibition of 20% or more. The initial 30 μm concentration was selected based on the results of an exploratory dose-ranging study in dogs, where intranasal administration of 2.5 mg / kg of BPL-5MEO resulted in a mean C12 of 803 ng / mL (3.67 μM) of 5MeODMT. max The following was obtained. The 30 μM solution used in Phase 1 provided an 8-fold margin for this concentration.

[0129] In Phase 1, 5MeODMT at a concentration of 30 μM in the protein-free perfusion inhibited the hERG potassium ion current by 77.8 ± 7.4% (n=3). Therefore, Phase 2 was conducted using concentrations of 1, 3, 10, and 35 μM of 5MeODMT in the protein-free perfusion (corresponding to 0.2, 0.6, 2.0, and 7.2 μg / mL of the unbound drug substance).

[0130] In Phase 2, as shown in Table 9, 5MeODMT inhibited the hERG potassium ion channel current in a concentration-dependent manner.

[0131] [Table 13]

[0132] in vivo testing The pharmacological effects of BPL-5MEO on cardiovascular function (arterial blood pressure and ECG) in conscious male beagle dogs were monitored by telemetry after a single intranasal administration. Ta.

[0133] The highest dose level was selected based on the results of a maximum tolerated dose (MTD) toxicity study in dogs (Study 62958), in which repeated administration of 2.5 mg / kg / day of BPL-MEO once daily for 5 consecutive days was poorly tolerated and associated with transient clinical observations of moderate to severe dyscoordination, vocalization, salivation, tremors, circling, sneezing, decreased activity, and respiratory distress, which resolved within 60 minutes after administration. Therefore, the highest dose selected for this study was 1.2 mg / kg / day. The lowest dose of 0.4 mg / kg / day was selected considering the maximum clinical dose of 14 mg / day, and the intermediate dose of 0.8 mg / kg / day was selected to allow for dose-response evaluation.

[0134] BPL-5MEO and the control / vehicle were administered to a total of four dogs by intranasal administration into both nostrils per session. Each dog received four doses (three dose levels of control / vehicle and BPL-5MEO) according to a Latin square design, ensuring that each dog received different doses in a unique order, as shown in Table 10. A washout period of at least two days was permitted between each consecutive dose.

[0135] [Table 14]

[0136] The low, medium, and high doses were 0.4, 0.8, and 1.2 mg / kg / day, respectively. The nominal dose level refers to the free base in the form of a salt of 5 MeODMT. The dose volume administered to each animal was 7 μL / kg / nostril. None of the animals exceeded a dose volume of 100 μL / nasal cavity.

[0137] The control vehicle was 0.1% hydroxypropyl methylcellulose (HPMC) in water. Arterial pressure and pulse rate, ECG (heart rate [HR], RR, PR, QT and QTcV intervals, and QRS complex duration), body temperature, and telemetry signals of spontaneous movement were continuously recorded over a telemetry recording period of at least 1.5 hours before the start of medication and at least 24 hours after medication. Systolic, diastolic, and mean arterial pressure and pulse rate were acquired from a transmitter catheter inserted into the femoral artery. ECG was acquired from the biopotential leads of the telemetry transmitter in a lead II configuration.

[0138] During the study, all animals were monitored for mortality and clinical signs. Body weight was recorded only for the purpose of confirming general health status and calculating dosage. During the trial, there were no deaths or clinical signs associated with BPL-5MEO.

[0139] The morphology of the P-QRS-T waveform remained normal, and no rhythm or conduction abnormalities were observed in the ECG between the control and treatment groups. (Average values ​​were averaged over approximately 0-150 minutes after administration.) There were minor differences in the percentage change in HR between all dose levels and the control vehicle. During this period, the mean percentage increase in mean HR was 3.7% in the control vehicle compared to baseline, while the increases observed at the low, medium, and high dose levels of BPL-5MEO were 7.6%, 10.3%, and 17.2%, respectively. However, arterial pressure did not appear to show a sufficiently significant difference to affect HR. No other findings were observed. The mean increase in HR observed at all dose levels was non-adverse and reversible and did not show a typical dose-response relationship.

[0140] In conclusion, single intranasal infusions of BPL-5MEO at doses of 0.4, 0.8, and 1.2 mg / kg / day were well-tolerated and did not affect the cardiovascular system of conscious male beagle dogs.

[0141] Example 12 Absorption and Pharmacokinetics In a 14-day intranasal toxicology (ITR Report 700041) in male and female rats, the plasma concentration of 5MeODMT increased as a function of the dose administered. Peak (C max ) concentration was reached within 2 - 5 minutes (T max ) after dosing, and the apparent t 1 / 2 was in the range of 6.8 - 9.4 minutes. Values tended to be lower on day 14 compared to day 1. There was no evidence of clear sex differences or accumulation due to repeated dosing.

[0142] In a 14-day intranasal toxicology study (ITR Report 62959) in male and female dogs, the plasma concentration of 5MeODMT increased as a function of the dose administered. Peak concentration was reached within 3 - 14 minutes (T max ) after dosing, and the apparent elimination half-life was in the range of 19 - 95 minutes. Values did not differ significantly between day 1 and day 14. There was no evidence of clear sex differences or accumulation due to repeated dosing.

[0143] Data across the dose ranges tested in rats (5, 20, 75 mg / kg) as well as dogs (0.4, 0.8, 1.5 and 2.5 mg / kg) showed that exposure generally increased in a dose-dependent manner, but some increases were higher or lower than the dose ratio between different doses, indicating that it was not consistently dose-proportional. The results do not show saturation of MAOA-mediated metabolism at the doses tested in these species as previously seen in mice.

[0144] Example 13 Toxicology The toxicology program completed with BPL-5MEO consisted of non-pivotal single / repeated dose studies to determine the MTD to support the selection of the highest dose in a 14-day pivotal GLP intranasal toxicology study in male and female Sprague Dawley rats and beagle dogs. Since the clinical route of administration was used, the intranasal route of administration was employed. The species selected were based on information from the published literature, preliminary PK information, the availability of past control information from the test laboratories, and the standard use of intranasal administration and its approval as a suitable surrogate. The experimental design of the 14-day pivotal test included an evaluation of systemic exposure (toxicokinetics) and a 14-day recovery period to evaluate the reversibility of adverse or delayed responses. To characterize the potential toxicity of the parent drug with a very short half-life, once-daily dosing for 14 consecutive days in the pivotal test was intended to provide sufficient systemic exposure. 1. Non-pivotal single / repeated dose and tolerance studies a. Maximum tolerance dose in rats, followed by 7-day repeated dose toxicology (Study 700040) The objective of this non-GLP study was to determine the maximum tolerance dose and the toxicity profile of BPL-5MEO following intranasal administration in rats. The study consisted of two parts. The objective of the first part (dose escalation phase) was to determine the MTD of BPL-5MEO following single intranasal administration to Sprague-Dawley rats. The doses used in the first part were 15, 30, 50, 65, and 75 mg / kg. Each subsequent dose was administered at least 24 hours after the start of the previous dose. Two males and two females were used per dose group. The objective of the second part (main study phase) was to determine the toxicity of BPL-5MEO at the MTD of 75 mg / kg following once-daily intranasal administration to Sprague-Dawley rats for 7 consecutive days.

[0145] All dose formulation samples taken and analyzed were between 89.2% and 101.3% of the nominal concentration and thus met the accuracy acceptance criteria (100 ± 15% of the nominal concentration). The analysis was performed using a non-GLP HPLC-UV assay.

[0146] All female groups were administered the target dose in both halves. However, the maximum feasible loading dose was kept below 25 μL / nasal cavity regardless of body weight, so the mean doses achieved in males in 30 were still 99.3%, 90.0%, 88.2%, and 89.6%, respectively, and were considered acceptable.

[0147] In Phase I, mortality, clinical signs, and body weight were assessed. All animals were observed for 14 days after administration, then euthanized on day 15 and subjected to macroscopic necropsy. The necropsy consisted of an external examination including reference to all clinically documented lesions, and a detailed internal examination.

[0148] A single intranasal administration of 5 MeODMT at dose levels up to 75 mg / kg was well tolerated. No deaths or macroscopic pathological findings were reported at any dose. Weight gain was slightly suppressed in females at 75 mg / kg. A range of clinical signs were observed, including dyscoordination, shallow or increased breathing, sneezing, salivation, decreased activity, piloerection, white paste-like substance around the penis (in males), ptosis, lying on the cage floor, sensitivity to touch, and tremors. The incidence and severity of these findings varied as a function of dose, were transient, and resolved mostly within 1 hour post-administration. Based on clinical signs and the maximum viable volume / dose, 75 mg / kg was determined to be the MTD, and this dose was selected for Phase 2.

[0149] In Phase 2, mortality, clinical signs, and body weight were assessed. After administration, all animals were euthanized and subjected to necropsy on day 8. The necropsy consisted of an external examination, including reference to all clinically documented lesions, and a detailed internal examination. Study-specific tissues / organs were collected and stored, and prepared and preserved promptly after euthanasia of the animals, but no further microscopic examination was performed.

[0150] Intranasal administration of 75 mg / kg of 5 MeODMT for seven consecutive days was well tolerated. There were no deaths. Weight gain was slightly suppressed in both sexes. Transient clinical signs similar to those of Phase I included dyscoordination, pupillary dilation, increased or shallow breathing, gasping, sneezing, salivation, pallor, decreased activity, lying on the cage floor, erect hair, white paste-like substance around the penis (in males), penile erection (in males), cold to the touch, partial or complete eye closure, sensitivity to touch, and tremors. These signs were generally less pronounced in terms of severity and incidence during the last few days of administration in this phase and resolved within one hour after daily administration. Notable macroscopic findings were limited to dark / pale areas of the lungs in 2 / 10 animals, but in the absence of histopathological examination, the possibility of these findings being associated with the test substance could not be ruled out. b. Maximum tolerable dose in dogs, followed by repeated dose toxicology over 7 days. (Exam 62958) The purpose of this study is to evaluate the effects of the test product, 5MeODMT, after intranasal infusion in dogs. The objective was to determine the maximum tolerated dose and toxicity (as hydrochloride). To support these objectives, the study consisted of two phases.

[0151] The test substance was administered once by intranasal infusion to one male and one female dog at five dose levels until the maximum tolerated dose (MTD) was determined, as described in Table 11.

[0152] [Table 15]

[0153] There were no BPL-5MEO-related effects on mortality or body weight. A slight decrease in food intake was observed after administration on day 1 (dose 1) and day 9 (dose 2) in males, and on day 4 (dose 1) and day 9 (dose 2) in females. A range of clinical signs were observed, including cage wire gnawing, pupillary dilation, respiratory changes, impaired coordination, decreased activity, vocalization, salivation, penile erection (in males), and tremors. After the final escalation dose of 3.5 mg / kg / day, male animals exhibited convulsions immediately after administration, lasting 8 minutes. All clinical signs disappeared within 1 hour after administration, except for decreased activity, pupillary dilation, and lying on the cage floor, which were observed several times 1 hour or several minutes after administration. The MTD of the test product was considered to be 2.5 mg / kg.

[0154] In Phase 2 (dose confirmation), BPL-5MEO was administered to one male and one female dog with MTD (Most Transient Disease) once daily by intranasal infusion for 5 consecutive days, followed by twice daily (with at least 4 hours between doses) on days 6 and 7. During Phase 2, mortality, clinical signs, body weight, and food intake were assessed. A series of blood samples were taken on days 1 and 7 to determine the plasma concentration of 5MeODMT using LC / MS / MS. After the last dose, all animals were euthanized and subjected to necropsy on day 8. The necropsy consisted of an external examination, including reference to all clinically documented lesions, and a detailed internal examination. Post-necropsy, study-specific tissues / organs were collected and preserved, but no further microscopic examination was performed.

[0155] There were no deaths or effects on body weight related to the test substance. A slight decrease in food intake was observed in male animals on day 7 and in female animals on days 5 and 7. A range of clinical signs were observed, including muscle rigidity, cage wire gnawing, pupil dilation, respiratory changes, decreased activity, coordination disorders, vocalization, salivation, penile erection (in males), and tremors. All clinical signs disappeared within one hour after administration, except for decreased activity, pupil dilation, and lying on the cage floor, which were observed several times one hour and several minutes after administration. All observations were considered transient.

[0156] Toxicokinetic evaluations were conducted on days 1 and 7. The maximum plasma concentration (C max ) of BPL-5MEO ranged from 541 to 803 ng / mL and was reached within 2 to 15 minutes after dosing in both sexes (T ). The dose-normalized AUC ranged from 2980 to 7320 min * kg * ng / mL / mg in both sexes. After T max , the plasma concentration of BPL-5MEO decreased with an estimated t 1 / 2 of 19.1 to 34 minutes in both sexes. In all cases, there were no sex differences in any of the measured toxicokinetic parameters. Over the 7-day treatment period, BPL-5MEO did not accumulate when administered daily by intranasal instillation. 2. Pivotal trial a. 14-day repeated-dose intranasal toxicity study in rats followed by a 14-day recovery period (Study 700041) The objective of this GLP study was to determine the toxicity and toxicokinetic (TK) profile of BPL-5MEO after 14 consecutive days of intranasal administration to Sprague Dawley rats and to evaluate the persistence, delay, or reversibility of changes after a 14-day recovery period.

[0157] BPL-5MEO and control / vehicle were administered once daily to groups of rats by intranasal administration for 14 consecutive days as described in Table 12.

[0158]

Table 16

[0159] ​​Animals were monitored for death, clinical signs, respiratory measurements, body weight, food intake, and body temperature. Ophthalmic and respiratory function tests were performed on all animals at scheduled times. Clinicopathological evaluations (hematology, coagulation, clinical chemistry, and urinalysis) were assessed at the end of the study. Blood samples were taken from the jugular vein of TK animals for up to 8 hours post-treatment on days 1 and 14 for biological analysis of 5MeODMT concentration in plasma and subsequent calculation of toxicokinetic parameters. After administration, the primary animals were euthanized and subjected to a complete necropsy on day 15. The recovered animals were observed for a further 14 days before being euthanized and subjected to a complete necropsy on day 28. The TK animals were euthanized after the final blood collection and disposed of without further examination. At the final euthanasia, selected tissues / organs were weighed, and a standard set of tissues, including turbinates (4 sections) and brain (7 sections), was microscopically evaluated for all primary and recovered test animals.

[0160] After administration, the animals in the main group were euthanized and subjected to necropsy on day 15. The animals in the recovery group were observed for 14 days, then euthanized and subjected to necropsy on day 28. For toxicokinetics, at days 1 and 14 of the treatment period, and at 2, 5, 10, 15 and 30 minutes of treatment, and At 1.0, 3.0, and 8 hours after administration, a series of eight blood samples (approximately 0.5 mL each) were collected from all rats in the toxicokinetics group (3 rats / sex / time). For the control rats in the toxicokinetics group (3 rats / sex), only one sample was collected at 15 minutes after administration on days 1 and 14.

[0161] Toxicity was assessed based on the following monitored parameters: death / morbidity, clinical observation, weight / gain, food intake, fundus examination, clinicopathology (hematology, coagulation, chemistry, and urinalysis), autopsy observation, weight of selected organs, and microscopic examination of a standard tissue sample including four sections of the nasal cavity and seven sections of the brain. result All samples met the tolerance criteria for accuracy (100 ± 10% of the nominal concentration).

[0162] All animals received the medication without major complications, and no sneezing was observed. All groups received the target dose between days 1 and 10. To ensure the maximum feasible loading dose did not exceed 25 μL / nasal cavity (due to the limited surface area of ​​the nasal cavity), male animals in all groups received a slightly lower dose level between days 11 and 14 once their body weight exceeded 333 g. This was considered to have no impact on the study data due to the minimal difference.

[0163] No deaths occurred during the study period. The clinical signs observed were as follows: Group 2 (low dose) Both male and female animals exhibited impaired coordination, tremors, excessive salivation, decreased activity, lying on the cage floor, and sensitivity to touch. On day 3, increased respiration was also observed in one female animal. Group 3 (medium dose) Both male and female animals exhibited impaired coordination, tremors (or shaking), increased or shallow breathing, dilated pupils, salivation, decreased activity, partial eye closure, lying on the cage floor, and sensitivity to touch. Male animals also exhibited penile erection. Group 4 (high dose) Both male and female animals exhibited impaired coordination, tremors (or shaking), increased or shallow breathing, dilated pupils, salivation, decreased activity, partial eye closure, lying on the cage floor, and sensitivity to touch. Male animals also exhibited penile erection.

[0164] While increased respiration was recorded in the intermediate and high-dose groups, respiratory values ​​measured using plethysmography demonstrated that the respiratory rate was actually decreasing. All of the above clinical signs were considered transient in all groups.

[0165] Between days 1 and 14, a slight, generally dose-dependent suppression of weight gain was observed in both sexes. At dose levels of 75 mg / kg / day or less, there were no changes in food intake that could be attributed to the 14-day treatment.

[0166] On day 14, slight increases in body temperature were observed in all treated male animals 15 and 30 minutes after administration, and in females on day 14, increases in body temperature were observed in 1 or all treatment groups at all time points (up to 2 hours after administration). These increases in body temperature were more pronounced in the moderate (20 mg / kg / day) and high (75 mg / kg / day) dose groups.

[0167] Compared to pre-treatment or control groups, a decrease in respiratory rate was observed 20 minutes after administration, resulting in a decrease in minute ventilation. Tidal volume was similar to either pre-treatment or control values. In female animals in group 2, respiratory measurement 20 minutes after administration on day 1 was inadvertently not performed. This can be extrapolated from the male animals in the same group, thus affecting the test data. It was deemed to have no effect. There were no significant differences between genders.

[0168] No adverse effects on the eyes were observed when BPL-5MEO was administered at dose levels of 75 mg / kg / day or higher for 14 days. All other clinical observations, including changes in body weight, food intake, and body temperature, were sporadic, comparable to pre-treatment signs or control animals, and not dose-related; therefore, they were considered unrelated to BPL-5MEO.

[0169] Compared to the control group, platelet count, neutrophil count, monocyte count, and basophil count were slightly increased in both the moderate and high-dose groups, but these values ​​remained within the historical range. On day 28, all of these values ​​were compared to those of the control group.

[0170] All changes in hematological parameters, including those that reached statistical significance, were minor (within the normal physiological range), comparable to control values, and / or dose-independent, and therefore not attributable to BPL-5MEO administration.

[0171] Compared to the control group, activated partial thromboplastin time (APTT) increased in both the moderate (20 mg / kg / day) and high (75 mg / kg / day) dose groups. Coagulation values ​​on day 28 were all similar to those of the control group. All other changes in coagulation parameters were minor (within the normal physiological range), similar to control values, and / or dose-independent, and therefore not attributable to BPL-5MEO administration.

[0172] No changes in clinical chemistry or urinalysis parameters were observed that could be attributed to the administration of BPL-5MEO at dose levels of 75 mg / kg / day or less for 14 days. All parameter changes, including those in clinical chemistry that reached statistical significance, were minor (within the normal physiological range), comparable to control values, and / or dose-independent, and therefore not attributable to BPL-5MEO administration.

[0173] Compared to the control group, a decrease in thymic weight (absolute and relative to final body weight) was observed in male animals, as shown in Table 13.

[0174] [Table 17]

[0175] All changes in organ weight parameters, including those that reached statistical significance, were minor, comparable to control values, and / or dose-independent, and therefore not attributable to BPL-5MeO administration.

[0176] In both the primary and recovery groups of rats, macroscopic changes associated with treatment with BPL-5MEO were observed. No findings were observed. In the main group of animals, microscopic findings associated with treatment with BPL-5MEO were observed in nasal cavity sections 1, 2, 3, and 4 of the main rat.

[0177] Minimal to mild changes were observed in the respiratory epithelium, transitional epithelium, and / or olfactory epithelium of nasal cavities 1, 2, 3, and 4. The incidence and severity of changes were higher in males than in females and were proportional to the dose of BPL-5MEO.

[0178] Microscopic changes observed in rats administered 75 mg / kg / day of BPL-5MEO (group 4) included: minimal to mild degeneration, hyperplasia, and squamous metaplasia, minimal mononuclear cell infiltration and / or luminal exudate of the respiratory epithelium in nasal cavities 1, 2, 3, and / or 4; minimal hyperplasia of the transitional epithelium in nasal cavity 1; and minimal to mild degeneration and / or minimal mononuclear cell infiltration and erosion of the olfactory epithelium in nasal cavities 2, 3, and / or 4. Minimal degeneration of the olfactory epithelium in nasal cavities 2 and 3 was observed in male and / or female rats administered 5 and / or 20 mg / kg / day of BPL-5MEO (groups 2 and 3). Minimal degeneration of the respiratory epithelium in nasal cavities 1 and 2 was observed in male and / or female rats administered 20 mg / kg / day of BPL-5MEO (group 3).

[0179] In the recovered group of animals, microscopic findings associated with treatment with BPL-5MEO were observed in nasal cavity sections 1, 2, 3, and 4 of recovered rats. Minimal to mild changes were observed in the respiratory and olfactory epithelium of nasal cavities 1, 2, 3, and / or 4. The incidence and severity of changes were higher in males than in females. Microscopic changes included minimal to mild degeneration of the respiratory epithelium of nasal cavities 1 and 2, as well as minimal degeneration of the olfactory epithelium of nasal cavities 2, 3, and 4, showing an incomplete but progressive and continuous reversal of epithelial degeneration after a 14-day recovery period. After a 14-day recovery period, a complete reversal of all other microscopic changes previously observed in the nasal cavities of major rats was seen, including reversal of epithelial hyperplasia, squamous metaplasia, mononuclear cell infiltration, erosions, and luminal exudate.

[0180] Other microscopic findings in both the primary and recovery groups were not dose-related, had low incidence or severity, and / or were also observed in control animals, thus they were considered procedure-related or incidental. Toxicokinetics Exposure to 5MeODMT on days 1 and 14 across the dose range (area under the plasma drug concentration-time curve [AUC] from administration to the final quantifiable concentration) 0-Tlast Based on the [value], the increase was generally dose-dependent (with the exception of group 4, described below), but some increases were not consistently dose-proportional, as they were higher or lower than the dose ratio between different doses. Furthermore, at day 14, the exposure in female group 4 (75 mg / kg / day) was reduced compared to female group 3 (20 mg / kg / day).

[0181] The sex ratio ranged from 0.4 to 6.2, but since the sex ratio varied randomly between treatment groups and between treatment opportunities, it was considered that there were no sex-related differences. Accumulation ratio (AUC 0-Tlast Based on the data, the levels were sporadic, ranging from 0.3 to 2.9 (day 14 / day 1). This suggests that when administered once daily for 14 consecutive days (2 weeks) to Sprague Dawley rats by intranasal infusion at doses up to 75 mg / kg / day, 5MeODMT does not accumulate.

