Crystalline hydrobromide salt of 5-MeO-DMT

Abstract

Crystalline 5-methoxy-N,N-dimethyltryptamine hydrobromide salt (5-MeO-DMT HBr) is provided.

Description

[Technical field]

[0001] The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) hydrobromide (an acid addition salt of 5-MeO-DMT). The present invention further relates to the preparation and use of this salt, polymorphs, and compositions containing this salt. [Background technology]

[0002] 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) has the following formula: [ka]

[0003] 5-MeO-DMT is a naturally occurring serotonergic hallucinogenic tryptamine that acts as a 5-HT1A and 5-HT2A receptor agonist.

[0004] 5-MeO-DMT was first isolated from the bark of Dictyoloma incanescens, but is also found in other plants and has been identified as the major active component of the venom of the Incilius alvarius (Bufo alvarius) toad.

[0005] Based on its physiological activity, medical uses of 5-MeO-DMT have recently attracted attention. Such uses are disclosed in WO2020 / 169850A1 and WO2020 / 169851A1, which relate to improved methods for the treatment of psychiatric disorders, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, post-traumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorders and psychoactive substance abuse, comprising administering a therapeutically effective amount of 5-MeO-DMT to a patient in need thereof.

[0006] The chemical synthesis of 5-MeO-DMT was reported by Hoshino and Shimodaira in 1936 (Bulletin of the Chemical Society of Japan, 11(3), 221-224).

[0007] Somei et al. (Chem. Pharm. Bull. 49(1), 87-96 (2001)) reported the synthesis of serotonin, N-methylserotonin, bufotenin, 5-methoxy-N-methyltryptamine, bufobutanoic acid, N-(indol-3-yl)methyl-5-methoxy-N-methyltryptamine, and lespedamine. In the synthesis of bufotenin, a mixture of compounds containing 5-MeO-DMT is obtained, from which the components are purified by column chromatography. 5-MeO-DMT is then recrystallized from Et2O-hexane.

[0008] WO2020 / 254584A1 relates to a method for purifying 5-MeO-DMT by crystallization, and to a form of 5-MeO-DMT that meets certain purity requirements.

[0009] Certain salts of 5-MeO-DMT have also been proposed, however the salts described thus far have significant drawbacks.

[0010] Some salts are hygroscopic and lack stability, especially thermal stability. When preparing salts based on dibasic acids, a mixed phase of mono- and hemi-salts may result. WO2020 / 169850A1 and WO2020 / 169851A1 contemplate the use of pharma- ceutically acceptable salts of 5-MeO-DMT. An example of such a salt is the hydrochloride salt.

[0011] WO2021 / 250435A1 describes a composition containing the hydrochloride salt. A polymorph has been identified that melts at about 146°C, shows the onset of thermal decomposition between 120-165°C, shows significant water uptake above 70% RH, and completely deliquesces at high relative humidity.

[0012] The hygroscopic nature of the hydrochloride salt according to WO2021 / 250435A1 is expected to limit its usefulness.

[0013] WO2021 / 250435A1 also generally refers to benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, bromide, iodide, oxalate, or triflate salts, but does not provide details of preparation methods, properties, etc.

[0014] AMSherwood et al. (https: / / dx.doi.org / 10.1021 / acsomega.0c05099) report a synthetic method to obtain salts of 5-MeO-DMT, specifically the succinate salt (1:1).

[0015] However, our studies have shown that the succinate salt has a complex polymorphic landscape that exhibits tendencies towards hydration and solvation.

[0016] Additional acids that may form salts include fumaric acid, which has been suggested to be a Michael acceptor that forms covalent products with amine-containing APIs under mild conditions. Furthermore, fumarate salts are unstable to salt formation, as they disproportionate in a variety of solvents.

[0017] WO2021 / 250434A1 describes a benzoate salt that exists in various polymorphic forms.

[0018] WO2020 / 169850A1 and WO2020 / 169851A1 in particular also propose the administration of 5-MeO-DMT and its salts by various routes, among them buccal and sublingual administration.

[0019] In light of this, there is a need for additional salts and specific forms of salts with improved properties, particularly salts and salt forms that are crystalline, have favorable polymorphic properties, have favorable flow properties, are low in hygroscopicity, are chemically pure, have good solubility in typical pharmaceutical vehicles such as water for injection, exhibit high chemical stability under conditions typically encountered during formulation and storage, and / or exhibit high thermal stability.

[0020] Additionally, there is a need for forms of 5-MeO-DMT that are particularly suited for specific routes of administration, such as buccal or sublingual administration. Summary of the Invention

[0021] The present invention relates to a crystalline hydrobromide salt of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT HBr).

[0022] The present invention provides salts of high chemical purity, i.e. at least 99.5% area, preferably at least 99.8% area, especially at least about 99.9% area, as assessed by HPLC as specifically defined herein. Preferably, the salts are free of impurities of 0.1% area or more.

[0023] The present invention also provides a stable polymorph of this salt. This form has a melting point of 174°C. The preferred polymorphic form is characterized by an X-ray diffraction pattern measured using Cu Kα radiation, which includes peaks at 14.5°2θ±0.2°2θ; 17.0°2θ±0.2°2θ; 24.2°2θ±0.2°2θ. This polymorph can be further characterized by X-ray diffraction, as detailed herein.

[0024] The present invention also provides salts that have favorable flow properties.

