Formulations and methods of use of psilocybin analogs

Abstract

The present disclosure relates to pharmaceutical compositions formulated with psilocin and / or deuterated psilocin compounds, or pharma- ceutically acceptable salts, polymorphs, stereoisomers, or solvates thereof, and organic acid agents as pharma-ceutically acceptable vehicles. Use in the treatment of diseases, such as diseases associated with the 5-HT2 receptor, is also disclosed. [Formula 1] JPEG2024540282000088.jpg4672

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 276,117, filed November 5, 2021, and Patent Cooperation Treaty Application No. PCT / EP / 2022 / 056991, filed March 17, 2022, each of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates generally to psilocin compounds and their pharmaceutically acceptable salts, polymorphs, stereoisomers, or solvates, compositions, and in some embodiments, to serotonin 5-HT2 receptor agonists and their use in treating diseases associated with the 5-HT2 receptor. [Background technology]

[0003] Psilocybin (PY) and psilocin (PI) are tryptamine alkaloids and structural analogs of the neurotransmitter serotonin. Psilocybin is a prodrug of psilocin; that is, when consumed, psilocybin is rapidly metabolized to its active form, psilocin (4-hydroxy-N,N-dimethyltryptamine). Specifically, a chemical process called dephosphorylation removes the phosphate group on psilocybin, producing psilocin. [ka]

[0004] In vitro, psilocin has been reported to be a short-lived and unstable molecule. For this reason, psilocin has been little studied and is not generally recognized as a viable therapeutic option. Vaupel et al. investigated the effects of psilocin ascorbate on food intake in dogs (D.B. Vaupel, M. Nozaki, W.R. Martin, L.D.Bright, E.C. Morton, "The inhibition of food intake in the dog by LSD, mescaline, psilocin, d-amphetamine, and phenylisopropylamine derivatives," Life Sciences, Volume 24, Issue 26, 1979, pp. 2427-2431).

[0005] Migliaccio et al. studied the solution structure of psilocin monooxalate in water (Gerald P. Migliaccio, Tiee-Leou N. Shieh, Stephen R. Byrn, Bruce A. Hathaway, and David E. Nichols, Comparison of solution conformational preferences for the hallucinogens bufotenin and psilocin using 360-MHz proton NMR spectroscopy, Journal of Medicinal Chemistry, 1981 24, 2, 206-209).

[0006] Aghajanian et al. used microiontophoresis to study the effects of psilocin tartrate on serotonergic neurons in rats (Aghajanian GK, Hailgler HJ. Hallucinogenic indoleamines: Preferential action upon presynaptic serotonin receptors. Psychopharmacol Commun. 1975, 1, 6, 619-29).

[0007] Kuhnert-Brandstatter et al. reported the preparation of three polymorphs of psilocycin (Kuhnert, M. et al., Polymorphic Modifications and Solvates of Psilocin and Psilocybin, 1976, Archive der Pharmazie, 309:625-631).

[0008] US Patent No. 11,312,684 B1 describes syrosin salts with improved physical properties and handling.

[0009] Therefore, therapeutic applications involving the use of psilocin have generally been achieved through the administration of precursors, psilocybin, or other prodrug approaches. However, psilocybin has a slow onset of action and a prolonged duration of drug action, often requiring 7–8 hours of monitored clinical observation before the patient is discharged. Because psilocybin must be metabolized to release the active form, there is also a high level of variability during delivery. Therefore, a need exists for a stabilized psilocin that does not rely on prodrug degradation to deliver the pharmacologically active drug, has less variability in drug exposure, and has a faster / faster onset of therapeutic action and a shorter duration of drug action (i.e., shorter duration of therapeutic effect) than psilocybin. Summary of the Invention

[0010] The present disclosure is based, at least in part, on the identification of novel stable forms of psilocin and deuterated psilocin, including novel polymorphs of psilocin / deuterated psilocin, novel salt forms of psilocin / deuterated psilocin, and polymorphs thereof, that provide a fast therapeutic onset, a short duration of drug action, and low variability in drug exposure (e.g., compared to psilocybin and other prodrug approaches), as well as compositions thereof and methods of using the same to treat diseases associated with the serotonin 5-HT2 receptor. More specifically, the present disclosure provides a novel method for treating diseases associated with the 5-HT2 receptor, e.g., without hallucinogenic side effects, and for treating serotonin-related disorders. 2A Provided are stabilized forms of psilocin and deuterated psilocin, and compositions thereof, that can be used to treat neuropsychiatric disorders, central nervous system (CNS) disorders, and other disorders, such as those associated with inflammation, through various dosing regimens (e.g., single, once-daily, once-weekly sub-psychedelic dosing, etc.) to selectively engage R.

[0011] The disclosed stabilized forms of psilocin and deuterated psilocin do not rely on prodrug metabolism for release of the active drug, as is the case with psilocybin administration or related prodrug approaches, and therefore may provide a fast / rapid therapeutic onset, a short duration of drug action (i.e., a short duration of therapeutic effect), and low subject-to-subject variability. Instead, the inventors have identified dosage forms that provide rapid release of stabilized forms of psilocin and deuterated psilocin with fast and reliable onset characteristics, including oral dosage forms that allow for pre-gastric absorption, e.g., by administering the compounds herein through the mucosal lining of the oral cavity.

[0012] Thus, the present disclosure provides: (1) A pharmaceutical composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and a pharmaceutically acceptable vehicle comprising an organic acid agent, [ka] During the ceremony, R2, R5, R6, and R7 are independently selected from the group consisting of hydrogen and deuterium; R8 and R9 are independently -CH 3- , -CH2D -、 -CHD 2- -CD3, and -CD4; A pharmaceutical composition wherein X1, X2, Y1, and Y2 are independently selected from the group consisting of hydrogen and deuterium.

[0013] (2) The pharmaceutical composition according to (1), wherein R2, R5, R6, and R7 are hydrogen.

[0014] (3) The pharmaceutical composition according to (1), wherein at least one of R2, R5, R6, and R7 is deuterium.

[0015] (4) The pharmaceutical composition according to any one of (1) to (3), wherein R8 and R9 are -CH3.

[0016] (5) The pharmaceutical composition according to any one of (1) to (3), wherein R8 and R9 are -CD3.

[0017] (6) The pharmaceutical composition according to any one of (1) to (5), wherein X1, X2, Y1, and Y2 are deuterium.

[0018] (7) The pharmaceutical composition according to any one of (1) to (6), wherein X1 and X2 are deuterium.

[0019] (8) The pharmaceutical composition according to any one of (1) to (7), wherein Y1 and Y2 are deuterium.

[0020] (9) The pharmaceutical composition according to any one of (1) to (5) or (7), wherein Y1 and Y2 are hydrogen.

[0021] (10) The compound of formula (I) [ka] or at least one selected from the group consisting of a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof.

[0022] (11) The compound of formula (I) [ka] or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof.

[0023] (12) The compound of formula (I) [ka] or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof.

[0024] (13) The compound of formula (I) [ka] or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof.

[0025] (14) The pharmaceutical composition according to (11), wherein the compound of formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3) as determined by X-ray powder diffraction.

[0026] (15) The crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3) was measured at 7.582°, 8.395°, 9.647°, 10.444°, 11.319°, 12.614°, 13.372°, 14.222°, 15.157°, 16.524°, 16.787°, 17.693°, 19.468°, 19.699°, 20.901°, 21.132°, 21.859°, 22.547°, 23.699°, 24.630°, 25.034°. 20. The pharmaceutical composition according to claim 14, characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 25.264°, 26.867°, 27.399°, 27.929°, 28.219°, 28.871°, 29.430°, 30.120°, 30.675°, 31.373°, 32.365°, 33.880°, 34.418°, 34.792°, 35.884°, 36.254°, 37.156°, 38.200°, and 38.417°.

[0027] (16) The crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3) was observed at 8.124°, 8.357°, 10.059°, 12.630°, 13.420°, 13.743°, 14.053°, 15.220°, 16.272°, 16.763°, 16.954°, 17.328°, 17.662°, 18.062°, 18.742°, 19.413°, 19.658°, 20.172°, 20.836°, 21.267°, 22.062°, 23.062°, 24.062°, 25.062°, 26.062°, 27.062°, 28.062°, 29.062°, 30.062°, 31.062°, 32.062°, 33.062°, 34.062°, 35.062°, 36.062°, 37.062°, 38.062°, 39.062°, 40.062°, 41.062°, 42.062°, 43.062°, 44.062°, 45.062°, 46.062°, 47.062°, 48.062°, 49.062°, 50.062°, 51.062°, 52.062 The pharmaceutical composition according to (14), characterized by an X-ray powder diffraction pattern including at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 1.833°, 22.213°, 22.504°, 23.334°, 23.701°, 24.385°, 25.431°, 25.721°, 26.049°, 27.291°, 28.368°, 30.349°, 30.656°, 31.337°, 31.538°, 32.091°, 35.870°, 38.514°, and 41.361°.

[0028] (17) The pharmaceutical composition according to (13), wherein the compound of formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7) as determined by X-ray powder diffraction.

[0029] (18) The crystalline form of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7) was measured at 7.563°, 8.375°, 12.626°, 13.383°, 15.211°, 16.753°, 17.671°, 19.668°, 21.112°, 21.863°, 22.201°, 22.560°, 23.711°, 24.592°, 25.415°. The pharmaceutical composition according to (17), characterized by an X-ray powder diffraction pattern including at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 26.820°, 27.357°, 27.921°, 28.228°, 29.253°, 30.653°, 31.364°, 32.401°, 33.797°, 34.445°, and 39.867°.

[0030] (19) The pharmaceutical composition according to any one of (1) to (13), wherein the compound of formula (I) is amorphous as determined by X-ray powder diffraction.

[0031] (20) The pharmaceutical composition according to (19), wherein the compound of formula (I) is amorphous as determined by X-ray powder diffraction and has a glass transition point of about 26°C to about 30°C as determined by differential scanning calorimetry (DSC).

[0032] (21) The pharmaceutical composition according to (19) or (20), wherein the amorphous form of the compound of formula (I) is prepared by melting a crystalline form of the compound of formula (I) above the melting point of the crystalline form, followed by rapid cooling to the glass transition temperature.

[0033] (22) The pharmaceutical composition according to any one of (19) to (21), wherein the compound of formula (I) is in the amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3) as determined by X-ray powder diffraction.

[0034] (23) The pharmaceutical composition according to any one of (19) to (21), wherein the compound of formula (I) is in the amorphous form of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7) as determined by X-ray powder diffraction.

[0035] (24) The pharmaceutical composition according to any one of (1) to (13), wherein the compound of formula (I) is present as a pharmaceutically acceptable salt of the compound of formula (I).

[0036] (25) The pharmaceutical composition according to (24), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, hemimalonate, fumarate, hemisuccinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, methanesulfonate, toluenesulfonate, glucuronate, or glutarate salt of the compound of formula (I).

[0037] (26) The pharmaceutical composition according to (24) or (25), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, hemimalonate, fumarate, hemisuccinate, oxalate, benzoate, or salicylate of the compound of formula (I).

[0038] (27) The pharmaceutical composition according to any one of (24) to (26), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a benzenesulfonate salt of the compound of formula (I).

[0039] (28) The pharmaceutical composition according to (27), wherein the benzenesulfonate salt of the compound of formula (I) is benzenesulfonate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3a).

[0040] (29) The benzenesulfonate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3a) was crystalline and showed the following peaks: 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 19.503°, 20.760°, 21.070°, 22.007°, 22.745°. , 23.340°, 24.187°, 25.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988° (2θ±0.2°).

[0041] (30) The pharmaceutical composition according to (27), wherein the benzenesulfonate salt of the compound of formula (I) is benzenesulfonate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7a).

[0042] (31) The benzenesulfonate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7a) was crystalline and showed the following peak positions: 7.002°, 7.733°, 11.768°, 12.516°, 12.882°, 13.546°, 13.968°, 14.788°, 15.225°, 15.474°, 18.370°, 19.737°, 20.703°, 21.050°, 21.873°, 21.982°, 22.315°, 22.639°, 23. 30. The pharmaceutical composition according to claim 30, characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 282°, 23.775°, 24.125°, 25.193°, 25.475°, 25.931°, 26.813°, 27.778°, 28.127°, 30.866°, 31.207°, 32.941°, 33.222°, 33.698°, 36.803°, 38.668°, and 39.289°.

[0043] (32) The pharmaceutical composition according to any one of (24) to (26), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a tartrate of the compound of formula (I).

[0044] (33) The pharmaceutical composition according to (32), wherein the tartrate salt of the compound of formula (I) is the tartrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3b).

[0045] (34) The tartrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3b) was crystalline and showed the following peak positions: 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 28.060°, 29.060°, 30.060°, 31.060°, 32.060°, 33.060°, 34.060°, 35.060°, 36.060°, 37.060°, 38.060°, 39.060°, 40.060°, 41.060°, 42.060°, 43.060°, 44.060°, 45.060°, 46.060°, 47.060°, 48.060°, 49.060°, 50.060°, 51.060°, 52.060°, 53.060°, 54.060°, 55.060°, 56.060°, 57.0 33. The pharmaceutical composition according to claim 33, characterized by an X-ray powder diffraction pattern including at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 7.502°, 28.179°, 28.597°, 29.035°, 29.257°, ​​29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049°.

[0046] (35) The pharmaceutical composition according to (32), wherein the tartrate salt of the compound of formula (I) is the tartrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7b).

[0047] (36) The tartrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7b) was crystalline and showed the following peaks: 6.798°, 11.360°, 12.764°, 13.535°, 14.837°, 15.973°, 16.351°, 17.367°, 18.937°, 20.168°, 20.929°, 21.946°, 22.719°, 23.604°, 23.814°, 24.874°, 25.609°, 26.622°, 27.621°, 28.622°, 29.622°, 30.622°, 31.622°, 32.622°, 33.622°, 34.622°, 35.622°, 36.622°, 37.622°, 38.622°, 39.622°, 40.622°, 41.622°, 42.622°, 43.622°, 44.622°, 45.622°, 46.622°, 47.622°, 48.622°, 49.622°, 50.622°, 51.622°, 52.622°, 53.622°, 54.622°, 55.622°, 56.622°, 57.622°, 58.622°, 59.622°, 60. The pharmaceutical composition according to (35), characterized by an X-ray powder diffraction pattern including at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 6.745°, 27.111°, 27.558°, 28.653°, 29.630°, 31.129°, 31.567°, 32.180°, 33.073°, 34.096°, 34.460°, 36.226°, 37.497°, 38.727°, and 41.126°.

[0048] (37) The tartrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7b) was crystalline and showed the following peaks: 6.479°, 10.486°, 10.862°, 11.913°, 12.222°, 12.972°, 13.161°, 13.467°, 14.230°, 15.372°, 15.736°, 16.053°, 16.45°. 7°, 16.613°, 17.009°, 17.695°, 17.913°, 18.486°, 18.795°, 19.479°, 20.101°, 20.416°, 20.818°, 21.352°, 22.106°, 22.320°, 22.629°, 22.964°, 23.698°, 23.950°, 24.175°, 24.439°, 24. .818°, 25.079°, 25.880°, 26.528°, 27.297°, 27.752°, 28.124°, 28.349°, 28.631°, 29.075°, 29.819°, 30.202°, ​​30.562°, 31.025°, 31.207°, 31.650°, 31.953°, 33.721°, 34.362°, 34.651° , 34.994°, 35.512°, 35.982°, 36.450°, 37.476°, 38.287°, 39.699°, 39.980°, 40.951°, and 41.870° (2θ±0.2°).

[0049] (38) The pharmaceutical composition according to any one of (24) to (26), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a hemifumarate salt of the compound of formula (I).

[0050] (39) The pharmaceutical composition according to (38), wherein the hemifumarate salt of the compound of formula (I) is the hemifumarate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3c).

[0051] (40) The hemifumarate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3c) was crystalline and showed the following alignments: 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°, 21.068°, 21.335°, 21.837°. 39. The pharmaceutical composition according to claim 39, characterized by an X-ray powder diffraction pattern including at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999°.

[0052] (41) The pharmaceutical composition according to (38), wherein the hemifumarate salt of the compound of formula (I) is hemifumarate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7c).

[0053] (42) The hemifumarate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7c) was crystalline and showed the following peaks: 8.483°, 8.733°, 11.080°, 11.351°, 11.622°, 12.615°, 13.258, 14.977°, 15.557°, 16.089°, 16.319°, 16.606°, 17.013°, 18.928°, 18.884°, 19.429°, 1 The pharmaceutical composition according to (41), characterized by an X-ray powder diffraction pattern including at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.734°, 20.643°, 21.484°, 22.067°, 23.433°, 24.466°, 24.885°, 26.740°, 27.900°, 28.557°, 29.523°, 32.888°, 34.183°, and 36.808°.

[0054] (43) The hemifumarate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7c) was crystalline and showed the following peak positions: 9.746°, 11.354°, 12.338°, 13.762°, 16.111°, 16.644°, 19.929°, 20.180°, 21.576°, 22.758°, 23.348°, 23.938°, 24.7 The pharmaceutical composition according to (41), characterized by an X-ray powder diffraction pattern including at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 24°, 25.226°, 26.203°, 27.910°, 29.056°, 29.499°, 32.753°, 35.567°, 37.279°, 37.347°, and 39.481°.

[0055] (44) The pharmaceutical composition according to any one of (24) to (26), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a citrate salt of the compound of formula (I).

[0056] (45) The pharmaceutical composition according to (44), wherein the citrate salt of the compound of formula (I) is the citrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3e).

[0057] (46) The pharmaceutical composition according to (45), wherein the citrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3e) is amorphous by X-ray powder diffraction.

[0058] (47) The pharmaceutical composition according to (44), wherein the citrate salt of the compound of formula (I) is the citrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7e).

[0059] (48) The pharmaceutical composition according to (47), wherein the citrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7e) is amorphous by X-ray powder diffraction.

[0060] (49) The pharmaceutical composition according to any one of (24) to (26), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a hemisuccinate salt of the compound of formula (I).

[0061] (50) The pharmaceutical composition according to any one of (24) to (26), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a benzoate of the compound of formula (I).

[0062] (51) The pharmaceutical composition according to (50), wherein the benzoate salt of the compound of formula (I) is the benzoate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3j).

[0063] (52) The benzoate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3j) was crystalline and showed the following peak positions: 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.831°, 20.868°, 21.447°, 22.860°, 23.878°, 24.94°. 4°, 25.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597° (2θ±0.2°).

[0064] (53) The pharmaceutical composition according to (50), wherein the benzoate salt of the compound of formula (I) is the benzoate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7j).

[0065] (54) The benzoate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7j) was crystalline and showed the following peak positions: 9.492°, 11.011°, 12.391°, 13.440°, 14.609°, 15.432°, 16.394°, 18.259°, 18.967°, 19.356°, 19.827°, 20.843°, 21.476°, 22.062°, 22.805°, 23.862°, 24.963°, 25.062°, 26.062°, 27.062°, 28.062°, 29.062°, 30.062°, 31.062°, 32.062°, 33.062°, 34.062°, 35.062°, 36.062°, 37.062°, 38.062°, 39.062°, 40.062°, 41.062°, 42.062°, 43.062°, 44.062°, 45.062°, 46.062°, 47.062°, 48.062°, 49.062°, 50.062°, 51.062°, 52.062°, 53.062°, 54.062°, 55.062°, 56.062°, 57.062°, 58.062°, 59.0 53. The pharmaceutical composition according to claim 53, characterized by an X-ray powder diffraction pattern including at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 5.734°, 26.170°, 26.992°, 27.738°, 28.593°, 30.073°, 30.746°, 31.041°, 31.799°, 32.794°, 33.551°, 34.480°, 35.430°, 37.685°, and 38.643°.