[0182] The mean toxicokinetic parameters for groups 2, 3, and 4 are shown in Table 14.

[0183] [Table 18]

[0184] conclusion Intranasal administration of BPL-5MEO at doses of 75 mg / kg / day or less for 14 consecutive days demonstrated tolerability, with no BPL-5MEO-related effects on death, fundus examination, clinical chemistry, macroscopic findings, or urinalysis. Slight dose-dependent suppression of weight gain was observed in both sexes. Transient clinical signs included dyscoordination, tremors (or shaking), increased or shallow breathing, pupillary dilation, salivation, decreased activity, partial eye closure, lying on the cage floor, and sensitivity to touch. Male animals also exhibited penile erection. Slight dose-dependent hyperthermia was observed in both sexes.

[0185] A decrease in respiratory rate was observed 20 minutes after administration, resulting in a decrease in minute ventilation. Platelet count, neutrophil count, monocyte count, and basophil count were slightly increased in both the intermediate and high-dose groups of both sexes. APTT was increased in both sexes in the major animals of the intermediate (20 mg / kg / day) and high (75 mg / kg / day) dose groups. A decrease in thymic weight (absolute and relative to final body weight) was observed in male animals. Microscopic changes were observed in nasal cavities 1, 2, 3 and / or 4, including respiratory epithelium, olfactory epithelium, and transitional epithelium. The incidence and severity of findings were higher in males than in females, proportional to the dose of BPL-5MEO, and were incompletely but progressively reversed after a 14-day recovery period.

[0186] NOAEL was reported as the minimum dose of 5 mg / kg. b. 14-day repeated-dose intranasal toxicity study in dogs, followed by a 14-day recovery period (Study 62959) The purpose of this GLP trial (Trial 62959) was to determine the toxicity and TK profile of BPL-5MEO after intranasal infusion in Beagle dogs over 14 consecutive days. The objective was to assess the persistence, delayed onset, or reversibility of changes after the recovery period.

[0187] BPL-5MEO and the control / vehicle were administered to the dog group once daily by intranasal infusion for 14 consecutive days as shown in Table 15.

[0188] [Table 19]

[0189] Mortality, clinical signs, olfactory reflex, body weight, food intake, fundus examination, and electrocardiogram were evaluated. In addition, clinicopathological evaluations (hematology, coagulation, clinical chemistry, and urinalysis) were performed once before and after the procedure. Blood samples were taken from the jugular vein of all animals at up to eight time points relative to the procedure, on days 1 and 14, for analysis of the concentration of the test substance in plasma and subsequent calculation of toxicokinetic parameters. After administration, the primary animals were euthanized and subjected to a complete necropsy on day 15. The recovered animals were observed for a further 14 days without the test substance, then euthanized and subjected to a complete necropsy on day 28. All primary and recovered animals underwent a complete necropsy, selected tissues / organs were preserved, and a standard set of tissues was microscopically evaluated.

[0190] For toxicokinetics, a series of eight blood samples were collected from the jugular vein of all treated animals at 2, 5, 10, 15, 30, and 60 minutes, and 3 and 8 hours, respectively, after administration on days 1 and 14 of the treatment period. In Group 1, only one sample was collected at 15 minutes after administration on days 1 and 14 to confirm the absence of BPL-5MEO in the vehicle control group animals. Blood samples were analyzed for plasma BPL-5MEO concentration and subsequent TK parameter calculations. result All drug formulation samples collected and analyzed met the acceptable accuracy criteria (100 ± 10% of the nominal concentration).

[0191] No deaths occurred when BPL-5MEO was administered intranasally once daily for 14 consecutive days into both nostrils of beagle dogs at dose levels up to 1.5 mg / kg / day. In high-dose animals, initial administration of 2.5 mg / kg to a subset of dogs resulted in severe clinical signs of muscle rigidity, tachycardia, tachypnea, hyperthermia, and aggression after the first day of administration. The dose exceeded the MTD. Subsequently, the high dose was reduced to 1.5 mg / kg / day on day 2, and this dose was well-tolerated. Animals in all treatment groups exhibited transient clinical observations of coordination disorders, vocalizations, pupillary dilation, decreased or increased activity, increased respiration, cage wire gnawing, excessive licking of the nose or lips, and circling. Eye discharge and tremors were also observed in the medium and high-dose groups. Penile erection was also recorded in male animals receiving high doses. All of these clinical signs were considered exacerbations of pharmacological symptoms, occurring within 10–30 minutes of administration and resolving within 90 minutes.

[0192] Compared to the control group, triglyceride levels were elevated in one-third of females in group 3, one-fifth of males in group 4, and four-fifths of females in group 4, as shown in Table 16. No other clinical or pathological findings were associated with the treatment.

[0193] [Table 20]

[0194] All other changes in clinical chemistry parameters, including those that reached statistical significance, were minor (within the normal physiological range), comparable to control values, and / or dose-independent, and therefore not attributable to BPL-5MEO administration.

[0195] There were no changes in olfactory reflex, food intake, body weight, eye effects, or ECG that could be clearly attributable to treatment with BPL-5MEO at dose levels of 1.5 mg / kg / day or less for 14 days. All changes in body weight were minor and not toxicologically related, and therefore not attributable to the administration of the test substance. All changes in food intake, including those that were statistically significant, were minor and not toxicologically related, and therefore not attributable to the administration of the test substance.

[0196] Animals exhibited hyperthermia on day 1 at a dose level of 2.5 mg / kg / day. On day 14, transient increases in body temperature were observed 15 and 30 minutes after administration in both sexes in the high-dose group. All other changes in body temperature were minor and not toxicologically related, and therefore not attributable to the administration of the test substance.

[0197] Histopathological examination of male animals revealed mild to moderate cytoplasmic reduction in thymic lymphocytes at dose levels of 0.8 mg / kg / day (1 male) and 1.5 mg / kg / day (3 males), which was determined to be stress-related. Minimal epithelial metaplasia of the respiratory epithelium in the nasal cavity, observed at dose levels of 0.8 mg / kg / day (1 female) and 1.5 mg / kg / day (2 males), as well as minimal to mild mononuclear cell infiltration of the olfactory epithelium in the nasal cavity, observed at dose level of 1.5 mg / kg / day (1 male / 1 female), were caused by BPL-5MEO. It was considered a sign of irritation, but not harmful.

[0198] In animals euthanized after a 14-day recovery period, only minimal mononuclear cell infiltration in the olfactory epithelium of the nasal cavity was still observed at a dose level of 1.5 mg / kg / day (one female), but the severity was lower compared to animals euthanized in the terminal stage, suggesting recovery. Decreased thymic lymphocyte cell density was no longer observed. Toxicokinetics BPL-5MEO was not detected in any of the samples taken from control (group 1) animals on days 1 and 14.

[0199] The mean toxicokinetic parameters for groups 2, 3, and 4 are shown in the table below. Mean toxicokinetic parameters of trial 62959

[0200] [Table 21]

[0201] Exposure to BPL-5MEO on days 1 and 14 across the dose range (AUC 0-TlastThe exposure (based on the values) increased in a generally dose-dependent manner (with the exception of group 4, described below), but some increases were not consistently dose-proportional, as they were higher or lower than the dose ratio between different doses. Furthermore, at day 14, exposure in group 4 (1.5 mg / kg / day) was reduced compared to group 3 (0.8 mg / kg / day).

[0202] On the 14th day, compared to the females of group 4, the males of group 4 were T max Except for a slightly delayed onset, there were no significant sex-related differences in any of the measured toxicokinetic parameters. The sex ratio (male / female) was T in group 4. max Except for days 1 and 14, there were sporadic cases of 0. The range was 5 to 1.7.

[0203] Accumulation ratio (AUC 0-Tlast Based on the results, the levels were sporadic, ranging from 0.6 to 2.0 (day 14 / day 1). This suggests that BPL-5MEO does not accumulate when administered once daily for 14 consecutive days (2 weeks) to beagle dogs by intranasal infusion at doses up to 1.5 mg / kg / day. conclusion Based on the tested parameters in which all observed changes were considered non-adverse or related to exaggerated pharmacological effects, the reported NOAEL of BPL-5MEO when administered intranasally for 14 consecutive days, followed by a 14-day recovery period, was 421 ng / mL. max , and an AUC of 213(220) h*ng / mL 0-Tlast (AUC INF_obs This was considered to be equivalent to 1.5 mg / kg / day (combined for both sexes). Toxicokinetics Considerations Based on preliminary data from another ongoing study in dogs, it has been observed that the site of blood sampling in dogs may affect the measured plasma exposure. Samples from the jugular vein may show higher apparent exposure levels than samples from the cranial vein, which may be due to the local transmucosal administration route (as reported in the scientific literature (Illum, 2003; Sohlberg, 2013)). Therefore, the dose escalation criteria for a Phase 1 single dose escalation study should be based on clinical criteria. Based on assessments of safety factors and exposure, a maximum dose of 14 mg is specified. The table below summarizes clinical observations from toxicity studies conducted in rats and dogs with BPL-5MEO. These clinical signs were considered to be related to the pharmacological activity of BPL-5MEO and showed dose-related increases in the severity of findings in both species, generally ranging from mild to moderate at 0.4–1.5 mg / kg in dogs and 1.5–5 mg / kg in rats. Overview of Clinical Observations in Applicant-Initiated Animal Studies

[0204] [Table 22]

[0205] Example 14 Genotoxicity The genotoxicity of 5MeODMT was evaluated in silico (computerized analysis) for structural alerts, in accordance with ICH S2(R1) guidance, and further evaluated in vitro using GLP assays to assess mutagenicity and chromosomal aberration induction. in silico 5MeODMT, its major active metabolite bufotenine, and the identified drug substance impurity MW234 were evaluated for quantitative structure-activity relationships regarding potential mutagenicity and / or carcinogenicity using two computational analysis methods: Derek Nexus and Leadscope Genetox Statistical Models. Neither analysis identified any structural alerts related to 5MeODMT or bufotenine, or to the potential or identified drug substance impurity MW234. in vitro mutagenicity The mutagenic potential of 5MeODMT was evaluated using the GLP bacterial reverse mutation test (Ames test) to assess its ability to induce reverse mutations at selected loci in Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537, and Escherichia coli tester strain WP2uvrA. These strains were treated with 5MeODMT at concentrations of 1.6, 5, 16, 50, 160, 500, 1600, and 5000 μg per plate, along with vehicle / negative control and appropriate positive control. The assay was performed in triplicate using the pre-incubation method in the absence and presence of the exogenous metabolic activator phenobarbital / 5,6-benzoflavone-induced rat liver S9 microsomal enzyme mixture (S9mix).

[0206] Slight cytotoxicity was observed in all S. typhimurium strains at a concentration of 1600 μg / plate. In the absence of S9 mix, higher levels of cytotoxicity were observed at 5000 μg / plate, but remained slight in these strains in the presence of S9 mix. No cytotoxicity was observed in E. coli strains, either in the absence or presence of S9 mix.

[0207] Overall, no increase in the number of reverse mutation colonies per plate (≥2 × vehicle / negative control value) mediated by 5MeODMT was observed in the S. typhimurium tester strains TA1535, TA100, and E. coli WP2uvrA, either in the absence or presence of S9, or in the presence of S9 mix in TA1537 and TA98. Three exceptions were observed: a 2.1-fold increase at 1600 μg / plate without S9 in E. coli WP2uvrA, a 2.0-fold increase in S. typhimurium TA1537 at 50 μg / plate with S9, and a 2.1-fold increase in S. typhimurium TA1535 at 1600 μg / plate with S9. However, these values ​​were within the laboratory's historical vehicle / negative control range and were not considered biologically relevant as they were dose-independent.

[0208] Two strains of S. typhimurium treated with 5MeODMT, TA1537 and TA98, showed slightly higher than twice the vehicle / negative control count in the absence of S9mix at 160 μg / plate and 500 μg / plate, respectively, with increases of 2.3 and 2.7 times for TA1537 and 2.2 and 2.4 times for TA98. The increase in colony count observed in these strains was still within the range of the laboratory's past vehicle / negative control and was not dose-related overall, thus failing to meet the criteria for a positive result. However, since increases were observed in TA98 and TA1537 at two adjacent dose levels, and the two strains showed a similar trend in the increase in reverse mutation colony count at the same concentration level, the results were deemed inconclusive. Therefore, bacterial reverse mutation tests were repeated for these two strains in the absence of S9mix to investigate these inconclusive results. In the repeated trials, a narrower concentration range of 15, 30, 60, 120, 250, 500, 1000, and 2000 μg per plate was used. Results from the repeated trials showed no increase in the number of reverse mutation colonies per plate for both 5MeODMT-treated strains at all tested concentration levels up to the maximum dose of 2000 μg / plate. Therefore, the slight increase observed in the initial trials for the S. typhimurium tester strains TA1537 and TA98 was not biologically relevant. It was concluded that...

[0209] In conclusion, the results of the bacterial reverse mutation assay showed that 5MeODM did not induce an increase in the number of reverse mutation colonies in any of the bacterial strains tested, either in the absence or in the presence of the rat liver S9 microsomal metabolic activation system. 5MeODM is not mutagenic in bacterial reverse mutation assays. The sensitivity and validity of the assay were confirmed by the expected responses of positive and negative controls. In vitro chromosomal aberration induction The chromosomal aberration-inducing performance of 5MeODMT was evaluated in an in vitro micronucleus test of GLP using Chinese hamster ovary (CHO)-K1 cells with flow cytometry. Exponentially growing cells were treated in double cycles with nine concentrations of 5MeODMT up to the recommended upper limit of 1 mM (approximately 300 μg / mL): 1.25, 2.5, 5.0, 10, 20, 40, 80, 150, and 300 μg / mL. Treatment with vehicle / negative and positive controls was performed simultaneously. Three treatment regimens were available: a 4-hour short-term exposure in the absence or presence of the exogenous metabolic activator phenobarbital / 5,6-benzoflavone rat liver S9 microsomal enzyme mixture (S9mix), and a 26-hour long-term exposure in the absence of S9mix, considered a confirmation phase.

[0210] Throughout the treatment period, no cytotoxicity or precipitation was observed in cells treated with 5MeODMT up to the maximum dose level of 300 μg / mL. In all treatment regimens, the in vitro micronucleus test results indicated that 5MeODMT did not induce an increase in micronuclei or hypodiploid cells, either in the absence or in the presence of the rat liver S9 microsomal metabolic activation system. In conclusion, 5MeODMT did not demonstrate chromosome-damaging ability in the in vitro micronucleus test using CHO-K1 cells. The expected responses of positive and negative controls confirmed the sensitivity and validity of the assay. Reproductive toxicity and developmental toxicity No reproductive or developmental toxicity studies were conducted. In 14-day pivotal GLP intranasal toxicity studies in rats and dogs, there was no evidence of adverse effects on reproductive tissue from systemic exposure to BPL-5MEO.

[0211] Example 15 Formulation BPL-5MEO is synthesized in accordance with Good Manufacturing Practice (GMP) standards and pre-filled into Aptar Unidose Intranasal Liquid Delivery System devices. These devices enable single, fixed-dose intranasal administration of BPL-5MEO. The liquid is pre-filled into standard single-dose nasal pump devices and administered using these devices. The excipients used in the formulation are water, 0.1% hydroxypropyl methylcellulose (HPMC), and sodium hydroxide (NaOH). Two concentrations of the formulation are available: 70 mg / mL (for dose levels below 7 mg) and 140 mg / mL (for dose levels above 7 mg).

[0212] In one embodiment, the composition comprises 5MeODMT hydrochloride, - water, - 0.1% hydroxypropyl methylcellulose (HPMC), - 0.1% sodium hydroxide (NaOH), and - 70 mg / ml 5 MeODMT A composition containing the following is provided.

[0213] In one embodiment, the composition comprises 5MeODMT benzoate, - water, - 0.1% hydroxypropyl methylcellulose (HPMC), - 0.1% sodium hydroxide (NaOH), and - 70 mg / ml 5 MeODMT A composition containing the following is provided.

[0214] In one embodiment, the composition comprises 5MeODMT hydrochloride, - water, - 0.1% hydroxypropyl methylcellulose (HPMC), - 0.1% sodium hydroxide (NaOH), and - 140 mg / ml of 5 MeODMT A composition containing the following is provided.

[0215] In one embodiment, the composition comprises 5MeODMT benzoate, - water, - 0.1% hydroxypropyl methylcellulose (HPMC), - 0.1% sodium hydroxide (NaOH), and - 140 mg / ml of 5 MeODMT A composition containing the following is provided.

[0216] In one embodiment, the intranasal composition comprises 5MeODMT hydrochloride, - water, - 0.1% hydroxypropyl methylcellulose (HPMC), - 0.1% sodium hydroxide (NaOH), and - 70 mg / ml 5 MeODMT An intranasal composition containing the following is provided.

[0217] In one embodiment, the intranasal composition contains 5MeODMT benzoate, - water, - 0.1% hydroxypropyl methylcellulose (HPMC), - 0.1% sodium hydroxide (NaOH), and - 70 mg / ml 5 MeODMT An intranasal composition containing the following is provided.

[0218] In one embodiment, the intranasal composition comprises 5MeODMT hydrochloride, - water, - 0.1% hydroxypropyl methylcellulose (HPMC), - 0.1% sodium hydroxide (NaOH), and - 140 mg / ml of 5 MeODMT An intranasal composition containing the following is provided.

[0219] In one embodiment, an intranasal composition containing 5MeODMT benzoate is provided. - water, - 0.1% hydroxypropyl methylcellulose (HPMC), - 0.1% sodium hydroxide (NaOH), and - 5 MeODMT at 140 mg / ml. The composition includes In one embodiment, the composition is 25-400 mg / mL, 25-300 mg / mL, 25-200 mg / mL, 25-100 mg / mL, 25-50 mg / mL, 50-400 mg / mL, 50-300 mg / mL, 60-400 mg / mL, 60-300 mg / mL, 150-400 mg / mL, 150-300 mg / mL, 200-300 mg / mL, Contains 5 MeODMT in concentrations of 200-400 mg / mL, 30-100 mg / mL, 300-400 mg / mL, 300-500 mg / mL, 45-75 mg / mL, 50-70 mg / mL, 55-65 mg / mL, or 50-60 mg / mL.

[0220] In one embodiment, an intranasal fluid delivery system comprising a 5MeODMT composition is provided. In one embodiment, a single-dose capsule of a 5MeODMT composition is provided.

[0221] In one embodiment, an intranasal composition is provided which contains 5MeODMT in a dose of 50 to 150 mg / ml in a liquid medium, wherein the 5MeODMT is formulated as a benzoate of 5MeODMT (5MeODMT benzoate).

[0222] In one embodiment, 5MeODMT benzoate exists as a suspension or emulsion in a liquid medium. In one embodiment, - 70-140 mg / ml of 5 MeODMT benzoate as a suspension or emulsion in a liquid medium. An intranasal fluid delivery system is provided, which includes the following:

[0223] Example 16: Administration BPL-5MEO is administered to subjects by trained research team members using a single-unit dose pump spray. Since each unit contains only one spray, it should not be tested before use. While seated, subjects are asked to blow their noses to clear their nasal passages. Once the tip of the device is inserted into the nostril, a hospital staff member presses the plunger to release the dose.

[0224] In one embodiment, a method is provided for administering 5MeODMT, comprising the step of administering 5MeODMT to a human subject as an intranasal spray, wherein the human subject is subject to patient preparation parameters, including blowing their nose to clear their nasal passages immediately before administration.

[0225] In this embodiment, the human subject is sitting. In one embodiment, a method is provided for the delivery of 5MeODMT to the brain of a human subject, comprising the step of administering 5MeODMT to the human subject as an intranasal spray, wherein the human subject is subject to patient preparation parameters, including blowing their nose to clear their nasal passages immediately before administration.

[0226] Example 17: X-ray powder diffraction (XRPD) of 5MeODMT benzoate The XRPD patterns of 5MeODMT benzoate were obtained before and after particle size reduction using a mortar and pestle. This reduced the intensity of the dominant diffraction, and the XRPD pattern of benzoate tended to be preferentially oriented before particle size reduction, revealing that this is due to the properties of the material and the particle size. The XRPD patterns of benzoate before and after particle size reduction can be seen in Figures 6 and 7, respectively. The superimposed XRPD patterns of benzoate before and after particle size reduction can be seen in Figure 8.

[0227] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, and 21.0°2θ±0.1°2θ in the XRPD diffractogram.

[0228] In the embodiment, 17.5, 17.7, and 21 in the XRPD diffractogram A crystalline 5MeODMT benzoate is provided, characterized by a peak at 0°2θ ± 0.2°2θ.

[0229] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, and 21.0°2θ±0.3°2θ in the XRPD diffractogram.

[0230] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, and 21.0°2θ±0.1°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0231] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, and 21.0°2θ±0.2°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0232] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, and 21.0°2θ±0.3°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0233] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, 21.0, and 25.3°2θ±0.1°2θ in the XRPD diffractogram.

[0234] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, 21.0, and 25.3°2θ±0.2°2θ in the XRPD diffractogram.

[0235] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, 21.0, and 25.3°2θ±0.3°2θ in the XRPD diffractogram.

[0236] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, 21.0, and 25.3°2θ±0.1°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0237] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, 21.0, and 25.3°2θ±0.2°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0238] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 17.5, 17.7, 21.0, and 25.3°2θ±0.3°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0239] In this embodiment, 9.0, 11.5, 14.5, 1 in the XRPD diffractogram A crystalline 5MeODMT benzoate is provided, characterized by peaks at 6.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, and 25.3°2θ±0.1°2θ.

[0240] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, and 25.3°2θ±0.2°2θ in the XRPD diffractogram.

[0241] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, and 25.3°2θ±0.3°2θ in the XRPD diffractogram.

[0242] In this embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, and 25.3°2θ±0.1°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0243] In this embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, and 25.3°2θ±0.2°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0244] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, and 25.3°2θ±0.3°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0245] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks 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 30.5°2θ±0.1°2θ in the XRPD diffractogram.

[0246] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks 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 30.5°2θ±0.2°2θ in the XRPD diffractogram.

[0247] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks 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 30.5°2θ±0.3°2θ in the XRPD diffractogram.

[0248] In the embodiment, the XRPD diffractograms measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å) show values ​​of 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, and 24.7. A crystalline 5MeODMT benzoate is provided, characterized by peaks 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 30.5°2θ±0.2°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0249] In this embodiment, a crystalline 5MeODMT benzoate is provided, characterized by peaks 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 30.5°2θ±0.3°2θ in an XRPD diffractogram measured by X-ray powder diffraction using an X-ray wavelength of 0.15406 nm (1.5406 Å).