[0025] The present invention also relates to a method for preparing a crystalline hydrobromide salt, which method comprises a salt-forming crystallization, in particular in which an isopropyl alcohol / water mixture is used as the solvent system, in particular an isopropyl alcohol / water mixture having an isopropyl alcohol / water ratio in the range of 80:20 to 98:2 (parts by volume), in particular an isopropyl alcohol / water ratio of about 90:10 (parts by volume).

[0026] The present invention further provides a pharmaceutical composition comprising a salt according to the invention. The pharmaceutical composition may be in a form for administration by injection or in a form for intranasal administration.

[0027] Additionally, the present invention generally provides pharma- ceutically acceptable acid addition salts of 5-MeO-DMT for particular routes of administration, such as buccal or sublingual administration. [Brief description of the drawings]

[0028] [Figure 1A] The XRPD profile of 5-MeO DMT free base (top) and the XRPD profile of 5-MeO DMT HBr pattern A (bottom) are shown. [Figure 1B] 1 shows the XRPD profile of 5-MeO DMT HBr pattern A. [Diagram 2] 5 shows a combined DSC / TGA thermogram of 5-MeO DMT HBr pattern A. [Figure 3A] The XRPD profile of 5-MeO DMT free base (top), the XRPD profile of 5-MeO DMT HBr pattern A (center), and the XRPD profile of 5-MeO DMT HBr pattern B (bottom) are shown. [Figure 3B] 1 shows the XRPD profile of 5-MeO DMT HBr pattern B. [Figure 4] 5 shows a combined DSC / TGA thermogram of 5-MeO DMT HBr pattern B. [Diagram 5] FIG. 1 shows DSC thermograms of 5-MeO DMT HBr salt form: Pattern A (upper curve) and Pattern B (lower curve). [Figure 6] 1 shows the XRPD profile of 5-MeO DMT HBr salt form: Pattern C (middle) compares Pattern A (top) and Pattern B (bottom). [Figure 7] 5 shows a combined DSC / TGA thermogram of 5-MeO DMT HBr pattern C. [Figure 8] FIG. 1 shows the XRPD profiles of 5-MeO DMT HBr salt form: Pattern B' (top) compared to Pattern B (bottom). [Figure 9] 5 shows a combined DSC / TGA thermograph of 5-MeO DMT HBr pattern B'. [Figure 10] 1 shows DVS analysis of 5-MeO DMT HBr pattern A. [Figure 11] 4 shows DVS analysis of 5-MeO DMT HBr pattern B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The present invention is based on the discovery that 5-methoxy-N,N-dimethyltryptamine hydrobromide (5-MeO-DMT HBr) is an acid addition salt having particularly advantageous properties.

[0030] In order to provide a salt suitable for pharmaceutical use, various requirements must be observed: The salt should have positive solid-state properties, which includes the possibility of obtaining the salt in crystalline form.

[0031] This form should have a high melting point and a sharp melting endotherm. The crystalline form should not exhibit polymorphism or at least the thermodynamically stable form should predominate.

[0032] The salts should not be prone to the formation of solvates under the conditions of preparation.

[0033] The salt should have a flowable nature that allows for easy processing.

[0034] The salt should be anhydrous and non-hygroscopic or only slightly hygroscopic, while at the same time exhibiting good water solubility.

[0035] Furthermore, the salts must not only be of high chemical purity, but also exhibit stability across a range of assays, both in the solid state and in solution.

[0036] The relevant forms of salts should be easy to prepare with high purity suitable for pharmaceutical use. The process should be scalable. Solvents required for preparation should be non-toxic.

[0037] To achieve the above object, the present invention provides 5-MeO-DMT HBr.

[0038] The salt exhibits positive solid state behavior. It can be obtained in crystalline forms that exhibit a predominant thermodynamically stable form (5-MeO-DMT HBr pattern B), which has a pronounced melting endotherm at 174° C. and is anhydrous.

[0039] This salt has good solubility in water and at the same time has low hygroscopicity.

[0040] The salt exhibits good stability over a range of evaluations, both in solid form and in solution.

[0041] To identify potentially useful salts, we performed three initial salt screens using 29 acids and the following solvent systems: isopropyl alcohol (IPA), isopropyl acetate (iPrOAc), and tetrahydrofuran:water (THF:HO). A hemi-salt screen was also performed with 0.5 equivalents of acid added.

[0042] As part of the screening, 5-MeO-DMT was charged to a crystallizer tube. Solvent was added and the resulting solution of API was heated to 50° C. The acid was charged in a single aliquot. The solution was held at temperature and allowed to equilibrate for 3 hours. The solution was then cooled to room temperature and allowed to equilibrate for 18 hours.

[0043] If a suspension was obtained, the solid was isolated by filtration and dried in vacuum at 40° C. for 18 hours.

[0044] If the solution persisted, further manipulation was required to obtain an isolable solid. The following methods were primarily used to induce nucleation / crystallization and / or obtain a solid: Reduce solvent volume by approximately 50% under a steady stream of nitrogen Addition of anti-solvent (heptane) at both ambient and elevated temperatures followed by equilibration -Solvent removal with a steady stream of nitrogen Repeated scratching and trituration of the resulting residue with a suitable solvent (mixture of diethyl ether, tert-butyl methyl ether (TBME), ethanol (EtOH) and heptane) followed by equilibration of the solid where a suspension was obtained. The mixture, which remained as a viscous mass, was allowed to evaporate slowly.

