Tryptamine prodrug solid forms

Abstract

The present disclosure relates to solid forms, such as salts, solvates, cocrystals and polymorphs, of Compound 1 as well as cocrystals of Compound 1 HO. Also disclosed are methods of preparing said solid forms, pharmaceutical compositions comprising the solid forms, and methods of treatment using said solid forms.

Description

TRYPTAMINE PRODRUG SOLID FORMSBACKGROUND

[0001] Classic serotonergic hallucinogenic drugs, a group of compounds which bind to 5- hydroxytryptamine (5-HT) receptors, are characterized by their capability to induce changes in sensory perception, emotion, thought, and sense of self, leading to remodeling in mental functions (Vollenweider, 2001; Kometer et al, 2012; Vollenweider et al., 1998) and referred to as mystical-type experiences occurring during psilocybin treatment. These changes have been repeatedly observed to predict subsequent effects on behavior and emotions, including reductions in depressive and anxious behavior (Griffiths et al., 2011; Griffiths et al., 2016; Ross et al., 2016).

[0002] Several lines of evidence suggested that serotonergic hallucinogens, such as psilocin and 3-(2-diisopropylaminoethyl)-lH-indol-4-ol (also called 4-OH-DiPT), have clinical potential for inducing therapeutically beneficial behavior changes in a variety of psychiatric conditions.Enduring changes in attitudes, depression, anxiety, wellbeing, substance misuse, and mindfulness have been documented after administration of a psychedelic. Mystical experiences, connectedness, emotional breakthrough and increased neural entropy are related to these longterm changes in psychological functioning (Aday et al., 2020).Compound 1 HC1 4-OH-DiPT Psilocin (4-OII-DMT)

[0003] Preparation and use of Compound 1 HC1 is described in PCT / CA2021 / 050907 (W02022000091) which is incorporated herein by reference.

[0004] Human clinical trials are reported, for example, in WO 2024 / 145719, which is incorporated herein by reference.

[0005] There remains a need for further solid forms of Compound 1 such as salts and cocrystals and pharmaceutical compositions comprising the same, and methods of treatment with same.SUMMARY

[0006] The present disclosure relates to solid forms of Compound 1 (shown below):

[0007] Solid forms of Compound 1 include salts of Compound 1, such as crystalline salts and amorphous salts. Other solid forms of Compound 1 include polymorphs of Compound 1 and isopropyl alcohol solvates such as crystalline isopropyl alcohol solvates.

[0008] In some aspects of the disclosure, methanol solvates of Compound 1 are excluded. In some aspects of the disclosure ethanol solvates of Compound 1 are excluded. In some aspects of the disclosure both methanol solvates and ethanol solvates of Compound 1 are excluded. In some aspects of the disclosure, solvates other than isopropyl alcohol solvates of Compound 1 are excluded. In some aspects of the disclosure, solvates of Compound 1 are excluded.

[0009] Other solid forms include cocrystals of Compound 1 and cocrystals of Compound 1 HC1.

[0010] In many aspects of the disclosure, solid forms of Compound 1 are provided.

[0011] In many aspects of the disclosure, salts of Compound 1 are provided.

[0012] In many aspects of the disclosure, cocrystals of Compound 1 are provided.

[0013] In many aspects of the disclosure, cocrystals of Compound 1 HO are provided.

[0014] In these and other aspects of the disclosure, polymorphs of Compound 1 are provided.

[0015] In these and other aspects of the disclosure, isopropanol solvates, including crystalline isopropanol solvates of Compound 1 are provided.

[0016] In many aspects of the disclosure, solvates of salts of Compound 1 are provided. In many aspects of the disclosure, solvates of cocrystals of Compound 1 are provided. In many aspects of the disclosure, solvates of Compound 1 HC1 are provided.

[0017] In many aspects of the disclosure, compositions, such as a pharmaceutical compositions, comprising a solid form of Compound 1 and one or more pharmaceutically acceptable excipients, are provided.

[0018] Aspects of the disclosure further include methods of treating a mental disorder in a subject in need thereof, comprising administering an effective amount of a solid form of Compound 1, such as an effective amount of a composition comprising a solid form of Compound 1 and a pharmaceutically acceptable excipient. In some embodiments, the mental disorder is a depressive condition, including unipolar and bipolar depressive conditions, such as but not limited to depression, depression from generalized anxiety, major depression, treatment resistant depression and postpartum depression.

[0019] Additional aspects of the disclosure include the use of solid forms of Compound 1 to treat a mental disorder in a subject in need thereof, or in the manufacture of a medicament for treating a mental disorder. In some embodiments, the mental disorder is a depressive condition, including unipolar and bipolar depressive conditions, such as but not limited to depression, depression from generalized anxiety, major depression, treatment resistant depression and postpartum depression.

[0020] Further aspects of the disclosure include methods of making solid forms of Compound 1.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings, where:

[0022] FIG. 1 shows high throughput XRPD (upper diffractogram) and high resolution XRPD (lower diffractogram) of a sample of Compound 1 Example 5.

[0023] FIG. 2 shows TGMS plot from 25 °C to 190 °C (heating rate 10 °C / min) of a sample of Compound 1 Example 5. Mass loss of 14.4% was observed between 40 °C and 120 °C, likely due to loss of solvent (e.g., IP A). Two endothermic events were observed, one just above 100 °C and another at about 150 °C. Decomposition stalled above 200 °C.

[0024] FIG. 3 shows DSC thermogram from 25 °C to 300 °C (heating rate 10 °C / min) of a sample of Compound 1 Example 5. The DSC trace of the starting material showed anendothermic event with an onset of about 98 °C due to the mass loss (e.g., solvent) and a sharper endothermic event with an onset of about 155 °C due to melting.

[0025] FIG. 4 is a cyclic DSC experiment on a sample of Compound 1 Example 5 on a cycle of 25oC-120°C-25oC-300°C, indicating formation of Compound 1 Form C.

[0026] FIG. 5 shows two XRPD patterns obtained after the cDSC experiment in which a sample of Compound 1 Example 5 was heated to 120 °C and the material changed to Compound 1 Form C. Overlay of HT-XRPD patterns collected for Compound 1 as received (Compound 1 Example 5, bottom pattern, also called “starting material”) and obtained after the cDSC analysis to 120°C (Compound 1 Form C, top pattern).

[0027] FIG. 6A shows a dynamic vapor sorption (DVS) plot of a sample of Compound 1 Example 5 in 10% relative humidity (RH) steps from 40% to 95% to 0% to 40%. The change in mass of the sample as a function of the time and the relative humidity % is shown.

[0028] FIG. 6B shows a DVS plot as change in mass as a function of change in relative humidity.

[0029] FIG. 7 shows comparison of HT-XRPD patterns for a sample of Compound 1 Example 5 (starting material) and Compound 1 Form B after subjected to DVS and accelerated aging conditions (AAC; 40 °C / 75% relative humidity).

[0030] FIG. 8A shows a microphotograph of Compound 1 Form D which is a 1.5 IPA solvate, prepared by crystallizing Compound 1 from IPA, 70 °C slowly cooling to room temperature. The crystal has an approximate size of 0.316mm x 0.159mm x 0.072 mm.

[0031] FIG. 8B shows the ORTEP diagram of Compound 1 Form D with thermal ellipsoids drawn at 50% probability.

[0032] FIG. 8C is the simulated XRPD pattern calculated from the single crystal solution of Compound 1 Form D.

[0033] FIG. 9 shows comparative XRPD patterns of (from bottom to top) starting material, Compound 1 Form B, Compound 1 Form C, and Compound 1 Form D.

[0034] FIG. 10 shows the HT-XRPD pattern of Compound 1 benzenesulfonate salt (Besl) compared to bcnzcncsulfonic acid and a sample from Compound 1 Example 5 (“starting material”).

[0035] FIG. 11 shows comparative HT-XRPD patterns of Compound 1 edisylates (Edyl, Edy2 ly, and Edy3 sticky) along with 1 ,2-ethanedisulfonic acid and starting material.

[0036] FIG. 12 shows a TGMS plot from 25 °C to 200 °C (heating rate of 10 °C / min) of Compound 1 Edyl. The sample lost about 1.2% of its mass between 40 °C and 70 °C and then 1.5% between 70 °C and 180 °C, most likely solvents from preparation of the sample (water and acetone respectively).

[0037] FIG. 13 shows DSC thermogram from 25 °C to 300 °C (heating rate of 10 °C / min) of Compound 1 Edyl, showing an endothermic event between about 25 °C and 75 °C, likely due to solvent evaporation, and then another endothermic event with an onset of about 145 °C.

[0038] FIG. 14 shows HT-XRPD pattern of Compound 1 gentisic acid salt (Genl), comparatively displayed with gentisic acid and starting material.

[0039] FIG. 15 shows TGMS plot from 25 °C to 200 °C (heating rate of 10 °C / min) of Compound 1 Genl, the sample having a 12.4% mass loss between 25 ° C and 180 °C, due to loss of THF (about 1 molar equivalent), suggesting Compound 1 Genl may be a stoichiometric solvate.

[0040] FIG. 16 shows the HT-XRPD pattern of Compound 1 HBr salt (HBrl) compared to starting material.

[0041] FIG. 17 shows HT-XRPD pattern of Compound 1 maleic acid salt (Mael) compared to stalling material and maleic acid.

[0042] FIG. 18 shows TGMS plot from 25 °C to 200 °C (heating rate of 10 °C / min) of Compound 1 malonic acid salt (Maol). The TGMS pattern indicates a mass loss of about 0.1% between 25 °C and 110 °C, followed by a second mass loss of about 11.6% between 110 °C and 200 °C.

[0043] FIG. 19A shows DSC thermogram between 25 °C to 300 °C (heating rate 10 °C / min) of Compound 1 Maol, having an onset temperature of an endotherm at about 145 °C.

[0044] FIG. 19B shows the ORTEP diagram of Compound 1 malonate salt recrystallized from IPA with thermal ellipsoids drawn at 50% probability.

[0045] FIG. 19C shows an overlay of the single crystal simulated pattern from the single crystal solution of the IPA recrystallized malonate salt of Compound 1 (bottom pattern), the corresponding experimental pattern of that salt (middle pattern), and previously prepared Compound 1 Maol not recrystallized from IPA (top pattern).

[0046] FIG. 20A shows a DVS plot of Compound 1 Maol from 40% to 95% to 0% to 40% RH in step increments of 10%.

[0047] FIG. 20B shows a DVS plot of Compound 1 Maol where change is mass is measured as a function of relative humidity.

[0048] FIG. 21 shows the HT-XRPD pattern of Compound 1 Maol before (bottom pattern) and after (top pattern) DVS treatment.

[0049] FIG. 22 shows an XRPD pattern of Compound 1 Maol recrystallized from IPA.

[0050] FIG. 23 shows a microphotograph of Compound 1 Maol recrystallized from IPA.

[0051] FIG. 24A shows an XRPD pattern of Compound 1 Maol not recrystallized from IPA.

[0052] FIG. 24B shows a peak-picked portion of an XRPD pattern of Compound 1 Maol not recrystallized from IPA.

[0053] FIG. 24C shows a peak-picked portion of an XRPD pattern of Compound 1 Maol not recrystallized from IPA.

[0054] FIG. 25 shows a TGMS plot from 25 °C to 200 °C (heating rate of 10 °C / min) of Compound 1 oxalic acid salt (Oxal), having a mass loss of about 0.2% between 25 °C and 120 °C, likely due to solvent loss, followed by a mass loss of 15.9% between 120 °C and 180 °C.

[0055] FIG. 26A shows a DSC thermogram from 25 °C to 300 °C (heating rate 10 °C / min) of Compound 1 Oxal , wherein there is an endothermic event having an onset at about 134.5 °C and a smaller one at an onset at about 156.5 °C.

[0056] FIG. 26B shows the ORTEP diagram of Compound 1 Oxal with thermal ellipsoids drawn at 50% probability.

[0057] FIG. 26C shows a microphotograph of Compound 1 oxalate salt.

[0058] FIG. 27A shows a DVS plot and change in mass as a function of time, where the DVS profile is 40% to 95% to 0% to 40% RH in steps of 10%.

[0059] FIG. 27B shows a DVS plot and change in mass as a function of RH.

[0060] FIG. 28 shows HT-XRPD patterns of Compound 1 Oxal before (bottom pattern) and after (top pattern) DVS.

[0061] FIG. 29A shows an XRPD pattern of Compound 1 Oxal.

[0062] FIG. 29B shows a peak-picked portion of an XRPD pattern of Compound 1 Oxal .

[0063] FIG. 29C shows a peak-picked portion of an XRPD pattern of Compound 1 Oxal.

[0064] FIG. 30 shows an HT-XRPD pattern of Compound 1 phosphoric acid salt (Phol) compared to starting material.

[0065] FIG. 31 shows an HT-XRPD pattern of Compound 1 salicylic acid salt (Sall) compared to starting material and salicylic acid.

[0066] FIG. 32 shows TGMS plot from 25 °C to 200 °C (heating rate of 10 °C / min) of Compound 1 Sall, where a mass loss of 0.8% between 25 °C and 130 °C was observed, followed by decomposition above 180 °C.

[0067] FIG. 33 shows DSC thermogram from 25 °C to 300 °C (heating rate 10 °C / min) of Compound 1 Sall having three broad endothermic events between 25 °C and 140 °C followed by decomposition above 180 °C.

[0068] FIG. 34 shows HT-XRPD patterns of Compound 1 Sull and Compound 1 Sul2 oily, both compared to starting material.

[0069] FIG. 35 shows TGMS plot from 25 °C to 200 °C (heating rate of 10 °C / min) Compound 1 Sull, having a mass loss of about 2.4% between 25 °C and 75 °C and another loss of 1.6% between 75 °C and 200 °C, both likely due to solvent evaporation.

[0070] FIG. 36 shows DSC thermogram from 25°C to 300 °C (heating rate 10 °C / min) of Compound 1 Sull, having a first broad endothermic event between 25 °C and 70 °C, and an endothermic event with an onset of about 154 °C.

[0071] FIG. 37 shows DSC thermogram from 25 °C to 300 °C (heating rate 10 °C / min) of Compound 1 tartaric acid salt (Tarl), having an endotherm onset of about 126 °C and one at about 161 °C.

[0072] FIG. 38 shows an HT-XRPD pattern of Compound 1 tartaric acid salt (Tarl) compared to tartaric acid and starting material.

[0073] FIG. 39 shows TGMS analysis from 25 °C to 200 °C (heating rate of 10 °C / min) of Compound 1 Tarl, having a mass loss of 0.3% between 25 °C and 135 °C, followed by decomposition above 160 °C.

[0074] FIG. 40A shows a DVS plot of Compound 1 Tarl profile 40% to 95% to 0% to 40% RH with change in humidity as a function of time.

[0075] FIG. 40B shows a DVS sorption desorption cycle plot of Compound 1 Tarl with change in mass as a function of humidity.

[0076] FIG. 41 shows an HT-XRPD pattern of Compound 1 Tarl compared to Compound 1 Form B. After DVS experimentation, some residual Compound 1 Form B was observed as a result of the temperature and humidity cycling.

[0077] FIG. 42A shows an XRPD pattern of Compound 1 Tarl.

[0078] FIG. 42B shows a peak-picked portion of an XRPD pattern of Compound 1 Tarl.

[0079] FIG. 42C shows a peak-picked portion of an XRPD pattern of Compound 1 Tarl.

[0080] FIG. 43 shows HT-XRPD patterns of Compound 1 Tosl compared to tosylic acid (p- toluenesulfonic acid) and starting material.

[0081] FIG. 44 shows HT-XRPD pattern of Compound 1 calcium salt compared to calcium hydroxide and starting material.

[0082] FIG. 45 shows an HR-XRPD pattern of Sori from Cocrystal Example 1.

[0083] FIG. 46 shows a peak-picked HR-XRPD pattern of Sori from Cocrystal Example 1.

[0084] FIG. 47A shows an HR-XRPD pattern of Sori from Cocrystal Example 2.

[0085] FIG. 47B shows a DSC thermogram of Sori from Cocrystal Example 2.

[0086] FIG. 48 shows a DSC thermogram of Sori from Cocrystal Example 1.

[0087] FIG. 49 shows an overlay of XRPD patterns of Sori , starting material, and sorbic acid.

[0088] FIG. 50 shows an HR-XRPD pattern of Cinl from Cocrystal Example 3.

[0089] FIG. 51 shows a peak-picked HR-XRPD pattern of Cinl from Cocrystal Example 3.

[0090] FIG. 52 shows a DSC thermogram of Cinl from Cocrystal Example 3.

[0091] FIG. 53 shows an overlay of XRPD patterns of Cinl, starting material, and cinnamic acid.

[0092] FIG. 54 shows an XRPD pattern of Van 1 from Cocrystal Example 4.

[0093] FIG. 55 shows a peak-picked XRPD pattern of Vanl from Cocrystal Example 4.

[0094] FIG. 56 shows a DSC thermogram of Vanl from Cocrystal Example 4.

[0095] FIG. 57 shows an overlay of XRPD patterns of Vanl, Vanillin and starting material.

[0096] FIG. 58 shows an XRPD pattern of Van2 from Cocrystal Example 5.

[0097] FIG. 59 shows a DSC thermogram of Van2 from Cocrystal Example 5.

[0098] FIG. 60 shows an overlay of XRPD patterns of Vanl, Van2, starting material, and vanillin.

[0099] FIG. 61 shows an XRPD pattern of Adil from Cocrystal Example 6.

[0100] FIG. 62 shows a DSC thermogram of Adil from Cocrystal Example 6.

[0101] FIG. 63 shows an overlay of XRPD pattern of Adil, starting material, and adipic acid.

[0102] FIG. 64 shows an XRPD pattern of Choi from Cocrystal Example 7.

[0103] FIG. 65 shows a DSC thermogram of Choi from Cocrystal Example 7.

[0104] FIG. 66 shows an overlay of XRPD patterns of Choi, starting material, and cholic acid.

[0105] FIG. 67 shows an XRPD pattern of Tbhl from Cocrystal Example 8.

[0106] FIG. 68 shows a DSC thermogram of Tbhl from Cocrystal Example 8.

[0107] FIG. 69 shows an overlay of XRPD patterns of Tbhl, starting material, and tert-butyl hydroquinone.

[0108] FIG. 70 shows an overlay XRPD pattern of Beni, starting material, and benzoic acid.

[0109] FIG. 71 shows a DSC thermogram of Ben! from Cocrystal Example 9.

[0110] FIG. 72 shows an overlay XRPD pattern of Ben2, starting material, and benzoic acid.

[0111] FIG. 73 shows an XRPD pattern of Abai from Cocrystal Example 11.

[0112] FIG. 74 shows a DSC thermogram of Abai from Cocrystal Example 11.

[0113] FIG. 75 shows an XRPD pattern of Aba2 from Cocrystal Example 12.

[0114] FIG. 76 shows a DSC thermogram of Aba2 from Cocrystal Example 12.

[0115] FIG. 77 shows a DSC thermogram of Aba3 from Cocrystal Example 13.

[0116] FIG. 78 shows an overlay of XRPD patterns of Abai, Aba2, Aba3, starting material, and 4-amino benzoic acid.

[0117] FIG. 79 shows an XRPD pattern of Mall in Potential Cocrystal Example 14.

[0118] FIG. 80 shows a DSC thermogram of Mall in Potential Cocrystal Example 14.

[0119] FIG. 81 shows an overlay of XRPD patterns of Mall, Malic acid, and starting material.

[0120] FIG. 82 shows an HR-XRPD pattern of Choi from Cocrystal Example 15.

[0121] FIG. 83 shows a DSC thermogram of Choi from Cocrystal Example 15.

[0122] FIG. 84 shows an XRPD pattern of Cho2 from Cocrystal Example 15.

[0123] FIG. 85 shows an overlay of XRPD patterns of Cho2, Choi, cholic acid, and Compound 1 HC1.

[0124] FIG. 86 shows an HR-XRPD pattern of Dbha2 from Cocrystal Example 16.

[0125] FIG. 87 shows a peak-picked HR-XRPD pattern of Dhba2 from Cocrystal Example 16.

[0126] FIG. 88 shows a DSC thermogram of Dhba2 from Cocrystal Example 16.

[0127] FIG. 89 shows an XRPD overlay of Dhba3 + Compound 1 HC1, Dhba2, Dhbal, 2,4- dihydroxy benzoic acid, and Compound 1 HC1.

[0128] FIG. 90 shows a molecular structure drawing of a single crystal structure of Compound 1 Form A.

[0129] FIG. 91 shows the molecular structure for both symmetry unrelated zwitterions of Compound 1.

[0130] FIG. 92 shows the crystal packing of Compound 1 Form A.

[0131] FIG. 93 shows a comparison of x-ray powder diffraction patterns of Compound 1 Form A (1:1), Compound 1 Form D (1:1.5), and the sample from Compound 1 Example 5.

[0132] FIG. 94 shows the Rietveld analysis of the x-ray powder diffraction pattern of the sample from Compound 1 Example 5.

[0133] FIG. 95 shows an x-ray powder diffraction pattern of amorphous Compound 1 HC1.

[0134] FIG. 96 shows an x-ray powder diffraction pattern of amorphous Compound 1 HC1.

[0135] FIG. 97 shows the simulated x-ray powder diffraction pattern based on the single crystal of Compound 1 Form D (1:1.5 IPA solvate) collected at 299K.

[0136] FIG. 98 shows the simulated x-ray powder diffraction pattern based on the single crystal of Compound 1 Form D (1:1.5 IPA solvate) collected at 170 K.

[0137] FIG. 99 shows the simulated x-ray powder diffraction pattern based on the single crystal of Compound 1 Form A (1:1 IPA solvate) collected at 300K.

[0138] FIG. 100 shows the simulated x-ray powder diffraction pattern based on the single crystal of Compound 1 Form A (1:1 IPA solvate) collected at 90K.DETAILED DESCRIPTION

[0139] When describing the embodiments of the present disclosure, the following terms, if present, have the following meanings, unless otherwise indicated. If not otherwise defined, terms have their customary meaning in the relevant art.

[0140] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present.For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or“B” or “A and B.”

[0141] It will be understood by those within the art that, in general, solid forms, such as cocrystals, solvates, polymorphs, crystalline, and amorphous forms, can be characterized by spectroscopic, spectrometric, diffraction, and thermal analyses. In some embodiments, solid forms of the present disclosure are characterized by X-ray powder diffraction, single crystal X- ray diffraction, and thermal techniques such as differential scanning calorimetry. In someembodiments of the solid forms of the present disclosure, solid forms are characterized by X-ray powder diffraction peaks in °20.

[0142] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0143] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the ail, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0144] For example, the language “having and x-ray powder diffraction (XRPD) pattern comprising one or more peaks at about a°29, about b°29, or about c°29” means the XRPD pattern has at least one peak at a°29, b°29, or c°29. Additional peaks are optional and any one or more of a, b, or c may be present.

[0145] As defined herein, “AAC” is understood to mean accelerated aging condition (40 °C / 75% relative humidity) for two days.

[0146] As defined herein, “XRPD” or “XPD” is understood to mean X-ray powder diffraction. Unless otherwise specified, all XRPD peaks and patterns are given in °29 using Cu Kai radiation at a wavelength of 1.54056 A.

[0147] As defined herein, the term “DSC” means differential scanning calorimetry.

[0148] As defined herein, “DVS” is understood to mean dynamic vapor sorption.

[0149] As defined herein, “TG” and “TGA” are understood to mean thermogravimetry or thcrmogravimctric analysis. The abbreviation “DT” or “DTA” arc understood to mean differential thermal analysis. The abbreviations “TG / DT” and “TG / DTA” are understood to mean thermogravimetry / differential thermal analysis.