[0250] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by a peak in the XRPD diffractogram substantially shown in Figure 6, 7, or 8. In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by a peak in the XRPD diffractogram substantially shown in Figure 6.

[0251] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by a peak in the XRPD diffractogram substantially shown in Figure 7. In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by a peak in the XRPD diffractogram substantially shown in Figure 8.

[0252] In the embodiment, - Peaks in the XRPD diffractogram described earlier or later, - Endothermic events in DSC thermography, which are described earlier or later. - The start of decomposition in the TGA thermograph, which will be described earlier or later. - DVS isotherm profiles described earlier or later, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the crystal structures described earlier or later.

[0253] Example 18: Thermal analysis of 5MeODMT benzoate A differential scanning calorimetry (DSC) thermograph of 5MeODMT benzoate contained one endothermic event with a start temperature of 123.34°C, a peak temperature of 124.47°C, and an enthalpy of 134.72 J / g. No other thermal events were observed. The DSC thermograph acquired at 10°C / min can be seen in Figure 9.

[0254] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having an onset temperature between 120 and 130°C in a DSC thermograph. In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having an onset temperature between 120 and 130°C in a DSC thermograph substantially shown in Figure 9.

[0255] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having starting temperatures between 120-130°C, 121-129°C, 122-128°C, 123-127°C, and 124-126°C in a DSC thermograph.

[0256] In one embodiment, the DSC thermograph substantially shown in Figure 9 shows 120-130°C. A crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having an onset temperature between 121-129°C, 122-128°C, 123-127°C, and 124-126°C.

[0257] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having a starting temperature of 123°C in a DSC thermograph. In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having an onset temperature of 123°C in a DSC thermograph substantially shown in Figure 9.

[0258] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having an onset temperature of 124°C in a DSC thermograph. In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having an onset temperature of 124°C in a DSC thermograph substantially shown in Figure 9.

[0259] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having an onset temperature between 120 and 130°C and a peak between 122 and 128°C in a DSC thermograph.

[0260] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event having an onset temperature between 120 and 130°C and a peak between 122 and 128°C in a DSC thermograph substantially shown in Figure 9.

[0261] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event with starting temperatures between 120-130°C, 121-129°C, 122-128°C, and 123-127°C, and a peak between 124-126°C, as seen in a DSC thermograph.

[0262] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event with starting temperatures between 120-130°C, 121-129°C, 122-128°C, and 123-127°C, and peaks between 124-126°C, as substantially shown in the DSC thermograph in Figure 9.

[0263] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event in a DSC thermograph with starting temperatures between 120-130°C, 121-129°C, 122-128°C, and 123-127°C, a peak between 124-126°C, and an enthalpy between -130 and -140 J / g.

[0264] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event in the DSC thermograph substantially shown in Figure 9, with starting temperatures between 120-130°C, 121-129°C, 122-128°C, and 123-127°C, a peak between 124-126°C, and an enthalpy between -130 and -140 J / g.

[0265] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event in a DSC thermograph with starting temperatures between 120-130°C, 121-129°C, 122-128°C, and 123-127°C, a peak between 124-126°C, and an enthalpy between -130 and -135 J / g.

[0266] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by an endothermic event in a DSC thermograph substantially shown in Figure 9, with starting temperatures between 120–130°C, 121–129°C, 122–128°C, and 123–127°C, a peak between 124–126°C, and an enthalpy between -130 and -135 J / g.

[0267] Thermogravimetric analysis (TGA) of 5MeODMT benzoate revealed that decomposition begins at approximately 131°C, after melting at approximately 125°C. The TGA thermograph acquired at 10°C / min can be seen in Figure 10.

[0268] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by the initiation of decomposition between 128-135°C, 129-134°C, 130-133°C, or 130-132°C in a TGA thermograph.

[0269] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by the initiation of decomposition between 128–135°C, 129–134°C, 130–133°C, or 130–132°C in a TGA thermograph substantially shown in Figure 10.

[0270] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by the initiation of decomposition at 131°C in a TGA thermograph. In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by the initiation of decomposition at 131°C in a TGA thermograph substantially shown in Figure 10.

[0271] In the embodiment, - Endothermic events in DSC thermographs with starting temperatures between 120-130°C, 121-129°C, 122-128°C, 123-127°C, and 124-126°C, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the following decomposition initiations on a TGA thermograph: between 128 and 135°C, between 129 and 134°C, between 130 and 133°C, or between 130 and 132°C.

[0272] In the embodiment, - Endothermic events with starting temperatures between 120-130°C, 121-129°C, 122-128°C, 123-127°C, and 124-126°C in the DSC thermograph substantially shown in Figure 9, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the initiation of decomposition between 128–135°C, 129–134°C, 130–133°C, or 130–132°C in a TGA thermograph substantially shown in Figure 10.

[0273] In the embodiment, - Endothermic events with an onset temperature of 123°C in DSC thermography, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the initiation of decomposition at 131°C in a TGA thermograph.

[0274] In the embodiment, - In DSC thermographs, start temperatures between 120-130°C, 121-129°C, 122-128°C, 123-127°C, and 124-126°C, and endothermic events with peaks between 124-126°C, as well as - Between 128 and 135°C, between 129 and 134°C, and 130°C in TGA thermographs A crystalline 5MeODMT benzoate is provided, characterized by one or more of the following: the initiation of decomposition between ~133°C or between 130 and 132°C.

[0275] In the embodiment, - Starting temperatures between 120-130°C, 121-129°C, 122-128°C, 123-127°C, and 124-126°C in the DSC thermograph substantially shown in Figure 9, and endothermic events with peaks between 124-126°C, as well as - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the initiation of decomposition between 128–135°C, 129–134°C, 130–133°C, or 130–132°C in a TGA thermograph substantially shown in Figure 10.

[0276] In the embodiment, - DSC thermograph showing an endothermic event with a starting temperature of 123°C and a peak at 124°C, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the initiation of decomposition at 131°C in a TGA thermograph.

[0277] In the embodiment, - The DSC thermograph substantially shown in Figure 9 shows an endothermic event with a starting temperature of 123°C and a peak at 124°C, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the decomposition initiation at 131°C in the TGA thermograph substantially shown in Figure 10.

[0278] In the embodiment, - In DSC thermographs, start temperatures between 120-130°C, 121-129°C, 122-128°C, 123-127°C, and 124-126°C, peaks between 124-126°C, and endothermic events with enthalpies between -130 and -140 J / g, as well as - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the following decomposition initiations on a TGA thermograph: between 128 and 135°C, between 129 and 134°C, between 130 and 133°C, or between 130 and 132°C.

[0279] In the embodiment, - Starting temperatures between 120-130°C, 121-129°C, 122-128°C, 123-127°C, and 124-126°C in the DSC thermograph substantially shown in Figure 9, peaks between 124-126°C, and endothermic events with enthalpies between -130 and -140 J / g, as well as - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the initiation of decomposition between 128–135°C, 129–134°C, 130–133°C, or 130–132°C in a TGA thermograph substantially shown in Figure 10.

[0280] In the embodiment, - An endothermic event with an onset temperature of 123°C, a peak at 124°C, and an enthalpy of -135°C in the DSC thermograph, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the initiation of decomposition at 131°C in a TGA thermograph.

[0281] In the embodiment, - The endothermic event with an onset temperature of 123°C, a peak of 124°C, and an enthalpy of -135°C in the DSC thermograph substantially shown in Figure 9, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the decomposition initiation at 131°C in the TGA thermograph substantially shown in Figure 10.

[0282] The combined TGA / DSC thermograph acquired at 10°C / min can be seen in Figure 11. Example 19: Dynamic vapor adsorption (DVS) of 5MeODMT benzoate The DVS profile of 5MeODMT benzoate showed reversible water uptake / loss across the humidity range and no hysteresis. Water uptake / loss from 0–90% was gradual, reaching a maximum of approximately 0.20%, which was a result of solid wetting. There was no evidence of morphological / modification changes as a result of exposure of 5MeODMT benzoate to variable humidity. The DVS isotherms can be seen in Figure 12.

[0283] The DVS isotherm of 5MeODMT hydrochloride, lot 20 / 20 / 126-FP (Figure 17) showed significant moisture absorption from 70% RH during the first adsorption cycle. Approximately 23% between 70 and 80% RH. w / w Uptake was observed, but only 0.3% was observed at 0-70%RH. w / w Less than 20% moisture absorption was observed. When raised and maintained at 90% RH before the start of the second desorption cycle, an additional 20% w / w Moisture absorption is observed. Subsequent adsorption and desorption cycles follow a similar profile, although some hysteresis is observed between operations that do not coincide with the initial desorption step. These are approximately 6-9% of the minimum mass recorded at 0%RH. w / w Returning to the top, this indicates significant moisture retention. Upon completion of the DVS cycle, the input material was shown to have completed deliquescence.

[0284] To investigate the material behavior above 60% RH, modified DVS isotherms were performed on lot 20 / 45 / 006-FP (same crystalline form). In the two-cycle DVS, desorption began from 40–0% RH, adsorption began from 0–60% RH, and then increased by 5% RH increments to 65, 70, 75, 80, and finally up to 85% RH. This was done to obtain a detailed profiling of the material against humidity at these elevated levels.

[0285] In the first desorption-adsorption profile, no significant moisture absorption / loss was observed between 0 and 70% RH (Figure 18), followed by an increase of approximately 0.46% w / w at 70–75% RH. Further uptake of approximately 7% was observed at 75–80% RH, and then approximately 40% uptake at 80–85% w / w. Upon separation of the material after DVS analysis, complete deliquescence of the solid was observed, which was thought to have occurred above 80% RH.

[0286] Temperature and humidity are critical factors in the processing and storage of pharmaceuticals. DVS provides a versatile and highly sensitive technology for evaluating the stability of pharmaceutical formulations. The DVS profile showed that the stability of the benzoate of 5MeODMT was significantly higher than that of its hydrochloride, and therefore, it is a salt that is more promising for development as a pharmaceutical composition.

[0287] Accordingly, embodiments of the present invention provide a 5MeODMT stability-enhancing composition comprising a benzoate. Further, a 5MeODMT composition having improved stability comprising a benzoate is provided.

[0288] In the embodiment, therefore, the increased storage compared to the pharmaceutical composition of 5MeODMT hydrochloride A pharmaceutical composition of 5MeODMT benzoate with a shelf life is provided. In this embodiment, the pharmaceutical composition may be a nasal inhalation composition.

[0289] It is advantageous that 5MeODMT benzoate maintains a low / consistent moisture content throughout its shelf life, retains its ability to be consistently formulated, and retains its ability to be inhaled as a free-flowing powder.

[0290] In one embodiment, a crystalline 5MeODMT benzoate is provided, characterized by the DVS isotherm profile substantially shown in Figure 12. In the embodiment, - Starting temperatures between 120-130°C, 121-129°C, 122-128°C, 123-127°C, and 124-126°C in the DSC thermograph substantially shown in Figure 9, a peak between 124-126°C if necessary, and an endothermic event with an enthalpy between -130 and -140 J / g if necessary. - The onset of decomposition between 128–135°C, 129–134°C, 130–133°C, or 130–132°C in the TGA thermograph substantially shown in Figure 10, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the DVS isotherm profiles substantially shown in Figure 12.

[0291] In the embodiment, - A DSC thermograph substantially shown in Figure 9 has an onset temperature of 123°C, a peak of 124°C if necessary, and an endothermic event with an enthalpy of -135°C if necessary. - The onset of decomposition at 131°C in the TGA thermograph substantially shown in Figure 10, and - A crystalline 5MeODMT benzoate is provided, characterized by one or more of the DVS isotherm profiles substantially shown in Figure 12.

[0292] Those skilled in the art will understand that features used in the definition of one or more embodiments described earlier or later may be substituted with those of one or more other embodiments.

[0293] Example 20: Optical microscopy of 5MeODMT benzoate An Olympus BX53M polarizing microscope and an Olympus SC50 digital video camera were used for image storage, and optical microscopy was performed using imaging software Olympus Stream Basic, V2.4. The image scale bars were checked in months against external counting lines, 1.5 / 0.6 / 0.01 mm DIV.

[0294] Small amounts of each sample were placed on a glass slide and dispersed using mineral dispersion oil if necessary. The samples were observed at appropriate magnification, and various images were recorded.

[0295] Optical microscope images of 5MeODMT benzoate were obtained. The material consists of large rhombohedral / trigonal crystals ranging from 400 to 1000 microns. Smaller crystals attached to larger crystals are also present. Some of the small crystals, starting from 10 microns, are the result of mechanical wear, while others are formed by crystallization. Large aggregates composed of various crystal habits are also present. Figures 13-16 show various optical microscope images of 5MeODMT benzoate at various magnifications.

[0296] Example 21: Further characterization of 5MeODMT benzoate An investigation into the polymorphism tendency of 5MeODMT benzoate revealed the isolation of two solids with different XRPD patterns, suggesting a low polymorphism.

[0297] Equilibration of 5MeODMT benzoate in a solvent with thermal control induced morphological or stylistic changes that were not expected from the solvate. Investigations into the antisolvent-mediated crystallization of 5MeODMT benzoate did not yield any solids exhibiting morphological or stylistic changes.

[0298] Investigations into the controlled cooling crystallization of 5MeODMT benzoate did not yield any solids exhibiting any morphological or stylistic changes. Investigations into reverse antisolvent-mediated crystallization of 5MeODMT benzoate induced morphological or stylistic changes.

[0299] Two forms of 5MeODMT benzoate have been identified: form A (see Example 17; hereafter referred to as form A) and a second form B that is considered metastable.

[0300] In thermally controlled equilibration studies of 5MeODMT benzoate in various solvents, most solvents resulted in a return to pattern A according to XRPD. The equilibration solvents toluene, chlorobenzene, and anisole induced morphological or stylistic changes in 5MeODMT benzoate, which are defined as pattern B according to XRPD. Solvate formation can be ruled out based on TGA.

[0301] In an investigation of antisolvent-mediated crystallization of 5MeODMT benzoate, a solid matching pattern A by XRPD was obtained, indicating no morphological or stylistic changes. In the controlled cooling crystallization study of 5MeODMT benzoate, a solid matching pattern A by XRPD was obtained, indicating no morphological or stylistic changes.

[0302] Investigations of reverse antisolvent-mediated crystallization of 5MeODMT benzoate showed that most mixtures reverted to pattern A form. Methanol:toluene and IPA:toluene mixtures produced materials that appeared to be pattern B form solids with improved properties compared to pattern B form isolated by solvent equilibration.

[0303] XRPD testing (Figure 19) revealed a powder pattern of 5MeODMT benzoate that was consistent with that found in previous XRPD testing (see Example 17, Pattern A).

[0304] DSC analysis (Figure 20) revealed a single sharp endothermic reaction with a start at 122.95°C and a peak at 124.41°C, consistent with pattern A morphology (see Example 18, which has a start at 123.34°C and a peak at 124.47°C).

[0305] Further XRPD testing of multiple lots of 5MeODMT benzoate can be seen in Figure 21, and they match pattern A. DSC analysis of 5MeODMT benzoate lots C1, D1, and E1 revealed a common endothermic event with peak temperatures ranging from 123.76°C to 123.88°C (Figure 22). TGA analysis of C1, D1, and E1 revealed a very small weight loss prior to major decomposition (Figure 23).

[0306] The XRPD patterns of P1 (toluene), Q1 (chlorobenzene), and R1 (anisole) revealed a novel diffraction pattern called "Pattern B." These samples contained three common diffractions between 18.5 and 20°²θ (Figure 24).

[0307] The selected samples of pattern A morphology, C1 (IPA:heptane[1:1]), D1 (3-methyl-1-butanol:heptane[1:1]), and E1 (TBME), were thermally characterized.

[0308] DSC analysis of samples P1, Q1, and R1 revealed a major common endothermic event with peak temperatures between 123.73°C and 124.40°C, and a smaller common endothermic-exothermic event between 113.01°C and 115.27°C.

[0309] Sample R1 contained a unique endothermic event with a peak temperature of 117.24°C, between the smaller endothermic-exothermic event and the main endothermic event. TGA testing revealed very slight weight loss in samples P1 and Q1. Sample R1 showed a weight loss of 0.293% before decomposition. P1, Q1, and R1 at 10°C·min -1The DSC thermograph can be seen in Figure 25. 5MeODMT benzoate lots P1, Q1, and R1 at 10°C·min. -1 A magnified view of the DSC thermograph can be seen in Figure 26. 5MeODMT benzoate lots P1, Q1, and R1 at 10°C·min. -1 The TGA thermograph can be seen in Figure 27.

[0310] XRPD analysis of samples P2, Q2, and R2 (thermal-cycled suspension) revealed that P2 and Q2 transformed into pattern A morphology. However, R2 remained unchanged, resembling pattern B morphology, although its large diffraction was consistent with pattern B. XRPD diffractograms of lots R1 and R2 (thermal-cycled suspension) compared to the reference pattern A XRPD diffractogram can be seen in Figure 28.

[0311] DSC analysis of P2 revealed only the major endothermic events characteristic of pattern A morphology, which are present with a peak temperature of 124.48°C (Figures 29-31). DSC revealed that in sample Q2, the smaller endothermic-exothermic reaction was smaller, with peak temperatures of 113.41°C and 114.32°C, but the major endothermic reaction remained unaffected, with a peak temperature of 124.23°C (Figures 29-31).

[0312] DSC analysis of sample R2 revealed that the endothermic event in the smaller endothermic-exothermic phase had two peaks at 111.53°C and 113.49°C, followed by an exothermic event with a peak temperature of 114.39°C. The smaller event was much larger compared to R1, and the second smaller endothermic event was absent (Figures 29-31).

[0313] TGA analysis revealed very slight weight loss in samples P2 and Q2. Sample R2 showed a weight loss of 0.583% before decomposition. The increase in weight loss corresponds to an increase in the magnitude of the smaller event revealed by DSC (Figures 29-31).

[0314] Solvent-mediated equilibration of 5MeODMT benzoate with temperature control revealed that the salt is stable against mode or morphological changes, except in solvents toluene, chlorobenzene, and anisole. Solids isolated from these solvents exhibited different XRPD patterns and thermal events, indicating modes of morphological change of the salt. Solvate formation can be ruled out based on TGA.

[0315] In this embodiment, the above-described crystalline 5MeODMT benzoate is provided. Antisolvent-driven crystallization of 5MeODMT benzoate (Condition-driven crystallization) Equilibration of Pattern A in various solvents and solvent mixtures by thermal control identified a wide range of potentially suitable solvents and antisolvents. The antisolvent-driven crystallization of 5MeODMT benzoate was investigated.

[0316] 6 × 220 mg of 5MeODMT benzoate were dissolved in six different solvents at 50°C (details in the table below), and the stock solutions were clarified through a 0.45 μm syringe filter. Aliquots of each solution containing 50 mg of 5MeODMT benzoate were placed into four crystallization tubes.

[0317] Solutions of 5MeODMT benzoate with THF and acetonitrile crystallized after clarification. All crystallization tubes were heated to 55°C to obtain the solutions, which were then cooled to 50°C. The samples were stirred at 400 rpm via a stirrer beads throughout the experiment.

[0318] Various antisolvents (detailed in the table below), 2.5 vol., were added to the solution and mixture, then the mixture was equilibrated at 50°C for 30 minutes, and the addition of antisolvents was repeated. The mixture was cooled to 25°C over approximately 1.5 hours and then allowed to equilibrate for 17 hours.

[0319] The suspension was separated via an isolute and vacuum-dried for 1 minute to remove excess solvent. The isolute was then transferred to a vacuum oven at 50°C for 24 hours. The remaining solution was heated to 50°C, and 5 vol. of the antisolvent was added. The mixture was allowed to equilibrate for 30 minutes, and the process was repeated. An additional 10 vol. of the antisolvent was added, the mixture was allowed to equilibrate for 30 minutes, and then cooled to 25°C over 1.5 hours, followed by another 30 minutes of equilibration.

[0320] The suspension was separated via an isolute, vacuum-dried to remove excess solvent, and then dried in a vacuum oven at 50°C for 24 hours. The remaining solution was reduced to approximately 0.25 ml under N2 flow at 25°C. 20 vol. of the antisolvent was added, and the mixture was equilibrated for 30 minutes.

[0321] In this embodiment, the above-described crystalline 5MeODMT benzoate is provided.

[0322] [Table 23]

[0323] Despite the initial suggestion that water is a potentially suitable antisolvent, suspensions could not be obtained when water was used as the antisolvent. All of the THF, acetone, and MeCN-containing mixtures (except water) were obtained as suspensions by cooling to 25°C with 10 volumes of antisolvent. All of the other mixtures (except water) required either increasing the amount of antisolvent added or significantly reducing the solution volume before adding the antisolvent to obtain a suspension.

[0324] XRPD analysis of all isolated and dried solid samples showed pattern A, as shown in Figures 32 and 33. XRPD characterization of 5MeODMT benzoate solids isolated from antisolvent-mediated crystallization also matches pattern A. This means that under the conditions investigated, there is no morphological / morphological change of 5MeODMT benzoate. Investigation of controlled cooling crystallization of 5MeODMT benzoate Observations from both the initial equilibration study and the first antisolvent-based study of 5MeODMT benzoate identified a potentially suitable solvent for dissolving 5MeODMT benzoate at a temperature at which a saturated solution can subsequently be obtained through controlled slow cooling.

[0325] 25 ± 0.5 mg of 5MeODMT benzoate was dissolved in the minimum volume of solvent at 50°C (details in the table below). The solution was clarified in a preheated crystallization tube through a 0.45 μm Teflon® syringe filter and cooled from 50°C to -10°C over 60 hours (cooling rate of 1°C / hour - 1), and held at -10°C for 50 hours (without stirring).

[0326] In some crystallizations, large off-white crystals were found at the bottom of the crystallization tube (details in the table below). The crystals were directly transferred from the crystallization tube to the XRPD sample holder and left exposed to the air for approximately one hour before analysis.

[0327] The remaining mixture was opened to the atmosphere to partially evaporate the solvent and stirred at ambient temperature and 400 rpm for 18 hours.

[0328] [Table 24]

[0329] XRPD analysis of the solid sample (observed as relatively large particles) isolated after cooling the solution revealed evidence of preferred orientation (Figure 34). The particle size of the samples was reduced by particle size reduction using a mortar and pestle. Subsequent re-examination by XRPD revealed that all solids were pattern A (Figure 35).

[0330] XRPD characterization of 5MeODMT benzoate solids isolated to date from single-solvent crystallization of 5MeODMT benzoate is consistent with pattern A. This means that, under the conditions investigated, no morphological or stylistic altered 5MeODMT benzoate exists.