[0045] Samples requiring trituration were allowed to equilibrate for an additional 24 hours at controlled temperature to produce a mobile suspension, which was then filtered.

[0046] As a result of the above experiments, a crystalline hydrobromide salt with a 1:1 stoichiometry of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) was identified.

[0047] Accordingly, the present invention provides crystalline 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) hydrobromide.

[0048] The salts are provided in a highly pure form suitable for pharmaceutical use.

[0049] Purity can be analyzed by reverse phase HPLC with UV detection at 220 nm.

[0050] A suitable column is a USP L11 column (wherein the phenyl group is chemically bonded to porous silica particles with a diameter of 1.5-10 μm), preferably a column containing particles with a particle size of 3.0 μm and a pore size of 120 Å, where the phenyl group is bonded via a C4-spacer (phenylbutyl bonded phase). A suitable column length is 150 mm and the internal diameter is 4.6 mm.

[0051] A commercially available column manufactured by YMC CO., LTD. (Triart Phenyl: 150×4.6 mm, particle size 3.0 μm, TPH12S03-1546PTH) can be used.

[0052] The analysis is carried out at a column temperature of 30°C.

[0053] The column is eluted with a solvent gradient based on mobile phase A (0.05 vol.% TFA in WFI) and mobile phase B (0.05 vol.% TFA in acetonitrile) at a flow rate of 1.0 ml / min, the solvent gradient being established by the following gradient program: [Table 1]

[0054] According to the invention, the hydrobromide salt has a chemical purity of at least 99.5% area, preferably at least 99.8% area, especially at least about 99.9% area, as assessed by HPLC as described above.

[0055] Further according to the invention, the salts contain no impurities greater than 0.1% area as assessed by HPLC.

[0056] The hydrobromide salt of 5-MeO-DMT is obtained in two polymorphs, referred to herein as 5-MeO-DMT HBr Pattern A and 5-MeO-DMT HBr Pattern B. The melting behavior of both forms was characterized.

[0057] The DSC thermograph of 5-MeO-DMT HBr pattern A showed a positive thermal profile with a peak temperature of 154° C. and a single endothermic event with an onset temperature of 150° C. (FIG. 2).

[0058] The DSC thermograph of 5-MeO-DMT HBr pattern B showed a positive thermal profile with a single main melting endotherm with a peak temperature of 174° C. and an onset temperature of 171° C. (FIG. 4).

[0059] Thermal data indicates that 5-MeO-DMT HBr Pattern B represents a more stable polymorph compared to 5-MeO-DMT HBr Pattern A. 5-MeO-DMT HBr Pattern A is metastable. In accordance with the present invention, 5-MeO-DMT HBr Pattern B is the preferred polymorph of 5-MeO-DMT HBr.

[0060] 5-MeO-DMT HBr Pattern A and 5-MeO-DMT HBr Pattern B showed distinctly different X-ray diffraction patterns (see FIG. 3A for comparison). The XRPD data measured using Cu Kα radiation are summarized in the table below. [Table 2]

[0061] One of ordinary skill in the art will appreciate that, given the typical precision of measurement methods, when comparing XRPD data, the °2θ values ​​characterizing the peak positions are rounded to the nearest tenth. Further, one of ordinary skill in the art will appreciate that the rounded peak positions are subject to an error of ±0.2 °2θ.

[0062] 5-MeO-DMT HBr Pattern A is characterized in particular by the 3 most intense peaks per table above; the 4 most intense peaks per table above; the 5 most intense peaks per table above; the 6 most intense peaks per table above; the 7 most intense peaks per table above; the 8 most intense peaks per table above; the 9 most intense peaks per table above.

[0063] 5-MeO-DMT HBr Pattern A is specifically characterized by an X-ray diffraction pattern which includes the ten most intense peaks from the table above: namely, peaks at 5.9°2θ±0.2°2θ; 13.8°2θ±0.2°2θ; 14.5°2θ±0.2°2θ; 18.4°2θ±0.2°2θ; 19.6°2θ±0.2°2θ; 23.4°2θ±0.2°2θ; 24.0°2θ±0.2°2θ; 24.7°2θ±0.2°2θ; 24.9°2θ±0.2°2θ; and 27.3°2θ±0.2°2θ. [Table 3]

[0064] One of ordinary skill in the art will appreciate that, given the typical precision of measurement methods, when comparing XRPD data, the °2θ values ​​characterizing the peak positions are rounded to the nearest tenth. Further, one of ordinary skill in the art will appreciate that the rounded peak positions are subject to an error of ±0.2 °2θ.

[0065] 5-MeO-DMT HBr pattern B is characterized in particular by the 3 most intense peaks per table above; the 4 most intense peaks per table above; the 5 most intense peaks per table above; the 6 most intense peaks per table above; the 7 most intense peaks per table above; the 8 most intense peaks per table above; the 9 most intense peaks per table above. In a particularly preferred embodiment, 5-MeO-DMT HBr pattern B is characterized by an X-ray diffraction pattern comprising the ten most intense peaks from the table above: i.e., a peak at 14.5°2θ±0.2°2θ; 16.7°2θ±0.2°2θ; 17.0°2θ±0.2°2θ; 20.6°2θ±0.2°2θ; 20.7°2θ±0.2°2θ; 21.4°2θ±0.2°2θ; 24.2°2θ±0.2°2θ; 24.8°2θ±0.2°2θ; 25.3°2θ±0.2°2θ; and 27.4°2θ±0.2°2θ.