[0150] The term “about,” as used herein, means approximately, in the region of, roughly or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%. When used in the context of XRPD peak values (i.e., the positions of an XRPD peak along the x axis of the diffractogram), the term “about” typically indicates a peak value on the order of ±0.20°29. A well calibrated XRPD instrument often has reproducibility to within less than 0.1 °20. However, the ±0.2°29 value takes into account instrument, sample preparation, and operator variability. Thus, “about” in some embodiments may be ±0.10°20 or ±O.O5°20. Unless otherwise provided, however in the context of XRPD values, it means ±O.2O°20. In some embodiments, when used in the context of XRPD peak values “about” can indicate a peak value at exactly the disclosed peak value. In the context of DSC measurements, it means on the order of ±1°C for well-calibrated DSC instruments.

[0151] The term “substantially,” as used herein, means greater than 85% (i.e., greater than 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, or 100%).

[0152] The term “substantially the same as” as used herein applies primarily to XRPD patterns and DSC thermograms. As applied to XRPD patterns, for example, the language “substantially the same as” regarding two patterns means that to normal experimental variability, the two patterns represent the same solid form provided the chemical entities they each represent are the same. Thus, “Compound A having substantially the same XRPD pattern as that of FIG. 2” means FIG. 2 represents Compound A and the two patterns represent the same solid form of Compound A. When comparing XRPD patterns or analyzing XRPD patterns, the x-position of a peak (in °20) is generally more relevant for characterization purposes than the intensity because intensity is materially more sensitive to sample orientation than position in °20 which is set by Bragg’s law. In some cases, by rotating a sample, it is even possible that a peak be reduced in intensity such that it is indistinguishable from noise. With regards to DSC, “substantially the same as”means that a particular compound has a DSC thermogram that is not meaningfully distinguished from the reference DSC thermogram.

[0153] The term “at least one,” as used herein in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0154] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise.

[0155] As used herein, “subject” refers to the person or organism to which the therapeutic agent or composition is, or is intended to be, administered. As such, subjects of the invention may include but are not limited to mammals, e.g., humans and other primates, such as chimpanzees, baboons, and other ape and monkey species. In preferred embodiments, the subject is a human. The term subject includes a person or organism of any age, weight, or other physical characteristic, including an adult, an adolescent, a child, an infant or a newborn.

[0156] The term “solid forms,” as used herein, refers to a compound in the solid state such as a crystalline or amorphous form. Such forms may be salts or cocrystals, for example.

[0157] The term “solid form of Compound 1” as used herein, refers to a solid salt of Compound 1, a cocrystal of Compound 1, a cocrystal of Compound 1 HC1, or a solvate of Compound 1. Solvates and salts may be crystalline or amorphous.

[0158] The term “Compound 1” in and by itself means the structurewhether in neutral or zwitterion form.

[0159] The term “Compound 1 Form A” means the crystalline Compound 1 in the crystalline form known as Form A. Compound 1 Form A contains IPA in ratio of 1:1 with Compound 1.

[0160] The term “Compound 1 Form B” means the crystalline form Compound 1 which can be prepared, for example, as set forth in the DVS experiment of Compound 1 Example 2.

[0161] The term “Compound 1 Form C” means the crystalline form of Compound 1 which can be prepared, for example, as set forth in the cyclic DSC experiments of Compound 1 Example 3.

[0162] The term “Compound 1 Form D” means the 1.5 IPA solvate of Compound 1 which can be prepared, for example, as set forth in Compound 1 Example 4. Compound 1 Form D may be referred also as a sesqui IPA solvate or 1.5 IPA solvate of Compound 1.

[0163] The term “solvate,” as used herein, refers to solid form of a compound or mixture of compounds that comprises one or more solvents in its crystal lattice. A hydrate is a solvate when the solvent is water.

[0164] The term “effective,” as used herein, refers to an amount of a compound, composition or component which, when used within the context of its intended use, effects an intended result. The term “effective” subsumes all other effective amounts or effective concentration terms, which are otherwise described or used in the present application.

[0165] The phrase “therapeutically effective amount” and the like, as used herein, indicate an amount necessary to administer to a patient, or to a cell, tissue, or organ of a patient, to achieve a therapeutic effect, such as an ameliorating or alternatively a curative effect. The therapeutically effective amount is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.Determination of the appropriate therapeutically effective amount is within the routine level of skill in the art.

[0166] The term “starting material” and the term “Starting Material”, as used herein, refer to, unless otherwise defined, the Compound 1 material made in Compound 1 Example 5.

[0167] The terms “treat”, “treating”, and “treatment”, etc., as used herein, refer to any action providing a benefit to a patient or subject for which the solid forms of Compound 1 of the disclosure may be administered, including the treatment of any disease state or condition, which is causally related (e.g. modulated) to 5-HTSA agonism, including one or more symptoms thereof.

[0168] In many aspects of the disclosure, solid forms of Compound 1 are provided. Examples of solid forms of Compound 1 a include solid salts of Compound 1, solvates of Compound 1, cocrystals of Compound 1, and cocrystals of Compound 1 HC1. The solid forms herein may also be solvates and / or hydrates. Solid forms further include polymorphs of Compound 1 or polymorphs of salts of Compound 1. An exemplary solvate is an isopropanol solvate, including crystalline isopropanol solvates. Compound 1 is represented by the following structure:Compound 1

[0169] In some embodiments, the present disclosure provides a salt of Compound 1.

[0170] In some embodiments, the present disclosure provides a cocrystal of Compound 1. In some embodiments, the present disclosure provides a cocrystal of Compound 1 HC1.

[0171] In some embodiments, when the disclosure provides a salt, the solid form of Compound 1 is not a hydrochloride salt. In some embodiments, the solid form of Compound 1 is not a crystalline hydrochloride salt. In some embodiments, methanol and ethanol solvates of Compound 1 are excluded. In some embodiments, crystalline methanol and ethanol solvates of Compound 1 are excluded. In some embodiments, alcohol solvates of Compound 1 are excluded.In some embodiments propanol solvates are excluded. Tn some embodiments, isopropyl alcohol solvates arc excluded. In some embodiments, non-crystallinc or crystalline isopropyl alcohol solvates are excluded. In some embodiments, acetone solvates are excluded.

[0172] Examples of solid forms of Compound 1 include salts of Compound 1, cocrystals of Compound 1, cocrystals of Compound 1 HC1, polymorphs of Compound 1 (including as a zwitterion) and isopropyl alcohol solvates of Compound 1 including crystalline isopropanol solvates of Compound 1.

[0173] The salts of Compound 1 may be crystalline or amorphous.

[0174] In some embodiments, amorphous Compound 1 HC1 is provided.

[0175] In some embodiments, the salt of Compound 1 is an inorganic salt. In some embodiments, the salt of Compound 1 is a crystalline inorganic salt. In some embodiments, the salt of Compound 1 is a hydrobromide salt. In some embodiments, the salt of Compound 1 is a calcium salt. In some embodiments, the salt of Compound 1 is a phosphoric acid salt. In some embodiments, the salt of Compound 1 is a sulfuric acid salt.

[0176] In some embodiments, the salt of Compound 1 is an organic salt. In some embodiments, the salt of Compound 1 is a crystalline organic salt. In some embodiments, the salt of Compound 1 is a sulfonic acid salt. In some embodiments, the salt of Compound 1 is a crystalline sulfonic acid salt. In some embodiments, the sulfonic acid salt of Compound 1 is an aromatic sulfonic acid salt. In some embodiments, the sulfonic acid salt of Compound 1 is a crystalline aromatic sulfonic acid salt. In some embodiments, the aromatic sulfonic acid salt of Compound 1 is a benzenesulfonic acid salt. In some embodiments, the aromatic sulfonic acid salt of Compound 1 is a p-toluene sulfonic acid salt.

[0177] In some embodiments, the sulfonic acid salt of Compound 1 is a non-aromatic acid salt. In some embodiments, the sulfonic acid salt of Compound 1 is a crystalline non-aromatic acid salt. In some embodiments, the non-aromatic sulfonic acid salt of Compound 1 is an ethanesulfonic acid salt. In some embodiments, the non-aromatic sulfonic acid salt of Compound 1 is a 1,2-ethanedisulfonic acid salt.

[0178] In some embodiments, the salt of Compound 1 is an aromatic acid salt. In some embodiments, the salt of Compound 1 is a crystalline aromatic acid salt. In some embodiments,the salt of Compound l is a benzoic acid salt such as a gentisic acid salt. In some embodiments, the salt of Compound 1 is a salicylic acid salt.

[0179] In some embodiments, the salt of Compound 1 is a non-aromatic salt. In some embodiments, the salt of Compound 1 is a crystalline non-aromatic salt.

[0180] In some embodiments, the organic acid salt has at least two carboxylic acid groups (e.g., oxalic acid). In some embodiments, the organic acid salt is non-aromatic and has at least two carboxylic acid groups (e.g., oxalic acid). In some embodiments, the organic acid salt is a C2-C4 organic acid salt. In some embodiments, the crystalline organic acid salt comprises a C2-C4 organic acid. In some embodiments, the crystalline organic acid salt comprises a C3 organic acid salt. In some embodiments, the organic acid salt is an oxalic acid salt. In some embodiments, the organic acid salt is a malonic acid salt. In some embodiments, the organic acid salt is a maleic acid salt. In some embodiments, the organic acid salt has at least one alcohol group. In some embodiments, the crystalline organic acid salt comprises at least one alcohol group. In some embodiments, the organic acid salt is a tartaric acid salt. In some embodiments, the tartaric acid is L-(+)-tartaric acid.

[0181] In some embodiments, the salt of Compound 1 is a crystalline HBr salt.

[0182] In some embodiments, the crystalline HBr salt of Compound 1 has an XRPD pattern substantially the same as that of FIG. 16 (referred to herein as “HBrl”; top pattern).

[0183] In some embodiments, the salt of Compound 1 is a crystalline calcium salt.

[0184] In some embodiments, the salt of Compound 1 is a crystalline phosphoric acid salt. In some embodiments, the salt of Compound 1 is a crystalline monobasic phosphoric acid salt (e.g., NaH2PO4). In some embodiments, the salt of Compound 1 is a crystalline phosphoric acid salt having an XRPD pattern substantially the same as that of FIG. 30 (referred to herein as “Phol”; top pattern).

[0185] In some embodiments, the salt of Compound 1 is a crystalline sulfuric acid salt. In some embodiments, the salt of Compound l is a crystalline sulfuric acid salt having an XRPD pattern substantially the same as that of FIG. 34 (referred to herein as “Sull”; middle pattern).

[0186] In some embodiments, the salt of Compound l is a crystalline sulfuric acid salt having an XRPD pattern substantially the same as that of FIG. 34 (referred to herein as “Sul2” or “Sul 2 oily”; top pattern).

[0187] In some embodiments, the salt of Compound 1 is a crystalline benzenesulfonic acid salt. In some embodiments, the salt of Compound 1 is a crystalline benzenesulfonic acid salt having an XRPD pattern substantially the same as that of FIG. 10 (referred to herein as “Best”; top pattern).

[0188] In some embodiments, the salt of Compound 1 is a 1,2-ethanedisulfonic acid salt.

[0189] In some embodiments, the salt of Compound l is a crystalline 1 ,2-ethanedisulsfonic acid salt. In some embodiments, the salt of Compound 1 and 1 ,2-cthancdisulfonic acid arc in a ratio of 1:1. In some embodiments, the salt of Compound 1 and 1,2-ethanedisulfonic acid arc in a ratio of 2:1.

[0190] In some embodiments, the salt of Compound 1 is Form A crystalline 1,2- ethanedisulsfonic acid salt having an XRPD diffraction pattern substantially the same as that of FIG. 11 (referred to herein as “Edyl”; middle pattern).

[0191] In some embodiments, Form A crystalline 1,2-ethanedisulsfonic acid salt has a differential scanning calorimetry endotherm onset of about 145 °C.

[0192] In some embodiments, Form A crystalline 1,2-cthancdisulsfonic acid salt has a differential scanning calorimetry thermogram substantially the same as that of FIG. 13.

[0193] In some embodiments, the salt of Compound 1 is Form B crystalline 1,2- ethanedisulsfonic acid salt.

[0194] In some embodiments, Form B crystalline 1,2-ethanedisulsfonic acid salt has an XRPD pattern substantially the same as that of FIG. 11 (referred to herein as “Edy2” or “Edy2 ly”; second pattern from top).

[0195] In some embodiments, the salt of Compound 1 is Form C crystalline 1 ,2- cthancdisulsfonic acid salt.

[0196] In some embodiments, the salt of Compound 1 is Form C crystalline 1 ,2- cthancdisulsfonic acid salt having an XRPD pattern substantially the same as that of FIG. 11 (referred to herein as “Edy3” or “Edy3 sticky”; top pattern).

[0197] In some embodiments, the salt of Compound 1 is a crystalline salicylic acid salt. In some embodiments, the salt of Compound 1 is a crystalline salicylic acid salt having an XRPD pattern substantially the same as that of FIG. 31 (referred to herein as “Sall”; top pattern).

[0198] In some embodiments, the salt of Compound 1 is a crystalline salicylic acid salt having a differential scanning calorimetry thermogram substantially the same as that of FIG. 33.

[0199] In some embodiments, the salt of Compound l is a crystalline salicylic acid salt having a differential scanning calorimetry endotherm onset of about 74°C.

[0200] In some embodiments, the salt of Compound 1 is a crystalline oxalic acid salt. In some embodiments, the salt of Compound 1 is a crystalline oxalic acid salt having an XRPD pattern comprising a peak at about 8.4°20. In some embodiments, the salt of Compound 1 is a crystalline oxalic acid salt having an XRPD pattern comprising a peak at about 8.8°29. In some embodiments, the salt of Compound 1 is a crystalline oxalic acid salt having an XRPD pattern comprising a peak at about 1O.3°20. In some embodiments, the salt of Compound 1 is a crystalline oxalic acid salt having an XRPD pattern comprising one or more peaks at about 8.4°20, about 8.8°20, about 10.3°20, about 11 ,O°20, about 11 ,3°26, about 12.9°20, about 13.4°20, or about 13.5°20.

[0201] In some embodiments, the salt of Compound 1 is a crystalline oxalic acid salt having an XRPD pattern substantially the same as that of FIG. 29A (referred to herein as “Oxal”).

[0202] In some embodiments, the salt of Compound 1 is a crystalline oxalic acid salt having a differential scanning calorimetry endotherm onset of about 134.5°C.

[0203] In some embodiments, the salt of Compound 1 is a crystalline oxalic acid salt having a differential scanning calorimetry thermogram substantially the same as that of FIG. 26A.

[0204] A single crystal of an oxalic acid salt of Compound 1 was prepared in accordance with Example 5.7.7, and the single crystal solution was solved (FIG. 26B). A microphotograph of the crystal used is set forth in FIG. 26C.

[0205] In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt.

[0206] In some embodiments, the salt of Compound 1 and malonic acid are in a ratio of 1 : 1 . In some embodiments, the salt of Compound 1 and malonic acid arc in a ratio of 2:1. In some embodiments, solid forms of Compound 1 malonate salt further comprise Compound 1 zwitterion.

[0207] In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt having an XRPD pattern comprising a peak at about 7.9°29. In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt having an XRPD pattern comprising a peak at about 9.9°20. In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt having an XRPD pattern comprising a peak at about 12.7°20. In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt having an XRPD pattern comprising a peak at about 13.9°20. In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt having an XRPD comprising a peak at about 16.O°20.

[0208] In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt having an XRPD pattern substantially the same as that of FIG. 24A (referred to herein as “Maol”).

[0209] In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt having an XRPD pattern comprising one or more peaks at about 7.9°20, about 9.9°29, about 12.7°20, about 13.9°20, or about 15.9°20.

[0210] In some embodiments, the salt of Compound l is a crystalline malonic acid salt having a differential scanning calorimetry endotherm onset of about 145 °C.

[0211] In some embodiments, the salt of Compound 1 is a crystalline malonic acid salt having a differential scanning calorimetry thermogram substantially the same as that of FIG. 19 A.

[0212] A single crystal of a malonic acid salt of Compound 1 was prepared in accordance with Example 5.7.6, and the single crystal solution was solved (FIG. 19B).

[0213] In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt.

[0214] In some embodiments, the salt of Compound 1 is a crystalline L-(+)-tartaric acid salt.

[0215] In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having anXRPD pattern comprising a peak at about 6.5°20. In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having an XRPD pattern comprising a peak at about 13.1°20. In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having an XRPDpattern comprising a peak at about 13.9°20. In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having an XRPD pattern comprising a peak at about 14.4°20. In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having an XRPD pattern comprising a peak at about 14.8°20. In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having an XRPD pattern comprising a peak at about 16.4°20. In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having an XRPD pattern comprising a peak at about 18.7°20.

[0216] In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having an XRPD pattern comprising one or more peaks at about 6.5°20, about 13.1°20, about 13.9°20, about 14.4°20, about 14.8°20, about 16.4°20, or about 18.7°20.

[0217] In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having an XRPD pattern substantially the same as that of FIG. 42A (referred to herein as “Tarl”).

[0218] In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having a differential scanning calorimetry endotherm onset of about 129°C.

[0219] In some embodiments, the salt of Compound 1 is a crystalline tartaric acid salt having a differential scanning calorimetry thermogram substantially the same as that of FIG. 37.

[0220] In some embodiments, the salt of Compound 1 is crystalline maleic acid salt.

[0221] In some embodiments, the salt of Compound 1 is crystalline maleic acid salt having an XRPD pattern substantially the same as that of FIG. 17 (referred to herein as “Mael”; top pattern).

[0222] In some embodiments, the present disclosure provides a solvate of Compound 1. In some embodiments, a solvate of Compound 1, as the neutral compound or as the zwitterion, can exist independently in their own unit cells.

[0223] In some embodiments, a solid form of Compound 1 is a hydrate having a DVS plot substantially the same as that of FIG. 6A. In some embodiments, Form B is a hydrate of Compound 1.

[0224] In some embodiments, the solid form of Compound 1 is Form C, having an XRPD pattern substantially the same as that of FIG. 9 (second pattern from top).

[0225] In some embodiments, the solid form of Compound 1 is Form D, a 1 : 1.5 IPA solvate.

[0226] In many embodiments, cocrystals of a coformer and Compound 1 are provided. In many of these embodiments, the coformer is the organic coformer. In many such embodiments, the organic coformer is an organic acid. The organic acid may be aromatic or non-aromatic.

[0227] Examples of aromatic coformers include benzoic acid and substituted benzoic acids such as 4-aminobenzoic acid. Another aromatic acid example is cinnamic acid.

[0228] In some embodiments, the organic acid is an alkyl organic acid. The salt may be a mono organic acid such as cholic acid or a di-acid such as adipic acid. The organic salt may be an alkenyl organic acid such as sorbic acid.

[0229] In some embodiments, the coformer is a phenol such as t-butylhydroquinone. In some embodiments, the coformer is an aldehyde such as vanillin.

[0230] In some embodiments, a cocrystal of sorbic acid and Compound 1 is provided. In some embodiments, the cocrystal is referred to herein as Sori. An x-ray powder diffraction pattern of Sori is shown in FIG. 46 and also in FIG. 47A. In some embodiments, cocrystal of sorbic acid and Compound 1 is provided having an x-ray powder diffraction pattern comprising a peak at about 8.2°20. In some embodiments, a cocrystal of sorbic acid and Compound 1 is provided having an x-ray powder diffraction pattern comprising one or more peaks at about 8.2°20, about 8.8°20, about 9.6°20, about 9.9°20, and about 11.9°20. In some embodiments, a cocrystal of sorbic acid and Compound 1 is provided having an x-ray powder diffraction pattern substantially the same as that of FIG. 45, FIG. 46, or FIG. 47A. In these and other embodiments, a cocrystal of sorbic acid and Compound 1 is provided having an onset DSC endotherm at about 130°C. An onset DSC endotherm at about 132°C is also seen as in FIG 47B as that of a cocrystal or sorbic acid and Compound 1 (Sori) when made via a sonification-based approach.

[0231] FIG. 49 shows an overlay x-ray powder diffraction pattern of Sori, starting material, and sorbic acid. The overlay x-ray powder diffraction pattern shows that Sori is not a superposition of Compound 1 and sorbic acid. Accordingly, Sori is not a physical mixture of Compound 1 and sorbic acid and the data instead indicate Sori to be a cocrystal of Compound 1 and sorbic acid.

[0232] In some embodiments, a cocrystal of cinnamic acid and Compound 1 is provided. In some embodiments, the cocrystal is referred to herein as Cinl. An x-ray powder diffractionpattern of Cinl is shown in FIG. 50 and also in FIG. 51 . In some embodiments, a cocrystal of cinnamic acid and Compound 1 is provided having an x-ray powder diffraction pattern comprising a peak at about 6.6°29. In some embodiments, a cocrystal of cinnamic acid and Compound 1 is provided having an x-ray powder diffraction pattern comprising a peak at about 11.0°29. In some embodiments, a cocrystal of cinnamic acid and Compound 1 is provided having an x-ray powder diffraction pattern comprising one or more peaks at about 6.6°29, about 9.2°29, about 11.0°29, about 11.8°29, and about 20.3°29. In some embodiments, a cocrystal of cinnamic acid and Compound 1 is provided having an x-ray powder diffraction pattern substantially the same as that of FIG. 50 or FIG. 51. In these and other embodiments, a cocrystal of cinnamic acid and Compound 1 is provided having an onset DSC endotherm at about 95 °C as seen, for example, in FIG. 52.

[0233] FIG. 53 shows an overlay x-ray powder diffraction pattern of Cinl, starting material, and cinnamic acid. The overlay x-ray powder diffraction pattern shows that Cinl is not a superposition of Compound 1 and cinnamic acid. Accordingly, Cinl is not a physical mixture of Compound 1 and cinnamic acid and the data instead indicate Cinl to be a cocrystal of Compound 1 and cinnamic acid.

[0234] In some embodiments, a cocrystal of vanillin and Compound 1 is provided. In some embodiments, the cocrystal is referred to as Vanl. The x-ray powder diffraction pattern of Vanl is shown in FIG. 54 and also in FIG. 55. In some embodiments, a cocrystal of vanillin and Compound 1 is provided having an x-ray powder diffraction pattern comprising a peak at about 8.6°29. In some embodiments, a cocrystal of vanillin and Compound 1 is provided having an x- ray powder diffraction pattern comprising a peak at about 10.4°29. In some embodiments, a cocrystal of vanillin and Compound 1 is provided having an x-ray powder diffraction pattern having one or more peaks at about 8.6°29, about 10.4°29, about 11.4°29, about 11.7°29, about 13.1°29, and 13.9°29. In some embodiments, a cocrystal of vanillin and Compound 1 having an x-ray powder diffraction pattern substantially the same as that of FIG. 54 and FIG. 55. In these and other embodiments, a cocrystal of vanillin and Compound 1 is provided having an onset DSC endotherm at about 120°C (as seen in FIG. 56).

[0235] FIG. 57 shows an overlay x-ray powder diffraction pattern of Vanl, starting material, and vanillin. The overlay x-ray powder diffraction pattern shows that Vanl is not a superposition ofCompound 1 and vanillin. Accordingly, Vanl is not a physical mixture of Compound 1 and vanillin and the data instead indicate Vanl to be a cocrystal of Compound 1 and vanillin.