[0331] In this embodiment, the above-described crystalline 5MeODMT benzoate is provided. Reverse addition antisolvent-driven crystallization of 5MeODMT benzoate The first antisolvent-driven crystallization of 5MeODMT benzoate revealed the selection of appropriate solvent / antisolvent mixtures. By utilizing relatively slow addition of the antisolvent and cooling from high temperatures, only solids classified as pattern A by XRPD were obtained. To potentially rapidly precipitate novel and / or metastable solid morphologies of 5MeODMT benzoate, appropriate solvent / antisolvent mixtures were re-examined by reverse addition of a high-temperature stock solution to a low-temperature antisolvent.

[0332] 165 ± 0.5 mg of 5MeODMT benzoate was placed in vials A to F and dissolved in the minimum amount of solvent at 50°C, as detailed in the table below. One ml of the antisolvent was placed in a crystallization tube, then cooled to -10°C and stirred at 400 rpm.

[0333] An aliquot of approximately 50 mg of a stock solution of 5MeODMT benzoate was added directly to the antisolvent. In all crystallization tubes, suspensions were obtained within 5 minutes of adding the 5MeODMT benzoate solution.

[0334] The suspension was immediately separated under vacuum via an isolute, then transferred to a vacuum oven and dried at 50°C for 18 hours.

[0335] [Table 25]

[0336] XRPD analysis of most isolated solids (excluding A1 and B1) was consistent with pattern A (Figures 36 and 37). XRPD analysis of solids A1 and B1 matched each other but did not match pattern A (Figures 38, 39).

[0337] Lots A1 and B1 shared diffraction with lot Q1 of 5MeODMT benzoate (the pattern previously identified as morphology B). However, upon closer examination, Q1 was observed to share diffraction with pattern A. Lot Q1 shared diffraction with both lots A1 and B1, as well as pattern A.

[0338] The diffraction patterns of lots A1 and B1 were considered to be characteristic of pattern B. The DSC thermograph of sample A1 (Figure 41) revealed an endothermic event with major peaks at approximately 110°C and 113.98°C, followed by an exothermic event with peaks at 114.72°C and 116.42°C, and then a second endothermic event with peaks at 123.00°C and 123.72°C.

[0339] The DSC analysis of sample B1 (Figures 42 and 43) showed a similar DSC thermograph to that of A1, but the first endothermic event was 90 J·g. -1 108J·g -1 Larger than the others, A1 contained only two peak temperatures, 109.00 and 110.32°C, instead of three. The subsequent exothermic event was 41 J·g -1 17J·g -1 And it was small. The second major endothermic reaction was also 80 J·g of A1. -1 In contrast, B1 is 38J·g -1 It was so small.

[0340] In this embodiment, the above-described crystalline 5MeODMT benzoate is provided. In one embodiment, a crystalline 5MeODMT salt is provided, characterized by an endothermic or exothermic event in a DSC thermograph substantially shown in any one of the figures.

[0341] In one embodiment, a composition comprising 5MeODMT benzoate pattern A form is provided. In one embodiment, a composition comprising 5MeODMT benzoate pattern B form is provided. In one embodiment, a composition is provided comprising a mixture of 5MeODMT benzoate in pattern A and pattern B.

[0342] Example 22: Production of amorphous 5MeODMT benzoate Rapid vacuum concentration 101.55 mg of 5MeODMT benzoate was dissolved in 4 mL of THF and clarified in a 100 mL round-bottom flask. The solution was concentrated under vacuum at 40°C and 200 rpm. The liquid evaporated from the flask, leaving a concentrated, colorless, transparent liquid residue around the flask.

[0343] The residue was dissolved in 4 ml of acetone and concentrated under vacuum at 40°C and 200 rpm. The liquid evaporated from the flask, leaving a concentrated, colorless, transparent liquid residue around the flask. Small crystals were visible on the inside of the flask, and these were isolated after 18 hours to obtain 21-01-051 A. Rapid cooling of molten material 5MeODMT benzoate was held at 125°C for 5 minutes using TGA, and then cooled to ambient temperature over 3 minutes to obtain 21-01-051 B. The sample was immediately analyzed and kept in a sealed container for 20 hours. Freeze drying 200 mg of 5MeODMT benzoate was dissolved in 10 ml of deionized water, clarified in a 500 ml round-bottom flask through a 0.45 μm nylon filter, and then frozen in a thin layer. The flask was then placed under vacuum and equilibrated to ambient temperature to obtain a fluffy white solid 21-01-051 C.

[0344] The solid transformed into gum over approximately one hour. The sample was immediately analyzed and kept in a sealed container for 20 hours. Freeze-drying for equilibration of amorphous solids Using 800 mg of 5MeODMT benzoate dissolved in 25 ml, lyophilization was repeated as described above to obtain 21-01-051 D. The solid was heated to 60°C for 10 minutes and then cooled to obtain 21-01-051 E. The sample was immediately analyzed.

[0345] Figure 44 shows an XRPD comparison of 5MeODMT benzoate lot 21-01-051 A, E, particle size reduction E, and pattern A. Figure 45 shows the XRPD of 5MeODMT benzoate lot 21-01-051 B obtained from rapid cooling of the molten material.

[0346] Figure 46 shows the XRPD of 5MeODMT benzoate lot 21-01-051 C obtained by freeze-drying. The XRPD patterns of 5MeODMT benzoate 21-01-051 B and C were consistent with pattern A, indicating that the amorphous morphology transforms into pattern A morphology in a sealed container at ambient temperature and pressure.

[0347] The XRPD pattern of the solid, 5MeODMT benzoate 21-01-051 A, isolated by acetone concentration, was consistent with pattern A morphology. Rapid vacuum concentration did not produce amorphous forms.

[0348] XRPD patterns revealed that 5MeODMT benzoate 21-01-051 B and C have amorphous "halos," and that rapid cooling and freeze-drying of the molten material result in amorphous structures. It was shown that 5MeODMT benzoate is produced.

[0349] Figure 47 shows a comparison of XRPD levels after 20 hours for 5MeODMT benzoate lot 21-01-051 B, lot C, and pattern A. The XRPD pattern of 5MeODMT benzoate 21-01-051 E was consistent with pattern A, indicating that the amorphous form was converted to pattern A form at 60°C for 10 minutes.

[0350] Figure 48 shows a comparison of XRPD values ​​based on 5MeODMT benzoate lot 21-01-051 A, E, particle size reduction E, and pattern A. DSC testing revealed that amorphous 5MeODMT benzoate 21-01-051 C and D, obtained by freeze-drying, exhibited a broad endothermic shoulder leading to an exothermic event with a peak temperature between 65.63 and 70.84°C, followed by an endothermic event with a peak temperature between 120.20 and 121.22°C. The primary endothermic event was approximately 3°C lower compared to the pattern A morphological material.

[0351] Figure 49 shows 5MeODMT benzoate lot 21-01-051 A, C, and D isolated from acetone concentrate (051 A) and lyophilized (051 C and 051 D) at 10°C·min. -1 This shows a comparison of DSC thermographs.

[0352] DSC testing revealed that 20 hours later, 5MeODMT benzoate 21-01-051 C no longer contained a fever event, and the endothermic event at approximately 123°C more sharply matched pattern A morphology.

[0353] Figure 50 shows 5MeODMT benzoate lot 21-01-051 at 10°C and 20 hours later. -1 This shows a comparison of DSC thermographs. Amorphous 5MeODMT benzoate can be produced by aqueous solution and freeze-drying of rapidly cooled molten material.

[0354] Amorphous 5MeODMT benzoate transforms into a pattern A morphological material when left standing. In one embodiment, amorphous 5MeODMT benzoate is provided. In one embodiment, a composition comprising amorphous 5MeODMT benzoate is provided.

[0355] In one embodiment, a composition is provided comprising amorphous 5MeODMT benzoate produced as described above or below. Example 23: Further characterization of amorphous 5MeODMT benzoate Thermal analysis of amorphous 5MeODMT benzoate using DSC and hot-stage microscopy revealed crystallization events and endothermic melting. Endothermic melting does not correspond to the DSC thermograph of pattern A morphology.

[0356] Solvent-mediated equilibration of amorphous 5MeODMT benzoate by thermal control yielded pattern A by XRPD and DSC for all solvents except anisole. New variations were generated.

[0357] Amorphous 5MeODMT benzoate, 21-01-051 D (21-01-051), produced by freeze-drying, was examined using a hot-stage microscope at a heating rate of 5°C·min-1 to confirm its relevance with DSC thermography of the amorphous solid.

[0358] Initially, 5MeODMT benzoate was a sticky, translucent gum (Figure 52), but upon heating to 54.21°C, its viscosity decreased, and it spread into a thinner, more uniform layer (Figure 53). Crystallization began at 54.21°C (Figure 53) and neared completion at 74.21°C (Figure 54). The newly formed crystals began to melt at 114.24°C (Figure 55) and neared completion at 120.14°C (Figure 56).

[0359] Hot stage microscopy confirmed the events observed in the DSC thermograph (Figure 51), indicating exothermic crystallization at approximately 65°C and endothermic melting at approximately 115°C. Figure 51 shows a DSC thermograph of lot 21-01-051 D of 5MeODMT benzoate, a large-scale lyophilized material, with temperature markings corresponding to the hot stage microscope image.

[0360] Figure 52 shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 30.02°C. Figure 53 shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 54.21°C.

[0361] Figure 54 shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 74.21°C. Figure 55 shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 114.23°C.

[0362] Figure 56 shows a microscopic image of 5MeODMT benzoate lot 21-01-051 D at 120.14°C. Solvent-mediated equilibration of amorphous 5MeODMT benzoate with thermal manipulation The operation of stirring an amorphous form of a solid in a series of solvents can lead to dissolution and crystallization into a more ordered, energetically stable solid. In this way, alternative crystalline forms of the solid can potentially be generated for comparison and evaluation.

[0363] Amorphous 5MeODMT benzoate 21-01-51 D, 24 × 25 ± 2 mg, was transferred to a crystallization tube, and 0.125 mL of solvent was added, as detailed in the table below. The mixture was stirred at 25°C and 300 rpm for 30 minutes. 0.125 mL of solvent was added to the mixture and equilibrated for 18 hours.

[0364] The mixture was heated to 55°C for 8 hours, then cooled to 25°C over 1 hour, and finally equilibrated at 300 rpm for 18 hours. The observations after each procedure are detailed in the table below. For separation, the suspension was transferred to an isolute tube, dried under vacuum for 2 minutes, and then dried under vacuum at 50°C for 24 hours.

[0365] XRPD analysis of solids isolated from the equilibration of amorphous 5MeODMT benzoate with thermal control revealed that all powder patterns matched pattern A (Figures 57 and 58).

[0366] Figure 57 shows a comparison of XRPD patterns of solid 5MeODMT benzoate lot 21-01-054 isolated from the equilibration of amorphous 5MeODMT benzoate with thermal control. Figure 58 shows 5MeODMT benzoate lot 21-01-054 isolated from equilibration of amorphous 5MeODMT benzoate in α,α,α-trifluorotoluene with thermal control. This shows a comparison of the XRPD pattern with lot 20-37-64 (pattern A) of M.

[0367] DSC analysis of selected 5MeODMT benzoate solids classified as pattern A revealed a major endothermic event with an onset temperature between 121.88 and 123.39°C and a peak temperature between 123.66 and 124.11°C. This endothermic activity is characteristic of pattern A morphology (Figure 59).

[0368] The solid 5MeODMT benzoate 21-01-054 Q isolated from anisole contained events with peak temperatures of 111.64°C and 116.92°C within its major endothermic events (Figures 60 and 61). This is less obvious but consistent with the DSC thermograph of 5MeODMT benzoate, 20-37-64-R1, isolated after equilibration in anisole.

[0369] Figure 59 shows a DSC thermographic comparison of selected solids from lot 21-01-054 of 5MeODMT benzoate, classified as pattern A morphology, isolated from the equilibration of amorphous 5MeODMT benzoate with thermal control.

[0370] Figure 60 shows a magnified comparison of DSC thermographs of selected solids of lot 21-01-054 solid classified as pattern A, isolated from the equilibration of amorphous 5MeODMT benzoate with thermal control, highlighting the event of lot 21-01-054 Q, a solid isolated from anisole.

[0371] Figure 61 shows a magnified DSC thermograph highlighting the event of lot 21-01-054 Q isolated from anisole. Example 24: Pattern C Further characterization required additional 5MeODMT benzoate pattern B form material. A procedure involving immersion of a 5MeODMT benzoate / IPA solution in cold toluene was used.

[0372] 250 mg of 5MeODMT benzoate 20 / 20 / 150FP2 was dissolved in 5 ml of IPA, heated to 50°C, and clarified. 2 x 2 ml of the clarified solution, along with 100 mg of 5MeODMT benzoate, was added to 4 ml of toluene at -10°C and stirred at 750 rpm.

[0373] When added, both mixtures remained as a colorless, transparent solution. After 30 minutes, a solid formed in tube A. The solid, 21-01-060 A, was immediately isolated via an isolute and dried under vacuum for 2 minutes. Part of 21-01-060 A1 was taken out for XRPD analysis, and part of 21-01-060 A2 was dried under vacuum at 50°C for 20 hours.

[0374] After 50 minutes, a solid formed in tube B, which was equilibrated at -10°C and stirred at 750 rpm for 3 hours. The solid, 21-01-060 B, was immediately isolated via an isolute and dried under vacuum for 2 minutes. A portion of 21-01-060 B1 was taken out for XRPD analysis, and the remainder was dried under vacuum at 50°C for 20 hours to obtain 21-01-060 B2.

[0375] [Table 26]

[0376] Samples 21-01-060 A1 and 21-01-060 B1 were air-dried under ambient conditions for 20 hours and evaluated by XRPD and DSC. Immediately after isolation, 21-01-060 A1 was analyzed by XRPD. This revealed a novel diffraction pattern that did not match either pattern A or pattern B. This is called pattern C.

[0377] The XRPD pattern of 21-01-060 A1 (air-dried for 2 minutes) was reacquired after further air-drying for 1 hour under ambient conditions (Figure 62). The XRPD of 21-01-060 A1 (air-dried for 1 hour) showed additional diffraction compared to 21-01-060 A1 (air-dried for 2 minutes), suggesting a transformation to pattern B (Figure 63).

[0378] Figure 62 shows a comparison of XRPD patterns of 5MeODMT benzoate lot 21-01-060 A1, lot 21-01-049 B1, pattern B, and lot 20-37-64, pattern A, after air-drying for 2 minutes.

[0379] Figure 63 shows a comparison of XRPD patterns of 5MeODMT benzoate lot 21-01-060 A1 - air-dried for 1 hour and lot 21-01-060 A1 - air-dried for 2 minutes. Figure 64 shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-060 A1 - air-dried for 2 minutes, lot 21-01-060 A1 - air-dried for 1 hour, and lot 21-01-049 B1, pattern B.

[0380] DSC thermography of 5MeODMT benzoate 21-01-060 A1 (air-dried for 1 hour) (Figures 65 and 66) revealed a broad endothermic pattern with a peak temperature of 108°C, which is considered characteristic of solids of pattern C morphology.

[0381] Subsequently, exothermic activity with a peak temperature of 112.35°C follows, and the main endothermic activity has a peak temperature of 124.12°C, which is characteristic of pattern A. Therefore, this is considered to be a transformation from pattern C to pattern A.

[0382] Figure 65 shows the DSC thermograph of lot 21-01-060 A1 of 5MeODMT benzoate, immediately isolated from IPA / toluene and air-dried for 1 hour. Figure 66 shows a magnified DSC thermograph of lot 21-01-060 A1 of 5MeODMT benzoate, immediately isolated from IPA / toluene and air-dried for 1 hour.

[0383] The XRPD pattern of 5MeODMT benzoate lot 21-01-060 A1 was obtained after a total of 20 hours of air drying. This revealed that the pattern (Figure 67) is consistent with SPS5520 21-01-049 B1, pattern B, but includes diffractions suggestive of pattern C, such as 10.3°2θ (Figure 67).

[0384] Figure 67 shows a comparison of XRPD patterns based on pattern B for 5MeODMT benzoate lot 21-01-060 A1 air-dried for 20 hours, lot 21-01-060 A1 air-dried for 2 minutes, and lot 21-01-049 B1. 5MeODMT benzoate 21-01-060 B1 is produced by reverse antisolvent addition, 3 hours of equilibration, subsequent isolation, and air drying at ambient temperature. Immediately after isolation, the solid was analyzed by XRPD. This revealed a diffraction pattern consistent with 21-01-060 A1, pattern C (Figure 68).

[0385] The XRPD pattern (Figure 69) was reacquired after 20 hours of air drying, revealing that the solid still exhibited pattern C, but included diffraction at 17.2° and 19.5° 2θ, suggesting pattern B.

[0386] Figure 68 shows a comparison of the XRPD patterns of 5MeODMT benzoate lot 21-01-060 B1, isolated after 3 hours of equilibration and then air-dried for 2 minutes, and A1, isolated immediately and then air-dried for 2 minutes.

[0387] Figure 69 shows a comparison of the XRPD patterns of lot 21-01-049 B1 and lot 21-01-049 B1, pattern B, after being isolated after 3 hours of equilibration and then air-dried for 20 hours.

[0388] Example 25: Investigation of the effect of solvent vapor diffusion on amorphous 5MeODMT benzoate Exposure of amorphous solids to solvent vapors is considered a low-energy process that induces a change in the morphology or form of the solid to produce metastable forms and / or solvates from the amorphous solid for comparison and evaluation.

[0389] 497.44 mg of 5MeODMT benzoate was dissolved in 10 mL of deionized water, clarified in a 500 mL round-bottom flask, and freeze-dried as detailed above. 12 × 25 mg of the resulting fluffy white solid was placed in an HPLC vial and placed in a sealed container with approximately 2 mL of solvent. The solvent used and the observation results are detailed in the table below.

[0390] After 7 days of equilibration, the solids were transferred directly to an XRPD sample holder and analyzed by XRPD. DSCs were collected for all notable samples and selected pattern A morphology solids by XRPD.

[0391] [Table 27]

[0392] The XRPD patterns (Figure 70) for all samples except 21-01-058 D and 21-01-058 G, isolated from anisole and toluene respectively, were consistent with the pattern A morphology material (Figure 71).

[0393] Figure 70 shows a comparison of XRPD patterns of solid 5MeODMT benzoate lot 21-01-058 isolated from amorphous 5MeODMT benzoate exposed to solvent vapor. Figure 71 shows an XRPD pattern comparison of lot 21-01-058 K of 5MeODMT benzoate isolated from amorphous 5MeODMT benzoate exposed to solvent vapor with lot 20-37-64, pattern A.

[0394] A comparison of DSC thermographs of selected solids with pattern A morphology (Figure 72) revealed an endothermic event with a peak temperature between 123.69°C and 124.14°C, suggesting pattern A morphology and supporting the XRPD data.

[0395] The DSC thermograph of lot 21-01-058 G (not pattern A form by XRPD) clearly shows the smaller endothermic event before the major endothermic event, which is explained in detail below.

[0396] Figure 72 shows a DSC thermographic comparison of 5MeODMT benzoate lots 21-01-058 B, 21-01-058 F, 21-01-058 K, and 21-01-062 G.

[0397] Example 26: Pattern D Solid isolated from amorphous 5MeODMT benzoate after 7 days of exposure to anisole vapor, 5MeODMT benzoate 21-01-058 D XRPD of 5MeODMT benzoate lot 21-01-058 D, isolated from amorphous 5MeODMT benzoate exposed to anisole vapor, revealed a unique powder pattern (Figures 73 and 74). The diffraction pattern of 21-01-058 D is similar to pattern C, but differs in intensity and location (Figure 75).

[0398] Figure 73 shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-058 D, lot 20-37-64, pattern A, lot 21-01-049 B1, pattern B, and lot 21-01-060 B1, pattern C (air-dried for 20 hours).

[0399] Figure 74 shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-058 D, lot 21-01-049 B1, pattern B, and lot 21-01-060 B1, pattern C (air-dried for 20 hours).

[0400] Figure 75 shows a comparison of magnified XRPD patterns of 5MeODMT benzoate lot 21-01-058 D, lot 21-01-049 B1, pattern B, and lot 21-01-060 B1, pattern C (air-dried for 20 hours).

[0401] A DSC thermograph (Figure 76) of 5MeODMT benzoate lot 21-01-058 D, isolated from amorphous 5MeODMT benzoate exposed to anisole vapor, revealed an endothermic event with a peak temperature of 118.58°C. This supports the XRPD data and confirms the isolation of a novel pattern.

[0402] Figure 76 shows a DSC thermograph of lot 21-01-058 D of 5MeODMT benzoate isolated from exposure to anisole vapor in an amorphous form. Amorphous 5MeODMT benzoate exposed to anisole vapor yielded an anisole hemisolvate, referred to herein as pattern D. The XRPD pattern of pattern D is similar to pattern C, the toluene hemisolvate, but differs in peak position.

[0403] Amorphous 5MeODMT benzoate exposed to toluene vapor was predominantly in pattern A form, but also yielded a mixed form with pattern C form observed by XRPD and DSC, and some evidence of toluene hemisolvate.

[0404] Amorphous 5MeODMT benzoate, exposed to all other solvent vapors, reverted exclusively to pattern A by XRPD and DSC.

[0405] [Table 28]

[0406] Example 27: Pattern E Pattern C of 5MeODMT benzoate was isolated by reverse antisolvent addition of an isopropanol solution of 5MeODMT benzoate to toluene. This solid was considered to be a hemisolvate, and pattern B was obtained upon desolvation. Pattern B was approached by equilibration of 5MeODMT benzoate in anisole and chlorobenzene. Pattern B may also be approached from anisole and chlorobenzene hemisolvates; therefore, reverse antisolvent addition to chlorobenzene and anisole is considered to yield hemisolvates, similar to toluene.

[0407] 650 mg of 5MeODMT benzoate 20 / 20 / 150FP2 was added to a sample vial containing 13 ml of IPA and heated to 50°C. The clear solution was clarified through a 0.45 μm nylon syringe filter.

[0408] As detailed in the table below, 4 ml of the antisolvent was placed in a crystallization tube and cooled to -10°C while stirring at 750 rpm via a stirrer bead. 2 ml of IPA stock solution at 50°C was added to 4 ml of antisolvent at -10°C.

[0409] The observations are detailed in the table below, and B, D, and F were immediately isolated. Tubes A, C, and E were equilibrated for 3 hours and then isolated. The suspension was transferred to an isolute cartridge, dried under vacuum for 60 seconds or less, and analyzed immediately after exposure to air for 4 hours and 44 hours.