[0066] The HBr salt according to the invention, for example the salt obtained by the preparation method described below, has a Carr's index characterizing its flow properties of 25% or less, for example in the range of 16-25%, for example 20-25%. Additionally or alternatively, the salt has a Hausner coefficient of 1.34 or less, for example in the range of 1.19 to 1.34, for example in the range of 1.26 to 1.34.

[0067] The present invention also provides a method for preparing 5-MeO-DMT HBr, in particular 5-MeO-DMT HBr Pattern B.

[0068] The salt may be prepared by salt-forming crystallization.

[0069] For this purpose, 5-MeO-DMT free base is dissolved in a solvent.

[0070] Suitable solvents are IPA, IPA:water, isopropyl acetate, and THF:H2O (97:3). The preferred solvent is IPA:water.

[0071] The 5-MeO-DMT free base dissolves in the solvent at room temperature or with heating.

[0072] The solution of the free base is combined with HBr. HBr can be introduced in gaseous form or is preferably added in the form of a solution, for example a solution in ethanol, a solution in water, or a solution in ethanol / water. Suitable solutions are, for example, a 1M solution in ethanol or a 48 wt% solution in water.

[0073] When IPA:water is used as the solvent system, the final ratio of IPA to water in the composition is preferably within the range of 80:20 to 98:2 (parts by volume), especially about 90:10 (parts by volume).

[0074] The binding of the free 5-MeO-DMT with HBr can be carried out at room temperature or by heating, for example, at 50°C to 70°C.

[0075] After possible removal of part of the solvent and / or cooling, a solid precipitates out. This solid material can be isolated, for example, by filtration and dried. According to the present invention, the resulting solid material is crystalline 5-MeO-DMT hydrobromide.

[0076] Although the desired product can be obtained without the use of seeds, the present invention also encompasses the preparation method using seeds, particularly seeds of 5-MeO-DMT HBr pattern B.

[0077] In accordance with the present invention, the hydrobromide salt is preferably prepared from 5-MeO-DMT having a purity of at least 98% area as determined by the HPLC method described herein.

[0078] However, salt formation can also be utilized for purification.

[0079] The present invention further relates to pharma- ceutically acceptable acid addition salts of 5-MeO-DMT, generally for buccal or sublingual administration.

[0080] According to the present invention, a pharma- ceutically acceptable acid addition salt of 5-MeO-DMT may be used directly for buccal or sublingual administration or may be used to prepare a formulation for buccal or sublingual administration.

[0081] These routes of administration include sublingual (i.e., from the area under the tongue) or buccal (i.e., from the area between the cheek and gums) absorption through the oral mucosa. Administration via these routes can bypass first-pass metabolism and ensure a rapid onset of action.

[0082] Formulations for buccal or sublingual administration are designed to dissolve or disintegrate in saliva without the need for added water.

[0083] Therefore, it may be advantageous to use the active ingredient in a form that has high water solubility, as illustrated by the pharma- ceutically acceptable acid addition salts of 5-MeO-DMT, particularly 5-MeO-DMT HBr.

[0084] Furthermore, in order to avoid irritation, it is advantageous to use the active ingredient in a form which forms a solution in water having an acceptable pH value.

[0085] Suitable salts include acid addition salts, where the acid is selected from acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and triflic acid. A preferred example is the hydrobromide salt (5-MeO-DMT HBr). Such acid addition salts can be prepared according to the procedure illustrated in the section on preparation of the HBr salt.

[0086] Formulations of pharma- ceutically acceptable salts of 5-MeO-DMT for buccal or sublingual administration include, for example, tablets, films, sprays, creams, etc. Such formulations can be prepared by methods known for such purposes.

[0087] Preferred examples include fast dissolving tablets that disintegrate or dissolve instantly when administered buccally or sublingually, releasing drug within 60 seconds, for example within 30 seconds, without the need for water.

[0088] In a further embodiment, the 5-MeO-DMT HBr according to the present invention can be used to prepare a pharmaceutical composition. Such a composition can contain the salt in solid form, for example in the form of a dry powder, in the form of a suspension, or in the form of a solution.

[0089] The pharmaceutical compositions comprising 5-MeO-DMT HBr according to the present invention can be administered by various routes, for example, via injection, via nasal administration, or via inhalation. Preferably, the compositions are administered via injection or via nasal administration. EXAMPLES

[0090] The following examples are intended to further illustrate the invention.

[0091] Example 1 - 5-MeO-DMT used as starting material 5-MeO-DMT was characterized to provide baseline reference data for use in screening salts.

[0092] The solid was received as a fine beige powder with a purity of 98.91% area as determined by HPLC. The solid was shown to be crystalline by XRPD.

[0093] The DSC thermograph shows a sharp main melting endotherm with an onset of 68.3 °C and a peak temperature of 70.3 °C. The TGA thermograph shows that the material does not lose mass prior to decomposition, confirming that it is an anhydrous solid. 1 The H NMR spectrum is consistent with the molecular structure.

[0094] Example 2 - Crystallization of the hydrobromide salt from IPA 5-MeO-DMT (50 mg) was charged to a crystallizer tube. IPA (0.5 mL, 10 vol) was added and the resulting solution of 5-MeO-DMT was heated to 50° C. HBr (1 M in ethanol, 1 eq) was charged in a single aliquot. The solution was held at temperature and allowed to equilibrate for 3 h.

