WO2024086491A1 - N,n-diallyl-5-methoxytryptamine hemisuccinate - Google Patents

Abstract

Provided herein is 5-OMe-DALT hemisuccinate, including solid forms such as crystalline forms of 5-OMe-DALT hemisuccinate, useful in treatment of severe neurological disorders, severe pain, or addictive conditions. Also provided are pharmaceutical compositions containing the 5-OMe-DALT hemisuccinate and methods of using the 5-OMe-DALT hemisuccinate for treating a subject with a severe neurological disorder, severe pain, or addictive conditions.

Description

N,N-DIALLYL-5-METHOXYTRYPTAMINE HEMISUCCINATE

RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. provisional patent application no. 63/379,798, filed October 17, 2022. The contents of the above-referenced application are incorporated herein by reference in their entirety.

FIELD

[0002] Provided is N,N-diallyl-5-methoxytryptamine hemisuccinate (“5-OMe-DALT hemi succinate”), including solid forms such as crystalline forms thereof. Also provided are pharmaceutical compositions containing 5-OMe-DALT hemisuccinate and methods of using 5- OMe-DALT hemisuccinate.

BACKGROUND

[0003] Recently, there has been a large amount of research in the use of psychedelic drugs, including psilocin, psilocybin, MDMA and LSD, in the treatment of severe neurological disorders, including major depressive disorder, anxiety, stress and post-traumatic stress disorder (“PTSD”), that have been resistant to standard therapy. See, e.g., Krediet et al. Int. J. Neuropsychopharm. 2020, 23(6), 385-400; Weston et al. Depression Anxiety 2020, 37, 1261 - 1279; Carhart-Harris et al. Psychopharmacology 2018, 235, 399-408. Psychedelic drugs have also been studied in the treatment of severe pain. See, e.g., Castellanos et al. Reg. Anesth. Pain Med. 2020, 0, 1-9; Edinoff et al. Neur. Inter. 2022, 14, 423-436. Studies have shown that psilocybin is an effective treatment for major depressive disorder and the treatment effects last up to a year (see, e.g., Johns Hopkins Medicine Newsroom at hopkinsmedicine.org/news). Psilocybin treatment has been shown to increase global integration in the brain of depression patients (see, e.g., Daws, et al. Nature Med. 2022, 28, 844-851), leading to its therapeutic effect. However, due to the strict regulatory regime surrounding psychedelic drugs (most are listed as Schedule 1 drugs, severely limiting or banning their use in research), little research has been performed in a traditional pharmaceutical development setting to enable ultimate approval as pharmaceuticals.

[0004] Thus, there is a need for physical forms of psychedelic compounds that are suitable as active pharmaceutical ingredients (APIs) for use in pharmaceutical drug products (DPs). Such physical forms are useful in the treatment of severe neurological disorders. SUMMARY

[0005] Provided herein is 5-OMe-DALT hemi succinate. In another embodiment, provided is a solid form of 5-OMe-DALT hemisuccinate. In one embodiment, the solid form is crystalline. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate has powder X-ray diffraction peaks at about 7.3, about 11.1, about 11.6, about 13.7, about 14.5, about 14.9 and/or about 15.9 degrees 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate has powder X-ray diffraction peaks at about 8.6, about 10.8, about 13.1, about 13.7, about 13.8, about 14.4, about 14.5, about 14.8, about 15.7, about 16.2, about 17.3 and/or about 17.7 degrees 20. All XRPD diffraction peaks herein are ±0.2° 20.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 is a powder X-ray diffraction pattern of a crystalline solid form of 5-OMe- DALT hemisuccinate provided herein (Form A).

[0007] FIG. 2 is a powder X-ray diffraction pattern of a crystalline solid form of 5-OMe- DALT hemisuccinate provided herein (Form B).

[0008] FIG. 3 is a ’H nuclear magnetic resonance (NMR) spectrum of a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein (Form A) in DMSO-d6.

[0009] FIG 4 is a ^LH NMR spectrum of a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein (Form B) in DMSO-ds.

[0010] FIG. 5 is a Raman spectrum of a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein (Form A).

[0011] FIG. 6 is a Raman spectrum of a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein (Form B).

[0012] FIG. 7 shows thermal data (differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)) for a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein (Form A).

[0013] FIG. 8 shows thermal data (DSC and TGA) for a crystalline solid form of 5-OMe- DALT hemisuccinate provided herein (Form B).

[0014] FIG. 9 shows a dynamic vapor sorption (DVS) study of a crystalline solid form of 5- OMe-DALT hemisuccinate provided herein (Form A).

[0015] FIGs. 10A and 10B show optical microscopy data for a crystalline solid form of 5- OMe-DALT hemisuccinate provided herein (Form A). [0016] FTG. 11 is a powder X-ray diffraction pattern of a crystalline solid form of 5-OMe- DALT hemisuccinate provided herein (Form A) in a preferred orientation (PO). The peak at approximately 22.06° 20 disappears upon light grinding of the sample.

DETAILED DESCRIPTION

I. DEFINITIONS

[0017] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0019] The singular forms "a," "an," and "the" include plural references, unless the context clearly dictates otherwise.