[0410] 5MeODMT benzoate 21-01-064 E was damp after air-drying for 60 seconds.

[0411] [Table 29]

[0412] After the formation of a suspension obtained by adding a concentrated IPA solution to chlorobenzene at -10°C, 5MeODMT benzoate 21-01-064 D was immediately isolated. XRPD revealed that the diffraction pattern of 5MeODMT benzoate lot 21-01-064 D was similar to pattern C of 21-01-060 B1 (air-dried for 2 minutes) (Figure 77). Some diffractions, including 19 and 20°2θ, were slightly higher and lower compared to pattern C, but this is not due to sample presentation (Figure 78).

[0413] Lot 21-01-064 D of 5MeODMT benzoate exhibits a novel diffraction pattern, which is defined herein as pattern E. Figure 77 shows a comparison of the XRPD patterns of 5MeODMT benzoate lot 21-01-064 D and 21-01-060 B1 (air-dried for 2 minutes).

[0414] Figure 78 shows a comparison of the magnified XRPD patterns of 5MeODMT benzoate lot 21-01-064 D and 21-01-060 B1 (air-dried for 2 minutes). DSC thermography of 5MeODMT 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 smaller endothermic event with a peak temperature of 119.09°C.

[0415] Figure 79 shows the DSC thermograph of 5MeODMT benzoate lot 21-01-064 D at 10°C·min-1. The ¹H NMR spectrum of 5MeODMT benzoate lot 21-01-064 D, immediately isolated after equilibration, revealed that the salt has a stoichiometry of 1:1, and that the salt-to-solvent ratio is 1:0.512 for chlorobenzene and 1:0.013 for IPA.

[0416] The isolated salt is a chlorobenzene half-solvate. Since the remaining chlorobenzene is thought to be inhibiting the crystallization of 5MeODMT benzoate, there is no evidence of endothermic pattern A at approximately 123°C in the DSC thermograph, 21-01-064 D (Figure 79).

[0417] After equilibrating the suspension obtained by adding a concentrated IPA solution to chlorobenzene at -10°C for 3 hours, 5MeODMT benzoate 21-01-064 C was isolated. XRPD revealed that the diffraction pattern of 5MeODMT benzoate lot 21-01-064 C was consistent with pattern E of 21-01-064 D (Figure 80).

[0418] Figure 80 shows a comparison of the XRPD patterns of 5MeODMT benzoate lots 21-01-064 C and 21-01-064 D. Figure 81 shows 5MeODMT benzoate lot 21-01-064 C and 21-01 This shows a comparison of the enlarged XRPD patterns of -064 D.

[0419] DSC thermography of 5MeODMT benzoate lot 21-01-064 C revealed major endothermic events with peak temperatures of 111.39°C, 113.22°C, and 114.35°C (Figure 82).

[0420] The DSC thermograph for 21-01-064 C is similar to the thermograph for 21-01-064 D. Figure 82 shows a DSC thermograph of 5MeODMT benzoate lot 21-01-064 C at 10°C·min-1.

[0421] The ¹H NMR spectrum of 5MeODMT benzoate lot 21-01-064 C, isolated after 3 hours of equilibration, revealed that the salt has a stoichiometry of 1:1, and that the salt-to-solvent ratio is 1:0.506 for chlorobenzene and 1:0.004 for IPA.

[0422] The isolated salt is a chlorobenzene half-solvate. XRPD analysis of 5MeODMT benzoate lot 21-01-064 C (air-dried for 4 hours) revealed a diffraction pattern consistent with 21-01-064 C, pattern E.

[0423] XRPD analysis of 5MeODMT benzoate lot 21-01-064 C (air-dried for 44 hours) revealed diffraction patterns consistent with pattern E of 21-01-064 C and 21-01-064 C (air-dried for 4 hours).

[0424] XRPD of 5MeODMT benzoate lot 21-01-064 F revealed a diffraction pattern consistent with pattern D, 21-01-058 D, from a vapor diffusion investigation of amorphous 5MeODMT benzoate in anisole, but with higher crystallineity and lacking the smaller diffraction characteristic of pattern A.

[0425] XRPD of 5MeODMT benzoate 21-01-064 E is 21-01-064 We identified diffraction patterns that matched patterns F and D. XRPD analysis of 5MeODMT benzoate 21-01-064 E (air-dried for 4 hours) revealed a diffraction pattern consistent with pattern D of 21-01-064 E.

[0426] The XRPD of 5MeODMT benzoate 21-01-064 E (air-dried for 44 hours) revealed a diffraction pattern that is consistent with pattern D of 21-01-064 E, but also shows additional diffraction at 18.3°2θ, which is thought to suggest pattern B.

[0427] Example 28 Further consideration of patterns B to E Pattern B The following table summarizes lots of 5MeODMT benzoate that primarily exhibit the composition and crystallographic properties of Pattern B.

[0428] [Table 30]

[0429] The following table summarizes the thermal characteristics of Pattern B.

[0430] [Table 31]

[0431] 5MeODMT benzoate lot 21-01-049 B1 was obtained by adding the IPA solution to toluene as a reverse poor solvent, immediately isolating it, and vacuum drying it at 50°C. XRPD showed a diffraction pattern defined as pattern B. DSC analysis identified an endothermic event at 110°C, corresponding to the boiling point of toluene, followed by an exothermic event indicating melting and crystallization from pattern B to pattern A, and then an endothermic event indicating melting of the pattern A material. 1H NMR showed a small amount of residual toluene, but no IPA was detected.

[0432] Lot 21-01-060 A2 of 5MeODMT benzoate was produced by the same method as 049 B1, except that it was larger in scale, and yielded identical products on XRPD and DSC, but contained residual IPA on 1H NMR.

[0433] Lot 21-01-049 A1 of 5MeODMT benzoate was prepared by the same method as 049 B1, except that it was initially dissolved in methanol. XRPD showed a powder pattern matching pattern B and part of pattern C. 1H NMR showed a salt-to-toluene ratio of 1:0.03. DSC analysis showed a thermograph similar to 049 B1, but with a larger initial endothermic event at 110°C, and the subsequent endothermic melting of pattern B morphology was bimodal, showing peaks at lower temperatures. After melting of pattern B morphology, pattern A morphology crystallized and melted as expected.

[0434] Lot 21-01-060 B2 of 5MeODMT benzoate was prepared by the same method as for 060 A2, except that it was equilibrated for 3 hours and vacuum-dried before isolation. XRPD showed a mixture of pattern B and some pattern C. 1H NMR showed a salt-to-toluene ratio of 1:0.05. DSC analysis showed a thermograph similar to that of 049 A1 (a mixture of pattern B and C forms), but the melting endothermic event in pattern B form was not bimodal. The endothermic event at 110°C is considered to be a result of a slight increase in the amount of toluene in the sample in the form of toluene hemisolvate.

[0435] Lot 21-01-060 A1 (air-dried for 20 hours) of 5MeODMT benzoate was prepared using the same method as 060 A2, except that it was air-dried instead of being air-dried in a vacuum at 50°C. XRPD showed a mixture of patterns B and C. ¹H NMR showed a salt-to-toluene ratio of 1:0.04. However, 060 A1 contained a significantly higher amount of IPA than the other samples (1:0.2 instead of 1:0.05). This may have altered the endothermic event during DSC analysis of the sample, although a melting endothermic event in pattern A form is still present.

[0436] 5MeODMT benzoate lot 21-01-047 J was produced by crystallization from chlorobenzene at 50°C and vacuum drying at 50°C. XRPD showed that the sample was a mixture of pattern B and some pattern A. DSC analysis showed an endothermic event similar to that considered to be toluene loss, which is thought to indicate chlorobenzene loss. The endothermic melting of pattern B morphology occurs earlier than in the case of 049 B1, while the crystallization of pattern A morphology is very exothermic and accompanied by melting of pattern A morphology.

[0437] The 5MeODMT benzoate material in pattern B exhibits characteristic endothermic-exothermic phenomena when it melts and crystallizes into pattern A. Since pattern B is produced by the desolvation of the semisolvate, the endothermic properties of the residual semisolvate are present in all isolated samples.

[0438] These solids, which can be considered a semi-solvate version of salts, contain low levels of toluene. Therefore, the thermal properties are altered by the loss of toluene. Pattern C The following table summarizes lots of 5MeODMT benzoate that primarily exhibit the composition and crystallographic properties of Pattern C.

[0439] [Table 32]

[0440] The following table summarizes the thermal properties, primarily those of Pattern C.

[0441] [Table 33]

[0442] Lot 21-01-064 B of 5MeODMT benzoate was produced by adding an IPA solution to toluene as a reverse poor solvent. XRPD showed pattern C, which is supported by a 1:0.5 salt-to-toluene ratio by 1H NMR, indicating a toluene hemisolvate. DSC analysis showed a bimodal endothermic event with peak temperatures of 111.3°C and 112.1°C, indicating that the endothermic event at 111°C of the pattern B mixture was a result of residual pattern C. The presence of an endothermic event exhibiting pattern B morphology suggests a conversion to pattern B morphology, and then to pattern A morphology.

[0443] Lot 21-01-064 A of 5MeODMT benzoate was prepared by the same method as 064 B, except that it was equilibrated for 3 hours before isolation. XRPD and 1H NMR showed identical characteristics to 064 B. However, DSC analysis revealed a different major multimodal endothermic event with a peak temperature of 115.0°C.

[0444] Except for longer air-drying, 5MeODMT benzoate lots 21-01-064 A (air-dried 44 hours) and 21-01-060 B1 (air-dried 20 hours) were produced, similar to 064 A. XRPD showed a mixture of pattern C and pattern B for both, and 1H NMR showed less toluene in 060 B1 than in 064 A, which is thought to be a result of air-drying, thus supporting the presence of pattern B morphology in the samples by XRPD. DSC analysis showed an endothermic event with a peak temperature of 111.3°C for both, followed by several intrinsic endothermic events.

[0445] By air-drying 064 A, lot 21-01-064 A (air-dried for 4 hours) of 5MeODMT benzoate was produced. XRPD showed a mixture of pattern C and some pattern B. DSC analysis showed a wide range of exothermic events between 105 and 113°C, followed by weak endothermic events showing pattern C morphology, and then endothermic events showing pattern B morphology. The change in heating rate was the cause of the change in thermal behavior, as the DSC thermograph of the 21-01-064 A (air-dried for 44 hours) sample was similar to that of 21-01-064 A, and the transformation to pattern C morphology occurred in situ during the analysis.

[0446] 5MeODMT benzoate 21-01-060 A1 (air-dried for 1 hour) was prepared by the same method as 064 A, except that it was immediately isolated. XRPD showed a mixture of pattern C and some pattern B. DSC testing showed a thermograph exhibiting pattern B morphology with a smaller exothermic event at approximately 109°C.

[0447] The 5MeODMT benzoate pattern C form is a toluene hemisolvate and does not exhibit characteristic endothermic phenomena except for melting at 110°C–115°C. The XRPD pattern of the toluene hemisolvate of 5MeODMT benzoate differs from that of 5MeODMT benzoate. Desolvation may occur under ambient conditions, and it is considered that the pattern B form is produced.

[0448] The thermal properties are affected by toluene loss during DSC testing. Pattern D The table below provides an overview of the composition and crystallographic properties, primarily those of pattern D.

[0449] [Table 34]

[0450] The table below provides an overview of the thermal properties, primarily those of Pattern D.

[0451] [Table 35]

[0452] 5MeODMT benzoate lot 21-01-064 F was generated by adding an IPA solution to anisole as a reverse poor solvent and immediately isolating it. XRPD showed a diffraction pattern consistent with pattern D, which was supported by a 1:0.503 ratio of anisole by 1H NMR, indicating a semisolvate. DSC analysis showed a bimodal endothermic event with peak temperatures of 118.61°C and 119.21°C.

[0453] 5MeODMT benzoate lot 21-01-064 E was produced by adding anisole in reverse poor solvent to an IPA solution and equilibrating for 3 hours before isolation. XRPD showed pattern D, which was not supported by 1H NMR indicating a salt-to-anisole ratio of 1:1.04, and the isolated solid was wet after isolation. DSC analysis showed a broad endothermic event with very poor clarity and peak temperatures at 113.51°C and 161.93°C, the endothermic event at 113.51°C being thought to be the result of melting of the hemisolvate shown by XRPD, followed by evaporation of anisole. DSC thermography showed solvent content Due to its quantity, it is not considered to represent the Pattern D form.

[0454] Exposure of the amorphous form to anisole vapor produced 5MeODMT benzoate lot 21-01-058 D. XRPD showed diffraction of a mixture of pattern D and some pattern A, which was supported by 1H NMR indicating a salt-to-anisole ratio of 1:0.47 and an anisole hesolvate. DSC analysis showed an endothermic event with a peak temperature of 118.6°C, which is consistent with data collected from 064 F. However, melting of the pattern A form was not shown on the DSC thermograph, which may have been altered by the free anisole solvent present in the sample.

[0455] Lot 21-01-064 E (air-dried 4 hours) was produced by air-drying 064 E for 4 hours. XRPD showed pattern D. DSC analysis was performed at 2.5°C / min-1 to separate the bimodal endothermic events observed on the thermograph of 064 E. DSC analysis showed the smaller endothermic event with a peak temperature of 111.24°C, which is consistent with the broad endothermic event observed in 064 E. The good resolution of this endothermic event is thought to be a result of a slower heating rate or due to the removal of residual anisole by air-drying. This was followed by a major endothermic event with a peak temperature of 117.90°C, consistent with 058 D and 064 F.

[0456] By further air-drying 064 E (air-dried for 4 hours) for 40 hours, 5MeODMT benzoate lot 21-01-064 E (air-dried for 44 hours) was produced. XRPD showed diffraction of a mixture of pattern D and some pattern B. DSC analysis showed a thermograph consistent with 064 E (air-dried for 4 hours). The content of pattern B morphology was not evident in the DSC thermograph, which is thought to be caused by the free anisole solvent present in the sample, similar to 058 D.

[0457] The 5MeODMT benzoate pattern D form is an anisole hemisolvate, which was directly produced by exposing the amorphous form to anisole vapor and then adding a reverse poor solvent to cold anisole from an IPA solution. While its characteristic thermal behavior has not been identified, an endothermic event around 118°C is common, and the lack of recrystallization to pattern B or A forms is thought to be due to the presence of residual anisole. Pattern E The following table provides an overview of the composition and crystallographic properties, primarily those of pattern E.

[0458] [Table 36]

[0459] The table below mainly outlines the thermal properties of pattern E, while the endothermic event at 123.7°C is characteristic of pattern A.

[0460] [Table 37]

[0461] Lot 21-01-064 D of 5MeODMT benzoate was produced by adding an IPA solution to chlorobenzene as a reverse poor solvent. XRPD showed pattern E, which was supported by 1H NMR indicating a salt-to-chlorobenzene ratio of 1:0.506 and representing a chlorobenzene hesolvate. DSC analysis showed a bimodal endothermic event with peak temperatures of 111.3°C and 113.1°C, followed by the smaller endothermic event with a peak temperature of 119.1°C.

[0462] Lot 21-01-064 C was prepared by adding an IPA solution to cold chlorobenzene as a reverse poor solvent, equilibrating for 3 hours, and then isolating the solution. The XRPD showed pattern E, which was supported by 1H NMR indicating a salt-to-chlorobenzene ratio of 1:0.512 and indicating a hemisolvate. DSC analysis showed a trimodal endothermic event with peak temperatures at 111.3°C, 113.1°C, and 114.3°C. There were similarities in the DSC thermographs of 064 D and C, but the endothermic event at 119.1°C was absent in 064 C, and 064 D did not show a trimodal endothermic event. The difference in the DSC thermographs is noteworthy, given that the XRPD patterns were identical and the 1H NMR indicated a hemisolvate.

[0463] Lot 21-01-064 C (air-dried 4 hours) was produced by air-drying 064 C for 4 hours. XRPD showed pattern E. DSC testing was performed at 2.5°C. -1 The experiment was conducted, and following a broad exothermic event, a smaller endothermic event was observed at 114.3°C, but it was much weaker compared to the same endothermic event at 064°C. This was followed by a major endothermic event at 123.7°C, exhibiting pattern A morphology. The DSC thermograph showed 2.5°C mins from the previous experiment. -1 This is similar to the DSC test, and pattern A morphology is produced during the DSC test.

[0464] Lot 21-01-064 C (air-dried 4 hours) was produced by further air-drying 064 C (air-dried 4 hours) for 40 hours. XPRD is pattern E was observed. DSC testing revealed a bimodal endothermic event with peak temperatures of 115.1°C and 115.8°C. The endothermic event for 064°C (air-dried for 44 hours) was similar to that of 064°C, but with a peak at a slightly higher temperature.

[0465] The 5MeODMT benzoate pattern E form is a chlorobenzene hesolvate and lacks distinct thermal properties, except for a multi-modal endothermic event between 110 and 117°C. Similar to the anisole hesolvate, patterns A and B do not recrystallize from the molten material. The chlorobenzene hesolvate does not appear to desolvate when exposed to ambient conditions and remained solvated for 44 hours.

[0466] Example 29 semi-solvate When the suspension was equilibrated in poor solvents (toluene, anisole, and chlorobenzene) at -10°C, the expected half-solvates were obtained by XRPD, 1H NMR spectroscopy, and TGA.

[0467] The partial desolvation of a half-solvate results in a multi-modal endothermic event observed on a DSC thermograph, which is considered a consequence of changes in composition and the applied heating rate. When the semisolvates were desolvated in a vacuum at 50°C for 22 hours, material with pattern B morphology was obtained by XRPD and DSC, but some residual semisolvates remained in all samples.

[0468] The DSC thermograph of the half-solvate was similar to that of the one isolated from IPA / poor solvent, but there were small differences that could be attributed to the preparation method. When toluene and chlorobenzene hesosolates of 5MeODMT benzoate were vacuum-dried at 50°C for 67 hours, pattern A was obtained, while anisole hesosolate mainly yielded pattern B.

[0469] When a 5MeODMT benzoate / IPA solution was added to toluene at -10°C and air-dried for 5 minutes, a toluene half-solvate was obtained when 1 g of the solution was added. When the toluene half-solvate of 5MeODMT benzoate was dried at 50°C for 24 hours, morphology pattern B was obtained.

[0470] The 5MeODMT benzoate batches 20 / 53 / 057-FP and 20 / 20 / 123FP exhibited similar particle habituation, including large hexagonal / rhombic plates (approximately 500 μm to 1 mm in length), several smaller plates showing adhesion to the plate surface, and significant evidence of broken particles and plates, which were thought to be due to abrasion.

[0471] This differed from batches 20 / 20 / 150FP2 T=0 and 20 / 20 / 154FP, which exhibited similar particle crystal habits, including clusters of adhering, jagged, irregular plates (approximately 250–600 μm in length), as well as broken, irregular plates and crystals (some <20 μm in length) indicating particle abrasion.

[0472] Significant differences in particle size and crystal habit between batches are thought to affect the isolation, fluidity, and dynamic dissolution rate of the solid, highlighting the importance of controlled crystallization. Example 30 Patterns F and G The methyl benzoate hesosoldate of 5MeODMT benzoate (pattern F form) was isolated by controlled cooling of a clarified methyl benzoate solution of 5MeODMT benzoate from 50°C to -10°C.

[0473] The 2-chlorotoluene hesolvate of 5MeODMT benzoate (pattern G form) was isolated by controlled cooling of a clarified 2-chlorotoluene solution of 5MeODMT benzoate from 80°C to -10°C.

[0474] Equilibration with α,α,α-trifluorotoluene did not yield the hesolvate expected from a monosubstituted aromatic solvent. Equilibration with cumene yielded pattern B, which is indicative of the cumene hesolvate.

[0475] DVS testing of amorphous 5MeODMT benzoate showed a weight loss of approximately 2%, indicating the removal of the component and confirming that stable hydrate of 5MeODMT benzoate could not be isolated.

[0476] Form A is the most stable version of 5MeODMT benzoate and a thermodynamically favorable product; however, when isolated from a few selected solvents, each yielded a semi-solvate.

[0477] Stability tests showed that all patterns converted to pattern A form when vacuum-dried at 50°C. However, pattern B form remained stable when exposed to air at approximately 20°C for up to 12 days. Pattern C form partially converted to pattern B form within 24 hours when exposed to air at approximately 20°C, but did not further convert from the pattern B / C mixed version for a further 11 days.

[0478] The FTIR spectra of patterns A, B, and C were generally similar, but pattern A had several distinctive bands, while patterns B and C did not have any bands that were otherwise represented by and shared with each other. Investigation of controlled cooling crystallization with a wider range of solvent options. Initial studies of the cold crystallization of 5MeODMT benzoates showed that pattern A morphology was isolated from most solvents except chlorobenzene and was consistent with pattern B morphology. The range of solvents was expanded, with a focus on esters and aromatics.

[0479] 50 mg ± 1 mg of 5MeODMT benzoate lot 20 / 20 / 150FP2 was loaded into crystallization tubes A-L. A minimum amount of solvent was added at 50°C, and clear solutions were obtained as detailed in the table below. Crystallization tubes I, J, K, and L remained as a suspension of 12.5 mg / ml at 50°C, so they were heated to 80°C to obtain clear solutions.

[0480] The solution was clarified in a crystallization tube at 50°C, cooled to -10°C at a rate of 10°C / hour - 1, and equilibrated at -10°C for 12 hours. After that, it was stirred at -10°C and 400 rpm for 30 minutes to obtain a fluid suspension for all samples except sample I, which remained as a solution. Further equilibration was performed by stirring at -10°C and 400 rpm for 3 hours to obtain a dilute suspension. All samples were isolated in an isolate cartridge and air-dried for 5 minutes before characterization.

[0481] Sample F, isolated from methyl benzoate, became a thick white paste after air-drying for 5 minutes, and a dry powder was obtained by air-drying it for a further 30 minutes on an XRPD sample holder.

[0482] [Table 38]

[0483] 5MeODMT benzoate lot 21-01-073: B, C, D, E, G, H, and L were isolated from n-propyl acetate, isopropyl acetate, isobutyl acetate, ethyl formate, methyl propionate, 4-methyl-2-pentanone, and α,α,α-trifluorotoluene, respectively.

[0484] The XRPD of these samples showed a powder pattern consistent with 5MeODMT benzoate lot 20-37-64, pattern A. The DSC thermograph of the selected pattern A material showed a common endothermic event characteristic of pattern A morphology, with a peak temperature in the range of 123.07°C to 124.17°C and an enthalpy of approximately 140 J.g-1. After controlled cooling, the 5MeODMT benzoate lot 21-01-073 B, E, H, and L were isolated and air-dried for 5 minutes. 1 The 1H NMR spectrum showed that the salt has a stoichiometry of 1:1, and that the salt-to-solvent ratio is in the range of 1:0.0155 to 1:0.027.