[0095] The solution was then cooled to room temperature and equilibrated for 18 hours.

[0096] No precipitation was observed.

[0097] After reducing the solvent volume by approximately 50% under a steady stream of nitrogen, the mixture remained a solution.

[0098] A poor solvent (heptane; 10 vol.) was added to give a suspension, and the solid was isolated by filtration and dried in vacuum at 40° C. for 18 h.

[0099] Off-white crystals were obtained.

[0100] Example 3 - Crystallization of the hydrobromide salt from isopropyl acetate 5-MeO-DMT (50 mg) was charged to a crystallizer tube. Isopropyl acetate (0.5 mL, 10 vol) was added and the resulting solution of 5-MeO-DMT was heated to 50° C. HBr (1 M in ethanol, 1 eq) was charged in a single aliquot. The mixture was held at temperature and allowed to equilibrate for 3 h.

[0101] After 1 h a suspension had formed.

[0102] The suspension was finally cooled to room temperature and equilibrated for 18 h.

[0103] The solid was isolated by filtration and dried in vacuum at 40° C. for 18 hours.

[0104] Off-white crystals were obtained.

[0105] Example 4 - Crystallization of the hydrobromide salt from THF:H2O (97:3) 5-MeO-DMT (50 mg) was charged to a crystallizer tube. THF:H2O (97:3) (0.5 mL, 10 vol) was added and the resulting solution of 5-MeO-DMT was heated to 50 °C. HBr (1 M in ethanol, 1 eq) was charged in a single aliquot. The solution was held at temperature and allowed to equilibrate for 3 h.

[0106] The solution was then cooled to room temperature and equilibrated for 18 hours.

[0107] The salt did not precipitate easily, so further manipulation was required.

[0108] No precipitation was observed.

[0109] The solvent volume was reduced by 50% under a steady stream of nitrogen and anti-solvent (heptane; 10 vol.) was added, which resulted in the formation of a viscous material which was dispersed into a suspension by trituration with diethyl ether and then filtered.

[0110] Off-white crystals were obtained.

[0111] Example 5 - Characterization of the hydrobromide salt (5-MeO-DMT HBr Pattern A) The XRPD profiles of the salts obtained in either Examples 2, 3, or 4 are shown in Figures 1A and 1B. Only one crystalline form of the HBr salt was isolated, which was designated 5-MeO-DMT HBr Pattern A.

[0112] Powder X-ray diffraction patterns were collected on a PANalytical diffractometer using Cu Kα radiation (45 kV, 40 mA), a θ-θ goniometer, a collecting mirror, a divergence slit (½ inch), Soller slits (4 mm) for the incident and divergent beams, and a PIXcel detector. The software used for data collection was X'Pert Data Collector, version 2.2f, and data were displayed in X'Pert Data Viewer, version 1.2d. XRPD patterns were acquired under ambient conditions using a PANalytical X'Pert PRO via a transparent foil sample stage (polyimide-Kapton, 12.7 μm thick film). The data collection range was 2.994–35° 2θ, with a continuous scan speed of 0.20–2004° s -1 It was.

[0113] DSC thermographs of 5-MeO-DMT HBr pattern A were measured using a PerkinElmer Pyris 6000 DSC equipped with a 45-position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predefined amount of sample, between 0.5 and 3.0 mg, was placed in an aluminum pan with a pinhole and incubated at 20 °C for 1 min. -1 The mixture was heated at 30 to 350°C or to various temperatures depending on the experiment. -1A dry nitrogen purge of 10000 s was maintained over the sample. Instrument control, data acquisition, and analysis were performed using Pyris Software v11.1.1 revision H. The thermograph shows a positive heat profile with a peak temperature of 154 °C and an endothermic onset of 150 °C (Figure 2).

[0114] The corresponding TGA thermographs were measured using a PerkinElmer Pyris 1 TGA equipped with a 20-position autosampler. The instrument was calibrated with certified weights and for temperature with certified Alumel and Perkalloy. A preset amount of sample (1–5 mg) was loaded into a pre-prepared aluminum crucible and heated at 20 °C.min-1 from ambient to 400 °C. A nitrogen purge of 20 ml.min-1 was maintained over the sample. Instrument control, data collection, and analysis were performed using Pyris Software v11.1.1 revision H. The TGA thermograph showed a 0.2% loss before the main melting endotherm, indicating mild hydration / solvation (Figure 2).

[0115] 5-MeO-DMT HBr 1 The 1 H NMR spectrum indicates successful salt formation by the shift of relevant signals, especially the methyl group of the amine signal shifting from 2.2 ppm to 2.8 ppm.

[0116] Example 6 - Preparation and characterization of the hydrobromide salt (5-MeO-DMT HBr pattern B) The 5-MeO-DMT HBr was scaled up to 100 mg, and the method followed the same procedure used to isolate the salt from the initial screen, using iPrOAc as the solvent.

[0117] A suspension was formed when solutions of 5-MeO-DMT and acid were combined at 50° C. Isolation of the solid was carried out as above.

[0118] The XRPD profile of the salt isolated after 100 mg scale-up of 5-MeO-DMT HBr is shown below. The crystallographic structure of the material was assigned as 5-MeO-DMT HBr Pattern B (Figure 3A,B) since it differed from the free base API and 5-MeO-DMT HBr Pattern A. The two different patterns of the HBr salt are the result of polymorphism, as TGA analysis showed no loss of water or residual solvent in the anhydrous form of either HBr salt.