[0020] As used herein "subject" is an animal, such as a mammal, including human, such as a patient.

[0021] As used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmacokinetic behavior of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test for such activities.

[0022] As used herein, pharmaceutically acceptable derivatives of a compound include, but are not limited to, salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates or hydrates thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl- 2-pyrrolidin-T-ylmethylbenzimidazole, di ethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, mesylates, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) where R is alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

[0023] As used herein, a “severe neurological disorder” is a disorder that is resistant to standard psychiatric or psychologic therapy. In one embodiment, a severe neurological disorder is major depressive disorder, treatment resistant depression, persistent depressive disorder, PTSD, anxiety or stress.

[0024] As used herein, “severe pain” includes fibromyalgia, phantom limb pain, cluster headache, post operative pain, pain associated with cancer, and chronic neuropathic pain. See, e.g., Castellanos et al. Reg. Anesth. Pain Med. 2020, 0, 1-9.

[0025] As used herein, PTSD is a mental health condition that's triggered by a terrifying event - either experiencing it or witnessing it. Symptoms may include flashbacks, nightmares and severe anxiety, as well as uncontrollable thoughts about the event.

[0026] As used herein, “major depressive disorder” includes major depression with a specific feature such as anxious distress, mixed features (depression and mania), melancholic features, atypical features (temporary cheeriness), psychotic features, catatonia, peripartum onset and seasonal pattern (sunlight dependent). [0027] As used herein, an “addictive condition” is one that causes a compulsive or obsessive pursuit of “reward” and lack of concern over consequences. In one embodiment, an addictive condition is drug abuse, alcohol use disorder or alcoholism, nicotine addiction or smoking addiction, or gambling addiction. See, e.g., Bogenschutz et al. JAMA Psychiatry, August 24, 2022, E1-E10.

[0028] As used herein, treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating severe neurological disorders, including major depressive disorder, persistent depressive disorder, PTSD, anxiety or stress.

[0029] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or pharmaceutical composition.

[0030] As used herein, and unless otherwise indicated, the terms "manage," "managing" and "management" encompass preventing the recurrence of the specified disease or disorder in a subject who has already suffered from the disease or disorder, and/or lengthening the time that a subject who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a subject responds to the disease or disorder.

II. CRYSTALLINE FORMS OF 5-OMe-DALT HEMISUCCINATE

[0031] Provided herein are two crystalline forms of 5-MeO-DALT hemi-succinate - Form A (anhydrate) and Form B (hydrate). It was found that precise conditions are required to prepare each of these forms, otherwise disproportionation of the salt to give free base (FB) may occur. Also, if the preparation conditions are not controlled, Form A may give a preferred orientation (PO) crystal form (see, e.g., FIG. 11).

[0032] In one embodiment, the crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has improved properties over the free base of 5-OMe-DALT and/or over other salt forms of 5-OMe-DALT. Such improved properties include one or more of: stability, pharmacokinetics (PK), pharmacodynamics (PD), absorption, distribution, metabolism or excretion (ADME), flowability, non-hygroscopicity, hydrostatic properties, etc. While the crystalline solid form of 5-OMe-DALT hemisuccinate provided herein may not be superior in each aspect, it is overall superior as an API as compared to the free base and other salt forms of 5-OMe-DALT known in the art.

A. FORM A

[0033] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 7.3° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 11.1° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 11.6° 26. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X- ray powder diffraction peak at 13.7° 20. In another embodiment, a crystalline solid form of 5- OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 14.9° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 15.9° 20.

[0034] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3 and 11.1° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 11.1 and 13.7° 20. In another embodiment, a crystalline solid form of 5- OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3 and 13.7° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3 and 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 11.1 and 14.5° 20.

[0035] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 11.1, 13.7 and 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3, 13.7 and 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3, 11.1 and 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3, 11.1 and 13.7° 20. [0036] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3, 11.1, 13.7 and 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 11.1, 13.7, 14.5 and 14.9° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 11.1, 13.7, 14.5 and 15.9° 20.

[0037] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3, 11.1, 11.6, 13.7 and 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 7.3, 11.1, 11.6, 13.7, 14.5 and 14.9° 20.

[0038] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a powder X-ray diffraction pattern substantially the same as FIG. 1.

[0039] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has the following powder X-ray diffraction peaks (±0.2° 20): 7.3, 11.1, 11.6, 13.7, 14.5, 14.9, 15.9, 18.8, 19.0.

[0040] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a ’H NMR spectrum substantially the same as FIG. 3.

[0041] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has Raman spectroscopy peaks at 1644, 1622, 1586, 1547 ±4 cm'¹. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a Raman spectrum substantially the same as FIG. 5.

[0042] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a DSC thermal melt peak temperature (endothermic) of about 110 to about 120 °C. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a DSC thermal melt peak temperature (endothermic) of about 110 to about 115 °C. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a DSC thermal melt peak temperature (endothermic) of about 112 to about 114 °C. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a DSC thermal melt peak temperature (endothermic) of about 113 °C. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a DSC thermal melt peak temperature (endothermic) of about 112.8 °C.

