Compositions containing benzoate salt of 5-methoxy-N,N-dimethyltryptamine

Abstract

A composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5MeODMT).

Description

Field of the Invention

[0001] The present invention relates to pharmaceutically acceptable salts of 5-methoxy-N,N-dimethyltryptamine. In particular, but not exclusively, the present invention relates to its preparation and use as a medicament. Background of the Invention

[0003] 5-Methoxy-N,N-dimethyltryptamine (5MeODMT) is a pharmacologically active compound of the tryptamine class and has the chemical formula:

[0004]

[0005] 5MeODMT is a psychoactive / psychedelic substance found in nature and is believed to act primarily through serotonin receptors. 5MeODMT is also believed to have a 2 Isoforms and 5-HT 1A Isoforms have high affinity, and / or inhibit monoamine reuptake.

[0006] However, 5MeODMT is not well understood and the uses of this compound have not been well explored. In addition, 5MeODMT is not easy to handle and there are challenges in formulating it for effective delivery in pharmaceutically useful compositions.

[0007] There remains a need in the art for improved formulations and uses of 5MeODMT. SUMMARY OF THE INVENTION

[0009] As disclosed herein, a composition is provided, the composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable salt of 5-methoxy-N,N-dimethyltryptamine (5MeODMT).

[0010] In an embodiment, the salt anion is an aryl carboxylate. In an embodiment, the aryl carboxylate is substituted with one to three R groups.

[0011] In an embodiment, one or more R groups are independently selected from: alkynyl, carbonyl, aldehyde, haloformyl, alkyl, halide, hydroxyl, alkoxy, carbonate, carboxylate, carboxyl, carboalkoxy, methoxy, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate, carboxylic anhydride, formamide, secondary amine, tertiary amine or quaternary amine , primary or secondary ketimine, primary or secondary aldimine, imide, azide, azo, cyanate, isocyanate, nitrate, nitrile, isonitrile, nitrosooxy, nitro, nitroso, oxime, pyridyl, carbamate, mercapto, sulfide, disulfide, sulfinyl, sulfonyl, sulfinyl, sulfonyl, thiocyanate, isothiocyanate, carbonothioyl, carbothioic S-acid, carbothioic O-acid, thioester, thionoester, dithiocarboxylic acid, carbodisulfide, phosphino, phosphono, phosphate, borono, borate, borino or borinate.

[0012] In an embodiment, one or more R groups are independently selected from: C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkenyl or C 1 -C 6 alkynyl, and wherein each of these may be optionally substituted with one to three R groups as previously described.

[0013] In a first aspect of the present invention, a composition is provided, comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5MeODMT).

[0014] The present invention provides improved formulations and uses of 5MeODMT salts.

[0015] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 0.05 mg to 100 mg.

[0016] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 0.1 mg to 50 mg.

[0017] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 0.5 mg to 25 mg.

[0018] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 0.5 mg to 10 mg.

[0019] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 1 mg to 10 mg.

[0020] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 1 mg to 8 mg.

[0021] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 3 mg to 15 mg.

[0022] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 0.005 mg to 100 mg.

[0023] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 0.001 mg to 100 mg.

[0024] In an embodiment, the composition comprises 5MeODMT in a dosage amount ranging from 0.0005 mg to 100 mg.

[0025] The level of active agent may be adjusted as required, for example, to suit a particular patient group (eg, the elderly) or the condition being treated.

[0026] In an embodiment, the composition is formulated in a dosage form selected from the group consisting of an oral dosage form, a transdermal dosage form, an inhalable dosage form, an intravenous dosage form, or a rectal dosage form.

[0027] It would be advantageous to be able to deliver the active agent in different forms, for example to suit a particular patient group (eg the elderly) or the condition being treated.

[0028] In an embodiment, the composition is formulated in a dosage form selected from the group consisting of tablets, capsules, granules, powders, free-flowing powders, inhalable powders, aerosols, nebulized dosage forms, vaping dosage forms, buccal dosage forms, sublingual dosage forms, sublabial dosage forms, injectable dosage forms, or suppository dosage forms.

[0029] In an embodiment, the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler, or a pressurized metered dose inhaler.

[0030] In embodiments, the powder comprises particles having a median diameter of less than 2000 μm, 1000 μm, 500 μm, 250 μm, 100 μm, 50 μm or 1 μm.

[0031] In embodiments, the powder comprises particles having a median diameter greater than 500 μm, 250 μm, 100 μm, 50 μm, 1 μm or 0.5 μm.

[0032] In an embodiment, the powder comprises particles, and wherein the powder has a particle size distribution of d10 = 20 μm - 60 μm, and / or d50 = 80 μm - 120 μm, and / or d90 = 130 μm - 300 μm.

[0033] The properties of the powder can be adjusted to suit the requirements. For example, if it is made for nasal inhalation, the particles can be adjusted to be much finer than if the powder is to be formulated into a gelatin capsule, or different again if the powder is to be compacted into a tablet.

[0034] In embodiments, the 5MeODMT salt is amorphous or crystalline.

[0035] In an embodiment, the 5MeODMT salt is in a polymorphic crystalline form, optionally the 5MeODMT salt is polymorph A.

[0036] In an embodiment, the 5MeODMT salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate or triflate salt, optionally the salt is a chloride, benzoate or fumarate salt.

[0037] In an embodiment, the 5MeODMT salt is formulated as a composition for mucosal delivery. In an embodiment, the 5MeODMT salt is a benzoate salt.

[0038] In an embodiment, 5MeODMT benzoate conforms to Form A as characterized by an XRPD diffraction pattern.

[0039] In an embodiment, 5MeODMT benzoate is characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, and 21.0°2θ±0.1°2θ, as determined by using The wavelength of the x-rays measured by x-ray powder diffraction.

[0040] In an embodiment, 5MeODMT benzoate is characterized by Figure 6 or Figure 7 The peaks in the XRPD diffraction pattern are generally illustrated in FIG.

[0041] In embodiments, 5MeODMT benzoate is characterized by a peak at about 3130 cm in a Fourier transform infrared spectroscopy (FTIR) spectrum. -1 、1540cm -1 、1460cm -1 、1160cm -1 and 690cm -1 The belt at the place.

[0042] In an embodiment, 5MeODMT benzoate is characterized by Fig.93 FTIR spectrum of batch FP2 is generally shown in FIG.

[0043] In an embodiment, 5MeODMT benzoate conforms to Pattern B by XRPD.

[0044] In embodiments, 5MeODMT benzoate conforms to Form B characterized by peaks in the XRPD diffractogram between 18.5° 2θ ± 0.1° 2θ and 20° 2θ ± 0.1° 2θ.

[0045] In an embodiment, 5MeODMT benzoate conforms to Formula B as generally illustrated by: Fig.24 XRPD diffraction patterns of batches P1, R1 and Q1 are generally shown in FIG.

[0046] In an embodiment, 5MeODMT benzoate conforms to Formula B as generally illustrated by: Fig.28 XRPD diffraction pattern of batch R2 generally shown in FIG.

[0047] In an embodiment, 5MeODMT benzoate conforms to Formula B as generally illustrated by: Fig.38 or Fig.39 XRPD diffraction patterns of batches A1 and B1 are generally shown in FIG.

[0048] In embodiments, 5MeODMT benzoate corresponds to Form B characterized by: Fig.93 FTIR spectrum of batch C2 is generally shown in FIG.

[0049] In embodiments, 5MeODMT benzoate corresponds to Form C characterized by a second broad endothermic peak having a peak temperature of 108°C in the DSC thermograph.

[0050] In embodiments, 5MeODMT benzoate corresponds to Form C characterized by: Fig.65DSC temperature record diagram generally shown in FIG.

[0051] In an embodiment, 5MeODMT benzoate corresponds to Form C characterized by: Fig.66 DSC temperature record diagram generally shown in FIG.

[0052] In an embodiment, 5MeODMT benzoate conforms to Pattern C by XRPD.

[0053] In embodiments, 5MeODMT benzoate conforms to Form C characterized by a peak in the XRPD diffractogram at 10.3° 2θ ± 0.1° 2θ.

[0054] In an embodiment, 5MeODMT benzoate conforms to Formula C, which is generally illustrated by: Fig.68 XRPD diffraction pattern of Batch A1 generally shown in FIG.

[0055] In an embodiment, 5MeODMT benzoate corresponds to Form C characterized by: Fig.93 FTIR spectrum of batch C1 is generally shown in FIG.

[0056] In an embodiment, 5MeODMT benzoate conforms to Pattern D of XRPD.

[0057] In an embodiment, 5MeODMT benzoate conforms to Formula D illustrated generally as follows: Fig.73 or Fig.74 XRPD diffraction pattern in.

[0058] In embodiments, 5MeODMT benzoate corresponds to Form D characterized by an endothermic event at 118°C in the DSC thermogram.

[0059] In embodiments, 5MeODMT benzoate corresponds to Form D characterized by an endothermic event at 118.58°C in the DSC thermogram.

[0060] In an embodiment, 5MeODMT benzoate conforms to Pattern E by XRPD.

[0061] In embodiments, 5MeODMT benzoate corresponds to Pattern E as generally illustrated by: Fig.77 or Fig.78 XRPD diffraction pattern of batch D.

[0062] In embodiments, 5MeODMT benzoate corresponds to Form Pattern E as characterized by a major doublet endothermic event in the DSC thermogram having peak temperatures of 110.31 °C and 113.13 °C.

[0063] In embodiments, 5MeODMT benzoate corresponds to Form E as characterized by a minor endothermic event in the DSC thermogram having a peak temperature of 119.09°C.

[0064] In an embodiment, 5MeODMT benzoate corresponds to Form E as characterized by: Fig.79 DSC temperature record diagram generally shown in FIG.

[0065] In embodiments, 5MeODMT benzoate corresponds to Pattern E as generally illustrated by: Fig.80 XRPD diffraction pattern in.

[0066] In an embodiment, 5MeODMT benzoate corresponds to Pattern F by XRPD.

[0067] In an embodiment, 5MeODMT benzoate conforms to Form F characterized by: Fig.84 XRPD diffraction pattern of Batch F (reproduced) generally shown in FIG.

[0068] In an embodiment, 5MeODMT benzoate conforms to Form F characterized by: Fig.85 XRPD diffraction pattern of Batch F (reproduced) generally shown in FIG.

[0069] In an embodiment, 5MeODMT benzoate conforms to Form F characterized by: Fig.89 XRPD diffraction pattern of Batch F (reproduced) generally shown in FIG.

[0070] In embodiments, 5MeODMT benzoate corresponds to Form Pattern F characterized by endothermic events at 90°C, 106°C, and 180°C in the DSC thermogram.

[0071] In embodiments, 5MeODMT benzoate corresponds to Form Pattern F characterized by endothermic events at 90.50°C, 106.65°C, and 180.35°C in the DSC thermogram.

[0072] In an embodiment, 5MeODMT benzoate conforms to Pattern G by XRPD.

[0073] In an embodiment, 5MeODMT benzoate conforms to Form G characterized by: Fig.87XRPD diffraction pattern of Batch K generally shown in FIG.

[0074] In embodiments, 5MeODMT benzoate corresponds to Form G characterized by an endothermic event at 119.61 °C in the DSC thermogram.

[0075] In an embodiment, the composition comprises 5MeODMT benzoate that conforms to a mixture of two or more of Patterns A through G of the XRPD.

[0076] For the salt, the dosage amount is the equivalent amount of the free base delivered when the salt is taken. Thus, a 100 mg dosage of 5MeODMT corresponds to 117 mg of the hydrochloride salt (i.e., both provide the same molar amount of active substance). The greater mass of the salt required is due to the greater molecular weight of the hydrochloride salt (i.e., 218.3 g / mol for the free base, compared to 254.8 g / mol for the salt). Similarly, for the deuterated or tritiated forms of 5MeODMT (also considered within the scope of the present invention), a slight increase in mass can be expected due to the increased molecular weight of these isotopic compounds.

[0077] Amorphous and crystalline materials often show different chemical / physical properties, such as improved dissolution rate in solvents, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical / physical properties.

[0078] In an embodiment, the composition comprises one or more pharmaceutically acceptable carriers or excipients.

[0079] In embodiments, the composition comprises one or more of the following: a mucoadhesion enhancer, a permeation enhancer, a cationic polymer, a cyclodextrin, a tight junction modulator, an enzyme inhibitor, a surfactant, a chelating agent, and a polysaccharide.

[0080] In an embodiment, the composition comprises one or more of the following: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(tetrapropyl)-N,N-dimethyl chitosan, n-butyl-(tetrabutyl)-N,N-dimethyl chitosan and n-hexyl (tetrahexyl)-N,N-dimethyl chitosan, chitosan chloride), β-cyclodextrin, clostridium perfringens enterotoxin, zonula occlusive toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate, sodium lauryl sulfate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleic acid (oleyl succinate), choline chloride, choline chloride, β-cyclodextrin, clostridium perfringens enterotoxin, zonula occlusive toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate, sodium lauryl sulfate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleic acid, acid), oleyl alcohol, sodium caprate, DHA, EPA, dipalmitoylphosphatidylcholine, soy lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose and citric acid.

[0081] In embodiments, the compositions disclosed herein are for use as a medicament. In embodiments, the compositions disclosed herein are for use in a method of treating a human or animal subject by therapy.

[0082] In embodiments, the method of treatment is a method of treating:

[0083] Conditions caused by dysfunction of the central nervous system,

[0084] Conditions caused by dysfunction of the peripheral nervous system,

[0085] Conditions that benefit from sleep regulation (such as insomnia),

[0086] Conditions that benefit from analgesics (such as chronic pain),

[0087] Migraine,

[0088] Trigeminal autonomic headaches (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting neuralgiform headache with cranial autonomic symptoms (SUNA)),

[0089] Conditions that benefit from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia),

[0090] Conditions that benefit from anti-inflammatory treatment,

[0091] Depression,

[0092] Refractory depression,

[0093] anxiety,

[0094] Substance use disorders,

[0095] Addiction disorders,

[0096] Gambling disorder,

[0097] Eating disorders,

[0098] obsessive compulsive disorder, or

[0099] body dysmorphic disorder,

[0100] Optionally, the condition is SUNCT and / or SUNA.

[0101] Treatment of the above conditions may be beneficially improved by employing the present invention.

[0102] In an embodiment, the method of treatment is a method of treating alcohol-related diseases and disorders, eating disorders, impulse control disorders, nicotine-related disorders, tobacco-related disorders, methamphetamine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, benzodiazepines Abuse or dependence-related disorder and / or opioid-related disorder.

[0103] In embodiments, the method of treatment is a method of treating tobacco addiction. In embodiments, the method is a method of reducing tobacco use. In embodiments, the method of treatment is a method of treating nicotine addiction. In embodiments, the method is a method of reducing nicotine use.

[0104] In an embodiment, the method of treatment is a method of treating alcohol abuse and / or alcohol addiction. In an embodiment, the method of treatment is a method of reducing alcohol use.

[0105] In embodiments, the method of treatment is a method of treating or preventing heavy drug use.

[0106] In embodiments, the method of treatment is a method of treating or preventing heavy drug use, including but not limited to alcohol, tobacco, nicotine, cocaine, methamphetamine, other stimulants, phencyclidine, other hallucinogens, marijuana, sedatives, tranquilizers, sleeping pills, and opiates. One of ordinary skill in the art will appreciate that heavy use or abuse of a substance does not necessarily mean that the subject is dependent on the substance.

[0107] In embodiments, the method of treatment is a method of treating more than one of the above conditions, for example, the method of treatment may be a method of treating depression and anxiety.

[0108] In embodiments, the composition is administered once per year or more.

[0109] In embodiments, the composition is administered once a month or more.

[0110] In embodiments, the composition is administered once a week or more.

[0111] In embodiments, the composition is administered once or more daily.

[0112] In embodiments, the composition is administered at a frequency to avoid reactions such as tachyphylaxis.

[0113] In embodiments, the composition is administered with a complementary therapy and / or with an additional active agent.

[0114] In an embodiment, the additional active agent is a psychedelic compound, optionally a tryptamine.

[0115] In an embodiment, the additional active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin, or a prodrug thereof.

[0116] In an embodiment, the additional active agent is an antidepressant compound.

[0117] In an embodiment, the additional active agent is selected from a SSRI, SNRI, TCA or other antidepressant compound.

[0118] In an embodiment, the additional active agent is selected from citalopram (Celexa, Cipramil), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox, Faverin), paroxetine (Paxil, Seroxat), sertraline (Zoloft, Lustral), desvenlafaxine (Desvenlafaxine) (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), venlafaxine (Effexor), vilazodone (Viibryd), vortioxetine (Trintellix), nefazodone (Dutonin, Nefadar, Serzone), trazodone (Desyrel), reboxetine (Edronax), tenisazine (Lucelan, Metatone), viloxazine (Vivalan), bupropion (Wellbutrin), amitriptyline (Elavil, Endep), amitriptyline oxytocin (Amioxid, Ambivalon, Equilibrin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), diphenhydramine (Novozempic, Nifedipine), and fenpropiphenazone (Norvozempic, Nifedipine). veril, Victoril), dimethoate (Istonil), dosulpiride (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Lomont, Gamanil), melitracen (Dixeran, Melixeran, Trausabun), nitroxazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxetine (Agedal, Elronon, Nogedal), opipramol (Insidon), pipofilazine (Azafen / Azaph en), protriptyline (Vivactil), trimipramine (Surmontil), amoxapine (Asendin), maprotiline (Ludiomil), mianserin (Tolvon), mirtazapine (Remeron), setiptiline (Tecipul), isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl, Zelapar, Emsam), caroxadone (Surodil, Timostenil), metrilin (Inkazan), moclobemide (Aurorix,Manerix), pyrindole (Pirazidol), toloxatone (Humoryl), agomelatine (Valdoxan), esketamine (Spravato), ketamine (Ketalar), tandospirone (Sediel), tianeptine (Stablon, Coaxil), amisulpride (Solian), aripiprazole (Abilify), epiriprazole (Rexulti), lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), trifluoperazine (Stelazine), buspirone (Buspar), lithium (Eskalith, Lithobid), modafinil (Provigil), thyroxine (T4), triiodothyronine (T3).

[0119] In an embodiment, the additional active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline).

[0120] In an embodiment, the complementary treatment is psychotherapy.

[0121] In an embodiment, a composition is provided, comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5MeODMT for use in a method for treating refractory depression.

[0122] In an embodiment, a composition is provided, comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5MeODMT for use in a method of treating depression.

[0123] In an embodiment, a composition is provided, comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5MeODMT for use in a method of treating PTSD.

[0124] In an embodiment, a composition is provided, comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5MeODMT for use in a method of treating an addiction disorder / substance misuse disorder.

[0125] In an embodiment, a nasal inhalation composition is provided, comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5MeODMT for use in a method for treating refractory depression.

[0126] Treatment of the above conditions may be beneficially improved by employing the present invention in conjunction with some complementary treatment; furthermore, these treatments may occur less regularly than some other treatments which may require daily treatment or even multiple treatments per day.

[0127] For the sake of brevity only, the various forms of 5MeODMT benzoate may be referred to hereinafter as 'pattern #', where # refers to the corresponding XRPD pattern obtained for that form. For example, 'pattern A' may be used as an abbreviation to refer to a form of 5MeODMT benzoate that produces XRPD pattern A. Similarly, 'pattern B' may be used as an abbreviation to refer to a form of 5MeODMT benzoate that produces XRPD pattern B, and so on.

[0128] The present invention will now be further described with reference to the following and accompanying drawings, in which: BRIEF DESCRIPTION OF THE DRAWINGS

[0130] Figure 1 is a schematic route for the synthesis of 5MeODMT.

[0131] Figure 2 is an additional schematic route for the synthesis of 5MeODMT.

[0132] Figure 3 is a schematic route for preparing the powder form of 5MeODMT.

[0133] Figure 4 Overview of the slug mucosal irritation (SMI) test. (A) First 15-minute contact period between the slug and the test item. (B) The slug is transferred to a wet paper towel in a new petri dish for 1 hour. (C) Second 15-minute contact period between the slug and the test item. (D) The slug is transferred to a wet paper towel in a new petri dish for 1 hour. (E) Third 15-minute contact period between the slug and the test item.

[0134] Figure 5 is a graph showing that according to the experiments detailed in Example 9, the benzoate salt of 5MeODMT has higher permeation compared to the hydrochloride salt.

[0135] Figure 6 Shown is the XRPD diffractogram of 5MeODMT benzoate before particle size reduction.

[0136] Figure 7Shown is the XRPD diffractogram of 5MeODMT benzoate after particle size reduction.

[0137] Figure 8 Shows the superposition of Figure 6 and Figure 7 XRPD diffraction pattern of .

[0138] Fig. 9 Shown is the DSC thermogram of 5MeODMT benzoate.

[0139] Fig.10 Shown is the TGA thermogram of 5MeODMT benzoate.

[0140] Fig.11 Shown is a combined TGA / DSC thermogram of 5MeODMT benzoate salt.

[0141] Fig.12 Shown is the dynamic vapor sorption (DVS) isotherm of 5MeODMT benzoate.

[0142] Fig.13 Shown are optical micrographs of 5MeODMT benzoate (A) and dark field (B) at ×4 magnification.

[0143] Fig.14 Two additional light micrographs of 5MeODMT benzoate (A) and dark field (B) at ×4 magnification are shown.

[0144] Fig.15 Optical micrographs of 5MeODMT benzoate (A) and dark field (B) at ×10 magnification are shown.

[0145] Fig.16 Additional light micrographs of 5MeODMT benzoate (A) and dark field (B) at ×10 magnification are shown.

[0146] Fig.17 The DVS isotherm of 5MeODMT hydrochloride (Batch 20 / 20 / 126-FP) is shown.

[0147] Fig.18 The DVS isotherm of 5MeODMT hydrochloride (Batch 20 / 45 / 006-FP) is shown.

[0148] Fig.19 Shown is a comparison of the XRPD patterns of two different batches of 5MeODMT benzoate.

[0149] Fig. 20 The DSC thermogram of another batch of 5MeODMT benzoate is shown.

[0150] Fig.21 Additional XRPD characterization of various batches of 5MeODMT benzoate salt is shown.

[0151] Fig. 22 Shown are the DSC thermogram results for 5MeODMT benzoate batches C1, D1 and E1.

[0152] Fig.23 The 5MeODMT benzoate batches C1, D1 and E1 are shown at 10°C.min -1 TGA temperature record results.

[0153] Fig.24 A comparison of the XRPD patterns of 5MeODMT benzoate salts P1 (toluene), Q1 (chlorobenzene), and R1 (anisole) relative to the XRPD pattern of Form A is shown.

[0154] Fig.25 The results of 5MeODMT batches P1, Q1 and R1 at 10°C.min are shown. -1 DSC temperature record diagram.

[0155] Fig.26 The results of 5MeODMT batches P1, Q1 and R1 at 10°C.min are shown. -1 Extension of the DSC thermogram.

[0156] Fig. 27 The results of 5MeODMT batches P1, Q1 and R1 at 10°C.min are shown. -1 TGA temperature record diagram.

[0157] Fig.28 Shown is a comparison of XRPD patterns of 5MeODMT benzoate batches R1 and R2 (thermocycled suspensions) compared to the reference Form A XRPD diffraction pattern.

[0158] Fig.29 The 5MeODMT benzoate batches P2, Q2 and R2 are shown at 10°C.min -1 DSC temperature record diagram.

[0159] Fig.30 The 5MeODMT benzoate batches P2, Q2 and R2 are shown at 10°C.min -1 Extension of the DSC thermogram.

[0160] Fig.31 The 5MeODMT benzoate batches P2, Q2 and R2 are shown at 10°C.min -1 TGA temperature record diagram.

[0161] Fig.32 Shown is an overlay of XRPD patterns of samples isolated via anti-solvent mediated crystallization of 5MeODMT benzoate.

[0162] Fig.33 Shown is an overlay of the XRPD patterns of 5MeODMT benzoate batch F1 and reference Pattern A form / material.

[0163] Fig.34 Shown is an overlay of the XRPD patterns of a sample of 5MeODMT benzoate isolated by cooling and a Form A reference.

[0164] Fig.35 Shown is an overlay of the XRPD patterns of a 5MeODMT benzoate sample isolated by particle size reduction followed by cooling and a Form A reference.

[0165] Fig.36 Shown is a comparison of the XRPD patterns of all samples from the reverse addition antisolvent driven crystallization of 5MeODMT benzoate except A1 and B1.

[0166] Fig.37 Shown is the XRPD pattern of 5MeODMT benzoate F3 compared to the known Form A reference.

[0167] Fig.38 A comparison of the XRPD patterns of 5MeODMT benzoate salts A1 and B1 is shown.

[0168] Fig.39 XRPD patterns of 5MeODMT benzoate salts A1, Q1 and that of reference Form A are shown.

[0169] Fig.40 XRPD patterns of 5MeODMT benzoate salts B1, Q1 and that of reference Form A are shown.

[0170] Fig.41 The separation of 5MeODMT benzoate sample A1 from methanol and toluene at 10 °C.min is shown. -1 DSC temperature record diagram.

[0171] Fig.42 The separation of 5MeODMT benzoate B1 from isopropanol and toluene at 10 °C.min -1 DSC temperature record diagram.

[0172] Fig.43 The separation of 5MeODMT benzoate B1 from isopropanol and toluene at 10 °C.min -1 Extension of the DSC thermogram.

[0173] Fig.44Shown is an XRPD comparison of 5MeODMT benzoate batches 21-01-051A, 21-01-051E; reduced particle size 21-01-051E and Pattern A reference.

[0174] Fig.45 Shown is the XRPD of 5MeODMT benzoate batch 21-01-051B obtained from the quenched melt.

[0175] Fig.46 Shown is the XRPD of 5MeODMT benzoate batch 21-01-051C obtained by lyophilization.

[0176] Fig.47 Shown is an XRPD comparison of 5MeODMT benzoate batch 21-01-051B after 20 hours, 5MeODMT benzoate batch 21-01-051C after 20 hours, and Pattern A reference.

[0177] Fig.48 Shown is an XRPD comparison of 5MeODMT benzoate batches 21-01-051A, 21-01-051E; reduced particle size 21-01-051E and Pattern A reference.

[0178] Fig.49 5MeODMT benzoate batches 21-01-051A, 21-01-051C and 21-01-051D isolated from acetone concentrate (051A) and isolated by lyophilization (051C and 051D) are shown at 10°C.min -1 Comparison of DSC thermograms.

[0179] Fig.50 5MeODMT benzoate batch 21-01-051C and 5MeODMT benzoate batch 21-01-051C after 20 hours at 10°C.min are shown. -1 Comparison of DSC thermograms.

[0180] Fig.51 Shown is the DSC thermogram of large scale lyophilized material 5MeODMT benzoate batch 21-01-051D, where the temperature stamps correspond to the hot stage microscopy images.

[0181] Fig.52 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 30.02°C.

[0182] Fig.53Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 54.21 °C.

[0183] Fig.54 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 74.21°C.

[0184] Fig.55 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 114.23°C.

[0185] Fig.56 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 120.14°C.

[0186] Fig.57 Shown is a comparison of XRPD patterns of 5MeODMT benzoate batch 21-01-054 solid isolated from amorphous 5MeODMT benzoate in equilibrium with thermal modulation.

[0187] Fig.58 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-054M isolated from equilibrium of amorphous 5MeODMT benzoate in α,α,α-trifluorotoluene with thermal modulation and batch 20-37-64 (Formula A).

[0188] Fig.59 Shown is a comparison of DSC thermograms of a selection of 5MeODMT benzoate batch 21-01-054 solids classified as Form A isolated from equilibrium of amorphous 5MeODMT benzoate under thermal modulation.

[0189] Fig.60 Shown is an expanded comparison of DSC thermograms of solid 5MeODMT benzoate batch 21-01-054 isolated from amorphous 5MeODMT benzoate in equilibrium with thermal modulation, classified as Form A, highlighting events in solid batch 21-01-054Q isolated from anisole.

[0190] Fig.61 An expanded DSC thermogram expansion is shown highlighting events in batch 21-01-054Q isolated from anisole.

[0191] Fig.62 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060A1 air dried 2 minutes, batch 21-01-049B1 Pattern B, and batch 20-37-64 Pattern A.

[0192] Fig.63 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060A1 - air dried for 1 hour and batch 21-01-060A1 - air dried for 2 minutes.

[0193] Fig.64 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060A1 - air dried for 2 minutes, batch 21-01-060A1 - air dried for 1 hour, and batch 21-01-049B1 Pattern B.

[0194] Fig.65 Shown is the DSC thermogram of 5 MeODMT benzoate batch 21-01-060A1 immediately isolated from IPA / toluene and air dried for 1 hour.

[0195] Fig.66 Shown is an extension of the DSC thermogram of 5 MeODMT benzoate batch 21-01-060A1 immediately isolated from IPA / toluene and air dried for 1 hour.

[0196] Fig.67 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060A1 air dried for 20 hours, batch 21-01-060A1 air dried for 2 minutes, and batch 21-01-049B1 Pattern B reference.

[0197] Fig.68 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060B1 isolated after 3 hours equilibration and then air dried for 2 min and 5MeODMT benzoate batch 21-01-060A1 isolated immediately and then air dried for 2 minutes.

[0198] Fig.69 Shown is a comparison of XRPD patterns of 5MeODMT benzoate batch 21-01-060B1 isolated after 3 hours equilibration and then air dried for 20 hours and 5MeODMT benzoate batch 21-01-060B1 isolated after 3 hours equilibration and then air dried for 2 minutes, and batch 21-01-049B1 Pattern B.

[0199] Fig.70 Shown is a comparison of XRPD patterns of 5MeODMT benzoate batch 21-01-058 solids isolated from amorphous 5MeODMT benzoate exposed to solvent vapor.

[0200] Fig.71Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-058K and batch 20-37-64 Form A isolated from amorphous 5MeODMT benzoate exposed to solvent vapor.

[0201] Fig.72 Shown is a comparison of the DSC thermograms of 5MeODMT benzoate batch 21-01-058B, batch 21-01-058F, batch 21-01-058K, and batch 21-01-062G.