[0236] Another cocrystal of vanillin and Compound 1 is described herein and is referred to as Van2. Van2 has an x-ray powder diffraction pattern as set forth in FIG. 58. In some embodiments, Van2 has an x-ray powder diffraction pattern comprising a peak at about 9.8°20.

[0237] FIG. 60 shows an overlay x-ray powder diffraction pattern of Van2, starting material, and vanillin. The overlay x-ray powder diffraction pattern shows that Van2 is not a superposition of Compound 1 and vanillin. Accordingly, Van2 is not a physical mixture of Compound 1 and vanillin and the data instead indicate Van2 to be a cocrystal of Compound 1 and vanillin.Further, the overlay x-ray powder diffraction pattern indicates that Vanl and Van 2 are distinct cocrystals.

[0238] In some embodiments, a cocrystal of adipic acid and Compound 1 is provided. In some embodiments, the cocrystal is referred to as Adil. An x-ray powder diffraction pattern of Adil is set forth in FIG. 61. In some embodiments, a cocrystal of adipic acid and Compound 1 has an x- ray powder diffraction pattern having one or more of the peaks set forth in FIG. 61. In some embodiments, a cocrystal of adipic acid and Compound 1 has an x-ray powder diffraction pattern substantially the same as that of FIG. 61. In these and other embodiments, Adil has a DSC thermogram onset of about 75°C as seen in FIG. 62.

[0239] FIG. 63 shows an overlay x-ray powder diffraction pattern of Adil, starting material, and adipic acid. The overlay x-ray powder diffraction pattern shows that Adil is not a superposition of Compound 1 and adipic acid. Accordingly, Adil is not a physical mixture of Compound 1 and adipic acid and the data instead indicate Adil to be a cocrystal of Compound 1 and adipic acid.

[0240] In some embodiments, a cocrystal of cholic acid and Compound 1 is provided. In some embodiments, the cocrystal of cholic acid and Compound 1 is referred to as Choi. An x-ray powder diffraction pattern of Choi is set forth in FIG. 64. In some embodiments, a cocrystal of cholic acid and Compound 1 has an x-ray powder diffraction pattern substantially the same as that of FIG. 64. In some embodiments, a cocrystal of cholic acid and Compound 1 has an x-ray powder diffraction pattern substantially the same as that of FIG. 64.

[0241] FIG. 66 shows an overlay x-ray powder diffraction pattern of Cho! , starting material, and cholic acid. The overlay x-ray powder diffraction pattern shows that Choi is not a superposition of Compound 1 and cholic acid. Accordingly, Choi is not a physical mixture of Compound 1 and cholic acid and the data instead indicate Choi to be a cocrystal of Compound 1 and cholic acid.

[0242] In some embodiments, a cocrystal of t-butylhydroquinone and Compound 1 is provided. In some embodiments, the cocrystal is referred to herein as Tbhl. An x-ray powder diffraction pattern of Tbhl is shown in FIG. 67. In some embodiments, a cocrystal of t-butylhydroquinone and Compound 1 have an x-ray powder diffraction pattern comprising one or more of the peaks set forth in FIG. 67. In some embodiments, a cocrystal of t-butylhydroquinone and Compound 1 have an x-ray powder diffraction pattern substantially the same as that of FIG. 67. In these and other embodiments, a cocrystal of t-butylhydroquinone and Compound 1 is provided having an onset of DSC thermogram at about 68°C, as seen in FIG. 68.

[0243] FIG. 69 shows an overlay x-ray powder diffraction pattern of Tbhl, starting material, and t-butylhydroquinone. The overlay x-ray powder diffraction pattern shows that Tbhl is not a superposition of Compound 1 and t-butylhydroquinone. Accordingly, Tbhl is not a physical mixture of Compound 1 and t-butylhydroquinone and the data instead indicate Tbhl to be a cocrystal of Compound 1 and t-butylhydroquinone.

[0244] In some embodiments, a cocrystal of benzoic acid and Compound 1 is provided. In some embodiments, the cocrystal is referred to as Beni. An x-ray powder diffraction pattern showing an overlay of Beni, benzoic acid, and starting material is shown in FIG.70. In some embodiments, a cocrystal of benzoic acid and Compound 1 is provided having an x-ray powder diffraction pattern substantially the same as the Beni x-ray powder diffraction pattern in FIG. 70.

[0245] FIG. 70 shows an overlay x-ray powder diffraction pattern of Beni, starting material, and benzoic acid. The overlay x-ray powder diffraction pattern shows that Beni is not a superposition of Compound 1 and benzoic acid. Accordingly, Beni is not a physical mixture of Compound 1 and benzoic acid and the data instead indicate Beni to be a cocrystal of Compound 1 and benzoic acid.

[0246] Another cocrystal of benzoic acid and Compound 1 is referred to herein as Ben2. The Bcn2 x-ray powder diffraction pattern is shown in FIG. 72. FIG. 72 is an overlay x-ray powder diffraction pattern of Ben2, starting material, and benzoic acid.

[0247] FIG. 72 shows an overlay x-ray powder diffraction pattern of Ben2, starling material, and benzoic acid. The overlay x-ray powder diffraction pattern shows that Ben2 is not a superposition of Compound 1 and benzoic acid. Accordingly, Ben2 is not a physical mixture of Compound 1 and benzoic acid and the data instead indicate Ben2 to be a cocrystal of Compound 1 and benzoic acid.

[0248] In some embodiments, a cocrystal of 4- aminobenzoic acid and Compound 1 is provided. In some embodiments, the cocrystal is referred to herein as Abai. An x-ray powder diffraction pattern of Abai is shown in FIG. 73. In some embodiments, a cocrystal of 4- aminobenzoic acid and Compound 1 is provided having an x-ray powder diffraction pattern substantially the same as that shown in FIG. 73. In these and other embodiments, a cocrystal of 4-aminobenzoic acid and Compound 1 has a DSC endotherm at an onset of about 64°C (as seen in FIG. 74).

[0249] Another cocrystal of 4-aminobenzoic acid and Compound 1 is referred to herein as Aba2. Aba2 has an x-ray powder diffraction pattern as set forth in FIG. 75. The DSC thermogram of Aba2 shows a DSC onset temperature of about 77 °C (as seen in FIG. 76).

[0250] A further cocrystal of 4-aminobenzoic acid and Compound 1 is referred to herein as Aba3. The x-ray powder diffraction pattern of Aba3 can be see in the overlay x-ray powder diffraction pattern in FIG. 78 of Abai, Aba2, Aba3, Compound 1 and 4-aminobenzoic acid. The DSC thermogram of Aba3 shows a DSC onset temperature of about 68°C (as seen in FIG. 77).

[0251] FIG. 78 is an overlay x-ray powder diffraction pattern of Abai, Aba2, Aba3, 4- aminobenzoic acid, and starting material. The x-ray powder diffraction pattern indicates that Abai, Aba2, and Aba3 are different from each other and are cocrystal and are not physical mixtures of 4-aminobenzoic acid and Compound 1.

[0252] In some embodiments, a crystalline solid of malic acid and Compound 1 is provided. In some embodiments, a crystalline solid of malic acid and Compound 1 having an x-ray powder diffraction pattern comprising a peak at about 12.9°20 is provided. In some embodiments, a crystalline solid of malic acid and Compound 1 having an x-ray powder diffraction patterncomprising one or more peaks at about 12.9°20, about 14.4°20, about 14.6°20, about 15.5°20, and about 16.5°20 is provided. In some embodiments, a crystalline solid of malic acid and Compound 1 having an x-ray powder diffraction pattern substantially the same as FIG. 79 is provided. In these and other embodiments, a crystalline solid of a malic acid and Compound 1 having a DSC endotherm onset of about 109°C is provided (as seen in FIG. 80).

[0253] FIG. 81 shows an overlay x-ray powder diffraction pattern of Mall, stalling material, and malic acid. The overlay x-ray powder diffraction pattern shows that Mall is not a superposition of Compound 1 and malic acid. Accordingly, Mall is not a physical mixture of Compound 1 and malic acid and the data instead indicate Mall to be a potential cocrystal of Compound 1 and malic acid.

[0254] In many embodiments, cocrystals of a coformer and Compound 1 HC1 are provided. In many such embodiments, the coformer is an organic coformer such as an organic acid. In many embodiments, the organic acid is an aromatic acid.

[0255] In some embodiments, a cocrystal of cholic acid and Compound 1 HC1 is provided. In some embodiments, the cocrystal is referred to as Choi. An x-ray powder diffraction pattern of Choi is shown in FIG. 82. In some embodiments, a cocrystal of cholic acid and Compound 1 HC1 having an x-ray powder diffraction pattern comprising one or more peaks of FIG. 82 is provided. In some embodiments, a cocrystal of cholic acid and Compound 1 HC1 having an x-ray powder diffraction pattern comprising one or more peaks of FIG. 82 is provided. In these and other embodiments, a cocrystal of cholic acid and Compound 1 HC1 having a DSC endotherm with an onset of about 162°C.

[0256] Another cocrystal of cholic acid and Compound 1 HC1 is referred to herein as Cho2. FIG. 85 is an overlay of Choi, Cho2, cholic acid, and Compound 1 HC1. The overlay x-ray powder diffraction pattern indicates that Choi and Cho2 are different and are also not physical mixtures of Compound 1 HO and cholic acid. In some embodiments, a cocrystal of cholic acid and Compound 1 HC1 having an x-ray powder diffraction pattern substantially the same as the Cho2 x-ray powder diffraction pattern of FIG. 84.

[0257] In some embodiments, a cocrystal of 2,4-dihydroxy benzoic acid and Compound 1 HO is provided. In some embodiments, the cocrystal of 2,4-dihydroxy benzoic acid and Compound 1 is referred to herein as Dhbal. Upon exposure to AAC, Dhbal changed to cocrystal Dhba2. FIG.86 is an x-ray powder diffraction pattern of Dhba2. FIG. 87 is a peak-picked x-ray powder diffraction pattern of Dhba2. Another cocrystal of 2,4-dihydroxy benzoic acid and Compound 1 HC1 is referred to herein as Dhba3. An x-ray powder diffraction pattern can be seen in the overlay of FIG. 89. The overlay x-ray powder diffraction pattern indicates Dhbal, Dhba2, and Dhba3 are different and also not physical mixtures of Compound 1 HC1 and 2,4- dihydroxybenzoic acid.

[0258] In some embodiments, Compound 1 Form A is provided. In some embodiments, Compound 1 Form B is provided. In some embodiments, Compound 1 Form C is provided. In some embodiments, Compound 1 Form D is provided.

[0259] In some embodiments, Compound 1 Form A has an x-ray powder diffraction pattern comprising a peak at about 4.1°20. In some embodiments, Compound 1 Form A has an x-ray powder diffraction pattern comprising a peak at about 7.6°20 or about 7.7°20. In some embodiments, Compound 1 Form A has an x-ray powder diffraction pattern comprising a peak at about 8.1°20 or about 8.3°29. In some embodiments, Compound 1 Form A has an x-ray powder diffraction pattern comprising a peak at about 1O.4°20 or about 1O.6°20. In some embodiments, Compound 1 Form A has an x-ray powder diffraction pattern comprising a peak at about 1O.8°20 or about 1 l.O°20. The location of the peaks may depend on the temperature of the collection of the diffractogram. Compound 1 Form A at 300K for example has peaks that are slightly shifted from that of 90K. In some embodiments, Compound 1 Form A has an x-ray powder diffraction pattern comprising one or more peaks at about 7.6°20, about 7.8°20, about 8.1°20, about 8.3°20, about 1O.4°20, about 1O.6°20, about 1O.8°20, or about l l.O°20. In some embodiments, Compound 1 Form A has an x-ray powder diffraction pattern substantially the same as that of FIG. 99 and FIG. 100.

[0260] In some embodiments, Compound 1 Form D has an x-ray powder diffraction pattern comprising a peak at about 8.O°20 or about 8.2°20. In some embodiments, Compound 1 Form D has an x-ray powder diffraction pattern comprising a peak at about 8.8°20 or about 8.9°20. In some embodiments, Compound 1 Form D has an x-ray powder diffraction pattern comprising a peak at about 1O.1°20 or about 1O.2°20. In some embodiments, Compound 1 Form D has an x- ray powder diffraction pattern comprising a peak at about 1O.4°20 or about 1O.5°20. The location of the peaks may depend on the temperature of the collection of the diffractogram. Compound 1Form D at 299K for example has peaks that are slightly shifted from that of 99K. In some embodiments, Compound 1 Form D has an x-ray powder diffraction pattern substantially the same as that of FIG. 97 and FIG. 98.

[0261] In another aspect, the present disclosure also provides compositions, including pharmaceutical compositions, comprising a solid form of Compound 1 of the disclosure (e.g., a salt or a cocrystal of Compound 1 or a cocrystal of Compound 1 HO) or a solvate of Compound 1 such as an 1PA solvate in combination with a pharmaceutically acceptable excipient. The application further provides pharmaceutical compositions comprising a therapeutically effective amount of a solid form of Compound 1 of the disclosure, in combination with a pharmaceutically acceptable excipient.

[0262] The solid form of Compound 1 of the disclosure can be administered in a pharmaceutical composition to a patient or subject in single or divided doses. The pharmaceutical composition may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, transdermally, sublingually, via suppository administration, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular-, intra-articular, intra-synovial, intra-stemal, intra-thecal, intra-hepatic, intra- lesional and intra-cranial injection or by infusion. In certain embodiments, the pharmaceutical composition is administered via subcutaneous injection.

[0263] The pharmaceutical compositions described herein may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that may be used in these pharmaceutical compositions include, fillers, diluents, binders, disintegrants, glidants, lubricants, viscosity donors, or surfactants.

[0264] The amount of the solid form of Compound 1 of the present disclosure (e.g., salt, polymorph, hydrate, or solvate described herein) in a pharmaceutical composition of the invention may be combined with one or more pharmaceutically acceptable excipients to produce single dosage forms, which will vary depending upon the host and disease treated, as well as the particular mode of administration. In certain embodiments, the single dosage form can be formulated to contain between about 0.05 milligram and about 750 milligrams of a solid form of Compound 1 of the disclosure, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams, alone or in combination withat least one other therapeutic compound described herein. In some embodiments, a pharmaceutical composition comprises a solid form of Compound 1 of the disclosure in an amount from 15 to 50 mg, 20 to 45 mg, 25 to 40 mg, or 30 to 35 mg. The solid form of Compound 1 of the disclosure or a pharmaceutical composition thereof, is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of a solid form of Compound 1 of the disclosure per unit dosage form.

[0265] It should be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the severity of the particular disease or condition being treated, the activity and bioavailability of the solid form of Compound 1 of the disclosure, in the particular dosage form, the age, weight, health and sex of the patient, the rates of metabolism and excretion of, and the judgment of the treating physician, among other factors.

[0266] In one aspect, a patient or subject in need of therapy using a pharmaceutical composition comprising a solid form of Compound 1 according to the methods described herein is treated by administering to the patient (subject) a therapeutically effective amount of the composition thereof.

[0267] The solid form of Compound 1 of the disclosure is included in the pharmaceutical composition in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing undue adverse effects in the patient treated. In some embodiments, a dose of a solid form of Compound 1 of the disclosure for all of the herein- mentioned conditions is in the range from about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient / patient per day.

[0268] In some embodiments, a solid form of Compound 1 of the disclosure is administered to achieve peak plasma concentrations of about 0.00001-30 mM, preferably about 0.1-30 pM. This is achieved, for example, by oral administration of a tablet or capsule, by the subcutaneous injection of a solution or formulation of a solid form of Compound 1 of the disclosure.

[0269] In an additional aspect, the present disclosure provides a method of treating a psychological disease or disorder (e.g., postpartum depression) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a solid form ofCompound 1 of the disclosure, or a therapeutically effective amount of a pharmaceutical composition comprising compound 1 prepared from a solid form of Compound 1 of the disclosure.

[0270] In certain embodiments, the psychological disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, treatment-resistant depression (TRD), alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

[0271] In certain embodiments, the psychological disease or disorder is selected from depression, MDD, PPD, drug-resistant depression, and treatment-resistant depression (TRD). In certain embodiments, the psychological disease or disorder is PPD.

[0272] In certain embodiments, the subject is female. In certain embodiments, the subject is a human female. In certain embodiments, the subject is a female that is at least 18 years old.

[0273] In certain embodiments, the subject is no more than 15 months postpartum, e.g., no more than 14 months postpartum, no more than 13 months postpartum, no more than 12 months postpartum, no more than 1 1 months postpartum, no more than 10 months postpartum, no more than 9 months postpartum, no more than 6 months postpartum, or no more than 3 months postpartum. In certain embodiments, the subject is from 1 to 15 months postpartum, e.g., from 1 to 12 months, from 1 to 9 months, from 1 to 6 months, from 1 to 3 months, from 3 to 15 months, from 3 to 12 months, from 3 to 9 months, from 3 to 6 months, from 6 to 15 moths, from 6 to 12 months, from 6 to 9 months, from 9 to 15 months, from 9 to 12 months, or from 12 to 15 months postpartum.

[0274] In certain embodiments, the subject is not breastfeeding.

[0275] In certain embodiments, the subject has been diagnosed with PPD, i.e., the subject experienced a major depressive episode that began at any time during the period starting at the beginning of the second trimester (>14 weeks) of pregnancy through 4 weeks following delivery,confirmed by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders Clinical Trial Version (SCID-5-CT).

[0276] In certain embodiments, the subject has been on a stable regimen of a selective serotonin reuptake inhibitor (SSRI) for at least 30 days prior to administration, e.g., at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 or more months prior to administration.

[0277] Exemplary SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, indalpine, and zimelidine.

[0278] In certain embodiments, the subject has been on a stable psychotherapy regimen for at least 30 days prior to administration, e.g. at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 or more months prior to administration of a solid form of Compound 1 of the disclosure. Exemplary psychotherapies include cognitive behavioral therapy (CBT) (e.g., dialectical behavior therapy (DBT), rational emotive behavior therapy (REBT), acceptance and commitment therapy (ACT)), behavioral therapy (e.g., systematic desensitization, aversion therapy, flooding), psychodynamic therapy, humanistic therapy (e.g., gestalt therapy, person-centered therapy, existential therapy), interpersonal therapy, and supporting therapy.

[0279] In certain embodiments, a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising Compound 1 prepared from a solid form of Compound 1 of the disclosure, is administered in a medical facility (e.g., hospital, out-patient care, doctor’s office, or clinic). In certain embodiments, the subject remains in the medical facility for at least 8 hours following administration, e.g., for observation to ensure that the subject is ready to discharge. In certain embodiments, the subject remains in the medical facility for a least 12 hours, at least 16 hours, at least 20 hours, or at least 24 hours following administration.

[0280] In certain embodiments, a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising compound 1 prepared from a solid form of Compound 1 of the disclosure, is administered to the subject by a medically trained professional, e.g., a pharmacist, nurse, or doctor.

[0281] In certain embodiments, a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising Compound 1 prepared from a solid form of Compound 1 of the disclosure, is administered to the subject via injection, e.g., subcutaneous injection.

[0282] In certain embodiments, a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising Compound 1 prepared from a solid form of Compound 1 of the disclosure, is administered in the form of a solution suitable for injection, e.g., intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous injections. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle free injectors and infusion techniques.

[0283] In certain embodiments, parenteral formulations are aqueous solutions which contain excipients such as salts, carbohydrates and pH adjusting or buffering agents (preferably to a pH of from 3.0 and 7.0, preferably 4.0 to 6.0, and more preferably 4.5 to 5.5). In other embodiments, the parenteral formulation is formulated as a sterile non aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen free water or pre-fabricated, ready-to-mix aqueous buffer. Osmotic agents may be included to control tonicity.

[0284] The preparation of parenteral kits for reconstitution at point-of-care under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0285] In certain embodiments, an injectable solution is produced by aseptically placing a solid form of Compound 1 of the disclosure into a vial as a sterile filtered solution, aseptically freeze- drying and sealing. For use, the contents of the vial are mixed with, for example, 2 mL of physiological saline for injection, optionally with an appropriate amount of osmotic complements and pH adjusters to achieve a slightly acidic to neutral pH (e.g. pH 4-7), to produce an injectable preparation with low irritation but retain solubility and / or stability of the prodrug.

[0286] In certain embodiments, from 20 mg to 60 mg of a solid form of Compound 1 of the disclosure (e.g., calculated as the free base or salt) is administered to the subject in a single dose, e.g., from 20 mg to 50 mg, from 20 mg to 40 mg, from 20 mg to 30 mg, from 30 mg to 60 mg, from 30 mg to 50 mg, from 30 mg to 40 mg, from 40 mg to 60 mg, from 40 mg to 50 mg, or from 50 mg to 60 mg.

[0287] In certain embodiments, from 20 mg / mL to 60 mg / mL of a solid form of Compound 1 of the disclosure (c.g., calculated as the free base or salt) is administered to the subject in a single dose in the form of a solution, e.g., from 20 mg / mL to 50 mg / mL, from 20 mg / mL to 40 mg / mL, from 20 mg / mL to 30 mg / mL, from 30 mg / mL to 60 mg / mL, from 30 mg / mL to 50 mg / mL, from 30 mg / mL to 40 mg / mL, from 40 mg / mL to 60 mg / mL, from 40 mg / mL to 50 mg / mL, or from 50 mg / mL to 60 mg / mL. In certain embodiments, 30 mg / mL of a salt of Compound 1 (calculated as the free base) is administered to the subject in a single dose in the form of a solution.

[0288] In certain embodiments, the dose is divided into two or more parts, e.g., to alleviate any anxiety relative to therapy. For example, the medical profession may choose to divide the therapeutic dose and thereby reduce the initial onset of psychoactivity before applying the full complement of the dosage to achieve the full effect.

[0289] In certain embodiments, the subject exhibits reduced depressive symptoms following administration of a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising Compound 1 prepared from a solid form of Compound 1 of the disclosure, compared to the subject’s depressive symptoms prior to administration (baseline). In certain embodiments, the subject’s Montgomery-Asberg Depression Rating Scale (MADRS) score following administration is reduced by at least 50% compared to the subject’s MADRS score prior to administration (baseline), e.g., at least 60%, at least 70%, at least 80%, or at least 90% reduced.

[0290] In certain embodiments, the subject exhibits reduced anxiety symptoms following administration of a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising Compound 1 prepared from a solid form of Compound 1 of the disclosure, compared to the subject’s anxiety symptoms prior to administration (baseline).

[0291] In certain embodiments, the subject’s Hamilton Rating Scale for Anxiety (HAM-A) score following administration of a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising Compound 1 prepared from a solid form of Compound 1 of the disclosure, is improved compared to the subject’s HAM-A score prior to administration (baseline). Improvement with respect to HAM-A score refers to a later timepoint score that is lower than the baseline score.

[0292] In certain embodiments, the subject exhibits improved maternal behaviors following administration of a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising Compound 1 prepared from a solid form of Compound 1 of the disclosure, compared to the subject’s maternal behaviors prior to administration (baseline).

[0293] In certain embodiments, the subject’s Barkin Index of Maternal Functioning (BIMF) score is improved following administration of a solid form of Compound 1 of the disclosure, or a pharmaceutical composition comprising Compound 1 prepared from a solid form of Compound 1 of the disclosure, compared to the subject’s BIMF score prior to administration (baseline). Improvement with respect to BIMF refers to a later timepoint score that is higher than the baseline score.EMBODIMENTS

[0294] Embodiment 1. A solid form of Compound 1:or zwitterion thereof and other than a solid form of Compound 1 HO and other than a methanol solvate of Compound 1 and other than an ethanol solvate of Compound 1.