[0066] (55) The pharmaceutical composition according to (24), wherein the pharmaceutically acceptable salt of the compound of formula (I) is a fatty acid salt of the compound of formula (I).

[0067] (56) The pharmaceutical composition according to (55), wherein the fatty acid salt of the compound of formula (I) is an adipate, laurate, linoleate, myristate, caprate, stearate, oleate, caprylate, palmitate, sebacate, undecylenate, or caproate salt of the compound of formula (I).

[0068] (57) The pharmaceutical composition according to any one of (1) to (56), wherein the organic acid agent is a hydroxy acid and / or enedioic acid.

[0069] (58) The pharmaceutical composition according to any one of (1) to (57), wherein the organic acid agent is at least one selected from the group consisting of glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and maleic acid.

[0070] (59) The pharmaceutical composition according to any one of (1) to (58), wherein the organic acid agent is citric acid and / or tartaric acid.

[0071] (60) The pharmaceutical composition according to any one of (1) to (59), wherein the organic acid agent is citric acid.

[0072] (61) The pharmaceutical composition according to any one of (1) to (60), wherein the organic acid agent is not coated.

[0073] (62) The pharmaceutical composition according to any one of (1) to (60), wherein the organic acid agent is coated.

[0074] (63) The pharmaceutical composition according to (62), wherein the organic acid agent is coated with a water-soluble polymer.

[0075] (64) The pharmaceutical composition according to (62), wherein the organic acid agent is coated with an anti-caking agent.

[0076] (65) The pharmaceutical composition according to (62), wherein the organic acid agent is coated with a pH adjuster.

[0077] (66) The pharmaceutical composition according to (65), wherein the pH adjuster is an alkali metal salt of an organic acid agent.

[0078] (67) The pharmaceutical composition according to (66), wherein the organic acid agent is citric acid and the alkali metal salt of the organic acid agent is sodium citrate.

[0079] (68) The pharmaceutical composition according to any one of (62) to (67), wherein the organic acid agent is present in the pharmaceutical composition in the form of coated granules agglomerated together with the carbon dioxide source.

[0080] (69) The pharmaceutical composition according to any one of (1) to (68), wherein the organic acid agent is present in the pharmaceutical composition in an amount of at least 5% by weight to 40% by weight, based on the total weight (dry weight) of the pharmaceutical composition.

[0081] (70) The pharmaceutical composition according to any one of (1) to (69), which is in a solid dosage form.

[0082] (71) The pharmaceutical composition according to any one of (1) to (70), which is in a solid dosage form adapted for oral administration.

[0083] (72) The pharmaceutical composition according to (71), which is in an oral dosage form.

[0084] (73) The pharmaceutical composition according to (71) or (72), which is in an orally dispersible dosage form.

[0085] (74) The pharmaceutical composition according to any one of (71) to (73), which is in the form of an orally disintegrating tablet (ODT).

[0086] (75) The pharmaceutical composition according to any one of (1) to (74), which is in an effervescent dosage form.

[0087] (76) The pharmaceutical composition according to (75), wherein the pharmaceutically acceptable vehicle further comprises a carbon dioxide source.

[0088] (77) The pharmaceutical composition according to (76), wherein the carbon dioxide source is at least one selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, and sesquicarbonate.

[0089] (78) An oral liquid dosage form prepared by reconstituting a solid dosage form of the pharmaceutical composition according to any one of (1) to (77) in a pharmaceutically acceptable aqueous medium.

[0090] (79) The oral liquid dosage form according to (78), wherein the pharmaceutically acceptable aqueous medium is water or juice.

[0091] (80) A method for treating a subject having a disease or disorder associated with the serotonin 5-HT2 receptor, comprising: A method comprising administering a therapeutically effective amount of the pharmaceutical composition according to any one of (1) to (77) to the subject.

[0092] (81) The method according to (80), wherein the disease or disorder is a disorder of the central nervous system (CNS).

[0093] (82) The method according to (81), wherein the central nervous system (CNS) disorder is at least one selected from the group consisting of major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorder, eating disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset dysfluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), chronic fatigue syndrome, Lyme disease, gambling disorder, paraphilic disorder, sexual dysfunction, peripheral neuropathy, and obesity.

[0094] (83) The method according to (81), wherein the central nervous system (CNS) disorder is major depressive disorder (MDD).

[0095] (84) The method according to (81), wherein the central nervous system (CNS) disorder is treatment-resistant depression (TRD).

[0096] (85) The method according to (81), wherein the central nervous system (CNS) disorder is generalized anxiety disorder (GAD).

[0097] (86) The method according to (81), wherein the central nervous system (CNS) disorder is social anxiety disorder.

[0098] (87) The method according to (81), wherein the central nervous system (CNS) disorder is obsessive-compulsive disorder (OCD).

[0099] (88) The method according to (81), wherein the central nervous system (CNS) disorder is cluster headache or migraine.

[0100] (89) The method according to (81), wherein the central nervous system (CNS) disorder is a substance use disorder.

[0101] (90) The method according to (89), wherein the substance use disorder is alcohol use disorder and / or nicotine use disorder.

[0102] (91) The method according to (80), wherein the disease or disorder is a condition of the autonomic nervous system (ANS).

[0103] (92) The method according to any one of (80) to (91), wherein the pharmaceutical composition is orally administered to the subject.

[0104] (93) The method according to any one of (80) to (92), wherein the pharmaceutical composition is administered orally to the subject.

[0105] (94) The method according to any one of (80) to (92), wherein the pharmaceutical composition is administered by reconstituting a solid dosage form of the pharmaceutical composition in a pharmaceutically acceptable aqueous medium to form an oral liquid dosage form, and then administering the oral liquid dosage form to the subject.

[0106] (95) The method according to any one of (80) to (94), wherein the pharmaceutical composition is administered to the subject in an amount that provides the compound of formula (I) at a hallucinogenic dose of about 0.083 mg / kg to about 5 mg / kg.

[0107] (96) The method of (95), wherein the pharmaceutical composition is administered to provide a hallucinogenic dose no more than once a week over the course of treatment.

[0108] (97) The method according to any one of (80) to (94), wherein the pharmaceutical composition is administered to the subject in an amount that provides a non-hallucinogenic dose of the compound of formula (I) of about 0.00001 mg / kg to less than about 0.083 mg / kg.

[0109] (98) The method of (97), wherein the pharmaceutical composition is administered to provide a non-hallucinogenic dose one or more times daily over the course of treatment.

[0110] (99) Use of the pharmaceutical composition according to any one of (1) to (77) for treating a subject having a disease or disorder associated with the serotonin 5-HT2 receptor.

[0111] (100) Use of the oral liquid dosage form according to (78) or (79) for treating a subject having a disease or disorder associated with the serotonin 5-HT2 receptor. [Brief explanation of the drawings]

[0112] The foregoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the claims that follow. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings.