[0043] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein is anhydrous. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein loses less than about 1 wt %, less than about 0.5 wt %, less than about 0.2 wt %, or about 0.1 wt % upon heating from room temperature to 100 °C. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein exhibits thermal data (DSC and TGA) substantially the same as FIG. 7.

[0044] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein is non-hygroscopic. In another embodiment, a crystalline solid form of 5-OMe- DALT hemisuccinate provided herein is slightly hygroscopic. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein shows less than about 1%, less than about 0.6%, or about 0.4% moisture uptake in a DVS study. In one embodiment, the crystalline form of the 5-OMe-DALT hemisuccinate provided herein remains unchanged post-DVS. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a DVS curve substantially the same as FIG. 9.

[0045] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein appears substantially the same as FIG. 10 under optical microscopy.

B. FORM B

[0046] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 8.6° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 10.8° 2G. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 13.1° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X- ray powder diffraction peak at 13.7° 20. In another embodiment, a crystalline solid form of 5- OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 13.8° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 14.4° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 14.8° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 15.7° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 16.2° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has an X- ray powder diffraction peak at 17.3° 20. In another embodiment, a crystalline solid form of 5- OMe-DALT hemisuccinate provided herein has an X-ray powder diffraction peak at 17.7° 20. [0047] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6 and 10.8° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8 and 13.1° 20. In another embodiment, a crystalline solid form of 5- OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1 and 14.4° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1, 14.4 and 14.8° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1 and 13.7° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1, 13.7 and 13.8° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1, 13.7, 13.8 and 14.4° 20. In another embodiment, a crystalline solid form of 5-OMe- DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1, 13.7, 13.8, 14.4 and 14.5° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1, 13.7, 13.8,

14.4, 14.5 and 14.8° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1, 13.7, 13.8,

14.4, 14.5, 14.8 and 15.7° 20. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1, 13.7, 13.8,

14.4, 14.5, 14.8, 15.7 and 16.2° 20. In another embodiment, a crystalline solid form of 5-OMe- DALT hemisuccinate provided herein has X-ray powder diffraction peaks at 8.6, 10.8, 13.1, 13.7, 13.8, 14.4, 14.5, 14.8, 15.7. 16.2 and 17.3° 20. [0048] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a powder X-ray diffraction pattern substantially the same as FIG. 2.

[0049] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has the following powder X-ray diffraction peaks (±0.2° 20): 8.6, 10.8, 13.1, 13.7, 13.8, 14.4, 14.5, 14.8, 15.7, 16.2, 17.3, 17.7, 18.5, 18.9, 19.9.

[0050] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a ^LH NMR spectrum substantially the same as FIG. 4.

[0051] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has Raman spectroscopy peaks at about 1647, 1625, 1589, 1549 ±4 cm'¹. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has a Raman spectrum substantially the same as FIG. 6.

[0052] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein is a hydrate. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein is an unstable hydrate. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein is an unstable hydrate that converts to a stable anhydrate upon exposure to ambient temperature and humidity.

[0053] In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein loses about 0.5 to about 2 wt %, about 0.75 to about 1.5 wt %, about 1 wt %, or about 1.06 wt. % upon heating from room temperature to 100 °C. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein shows endotherms at about 60 °C and about 110 °C, and an exotherm at about 131 °C, in a DSC study. In another embodiment, a crystalline solid form of 5-OMe-DALT hemisuccinate provided herein has thermal data (DSC and TGA) substantially the same as FIG. 8.

III. SYNTHESIS OF THE SOLID FORMS

[0054] The solid forms of 5-OMe-DALT hemisuccinate, including crystalline solid forms of 5- OMe-DALT hemisuccinate, provided herein may be prepared according to methods well known to those of skill in the art. In one embodiment, for preparation of Form A, 5-OMe-DALT free base was dissolved in an appropriate solvent such as acetone and succinic acid was added. After stirring for one day, the mixture was placed in a -20 °C freezer for 30 minutes followed immediately by vacuum fdtration. In another embodiment, for preparation of Form B, 5-OMe- DALT hemisuccinate was mixed with water for one week. After centrifugation, the supernatant was decanted to provide Form B as a wet paste.

IV. PHARMACEUTICAL COMPOSITIONS

[0055] The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the crystalline forms of 5-OMe-DALT hemisuccinate provided herein and a pharmaceutically acceptable carrier, diluent or excipient.

[0056] The crystalline forms of 5-OMe-DALT hemisuccinate can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Typically, the crystalline forms of 5-OMe-DALT hemisuccinate described herein are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[0057] In the compositions, effective concentrations of one or more crystalline forms of 5- OMe-DALT hemisuccinate is (are) mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentrations of the crystalline forms of 5-OMe-DALT hemisuccinate in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and/or progression of a disease or disorder disclosed herein.

[0058] Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of a crystalline form of 5-OMe-DALT hemisuccinate is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the crystalline forms of 5-OMe-DALT hemisuccinate provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0059] In addition, the crystalline forms of 5-OMe-DALT hemisuccinate may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as liposomes designed to cross the blood-brain barrier, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a crystalline form of 5-OMe-DALT hemisuccinate provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated 5-OMe-DALT hemi succinate, pelleted by centrifugation, and then resuspended in PBS.