[0119] The DSC thermograph of 5-MeO-DMT HBr pattern B shows a positive thermal profile with a single main melting endotherm with a peak temperature of 174 °C and an onset temperature of 171 °C (Figure 4). The corresponding TGA thermograph shows no weight loss prior to the main melt, indicative of the anhydrous form of the HBr salt (Figure 4).

[0120] Comparing the DSC thermograms of the two 5-MeO-DMT HBr salt forms, pattern B shows a superior thermal profile with a sharper melting point 20 °C higher than 5-MeO-DMT HBr pattern A (Figure 5).

[0121] 5-MeO-DMT HBr Pattern B 1 The 1 H NMR spectrum indicates successful salt formation by the shift of relevant signals, especially the methyl group of the amine signal shifting from 2.2 ppm to 2.85 ppm.

[0122] Example 7 - Chemical Purity The chemical purity of the isolated solid hydrobromide salt was assessed by HPLC analysis, also to assess whether any improvements were made due to the formation of the salt.

[0123] The purity of the 5-MeO-DMT free base used in the above salt formation experiment was 98.91% area, and contained 0.20% area of ​​an impurity with an RTT of 0.3 and 0.74% area of ​​an impurity with an RRT of 0.96.

[0124] The purity of 5-MeO-DMT HBr pattern A obtained in Example 2 was 99.59% area, and the purity of 5-MeO-DMT HBr pattern B (Example 6) was 99.91% area.

[0125] 5-MeO-DMT HPLC Method: System: Agilent 1100 / 1200 series liquid chromatograph or equivalent Column: Triart Phenyl: 150 x 4.6 mm, particle size 3.0 μm (e.g., YMC, part number: TPH12S03-1546PTH) Mobile phase A: Water: Trifluoroacetic acid (100:0.05, parts by volume) Mobile phase B: Acetonitrile:Trifluoroacetic acid (100:0.05, parts by volume) Flow rate: 1.0ml / min Injection volume: 5μl Detection: 220nm UV detection Column temperature: 30℃ Post run: 5 minutes Gradient: [Table 4] Sample preparation: Prepare samples at 0.30 mg / ml in acetonitrile / water (50:50).

[0126] The residual solvents are shown in the table below. [Table 5]

[0127] Example 8 - Solubility 5-MeO-DMT free base and 5-MeO-DMT hydrobromide (30 mg) were weighed into a crystallization tube, water for injection (WFI; 150 μL, 5 vol) was charged, and the sample was allowed to equilibrate for 24 hours (25° C.).

[0128] The free base became a suspension. An additional 850 μl of water was added. The mixture was still a suspension. The solubility determined after 24 hours of equilibration by analysis of the filtrate was 3.29 mg / ml at 25° C. The pH value of the suspension after 24 hours was measured at 25° C. to be 9.93.

[0129] In the case of 5-MeO-DMT HBr, a solution was obtained. The solubility measured after 24 hours of equilibration was greater than 200 mg / mL at 25° C. The pH value of the solution after 24 hours was measured at 25° C. to be 6.84.

[0130] Example 9 - Stability (5-MeO-DMT HBr Pattern A) Approximately 10 mg of 5-MeO-DMT HBr Pattern A was weighed into a Type 1 glass vial. An HDPE screw cap was loosely fitted onto the vial to allow for moisture ingress.

[0131] Accelerated stability studies were performed in an ICH standard 40°C / 75% relative humidity stability cabinet.

[0132] After storage at 40 °C / 75% RH for 5 days, 5-MeO-DMT HBr Pattern A showed a change in the crystalline pattern by XRPD analysis, and this resulting pattern was designated 5-MeO-DMT HBr Pattern C for descriptive purposes.

[0133] As shown in Figure 6, pattern C shows similarity to pattern B.

[0134] The DSC thermograph of 5-MeO-DMT HBr Pattern C shows a main melting endotherm with a peak temperature of 174° C. and an onset temperature of 172° C. The small event shown at 150° C. is presumed to be the melting of the Pattern A phase of the material followed by a recrystallization event to produce the pure Pattern B phase, which is known to melt at 174° C. (FIG. 7). The corresponding TGA thermograph shows no mass loss prior to the main melting of the material, indicating the anhydrous form of the HBr salt (FIG. 7).

[0135] It was concluded that pattern C was a mixed phase of patterns A and B of the HBr salt.

[0136] Example 10 - Stability (5-MeO-DMT HBr Pattern B) After 5 days of storage at 40 °C / 75% RH, 5-MeO-DMT HBr produced a crystalline pattern by XRPD analysis similar to the input form of pattern B. There are minor differences between the two XRPD profiles, including an additional peak in the 17-19 °2θ region. This pattern is designated 5-MeO-DMT HBr pattern B' for illustration (Figure 8).

[0137] The DSC thermograph of 5-MeO-DMT HBr, pattern B', shows a positive thermal profile with a single endothermic event with a peak temperature of 173° C. (1° C. lower than 5-MeO-DMT HBr pattern B) and an onset temperature of 171° C. (FIG. 9). The corresponding TGA thermograph shows no loss of mass prior to the main melting endotherm, indicative of the anhydrous form of the HBr salt (FIG. 9).