[0113] [Figure 1A] 1A-1D show the synthetic route (FIG. 1A), 1H NMR spectrum (FIG. 1B-1C), and high-resolution mass spectrometry (HRMS) spectrum (FIG. 1D) of compound I-3 (PI-d10). [Figure 1B] Same as above. [Figure 1C] Same as above. [Figure 1D] Same as above. [Figure 2A] Figures 2A-2C show the X-ray powder diffraction (XRPD) pattern (pattern 1) of compound I-3, enlarged and annotated in Figures 2B and 2C. [Figure 2B] Same as above. [Figure 2C] Same as above. [Figure 3A]Figures 3A-3D show the X-ray powder diffraction (XRPD) pattern (Pattern 1) of I-7a (Figure 3A), Figure 3B is an enlarged and annotated XRPD pattern (Pattern 1) of I-7 (PI-d0, free base) (Figure 3C), and a comparison between the XRPD patterns (Pattern 1) of I-7a (benzenesulfonate salt) and I-7 (PI-d0, free base) (Figure 3D). [Figure 3B] Same as above. [Figure 3C] Same as above. [Figure 3D] Same as above. [Figure 4] FIG. 4 shows the differential scanning calorimetry (DSC) curve of I-7a. [Figure 5] FIG. 5 shows the thermogravimetric analysis (TGA) curve of I-7a. [Figure 6A] Figures 6A and 6B show the 1H NMR spectrum of I-7a. [Figure 6B] Same as above. [Figure 7] FIG. 7 shows the ultra-performance liquid chromatogram (UPLC) of I-7a. [Figure 8] FIG. 8 shows the DVS isotherm plot of I-7a. [Figure 9] FIG. 9 shows the XRPD pattern of I-7a before and after DVS analysis (pattern 1). [Figure 10] Figure 10 shows the XRPD patterns of I-7a after storage of the solid sample for 22 days under the following conditions: i) 25°C, sealed vial; ii) 25°C / 96% RH; and iii) 40°C / 75% RH, compared with a fresh sample. [Figure 11] FIG. 11 shows the XRPD patterns of I-7a after maturation in 12 different solvents. [Figure 12] FIG. 12 shows the XRPD patterns of two different crystalline polymorphs of I-7b, Pattern 1 (prepared from acetonitrile or THF) and Pattern 2 (prepared from 1,4-dioxane). [Figure 13] FIG. 13 shows the DSC curve of I-7b (pattern 1). [Figure 14]FIG. 14 shows the TGA curve of I-7b (pattern 1). [Figure 15A] 15A to 15B show the 1H NMR spectrum of I-7b (pattern 1). [Figure 15B] Same as above. [Figure 16] FIG. 16 shows the DVS isotherm plot of I-7b (pattern 1). [Figure 17] FIG. 17 shows the DVS change in mass plot of I-7b (pattern 1). [Figure 18] Figure 18 shows the XRPD patterns of I-7b (pattern 1) after 22 days of storage of the solid sample under the following conditions: i) 25°C, sealed vial, ii) 25°C / 96% RH, and iii) 40°C / 75% RH, compared to the fresh sample, and shows a change in form to the pattern 3 polymorph for samples ii), iii), and after DVS. [Figure 19A] 19A-19B show DSC plots of I-7b (pattern 1) before (FIG. 19A) and after (FIG. 19B) DVS. [Figure 19B] Same as above. [Figure 20A] 20A-20B show TGA plots of I-7b (pattern 1) before (FIG. 20A) and after (FIG. 20B) DVS. [Figure 20B] Same as above. [Figure 21] FIG. 21 shows the XRPD patterns of I-7b (pattern 1) after maturation in 12 different solvents. [Figure 22] FIG. 22 shows the XRPD pattern of I-7b (amorphous) obtained from salt formation with 0.5 equivalents of L-tartaric acid from either 1,4-dioxane or THF. [Figure 23] FIG. 23 shows the XRPD patterns of three different crystalline polymorphs of I-7c: a polymorph with pattern 1 (prepared from THF), a polymorph with pattern 2 (prepared from acetonitrile), and a polymorph with pattern 3 (prepared from 1,4-dioxane). [Figure 24] FIG. 24 shows the DSC curve of I-7c (pattern 1). [Figure 25] FIG. 25 shows the TGA plot of I-7c (pattern 1). [Figure 26A] 26A-26B show the DSC plot (FIG. 26A) and TGA plot (FIG. 26B) of I-7c (pattern 2). [Figure 26B] Same as above. [Figure 27] FIG. 27 shows the DSC curve of I-7c (pattern 3). [Figure 28] FIG. 28 shows the TGA plot of I-7c (pattern 3). [Figure 29] Figure 29 shows the XRPD patterns of four different crystalline polymorphs of I-7c: a polymorph with pattern 1 (made from either 0.5 or 1 equivalent of fumaric acid and THF), a polymorph with pattern 2 (made from 0.5 equivalents of fumaric acid and acetonitrile), a polymorph with pattern 3 (made from either 0.5 or 1 equivalent of fumaric acid in 1,4-dioxane), and a polymorph with pattern 4 (made from 1 equivalent of fumaric acid in acetonitrile). [Figure 30A] 30A-30B show the DSC plot (FIG. 30A) and TGA plot (FIG. 30B) of I-7c (pattern 4). [Figure 30B] Same as above. [Figure 31A] 31A-31B show the DVS (FIG. 31A) and DVS change in mass plot (FIG. 31B) of I-7c (pattern 4). [Figure 31B] Same as above. [Figure 32] FIG. 32 shows the XRPD patterns of two different crystalline polymorphs of I-7d: a polymorph with pattern 1 (prepared from 1,4-dioxane) and a polymorph with pattern 2 (prepared from THF / heptane). [Figure 33] FIG. 33 shows the DSC curve of I-7d (pattern 1). [Figure 34] FIG. 34 shows the TGA plot of I-7d (pattern 1). [Figure 35] FIG. 35 shows the DSC curve of I-7d (pattern 2). [Figure 36] FIG. 36 shows the TGA curve of I-7d (pattern 2). [Figure 37A] 37A-37B show the XRPD patterns of I-7e (amorphous) after lyophilization (FIG. 37A) and after slurrying in THF (FIG. 37B). [Figure 37B] Same as above. [Figure 38A] 38A-38B show the 1H NMR spectrum of I-7e. [Figure 38B] Same as above. [Figure 39] FIG. 39 shows the XRPD pattern of I-7f (pattern 1) compared to the free base. [Figure 40] FIG. 40 shows the DSC curve of I-7f. [Figure 41] Figure 41 shows the TGA plot of I-7f. [Figure 42] FIG. 42 shows the XRPD patterns of I-7c before (pattern 5, obtained from scale-up using 1 equivalent of fumaric acid in acetonitrile) and after DVS (pattern 6). [Figure 43] FIG. 43 shows the DSC plot of I-7c before DVS (polymorph 5, obtained from scale-up using 1 equivalent of fumaric acid in acetonitrile). [Figure 44] FIG. 44 shows the DSC plot of polymorph 5 of I-7c obtained after DVS (pattern 6). [Figure 45A] Figures 45A-45B show TGA plots of I-7c before DVS (Figure 45A, polymorph 5, obtained from scale-up using 1 equivalent of fumaric acid in acetonitrile) and after DVS (Figure 45B, pattern 6). [Figure 45B] Same as above. [Figure 46] FIG. 46 shows the XRPD patterns of I-7c (pattern 5) after maturation in 12 different solvents to form pattern (P) 1, 6, 7, 8, 9, 10, and 11 polymorphs. [Figure 47]FIG. 47 shows the XRPD patterns of I-7h (pattern 1) formed from either 1,4-dioxane or THF. [Figure 48] FIG. 48 shows the DSC curve of I-7h (pattern 1). [Figure 49] FIG. 49 shows the TGA plot of I-7h (pattern 1). [Figure 50] Figure 50 shows the XRPD patterns of six different crystalline polymorphs of I-7i: a polymorph having Pattern 1 (made from 0.5 equivalents of oxalic acid and THF), a polymorph having Pattern 2 (made from 1 equivalent of oxalic acid and THF), a polymorph having Pattern 3 (made from 0.5 equivalents of oxalic acid and acetonitrile), a polymorph having Pattern 4 (made from 1 equivalent of oxalic acid and acetonitrile), a polymorph having Pattern 5 (made from 0.5 equivalents of oxalic acid and 1,4-dioxane), and a polymorph having Pattern 6 (made from 1 equivalent of oxalic acid and 1,4-dioxane). [Figure 51] FIG. 51 shows the DSC curves of I-7i (polymorphs of patterns 1 to 6). [Figure 52] FIG. 52 shows the TGA plot of I-7i (polymorphs of patterns 2-6). [Figure 53A] Figures 53A-53B show the XRPD patterns of I-7j (pattern 1), with Figure 53B enlarged and annotated. [Figure 53B] Same as above. [Figure 54] Figure 54 shows the TGA plot of I-7j (pattern 1). [Figure 55] FIG. 55 shows the DSC curve of I-7j (pattern 1). [Figure 56] Figure 56 shows the XRPD patterns of I-7j (pattern 1) after storing the solid sample for 22 days under the following conditions: i) 25°C, sealed vial, ii) 25°C / 96% RH, and iii) 40°C / 75% RH, compared to a fresh sample. [Figure 57] Figure 57 shows the XRPD patterns of I-7j (pattern 1) after maturation in 12 different solvents. [Figure 58] FIG. 58 shows the DVS isotherm of I-7j (pattern 1). [Figure 59A] Figures 59A-59C show that no change occurred in I-7j (pattern 1) after being subjected to DVS conditions (post-DVS) by XRPD (Figure 59A, compare pre-DVS pattern from material obtained from THF and acetonitrile) and H NMR (Figures 59B and 59C). [Figure 59B] Same as above. [Figure 59C] Same as above. [Figure 60] Figure 60 shows the XRPD patterns of three different crystalline polymorphs of I-7k: a polymorph with pattern 1 (made from acetonitrile / TBME), a polymorph with pattern 2 (made from THF / heptane), and a polymorph with pattern 3 (made from 1,4-dioxane / heptane). [Figure 61] Figure 61 shows the DSC curves of three different crystalline polymorphs of I-7k. [Figure 62] Figure 62 shows the TGA plots of three different crystalline polymorphs of I-7k. [Figure 63A] Figures 63A-63F show the XRPD pattern of I-3a (Pattern 1) (Figure 63A), an enlarged and annotated version of the XRPD plot (Figures 63B-63C), a comparative XRPD plot of I-3a (Pattern 1) to the I-7a species (Figure 63D), and the single crystal X-ray structure of I-3a (Pattern 1) (Figures 63E-63F). [Figure 63B] Same as above. [Figure 63C] Same as above. [Figure 63D] Same as above. [Figure 63E] Same as above. [Figure 63F] Same as above. [Figure 64A] Figures 64A-64B show a comparison of species I-3a (pattern 1) and I-7a by DSC (Figure 64A) and TGA (Figure 64B). [Figure 64B] Same as above. [Figure 65A]65A-65B show the 1H NMR spectrum of I-3a (pattern 1). [Figure 65B] Same as above. [Figure 66] Figure 66 shows the XRPD pattern of I-3b (pattern 1, obtained from an unseeded experiment) compared to the crystalline polymorphs of I-7b, pattern 1 (from THF) and pattern 2 (from 1,4-dioxane). [Figure 67] FIG. 67 shows the DSC curves of I-3b (pattern 1, obtained from an unseeded experiment) compared to the crystalline polymorphs of I-7b, pattern 1 (from THF) and pattern 2 (from 1,4-dioxane). [Figure 68] Figure 68 shows the TGA plot of I-3b (pattern 1, obtained from an unseeded experiment) compared to the crystalline polymorphs of I-7b, pattern 1 (from THF) and pattern 2 (from 1,4-dioxane). [Figure 69A] Figures 69A-69D show the XRPD pattern of I-3b (Pattern 2, obtained from a seeded experiment) (Figure 69A), the enlarged and annotated XRPD of I-3b (Pattern 2, obtained from a seeded experiment) (Figure 69B), and the single crystal X-ray structure of I-3b (Pattern 2) (Figures 69C-69D), compared to the seeds of the crystalline polymorph of I-7b in Pattern 1 and the crystalline polymorph of I-3b in Pattern 1 obtained from an unseeded experiment. [Figure 69B] Same as above. [Figure 69C] Same as above. [Figure 69D] Same as above. [Figure 70] FIG. 70 shows the DSC curve of I-3b (pattern 2). [Figure 71] Figure 71 shows the TGA plot of I-3b (pattern 2). [Figure 72] FIG. 72 shows the XRPD patterns of I-3c (pattern 1, obtained from an unseeded experiment) versus patterns 1-4 of the crystalline polymorphs of I-7c. [Figure 73] FIG. 73 shows the DSC curve of I-3c (pattern 1) compared to the DSC curves of polymorphic patterns 1-4 of I-7c. [Figure 74] Figure 74 shows the TGA plot of I-3c (pattern 1) compared to the TGA plots of polymorphic patterns 1-4 of I-7c. [Figure 75A] Figures 75A-75B show the XRPD patterns of I-3c (pattern 2, obtained from a seeded experiment) compared to the crystalline polymorph of I-3c, pattern 1, obtained from an unseeded experiment, and the seeds of the I-7c crystalline polymorph, pattern 4 (Figure 75A), and the XRPD pattern of I-3c (pattern 2, obtained from a seeded experiment) alone (Figure 75B). [Figure 75B] Same as above. [Figure 76] Figure 76 shows the DSC curves of I-3c (pattern 2, obtained from a seeded experiment) compared to the crystalline polymorph of I-3c, pattern 1, obtained from an unseeded experiment, and the seeds of the I-7c crystalline polymorph, pattern 4. [Figure 77] Figure 77 shows a TGA plot of I-3c (pattern 2, obtained from a seeded experiment) compared to the crystalline polymorph of I-3c, pattern 1, obtained from an unseeded experiment, and seeds of the I-7c crystalline polymorph, pattern 4. [Figure 78A] Figures 78A-78E show the XRPD pattern of I-3j (Pattern 1) (Figure 78A), an enlarged and annotated version (Figure 78B), a comparison of the XRPD patterns of I-3j (Pattern 1) and I-7j species (Figure 78C), and the single crystalline X-ray structure of I-3j (Pattern 1) (Figures 78D-78E). [Figure 78B] Same as above. [Figure 78C] Same as above. [Figure 78D] Same as above. [Figure 78E] Same as above. [Figure 79A] 79A-79B show the 1H NMR spectrum of I-3j (pattern 1). [Figure 79B] Same as above. [Figure 80] FIG. 80 shows the DSC plot of I-3j (Pattern 1) compared to I-7j (Pattern 1). [Figure 81]FIG. 81 shows the DVS isotherm plot of I-3j (pattern 1). [Figure 82] Figure 82 shows the DVS change in mass plot of I-3j (pattern 1). [Figure 83] Figure 83 shows the XRPD patterns of I-3j (pattern 1) after 22 days of storage of the solid sample under the following conditions: i) 25°C, sealed vial; ii) 25°C / 96% RH; and iii) 40°C / 75% RH, and compares it with the fresh and post-DVS samples. [Figure 84] Figure 84 shows the XRPD patterns of I-3j (pattern 1) after maturation in 12 different solvents. [Figure 85] Figure 85 shows the XRPD diffraction peaks of compound I-3 (pattern 1) obtained by grinding, cooling, and freeze-drying solutions of I-3 (PI-d10, free base) in 1,4-dioxane, t-BuOH, 1,4-dioxane / water, and MeCN / water. [Figure 86] FIG. 86 shows the DSC plot of compound I-3 (PI-d10, free base) (Pattern 1). [Figure 87] Figure 87 shows the XRPD of the amorphous form of compound I-3 (PI-d10, free base) obtained from a DSC melt / crush cooling experiment (>185°C / 30°C) compared to the XRPD pattern of compound I-3 obtained from the amorphous form that was crystallized upon standing overnight (Pattern 2). [Figure 88] Figure 88 shows the XRPD pattern of I-3 (Pattern 2) obtained from the DSC scale-up experiment. [Figure 89] Figure 89 shows the annotated XRPD pattern of I-3 (pattern 2) obtained from the DSC scale-up experiment. [Figure 90] FIG. 90 shows the XRPD pattern of I-3m (pattern 1) compared to diffraction patterns 1 and 2 of the free base I-3. [Figure 91] FIG. 91 shows the XRPD pattern of I-3n (pattern 1) compared to diffraction patterns 1 and 2 of the free base I-3. [Figure 92]FIG. 92 shows the XRPD pattern of I-3o (pattern 1) compared to diffraction patterns 1 and 2 of the free base I-3. [Figure 93] FIG. 93 shows the XRPD pattern of I-3p (pattern 1) compared to diffraction patterns 1 and 2 of the free base I-3. [Figure 94] Figure 94 shows the XRPD patterns of two different polymorphs of I-3q (pattern 1 obtained from commercial stearic acid and pattern 2 obtained from demineralized sodium stearate) compared to diffraction patterns 1 and 2 of the free base I-3. [Figure 95] Figure 95 shows the XRPD patterns of two different polymorphs of I-3r (pattern 1 obtained from desalted sodium oleate and pattern 2 obtained from commercially available oleic acid) compared to diffraction patterns 1 and 2 of the free base I-3. [Figure 96] FIG. 96 shows the XRPD pattern of I-3s (pattern 1) compared to diffraction patterns 1 and 2 of the free base I-3. [Figure 97] FIG. 97 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of acetic acid with and without metal ions at 40° C. compared to those solutions without acetic acid. [Figure 98] Figure 98 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of ascorbic acid with and without metal ions at 40°C compared to those solutions without ascorbic acid. [Figure 99] Figure 99 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of benzenesulfonic acid with and without metal ions at 40°C compared to solutions without benzenesulfonic acid. [Figure 100] Figure 100 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of fumaric acid with and without metal ions at 40°C compared to those solutions without fumaric acid. [Figure 101]Figure 101 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of malonic acid with and without metal ions at 40°C compared to those solutions without malonic acid. [Figure 102] FIG. 102 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of succinic acid with and without metal ions at 40° C. compared to those solutions without succinic acid. [Figure 103] FIG. 103 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of tartaric acid with and without metal ions at 40° C. compared to those solutions without tartaric acid. [Figure 104] FIG. 104 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of citric acid with and without metal ions at 40° C. compared to those solutions without citric acid. [Figure 105] FIG. 105 shows the stability of I-7 (PI-d0) over 24 hours in dilute solutions of citric acid with and without metal ions at 4° C. compared to those solutions without citric acid. [Figure 106] FIG. 106 shows the stability of I-7 (PI-d0) over 24 hours in dilute solutions of citric acid with and without metal ions at 23° C. compared to those solutions without citric acid. [Figure 107] FIG. 107 shows the stability of I-7 (PI-d0) over 24 hours in dilute solutions of citric acid with and without metal ions at 40° C. compared to those solutions without citric acid. [Figure 108A] Figures 108A-108C show the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of sodium citrate buffer with and without metal ions at 4°C (Figure 108A), 23°C (Figure 108B), and 40°C (Figure 108C), compared to those solutions without sodium citrate buffer. [Figure 108B] Same as above. [Figure 108C] Same as above. [Figure 109]Figure 109 shows the stability of I-7 (PI-d0) over 24 hours in 0.1 M solutions of phosphate buffer (pH 6.0), phosphate buffer (pH 7.5), and sodium citrate buffer (6.0) at 40°C. [Figure 110] Figure 110 shows the long-term stability (up to 25 days) of I-7 (PI-d0) in sodium citrate buffer (0.1 M, pH 6.01) at 4°C and 23°C. [Figure 111] Figure 111 shows the long-term stability (up to 25 days) of I-7 (PI-d0) in citric acid solution (0.1 M, pH 1.60) at 4°C and 23°C. [Figure 112] Figure 112 shows the stability of I-7 (PI-d0) over 24 hours in 20 μM solutions of ethylenediaminetetraacetic acid (EDTA) with and without metal ions at 40°C compared to those solutions without EDTA. [Figure 113] Figure 113 shows the stability of I-7 (PI-d0) over 24 hours in 20 μM solutions of ascorbic acid with or without metal ions at 40°C compared to those solutions without ascorbic acid. [Figure 114] Figure 114 shows the stability of I-7 (PI-d0) over 24 hours in 20 μM solutions of sodium metabisulfite with and without metal ions at 40°C compared to those solutions without sodium metabisulfite. [Figure 115] Figure 115 shows the stability of I-7 (PI-d0) over 24 hours in 20 μM solutions of L-cysteine ​​with and without metal ions at 40°C compared to those solutions without L-cysteine. [Figure 116] Figure 116 shows the stability of I-7 (PI-d0) over 24 hours in 20 μM solutions of propyl gallate with and without metal ions at 40°C compared to those solutions without propyl gallate. [Figure 117]Figure 117 shows the stability of I-7 (PI-d0) over 24 hours in 1% w / w solutions of CAVASOL® W7 HP with and without metal ions at 40°C compared to those solutions without CAVASOL® W7 HP. [Figure 118] Figure 118 shows the stability of I-7 (PI-d0) in 1% w / w solutions of CAVASOL® W7 M with and without metal ions over 24 hours at 40°C compared to those solutions without CAVASOL® W7 M. [Figure 119] Figure 119 shows the stability of I-7 (PI-d0) over 24 hours in 1% w / w solutions of CAVITRON® W7 HP7 with and without metal ions at 40°C compared to those solutions without CAVITRON® W7 HP7. [Figure 120] Figure 120 shows the solubility of I-3 (PI-d10) (Pattern 1), I-7 (PI-d0) (Pattern 1), I-3j (Pattern 1), I-7a (Pattern 1), I-7b (Pattern 1), I-7c (Pattern 5), and I-7j (Pattern 1) in FaSSGF (fasted state simulated gastric fluid) (pH 1.6) at 37°C for 2 and 6 hours. [Figure 121] Figure 121 shows the solubility of I-3 (PI-d10) (Pattern 1), I-7 (PI-d0) (Pattern 1), I-3j (Pattern 1), I-7a (Pattern 1), I-7b (Pattern 1), I-7c (Pattern 5), and I-7j (Pattern 1) in water at room temperature for 2 and 6 hours. [Figure 122] Figure 122 shows the TGA plot of I-7 (API) used in the ODT formulation. [Figure 123] Figure 123 shows the DSC curve of I-7 (API) used in the ODT formulation. [Figure 124] Figure 124 shows the XRPD pattern of I-7 (Pattern 1) (API) used in the ODT formulation. [Figure 125]Figure 125 shows a TGA plot of the ODT dosage form made from Batch 1a (SH24) formulated with the citrate salt of psilocin at pH 3.55. [Figure 126] FIG. 126 shows the DSC curve of the ODT dosage form made from Batch 1a (SH24) formulated with the citrate salt of psilocin at pH 3.55. [Figure 127] Figure 127 shows the XRPD pattern of the ODT dosage form made from Batch 1a (SH24) formulated with the citrate salt of psilocin at pH 3.55. [Figure 128] Figure 128 shows the appearance of ODT dosage forms formed from Batch 1a (SH24) formulated with the citrate salt of psilocin at pH 3.55. [Figure 129] Figure 129 shows a DSC plot of the ODT dosage form made from Batch 1b (SH24) formulated with the citrate salt of psilocin at pH 4.50. [Figure 130] Figure 130 shows the XRPD pattern of the ODT dosage form made from Batch 1b (SH24) formulated with the citrate salt of psilocin at pH 4.50. [Figure 131] Figure 131 shows the appearance of the ODT dosage form formed from Batch 1b (SH24) formulated with the citrate salt of psilocin at pH 4.50. [Figure 132] FIG. 132 shows a DSC plot of the ODT dosage form made from Batch 1c (SH24) formulated with the citrate salt of psilocin at pH 7.56. [Figure 133] Figure 133 shows the XRPD pattern of the ODT dosage form made from Batch 1c (SH24) formulated with the citrate salt of psilocin at pH 7.56. [Figure 134] Figure 134 shows the appearance of the ODT dosage form formed from Batch 1c (SH24) formulated with the citrate salt of psilocin at pH 7.56. [Figure 135] Figure 135 shows the DSC curve of the ODT dosage form made from Batch 2a (SH24) formulated with the tartrate salt of psilocin at pH 3.13. [Figure 136] Figure 136 shows the XRPD pattern of the ODT dosage form made from Batch 2a (SH24) formulated with the tartrate salt of psilocin at pH 3.13. [Figure 137] Figure 137 shows the appearance of the ODT dosage form formed from Batch 2a (SH24) formulated with the tartrate salt of psilocin at pH 3.13. [Figure 138] Figure 138 shows a DSC plot of the ODT dosage form made from Batch 2b (SH24) formulated with the tartrate salt of psilocin at pH 4.33. [Figure 139] Figure 139 shows the XRPD pattern of the ODT dosage form made from Batch 2b (SH24) formulated with the tartrate salt of psilocin at pH 4.33. [Figure 140] Figure 140 shows the appearance of the ODT dosage form formed from batch 2b (SH24) formulated with the tartrate salt of psilocin at p4.33. [Figure 141] Figure 141 shows the DSC curve of the ODT dosage form made from Batch 2c (SH24) formulated with the tartrate salt of psilocin at pH 7.94. [Figure 142] Figure 142 shows the XRPD pattern of the ODT dosage form made from Batch 2c (SH24) formulated with the tartrate salt of psilocin at pH 7.94. [Figure 143] Figure 143 shows the TGA plot of the placebo ODT dosage form. [Figure 144] Figure 144 shows the DSC curve of the placebo ODT dosage form. [Figure 145] Figure 145 shows the XRPD pattern of the placebo ODT dosage form. [Figure 146] FIG. 146 shows the plasma concentration-time curves of orally and intravenously administered psilocybin in rats. [Figure 147] FIG. 147 shows the plasma concentration-time curves of PI-d0+PI-d10 (PI-total) when PI-d0 and PI-d10 were co-administered orally and intravenously to rats. [Figure 148]FIG. 148 is a plasma concentration-time curve comparing PI-total plasma levels after oral PI-d0+PI-d10 and oral psilocybin in rats. [Figure 149] FIG. 149 is a tissue concentration-time curve comparing brain and plasma psilocybin levels following intravenous administration of psilocybin in rats. [Figure 150] FIG. 150 is a tissue concentration-time curve comparing brain and plasma PI-total levels after intravenous co-administration of PI-d0 and PI-d10 in rats. [Figure 151] FIG. 151 is a brain concentration-time curve comparing brain PI levels after intravenous administration of psilocybin with PI-total levels after intravenous co-administration of PI-d0 and PI-d10 in rats. [Figure 152A] Figures 152A-152B show the plasma concentration-time curves following intravenous and oral administration of psilocin-d10 to dogs (Figure 152A), as well as the bioavailability profile of psilocin-d10 to dogs, which was 91.3% (Figure 152B). [Figure 152B] Same as above. [Figure 153A] Figures 153A-153B show the plasma concentration-time profiles of psilocybin after PI-d0 (Figure 153A) and PI-d10 (Figure 153B) using orally disintegrating tablet (ODT) and powder in capsule (PIC) dosage forms. [Figure 153B] Same as above. [Fig. 154] Figure 154 shows a comparison of exposure between PI-d0 after psilocybin administration and PI-d10 after PI-d10 administration for both ODT and PIC dosage forms as assessed by Cmax. [Figure 155] Figure 155 shows a comparison of exposure between PI-d0 after psilocybin administration and PI-d10 after PI-d10 administration for both ODT and PIC dosage forms as assessed by AUCinf. DETAILED DESCRIPTION OF THE INVENTION

[0114] In the following detailed description of embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present disclosure. However, it will be apparent to those skilled in the art that embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0115] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0116] When a substituent or group is described as "containing deuterium" or "containing deuterium," it is to be understood that the substituent or group itself can be deuterium, or the substituent or group can contain at least one deuterium substitution in its chemical structure. For example, if the substituent "-R" is defined as containing deuterium, it is to be understood that -R can be -D (-deuterium), or a group such as -CD consistent with the other requirements set forth for -R.

[0117] As used herein, the term "fat" refers to a compound having a long-chain (linear) hydrophobic moiety composed of hydrogen and 4 to 26 carbon atoms, and may be fully saturated or partially unsaturated.

[0118] The phrases "pharmaceutically acceptable," "physiologically acceptable," and the like are used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. When referring to salts, the phrases "pharmaceutically acceptable salt," "physiologically acceptable salt," and the like mean salts that are acceptable for administration to a patient, such as a mammal (salts having counterions that have acceptable mammalian safety for a given administration regimen). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases such as sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and, where the molecule contains a basic functional group, from addition salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, sulfamate, phosphates, nitrates, perchlorates, and the like, as well as from addition salts with organic acids such as formates, tartrates, besylates, mesylates, acetates, maleates, malonates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemixalates, hemifumarates, propionates, stearates, tartrates, lactates, citrates, ascorbates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, isethionates, and the like. The term "salt thereof" refers to a compound formed when the proton of an acid is replaced by a cation, such as a metal cation or an organic cation. Where applicable, the salt is a pharmaceutically acceptable salt, but this is not required for salts of intermediate compounds that are not intended for administration to patients. For example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation, and has a conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0119] "Solvate" refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate can exist in an ordered and / or irregular arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Thus, exemplary solvates include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.

[0120] "Stereoisomer" and "stereoisomers" refer to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms of the compounds, such as racemates and optically pure stereoisomers, are contemplated herein. Chemical formulas and compounds that have at least one stereocenter but are drawn without reference to stereochemistry are intended to include both the racemate and the individual stereoisomers, such as R- and / or S-stereoisomers, each permutation of the diastereomers, so long as such diastereomers are geometrically feasible.

[0121] "Tautomer" refers to alternative forms of molecules that differ only in the electronic bonding of the atoms and / or in the position of the protons, such as enol-keto, imine-enamine, and neutral / zwitterionic tautomers, or tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Other tautomeric ring atom configurations are also possible.

[0122] A "crystalline" solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules that form a crystal lattice with long-range order, and thus exhibits sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern. In some cases, a crystalline solid may exist in different crystalline forms known as "polymorphs," which have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have various solid-state physical properties that affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility of the compound, as well as the safety and efficacy of pharmaceuticals based on the compound. Further refinement in terms of macroscopic physical purity or optical purity may be performed in the process of preparing polymorphs. Crystalline forms of a substance, including polymorphs, may be designated throughout this disclosure by "pattern" numbers (e.g., pattern 1, pattern 2, etc.) based on their characterized X-ray powder diffraction (XRPD) patterns. As used herein, the term "amorphous" refers to a solid material that has substantially no long-range order in its molecular positions; the molecules are arranged randomly, with no clearly defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions, and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have a substantially sharp, characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids. Thus, an "amorphous" subject compound / material is one characterized as having substantially no crystallinity, e.g., less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, or 0%, i.e., at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined, for example, by XRPD.For example, in some embodiments, the percent crystallinity may be determined by measuring the intensity of one or more peaks in an XRPD diffractogram compared to a reference peak, which may be a known standard or an internal standard. Other characterization techniques, such as modulated differential scanning calorimetry (mDSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, including quantitative methods that provide the above percentages in terms of weight percent, may also be used to determine the percent amorphous or crystalline of the subject compounds / materials.

[0123] Reference to an X-ray powder diffraction (XRPD) pattern of a compound / salt etc. of the present disclosure characterized by an X-ray powder diffraction pattern comprising "at least three characteristic peaks" should be understood to include substances / compounds / salts characterized as having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more (including all) of the listed characteristic XRPD diffraction peaks. Furthermore, "a substance / compound / salt comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from is open to the inclusion of other XRPD diffraction peaks not listed."