[0060] The crystalline form of 5-OMe-DALT hemisuccinate is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect. The therapeutically effective concentration may be determined empirically by testing the crystalline forms of 5-OMe-DALT hemisuccinate in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans. In some embodiments, the crystalline form of 5-OMe-DALT hemisuccinate is administered in a method to achieve a therapeutically effective concentration of the drug. In some embodiments, a companion diagnostic (see, e.g., Olsen D and Jorgensen J T, Front. Oncol., 2014 May 16, 4: 105, doi: 10.3389/fonC.2014.00105) is used to determine the therapeutic concentration and safety profile of the active compound in specific subjects or subject populations.

[0061] The concentration of crystalline form of 5-OMe-DALT hemisuccinate in the pharmaceutical composition will depend on absorption, tissue distribution, inactivation and excretion rates of the crystalline form of 5-OMe-DALT hemi succinate, the physicochemical characteristics of the crystalline form of 5-OMe-DALT hemi succinate, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of a disease or disorder disclosed herein.

[0062] In one embodiment, the pharmaceutical compositions provide a dosage of from about 0.01 mg to about 20 mg of crystalline form of 5-OMe-DALT hemisuccinate per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 0.1 mg to about 500 mg and in certain embodiments, from about 1 to about 200 mg of 5-OMe- DALT per dosage unit form. [0063] The crystalline form of 5-OMe-DALT hemisuccinate may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. [0064] Thus, effective concentrations or amounts of one or more of the crystalline forms of 5- OMe-DALT hemisuccinate described herein are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Crystalline forms of 5-OMe-DALT hemisuccinate are included in an amount effective for ameliorating one or more symptoms of, or for treating, retarding progression, or preventing a disease disclosed herein. The concentration of crystalline form of 5-OMe-DALT hemisuccinate in the composition will depend on absorption, tissue distribution, inactivation, excretion rates of 5-OMe-DALT, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.

[0065] The compositions are intended to be administered by a suitable route, including but not limited to oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, dermal, transdermal, buccal, rectal, topical, local, nasal or inhalation. For oral administration, capsules and tablets can be formulated. The compositions are in liquid, semiliquid or solid form and are formulated in a manner suitable for each route of administration. [0066] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, pens, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.

[0067] In instances in which the crystalline forms of 5-OMe-DALT hemisuccinate exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using pharmaceutically acceptable cosolvents as known to one skilled in the art.

[0068] Upon mixing or addition of the crystalline forms of 5-OMe-DALT hemi succinate, the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the crystalline forms of 5-OMe-DALT hemisuccinate in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.

[0069] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, buccal delivery preparations, sterile parenteral solutions or suspensions, inhaled preparations, intranasal preparations, transdermal and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the crystalline forms of 5-OMe-DALT hemi succinate. The crystalline forms of 5-OMe-DALT hemisuccinate are formulated and administered in unit dosage forms or multiple dosage forms. Unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the crystalline form of 5-OMe-DALT hemisuccinate sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle, inhaled or intranasal delivery device or diluent. Examples of unit dose forms include ampules, syringes, individually packaged tablets or capsules, and devices for inhaled or intranasal delivery. Unit dose forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or devices for inhalation or intranasal delivery. Hence, multiple dose form is a multiple of unit doses which are not segregated in packaging.

[0070] Sustained-release preparations can also be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the crystalline form of 5-OMe-DALT hemisuccinate provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid- glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3 -hydroxybutyric acid.

[0071] Dosage forms or compositions containing a crystalline form of 5-OMe-DALT hemisuccinate in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium croscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders, thin fdms and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, poly anhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001% 100% 5-OMe-DALT, in certain embodiments, about 0.1 85% or about 75-95%.

[0072] The crystalline forms of 5-OMe-DALT hemisuccinate may be prepared with carriers that protect the 5-OMe-DALT against rapid elimination from the body, such as time release formulations or coatings.

[0073] The compositions may include other active compounds to obtain desired combinations of properties. The crystalline forms of 5-OMe-DALT hemisuccinate provided herein may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to herein, such as severe neurological disorders. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein. [0074] Lactose-free compositions provided herein can contain excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions contain an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms contain a crystalline forms of 5-OMe-DALT hemisuccinate, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate.

[0075] Further encompassed are anhydrous pharmaceutical compositions and dosage forms containing a crystalline form of 5-OMe-DALT hemisuccinate provided herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment and use of formulations.

[0076] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

[0077] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, strip packs, and the addition of a desiccant canister.

V. DOSING

[0078] The crystalline forms of 5-OMe-DALT hemisuccinate and pharmaceutical compositions provided herein may be dosed in certain therapeutically or prophylactically effective amounts, certain time intervals, certain dosage forms, and certain dosage administration methods as described below.

[0079] In certain embodiments, a therapeutically or prophylactically effective amount of the crystalline form of 5-OMe-DALT hemisuccinate is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 to about 5 mg per day.

[0080] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.