[0202] Fig.73 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-058D, batch 20-37-64 pattern A, batch 21-01-049B1 pattern B, and batch 21-01-060B1 pattern C (air dried for 20 hours).

[0203] Fig.74 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate salt batch 21-01-058D, batch 21-01-049B1 Pattern B, and batch 21-01-060B1 Pattern C (air dried for 20 hours).

[0204] Fig.75 Shown is an expanded comparison of the XRPD patterns of 5MeODMT benzoate salt batch 21-01-058D, batch 21-01-049B1 Pattern B, and batch 21-01-060B1 Pattern C (air dried for 20 hours).

[0205] Fig.76 Shown is the DSC thermogram of 5MeODMT benzoate batch 21-01-058D isolated by exposing anisole vapor to the amorphous form.

[0206] Fig.77 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-064D and 21-01-060B1 (air dried for 2 minutes).

[0207] Fig.78 Shown is an expanded comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-064D and 21-01-060B1 (air dried for 2 minutes).

[0208] Fig.79 5MeODMT benzoate batch 21-01-064D is shown at 10°C.min -1 DSC temperature record diagram.

[0209] Fig.80Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-064C and 21-01-064D.

[0210] Fig.81 Shown is an expanded comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-064C and 21-01-064D.

[0211] Fig.82 5MeODMT benzoate batch 21-01-064C is shown at 10°C.min -1 DSC temperature record diagram.

[0212] Fig.83 A comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073A, 21-01-049B1 Pattern B, and 20-37-64 Pattern A are shown.

[0213] Fig.84 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073F and a reproduction of 21-01-073F.

[0214] Fig.85 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073F reproduction, 21-01-049B1 Pattern B, and 20-37-64 Pattern A.

[0215] Fig.86 Shown is an expanded comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073F replicate, 21-01-049B1 Pattern B, and 20-37-64 Pattern A.

[0216] Fig.87 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073K, 21-01-049B1 Pattern B, and 20-37-64.

[0217] Fig.88 Shown is the XRPD of 5MeODMT benzoate batch 21-01-078.

[0218] Fig.89 Shown is the DVS isotherm plot for 5MeODMT benzoate batch 21-01-078.

[0219] Fig.90 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-078 (post-DVS) and 20-37-64.

[0220] Fig.91Shown are FTIR overlays of 5MeODMT benzoate Pattern A Form (20-20-150FP2), Pattern B Form (21-01-071C2), and Pattern C Form (21-01-071C1).

[0221] Fig.92 The 5MeODMT benzoate forms A (20-20-150FP2), B (21-01-071C2) and C (21-01-071C1) were shown at 450 cm -1 Up to 2000cm -1 FTIR overlay.

[0222] Fig.93 The 5MeODMT benzoate forms A (20-20-150FP2), B (21-01-071C2) and C (21-01-071C1) were shown at 450 cm -1 Up to 2000cm -1 FTIR superposition; spectral separation.

[0223] Fig.94 Forced swim test results, Time Immobile, for 5MeODMT benzoate, vehicle, and imipramine are shown.

[0224] Fig.95 Shown are the results of the forced swim test, Latency to Immobility, for 5MeODMT benzoate, vehicle and imipramine.

[0225] Fig.96 Shown are group mean plasma concentrations (ng / mL) of 5MeODMT in male beagle dogs - Group 2 (HCl salt) and Group 4 (benzoate salt) - for dose levels (0.4 mg / kg); wherein the mean plasma concentrations for Group 2 and Group 4 were generally similar over dosing time. DETAILED DESCRIPTION OF THE INVENTION

[0227] Figure 1 Shown is a one-step synthesis of 5MeODMT from the reaction of 4-methoxyphenylhydrazine hydrochloride and (N,N)-dimethylaminobutyraldehyde dimethyl acetal.

[0228] Figure 2 A three-step synthesis of 5MeODMT is shown. 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.

[0229] Figure 3 A schematic route for forming a powder form of 5MeODMT using a spray drying process is shown. Example

[0230] Example 1: One-step synthesis of 5MeODMT (free base)

[0231] The reaction is schematically represented in Figure 1 Shown in.

[0232] Hydrazine (1.0 eq.), diethyl acetal (1.2 eq.), and aqueous sulfuric acid (0.1 eq.) were heated together at 65-75° C. for 18 hours. MTBE (10 vol.) was added followed by adjustment to about pH 10 using 12% caustic (about 1.1 eq.). The layers were separated and the aqueous fraction was back extracted with MTBE (10 vol.). The combined organic fractions were washed twice with water (10 vol.) and then evaporated to dryness under vacuum. Yield 100%.

[0233] Example 2: Synthesis of 5MeODMT (free base) in three steps

[0234] The reaction is schematically represented in Figure 2 Shown in.

[0235] Step 1 - Methyl tert-butyl ether (MTBE) (15 vol) was added to the reaction vessel and cooled to -20°C to -30°C before adding oxalyl chloride (1.5 eq), maintaining the temperature at no more than -20°C. A solution of 5-methoxyindole (1.0 eq) in THF (1 vol) was added to the reaction vessel, maintaining the temperature at no more than -20°C. The reaction was allowed to warm to 0°C-5°C and stirred for at least 1 hour, ensuring that no more than 2% of the starting material indole remained.

[0236] The reaction was cooled to between -20°C and -30°C and a solution of methanol (1 vol) and MTBE (1 vol) was added maintaining the temperature at no more than -20°C. The reaction was allowed to warm to 0-5°C over not less than 30 minutes and stirring was continued for at least 1 hour.

[0237] Filter and wash the solid with MTBE cooled to 0°C-5°C. Add the washed filtered solid and methanol (20 volumes) to the reaction vessel. Heat to 60°C-65°C, and stir for no more than 30 minutes. Cool to 0°C-5°C over no less than 2 hours, and stir for no less than 2 hours. Filter and wash the solid with MTBE cooled to 0°C-5°C. Dry the obtained solid at no more than 40°C for no less than 12 hours. Yield 95%.

[0238] Step 2 - The compound obtained in step 1 (1.0 eq) was added to a reaction vessel along with dimethylamine hydrochloride (3.0 eq) and methanol (2 vols). 25% NaOMe (3.5 eq) in methanol was added to the reaction, maintaining the temperature at no more than 30°C. Heating and stirring were continued for no less than 5 hours, ensuring that no more than 0.5% of the starting material from step 1 remained. The temperature was adjusted to 0°C-5°C over no less than 2 hours, then water (5 vols) was added over no less than 1 hour, and stirring was continued at 0°C-5°C for no less than 1 hour.

[0239] Filter and wash the solid with water cooled to 0-5°C, and dry the obtained solid at no more than 40°C for no less than 12 hours. Yield 85%.

[0240] Step 3 - The compound obtained in step 2 (1.0 equiv) was added to the reaction vessel. 1 M LiAlH in THF (8 vol) was added to the reaction. 4 (1.5 eq.), maintaining no more than 40° C. Heating at reflux was continued for no less than 4 hours, ensuring that no more than 2% of the starting material from Step 2 remained.

[0241] Adjust to 0°C-5°C and add water (0.25 vol) in THF (0.75 vol) over not less than 30 minutes, maintaining not more than 10°C. Then add 15% caustic (0.25 vol), maintaining the temperature not more than 10°C. Add water (0.65 vol), maintaining the temperature not more than 10°C. Add THF (0.25 vol) as a container rinse, and stir the contents at 0°C-5°C for not less than 30 minutes. Add sodium sulfate (100 wt%), and stir the contents at 0°C-5°C for not less than 30 minutes.

[0242] Filter and wash solid with toluene (2×10 volumes), and keep liquid separation.THF liquid is reloaded in a clean container and distilled to minimum volume under vacuum.Toluene liquid is loaded and distilled to about 10 volumes under vacuum.Then add water (5 volumes) and stir to continue for no less than 15 minutes.Stop, settle and remove water layer to waste.Load 4% HCl to pH (about 4 volumes) between 1-2 and stir to continue for no less than 15 minutes.Stop, settle and remove organic layer to waste.Load MTBE (15 volumes).Load 15% caustic to pH (about 0.9 volume) between 11-13.Stirring continues for no less than 15 minutes.Stop, settle and remove water layer to waste.Load water (5 volumes).Stirring continues for no less than 15 minutes.Stop, settle and remove water layer to waste.

[0243] Example 3: Synthesis of 5MeODMT hydrochloride

[0244] 5MeODMT (free base) was dissolved in toluene (1.0 vol to 2.5 vol). Isopropyl alcohol (IPA) (2.5 vol) was then added followed by 1.25 M HCl in IPA (1.0 eq) and the temperature was adjusted to 0-5°C over 1 hour.

[0245] If no precipitation / crystallization occurs, toluene (6.25 vol) is added over 30 minutes. The mixture is then stirred at 0°C-5°C for 2 hours. The resulting solid is filtered and washed with toluene (3.8 vol). The solid is dried at ambient temperature under vacuum. Yield 58%.

[0246] Example 4: Synthesis of 5MeODMT Benzoate

[0247] 5MeODMT (free base) was dissolved in toluene (1 eq) and benzoic acid (1 eq) in toluene (10 vol) was added over a period of 20 min and stirred at room temperature for 2 h. The resulting precipitate / crystallization was filtered and washed with toluene (2.5 vol) and dried under vacuum at room temperature.

[0248] Isopropyl acetate (IPAc) (15.8 volumes) was added to the solid obtained above and the temperature was raised to about 73°C until the solid dissolved. The solution was allowed to cool to 0°C-5°C over 2 hours and maintained at this temperature for 1 hour with stirring. The resulting benzoate was filtered and dried under vacuum at room temperature. Yield 68%.

[0249] Example 5: Synthesis of 5MeODMT Fumarate

[0250] 5MeODMT (free base) was added to a solution of fumaric acid (0.5 eq.) in IPA at 40-45°C over 15 minutes. The resulting solution was cooled at room temperature and stirred for 16 hours. The solution was then cooled to 0-5°C with stirring for 2 hours. The resulting precipitate / crystallization was filtered and rinsed with toluene (2.5 volumes). Yield 68%.

[0251] Example 6: 5MeODMT powder

[0252] A schematic route for preparing the powder form of 5MeODMT (or its salt) is given in Figure 3 Shown in.

[0253] The three main steps in the process are:

[0254] 1. Spray drying a solution containing the substance of interest (e.g., 5MeODMT or a salt thereof, including any excipients). This can be accomplished via an atomizing nozzle, such as with a rotary atomizer, a pressure atomizer, a two-fluid nozzle, an ultrasonic atomizer, a four-fluid nozzle. This is done to form droplets that can produce co-formed particles within the desired particle size range.

[0255] 2. Drying the atomized droplets (eg, with nitrogen, optionally at elevated temperature).

[0256] 3. Separating and collecting the dried particles from the gas stream (eg, using a cyclone separator to capture the desired size fraction).

[0257] Example 7: Slug mucous membrane irritation assay

[0258] The slug mucosal irritation (SMI) assay was originally developed at the Laboratory of Pharmaceutical Technology (UGent) to predict the mucosal irritation efficacy of pharmaceutical preparations and ingredients. The test utilized the terrestrial slug Portuguese slug (Arion lusitanicus). The body wall of the slug is a mucosal surface comprising different layers. An outer single-layer columnar epithelium comprising cells with cilia, cells with microvilli, and mucus-secreting cells covers the subepithelial connective tissue. Slugs placed on irritating substances will produce mucus. In addition, tissue damage can be induced, which causes proteins and enzymes to be released from the mucosal surface. Several studies have shown that the SMI assay is a useful tool for evaluating the local tolerance of pharmaceutical preparations and ingredients. A classification prediction model that distinguishes between irritation (mucus production) and tissue damage (release of proteins and enzymes) has been developed. In addition, several studies on ophthalmic preparations have shown that increased mucus production is associated with an increased incidence of stinging, itching, and burning. In 2010, a clinical trial was established to evaluate the stinging and burning of several diluted shampoos. A 5% shampoo dilution or artificial tears was instilled into the eye, and the discomfort was scored on a 5-point scale by the participant during several time points up to 30 min after instillation. The same shampoo was tested using the stinging, itching, and burning (SIB) protocol in the SMI assay. The study showed that increased mucus production was associated with an increased incidence of stinging and burning in human eye irritation testing. The assay reliably predicted nasal irritation and the correlation of stinging and burning using several OTC nasal preparations, isotonic saline, and hypertonic saline.

[0259] Furthermore, the test was validated using reference chemicals for eye irritation (ECETOC Eye Reference Database). These studies have shown that the SMI assay can be used as an alternative method for in vivo eye irritation testing. Furthermore, a multicenter pre-validation study with four participating laboratories showed that the SMI assay is a relevant, easily transferable and reproducible alternative method to predict the eye irritation potency of chemicals.

[0260] The purpose of this assay is to assess the potential for stinging, itching or burning of the test items defined below. Using the target values ​​obtained for mucus production, the potential for stinging, itching or burning of the test items can be estimated by a prediction model including four categories (none, mild, moderate and severe).

[0261] Comparison items:

[0262] ●Negative Control-Name: Phosphate Buffered Saline (PBS)

[0263] ● Positive Control - Name: 1% (w / v) Benzalkonium Chloride in PBS

[0264] Test items:

[0265] Compound 1

[0266] Name: 10% (w / v) disodium fumarate in PBS

[0267] CASRN: 17013-01-3

[0268] Batch: KBSJ-P0

[0269] Description: Colorless solution

[0270] Storage conditions: room temperature (reconstitute on the day of the experiment)

[0271] Compound 2

[0272] Name: 10% (w / v) sodium dihydrogen phosphate in PBS

[0273] CASRN: 7558-80-7

[0274] Batch: 2A / 220991

[0275] Description: Colorless solution

[0276] Storage conditions: room temperature (reconstitute on the day of the experiment)

[0277] Compound 3

[0278] Name: 10% (w / v) sodium acetate in PBS

[0279] CASRN: 127-09-3

[0280] Batch: 5A / 233258

[0281] Description: Colorless solution

[0282] Storage conditions: room temperature (reconstitute on the day of the experiment)

[0283] Compound 4

[0284] Name: 10% (w / v) sodium citrate in PBS

[0285] CASRN: 68-04-2

[0286] Vial batch: 5A / 241516

[0287] Description: Colorless solution

[0288] Storage conditions: room temperature (reconstitute on the day of the experiment)

[0289] Test system: Slugs (Portuguese slug); 3 slugs per treatment group. Parent slugs of Portuguese slugs collected in local gardens along Gent and Aalter (Belgium) were bred in the laboratory in an acclimatization chamber (18°C-20°C). The slugs were kept in plastic containers and fed with lettuce, cucumber, carrot and commercial dog food.

[0290] Test Design: A single study was conducted. Treatment duration was 15 minutes, 3 times on the same day.

[0291] Slug Preparation:

[0292] Two days before the start of the experiment, slugs weighing between 3 g and 6 g were isolated from the culture. The body wall was carefully examined for signs of macroscopic damage. Only slugs with clear tubercles and foot surfaces showing no signs of damage were used for testing purposes. The slugs were placed in a plastic box lined with a paper towel moistened with PBS and kept at 18°C-20°C. The body wall of the slugs was moistened daily with 300 μl PBS using a micropipette.

[0293] Testing Procedure:

[0294] The stinging, itching, or burning efficacy of the test items was evaluated by placing three slugs per treatment group on 100 μL of the test item in a petri dish for 15 min ± 1 min three times daily. After each 15-min contact period, the slugs were transferred to a fresh petri dish on a paper towel moistened with 1 mL of PBS for 60 min to prevent drying. An overview of the test procedure can be found at Figure 4 Seen in.

[0295] Mucus Production:

[0296] The amount of mucus produced during each contact period was measured by weighing the petri dishes with the test items before and after each 15-min contact period. Mucus production is expressed as % of body weight. Slugs were weighed before and after each 15-min contact.

[0297] Classification prediction model

[0298] Based on the endpoints measured by SMI, a classification prediction model was used to estimate the stinging, itching, or burning potency of the test items.

[0299] Evaluation of the test results is based on the total amount of mucus produced during 3 repeated contact periods with the test item.

[0300] For each slug, mucus production was expressed as % of body weight by dividing the weight of mucus produced during each contact period by the body weight of the slug before the start of that contact period. Total mucus was calculated for each slug and then the mean for each treatment group was calculated. The classification prediction model shown in Table 1 was used to classify the compounds.

[0301] Table 1 Cut-off values ​​for categories – efficacy for nasal discomfort

[0302]

[0303] Acceptance Criteria

[0304] Before a test is considered valid, the following criteria must be met:

[0305] - Negative controls should be classified as not causing stinging, itching and burning (total mucus production <

[0306] 5.5% )

[0307] - Positive control items should be classified as causing severe stinging, itching, and burning (total mucus production ≥17.5%)

[0308] Stimulus Possibility

[0309] Table 2 Amount of mucus (MP) produced during each 15-min contact period (CP) and the total amount of mucus produced

[0310]

[0311] NC: negative control; PC: positive control; BAC: benzalkonium chloride

[0312] 1 Mean ± SD, n = 3

[0313] 2 None: total MP < 5.5%; Mild: 5.5% ≤ total MP < 10%; Moderate: 10% ≤ total MP < 17.5%; Severe: total MP ≥ 17.5%

[0314] The average amount of mucus produced during each 15-min contact period and the total mucus production (total MP) are presented in Table 2. According to the classification prediction model of the SMI test, the negative control (untreated slugs) did not induce a response in the 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%), resulting in a classification as a severe stinging, itching and burning (SIB) reaction. The acceptance criteria were met and the experiment was considered valid.

[0315] A total of 4 different solutions were tested. The amount of mucus produced during each 15-min contact period was between 10% and 17.5%, indicating a moderate SIB reaction. The test items can be ranked according to increasing total mucus production: sodium acetate (10% w / v) < sodium citrate (10% w / v) < disodium fumarate (10% w / v) < monosodium phosphate (10% w / v).

[0316] Numeric data

[0317]

[0318] Table 3 Amount of mucus (MP) produced during each 15-min contact period (CP) and the total amount of mucus produced

[0319]

[0320] NC: negative control; PC: positive control; BAC: benzalkonium chloride

[0321] 1 Mean ± SD, n = 3

[0322] 2 None: total MP < 5.5%; Mild: 5.5% ≤ total MP < 10%; Moderate: 10% ≤ total MP < 17.5%; Severe: total MP ≥ 17.5%

[0323] Table 4 Amount of mucus (MP) produced during each 30-min contact period (CP) and the total amount of mucus produced (code 00E04)

[0324]

[0325] Table 5 Amount of mucus (MP) produced during each 60-min contact period (CP) and the total amount of mucus produced

[0326]

[0327] Table 6 Amount of mucus (MP) produced during the 60-min contact period (CP)

[0328]

[0329] result

[0330] The total MP of the 60-min treatment (historical data) was compared with the total MP of the SIB regimen (3 × 15-min treatments; current data). In the following table, a ranking from lowest to highest SIB response is proposed:

[0331]

[0332]

[0333] Sodium oxalate appears to be the most irritating salt, as a concentration of 1% resulted in 11.2% of total MP after 1 hour of contact. Sodium benzoate is the least irritating salt.

[0334] Example 8: Additional Slug Membrane Irritation (SMI) Test

[0335] 5MeODMT is known to be highly irritating to the mucosal lining as a free base compound; therefore, it is usually prepared as a salt for insufflation. The hydrochloric acid (HCl) salt of 5MeODMT is most commonly used due to its ease of crystallization. However, it is known that the HCl salt of 5MeODMT is still quite irritating to the mucosal lining.

[0336] Following the results above indicating that sodium benzoate was the least irritating of the salts studied; an additional SMI test was performed on 5MeODMT benzoate and the common 5MeODMT HCl salt according to the method described previously (method of Example 7). The results of this SMI test are shown below:

[0337] Compound Concentration (w / v) Total MP (% body weight) 5MeODMT Benzoate 10％ 7.38 5MeODMT HCl 10％ 10.27 Benzalkonium chloride (positive control) 10％ 17.56 PBS (negative control) 10％ -0.77

[0338] 5MeODMT benzoate produced 'mild' irritation compared to 5MeODMT HCl which was rated 'moderate' in the test.

[0339] Example 9: Permeation Data

[0340] The use of sheep nasal epithelium to study nasal drug absorption is a technique well known to those skilled in the art.

[0341] The applicant has studied the permeation of 5MeODMT benzoate and 5MeODMT HCl. Dosing solutions corresponding to a concentration of 1.25% were prepared in water and applied to the nasal epithelium of sheep. The mean cumulative permeation (μg / cm 2 ) are shown in the following table (mean ± SD, n = 5):

[0342]

[0343] The cumulative amount of 5MeODMT benzoate and 5MeODMT hydrochloride that permeated through the sheep nasal epithelium per unit area after application of a 1.25% dosing solution prepared in water (mean ± SD, n = 5) can be found at Figure 5 Seen in.

[0344] As can be clearly seen, benzoate has a higher permeation across the epithelium.

[0345] The above data obtained in the above tests show that 5MeODMT benzoate gives higher penetration and less mucosal irritation than the commonly used HCl salt; and therefore, this combination of properties makes benzoate an ideal candidate for mucosal delivery. For example, less 5MeODMT benzoate may be needed to provide the same benefit as the HCl salt when inhaled, and benzoate is less irritating and therefore provides a synergistic benefit. Smaller amounts of the compound also make inhalation easier to accomplish.

[0346] Example 10: Effects on central nervous system function

[0347] In the following examples, BPL-5MEO refers to 5-methoxy-N,N-dimethyltryptamine (5MeODMT).

[0348] In the following examples, the hydrochloride salt of 5MeODMT was used.

[0349] The following examples (10-14) summarize the safety pharmacology studies initiated by the applicant to evaluate the effects of BPL-5MEO on CNS, cardiovascular and respiratory system functions. The study design is based on the International Council for Harmonisation (ICH) S7A / B guidelines and is conducted in accordance with GLP regulations.

[0350] The pharmacological effects of BPL-5MEO on CNS function were evaluated using the Functional Observational Battery (FOB) in male Sprague-Dawley rats following a single intranasal administration (ITR Research 15951).

[0351] The test items and control / vehicle items were administered by single-dose intranasal administration to both nostrils as shown in Table 7.

[0352] Table 7: Experimental design of study 15951

[0353]

[0354] a The observer performing the FOB was unaware of the specific treatment administered to the animals.

[0355] b Control animals were administered 0.1% hydroxypropylmethylcellulose (HPMC) in water.

[0356] c Regardless of their body weight, all animals received a dose volume of no more than 25 μL / nostril.

[0357] The parameters monitored included mortality and clinical signs. General behavioral changes were assessed using FOB at 6 time points: before dosing, and 15 minutes, 1 hour, 2 hours, 4 hours, and 24 hours after dosing. On each occasion, FOB was performed in 4 phases: when the animals were in their home cages, when the animals were handled, when the animals were free to move in an open field, and when they were exposed to different stimuli for responsiveness evaluation. On each occasion detailed above, body temperature and neuromuscular strength were also measured.

[0358] The FOB examinations were grouped according to the functional domains of the nervous system as shown in Table 8.

[0359] Table 8: Functional domains of the nervous system and related observations

[0360]

[0361]

[0362] There was no treatment-related mortality / morbidity. Transient BPL-5MEO-related clinical signs were noted immediately after dosing and consisted primarily of decreased activity, lying on the cage floor, shallow / increased breathing, and dilated pupils in all dose groups. Tremors, salivation, and gasping were observed in some animals at the 3 mg / kg and 10 mg / kg doses, and convulsions were noted in one animal at 10 mg / kg.

[0363] In the behavioral domain of FOB, a single intranasal administration of BPL-5MEO at doses of 1.5 mg / kg, 3 mg / kg, and 10 mg / kg resulted in a transient decrease in activity, lying on the cage floor, and reduced rearing 15 minutes after dosing. All behavioral parameters were comparable to control animals 1 hour after dosing.

[0364] In the neurological (sensorimotor) / neuromuscular domain of FOB, single intranasal administration of BPL-5MEO at 1 mg / kg, 5 mg / kg and 10 mg / kg resulted in transient gait changes (dyskinesia) at all dose levels. All neurological (sensorimotor) / neuromuscular parameters were comparable to control animals 1 hour after dosing.

[0365] In the autonomic nervous system domain, single intranasal administration of BPL-5MEO at 1 mg / kg, 5 mg / kg and 10 mg / kg was associated with changes in salivation, piloerection, increased respiration, dilated pupils and body temperature noted at all dose levels. All autonomic nervous system parameters were comparable to control animals 2 hours after dosing.

[0366] In summary, single intranasal administration of BPL-5MEO at doses of 1.5 mg / kg, 3 mg / kg, and 10 mg / kg resulted in transient clinical signs consistent with observable changes in behavioral parameters, neurological (sensorimotor) / neuromuscular parameters, and autonomic nervous system parameters that completely resolved within 1 or 2 hours post-dose.

[0367] Example 11: Effects on cardiovascular function

[0368] In vitro studies

[0369] The effect of 5MeODMT on hERG potassium channel current (I Kr ), the rapidly activating, delayed rectifier cardiac potassium current in vitro (CRL study 1020-5458). This assay is used as a screening test to assess the potential risk of QT prolongation.

[0370] The study was conducted in 2 phases: Phase 1 evaluated the initial and steady-state inhibition of hERG at the selected concentration of 30 μM 5MeODMT; if the results from Phase 1 showed 20% or more inhibition, Phase 2 evaluated the concentration response. The initial concentration of 30 μM was selected based on the results of an exploratory dose-range finding study in dogs, in which intranasal administration of 2.5 mg / kg BPL-5MEO resulted in a mean C 最大 803 ng / mL (3.67 μM) of 5MeODMT. The 30 μM solution used in stage 1 provides an 8-fold margin over this concentration.

[0371] In phase 1, 5MeODMT at a concentration of 30 μM in protein-free perfusate inhibited hERG potassium current by 77.8% ± 7.4% (n = 3). Therefore, phase 2 was performed using 5MeODMT at concentrations of 1 μM, 3 μM, 10 μM, and 35 μM in protein-free perfusate (corresponding to 0.2 μg / mL, 0.6 μg / mL, 2.0 μg / mL, and 7.2 μg / mL of unbound drug substance).

[0372] In phase 2, 5MeODMT inhibited hERG potassium channel currents in a concentration-dependent manner, as presented in Table 9.

[0373] Table 9: Mean percent inhibition of hERG potassium channel currents by 5MeODMT (in protein-free perfusate)

[0374]

[0375]

[0376] Calculation of IC of 5MeODMT on hERG potassium channel current 50 The calculated IC of the positive control terfenadine on hERG potassium channel current was 8.69 μM (95% confidence limits 5.78 μM-13.06 μM). 50 It is 12.8 nM (95% confidence limits 6.8 nM-24.3 nM).

[0377] In vivo studies

[0378] The pharmacological effects of BPL-5MEO on cardiovascular function (arterial blood pressure and ECG) were monitored by telemetry following a single intranasal administration in conscious male beagle dogs.

[0379] The highest dose level is based on the results of the intranasal maximum tolerated dose (MTD) toxicity study (study 62958) from dogs, where the daily repeated administration of 2.5 mg / kg / day BPL-5MEO for 5 consecutive days once a day is barely tolerable and is associated with short-term clinical observations of moderate to severe incoordination, vocalization, salivation, trembling, circling, sneezing, decreased activity and labored breathing, which resolve within 60 minutes after administration. Therefore, the highest dose selected for this study is 1.2 mg / kg / day. The lowest dose of 0.4 mg / kg / day is based on the consideration of the maximum clinical dose of 14 mg / day, wherein the mid-dose of 0.8 mg / kg / day is selected to provide a dose-response assessment.

[0380] BPL-5MEO and control / vehicle were administered by intranasal instillation into both nostrils, with a total of 4 dogs per session. Each dog received 4 administrations (control / vehicle and 3 dose levels of BPL-5MEO) according to a Latin-square design, so that each dog received multiple administrations in a unique order, as shown in Table 10. A washout period of at least 2 days was allowed between each consecutive dose.

[0381] Table 10: Latin Square Design for Canine Cardiovascular Studies

[0382]

[0383] a Due to low implant battery, animal 1004A was replaced with animal 1104A prior to dosing for test session 3.

[0384] The low, medium and high doses are 0.4 mg / kg / day, 0.8 mg / kg / day and 1.2 mg / kg / day respectively. The nominal dose levels refer to the free base in the form of the 5MeODMT salt.

[0385] The dose volume administered to each animal was 7 μL / kg / nostril. No animal exceeded a dose volume of 100 μL / nostril.

[0386] The control / vehicle was 0.1% hydroxypropylmethylcellulose (HPMC) in water.

[0387] Arterial blood 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 activity were recorded continuously during the telemetry recording period at least 1.5 hours before the start of dosing and for at least 24 hours after dosing. Systolic, diastolic, and mean arterial blood pressures and pulse rate were obtained from a transmitter catheter inserted in the femoral artery. ECG was obtained from biopotential leads, telemetry transmitters in Lead II configuration.

[0388] All animals were also monitored for mortality and clinical signs during the study. Body weights were recorded only for general health status checks and dose calculation purposes.

[0389] There were no deaths and no BPL-5MEO-related clinical signs during the study period.

[0390] Between the control group and the treatment group, the morphology of the P-QRS-T waveform remained normal, and no dysrhythmia or conduction abnormality was observed in the ECG. Between all dose levels and the control vehicle, there was a slight difference in the % change of the average HR averaged between about 0 minutes and 150 minutes after administration. Although the average % increase of average HR in the control vehicle during this time period increased by 3.7%, compared with baseline, the increase observed in the case of low dose levels, medium dose levels and high dose levels of BPL-5MEO was 7.6%, 10.3% and 17.2% respectively. However, arterial blood pressure does not seem to show any significant difference that is enough to have any effect on HR. No other findings were observed. The increase observed in the case of average HR at all dose levels is non-adverse, reversible, and does not show a typical dose relationship.