[0124] It will be understood that the compounds herein may exist in different salt, solvate, stereoisomer, tautomer, crystalline / amorphous (or polymorph) forms, and that the present disclosure is intended to include all permutations thereof, for example, solvates of pharmaceutically acceptable salts of stereoisomers of the subject compounds.

[0125] As used herein, the term "steady state" describes a stable or steady state level of a molecule concentration, such as the concentration of any compound described herein.

[0126] As used herein, the terms "stable," "stability," and the like include chemical stability and solid-state (physical) stability. The term "chemical stability" means that a compound can be stored under normal storage conditions, either in an isolated form or in a formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no chemical degradation or decomposition. "Solid-state stability" means that a compound can be stored under normal storage conditions, either in an isolated solid form or in a solid formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no solid-state changes (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid-state phase transition).

[0127] A "psilocybin-based" drug is any prodrug of a psilocin-type compound, such as an alkyl / aryl ester, α-amino ester (e.g., amino acid ester), hemiester, bisester, phosphate ester, sulfate ester, etc., that upon administration releases psilocin or a deuterated analog thereof (e.g., a compound of Formula (I)) as the active ingredient. Psilocybin-based drugs include psilocybin itself (the dihydrogen phosphate ester of psilocin, as well as other neutral or zwitterionic forms).

[0128] As used herein, the term "composition" is equivalent to the term "formulation."

[0129] As used herein, the term "active ingredient" is equivalent to the term "active pharmaceutical ingredient" (API).

[0130] The term "tamper-resistant" is art-recognized to describe aspects of a pharmaceutical formulation that make it difficult to abuse the drug portion of the formulation using the formulation, whether via extraction for intravenous use, intradermal use, or via crushing for purified cocaine use, thereby reducing the risk of drug abuse.

[0131] As used herein, the term "treating" or "treatment" means treating or treating a disease or medical condition in a patient, e.g., a mammal (particularly a human), including ameliorating a disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a patient, inhibiting a disease or medical condition, e.g., by slowing or arresting the onset of the disease or medical condition in a patient, or alleviating one or more symptoms of a disease or medical condition in a patient. In one embodiment, prophylactic treatment may prevent the occurrence of a disease or medical condition in a subject.

[0132] A "patient" or "subject," as used interchangeably herein, can be any mammal, including, for example, human and non-human subjects. The patient or subject can have the condition being treated or can be susceptible to the condition being treated.

[0133] As used herein, unless otherwise specified, the terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of a disease, disorder, or condition, or one or more symptoms thereof. The term encompasses the inhibition or reduction of symptoms of a particular disease, disorder, or condition. Subjects with a family history of a disease, disorder, or condition are particularly, in certain embodiments, candidates for a preventative regimen. Additionally, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be used interchangeably with the term "prophylactic treatment."

[0134] As used herein, and unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. Often, the beneficial effects a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term "managing" encompasses treating a subject afflicted with a particular disease, disorder, or condition in an effort to prevent or minimize the recurrence of the disease, disorder, or condition, or one or more symptoms thereof.

[0135] "Pharmaceutically effective amount" and "therapeutically effective amount" refer to that amount of a compound sufficient to treat a particular disorder or disease, or one or more symptoms thereof, and / or prevent the disease or disorder from occurring.

[0136] As used herein, and unless otherwise specified, a "prophylactically effective amount" of an active ingredient is an amount sufficient to prevent a disease, disorder, or condition, or to prevent its recurrence. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effect of another prophylactic agent.

[0137] The term "administration schedule" refers to a plan that chronologically shows the type, amount, duration, and procedure of drug treatment, including the dosage, administration method, administration order, and administration date of each drug. The designated administration date is determined before the start of drug administration. Administration continues by repeating a series of administration schedules, each of which is considered a "course." A "continuous" administration schedule means daily administration without interruption during the treatment course. If the administration schedule follows an "intermittent" administration schedule, days of administration may be followed by "rest days" or non-administration days of the drug during the course. A "drug holiday" indicates that the drug is not being administered according to a specified administration schedule. For example, after receiving one or several courses of treatment, a subject may be instructed to take a prescribed drug holiday as part of the administration schedule, for example, before resuming active treatment.

[0138] The term "toxic spike" is used herein to describe a neural spike at concentrations of any compound described herein that produces sedative or psychotomimetic side effects (e.g., hallucinations, dizziness, and nausea), or any undesirable and / or unintended secondary effects resulting in a subjective experience qualitatively different from that of the normal state produced by administering the pharmaceutical to an individual. These experiences may include derealization, depersonalization, hallucinations, and / or sensory distortions in vision, hearing, smell, touch, proprioception, and / or other perceptual modifications, and / or other substantial subjective changes in cognition, memory, emotion, and consciousness. When unwanted and / or unintended, such side effects may affect not only immediate effects but also treatment compliance. In particular, side effects may be more pronounced at blood concentration levels of approximately 250, 300, 400, or 500 ng / L or greater.

[0139] As used herein, and unless otherwise specified, a "neuropsychiatric disease or disorder" is a behavioral or psychological problem associated with a known neurological condition, typically defined as a constellation of coexisting symptoms. Examples of neuropsychiatric disorders include, but are not limited to, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, and manic depression, depression, or any combination thereof.

[0140] As used herein, "inflammatory condition" and "inflammatory disease" include rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthropathies (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystalline arthropathies (e.g., gout, pseudogout, calcium pyrophosphate deposition disease), multiple sclerosis, Lyme disease, polymyalgia rheumatica, connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjogren's syndrome), vasculitis (e.g., nodular polyposis), and the like. It broadly refers to chronic or acute inflammatory conditions, including, but not limited to, vascular diseases including arteritis, Wegener's granulomatosis, Churg-Strauss syndrome), inflammatory conditions resulting from trauma or ischemia, sarcoidosis, atherosclerosis, and vascular occlusive diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis, uveitis, corneal disease, iritis, iridocyclitis, glaucoma, and cataracts.

[0141] All diseases and disorders listed herein may be defined as set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association, or the International Classification of Diseases (ICD), published by the World Health Organization.

[0142] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. As used throughout this description and the claims that follow, the meaning of "a," "an," and "the" includes plural references as well as singular references, unless the context clearly indicates otherwise. The term "about" in connection with a numerical value means that the value varies above or below 5%. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

[0143] compound Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof: [ka] During the ceremony, R2, R5, R6, and R7 are independently selected from the group consisting of hydrogen and deuterium; R8 and R9 are independently -CH 3- , -CH2D -、 -CHD 2- -CD3, and -CD4; X1, X2, Y1, and Y2 are independently selected from the group consisting of hydrogen and deuterium.

[0144] In some embodiments, R2, R5, R6, and R7 are independently selected from the group consisting of hydrogen and deuterium. In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is hydrogen.

[0145] R2, R5, R6, and R7 may be the same, for example, R2, R5, R6, and R7 may each be hydrogen, or alternatively, R2, R5, R6, and R7 may each be deuterium. In some embodiments, at least one of R2, R5, R6, and R7 is deuterium. In some embodiments, at least two of R2, R5, R6, and R7 are deuterium. In some embodiments, at least three of R2, R5, R6, and R7 are deuterium.

[0146] In some embodiments, R8 and R9 are independently -CH 3- , -CH2D -、 -CHD 2-and -CD3. R8 and R9 may be the same or different. In some embodiments, R8 and R9 are the same. In some embodiments, R8 and R9 are independently selected from the group consisting of -CH 3- and -CD3. In some embodiments, R8 and R9 are methyl (-CH3). In some embodiments, R8 and R9 are partially deuterated methyl groups, i.e., -CDH2 or -CD2H. In some embodiments, R8 and R9 are fully deuterated methyl groups (-CD3). In some embodiments, at least one of R8 and R9 is -CD3.

[0147] In some embodiments, X1, X2, Y1, and Y2 are independently selected from the group consisting of hydrogen and deuterium. X1 and X2 may be the same or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium.

[0148] Y1 and Y2 may be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, X1, X2, Y1, and Y2 are hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium.

[0149] In some embodiments, X1, X2, Y1, Y2, R2, R5, R6, R7, R8, and R9 are each hydrogen. In some embodiments, at least one of X1, X2, Y1, Y2, R2, R5, R6, R7, R8, and R9 is deuterium. In some embodiments, at least X1, X2, R8, and R9 comprise deuterium. In some embodiments, at least X1, X2, Y1, Y2, R8, and R9 comprise deuterium. In some embodiments, X1, X2, Y1, and Y2 are deuterium, and R8 and R9 are fully deuterated methyl groups (-CD3).

[0150] The compound of formula (I) may contain an asymmetric center. In such cases, although formula (I) is drawn without regard to stereochemistry, the compound may exist as different stereoisomers. Thus, the present disclosure includes all possible stereoisomers, including not only racemates but also individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and non-racemic mixtures thereof. If a compound is desired as a single enantiomer, it can be obtained, for example, by stereospecific synthesis, as known in the art.

[0151] In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are asymmetric. In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are racemic. In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are enantiomerically enriched (one enantiomer is present in a higher proportion), including enantiomerically pure. In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are provided as a single diastereomer. In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixture can include an equal mixture or a mixture enriched in a particular diastereomer (one diastereomer is present in a higher percentage than another).

[0152] In some embodiments, the compounds of Formula (I) are agonists of the serotonin 5-HT2 receptor.

[0153] In some embodiments, the compound of formula (I) is a serotonin 5-HT 2A It is an agonist of the receptor.

[0154] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof.

[0155] A list of compound numbers, IUPAC names, and substituents for the compounds identified above is provided in Table 1. [Table 1]

[0156] In some embodiments, the compounds of the present disclosure are provided as free bases in crystalline form, as determined, for example, by XRPD and / or mDSC. Thus, pharmaceutical compositions may be prepared from the compound of Formula (I) as a free base in one or more crystalline (e.g., polymorphic) forms and used in the treatments described herein. In some embodiments, a crystalline form of the compound of Formula (I) as a free base is provided. For example, a pharmaceutical composition may include the free base of the compound of Formula (I), wherein at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 99% by weight, or at least 99.5% by weight of the free base of the compound of Formula (I) present in the pharmaceutical composition is in crystalline form, as determined, for example, by X-ray powder diffraction and / or mDSC. In some embodiments, a highly pure crystalline form of the compound of Formula (I) as a free base is provided. For example, the pharmaceutical composition may comprise the free base of the compound of formula (I), wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the free base of the compound of formula (I) present in the pharmaceutical composition is in crystalline form as determined, for example, by X-ray powder diffraction and / or mDSC.

[0157] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-2,5,6,7-d4-4-ol (I-1), as determined by X-ray powder diffraction.

[0158] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-2,5,6,7-d4-4-ol (I-2), as determined by X-ray powder diffraction.

[0159] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3), as determined by X-ray powder diffraction. In some embodiments, I-3 has the following peaks as determined by XRPD using a CuKα radiation source, for example, as shown in Figures 2A-2C: 7.582°, 8.395°, 9.647°, 10.444°, 11.319°, 12.614°, 13.372°, 14.222°, 15.157°, 16.524°, 16.787°, 17.693°, 19.468°, 19.699°, 20.901°, 21.132°, 21.859°, 22.547°, 23.699°, 24.630°, 25.034°, 26.034°, 27.034°, 28.034°, 29.034°, 30.034°, 31.034°, 32.034°, 33.034°, 34.034°, 35.034°, 36.034°, 37.034°, 38.034°, 39.034°, 40.034°, 41.034°, 42.034°, 43.034°, 44.034°, 45.034°, 46.034°, 47.034°, 48.034°, 49.034°, 50.034°, 51.034°, 52.034°, 53.034°, 54.034°, 55.034°, 56.034°, 57.0 A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 25.264°, 26.867°, 27.399°, 27.929°, 28.219°, 28.871°, 29.430°, 30.120°, 30.675°, 31.373°, 32.365°, 33.880°, 34.418°, 34.792°, 35.884°, 36.254°, 37.156°, 38.200°, and 38.417°.In some embodiments, I-3 has the following peaks as determined by XRPD using a CuKα radiation source, for example, as shown in Figures 88-89: 8.124°, 8.357°, 10.059°, 12.630°, 13.420°, 13.743°, 14.053°, 15.220°, 16.272°, 16.763°, 16.954°, 17.328°, 17.662°, 18.062°, 18.742°, 19.413°, 19.658°, 20.172°, 20.836°, 21.267°, 21.8 A crystalline solid form (Pattern 2) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 33°, 22.213°, 22.504°, 23.334°, 23.701°, 24.385°, 25.431°, 25.721°, 26.049°, 27.291°, 28.368°, 30.349°, 30.656°, 31.337°, 31.538°, 32.091°, 35.870°, 38.514°, and 41.361°.

[0160] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol (I-4), as determined by X-ray powder diffraction.

[0161] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-5), as determined by X-ray powder diffraction.

[0162] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl-2,2-d2)-1H-indol-4-ol (I-6), as determined by X-ray powder diffraction.

[0163] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7) as determined by X-ray powder diffraction. In some embodiments, I-7 exhibits the following peaks as determined by XRPD using a CuKα radiation source: 7.563°, 8.375°, 12.626°, 13.383°, 15.211°, 16.753°, 17.671°, 19.668°, 21.112°, 21.863°, 22.201°, 22.560°, 23.711°, 24.592°, 25.022°, 26.021°, 27.022°, 28.021°, 29.022°, 30.022°, 31.022°, 32.022°, 33.022°, 34.022°, 35.022°, 36.022°, 37.022°, 38.022°, 39.022°, 40.022°, 41.022°, 42.022°, 43.022°, 44.022°, 45.022°, 46.022°, 47.022°, 48.022°, 49.022°, 50.022°, 51.022°, 52.022°, 53.022°, 54.022°, 55.022°, 56.022°, 57.022°, 58.022°, A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 5.415°, 26.820°, 27.357°, 27.921°, 28.228°, 29.253°, 30.653°, 31.364°, 32.401°, 33.797°, 34.445°, and 39.867°.

[0164] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indol-4-ol (I-8), as determined by X-ray powder diffraction.

[0165] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl-1,1-d2)-1H-indol-4-ol (I-9), as determined by X-ray powder diffraction.

[0166] In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol (I-10), as determined by X-ray powder diffraction.

[0167] In some embodiments, the compounds of the present disclosure are provided as free bases in amorphous form, as determined, for example, by XRPD and / or mDSC. Thus, pharmaceutical compositions may be prepared from the compound of Formula (I) as a free base in one or more amorphous (e.g., polymorphic) forms and used in the treatments described herein. In some embodiments, highly pure amorphous forms of the compound of Formula (I) as a free base are provided. For example, a pharmaceutical composition may include the free base of the compound of Formula (I), wherein at least 92% by weight, at least 94% by weight, at least 96% by weight, at least 98% by weight, at least 99% by weight, or at least 99.5% by weight of the free base of the compound of Formula (I) present in the pharmaceutical composition is in amorphous form, as determined, for example, by X-ray powder diffraction and / or mDSC.

[0168] Numerous attempts to create amorphous forms of the compounds of the present disclosure have proven unsuccessful, including crush-freeze-drying, rapid evaporation from multiple organic solvents, and anti-solvent precipitation. Crush-freeze-drying and rapid evaporation techniques each yielded only crystalline material, while anti-solvent precipitation failed to produce solid material. Significant experimental work has led to the production of amorphous forms of compounds of formula (I), such as compound I-3 (psilocin-d). 10 It has been discovered that amorphous I-3 (PI-d) can be prepared by a melt / grind / cool procedure. Briefly, the crystalline free base material can be heated above its melting point, e.g., at least 180°C, at least 181°C, at least 182°C, at least 183°C, at least 184°C, or at least 185°C, as determined by differential scanning calorimetry (DSC) or a similar technique, followed by rapid cooling to near (e.g., ±5°C) the glass transition of the material, e.g., about 26°C, about 27°C, about 28°C, about 29°C, or about 30°C. For example, amorphous I-3 (PI-d) can be prepared by a melt / grind / cool procedure. 10It has been found that crystalline I-3 (I, free base) can be prepared by a DSC melt / grind / cool procedure in which crystalline I-3 is heated above its melting point (185°C) and then rapidly cooled to 30°C (glass transition temperature 27°C). The amorphous nature of the compound of formula (I) can be determined, for example, by XRPD.

[0169] In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-2,5,6,7-d4-4-ol (I-1) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-2,5,6,7-d4-4-ol (I-2) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol (I-4) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(dimethylamino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-5) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(dimethylamino)ethyl-2,2-d2)-1H-indol-4-ol (I-6) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indol-4-ol (I-8) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(dimethylamino)ethyl-1,1-d2)-1H-indol-4-ol (I-9) as determined by X-ray powder diffraction.In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol (I-10), as determined by X-ray powder diffraction.

[0170] Such amorphous forms (free bases) of the compound of Formula (I) may have an advantageous dissolution rate in water compared to crystalline forms, thereby enabling rapid systemic absorption for rapid therapeutic onset and short duration of drug action. Furthermore, in some embodiments, pharmaceutical compositions can be prepared that include amorphous forms (free bases) of the compound of Formula (I). The pharmaceutical compositions of the present disclosure, such as those described herein, can act to stabilize amorphous forms of the compound of Formula (I), which are unstable and prone to crystallization. Thus, pharmaceutical compositions can be used to stabilize these amorphous forms and deliver them to subjects in need of treatment for, for example, symptoms or diseases associated with the serotonin 5-HT2 receptor.

[0171] Salt Form Disclosed herein is a pharmaceutically acceptable salt of a compound of formula (I), or its pharmaceutically acceptable polymorph, stereoisomer, or solvate. The acid used to form a pharmaceutically acceptable salt of a compound of formula (I) may be a mono-, di-, tri-, tetra-, or more acid group. The acid group may be, for example, a carboxylic acid, a sulfonic acid, a phosphonic acid, or other acidic moiety containing at least one replaceable hydrogen atom.Examples of acids, which may be organic or inorganic, for use in preparing the pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene -2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo -Glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, These include, but are not limited to, tartaric acids (e.g., DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexanedio) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0172] Certain salts are preferred from the above list because they have physical and pharmaceutical characteristics / properties that make them more suitable for pharmaceutical preparation and administration. For example, preferred salt forms of the compounds disclosed herein (e.g., compounds of Formula (I)) have one or more of the following characteristics: they tend to form salts and are easy to prepare in high yields; they are stable and have well-defined physical properties, such as crystallinity, defined and reproducible polymorphism, if polymorphism exists, and high enthalpy of fusion; they are little or no hygroscopic; they are free-flowing, do not aggregate / adhere to surfaces, and have a regular morphology; they have an acceptable aqueous solubility and dissolution rate for the intended dosage form; and / or they are physiologically acceptable, e.g., do not cause undue irritation.