[0081] In one embodiment, the recommended daily dose range of the crystalline form of 5- OMe-DALT hemisuccinate provided herein for the conditions described herein lie within the range of from about 0.5 mg to about 50 mg per day, in one embodiment given as a single once-a- day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

[0082] In a specific embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In a specific embodiment, the crystalline form of 5-OMe-DALT hemisuccinate can be administered in an amount of about 25 mg/day. In a particular embodiment, the crystalline form of 5-OMe-DALT hemisuccinate can be administered in an amount of about 10 mg/day. In a particular embodiment, the crystalline form of 5-OMe-DALT hemisuccinate can be administered in an amount of about 5 mg/day. In a particular embodiment, the crystalline form of 5-OMe- DALT hemisuccinate can be administered in an amount of about 4 mg/day. In a particular embodiment, the crystalline form of 5-OMe-DALT hemisuccinate can be administered in an amount of about 3 mg/day. [0083] In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 to about 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day.

[0084] In certain embodiments, the amount of the crystalline form of 5-OMe-DALT hemisuccinate administered is sufficient to provide a maximum plasma concentration (peak concentration) of 5-OMe-DALT, ranging from about 0.001 to about 50 pM, about 0.002 to about 200 pM, about 0.005 to about 100 pM, about 0.01 to about 50 pM, from about 1 to about 50 pM, about 0.02 to about 25 pM, from about 0.05 to about 20 pM, from about 0.1 to about 20 pM, from about 0.5 to about 20 pM, or from about 1 to about 20 pM.

[0085] The methods provided herein encompass treating a patient regardless of subject's age, although some diseases or disorders are more common in certain age groups.

[0086] Depending on the disease to be treated and the subject's condition, the crystalline form of 5-OMe-DALT hemisuccinate provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The crystalline form of 5-OMe-DALT hemisuccinate provided herein may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

[0087] In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered orally. In another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered parenterally. In yet another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered intravenously. [0088] The crystalline form of 5-OMe-DALT hemisuccinate provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The crystalline form of 5-OMe-DALT hemisuccinate can be administered repeatedly if necessary, for example, until the subject experiences stable neurology, or until the subject experiences neurological progression or unacceptable toxicity. Stable neurology or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, neurological examination and other commonly accepted evaluation modalities.

[0089] The crystalline form of 5-OMe-DALT hemisuccinate provided herein can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once or more than once each day, for example, for a period of time. The term "continuous" is intended to mean that a therapeutic compound, such as the crystalline form of 5-OMe-DALT hemisuccinate provided herein, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term "intermittent" or "intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the crystalline form of 5-OMe- DALT hemisuccinate provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term "cycling" as used herein is intended to mean that a therapeutic compound, such as the crystalline form of 5-OMe-DALT hemisuccinate provided herein, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days.

[0090] In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once a day. In another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered twice a day. In yet another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered three times a day. In still another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered four times a day.

[0091] In certain embodiments, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day for 4 days. In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day for 5 days. In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day for 6 days. In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day for one week. In another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day for two weeks. In yet another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day for three weeks. In still another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered once per day for four weeks.

VI. METHODS OF TREATMENT

[0092] In another embodiment, a method of treating a subject having a severe neurological disorder with a crystalline form of 5-OMe-DALT hemisuccinate or a pharmaceutical composition containing a crystalline form of 5-OMe-DALT hemisuccinate is provided. In one embodiment, the severe neurological disorder is major depressive disorder. In another embodiment, the severe neurological disorder is major depressive disorder having one or more specific features such as anxious distress, mixed features (depression and mania), melancholic features, atypical features (temporary cheeriness), psychotic features, catatonia, peripartum onset and seasonal pattern (sunlight dependent).

[0093] In another embodiment, the severe neurological disorder is PTSD. In another embodiment, the severe neurological disorder is anxiety. In another embodiment, the severe neurological disorder is stress.

[0094] In another embodiment, the methods of treatment provided herein include treating a subject having a severe neurological disorder with a crystalline form of 5-OMe-DALT hemisuccinate or a pharmaceutical composition containing a crystalline form of 5-OMe-DALT hemisuccinate provided herein, in combination with standard psychological and psychiatric treatments known to those of skill in the art. See, e.g., Gartlehner et al. BMJ Open 2017, 7, e014912; Reiff et al. Am. J. Psychiatry 2020, 177(5), 391-410; Yehuda et al. Nat. Rev. 2015, 1, 1-22; Allegri et al. Minerva Anest. 2012, 78(2), 222-235.

[0095] In another embodiment, a method of treating a subject having severe pain with a crystalline form of 5-OMe-DALT hemisuccinate or a pharmaceutical composition containing a crystalline form of 5-OMe-DALT hemisuccinate is provided. In one embodiment, the severe pain is fibromyalgia. In another embodiment, the severe pain is phantom limb pain. In another embodiment, the severe pain is cluster headache. In another embodiment, the severe pain is post operative pain.

[0096] In another embodiment, a method of treating an addictive condition with a crystalline form of 5-OMe-DALT hemisuccinate or a pharmaceutical composition containing a crystalline form of 5-OMe-DALT hemisuccinate is provided. In one embodiment, the addictive condition is drug abuse. In another embodiment, the addictive condition is alcohol abuse or alcoholism. In another embodiment, the addictive condition is nicotine addiction or smoking addiction. In another embodiment, the addictive condition is gambling addiction.