[0295] Embodiment 2. The solid form of Compound 1 HC1 of Embodiment 1 wherein the solid form of Compound 1 HC1 is not a cocrystal of Compound 1 HC1.

[0296] Embodiment 3. The solid form of Compound 1 HO of Embodiments 1 or 2 wherein the solid form is a salt of Compound 1 HC1.

[0297] Embodiment 4. The solid form of Compound 1 HO of any one of Embodiments 1 to 3, wherein the salt is not a hydrochloride salt.

[0298] Embodiment 5. The solid form of Compound 1 HO of any one of Embodiments 1 to 4, wherein the salt is an organic salt.

[0299] Embodiment 6. The solid form of Embodiment 5, wherein the salt is a hydrobromide salt.

[0300] Embodiment 7. The solid form of Embodiment 5, wherein the salt is a calcium salt.

[0301] Embodiment 8. The solid form of Embodiment 5, wherein the salt is a phosphoric acid salt.

[0302] Embodiment 9. The solid form of Embodiment 5, wherein the salt is a sulfuric acid salt.

[0303] Embodiment 10. An organic salt of Compound 1 and wherein the organic salt is optionally in solid form.

[0304] Embodiment 11. An inorganic salt of Compound 1 other than an HC1 salt.

[0305] Embodiment 12. The solid form of Embodiment 10, wherein the organic acid salt is a sulfonic acid salt.

[0306] Embodiment 13. The solid form of Embodiment 12, wherein the sulfonic acid salt is an aromatic sulfonic acid salt.

[0307] Embodiment 14. The solid form of Embodiment 13, wherein the aromatic sulfonic acid salt is a benzenesulfonic acid salt.

[0308] Embodiment 15. The solid form of Embodiment 13, wherein the aromatic sulfonic acid salt is a p-toluenesulfonic acid salt.

[0309] Embodiment 16. The solid form of Embodiment 12, wherein the sulfonic acid salt is a non-aromatic acid salt.

[0310] Embodiment 17. The solid form of Embodiment 15, wherein the non-aromatic sulfonic acid salt is a 1,2-ethanedi sulfonic acid salt.

[0311] Embodiment 18. The solid form of Embodiment 10, wherein the organic acid salt is an aromatic acid salt.

[0312] Embodiment 19. The solid form of Embodiment 18, wherein the aromatic acid salt is a benzoic acid salt, e.g., a gentisic acid salt.

[0313] Embodiment 20. The solid form of Embodiment 18, wherein the aromatic acid salt is a salicylic acid salt.

[0314] Embodiment 21 . The solid form of Embodiment 10, wherein the organic acid salt is a non-aromatic salt.

[0315] Embodiment 22. The solid form of Embodiment 21, wherein the non-aromatic salt has at least two carboxylic acid groups.

[0316] Embodiment 23. The solid form of Embodiment 10, wherein the organic acid salt is a C2-C4 organic acid salt.

[0317] Embodiment 24. The solid form of Embodiment 23, wherein the organic acid salt is an oxalic acid salt.

[0318] Embodiment 25. The solid form of Embodiment 23, wherein the organic acid salt is a C3 organic acid salt.

[0319] Embodiment 26. The solid form of Embodiment 25, wherein the organic acid salt is a malonic acid salt.

[0320] Embodiment 27. The solid form of Embodiment 23, wherein the organic acid salt has at least one alcohol group.

[0321] Embodiment 28. The solid form of Embodiment 27, wherein the organic acid salt is a tartaric acid salt.

[0322] Embodiment 29. The solid form of Embodiment 28, where the tartaric acid salt is L-(+)- tartaric acid salt.

[0323] Embodiment 30. The solid form of Embodiment 23, wherein the organic acid salt is a maleic acid salt.

[0324] Embodiment 31. The solid form of Embodiment 5, wherein the salt is a crystalline HBr salt.

[0325] Embodiment 32. The solid form of Embodiment 31, wherein the crystalline HBr salt has an XRPD pattern substantially the same as that of HBrl of FIG. 16.

[0326] Embodiment 33. The solid form of Embodiment 5, wherein the salt is a crystalline calcium salt.

[0327] Embodiment 34. The solid form of Embodiment 5, wherein the salt is a crystalline phosphoric acid salt.

[0328] Embodiment 35. The solid form of Embodiment 34, wherein the crystalline phosphoric acid salt has an XRPD pattern substantially the same as that of Phol of FIG. 30.

[0329] Embodiment 36. The solid form of Embodiment 5, wherein the salt is a crystalline sulfuric acid salt.

[0330] Embodiment 37. The solid form of Embodiment 36, wherein the crystalline sulfuric acid salt has an XRPD pattern substantially the same as that of Sull of FIG. 34.

[0331] Embodiment 38. The solid form of Embodiment 36, wherein the crystalline sulfuric acid salt has an XRPD pattern substantially the same as that of Sul2 of FIG. 34.

[0332] Embodiment 39. The solid form of Embodiment 10, wherein the salt is a crystalline benzenesulfonic acid salt.

[0333] Embodiment 40. The solid form of Embodiment 39, wherein the crystalline benzenesulfonic acid salt has an XRPD pattern substantially the same as that of Besl of FIG. 10.

[0334] Embodiment 41. The solid form of Embodiment 10, wherein the salt is a crystalline 1,2- ethanedisulfonic acid salt.

[0335] Embodiment 42. The solid form of Embodiment 41, wherein the salt is Form A crystalline 1,2-ethanedisulfonic acid salt.

[0336] Embodiment 43. The solid form of Embodiment 42, wherein the Form A crystalline 1,2- ethanedisulfonic acid salt has an XRPD pattern substantially the same as Edyl of FIG. 11.

[0337] Embodiment 44. The solid form of Embodiment 42 or 43, wherein the Form A crystalline 1,2-ethanedisulfonic acid salt has a differential scanning calorimetry endotherm onset of about 145 °C.

[0338] Embodiment 45. The solid form of any one of Embodiments 42 to 44, wherein the Form A crystalline 1,2-ethanedisulfonic acid salt has a differential scanning calorimetry thermogram substantially the same as that of FIG. 13.

[0339] Embodiment 46. The solid form of Embodiment 41, wherein the salt is Form B crystalline 1,2-ethanedisulfonic acid salt (Compound 1 Edy2).

[0340] Embodiment 47. The solid form of Embodiment 46, wherein the Form B crystalline 1 ,2- cthancdisulfonic acid salt has an XRPD pattern substantially the same as that of Edy2 of FIG. 11.

[0341] Embodiment 48. The solid form of Embodiment 41, wherein the salt is Form C crystalline 1,2-ethanedisulfonic acid salt (Compound 1 Edy3).

[0342] Embodiment 49. The solid form of Embodiment 48, wherein the Form C crystalline 1,2- ethanedisulfonic acid salt has an XRPD pattern substantially the same as that of Edy3 of FIG. 11.

[0343] Embodiment 50. The solid form of Embodiment 10, wherein the salt is a crystalline salicylic acid salt.

[0344] Embodiment 51. The solid form of Embodiment 50, wherein the crystalline salicylic acid salt has an XRPD pattern substantially the same as that of Sall of FIG. 31.

[0345] Embodiment 52. The solid form of Embodiment 50 or 51, wherein the crystalline salicylic acid salt has a differential scanning calorimetry endotherm onset of about 74°C.

[0346] Embodiment 53. The solid form of any one of Embodiments 50 to 52, wherein the crystalline salicylic acid salt has a differential scanning calorimetry thermogram substantially the same as that of FIG. 33.

[0347] Embodiment 54. The solid form of Embodiment 10, wherein the salt is a crystalline oxalic acid salt.

[0348] Embodiment 55. The solid form of Embodiment 54, wherein the crystalline oxalic acid salt has an XRPD pattern comprising a peak at about 8.4°20.

[0349] Embodiment 56. The solid form of Embodiment 54, wherein the crystalline oxalic acid salt has an XRPD pattern comprising a peak at about 8.8°29.

[0350] Embodiment 57. The solid form of Embodiment 54, wherein the crystalline oxalic acid salt has an XRPD pattern comprising a peak at about 10.3°29.

[0351] Embodiment 58. The solid form of Embodiment 54, wherein the crystalline oxalic acid salt has an XRPD pattern comprising one or more peaks at about 8.4°29, about 8.8°29, about 10.3°2e, about 11.0°29, about 11.3°29, about 12.9°29, about 13.4°29, or about 13.5°29.

[0352] Embodiment 59. The solid form of any one of Embodiments 54 to 58, wherein the crystalline oxalic acid salt has a differential calorimetry endotherm onset of about 134.5°C.

[0353] Embodiment 60. The solid form of any one of Embodiments 50 to 58, wherein the crystalline oxalic acid salt has a differential calorimetry thermogram substantially the same as that of FIG. 26A.

[0354] Embodiment 61. The solid form of Embodiment 54, having a unit cell with the following parameters: about 10.4, about 11.0, about 11.1, about 72.3, about 78.4, about 75.8, and about 1160.3 at the temperature of 90K.

[0355] Embodiment 62. The solid form of Embodiment 54, having a unit cell, having the following parameters: about 10.5, about 11.1, about 11.1, about 72.4, about 79.0, about 76.2, and about 1194.9 at the temperature of 300K.

[0356] Embodiment 63. The solid form of any one of Embodiments 54 to 60, wherein the crystalline oxalic acid salt has an XRPD pattern substantially the same as that of Oxal of FIG. 29A.

[0357] Embodiment 64. The solid form of Embodiment 10, wherein the salt is a crystalline malonic acid salt.

[0358] Embodiment 65. The solid form of Embodiment 64, wherein the crystalline malonic acid salt has an XRPD pattern comprising a peak at about 7.9°20.

[0359] Embodiment 66. The solid form of Embodiment 64, wherein the crystalline malonic acid salt has an XRPD pattern comprising a peak at about 9.9°20.

[0360] Embodiment 67. The solid form of Embodiment 64, wherein the crystalline malonic acid salt has an XRPD pattern comprising a peak at about 12.7°20.

[0361] Embodiment 68. The solid form of Embodiment 64, wherein the crystalline malonic acid salt has an XRPD pattern comprising a peak at about 13.9°20.

[0362] Embodiment 69. The solid form of Embodiment 64, wherein the crystalline malonic acid salt has an XRPD pattern comprising a peak at about 15.9°20.

[0363] Embodiment 70. The solid form of Embodiment 64, wherein the crystalline malonic acid salt has an XRPD diffraction pattern comprising one or more peaks at about 7.9°20, about 9.9°20, about 12.7°20, about 13.9°20, or about 15.9°20.

[0364] Embodiment 71 . The solid form of any one of Embodiments 64 to 70, wherein the crystalline malonic acid salt has a differential calorimetry endotherm onset of about 145°C.

[0365] Embodiment 72. The solid form of any one of Embodiments 64, wherein the crystalline malonic acid salt has a differential calorimetry thermogram substantially the same as that of FIG. 19A.

[0366] Embodiment 73. The solid form of Embodiment 64, having a unit cell with the following parameters: about 9.0, about 10.8, about 23.0, about 100.6, and about 2218.3 at the temperature of 90K.

[0367] Embodiment 74. The solid form of Embodiment 64, having a unit cell with the following parameters: about 9.1, about 11.1, about 23.0, about 101.2, and about 2282.3 at the temperature of 300K.

[0368] Embodiment 75. The solid form of any one of Embodiments 64 to 74, wherein the crystalline malonic acid salt has an XRPD pattern substantially the same as that of Mao 1 of FIG. 24A.

[0369] Embodiment 76. The solid form of Embodiment 10, wherein the salt is a crystalline tartaric acid salt.

[0370] Embodiment 77. The solid form of Embodiment 76, wherein the tartaric acid salt is the (+)-L-tartaric acid salt.

[0371] Embodiment 78. The solid form of Embodiment 76 or 77, wherein the crystalline tartaric acid salt has an XRPD pattern comprising a peak at about 6.5°20.

[0372] Embodiment 79. The solid form of Embodiment 76 or 77, wherein the crystalline tartaric acid salt has an XRPD pattern comprising a peak at about 13.1°20.

[0373] Embodiment 80. The solid form of Embodiment 76 or 77, wherein the crystalline tartaric acid salt has an XRPD pattern comprising a peak at about 13.9°20.

[0374] Embodiment 81. The solid form of Embodiment 76 or 77, wherein the crystalline tartaric acid salt has an XRPD pattern comprising a peak at about 14.4°20.

[0375] Embodiment 82. The solid form of Embodiment 76 or 77, wherein the crystalline tartaric acid salt has an XRPD pattern comprising a peak at about 14.8°20.

[0376] Embodiment 83. The solid form of Embodiment 76 or 77, wherein the crystalline tartaric acid salt has an XRPD pattern comprising a peak at about 16.4°20.

[0377] Embodiment 84. The solid form of Embodiment 76 or 77, wherein the crystalline tartaric acid salt has an XRPD pattern comprising a peak at about 18.7°29.

[0378] Embodiment 85. The solid form of Embodiments 76 or 77, wherein the crystalline tartaric acid salt has an XRPD pattern comprising one or more peaks at about 6.5°20, about 13.1°29, about 13.9°29, about 14.4°2e, about 14.8°26, about 16.4°20, or about 18.7°20.

[0379] Embodiment 86. The solid form of any one of Embodiments 76 to 85, wherein the crystalline tartaric acid salt has a differential calorimetry endotherm onset of about 129°C.

[0380] Embodiment 87. The solid form of any one of Embodiments 76 to 85, wherein the crystalline tartaric acid salt has a differential calorimetry thermogram substantially the same as that of FIG. 37.

[0381] Embodiment 88. The solid form of any one of Embodiments 76 to 87, wherein the crystalline tartaric acid salt has an XRPD pattern substantially the same as that of Tarl of FIG. 42A.

[0382] Embodiment 89. The solid form of Embodiment 10, wherein the salt is a crystalline maleic acid salt.

[0383] Embodiment 90. The solid form of Embodiment 89, wherein the crystalline maleic acid salt has an XRPD pattern substantially the same as that of Mael of FIG. 17.

[0384] Embodiment 91. The solid form of any one of Embodiments 1 to 30, wherein the salt is crystalline.

[0385] Embodiment 92. The solid form of any one of Embodiments 1 to 30, wherein the salt is amorphous.

[0386] Embodiment 93. A hydrate or solvate of Compound 1:or a zwitterion thereof, other than a methanol or ethanol solvate.

[0387] Embodiment 94. The solid form of Embodiment 93.

[0388] Embodiment 95. An isopropanol solvate of Compound 1:or a zwitterion thereof.

[0389] Embodiment 96. The solid form of Embodiment 95, wherein the solid is Compound 1 Form A having an XRPD pattern substantially the same as that of FIG. 93 (top pattern).

[0390] Embodiment 97. The solid form of Embodiment 95, wherein the solid is Compound 1 Form A by a differential scanning calorimetry endotherm onset of about 107 °C.

[0391] Embodiment 98. The solid form of Embodiment 95, wherein the solid form is Compound 1 Form A.

[0392] Embodiment 99. The solid form of Embodiment 95, wherein the solid form is a hydrate of Compound 1.

[0393] Embodiment 100. The solid form of Embodiment 1, wherein the solid form is Compound 1 Form B.

[0394] Embodiment 101. The solid form of Embodiment 1, wherein the solid form is Compound 1 Form C.

[0395] Embodiment 102. The solid form of Embodiment 95, wherein the solid form is Compound 1 Form D.

[0396] Embodiment 103. The solid form of Embodiment 95, wherein the solid form is an isopropanol solvate of Compound 1 and the solvate is optionally crystalline.

[0397] Embodiment 104. The solid form of Embodiment 103, wherein the isopropanol solvate is a crystalline sesquisolvate.

[0398] Embodiment 105. A pharmaceutical composition comprising a solvate of Compound 1 or a salt of Compound 1 according to any one of Embodiments 1 to 104 and a pharmaceutically acceptable excipient.

[0399] Embodiment 106. A pharmaceutical composition prepared from a solid form according to any one of Embodiments 1 to 104.

[0400] Embodiment 107. A kit comprising a solid form of any one of Embodiments 1 to 104 and a pharmaceutically acceptable excipient.

[0401] Embodiment 108. A method of treating a disease or disorder, the method comprising administering to a subject a solid form according to any one of Embodiments 1 to 104 or a pharmaceutical composition according to Embodiment 105 or 106.

[0402] Embodiment 109. The method of Embodiment 108, wherein the disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, treatment-resistant depression (TRD), alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

[0403] Embodiment 110. The method of Embodiment 109, wherein the disease or disorder is selected from depression, MDD, PPD, drug-resistant depression, and treatment-resistant depression (TRD).

[0404] Embodiment 111. The method of Embodiment 109, wherein the disease or disorder isPPD.

[0405] Embodiment 1 12. A cocrystal of Compound 1:and coformer.

[0406] Embodiment 113. The cocrystal of Embodiment 112 wherein the coformer is an organic coformer.

[0407] Embodiment 114. The cocrystal of Embodiment 113 wherein the organic coformer is an organic acid.

[0408] Embodiment 115. The cocrystal of Embodiment 114 wherein the organic acid is an aromatic acid.

[0409] Embodiment 116. The cocrystal of Embodiment 115 wherein the aromatic acid is benzoic acid.

[0410] Embodiment 117. The cocrystal of Embodiment 115 wherein the organic acid is a substituted benzoic acid.

[0411] Embodiment 118. The cocrystal of Embodiment 117 wherein the substituted benzoic acid is 4- aminobenzoic acid.

[0412] Embodiment 1 19. The cocrystal of Embodiment 1 17 wherein the substituted benzoic acid is cinnamic acid.

[0413] Embodiment 120. The cocrystal of Embodiment 114 wherein the organic acid is a nonaromatic acid.

[0414] Embodiment 121. The cocrystal of Embodiment 120 wherein the non-aromatic acid is an alkyl organic acid.

[0415] Embodiment 122. The cocrystal of Embodiment 121 wherein the alkyl organic acid is a mono-organic acid.

[0416] Embodiment 123. The cocrystal of Embodiment 122 wherein the mono-organic acid is cholic acid.

[0417] Embodiment 124. The cocrystal of Embodiment 120 wherein the alkyl organic acid is a di-organic acid.

[0418] Embodiment 125. The cocrystal of Embodiment 124 wherein the di-organic acid is adipic acid.

[0419] Embodiment 126. The cocrystal of Embodiment 120 wherein the non-aromatic acid is an alkenyl acid.

[0420] Embodiment 127. The cocrystal of Embodiment 126 wherein the alkenyl acid is sorbic acid.

[0421] Embodiment 128. The cocrystal of Embodiment 113 wherein the organic coformer is a phenol.

[0422] Embodiment 129. The cocrystal of Embodiment 128 wherein the phenol is t- butylhydroquinone.

[0423] Embodiment 130. The cocrystal of Embodiment 113 wherein the organic coformer is an aldehyde.

[0424] Embodiment 131. The cocrystal of Embodiment 130 wherein the aldehyde is vanillin.

[0425] Embodiment 132. A cocrystal of Compound 1:and sorbic acid.

[0426] Embodiment 133. The cocrystal of Embodiment 132 wherein the cocrystal has an x-ray powder diffraction pattern comprising a peak at about 8.2°20.

[0427] Embodiment 134. The cocrystal of Embodiment 133 wherein the cocrystal has an x-ray powder diffraction pattern comprising one or more peaks at about 8.2°20, about 8.8°20, about 9.6°20, about 9.9°20, and about 11.9°20.

[0428] Embodiment 135. The cocrystal of any one of Embodiments 132 to 134 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 45, FIG. 46, or FIG. 47A.

[0429] Embodiment 136. The cocrystal of any one of Embodiments 132 to 135 wherein the cocrystal has a DSC endotherm onset at about 129°C or 131 °C.

[0430] Embodiment 137. A cocrystal of Compound 1:and cinnamic acid.

[0431] Embodiment 138. The cocrystal of Embodiment 137 wherein the cocrystal has an x-ray powder diffraction pattern comprising a peak at about 6.6°20.

[0432] Embodiment 139. The cocrystal of Embodiment 137 or 138 wherein the cocrystal has an x-ray powder diffraction pattern comprising a peak at about 1 l.O°20.

[0433] Embodiment 140. The cocrystal of Embodiment 137 wherein the cocrystal has an x-ray powder diffraction pattern comprising one or more peaks at about 6.6°20, about 9.2°20, about l l.O°20, about 11.8°20, and about 2O.3°20.

[0434] Embodiment 141. The cocrystal of any one of Embodiments 132 to 134 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 50 or FIG. 51.

[0435] Embodiment 142. The cocrystal of any one of Embodiments 137 to 141 wherein the cocrystal has a DSC endotherm onset at about 95°C.

[0436] Embodiment 143. A cocrystal of Compound 1:and vanillin.

[0437] Embodiment 144. The cocrystal of Embodiment 143 wherein the cocrystal has an x-ray powder diffraction pattern comprising a peak at about 8.6°20.

[0438] Embodiment 145. The cocrystal of Embodiment 144 wherein the cocrystal has an x-ray powder diffraction pattern comprising a peak at about 10.4°20.

[0439] Embodiment 146. The cocrystal of Embodiment 144 wherein the cocrystal has an x-ray powder diffraction pattern comprising one or more peaks at about 8.6°20, about 1O.4°20, about 11.4°20, about 1 1.7°20, about 13.1 °20, and about 1 .9°20.

[0440] Embodiment 147. The cocrystal of Embodiment 143 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 54 or FIG. 55.

[0441] Embodiment 148. The cocrystal of any one of Embodiments 143 to 147 wherein the cocrystal has a DSC endotherm onset at about 120°C or 74°C or 113°C.

[0442] Embodiment 149. The cocrystal of Embodiment 143 or 148 wherein the cocrystal has an x-ray powder diffraction pattern comprising a peak at about 9.6°20.

[0443] Embodiment 150. The cocrystal of Embodiment 143 or 149 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 58.

[0444] Embodiment 151. A cocrystal of Compound 1:and adipic acid.

[0445] Embodiment 152. The cocrystal of Embodiment 151 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 61.

[0446] Embodiment 153. A cocrystal of Compound 1:and cholic acid.

[0447] Embodiment 154. The cocrystal of Embodiment 153 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 64.

[0448] Embodiment 155. A cocrystal of Compound 1:and t-butylhydroquinone.

[0449] Embodiment 156. The cocrystal of Embodiment 155 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 67.

[0450] Embodiment 157. The cocrystal of Embodiments 155 or 156 wherein the cocrystal has aDSC endotherm onset at about 68°C.

[0451] Embodiment 158. A cocrystal of Compound 1:and benzoic acid.

[0452] Embodiment 159. The cocrystal of Embodiment 158 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 70.

[0453] Embodiment 160. The cocrystal of Embodiment 158 referred to herein as Ben2.

[0454] Embodiment 161. A cocrystal of Compound 1:and 4- aminobenzoic acid.

[0455] Embodiment 162. The cocrystal of Embodiment 161 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 73.

[0456] Embodiment 163. The cocrystal of Embodiments 161 or 162 wherein the cocrystal has a DSC endotherm onset at about 64°C.

[0457] Embodiment 164. The cocrystal of Embodiment 161 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 75.

[0458] Embodiment 165. The cocrystal of Embodiments 161 wherein the cocrystal has a DSC endotherm onset at about 77°C.

[0459] Embodiment 166. The cocrystal of Embodiment 161 or 165 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 75.

[0460] Embodiment 167. The cocrystal of Embodiment 161 referred to herein as Aba3.

[0461] Embodiment 168. A crystalline form of Compound 1:and malic acid.