[0138] Attempts to reproduce the formation of 5-MeO-DMT HBr pattern B' were unsuccessful. 5-MeO-DMT HBr pattern B' was not isolated by equilibrating pattern B at 90% relative humidity. It was therefore concluded that pattern B' is not a true form of the HBr salt and that the differences in XRPD diffraction are due to contamination within the sample.

[0139] Example 11-5-Accelerated stability study of MeO-DMT salt After storage in an ICH-standard stability cabinet at 40° C. / 75% RH for 5 days, the chemical purity of the 5-MeO-DMT salt was assessed by HPLC.

[0140] The initial purity of 5-MeO-DMT HBr pattern A was 99.59% area. After 5 days the purity was 99.55% area.

[0141] The initial purity of 5-MeO-DMT HBr pattern B was 99.91% area. After 5 days the purity was 99.83% area.

[0142] The results indicate that these salts are stable upon storage at 40°C / 75% RH for 5 days with only slight loss of chemical purity.

[0143] Example 12-5-DVS Analysis of MeO-DMT HBr Dynamic vapor sorption (DVS) data was collected for both 5-MeO-DMT HBr Pattern A and Pattern B. The DSV data is shown in Figure 10 (Pattern A) and Figure 11 (Pattern B). The DVS profiles are nearly identical. Neither form showed any change after equilibration at extreme relative humidities.

[0144] The DVS profile of 5-MeO-DMT HBr pattern A shows that in the first sorption cycle, the solid absorbs 0.13% water up to 60% RH, and then increases by a further 1.56 wt% between 60% and 90% RH. This results in a total water absorption of 1.7 wt% over the humidity range. This water absorption is reversible, as it is lost in the subsequent desorption cycle. Hysteresis is observed, with water absorption being easier than desorption.

[0145] The DVS profile of 5-MeO-DMT HBr pattern B shows that in the first sorption cycle, the solid absorbs 0.14% water up to 60% RH, and then increases by a further 1.57 wt% between 60% and 90% RH. This results in a total water absorption of 1.71 wt% over the humidity range. This water absorption is reversible, as it is lost in the subsequent desorption cycle. Hysteresis is observed, with water absorption being easier than desorption.

[0146] The DVS profile indicates slight hygroscopicity.

[0147] Example 13 - Stability in aqueous solution The stability of 5 MeO DMT HBr was evaluated in WFI under conditions of 40° C. / 75% RH for 14 days.

[0148] The salt was weighed into a sample vial and WFI was added to a concentration of 100 mg / mL. The solution was stirred at 25° C. until completely dissolved. The solution was then clarified into a sample vial and allowed to stand for 14 days. The chemical purity of the solution was assessed at intervals by HPLC as described above. [Table 6]

[0149] Example 14-Scale-up of the preparation of 5-MeO-DMT HBr Pattern B a) Preparation on a 5 g scale The formation of 5-MeO-DMT HBr Pattern B was scaled up to 5.0 g using the method described above.

[0150] A stock solution of HBr acid was prepared in ethanol at 1M concentration. 5-MeO-DMT free base (5.0 g) was weighed into a round bottom flask and dissolved in 50 mL of iPrOAc (10 vol) at 50 °C. HBr acid solution was then immediately charged with 1 equivalent. The mixture was equilibrated at room temperature for 18 hours. The resulting suspension was isolated by vacuum filtration and dried in vacuum for 18 hours (6.28 g, 91.68% yield).

[0151] XPRD analysis of the resulting solid showed that 5-MeO-DMT HBr pattern B was successfully prepared.

[0152] b) Larger scale production methods / processes Salt-forming crystallization was performed to prepare the HBr salt on a 106 g scale. 5-MeO-DMT (106 g, 0.486 mol) was combined with IPA (8.9 vol, 1270 mL). The resulting solution was stirred at a speed of 275 rpm. Deionized water (90 mL) was added to the reaction vessel, resulting in a slightly opaque dark brown solution (no change from IPA alone). The solution was clarified through a 1 micron filter into a jacketed vessel without issue.

[0153] The mixture was heated to 45° C. and then HBr acid (48% aq) (1.0 eq, 81 g) was added dropwise over 5 min. An additional 7 mL of water was then added to the vial containing HBr and added to the reaction mixture to give a final IPA to water composition of 90:10 (by volume).

[0154] The mixture was then cooled to 43° C. and seeded with 5-MeO-DMT HBr pattern B (0.1% seed loading, 106 mg). The mixture was held at 43° C. for 30 minutes, where it was observed that the seeds were retained and crystallization proceeded only slightly. The mixture was then cooled to 41° C. and stirred for an additional 1.5 hours to allow mild crystallization to occur.

[0155] The mixture was then cooled at 5° C. / hr to 5° C. and equilibrated for 18 h.

[0156] The solids were then filtered under vacuum. Filtered easily through a 150mm diameter Buchner filter / paper filter media, taking 60 seconds for the majority to pass through the cake surface. A 1 volume vessel rinse was done with 5% water / IPA to pass through the cake, and a final rinse with IPA. The cake was dried under air / vacuum for 20 minutes. Wet cake filter depth in 150mm diameter filter: 9mm.

[0157] An off-white solid was isolated. A wet mass of 150.88 g was recorded. The solid was dried at 50° C. for approximately 20 hours. 5-MeO-DMT HBr was isolated as an off-white solid (78% yield).