VII. COMBINATION THERAPY WITH A SECOND ACTIVE AGENT

[0097] The crystalline form of 5-OMe-DALT hemisuccinate provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of severe neurological disorders.

[0098] In one embodiment, provided herein is a method of treating, preventing, or managing major depressive disorder, comprising administering to a subject a crystalline form of 5-OMe- DALT hemisuccinate provided herein in combination with one or more second active agents. In one embodiment, provided herein is a method of treating, preventing, or managing PTSD, comprising administering to a subject a crystalline form of 5-OMe-DALT hemisuccinate provided herein in combination with one or more second active agents. In one embodiment, provided herein is a method of treating, preventing, or managing anxiety, comprising administering to a subject a crystalline form of 5-OMe-DALT hemisuccinate provided herein in combination with one or more second active agents. In one embodiment, provided herein is a method of treating, preventing, or managing stress, comprising administering to a subject a crystalline form of 5-OMe-DALT hemisuccinate provided herein in combination with one or more second active agents.

[0099] As used herein, the term "in combination" includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a crystalline form of 5-OMe-DALT hemisuccinate provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.

[0100] Administration of the crystalline form of 5-OMe-DALT hemisuccinate provided herein and one or more second active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disorder being treated.

[0101] The route of administration of the crystalline form of 5-OMe-DALT hemisuccinate provided herein is independent of the route of administration of a second therapy. In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered orally. In another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered intravenously. Thus, in accordance with these embodiments, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein is administered by one mode of administration, e.g., by IV, whereas the second agent is administered by another mode of administration, e.g., orally.

[0102] In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disorder being treated or managed, the severity and stage of the disorder, and the amount of the crystalline form of 5-OMe-DALT hemisuccinate provided herein and any optional additional active agents concurrently administered to the subject.

[0103] One or more second active ingredients or agents can be used together with the crystalline form of 5-OMe-DALT hemisuccinate provided herein in the methods and compositions provided herein. Second active agents can be small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

[0104] In one embodiment, the crystalline form of 5-OMe-DALT hemisuccinate provided herein can be administered in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 25 mg, or from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent, prior to, during, or after the use of conventional therapy.

[0105] In one embodiment, second active agents for use in the compositions and methods provided herein include other drugs known in the treatment of severe depression, severe pain, or an addiction condition. Such drugs are well known to those of skill in the art.

[0106] For example, drugs used in the treatment of severe depression include SSRIs including citalopram, escitalopram, paroxetine, fluoxetine, vortioxetine, vilazodone and sertraline, SNRIs including duloxetine, venlafaxine, levomilnacipran and dexvenlafaxine, tricyclic and tetracyclic antidepressants including amoxapine, amitriptyline, maprotiline, desipramine, nortriptyline, doxepin, trimipramine, imipramine and protriptyline, atypical antidepressants such as trazodone, mirtazapine, bupropion and nefazodone, MAOIs including selegiline, isocarboxazid, phenelzine and tranylcypromine, NMDA antagonists such as exketamine and neuroactive steroid GABA-A receptor positive modulators including brexanolone. [0107] Non-limiting examples of drugs used in the treatment of severe pain include acetaminophen, NSAIDs such as aspirin, diclofenac, ibuprofen, indomethacin, meloxicam, naproxen and celecoxib, antidepressants such as serotonin and norepinephrine reuptake inhibitors including duloxetine and tricyclic antidepressants including amitriptyline, antiepileptic medications such as gabapentin, pregabalin, oxcarbazepine and carbamazepine, local anesthetics such as lidocaine, opioid agents such as morphine hydrocodone, oxycodone, hydromorphone, oxymorphone, fentanyl and tramadol.

[0108] Non-limiting examples of drugs used in the treatment of an addiction condition include methadone, buprenorphine and naltrexone (for opioid addiction), bupropion and varenicline (for tobacco addiction), naltrexone, acamprosate and disulfiram (for alcohol addiction). Behavioral therapy (in-patient and out-patient) is also commonly used in the treatment of addiction.

VIII. EXAMPLES

[0109] The examples below are meant to illustrate certain embodiments provided herein, and not to limit the scope of this disclosure.

Abbreviations: ACN - acetonitrile; IPA - isopropyl alcohol; THF - tetrahydrofuran; RT = room temperature; FB = free base; PO = preferred orientation; acid = succinic acid; SL = slurry; AS = anti-solvent

[0110] X-Ray Powder Diffraction (XRPD)

[0U1] A Rigaku SmartLab X-Ray Diffractometer was configured in Bragg-Brentano reflection ge-ometry equipped with a beam stop and knife edge to reduce incident beam and air scatter. Data collection parameters are shown in the following table. Powder samples were prepared in a low background Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sample holder.

[0112] XRPD Data Collection Parameters

[0113] Nuclear Magnetic Resonance (NMR)

[0114] The ^XH NMR spectra were acquired on a Bruker Neo 400 MHz spectrometer (observed 400.15 MHz) using TopSpin 4.1.4 GxP software. Samples were prepared by dissolving material in DMSO-de. Solutions were placed into individual 5-mm NMR tubes for subsequent spectral acquisition. Chemical shifts are reported in ppm (5) relative to the solvent peak. The probe was set to keep the sample at a constant 298 °K.