[0173] crystalline A pharmaceutically acceptable salt of a compound of Formula (I) may be crystalline or amorphous, for example, as determined by X-ray powder diffraction (XRPD) and / or mDSC. In some embodiments, the salt of a compound of Formula (I) is amorphous. Amorphous forms typically have higher aqueous solubility and dissolution rate than their crystalline counterparts and may therefore be suitable for fast-acting dosage forms adapted to rapidly release the active ingredient, such as orodispersible dosage forms (ODx) and immediate release (IR) dosage forms. The salt of a compound of Formula (I) may be in a stable amorphous form. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is provided in an amorphous form, for example, as determined by XRPD and / or mDSC. Thus, pharmaceutical compositions may be prepared from one or more amorphous forms of a pharmaceutically acceptable salt of a compound of Formula (I) and used in the treatments described herein. In some embodiments, a highly pure amorphous form of a pharmaceutically acceptable salt of a compound of Formula (I) is provided. For example, a pharmaceutical composition may comprise a pharmaceutically acceptable salt of a compound of Formula (I), wherein at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of a compound of Formula (I) present in the pharmaceutical composition is in amorphous form, as determined, for example, by X-ray powder diffraction and / or mDSC.

[0174] In some embodiments, the salt of the compound of formula (I) is crystalline. Crystalline forms are advantageous in terms of stability and provide well-defined physical properties that are desirable for pharmaceutical preparation and administration. The salt of the compound of formula (I) can be in a stable crystalline form. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) has a crystallinity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.5%, and up to 100%, as determined by XRPD and / or mDSC analysis. For example, a pharmaceutical composition may be provided containing a pharmaceutically acceptable salt of the compound of Formula (I), wherein at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of Formula (I) present in the pharmaceutical composition is in crystalline form, for example, as determined by X-ray powder diffraction and / or mDSC. In some embodiments, a highly pure crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I) is provided. For example, a pharmaceutical composition may be provided containing a pharmaceutically acceptable salt of the compound of Formula (I), wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of Formula (I) present in the pharmaceutical composition is in crystalline form, for example, as determined by X-ray powder diffraction and / or mDSC. For example, salt forms having a high degree of crystallinity, as determined by discrete and sharp Bragg diffraction in an X-ray diffractogram, are preferred.

[0175] XRPD analysis can be performed, for example, on a Bruker AXS D2 diffractometer using CuKα radiation (wavelength = 1.54060 Å). The instrument may be equipped with a fine focus X-ray tube. The tube voltage and amperage can be set to 30 kV and 10 mA, respectively, and a θ-θ geometry can be used using a LynxEye detector from 5 to 42°2θ, with a step size of 0.024°2θ and a collection time of 0.1 seconds per step.

[0176] With respect to pharmaceutical production processes, advantageous salt forms of the compound of formula (I) are those that readily give solid materials, either crystalline or amorphous, without oil, in acceptable yields and with favorable volume factors, and are suitable for large-scale production.

[0177] While salt forms of the compound of Formula (I) can exist in different polymorphic forms (i.e., forms having different crystalline structures), preferred salt forms of the present disclosure are those that can be produced as a single crystalline form or a single polymorphic form (including a single amorphous form) as measured by XRPD and / or mDSC and / or differential scanning calorimetry (DSC). It is also generally desirable for the salt to be free-flowing, not aggregate / adhere to surfaces, and have an ordered morphology.

[0178] Chemical / Solid State Stability In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has an onset of melting from about 90°C, from about 100°C, from about 110°C, from about 120°C, from about 130°C, from about 140°C, from about 150°C, from about 160°C, from about 170°C, from about 180°C, from about 190°C, and up to about 250°C, up to about 240°C, up to about 230°C, up to about 225°C, up to about 210°C, up to about 200°C, as determined by DSC.

[0179] Pharmaceutically acceptable salts of compounds of formula (I) may be characterized as non-hygroscopic or slightly hygroscopic, preferably non-hygroscopic. Hygroscopicity, as used herein, can be measured using a dynamic vapor sorption (DVS) analyzer by performing moisture sorption / desorption isotherms starting at 40% relative humidity (RH), increasing the humidity up to 90% RH, decreasing the humidity to 0% RH, increasing the humidity to 90% RH, decreasing the humidity to 0% RH, and finally increasing the humidity back to the starting 40% RH, and is classified according to the following: Non-hygroscopic: <0.2%. Slightly hygroscopic: ≥0.2% to <2%. Hygroscopic: ≥2% to <15%. Very hygroscopic: ≥15%. Deliquescent: Sufficient water is absorbed to form a liquid. All values ​​are measured as weight gain (w / w due to water gain) at >90% RH and 25°C.

[0180] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) has a weight gain >90% RH as measured by DVS of less than 1% w / w, less than 0.8% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, less than 0.1% w / w, less than 0.08% w / w, less than 0.06% w / w, less than 0.05% w / w, less than 0.02% w / w.

[0181] Dry powder samples of the free base and salts can be maintained / stored in open or closed environments, such as open or closed flasks / vials, without significant degradation or physical change (e.g., change in morphology, decomposition, etc.) under ambient or stress conditions, e.g., 25°C / 90+% RH, 40°C / 75% RH, etc. For example, dry powder samples of the free base and salt forms disclosed herein can have less than 10%, less than 5%, and less than 1% change in purity or morphology when stored under ambient or stress conditions (e.g., elevated temperature, e.g., 40°C, and / or humidity).

[0182] The solution-phase compositions of the free base and salts can be maintained / stored in an open or closed environment, such as an open or closed flask / vial, under ambient or stress conditions, e.g., 25°C / 90+% RH, 40°C / 75% RH, etc., without significant decomposition. Thus, in some embodiments, the present disclosure provides stable solution-phase compositions of the free base and salt forms of the compound of Formula (I) (e.g., stable solvates of the free base or salt form of the compound of Formula (I) in a solvated form, preferably a fully solvated form), that can be stored for extended periods of time as a solution, e.g., in the form of an aqueous solution, an organic solvent solution, or an aqueous-organic solvent mixture, without significant decomposition or physical changes, such as oiling of the solution. The solvent that can be used to form the solution-phase composition can be any one or more of the solvents described herein, e.g., water, ethanol, fruit juice, etc. In some embodiments, the solution-phase composition is an aqueous-phase composition comprising the free base or pharmaceutically acceptable salt of the compound of Formula (I) solvated with water (and optionally containing other components, such as those found in fruit juice). The identification of stable solution phase compositions of compounds of Formula (I) and their salts is advantageous at least because such compositions do not need to be used immediately after preparation, e.g., within 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, 45 seconds, 30 seconds, 15 seconds, or 10 seconds after preparation. Instead, the stable solution phase compositions of compounds of Formula (I) and their salts described herein can be prepared in advance, if desired, and optionally stored, and can be administered within hours, days, or even weeks after preparation without substantially affecting efficacy, e.g., without significant degradation of the psilocin or psilocin-type active agent.

[0183] In some embodiments, aqueous solutions formed from pharmaceutically acceptable salts of the compound of Formula (I) are characterized by increased stability compared to aqueous solutions prepared from the compound of Formula (I) (free base) but otherwise substantially the same. For example, the pharmaceutically acceptable salts of the compound of Formula (I) may be at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more stable in terms of percent (active) remaining in aqueous solutions exposed to 40°C for 24 hours, regardless of the presence or absence of metal ions, compared to aqueous solutions prepared using the compound of Formula (I) (free base), but otherwise substantially the same. Such improved stability behavior can also be found in pharmaceutical compositions of the present disclosure.

[0184] Samples are taken at predetermined time points and analyzed for stability, morphological changes, etc., e.g. 1 Analysis can be performed using H NMR, XRPD, HPLC with UV-visible multi-wavelength detector, UPLC, etc.

[0185] Physiological acceptability Suitable salt forms of the compounds of formula (I) are physiologically acceptable. Thus, preferred addition salts of compounds of formula (I) are formed with organic acids, preferably organic acids having a moderate or mild acidity, for example, a pK in water of -3.0 or more, -2.0 or more, -1.0 or more, 0 or more, 1.0 or more, 1.5 or more, 2.0 or more, 2.5 or more, 3.0 or more, 3.5 or more, 4.0 or more, 4.5 or more, for example, 3.0 to 6.5. a Furthermore, depending, for example, on the route of administration and the optional use of taste-masking agents such as sweeteners, flavorings, etc., it may be desirable to use acid addition salts that impart a pleasant taste profile (e.g., sweet, citrusy, etc.), while unpleasant-tasting salt forms (e.g., bitter, astringent, etc.) may still be acceptable.

[0186] solubility The aqueous solubility of a salt form of the compound of Formula (I) can be determined by equilibrating an excess of the solid with 1 mL of water at 22°C for 24 hours. A 200 μL aliquot can be centrifuged at 15,000 rpm for 15 minutes. The supernatant can be analyzed by HPLC, and the solubility can be expressed as free base equivalents (mg FB / mL). For example, a pharmaceutically acceptable salt of the compound of Formula (I) can be prepared, and the solubility and pH of the solution can be measured.

[0187] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has an aqueous solubility at 22°C of from about 1 mg / mL to about 400 mg / mL. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has an aqueous solubility of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, and up to about 400 mg / mL, up to about 380 mg / mL, up to about 360 mg / mL, up to about 340 mg / mL, up to about 320 mg / mL, up to about 300 mg / mL, up to about 280 mg / mL, up to about 260 mg / mL, or up to about 250 mg / mL. Some salt forms of the compounds described herein exhibit the above solubility and are capable of achieving a final water pH of approximately 3-6 without gelling.

[0188] In some embodiments, the salt of the compound of Formula (I) has an aqueous solubility of about 200 mg / mL to about 400 mg / mL. In some embodiments, the salt of the compound of Formula (I) has an aqueous solubility of about 150 mg / mL to about 250 mg / mL. In some embodiments, the salt of the compound of Formula (I) has an aqueous solubility of greater than about 1 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL.

[0189] In some embodiments, the salt form of the compound of Formula (I) has a dissolution rate that allows for rapid systemic absorption for a rapid therapeutic onset and a short duration of drug action. In some embodiments, the salt of the compound of Formula (I) is soluble in aqueous media below about pH 7.5, e.g., pH 1-7, pH 3-7, or pH 4-7.

[0190] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, hemimalonate, malonate, fumarate, succinate, hemisuccinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, methanesulfonate, toluenesulfonate, glucuronate, or glutarate salt of a compound of Formula (I). In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a salt formed with a sulfonic acid (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a salt formed with a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, etc.). A pharmaceutically acceptable salt of a compound of Formula (I) may be a hemi-acid salt of any of the salts listed above when the acid used to form the salt contains two or more acidic groups (e.g., two or more carboxylic acid moieties).

[0191] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a benzenesulfonate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a tartrate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a hemifumarate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is an acetate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a citrate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a hemimalonate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a fumarate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a hemisuccinate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is an oxalate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a benzoate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a salicylate. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is an ascorbate. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a hydrochloride salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a maleate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a malate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a methanesulfonate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a toluenesulfonate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a glucuronate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a glutarate salt.

[0192] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, hemimalonate, fumarate, hemisuccinate, oxalate, benzoate, or salicylate salt of the compound of Formula (I), with the benzenesulfonate, hemisuccinate, or benzoate salt of the compound of Formula (I) being preferred, and the benzenesulfonate or benzoate salt of the compound of Formula (I) being particularly preferred.

[0193] Exemplary pharmaceutically acceptable salt forms (ie, addition salt forms) of the above-identified compounds are provided in Table 2. [Table 2] JPEG2024540282000012.jpg125164

[0194] In some embodiments, the pharmaceutically acceptable salt is the benzenesulfonic acid salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3a). In some embodiments, salt I-3a has peaks of 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 19.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, as determined by XRPD using a CuKα radiation source, as shown, for example, in Figures 63A-63D. and 40.988° (2θ±0.2°).

[0195] In some embodiments, the pharmaceutically acceptable salt is the benzenesulfonate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7a). In some embodiments, salt I-7a exhibits peaks of 7.002°, 7.733°, 11.768°, 12.516°, 12.882°, 13.546°, 13.968°, 14.788°, 15.225°, 15.474°, 18.370°, 19.737°, 20.703°, 21.050°, 21.873°, 21.982°, 22.315°, 22.639°, 23.025°, as determined by XRPD using a CuKα radiation source, for example, as shown in Figures 3A-3B. A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 282°, 23.775°, 24.125°, 25.193°, 25.475°, 25.931°, 26.813°, 27.778°, 28.127°, 30.866°, 31.207°, 32.941°, 33.222°, 33.698°, 36.803°, 38.668°, and 39.289°.

[0196] In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3j). In some embodiments, salt I-3j exhibits peaks of 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.831°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.024°, 26.024°, 27.024°, 28.024°, 29.024°, 30.024°, 31.024°, 32.024°, 33.024°, 34.024°, 35.024°, 36.024°, 37.024°, 38.024°, 39.024°, 40.024°, 41.024°, 42.024°, 43.024°, 44.024°, 45.024°, 46.024°, 47.024°, 48.024°, 49.024°, 50.024°, 51.024°, 52.024°, 53.024°, 54.024°, 55.024°, 56.024°, 57.0 A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 5.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597°.

[0197] In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7j). In some embodiments, salt I-7j exhibits peaks of 9.492°, 11.011°, 12.391°, 13.440°, 14.609°, 15.432°, 16.394°, 18.259°, 18.967°, 19.356°, 19.827°, 20.843°, 21.476°, 22.062°, 22.805°, 23.862°, 24.96°, as determined by XRPD using a CuKα radiation source, for example, as shown in Figures 53A-53B. and 38.643°, 39.3°, 40.3°, 41.3°, 42.3°, 43.3°, 44.3°, 45.734°, 46.170°, 46.992°, 47.738°, 48.593°, 49.3°, 50.073°, 51.041°, 52.794°, 53.551°, 54.480°, 55.430°, 56.3°, 57.3°, 58.3°, 59.3°, 60.3°, 61.3°, 62.3°, 63.3°, 64.3°, 65.734°, 66.170°, 67.3°, 68.3°, 69.3°, 70.3°, 71.3°, 72.3°, 73.3°, 74.3°, 75.3°, 76.3°, 77.3°, 78.3°, 79.3°, 80.3°, 81.3°, 82.3°, 83.3°, 84.3°, 85.3°, 86.3°, 87.3°, 88.3°, 89.3°, 90.3°, 91.3°, 92.3°, 93.3°, 94.3°, 95.3°, 96.3°, 97.3°, 98.3°, 99.3°, 99.3°, 90.3°, 91.3°, 92.3°, 93.3°, 94.3°

[0198] In some embodiments, the pharmaceutically acceptable salt is the citrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3e). In some embodiments, salt I-3e is in the form of an amorphous solid as characterized by X-ray powder diffraction (XRPD).

[0199] In some embodiments, the pharmaceutically acceptable salt is the citrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7e). In some embodiments, salt I-7e is in the form of an amorphous solid when characterized by X-ray powder diffraction (XRPD), for example, as shown in Figures 37A-37B.

[0200] In some embodiments, the pharmaceutically acceptable salt is the tartrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3b). In some embodiments, salt I-3b is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in Figure 66. In some embodiments, salt I-3b has a molecular weight of 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.50°, as determined by XRPD using a CuKα radiation source, as shown, for example, in Figures 69A-69B. and 41.049°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049°.

[0201] In some embodiments, the pharmaceutically acceptable salt is the tartrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7b). In some embodiments, salt I-7b has peaks of 6.798°, 11.360°, 12.764°, 13.535°, 14.837°, 15.973°, 16.351°, 17.367°, 18.937°, 20.168°, 20.929°, 21.946°, 22.719°, 23.604°, 23.814°, 24.874°, 25.609°, 26.798°, 27.798°, 28.798°, 29.798°, 30.798°, 31.798°, 32.798°, 33.798°, 34.798°, 35.798°, 36.798°, 37.798°, 38.798°, 39.798°, 40.798°, 41.798°, 42.798°, 43.798°, 44.798°, 45.798°, 46.798°, 47.798°, 48.798°, 49.798°, 50.798°, 51.798°, 52.798°, 53.798°, 54.798°, 55.798°, 56.798°, 57.798°, 58.798°, 59. 12. In some embodiments, salt I-7b is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 26.745°, 27.111°, 27.558°, 28.653°, 29.630°, 31.129°, 31.567°, 32.180°, 33.073°, 34.096°, 34.460°, 36.226°, 37.497°, 38.727°, and 41.126° (Pattern 1). In some embodiments, salt I-7b is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 2, as shown, for example, in FIG.In some embodiments, salt I-7b exhibits the following peaks as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 18 : 6.479°, 10.486°, 10.862°, 11.913°, 12.222°, 12.972°, 13.161°, 13.467°, 14.230°, 15.372°, 15.736°, 16.053°, 17.282°, 18.292°, 19.292°, 20.292°, 21.292°, 22.292°, 23.292°, 24.292°, 25.292°, 26.292°, 27.292°, 28.292°, 29.292°, 30.292°, 31.292°, 32.292°, 33.292°, 34.292°, 35.292°, 36.292°, 37.292°, 38.292°, 40.292°, 41.292°, 42.292°, 43.292°, 44.292°, 45.292°, 46.292°, 47.292°, 48.292°, 49.292°, 50.292°, 51.292°, 52.292°, 53.292°, 54.292°, 55.292°, 56.292°, 57.292°, 16.457°, 16.613°, 17.009°, 17.695°, 17.913°, 18.486°, 18.795°, 19.479°, 20.101°, 20.416°, 20.818°, 21.352°, 22.106°, 22.320°, 22.629°, 22.964°, 23.698°, 23.950°, 24.175°, 24.439°, 24.818°, 25.079°, 25.880°, 26.528°, 27.297°, 27.752°, 28.124°, 28.349°, 28.631°, 29.075°, 29.819°, 30.202°, ​​30.562°, 31.025°, 31.207°, 31.650°, 31.953°, 33.721°, 34.362°, 34.651° , a crystalline solid form (pattern 3) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 34.994°, 35.512°, 35.982°, 36.450°, 37.476°, 38.287°, 39.699°, 39.980°, 40.951°, and 41.870°.

[0202] In some embodiments, the pharmaceutically acceptable salt is the hemifumarate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7c). In some embodiments, salt I-7c is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, 2, 3, or 4, e.g., as shown in Figures 23 and 29. In some embodiments, salt I-7c exhibits the following peaks as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 42 : 8.483°, 8.733°, 11.080°, 11.351°, 11.622°, 12.615°, 13.258, 14.977°, 15.557°, 16.089°, 16.319°, 16.606°, 17.013°, 18.928°, 18.884°, 19.429°, 19.518°, 20.518°, 21.518°, 22.518°, 23.518°, 24.518°, 25.518°, 26.518°, 27.518°, 28.518°, 29.518°, 30.518°, 31.518°, 32.518°, 33.518°, 34.518°, 35.518°, 36.518°, 37.518°, 38.518°, 39.518°, 40.518°, 42.518°, 43.518°, 44.518°, 45.518°, 46.518°, 47.518°, 48.518°, 49.518°, 50.518°, 52.518°, 53.518°, 54.518°, 55.518°, 56.518°, 5 A crystalline solid form (Pattern 5) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.734°, 20.643°, 21.484°, 22.067°, 23.433°, 24.466°, 24.885°, 26.740°, 27.900°, 28.557°, 29.523°, 32.888°, 34.183°, and 36.808°. In some embodiments, salt I-7c exhibits the following peaks as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 42: 9.746°, 11.354°, 12.338°, 13.762°, 16.111°, 16.644°, 19.929°, 20.180°, 21.576°, 22.758°, 23.348°, 23.938°, 24.7 A crystalline solid form (Pattern 6) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 24°, 25.226°, 26.203°, 27.910°, 29.056°, 29.499°, 32.753°, 35.567°, 37.279°, 37.347°, and 39.481°.