[0391] In conclusion, single intranasal instillation of BPL-5MEO into both nostrils at doses of 0.4 mg / kg / day, 0.8 mg / kg / day, and 1.2 mg / kg / day was well tolerated and did not produce any effects on the cardiovascular system in conscious male beagle dogs.

[0392] Example 12: Absorption and Pharmacokinetics

[0393] In a 14-day intranasal toxicology study in male and female rats (ITR Report 700041), plasma concentrations of 5-MeODMT increased with the administered dose. 最大 ) reaches the peak value (C 最大 ) concentration, where the apparent t 1 / 2 The range was from 6.8 to 9.4 minutes. There was a decreasing trend in the values ​​on Day 14 compared with Day 1. There were no significant gender differences and no evidence of accumulation with repeated dosing.

[0394] In a 14-day intranasal toxicology study in male and female dogs (ITR Report 62959), plasma concentrations of 5MeODMT increased with the administered dose. 最大 ) with an apparent elimination half-life ranging from 19 minutes to 95 minutes. These values ​​were not significantly different between Day 1 and Day 14. There were no significant gender differences and no signs of accumulation with repeated dosing.

[0395] The data show that exposure generally increased dose-dependently, but not always in a dose-proportional manner, over the dose range studied in rats (5 mg / kg, 20 mg / kg, 75 mg / kg) and dogs (0.4 mg / kg, 0.8 mg / kg, 1.5 mg / kg, and 2.5 mg / kg), as some increases were greater or less than dose-proportional between different doses. These results do not indicate that MAOA-mediated metabolism is saturated at the doses studied in these species, as previously seen in mice.

[0396] Example 13: Toxicology

[0397] The toxicology program completed with BPL-5MEO consists of a non-critical single / repeated dose intranasal study to determine the MTD in order to help select the highest dose of a key 14-day GLP intranasal toxicology study in male and female Sprague Dawley rats and beagles. The intranasal route of administration is used because it is a clinical route of administration. The selected species is based on information from published literature, preliminary PK information, the availability of historical control information from the testing laboratory, and the standard use and acceptance of these species as appropriate substitutes for intranasal administration. The experimental design of the key 14-day study includes an assessment of systemic exposure (toxicokinetics) and a 14-day recovery period to assess the reversibility of any adverse or delayed response. In the key study, once-daily dosing for 14 consecutive days is intended to provide sufficient systemic exposure to characterize the toxic potential of the drug substance with a very short half-life.

[0398] 1. Non-pivotal single / repeated dose and tolerability studies

[0399] a. Maximum tolerated dose in rats followed by 7-day repeat dose toxicology (Study 700040)

[0400] The purpose of this non-GLP study is to determine the maximum tolerated dose and toxicity profile of BPL-5MEO after intranasal instillation in rats. This study consists of 2 parts. The purpose of the first part (dose escalation phase) is to determine the MTD of BPL-5MEO after a single intranasal administration to Sprague-Dawley rats. The dosage used in Part 1 is 15mg / kg, 30mg / kg, 50mg / kg, 65mg / kg and 75mg / kg. Each subsequent dose is administered at least 24 hours after starting from the previous dose. There are 2 males and 2 females in each dosage group. The purpose of the second part (main research phase) is to determine the toxicity of BPL-5MEO at the MTD of 75mg / kg after intranasal administration once a day to Sprague-Dawley rats for 7 consecutive days.

[0401] All dose formulation samples collected and analyzed were between 89.2% and 101.3% of the nominal concentration and therefore met the acceptance criteria for accuracy (100% ± 15% of their nominal concentration).Analysis was performed using a non-GLP HPLC-UV assay.

[0402] All female groups received their target doses in both parts. However, because the maximum feasible loading dose did not exceed 25 μL / nostril, the average achieved doses for males at 30 μL were still 99.3%, 90.0%, 88.2%, and 89.6%, respectively, regardless of body weight, and were considered acceptable.

[0403] During Phase I, assessments of mortality, clinical signs, and body weight were performed. All animals were observed for 14 days after dosing, after which they were euthanized on Day 15 and subjected to gross necropsy. The necropsy consisted of an external inspection including reference to all clinically recorded lesions as well as a detailed internal inspection.

[0404] Single intranasal administration of 5MeODMT at a dosage level of up to 75mg / kg is tolerable. There is no mortality and obvious pathological findings at any dose. Female weight gain is slightly inhibited at 75mg / kg. A series of clinical signs were observed, and included uncoordinated, shallow or increased breathing, sneezing, salivation, decreased activity, erection of hair, white paste around the penis (for males), ptosis, lying on the bottom of the cage, and sensitivity to touch and tremor. The incidence and severity of these findings evolve with the changes in the dose applied, and are short-lived, with most of them disappearing within 1 hour after administration. Based on clinical signs and the maximum feasible volume / dose, 75mg / kg was judged to be MTD, and this dose was selected for Phase 2.

[0405] During Phase 2, assessments of mortality, clinical signs, and body weight were performed. After dosing, all animals were euthanized on the 8th day and subjected to autopsy. The autopsy consisted of an external inspection and a detailed internal inspection, which included reference to all clinically recorded lesions. Specific tissues / organs planned for the study were collected and retained, then trimmed and preserved immediately after the animals were euthanized, but these tissues / organs were not further examined with a microscope.

[0406] It is tolerable to continue 7 consecutive days with 75mg / kg intranasal administration of 5MeODMT. There is no mortality. The weight gain of both sexes is slightly inhibited. The transient clinical signs similar to the clinical signs of Phase I include incoordination, pupil dilation, increased or shallow breathing, wheezing, sneezing, salivation, pale color, reduced activity, lying on the bottom of the cage, erect hair, white paste around the penis (for males), penis erection (for males), touch cold, partially or completely close eyes, sensitive to touch and trembling. These signs are usually less obvious in terms of severity and incidence during the last few administration days of this stage, and disappear within 1 hour after administration after administration every day. Notable macroscopic observations are limited to the dark / light areas of the lungs of 2 / 10 animals; However, in the absence of histopathological examination, the possible test item relationship of these findings cannot be ruled out.

[0407] b. Maximum tolerated dose in dogs followed by 7-day repeat dose toxicology (Study 62958)

[0408] The objectives of this study were to determine the maximum tolerated dose and toxicity of the test item 5MeODMT (as the hydrochloride salt) following intranasal instillation in dogs. To support these objectives, the study consisted of 2 separate phases.

[0409] The test item was administered once by intranasal instillation to one male and one female dog up to 5 dose levels until the highest tolerated dose (MTD) was determined as described in Table 11.

[0410] Table 11: Doses Administered in the Dose Escalation Phase in Study 62958

[0411]

[0412] aEach subsequent dose was administered after a minimum 3-day washout period between doses.

[0413] b Dosage levels refer to the free base in the salt form of BPL-5MEO.

[0414] cTarget dose concentrations were calculated based on an estimated body weight of 10 kg.

[0415] dThese animals were dosed at a higher dose level of 5 mg / kg.

[0416] There is no BPL-5MEO-related effect on mortality or body weight. Males were at the 1st day (dose 1) and the 9th day (dose 2) and females were at the 4th day (dose 1) and the 9th day (dose 2), and a slight reduction in food intake was observed after administration. A series of clinical signs were observed, and included gnawing cage wires, dilated pupils, respiratory changes, incoordination, reduced activity, vocalization, salivation, penis erection (for males) and trembling. After the last increasing dose of 3.5mg / kg / day, male animals had convulsions soon after administration, which lasted for 8 minutes. All clinical signs disappeared within one hour after administration, except reduced activity, dilated pupils and lying on the bottom of the cage, which occurred in rare cases 1 hour after administration or a few minutes afterwards. The MTD of the test item is considered to be 2.5mg / kg.

[0417] In the 2nd stage (dose confirmation), BPL-5MEO was applied to a male dog and a female dog with MTD by intranasal instillation once a day for 5 consecutive days and then twice a day (minimum 4 hours interval) on the 6th and 7th days. During the 2nd stage, the assessment of mortality, clinical signs, body weight and food consumption was carried out. A series of blood samples were collected on the 1st and 7th days to determine the plasma concentration of 5MeODMT using the LC / MS / MS method. After the last administration, all animals were euthanized on the 8th day and experienced autopsy. Autopsy consists of external inspection and detailed internal inspection, and the external inspection includes reference to the lesions of all clinical records. The specific tissues / organs of the research plan are collected and preserved after autopsy, but are not further examined with a microscope.

[0418] There was no test item-related effect on mortality or body weight. A slight reduction in food intake was observed for male animals on the 7th day, and a slight reduction in food intake was observed for female animals on the 5th and 7th days. A series of clinical signs were observed, and included muscle stiffness, gnawing cage wires, dilated pupils, respiratory changes, reduced activity, incoordination, vocalization, salivation, erectile dysfunction (for males) and trembling. All clinical signs disappeared within one hour after administration, except reduced activity, dilated pupils and lying on the bottom of the cage, which occurred in rare cases 1 hour after administration or a few minutes later. All observations were considered to be short-lived.

[0419] Toxicokinetic assessments were performed on days 1 and 7; maximum BPL-5MEO plasma concentrations (C 最大 ) ranged from 541 ng / mL to 803 ng / mL and was reached within 2 to 15 minutes after administration in both sexes (T 最大). In both sexes, the dose-normalized AUC ranged from 2980 min*kg*ng / mL / mg to 7320 min*kg*ng / mL / mg. 最大 Thereafter, BPL-5MEO plasma concentrations increased with an estimated t from 19.1 min to 34 min in both sexes. 1 / 2 In either case, there were no sex differences in any of the measured toxicokinetic parameters. BPL-5MEO did not accumulate when administered daily by intranasal instillation during the 7-day treatment period.

[0420] 2. Key research

[0421] a. A 14-day repeated dose intranasal toxicity study in rats followed by a 14-day recovery period (Study 700041)

[0422] The objectives of this GLP study were to determine the toxicity and toxicokinetic (TK) profile of BPL-5MEO following intranasal instillation for 14 consecutive days in Sprague Dawley rats and to assess the persistence, delayed onset, or reversibility of any changes after a 14-day recovery period.

[0423] BPL-5MEO and control / vehicle were administered to groups of rats once daily by intranasal instillation for 14 consecutive days as described in Table 12.

[0424] Table 12: Doses Administered in a 14-Day Repeat Dose Study in Rats

[0425]

[0426] a Vehicle control animals were administered 0.1% hydroxypropylmethylcellulose (HPMC) in water.

[0427] bNominal dose levels refer to the free base in 5MeODMT salt form.

[0428] c The dose volume administered to each animal was 75 μL / kg / nostril.

[0429] d Regardless of their body weight, all animals received a dose volume of no more than 25 μL / nostril.

[0430] The mortality rate, clinical signs, respiratory measurements, body weight, food consumption and body temperature of the monitoring animals were performed. Ophthalmoscopic examination and respiratory function tests were performed on all animals at the scheduled time point. Clinical pathology assessment (hematology, coagulation, clinical chemistry and urinalysis) was evaluated at termination. At most 8 hours after treatment, blood samples were collected from the jugular vein from TK animals on the 1st and 14th days for the bioanalysis of 5MeODMT concentration in plasma and the calculation of toxicokinetic parameters subsequently. After administration, the main animals were euthanized on the 15th day and a complete autopsy was performed. The recovered animals were observed for another 14 days, and then euthanized on the 28th day and a complete autopsy was performed. TK animals were euthanized after the last blood collection and were discarded without further examination. At the time of terminal euthanasia, for all main research animals and recovery research animals, selected tissues / organs were weighed, and a microscopic evaluation of a group of standard tissues including nasal concha (4 sections) and brain (7 sections) was performed.

[0431] After administration, the animals in the main group on the 15th day were euthanized and subjected to autopsy. The animals in the recovery group were observed to continue for 14 days, and then euthanized and subjected to autopsy on the 28th day. For toxicokinetics, at the 1st and 14th days of the treatment period, 2 minutes, 5 minutes, 10 minutes, 15 minutes and 30 minutes and 1.0 hour, 3.0 hours and 8 hours after treatment, a series of 8 blood samples (each about 0.5mL) were collected from all rats of the toxicokinetics group (3 rats / sex / time point). For the control rats (3 rats / sex) in the toxicokinetics group, only 1 sample was collected at the time point of 15 minutes after the administration on the 1st and 14th days.

[0432] Toxicity was based on the following monitored parameters: mortality / morbidity, clinical observations, body weight / weight gain, food consumption, ophthalmoscopy, clinical pathology (hematology, coagulation, chemistry, and urinalysis), necropsy observations, selected organ weights, and microscopic examination of a complete set of standard tissues including 4 cross levels of the nasal cavity and 7 brain sections.

[0433] result

[0434] All samples met the acceptance criteria for accuracy (100% ± 10% of their nominal concentration).

[0435] All animals were dosed without any major incidents, and no sneezing was noted. All groups received their target doses on days 1 to 10. Because the maximum feasible loading dose did not exceed 25 μL / nostril (due to limited nasal surface area), male animals in all groups received slightly lower dose levels on days 11 to 14 once body weight exceeded 333 g. This was not considered to have an impact on the study data, as the differences were negligible.

[0436] No mortality occurred during the course of the study.

[0437] The clinical signs observed were as follows:

[0438] Group 2 (low dose)

[0439] Both male and female animals showed incoordination, tremors, salivation, decreased activity, lying on the cage floor, and sensitivity to touch. For one female animal on day 3, increased breathing was also observed.

[0440] Group 3 (medium dose)

[0441] Both male and female animals exhibited incoordination, tremors (or tremors), increased or shallow breathing, pupil dilation, salivation, decreased activity, partially closed eyes, lying on the cage floor, and sensitivity to touch. Male animals also exhibited penile erections.

[0442] Group 4 (high dose)

[0443] Both male and female animals exhibited incoordination, tremors (or tremors), increased or shallow breathing, pupil dilation, salivation, decreased activity, partially closed eyes, lying on the cage floor, and sensitivity to touch. Male animals also exhibited penile erections.

[0444] Increased respiration was noted in the medium and high dose groups, however, respiratory values ​​measured using a plethysmograph demonstrated that there was actually a decrease in respiratory rate.

[0445] For all groups, all of the above clinical signs were considered transient.

[0446] A slight, generally dose-dependent inhibition of body weight gain was observed for both sexes between Days 1 and 14. There were no changes in food consumption, which can be attributed to treatment at dose levels ≤ 75 mg / kg / day for 14 days.

[0447] On Day 14, slight increases in body temperature were observed at 15 and 30 minutes post-dose for all treated males, and for females on Day 14, increases in body temperature were observed in one or all treatment groups for all time points (up to 2 hours post-dose). These increases in body temperature were more pronounced in the mid-dose group (20 mg / kg / day) and the high-dose group (75 mg / kg / day).

[0448] A decrease in respiratory rate was observed at the 20 minute post-dose time point when compared to pre-treatment or control groups, which resulted in a decrease in respiratory minute volume. Tidal volume values ​​were comparable to pre-dose or control values. Respiratory measurements at 20 minutes post-dose on Day 1 were not inadvertently performed on Group 2 female animals. This was not considered to have an impact on the study data, as the data could be extrapolated from male animals in the same group. There was no significance between genders.

[0449] There were no adverse ocular effects caused by administration of BPL-5MEO at dose levels ≤ 75 mg / kg day for 14 days.

[0450] All other clinical observations, changes in body weight, changes in food consumption, and changes in body temperature were considered unrelated to BPL-5MEO as they were incidental, comparable to pre-treatment signs or control animals, and unrelated to dose.

[0451] When compared to the control group, platelet, neutrophil, monocyte, and basophil counts increased slightly in both sexes in the mid-dose and high-dose groups, however, these values ​​remained within historical ranges. At day 28, all of these values ​​were compared to those in the control group.

[0452] All changes in hematological parameters, including those that reached statistical significance, were not attributable to the administration of BPL-5MEO as they were minor (within the normal physiological range), comparable to control values, and / or were not dose related.

[0453] When compared to the control group, the activated partial thromboplastin time (APTT) increased in both sexes in the medium dose group (20 mg / kg / day) and the high dose group (75 mg / kg / day). All coagulation values ​​at day 28 were comparable to the control group. All other changes in coagulation parameters were not attributed to the administration of BPL-5MEO, as they were small (within the normal physiological range), comparable to control values, and / or dose-independent.

[0454] There were no changes in clinical chemistry parameters and urinalysis parameters that could be attributed to the administration of BPL-5MEO for 14 days at a dose level of ≤75 mg / kg / day. All changes in parameters, including those that reached statistical significance, were not attributed to the administration of BPL-5MEO because they were small (within the normal physiological range), comparable to control values, and / or dose-independent.

[0455] There was a decrease in thymus weights (absolute weight and relative to terminal body weight) observed in male animals compared to control values, as shown in Table 13.

[0456] Table 13: Comparison of thymus weights of male animals with those of the control group

[0457]

[0458]

[0459] aFor the control group, organ weights are reported in grams, for the other groups, percentages compared to control values ​​are shown.

[0460] All changes in organ weight parameters, including those that reached statistical significance, were not attributable to the administration of BPL-5MeO as they were minor, comparable to control values, and / or independent of dose.

[0461] There were no microscopic findings associated with treatment with BPL-5MEO in rats in either of the primary recovery groups.

[0462] For animals in the main group, microscopic findings associated with treatment with BPL-5MEO were noted in nasal sections 1, 2, 3, and 4 of the main rats.

[0463] A range of minimal to mild changes were noted 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 greater in males compared to females and were proportional to the dose of BPL-5MEO.

[0464] Microscopic changes observed in rats dosed with 75 mg / kg / day of BPL-5MEO (Group 4) included minimal to mild degeneration, hyperplasia, and squamous metaplasia of the respiratory epithelium in nasal cavities 1, 2, 3, and / or 4, minimal mononuclear infiltration and / or luminal exudates; minimal hyperplasia of the transitional epithelium in nasal cavity 1; and minimal to mild degeneration and / or minimal mononuclear infiltration and erosion of the olfactory epithelium in nasal cavities 2, 3, and / or 4. Minimal degeneration of the olfactory epithelium of nasal cavities 2 and 3 was noted in male and / or female rats dosed with 5 mg / kg / day and / or 20 mg / kg / day of BPL-5MEO (Groups 2 and 3). Minimal degeneration of the respiratory epithelium of nasal cavities 1 and 2 was noted in male and / or female rats dosed with 20 mg / kg / day of BPL-5MEO (Group 3).

[0465] For animals in the recovery group, microscopic findings associated with treatment with BPL-5MEO were noted in nasal sections 1, 2, 3, and 4 of the recovery rats. Minimal to mild changes were noted in the respiratory epithelium and olfactory epithelium of nasal cavities 1, 2, 3, and / or 4. The incidence and severity of the changes were greater in males compared to females. Microscopic changes included minimal to mild degeneration of the respiratory epithelium in nasal cavities 1 and 2 and minimal degeneration of the olfactory epithelium in nasal cavities 2, 3, and 4, indicating an incomplete but progressive ongoing reversal of epithelial degeneration after a 14-day recovery period. After a 14-day recovery period, there was complete reversal of all other microscopic changes previously noted in the nasal cavities of the primary rats, including reversal of epithelial hyperplasia, squamous metaplasia, mononuclear infiltration, erosion, and luminal exudates.

[0466] Other microscopic findings in both the main and recovery groups were considered procedure-related or incidental because they were not dose-related, had a low incidence or severity, and / or because they were also seen in control animals.

[0467] Toxicokinetics

[0468] Across the dose range, exposure to 5MeODMT (based on the area under the plasma drug concentration-time curve [AUC 0-T最后 ] values) generally increased dose-dependently (except for Group 4 as stated below), but not always in a dose-proportional manner, as some increases were greater or less than dose-proportional between different doses. In addition, on Day 14, the exposure of Female Group 4 (75 mg / kg / day) was reduced compared to Female Group 3 (20 mg / kg / day).

[0469] The sex ratio ranged between 0.4 and 6.2, but because the sex ratio varied randomly between dose groups and sites, no sex-related differences were considered.

[0470] Cumulative ratios (based on AUC 0-T最后 ) showed that 5MeODMT did not accumulate when administered once daily by intranasal instillation at doses up to 75 mg / kg / day for 14 consecutive days (2 weeks) in Sprague Dawley rats.

[0471] The mean toxicokinetic parameters for Groups 2, 3, and 4 are presented in Table 14.

[0472] Table 14: Mean Toxicokinetic Parameters from Study 700041

[0473]

[0474]

[0475] Abbreviation: AUC 0-T最后 = Area under the plasma drug concentration-time curve from the time of dosing to the last quantifiable concentration; AUC INF_obs = the area under the plasma drug concentration-time curve extrapolated from the time of administration to infinity; C 最大 = maximum plasma concentration; h = hours; SE = standard error of the mean; t 1 / 2 = terminal elimination half-life; T 最大 = time to reach maximum plasma concentration.

[0476] in conclusion

[0477] BPL-5MEO was tolerated for 14 consecutive days with a dose level of ≤75 mg / kg / day intranasal administration, with no BPL-5MEO-related effects on mortality, ophthalmology, clinical chemistry, microscopic findings, and urinalysis. For both sexes, a slight dose-dependent inhibition of weight gain was observed. Transient clinical signs included incoordination, tremor (or tremor), increased or shallow breathing, pupil dilation, salivation, decreased activity, partially closed eyes, lying on the bottom of the cage, and sensitivity to touch. Male animals also showed penile erection. For both sexes, a slight dose-dependent increase in body temperature was observed.

[0478] The reduction of respiratory rate was observed at 20 minutes after administration, which resulted in a reduction in respiratory volume per minute. In the medium-dose group and the high-dose group, platelet, neutrophil, monocyte and basophil counts increased slightly in both sexes. In the medium-dose group (20mg / kg / day) and the high-dose group (75mg / kg / day), for both sexes of the main animals, APTT increased. The thymus weight (absolute weight and relative to terminal body weight) observed in male animals was reduced. Microscopic changes were noted in the nasal cavity 1, 2, 3 and / or 4 involving respiratory epithelium, olfactory epithelium and transitional epithelium. Compared with females, the incidence and severity found were greater in males, and were proportional to the dose of BPL-5MEO, with incomplete but progressive continuous reversal after a 14-day recovery period.

[0479] The NOAEL was reported for the lowest dose of 5 mg / kg.

[0480] b. 14-day repeat-dose intranasal toxicity study in dogs followed by a 14-day recovery period (Study 62959)

[0481] The objectives of this GLP study (Study 62959) were to determine the toxicity and TK profile of BPL-5MEO following intranasal instillation for 14 consecutive days in beagle dogs and to assess the persistence, delayed onset, or reversibility of any changes after a 14-day recovery period.

[0482] BPL-5MEO and control / vehicle were administered to groups of dogs once daily by intranasal instillation for 14 consecutive days as described in Table 15.

[0483] Table 15: Doses Administered in a 14-Day Repeat Dose Study in Dogs

[0484]

[0485] a Vehicle control animals were administered 0.1% hydroxypropylmethylcellulose (HPMC) in water.

[0486] b Dosage levels refer to the free base in the form of 5MeODMT salt.

[0487] c Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia, and aggression following dosing at a dose level of 2.5 mg / kg on Day 1. For Replicate B and Replicate C, the dose level was subsequently reduced to 1.5 mg / kg on Day 1. Replicate A received 1.5 mg / kg on Days 2 to 14.

[0488] d The dose volume administered to each animal was 10 μL / kg / nostril.

[0489] e Regardless of their body weight, all animals received a dose volume of no more than 100 μL / nostril.

[0490] The assessment of mortality, clinical signs, olfactory reflex, body weight, food consumption, ophthalmology and electrocardiogram was carried out. In addition, before treatment and when termination, clinical pathology assessment (hematology, coagulation, clinical chemistry and urinalysis) was also evaluated. On the 1st day and the 14th day, at up to 8 time points relative to treatment, blood samples were collected from the jugular vein of all animals for the analysis of test item concentration in plasma and the calculation of toxicokinetic parameters subsequently. After administration, euthanasia was performed on the 15th day main animal, and a complete autopsy was performed. The animal recovered was observed to continue other 14 days (without test article), and then euthanasia was performed on the 28th day and a complete autopsy was performed. All main research animals and recovery research animals experienced a complete autopsy, retained selected tissue / organ, and carried out a microscopic evaluation of a group of standard tissues.

[0491] For toxicokinetics, a series of 8 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 after treatment on each of the 1st and 14th days of the treatment period. For Group 1, only one sample was collected 15 minutes after dosing on the 1st and 14th days to confirm the absence of BPL-5MEO in the animals of the vehicle control group. The BPL-5MEO concentration in the plasma of the blood samples was analyzed and used for the calculation of the subsequent TK parameters.

[0492] result

[0493] All dose formulation samples collected and analyzed met the acceptance criteria for accuracy (100% ± 10% of their nominal concentration).

[0494] The daily intranasal administration of BPL-5MEO to the two nostrils of beagle dogs for 14 consecutive days at a dosage level of up to 1.5mg / kg / day did not cause any mortality. The high-dose animals were initially given a subset of dogs with 2.5mg / kg, and on the 1st day, after administration, muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia and severe clinical signs of aggression were shown, and the dosage exceeded the MTD. The high dose was subsequently reduced to 1.5mg / kg / day on the 2nd day, and the dosage was tolerated. The animals in all treatment groups showed the short-term clinical observations of incoordination, vocalization, pupil dilation, reduced or increased activity, increased breathing, gnawing cage wires, excessive licking of the nose or lips and circling. In addition, eye discharge and trembling were observed in the medium-dose group and the high-dose group. Penile erection was also recorded for high-dose male animals. All these clinical signs are considered to be pharmacological manifestations of aggravation, occurring within 10 minutes to 30 minutes of administration, and disappearing within 90 minutes.

[0495] When compared to the control group, 1 / 3 of the Group 3 females, 1 / 5 of the Group 4 males, and 4 / 5 of the Group 4 females had increased triglyceride levels, these data are presented in Table 16. There were no other treatment-related clinical pathological findings.

[0496] Table 16: Mean ± SD of triglyceride values ​​on day 14 compared with the control group

[0497]

[0498] Abbreviation: SD = standard deviation

[0499] aFor the control group, the control values ​​are mentioned, and for the other groups, the percentages compared to the control values ​​are shown.

[0500] b Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia, and aggression following dosing at a dose level of 2.5 mg / kg on Day 1. For Replicate B and Replicate C, the dose level was subsequently reduced to 1.5 mg / kg on Day 1. Replicate A received 1.5 mg / kg on Days 2-14.

[0501] All other changes in clinical chemistry parameters, including those that achieved statistical significance, were not attributable to administration of BPL-5MEO as they were minor (within the normal physiological range), comparable to control values, and / or were not dose related.

[0502] There were no changes in olfactory reflexes, food consumption, body weight, ocular effects, or ECG that could be clearly attributed to treatment with BPL-5MEO at dose levels of ≤1.5 mg / kg / day for 14 days. All body weight changes were not attributed to the administration of the test items because they were minor and toxicologically irrelevant. All food consumption changes, including those with statistical significance, were not attributed to the administration of the test items because they were minor and toxicologically irrelevant.

[0503] Animals showed hyperthermia at the 2.5 mg / kg / day dose level on Day 1. On Day 14, transient temperature increases were observed in both sexes at 15 and 30 minutes post-dose for the high dose group. All other changes in body temperature were not attributed to administration of the test item as they were minor and toxicologically irrelevant.

[0504] Histopathological findings in the main animals included minimal to moderate decreased cellularity of thymic lymphocytes at the 0.8 mg / kg / day (1 male) and 1.5 mg / kg / day (3 males) dose levels, which was determined to be stress-related. Minimal epithelial metaplasia of the respiratory epithelium in the nasal cavity found at the 0.8 mg / kg / day (1 female) and 1.5 mg / kg / day (2 males) dose levels and minimal to mild mononuclear cell infiltration of the olfactory epithelium in the nasal cavity observed at the 1.5 mg / kg / day (1 male / 1 female) dose level were considered signs of irritation caused by BPL-5MEO, but not adverse.

[0505] In animals euthanized after a 14-day recovery period, at the 1.5 mg / kg / day dose level (1 female), only minimal mononuclear cell infiltration of the olfactory epithelium in the nasal cavity remained, but at a lower severity when compared to terminally euthanized animals, indicating recovery. Reduced cellularity of thymic lymphocytes was no longer observed.

[0506] Toxicokinetics

[0507] On days 1 and 14, BPL-5MEO was not detected in any samples collected from control (Group 1) animals.

[0508] The mean toxicokinetic parameters for Groups 2, 3, and 4 are presented in the table below.

[0509] Mean Toxicokinetic Parameters from Study 62959

[0510]

[0511] Abbreviation: AUC 0-T最后= Area under the plasma drug concentration-time curve from the time of dosing to the last quantifiable concentration; AUC INF_obs = the area under the plasma drug concentration-time curve extrapolated from the time of administration to infinity; C 最大 = maximum plasma concentration; h = hour; t 1 / 2 = terminal elimination half-life; T 最大 = time to reach maximum plasma concentration.

[0512] a Replicate A high dose animals showed severe clinical signs of muscle stiffness (rigidity), tachycardia, tachypnea, hyperthermia, and aggression following dosing at a dose level of 2.5 mg / kg on Day 1. For Replicate B and Replicate C, the dose level was subsequently reduced to 1.5 mg / kg on Day 1. Replicate A received 1.5 mg / kg on Days 2-14.

[0513] Across the dose range, exposure to BPL-5MEO (based on AUC 0-T最后 The values ​​(values) generally increased dose-dependently (except for Group 4 as stated below), but not always in a dose-proportional manner, as some increases were greater or less than dose-proportional between different doses. In addition, on Day 14, exposure was reduced in Group 4 (1.5 mg / kg / day) compared to Group 3 (0.8 mg / kg / day).

[0514] There were no significant sex-related differences in any of the measured toxicokinetic parameters except on Day 14, where T 最大 It occurred slightly later in group 4 males. 最大 Otherwise, the sex ratio (male / female) ranged sporadically from 0.5 to 1.7 on days 1 and 14.

[0515] Cumulative ratios (based on AUC 0-T最后 ) showed that BPL-5MEO did not accumulate when administered once daily by intranasal instillation in beagle dogs at doses up to 1.5 mg / kg / day for 14 consecutive days (2 weeks).