[0115] Thermal Analysis (TGA/DSC)

[0116] Therm ogravim etric Analysis (TGA)

[0117] The TGA analysis was carried out using a TA Instruments Q5500 Discovery Series instrument. The instrument balance was calibrated using class M weights and the temperature calibration was performed using alumel. The nitrogen purge was ~40 Ml per minute at the balance and ~60 Ml per minute at the furnace. Each sample was placed into a pre-tared platinum pan and heated from approximately 25 °C to 300 °C at a rate of 10 °C per minute.

[0118] Differential Scanning Calorimetry (DSC)

[0119] DSC analyses were carried out using a TA Instruments Q2500 Discovery Series instrument. The instrument temperature calibration was performed using indium. The DSC cell was kept under a nitrogen purge of ~50 Ml per minute during each analysis. The sample was placed in a standard, crimped, aluminum pan and was heated from approximately 25 °C to 300 °C at a rate of 10 °C per minute.

[0120] Fourier-Transform (FT) Raman Spectroscopy

[0121] FT-Raman spectra were acquired using a Nicolet Is50 Raman module that was equipped with a 1064 nm near-infrared laser. The system was configured with an indium gallium arsenide (InGaAs) detector and a calcium fluoride (CaFz) beam splitter. Each sample was placed onto the automated XYZ stage and analyzed using a laser power of 0.5 W. Raman spectra were collected with 256 signal -averaged scans at a resolution of 4 cm^-1 over the spectral range from 3700 to 100 cm^-1. Data acquisition and processing were performed using OMNIC 9.11 software. EXAMPLE 1

[0122] Preparation of 5-OMe-DALT hemisuccinate Form A

[0123] In a 50 mL Erlenmeyer flask equipped with a magnetic stir bar, 1 g of 5-OMe-DALT free-base and 218 mg of succinic acid were combined in 10 mL of acetone and stirred for 24 hours at room temperature. After 24 hours, the flask was placed in a -20 °C freezer for 30 minutes immediately followed by vacuum filtration.

EXAMPLE 2

[0124] Preparation of 5-OMe-DALT hemisuccinate Form B

[0125] In a 1 dram vial, 24.5 mg of 5-OMe-DALT succinate along with a magnetic stir bar was added. Using a micropipette, 400 mL of FLO was added to the vial and set to stir for 1 week at room temperature. After 1 week the stir bar was removed, the vial centrifuged, and the supernatant decanted, resulting in a wet paste that was analyzed directly.

EXAMPLE 3

[0126] Reaction crystallization experiments were performed by adding solid succinic acid (0.5 eq) to organic solutions of 5-OMe-DALT. Once succinic acid was added, the solutions were set to stir for 1 day. Subsequently, the samples were cooled to 2 °C to force precipitation. The supernatant was decanted, solids dried in the open air, and analyzed via XRPD. Conditions and results are shown in the table below. Form A was predominantly obtained with some patterns exhibiting preferred orientation. Additionally, there was one experiment that showed evidence of free-base and potential disproportionation.

PO = preferred orientation, FB = free base, acid = succinic acid EXAMPLE 4

[0127] Milling experiments use mechanical energy in the presence of minimal solvent to generate new solid forms either solvated or unsolvated. Each solvent shown in the table below (20 m ) was placed in the respective milling cup that contained ~25 mg of 5-OMe-DALT hemisuccinate Form A. Each sample was milled for 15 minutes followed by XRPD analysis. Form A was the result from all milling experiments.

EXAMPLE 5

[0128] Slurries of 5-OMe-DALT hemi-succinate were carried out. As shown in the table below, the slurries were made by using 400 mL of the respective solvent followed by adding 5- OMe-DALT hemi-succinate until saturation was achieved and additional solvent was present. Pure synthesized hemi-succinate was lyophilized from 1,4-di oxane for use in the slurry experiments. Slurries were stirred magnetically at room temperature for 1 week. After 1 week, the supernatant was decanted, and the wet sold analyzed via XRPD.

FB = free base

EXAMPLE 6

[0129] To investigate the dependence of water activity on the formation of different solid forms, an array of competitive slurries was performed at high and low water activity. Mixtures of water and isopropanol were prepared to achieve various water activities. A saturated solution of 5-OMe-DALT hemi-succinate (form A) was created, and then a small amount of each form (forms A and B) was added. These experiments are outlined in the table below. Form A is the most stable form at and below water activity of about 0.6, and form B is the most stable form at and above water activity of about 0.7. The slurries were stirred magnetically at room temperature for 1 week. Each sample was then centrifuged, the supernatant decanted, and the wet sold analyzed via XRPD.

[0130] This disclosure is not to be limited in scope by the embodiments disclosed in the examples which are intended as single illustrations of individual aspects, and any equivalents are within the scope of this disclosure. Various modifications in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. [0001] Various references such as patents, patent applications, and publications are cited herein, the disclosures of which are hereby incorporated by reference herein in their entireties.

Claims

WHAT IS CLAIMED IS:

1. 5-OMe-D ALT hemisuccinate.