[0203] In some embodiments, the pharmaceutically acceptable salt is the hemifumarate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3c). In some embodiments, salt I-3c is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, as shown, for example, in Figures 72 and 75A. In some embodiments, salt I-3c has the following peaks as determined by XRPD using a CuKα radiation source, e.g., as shown in Figure 75B: 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429° , 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999° (Pattern 2).

[0204] In some embodiments, the pharmaceutically acceptable salt is the acetate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7d). In some embodiments, salt I-7d is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1 or 2, e.g., as shown in Figure 32.

[0205] In some embodiments, the pharmaceutically acceptable salt is the hemimalonate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7f). In some embodiments, salt I-7f is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, as shown in Figure 39.

[0206] In some embodiments, the pharmaceutically acceptable salt is the hemisuccinate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7h). In some embodiments, salt I-7h is a crystalline solid form characterized by X-ray powder diffraction of pattern 1, e.g., as shown in Figure 47.

[0207] In some embodiments, the pharmaceutically acceptable salt is the oxalate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7i). In some embodiments, salt I-7i is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, 2, 3, 4, 5, or 6, e.g., as shown in Figure 50.

[0208] In some embodiments, the pharmaceutically acceptable salt is the salicylate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7k). In some embodiments, salt I-7k is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, 2, or 3, e.g., as shown in Figure 60.

[0209] Without being bound by any particular theory, it is believed that the novel salts of the compound of formula (I) are stable and have a faster / rapid onset of therapeutic action, a shorter duration of drug action (i.e., a shorter duration of therapeutic effect), and less variable exposure than psilocybin-based drugs (e.g., psilocybin).

[0210] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is a fatty acid salt. The fatty acid used to prepare the fatty acid salt of the compound of Formula (I) may be a fatty monoacid or a fatty diacid, and may contain a fatty hydrocarbon moiety consisting of hydrogen and 4, 6, 8, 10, 12, 14, 16, and up to 26, up to 24, up to 22, up to 20, or up to 18 carbon atoms, and may be fully saturated or partially unsaturated. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is an adipate, laurate, linoleate, myristate, caprate, stearate, oleate, caprylate, palmitate, sebacate, undecylenate, or caproate salt of the compound of Formula (I). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is an adipate, laurate, linoleate, myristate, caprate, stearate, oleate, or caprylate salt of the compound of Formula (I), with the laurate, linoleate, caprate, or caprylate salt of the compound of Formula (I) being preferred.

[0211] Exemplary pharmaceutically acceptable fatty acid salt forms (ie, addition salt forms) of the above-identified compounds are provided in Table 3. [Table 3]

[0212] In some embodiments, the pharmaceutically acceptable salt is the laurate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3m). In some embodiments, salt I-3m is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, as shown in Figure 90.

[0213] In some embodiments, the pharmaceutically acceptable salt is the linoleic acid salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3n). In some embodiments, salt I-3n is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, as shown in Figure 91.

[0214] In some embodiments, the pharmaceutically acceptable salt is the myristate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3o). In some embodiments, salt I-3o is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, as shown in Figure 92.

[0215] In some embodiments, the pharmaceutically acceptable salt is the caprate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3p). In some embodiments, salt I-3p is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, as shown in Figure 93.

[0216] In some embodiments, the pharmaceutically acceptable salt is the stearate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3q). In some embodiments, salt I-3q is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1 or 2, e.g., as shown in Figure 94.

[0217] In some embodiments, the pharmaceutically acceptable salt is the oleate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3r). In some embodiments, salt I-3r is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1 or 2, e.g., as shown in Figure 95.

[0218] In some embodiments, the pharmaceutically acceptable salt is the caprylic acid salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3s). In some embodiments, salt I-3s is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, as shown in Figure 96.

[0219] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has a solubility in corn oil at 22°C of about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, and up to about 2 mg / mL, up to about 1.9 mg / mL, up to about 1.8 mg / mL, up to about 1.7 mg / mL, up to about 1.6 mg / mL, up to about 1.5 mg / mL, up to about 1.4 mg / mL, up to about 1.3 mg / mL, up to about 1.2 mg / mL.

[0220] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has a solubility in Crodamol® GTCC (medium chain glycerides, from Croda) at 22°C of about 0.4 mg / mL, about 0.6 mg / mL, about 0.8 mg / mL, about 1 mg / mL, about 1.2 mg / mL, about 1.4 mg / mL, about 1.6 mg / mL, and up to about 4 mg / mL, up to about 3.8 mg / mL, up to about 3.6 mg / mL, up to about 3.4 mg / mL, up to about 3.2 mg / mL, up to about 3 mg / mL, up to about 2.8 mg / mL, up to about 2.6 mg / mL, up to about 2.4 mg / mL, up to about 2.2 mg / mL.

[0221] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has a solubility of about 0.8 mg / mL, about 1 mg / mL, about 1.2 mg / mL, about 1.4 mg / mL, about 1.6 mg / mL, about 1.8 mg / mL, about 2 mg / mL, and up to about 5 mg / mL, up to about 4.8 mg / mL, up to about 4.6 mg / mL, up to about 4.4 mg / mL, up to about 4.2 mg / mL, up to about 4 mg / mL, up to about 3.8 mg / mL, up to about 3.6 mg / mL, up to about 3.4 mg / mL, up to about 3.2 mg / mL, up to about 3 mg / mL, up to about 2.8 mg / mL, up to about 2.6 mg / mL, up to about 2.4 mg / mL, up to about 2.2 mg / mL in Maisine® CC (a mixture of unsaturated mono-, di-, and triglycerides, from Gattefosse) at 22°C.

[0222] Due to their relatively hydrophobic nature, fatty acid salts of compounds of formula (I) can be advantageous when used in drugs that are adapted to modified, controlled, sustained-release, or sustained-release profiles.As a result, fatty acid salts of compounds of formula (I) are well suited to dosage forms that are adapted to provide low doses of active pharmaceutical ingredients (API) over long periods of time (e.g., subcutaneous, transdermal, etc.) and / or administration routes, as well as non-hallucinogenic administration regimens.Non-limiting examples of such dosage forms include, but are not limited to, depots, patches including microneedle patches, liposomes, micelles, microspheres, nanosystems, or other controlled release devices as described herein.

[0223] Also disclosed herein is a method for stabilizing a compound of formula (I), comprising preparing a pharmaceutically acceptable salt of a compound of formula (I).

[0224] Also disclosed herein are methods for preparing pharmaceutically acceptable salts of compounds of Formula (I). In some embodiments, the methods comprise: (a) suspending the free base of the compound of formula (I) in a solvent or mixture of solvents; (b) contacting an acid with a compound of formula (I) to provide a mixture; (c) optionally heating the mixture; (d) optionally cooling the mixture; (e) isolating the salt.

[0225] A variety of solvents can be used in the disclosed methods, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent used in the method of preparing the salt is a protic solvent. In some embodiments, the solvent used in the method of preparing the salt is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxane (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ethereal solvents (e.g., t-butyl methyl ether (TBME)), hexane, heptane, and octane, and combinations thereof. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is tetrahydrofuran.

[0226] Acids suitable for use in preparing pharmaceutically acceptable acid addition salts can include those previously described. The acid can be an inorganic acid, such as hydrochloric acid, or an organic acid, with organic acids being preferred. In some embodiments, the acid is an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, maleic acid, malonic acid, (-)-L-malic acid, (+)-L-tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, D-glucuronic acid, glutarate, and acetic acid. In some embodiments, the acid is an organic acid selected from the group consisting of benzenesulfonic acid, (+)-L-tartaric acid, fumaric acid, acetic acid, citric acid, malonic acid, succinic acid, oxalic acid, benzoic acid, and salicylic acid, with benzenesulfonic acid, succinic acid, and benzoic acid being preferred. In some embodiments, the acid is a fatty acid, such as adipic (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, caprylic (octano) acid, palmitic (hexadeceno) acid, sebacic acid, undecylenic acid, caproic acid, and the like, with specific mention being made of adipic (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, and caprylic (octano) acid.

[0227] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with the compound of Formula (I). In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with the compound of Formula (I). For example, when the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt, using a substoichiometric amount of acid may be desirable.

[0228] In some embodiments, the mixture is heated, for example, to reflux, before cooling.

[0229] In some embodiments, the mixture is cooled, causing the salt to precipitate from solution. In some embodiments, the salt precipitates from solution in a crystalline form. In some embodiments, the salt precipitates from solution in an amorphous form.

[0230] Isolation of the salt can be accomplished by a variety of well-known isolation techniques, such as filtration, decantation, etc. In some embodiments, the isolation step comprises filtering the mixture.

[0231] After isolation, additional crystallization and / or recrystallization steps may also be optionally performed, if desired, to, for example, increase purity, crystallinity, etc.

[0232] In some embodiments, a compound of the present disclosure, e.g., a compound of Formula (I), or any pharmaceutically acceptable salt, polymorph, or stereoisomer thereof, is in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanolate salts, ethanolate salts, isopropanolate salts, etc., with hydrates and ethanolate salts being preferred. Solvates can be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. Solvates of the compounds of the present disclosure may be in the form of isolatable solvates. In one non-limiting example, as a hydrate, the compound may be a monohydrate, a dihydrate, etc. Solvates of the compounds of the present disclosure also include solution-phase forms. Thus, in some embodiments, the present disclosure provides a solution-phase composition of a compound of the present disclosure, or any pharmaceutically acceptable salt thereof, in a solvated form, preferably a fully solvated form.

[0233] Pharmaceutical Composition Also disclosed herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and a pharmaceutically acceptable vehicle. The pharmaceutical compositions may contain one or more compounds, salt forms, polymorphs, stereoisomers, and / or solvates of the present disclosure.

[0234] Pharmaceutical compositions may comprise a single compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, or a mixture of compounds of Formula (I), either in free base or salt form, including one or more polymorphs of such materials. Pharmaceutical compositions may be formed from isotopic mixtures of the disclosed compounds. In some embodiments, the subject compound of Formula (I) may be present in a pharmaceutical composition with a purity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight, based on the total weight of the isotopic substitutions of the compound of Formula (I) present in the pharmaceutical composition. For example, a pharmaceutical composition formulated with psirosin d-10 (compound I-3; 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol) in either the free base or salt form of the subject compound, its stereoisomer, solvate, or mixture may additionally contain an isotopologue of the subject compound, such as psirosin d-9, psirosin d-8 (compound I-4; 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol), e.g., as the free base or salt form, or a polymorph, stereoisomer, solvate, or mixture thereof. In some embodiments, the composition is substantially free of other isotopologues of either the free base or salt form of the compound, e.g., the composition has less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or 0.5 mole percent of other isotopologues of the compound.

[0235] In some embodiments, any position in a deuterium-bearing compound has a minimum deuterium incorporation that is greater than the naturally occurring percentage in hydrogen (about 0.016 atomic percent). In some embodiments, any position in a deuterium-bearing compound has a minimum deuterium incorporation of at least 10 atomic percent, at least 20 atomic percent, at least 25 atomic percent, at least 30 atomic percent, at least 40 atomic percent, at least 45 atomic percent, at least 50 atomic percent, at least 60 atomic percent, at least 70 atomic percent, at least 80 atomic percent, at least 90 atomic percent, at least 95 atomic percent, or at least 99 atomic percent at the deuteration site.

[0236] Pharmaceutical compositions can be formulated using enantiomerically pure compounds of the present disclosure, such as compounds of Formula (I), or racemic mixtures of compounds. As described herein, racemic compounds of Formula (I) can contain about 50% of the R- and S-stereoisomers based on a molar ratio of one of the isomers (about 48 to about 52 mole %, or about a 1:1 ratio). In some embodiments, a composition, medicament, or method of treatment can involve combining separately produced R- and S-stereoisomers of a compound in an approximately equal molar ratio (e.g., about 48 to 52%). In some embodiments, a medicament or pharmaceutical composition can include a mixture of different ratios of R- and S-stereoisomers of distinct compounds. In some embodiments, a pharmaceutical composition contains an excess (greater than 50%) of the R-enantiomer. Suitable R / S molar ratios can be about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher. In some embodiments, the pharmaceutical composition can contain an excess of the S-enantiomer, reversing the provided ratio of R / S. Other suitable amounts of R / S can also be selected. For example, the R-enantiomer can be enriched, e.g., at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. In other embodiments, the S-enantiomer can be enriched, e.g., at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. Ratios between all of these exemplary embodiments, as well as larger and smaller ratios, are still within the scope of the present disclosure. The composition may contain a mixture of the racemate and a separate compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof.

[0237] Pharmaceutical compositions may be formulated with one or more polymorphs of the compound of Formula (I) and / or its salt forms, including crystalline and / or amorphous polymorphs of the compound or its salts. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a single crystalline polymorph. In some embodiments, the pharmaceutical composition comprises a mixture of amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a single amorphous polymorph. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline and amorphous polymorphs.

[0238] In some embodiments, the pharmaceutical composition comprises a crystalline form of the compound of Formula (I) (or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof). In some embodiments, the pharmaceutical composition comprises a highly pure crystalline form of the compound of Formula (I) as the free base. For example, the pharmaceutical composition may comprise the free base of the compound of Formula (I), wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the free base of the compound of Formula (I) present in the pharmaceutical composition is in crystalline form, as determined, for example, by X-ray powder diffraction and / or mDSC. In some embodiments, the pharmaceutical composition comprises a highly pure crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I). For example, the pharmaceutical composition may comprise a pharmaceutically acceptable salt of the compound of formula (I), wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of formula (I) present in the pharmaceutical composition is in crystalline form as determined, for example, by X-ray powder diffraction and / or mDSC.

[0239] In some embodiments, the pharmaceutical composition comprises an amorphous form of the compound of Formula (I) (or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof). In some embodiments, only the amorphous form of the compound of Formula (I) (or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof) is present in the pharmaceutical composition; e.g., no crystalline form of the compound of Formula (I) is detected, e.g., by XRPD. In some embodiments, the pharmaceutical composition comprises a highly pure amorphous form of the compound of Formula (I) as the free base. For example, the pharmaceutical composition may comprise the free base of the compound of Formula (I), wherein at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or at least 99.5% by weight of the free base of the compound of Formula (I) present in the pharmaceutical composition is in amorphous form, as determined, e.g., by X-ray powder diffraction and / or mDSC. In some embodiments, the pharmaceutical composition comprises a highly pure amorphous form of a pharmaceutically acceptable salt of the compound of Formula (I). For example, the pharmaceutical composition may comprise a pharmaceutically acceptable salt of the compound of Formula (I), wherein at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of Formula (I) present in the pharmaceutical composition is in amorphous form as determined, for example, by X-ray powder diffraction and / or mDSC.

[0240] In some embodiments, the compound of Formula (I) (or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) is chemically pure, e.g., has a chemical purity of greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% by HPLC. In some embodiments, the compound of Formula (I) (or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) has no single impurity of greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, the compound of Formula (I) (or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, the compound of formula (I) (or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) has no more than 1 area%, more than 0.5 area%, more than 0.4 area%, more than 0.3 area%, or more than 0.2 area% of a single impurity as measured by HPLC.

[0241] Generally, pharmaceutical compositions containing about 0.1 to about 1000 mg, about 1 to about 500 mg, about 2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, or about 500 mg of one or more compounds disclosed herein as active pharmaceutical ingredients (API), either in free base or salt form, may be provided herein. The amount of the compound of Formula (I) (on an active basis) in a unit dose preparation may be varied or adjusted within the above ranges as deemed appropriate, using sound medical judgment, depending on the particular application, route of administration, potency of the active ingredient, and the like. The compositions may also contain other compatible therapeutic agents, if desired.

[0242] In some embodiments, the pharmaceutical composition comprises at least 0.1%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, and up to 99.9%, up to 99.5%, up to 99%, up to 98%, up to 97%, up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, or any range therebetween, by weight of a compound of Formula (I) (on an active form basis), based on the total weight of the pharmaceutical composition (or on a dry weight basis). A dry weight basis may refer to a pharmaceutical composition that is a solid dosage form, or a liquid dosage form, after subtracting the weight contribution from water or other pharmaceutically acceptable aqueous medium (e.g., fruit juice).

[0243] In addition to the compound of formula (I) or its pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate, the pharmaceutical composition of the present disclosure also includes a pharmaceutically acceptable vehicle. A "pharmaceutically acceptable vehicle" may be a solvent approved by a federal or state government regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in mammals, such as humans. The term "vehicle" refers to a diluent, adjuvant, excipient, or carrier in which the compound of the present disclosure is formulated for administration to a mammal. Such a pharmaceutically acceptable vehicle may be solid or liquid. Pharmaceutically acceptable vehicles include water, saline, juices, including fruit juices (e.g., orange juice such as Tang's, grape juice, apple juice, cranberry juice, pineapple juice, etc.), oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc., acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Pharmaceutically acceptable vehicles include, but are not limited to, adjuvants, stabilizers, solubilizers, thickeners, lubricants, binders, granulators, bulking agents, diluents, disintegrants, humectants, glidants, anti-caking agents, colorants, sweeteners, dye flow inhibitors, preservatives, antioxidants, cryoprotectants, complexing agents, flavoring agents, matrix formers, performance modifiers, sustained-release polymers, solvents, pH adjusters, carbon dioxide sources, or other pharmaceutical excipients described herein.

[0244] Among these pharmaceutically acceptable vehicles, some organic acids have been identified as providing both stabilizing and solubilizing functions to the psilocin and deuterated psilocin compounds of the present disclosure (e.g., the compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof), thereby improving the delivery and therapeutic properties of the dosage forms of the present disclosure. These organic acid vehicles, which provide inherent stabilizing and solubilizing effects (acting as stabilizers / solubilizers), may be referred to herein as "organic acid agents." In a preferred embodiment, the pharmaceutical composition comprises the compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and an organic acid agent. The pharmaceutical composition may optionally be formulated with other pharmaceutically acceptable vehicles, if necessary or desired.

[0245] In some embodiments, a solid dosage form is formulated with an organic acid agent, in which case the organic acid agent is considered to be separate and distinct from the compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof. That is, when formulated into a solid dosage form, the organic acid agent is not considered to form a salt with the compound of Formula (I). For example, in embodiments where the pharmaceutical composition is a solid dosage form formulated with the free base of the compound of Formula (I), the organic acid agent is not considered to form an addition salt with the compound of Formula (I); instead, the compound of Formula (I) remains as a free base, at least until dissolved / disintegrated in an appropriate medium (e.g., water, juice, saline, saliva, etc.). In another example, when a pharmaceutical composition is formulated using a salt form of the compound of Formula (I), the organic acid agent remains separate from the salt form and provides a stabilizing / solubilizing effect that exceeds the effect provided by the salt form of the compound of Formula (I).

[0246] The organic acid agent may be any organic acid described herein and may be a mono-, di-, tri-, tetra-, or more acid group. One organic acid agent or a mixture of organic acid agents may be used. In addition to an acid group (e.g., one or more carboxylic acid moieties), the organic acid agent may also contain one or more hydroxyl functional groups as part of its structure (i.e., the organic acid agent may be a hydroxy acid). In some embodiments, the organic acid agent is an alpha-hydroxy acid. In some embodiments, the organic acid agent is a beta-hydroxy acid. In some embodiments, the organic acid agent is a gamma-hydroxy acid. Examples of hydroxy acids include, but are not limited to, glycolic acid, lactic acid, citric acid, tartaric acid, and malic acid. In some embodiments, the organic acid agent is citric acid and / or tartaric acid. In some embodiments, the organic acid agent is citric acid. In some embodiments, the organic acid agent is tartaric acid. In some embodiments, the organic acid agent is an enedioic acid, examples of which include, but are not limited to, fumaric acid and maleic acid. In some embodiments, the organic acid agent is fumaric acid. In some embodiments, the organic acid agent is maleic acid. Mixtures and / or hydrates of the disclosed organic acid agents may also be used in the pharmaceutical compositions of the present disclosure. In some embodiments, the organic acid agent is not a sulfonic acid (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, the organic acid agent is not a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.).