[0516] in conclusion

[0517] Based on the parameters examined with all changes noted considered to be non-adverse or related to exaggerated pharmacological effects, the reported NOAEL for BPL-5MEO when administered via intranasal administration for 14 consecutive days followed by a 14-day recovery period is believed to be 1.5 mg / kg / day, corresponding to a C of 421 ng / mL. 最大 and AUC of 213(220)h*ng / mL 0-T最后(AUC INF_obs )(combination of both genders).

[0518] Toxicokinetic considerations

[0519] Based on preliminary data from another ongoing study in dogs, it has been observed that the blood sampling site in dogs may affect the measured plasma exposure. Samples from the jugular vein may result in higher apparent exposure levels than samples from the cephalic vein, which may be due to local transmucosal administration routes (also reported in the scientific literature (Illum, 2003; Sohlberg, 2013)). Therefore, the dose escalation criteria for the Phase 1 single ascending dose study are based on the evaluation of clinical criteria, safety factors and exposure. The maximum dose of 14 mg has been specified. The table below summarizes the clinical observations in the toxicity studies of rats and dogs conducted with BPL-5MEO. These clinical signs are considered to be related to the pharmacological activity of BPL-5MEO, and confirm the discovery of dose-related increases in the severity of both species, usually in dogs with 0.4 mg / kg to 1.5 mg / kg and in rats with 1.5 mg / kg to 5 mg / kg ranging from mild to moderate.

[0520] Summary of clinical observations from applicant-sponsored animal studies

[0521]

[0522]

[0523] Abbreviation: HED = Human Equivalent Dose (for a 60 kg human)

[0524] a = NOAEL determined in a 14-day toxicology study for both species.

[0525] b = preliminary data, ongoing studies (mild tremor observed at 1.0 mg / kg = 33 mg HED)

[0526] NOTE: These signs are of short duration and usually resolve within one to two hours in both species.

[0527] Example 14: Genotoxicity

[0528] Following ICH S2(R1) guidelines, the genotoxic potential of 5MeODMT was evaluated via in silico (computational analysis) for structural alerts and in vitro in a GLP assay to assess mutagenic and clastogenic potential.

[0529] Through bioinformatics

[0530] Quantitative structure activity relationships for the mutagenic and / or carcinogenic potential of 5MeODMT, its major active metabolite toad tryptamine, and the identified drug substance impurity MW 234 were evaluated using two computational analysis approaches, Derek Nexus and Leadscope Genetox statistical models. The evaluations from both analyses did not identify any structural alerts related to 5MeODMT or toad tryptamine, nor did they identify a possible or identified drug substance impurity MW 234.

[0531] In vitro mutagenicity

[0532] The mutagenic potential of 5MeODMT was evaluated for the following in the GLP bacterial reverse mutation test (Ames test): the ability to induce reverse mutations in the selected loci of the Salmonella typhimurium test strains TA98, TA100, TA1535 and TA1537 and the Escherichia coli test strain WP2uvrA. These strains were treated with 5MeODMT at a concentration of 1.6 μg, 5 μg, 16 μg, 50 μg, 160 μg, 500 μg, 1600 μg and 5000 μg per plate together with vehicle / negative control and appropriate positive control. In the absence and presence of an exogenous metabolic activation system phenobarbital / 5,6-benzoflavone-induced rat liver S9 microsomal enzyme mixture (S9 mixture), the pre-incubation method was used to measure in triplicate.

[0533] At a concentration of 1600 μg / plate, slight cytotoxicity was observed in all S. typhimurium strains. Although higher levels of cytotoxicity were observed at 5000 μg / plate in the absence of the S9 mixture, cytotoxicity was still slight in the presence of the S9 mixture in these strains. No cytotoxicity was noted in the E. coli strains in the absence or presence of the S9 mixture.

[0534] Overall, no increase in the number of revertant colonies per plate (≥2× of vehicle / negative value) was observed using 5MeODMT in either the absence and presence of S9 in S. Typhimurium test strains TA1535, TA100, E. coli WP2uvrA, or TA1537 and TA98 in the presence of the S9 mixture. The three exceptions were a 2.1-fold increase at 1600 μg / plate observed in E. coli WP2uvrA without S9, a 2.0-fold increase at 50 μg / plate in S. Typhimurium TA1537 with S9, and a 2.1-fold increase at 1600 μg / plate in S. Typhimurium TA1535 with S9. However, these values ​​are not considered biologically relevant because they are within the laboratory's historical vehicle / negative control range and are independent of dose.

[0535] In the absence of the S9 mixture, two strains of the 5MeODMT-treated Salmonella typhimurium strains, TA1537 and TA98, showed a number of revertant colony counts slightly higher than twice the vehicle value / negative value at 160 μg / plate and 500 μg / plate, with a fold increase of 2.3 and 2.7 times in TA1537 and a fold increase of 2.2 and 2.4 times in TA98. The increased colony counts observed in these strains were still within the laboratory's historical vehicle / negative control range and were independent of the overall dose; therefore, they did not meet the criteria for a positive result. However, because increases were observed in TA98 and TA1537 at 2 adjacent dose levels and these two strains showed a similar increasing trend in revertant colony counts at the same concentration level, the results were judged to be equivocal. Therefore, the bacterial reverse mutation test was repeated for these two strains in the absence of the S9 mixture in order to investigate these equivocal results. Repeat testing used a narrower concentration range of 15 μg, 30 μg, 60 μg, 120 μg, 250 μg, 500 μg, 1000 μg and 2000 μg per plate. Results from the repeat testing showed that at all concentration levels tested up to the maximum dose of 2000 μg / plate, there was no increase in the number of revertant colonies per plate for both strains treated with 5MeODMT. Therefore, it was concluded that the small increase observed in the first test of the Salmonella typhimurium test strains TA 1537 and TA98 was not biologically relevant.

[0536] In summary, the results of the bacterial reverse mutation assay indicate that 5MeODMT did not induce any increase in the number of revertant colonies of any tested bacterial strain in the absence or presence of the rat liver S9 microsomal metabolic activation system. 5MeODMT has no mutagenic potential in the bacterial reverse mutation assay. The expected responses of the positive and negative controls confirm the sensitivity and effectiveness of the assay.

[0537] In vitro clastogenicity

[0538] Flow cytometry was used to evaluate the clastogenic potential of 5MeODMT in a GLP in vitro micronucleus test using Chinese hamster ovary (CHO)-K1 cells. Exponentially growing cells were treated in duplicate with 9 concentrations of 5MeODMT up to the recommended upper limit of 1 mM (corresponding to about 300 μg / mL): 1.25 μg / mL, 2.5 μg / mL, 5.0 μg / mL, 10 μg / mL, 20 μg / mL, 40 μg / mL, 80 μg / mL, 150 μg / mL, and 300 μg / mL. Treatment with vehicle / negative control and positive control was performed simultaneously. There were 3 treatment schemes: a short exposure of 4 hours in either the absence or presence of an exogenous metabolic activation system phenobarbital / 5,6-benzoflavone rat liver S9 microsomal enzyme mixture (S9 mixture), and an extended exposure of 26 hours considered as a confirmation stage in the absence of an S9 mixture.

[0539] In the whole treatment period, no cytotoxicity or precipitation was observed in the cells processed by 5MeODMT at the maximum dose level of up to 300 μ g / mL. In all treatment schemes, the results of the in vitro micronucleus test indicated that 5MeODMT did not induce any increase in micronucleus cells or hypodiploid cells in the absence or presence of either rat liver S9 microsomal metabolic activation system. In a word, 5MeODMT did not show chromosome damage potential in the in vitro micronucleus test using CHO-K1 cells. The expected response of the positive control and the negative control confirmed the sensitivity and effectiveness of the assay.

[0540] Reproductive and developmental toxicity

[0541] Reproductive and developmental toxicity studies have not been conducted. In the 14-day pivotal GLP intranasal toxicity studies in rats and dogs, there was no evidence of adverse effects on reproductive tissues following systemic exposure to BPL-5MEO.

[0542] Example 15: Formulation

[0543] BPL-5MEO has been synthesized according to good manufacturing practice (GMP) standards and pre-filled into the Aptar Unidose intranasal liquid delivery system device. The device allows a single fixed dose of BPL-5MEO to be administered intranasally. The liquid is pre-filled and administered using a standard single unit dose nasal pump device. The excipients used in the formulation are water, 0.1% hydroxypropyl methylcellulose (HPMC) and sodium hydroxide (NaOH). Two concentrations of formulations will be used, 70 mg / mL (for dosage levels lower than 7 mg) and 140 mg / mL (for dosage levels higher than 7 mg).

[0544] In an embodiment, a composition comprising 5MeODMT hydrochloride is provided, wherein the composition comprises:

[0545] -water;

[0546] -0.1% Hydroxypropyl methylcellulose (HPMC);

[0547] - 0.1% sodium hydroxide (NaOH); and

[0548] -70mg / ml 5MeODMT.

[0549] In an embodiment, a composition comprising 5MeODMT benzoate is provided, wherein the composition comprises:

[0550] -water;

[0551] -0.1% Hydroxypropyl methylcellulose (HPMC);

[0552] - 0.1% sodium hydroxide (NaOH); and

[0553] -70mg / ml 5MeODMT.

[0554] In an embodiment, a composition comprising 5MeODMT hydrochloride is provided, wherein the composition comprises:

[0555] -water;

[0556] -0.1% Hydroxypropyl methylcellulose (HPMC);

[0557] - 0.1% sodium hydroxide (NaOH); and

[0558] -140mg / ml 5MeODMT.

[0559] In an embodiment, a composition comprising 5MeODMT benzoate is provided, wherein the composition comprises:

[0560] -water;

[0561] -0.1% Hydroxypropyl methylcellulose (HPMC);

[0562] - 0.1% sodium hydroxide (NaOH); and

[0563] -140mg / ml 5MeODMT.

[0564] In an embodiment, an intranasal composition comprising 5MeODMT hydrochloride is provided, wherein the composition comprises:

[0565] -water;

[0566] -0.1% Hydroxypropyl methylcellulose (HPMC);

[0567] - 0.1% sodium hydroxide (NaOH); and

[0568] -70mg / ml 5MeODMT.

[0569] In an embodiment, an intranasal composition comprising 5MeODMT benzoate is provided, wherein the composition comprises:

[0570] -water;

[0571] -0.1% Hydroxypropyl methylcellulose (HPMC);

[0572] - 0.1% sodium hydroxide (NaOH); and

[0573] -70mg / ml 5MeODMT.

[0574] In an embodiment, an intranasal composition comprising 5MeODMT hydrochloride is provided, wherein the composition comprises:

[0575] -water;

[0576] -0.1% Hydroxypropyl methylcellulose (HPMC);

[0577] - 0.1% sodium hydroxide (NaOH); and

[0578] -140mg / ml 5MeODMT.

[0579] In an embodiment, an intranasal composition comprising 5MeODMT benzoate is provided, wherein the composition comprises:

[0580] -water;

[0581] -0.1% Hydroxypropyl methylcellulose (HPMC);

[0582] - 0.1% sodium hydroxide (NaOH); and

[0583] -140mg / ml 5MeODMT.

[0584] In embodiments, the composition comprises 25 mg / mL-400 mg / mL; 25 mg / mL-300 mg / mL; 25 mg / mL-200 mg / mL; 25 mg / mL-100 mg / mL; 25 mg / mL-50 mg / mL; 50 mg / mL-400 mg / mL; 50 mg / mL-300 mg / mL; 60 mg / mL-400 mg / mL; 60 mg / mL-300 mg / mL; 150 mg / mL-400 mg / mL; L; 150mg / mL-300mg / mL; 200mg / mL-300mg / mL; 200mg / mL-400mg / mL; 30mg / mL-100mg / mL; 300mg / mL-400mg / mL; 300mg / mL-500mg / mL; 45mg / mL-75mg / mL; 50mg / mL-70mg / mL; 55mg / mL-65mg / mL; or 50mg / mL-60mg / mL of 5MeODMT.

[0585] In an embodiment, an intranasal liquid delivery system of a composition comprising 5MeODMT is provided.

[0586] In an embodiment, a single unit dose capsule of a composition of 5 MeODMT is provided.

[0587] In an embodiment, an intranasal composition is provided comprising 5MeODMT in a dosage amount of 50 mg / ml-150 mg / ml in a liquid medium, wherein the 5MeODMT is formulated as a benzoate salt of 5MeODMT (5MeODMT benzoate).

[0588] In an embodiment, 5MeODMT benzoate is present as a suspension or emulsion in a liquid medium.

[0589] In an embodiment, an intranasal liquid delivery system is provided, comprising:

[0590] - 70 mg / ml to 140 mg / ml of 5MeODMT benzoate as a suspension or emulsion in a liquid medium.

[0591] Example 16: Administration

[0592] BPL-5MEO was administered to subjects by a trained member of the research team using a single unit dose pump sprayer. This unit contains only 1 sprayer, so it should not be tested before use. While sitting, subjects were asked to blow their nose to clear the nasal passages. Once the tip of the device was placed in the nostril, the clinic staff would press the piston to release the dose.

[0593] In an embodiment, a method for administering 5MeODMT is provided, the method comprising administering 5MeODMT as an intranasal spray to a human subject, wherein the human subject has followed patient preparation parameters including blowing their nose to clear their nasal passages immediately prior to administration.

[0594] In an embodiment, the human subject is seated.

[0595] In an embodiment, a method for delivering 5MeODMT to the brain of a human subject is provided, the method comprising administering 5MeODMT to the human subject as an intranasal spray, wherein the human subject has followed patient preparation parameters including blowing their nose to clear their nasal passages immediately prior to administration.

[0596] Example 17: X-ray powder diffraction (XRPD) of 5MeODMT benzoate

[0597] The XRPD patterns of 5MeODMT benzoate were obtained before and after particle size reduction with a mortar and pestle. This reduced the intensity of the main diffraction and revealed that the XRPD pattern of the benzoate tended to have a preferred orientation before particle size reduction, which changes with the habit and particle size of the material. The XRPD patterns of the benzoate before and after particle size reduction can be found at Figure 6 and Figure 7 The XRPD patterns of the benzoate salt before and after particle size reduction superimposed on each other can be seen in Figure 8 Seen in.

[0598] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, and 21.0°2θ±0.1°2θ.

[0599] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, and 21.0°2θ±0.2°2θ.

[0600] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.3°2θ, 17.7°2θ±0.3°2θ, and 21.0°2θ±0.3°2θ.

[0601] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, and 21.0°2θ±0.1°2θ, as determined by using The wavelength of the x-rays measured by x-ray powder diffraction.

[0602] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, and 21.0°2θ±0.2°2θ, as determined by using The wavelength of the x-rays measured by x-ray powder diffraction.

[0603] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.3°2θ, 17.7°2θ±0.3°2θ, and 21.0°2θ±0.3°2θ, as determined by using The wavelength of the x-rays measured by x-ray powder diffraction.

[0604] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, 21.0°2θ±0.1°2θ, and 25.3°2θ±0.1°2θ.

[0605] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, 21.0°2θ±0.2°2θ, and 25.3°2θ±0.2°2θ.

[0606] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.3°2θ, 17.7°2θ±0.3°2θ, 21.0°2θ±0.3°2θ, and 25.3°2θ±0.3°2θ.

[0607] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, 21.0°2θ±0.1°2θ, and 25.3°2θ±0.1°2θ, as determined by using The wavelength of the x-rays measured by x-ray powder diffraction.

[0608] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, 21.0°2θ±0.2°2θ, and 25.3°2θ±0.2°2θ, as determined by using The wavelength of the x-rays measured by x-ray powder diffraction.

[0609] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 17.5°2θ±0.3°2θ, 17.7°2θ±0.3°2θ, 21.0°2θ±0.3°2θ, and 25.3°2θ±0.3°2θ, as determined by using The wavelength of the x-rays measured by x-ray powder diffraction.

[0610] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.1°2θ, 11.5°2θ±0.1°2θ, 14.5°2θ±0.1°2θ, 16.5°2θ±0.1°2θ, 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, 18.5°2θ±0.1°2θ, 21.0°2θ±0.1°2θ, 22.7°2θ±0.1°2θ, 24.7°2θ±0.1°2θ, and 25.3°2θ±0.1°2θ.

[0611] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.2°2θ, 11.5°2θ±0.2°2θ, 14.5°2θ±0.2°2θ, 16.5°2θ±0.2°2θ, 17.5°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, 18.5°2θ±0.2°2θ, 21.0°2θ±0.2°2θ, 22.7°2θ±0.2°2θ, 24.7°2θ±0.2°2θ, and 25.3°2θ±0.2°2θ.

[0612] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.3°2θ, 11.5°2θ±0.3°2θ, 14.5°2θ±0.3°2θ, 16.5°2θ±0.3°2θ, 17.5°2θ±0.3°2θ, 17.7°2θ±0.3°2θ, 18.5°2θ±0.3°2θ, 21.0°2θ±0.3°2θ, 22.7°2θ±0.3°2θ, 24.7°2θ±0.3°2θ, and 25.3°2θ±0.3°2θ.

[0613] In embodiments, a crystalline 5MeODMT benzoate salt is provided characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.1°2θ, 11.5°2θ±0.1°2θ, 14.5°2θ±0.1°2θ, 16.5°2θ±0.1°2θ, 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, 18.5°2θ±0.1°2θ, 21.0°2θ±0.1°2θ, 22.7°2θ±0.1°2θ, 24.7°2θ±0.1°2θ, and 25.3°2θ±0.1°2θ. The wavelength of the x-rays measured by x-ray powder diffraction.

[0614] In embodiments, a crystalline 5MeODMT benzoate salt is provided characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.2°2θ, 11.5°2θ±0.2°2θ, 14.5°2θ±0.2°2θ, 16.5°2θ±0.2°2θ, 17.5°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, 18.5°2θ±0.2°2θ, 21.0°2θ±0.2°2θ, 22.7°2θ±0.2°2θ, 24.7°2θ±0.2°2θ, and 25.3°2θ±0.2°2θ. The wavelength of the x-rays measured by x-ray powder diffraction.

[0615] In embodiments, a crystalline 5MeODMT benzoate salt is provided characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.3°2θ, 11.5°2θ±0.3°2θ, 14.5°2θ±0.3°2θ, 16.5°2θ±0.3°2θ, 17.5°2θ±0.3°2θ, 17.7°2θ±0.3°2θ, 18.5°2θ±0.3°2θ, 21.0°2θ±0.3°2θ, 22.7°2θ±0.3°2θ, 24.7°2θ±0.3°2θ, and 25.3°2θ±0.3°2θ. The wavelength of the x-rays measured by x-ray powder diffraction.

[0616] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.1°2θ, 11.5°2θ±0.1°2θ, 14.5°2θ±0.1°2θ, 16.3°2θ±0.1°2θ, 16.5°2θ±0.1°2θ, 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, 18.5°2θ±0.1°2θ, 21.0°2θ±0.1°2θ, 22.7°2θ±0.1°2θ, 24.7°2θ±0.1°2θ, 25.3°2θ±0.1°2θ, and 30.5°2θ±0.1°2θ.

[0617] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.2°2θ, 11.5°2θ±0.2°2θ, 14.5°2θ±0.2°2θ, 16.3°2θ±0.2°2θ, 16.5°2θ±0.2°2θ, 17.5°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, 18.5°2θ±0.2°2θ, 21.0°2θ±0.2°2θ, 22.7°2θ±0.2°2θ, 24.7°2θ±0.2°2θ, 25.3°2θ±0.2°2θ, and 30.5°2θ±0.2°2θ.

[0618] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.3°2θ, 11.5°2θ±0.3°2θ, 14.5°2θ±0.3°2θ, 16.3°2θ±0.3°2θ, 16.5°2θ±0.3°2θ, 17.5°2θ±0.3°2θ, 17.7°2θ±0.3°2θ, 18.5°2θ±0.3°2θ, 21.0°2θ±0.3°2θ, 22.7°2θ±0.3°2θ, 24.7°2θ±0.3°2θ, 25.3°2θ±0.3°2θ, and 30.5°2θ±0.3°2θ.

[0619] In embodiments, a crystalline 5MeODMT benzoate salt is provided characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.1°2θ, 11.5°2θ±0.1°2θ, 14.5°2θ±0.1°2θ, 16.3°2θ±0.1°2θ, 16.5°2θ±0.1°2θ, 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, 18.5°2θ±0.1°2θ, 21.0°2θ±0.1°2θ, 22.7°2θ±0.1°2θ, 24.7°2θ±0.1°2θ, 25.3°2θ±0.1°2θ, and 30.5°2θ±0.1°2θ. The wavelength of the x-rays measured by x-ray powder diffraction.

[0620] In embodiments, a crystalline 5MeODMT benzoate salt is provided characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.2°2θ, 11.5°2θ±0.2°2θ, 14.5°2θ±0.2°2θ, 16.3°2θ±0.2°2θ, 16.5°2θ±0.2°2θ, 17.5°2θ±0.2°2θ, 17.7°2θ±0.2°2θ, 18.5°2θ±0.2°2θ, 21.0°2θ±0.2°2θ, 22.7°2θ±0.2°2θ, 24.7°2θ±0.2°2θ, 25.3°2θ±0.2°2θ, and 30.5°2θ±0.2°2θ. The wavelength of the x-rays measured by x-ray powder diffraction.

[0621] In embodiments, a crystalline 5MeODMT benzoate salt is provided characterized by peaks in an XRPD diffraction pattern at 9.0°2θ±0.3°2θ, 11.5°2θ±0.3°2θ, 14.5°2θ±0.3°2θ, 16.3°2θ±0.3°2θ, 16.5°2θ±0.3°2θ, 17.5°2θ±0.3°2θ, 17.7°2θ±0.3°2θ, 18.5°2θ±0.3°2θ, 21.0°2θ±0.3°2θ, 22.7°2θ±0.3°2θ, 24.7°2θ±0.3°2θ, 25.3°2θ±0.3°2θ, and 30.5°2θ±0.3°2θ. The wavelength of the x-rays measured by x-ray powder diffraction.

[0622] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that Figure 6 , Figure 7 or Figure 8 The peaks in the XRPD diffraction pattern are generally shown in FIG.

[0623] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that Figure 6 The peaks in the XRPD diffraction pattern are generally shown in FIG.

[0624] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that Figure 7 The peaks in the XRPD diffraction pattern are generally shown in FIG.

[0625] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that Figure 8 The peaks in the XRPD diffraction pattern are generally shown in FIG.

[0626] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0627] - peaks in the XRPD diffractogram as described previously or subsequently;

[0628] - an endothermic event in a DSC thermogram as previously or subsequently described;

[0629] - onset of decomposition in a TGA thermogram as described previously or subsequently;

[0630] - a DVS isotherm profile as previously or subsequently described; and

[0631] - a crystalline structure as previously or subsequently described.

[0632] Example 18: Thermal Analysis of 5MeODMT Benzoate

[0633] The differential scanning calorimetry (DSC) thermogram of 5MeODMT benzoate contains one endotherm with an onset temperature of 123.34°C, a peak of 124.47°C, and an enthalpy of 134.72 J / g. No other thermal events were present. The DSC thermogram obtained at 10°C / min can be found at Fig. 9 Seen in.

[0634] In an embodiment, a crystalline 5MeODMT benzoate salt is provided characterized by an endothermic event in a DSC thermogram having an onset temperature between 120°C and 130°C.

[0635] In embodiments, a crystalline 5MeODMT benzoate salt is provided, characterized in that the endothermic event in the DSC thermogram has an onset temperature between 120°C and 130°C, such as Fig. 9 As roughly shown in the figure.

[0636] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that an endothermic event in a DSC thermogram has an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C.

[0637] In embodiments, a crystalline 5MeODMT benzoate salt is provided, characterized in that the endothermic event in the DSC thermogram has an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C, such as Fig. 9 As roughly shown in the figure.

[0638] In an embodiment, a crystalline 5MeODMT benzoate salt is provided characterized by an endothermic event in a DSC thermogram having an onset temperature of 123°C.

[0639] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that the endothermic event in the DSC thermogram has an onset temperature of 123°C, such as Fig. 9 As roughly shown in the figure.

[0640] In an embodiment, a crystalline 5MeODMT benzoate salt is provided characterized by an endothermic event in a DSC thermogram having an onset temperature of 124°C.

[0641] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that the endothermic event in the DSC thermogram has an onset temperature of 124°C, such as Fig. 9 As roughly shown in the figure.

[0642] In an embodiment, a crystalline 5MeODMT benzoate salt is provided characterized by an endothermic event in a DSC thermogram having an onset temperature between 120°C and 130°C and a peak between 122°C and 128°C.

[0643] In embodiments, a crystalline 5MeODMT benzoate salt is provided, characterized in that the endothermic event in the DSC thermogram has an onset temperature between 120°C and 130°C and a peak temperature between 122°C and 128°C, such as Fig. 9 As roughly shown in the figure.

[0644] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that an endothermic event in a DSC thermogram has an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, and a peak between 124°C and 126°C.

[0645] In embodiments, a crystalline 5MeODMT benzoate salt is provided, characterized in that an endothermic event in a DSC thermogram has an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, and a peak temperature between 124°C and 126°C, such as Fig. 9 As roughly shown in the figure.

[0646] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that an endothermic event in a DSC thermogram has an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, and a peak temperature between 124°C and 126°C and an enthalpy between -130 J / g and -140 J / g.

[0647] In embodiments, a crystalline 5MeODMT benzoate salt is provided, characterized in that an endothermic event in a DSC thermogram has an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, and a peak temperature between 124°C and 126°C and an enthalpy between -130 J / g and -140 J / g, such as Fig. 9 As roughly shown in the figure.

[0648] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that an endothermic event in a DSC thermogram has an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, and a peak temperature between 124°C and 126°C and an enthalpy between -130 J / g and -135 J / g.

[0649] In embodiments, a crystalline 5MeODMT benzoate salt is provided, characterized in that an endothermic event in a DSC thermogram has an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, and a peak temperature between 124°C and 126°C and an enthalpy between -130 J / g and -135 J / g, such as Fig. 9 As roughly shown in the figure.

[0650] Thermogravimetric analysis (TGA) thermogram of 5MeODMT benzoate revealed that the onset of decomposition was about 131°C, which exceeded melting at about 125°C. The TGA thermogram obtained at 10°C / min was Fig.10 It can be seen in.

[0651] In embodiments, a crystalline 5MeODMT benzoate salt is provided characterized by a decomposition onset in a TGA thermogram between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C, or between 130°C and 132°C.

[0652] In embodiments, a crystalline 5MeODMT benzoate salt is provided characterized by a decomposition onset between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C, or between 130°C and 132°C in a TGA thermogram, such as Fig.10 As roughly shown in the figure.

[0653] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by a decomposition onset of 131°C in the TGA thermogram.

[0654] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that Fig.10 The decomposition onset is 131° C. in the TGA thermogram generally illustrated in FIG.

[0655] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0656] - an endothermic event in the DSC thermogram having an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C; and

[0657] - onset of decomposition between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C or between 130°C and 132°C in the TGA thermogram.

[0658] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0659] - an endothermic event in the DSC thermogram having an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C, such as Fig. 9 as generally shown in the diagram; and

[0660] - onset of decomposition between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C or between 130°C and 132°C in the TGA thermogram, such as Fig.10 As roughly shown in the figure.

[0661] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0662] - an endothermic event in the DSC thermogram with an onset temperature of 123°C; and

[0663] - Decomposition onset at 131°C in the TGA thermogram.

[0664] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0665] - an endothermic event in the DSC thermogram having an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C, and a peak between 124°C and 126°C; and

[0666] - onset of decomposition between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C or between 130°C and 132°C in the TGA thermogram.

[0667] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0668] - an endothermic event in the DSC thermogram having an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C, and a peak between 124°C and 126°C, such as Fig. 9 as generally shown in the diagram; and

[0669] - onset of decomposition between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C or between 130°C and 132°C in the TGA thermogram, such as Fig.10 As roughly shown in the figure.

[0670] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0671] - an endothermic event in the DSC thermogram with an onset temperature of 123°C, a peak temperature of 124°C; and

[0672] - Decomposition onset at 131°C in the TGA thermogram.

[0673] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0674] - The endothermic event in the DSC thermogram has an onset temperature of 123°C, a peak temperature of 124°C, such as Fig. 9 as generally shown in the diagram; and

[0675] -Decomposition onset at 131°C in the TGA thermogram, such as Fig.10 As roughly shown in the figure.

[0676] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0677] - an endothermic event in the DSC thermogram having an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C, a peak between 124°C and 126°C and an enthalpy between -130 J / g and -140 J / g; and

[0678] - onset of decomposition between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C or between 130°C and 132°C in the TGA thermogram.

[0679] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0680] - Endothermic events in the DSC thermogram have onset temperatures between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C, peaks between 124°C and 126°C and enthalpies between -130 J / g and -140 J / g, such as Fig. 9 as generally shown in the diagram; and

[0681] - onset of decomposition between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C or between 130°C and 132°C in the TGA thermogram, such as Fig.10 As roughly shown in the figure.

[0682] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0683] - an endothermic event in the DSC thermogram with an onset temperature of 123°C, a peak of 124°C and an enthalpy of -135 J / g; and

[0684] - Decomposition onset at 131°C in the TGA thermogram.

[0685] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0686] -The endothermic event in the DSC thermogram has an onset temperature of 123°C, a peak of 124°C, and an enthalpy of -135 J / g, as Fig. 9 as generally shown in the diagram; and

[0687] -Decomposition onset at 131°C in the TGA thermogram, such as Fig.10 As roughly shown in the figure.

[0688] The combined TGA / DSC thermogram obtained at 10°C / min can be found at Fig.11 Seen in.

[0689] Example 19: Dynamic Vapor Sorption (DVS) of 5MeODMT Benzoate

[0690] The DVS profile of 5MeODMT benzoate reveals reversible water uptake / loss over a range of humidity with no hysteresis. The water uptake / loss from 0% to 90% is gradual and totals to a maximum of about 0.20% and is a result of solid wetting. There is no evidence of form / version changes due to exposure of 5MeODMT benzoate to variable humidity. The DVS isotherm can be found at Fig.12 Seen in.