[0158] Example 15 - Further scale-up A nitrogen purged 50 L vessel was charged with 5-MeO-DMT (750.3 g, 3.44 mol), 2-propanol (6160 mL), and purified water (190 mL) and stirred at 15-25° C. for 76 minutes. The solution was transferred to a 10 L carboy, checked for particles, and then passed through a 1.2 micron in-line filter back into the 50 L vessel and a solution of polished filtered HBr in 2-propanol (350 mL) (prepared using 390 mL of 48% aqueous HBr and 3080 mL of purified water) was added dropwise over 1 hour at 15-25° C., followed by seeding with 5-MeO-DMT HBr seeds (0.8 g). The batch was stirred for 1 hour at 15-25° C., after which the remaining polished filtered HBr in 2-propanol solution (3060 mL) was added dropwise over 4 hours. The batch was stirred at 15-25 °C for 1 h, then cooled at 5 °C / h to 0-10 °C and equilibrated for 24 h. The solid was then isolated by filtration, washed with polished filtered 2-propanol (1060 mL), and the solid was dried under vacuum at 60 °C.

[0159] Yield = 874.3g.

[0160] Example 16 - Particle size measurement The particle size distribution of the samples obtained as in the above examples was measured using a laser light scattering method, and the results are summarized in the table below. [Table 7]

[0161] HBr salt has a D of about 240 μm 50 and the crystal habit is shown to be hexagonal.

[0162] Example 17 - Flow properties The bulk and tapped densities of the HBr salt samples obtained above were measured by standard methods. Bulk density: 0.19g / cm 3 Tap density: 0.25g / cm 3

[0163] From this, the Carr's index, which indicates flow properties, can be calculated (100 x (tap density - bulk density / 100)). This index is 24%. The Hausner coefficient (tap density / bulk density), which also indicates flow properties, is 1.31.

[0164] For the free base, the following values ​​were measured: Bulk density: 0.32g / cm 3 Tap density: 0.54g / cm 3

[0165] The results showed a Kerr index of 41% and a Hausner coefficient of 1.68, indicating extremely poor fluidity.

[0166] Thus, the HBr salt of the present invention has significantly improved flow properties.

Claims

1. Crystalline hydrobromide of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT HBr).

2. The salt according to claim 1, wherein a USP L11 column with UV detection at 220 nm, length 150 mm and inner diameter 4.6 mm is used, the column temperature is 30°C, and the column is eluted at a flow rate of 1.0 ml / min using a solvent gradient based on mobile phase A (0.05% TFA in WFI) and mobile phase B (0.05% TFA in acetonitrile), and the solvent gradient has a chemical purity of at least 99.5% area, preferably at least 99.8% area, and particularly at least about 99.9% area, as determined by HPLC evaluation by the following gradient program: Table 1

3. The salt according to claim 1, which, when evaluated by the HPLC method defined in claim 2, does not contain impurities at a level of 0.1% area or more.

4. The salt according to claim 1, having a melting point of 174°C.

5. The salt according to claim 1, characterized by an X-ray diffraction pattern measuring using Cu Kα radiation, which includes peaks at 14.5°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, and 24.2°2θ±0.2°2θ.

6. The salt according to claim 1, characterized by an X-ray diffraction pattern measuring using Cu Kα rays, which includes peaks at 14.5°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, and 24.2°2θ±0.2°2θ.

7. The salt according to claim 1, characterized by an X-ray diffraction pattern measuring using Cu Kα rays, which includes peaks at 14.5°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, and 24.2°2θ±0.2°2θ.

8. The salt according to claim 1, characterized by an X-ray diffraction pattern measuring using Cu Kα rays, which includes peaks at 14.5°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, 21.4°2θ±0.2°2θ, and 24.2°2θ±0.2°2θ.

9. The salt according to claim 1, characterized by an X-ray diffraction pattern measuring using Cu Kα rays, which includes peaks at 14.5°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, 21.4°2θ±0.2°2θ, 24.2°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ.

10. The salt according to claim 1, characterized by an X-ray diffraction pattern measuring using Cu Kα rays, which includes peaks at 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, 21.4°2θ±0.2°2θ, 24.2°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ.

11. The salt according to claim 1, characterized by an X-ray diffraction pattern measuring using Cu Kα rays, which includes peaks at 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, 21.4°2θ±0.2°2θ, 24.2°2θ±0.2°2θ, 24.8°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ.

12. The salt according to claim 1, characterized by an X-ray diffraction pattern measuring using Cu Kα rays, which includes peaks at 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, 21.4°2θ±0.2°2θ, 24.2°2θ±0.2°2θ, 24.8°2θ±0.2°2θ, 25.3°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ.

13. The salt according to claim 1, characterized in essence by an X-ray diffraction pattern as shown in Figure 3B.

14. The salt according to claim 1, characterized in that the content of 5-MeO-DMT HBr pattern A is less than 5 wt%, preferably less than 2 wt%, and particularly less than 1 wt%.

15. A method for preparing a crystalline hydrobromide according to any one of claims 1 to 14, the method comprising salt formation crystallization.

16. The method according to claim 15, wherein an isopropyl alcohol / water mixture, particularly one having an isopropyl alcohol / water ratio in the range of 80:20 to 98:2 (parts by volume), and especially one having an isopropyl alcohol / water ratio of about 90:10 (parts by volume), is used as the solvent system.

17. A pharmaceutical composition comprising the salt described in any one of claims 1 to 14.

18. The pharmaceutical composition according to claim 17, which is in a form for administration by injection.

19. The pharmaceutical composition according to claim 17, in a form for intranasal administration.

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