[0462] Embodiment 169. The crystalline compound of Embodiment 168 wherein the cocrystal has an x-ray powder diffraction pattern comprising a peak at about 12.9°26.

[0463] Embodiment 170. The crystalline compound of Embodiment 168 wherein the cocrystal has an x-ray powder diffraction pattern comprising one or more peaks at about 12.9°20, about 14.4°20, about 14.6°29, about 15.5°2e, and about 16.5°26.

[0464] Embodiment 171. The crystalline compound of Embodiment 168 wherein the cocrystal has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 79.

[0465] Embodiment 172. The crystalline compound of any one of Embodiments 168 to 171 wherein the cocrystal has a DSC endotherm onset at about 109°C.

[0466] Embodiment 173. A cocrystal of Compound 1:HC1 and a coformer.

[0467] Embodiment 174. The cocrystal of Embodiment 173 wherein the coformer is an organic coformcr.

[0468] Embodiment 175. The cocrystal of Embodiment 174 wherein the organic coformer is an organic acid.

[0469] Embodiment 176. The cocrystal of Embodiment 175 wherein the organic acid is cholic acid.

[0470] Embodiment 177. The cocrystal of Embodiment 175 wherein the organic acid is an aromatic organic acid.

[0471] Embodiment 178. The cocrystal of Embodiment 177 wherein the aromatic organic acid is 2,4-dihydroxybenzoic acid.

[0472] Embodiment 179. A cocrystal of Compound 1:and cholic acid.

[0473] Embodiment 180. The cocrystal of Embodiment 179 wherein the cocrystal has an x-ray powder diffraction pattern substantially the same as that of FIG. 82.

[0474] Embodiment 181. The cocrystal of Embodiment 179 or 180 wherein the cocrystal has a DSC endotherm at about 162°C.

[0475] Embodiment 182. The cocrystal of Embodiment 179 wherein the cocrystal has an x-ray powder diffraction pattern substantially the same as that of FIG. 84.

[0476] Embodiment 183. A cocrystal of Compound 1:and 2,4-dihydroxybenzoic acid.

[0477] Embodiment 184. The cocrystal of Embodiment 183, wherein the cocrystal has an x-ray powder diffraction pattern substantially the same as that of FIG. 86.

[0478] Embodiment 185. The cocrystal of Embodiment 183, wherein the cocrystal has an x-ray powder diffraction pattern substantially the same as that of FIG 89 for Dhba3.

[0479] Embodiment 186. Amorphous Compound 1 HC1.

[0480] Embodiment 187. The solid form of Embodiment 95 or Embodiment 98, wherein the isopropanol solvate of Compound 1 has an x-ray powder diffraction pattern comprising one or more peaks at about 7.6°29, about 8.3°20, about 10.4°29, about 10.8°29, about 11.7°29, and about 12.3°29.

[0481] Embodiment 188. The solid form of Embodiment 95 or Embodiment 98, wherein the isopropanol solvate of Compound 1 has an x-ray powder diffraction pattern comprising one or more peaks at about 6.7°29, about 7.7°29, about 8.3°29, about 10.6°29, about 11.0°29, about 11.7°29, and about 12.4°29.

[0482] Embodiment 189. The solid form of Embodiment 95 or Embodiment 98, wherein the isopropanol solvate of Compound 1 has an x-ray powder diffraction pattern comprising peaks substantially the same as that of FIG. 99 or FIG. 100.

[0483] Embodiment 190. The solid form of Embodiment 95 or Embodiment 102, wherein the isopropanol solvate of Compound 1 has an x-ray powder diffraction pattern comprising one or more peaks at about 8.2°29, about 9.5°29, about 10.1°29, about 13.6°29, and about 15.0°29.

[0484] Embodiment 191. The solid form of Embodiment 95 or Embodiment 102, wherein the isopropanol solvate of Compound 1 has an x-ray powder diffraction pattern comprising one or more peaks at about 8.2°29, about 9.7°29, about 10.1°29, about 13.7°29, and about 15.1°29.

[0485] Embodiment 192. The solid form of Embodiment 95 or Embodiment 102, wherein the isopropanol solvate of Compound 1 has an x-ray powder diffraction pattern comprising substantially the same as that of FIG. 97 or FIG.98.

[0486] Embodiment 193. A pharmaceutical composition comprising a solid form of Compound 1, a salt of Compound 1, a solvate of Compound 1, a cocrystal of Compound 1, a crystalline form comprising Compound 1, a cocrystal of Compound 1 HC1, or amorphous Compound 1 HC1 according to any one of Embodiments 112 to 186 and a pharmaceutically acceptable excipient.

[0487] Embodiment 194. A pharmaceutical composition prepared from a solid form of Compound 1, a salt of Compound 1, a solvate of Compound 1, a cocrystal of Compound 1, a crystalline form comprising Compound 1, a cocrystal of Compound 1 HC1, or amorphous Compound 1 HC1 according to any one of Embodiments 112 to 186.

[0488] Embodiment 195. A kit comprising a solid form of Compound 1, a salt of Compound 1, a solvate of Compound 1, a cocrystal of Compound 1, a crystalline form comprising Compound 1, a cocrystal of Compound 1 HC1, or amorphous Compound 1 HC1 according to any one of Embodiments 112 to 192 and a pharmaceutically acceptable excipient.

[0489] Embodiment 196. A method of treating a disease or disorder, the method comprising administering to a subject a solid form of Compound 1, a salt of Compound 1, a solvate of Compound 1, a cocrystal of Compound 1, a crystalline form comprising Compound 1, a cocrystal of Compound 1 HC1, or amorphous Compound 1 HO according to any one of Embodiments 112 to 192 or a pharmaceutical composition according to Embodiment 187 or a kit according to Embodiment 195.

[0490] Embodiment 197. The method of Embodiment 196, wherein the disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, treatment-resistant depression (TRD), alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), adjustment disorder, and post-traumatic stress disorder (PTSD).

[0491] Embodiment 198. The method of Embodiment 197, wherein the disease or disorder is selected from depression, MDD, PPD, drug-resistant depression, treatment-resistant depression (TRD).

[0492] Embodiment 199. The method of Embodiment 198, wherein the disease or disorder is PPD.

[0493] Embodiment 200. A salt of Compound 1 other than an HC1 salt.

[0494] Embodiment 201. A solvate of Compound 1 other than a methanol solvate or ethanol solvate.

[0495] Embodiment 202. The salt of Embodiment 200, wherein the salt is a hydrobromide salt.

[0496] Embodiment 203. The salt of Embodiment 200, wherein the salt is a calcium salt.

[0497] Embodiment 204. The salt of Embodiment 200, wherein the salt is a phosphoric acid salt.

[0498] Embodiment 205. The salt of Embodiment 200, wherein the salt is a sulfuric acid salt.

[0499] Embodiment 206. A pharmaceutical composition comprising a salt or solvate of Compound 1 , according to any one of Embodiments 200 to 205 and a pharmaceutically acceptable excipient.

[0500] Embodiment 207. A pharmaceutical composition prepared from a salt or solvate of Compound 1, according to any one of Embodiments 200 to 205.

[0501] Embodiment 208. A kit comprising a salt or solvate of Compound 1, according to any one of Embodiments 200 to 205 and a pharmaceutically acceptable excipient.

[0502] Embodiment 209. A method of treating a disease or disorder, the method comprising administering to a subject a salt or solvate of Compound 1, according to any one of Embodiments 200 to 205 or a pharmaceutical composition according to Embodiment 206 or a kit according to Embodiment 208.

[0503] Embodiment 210. The method of Embodiment 209, wherein the disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, treatment-resistant depression (TRD), alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), adjustment disorder, and post-traumatic stress disorder (PTSD).

[0504] Embodiment 211. The method of Embodiment 210, wherein the disease or disorder is selected from depression, MDD, PPD, drug-resistant depression, treatment-resistant depression (TRD).

[0505] Embodiment 212. The method of Embodiment 211, wherein the disease or disorder isPPD.

[0506] Embodiment 213. Use of a solid form of any one of Embodiments 1-104 or 186-192, a cocrystal of any one of Embodiments 112-167 or 173-185, or a crystalline compound of any one of Embodiments 168-172 for treatment of a disease or disorder.

[0507] Embodiment 214. The use of Embodiment 213, wherein the disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, treatment-resistant depression (TRD), alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

[0508] Embodiment 215. The use of Embodiment 214, wherein the disease or disorder is selected from depression, MDD, PPD, drug-resistant depression, and treatment-resistant depression (TRD).

[0509] Embodiment 216. The use of Embodiment 215, wherein the disease or disorder is PPD.

[0510] Embodiment 217. Use of a solid form of any one of Embodiments 1-104 or 186-192, a cocrystal of any one of Embodiments 112-167 or 173-185, or a crystalline compound of any one of Embodiments 168-172 in the manufacture of a medicament for treatment of a disease or disorder.

[0511] Embodiment 218. The use of Embodiment 217, wherein the disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, treatment-resistant depression (TRD), alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

[0512] Embodiment 219. The use of Embodiment 218, wherein the disease or disorder is selected from depression, MDD, PPD, drug-resistant depression, and treatment-resistant depression (TRD).

[0513] Embodiment 220. The use of Embodiment 219, wherein the disease or disorder is PPD.EXAMPLES

[0514] The examples and preparations provided below further illustrate and exemplify the compounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations.

[0515] Various abbreviations are used herein. Table A provides definitions of such abbreviationsTable A - AbbreviationsANALYTICAL TECHNIQUES TGA

[0516] Mass loss due to solvent or water loss from the crystals was determined by TGA (thermogravimetric analysis). Monitoring the sample weight, during heating in a TGA / DSC 3+ STARe system equipped automatic sample robot (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve and a heat flow signal. The TGA / DSC 3+ was calibrated for temperature with samples of indium and aluminum. Samples (circa 2 mg) were weighed in 100 pL aluminum crucibles and hermetically sealed. The lids were pin-holed, and the crucibles heated in the TGA from 25 to 300°C at a heating rate of 10°C / min.

[0517] The gases coming from the TGA samples were analyzed by a mass spectrometer, for example, Omnistar GSD 350 (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer, which analyzes mass fragments in the range of m / z 0-200.DSC analysis

[0518] Thermal events were obtained from DSC (differential scanning calorimetry) thermograms, which were recorded with a heat flux DSC3+ STARe system equipped with an automatic sample robot (Mettler-Toledo GmbH, Switzerland). The DSC3+ was calibrated for temperature and enthalpy with a small piece of indium (m.p. = 156.6°C; 8Hf = 28.45 J / g) and zinc (m.p. = 419.6°C; 8Hf = 107.5 J / g). Samples (circa 2 mg) were hermitically sealed in standard 40 pL aluminum pans, pin-holed and heated in the DSC from 25 °C to 300°C, at a heating rate of 10°C / min if not specified differently. Dry N2 gas, at a flow rate of 50 mL / min was used to purge the DSC equipment during measurement.H-NMR spectroscopy

[0519] 1H-NMR spectroscopy was used for compound integrity. The solids were dissolved in DMSO -d.6 and measured as soon as possible (<1 h) after preparation.

[0520] The spectra were recorded at room temperature on a 400 MHz instrument (Brukcr BioSpin GmbH) using standard pulse sequences. The data was processed with ACD Labs software Spectrus Processor 2023.1.2 (Advanced Chemistry Development Inc. Canada).DVS analysis

[0521] Moisture sorption isotherms DVS (dynamic vapor sorption) were collected on a DVS Adventure system from Surface Measurement Systems (London, UK). Sample sizes were 5-10 mg of solid material. A full sorption and desorption isotherm was recorded by varying the relative humidity from 40 to 95 to 0 to 95 to 40% in steps of 10% at a constant temperature of 25 °C. Weight equilibration per step was set at 0.002% dm / dt for 10 min or a maximum equilibration time of 6 h. Afterwards the sample was measured by HT-XRPD.

[0522] Hygroscopicity was classified according to Table 1 and measured by DVS.Table 1 - Hygroscopicity Criteriai Very hygroscopica Percent water uptake at 25°C / 80% RH in first adsorption cycle of sorption isotherm.UPLC analysisUPLC: Agilent 1290Detector 1: UV detector set at 276 nm (UV absorbance peak also at 220 nm to check for potential impurities)Detector 2: MSD XT in Positive Scan ModeUPLC Conditions:Auto sampler temp.: RTColumn: Agilent Zorbax Eclipse Plus C18 (50 x 2.1 mm; 1.8 pm)Mobile phase AMO mM ammonium acetate in waterMobile phase B: acetonitrileTable 1A - Gradient:Run time: 3.5 minutesSample PreparationConcentration: ca. 1 mg / mLSolvent: ACN / water 50 / 50Injection volume: 1 pLRetention time: 1.10 min m / z API: 375.4 [MH]+XRPD METHODSCapillary (transmission) - For Salt Examples and Cocrystal Example 2

[0523] HR-XRPD data were collected on D8 Advance diffractometer using Cu Kai radiation (1.54056 A) with germanium monochromator at room temperature. Diffraction data were collected in the 20 range 1.5 - 41.5°. Detector scan on solid state LynxEye detector was performed using 0.0157° per step with 10 sec / step scan speed. The samples were measured in 8 mm long glass capillary with 0.3 mm outer diameterHR-XRPD - Flat Sample (reflection) - For Cocrystal Examples other than Cocrystal Example 2

[0524] The X-Ray powder diffraction experiment was performed on a D8 Eco BrukerAXS diffractometer using Cu Ka radiation (1.54178 A) with Ni filter at RT. Diffraction data were collected in the 2q range 2.5 - 41.5°. Locked Coupled (2 theta / theta) scan on solid state LynxEye2 (ID mode) detector was performed using 0.0149° per step with 0.5 sec / step scan speed. The samples were measured on background free sample holder on Si

[0111] crystal plane. The measurements were performed with 0.25 fixed slits.Peak Picking Process for Peak-Picked HR-XRPD patterns

[0525] For the peak searching Broker Eva (Broker AXS, 2011 ) software was used after background subtraction. The peak search is controlled by two parameters: peak width and threshold. The peak width of the sliding interval on which the Savitzky-Golay filter is applied and the peaks are located by the second derivative method. The range is from four to 56 times the step size. The algorithm uses five to 57 data points centered on the desired point.

[0526] Ideally, the peak width should be close to twice the peaks’ full width at half maximum (FWHM) value. As a rule, the acceptable values for data of reasonable quality range from FWHM to FWHM x 4. The actual range of acceptable peak width values depends on data quality. This is the criterion which allows elimination of artificial peaks. This is based on the comparison of the computed maximum with the middle of the chord joining the two inflection points on both sides of the maximum. If IP is the peak intensity at the computed maximum, IM is the intensity at the chord center, and T is the threshold.

[0527] If no treatment has been applied to the data and if it is X-ray powder diffraction data, the natural value for the threshold T is 1. The range is from 0 to 5.HT-XRPD

[0528] HT-XRPD (high-throughput X-ray powder diffraction) patterns were obtained via mounting on a Broker General Area Detector Diffraction System (GADDS) equipped with a VANTEC-500 gas area detector corrected for intensity and geometric variations. The calibration of the measurement accuracy (peaks position) was performed using NIST SRM1976 standard (Corundum).

[0529] Data collection was carried out at room temperature using monochromatic Cu Ka radiation in the 20 region between 1.5° and 41.5°, which is the most distinctive part of the XRPD pattern. The diffraction pattern of each well was collected in two 29 ranges (1.5°< 20 < 21.5° for the first frame, and 19.5°< 20 < 41.5° for the second) with an exposure time of 90s for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.Indexing

[0530] Cell parameters as well as crystal system were obtained using LSI- Index (Coelho, 2003; Coelho & Kern, 2005) indexing program. The space group was selected on reflections condition and density of the crystal. The cell parameters, purity as well as instrument parameters were refined using Whole Powder Pattern Decomposition method (Pawley, 1981). The following criteria of fit were used:• Yo,mand Ye,mare the observed and calculated data, respectively at data point m,• M the number of data points,• P the number of parameters,• H^the weight given to data point m which for counting statistics is given by Wm=l / <j(Yo,m)2 where a(Yo,m) is the error in Yo,,„,

[0531] After correcting the unit cell parameters in the single crystal data for RT, the Rietveld (Rietveld, 1969) analysis was applied, using the same criteria of fit.COMPOUND 1 EXAMPLESCompound 1 Example 1 - Compound 1

[0532] Compound 1 are generally prepared as follows.I II Compound 1

[0533] 4-HO-DiPT-HCl (I, which is commercially available) is suspended in methyl tert-butyl ether and charged with a pH 10.0 sodium carbonate buffer to remove the HC1. The resulting organic phase is concentrated to near dryness, and then diluted with isopropyl alcohol, and then treated glutaric anhydride. Precipitation may occur spontaneously. The resulting solids are collected, washed with isopropyl alcohol and dried under nitrogen and / or vacuum resulting in Compound 1. Said Compound 1 may be an IPA solvate.

[0534] Compound 1 can be drawn in neutral and ionic forms (zwitterionic means containing one positive and one negative charge). The structure carries amino and carboxylic functions and is thus similar in structure to an amino-acid, the archetypical zwitterion. In the present disclosure, the terms neutral and zwitterion are considered synonymous and may indicate either structure. Generally, the zwitterionic form is the form present in majority in neutral aqueous solution, as neutral (pH7) is between the pKa of the carboxy function (pKa~4) and the tertiary amino function (pKa~9).Compound 1 Example 2 - Compound 1 Form B

[0535] A DVS measurement was carried out on a sample of Compound 1 from Compound 1 Example 5 with a RH profile 40% to 95% to 0% to 40% at a constant temperature of 25°C. The relative humidity was changed in steps of 10%, after equilibrium was reached within dm / dt of 0.002% / min for 10 min or a maximum equilibration time of 6 h. The change in mass of the sample as a function of the time and the relative humidity % is shown in FIG. 6A. The sorption and desorption cycles are shown as a function of the RH in FIG. 6B.

[0536] In the first sorption cycle (FIG. 6B) between 40% and 95% RH (red line; cycle 1 sorption), a mass loss of 10.3% was observed, while the mass change during desorption between 95%-0% RH (blue line; cycle 1 desorption) was about 6.3%.

[0537] The initial mass loss observed between 40% to 95% RH could be an indication that the IPA molecules present in the starting material were being replaced by water molecules. The mass of the sample remains relatively stable between 95% to 10% RH (6.3% - 4.3% water content is equal to about 1.4 to 0.9 molar equivalent) and a steep drop is observed below 10% RH. The water uptake between 0 to 40% RH is completely reversible and at 40% RH the sample contains about 1.1 molar equivalent of water (4.9%).

[0538] The solid recovered after the DVS measurement was analyzed by HT-XRPD (FIG. 7). The XRPD pattern was different than the starting material and confirmed that the solid phase had changed during the DVS analysis. The novel pattern was designated Compound 1 Form B.

[0539] Exposure of the starting material to accelerated aging conditions (40°C / 75% RH, AAC) for two days also resulted in the conversion of the starting material to Compound 1 Form B (FIG. 7).Compound 1 Example 3 - Compound 1 Form C

[0540] Two cycling DSC experiments were performed on the starting material (Compound 1 Example 5), to investigate the phase conversion after solvent loss. In one experiment, the solid was heated to 120°C and cooled back to 25 °C. The obtained solid was analyzed by XRPD. The starting material was subjected to a temperature profile from 25°C to 120°C to 25°C to 300°C (FIG. 4). The second experiment showed that, during the second heating stage, the endothermic event around 107°C disappeared and only the melting event at 154.6°C (onset) was observed. The melting event at 154.6°C (onset) was due to melting of Form C (anhydrous form).

[0541] The XRPD pattern obtained after the cycling DSC experiment in which the starting material was heated to 120°C is shown in FIG. 5. The pattern was different than that of the starting material and was designated Form C (top pattern).Compound 1 Example 4 - Compound 1 Form D: Single Crystal

[0542] Approximately 10 mg of a sample from Compound 1 Example 5 was suspended in 20 pL of IPA in an 8 mL vial at RT. The vial was sealed and heated up to about 70°C and slowly cooled to RT. After several hours, plate-like crystals appeared. One plate like crystal was selected, with approximate size of 0.316 x 0.159 x 0.072 mm3, presented in FIG. 8A.

[0543] The crystal was measured at two temperatures (RT / 299 K and LT / 185 K), 185K was the lowest possible temperature measurement because the crystal had a reversible phase transition just below 185 K. The analyzed sample crystallized as an isopropanol solvate, in monoclinic C2 / c space group with one molecule of API and 1.5 molecule of isopropanol per asymmetric unit. The final crystal parameters as well as refinement details are presented in Table 2. This is referred to as Compound 1 Form D and is an isopropyl alcohol (IPA) solvate. This is referred to as Compound 1 Form D and is an isopropyl alcohol (IPA) solvate as a sesquisolvate of IPA.Table 2 - Crystal data for Compound 1 Form D IPA solvate. Data were collected and refined at 185K and at 299K.

[0544] The crystal is stabilized by intramolecular hydrogen bonds that form three dimensional structures. Two tunnels are formed around the symmetry inversion centers and run along the c axis. One of these tunnels is filled with disordered molecules, while the other remained empty.The volume of this void was calculated as 195.6 A , which is 3.6% of the unit cell. FIG. 8B shows the ORTEP drawing for this crystal. The Compound 1 Form D pattern is simulated from the single crystal structure. It also is shown in FIG. 8C.

[0545] Table 2A is the peak table for the Compound 1 Form D simulated x-ray powder diffraction pattern calculated from the single crystal structure of Compound 1 Form D at 299KTable 2A - Peak Table for FIG. 97

[0546] Table 2B is the peak table for the Compound 1 Form D simulated x-ray powder diffraction pattern calculated from the single crystal structure of Compound 1 Form D at 170K.Table 2B - Peak Table for FIG. 98

[0547] Starting material, Forms B, C, and D (IPA solvate; 1:1.5) of Compound 1 have the diffraction patterns as shown in FIG. 9.Compound 1 Example 5 - Mixture of Compound 1 Form A and Compound 1 Form D - also referred to herein as “starting material”

[0548] 50 grams of 4-HO-DiPT-HCl (commercially available) was suspended in 10 volumes of MTBE and strongly agitated. 15 volumes of pH 10.0 carbonate buffer were charged and agitated at room temperature for 2.5 hours. The resulting phases separated, and the aqueous layer was back extracted with 5 volumes of MTBE. The organic layers were combined and washed with water and concentrated to near dryness yielding a greenish foam.

[0549] Four 4 volumes of IPA were added, mixed to dissolve the foam and then evaporated to remove residual MTBE. The product was dissolved in about 15 volumes of IPA to which was added 1.1 equivalents of glutaric anhydride all at once with agitation. The anhydride initially dissolved and as the reaction proceeded the precipitation of the zwitterionic Compound 1 was observed. The resulting suspension was agitated overnight and the solids were collected by filtration, washed with IPA and dried under vacuum and nitrogen and found to contain 15.2% w / w IPA. Further drying overnight under vacuum and nitrogen and the IPA content was measured to be 14.4% IPA w / w.

[0550] The material was analyzed by XRPD, DSC, TGMS, UPLC and1H-NMR to confirm identity and purity of the compound and to provide reference data. It was found to have about 1 mole of IPA as measured with 'H-NMR indicating a solvate of IPA of about 1:1 stoichiometry with Compound 1.

[0551] Both HT-XRPD and HR-XRPD patterns collected. Indexing of the HR-XRPD data was not achieved which may be due to the fact that, as discussed in Example 1 Compound 6, thesample was found to be a mixture of predominately Compound 1 Form A with a smaller component of Compound 1 Form D.