[0485] Lot 21-01-073 A of 5MeODMT benzoate was isolated by controlled cooling of a methyl acetate solution from 50°C to -10°C and air-dried for 5 minutes. The XRPD of 5MeODMT benzoate lot 21-01-073 A was consistent with 5MeODMT benzoate lot 20-37-64, pattern A (Figure 83), but showed a diffraction pattern characterized by stronger diffraction at 21 and 24.6°2θ. This difference in intensity was thought to be due to a preferred orientation.

[0486] Figure 83 shows a comparison of XRPD patterns for 5MeODMT benzoate lot 21-01-073A, 21-01-049B1, pattern B, and 20-37-64, pattern A. This indicates.

[0487] The DSC thermograph of 5MeODMT benzoate lot 21-01-073 A showed an endothermic event with a peak temperature of 123.58°C, which is characteristic of pattern A morphology.

[0488] The ¹H NMR spectrum of 5MeODMT benzoate lot 21-01-073 A, isolated after controlled cooling and air-dried for 5 minutes, showed that the salt's stoichiometry was 1:1, and further, the ratio of methyl acetate salt to solvent was 1:0.033. 5MeODMT benzoate lot 21-01-073 F was isolated by controlled cooling of the methyl benzoate solution from 50°C to -10°C and air-dried for 5 minutes. After 5 minutes of air-drying, the sample became paste-like, and further air-drying for 30 minutes yielded a moist powder.

[0489] XRPD of 5MeODMT benzoate lot 21-01-073 F showed an XRPD pattern with an amorphous halo (Figure 84). The sample was further air-dried and re-run. XRPD of 5MeODMT benzoate 21-01-073 F (re-run) showed a diffraction pattern consistent with the initial measurement, but with a reduced amorphous halo (Figure 85). The diffraction pattern showed some similarity to both patterns A and B (Figure 86), but the presence of intrinsic diffraction, as well as the absence of characteristic pattern A and pattern B diffractions, suggests that this material is an intrinsic solid-state version, which is identified herein as pattern F morphology.

[0490] Figure 84 shows a comparison of the XRPD patterns of 5MeODMT benzoate lot 21-01-073 F and 21-01-073 F after rerun. Figure 85 shows a comparison of XRPD patterns for a rerun of 5MeODMT benzoate lot 21-01-073 F, 21-01-049 B1, pattern B, and 20-37-64, pattern A.

[0491] Figure 86 shows a comparison of XRPD pattern enlargements for a rerun of 5MeODMT benzoate lot 21-01-073 F, 21-01-049 B1, pattern B, and 20-37-64, pattern A.

[0492] The DSC thermograph of 5MeODMT benzoate lot 21-01-073 F (re-run) showed a broad endothermic event with a peak temperature of 90.50°C, followed by a smaller endothermic event with a peak temperature of 106.65°C. This was followed by a broad, shallow endothermic event with a peak temperature of 180.35°C.

[0493] After storing the sample in a sealed container for 24 hours, DSC analysis was repeated. The DSC thermograph showed 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 another endothermic event with a peak temperature of 113.77°C.

[0494] The ¹H NMR spectrum of 5MeODMT benzoate lot 21-01-073 F, isolated after controlled cooling and air-dried for 5 minutes, showed a salt stoichiometry of 1:1 and a salt-to-solvent ratio of 1:0.59. The paste-like consistency after air-drying indicated the presence of methyl benzoate, and the wet powder appearance after 30 minutes of air-drying indicated residual methyl benzoate. However, the close stoichiometry of 1:0.5, combined with the inherent diffraction pattern and DSC thermograph indicating the tendency of 5MeODMT benzoate to form a hemisolvate with aromatic solvents, suggests that this sample is a methyl benzoate hemisolvate.

[0495] Lot 21-01-073 I of 5MeODMT benzoate was isolated by controlled cooling of a cumene solution of 5MeODMT benzoate from 50°C to -10°C and air-dried for 5 minutes.

[0496] The XRPD of 5MeODMT benzoate lot 21-01-073 I showed that the diffraction pattern was consistent with SPS5520 21-01-049 B1, pattern B. The DSC thermograph of 5MeODMT benzoate lot 21-01-073 I showed an endothermic event with a peak temperature of 109.24°C and a broad shoulder at approximately 100°C. This was followed by an exothermic event with a peak temperature of 111.35°C, and then an endothermic event with a peak temperature of 120.31°C. This was followed by a broad exothermic event with a peak temperature of 146.19°C. This thermal profile is similar to that of previous pattern B samples, but exothermic activity was observed after final melting.

[0497] The ¹H NMR spectrum of 5MeODMT benzoate lot 21-01-073 I, isolated after controlled cooling and air-dried for 5 minutes, showed that the salt has a stoichiometry of 1:1 and a salt-to-solvent ratio of 1:0.035.

[0498] Lot 21-01-073 J of 5MeODMT benzoate was isolated by controlled cooling of a toluene solution of 5MeODMT benzoate from 50°C to -10°C and air-dried for 5 minutes.

[0499] The XRPD of 5MeODMT benzoate lot 21-01-073 J showed that the diffraction pattern was consistent with that of 5MeODMT benzoate lot 21-01-064 A, pattern C.

[0500] The DSC thermograph of 5MeODMT benzoate lot 21-01-073 J showed an endothermic event with peak temperatures of 110.00°C, 115.03°C, and 120.60°C. The DSC thermograph is similar to that of 5MeODMT benzoate lot 21-01-071 C1, a previously isolated pattern C morphology material, but differs in the smaller peak, which is thought to be a result of sample preparation.

[0501] The ¹H NMR spectrum of 5MeODMT benzoate lot 21-01-073 J, isolated after controlled cooling and air-dried for 5 minutes, showed that the salt has a stoichiometry of 1:1 and a salt-to-solvent ratio of 1:0.473, confirming the isolation of the toluene hesolvate in pattern C form.

[0502] Lot 21-01-073 K of 5MeODMT benzoate was isolated by controlled cooling of a 2-chlorotoluene solution of 5MeODMT benzoate from 50°C to -10°C and air-dried for 5 minutes.

[0503] The XRPD of 5MeODMT benzoate lot 21-01-073 K showed a unique diffraction pattern (Figure 87), which is identified herein as pattern G. Figure 87 shows a comparison of the XRPD patterns of 5MeODMT benzoate lots 21-01-073 K, 21-01-049 B1, pattern B, and 20-37-64.

[0504] The DSC thermograph of 5MeODMT benzoate lot 21-01-073 K showed an endothermic event with peak temperatures of 111.28°C and 119.61°C. The 1H NMR spectrum of 5MeODMT benzoate lot 21-01-073 K, isolated after controlled cooling and air-dried for 5 minutes, showed that the salt has a stoichiometric ratio of 1:1, and further Since the ratio of salt to solvent was shown to be 1:0.516, the pattern G form is considered to correspond to 2-chlorotoluene halfsolvate.

[0505] The table below summarizes the samples isolated from this controlled cooling experiment and the resulting XRPD patterns.

[0506] [Table 39]

[0507] Example 31 DVS testing of amorphous 5MeODMT benzoate produced by freeze-drying 150 mg of 5MeODMT benzoate 20 / 20 / 150FP2 was dissolved in 5 ml of deionized (DI) water to obtain a clear solution. The solution was clarified in a 500 ml round-bottom flask, and the flask was rotated in an acetone / dry ice bath, causing a thin layer of the solution to freeze around the flask. The ice sublimated in vacuum at ambient temperature, yielding a cottony white solid. This solid was removed from the round-bottom flask and transferred to a DVS apparatus. During this transfer, the solid crumbled into a sticky gum.

[0508] The samples were tested by DVS from 40% RH and subjected to two cycles between 0% RH and 90% RH. XRPD was collected from a portion of the samples after freeze-drying and DVS testing.

[0509] The XRPD of 5MeODMT benzoate before DVS analysis showed the expected amorphous diffraction pattern (Figure 88). Figure 88 shows the XRPD of 5MeODMT benzoate lot 21-01-078.

[0510] DVS testing showed an initial weight loss of approximately 1.4% from the start of the study during the first desorption cycle (Figure 89), which was much lower than the 5 wt% required for 5MeODMT benzoic acid monohydrate. During the first adsorption, the weight loss continued despite the RH rising to 70% RH. At 80% and 90% RH during the first adsorption cycle, the weight increased slightly. Following this, the weight decreased minimally during the second desorption cycle, and in subsequent adsorption cycles, there was no change in weight up to 50% RH, with a weight increase of 0.2% between 50% RH and 90% RH. To occur.

[0511] Figure 89 shows the DVS isothermal plot of 5MeODMT benzoate lot 21-01-078. XRPD of lot 21-01-078 of 5MeODMT benzoate after DVS testing at 90%RH showed a diffraction pattern consistent with pattern A (Figure 90).

[0512] Figure 90 shows a comparison of the XRPD patterns of 5MeODMT benzoate lot 21-01-078 (after DVS) and 20-37-64. Amorphous 5MeODMT benzoate is unstable and converts to pattern A form under all tested conditions. Under ambient conditions, the amorphous version is thought to absorb moisture from the atmosphere, which is then removed from the sample after conversion to pattern A form. Such a conversion is not considered to be hydrate-mediated, as no evidence of 5MeODMT benzoate hydrate has been observed. Alternatively, the freeze-drying process may appear complete when some moisture remains bound to the solid. When the freeze-drying container is evacuated to atmospheric pressure, the low-density, bulky solid shrinks, trapping moisture to form a gum, which is then discharged as an amorphous gum, converting to the more stable, regular pattern A form version.

[0513] Example 32: FTIR spectroscopy of 5MeODMT benzoate patterns A, B, and C Figure 91 shows FTIR polymerization of 5MeODMT benzoate in pattern A (20-20-150FP2), pattern B (21-01-071 C2), and pattern C (21-010071 C1).

[0514] Figure 92 shows the FTIR polymerization of 5MeODMT benzoate in patterns A (20-20-150FP2), B (21-01-071 C2), and C (21-010071 C1) at 450-2000 cm⁻¹.

[0515] Figure 93 shows the FTIR polymerization of 5MeODMT benzoate patterns A (20-20-150FP2), B (21-01-071 C2), and C (21-010071 C1) at 450-2000 cm⁻¹, with separated spectra.

[0516] FTIR studies reveal that pattern A morphology exhibits several bands of significantly different intensity compared to patterns B and C. Such prominent bands were observed at approximately 3130, 1540, 1460, 1160, and 690 cm⁻¹, while key bands present in patterns B and C that are absent (or significantly reduced in intensity) include those observed at approximately 3230 and 1640 cm⁻¹.

[0517] Patterns B and C clearly demonstrated that the difference in FTIR values ​​between them was much smaller compared to that of pattern A. This was expected, considering that the pattern C form semisolvate desolvated somewhat easily to obtain the pattern B form, and that the crystal lattice changed relatively little compared to the energy required to induce the conversion from pattern B form to pattern A form (i.e., vacuum drying at high temperature), and that the crystal lattice was reconstructed more significantly than would be by easy desolvation.

[0518] Example 33: Stability of Patterns B and C When 5MeODMT benzoate pattern C is dried under vacuum at 50°C for 24 hours, it has historically often yielded pattern B, which, when observed with a hot stage microscope, is known to transform into pattern A at 90°C. The stability of pattern A and pattern B under both atmospheric conditions and under vacuum at 50°C was investigated to determine the inter-morphological relationship. The relationship was determined.

[0519] 5MeODMT benzoate lot 21-01-071 C1, pattern C, and lot 21-01-071 C2, pattern B were placed in XRPD sample holders and sample vials and left exposed to the air for 12 days.

[0520] 5MeODMT benzoate, lot 21-01-071 C1, pattern C form, was dried under vacuum at 50°C for 5 days. XRPD was performed regularly. DSC and 1H NMR spectroscopy were performed on samples in which significant differences in diffraction patterns were observed.

[0521] The table below shows an overview of the solid-state transformation by XRPD during stability testing.

[0522] [Table 40]

[0523] Example 34: Competitive equilibration of 5MeODMT benzoate in solvents in patterns A, B, and C. The relationships between the A, B, and C forms of 5MeODMT benzoate were investigated to determine the thermodynamically stable forms and hierarchy. Competitive equilibrations were performed between forms A and B, and between forms A and C, in various solvents including IPA and toluene. Form A was expected to be the most stable form, given its melting point of 124°C and its predominance in most of the investigations conducted.

[0524] 15 mg of 5MeODMT benzoate 20 / 20 / 150FP2, pattern A form, was added to all crystallization tubes. 30 mg of 5MeODMT benzoate lot 21-01-071 C2, pattern B form, was added to crystallization tubes A and B. 30 mg of 5MeODMT benzoate toluene half-solvate lot 21-01-071 C1, pattern C form, was added to crystallization tube C. 0.5 ml of solvent was added to the crystallization tubes, as detailed in the table below. The suspension was stirred at 20±2°C and 100 rpm for 24 hours. The suspension was separated via an isolute cartridge, air-dried for 5 minutes, and characterized by XRPD and DSC.

[0525] [Table 41]

[0526] XRPD analysis of all samples revealed that the vast majority yielded pattern A. Sample AC5, isolated from MEK, revealed additional diffraction at 8.8°2θ, which is thought to be caused by the splitting of the diffraction at 9°2θ due to the good inter-diffraction resolution of this sample.

[0527] DSC thermographs of most samples exhibiting pattern A morphology revealed endothermic events with peak temperatures in the range of 123.74°C to 124.22°C, suggesting pattern A morphology. 5MeODMT benzoate isolated from isopropyl acetate, lot 21-01-079 The DSC thermograph of AB3 revealed a series of events between 109°C and 115°C, followed by a smaller endothermic event with a peak temperature of 115.69°C. This was followed by a major endothermic event with a peak temperature of 123.85°C, suggesting pattern A morphology.

[0528] The smaller endothermic event is thought to be due to an incomplete transformation from pattern B to pattern A via equilibrium. XRPDs of 5MeODMT benzoate lot 21-01-079 AB2 and AC2, both equilibrated in toluene, revealed diffraction patterns consistent with those of 5MeODMT benzoate lot 21-01-064 A toluene half-solvate, pattern C morphology.

[0529] DSC thermography of 5MeODMT benzoate lot 21-01-079 AB2 revealed a bimodal endothermic phenomenon with peak temperatures of 114.96°C and 121.92°C. The thermal properties are similar to those of previously isolated pattern C samples, including 5MeODMT benzoate lot 21-01-073 J.

[0530] The DSC thermograph of 5MeODMT benzoate lot 21-01-079 AC2 revealed a smaller endothermic event with a peak temperature of 110.11°C, followed by partially overlapping endothermic and exothermic events between 110.73°C and 113.23°C. This was then followed by an endothermic event with a peak temperature of 122.82°C, which was similar to the melt of pattern A morphology when recrystallized from pattern B morphology.

[0531] Competitive equilibration of both pattern A / B and pattern A / C mixtures in solvents where the formation of hemisolvates had not been previously observed explicitly demonstrated conversion to pattern A. All other hemisolvates are expected to convert to pattern A in these solvents.

[0532] Competitive equilibration of both pattern A / B and pattern A / C forms in toluene explicitly demonstrated conversion to pattern C form. Equilibration of 5MeODMT benzoates in solvents prone to forming hemisolvates (typically aromatic solvents) is expected to yield its particular 5MeODMT benzoate hemisolvate, overriding the otherwise thermodynamically stable pattern A solid form mode.

[0533] Example 35: Administration of 5MeODMT salt The physical environment of the participant / patient / subject is of paramount importance in many characteristics of psychedelic experiences. The space should be private, meaning it should be free from the possibility of intrusion by others. Ideally, external noise (e.g., hallways, streets) should be minimized. Medication sessions should take place in a room that feels more like a living room or private room than a clinical setting. Artwork, plants, flowers, soft furniture, soft lighting, and related decorations should be used to create a cozy, relaxing aesthetic. Artwork that tends to evoke specific religious imagery, ideological connotations, or negative emotions should be avoided. The medication room may also be furnished with comfortable furniture for the participant and the therapist, who may sit on either side of the participant. Participants experiencing the effects of 5MEODMT may exhibit spontaneous movements or slide off the bed or sofa while lying face down. Therefore, it is important to ensure that there are no sharp or hard objects nearby that could cause a participant to fall. Additionally, pillows may be helpful in providing physical support for participants as they move during the experience. The therapist can physically support the participant by placing a pillow between their hand and the participant's body.

[0534] Since music may be incorporated into the experience, the medication room should be equipped with a stereo. The room should shield participants from the sights and sounds of the outside world, and participants should have no reason to worry about being observed or disturbed by anyone other than the therapist.

[0535] The space may also include the following: - Safety procedures and medical devices necessary to respond to unexpected medical complications. Participants should be made aware of these procedures and devices, but they should be kept out of sight as much as possible. - A secure, locked space for research materials and documents, either in or near the session room. - An authorized safe for storing 5MEODMT in or near the session room. - Audio and video recording equipment. If permitted by the research protocol, participants should have already consented to being recorded and should be aware of the equipment, but it should be placed as inconspicuously as possible. Participants can request to stop recording at any time. physical space The space may be large enough to accommodate two therapist chairs, a stereo system, and a cabinet for storing participants' belongings and any additional supplies the therapists may need during the day. The space may accommodate a bed or chaise lounge on which participants can sit or lie comfortably surrounded by pillows. The space should be at least 30 to ensure that participants do not feel cramped or too physically close to the therapists. 2 kilometers (100 2 (feet) or 10 2 It could be in meters. Participants should have the freedom to explore various postures, such as sitting or stretching on the floor. Toilets should be directly accessible from or near the session room. music In the 5MEODMT session, in order to create a calm atmosphere, A set playlist of nature sounds may be used. These nature sounds are thought to act as background elements, drowning out external noise and helping participants stay focused on the experience. Participants are not instructed to listen to the sounds in a specific way, but may be asked to focus on them before and after the session as a way to ground their senses and relax. There is. Discontinuation of drug therapy Discontinuing medication can be difficult for participants. Participants are expected to discontinue all contraindicated medications and complete a check-in period prior to preparation-1 with their therapist. Research team members, including the therapist, may provide support through check-in calls with participants as needed during the check-in period, but preparation-1 should not begin until the check-in is complete and the participant's willingness to continue therapy is confirmed. Preparation session This treatment model includes three 60-90 minute preparatory sessions with a therapist. These are conducted 7 days, 4 days, and 1 day before the 5MEODMT session. The preparatory sessions are designed to be conducted remotely, but in person is possible if available. Preparation Session 1 The following items may be covered in the first preparatory session: Get to know the participants The therapist spends part of the preparation session time getting to know the participant. - How did you learn about the procedure and what are the participants' expectations? - Current living situation, including living situation, work, school, and important relationships. - Participants' own understanding of depression, - Participants may be asked open-ended questions about major life events they feel might be relevant.

[0536] Therapists must be attentive to how participants speak about themselves and their relationship with depression, and how they engage with the therapist and the research environment, and must be attentive to establishing trust and communication with the participants. Clinical impressions that make it difficult to form a trusting relationship with the therapist, or other clinical factors that may hinder the participant's ability to engage in treatment, should be noted and discussed within the research team. Even at the preparatory session stage, therapists can learn more about participants who may be grounds for exclusion from the study. Establishing the role of the therapist In the 5MEODMT adjunctive therapy treatment model, the therapist forms a relationship with the research participant, who becomes part of the container in which the 5MDE (the subjective experience of 5MeODMT) is administered. This formation of the relationship is intentional on the part of the therapist and is characterized by the therapist establishing transparency and trust, taking clinical responsibility for the patient's health as well as the patient's relational and emotional safety. The therapeutic relationship is understood as a critical component of the set and setting for the therapeutic use of 5MDE. Communication and the establishment of this relationship are both explicit (overt) and implicit (hidden) in the therapist's behavior and habits during the treatment. Description of a treatment model in which participants become active participants in their own process. In the first preparatory session, the therapist should explain to the participants the treatment model used in this research study. The explanation should include the following: Realistic aspects: - How many meetings are there with the therapist, and how long are they? - The therapy is thought to work as follows: - So that participants know what to expect and can fully embrace their experience. To create a safe container for the experience, - To help participants focus on and explore their own reactions to the experience. - To facilitate a process in which participants independently decide how to put their insights into practice in their lives. The role of that therapist is, - Throughout the session, engage in a series of activities to support participants, draw out their unique experiences and insights, and facilitate the participant's process of realizing the resulting life changes. - That therapy, - This is not a place to delve deeply into the participant's personal history, nor is it a place to engage in specific problem-solving or CBT, to receive psychodynamic interpretations, general advice, or other interventions that the participant may be familiar with. Establishing physical, emotional, and psychological / relational safety Beginning with the first preparatory session, the therapist establishes a physically, emotionally, and psychologically safe environment. The therapist explains the 5MEODMT safety and safety procedures regarding the participant's physical well-being during the session. Regarding emotional safety, the therapist states that all emotional experiences are welcome and there is no area of ​​experience that the participant is not welcome to share. Safety can also be established by the therapist's calm and reassuring presence, and the use of words is not always necessary.

[0537] While self-disclosure is not prohibited, it should be used very sparingly. Participants may seek reassurance by asking personal questions of the therapist. If the therapist chooses to disclose information, it should be brief and done on the condition that the participant shares why that personal information is important to them.

[0538] Psychological / relational safety is established by ensuring participants' preferences regarding the use of touch are respected. Participants are also reassured that if they choose not to participate in the 5MDE experience, they can do so at any point before drug administration, and this choice will be respected, and they will still be able to receive therapy sessions even if they make that choice.

[0539] Therapists can use the following techniques to establish safety with participants: Ask free-form questions that encourage the expression of doubts, hesitations, or concerns.

[0540] Do you have any questions for me? What would you like to know more about 5MeODMT? ...What would be useful in that situation?

[0541] If you feel that way, how can I help? Rather than attempting to modify or resolve the emotions and experiences of any participant, we encourage and engage with them.

[0542] Participants express doubts about the 5MEODMT experience: Thank you for sharing your doubts. Now, in light of your presence here, what are your thoughts on it? Participants express fear regarding the 5MDE experience: Can you tell me more about your fear and how it manifests? How can I help you if you are going through a similar experience?