[0691] The DVS isotherm of 5MeODMT hydrochloride batch 20 / 20 / 126-FP was found to be Fig.17 ) experienced significant moisture uptake after the first adsorption cycle starting at 70% RH. About 23% w / w uptake was observed between 70% RH-80% RH, while less than 0.3% w / w moisture uptake was observed from 0% RH-70% RH. Before the second desorption cycle began, an additional 20% w / w moisture uptake was observed until and when maintained at 90% RH. Subsequent adsorption and desorption cycles followed a similar profile with some observed hysteresis between operations that did not match the original desorption step. These returned to about 6% w / w-9% w / w above the minimum mass recorded at 0% RH, indicating significant retention of moisture. After completing the DVS cycle, it was noted that the input material had completed deliquescence.

[0692] An altered DVS isotherm of batch 20 / 45 / 006-FP (same crystalline modification) was performed to examine the material behavior starting at 60% RH and above. 2 cycles of DVS with desorption starting from 40% RH - 0% RH and adsorption from 0% RH - 60% RH at 10% RH intervals followed by incremental 5% RH increases to 65% RH, 70% RH, 75% RH, 80% RH and finally to 85% RH. This was to obtain an in-depth profiling of the material for these elevated levels of humidity.

[0693] Note that there is no significant water uptake / loss in the first desorption-adsorption profile between 0% RH-70% RH ( Fig.18 ), followed by an increase of about 0.46% w / w from 70% RH-75% RH. An additional about 7% absorption was observed from 75% RH-80% RH, and then about 40% absorption was observed from 80% RH-85% RH. Complete deliquescence of the solid was observed when the material was separated after DVS analysis, which may occur above 80% RH.

[0694] Temperature and humidity are important factors in the processing and storage of pharmaceuticals. DVS provides a versatile and sensitive technique for evaluating the stability of pharmaceutical formulations.

[0695] The DVS profiles show that the stability of the benzoate salt of 5MeODMT is significantly higher than that of the hydrochloride salt and is therefore a more promising salt for development as a pharmaceutical composition.

[0696] Thus, in an embodiment of the present invention, provided is a composition of 5MeODMT with increased stability, wherein the composition comprises a benzoate. Also provided is a composition of 5MeODMT with increased stability, wherein the composition comprises a benzoate.

[0697] Thus, in an embodiment, a pharmaceutical composition of 5MeODMT benzoate salt is provided which has an increased shelf life compared to a pharmaceutical composition of 5MeODMT hydrochloride salt.

[0698] In an embodiment, the pharmaceutical composition may be a nasal inhalation composition.

[0699] Advantageously, 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 in a free-flowing powder form.

[0700] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized in that Fig.12 The DVS isotherm profile is generally shown in FIG.

[0701] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0702] - an endothermic event in the DSC thermogram having an onset temperature between 120°C and 130°C, between 121°C and 129°C, between 122°C and 128°C, between 123°C and 127°C, between 124°C and 126°C, optionally a peak between 124°C and 126°C and optionally an enthalpy between -130 J / g and -140 J / g, such as Fig. 9 As generally shown in the diagram;

[0703] - onset of decomposition between 128°C and 135°C, between 129°C and 134°C, between 130°C and 133°C or between 130°C and 132°C in the TGA thermogram, such as Fig.10 as generally shown in the diagram; and

[0704] -like Fig.12 The DVS isotherm profile is generally shown in FIG.

[0705] In an embodiment, a crystalline 5MeODMT benzoate salt is provided, characterized by one or more of the following:

[0706] -like Fig. 9 an endothermic event in a DSC thermogram generally illustrated in FIG. 5 having an onset temperature of 123° C., optionally a peak of 124° C., and optionally an enthalpy of −135 J / g;

[0707] -Decomposition onset at 131°C in the TGA thermogram, such as Fig.10 as generally shown in the diagram; and

[0708] -like Fig.12 The DVS isotherm profile is generally shown in FIG.

[0709] Those skilled in the art will appreciate that defining features of one or more of the previously or subsequently described embodiments may be interchanged with defining features of one or more other embodiments.

[0710] Example 20: Optical Microscopy of 5MeODMT Benzoate

[0711] Optical microscopy was performed using an Olympus BX53M polarized light microscope and an Olympus SC50 digital camera for image capture using imaging software Olympus Stream Basic version 2.4. Image scale was verified monthly against an external latitude and longitude grid 1.5 / 0.6 / 0.01 mm DIV.

[0712] A small amount of each sample was placed on a glass slide and dispersed with mineral dispersing oil if necessary. The samples were observed at an appropriate magnification and multiple images were recorded.

[0713] Optical micrographs of 5MeODMT benzoate were obtained. The material includes large rhombic / triangular crystals ranging from 400 microns to 1000 microns. There are also small crystals attached to the large crystals. Some of the small crystals from 10 microns are the result of mechanical abrasion, but others have been formed by crystallization. There are also large aggregates including a variety of habits. Figures 13 to 16 Various optical micrographs of 5MeODMT benzoate at various magnifications are shown.

[0714] Example 21: Further characterization of 5MeODMT benzoate.

[0715] The propensity of 5MeODMT benzoate to polymorphism was investigated and was considered low, with an isolated solid having two distinct XRPD patterns.

[0716] The equilibration of 5MeODMT benzoate in solvent under thermal modulation induces changes in form or modification that are not considered to be solvates.

[0717] Antisolvent mediated crystallization studies of 5MeODMT benzoate did not provide any solids indicative of a change in form or modification.

[0718] Controlled cooling crystallization studies of 5MeODMT benzoate did not provide any solids indicating a change in form or modification.

[0719] Reverse antisolvent-mediated crystallization studies of 5MeODMT benzoate did induce form or variant changes.

[0720] Two variants of 5MeODMT benzoate have been identified, a variant, Form A (see Example 17, hereinafter referred to as Form A) and a second Form B, believed to be metastable.

[0721] Equilibrium studies of 5MeODMT benzoate in a range of solvents with thermal modulation returned XRPD Form A from most solvents. The equilibrium solvents toluene, chlorobenzene and anisole induced a change in form or variant of 5MeODMT benzoate and were defined as XRPD Form B. The formation of solvates could be ruled out based on TGA.

[0722] Antisolvent mediated crystallization studies of 5MeODMT benzoate provided a solid consistent with Form A by XRPD, indicating no changes in form or modification.

[0723] Controlled cooling crystallization studies of 5MeODMT benzoate provided a solid consistent with Form A by XRPD, indicating no change in form or modification.

[0724] Reverse antisolvent mediated crystallization studies of 5MeODMT benzoate returned Form A from most mixtures. Methanol:toluene and IPA:toluene mixtures produced material believed to be Form B, with improved properties compared to the Form B solid isolated via solvent equilibration.

[0725] XRPD inspection( Fig.19 ) revealed a powder form of 5MeODMT benzoate that was consistent with the form found in previous XRPD examination (see Example 17, Form A).

[0726] DSC inspection Fig. 20 ) revealed a sharp endotherm with an onset of 122.95°C and a peak at 124.41°C, which matched the Form A (see Example 18, where the onset was 123.34°C and the peak was at 124.47°C).

[0727] Additional XRPD examination of multiple batches of 5MeODMT benzoate can be found at Fig.21 As seen in the figure, the matching type is A.

[0728] DSC examination of 5MeODMT benzoate batches C1, D1 and E1 revealed a common endothermic event with peak temperatures ranging from 123.76°C to 123.88°C ( Fig. 22 ). TGA analysis of C1, D1, and E1 revealed negligible weight loss prior to major decomposition ( Fig.23 ).

[0729] The XRPD patterns of P1 (toluene), Q1 (chlorobenzene) and R1 (anisole) revealed a new diffraction pattern called 'Form B'. These samples contain 3 common diffraction patterns between 18.5° 2θ and 20° 2θ ( Fig.24 ).

[0730] A series of samples in the form of Pattern A: C1 (IPA:heptane [1:1]), D1 (3-methyl-1-butanol:heptane [1:1]) and E1 (TBME) were thermally characterized.

[0731] DSC examination 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 minor common endothermic-exothermic event between 113.01°C and 115.27°C.

[0732] Sample R1 contains a unique endothermic event between the minor endothermic-exothermic event and the major endotherm with a peak temperature of 117.24°C.

[0733] TGA examination revealed negligible weight loss for samples P1 and Q1. For sample R1, there was a weight loss of 0.293% by weight before decomposition. P1, Q1, and R1 were heated at 10°C.min -1 The DSC temperature record can be found in Fig.25 5MeODMT benzoate batches P1, Q1 and R1 were heated at 10°C.min -1 The DSC thermogram extension can be found in Fig.26 Seen in.

[0734] 5MeODMT benzoate batches P1, Q1 and R1 were heated at 10°C.min -1 The TGA temperature record can be found in Fig. 27 Seen in.

[0735] XRPD examination of samples P2, Q2, and R2 (thermocycled suspensions) revealed that P2 and Q2 had converted to Form A. However, R2 remained in Form B, but with larger diffractions consistent with Form B. Comparison of the XRPD diffractograms of batches R1 and R2 (thermocycled suspensions) with the reference Form A XRPD diffractogram can be seen at Fig.28 Seen in.

[0736] DSC examination of P2 revealed the presence of only a major endothermic event characteristic of Form A, with a peak temperature of 124.48 °C ( Figure 29-Figure 31 ).

[0737] DSC revealed that the minor endotherms-exotherms of sample Q2 were smaller, with peak temperatures of 113.41°C and 114.32°C, but the major endotherm was unaffected, with a peak temperature of 124.23°C ( Figure 29-Figure 31 ).

[0738] DSC examination of sample R2 revealed an endothermic event in a secondary endothermic-exothermic with two peaks at 111.53°C and 113.49°C, followed by an exotherm with a peak temperature of 114.39°C, the secondary event was much larger than that of R1, and the second secondary endothermic event was absent ( Figure 29-Figure 31 ).

[0739] TGA examination revealed negligible weight loss for samples P2 and Q2. For sample R2, there was a 0.583% weight loss before decomposition. The increase in weight loss corresponds to an increase in the size of the secondary event revealed by DSC ( Figure 29-Figure 31 ).

[0740] The solvent-mediated equilibrium of 5MeODMT benzoate under temperature modulation reveals that the salt is stable to variant or form changes except solvents toluene, chlorobenzene and anisole. The solids isolated from these solvents have different XRPD patterns and thermal events, indicating variant or form changes of the salt. The formation of solvates can be excluded based on TGA.

[0741] In an embodiment, there is provided a crystalline 5MeODMT benzoate salt as described above.

[0742] Antisolvent addition driven crystallization of 5MeODMT benzoate

[0743] Equilibration of Form A in various solvents and solvent mixtures under thermal modulation identified a range of potentially suitable solvents and antisolvents.Antisolvent driven crystallization studies of 5MeODMT benzoate from solution were performed.

[0744] 5MeODMT benzoate 6 x 220 mg was dissolved in 6 solvents (detailed in the table below) at 50°C and the stock solution was clarified through a 0.45 μm syringe filter. An aliquot of each solution containing 50 mg of 5MeODMT benzoate was loaded into 4 crystallization tubes.

[0745] A solution of 5MeODMT benzoate in THF and acetonitrile crystallized after clarification. All crystallization tubes were heated to 55° C. to provide solutions, and cooled to 50° C. The samples were stirred via a stirrer bead at 400 rpm for the duration of the experiment.

[0746] 2.5 volumes of various anti-solvents (detailed in the table below) were loaded to the solutions and mixtures were then equilibrated at 50°C for 30 minutes and the anti-solvent addition was repeated.

[0747] The mixture was cooled to 25°C over approximately 1.5 hours and equilibration was continued for 17 hours.

[0748] The suspension was separated via isolute and vacuum dried for 1 minute to remove excess solvent. The isolute was transferred to a vacuum oven at 50°C for 24 hours.

[0749] The remaining solution was heated to 50°C and 5 volumes of antisolvent were loaded. The mixture was equilibrated for 30 minutes and then repeated. 10 volumes of additional antisolvent were loaded, equilibrated for 30 minutes, cooled to 25°C over 1.5 hours and equilibrated for 30 minutes.

[0750] The suspension was separated via isolute and vacuum dried to remove excess solvent, and then dried in a vacuum oven at 50°C for 24 hours.

[0751] In N 2 The remaining solution was reduced to approximately 0.25 mL volume under flow at 25° C. 20 volumes of antisolvent were loaded and the mixture was equilibrated for 30 minutes.

[0752] In an embodiment, there is provided a crystalline 5MeODMT benzoate salt as described above.

[0753]

[0754]

[0755] Although water was initially suggested as a potentially suitable anti-solvent, the use of water as an anti-solvent failed to provide a suspension.

[0756] All mixtures containing THF, acetone and MeCN (excluding water) provided suspensions by cooling to 25° C. with 10 volumes of antisolvent. All other mixtures (excluding water) required either increased antisolvent loading or significant solution volume reduction and antisolvent addition to provide suspensions.

[0757] XRPD examination of all isolated and dried solid samples was performed as Fig.32 and Fig.33 Form A is shown in Figure 2. XRPD characterization of the 5MeODMT benzoate solid isolated from anti-solvent mediated crystallization was consistent with Form A. This means that under the conditions studied, there is no form / variation change of the 5MeODMT benzoate.

[0758] Controlled Cooling Crystallization of 5MeODMT Benzoate

[0759] Observations from both the initial equilibrium studies and the first antisolvent-based studies of 5MeODMT benzoate identified potentially suitable solvents for dissolving 5MeODMT benzoate at a temperature that provided a saturated solution that could then be subjected to a controlled gradual cooling operation.

[0760] 25 mg ± 0.5 mg of 5MeODMT benzoate was dissolved in a minimum volume of solvent (detailed in the table below) at 50° C. The solution was clarified through a 0.45 μm Teflon syringe filter into a preheated crystallization tube and cooled from 50° C. to -10° C. over 60 hours (1° C. cooling rate per hour) and kept at -10° C. for 50 hours (without stirring).

[0761] Several crystallizations included large off-white crystals on the bottom of the crystallization tube (detailed in the table below). The crystals were transferred directly from the crystallization tube to the XRPD sample holder and left open to the atmosphere for approximately 1 hour prior to analysis.

[0762] The remaining mixture was stirred at 400 rpm at ambient temperature, open to the atmosphere to allow partial evaporation of the solvent over 18 hours.

[0763]

[0764]

[0765] XRPD examination of a solid sample (observed as relatively large particles) isolated after the solution was cooled revealed evidence of a preferred orientation ( Fig.34 ).

[0766] The samples were reduced in particle size via particle size reduction using a mortar and pestle. Subsequent re-examination by XRPD revealed that all solids were Form A ( Fig.35 ).

[0767] XRPD characterization of the 5MeODMT benzoate solids isolated to date from single solvent mediated crystallizations of 5MeODMT benzoate is consistent with Form A. This means that under the conditions investigated, there is no change in form or modification of the 5MeODMT benzoate.

[0768] In an embodiment, there is provided a crystalline 5MeODMT benzoate salt as described above.

[0769] Reverse addition antisolvent driven crystallization of 5MeODMT benzoate

[0770] The first antisolvent driven crystallization of 5MeODMT benzoate revealed a range of suitable solvent / antisolvent mixtures. Relatively gradual antisolvent addition and cooling from elevated temperature provided only solids classified as XRPD Form A. Suitable solvent / antisolvent mixtures were re-examined with the reverse addition of hot stock solution into cold antisolvent to potentially rapidly precipitate new and / or metastable solid form variants of 5MeODMT benzoate.

[0771] 165 mg ± 0.5 mg of 5MeODMT benzoate was loaded into vials A to F and dissolved at 50°C in a minimal amount of solvent as detailed in the table below.

[0772] 1 ml of anti-solvent was loaded into the crystallization tube, which was then cooled to -10°C and stirred at 400 rpm.

[0773] An aliquot of approximately 50 mg of the stock solution of 5MeODMT benzoate was loaded directly into the antisolvent.

[0774] All crystallization tubes provided suspension within 5 min of the addition of 5 MeODMT benzoate solution.

[0775] The suspension was immediately separated via isolute in vacuo, then transferred to a vacuum oven and dried at 50°C for 18 hours.

[0776] Table - Summary of solvents, antisolvents and observations

[0777]

[0778] XRPD examination of most of the isolated solids (except A1 and B1) was consistent with Form A (see Fig.36 and Fig.37 ).

[0779] XRPD examination of solids A1 and B1 was consistent with each other, but inconsistent with Form A ( Fig.38 , Fig.39 ).

[0780] Batches A1 and B1 share diffraction with 5MeODMT benzoate batch Q1 (previously identified as a pattern of Form B). However, upon closer inspection, it was observed that Q1 shares diffraction with Pattern A. This is because batch Q1 shares diffraction with both batches A1 and B1, as well as Pattern A.

[0781] The diffraction patterns of Batch A1 and Batch B1 are considered to be characteristic of Pattern B.

[0782] DSC temperature record diagram of sample A1 ( Fig.41) revealed an endothermic event with an onset around 110°C and a major peak at 113.98°C, followed by an exotherm with an onset at 114.72°C and a peak at 116.42°C, followed by a second endotherm with an onset at 123.00°C and a peak at 123.72°C.

[0783] DSC examination of sample B1 ( Fig.42 and Fig.43 ) revealed a similar DSC thermogram to A1, but with a larger first endothermic event, comparable to 90 J.g -1 Compared with 108J.g -1 , and contains only two peak temperatures at 109.00°C and 110.32°C, rather than the three peak temperatures present in A1. The subsequent exothermic event is smaller, with a charge of 41 J.g -1 Compared with 17J.g -1 The second main heat absorption of B1 is also smaller, compared with 80 J.g of A1. -1 Compared with 38J.g -1 .

[0784] In an embodiment, there is provided a crystalline 5MeODMT benzoate salt as described above.

[0785] In an embodiment, there is provided a crystalline 5MeODMT salt characterized by an endothermic or exothermic event in a DSC thermogram as generally illustrated in any one of the accompanying drawings.

[0786] In an embodiment, a composition comprising 5MeODMT benzoate Form A is provided.

[0787] In an embodiment, a composition comprising 5MeODMT benzoate Pattern B form is provided.

[0788] In an embodiment, a composition comprising a mixture of 5MeODMT benzoate pattern A form and 5MeODMT benzoate pattern B form is provided.

[0789] Example 22: Production of Amorphous 5MeODMT Benzoate

[0790] Rapid concentration in a vacuum

[0791] 101.55 mg of 5MeODMT benzoate was dissolved in 4 mL of THF and clarified into a 100 mL round bottom flask. The solution was concentrated in vacuum at 40°C at 200 rpm. The liquid evaporated from the flask, leaving a concentrated clear colorless liquid residue around the flask.

[0792] The residue was dissolved in 4 ml of acetone and concentrated in vacuo at 40°C at 200 rpm. The liquid evaporated from the flask, leaving a concentrated clear, colorless liquid residue around the flask. Small crystals were visible inside the flask, which were separated after 18 hours to provide 21-01-051A.

[0793] Quenching of the melt

[0794] 5MeODMT benzoate was held at 125°C for 5 minutes by TGA, then cooled to ambient temperature over 3 minutes to provide 21-01-051 B. Samples were analyzed immediately and after 20 hours in a sealed container.

[0795] Freeze-drying

[0796] 200 mg of 5MeODMT benzoate was dissolved in 10 ml of deionized water and clarified through a 0.45 μm nylon filter into a 500 mL round bottom flask and then frozen into a thin layer. The flask was transferred to vacuum and equilibrated to ambient temperature, providing a fluffy white solid 21-01-051C.

[0797] The solid converted to a gum in about 1 hour. Samples were analyzed immediately and after 20 hours in a sealed container.

[0798] Lyophilization for equilibration of amorphous solids

[0799] Lyophilization was repeated as described above with 800 mg of 5MeODMT benzoate dissolved in 25 ml to provide 21-01-051 D. The solid was heated to 60° C. for 10 minutes and then cooled to yield 21-01-051 E. The sample was analyzed immediately.

[0800] Fig.44 Shown is an XRPD comparison of 5MeODMT benzoate batches 21-01-051A, 21-01-051E, reduced particle size 21-01-051E, and Pattern A reference.

[0801] Fig.45 Shown is the XRPD of 5MeODMT benzoate batch 21-01-051B obtained from the quenched melt.

[0802] Fig.46 Shown is the XRPD of 5MeODMT benzoate batch 21-01-051C obtained by lyophilization.

[0803] The XRPD patterns of 5MeODMT benzoate salts 21-01-051B and 21-01-051C were consistent with Form A, indicating that the amorphous form converted to Form A at ambient temperature and pressure in a sealed container.

[0804] The XRPD pattern of the solid 5MeODMT benzoate salt 21-01-051A isolated by concentration in acetone was consistent with Form A. Rapid concentration in vacuo did not yield the amorphous modification.

[0805] The XRPD patterns revealed that the 5MeODMT benzoate salts 21-01-051B and 21-01-051C had an amorphous 'halo', indicating that quenching the molten material and lyophilization produced the amorphous 5MeODMT benzoate salt.

[0806] Fig.47 Shown is an XRPD comparison of 5MeODMT benzoate batch 21-01-051B after 20 hours, 5MeODMT benzoate batch 21-01-051C after 20 hours, and Pattern A reference.

[0807] The XRPD pattern of 5MeODMT benzoate salt 21-01-051E was consistent with Form A, indicating that the amorphous form converted to Form A at 60°C for 10 minutes.

[0808] Fig.48 Shown is an XRPD comparison of 5MeODMT benzoate batches 21-01-051A, 21-01-051E, reduced particle size 21-01-051E, and Pattern A reference.

[0809] DSC examination revealed that the amorphous 5MeODMT benzoate salts 21-01-051C and 21-01-051D obtained by lyophilization contained an exothermic event with a peak temperature between 65.63° C. and 70.84° C., followed by a broad endothermic shoulder, resulting in an endothermic event with a peak temperature between 120.20° C. and 121.22° C. The main endothermic event was about 3° C. lower than the Form A material.

[0810] Fig.49 5MeODMT benzoate batches 21-01-051A, 21-01-051C and 21-01-051D isolated from acetone concentrate (051A) and by lyophilization (051C and 051D) are shown at 10°C.min -1 Comparison of DSC thermograms.

[0811] DSC examination revealed that after 20 hours 5MeODMT benzoate salt 21-01-051C no longer contained an exothermic event and the endothermic event at about 123 °C was sharper and consistent with Pattern A Form.

[0812] Fig.505MeODMT benzoate batch 21-01-051C and 5MeODMT benzoate batch 21-01-051C after 20 hours at 10°C.min are shown. -1 Comparison of DSC thermograms.

[0813] Amorphous 5MeODMT benzoate can be produced by lyophilization of aqueous solution and quenched melt.

[0814] Amorphous 5MeODMT benzoate will convert to Form A material upon standing.

[0815] In one embodiment, an amorphous 5MeODMT benzoate salt is provided. In one embodiment, a composition comprising an amorphous 5MeODMT benzoate salt is provided.

[0816] In one embodiment, a composition comprising amorphous 5MeODMT benzoate produced as described above or in detail below is provided.

[0817] Example 23: Further Characterization of Amorphous 5MeODMT Benzoate

[0818] Thermal examination of amorphous 5MeODMT benzoate by DSC and hot stage microscopy revealed a crystallization event and an endothermic melt. The endothermic melt was inconsistent with the DSC thermogram of the Form A form.

[0819] Solvent-mediated equilibration of amorphous 5MeODMT benzoate under thermal modulation afforded Form A by XRPD and DSC from all solvents except anisole. A new variation was generated.

[0820] Amorphous 5MeODMT benzoate 21-01-051D (21-01-051) produced by lyophilization was observed by hot stage microscopy at 5°C.min -1 The heating rate was checked for confirmation with the DSC thermogram of the amorphous solid.

[0821] Initially, 5MeODMT benzoate is a viscous, translucent glue ( Fig.52 ), which decreases in viscosity and spreads into a thinner uniform layer when heated to 54.21°C ( Fig.53 ). At 54.21℃, the liquid begins to crystallize ( Fig.53 ), which is nearly complete at 74.21℃ ( Fig.54 The newly formed crystals begin to melt at 114.24°C ( Fig.55 ), which is nearly complete at 120.14℃ ( Fig.56 ).

[0822] Hot stage microscopy confirmed the events in the DSC thermogram ( Fig.51 ); a crystallization exotherm at about 65°C and a melting endotherm at about 115°C.

[0823] Fig.51 Shown is the DSC thermogram of large scale lyophilized material 5MeODMT benzoate batch 21-01-051D, where the temperature markers correspond to the hot stage microscopy images.

[0824] Fig.52 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 30.02°C.

[0825] Fig.53 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 54.21 °C.

[0826] Fig.54 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 74.21°C.

[0827] Fig.55 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 114.23°C.

[0828] Fig.56 Shown is a photomicrograph image of 5MeODMT benzoate batch 21-01-051D at 120.14°C.

[0829] Solvent-mediated equilibration of amorphous 5MeODMT benzoate under thermal manipulation

[0830] The act of stirring a solid of an amorphous modification in a range of solvents can lead to dissolution and crystallization into a more ordered and more energetically stable solid. In this way, alternative crystalline forms of the solid can potentially be produced for comparison and evaluation.

[0831] 24 x 25 mg ± 2 mg of amorphous 5MeODMT benzoate 21-01-51D was transferred to a crystallization tube and loaded with 0.125 mL of solvent as detailed in the table below. The mixture was stirred at 300 rpm at 25°C for 30 minutes. 0.125 mL of solvent was loaded to the relevant mixture and equilibration was continued for 18 hours.

[0832] The mixture was heated to 55°C for 8 hours, then cooled to 25°C over 1 hour, and then equilibrated at 300 rpm for 18 hours, with observations after each maneuver detailed in the table below.

[0833] The suspension was transferred to an Isolute tube for separation and dried under vacuum for 2 min and then dried in vacuum at 50°C for 24 hours.

[0834] XRPD examination of solids isolated from amorphous 5MeODMT benzoate in equilibrium under thermal modulation revealed that all powder forms were consistent with Form A ( Fig.57 and Fig.58 ).

[0835] Fig.57 Shown is a comparison of XRPD patterns of 5MeODMT benzoate batch 21-01-054 solid isolated from amorphous 5MeODMT benzoate in equilibrium with thermal modulation.

[0836] Fig.58 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-054M isolated from equilibrium of amorphous 5MeODMT benzoate in α,α,α-trifluorotoluene with thermal modulation and batch 20-37-64 (Formula A).

[0837] DSC examination of a selection of 5MeODMT benzoate solids classified as Form A revealed a major endothermic event with an onset temperature between 121.88°C and 123.39°C and a peak temperature between 123.66°C and 124.11°C. This endotherm is characteristic of Form A ( Fig.59 ).

[0838] The 5MeODMT benzoate 21-01-054Q solid isolated from anisole contained events with peak temperatures of 111.64°C and 116.92°C within the main endothermic event ( Fig.60 , Fig.61 ). This is consistent with the DSC temperature record of the 5MeODMT benzoate 20-37-64-R1 isolated after equilibration in anisole. Figure 1 Although not obvious.

[0839] Fig.59 Shown is a comparison of DSC thermograms of select solids of 5MeODMT benzoate batch 21-01-054 isolated from amorphous 5MeODMT benzoate in equilibrium under thermal modulation, classified as Form A.

[0840] Fig.60Shown is an expanded comparison of DSC thermograms of a selection of 5MeODMT benzoate batch 21-01-054 solids isolated from amorphous 5MeODMT benzoate in equilibrium under thermal modulation, classified as Form A, highlighting events in solid batch 21-01-054Q isolated from anisole.

[0841] Fig.61 An expanded DSC thermogram expansion is shown highlighting events in batch 21-01-054Q isolated from anisole.

[0842] Example 24: Type C

[0843] Additional 5MeODMT benzoate Pattern B Form material was required for further characterization.A procedure was employed to load the 5MeODMT benzoate / IPA solution into cold toluene.

[0844] 250 mg of 5MeODMT benzoate 20 / 20 / 150FP2 was dissolved in 5 ml of IPA and heated to 50°C and clarified. 2 x 2 ml of the clarified solution, 100 mg of 5MeODMT benzoate was charged to 4 ml of toluene at -10°C and stirred at 750 rpm.

[0845] After the addition, both mixtures remained clear colorless solutions.

[0846] After 30 minutes, solid had formed in tube A. Solid 21-01-060A was immediately isolated via isolute and dried in vacuum for 2 minutes. Portion 21-01-060A1 was taken for XRPD analysis, portion 21-01-060A2 was dried in vacuum at 50°C for 20 hours.

[0847] After 50 minutes, solids had formed in tube B and were allowed to equilibrate at -10°C and stirred at 750 rpm for 3 hours. Solid 21-01-060B was immediately separated via isolute and dried in vacuum for 2 minutes. A portion 21-01-060B1 was taken out for XRPD analysis and the remaining portion 21-01-060B2 was dried in vacuum at 50°C for 20 hours.

[0848]

[0849] Samples 21-01-060A1 and 21-01-060B1 were air dried at ambient conditions for 20 hours and evaluated by XRPD and DSC.

[0850] Immediately after isolation, 21-01-060A1 was analyzed by XRPD. This revealed a new diffraction pattern that was not consistent with either Form A or Form B. This was referred to as Form C.

[0851] After air drying for an additional hour under ambient conditions, the XRPD pattern of 21-01-060A1 (air dried for 2 min) was recovered ( Fig.62 There are additional diffractions in the XRPD of 21-01-060A1 (air dried for 1 hour) compared to 21-01-060A1 (air dried for 2 min), indicating conversion to Form B ( Fig.63 ).

[0852] Fig.62 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060A1 air dried 2 minutes, batch 21-01-049B1 Pattern B, and batch 20-37-64 Pattern A.

[0853] Fig.63 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060A1 - air dried for 1 hour and batch 21-01-060A1 - air dried for 2 minutes.