[0552] The chemical purity was assessed by LCMS analysis. Compound 1 was detected at a retention time of 1.10 min and confirmed the chemical purity of 97.6% (area%). The MS spectrum (positive scan mode) showed an ion with a m / z of 375.4 that corresponds to the species [M+l]+.

[0553] The TGMS analysis (FIG. 2) showed a mass loss of 14.4% between 40-120°C, due to loss of solvent (equal to 1 molar equivalent of IP A). Decomposition started above 200°C. The DSC signal showed an endothermic event coinciding with the mass loss and a second endothermic event around 150°C.

[0554] The DSC trace of the starting material (FIG. 3) showed an endothermic event around 98°C (onset) due to the mass loss and a sharper endothermic event at 157.6°C (Tpeak) (onset at 155°C) due to melting.Compound 1 Example 6 - Single Crystal Preparation and Diffraction of a 1:1 IPA Solvate of Compound 1 (Compound 1 Form A)

[0555] During an attempt to grow a single crystal of Cinl, single crystal of the free based mono- IPA solvate was found and analyzed.

[0556] Crystallization by sonication was performed on a physical mixture of Compound l:cinnamic acid with a ratio of 1:1.1. A sample of Compound 1 from Compound 1 Example 5 and Cinnamic acid were weighed into a 1.8 mL glass vial.

[0557] A drop of 20 pL of DME was added to the freeze-dried mixture. The vial was placed in a sonication bath at room temperature for 10 min.

[0558] The obtained solids were dried under vacuum overnight at 50°C, harvested and analyzed by HT-XRPD. This solid was identified as Cinl by analytical techniques such as HR-XRPD with indexing,S).

[0559] Solids of Cinl were dissolved in IPA at reflux temperature. Upon cooling of the solution, crystals appeared.

[0560] From these solids, a crystal was obtained for single crystal analysis.

[0561] From these solids, a crystal was obtained and upon analysis as described below, was found to be a 1:1 solvate of isopropyl alcohol and Compound 1 (Compound 1 Form A).

[0562] The crystal identified had an approximate size of 0.250 x 0.094 x 0.068 mm and was selected for single crystal diffraction. During the data collection it appeared that the analyzed single crystal represented a Compound 1:IPA solvate in a 1:1 ratio.

[0563] The crystal was measured at two temperatures: 300 K for unit cell parameters used for the Rietveld (Rietveld, 1969) analysis and 90 K, for additional structural data. The crystal crystallizes as IPA solvate (1:1) in the triclinic P-1 space group with 2 molecules of Compound 1 and 2 molecules of isopropanol per asymmetric unit as it is presented in FIG.90. The final crystal parameters as well as the refinement details are presented in Table 3.Table 3 - Crystal Parameters for 1:1 IPA Solvate of Compound 1

[0564] Solvent molecules are connected to one O atom of the carboxylate group, while the other carboxylate O atom is connected to the heteroaromatic N atom as it is presented in FIG. 90. FIG. 91 presents the molecular structure for both symmetry unrelated zwitterions of Compound 1. In FIG. 91, A shows molecule 1 (numbering from 0101 to C127), while B shows molecule 2 (numbering from 0201 to C227). All thermal ellipsoids for FIG. 90 and FIG. 91 are drawn at 50% probability.

[0565] The last observed electrostatic interaction was found between the protonated N+ atom and the same carboxylate O atom that is an acceptor of the hydrogen bonds from the isopropanol from the symmetry unrelated Compound 1 molecule. These hydrogen bonds form a 2D sheet like structure which is observed in FIG. 92. The full geometry of hydrogen bonds is presented in Table 4.Table 4 - H-bond Geometry for 1:1 IPA solvate of Compound 1Symmetry transformations; (i) x, y+1, z; (ii) 1-x, 1-y, 1-z; (iii) 2-x, -y, -z

[0566] The comparison of the simulated powder pattern based on Compound 1:IPA solvate (1:1) single crystal data revealed that it looks similar to the diffractogram collected for Compound 1 Example 5 (FIG. 93). There are several peaks that can be found in the collected data, that are not seen in the simulated pattern. These peaks can be attributed to the Compound 1: IPA solvate in the form of 1 Compound 1 molecule to 1.5 IPA molecules (1:1.5 form), for which the single crystal diffraction is set forth in Compound 1 Example 4 (Compound 1 Form D).

[0567] The Rietveld analysis confirmed that batch from Compound 1 Example 5 comprised of 91.9(14)% w / w of Compound 1:IPA (1:1) (Compound 1 Form A) and 8.1(14)% w / w of Compound 1:IPA (1:1.5) (Compound 1 Form D), presented in FIG. 94 and Table 5.Table 5 - Rietveld Analysis of Sample of Compound 1 Example 5

[0568] For this Compound 1 Example 6, HR-XRPD data were collected on D8 Advance diffractometer using Cu Kai radiation (1.54056 A) with germanium monochromator at RT. Diffraction data were collected in the 20 range 1.5 - 41.5°. Detector scan on solid state LynxEye detector was performed using 0.0157° per step with 6 sec / step scan speed. The samples were measured in 8 mm long glass capillary with 0.5 mm outer diameter. Microphotography was performed on a Leica DM 2500 M Microscope. Equipped with 2-gear focusing (coarse / fine with 1 pm micrometer scale with top focus stop), sturdy incident light axis with 4x and 5x reflector turrets - 4x reflector turret for BF / DF / POL / DIC and Fluo and HI PLAN EPI Objectives: 5x, lOx, and 20 x magnification. The light was generated by 12 V 100 W halogen lamp. The sample was placed in between two Fisher microscope clear slides in drop of silica oil. Images were collected on Qlmaging MicroPublisher 3.3 RTV and recorded using QCapture 2.9.13 Software, The scaling was performed manually based on previously collected data for scaled C-Chip Disposable Hemocytometer DHC-N01 produced by NanoEntek.

[0569] Cell parameters as well as crystal system were obtained using LSI- Index (Coelho, 2003; Coelho & Kern, 2005) indexing program. The space group was selected on reflections condition and density of the crystal. The cell parameters, purity as well as instrument parameters wererefined using Whole Powder Pattern Decomposition method (Pawley, 1981). The following criteria of fit were used:• Y0,m and Yc,mare the observed and calculated data, respectively at data point m,• M the number of data points,• P the number of parameters,• wmthe weighting given to data point m which for counting statistics is given by Wm=l / c(Yo,m)2where c(Yo,m) is the error in Yo,m,

[0570] After correcting the unit cell parameters in the single crystal data for RT, the Rietveld (Rietveld, 1969) analysis was applied, using the same criteria of fit.

[0571] A colorless, plate-like specimen of C21H30N2O4 • CaHsO, approximate dimensions 0.068 mm x 0.094 mm x 0.250 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured (X = 1.54178 A).Measurements at 90K

[0572] A total of 3867 frames were collected. The total exposure time was 12.29 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using a triclinic unit cell yielded a total of 101658 reflections to a maximum 0 angle of 80.18° (0.78 A resolution), of which 10584 were independent (average redundancy 9.605, completeness = 97.1%, Rmt = 5.19%, Rsig= 2.64%) and 9386 (88.68%) were greater than 2o(F2). The final cell constants of a = 8.8906(6) A, b = 13.5400(8) A, c = 21.6784(12) A, a = 84.431(2)°, 0 = 80.468(2)°, y = 75.807(2)°, volume = 2490.7(3) A3, are based upon the refinement of the XYZ-centroids of 9961 reflections above 20 oil) with 8.123° < 20 < 159.5°. Data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.786. Thecalculated minimum and maximum transmission coefficients (based on crystal size) are 0.8540 and 0.9570.

[0573] The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P -1, with Z = 4 for the formula unit, C21H30N2O4 • C;HxO. The final anisotropic full-matrix least- squares refinement on F2with 875 variables converged at R1 = 5.11%, for the observed data and wR2 = 13.02% for all data. The goodness-of-fit was 1.071. The largest peak in the final difference electron density synthesis was 0.363 e7A and the largest hole was -0.476 e7A3with an RMS deviation of 0.043 e7A3. On the basis of the final model, the calculated density was 1.159 g / cm3and F(000), 944 e‘.Measurements at 299-300K

[0574] A total of 3026 frames were collected. The total exposure time was 12.43 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using a triclinic unit cell yielded a total of 66865 reflections to a maximum 0 angle of 72.74° (0.81 A resolution), of which 9213 were independent (average redundancy 7.258, completeness = 90.0%, Rint = 5.56%, Rsig = 3.26%) and 7145 (77.55%) were greater than 2o(F2). The final cell constants of a = 8.9773(4) A, b = 13.8649(7) A, c = 21.7569(9) A, a = 84.597(2)°, 0 = 79.305(2)°, y = 75.615(2)°, volume = 2574.3(2) A3, are based upon the refinement of the XYZ-centroids of 9703 reflections above 20 o(I) with 7.961° < 20 < 144.6°. Data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.848. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.8590 and 0.9580.

[0575] The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P -1, with Z = 4 for the formula unit, C21H30N2O4 • C3H8O. The final anisotropic full-matrix least- squares refinement on F2 with 579 variables converged at R1 = 9.64%, for the observed data and wR2 = 22.50% for all data. The goodness-of-fit was 1.118. The largest peak in the final difference electron density synthesis was 0.484 e- / A3 and the largest hole was -0.461 e- / A3 with an RMS deviation of 0.044 e- / A3. On the basis of the final model, the calculated density was 1.121 g / cm3 and F(000), 944 e-.

[0576] Table 5A is the peak table for the Compound 1 Form A simulated x-ray powder diffraction pattern calculated from the single crystal structure of Compound 1 Form A at 300K16Table 5A - Peak Table for FIG. 99

[0577] Table 5B is the peak table for the Compound 1 Form A simulated x-ray powder diffraction pattern calculated from the single crystal structure of Compound 1 Form A at 90KTable 5B - Peak Table for FIG. 100Salt Screen General Procedure Example

[0578] Unless otherwise indicated, all salt examples herein were prepared by the procedure in this Example.

[0579] During salt screening experiments, some counterions tested produced oils. Others, which produced solid salts, are provided for herein. In sum, nearly 70 salt screening experiments were performed. A stoichiometric amount of counterion (in aqueous solution) was added to a suspension of Compound 1 from Compound 1 Example 5 (also referred to herein as “startingmaterial”). Different stoichiometries were tested based on the pKas of the molecule and counterions. Subsequently, the mixtures were subjected to a thermal profile. The solids were separated by centrifugation, dried and analyzed by HT-XRPD. If the expected salts were dissolved, the solvents were evaporated. The obtained solids were harvested and analyzed by HT-XRPD. Salts were identified, for example, by shifts in1H-NMR or by differences in x-ray powder diffraction patterns when compared to the starting material and counterion.

[0580] In many examples, salts were exposed to AAC as indicated. In some examples, other solvents were used as indicated.Results from Salt Screen General Procedure

[0581] XRPD patterns that were different than any of the known zwitterion polymorphs and the counterions were considered potential salt forms and were classified by the counterion abbreviation followed by a number for each unique pattern (i.e. a potential salt form with sulfuric acid was named ‘Sull’). In many cases where solids were obtained after evaporation, the solids became deliquescent while harvesting. These materials were classified as ‘oily’.

[0582] All oily substances that were obtained from the salt formation experiments were resuspended in TBME, heptane or ethyl acetate in an attempt to crystallize these materials.

[0583] All obtained solids were subsequently exposed to accelerated ageing conditions (AAC) (e.g. 40°C / 75% RH) for 48 hours, followed by re-analysis by HT-XRPD and visual inspection to investigate their physical stability and hygroscopic behavior under short-term stress conditions. Counterion, equivalents, resulting form name, and conditions to achieve that form are summarized in Table 6.Table 6 - Summary of Compound 1 solid form preparations with accompanying counterion and conditions for preparing.

[0584] Tarl, Maol and Oxal were physically stable upon exposure to AAC. These salts had very little residual solvent losses prior to melting, suggesting that these salts are non-solvated salt forms of Compound 1. The tartrate salt melted around 163°C, the malonate salt melted around 148°C, and the oxalate salt melted around 137°C. Based on the 'H-NMR spectra, Tarl was a mono-tartrate salt, Maol was a hemi-malonate salt, and the stoichiometry of the oxalate salt could not be determined (the chemical shifts of the Compound 1 peaks indicate salt formation). For Maol and Oxal, suitable crystals were obtained for single crystal analysis. The crystals of Maol appeared to comprise zwitterionic Compound 1, monoprotonated Compound 1, and malonate mono deprotonated anions in the ratio 1: 1:1, while the crystals of Oxal appeared to comprise protonated Compound 1 molecules, oxalic acid and oxalate anions in the ratio l:0.5:0.5

[0585] DVS analysis on the tartrate salt Tarl indicated that Tarl was non-hygroscopic. However, afterwards a trace of the zwitterion was observed as a mixture with Tarl, therefore some dissociation took place or already a trace of zwitterion was present before the analysis.

[0586] Maol was slightly hygroscopic, while Oxal was non-hygroscopic. Both Maol and Oxal were physically stable during the DVS analysis and no form changes occurred.

[0587] Edyl converted to Edy2, and Sall and Sull became deliquescent after exposure to AAC for two days. These salts show more solvent content, complex thermal behavior, and lower purities.

[0588] Genl is most likely a THF solvate of the zwitterion, no counterion was detected in the H-NMR spectrum and the UPLC chromatogram despite the aromatic nature of the counterion.

[0589] Compound 1 HO, including for seeds, may be prepared, for example as set forth in Compound 1 Examples 7, 8, and / or 9. For cocrystal screens of Compound 1 HC1, the Compound 1 HC1 was prepared in general accordance of Compound 1 Example 8.Compound 1 Example 7 - Synthesis of N,N diisopropyltryptamine-4-glutarate and HC1 salt

[0590] In an oven-dried 50 mL round bottom flask containing 1.2 mL of anhydrous DCM was added glutaric anhydride (0.205 g, 1.8 mmol, 1.8 eq.) and the suspension was stirred under Ar. A solution of 4-OH-DiPT (0.26 g, 1 mmol, 1 eq.) in 1.5 mL anhydrous DCM was added, followed by addition of 4-dimcthylaminopyridinc (DMAP) (37 mg, 0.3 mmol, 0.3 eq.) and trimcthylaminc (0.18 mL, 1.3 eq.) and the resulting suspension was stirred overnight at r.t. under Ar.

[0591] The mixture was decanted, and the solid was triturated with anhydrous DCM (3 mL) with a few drops of anhydrous MeCN. The suspension was acidified with IM HC1 (~1.1 eq.) and concentrated to dryness. The crude product was purified by C18 reverse-phase column chromatography (40 g, A: 0.05% HC1 in H2O, B: 0.05% HC1 in MeCN).

[0592] The structure was confirmed by NMR. Purity was determined by HPLC (>97%). The solid was resuspended in IM HCLdioxane to form the HC1 salt which was filtered, washed with ether and dried. Yield (>95%, purity >95%; DSC endotherm 174 °C). The solid could be dissolved in water up to 50 mg / mL and lyophilized to form a white "cake".Compound 1 Example 8 - HC1 salt of N,N diisopropyltryptamine-4-glutarate

[0593] In a 3-ncck 1 L round bottom flask under argon was added 4-OH-DiPT (31.8 g, 0.122 mol, 1 eq.), dissolved in 160 mL of anhydrous pyridine (160 mL). After stirring for 15 mins, glutaric anhydride (18.1 g, 0.158 mol, 1.3 eq.) was added in portions. The resulting suspension was stirred at r.t. overnight.

[0594] Anhydrous DCM (160 mL) was added to the suspension and it was cooled to 0° C. with for 2 h. The solid was filtered and washed with 60 mL of cold anhydrous DCM and dried overnight.

[0595] The dried solid was triturated with 160 mL of anhydrous DCM, followed by 160 mL of anhydrous THF, and then 160 mL of anhydrous DCM at 0° C. After drying, 33.0 g was obtained with 72% yield and 98.1% purity by HPLC. The structure of the zwitterion was confirmed by 1H-NMR (DMSO-cfe) and MS LM+H]+=375.2.

[0596] In a 100 mL round bottom flask was charged 18 mL of anhydrous diethyl ether HC1 solution (4M in dioxane, 2.4 mL, 9.6 mmol, 1.2 eq.) was added slowly and stirred at r.t. for 10 mins. The zwitterion from above (3.0 g, 8.0 mmol) was added in portions and the resulting suspension was stirred for 2 h. The solid was filtered off and washed with 6 mL of EtoO. The solid was dried yielding 3.16 g of the corresponding hemiester tryptamine HO salt (96% yield, 99.0% purity by HPLC, [M+H]+=375.1).Compound 1 Example 9 - Compound 1 HC1 for cocrystal screens

[0597] Compound 1 HC1 may be prepared by mixing Compound 1, such as starting material or Compound 1 Form A with IPA under agitation and treating with 3M HC1 in IPA. Optionally, Compound 1 HC1 seeds in IPA as a suspension may be introduced. Such seeds may be made, for example, in accordance with Compound 1 Example 7 or Compound 1 Example 8. The reaction vessel is then cooled to 4°C and filtered to collect Compound 1 HC1 which may be optionally washed with heptane.Compound 1 Example 10 - Amorphous HC1 salt of N,N diisopropyltryptamine-4- glutarate

[0598] Approximately 12 mg of the HC1 salt of Compound 1 was weighed into 1.5 mL vials and aliquots of water or a 10 / 90 mix of THF: water were added until the solids were dissolved or a maximum volume of 0.25 mL was added. The solutions were frozen in liquid nitrogen and dried in a freeze dryer (Christ, Alpha 2-4 LD) overnight to provide amorphous Compound 1 HC1, which were analyzed by x-ray powder diffraction and Thermogravimetric Analysis coupled with Mass Spectroscopy (“TGMS”). TGMS showed a mass loss of 1.5% for the Compound 1 sample prepared with water and a mass loss of 1.1% for the Compound 1 sample prepared with the10 / 90 mix of THF: water. X-ray powder diffraction of the sample prepared in water (FIG. 1 ) and THF:watcr (FIG. 2) indicated that both samples were amorphous.SALT EXPERIMENT EXAMPLESSalt Experiment Example 1 - Benzenesulfonic Acid Salt

[0599] The crystalline pattern Best was observed after exposure to AAC for two days. The material obtained from the screen was an amorphous oily substance after recrystallization in ethyl acetate and crystallized upon exposure to AAC for two days.Salt Experiment Example 2 - Edisylic Acid Salts 1, 2, and 3

[0600] With 1 ,2-ethanedi sulfonic acid, three polymorphic forms were observed, Edyl (Form A), Edy2 (Form B) and Edy3 (Form C). The XRPDs of the potential salts, compared to the starting materials, are shown in FIG. 11. Edy2 was obtained in low yield after AAC and was therefore not further characterized. Edy3 was a sticky substance and therefore not further characterized. The solid obtained from the experiment performed in acetone with 0.55 molar equivalent of 1,2- ethanedisulfonic acid was further analyzed by UPLC and TGMS. The TGMS analysis of Edyl (FIG. 12) showed a mass loss of 1.2% between 40°C-70°C, and a mass loss of 1.5% between 70°C-180°C, most likely due to water and acetone, respectively.

[0601] The TGMS analysis of Edyl (FIG. 12) showed a mass loss of 1.2% between 40°C-70°C, and a mass loss of 1 .5% between 70°C-l 80°C, most likely due to water and acetone, respectively.

[0602] The DSC trace of the Edyl (Form A) (FIG. 13) showed an endothermic event between 25°C-75°C due to a residual solvent mass loss. Two small endothermic events were observed between 75°C-130°C. The larger endothermic event around 160.8°C might be due to melting and the beginning of degradation.Salt Experiment Example 3 - Gentisic Acid Salt

[0603] The HT-XRPD pattern of the resulting solid is shown in FIG. 14. Compound 1 Genl was physically unstable upon exposure to AAC for two days and became deliquescent. The solid obtained from the experiment performed in THF with 1.1 molar equivalent of gentisic acid was further analyzed.

[0604] The TGMS analysis of Compound 1 Genl (FIG. 15) showed a mass loss of 12.4% between 25-180°C, due to THF (~1 molar equivalent of THF). No degradation was observed below 200°C. This experiment is understood to create a THF-solvate of Compound 1.Salt Experiment Example 4 - Hydrobromic Acid Salt

[0605] With hydrobromic acid, a novel crystalline pattern was observed from oils that were exposed to AAC for two days. The HT-XRPD pattern of Compound 1 HBrl compared to starting material is shown in FIG. 16.Salt Experiment Example 5 - Maleic Acid Salt

[0606] With maleic acid, a novel pattern was observed in one sample that was exposed to AAC for two days. The XRPD pattern of Compound 1 Mael, compared to the starting materials, is shown in FIG. 17.Salt Experiment Example 6 - Malonic Acid Salt

[0607] Compound 1 Mao 1 obtained from an experiment performed in IPA and 1.1 molar equivalent of malonic acid was used for further characterization.

[0608] The TGMS analysis of Compound 1 Maol (FIG. 18) showed a mass loss of 0.1% between 25°C-110°C, due to residual moisture. A second mass loss of 11.6% was observed between 110°C-200°C, which was most likely due to partial degradation. The second mass loss coincided with an endothermic event, that could be a melting and / or partial degradation event. The mass loss was not due to solvent as no solvent was detected by1H-NMR.

[0609] The DSC trace of Compound 1 Maol (FIG. 19A) showed an endothermic event at 144.7°C (onset), possibly due to the melting.

[0610] A DVS measurement was carried out on Maol with a RH (relative humidity) profile 40% to 95% to 0% to 40% at a constant temperature of 25 °C. The relative humidity was changed in steps of 10%, after equilibrium was reached within dm / dt of 0.002% / min for 10 min or a maximum equilibration time of 6 h. The change in mass of the sample as function of the time and the relative humidity % is shown in FIG. 20A. The sorption and desorption cycles are shown as a function of the RH in FIG. 20B.

[0611] In the first sorption cycle (FIG. 20B) between 40 and 95% RH (red line; cycle 1), a mass increase of 2.7% was observed, while the mass change during desorption between 95 - 0% RH(blue line; cycle 1 desorption) was 3.3%. In the second sorption (green; cycle 2 sorption) from 0 to 40% RH (green line), the mass uptake was 0.5%. The sorption and desorption were reversible and no hysteresis was observed, suggesting that no form conversion took place and water sorption only took place at the surface of the crystals.

[0612] Based on the difference in mass between 40 and 80% RH (0.8%), Maol was considered to be slightly hygroscopic.

[0613] The solid recovered after the DVS measurement was analyzed by HT-XRPD (FIG. 21). The pattern was identical to Maol before the DVS measurement, confirming no form change had occurred.

[0614] The Maol XRPD was collected first using flat sample in reflection mode (FIG. 22, FIG. 24A, FIG. 24B, and FIG. 24C). Selected peaks are presented below in Table 7, while the diffractogram is available in FIG. 24A.Table 7 - Peak picks of FIG. 24A.[06151 The material was recrystallized from isopropanol through cooling crystallization. This experiment resulted in relatively thick plate-like crystals out of which one was used for single crystal diffraction (FIG. 23).

[0616] The crystal that recrystallized out of IPA crystallized in monoclinic chiral space group P21 space group. The crystal comprises three types of molecules: zwitterionic Compound 1, monoprotonated Compound 1, and malonate mono deprotonated anions in the ratio 1:1:1. Table 8 presents the unit cell constants and final refinement parameters for the recrystallized material. An ORTEP drawing of the single crystal can be found in FIG. 19B.Table 8 - Crystalline data for Compound 1 Maol.