[0543] Use assertive statements to create an environment that values ​​participants' time and effort: I am truly grateful for your willingness to dedicate time to this procedure and participate in the research. Your experience is unique to you, and I appreciate the opportunity to see you through this process. Expected potential subjective drug effects (unity, suicidal thoughts, emptiness) It can be helpful to discuss the concept of "altered states of consciousness" with participants. Historically, "altered states of consciousness" were often associated with experiences induced by psychedelic compounds. However, changes in consciousness are experienced daily, such as shifts in mood or feelings, or transitions from a awake, alert state to fatigue and drowsiness. "Altered states of consciousness" emphasize experiences that are not typically common in everyday life, but can still occur within a person's experience.

[0544] The therapist can begin the conversation by asking participants about their existing knowledge of the 5MEODMT effect and listening to any specific expectations or thoughts they may have about it. The therapist should encourage an open attitude towards the experience, guiding participants to explore what kinds / thoughts they might have and to accept the possibility that it's impossible to imagine what it will be like. Participants may have specific expectations based on media, previous experiences with 5MEODMT or other hallucinogens, or other types of unusual states of consciousness. It is important for the therapist to provide a balanced explanation of what the participant might experience.

[0545] The level of comfort with "not knowing" what something is or what to expect varies from person to person. Therapists may explore a participant's level of comfort with the unknown, their relationship with the idea that the future is never fully known in any situation, and how they typically cope with this. Some depressed participants may have a deep fear of the unknown, an anticipation of what to expect in the future (more negative experiences), which may result in a feedback loop of fear and depression. Therapists should draw out and explore this area during the preparation phase.

[0546] Common 5MeODMT Experiences: The therapist should also introduce several key terms and commonly reported experiences known to occur under 5MeODMT. These include a sense of unity, a sense of death, and a feeling of entering or experiencing “emptiness” (a state of no physical substance). Some participants may have pre-existing spiritual, philosophical, or religious belief systems through which they interpret or give meaning to these experiences. The therapist should ask about this and address it using the participant’s own explanations and terminology, without taking a stance on whether it is right or wrong. Social support and social media Participant social support may be assessed during preparatory sessions and determined by the therapist to be sufficient to support the patient throughout the process of change, particularly if either disappointment reduction or dramatic symptom reduction occurs. If a participant has a non-study psychotherapist, the study therapist may, with the participant's permission, call the participant's therapist to explain the nature of the study and the therapeutic approach and answer any questions the therapist may have. The study therapist may also be close to the participant and educate friends or family who have questions about the nature of the study, the 5MEODMT experience, and what to expect. The therapist should discuss social support with the participant, including preparing the participant for the various reactions that their friends and family may have.

[0547] Therapists may advise participants to be careful not to draw excessive social opinion when posting about their experiences on social media. Social media in a way that could disrupt inadequate social support or the therapeutic process. The use of 5MEODMT may be discussed and resolved prior to administration of 5MEODMT. Preparation Session 2 The following items may be covered in the second preparatory session. Preparing for a drug experience: Trust, surrender (release), accept, transcend.

[0548] There are several key attitudes associated with psychedelic experiences that are thought to foster positive and clinically useful experiences. The more relaxed a participant is in their stance towards their experience, the less likely they are to inadvertently create a stress and distress loop that increases their focus on the negative aspects and interpretations. Therapists can educate participants with the aim of consciously cultivating a trusting attitude, surrendering to the experience, and releasing attempts to control it. Therapists can encourage participants to develop an attitude of welcoming and accepting all experiences they may have as part of their 5MEODMT experience. Therapists may suggest to participants that all aspects of the experience (emotions, sensations, and thoughts) can be welcomed. Previous research using hallucinogens has indicated that the ability to immerse oneself in an experience can contribute to the efficacy of mystical experiences. Drug administration The therapist should explain on the day of the session that a member of the research team will enter the room briefly to administer the research drug. The therapist should also explain the participant's position, for example, that the participant will be sitting on a bed or sofa, that a member of the research team will insert a nasal spray device into one nostril, and that the therapist will ask if they can help the participant lie down on the bed or sofa immediately afterward. Session procedures including boundaries, touch usage, and safety. The therapist explains the session process. The session includes the timing of medication administration and the physical environment of the administration room. It begins with the participant entering the room and engaging with the therapist during the session opening. The session opening is the formal moment when the participant and therapist are seated together in the room, everything is ready, and the playlist begins. If the participant is receptive to the breathing exercises, the therapist may guide the participant through the breathing exercises they have chosen and ask the participant to reflect during the preparation session on the values ​​they choose, or any other values ​​or intentions that are important to them. Once the participant signals that they are ready, a member of the research team administers the nasal spray to the participant. Trust and safety are conveyed not only verbally but also nonverbally through how the therapist behaves in front of the participant. If the therapist is feeling excessively anxious or fearful, the participant may sense it. Throughout the medication session, it is important for the therapist to remain focused, especially when the participant is experiencing intense emotions, unusual physical expressions, or seeking support. Physical changes and transformations in bodily sensations Some participants may experience increased body awareness, such as feeling a stronger heartbeat or a physical sensation in their temples. Others may experience bodily aches, changes in breathing or shortness of breath, or other unusual physiological experiences. It is important for the therapist to communicate that these perceptual changes are normal and should not be the focus of preconception or fear. If these sensations occur, participants should be encouraged to tell the therapist if they wish. The therapist should reassure participants that these sensations are expected and normal to have. The therapist can inform and reassure participants that naturally occurring 5MEODMT has been consumed in other contexts for hundreds of years, has not been shown to be physically harmful, and that these changes are expected and will soon resolve. Discussion of expectations and intentions Expectations can be defined as mental expressions and beliefs about what something will be like in the future. Expectations may be explicitly identifiable or subconsciously obvious. Both types of expectations can be important in treatment. Therapists may use explicit expectations. When asking about expectations, the therapist should encourage participants to acknowledge and set them aside so that they do not become involved in comparing their experiences with their expectations. The therapist should also listen to subperceptual expectations that participants may become aware of throughout the therapy. Will is the way in which one engages in behavior or experience. In 5MEODMT procedures, participants' wills can change significantly, and this may be expected, so it may be important for the therapist to draw out and understand the participant's will. The therapist is to involve the participant in the process of identifying and setting their will so that it becomes explicit and can be referenced later during integration. The purpose of will is to identify and release it, knowing that it may become part of 5MED. Recurrence of acute effects Some individuals who used 5MEODMT in a non-clinical setting reported re-experiencing the subjective effects of 5MEODMT several days later. In these cases, the dose, purity, or other factors used were not monitored. It is unclear, but presumed, whether these reactivations would occur in a controlled clinical study setting is unknown. Nevertheless, it is important to make participants aware of this phenomenon. The reactivation experience is often reported to be pleasant, brief (lasting from just a moment to a few minutes), and not frequent enough to disrupt a person's life. For some, these reactivations are considered part of the integration process. If a participant realizes that certain activities, such as certain meditative states, stimulants, or other drugs, trigger reactivations, and if the participant finds these reactivations unpleasant, they should be advised to avoid such triggers. In therapy, treating the 5MEODMT experience as part of the integration process may also be effective. Discussion on the use of touch Therapists in this modality may involve two types of touch: therapeutic touch and touch for safety reasons. During preparation, the therapist should explain and define each. Therapeutic touch is touch intended to connect with, soothe, or otherwise communicate with the participant for therapeutic purposes. This is always consensual, non-sexual, and the participant is encouraged to refuse or stop therapeutic touch at any time. Touch for safety reasons includes supporting a participant who has difficulty walking by offering an arm to hold them, or preventing a patient from leaving the room while under the effects of acute medication. This touch is agreed upon beforehand, is always non-sexual, and is limited to specific safety concerns. The therapist should discuss both of these with the participant and establish boundaries before the session. Post-session preparation (what to expect, what to do, and how to allocate time for integration) Participants should be encouraged to take time to rest and integrate their experience after the session day. Research therapists should ask participants to plan to rest at least all day of the session and the day after. The therapist should explain that they will stay in the room with the participant for a while after the acute effects of 5MeODMT have worn off. This time is for the participant to readjust to their experience after the acute effects have subsided. Participants will be asked to share anything they can remember about their experience and any reactions they may have. Participants will not be asked to share anything they do not wish to share, and they are welcome to choose not to make their experience public. Participants may choose to write or draw about their experience, and art supplies and writing implements will be available. Participants may be encouraged to spend some time, perhaps an hour or so, simply reflecting on their experience with the therapist's support. Participants will then meet with the research team for a safety assessment before going home. Upon returning home, participants are encouraged to rest and continue to reflect on the experience and any insights, thoughts, or new understandings they may gain from it. Participants should be reminded that they do not need to share their experience with others unless they wish to, and should be encouraged to continue to focus on it in the way they feel is most effective. Participants should refrain from returning to work, driving, drinking alcohol, using drugs, or being the sole caregiver for children or dependents for the duration of the day. For medication sessions, the therapist teaches breathing exercises. When stressed, breathing becomes short and shallow, while when relaxed, breathing becomes long and slow. The connection between breathing and breathing is a way of regulating and controlling a person's mental state. Therapists can teach and practice two breathing techniques with participants. These are designed to help participants relax their mind and body, cope with stressful or unpleasant experiences, and develop autonomy through self-practice. These are not intended for use during the acute effects of 5MeODMT, but can be used before and after medication.

[0549] When teaching a practice, the therapist elicits individual responses from participants to each practice in order to assess whether it is appropriate for them to use it. Breathing practices include balancing breathing, diaphragmatic breathing, and counting breaths. Preparation Session 3 Value card sort using prompts The therapy protocol may utilize a customized personal value card sort to help therapeutically focus on and assist in the transformation of self-perception. This is done by asking how a person engages with the values ​​they selected before the session and how they engage with them afterward, drawing attention to transformations and changes, and using these as guidelines for the kind of changes the participant may wish to bring about. It is used as a way to elicit conversations about the participant's self-perception, beliefs about themselves, and changes in these perceptions / beliefs throughout the therapy. The therapist may involve the participant in a third preparatory session, such as one to two days before the medication session, to practice sorting the cards.

[0550] The instructions for sorting value cards are: 1. Place the five anchor cards in order from 1 to 5 in front of the participants, from left to right, in order from least important to most important. 2. Shuffle the 100 value cards, setting aside the two blank cards. 3. Instruct participants to sort the cards using the following script: "I have placed five title cards in front of you: Not important to you, Somewhat important, Important, Very important, and Most important. Now I will give you a deck of 100 personal value cards. Look at each card and place it below the five title cards. There are also two blank cards. If there are any values ​​you would like to include, write them on the card and place it in either deck. I would like you to sort all 100 cards, but you may use the two additional cards if you wish. Do you have any questions?" 4. Once the participants have finished sorting, thank them and encourage them to remove the other cards from the table and look at the “most important” category. 5. Read the following aloud: "For the second task, focus on the top values ​​you placed in the 'most important' category and select your top five." 6. Once the participant has selected their top five cards, thank them and read the following sentence: "For the third task, focus on the top five values ​​you have chosen and rank them from most important to least important." 7. Once the participants have finished ranking, confirm to ensure you understand how the cards were sorted (ascending or descending). Point to the number 1 card and say, "I just want to make sure this is correct, is this your number one value?" 8. Record values ​​by taking photos of scoring sheets, journals, or cards. Participants should also record the cards they chose. Reporting and discussion Next, use the following free-form script, or several similar scripts depending on the work situation, to encourage participants to engage in a structured discussion of each value. - You have chosen _ as your number _ value. - Could you tell me more about what _ means to you? - In what ways has _ been expressed in your life? - What are some ways to see more of _ in your life? How does the decision of whether or not to do something relate to this value system? - How much _ do you want in your life? - How can you tell if _ is increasing or decreasing in your life? - How does _ relate to the change you are trying to bring about (or are thinking about bringing about)?

[0551] Afterward, participants are encouraged to use the remaining cards to write their answers to the same questions in their journals. In later sessions, it can be helpful to revisit these questions to confirm values ​​and see how the answers have changed and how participants are currently relating to their values. Assistant Therapist The session can be conducted by a therapist and an assistant therapist, allowing a second person to assist in case of adverse events or physical complications affecting the participant's safety. The assistant attending the session should be introduced in preparatory session 3 and included in the conversation to get to know the participant. Therapeutic work specific to each session Therapists should aim to complete the therapeutic tasks outlined above, following the chart below, while acknowledging that there may be some variations based on the individual needs of each participant.

[0552] [Table 42]

[0553] 5MeODMT Experience Session The therapist will be with the participant throughout the session, including pre- and post-treatment time. This is the only session that must be conducted in person. The location and therapist must allocate approximately 3 hours for the session, including pre- and post-treatment time. This does not include the time allocated for pre-session baseline measurements and registration verification. The minimum time the participant must be under observation after 5MEODMT administration will be determined by approval from the local regulatory authority. Before the experience (approximately 30 minutes) After participants have completed all registration verification and randomization procedures and have been cleared to participate, the therapist, assistant therapist, and participant will be in the room together to review all aspects of the room and safety procedures. The therapist should introduce the participant to the team member who will administer the 5MEODMT and help them feel comfortable. The therapist will introduce the assistant therapist and review the room's safety features and any equipment present. Participants will have time to ask questions. The therapist will ask about their reactions to the situation and how the participant feels about their session. Participants should not be rushed into taking the medication by the therapist. The therapist will ask the participant to have some time to relax before taking the medication. Participants will be asked to lie down, close their eyes, listen to music, and, if they wish, engage in at least one breathing exercise under the therapist's guidance. Once the participant is calm and comfortable, the therapist will begin the session opening. This implementation will help include and highlight the unique aspects of the experience. The therapist will contact the research team member to come into the room and administer the 5MEODMT. Team members should be careful not to disrupt the pleasant atmosphere in the room. When administering 5MEODMT, participants should remain seated as the effects are felt quickly, then transition to a prone position and remain prone for the duration of the 5MEODMT's effects. Experience (approximately 60 minutes) The onset of acute effects is expected to occur very rapidly after administration. Therapists should keep track of the administration time so they can notice the participant's response in relation to the expected duration of the effects. Some participants may want to know how long they experienced the effects of 5MEODMT, so it is appropriate to share this information if asked. For most of the time, participants may be silently and inwardly focused, engaged in their experience. It is important for the therapist to be attentively aware of the participant but not to interrupt the participant's experience unless it is clear that the participant is seeking the therapist's support. Therapists are encouraged to engage in self-regulation techniques while the participant is experiencing. This may take the form of slow, intentional inhalation and exhalation, or other activities that help the therapist ground and self-regulate. This is in the benefit of both the therapist and the participant, as participants in an elevated, abnormal state are particularly sensitive to and may pick up on their therapist's anxieties. When the 5MEODMT experience appears to be subsiding, and the therapist chooses to engage verbally, it is best for the therapist to follow the participant's lead. The therapist may want to ask the participant about their experience, but it is preferable to wait until the participant is ready to share on their own. The participant may wish to remain in a period of silence even after the obvious acute 5MEODMT effect has subsided. The therapist should greet the participant with a friendly smile and welcoming nonverbal gestures, and allow the participant to take the lead in sharing when they feel ready. After the experience (approximately 90 minutes) The therapist encourages the participant to reflect on their experience for at least one hour after the acute effects of 5MEODMT have worn off and the participant has regained awareness of their surroundings and circumstances in the treatment room. Reflecting on an experience means continuing to focus attention on it in a way that feels most appropriate to the participant, without turning to distractions, entertainment, or everyday concerns. During this time, the therapist will allow the participant to describe their experience if they choose to do so. The therapist encourages the participant to share their experience and respects their choice not to share if they are not ready. When the participant shares their experience, the therapist is supposed to listen attentively and encourage the participant to express whatever they want to share without attempting to interpret or assign meaning. The therapist simply practices listening while encouraging the participant to describe their experience as much as possible. The therapist may also suggest the participant take a break and listen to music, or write or draw about aspects of the experience that the participant wishes to discuss. At the end of this time, the therapist confirms with the participant that they feel ready to conclude the session, conducts a session closing, and contacts the research team for a final assessment. Integration Session A key principle of integration sessions is to help participants focus on a shift in their perception of themselves and what that means in relation to depression. For the purposes of this study, the self is broadly defined as the narrative or historical self, a coherent sense of "I" that moves through experience, and "self-identity" as it may be used. It is important to remember that the sense of the self, or "I," is reflected in both the experiencer's self-experience and the experience of the experienced object, so the description may reflect a shift in internal processes, even if it is superficially a change in perception of the external world. To this end, the following therapeutic work will advance the integration session.

[0554] These sessions are less structured than the preparation sessions to accommodate variations in participant responses. There are three tasks. The first task should be done in all sessions, while the second and third tasks can be introduced and worked on if participants are ready and willing. The tasks are as follows: Listening to and hearing about participants' experiences The therapist asks free-form questions about the participant's experience and listens with curiosity, without making assumptions about the participant's explanation. The therapist asks the participant to focus solely on the 5MDE and related materials, ensuring that the time spent together is focused on the treatment. The therapist directs the questions to the participant's experience and asks them to attune to any of the three types of self-perceptions the participant may identify. Reintroduction of values ​​and discussion of relationships with each other The therapist reintroduces the values ​​identified through the value card sort during preparation and, if appropriate during the integration session, returns to those values. Participating in a structured discussion of values ​​is not mandatory, but it serves as a necessary framework to focus the session on the participant's transformation of their sense of self. A therapist might, for example, ask a client to re-examine their values. Therapist: Before the 5MDE, we discussed a list of your values ​​and how you relate to each of them. Let's return to that and explore in more detail how those relationships may have shifted. For example, you listed "family" as one of the things important to you, but you were concerned about not being healthy enough to participate in family interactions. You mentioned that you often feel isolated from your family because you spend every night working on your computer in your makeshift garage office. How do you relate to the value of "family" now?

[0555] In the dialogue, the therapist can keep the focus on, for example, how the participant is shifting their relationship with their values ​​regarding "family" by asking about what the participant is aware of in this area.

[0556] The process involves creating ways for participants to act to strengthen their relationship with their chosen values ​​and identifying value-driven behaviors in their lives as a practice of integration. Integration can be understood as the process of embodying or realizing the insights they possess. At least one integration session will allow the therapist to guide the participant through this stage. In the earliest integration sessions where participants feel they have made progress, the therapist should introduce the idea of ​​identifying value-based behaviors they can take in their lives as a practice of integration. After explaining the concept as described above, the therapist can encourage participants to recall the values ​​they have identified (or other values ​​that are important to them), to recall insights or experiences from their 5MEODMT sessions, and to think creatively about what they might try to do differently, intentionally, to bring about positive changes in their relationship with their values, based on those insights and experiences. item 1. A method of administering 5MeODMT or a pharmaceutically acceptable salt thereof to a patient diagnosed with depression, • Steps to discontinue the patient's use of any mood-altering substance, or any other substance, drug therapy, or formulation that may affect serotonergic function. • Relaxation steps for the patient, such as being instructed to lie down, close their eyes, listen to music, and / or engage in one or more breathing exercises guided by the therapist. • If necessary, the patient may take steps to clear their nasal passages by blowing their nose, for example, while sitting. A method comprising the step of administering 5MeODMT, wherein, if necessary, the patient is in a prone position, and, if necessary, the patient is in a prone position for the duration of the effect of 5MeODMT.

[0557] 2. The method according to item 1, wherein the patient discontinued the use of monoamine oxidase (MAO) inhibitors, CYP2D6 inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), lithium, antipsychotics, triptans, tramadol, 5-hydroxytryptophan, herbal preparations that may contain 5-HTP, St. John's wort, and any benzodiazepines prior to administration of 5MeODMT.

[0558] The method according to item 1 or item 2, wherein 3.5 MeODMT is administered via the Aptar Unidose (UDS) liquid delivery system. The method according to item 1, item 2, or item 3, wherein 4,5MeODMT is a benzoate, and optionally a polymorph of a benzoate.

[0559] 5. The patient participates in at least one psychological support session prior to administration of 5MeODMT, as described in any one of items 1 through 4. 6. The patient participates in at least three psychological support sessions prior to administration of 5MeODMT, as described in item 5.

[0560] 7. The method described in item 6, wherein the patient participates in three psychological support sessions, which take place 7 days, 4 days, and 1 day before administration of 5MeODMT. 8. The method described in any one of items 5 through 7, wherein the length of the psychological support session is 60 to 90 minutes.

[0561] 9. At least one therapeutic intention is discussed during the psychological support session, as described in any one of items 5 through 8. 10. The method described in any one of items 5 through 9, in which self-directed questioning and processing of experiences are practiced during a psychological support session.

[0562] 11. The method described in any one of items 1 through 10, wherein the patient participates in at least one psychological support session after administration of 5MeODMT. 12. The method described in item 11, wherein the patient participates in at least three psychological support sessions after administration of 5MeODMT.

[0563] 13. The method described in item 11 or item 12, wherein the patient participates in three psychological support sessions, which are conducted one day, four days, and seven days after administration of 5MeODMT.

[0564] 14. The method described in any one of items 11 to 13, wherein the length of the psychological support session is 60 to 90 minutes. The method according to any one of items 1 to 14, wherein 15.5 MeODMT is administered to the patient in a room having a substantially nonclinical appearance.

[0565] 16. The room contains soft furniture, as described in item 15. 17. The room is decorated using muted colors, as described in item 15 or 16. 18. A room containing a high-resolution sound system as described in any one of items 15 to 17.

[0566] 19. The room contains food and beverages for the patient and therapist, as described in any one of items 15 to 18. 20. The room includes an authorized safe for storing 5 MeODMT, as described in any one of items 15 to 19.

[0567] 21. The room is isolated so that the patient is protected from the sights and sounds of the outside world, as described in any one of items 15 to 20. 22. The method described in any one of items 15 to 21, wherein the room does not contain any works of art or decorations that have specific religious imagery, ideological connotations, or other such works of art or decorations that could evoke negative feelings in the patient.

[0568] 23. A room containing a bed or a chaise lounge, as described in any one of items 15 to 22. 24. The method described in item 23, wherein the patient lies down on a bed or couch for approximately 0.5 to 8 hours, or a substantial portion thereof, after administration of 5 MeODMT.

[0569] 25. The patient listens to music for approximately 0.5 to 8 hours after administration of 5 MeODMT, or for a substantial portion thereof, as described in any one of items 1 to 24. 26. The method described in any one of items 1 to 25, wherein the patient wears an eye mask for approximately 0.5 to 8 hours after administration of 5 MeODMT, or for a substantial portion thereof.

[0570] 27. The method described in any one of items 1 through 26, wherein a therapist provides psychological support to the patient for approximately 0.5 to 8 hours after administration of 5 MeODMT. 28. The method described in any one of items 1 through 27, wherein a therapist uses guided imagery and / or breathing exercises to calm a patient and / or to focus the patient's attention.