[0854] Fig.64 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060A1 - air dried for 2 minutes, batch 21-01-060A1 - air dried for 1 hour, and batch 21-01-049B1 Pattern B.

[0855] DSC thermogram of 5MeODMT benzoate 21-01-060A1 (air dried for 1 hour) Fig.65 and Fig.66 ) revealed a second broad endothermic peak with a peak temperature of 108°C, which is considered to be characteristic of the Form C solid.

[0856] This was followed by an exotherm with a peak temperature of 112.35°C, which was considered to be the conversion of the Form C form to the Form A form, since the major endotherm had a peak temperature of 124.12°C, which was characteristic of the Form A form.

[0857] Fig.65 Shown is the DSC thermogram of 5 MeODMT benzoate batch 21-01-060A1 immediately isolated from IPA / toluene and air dried for 1 hour.

[0858] Fig.66 Shown is an extension of the DSC thermogram of 5 MeODMT benzoate batch 21-01-060A1 immediately isolated from IPA / toluene and air dried for 1 hour.

[0859] After a total of 20 hours of air drying, the XRPD pattern of 5MeODMT benzoate batch 21-01-060A1 was obtained. This revealed the pattern ( Fig.67 ) is consistent with SPS5520 21-01-049B1 Type B, but contains diffraction indicative of Type C, such as 10.3° 2θ ( Fig.67 ).

[0860] Fig.67 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060A1 air dried for 20 hours, batch 21-01-060A1 air dried for 2 minutes, and batch 21-01-049B1 Pattern B reference.

[0861] 5MeODMT benzoate 21-01-060B1 was produced by reverse antisolvent addition, equilibration for 3 hours, then separation and air drying at ambient temperature.

[0862] Immediately after isolation, the solid was analyzed by XRPD. This revealed a diffraction pattern consistent with 21-01-060A1 Form C ( Fig.68 ).

[0863] The XRPD pattern was recovered after air drying for 20 hours ( Fig.69 ), and revealed that the solid was still Form C, but contained diffractions at 17.2° 2θ and 19.5° 2θ, indicative of Form B.

[0864] Fig.68 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-060B1 isolated after 3 hours equilibration and then air dried for 2 min and 5MeODMT benzoate batch 21-01-060A1 isolated immediately and then air dried for 2 minutes.

[0865] Fig.69 Shown is a comparison of XRPD patterns of 5MeODMT benzoate batch 21-01-060B1 isolated after 3 hours equilibration and then air dried for 20 hours and 5MeODMT benzoate batch 21-01-060B1 isolated after 3 hours equilibration and then air dried for 2 minutes, and batch 21-01-049B1 Pattern B.

[0866] Example 25: Study on the Effect of Solvent Vapor Diffusion on Amorphous 5MeODMT Benzoate

[0867] Subjecting an amorphous solid to solvent vapors is considered a low energy process for inducing a change in form or modification of a solid in order to generate metastable modifications and / or solvates from the amorphous solid for comparison and evaluation.

[0868] 497.44 mg of 5MeODMT benzoate was dissolved in 10 mL of deionized water and clarified into a 500 mL round bottom flask and lyophilized as previously detailed. 12 x 25 mg of the resulting fluffy white solid was loaded into an HPLC vial and placed in a sealed container with approximately 2 mL of solvent. The solvents employed and the observations are detailed in the table below.

[0869] After equilibration for 7 days, the solids were directly transferred to the XRPD sample holder and analyzed by XRPD. DSC of all significant samples were collected by XRPD and selections of Pattern A Form solids.

[0870]

[0871] The XRPD patterns of all samples except 21-01-058D and 21-01-058G, which were isolated from anisole and toluene, respectively, were ( Fig.70 ) is consistent with Type A material ( Fig.71 ).

[0872] Fig.70 Shown is a comparison of XRPD patterns of 5MeODMT benzoate batch 21-01-058 solids isolated from amorphous 5MeODMT benzoate exposed to solvent vapor.

[0873] Fig.71 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-058K and batch 20-37-64 Form A isolated from amorphous 5MeODMT benzoate exposed to solvent vapor.

[0874] Comparison of DSC thermograms of selected solids of Form A ( Fig.72 ) revealed an endothermic event with peak temperatures between 123.69°C and 124.14°C, which is indicative of Pattern A form and confirms the XRPD data.

[0875] The DSC thermogram of batch 21-01-058G (not Form A according to XRPD) exhibits a secondary endothermic event preceding the primary endotherm and is described in detail below.

[0876] Fig.72 Shown is a comparison of the DSC thermograms of 5MeODMT benzoate batch 21-01-058B, batch 21-01-058F, batch 21-01-058K, and batch 21-01-062G.

[0877] Example 26: Type D

[0878] Solid 5MeODMT benzoate isolated from amorphous 5MeODMT benzoate exposed to anisole vapor for 7 days 21-01-058D

[0879] XRPD of 5MeODMT benzoate batch 21-01-058D isolated from amorphous 5MeODMT benzoate exposed to anisole vapor revealed a unique powder pattern ( Fig.73 and Fig.74 ). The diffraction of 21-01-058D is similar to that of pattern C, but differs in intensity and position ( Fig.75 ).

[0880] Fig.73 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batch 21-01-058D, batch 20-37-64 pattern A, batch 21-01-049B1 pattern B, and batch 21-01-060B1 pattern C (air dried for 20 hours).

[0881] Fig.74 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate salt batch 21-01-058D, batch 21-01-049B1 Pattern B, and batch 21-01-060B1 Pattern C (air dried for 20 hours).

[0882] Fig.75 Shown is an expanded comparison of the XRPD patterns of 5MeODMT benzoate salt batch 21-01-058D, batch 21-01-049B1 Pattern B, and batch 21-01-060B1 Pattern C (air dried for 20 hours).

[0883] DSC thermogram of 5MeODMT benzoate batch 21-01-058D isolated from amorphous 5MeODMT benzoate exposed to anisole vapor ( Fig.76 ) revealed an endothermic event with a peak temperature of 118.58° C. This confirmed the XRPD data, confirming that a new variant had been isolated.

[0884] Fig.76 Shown is the DSC thermogram of 5MeODMT benzoate batch 21-01-058D isolated by exposing anisole vapor to the amorphous form.

[0885] Amorphous 5MeODMT benzoate salt exposed to anisole vapor provides anisole hemisolvate, designated herein as Form D. The XRPD pattern of Form D is similar to that of Form C toluene hemisolvate, but with differences in peak positions.

[0886] Amorphous 5MeODMT benzoate exposed to toluene vapor provided mixed form variations of predominantly Form A, with some evidence of Form C toluene hemisolvate as observed by XRPD and DSC.

[0887] Amorphous 5MeODMT benzoate salt exposed to all other solvent vapors returned exclusively to Form A by XRPD and DSC.

[0888]

[0889] Example 27: Type E

[0890] 5MeODMT benzoate Form C was isolated via reverse anti-solvent addition of an isopropanol solution of 5MeODMT benzoate to toluene, the solid being believed to be a hemisolvate which, when desolvated, afforded Form B. Form B has been obtained by equilibration of 5MeODMT benzoate in anisole and chlorobenzene. Form B can be obtained from anisole and chlorobenzene hemisolvate, and thus reverse anti-solvent addition to chlorobenzene and anisole is believed to afford the same hemisolvate as toluene.

[0891] 650 mg of 5MeODMT benzoate 20 / 20 / 150FP2 was loaded into a sample vial with 13 ml of IPA and heated to 50° C. The clear solution was clarified by passing through a 0.45 μm nylon syringe filter.

[0892] 4 ml of anti-solvent was loaded into the crystallization tube and cooled to -10°C with stirring via stirrer beads at 750 rpm as detailed in the table below.

[0893] 2 ml of IPA stock solution at 50 °C was loaded into 4 ml of cold antisolvent at -10 °C.

[0894] The observations are detailed in the table below, where B, D and F were immediately separated.

[0895] Tubes A, C and E were equilibrated for 3 hours and then separated.

[0896] The suspension was transferred to an isolute column and dried in vacuum for NMT 60 sec and analyzed immediately after opening to the atmosphere for 4 h and 44 h.

[0897] 5MeODMT benzoate 21-01-064E was wet after air drying for 60 seconds.

[0898]

[0899] 5MeODMT benzoate salt 21-01-064D was isolated immediately after formation of a suspension provided by addition of concentrated IPA solution to chlorobenzene at -10°C.

[0900] XRPD revealed that the diffraction pattern of 5MeODMT benzoate batch 21-01-064D was similar to that of 21-01-060B1 (air dried for 2 minutes) pattern C ( Fig.77 ). Compared with Form C, several diffractions including 19°2θ and 20°2θ are slightly higher or lower, which is not the result of the sample ( Fig.78 ).

[0901] 5MeODMT Benzoate Salt Batch 21-01-064D is a new diffraction pattern and is defined herein as Pattern E.

[0902] Fig.77 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-064D and 21-01-060B1 (air dried for 2 minutes).

[0903] Fig.78 Shown is an expanded comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-064D and 21-01-060B1 (air dried for 2 minutes).

[0904] The DSC thermogram of 5MeODMT benzoate batch 21-01-064D revealed a major double peak endothermic event with peak temperatures of 110.31°C and 113.13°C ( Fig.79 ), followed by a minor endothermic event with a peak temperature of 119.09 °C.

[0905] Fig.79 5MeODMT benzoate batch 21-01-064D is shown at 10°C.min -1 DSC temperature record diagram.

[0906] The 1H NMR spectrum of 5MeODMT benzoate salt batch 21-01-064D isolated immediately after equilibration revealed a 1:1 salt stoichiometry and also revealed a 1:0.512 salt to solvent ratio for chlorobenzene and a 1:0.013 salt to solvent ratio for IPA.

[0907] The isolated salt is the chlorobenzene hemisolvate.

[0908] In the DSC thermogram of 21-01-064D, there is no evidence of a Form A endotherm at about 123°C ( Fig.79 ), because residual chlorobenzene is believed to inhibit the crystallization of 5MeODMT benzoate.

[0909] 5MeODMT benzoate salt 21-01-064C was isolated after 3 hours of equilibration of a suspension provided by addition of concentrated IPA solution to chlorobenzene at -10 °C.

[0910] XRPD revealed that the diffraction pattern of 5MeODMT benzoate batch 21-01-064C was consistent with 21-01-064D Pattern E ( Fig.80 ).

[0911] Fig.80 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-064C and 21-01-064D.

[0912] Fig.81 Shown is an expanded comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-064C and 21-01-064D.

[0913] The DSC thermogram of 5MeODMT benzoate batch 21-01-064C revealed major endothermic events with peak temperatures of 111.39°C, 113.22°C and 114.35°C ( Fig.82 ).

[0914] The DSC thermogram of 21-01-064C is similar to the thermogram of 21-01-064D.

[0915] Fig.82 5MeODMT benzoate batch 21-01-064C is shown at 10°C.min -1 DSC temperature record diagram.

[0916] The 1H NMR spectrum of 5MeODMT benzoate salt batch 21-01-064C isolated after 3 hours equilibration revealed a 1:1 salt stoichiometry and also revealed a 1:0.506 salt to solvent ratio for chlorobenzene and a 1:0.004 salt to solvent ratio for IPA.

[0917] The isolated salt is the chlorobenzene hemisolvate.

[0918] XRPD of 5MeODMT benzoate salt batch 21-01-064C (air dried for 4 hours) revealed a diffraction pattern consistent with Pattern E of 21-01-064C.

[0919] XRPD of 5MeODMT benzoate batch 21-01-064C (air dried 44 hours) revealed a diffraction pattern consistent with Pattern E of 21-01-064C and 21-01-064C (air dried 4 hours).

[0920] The XRPD of 5MeODMT benzoate batch 21-01-064F revealed a diffraction pattern consistent with 21-01-058D Form D from vapor diffusion studies of amorphous 5MeODMT benzoate in anisole, but was more crystalline and did not contain the minor diffraction features of Form A.

[0921] XRPD of 5MeODMT benzoate salt 21-01-064E revealed a diffraction pattern consistent with Pattern D of 21-01-064F.

[0922] XRPD of 5MeODMT benzoate salt 21-01-064E (air dried for 4 hours) revealed a diffraction pattern consistent with Pattern D of 21-01-064E.

[0923] XRPD of 5MeODMT benzoate salt 21-01-064E (air dried for 44 hours) revealed a diffraction pattern consistent with 21-01-064E Form D, but with an additional diffraction at 18.3° 2θ which was considered indicative of Form B.

[0924] Example 28: Additional discussion of Type B to Type E

[0925] Type B

[0926] Below is a table summarizing batches of 5MeODMT benzoate salt having predominant Form B composition and crystallographic properties.

[0927]

[0928] Below is a table summarizing the main Type B thermal characteristics.

[0929]

[0930]

[0931] 5MeODMT benzoate batch 21-01-049B1 was produced by adding an IPA solution reverse antisolvent to toluene, immediately isolating, and then drying in vacuum at 50°C. XRPD revealed a diffraction pattern defined as Form B. DSC examination identified an endothermic event at 110°C consistent with the boiling point of toluene, followed by an endothermic event, followed by an exothermic event indicating melt crystallization of Form B to Form A, followed by an endothermic event indicating melting of Form A material. 1H NMR revealed a small amount of residual toluene and no IPA.

[0932] 5MeODMT benzoate batch 21-01-060A2 was produced by the same method as 049B1, except on a larger scale, and afforded the same product according to XRPD and DSC, but contained residual IPA according to 1H NMR.

[0933] 5MeODMT benzoate batch 21-01-049A1 was produced by the same method as 049B1, except that it was initially dissolved in methanol, and XRPD revealed a powder form consistent with Form B with some Form C. 1H NMR revealed a 1:0.03 salt to toluene ratio. DSC examination revealed a similar thermogram to 049B1, but the first endothermic event at 110°C was larger, and the subsequent endothermic melting of the Form B form was bimodal and peaked at a lower temperature. As the Form B form melted, the Form A form crystallized and melted as expected.

[0934] 5MeODMT benzoate batch 21-01-060B2 was produced by the same method as 060A2, but the equilibrium lasted for 3 hours before separation and drying in vacuum. XRPD revealed a mixture of Form B with some Form C. 1H NMR revealed a ratio of 1:0.05 salt to toluene. DSC examination revealed a similar thermogram to 049A1 (a mixture of Form B and Form C), but the Form B melting endothermic event was not bimodal. The endothermic event at 110°C was considered to be the result of a slightly increased amount of toluene in the sample in the form of a toluene hemisolvate.

[0935] 5MeODMT benzoate batch 21-01-060A1 (air dried for 20 hours) was produced by the same method as 060A2, but was air dried instead of dried in vacuum at 50°C. XRPD revealed a mixture of Form B and Form C. 1H NMR revealed a 1:0.04 ratio of salt to toluene. However, 060A1 contained much more IPA than the other samples (1:0.2 instead of 1:0.05). This may have altered the endothermic event during DSC examination of the sample, but there was a Form A form melting endothermic event.

[0936] 5MeODMT benzoate batch 21-01-047J was produced by crystallization from chlorobenzene at 50°C and drying in vacuum at 50°C. XRPD revealed that the sample was a mixture of Form B and some Form A. DSC examination revealed an endothermic event similar to that believed to be the loss of toluene, which was believed to indicate the loss of chlorobenzene. The melting endotherm of the Form B form occurred earlier than that of 049B1, but the crystallization of the Form A form was very exothermic and accompanied by the melting of the Form A form.

[0937] The 5MeODMT benzoate Form B material contains a characteristic endothermic-exothermic event upon its melting and subsequent crystallization to Form A, which is produced by desolvation of the hemisolvate, so the endothermic event characteristic of the residual hemisolvate is present in all isolated samples.

[0938] For those solids containing toluene at low levels, which are believed to be hemisolvate modifications of the salt, the thermal properties will be altered by the loss of toluene.

[0939] Type C

[0940] Below is a table summarizing batches of 5MeODMT benzoate salt having predominant Form C composition and crystallographic characteristics.

[0941]

[0942]

[0943] Below is a table summarizing the thermal characteristics of the main Type C models.

[0944]

[0945] 5MeODMT benzoate batch 21-01-064B was produced by adding the reverse antisolvent of IPA solution to toluene. XRPD revealed Form C, which was supported by a 1:0.5 salt to toluene ratio according to 1H NMR, indicating a toluene hemisolvate. DSC examination revealed a bimodal endothermic event with peak temperatures of 111.3°C and 112.1°C, indicating that the endothermic event at 111°C in the Form B mixture was the result of residual Form C. There was an endothermic event indicating Form B form, which indicated a transition to Form B form and then to Form A form.

[0946] 5MeODMT benzoate batch 21-01-064A was produced by the same method as 064B, but equilibrated for 3 hours before isolation. XRPD and 1H NMR revealed the same characteristics as 064B. However, DSC examination revealed a different major multimodal endothermic event with a peak temperature of 115.0°C.

[0947] 5MeODMT benzoate batches 21-01-064A (air dried for 44 hours) and 21-01-060B1 (air dried for 20 hours) were produced similarly to 064A, but air dried for longer periods of time. XRPD revealed a mixture of Form C and Form B for both, and 1H NMR revealed less toluene in 060B1 than in 064A, which is believed to be a result of air drying, which supports the presence of Form B in the sample according to XRPD. DSC examination revealed an endothermic event with a peak temperature of 111.3°C for both, followed by multiple unique endothermic events.

[0948] 5MeODMT benzoate batch 21-01-064A (air dried for 4 hours) was produced by air drying 064A. XRPD revealed a mixture of Form C with some Form B. DSC examination revealed a broad exothermic event between 105°C and 113°C, followed by a weak endothermic event indicating Form C form and an endothermic event indicating Form B form. The change in heating rate was the cause of the change in thermal behavior, as the DSC thermograph of the 21-01-064A (air dried for 44 hours) sample was similar to that of 21-01-064A. The transition to Form C form occurred in situ during the examination.

[0949] 5MeODMT benzoate salt 21-01-060A1 (air dried for 1 hour) was produced by the same method as 064A, but isolated immediately. XRPD revealed a mixture of Form C and some Form B. DSC examination revealed a thermogram indicative of a Form B form with a minor exothermic event at about 109°C.

[0950] 5MeODMT benzoate pattern C is a toluene hemisolvate that has no characteristic endothermic events except for melting between 110° C. and 115° C. The XRPD pattern of the toluene hemisolvate of 5MeODMT benzoate is different from that of the 5MeODMT benzoate. Desolvation can occur under ambient conditions and is believed to produce pattern B.

[0951] Thermal properties will be affected by the loss of toluene during the DSC examination.

[0952] Type D

[0953] The following table summarizes the composition and crystallographic properties of the major Form D.

[0954]

[0955] The table below shows a summary of the thermal characteristics of the main Type D models.

[0956]

[0957]

[0958] 5MeODMT benzoate batch 21-01-064F was produced by adding an IPA solution reverse antisolvent to anisole and immediately isolating. XRPD revealed a diffraction pattern consistent with Form D, which was supported by a 1:0.503 ratio of anisole according to 1H NMR, indicating a hemisolvate. DSC examination revealed a double peak endothermic event with peak temperatures of 118.61°C and 119.21°C.

[0959] 5MeODMT benzoate batch 21-01-064E was produced by adding an IPA solution reverse anti-solvent to anisole, then equilibrated for 3 hours before isolation. XRPD revealed Form D, but this was not supported by 1H NMR, which revealed a 1:1.04 ratio of salt to anisole, and the isolated solid was moist after isolation. DSC examination revealed a very poorly defined broad endothermic event with peak temperatures of 113.51°C and 161.93°C, the endothermic event at 113.51°C was believed to be the result of melting of the hemisolvate present according to XRPD followed by evaporation of anisole. Due to the solvent content, the DSC thermogram is not believed to represent the Form D form.

[0960] 5MeODMT benzoate batch 21-01-058D was produced by exposing the amorphous form to anisole vapor. XRPD revealed a mixture of Pattern D diffractions and some Pattern A diffractions, which was supported by 1H NMR, which revealed a 1:0.47 ratio of salt to anisole, indicating anisole hemisolvate. DSC examination revealed an endothermic event with a peak temperature of 118.6°C, which is consistent with the data collected from 064F. However, melting of the Pattern A form was not revealed in the DSC thermogram, which may be altered by the released anisole solvent present in the sample.

[0961] 5MeODMT Benzoate Batch 21-01-064E (Air Dry 4 Hours) was produced by air drying 064E for 4 hours. XRPD revealed Form D. DSC examination at 2.5°C.min -1 The DSC was performed to resolve the bimodal endothermic event observed in the thermogram of 064E. DSC examination revealed a minor endothermic event with a peak temperature of 111.24°C, which was consistent with the broad endothermic event observed in 064E. The better resolution of this endotherm was considered to be the 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, which was consistent with 058D and 064F.

[0962] 5MeODMT benzoate batch 21-01-064E (air dried 44 hours) was produced by air drying 064E (air dried 4 hours) for another 40 hours. XRPD revealed a mixture of pattern D diffraction with some pattern B diffraction. DSC inspection revealed a thermogram consistent with 064E (air dried 4 hours). The pattern B form content was not obvious in the DSC thermogram, which was believed to be caused by the released anisole solvent present in the sample, similar to 058D.

[0963] 5MeODMT benzoate Form D is an anisole hemisolvate and has been produced directly from exposure of the amorphous form to anisole vapor and by adding an IPA solution reverse antisolvent to cold anisole. Characteristic thermal behavior has not been determined, although endothermic events around 118°C are common, and the lack of recrystallization into Form B or Form A is believed to be due to the presence of residual anisole.

[0964] Type E

[0965] The following table summarizes the composition and crystallographic properties of the major Form E.

[0966]

[0967] The following table summarizes the thermal properties of the major Form E forms. The endothermic event at 123.7°C is characteristic of Form A.

[0968]

[0969] 5MeODMT benzoate batch 21-01-064D was produced by adding the reverse antisolvent of IPA solution to chlorobenzene. XRPD revealed Form E, which was supported by 1H NMR, which revealed a 1:0.506 ratio of salt to chlorobenzene, indicating a chlorobenzene hemisolvate. DSC examination revealed a bimodal endothermic event with peak temperatures of 111.3°C and 113.1°C, followed by a secondary endothermic event with a peak temperature of 119.1°C.

[0970] 5MeODMT benzoate batch 21-01-064C was produced by adding the IPA solution reverse antisolvent to cold chlorobenzene and then balancing for 3 hours before separation. XRPD revealed Form E, which was supported by 1H NMR, which revealed a ratio of 1:0.512 salt to chlorobenzene, indicating a hemisolvate. DSC examination revealed a three-peak endothermic event with peak temperatures of 111.3°C, 113.1°C, and 114.3°C. There were similarities between the DSC thermograms of 064D and 064C, but the endothermic event at 119.1°C was not present in 064C and 064D did not reveal a three-peak endothermic event. The differences in the DSC thermograms are noteworthy because the XRPD patterns are identical and 1H NMR reveals a hemisolvate.

[0971] 5MeODMT Benzoate Batch 21-01-064C (Air Dry 4 Hours) was produced by air drying 064C for 4 hours. XRPD revealed Form E. DSC examination was performed at 2.5°C.min -1 A broad exothermic event was performed and revealed, followed by a minor endothermic event at 114.3°C, but much weaker than the same endothermic event in 064C. This was followed by a major endothermic event at 123.7°C, indicating a Pattern A form. The DSC thermogram was similar to the previous 2.5°C.min -1 DSC inspection, and the Type A form is generated during the DSC inspection.

[0972] 5MeODMT benzoate batch 21-01-064C (air dried 44 hours) was produced by air drying 064C (air dried 4 hours) for an additional 40 hours. XPRD revealed Form E. DSC examination revealed a bimodal endothermic event with peak temperatures of 115.1° C. and 115.8° C. The endothermic event of 064C (air dried 44 hours) was similar to that of 064C, but the peak was at a slightly higher temperature.

[0973] 5MeODMT benzoate Form E is a chlorobenzene hemisolvate with no well-defined thermal characteristics other than a multimodal endothermic event between 110° C. and 117° C. Similarly, for the anisole hemisolvate, Forms A and B do not recrystallize from the melt. The chlorobenzene hemisolvate does not appear to desolvate upon opening to ambient conditions and does not desolvate within 44 hours.

[0974] Example 29: Hemisolvate

[0975] Equilibration of the suspension in antisolvents (toluene, anisole and chlorobenzene) at -10 °C afforded the expected hemisolvates according to XRPD and 1H NMR spectroscopy as well as TGA.

[0976] Partial desolvation of the hemisolvate is believed to provide the multi-peak endothermic event observed in the DSC thermogram as a result of varying the composition and the heating rate applied.

[0977] Desolvation of the hemisolvate in vacuo at 50°C for 22 hours afforded Form B material by XRPD, DSC, however, some residual hemisolvate remained in all samples.

[0978] The DSC thermogram of the hemisolvate is similar to that of the hemisolvate isolated from IPA / antisolvent, but with minor differences that are believed to be a result of how they were prepared.

[0979] Drying of the toluene hemisolvate and chlorobenzene hemisolvate of 5MeODMT benzoate in vacuo at 50°C for 67 hours afforded Form A, but the anisole hemisolvate afforded Form B as the major form.

[0980] Addition of 5 MeODMT benzoate / IPA solution to toluene at -10°C followed by air drying for 5 minutes afforded a toluene hemisolvate when performed with 1 g input.

[0981] Drying of 5MeODMT benzoate toluene hemisolvate at 50°C for 24 hours provided Pattern B Form.

[0982] 5MeODMT benzoate batches 20 / 53 / 057-FP and 20 / 20 / 123FP exhibited a similar particle habit of large hexagonal / diamond shaped plates (approximately 500 μm to 1 mm in length) and some smaller plates that showed accumulation on the plate surface as well as clear evidence of broken fine particles and plates, possibly due to abrasion.

[0983] This is in contrast to batches 20 / 20 / 150FP2 T=0 and 20 / 20 / 154FP which exhibited similar particle habits of accumulated, jagged clusters of irregular plates (approximately 250 μm to 600 μm in length) and broken irregular plates and crystallites (some <20 μm in length) indicative of particle abrasion.

[0984] Significant differences in particle size and habit between batches are believed to have an impact on the separation, flowability and kinetic dissolution rate of the solids, highlighting the importance of controlled crystallization.

[0985] Example 30: Type F and Type G

[0986] 5MeODMT benzoate methyl benzoate hemisolvate (Form F) has been isolated from a clear 5MeODMT benzoate methyl benzoate solution by controlled cooling from 50°C to -10°C.

[0987] 5MeODMT benzoate 2-chlorotoluene hemisolvate (Form G) has been isolated from a clear 5MeODMT benzoate 2-chlorotoluene solution by controlled cooling from 80°C to -10°C.

[0988] The equilibrium in α,α,α-trifluorotoluene did not provide a hemisolvate as expected from a monosubstituted aromatic solvent. The equilibrium in cumene provided the Pattern B form, indicating a cumene hemisolvate.

[0989] DVS examination of the amorphous 5MeODMT benzoate revealed a weight loss of approximately 2%, indicating elimination of components and confirming that no stable hydrate of 5MeODMT benzoate was isolated.

[0990] The Formula A form is the most stable modification of the 5MeODMT benzoate salt and is the thermodynamically favored product, except when isolated from small amounts of selected solvents, which afford the corresponding hemisolvate.

[0991] Stability studies revealed conversion of all forms to the Form A form when dried in vacuum at 50° C. Form B form, however, has been shown to be stable when open to the atmosphere at about 20° C. for up to 12 days. Form C form underwent partial conversion to Form B form within 24 hours when open to the atmosphere at about 20° C., but failed to undergo any further conversion from the Form B / Form C hybrid variant for an additional 11 days.

[0992] The FTIR spectra of Form A, Form B, and Form C are generally similar, although there are some unique bands present in the Form A form and no bands that are otherwise present and shared by the Form B and Form C forms.

[0993] Controlled Cooling Crystallization Studies Using Extended Solvent Selection

[0994] Initial cooling crystallization studies of 5MeODMT benzoate revealed that Form A was isolated from most solvents except chlorobenzene, which was consistent with Form B. The solvent range was expanded with an emphasis on esters and aromatic compounds.

[0995] 50 mg ± 1 mg of 5MeODMT benzoate batch 20 / 20 / 150FP2 was loaded into crystallization tube AL. Minimal solvent was loaded at 50°C to provide a clear solution as detailed in the table below. Crystallization tubes I, J, K and L were heated at 50°C at 12.5 mg.ml -1The suspension remained and was therefore heated to 80°C to provide a clear solution.

[0996] The solution was clarified into a crystallization tube at 50°C and heated at 10°C.hr -1 Cooling to -10°C at a rate of 1000 rpm, followed by equilibration at -10°C for 12 hours, followed by stirring at -10°C at 400 rpm for 30 minutes, provided a mobile suspension for all samples except sample I, which remained a solution. Additional equilibration with stirring at -10°C at 400 rpm for 3 hours provided a dilute suspension. All samples were separated via an isolute column and air dried for 5 minutes before characterization.

[0997] Sample F, isolated from methyl benzoate, was a viscous white paste after air drying for 5 minutes and was allowed to air dry on the XRPD sample holder for an additional 30 minutes before providing a dry powder.

[0998]

[0999]

[1000] 5MeODMT benzoate batches 21-01-073B, 21-01-073C, 21-01-073D, 21-01-073E, 21-01-073G, 21-01-073H and 21-01-073L were isolated from n-propyl acetate, isopropyl acetate, isobutyl acetate, ethyl formate, methyl propionate, 4-methyl-2-pentanone and α,α,α-trifluorotoluene, respectively.

[1001] XRPD of these samples revealed a powder form consistent with 5MeODMT benzoate batch 20-37-64 Form A.

[1002] Selected DSC thermograms of Form A material reveal a common endothermic event with peak temperatures ranging from 123.07°C to 124.17°C and an enthalpy of about 140 J.g-1, which is characteristic of Form A. 5 MeODMT benzoate salt batches 21-01-073B, 21-01-073E, 21-01-073H and 21-01-073L were isolated after controlled cooling and then air dried for 5 minutes. 1 H NMR spectroscopy revealed that the stoichiometry of the salt was 1:1 and also revealed that the ratio of salt to solvent ranged from 1:0.0155 to 1:0.027.