[0617] Comparison of the diffractograms of the solids recrystallized from IPA with that of Compound 1 MaOl and with the simulated powder diffraction pattern based on the single crystal data indicated that both analyzed materials comprised of the same crystalline form Compound 1 Maol (See FIG. 19C). Post recrystallization, capillary mode was used for x-ray powder diffraction with a D8 Eco Spectrometer at 0.0157 degrees per minute.Salt Experiment Example 7 - Oxalic Acid Salt

[0618] Oxal was physically stable upon exposure to AAC and the salt obtained from the experiment performed in IPA and 1.1 molar equivalent of oxalic acid was further characterized.

[0619] The TGMS analysis of Compound 1 Oxal (FIG. 25) showed a mass loss of 0.2% between 25°C-I20°C, due to residual water and / or solvent. The mass loss of 15.9% between I20°C-180°C coincided with an endothermic event and might have been due to a melting and(partial) degradation event. The mass loss was unlikely to be due to solvent as no solvent was detected by1H-NMR.

[0620] The DSC trace of the Compound 1 Oxal (FIG. 26A) showed a sharp endothermic event at Tpeak 136.9°C, most likely due to melting and a smaller endothermic event at 162.8°C, possibly due to partial degradation.

[0621] A DVS measurement was carried out on Compound 1 Oxal with a RH profile 40% to 95% to 0% to 40% at a constant temperature of 25°C. The relative humidity was changed in steps of 10%, after equilibrium was reached within dm / dt of 0.002% / min for 10 min or a maximum equilibration time of 6 h. The change in mass of the sample as function of the time and the relative humidity % is shown in FIG. 27A. The sorption and desorption cycles are shown as a function of the RH in FIG. 27B.

[0622] Based on the difference in mass between 40% and 80% RH (0.15%) Compound 1 Oxal could be considered non-hygroscopic. In the first sorption cycle between 40% and 95% RH, a mass increase of 0.5% was observed, while the mass change during desorption between 95% and 0% RH was 0.6%. In the second sorption from 0 to 40% RH, the mass uptake was 0.1%. The sorption and desorption were reversible, and no hysteresis was observed, suggesting that no form conversion took place and water sorption only took place at the surface of the crystals.

[0623] The solid recovered after the DVS measurement was analyzed by HT-XRPD (FIG. 28) The pattern was very similar as Compound 1 Oxal before the DVS measurement, confirming no form change had occurred. The recovered solid was also analyzed by HR-XRPD (FIG. 29A, FIG. 29B, and FIG. 29C).Table 9 - Peak Table for Compound 1 Oxal (FIG. 29A).

[0624] The crystal of Compound 1 Oxal selected for single crystal analysis is shown in FIG.26C. As it appeared, the Compound 1 Oxal crystallized in the primitive triclinic P-1 space group with protonated Compound 1 molecules, oxalic acid, and oxalate anions in the ratio l:0.5:0.5. Table 10 presents the unit cell constants and final crystal and refinement parameters.Table 10 - Crystal data for Compound 1 oxalate. Data were collected and refined at 90K and at 300K.Salt Experiment Example 8 - Phosphoric Acid Salt

[0625] With phosphoric acid, one salt form was observed, Compound 1 Phol. The HT-XRPD of Compound 1 Phol is shown in FIG. 30, compared with the stalling material. The crystalline pattern Compound 1 Phol was observed after exposure to A AC for two days.Salt Experiment Example 9 - Salicylic Acid Salt

[0626] With salicylic acid, one potential salt form was observed, and was obtained from the experiment performed in IPA with 1.1 molar equivalent of salicylic acid. The HT-XRPD pattern of Compound 1 Sall is shown in FIG. 31.

[0627] The TGMS analysis of Compound 1 Sall (FIG. 32) showed a mass loss of 0.8% between 25°C-130°C, due to residual moisture and IPA.

[0628] The DSC trace of Compound 1 Sall (FIG. 33) showed three broad endothermic events between 25°C and 140 °C, possibly due to melting and / or dissociation of the salt. Thermal degradation was observed above 180°C.Salt Experiment Example 10 - Sulfuric Acid Salt

[0629] With sulfuric acid, two salt forms were observed. The HT-XRPD patterns of Compound 1 Sull and Compound 1 Sul2 are shown in FIG. 34, compared to the starting material.

[0630] Compound 1 Sul! was obtained from an experiment performed in IPA with 0.55 molar equivalent sulfuric acid and recrystallized in ethyl acetate. Upon exposure to AAC for two days, the solid became partly deliquescent.

[0631] Compound 1 Sul2 was obtained only as an oily substance from experiments performed in THF and acetone, with 1.1 molar equivalent of sulfuric acid. The oily substances became deliquescent upon exposure to AAC for two day and lost crystallinity.

[0632] The TGMS analysis of Compound 1 Sull (FIG. 35) showed a mass loss of 2.4% between 25°C-75°C, due to residual moisture and a mass loss of 1.6% between 75°C-200°C, possibly due to ethyl acetate.

[0633] The DSC trace of the Compound 1 Sull (FIG. 36) showed complex thermal behavior. A first broad endothermic event was observed between 25°C-70°C, followed by an exothermic event around 124.6°C. The endothermic event at Tpeak 162.9°C could have been related to a melting event, followed by decomposition.Salt Experiment Example 11 - Tartaric Acid Salt

[0634] With L-(+)-tartaric acid, one potential salt form was obtained, Compound 1 Tarl. The HT-XRPD pattern of the potential tailrate salt is shown in FIG. 38, compared to the starting materials. Compound 1 Tarl was physically stable upon exposure to AAC for two days. From experiments that initially yielded an oily substance, crystallization to Compound 1 Tarl was observed after AAC. Compound 1 Tarl was also analyzed by HR-XRPD (FIG. 42A, FIG. 42B, and FIG. 42C).Table 11 - Peak Table for Compound 1 Tarl (FIG. 42A).

[0635] The solid obtained from the experiment performed in IPA with a 1.1 molar equivalent of L(+)-tartaric acid was used for further characterization of Compound 1 Tarl.

[0636] The TGMS analysis of Compound 1 Tarl (FIG. 39) showed a mass loss of 0.3% between 25°C-135°C, due to residual moisture. Thermal decomposition was observed above 160°C.

[0637] The DSC trace of the Compound 1 Tail (FIG. 37) showed an endothermic event at 128.8°C, and a larger endothermic event at Tpeak 163.3°C, most likely due to melting followed by decomposition events.

[0638] A DVS measurement was carried out on Compound 1 Tarl with a RH profile 40% to 95% to 0% to 40% at a constant temperature of 25 °C. The relative humidity was changed insteps of 10%, after equilibrium was reached within dm / dt of 0.002% / min for 10 min or a maximum equilibration time of 6 h. The change in mass of the sample as a function of the time and the relative humidity % is shown in FIG. 40A. The sorption and desorption cycles are shown as function of the RH in FIG. 40B.

[0639] In the first sorption cycle between 40% and 95% RH (red line; cycle 1), a mass loss of 10.3% was observed, while the mass change during desorption between 95%-0% RH (blue line; cycle 1 desorption) was about 6.3%.

[0640] The mass of the samples remained (FIG. 40B) around 1.2% between 40%-80% RH, and increased between 80%-95% RH to 2.4%. A total mass loss between 95%- 10% RH was observed of 2.4%. The water uptake between 0%-40% RH was reversible and at 40% RH the sample contains 0.7% of water. Based on the difference in mass between 40%-80% RH Tarl was considered non-hygroscopic.

[0641] The solid recovered after the DVS measurement was analyzed by HT-XRPD (FIG. 41). The pattern was very similar to Compound 1 Tarl before the DVS analysis, however a few additional peaks were observed. These additional peaks could have been due to traces of the Compound 1 zwitterion Form B, which would suggest that there was already (a trace of) free zwitterion present in the sample prior the DVS analysis, or that some dissociation of the salt occurred during the DVS analysis.Salt Experiment Example 12 - p-Toluenesulfonic Acid Salt

[0642] With p-toluenesulfonic acid, one potential salt form was observed, Compound 1 Tosl. The HT-XRPD pattern of the tosylate salt form is shown in FIG. 43, compared to the starting materials.

[0643] Compound 1 Tosl was physically stable upon exposure to AAC and a salt obtained from the experiment performed in IPA with 1.1 molar equivalent -tol ucncsul 1'on ic acid, and recrystallized from ethyl acetate.Salt Experiment Example 13 - Calcium Hydroxide Salt

[0644] A possible hit of salt formation was observed in the experiment performed in THF with 1.1 molar equivalent of calcium hydroxide after recrystallization in TBME. Besides the pattern of calcium hydroxide (CaO) additional peaks were observed, designated Cal. Upon exposure toAAC for two days the solid converted to calcium hydroxide, therefore salt formation was not confirmed. The pattern of the mixture of CaO+Cal is shown in FIG. 44.

[0645] From the solids identified from the salt experiment, characteristic data is summarized from the following salt experiments related to the salt forms described.Table 11A - Characteristic Salt Dataa according to single crystal data b confirmed by single crystal data“m” means melting in the Endothermic events“d” means decomposition in the Endothermic events“exo” means exothermic in the Endothermic eventsCOCRYSTAL EXAMPLESCocrystal with Compound 1 Free Base - General Procedures

[0646] Two different methods were used to generate cocrystals of Compound 1. In one method, a solvent based approach was used. In the other, sonication was used.

[0647] The general procedure of the solvent-based method is as follows. About 30 mg of a sample from Compound 1 Example 5 (also referred to herein as “starting material”) and 1.1 molar equivalent of the coformcr were weighed in 1.8 mL vials. 0.5 mL of the solvent was added to obtain a suspension. The mixture was cooled from 50°C to 5°C with a cooling rate of l°C / h and aged at 5°C for 3 days, while stirring. Solids were separated from the liquid phases bycentrifugation and analyzed by HT-XRPD as vacuum-dried solids (5 mbar at 50°C, up to 3 days).

[0648] The general procedure for the sonication method was as follows. About 30 mg of Compound 1 and 1.1 molar equivalent of the coformer were weighed into 1.8 mL glass vials. Drops of solvent were added until a pasty mixture was obtained. The vials were placed in a sonication bath at room temperature for 10 min. The obtained solids were dried under vacuum overnight at 50°C, harvested and analyzed by HT-XRPD.Cocrystal Example 1 - Sorbic acid cocrystal

[0649] A solvent-based approach was used to make a sorbic acid cocrystal referred to as Sori in acetonitrile as a solvent. FIG. 45 is an HR-XRPD pattern of Sori. FIG. 46 is a peak-picked XRPD pattern of Sori. Fig. 48 is a DSC thermogram of Sori (2.01 mg). FIG. 49 is an XRPD overlay of Sori, Compound 1, and sorbic acid.

[0650] Table 11B shows the picked peaks from FIG. 47ATable 11B - Picked peaks from FIG. 47A

[0651] By UPLC, the chemical purity of Sori was measured to be 97.7%. The Compound 1 peaks in!H-NMR spectrum of Sori were identical to those observed in the spectrum of the zwitterion of Compound 1 and 0.8 molar equivalent of sorbic acid was detected (at 1.8, 5.8, 6.3 and 7.3 ppm). No traces of solvent were detected. The TGMS analysis of Sori showed a minor mass loss of 0.4% between 25-110°C, due to residual moisture. A second mass loss was observed between 110-200°C is most likely due to the onset of degradation. The DSC trace ofthe Sori (FIG. 48) showed a melting event with an onset at about 130°C and a peat at about at about 132°C. The melting point of sorbic acid is about 135°C. Upon exposure to accelerated conditions of 40°C and 75% relative humidity for two days, the XRPD pattern showed evidence of both Sori and Compound 1.

[0652] A DVS measurement was carried out on Sori with a relative humidity profile 40-95-0- 40% at a constant temperature of 25 °C. The relative humidity (RH) was changed in steps of 10%, and equilibrium of 1 h per step. With a water uptake of 0.9% between 40-80% RH in the first sorption cycle, Sori is slightly hygroscopic.

[0653] A mass uptake of 7.9% was observed between 40-95% RH, although mass equilibrium was not reached at 90 and 95% RH. A total mass loss of 8.1% was observed during desorption from 95-0% RH. From 0-40% RH the mass uptake was 0.6%. The solid recovered after the DVS measurement was analyzed by XRPD which was the same as the pattern of the material before the analysis, confirming that Sori was physically stable during the DVS measurement.

[0654] The solubility of Sori at room temperature was measured to be 4.4 mg / mL.

[0655] The indexing of the HR-XRPD data revealed that Sori crystallizes in the centrosymmetric monoclinic P21 / n space group. Table 12 presents the unit cell parameters and final WPPD refinement parameters. The solid contained about 5% of a crystalline phase impurity.Table 12 - Crystal data and final refinement parameters for the HR-XRPD data Sori obtained in Cocrystal Example 1.

[0656] Table 13 shows 40 peaks associated with the indexing solution.Table 13 - Peak list for Sori from Cocrystal Example 1.Cocrystal Example 2 - Sorbic acid cocrystal

[0657] A sonication-based approach was used to make Sori with the solvent being isopropyl alcohol. FIG. 47 A is an HR-XRPD pattern of Sori. FIG. 47B is a DSC thermogram of Sori (1.58 mg). The indexing of the HR-XRPD data revealed that Sori crystallizes in the centrosymmetric monoclinic P21 / n space group. Table 14 shows the unit cell parameters and final WPPD refinement parameters. The solid contained about 5% of a crystalline phase impurity. Upon exposure to accelerated conditions of 40°C and 75%relative humidity for two days (AAC), the XRPD pattern remained that of Sori.

[0658] The TGMS analysis of Sori showed a small mass loss of 1.2% between 25-110°C, due to residual moisture or solvent. The onset of degradation starts upon melting of the solid. The DSC trace of the Sori (FIG. 47B) showed a melting event with an onset of about 132C and a peak at about 134°C. Also, a small endothermic event at peak at about 98°C is observed, due to the mass loss observed by TGMS analysis.Table 14 - Crystal data and final refinement parameters for the HR-XRPD data Sori obtained in Cocrystal Example 2.

[0659] Table 15 shows 40 diffraction peaks for Sori obtained from Cocrystal Example 2.Table 15 - Peak list for Sori in Cocrystal Example 2Cocrystal Example 3 - Cinnamic acid cocrystal

[0660] A sonication based approach was used to make a cocrystal of Compound 1 and cinnamic acid referred to as Cinl. The solvent used was 1,2-dimethoxyethane. FIG. 50 is an HR-XPRD pattern of Cinl. FIG. 51 is a peak-picked XRPD pattern of Cinl. Fig. 52 is a DSC thermogram of Cinl (1.37 mg). FIG. 53 is an overlay of XPRD patterns of Cinl, Compound 1, and cinnamic acid.

[0661] Cinl was found to be physically stable after two days at AAC by XRPD. The indexing of the HR-XRPD data revealed that Cinl crystallizes in the centrosymmetric monoclinic P21 / c space group. Table 16 shows the unit cell parameters and final WPPD refinement parameters. The solid contained about 2% of crystalline phase impurities. Table 17 shows 40 diffraction peaks for the HR-XRPD pattern of Cinl. The solubility of Cinl was measured to be less than 2.3 mg / mL at room temperature.Table 16. Unit cell parameters of Cinl.Table 17. Diffraction peaks for the HR-XRPD pattern of Cinl.

[0662] In the UPLC chromatogram of Cinl the API peak appeared at 1.1 minutes with a chemical purity of 96.7% (area %). Cinnamic acid was detected at 0.9 min. The Compound 1 peaks in the 'H-NMR spectrum of Cinl resonated at the same frequencies as the zwitterion of Compound 1. The ratio of Compound l:cinnamic acid was determined as 1:1.4. Traces of DME were also detected. The TGMS analysis of Cinl showed a mass loss of 0.5% between 25-70°C, due to residual water. The mass loss of 1.4% between 70-150°C coincided with an endothermic event, most likely melting and the release of DME. The mass loss of 0.1 molar equivalent of DME was in agreement with the observation by ' H-NMR. The onset of degradation was most likely observed around 180°C. The DSC thermogram of the Cinl (FIG. 52) showed an endothermic event with an onset at about 95C and peat at about 101°C, most likely due to melting.

[0663] A DVS measurement was carried out on Cinl with a RH profile 40-95-0-40% at a constant temperature of 25°C. The relative humidity was changed in steps of 10%, and equilibrium of 1 h per step.

[0664] With a water uptake of 0.7% between 40-80% RH at 25°C, Cinl is slightly hygroscopic.

[0665] A sorption of 1.9% was observed between 40-95% RH and weight equilibration was reached at each RH level. A total mass loss of 2.9% was observed during desorption from 95-0% RH. During the second sorption from 0-40% RH, a mass uptake of 0.6% was observed. The solid recovered after the DVS measurement was analyzed by XRPD and was the same as the pattern of the solid before the measurement, confirming that Cinl was physically stable during the DVS analysis.Cocrystal Example 4 - Vanillin cocrystal

[0666] A sonication based approach was used to make a cocrystal of Compound 1 and vanillin referred to as Vanl. The solvent used was 1,2-dimethoxyethane. FIG. 54 is an HR-XPRDpattern of Van 1 . FIG. 55 is a peak-picked XRPD pattern of Vanl . Fig. 56 is a DSC thermogram of Vanl (1.72 mg). FIG. 57 is an overlay of XPRD patterns of Vanl, Compound 1, and vanillin.

[0667] Vanl was found to be stable under AAC as determined by HR-XRPD. The indexing of the HR-XRPD data revealed that Vanl crystallizes in the orthorhombic face centered system; based on the reflection conditions, the C2221 space group was proposed. Table 18 presents the unit cell parameters and final WPPD refinement parameters and Table 19 is a peak list of 40 diffraction peaks for Vanl. The solubility of Vanl was measured to be about 8 / 1 mg / mL.Table 18 - Crystal data and final refinement parameters for VanlTable 19 - Peak Table for Vanl

[0668] In the UPLC chromatogram of Van 1, the Compound 1 peak appeared at 1.1 minutes with a chemical purity of 99.1% (area %). Compound 1 peaks in the 'H-NMR spectrum of Vanl were the same as for the zwitterion of Compound 1. The ratio of Compound livanillin was determined as 1:1.3. About 0.1 molar equivalent of DME was detected. The TGMS analysis of Vanl showed a mass loss of 0.2% between 25-105°C, due to residual moisture. Degradation started most likely after melting, which was observed around 120°C in the DSC. The DSC thermogram of Vanl (FIG. 56) showed two small overlapping endotherm with peak temperatures at 76°C and 79°C. The endothermic event having an onset of about 112°C and a peak at about 125 °C was mostlikely due to melting, followed by decomposition. A DVS measurement was carried out on Vanl with a RH profile 40-95-0-40% at a constant temperature of 25°C. The relative humidity was changed in steps of 10%, and equilibrium of 1 h per step.

[0669] With a water uptake of 0.2% between 40-80% RH at 25°C, Vanl is non-hygroscopic. A water uptake of 0.5% was observed during the first sorption cycle from 40-95% RH and weight equilibration was reached at each RH level. During desorption a total mass loss of 0.9% was observed between 95-0% RH. The water uptake observed during the second sorption cycle from 0-40% RH was 0.1%. The solid recovered after the DVS measurement was analyzed by XRPD and was the same as the pattern of the solid before the measurement, confirming that Vanl was physically stable during the DVS analysis.Cocrystal Example 5 - Vanillin cocrystal

[0670] A sonication based approach was used to make a cocrystal of Compound 1 and vanillin referred to as Van2. The solvent used was dioxane. FIG. 58 is an HR-XPRD pattern of Van2. Fig. 59 is a DSC thermogram of Van2 (1.7 mg). FIG. 60 is an overlay of XPRD patterns of Vanl, Van2, Compound 1, and vanillin.

[0671] Under AAC conditions, Vanl was detected in the XRPD and the sample became brown. The solubility of Van2 was measured to be about 17.7 mg / mL at room temperature.

[0672] In the UPLC chromatogram of Van2 the API peak appeared at 1.1 minutes with a chemical purity of 98.3% (area %).The Compound 1 peaks in the ’ H-NMR spectrum of Van2 were the same as for the zwitterion of Compound 1. The ratio of Compound 1: vanillin was determined as 1 : 1.3. About 0.4 molar equivalent of 1 ,4-dioxane was detected. The TGMS analysis of Van2 showed a mass loss of 8.4% between 25-125°C due 1,4-dioxane. The mass loss of 0.4 molar equivalent of 1,4-dioxane was in agreement with the amount of solvent estimated by 'H-NMR, Degradation most likely occurred above 130°C. The DSC thermogram of Van2 (FIG. 59) showed a very small endothermic event at 76°C, an endothermic event at 89°C and a third endothermic event with an onset of about 113°C and a peak at about 121°C, due to the mass loss and melting of the solid. Degradation likely started after melting of the solid.Cocrystal Example 6 - adipic acid cocrystal

[0673] A sonication based approach was used to make a cocrystal of Compound 1 and adipic acid referred to as Adil. The solvent used was dioxane. FIG. 61 is an HR-XPRD pattern ofAdi 1 . Fig. 62 is a DSC thermogram of Adil (1 .34 mg). FIG. 63 is an overlay of XPRD patterns of Adil, Compound 1, and adipic acid. Under AAC conditions, Adi was unstable and became deliquescent. The solubility of Adil was measured to be about 56.4 mg / mL at room temperature.

[0674] The indexing of Adil revealed that it crystallizes in centrosymmetric monoclinic P21 / n space group. Table 20 presents the unit cell parameters and final WPPD refinement parameters and Table 21 is a peak list of 40 diffraction peaks. The solid contained about 6% of crystalline phase impurities.Table 20. Unit cell parameters of AdilTable 21. Diffraction peaks of Adil.

[0675] In the UPLC chromatogram of Adil, the Compound 1 peak appeared at 1.1 minutes with a chemical purity of 96.4% (area %). The Compound 1 peaks in the1H-NMR spectrum of Adil resonate at the same frequences as the zwitterion of Compound 1. Protons resonating at 2.2 and 1.0 ppm correspond to 1.4 molar equivalent of adipic acid. Traces of 1,4-dioxane were detected as well (0.05 equivalent / 1%). The TGMS analysis of Adil showed a mass loss of 0.7% between 25-110°C due to 1,4-dioxane. The mass loss of 1.2% between 110-200°C might be due to partial degradation. The mass loss due to 1,4-dioxane was comparable to the amount of solvent estimated by1H-NMR. The DSC thermogram of Adil (FIG. 62) showed a broad endothermic event between 75-116°C. The thermal event was possibly due to the dissociation of the cocrystal The thermal event above 210°C is most likely due to thermal degradation.

[0676] A DVS measurement was carried out on Adil with a RH profile 40-95-0-40% at a constant temperature of 25°C. The relative humidity was changed in steps of 10%, and equilibrium of 1 h per step. With a mass uptake of 5.0% between 40-80% RH at 25°C, Adil can be considered moderately hygroscopic. Although weight equilibrium was not reached after 1 hour, and therefore the solid maybe even more hygroscopic.

[0677] A mass increase of 18.2% was observed in the first sorption cycle from 40-95% RH. A total mass loss of 15.5% was observed during the desorption cycle from 95-0% RH. Weight equilibrium was not reached between 80-95% RH during the first sorption cycle and also during desorption weight equilibrium was not reached at any of the RH levels. Possibly, the solid already started to deliquesce at 80% RH during the first sorption cycle. The solid had become deliquescent during the measurement and no material could be retrieved for XRPD analysis.Cocrystal Example 7 - cholic acid cocrystal

[0678] A solvent-based approach was used to make a cocrystal of Compound 1 and cholic acid referred to as Choi. The solvent used was acetonitrile. FIG. 64 is an HR-XPRD pattern of Choi. Fig. 65 is a DSC thermogram of Choi (1.46 mg). FIG. 66 is an overlay of XPRD patterns of Choi, Compound 1, and cholic acid.