[0571] 29. The method described in any one of items 1 through 28, wherein a therapist provides reassuring physical contact to a patient. 30. The therapist holds the patient's hand, arm, or shoulder, as described in item 29.

[0572] 31. The method described in any one of items 1 through 30, by which a therapist encourages a patient to engage in self-directed questioning and processing of experiences. 32. The method described in item 31, by which the therapist helps the patient to recognize at least one therapeutic intention.

[0573] 33. The therapist said: (1) Accepting the feeling of anxiety, (2) Allow the experience to unfold naturally, (3) Avoid psychological resistance to the experience, (4) Relax, and / or (5) The method described in any one of items 1 through 32, which involves encouraging the patient to engage in one or more activities that explore the patient's own mental space.

[0574] 34. The method described in any one of items 1 through 33, in which the therapist does not initiate a conversation with the patient. 35. If the patient initiates a conversation, the therapist responds to the patient in the manner described in item 34.

[0575] 36. Psychological support is provided to the patient remotely, as described in any one of items 5 through 35. 37. The method described in item 36, wherein psychological support is provided via a digital or electronic system.

[0576] 38. The method described in item 37, wherein the digital or electronic system is a mobile phone application. 39. The method described in item 38, wherein the digital or electronic system is a website.

[0577] Example 36: Forced swimming test of mice This study aimed to evaluate the effects of 5MeODMT benzoate at three doses in the mouse forced swim test (FST). The forced swim test is a model of behavioral despair and is sensitive to the detection of various types of antidepressants. Breeding Accommodation and acclimatization The animals underwent a 72-hour acclimatization period to the experimental facility before the start of the experiment. Four animals were housed per cage in polycarbonate cages filled with 1 / 4” bed-o'cob. Cages were changed and eutrophication was carried out according to standard operating procedures. The animals were maintained on a 12-hour light / 12-hour dark cycle, and all experimental activities were conducted between the animals' light cycles. All animal handling procedures were approved by the Canadian Council on Animal Science. The implementation followed the principles of Care (CCAC). Feed and water Certified Rodent Diet (LabDiet® 5001) was provided without restriction. Animals were not fasted before or after the experiment. Water was provided without restriction in glass bottles with stainless steel straws. Research design Test subjects Male CD-1 mice from Charles River Laboratories (St. Constant, Quebec, Canada) were used in this study. The animals generally weighed 25-30g at the time of testing. Event Schedule

[0578] [Table 43]

[0579] Treatment group The animals were randomly assigned to one of the following treatment groups.

[0580] [Table 44]

[0581] FST Pre-Behavioral Test On day 0, in addition to the forced swim test, animals were evaluated for signs of 5-HT (serotonin) syndrome. Animals were exposed to an activity chamber for 10 minutes at two time points after drug administration: (1) 5–15 minutes after drug administration and (2) 2.5 hours after drug administration. Compulsory swimming test Male CD-1 mice were given an appropriate dose of vehicle, test substance, or positive control (treatment summarized above). After an appropriate pre-treatment time, the animals were gently placed in a tall glass cylinder filled with water (20-25°C). After a period of active movement, each mouse assumed a characteristic, easily identifiable immobile posture. The swimming test involved scoring the duration of immobility. Latency to the first immobility was recorded (in seconds) over a 6-minute test session. The duration of immobility (in seconds) during the last 4 minutes of the test was also measured. Activity or inactivity for 0-2 minutes was not recorded. Test substance 5-MeODMT benzoate BEW: 1.59 (benzoate form) MW: 340.40 g / mol Dosage: 0.5, 1.5, 5 mg / kg (dose corrected for base) Route of administration, dose volume: SC, 10 mL / kg Pre-treatment time: 3 hours Vehicle: 0.9% physiological saline Imipramine BEW:1.13 MW: 280.415 g / mol Dosage: 30 mg / kg (dose corrected for base) Route of administration, dosage volume: IP., 10 mL / kg Pre-treatment time: 3 hours Vehicle: 0.9% physiological saline result After a 3-hour administration, low doses of 5MeODMT benzoate (0.5 and 1.5 mg / kg) over a 6-minute test session showed a positive trend in reduced duration of immobility and increased latency to immobility compared to vehicle-treated mice (immobility time 2-6 minutes, vehicle: 190.4 ± 7.7 seconds - 5MeODMT benzoate: 133.2 ± 24.9 seconds (0.5 mg / kg), 137.6 seconds). ±17.0 seconds (1.5 mg / kg), 156.8 ± 18.7 seconds (5 mg / kg) - Imipramine 46.8 ± 16.6 seconds, Figure 94. Latency to immobility: Vehicle: 95.5 ± 4.6 seconds - 5MeODMT 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 seconds, Figure 95).

[0582] Example 37: 5MEO-TOX-PK-DOG study The purpose of this toxicology study was to evaluate and compare the toxicology profiles of the test samples, 5MeODMT-HCl (in a 0.1% methoxide vehicle, group 2) and 5MeODMT-benzoate (in a 0.2% methoxide + 0.01% BZK vehicle, group 4).

[0583] On day 1, the vehicle or the active test formulation was administered intranasally to male beagle dogs at a dose level of 0.4 mg / kg in the active group (corresponding to free base). Following administration, a series of blood samples were collected from each dog at the following time points: before administration (0), and 2, 5, 8, 10, 15, 30, and 60 minutes after administration, as well as 2 and 8 hours after administration. Plasma samples were analyzed using validated methods to quantify the concentration of 5 MeODMT in each sample.

[0584] 5MeODMT was not detected in any samples taken from control animals on day 1 (not shown). The peak plasma exposure level (C) max The reported TK levels were 16.4 ng / mL and 35.4 ng / mL in groups 2 and 4, respectively (see table below). Figure 96 is a time-course plot of mean plasma concentrations, showing roughly similar TK profiles between HCl and benzoate preparations. Mean C on day 1 of 5MeODMT in groups 2 and 4 max value

[0585] [Table 45]

[0586] See also Figure 96, which shows the mean plasma concentrations (ng / mL) of the 5MeODMT groups in male Beagle dogs—group 2 (5MEODMT HCl preparation) and group 4 (5MEODMT benzoate preparation)—and the dose level (0.4 mg / kg); where the mean plasma concentrations of groups 2 and 4 are substantially the same at the time of administration.

[0587] Example 38: Further Embodiments In one embodiment, a polymorph of 5MeODMT benzoate is provided, characterized by an XRPD pattern substantially shown in any one of the figures or described earlier or later.

[0588] In one embodiment, a polymorph of 5MeODMT benzoate is provided, characterized by one or more peaks in an XRPD diffractogram substantially shown in any one of the figures or described earlier or later.

[0589] In one embodiment, a polymorph of 5MeODMT benzoate is provided, characterized by one or more endothermic events in a DSC thermograph substantially shown in any one of the figures or described earlier or later.

[0590] In one embodiment, a polymorph of 5MeODMT benzoate is provided, characterized by a TGA thermograph substantially shown in any one of the figures or described earlier or later.

[0591] In one embodiment, a polymorph of 5MeODMT benzoate is provided, characterized by a DVS isotherm profile substantially shown in any one of the figures or described earlier or later.

[0592] In one embodiment, polymorphs of 5MeODMT benzoate are provided, characterized by the appearance of the crystal substantially shown in any one of the figures or described earlier or later.

[0593] In one embodiment, a polymorph of 5MeODMT benzoate is provided, characterized by a particle size distribution substantially shown in any one of the figures or described earlier or later.

[0594] In one embodiment, a polymorph of 5MeODMT benzoate is provided, characterized by a FITR spectrum substantially shown in any one of the figures or described earlier or later.

[0595] In one embodiment, a polymorph of 5MeODMT benzoate is provided, which is produced as described above or below. In one embodiment, a method for producing the polymorph of 5MeODMT benzoate, which is described above or below, is provided.

[0596] In one embodiment, a composition is provided comprising a polymorph of 5MeODMT benzoate, which is described earlier or later. In one embodiment, a solvate of 5MeODMT benzoate is provided, characterized substantially as shown in any one of the figures or as described earlier or later.

[0597] In one embodiment, a 5MeODMT benzoate half-solvate is provided, characterized substantially as shown in any one of the figures or as described earlier or later.

[0598] In one embodiment, the use of any form of 5MeODMT benzoate described earlier or later in any treatment method described earlier or later is provided. Disclosed herein are conditions caused by dysfunction of the central nervous system, peripheral nervous system The use of the compositions described herein for the manufacture of a medicament for the treatment of any one of the following conditions: conditions caused by dysfunction of the nervous system; conditions that benefit from sleep regulation (such as insomnia); conditions that benefit from analgesics (such as chronic pain); migraines; trigeminal autonomic headaches (such as short-acting persistent hemiglinal headache with conjunctival hyperemia and lacrimation (SUNCT), and short-acting persistent hemiglinal headache with cephaloautonomic symptoms (SUNA)); conditions that benefit from neurogenesis (such as stroke, traumatic brain injury, and Parkinson's dementia); conditions that benefit from anti-inflammatory treatment; depression; treatment-resistant depression; anxiety; substance use disorders; addictive disorders; gambling disorders; eating disorders; obsessive-compulsive disorder; or body dysmorphic disorder.

[0599] Disclosed herein are methods for treating in a patient any one of the following conditions by administration of compositions described herein: conditions caused by central nervous system dysfunction, conditions caused by peripheral nervous system dysfunction, conditions that benefit from sleep regulation (such as insomnia), conditions that benefit from analgesics (such as chronic pain), migraines, trigeminal autonomic headaches (such as short-acting persistent hemiglinal headache with conjunctival hyperemia and lacrimation (SUNCT), and short-acting persistent hemiglinal headache with cranial autonomic symptoms (SUNA)), conditions that benefit from neurogenesis (such as stroke, traumatic brain injury, and Parkinson's dementia), conditions that benefit from anti-inflammatory treatment, depression, treatment-resistant depression, anxiety, substance use disorders, addictive disorders, gambling disorders, eating disorders, obsessive-compulsive disorder, or body dysmorphic disorder.

Claims

1. A composition containing a pharmaceutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5MeODMT) benzoate that is pharmaceutically acceptable.

2. The composition according to claim 1, having an increased shelf life compared to a composition containing 5MeODMMT hydrochloride.

3. The composition according to claim 1 or claim 2, having reduced mucosal hypersensitivity compared to a composition containing 5-MeODMMT hydrochloride.

4. The composition according to any one of claims 1 to 3, having improved permeability through the nasal epithelium compared to a composition containing 5-MeODMMT hydrochloride.

5. The composition according to any one of claims 1 to 4, characterized by peaks at 17.5, 17.7, and 21.0°2θ ± 0.1°2θ in the XRPD diffractogram.

6. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate is characterized by peaks at 17.5, 17.7, 21.0, and 25.3°2θ±0.1°2θ in the XRPD diffractogram.

7. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate is characterized by peaks at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, and 25.3°2θ±0.1°2θ in the XRPD diffractogram.

8. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate is characterized by peaks 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 30.5°2θ±0.1°2θ in the XRPD diffractogram.

9. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate is characterized by a peak in the XRPD diffractogram substantially shown in Figures 6, 7, or 8.

10. The composition according to any one of claims 1 to 9, wherein 5MeODMMT benzoate is characterized by an endothermic event having an onset temperature between 120 and 130°C on a DSC thermograph.

11. The composition according to any one of claims 1 to 9, wherein 5MeODMT benzoate is characterized by an endothermic event having an onset temperature between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, or between 124 and 126°C on a DSC thermograph.

12. The composition according to any one of claims 1 to 11, wherein 5MeODMT benzoate is characterized by an endothermic event having an onset temperature of 123°C on a DSC thermograph.

13. The composition according to any one of claims 1 to 12, wherein 5MeODMT benzoate is characterized by an endothermic event having a starting temperature of 124°C on a DSC thermograph.

14. The composition according to any one of claims 1 to 13, wherein 5MeODMT benzoate is characterized by an endothermic event having starting temperatures between 120 and 130°C, between 121 and 129°C, between 122 and 128°C, between 123 and 127°C, and a peak between 124 and 126°C in a DSC thermograph.

15. The composition according to any one of claims 10 to 14, wherein the 5MeODMMT benzoate is characterized by an enthalpy between -130 and -140 J / g on a DSC thermograph.

16. The composition according to any one of claims 10 to 15, wherein the 5MeODMMT benzoate is characterized by an enthalpy between -130 and -135 J / g on a DSC thermograph.

17. The composition according to any one of claims 1 to 16, characterized in that 5-MeODMMT benzoate is characterized by the initiation of decomposition between 128-135°C, 129-134°C, 130-133°C, or 130-132°C on a TGA thermograph.

18. The composition according to any one of claims 1 to 17, wherein 5MeODMMT benzoate is characterized by the initiation of decomposition at 131°C in a TGA thermograph.

19. The composition according to any one of claims 1 to 18, wherein the 5MeODMMT benzoate is characterized by the DVS isotherm profile substantially shown in Figure 12.

20. The composition according to any one of claims 1 to 19, wherein 5MeODMMT benzoate matches pattern A by XRPD.

21. The composition according to any one of claims 1 to 20, wherein 5MeODM-benzoate is characterized by bands at approximately 3130, 1540, 1460, 1160, and 690 cm⁻¹ in a Fourier transform infrared (FTIR) spectrum.

22. The composition according to any one of claims 1 to 20, wherein 5MeODMMT benzoate is characterized by the FTIR spectrum for lot FP2 substantially shown in Figure 93.

23. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate matches pattern B by XRPD.

24. The composition according to claim 23, wherein 5MeODMMT benzoate matches pattern B, characterized by a peak between 18.5 and 20°2θ ± 0.1°2θ in the XRPD diffractogram.

25. The composition according to claim 24, wherein the 5MeODMMT benzoate conforms to pattern B substantially shown by the XRPD diffractograms for lots P1, R1, and Q1 substantially shown in Figure 24.

26. The composition according to claim 25, wherein the 5MeODMMT benzoate conforms to pattern B substantially shown by the XRPD diffractogram for lot R2 substantially shown in Figure 28.

27. The composition according to claim 26, wherein the 5MeODMMT benzoate conforms to pattern B substantially shown by the XRPD diffractograms for lots A1 and B1 substantially shown in Figure 38 or 39.

28. The composition according to any one of claims 23 to 27, wherein the 5MeODMMT benzoate corresponds to pattern B morphology characterized by the FTIR spectrum for lot C2 substantially shown in Figure 93.

29. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate corresponds to pattern C, characterized by a smaller broad endothermic pattern having a peak temperature of 108°C on a DSC thermograph.

30. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate corresponds to pattern C characterized by the DSC thermograph substantially shown in Figure 65.

31. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate corresponds to pattern C, characterized by the DSC thermograph substantially shown in Figure 66.

32. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate matches pattern C by XRPD.

33. The composition according to claim 32, wherein 5MeODMMT benzoate matches pattern C, characterized by a peak at 10.3°2θ ± 0.1°2θ in the XRPD diffractogram.

34. The composition according to claim 33, wherein the 5MeODMMT benzoate conforms to pattern C substantially shown by the XRPD diffractogram for lot A1 substantially shown in Figure 68.

35. The composition according to any one of claims 24 to 32, wherein the 5MeODMMT benzoate corresponds to pattern C morphology characterized by the FTIR spectrum for lot C1 substantially shown in Figure 93.

36. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate matches pattern D by XRPD.

37. The composition according to claim 36, wherein the 5MeODMMT benzoate conforms to pattern D substantially shown by the XRPD diffractogram in Figure 73 or Figure 74.

38. The composition according to claim 36 or claim 37, wherein 5MeODMMT benzoate corresponds to pattern D characterized by an endothermic event at 118°C in a DSC thermograph.

39. The composition according to claim 38, wherein 5MeODMMT benzoate corresponds to pattern D, characterized by an endothermic event at 118.58°C in a DSC thermograph.

40. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate matches pattern E by XRPD.

41. 5MeODM benzoate is shown in Figure 77 or Figure 78 for lot D in XRPD The composition according to claim 40, which corresponds substantially to pattern E as shown by the fractogram.

42. The composition according to claim 40 or claim 41, wherein 5MeODMT corresponds to pattern E, characterized by a major bimodal endothermic event having peak temperatures of 110.31°C and 113.13°C in a DSC thermograph.

43. The composition according to any one of claims 40 to 42, wherein 5MeODMT corresponds to pattern E, characterized by the smaller endothermic event having a peak temperature of 119.09°C in a DSC thermograph.

44. The composition according to any one of claims 40 to 43, wherein 5MeODMT corresponds to pattern E, characterized by the DSC thermograph substantially shown in Figure 79.

45. The composition according to any one of claims 40 to 44, wherein 5MeODMMT benzoate corresponds to pattern E substantially shown by the XRPD diffractogram in Figure 80.

46. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate corresponds to pattern F by XRPD.

47. The composition according to claim 46, wherein the 5MeODMMT benzoate matches pattern F, characterized by the XRPD diffractogram for lot F (rerun) substantially shown in Figure 84.

48. The composition according to claim 46, wherein the 5MeODMMT benzoate matches pattern F, characterized by the XRPD diffractogram for lot F (rerun) substantially shown in Figure 85.

49. The composition according to claim 46, wherein the 5MeODMMT benzoate matches pattern F, characterized by the XRPD diffractogram for lot F (rerun) substantially shown in Figure 89.

50. The composition according to any one of claims 46 to 49, wherein 5MeODMMT benzoate corresponds to pattern F morphology characterized by endothermic events at 90°C, 106°C, and 180°C in a DSC thermograph.

51. The composition according to claim 50, wherein 5MeODMMT benzoate corresponds to pattern F, characterized by endothermic events at 90.50°C, 106.65°C, and 180.35°C in a DSC thermograph.

52. The composition according to any one of claims 1 to 4, wherein 5MeODMMT benzoate matches pattern G by XRPD.

53. The composition according to claim 52, wherein the 5MeODMMT benzoate conforms to pattern G characterized by the XRPD diffractogram for lot K substantially shown in Figure 87.

54. The composition according to claim 52 or claim 53, wherein 5MeODMMT benzoate corresponds to pattern G morphology characterized by an endothermic event at 119.61°C in a DSC thermograph.

55. The composition according to any one of claims 1 to 54, comprising a 5MeODMMT benzoate that matches a mixture of two or more patterns A to G determined by XRPD.

56. The composition according to any one of claims 1 to 55, comprising a dose of 5MeODMMT in the range of 0.05 mg to 100 mg.

57. The composition according to any one of claims 1 to 56, comprising a dose of 5MeODMMT in the range of 0.1 mg to 50 mg.

58. The composition according to any one of claims 1 to 57, comprising a dose of 5MeODMMT in the range of 0.5 mg to 25 mg.

59. The composition according to any one of claims 1 to 58, which is formulated into a dosage form selected from oral, transdermal, inhalable, intravenous, or rectal dosage forms.

60. The composition according to any one of claims 1 to 59, which is formulated into a dosage form selected from the following: tablets, capsules, granules, powders, free-flowing powders, inhalable powders, aerosols, sprays, vaping, buccal, sublingual, sublabial, injectable, or suppositories.

61. The composition according to claim 60, wherein the powder is suitable for administration by inhalation via a pharmaceutical dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-measured multiple-dose dry powder inhaler, a nasal inhaler, or a pressurized metered-dose inhaler.

62. The composition according to claim 60 or 61, wherein the powder contains particles, the particles having a median diameter of 2000 μm, 1000 μm, 500 μm, 250 μm, 100 μm, 50 μm, or less than 1 μm.

63. The composition according to any one of claims 60 to 62, wherein the powder contains particles, the particles having a median diameter greater than 500 μm, 250 μm, 100 μm, 50 μm, 1 μm, or 0.5 μm.

64. The composition according to any one of claims 60 to 63, wherein the powder contains particles, and the powder has a particle size distribution of d10 = 20 to 60 μm and / or d50 = 80 to 120 μm and / or d90 = 130 to 300 μm.

65. The composition according to any one of claims 1 to 64, wherein the 5MeODMMT benzoate composition is formulated for mucosal delivery.

66. A composition according to any one of claims 1 to 65, comprising one or more pharmaceutically acceptable carriers or excipients.

67. A composition according to any one of claims 1 to 66, comprising one or more of a mucosal adhesion enhancer, a permeability enhancer, a cationic polymer, a cyclodextrin, a tight junction modifier, an enzyme inhibitor, a surfactant, a chelating agent, and a polysaccharide.

68. A composition according to any one of claims 1 to 67 for use in a method of treating a human or animal subject by therapy.

69. The treatment method is A condition caused by dysfunction of the central nervous system. A condition caused by dysfunction of the peripheral nervous system. Conditions that benefit from sleep regulation (such as insomnia), Conditions that benefit from painkillers (such as chronic pain), Migraine, Trigeminal autonomic headache (including short-acting persistent hemiglinal headache with conjunctival congestion and lacrimation (SUNCT), and short-acting persistent hemiglinal headache with autonomic symptoms in the head (SUNA)), Conditions that benefit from neurogenesis (stroke, traumatic brain injury, Parkinson's dementia, etc.), A condition that benefits from anti-inflammatory treatment. Depression, Treatment-resistant depression, anxiety, Substance use disorder, Addiction disorder, Gambling disorder, Eating disorders, Obsessive-compulsive disorder, or The composition according to claim 68, which is a method for treating body dysmorphic disorder.

70. The composition according to claim 68 or 69, which is administered once or more times a year.

71. The composition according to any one of claims 68 to 70, which is administered once or more times a month.

72. The composition according to any one of claims 68 to 71, administered once or more times per week.

73. A composition according to any one of claims 68 to 72, which is administered once or more times a day.

74. The composition according to any one of claims 68 to 73, administered together with supplemental treatments and / or further activators.

75. The composition according to any one of claims 68 to 74, wherein the further activator is a psychedelic compound, optionally tryptamine, and further optionally the further activator is lysergic acid diethylamide (LSD), psilocybin, psilocine, or a prodrug thereof.

76. The composition according to any one of claims 68 to 74, wherein the further activator is an antidepressant.

77. The composition according to any one of claims 74 to 76, wherein the supplementary treatment is psychotherapy.

78. A nasal inhalation composition containing a pharmaceutically effective amount of pharmaceutically acceptable 5-methoxy-N,N-dimethyltryptamine (5MeODMMT) crystalline polymorphic benzoate for use in a method of treating treatment-resistant depression.

79. The composition according to claim 78, wherein the polymorph corresponds to pattern A by XRPD.

80. The composition according to claim 79, comprising two or more polymorphs of 5MeODMMT benzoate.

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