[1003] 5MeODMT benzoate batch 21-01-073A was isolated by controlled cooling of the methyl acetate solution from 50°C to -10°C, followed by air drying for 5 minutes.

[1004] XRPD of 5MeODMT benzoate batch 21-01-073A revealed a diffraction pattern consistent with 5MeODMT benzoate batch 20-37-64 pattern A ( Fig.83 ), but with stronger characteristic diffraction at 21°2θ and 24.6°2θ. The difference in intensity may be the result of preferred orientation.

[1005] Fig.83 A comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073A, 21-01-049B1 Pattern B, and 20-37-64 Pattern A are shown.

[1006] The DSC thermogram of 5MeODMT benzoate batch 21-01-073A revealed an endothermic event with a peak temperature of 123.58°C, which is characteristic of the Pattern A form.

[1007] The 1H NMR spectrum of 5MeODMT benzoate batch 21-01-073A, which was isolated after controlled cooling and then air dried for 5 minutes, revealed a 1:1 stoichiometry of the salt and also revealed a 1:0.033 salt to solvent ratio of methyl acetate. 5MeODMT benzoate batch 21-01-073F was isolated from a methyl benzoate solution by controlled cooling from 50°C to -10°C and then air dried for 5 minutes. After air drying for 5 minutes, the sample was a paste and further air drying for 30 minutes provided a moist powder.

[1008] XRPD of 5MeODMT benzoate batch 21-01-073F revealed an XRPD pattern with an amorphous halo ( Fig.84 The sample was reconstituted after further air drying. The XRPD of 5MeODMT benzoate 21-01-073F (reconstituted) revealed a diffraction pattern consistent with the initial measurement, but with a reduced amorphous halo ( Fig.85 ). The diffraction pattern shows some similarities to both Pattern A and Pattern B ( Fig.86 ), but the presence of the unique diffraction and the lack of the characteristic Form A and Form B diffraction indicate that this material is a unique solid form variant, identified herein as Form F.

[1009] Fig.84 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073F and a reproduction of 21-01-073F.

[1010] Fig.85 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073F reproduction, 21-01-049B1 Pattern B, and 20-37-64 Pattern A.

[1011] Fig.86 Shown is an expanded comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073F replicate, 21-01-049B1 Pattern B, and 20-37-64 Pattern A.

[1012] The DSC thermogram of 5MeODMT benzoate batch 21-01-073F (reproduced) revealed a broad endothermic event with a peak temperature of 90.50° C., which was followed by a small endothermic event with a peak temperature of 106.65° C. This was followed by a broad and shallow endothermic event with a peak temperature of 180.35° C.

[1013] After storing the sample in a sealed container for 24 hours, the DSC examination was repeated. The DSC thermogram revealed a major endothermic event with a peak temperature of 95.33° C., followed by an exothermic event with a peak temperature of 102.70° C. This was followed by an endothermic event with a peak temperature of 113.77° C.

[1014] The 1H NMR spectrum of 5MeODMT benzoate batch 21-01-073F, which was isolated after controlled cooling and then air-dried for 5 minutes, revealed a 1:1 stoichiometry of the salt and also revealed a 1:0.59 salt to solvent ratio. After air-drying, a pasty consistency indicated the presence of methyl benzoate, and a visually damp powder after air-drying for 30 minutes indicated that residual methyl benzoate was still present. However, due to the unique diffraction pattern and DSC thermogram combined with the stoichiometry close to 1:0.5 and the tendency of 5MeODMT benzoate to form hemisolvates with aromatic solvents, this sample was considered to be a methyl benzoate hemisolvate.

[1015] 5MeODMT benzoate batch 21-01-073I was isolated by controlled cooling of a 5MeODMT benzoate cumene solution from 50°C to -10°C, followed by air drying for 5 minutes.

[1016] XRPD of 5MeODMT benzoate batch 21-01-073I revealed a diffraction pattern consistent with SPS5520 21-01-049B1 Pattern B.

[1017] The DSC thermogram of 5MeODMT benzoate batch 21-01-073I reveals an endothermic event with a peak temperature of 109.24° C. and a broad shoulder at about 100° C. This is 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 is followed by a broad exothermic event with a peak temperature of 146.19° C. This thermal profile is similar to the historical Form B sample, although the exotherm after the final melt is known.

[1018] The 1H NMR spectrum of 5MeODMT benzoate salt batch 21-01-0731 isolated after controlled cooling and then air dried for 5 minutes revealed a 1:1 stoichiometry of the salt and also revealed a 1:0.035 salt to solvent ratio.

[1019] 5MeODMT benzoate batch 21-01-073J was isolated by controlled cooling of a 5MeODMT benzoate toluene solution from 50°C to -10°C, followed by air drying for 5 minutes.

[1020] XRPD of 5MeODMT benzoate batch 21-01-073J revealed a diffraction pattern consistent with 5MeODMT benzoate batch 21-01-064A Pattern C.

[1021] The DSC thermogram of 5MeODMT benzoate batch 21-01-073J revealed endothermic events with peak temperatures of 110.00° C., 115.03° C., and 120.60° C. The DSC thermogram was similar to the previously isolated Type C Form material 5MeODMT benzoate batch 21-01-071C1, although the minor peaks were different, which is believed to be a result of the sample preparation.

[1022] The 1H NMR spectrum of 5MeODMT benzoate batch 21-01-073J isolated after controlled cooling and then air-dried for 5 minutes revealed a 1:1 salt stoichiometry and also revealed a 1:0.473 salt to solvent ratio, confirming the isolation of the toluene hemisolvate in the Form C form.

[1023] 5MeODMT benzoate batch 21-01-073K was isolated by controlled cooling of a 5MeODMT benzoate 2-chlorotoluene solution from 50°C to -10°C, followed by air drying for 5 minutes.

[1024] XRPD of 5MeODMT benzoate batch 21-01-073K revealed a unique diffraction pattern ( Fig.87 ) and is identified herein as Type G.

[1025] Fig.87 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-073K, 21-01-049B1 Pattern B, and 20-37-64.

[1026] The DSC thermogram of 5MeODMT benzoate batch 21-01-073K revealed an endothermic event with peak temperatures of 111.28°C and 119.61°C.

[1027] The 1H NMR spectrum of 5MeODMT benzoate batch 21-01-073K isolated after controlled cooling and then air-dried for 5 minutes revealed a 1:1 stoichiometry of the salt and also revealed a 1:0.516 salt to solvent ratio, thus the Pattern G form is believed to correspond to 2-chlorotoluene hemisolvate.

[1028] The following table is a summary of the samples isolated from this controlled cooling experiment and the XRPD patterns provided.

[1029]

[1030]

[1031] Example 31: DVS examination of amorphous 5MeODMT benzoate produced via lyophilization

[1032] 150mg of 5MeODMT benzoate 20 / 20 / 150FP2 is dissolved in 5ml of deionized (DI) water to provide a clear solution. The solution is clarified in a 500ml round-bottomed flask, and the round-bottomed flask is rotated in an acetone / dry ice bath to freeze the solution in a thin layer around the flask. Ice is sublimed at ambient temperature in a vacuum to provide a fluffy white solid. The solid is taken out from the round-bottomed flask and transferred to a DVS instrument. During this transfer, the solid collapses into a viscous glue.

[1033] The samples were examined by DVS starting at 40% RH and cycling twice between 0% RH and 90% RH.

[1034] XRPD was collected on a portion of the samples after lyophilization and after DVS inspection.

[1035] XRPD of 5MeODMT benzoate before DVS analysis revealed the expected amorphous diffraction pattern ( Fig.88 ). Fig.88 Shown is the XRPD of 5MeODMT benzoate batch 21-01-078.

[1036] DVS examination showed an initial weight loss of approximately 1.4% from the start of the study during the first desorption cycle ( Fig.89 ), which is much lower than the 5wt% required for 5MeODMT benzoate monohydrate. Although RH increased to 70%RH during the first adsorption, the weight loss continued. There was a small weight increase at 80%RH and 90%RH in the first adsorption cycle. After this, the weight decreased to a minimum in the second desorption cycle, and in subsequent adsorption cycles, there was no change in weight until 50%RH, with a 0.2% weight increase between 50%RH and 90%RH.

[1037] Fig.89Shown is the DVS isotherm plot for 5MeODMT benzoate batch 21-01-078.

[1038] XRPD of 5MeODMT benzoate batch 21-01-078 revealed a diffraction pattern consistent with Form A after DVS examination at 90% RH ( Fig.90 ).

[1039] Fig.90 Shown is a comparison of the XRPD patterns of 5MeODMT benzoate batches 21-01-078 (post-DVS) and 20-37-64.

[1040] Amorphous 5MeODMT benzoate is unstable and undergoes a transition to the Form A form under all conditions studied. Under ambient conditions, it is believed that the amorphous variant absorbs moisture from the atmosphere, which is eliminated from the sample after conversion to the Form A form. Such conversion is not considered to be via a hydrate, because no evidence of a hydrate of 5MeODMT benzoate is observed. Alternatively, the freeze-drying process may appear to be complete when in fact some moisture is still bound to the solid. When the freeze-drying container is emptied to atmospheric pressure, the low-density, bulky solid shrinks, trapping moisture to provide glue, which is then discharged as an amorphous glue and converted into a more stable, ordered Form A form variant.

[1041] Example 32: FTIR Spectroscopy of 5MeODMT Benzoate Form A, Form B and Form C

[1042] Fig.91 Shown are FTIR overlays of 5MeODMT benzoate Pattern A Form (20-20-150FP2), Pattern B Form (21-01-071C2), and Pattern C Form (21-01-071C1).

[1043] Fig.92 The 5MeODMT benzoate forms A (20-20-150FP2), B (21-01-071C2) and C (21-01-071C1) were shown at 450 cm -1 Up to 2000cm -1 FTIR overlay.

[1044] Fig.93 The 5MeODMT benzoate forms A (20-20-150FP2), B (21-01-071C2) and C (21-01-071C1) were shown at 450 cm -1 Up to 2000cm -1 FTIR superposition; spectral separation.

[1045] Examination of the FTIR revealed that the Form A Form exhibited a number of bands of significantly different intensities compared to the Form B Form and the Form C Form. At about 3130 cm -1 、1540cm -1 、1460cm -1 、1160cm -1 and 690cm -1 Such a prominent band is observed at about 3230 cm-1, while the key missing (or significantly reduced intensity) band present in Forms B and C includes -1 and 1640cm -1 The band observed at .

[1046] The Form B form and the Form C form exhibit much less difference from each other in their FTIR when compared to the FTIR of the Form A form.

[1047] This is expected as the Form C Form hemisolvate is considered to desolvate somewhat readily to provide the Form B Form, resulting in relatively small changes to the lattice compared to the energy required to induce conversion of the Form B Form to the Form A Form (i.e.; drying at elevated temperatures in vacuum), which reorganizes the lattice to a greater extent than simple desolvation.

[1048] Example 33: Stability of Form B and Form C

[1049] Drying 5MeODMT benzoate Form C in vacuum at 50° C. for 24 hours historically generally provides Form B, and Form B is known to transform to Form A at 90° C. as observed by hot stage microscopy. The stability of Form A and Form B under atmospheric conditions and in vacuum at 50° C. was studied to determine the relationship between the forms.

[1050] 5MeODMT benzoate Batch 21-01-071C1 Pattern C Form and Batch 21-01-071C2 Pattern B Form were loaded into XRPD sample racks and sample vials and left open to the atmosphere for 12 days.

[1051] 5MeODMT benzoate batch 21-01-071C1 Pattern C Form was dried in vacuum at 50°C for 5 days.

[1052] XRPD was performed periodically.DSC and 1H NMR spectroscopy were performed on samples where significant differences in diffraction patterns were observed.

[1053] The table below shows a summary of solid form conversion by XRPD during stability testing.

[1054]

[1055] Example 34: Competition of 5MeODMT Benzoate Form A, Form B and Form C in Solvent balance

[1056] The relationship between Form A, Form B, and Form C of 5MeODMT benzoate was studied to determine thermodynamically stable variants and hierarchies. Competing equilibria were performed between Form A and Form B, and Form A and Form C in a variety of solvents including IPA and toluene. Given the melting point of Form A at 124°C and its ubiquity during most of the studies conducted, Form A was expected to be the most stable form.

[1057] 15mg of 5MeODMT benzoate 20 / 20 / 150FP2 pattern A form is loaded into all crystallization tubes.30mg of 5MeODMT benzoate batch 21-01-071C2 pattern B form is loaded into AB crystallization tube.30mg of 5MeODMT benzoate toluene hemisolvate batch 21-01-071C1 pattern C form is loaded into AC crystallization tube.0.5ml of solvent is loaded into crystallization tube, as detailed in the following table.Suspension is stirred at 20 ℃ ± 2 ℃ with 100rpm for 24 hours.Separate suspension via isolute column, and air-dry for 5 minutes and characterize by XRPD and DSC.

[1058]

[1059] XRPD of all samples revealed that most gave Form A.

[1060] Sample AC5 isolated from MEK reveals an additional diffraction at 8.8° 2θ, however this is believed to be caused by splitting of the diffraction at 9° 2θ due to better resolution between the diffractions of this sample.

[1061] The DSC thermograms of most Pattern A Form samples revealed endothermic events with peak temperatures ranging from 123.74°C to 124.22°C, indicative of the Pattern A Form.

[1062] The DSC thermogram of 5MeODMT benzoate isolated from isopropyl acetate, batch 21-01-079AB3, revealed a series of events between 109° C. and 115° C., followed by a minor 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., indicative of Pattern A form.

[1063] The minor endothermic event is believed to be due to incomplete conversion of Form B to Form A via equilibrium.

[1064] XRPD of both 5MeODMT benzoate batches 21-01-079AB2 and 21-01-079AC2, both equilibrated in toluene, revealed diffraction patterns consistent with 5MeODMT benzoate batch 21-01-064A toluene hemisolvate Pattern C Form.

[1065] The DSC thermogram of 5MeODMT benzoate batch 21-01-079AB2 revealed a bimodal endothermic event with peak temperatures of 114.96° C. and 121.92° C. The thermal characteristics were similar to previously isolated Form C samples including 5MeODMT benzoate batch 21-01-073J.

[1066] The DSC thermogram of 5MeODMT benzoate batch 21-01-079AC2 revealed a minor endothermic event with a peak temperature of 110.11° C., followed by endothermic and exothermic events superimposed between 110.73° C. and 113.23° C. This was followed by an endothermic event with a peak temperature of 122.82° C., which is comparable to the melting of Form A when recrystallized from Form B.

[1067] Both the Form A Form / Form B mixture and the Form A Form / Form C mixture exhibited conversion to Form A in a competitive equilibrium in solvents where hemisolvates had not previously been observed to produce hemisolvates. All other hemisolvates are expected to convert to Form A in these solvents.

[1068] Competing equilibria of both Form A / Form B and Form A / Form C in toluene exhibited conversion to Form C. It is expected that equilibrium of 5MeODMT benzoate in solvents with a tendency to form hemisolvates (typically aromatic solvents) will provide a specific 5MeODMT benzoate hemisolvate rather than other thermodynamically stable Form A solid form variants.

[1069] Example 35: Administration of 5MeODMT Salt

[1070] The physical environment of the participant / patient / subject is very important in many of the features of the psychedelic experience. The space should be private, meaning there should be no opportunity for intrusion by others. Ideally, sounds from the outside (e.g., hallways, streets, etc.) will be minimal. The dosing session should take place in a room that feels like a living room or study, rather than in a clinical setting. Artwork, plants, flowers, soft furniture, soft lighting, and related decorations should be used to create a comfortable and relaxing aesthetic. Artwork with any particular religious iconography, ideological connotations, or a tendency to evoke negative emotions should be avoided. The dosing room can also provide comfortable furniture for the participant and therapist, who can sit on either side of the participant. Participants under the influence of 5MEODMT may exhibit spontaneous movements or slide off the bed or couch in their prone position. Therefore, it is important to ensure that there are no sharp or hard objects nearby that the participant could fall on. Additionally, pillows may be useful to physically support the participant as they move during the experience. Therapists can provide physical support to the participant by placing a pillow between their hands and the participant's body.

[1071] Music may accompany the experience, so the dosing room should be equipped with a stereo. The room should protect the participant from the sights and sounds of the outside world, and the participant should not have any reason to fear being observed or disturbed by anyone other than the therapist.

[1072] This space can also contain:

[1073] -Safety procedures, tools and medical devices necessary to respond in the unlikely event of a medical complication. Participants should be made aware of these procedures and devices, but they should be kept hidden as much as possible.

[1074] -A secure and locked space for study materials and documents in or near the session room.

[1075] -An approved safe for storing 5MEODMT in or near the link room.

[1076] - Audio and video recording equipment: If permitted in the research protocol, participants will have consented to be recorded and should be aware of the equipment, but the equipment should be placed to be as unobtrusive as possible. Participants can request that recording stop at any time.

[1077] Physical Space

[1078] The space can be large enough to accommodate chairs for two therapists, stereo equipment, and storage cabinets for the participant's belongings and any additional supplies the therapist may need during the day. The space can accommodate a bed or sofa where the participant can sit up or lie down with a comfortable pillow environment. The space can be at least 100 2 feet or 10 2 The room should be 1.5 meters so that participants do not feel cramped or physically too close to the therapist. Participants should have space to explore a variety of positions, including sitting on the floor or stretching their bodies without restriction. The bathroom should be accessible directly from the session room or nearby.

[1079] music

[1080] 5MEODMT sessions may use a preset playlist of nature sounds to create a calming atmosphere. These nature sounds are meant to be a background element that helps drown out any noise outside and keep participants focused on their experience. Participants are not instructed to listen to the sounds in any particular way, but may be asked to focus on it as a way to ground their senses and relax before or after a session.

[1081] Medication discontinuation

[1082] Medication discontinuation can be challenging for participants. Participants should discontinue all contraindicated medications and complete a washout period prior to Prep-1 with a therapist. Research team members, including therapists, may provide supportive check-in calls to participants during the washout period as needed prior to this, but Prep-1 should not begin until washout is complete and the participant confirms intent to continue therapy.

[1083] Preparation

[1084] This treatment model involves three 60-90 minute preparatory sessions with a therapist. These take place 7, 4, and 1 day prior to the 5MEODMT session. The preparatory sessions are designed to be conducted via telehealth, but can also be conducted in person if possible.

[1085] Preparation 1

[1086] The following topics can be covered in the first preparation session.

[1087] Get to know the participants

[1088] The therapist will spend some preparation time getting to know the participant. The therapist may ask open-ended questions about:

[1089] - How they found out about the treatment and what their expectations were;

[1090] - Current life situation regarding living situation, work, school, and significant relationships;

[1091] -Awareness of their own depression;

[1092] -Key life events that the participant felt might be relevant.

[1093] Therapists should listen to how participants talk about themselves and their relationship to their depression, how they relate to the therapist and the learning environment, and remain attuned to building trust and rapport with the participant. Clinical impressions of difficulty in forming a trusting relationship with the therapist or any other clinical factors that may interfere with the participant's ability to engage in treatment should be noted and discussed with the research team. Although the therapist may learn more about the participant during the preparation phase, this may be a reason for exclusion from the study.

[1094] Establishing the Therapist’s Role

[1095] The therapist in the 5MEODMT adjunctive therapy treatment model forms a relationship with the research participant that becomes part of the container in which the 5MDE (subjective experience of 5MeODMT) occurs. 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 well-being, and for the patient's relational and emotional safety. The therapeutic relationship is understood as a key component of the set and setting for the therapeutic use of 5MDE. The communication and building of this relationship is both explicit (overt) and implicit (covert) in the therapist's actions and demeanor throughout the treatment process.

[1096] Explain the therapeutic model in which participants serve as active participants in their process.

[1097] Therapists should explain the treatment model used in this research study to participants during the first preparation session. The explanation should include:

[1098] Practical aspects:

[1099] -How many sessions with the therapist will occur, and how long they will last.

[1100] - This therapy is thought to work by:

[1101] - Create a safe container for the experience so that guests know what to expect and can fully engage in their experience,

[1102] - Help participants focus on and explore their own responses to the experience,

[1103] - Facilitate the process by which participants decide for themselves how they will put their insights into practice in their lives.

[1104] The role of the therapist is to:

[1105] -Support participants throughout the session, engaging in a range of activities to elicit participants’ unique experiences and insights, facilitating the process of participants implementing the resulting changes in their lives.

[1106] - Therapy is:

[1107] - It is not a place to delve into the participant’s personal history, address specific issues or engage in CBT, psychodynamic interpretation, get general advice or receive other interventions with which the participant may be familiar.

[1108] Establish physical, emotional, and psychological / relationship safety

[1109] Beginning with the first preparation session, the therapist establishes an environment of physical, emotional, and psychological safety. The therapist explains the safety of 5MEODMT and the safety procedures related to the physical health of the participants in this session. Regarding emotional safety, the therapist states that all emotional experiences are welcome and there are no areas of experience that participants are not welcome to share. Safety can also be established through the therapist's calm reassuring presence, which does not always require the use of words.

[1110] Self-disclosure is not prohibited, but should be used with great caution. Participants can seek safety by asking the therapist personal questions. If the therapist chooses to disclose, it should be brief and under the condition that the participant shares why this personal information is important to them.

[1111] Psychological / relational safety is established by assuring participants that their wishes regarding the use of touch will be respected. Additionally, participants should be reassured that if they choose not to participate in the 5MDE experience, they may do so at any point, all the way up to drug administration, and that this will be respected and that the treatment session will still be available to them if they make this choice.

[1112] Therapists can use the following techniques to establish safety with participants:

[1113] Ask open-ended questions that elicit expressions of doubt, hesitation, or concern:

[1114] Do you have any questions for me?

[1115] What else do you want to know about 5MeODMT?

[1116] What would you find helpful in the case of...?

[1117] How can I help you if you feel...?

[1118] Encourage and engage with the full range of participants’ emotions and experiences, rather than trying to fix or resolve them:

[1119] Participant expressing doubt about 5MEODMT experience: I appreciate you sharing this with me. What do you think of this, given that you are here at this time?

[1120] Participant expressed fear regarding 5MDE experiences: What else can you tell me about your fear and how it manifests for you? How can I be helpful to you when you are experiencing this?

[1121] Use affirmations to establish an environment where participants’ time and efforts are valued:

[1122] I really appreciate the time you have invested in this treatment and your willingness to participate in research.

[1123] Your experience is unique to you and I welcome the opportunity to watch you go through this process.

[1124] Expected potential subjective drug effects (unity, “feeling like dying,” “emptiness”)

[1125] It may be helpful to discuss the concept of “alternative states of consciousness” with participants. In the past, “altered states of consciousness” have often been associated with experiences produced by psychedelic compounds. However, altered states of consciousness are experienced daily as moods or sensations shift, or when people go from being awake and alert to feeling tired and drowsy. “Alternative states of consciousness” emphasizes the quality of experiences that are not typically an everyday occurrence but can still be within the human experience.

[1126] The therapist can begin this conversation by asking the participant about their prior knowledge of the 5MEODMT effect, and listening for specific expectations or thoughts about it. The therapist encourages openness to the experience, encouraging the participant to explore the types / thoughts they might have, and being open to the possibility that it will be unimaginable what this will be like. The participant may have specific expectations based on media, prior experiences with 5MEODMT or other psychedelics, or other types of non-ordinary states of consciousness. It is important for the therapist to provide a balanced description of what the participant may experience.

[1127] Different people have different comfort levels with “not knowing” what something will be like or “not knowing” what to expect. Therapists can explore the participant’s comfort level with the unknown, their relationship to the idea that the future is not fully knowable in any case, and how they generally relate to this. In participants with depression, there may be a deep fear of the unknown, and expectations of what is expected in the future (more often than not, negative experiences), leading to a feedback loop of feeling fearful and depressed. Therapists should elicit and explore this area during preparation.

[1128] Common 5MeODMT Experiences: The therapist should also introduce some key items and commonly reported experiences that are known to occur with 5MEODMT. These include feelings of unity, feelings of dying, and feelings of entering or experiencing "the void" (absence of physical reality). Some participants may have existing spiritual, philosophical, or religious belief systems through which they will interpret or give meaning to these experiences. The therapist should inquire about this and work with the participant's own interpretations and statements, rather than taking a position on whether these are right or wrong.

[1129] Social Support and Social Media

[1130] The participant's social support may be assessed during the preparation session and determined by the therapist to be sufficient to support the patient throughout the change process, especially in the case of disappointment or significant symptom reduction. In the case where the participant has a psychotherapist outside the study, the research therapist may call the participant's therapist with the participant's permission to describe the nature and treatment methods of the study and answer any questions the therapist may have. The research therapist may also educate any friends or family members who are close to the participant and 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 various reactions that their friends and family may have.

[1131] Therapists may advise participants to be cautious about posting on social media around their experiences so as not to trigger excessive public commentary. Inadequate social support or the use of social media in ways that could undermine the therapeutic process can be discussed and addressed prior to the administration of 5MEODMT.

[1132] Preparation 2

[1133] The following topics can be covered in the second preparation session.

[1134] Preparation for drug experience: trust, surrender (renunciation), acceptance, and transcendence.

[1135] There are several key attitudes toward psychedelic experiences that are considered conducive to positive and clinically useful experiences. The more participants can demonstrate a relaxed stance toward their experience, the less likely they are to struggle, unintentionally creating a cycle of stress and distress that heightens focus on negative aspects and interpretations. Therapists can educate participants with the goal of intentionally generating an attitude of trust, surrendering to the experience, and letting go of attempts to control the experience. Therapists can encourage participants to develop an attitude of welcoming and accepting all experiences they may have as part of their 5MEODMT experience. Therapists can suggest to participants that all aspects of the experience (feelings, sensations, and thoughts) can be welcome. Previous research on psychedelics has demonstrated that the ability to be absorbed by the experience can contribute to the potency of the mystical experience.

[1136] Drug administration

[1137] The therapist should explain that on the day of the session, a member of the research team will briefly enter the room to administer the study medication. The therapist should explain the positioning of the participant, e.g., they will be in a sitting position on a bed or couch, a member of the research team will insert a nasal spray device in one nostril, and they will be asked to allow the therapist to help them lie down on the bed or couch immediately afterwards.

[1138] Includes procedures for boundaries, use of touch, safety, etc.

[1139] The therapist will explain the process of the session. The session is encompassed by the timing of the administration and the physical environment of the administration room. The session begins when the participant enters the room and interacts with the therapist at the session opening. The session opening is a formal moment where the participant and therapist are seated in the room together, all preparations are made, and the playlist begins. If the participant would like to participate in a breathing exercise, the therapist may lead the participant's chosen breathing exercise and ask the participant to think about the values ​​they chose in the preparation session, 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 will administer the nasal spray to the participant. Trust and safety are not only communicated verbally, but this can be communicated non-verbally by how the therapist holds themselves in the presence of the participant. If the therapist is overly anxious or fearful, this can be sensed by the participant. It is important that the therapist is central throughout the administration session, especially when the participant is expressing strong emotions, unusual physical expressions, or seeking support.

[1140] Physical changes and shifts in how a person feels about their body

[1141] Some participants may experience heightened awareness of their bodies, such as a more intense sense of their heart rate or physical sensations in their temples. Other participants may be aware of tingling, changes in their bodies, or perceived difficulty breathing, or other unusual physiological experiences. It is important for the therapist to convey that these changes in perception are normal and should not become a focus of preoccupation or fear. If these feelings occur, the participant should be encouraged to communicate these feelings with the therapist if they wish. The therapist should reassure the participant that these feelings are expected and that it is normal to have them. The therapist can inform and remind the participant that naturally occurring 5MEODMT has been consumed in other settings for hundreds of years with no indication that it is physically harmful and that these changes are expected and will subside quickly.

[1142] Discuss expectations and intentions

[1143] Expectations can be defined as mental representations and beliefs about how things will be in the future. Sometimes expectations can be explicitly identified, and sometimes they are subperceptual, taken for granted. Both types of expectations can be important to therapy. Therapists should ask about explicit expectations, and encourage participants to acknowledge and set these aside so that they are not involved in comparing their experience to expectations. Therapists are also listening for subperceptual expectations that may come into consciousness through therapy. Intentions are the way things are related to behavior or experience. In 5MEODMT therapy, it can be important for the therapist to elicit and understand the intentions of the participants, as these intentions can vary greatly and may be taken for granted. The therapist engages the participant in the process of identifying and setting their intentions so that these intentions are explicit and can be referenced later in integration. The purpose of the intention is that it will be identified and then abandoned, knowing that it can be part of 5MED.

[1144] Acute effects recurrence

[1145] Some individuals who have used 5MEODMT in non-clinical situations have reported experiencing the subjective effects of 5MEODMT again in the days that followed. In these cases, the dose, purity, and other factors used were not monitored. The likelihood of these reactivations occurring in controlled clinical studies is unknown, but it is estimated to be less likely. Nevertheless, it is important for participants to be aware of this phenomenon. The experience of reactivation is generally reported to be pleasant, short-lived (lasting a few moments to a few minutes), and not occurring at a frequency sufficient to interfere with a person's life. These reactivations are considered by some to be part of the integration process. If participants notice that certain activities trigger reactivation, such as certain meditative states, stimulants, or other drugs, and participants find these reactivations unpleasant, participants should be advised to avoid such triggers. It can also be helpful to process 5MEODMT experiences as part of integration in therapy.

[1146] Discuss the use of touch

[1147] Therapists in this model may engage in two types of touch: therapeutic touch and touch for safety reasons. During preparation, therapists should explain and define each. Therapeutic touch is touch intended to connect with, comfort, or otherwise communicate with a participant for therapeutic purposes. It is always fully consented, non-sexual, and participants are encouraged to refuse or stop therapeutic touch at any time. Touch for safety reasons can include supporting a participant who has difficulty walking by extending an arm, or preventing a patient from leaving the room when under the effects of acute medication. This type of touch is consented to in advance, is always non-sexual, and is limited to specific safety concerns. Therapists should discuss both types of touch and establish boundaries with participants prior to the session.