[0679] Upon exposure to AAC for two days, Choi was unstable and became deliquescent. The solubility of Choi was not measured.

[0680] In the UPLC chromatogram of Choi the Compound 1 peak appeared at 1.1 minutes with a chemical purity of 96.4% (area %). The protons of cholic acid were detected in theJH- NMR spectrum of Choi in the range of 1-4.3 ppm. Due to the complex spectrum, the ratio of Compound l:cholic acid was difficult to determine, but possibly 1:1. About 0.4 molar equivalent of acetonitrile (4%) was detected as well (2.07 ppm). The TGMS analysis of Choi showed a mass loss of 0.8% between 25-75°C, due to residual moisture and acetonitrile. A second mass loss of 1.3% was observed between 75-200°C due to acetonitrile. A total mass loss of 2.1% could correspond to 0.2 molar equivalent of acetonitrile.

[0681] The DSC trace of the Choi (FIG. 65) showed a series of five weak and broad endothermic events at peak temperatures of 67, 96, 129, 159 and 199°C. Decomposition was observed around 260°C. A DVS measurement was carried out on Choi with a RH profile 40-95- 0-40% at a constant temperature of 25°C. The relative humidity was changed in steps of 10%,and equilibrium of 1 h per step. With a water uptake of 6.4% between 40-80% RH at 25°C in the first sorption cycle, Choi is moderately hygroscopic.

[0682] In the first sorption cycle between 40 and 95% RH, a mass increase of 12.4% was observed. Weight equilibration was reached within one hour at the RH levels from 40-80% RH, but not at 90 and 95% RH. The desorption cycle showed a total mass loss of 7.8% from 95-0% RH, although no weight equilibrium was reached in any of the relative humidity stages. The mass change remained close to 0% during the second sorption between 0-40% RH. A large hysteresis was observed between 0-95% RH. The solid recovered after the DVS measurement was analyzed by XRPD and was different than Choi before the DVS analysis, indicating that Choi was physically unstable during the DVS analysis.Cocrystal Example 8 - t-butylhydroquinone cocrystal

[0683] A sonication based approach was used to make a cocrystal of Compound 1 and t- butylhydroquinone referred to as Tbhl. The solvent used was dioxane. FIG. 67 is an HR-XPRD pattern of Tbhl. Fig. 68 is a DSC thermogram of Tbhl (1.85 mg). FIG. 69 is an overlay of XPRD patterns of Tbhl, Compound 1, and t-butylhydroquinone. After two days of AAC, the crystalline pattern was still present, but the solid had partly deliquesced. The solubility in water was measured to be less than 2.3 mg / mL at room temperature.

[0684] In the UPLC chromatogram of Tbhl, the Compound 1 peak appeared at 1.1 minutes with a chemical purity of 91.6% (area %). Tert-Butylhydroquinone was detected at 1.6 min. The Compound 1 peaks in theXH-NMR spectrum of Tbhl resonated at the same frequencies as the zwitterion of Compound 1. Tert-Butylhydroquinone was detected at 6.6 and 6.4 ppm. Also 1.0 equivalent of 1,4-dioxane (20%) was detected.

[0685] The TGMS analysis of Tbhl showed a mass loss of 3.3% between 25-95°C due to 1,4- dioxane (0.2 mol equivalent). The mass loss occurred simultaneously with an endothermic event in the DSC signal (red line). According to the NMR spectrum the solid contained 1 mol equivalent of dioxane, hence the mass loss between 95-200°C is most likely also due to loss of dioxane. The DSC thermogram of Tbhl (FIG. 68) showed an endothermic event at onset of about 68°C and a peak at about 81 °C, most likely due to melting, followed by further evaporation of the 1,4-dioxane and the start of degradation. A DVS measurement was carried out on Tbhl with a RH profile 40-95-0-40% at a constant temperature of 25°C. The relativeIl lhumidity was changed in steps of 10%, and equilibrium of 1 h per step. With a water uptake of 0.6% between 40-80% RH at 25°C, Tbhl is slightly hygroscopic.

[0686] During the first sorption cycle from 40-95% an increase in mass was observed of 0.9%. During the desorption cycle from 95-0% RH, a total mass loss of 5.3% was observed. During the second sorption cycle from 0-40% RH the mass change remained around 0%.

[0687] During the desorption cycle no weight equilibration was achieved at any of the RH levels and a large hysteresis was observed between 0-95% RH. The solid recovered after the DVS measurement was analyzed by XRPD and appeared to be different than the pattern of the solid before the DVS analysis.Cocrystal Example 9 - benzoic acid cocrystal

[0688] A solvent-based approach was used to make a cocrystal of Compound 1 and benzoic acid referred to as Beni . The solvent used was isopropyl alcohol. FIG. 70 is an overlay of XRPD patterns of Beni, Compound 1, and benzoic acid. FIG. 71 is a DSC thermogram of Beni (1.27 mg). Beni was physically unstable after AAC for two days and became deliquescent. The solubility of Beni was measured to be 7.1 mg / mL in water at room temperature

[0689] The1H-NMR spectrum confirmed the chemical integrity of Compound 1, with peak positions identical to the zwitterion of Compound 1. The 5 benzoic acid protons resonate in the aromatic region between 7.4 and 8.0 ppm, confirming the stoichiometric ratio of Compound hbenzoic acid of 1:0.5. Also 0.5 molar equivalent of IPA was detected.

[0690] In the UPLC chromatogram of Beni, the Compound 1 peak appeared at 1.1 min. The chemical purity of the salt was 91.5% (area %).The TGMS analysis of Beni showed a mass loss of 0.2% between 25-70°C, due to residual moisture. A mass loss of 4.9% was observed between 70-165°C due to IPA (0.4 molar equivalent). Thermal decomposition most likely started above 165°C. The DSC thermogram of Beni (FIG. 71) two overlapping endotherms with peak temperatures at 93 and 103°C and a broader endotherm with a peak temperature at 130°C, possibly due to melting and / or dissociation of the solid. Thermal degradation was observed above 200°C.Cocrystal Example 10 - benzoic acid cocrystal

[0691] A solvent-based approach was used to try to make a cocrystal of Compound 1 and benzoic acid referred to as Bcn2. The solvent used was acetonitrile. FIG. 72 is an overlay of XRPD patterns of Ben2, Compound 1, and benzoic acid. Ben2 was physically unstable upon exposure to AAC for two days and turned into a brownish oil. The solubility of Ben2 was not measured.

[0692] In the UPLC chromatogram of Ben2, the Compound 1 peak appeared at 1.1 minutes with a purity 96.3% (area %). The ' H-NMR spectrum of Ben2 confirmed the integrity of Compound 1, however only 0.1 molar equivalent of benzoic acid was detected (between 7.4 and 8.0 ppm), suggesting that Ben2 is not a cocrystal of Compound 1. Traces of ACN were observed at 2.1 ppm (~0.1 molar equivalent).Cocrystal Example 11 - 4-aminobenzoic acid cocrystal

[0693] A sonication based approach was used to make a cocrystal of Compound 1 and 4- aminobenzoic acid referred to as Abai. The solvent used was 1,2-dimethoxyethane. FIG. 73 is an HR-XPRD pattern of Abai. Fig. 74 is a DSC thermogram of Abai (1.4 mg). Abai was physically unstable upon exposure to AAC for two days and became deliquescent. Abai was measured to have a solubility of 23.4 mg / mL in water at room temperature.

[0694] In the UPLC chromatogram of Abai the Compound 1 peak appeared at 1.1 minutes with a chemical purity of 92.9% (area %). The peak for 4-aminobenzoic acid was observed at 0.2 min. The chemical shifts of Compound 1 in Abai in the ’ H-NMR spectrum were the same as the zwitterion of Compound 1, and 1.3 molar equivalent of 4-aminobenzoic acid was detected (7.6, 6.5, 5.9 ppm). Also 1 molar equivalent of DME was detected. The TGMS analysis of Abai showed a mass loss of 2.0% between 25-90°C, due to DME (0.1 mol equivalent). The continuous mass loss of 8.5% between 90-200°C was most likely also due to DME, as 1 molar equivalent was detected by ’H-NMR. The mass loss observed in the TGMS analysis was somewhat lower than in the NMR spectrum. The DSC thermogram of Abai (FIG. 74) showed an endothermic event with a peak temperature at 70°C, most likely due to melting.Cocrystal Example 12 - 4-aminobenzoic acid cocrystal

[0695] A sonication based approach was used to make a cocrystal of Compound 1 and 4- aminobenzoic acid referred to as Aba2. The solvent used was isopropyl alcohol. FIG. 75 is an HR-XPRD pattern of Aba2. Fig. 76 is a DSC thermogram of Aba2 (1.5 mg). Aba2 wasphysically unstable upon exposure to AAC for two days and became deliquescent. Aba2 was measured to have a solubility of 23.4 mg / mL in water at room temperature.

[0696] In the UPLC chromatogram of Aba2 the Compound 1 peak appeared at 1.1 minutes with a chemical purity of 97.3% (area %). The peak for 4-aminobenzoic acid was observed at 0.2 min. The chemical shifts of the1H-NMR spectrum of Compound Iwere the same as the zwitterion of Compound 1, and 1.4 molar equivalent of 4-aminobenzoic acid was detected (7.6, 6.5, 5.9 ppm). Approximately 1 molar equivalent of 1PA was detected. The TGMS analysis of Aba2 showed a mass loss of about 0.3% between 25-65°C, due to residual water. The continuous mass loss observe between 65-200°C was mostly related to IPA. The DSC thermogram of Aba2 (FIG. 76) showed a sharp endothermic events having an onset at about 77°C and a peak at about 83°C, most likely due to melting.Cocrystal Example 13 - 4-aminobenzoic acid cocrystal

[0697] A sonication based approach was used to make a cocrystal of Compound 1 and 4- aminobenzoic acid referred to as Aba3. The solvent used was dioxane. Fig. 77 is a DSC thermogram of Aba3 (1.24 mg). FIG. 78 is an XRPD overlay of Abai, Aba2, Aba3, Compound 1, and 4-aminobenzoic acid. Aba3 was physically unstable upon exposure to AAC for two days and became deliquescent. Aba3 was measured to have a solubility of 15.7 mg / mL in water at room temperature.

[0698] In the UPLC chromatogram of Aba3 the Compound 1 peak appeared at 1.1 minutes with a chemical purity of 96.0% (area %). The peak for 4-aminobenzoic acid was observed at 0.2 min. The chemical shifts of the 1 H-NMR spectrum of Compound 1 were the same as the zwitterion of Compound 1, and 1.5 molar equivalent of 4-aminobenzoic acid was detected (7.6, 6.5, 5.9 ppm). Approximately 0.5 molar equivalent of 1,4-dioxane was detected. The TGMS analysis of Aba3 showed a mass loss of 2.7% between 25-110°C due to 1,4-dioxane. The mass loss between 110- 200°C was also related to 1,4-dioxane.Potential Cocrystal Example 14 - malic acid cocrystal

[0699] A solvent-based approach was used to make a crystalline form of Compound 1 and malic acid referred to as Mall. Mall could be a mono-malate salt because the Compound 1 NMR peaks were at positions more similar to the HC1 salt than the free base. The solvent used was tetrahydrofuran. FIG. 79 is an HR- XRPD patterns of Mall. FIG. 80 is a DSC thermogram ofMai 1 (1 .27 mg). FIG. 81 is an XRPD overlay of Mall , malic acid, and Compound 1. Mall was physically unstable upon exposure to AAC and became an amorphous oily material. The solubility of Mall was measured to be about 2.2 mg / mL.

[0700] The indexing of the HR-XRPD data revealed that Mall crystallizes in the chiral monoclinic P21 space group. Table 22 presents the unit cell parameters and final WPPD refinement parameters, and Table 23 is a peak list of 40 diffraction peaks. The solid obtained from Exp. ID SON 16 appeared to be phase pure. Any impurities were below detection limit.Table 22. Unit cell parameters of Mall.Table 23. Diffraction peaks of Mall.

[0701] In the UPLC chromatogram of Mall the Compound 1 peak appeared at 1.1 minutes with a chemical purity of 98.0% (area %). The1H-NMR spectrum of Mall showed some shifts compared to the zwitterion of Compound 1 resonances, and was more similar to the spectrum of the HC1 salt of Compound 1. The Compound limalic acid ratio was determined as 1:1. Possibly, Mall is a malate salt of Compound 1. No solvents were detected in the spectrum.

[0702] The TGMS analysis of Mall showed a mass loss of 0.8% between 25-150°C, due to residual water and THF. Decomposition started around 150°C. The DSC thermogram of the Mall showed an endothermic event having an onset of about 109°C and a peak at about 115°C, most likely due to melting. The thermal events above 140°C most likely are due to thermal decomposition. A DVS measurement was carried out on Mall with a RH profile 40-95-0-40% ata constant temperature of 25°C. The relative humidity was changed in steps of 10%, and equilibrium of 1 h per step.

[0703] With a mass uptake of 1.0% between 40-80% RH at 25°C, the material can be considered slightly hygroscopic. In the first sorption cycle between 40 and 95% RH, a mass increase of 7.2% was observed, while the mass change during desorption between 95 - 0% RH was about 7.6%. In the second sorption cycle from 0-40% the water uptake was 0.2%. The solid had become deliquescent during the DVS analysis and got stuck to the sample holder, therefore the material could not be retrieved for XRPD analysis afterwards.Cocrystal with Compound 1 HC1 - General Procedures

[0704] Two different methods were used to generate cocrystals of Compound 1. In one method, a solvent based approach was used. In the other, sonication was used.

[0705] The general procedure of the solvent-based method is as follows. Stock solutions of API were prepared by adding solvent to the appropriate amount of API. The coformers were weighed into 1.8 mL vials and the Compound 1 HC1 stock solutions were added reaching a Compound 1 HCl / Coformer ratio of 1:1.1. On of three selected solvent mixtures was used: ethanol, acetonitrile / methanol 80 / 20 (v / v%) and tetrahydrofuran / water 85 / 15 (v / v%).

[0706] Mixtures were cooled from 50°C to 5°C with a cooling rate of l°C / h and aged at 5 °C for 3 days, while stirring. Solids were separated from the liquid phases by centrifugation and analyzed by HT-XRPD as vacuum-dried solids (5 mbar at 50°C, up to 3 days).

[0707] All solids were exposed to accelerated aging conditions (AAC, 40°C / 75% RH) for 2 days and re-measured by HT-XRPD to test their physical stability.

[0708] The general procedure for the sonication method was as follows. About 30 mg of Compound 1 and 1.1 molar equivalent of the coformer were weighed into 1.8 mL glass vials. Drops of solvent were added until a pasty mixture was obtained. The vials were placed in a sonication bath at room temperature for 10 min. The obtained solids were dried under vacuum overnight at 50°C, harvested and analyzed by HT-XRPD.

[0709] In the sonication approach, crystallization was performed on a freeze dried mixture of Compound 1 HCkCoformer with a ratio of 1:1.1. The coformers were weighed into 1.8 mL glass vials and a stock solution of Compound 1 HC1 in THF / water 10 / 90 (v / v%) was added. Thesolutions were frozen in liquid nitrogen and dried in a freeze-dryer (Christ, Alpha 2-4 LD) overnight to obtain a homogenous mixture of Compound 1 HCkCoformcr.

[0710] A drop of 20 p.L of solvent was added to the freeze dried mixture. The vials were placed in a sonication bath at Room temperature for 10 min.

[0711] The obtained solids were dried under vacuum overnight at 50°C, harvested and analyzed by HT-XRPD. Subsequently, all the solids in the plates were exposed to AAC (40°C / 75% RH) for 2 days and re-analyzed by HT-XRPD.

[0712] In some cases, as indicated, HR-XRPD data were collected.Cocrystal Example 15 - cholic acid cocrystal

[0713] A solvent-based method was used to make a cocrystal of cholic acid and Compound 1 HC1 referred to as Choi. The solvent used was acetonitrile / methanol 80 / 20 (v / v%). FIG. 82 is an HR-XRPD diffractogram of Choi. FIG. 83 is a DSC thermogram of Choi (1.13 mg).

[0714] The H-NMR spectrum of Choi showed Compound 1 HC1 peaks similar to the Compound 1 HC1 starting material. Cholic acid shows a complex spectrum, the ratio of Compound l::cholic acid is possibly 1:1. No solvent peaks were detected in the spectrum. The TGMS analysis of Choi showed a mass loss of 1.3% between 25-200°C, due to residual moisture and traces of solvent. No degradation was observed below 200°C. The DSC thermogram of Choi (FIG. 83) showed an exothermic event with a peak at about 145°C, a sharp endothermic event with an onset of about 162°C and a peak at about 166°C, followed by three overlapping endothermic events between 170-190°C. No mass loss occurred during any of these events, therefore they are possibly due to a solid phase transition and melting. Degradation most likely started around 200°C. Upon exposure to AAC, a new crystalline form, Cho2 was observed (FIG. 84). FIG. 84 is an x-ray powder diffraction pattern of Cho2. FIG. 85 is an overlay of Choi, Cho2, cholic acid, and Compound 1 HC1.Cocrystal Example 16 - 2,4-Dihydroxybenzoic acid cocrystal

[0715] A sonication-based approach was used to make a cocrystal of Compound 1 HC1 and 2,4- dihydrozybenzoic acid, referred to here as Dhbal. Dioaxne was used as a solvent. Dhbal was isolated as a sticky solid. Upon exposure to AAC, Dhba2 formed. Dhba2 was formed again from Dhbal made from DME in a sonication-based method. An HR-XRPD pattern was takenfrom that sample and is set forth in FIG. 86. A peak-picked HR-XRPD pattern is set forth in FIG. 87. A DSC thermogram of Dhba2 is set forth in FIG. 88 (1.58 mg).

[0716] Table 23A sets forth peaks picked from FIG. 87.Table 23A - Peaks picked from FIG. 87.

[0717] A solvent-based approach resulted in a cocrystal identified as Dhba3 in combination with Compound 1 HC1 with ethanol as the solvent and upon AAC, the solid converted to a mixture of Dhba2, DhbaO and Compound 1 HC1.

[0718] FIG. 89 is an XRPD overlay of Dhba3 / Compound 1 HC1, Dhba2, Dhbal, 2,4- dihydroxy benzoic acid, and Compound 1 HC1.

[0719] The API peaks in the H-NMR spectrum of Dhba2 were similar to Compound 1 HO. The protons of 2,4-dihydroxybenzoic acid were detected in the aromatic region and indicated a ratio of Compound l;Dhba of 1:1.0. No solvent traces were detected. In the UPLC chromatogram of Dhba2 the Compound 1 HC1 peak appeared at 1.12 minutes with a chemical purity of 99.4% (area %). 2,4-dihydroxybenzoic acid was observed at 0.26 min. The TGMS analysis of Dhba2 showed a mass loss of 1.2% between 25-130°C due to water (0.3 molar equivalent), and a second mass loss of 11 .2% between 130-200°C, overlapping with the onset of degradation. The DSC thermogram of Dhba2 (FIG. 88) showed an endothermic event with an onset at about 116°C and a peak at about 123°C, possibly due to melting. The broad endothermic event between 60-90°C is due to the mass loss observed in the TGMS analysis.

[0720] While aspects of this disclosure have been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the scope of the disclosure.

[0721] Accordingly, the preceding illustrates the principles of the disclosure. It will be appreciated that those skilled in the ail will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the disclosure and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the disclosure and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the disclosure as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure.

[0722] In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.

[0723] All references, issued patents, and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes. Particularly, US 11,292,765 B2, US 63 / 674,233, US 63 / 796,103, PCT / CA2021 / 050907, PCT / CA2022 / 0 1797, and PCT / CA2024 / 050007.

Claims

WHAT IS CLAIMED IS:

1. An isopropyl alcohol solvate of Compound 1:

2. The mono isopropyl alcohol solvate of the Compound 1 of claim 1.

3. The 1.5 isopropyl alcohol solvate of the Compound 1 of claim 1.

4. A salt of Compound 1 other than an HC1 salt.

5. The solid salt of the Compound 1 of claim 4.

6. The salt of claims 5 or 6, wherein the salt is an organic salt.

7. The organic salt of claim 6, wherein the organic salt is in crystalline form.

8. The organic salt of claims 6 or 7, wherein the organic salt is a benzenesulfonic acid salt, a p- toluenesulfonic acid salt, a 1,2-ethanedisulfonic acid salt, a gentisic acid salt, a salicylic acid salt, an oxalic acid salt, a malonic acid salt, a tartaric acid salt, or a maleic acid salt.

9. The salt of claims 4 or 5 wherein the salt is an inorganic salt.

10. The salt of claim 9, wherein the salt is a crystalline inorganic salt.

11. The salt of claims 9 or 10, wherein the inorganic salt is an HBr salt, a calcium salt, a phosphoric acid salt, or a sulfuric acid salt.

12. A cocrystal of Compound 1:

13. The cocrystal of the Compound 1 of claim 12 wherein the coformer is an organic coformer.

14. The cocrystal of the Compound 1 of claim 13 wherein the organic coformer is selected from selected from benzoic acid, 4- aminobenzoic acid, cinnamic acid, cholic acid, adipic acid, sorbic acid, t-butylhydroquinone, or vanillin.

15. A cocrystal of Compound 1 HC1 and a coformer.

16. The cocrystal of the Compound 1 HC1 of claim 15, wherein the coformer is an organic coformer.

17. The cocrystal of the Compound 1 HC1 of claims 15 or 16, wherein the organic coformer is cholic acid or 2,4-dihydroxybenzoic acid.

18. Crystalline Compound 1 malic acid.

19. Amorphous Compound 1 HC1.

20. A pharmaceutical composition comprising the solvate of any one of claims 1 to 3, the salt of any one of claims 4 to 11, the cocrystal of any one of claims 12 to 17, the crystalline compound of claim 18, or the amorphous compound of claim 19, and one or more pharmaceutically acceptable excipients.21 . A pharmaceutical composition prepared from the solvate of any one of claims 1 to 3, the salt of any one of claims 4 to 11, the cocrystal of any one of claims 12 to 17, the crystalline compound of claim 18, or the amorphous compound of claim 19.

22. A kit comprising the solvate of any one of claims 1 to 3, the salt of any one of claims 4 to 11, the cocrystal of any one of claims 12 to 17, the crystalline compound of claim 18, or the amorphous compound of claim 19, and one or more pharmaceutically acceptable excipients.

23. A method of treating a disease or disorder, the method comprising administering to a subject of the solvate of any one of claims 1 to 3, the salt of any one of claims 4 to 11, the cocrystal of any one of claims 12 to 17, the crystalline compound of claim 18, or the amorphous compound of claim 19, or a pharmaceutical composition of claim 20 or a kit of claim 21.

24. The method of claim 23, wherein the disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression (PPD), drug-resistant depression, treatment-resistant depression (TRD), alcoholism, tobaccoaddiction, cocaine addiction, opioid dependence, inflammation (e.g., neuroinflammation), cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), adjustment disorder, and post-traumatic stress disorder (PTSD).

25. The method of claim 24, wherein the disease or disorder is selected from depression, MDD, PPD, drug-resistant depression, and treatment-resistant depression (TRD).

26. The method of claim 25, wherein the disease or disorder is PPD.

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