[0247] In some embodiments, the pharmaceutical composition comprises at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, and up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 27%, up to 25%, up to 23%, up to 20%, up to 18%, up to 16%, or any range therebetween, by weight of an organic acid agent, based on the total weight of the pharmaceutical composition (or on a dry weight basis). For example, the pharmaceutical composition may contain 5% to 40% by weight of the organic acid agent, or 10% to 30% by weight of the organic agent, or 15% to 20% by weight of the organic acid agent, based on the total weight of the pharmaceutical composition (or on a dry weight basis). A dry weight basis may refer to a pharmaceutical composition that is in solid or liquid dosage form, after subtracting the weight contribution from water or other pharmaceutically acceptable aqueous medium (e.g., fruit juice).

[0248] In some embodiments, the weight ratio (active basis) of the organic acid agent to the compound of Formula (I) is from 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1 up to 20:1, up to 15:1, up to 10:1, up to 9:1, up to 8:1, up to 7:1, up to 6:1, or any range therebetween.

[0249] When a pharmaceutical composition is formulated containing a pharmaceutically acceptable salt of a compound of Formula (I), the acid used to form the pharmaceutically acceptable salt of the compound of Formula (I) and the organic acid agent (vehicle) may be the same. For example, the pharmaceutical composition may contain a tartrate salt of a compound of Formula (I) (e.g., I-1b, I-2b, I-3b, I-4b, I-5b, I-6b, I-7b, I-8b, I-9b, and / or I-10b) and tartaric acid as the organic acid agent (vehicle). In another example, the pharmaceutical composition may contain a citrate salt of a compound of Formula (I) (e.g., I-1e, I-2e, I-3e, I-4e, I-5e, I-6e, I-7e, I-8e, I-9e, and / or I-10e) and citric acid as the organic acid agent (vehicle).

[0250] When a pharmaceutical composition is formulated containing a pharmaceutically acceptable salt of a compound of Formula (I), the acid used to form the pharmaceutically acceptable salt of the compound of Formula (I) and the organic acid agent (vehicle) may be different. For example, the pharmaceutical composition may contain a benzenesulfonic acid salt of a compound of Formula (I) (e.g., I-1a, I-2a, I-3a, I-4a, I-5a, I-6a, I-7a, I-8a, I-9a, and / or I-10a) and citric acid and / or tartaric acid as an organic acid agent (vehicle). In another example, the pharmaceutical composition may contain a benzoic acid salt of a compound of Formula (I) (e.g., I-1j, I-2j, I-3j, I-4j, I-5j, I-6j, I-7j, I-8j, I-9j, and / or I-10j) and citric acid and / or tartaric acid as an organic acid agent (vehicle).

[0251] Any of the pharmaceutical compositions disclosed herein formulated with an organic acid agent may contain an uncoated organic acid agent, or may contain an organic acid agent coated with a pharmaceutically acceptable vehicle (coated organic acid agent). Examples of coated organic acid agents are described below.

[0252] The pharmaceutical compositions disclosed herein can be administered at once or at intervals of several times.It is understood that the exact dosage and duration of treatment can vary according to the age, weight and condition of the patient being treated, and can be empirically determined by using known test protocols or by extrapolating from in vivo or in vitro test or diagnostic data.It is understood that for any specific individual, specific dosage regimen should be adjusted over time according to individual need and the professional judgment of the person who manages or supervises the administration of the preparation.

[0253] If the patient's condition does not improve, at the physician's discretion, the compounds may be administered chronically, i.e., over an extended period throughout the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0254] If the patient's condition improves, the compound may be continued or temporarily discontinued for a period of time (i.e., a "drug holiday"), at the physician's discretion.

[0255] Once the patient's condition improves, a maintenance dose is administered as needed.Then, the dose or the frequency of administration, or both, can be reduced depending on the symptoms, until the improved condition is maintained.However, the patient may need to be treated intermittently for a long period of time if symptoms recur.

[0256] The pharmaceutical composition may take the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, suppositories, or sustained-release formulations thereof, or any other form suitable for administration to mammals. Administration of the subject compound may be systemic or local. In some cases, the pharmaceutical composition is formulated for administration to humans orally, intravenously, or intradermally, or as a pharmaceutical composition adapted for other administration routes, according to routine procedures. Examples of suitable pharmaceutically acceptable vehicles and their formulation methods are described in Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co., Easton, Pa., 19th ed., 1995, Chapters 86, 87, 88, 91, and 92, which are incorporated herein by reference. The choice of vehicle will be determined in part by the specific compound, salt form, and the specific method used to administer the composition. Accordingly, there are a wide variety of suitable formulations for the subject pharmaceutical composition. Liquid form preparations include solutions and emulsions, for example, water, water / propylene glycol solution or organic solvent.When administered to mammals, the compounds and compositions of the present disclosure and pharmaceutically acceptable vehicles can be sterilized.In some cases, for example, when the subject compound is administered orally, intravenously or intradermally, aqueous media such as water, saline, fruit juice and aqueous dextrose and glycerol solution are used as vehicles.

[0257] Any of the pharmaceutical compositions described herein may comprise (as an active ingredient) at least one compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof. As described below, pharmaceutical compositions comprising the compounds disclosed herein may be formulated in a variety of dosage forms, and may be specifically formulated for administration in solid, semi-solid, or liquid form, including those compatible with the following: A. Oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, films, or capsules, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue; B. Parenteral administration, e.g., by subcutaneous, intradermal, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; C. Topical / transdermal administration, e.g., creams, ointments, or controlled-release patches or sprays applied to the skin, or to orifices and / or mucosal surfaces such as in the vagina or rectum, e.g., pessaries, creams, or foams; D. Modified-release dosage forms, such as delayed-, extended-, prolonged-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-, etc., modified-release dosage forms and gastroretentive dosage forms, can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).

[0258] Tamper-resistant dosage forms / packaging of any of the disclosed pharmaceutical compositions are contemplated.

[0259] A. Oral administration The pharmaceutical compositions disclosed herein can be provided in solid, semi-solid or liquid dosage forms for oral administration.As used herein, oral administration includes, for example, enteral delivery, in which the drug is taken orally and swallowed, and oral administration through the mucosal lining of the oral cavity, for example, buccal, lingual and sublingual administration.Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent dosage forms (for example, effervescent or non-effervescent tablets, films, powders or granules), solutions, emulsions, suspensions, solutions, wafers, films, sprinkles, elixirs and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable vehicles (e.g., carriers or excipients), including, but not limited to, adjuvants, stabilizers, solubilizers, thickeners, lubricants, binders, granulators, bulking agents, diluents, disintegrants, wetting agents, glidants, anti-caking agents, colorants, sweeteners, dye flow inhibitors, preservatives, antioxidants, cryoprotectants, complexing agents, flavoring agents, matrix-forming agents, performance modifiers, sustained-release polymers, solvents, pH adjusters, and carbon dioxide sources. In some embodiments, the pharmaceutically acceptable vehicle comprises an organic acid agent, which, as discussed herein, has been found to offer unique advantages as both a stabilizer and a solubilizer, aiding in release from the dosage forms of the present disclosure and providing stabilization of the compounds herein.

[0260] In some embodiments, the pharmaceutical compositions of the present disclosure may be orodispersible dosage forms (ODx), including sublingual dosage forms, such as orally disintegrating tablets (ODTs) (sometimes referred to as rapid disintegrating tablets, orally disintegrating tablets, or rapidly dispersing tablets), or orodispersible films (ODFs) (or wafers). Such dosage forms may be particularly advantageous in the present disclosure, for example, when administered intraorally through the mucosal lining of the oral cavity, e.g., buccal, lingual, and sublingual administration, because they provide increased bioavailability and a more rapid onset of action compared to oral administration via the gastrointestinal tract, allowing pregastric absorption of the compounds / salts herein. Furthermore, orodispersible dosage forms may be advantageous for treating pediatric / adolescent patients or for treating patients who generally have difficulty swallowing conventional dosage forms, such as regular tablets or capsules.

[0261] In some embodiments, the orodispersible dosage form (ODx) is a sublingual dosage form that disintegrates / dissolves under the tongue, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the sublingual dosage form disintegrates / dissolves under the tongue, whereby when mixed with saliva, it is converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, which is then swallowed. In some embodiments, the orodispersible dosage form (ODx) is an oral dosage form that disintegrates / dissolves in the oral cavity, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the oral dosage form disintegrates / dissolves in the oral cavity, whereby when mixed with saliva, it is converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, which is then swallowed. In addition to the active ingredient(s), the pharmaceutical composition in orodispersible dosage form (ODx) may include one or more pharmaceutically acceptable vehicles (e.g., binders, fillers, diluents, disintegrants, cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, carbon dioxide sources, bioadhesives, etc., and / or any other pharmaceutically acceptable vehicle described herein, with specific mention of organic acid agents).

[0262] Orodispersible dosage forms can be prepared by various techniques, such as, for example, freeze drying (lyophilization), molding, spray drying, mass extrusion, or compression. In some embodiments, the orodispersible dosage form is prepared by freeze-drying. In some embodiments, the orodispersible dosage form disintegrates in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being received in the oral cavity. In some embodiments, the orodispersible dosage form dissolves in less than about 90 seconds, less than about 60 seconds, or less than about 30 seconds after being received in the oral cavity. In some embodiments, the orodispersible dosage form disperses in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being received in the oral cavity. In some embodiments, the pharmaceutical composition has a disintegration test of about 30 seconds or less, about 20 seconds or less, about 10 seconds or less, about 5 seconds or less, or about 2 seconds or less in the United States Pharmacopeia (USP). <701> The disintegration time is in the form of an orodispersible dosage form such as an orally disintegrating tablet (ODT) that conforms to the United States Pharmacopeia (USP) Disintegration Test. <701> In accordance with the above, orodispersible dosage forms having longer disintegration times, e.g., 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, or any range therebetween, or longer, are also contemplated, e.g., when adapted for sustained release.

[0263] In some embodiments, the pharmaceutical composition is in the form of a sublingual tablet prepared by direct compression, compression molding, or lyophilization. In some embodiments, the sublingual tablet is produced by direct compression, whereby a directly compressible pharmaceutical vehicle, such as an organic acid agent (optionally coated), a binder, a filler, or a lubricant, is mixed with the compound of Formula (I) (or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and compressed into a tablet by direct compression. In some embodiments, the sublingual tablet contains one or more binders / fillers / diluents, such as lactose, mannitol, microcrystalline cellulose, polyvinylpyrrolidone (PVP), etc. In some embodiments, the sublingual tablet contains a lubricant, such as magnesium stearate. Other pharmaceutically acceptable vehicles, such as soluble excipients, dry binders, pH adjusters / buffers, surfactants, sweeteners, and flavoring agents, may also be used. Non-limiting examples of sublingual tablet formulations include a compound of Formula (I) (or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof), an organic acid agent such as citric acid (which may optionally be coated), lactose, mannitol, PVP, and magnesium stearate, and optionally one or more additional pharmaceutically acceptable vehicles described herein.

[0264] In some embodiments, the sublingual tablet may comprise a single layer, a double layer, or a triple layer. In some embodiments, the single-layer sublingual tablet contains an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent such as citric acid). In some embodiments, the single-layer sublingual tablet is effervescent and formulated using an "effervescent couple," i.e., formulated using a combination of an organic acid agent and a carbon dioxide source. In some embodiments, the double-layer sublingual tablet contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent such as citric acid) in a first layer and an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) in a second layer. The second layer may optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicle compared to when the vehicle and active ingredient are contained in a single layer, which in some instances may increase the stability of the active ingredient and potentially increase the shelf life of the composition. In some embodiments, the bilayer sublingual tablet is an effervescent sublingual tablet, whereby the first layer is effervescent and comprises an effervescent couple and, optionally, other pharmaceutically acceptable vehicles; the second layer comprises an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and, optionally, one or more pharmaceutically acceptable vehicles; the second layer is either non-effervescent or effervescent. For trilayer sublingual tablets, each layer may be different, or two of the layers, e.g., the upper and lower layers, may have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing the active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof). In some embodiments, the lower and upper layers may contain one or more vehicle components, such as, for example, a solubilizer, a stabilizer, etc. (e.g., an organic acid agent such as citric acid).In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers may contain different vehicles, or different amounts of the same vehicle. The core layer typically contains an active ingredient, optionally with one or more pharmaceutically acceptable vehicles. As described above, the configuration of such a tri-layer sublingual tablet allows the active ingredient to be kept separate from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles. In some embodiments, the tri-layer sublingual tablet is an effervescent sublingual tablet, whereby at least one, at least two, or all three of the layers are effervescent (formulated using an effervescent couple). In some embodiments, the bottom and top layers are effervescent and comprise an organic acid agent (e.g., citric acid), a carbon dioxide source, and optionally other pharmaceutically acceptable vehicles, and the core layer comprises an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and optionally one or more pharmaceutically acceptable vehicles, and the core layer is either non-effervescent or effervescent.

[0265] In some embodiments, the pharmaceutical composition is in the form of a lyophilized orodispersible dosage form, such as a lyophilized ODT. In some embodiments, the lyophilized orodispersible dosage form (e.g., a lyophilized ODT) is prepared by sublimating water from a pre-frozen aqueous formulation of the drug, which contains a matrix-forming agent and other solvents as described herein, such as one or more lyoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc. In some embodiments, the orodispersible dosage form comprises a two-component framework of a lyophilized matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer, such as gelatin, dextran, alginate, and maltodextrin. This component maintains shape and provides mechanical strength to the dosage form (binder). In some embodiments, the second component is a matrix support / disintegration promoter, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and / or starch, which acts by adhering the porous framework provided by the water-soluble polymer and promoting the disintegration of the orodispersible dosage form. In some embodiments, the freeze-dried orodispersible dosage form (e.g., freeze-dried ODT) comprises gelatin and mannitol. In some embodiments, the freeze-dried orodispersible dosage form (e.g., freeze-dried ODT) comprises gelatin, mannitol, and one or more cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, and / or other pharmaceutically acceptable vehicles described herein, with specific mention of organic acid agents (e.g., citric acid). A non-limiting example of an ODT formulation is Zydis® orally dispersible tablets (available from Catalent).In some embodiments, the ODT formulation (e.g., Zydis® orally dispersible tablets) comprises one or more water-soluble polymers, such as gelatin, one or more matrix materials, fillers, or diluents, such as mannitol, a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and optionally a cryoprotectant, preservative, antioxidant, stabilizer, solubilizer, flavoring agent, and / or another pharmaceutically acceptable vehicle described herein. In some embodiments, the ODT formulation (e.g., Zydis® orally dispersible tablets) comprises gelatin, mannitol, a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and citric acid and / or tartaric acid.

[0266] In some embodiments, the ODT can comprise a single layer, a double layer, or a triple layer. In some embodiments, the single layer ODT contains an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent such as citric acid). In some embodiments, the single layer ODT is effervescent and formulated using an "effervescent couple," i.e., formulated using a combination of an organic acid agent and a carbon dioxide source. In some embodiments, the double layer ODT contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent such as citric acid) in a first layer and an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) in a second layer. The second layer may optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or a particular pharmaceutically acceptable vehicle, minimizing or completely preventing contact between the active ingredient and the vehicle compared to when the vehicle and active ingredient are contained in a single layer, which in some instances may increase the stability of the active ingredient and potentially increase the shelf life of the composition. In some embodiments, the bilayer ODT is an effervescent ODT, whereby the first layer is effervescent and comprises an effervescent couple and, optionally, another pharmaceutically acceptable vehicle, and the second layer comprises the active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and, optionally, one or more pharmaceutically acceptable vehicles), and the second layer is either non-effervescent or effervescent. For a three-layer ODT, each layer may be different and Two of the layers, e.g., the upper and lower layers, may have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof). In some embodiments, the lower and upper layers may contain one or more vehicle components, e.g., a solubilizer, a stabilizer, etc. (e.g., an organic acid agent such as citric acid). In some embodiments, the lower and upper layers have the same composition.Alternatively, the lower and upper layers may contain different vehicles, or different amounts of the same vehicle. The core layer typically contains an active ingredient, optionally with one or more pharmaceutically acceptable vehicles. As discussed above, the configuration of such a three-layer ODT keeps the active ingredient separate from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles. In some embodiments, the three-layer ODT is an effervescent ODT, whereby at least one, at least two, or all three of the layers are effervescent (formulated with an effervescent couple). In some embodiments, the bottom and top layers are effervescent and comprise an organic acid agent (e.g., citric acid), a carbon dioxide source, and optionally other pharmaceutically acceptable vehicles, and the core layer comprises an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and optionally one or more pharmaceutically acceptable vehicles, and the core layer is either non-effervescent or effervescent.

[0267] In some embodiments, the pharmaceutical composition is in the form of a freeze-dried orodispersible film (ODF) (or wafer). In some embodiments, the pharmaceutical composition is in the form of a freeze-dried ODF protected for long-term storage by special packaging that excludes moisture, oxygen, and light. In some embodiments, the freeze-dried ODF is prepared by creating a porous matrix by sublimating water from a pre-frozen aqueous formulation of the drug containing a matrix-forming agent and other vehicles, such as those described herein, such as one or more cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, and / or other pharmaceutically acceptable vehicles described herein. In some embodiments, the freeze-dried ODF comprises a thin, water-soluble film matrix. In some embodiments, the ODF comprises a two-component framework of a freeze-dried matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer, such as gelatin, dextran, alginate, and maltodextrin. This component maintains shape and provides mechanical strength to the film / wafer (binder). In some embodiments, the second component is a matrix support / disintegration promoter, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and / or starch, which acts by adhering the porous framework provided by the water-soluble polymer and promoting disintegration of the wafer. In some embodiments, the freeze-dried ODF includes gelatin and mannitol. In some embodiments, the freeze-dried ODF includes gelatin, mannitol, and one or more cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, and / or other pharmaceutically acceptable vehicles described herein, with specific mention of organic acid agents (e.g., citric acid).

[0268] In some embodiments, the ODF (or wafer) can comprise a single layer, a double layer, or a triple layer. In some embodiments, the single-layer ODF (or wafer) contains an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent such as citric acid). In some embodiments, the single-layer ODF (or wafer) is effervescent and formulated using an effervescent couple. In some embodiments, the double-layer ODF (or wafer) contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent such as citric acid) in a first layer and an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) in a second layer. The second layer may optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicle compared to when the vehicle and active ingredient are contained in a single layer, which in some instances may increase the stability of the active ingredient and potentially increase the shelf life of the composition. In some embodiments, the bilayer ODF (or wafer) is an effervescent ODF (or wafer), whereby the first layer is effervescent and comprises an effervescent couple and, optionally, other pharmaceutically acceptable vehicles; and the second layer comprises an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and, optionally, one or more pharmaceutically acceptable vehicles), wherein the second layer is either non-effervescent or effervescent. For a three-layer ODF (or wafer), each layer may be different, or two of the layers, e.g., the top and bottom layers, may have substantially the same composition. In some embodiments, the bottom and top layers surround a core layer containing the active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof).In some embodiments, the lower and upper layers may contain one or more vehicle components (e.g., organic acid agents such as citric acid), such as solubilizers, stabilizers, etc. In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers may contain different vehicles, or different amounts of the same vehicle. The core layer typically contains an active ingredient, optionally with one or more pharmaceutically acceptable vehicles. As described above, the construction of such a three-layer ODF (or wafer) keeps the active ingredient separate from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles. In some embodiments, the three-layer ODF (or wafer) is an effervescent ODF (or wafer), whereby at least one, at least two, or all three of the layers are effervescent (formulated using an effervescent couple). In some embodiments, the bottom and top layers are effervescent and comprise an organic acid agent (e.g., citric acid), a carbon dioxide source, and optionally other pharmaceutically acceptable vehicles, and the core layer comprises an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and optionally one or more pharmaceutically acceptable vehicles, and the core layer is either non-effervescent or effervescent.