[1148] Preparation after the session (what to expect, what to do, leaving time for integration)

[1149] Participants should be encouraged to take some time to rest and integrate their experience after their session day. The research therapist should ask participants to plan rest time after their session, at least for the entire session day and the day after the session. The therapist should explain that they will be together in the room for a period of time after the acute effects of 5MeODMT have worn off. This period of time will allow participants to re-acclimate to their experience after the acute effects. They will be asked to share what they can recall about their experience and any reactions they had. They will not be asked to share anything they do not want to share, and are also welcome to keep their experience confidential. They may choose to write or draw their experience, and art supplies and writing supplies will be available. They may be encouraged to spend some time continuing to maintain their experience, with the support of the therapist, for about an hour. They will then meet with the research team before returning home for a safety assessment. Once at home, they are encouraged to rest and continue to maintain the experience and the insights, ideas, or new understandings they may have from it. Participants should be reminded that they do not need to share their experience with others unless they wish, and are encouraged to continue to focus on the experience in the way they find most helpful. Participants should refrain from returning to work, driving, alcohol, drug use, or being the sole caregiver of a child or dependent for the remainder of the day.

[1150] Therapist teaches breathing exercises during medication administration

[1151] When stressed, breathing becomes shorter and shallower, and when relaxed, breathing becomes longer and slower. Operational breathing is a way to modulate and regulate one's mental state. Therapists may teach and practice two breathing techniques with participants. These are designed to help participants relax their mind and body, tolerate stressful or uncomfortable experiences, and develop autonomy through their own practice. These are not intended for use during the acute effects of 5MeODMT, but may be used before and after administration.

[1152] When teaching the exercises, the therapist elicits the participant's personal response to each exercise to assess the suitability of using it. Breathing exercises include: balanced breathing, diaphragmatic breathing, and counted breathing.

[1153] Preparation 3

[1154] Values ​​Card Sorting with Prompts

[1155] The treatment program can use a customized personal values ​​card sort to help the treatment focus on transformation in the sense of self. This is done by asking people how they relate to their chosen values ​​before the session, and how they relate to these values ​​afterwards, drawing attention to transformation, change, and using these as a guide to the kinds of changes that the participant may wish to make. It is used as a way to initiate a conversation about the participant's sense of self, beliefs about the self, and changes in these feelings / beliefs throughout the therapy. The therapist can engage the participant in a card sorting exercise in a third preparation session, so that it is conducted 1-2 days before the administration session.

[1156] Instructions for using the Values ​​Card Sorting are:

[1157] 1. Place the five anchor cards in front of the participant from left to right in order from 1-5, from least important to most important.

[1158] 2. Shuffle the 100 value cards; separate the 2 blank cards.

[1159] 3. Instruct participants to sort the cards using the following script: “I have placed five title cards in front of you—Not Important to Me, Somewhat Important to Me, Important to Me, Very Important to Me, and Most Important to Me. I am going to give you a stack of 100 personal values ​​cards. I want you to look at each card and place it under one of the five title cards. There are also two blank cards. If there is a value you would like to include, write it on the card and place it in whichever pile you would like. I want you to sort all 100 cards, but it is optional whether you use the other two cards. Do you have any questions?”

[1160] 4. When participants have finished sorting, thank them and invite them to look at the “most important” category, removing the other cards from the table.

[1161] 5. Read the following: “For the second assignment, I want you to focus on the highest values ​​you placed in the “most important” category and pick your top five.”

[1162] 6. When participants have chosen their top five cards, thank them and read the following: “For the third task, I would like you to focus on the top five values ​​you chose and rank them in order from most important to least important.”

[1163] 7. When participants have indicated they have completed the sorting, check to make sure you understand how the cards are sorted (ascending or descending). Point to point #1 and say, “I want to make sure I have this right—is this your number one value?”

[1164] 8. Record the values ​​on a rating sheet, in a journal, or by taking a photo of the card. Participants should also record their card choices.

[1165] Report and discussion:

[1166] Next, invite participants to engage in a structured discussion of each value using several of the following open-ended prompts, or similar prompts depending on your work environment:

[1167] -You chose __________ as your #__ value?

[1168] -Please tell me more about what _________ means to you?

[1169] -In what ways has _________ manifested itself in your life?

[1170] -In what ways would you like to see more of ______ in your life?

[1171] -How does your decision about ______ relate to this value?

[1172] -How much ______ do you want to have in your life?

[1173] -How do you know if _______ is increasing or decreasing in your life?

[1174] -How does _____ relate to the change you are trying to make (or considering making)?

[1175] Invite participants to use the remaining cards to record their responses to the same questions afterwards. In a later session, it may be helpful to review the values ​​and revisit these questions to see how the responses have changed and how participants currently relate to their values.

[1176] Assistant Therapist

[1177] Sessions may be conducted by the therapist with an assistant therapist so that a second person can assist in the event of any adverse events or physical complications to the participant's safety. The assistant who will be attending the session should be introduced in preparation for Session 3 and included in the conversation so that they get to know the participant.

[1178] Session-specific treatment tasks

[1179] Therapists should aim to accomplish the treatment tasks outlined above according to the diagram below, taking into account that some variation will occur based on the needs of the individual participant.

[1180]

[1181]

[1182] 5MeODMT experience session

[1183] The therapist is present with the participant during this session, including pre- and post-session time. This is the only session that must be conducted in person. Treatment centers and therapists should allocate approximately 3 hours for this session, including pre- and post-session time. This does not include the time allocated for baseline measurements of participation and confirmation of inclusion prior to the session. Local regulatory approval will determine the minimum length of time a participant must be observed after 5MEODMT administration.

[1184] Before the experience (about 30 minutes)

[1185] After the participant has completed all the inclusion confirmation and randomization procedures and is allowed to participate, the therapist, assistant therapist and participant will review all aspects of the room and safety procedures in the room together. The therapist should introduce the participant to the team member administering 5MEODMT to create a sense of familiarity. The therapist introduces any assistant therapist and reviews the safety performance of the room and the equipment present. Participants have time to ask any questions. The therapist will ask any response to the situation and how the participant feels about their session. Participants should not be rushed by the therapist. The therapist will ask the participant to participate in a period of relaxation before administering the drug. The participant will be asked to lie down, close his eyes, listen to music, and if willing, participate in at least one breathing exercise under the guidance of the therapist. When the participant settles down and feels comfortable, the therapist will start the session opening. This practice helps to include and emphasize the special nature of the experience. The therapist will contact members of the research team to the room and administer 5MEODMT. Team members should know not to destroy the quiet atmosphere of the room. The participant should be in a sitting position when the 5MEODMT is insufflated, and because the effects may be felt rapidly, the participant should transition to a prone position and remain prone for the duration of the effects of the 5MEODMT.

[1186] Experience (about 60 minutes)

[1187] The onset of the expected acute effect will occur very quickly after administration. Therapists should know the time of administration so that they can know the participant's response to the expected duration of the process. Some participants may want to know how long they have experienced the effects of 5MEODMT, and if asked, it is appropriate to share this information. Participants may be non-verbal for a large part of the time, focusing on the heart, and participating in their experience. It is important for therapists to pay attention to participants but not interfere with the participants' experience unless it is obvious that the participants are seeking support from the therapist. When participants are experiencing their experience, therapists are encouraged to participate in self-regulation techniques. This may be in the form of slow intentional inhalation and exhalation, or any other activity that helps therapists to root and self-regulate. This is both for the benefit of therapists and for the benefit of participants, because participants in highly unusual states may be particularly adaptable to or notice the anxiety of their therapists. It is best for therapists to follow the lead of participants when choosing verbal interactions, because the 5MEODMT experience seems to be fading. Therapists may be eager to ask participants about their experience, but it is preferred to wait until participants are ready to share themselves. Participants may want to remain silent for a while, even after the obvious acute 5MEODMT effect disappears. It is appropriate for the therapist to greet the participant with a friendly smile and welcoming nonverbal behavior, and to allow the participant to take the lead in sharing when they feel ready.

[1188] After the experience (about 90 minutes)

[1189] The therapist will encourage the participant to maintain their experience for a period of at least one hour after the acute effects of 5MEODMT have worn off and the participant is aware of their surroundings and situations in the treatment room again. Maintaining the experience means continuing to direct attention to it in a way that feels most suitable for the participant, rather than turning to distraction, entertainment, or the concerns of daily life. During this time, the therapist will invite the participant to describe their experience (if they choose to describe), and if the participant is not ready, the therapist will respect the choice of not describing. If the participant does describe their experience, the therapist will listen and encourage the participant to express anything they want to share without explaining or trying to give meaning. The therapist simply listens and encourages the participant to describe what they can describe about the experience. The therapist also provides the participant with the choice of resting and listening to music, or writing or drawing any aspects of their desired experience. At the end of this time period, the therapist will check with the participant that they feel ready to end the session, end the participation session, and contact the research team for exit assessment.

[1190] Integration

[1191] The key principle of the integration session is to help participants focus on the shifts in their perception of themselves and the implications of these shifts as they relate to their depression. For the purposes of this study, the self is broadly defined as the narrative or historical self, the sense of a coherent “I” that moves throughout the experience, and the self-identities a person may use. It is critical to remember that the sense of self or “I” is reflected in both the experiencer’s self-experience and the experience of the object of the experience, so the description may appear to be a change in perception of the external world, but reflect a shift in internal processes. To this end, the following therapeutic tasks will guide the integration session.

[1192] These sessions are less structured than the preparation sessions to accommodate variability in participant responses. There are three tasks: the first should be done at all sessions, the second and third can be introduced and engaged in if and when participants are ready and willing. The tasks are:

[1193] Listen and hear participants’ experiences

[1194] The therapist asks open-ended questions about the participant's experience and listens to the participant's description with non-judgmental curiosity. The therapist asks the participant to focus only on the 5MDE and related materials so that their time together is focused on therapy. The therapist should focus the inquiry on the participant's experience, asking them to tune into any aspects of the three types of self-feeling that they are able to identify.

[1195] Reintroduce the values ​​and discuss the relationship to each

[1196] The therapist will reintroduce the values ​​identified in the values ​​card sort from preparation and bring the discussion back to them if and when appropriate in the integration session. Engaging in a structured discussion of values ​​is by no means required, but it serves as a framework to direct the focus of the session toward a shift in the participant's sense of self where needed.

[1197] The therapist might, for example, ask for the reintroduction of the following values:

[1198] Therapist: Prior to your 5MDE, we discussed a list of values ​​that you hold, and how you relate to each of these values. I would like to draw our attention back to this point, and ask for some details about how these relationship approaches might be shifting. For example, you designated "family" as one thing that is important to you, but you worry that you don't feel good enough to be present for family relationships. You said that you isolate yourself from your family a lot because you work on your computer every night in your makeshift office in your garage. How do you relate to your "family" value now?

[1199] In the conversation, the therapist can continue to focus on the participant's transformation in terms of how he relates to his "family" values, for example by asking him what he has noticed in this area.

[1200] Create ways that participants can act to enhance their relationship with their chosen values; identify value-directed actions in their lives as integration practices. Integration can be understood as the process of embodying or practicing insights that a person has. In at least one of the integration sessions, as early as the therapist feels that the participant can engage in this stage, the therapist should introduce the idea of ​​identifying value-directed actions they can take in their lives as integration practices. Explaining the concept as above, the therapist can invite participants to recall the values ​​they identified (or any other values ​​that are important to them), recall the insights or experiences from their 5MEODMT session, and think creatively about what they might intentionally try to do differently in order to achieve positive changes in their relationship with their values ​​based on these insights and experiences.

[1201] project:

[1202] 1. A method of administering 5MeODMT or a pharmaceutically acceptable salt thereof to a patient diagnosed with depression, the method comprising:

[1203] The patient discontinues use of any mood-altering substances or any other substances, medications, or products that may affect serotonergic function;

[1204] ● Patient relaxation, such as the patient being instructed to lie down, close their eyes, and listen to music and / or engage in one or more breathing exercises guided by the therapist;

[1205] ● Optionally, by the patient clearing their nasal passages by blowing their nose, e.g. while sitting;

[1206] - Administration of 5MeODMT, optionally by insufflation, and optionally with the patient in the prone position for the duration of the effect of the 5MeODMT.

[1207] 2. The method of claim 1, wherein the patient has stopped taking 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, which may contain 5-HTP, St John's Wort, and any benzodiazepines prior to administration of 5MeODMT. Herbal products of this type.

[1208] 3. The method according to item 1 or item 2, wherein 5MeODMT is administered via the Aptar Unidose (UDS) liquid delivery system.

[1209] 4. The method according to item 1, item 2 or item 3, wherein 5MeODMT is a benzoate salt, optionally a polymorph of a benzoate salt.

[1210] 5. A method according to any one of items 1 to 4, wherein the patient participates in at least one psychological support session prior to administration of 5MeODMT.

[1211] 6. The method according to claim 5, wherein the patient participates in at least three psychological support sessions prior to administration of 5MeODMT.

[1212] 7. The method according to claim 6, wherein the patient participates in three psychological support sessions, wherein the sessions are conducted 7 days, 4 days and 1 day before the administration of 5MeODMT.

[1213] 8. The method according to any one of items 5 to 7, wherein the length of the psychological support session is 60 minutes to 90 minutes.

[1214] 9. A method according to any one of items 5 to 8, wherein at least one treatment intention is discussed during a psychological support session.

[1215] 10. A method according to any one of items 5 to 9, wherein self-directed inquiry and experiential processing is practiced during a psychological support session.

[1216] 11. A method according to any one of items 1 to 10, wherein the patient participates in at least one psychological support session after administration of 5MeODMT.

[1217] 12. The method according to claim 11, wherein the patient participates in at least three psychological support sessions after administration of 5MeODMT.

[1218] 13. The method according to item 11 or item 12, wherein the patient participates in three psychological support sessions, wherein the sessions are performed 1 day, 4 days and 7 days after the administration of 5MeODMT.

[1219] 14. The method according to any one of items 11 to 13, wherein the length of the psychological support session is 60 minutes to 90 minutes.

[1220] 15. A method according to any one of items 1 to 14, wherein 5MeODMT is administered to the patient in a chamber having a substantially non-clinical appearance.

[1221] 16. The method of item 15, wherein the chamber comprises soft furniture.

[1222] 17. The method according to item 15 or 16, wherein the chamber is decorated using pastel colors.

[1223] 18. A method according to any one of items 15 to 17, wherein the chamber comprises a high-resolution sound system.

[1224] 19. A method according to any one of items 15 to 18, wherein the chamber includes food and drinks for the patient and the therapist.

[1225] 20. A method according to any one of items 15 to 19, wherein the chamber comprises an approved safe for storing 5MeODMT.

[1226] 21. A method according to any one of items 15 to 20, wherein the chamber is insulated so that the patient is protected from the sights and sounds of the outside world.

[1227] 22. A method according to any one of items 15 to 21, wherein the chamber does not contain any artwork or decorations having any specific religious iconography, ideological connotations, or other such artwork or decorations that may cause negative emotions in the patient.

[1228] 23. A method according to any one of items 15 to 22, wherein the chamber comprises a bed or a sofa.

[1229] 24. The method according to claim 23, wherein the patient lies on a bed or sofa for about 0.5 hours to 8 hours or most of the time after administration of 5MeODMT.

[1230] 25. A method according to any one of items 1 to 24, wherein the patient listens to music for about 0.5 hours to 8 hours or a majority of the time after administration of 5MeODMT.

[1231] 26. A method according to any one of items 1 to 25, wherein the patient wears the eye patch for about 0.5 hours to 8 hours or a majority of the time after administration of 5MeODMT.

[1232] 27. A method according to any one of items 1 to 26, wherein the therapist provides psychological support to the patient for about 0.5 hours to 8 hours after administration of 5MeODMT.

[1233] 28. A method according to any one of items 1 to 27, wherein the therapist uses guided imagery and / or breathing exercises to calm and / or focus the patient.

[1234] 29. A method according to any one of items 1 to 28, wherein the therapist provides reassuring physical contact with the patient.

[1235] 30. The method of claim 29, wherein the therapist holds the patient's hand, arm or shoulder.

[1236] 31. A method according to any one of items 1 to 30, wherein the therapist encourages the patient to engage in self-directed inquiry and experiential processing.

[1237] 32. A method according to item 31, wherein the therapist reminds the patient of at least one treatment intention.

[1238] 33. A method according to any one of items 1 to 32, wherein the therapist advises the patient to do one or more of the following:

[1239] (1) Accept the feeling of anxiety,

[1240] (2) Allow the experience to unfold naturally,

[1241] (3) Avoid psychological resistance to the experience,

[1242] (4) Relaxation, and / or

[1243] (5) Explore the patient’s own psychological space.

[1244] 34. A method according to any one of items 1 to 33, wherein the therapist does not initiate a conversation with the patient.

[1245] 35. A method according to item 34, wherein if the patient initiates a conversation, the therapist responds to the patient.

[1246] 36. A method according to any one of items 5 to 35, wherein psychological support is provided to the patient remotely.

[1247] 37. The method of claim 36, wherein psychological support is provided via a digital or electronic system.

[1248] 38. The method according to item 37, wherein the digital system or electronic system is a mobile phone application.

[1249] 39. The method according to item 38, wherein the digital system or electronic system is a website.

[1250] Example 36: Mouse forced swimming test

[1251] The study aimed to evaluate the effects of three doses of 5MeODMT benzoate in the mouse forced swim test (FST), a model of behavioral despair and a sensitive test for multiple classes of antidepressant drugs.

[1252] Farming

[1253] Captivity and acclimation

[1254] Prior to the start of testing, animals underwent a 72-hour acclimation period to the testing facility. Animals were housed 4 per cage in polycarbonate cages covered with 1 / 4" bed-o'cob. Cages were changed and enrichment was provided according to standard operating procedures. Animals were maintained on a 12-hour light / 12-hour dark cycle, with all experimental activities occurring during the light cycle of the animals. All animal use procedures were performed in accordance with the principles of the Canadian Council on Animal Care (CCAC).

[1255] Food and water

[1256] Certified rodent diet ( 5001) was provided ad libitum. The animals were not fasted before or after the start of the experiment. Water was provided ad libitum in a glass bottle with a stainless steel straw.

[1257] Study Design

[1258] Test subjects

[1259] Male CD-1 mice from Charles River Laboratories (St. Constant, Quebec, Canada) were used as test subjects in this study. Animals typically weighed 25 g-30 g at the time of testing.

[1260] Timeline of events

[1261]

[1262] Treatment Group

[1263] Animals were randomly assigned to the following treatment groups:

[1264]

[1265] Behavioral testing before FST

[1266] In addition to the forced swim test, animals were evaluated for signs of 5-HT (serotonin) syndrome on day 0. Animals were exposed to activity chambers for 10 minutes at two time points after dosing: (1) 5-15 minutes after dosing, and (2) 2.5 hours after dosing.

[1267] Forced swim test

[1268] Male CD-1 mice received appropriate doses of vehicle, test article, or positive control (treatment summarized above). After an appropriate pre-treatment period, the animals were gently placed in a tall glass cylinder filled with water (20°C-25°C). After a period of vigorous activity, each mouse adopted a characteristic immobile posture that was easily recognizable. The swimming test involves scoring the duration of immobility. During the 6-minute test session, the latency of the first immobility was recorded (in seconds). The duration of immobility during the last 4 minutes of the test was also measured (in seconds). Activity or inactivity from 0 minutes to 2 minutes was not recorded.

[1269] Test Items

[1270] 5-MeODMT Benzoate

[1271] BEW: 1.59 (benzoate form)

[1272] MW: 340.40 g / mol

[1273] Dosage: 0.5mg / kg, 1.5mg / kg, 5mg / kg (corrected to base dose)

[1274] Route of administration, dose volume: SC., 10 mL / kg

[1275] Pre-treatment time: 3 hours

[1276] Vehicle: 0.9% saline

[1277] Imipramine

[1278] BEW: 1.13

[1279] MW: 280.415 g / mol

[1280] Dosage: 30 mg / kg (corrected to base dose)

[1281] Route of administration, dose volume: IP., 10mL / kg

[1282] Pre-treatment time: 3 hours

[1283] Vehicle: 0.9% saline

[1284] result

[1285] At 3 h post-dose, low-dose 5MeODMT benzoate (0.5 mg / kg and 1.5 mg / kg) showed a positive trend in reducing the duration of immobility and increasing the latency to immobility compared with vehicle-treated mice during the 6-min test session (immobility time 2 min-6 min, vehicle: 190.4 sec ± 7.7 sec – 5MeODMT benzoate: 133.2 sec ± 24.9 sec (0.5 mg / kg), 137.6 sec ± 17.0 sec (1.5 mg / kg), 156.8 sec ± 18.7 sec (5 mg / kg) – imipramine 46.8 sec ± 16.6 sec, Fig.94 Latency to immobility, vehicle: 95.5 sec ± 4.6 sec – 5MeODMT benzoate 121.8 sec ± 22.0 sec (0.5 mg / kg), 120.9 sec ± 13.3 sec (1.5 mg / kg), 85.0 sec ± 9.5 sec (5 mg / kg), imipramine 268.6 sec ± 30.3 sec, Fig.95 ).

[1286] Example 37: Study of 5MEO-TOX-PK-DOG

[1287] The objective of this toxicokinetic study was to evaluate and compare the toxicokinetic profiles of the test items 5MeODMT-HCl (in a vehicle of 0.1% metolose, Group 2) and 5MeODMT-benzoate (in a vehicle of 0.2% metolose + 0.01% BZK, Group 4).

[1288] On day 1, the vehicle or active test item formulation was intranasally administered to male beagle dogs at a dose level of 0.4 mg / kg in the active group (corresponding to the free base). After administration, a series of blood samples were collected from each dog at the following time points: pre-dose (0 minutes), 2 minutes, 5 minutes, 8 minutes, 10 minutes, 15 minutes, 30 minutes and 60 minutes, and 2 hours and 8 hours after administration. Plasma samples were analyzed using a validated method for quantification of the concentration of 5MeODMT in each sample.

[1289] 5MeODMT was not detected in any samples collected from control animals on day 1 (not shown). Peak plasma exposure levels (C 最大 ) were reported at 16.4 ng / mL and 35.4 ng / mL, respectively (see table below). Fig.96 A time-course graph of mean plasma concentrations is presented, showing broadly comparable TK profiles between the HCl and benzoate formulations.

[1290] Mean C of 5MeODMT in Group 2 and Group 4 on Day 1 最大 value

[1291]

[1292] See also Fig.96 , which shows the mean plasma concentrations (ng / mL) of 5MeODMT groups in male beagle dogs - Group 2 (5MEODMT HCl salt formulation) and Group 4 (5MEODMT benzoate salt formulation) - dose level (0.4 mg / kg); wherein the mean plasma concentrations of Group 2 and Group 4 were generally the same over the dosing time.

[1293] Example 38: Additional Embodiments

[1294] In one embodiment, there is provided a polymorph of 5MeODMT benzoate characterized by an XRPD pattern as substantially illustrated in any one of the accompanying drawings or as previously or subsequently described.

[1295] In one embodiment, there is provided a polymorph of 5MeODMT benzoate characterized by one or more peaks in an XRPD diffraction pattern as substantially illustrated in any one of the Figures or as previously or subsequently described.

[1296] In one embodiment, there is provided a polymorph of 5MeODMT benzoate characterized by one or more endothermic events in a DSC thermogram as generally illustrated in any one of the Figures or as previously or subsequently described.

[1297] In one embodiment, there is provided a polymorph of 5MeODMT benzoate characterized by a TGA thermogram as substantially illustrated in any one of the accompanying drawings or as previously or subsequently described.

[1298] In one embodiment, there is provided a polymorph of 5MeODMT benzoate characterized by a DVS isotherm profile as substantially illustrated in any one of the Figures or as previously or subsequently described.

[1299] In one embodiment, there is provided a polymorph of 5MeODMT benzoate characterized by a crystalline appearance as substantially illustrated in any one of the accompanying drawings or as previously or subsequently described.

[1300] In one embodiment, there is provided a polymorph of 5MeODMT benzoate characterized by a particle size distribution as substantially illustrated in any one of the accompanying drawings or as previously or subsequently described.

[1301] In one embodiment, there is provided a polymorph of 5MeODMT benzoate characterized by a FITR spectrum as substantially illustrated in any one of the accompanying drawings or as previously or subsequently described.

[1302] In one embodiment, there is provided a polymorph of 5MeODMT benzoate produced as previously or subsequently described. In one embodiment, there is provided a method of producing a polymorph of 5MeODMT benzoate as previously or subsequently described.

[1303] In one embodiment, there is provided a composition comprising a polymorph of 5MeODMT benzoate as previously or subsequently described.

[1304] In one embodiment there is provided a 5MeODMT benzoate solvate characterised as substantially as illustrated in any one of the accompanying drawings or as previously or subsequently described.

[1305] In one embodiment there is provided a 5MeODMT benzoate hemisolvate characterised as substantially as illustrated in any one of the accompanying drawings or as previously or subsequently described.

[1306] In one embodiment, there is provided any previously or subsequently described benzoate form of 5MeODMT for use in any previously or subsequently described method of treatment.

[1307] Disclosed herein is the use of a composition as described herein for the manufacture of a medicament for treating any of the following: a condition caused by dysfunction of the central nervous system, a condition caused by dysfunction of the peripheral nervous system, a condition that benefits from sleep regulation (such as insomnia), a condition that benefits from analgesics (such as chronic pain), migraine, trigeminal autonomic headaches (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting neuralgiform headache with cranial autonomic symptoms (SUNA)), a condition that benefits from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), a condition that benefits from anti-inflammatory treatment, depression, refractory depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorder, obsessive-compulsive disorder, or body dysmorphic disorder.

[1308] Disclosed herein are methods of treating any of the following in a patient by administering a composition as described herein: a condition caused by dysfunction of the central nervous system, a condition caused by dysfunction of the peripheral nervous system, a condition that benefits from sleep regulation (such as insomnia), a condition that benefits from analgesics (such as chronic pain), migraine, trigeminal autonomic headaches (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting neuralgiform headache with cranial autonomic symptoms (SUNA)), a condition that benefits from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), a condition that benefits from anti-inflammatory treatment, depression, refractory depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorder, obsessive-compulsive disorder, or body dysmorphic disorder.

Claims

A crystalline form of 1,5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) benzoate, wherein the crystalline form is characterized by peaks at 9.0°2θ±0.1°2θ, 11.5°2θ±0.1°2θ, 14.5°2θ±0.1°2θ, 16.3°2θ±0.1°2θ, 16.5°2θ±0.1°2θ, 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, 18.5°2θ±0.1°2θ, 21.0°2θ±0.1°2θ, 22.7°2θ±0.1°2θ, 24.7°2θ±0.1°2θ, 25.3°2θ±0.1°2θ and 30.5°2θ±0.1°2θ in an XRPD diffraction pattern.

2. A composition comprising a pharmaceutically effective amount of 5-MeO-DMT benzoate, wherein the 5-MeO-DMT benzoate is characterized by peaks at 9.0°2θ±0.1°2θ, 11.5°2θ±0.1°2θ, 14.5°2θ±0.1°2θ, 16.3°2θ±0.1°2θ, 16.5°2θ±0.1°2θ, 17.5°2θ±0.1°2θ, 17.7°2θ±0.1°2θ, 18.5°2θ±0.1°2θ, 21.0°2θ±0.1°2θ, 22.7°2θ±0.1°2θ, 24.7°2θ±0.1°2θ, 25.3°2θ±0.1°2θ, and 30.5°2θ±0.1°2θ in an XRPD diffraction pattern.

3. The composition according to claim 2, wherein the composition comprises 5-MeO-DMT benzoate in a dosage amount ranging from 0.05 mg to 100 mg.

4. The composition according to claim 3, wherein the composition comprises 5-MeO-DMT benzoate in a dosage amount ranging from 0.1 mg to 50 mg.

5. The composition according to claim 4, wherein the composition comprises 5-MeO-DMT benzoate in a dosage amount ranging from 0.5 mg to 25 mg.

6. The composition of claim 5, wherein the composition is formulated in a dosage form selected from the group consisting of an oral dosage form, a transdermal dosage form, an inhalable dosage form, an intravenous dosage form, or a rectal dosage form.

7. The composition according to claim 5, wherein the composition is formulated in a dosage form selected from the group consisting of an aerosolized dosage form, a buccal dosage form, an injectable dosage form or a suppository dosage form.

8. The composition of claim 5, wherein the composition is formulated in a sublingual dosage form.

9. The composition according to claim 5, wherein the composition is formulated in a dosage form selected from the group consisting of tablets, capsules, granules or powders.

10. The composition according to claim 5, wherein the composition is formulated in a dosage form selected from the group consisting of: a free-flowing powder or an aerosol.

11. The composition according to claim 5, wherein the composition is formulated in the form of an inhalable powder.

12. The composition of claim 11, wherein the inhalable powder is suitable for administration by inhalation via a drug dispenser which is a unit dose dry powder inhaler.

13. The composition of claim 11, wherein the inhalable powder is suitable for administration by inhalation via a medication dispenser which is a pre-metered multi-dose dry powder inhaler.

14. The composition of claim 11, wherein the inhalable powder is suitable for administration by inhalation via a medication dispenser, which is a nasal inhaler.

15. The composition of claim 11, wherein the inhalable powder is suitable for administration by inhalation via a medicament dispenser which is a pressurized metered dose inhaler.

16. The composition of claim 2, wherein the 5-MeO-DMT benzoate composition is formulated for mucosal delivery.

17. The composition according to any one of claims 12-15, wherein the composition comprises one or more pharmaceutically acceptable excipients.

18. The composition of claim 17, wherein the composition comprises one or more of the following: a mucoadhesion enhancer, a permeation enhancer, a cationic polymer, a tight junction modulator, an enzyme inhibitor, a surfactant, and a chelating agent.

19. The composition of claim 17, wherein the composition comprises a polysaccharide.

20. The composition of claim 17, wherein the composition comprises cyclodextrin.

21. Use of the composition according to any one of claims 2 to 20 in the preparation of a medicament for treating depression.

22. A nasal delivery device comprising a composition according to any one of claims 2 to 5.

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