2. The 5-OMe-D ALT hemisuccinate of claim 1 that is crystalline.

3. The 5-OMe-D ALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 7.3 ± 0.2° 20.

4. The 5-OMe-D ALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 11.1 ± 0.2° 20.

5. The 5-OMe-D ALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 13.7 ± 0.2° 20.

6. The 5-OMe-D ALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 14.5 ± 0.2° 20.

7. The 5-OMe-D ALT hemisuccinate of claim 2, characterized by an XRPD pattern having diffraction peaks at about 7.3 and 11.1 ± 0.2° 20.

8. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having diffraction peaks at about 11.1 and 13.7 ± 0.2° 20.

9. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having diffraction peaks at about 7.3 and 13.7 ± 0.2° 20.

10. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having diffraction peaks at about 7.3 and 14.5 ± 0.2° 20.

11. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having diffraction peaks at about 11.1 and 14.5 ± 0.2° 20.

12. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having diffraction peaks at about 11.1, 13.7 and 14.5 ± 0.2° 20.

13. The 5-OMe-DALT hemisuccinate of any one of claims 4, 5, 6, 8, 11 and 12, characterized by an XRPD pattern having a diffraction peak at about 7.3 ± 0.2° 20.

14. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having diffraction peaks at about 7.3, 11.1, 11.6, 13.7 and 14.5 ± 0.2° 20.

15. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having diffraction peaks at about 7.3, 11.1, 11.6, 13.7, 14.5 and 14.9 ± 0.2° 20.

16. The 5-OMe-DALT hemisuccinate of any one of claims 2-15, characterized by an XRPD pattern substantially the same as FIG. 1.

17. The 5-OMe-DALT hemisuccinate of any one of claims 2-16, characterized by a Raman spectrum substantially the same as FIG. 5.

18. The 5-OMe-DALT hemisuccinate of any one of claims 2-17, characterized by a DSC thermal melt peak temperature (endothermic) of about 112 °C.

19. The 5-OMe-DALT hemisuccinate of any one of claims 2-18, characterized by loss of about 0.1 wt % upon heating from room temperature to 100 °C.

20. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 8.6 ± 0.2° 20.

21. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 10.8 ± 0.2° 20.

22. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 14.4 ± 0.2° 20.

23. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 14.5 ± 0.2° 20.

24. The 5-OMe-DALT hemisuccinate of claim 2, characterized by an XRPD pattern having a diffraction peak at about 14.8 ± 0.2° 20.

25. The 5-OMe-DALT hemisuccinate of any one of claims 21-24, characterized by an XRPD pattern having a diffraction peak at about 8.6 ± 0.2° 20.

26. The 5-OMe-DALT hemisuccinate of any one of claims 22-24, characterized by an XRPD pattern having a diffraction peak at about 10.8 ± 0.2° 20.

27. The 5-OMe-DALT hemisuccinate of any one of claims 20-26, characterized by an XRPD pattern having diffraction peaks at about 8.6, 10.8, 14.4, 14.5 and 14.8 ± 0.2° 20.

28. The 5-OMe-DALT hemisuccinate of any one of claims 20-27, characterized by an XRPD pattern substantially the same as FIG. 2.

29. The 5-OMe-DALT hemisuccinate of any one of claims 20-28, characterized by a Raman spectrum substantially the same as FIG. 6.

30. The 5-OMe-DALT hemisuccinate of any one of claims 20-29, characterized by endotherms at about 59.8 °C and 110.6 °C, and an exotherm at about 131.2 °C, in a DSC study.

31. A pharmaceutical composition, comprising the 5-OMe-DALT hemisuccinate of any one of claims 1-30 and a pharmaceutically acceptable carrier.

32. A method of treating a subject having a severe neurological disorder, comprising administering to the subject the 5-OMe-DALT hemisuccinate of any one of claims 1-30 or the pharmaceutical composition of claim 31.

33. The method of claim 32, wherein the severe neurological disorder is major depressive disorder.

34. The method of claim 32, wherein the severe neurological disorder is PTSD.

35. The method of claim 32, wherein the severe neurological disorder is anxiety.

36. The method of claim 32, wherein the severe neurological disorder is stress.

37. A method of treating a subject having severe pain, comprising administering to the subject the 5-OMe-DALT hemisuccinate of any one of claims 1-30 or the pharmaceutical composition of claim 31.

38. The method of claim 37, wherein the pain is cluster headache

39. The method of claim 37, wherein the pain is phantom limb pain

40. The method of claim 37, wherein the pain is fibromyalgia

41. The method of claim 37, wherein the pain is post operative pain.

42. The method of claim 37, wherein the pain is pain associated with cancer.

43. A method of treating a subject having an addictive condition, comprising administering to the subject the 5-OMe-DALT hemisuccinate of any one of the claims 1-30 or the pharmaceutical composition of claim 31.

44. The method of claim 43, wherein the addictive condition is drug addiction.

45. The method of claim 43, wherein the addictive condition is alcohol addiction.

46. The method of claim 43, wherein the addictive condition is nicotine addiction.

47. The method of claim 43, wherein the addictive condition is gambling addiction.