[0269] Examples of pharmaceutically acceptable cryoprotectants include, but are not limited to, disaccharides such as sucrose and trehalose, anionic polymers such as sulfobutylether-β-cyclodextrin (SBECD) and hyaluronic acid, and hydroxylated cyclodextrins.

[0270] Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0271] Examples of pharmaceutically acceptable antioxidants that may be effective to further enhance the stability of the compositions include, but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​or its salts (cysteine ​​hydrochloride), sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid.

[0272] Examples of pharmaceutically acceptable stabilizers include, but are not limited to, organic acids (e.g., citric acid), fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerin, methionine, monothioglycerin, ascorbic acid, polysorbates, arginine, cyclodextrins, microcrystalline cellulose, modified cellulose (e.g., carboxymethylcellulose, sodium salt), sorbitol, and cellulose gels.

[0273] Examples of pharmaceutically acceptable solubilizers (or solubilizing agents) include, but are not limited to, organic acids (e.g., citric acid, fumaric acid, DL-malic acid, tartaric acid, lactic acid, maleic acid, etc.), hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyl 40 stearate, purified shellac, sodium dehydroacetate, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethylethylcellulose, powdered agar, guar gum, succinic acid, copolyvidone, cellulose acetate phthalate, sodium dioctyl sulfosuccinate, zein, nonfat powdered milk, sorbitan trioleate, aluminum lactate, palmitoyl palmitate, sorbitan hydroxybenzo ... Examples of suitable surfactants include ascorbyl tincture, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, poly(sodium 4-styrenesulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, lauromacrogol, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyltryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate. Of these, citric acid is preferred in some embodiments.

[0274] Flavoring agents include natural flavors extracted from plants such as fruit, and synthetic blends of compounds that produce a pleasant taste and taste-masking effect.Examples of flavoring agents include, but are not limited to, aspartame, saccharin (as sodium, potassium, or calcium saccharin), cyclamate (as sodium, potassium, or calcium salt), sucralose, acesulfame K, thaumatin, neohisperidin, dihydrochalcone, ammoniated glycyrrhizin, glucose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, wintergreen oil, peppermint oil, methyl salicylate, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, orange flavor, lemon, lime, and lemon lime.

[0275] Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance delivery of the compositions described herein.

[0276] For example, pharmaceutical compositions adapted for oral administration, such as tablets, including compressed tablets, can be formulated using a variety of vehicles, such as those described herein. Examples of suitable vehicles include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, anti-caking agents, colorants, dye flow inhibitors, sweeteners, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, adjuvants, thickeners, lubricants, granulators, cryoprotectants, complexing agents, matrix-forming agents, dispersing agents, performance modifiers, sustained-release polymers, solvents, pH adjusters, and carbon dioxide sources.

[0277] Binders or granulating agents impart cohesiveness to the tablet and ensure that the tablet remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, dextrin, molasses, and lactose; natural and synthetic gums such as acacia (gum arabic), alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isagol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan (larch). Suitable bulking agents include, but are not limited to, cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, and AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable bulking agents include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, partially hydrolyzed starch (e.g., maltodextrin), and mixtures thereof. In some embodiments, the binder, granulator, or filler is present in about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50% to about 99%, about 90%, about 80%, about 70%, about 60% by weight, or any range therebetween, based on the total weight of the pharmaceutical compositions disclosed herein.

[0278] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.When present in sufficient amounts, certain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol can impart the properties of some compressed tablets that can be disintegrated in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

[0279] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; gum, such as guar gum and Veegum HV, citrus pulp; cross-linked cellulose, such as croscarmellose; cross-linked polymer, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starch, such as corn starch, potato starch, tapioca starch, pregelatinized starch and partially hydrolyzed starch; clay; alain; and mixtures thereof.The amount of disintegrant in the pharmaceutical compositions disclosed herein varies depending on the type of formulation, and is easily recognized by those skilled in the art. In some embodiments, the pharmaceutical compositions disclosed herein contain, for example, about 0.5 wt%, about 1 wt%, about 3 wt%, about 5 wt%, about 10 wt%, about 15 wt% to about 50 wt%, about 40 wt%, about 30 wt%, or about 20 wt% of disintegrant, for example, about 1 to about 5 wt%, based on the total weight of the pharmaceutical composition.

[0280] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycols (PEG) (e.g., PEG 4,000, PEG 6,000, PEG 8,000, etc., the numbers referring to the approximate average molecular weight of the PEG); stearic acid; sodium lauryl sulfate; sodium stearyl fumarate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium, silica, or silica gel, such as AEROSIL® 200 (WR Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co., Boston, Mass.); and mixtures thereof. In some embodiments, the pharmaceutical compositions disclosed herein contain, for example, about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt % to about 20 wt %, about 15 wt %, about 10 wt %, or about 7 wt % of a lubricant, for example, about 0.1 wt % to about 5 wt % of a lubricant, based on the total weight of the pharmaceutical composition.

[0281] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, Mass.), and asbestos-free talc.

[0282] Suitable anti-caking agents include, but are not limited to, silicon dioxide.

[0283] Coloring agents include any of the approved, certified, water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on alumina hydrate, as well as color lakes and mixtures thereof. Color lakes are combinations of water-soluble dyes by adsorption onto hydrous heavy metal oxides, resulting in an insoluble form of the dye.

[0284] Sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, sucralose, and artificial sweetening agents, such as saccharin and aspartame.

[0285] Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.

[0286] Suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0287] Preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0288] Wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0289] Solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.

[0290] Examples of pH adjusters (including organic acid agents) include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, and phosphoric acid; bases including salts of organic acid agents, such as sodium acetate, potassium acetate, sodium citrate (e.g., monosodium citrate, disodium citrate, and / or trisodium citrate), potassium citrate (e.g., monopotassium citrate, dipotassium citrate, and / or tripotassium citrate), sodium tartrate (e.g., monosodium tartrate and / or disodium tartrate), potassium tartrate (e.g., monopotassium tartrate and / or dipotassium tartrate), potassium sodium tartrate, ammonium citrate (e.g., monoammonium citrate, diammonium citrate, and / or tripotassium citrate), and the like. or triammonium citrate), ammonium tartrate (e.g., monoammonium tartrate and / or diammonium tartrate), sodium fumarate (e.g., monosodium fumarate and / or disodium fumarate), potassium fumarate (e.g., monopotassium fumarate and / or dipotassium fumarate), sodium maleate (e.g., monosodium maleate and / or disodium maleate), potassium maleate (e.g., monopotassium maleate and / or dipotassium maleate), sodium lactate, potassium lactate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, etc., and buffers generally comprising a mixture of an acid and a salt of the acid.

[0291] Carbon dioxide sources include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, and sesquicarbonate. Carbon dioxide sources may be used alone or in combination.

[0292] As mentioned above, preferred dosage forms are those formulated with organic acid agents that can act as stabilizers and / or solubilizers in the disclosed pharmaceutical compositions.The organic acid agent can be any of those described herein, with citric acid and / or tartaric acid being specifically mentioned.

[0293] In some embodiments, tablets (e.g., conventional tablets, including compressed tablets) may comprise a single layer, a double layer, or a triple layer. In some embodiments, a single-layer tablet contains an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent such as citric acid). In some embodiments, a single-layer tablet is effervescent and is formulated with an effervescent couple. In some embodiments, a double-layer tablet contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent such as citric acid) in a first layer and an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) in a second layer. The second layer may optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or a particular pharmaceutically acceptable vehicle, minimizing or completely preventing contact between the active ingredient and the vehicle compared to when the vehicle and active ingredient are contained in a single layer, which in some cases may increase the stability of the active ingredient and possibly increase the shelf life of the composition. In some embodiments, the bilayer tablet is an effervescent tablet, whereby the first layer is effervescent and comprises an effervescent couple and, optionally, another pharmaceutically acceptable vehicle, and the second layer comprises the active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and, optionally, one or more pharmaceutically acceptable vehicles, and the second layer is either non-effervescent or effervescent. For trilayer tablets, each layer may be different, or Two of the layers, for example, the upper and lower layers, may have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof). In some embodiments, the lower and upper layers may contain one or more vehicle components, such as, for example, a solubilizer, a stabilizer, etc. (e.g., an organic acid agent such as citric acid). In some embodiments, the lower and upper layers have the same composition.Alternatively, the lower and upper layers may contain different vehicles, or different amounts of the same vehicle. The core layer typically contains an active ingredient, optionally with one or more pharmaceutically acceptable vehicles. As noted above, such trilayer tablet configurations keep the active ingredient separate from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles. In some embodiments, the trilayer tablet is an effervescent tablet, whereby at least one, at least two, or all three of the layers are effervescent (formulated with an effervescent couple). In some embodiments, the bottom and top layers are effervescent and comprise an organic acid agent (e.g., citric acid), a carbon dioxide source, and optionally other pharmaceutically acceptable vehicles, and the core layer comprises an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and optionally one or more pharmaceutically acceptable vehicles, and the core layer is either non-effervescent or effervescent.

[0294] It should be understood that many solvents (carriers, excipients, etc.) can serve multiple functions, even within the same formulation. Specific reference is made herein to pharmaceutical compositions containing organic acid agents that can serve multiple roles, for example, as stabilizers to stabilize the silosin compounds of the present disclosure in free base or salt form, as solubilizers to rapidly dissolve active substances to provide rapid onset of action, particularly for dosage forms adapted for rapid onset and short duration of drug action, such as orally dispersible dosage forms (e.g., ODTs and ODFs), as flavoring agents, pH adjusters, and / or antioxidants.

[0295] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more vehicles (e.g., carriers or excipients) described herein, including binders, disintegrants, sustained-release polymers, pH adjusters, lubricants, diluents, and / or coloring agents. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0296] The pharmaceutical compositions herein may be in the form of compressed tablets, tablet triturates, chewable lozenges, rapid-dissolving tablets, multiple compressed tablets, or any of the above-mentioned coated forms, such as enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Coated tablets are tablets coated with one or more layers of a pharmaceutically acceptable vehicle, or a mixture of vehicles, such as natural or synthetic resins, polymers, gums, fillers, sugars, plasticizers, polyols, waxes, organic bases, coloring substances approved by appropriate national or regional authorities, and flavoring substances. Such coating materials generally do not contain any active ingredient, such as the compounds described herein (e.g., the compound of Formula (I) or its pharmaceutically acceptable salts, polymorphs, stereoisomers, or solvates). Tablets may be coated for various reasons, such as to protect the active ingredient from burst release from the matrix, air, moisture, or light, to mask unpleasant tastes and odors, or to improve appearance. The coating material may be applied as a solution or suspension. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredients from the acidic stomach environment. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial for masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple-compressed tablets are compressed tablets produced using multiple compression cycles and include layered tablets, compression-coated tablets, and dry-coated tablets.

[0297] In some embodiments, a pharmaceutical composition (e.g., a tablet composition formulated for oral administration, such as a monolayer tablet composition) comprises any of the compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and a polymer.

[0298] In some embodiments, the tablet composition is a modified release tablet adapted for sustained release, for example, maximum sustained release.In some embodiments, in the formulations of the present disclosure, the release duration of any of the compounds described herein (e.g., compounds of formula (I), or its pharmaceutically acceptable salts, polymorphs, stereoisomers or solvates) is more than 4 hours, more than 6 hours, more than 8 hours, more than 10 hours, more than 12 hours, more than 16 hours, more than 20 hours, more than 24 hours, more than 28 hours, more than 32 hours, more than 36 hours, more than 48 hours.

[0299] In some embodiments, the tablet composition is adapted for tamper resistance. In some embodiments, the tablet composition comprises polyethylene oxide (PEO) of about 2,000 to about 7,000 KDa MW, e.g., in combination with HPMC. In some embodiments, the tablet composition may further comprise polyethylene glycol (PEG), e.g., PEG 8,000. In some embodiments, the tablet composition may further comprise a polymer carrying one or more negatively charged groups, e.g., polyacrylic acid. In some embodiments, the tablet composition comprising PEO is further subjected to heating / annealing, e.g., extrusion conditions.

[0300] In some embodiments, the pharmaceutical composition comprises a combination of (i) a water-insoluble, neutrally charged non-ionic matrix, (ii) a polymer carrying one or more negatively charged groups, and (iii) any of the compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof).

[0301] In some embodiments, the polymer carrying one or more negatively charged groups is selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite, hyaluronic acid, anionic gums, salts thereof, or mixtures thereof. In some embodiments, the anionic gum is selected from the group consisting of naturally occurring substances and semi-synthetic substances. In some embodiments, the naturally occurring substances are selected from the group consisting of alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, gum karaya, guar gum, and gum tragacanth. In some embodiments, the semi-synthetic substances are selected from the group consisting of carboxymethyl-chitin and cellulose gum.

[0302] Furthermore, without intending to be bound by theory, in some embodiments, the role played by a polymer bearing one or more negatively charged groups, e.g., a moiety of acidic nature such as the acidic polymers described herein, surprisingly results in significant retention of any of the compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) in the matrix. In some embodiments, this negative charge can be generated in situ, for example, based on the release of a proton due to the pKa and under certain pH conditions, or through electrostatic interactions / negative charge generation. It is further noted that the acidic polymer can be a salt of a corresponding weak acid that becomes the relevant protonated acid in the stomach. Without wishing to be bound by theory, this may neutralize the charge and reduce the interaction of any of the compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) with the matrix. Additionally, the release matrix may be further complemented with other inert pharmaceutical ingredients to aid in the preparation of a suitable solid dosage form, such as fillers, disintegrants, flow improvers, lubricants, colorants, taste masking agents, etc.

[0303] In some embodiments, the water-insoluble, neutrally charged nonionic matrix is ​​selected from a cellulosic polymer such as HPMC, alone or reinforced by blending with a member selected from the group consisting of starch, wax, neutral gum, polymethacrylate, PVA, PVA / PVP blends, and mixtures thereof. In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC).

[0304] In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC). In some embodiments, the tablet composition comprises about 1 wt%, about 5 wt%, about 10 wt%, about 20 wt%, about 30 wt%, about 40 wt%, about 50 wt%, about 60 wt%, about 70 wt%, about 80 wt%, or any range therebetween, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises, for example, about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, or any range therebetween, based on the total weight of the pharmaceutical composition, starch. In some embodiments, the pharmaceutical product comprises a combination of HPMC and starch.

[0305] Disclosed herein are pharmaceutical compositions in modified release dosage forms comprising a compound disclosed herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and one or more controlled-release vehicles described herein. Suitable controlled-release vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The pharmaceutical composition may also comprise a non-controlled-release vehicle.

[0306] In some embodiments, oral pharmaceutical compositions aimed at low-dose maintenance therapy may be formulated using compounds described herein that utilize their ability to bind anionic polymers.

[0307] Additionally, disclosed herein are pharmaceutical compositions in enteric-coated dosage forms comprising a compound disclosed herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and one or more controlled-release vehicles for use in enteric-coated dosage forms. The pharmaceutical composition may also include a non-controlled-release vehicle.

[0308] Further disclosed herein are pharmaceutical compositions in an effervescent dosage form comprising a compound disclosed herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof) and one or more pharmaceutically acceptable vehicles, which can be controlled-release vehicles and / or non-controlled-release vehicles. By effervescent, we mean that the dosage form releases gas when mixed with a liquid, including water, juice, saliva, and the like. Generally, the effervescent dosage forms of the present disclosure comprise an organic acid agent and a carbon dioxide source, referred to herein as an "effervescent couple." Such effervescent dosage forms effervescent (gas-releasing) through a chemical reaction between the organic acid agent and the carbon dioxide source. Effervescence occurs upon exposure to an aqueous environment, e.g., when placed in water, juice, or other drinkable liquid, or from the aqueous environment in the oral cavity, e.g., saliva in the mouth. Specifically, carbon dioxide gas is produced by the reaction between the organic acid agent and the carbon dioxide source upon contact with an aqueous medium, e.g., water, juice, or saliva. The use of a disintegrant is optional, however, effervescent dosage forms do not require a disintegrant as they facilitate in situ gas release, accelerating the disintegration process.

[0309] For purposes of clarity, "effervescent couple" refers to at least one organic acid agent and at least one carbon dioxide source, regardless of assembly. For example, the organic acid agent and carbon dioxide source may be mixed (as powders), layered on top of each other, agglomerated or otherwise "glued" together in the form of granules, or kept separate from each other, for example, in separate layers within a dosage form. Furthermore, the term "couple" in this context is not intended to be limited to only an organic acid agent and a carbon dioxide source, but is open to the inclusion of other materials unless otherwise specified. For example, an effervescent aggregate / granule made by combining (or gluing) an organic acid agent and a carbon dioxide source may include other vehicles, including a binder (adhesive), and the effervescent aggregate / granule may be referred to as an effervescent couple.

[0310] In some embodiments, the carbon dioxide source is sodium bicarbonate. In some embodiments, the carbon dioxide source is sodium carbonate. In some embodiments, the carbon dioxide source is potassium carbonate. In some embodiments, the carbon dioxide source is potassium bicarbonate. However, reactants that liberate oxygen or gases other than carbon dioxide and that are safe for human consumption are also contemplated for use in the disclosed effervescent dosage forms in addition to or in place of the carbon dioxide source. Without wishing to be bound by theory, it is believed that effervescence helps to rapidly disintegrate the dosage form and, for some routes of administration, such as the oral route, may help reduce the perception of grittiness by providing a distracting effervescent sensory experience.

[0311] In some embodiments, the effervescent dosage form is reconstituted in a drinkable fluid, such as water or juice, to form an oral liquid dosage form (e.g., a solution), which is then ingested. In some embodiments, the effervescent dosage form is placed in the oral cavity, where it comes into contact with an aqueous environment (saliva) and effervesces, causing disintegration / dissolution of the dosage form. Here, the contents of the effervescent dosage form are converted into a liquid or semisolid dosage form, such as a solution, syrup, or paste, by mixing with saliva, and then swallowed. Alternatively, the effervescent dosage form may be an intraoral dosage form, such as a buccal, lingual, or sublingual dosage form, where it is placed in the aqueous environment (saliva) of the oral cavity, effervescence causes disintegration / dissolution of the dosage form, and the contents are pregastricly absorbed through the oral mucosa. Such pregastric absorption may increase bioavailability and provide a rapid onset of action compared to oral administration via the digestive tract. In some embodiments, the effervescent dosage form is a sublingual dosage form that disintegrates / dissolves under the tongue, thereby allowing the contents (e.g., a compound of the present disclosure) to be absorbed through the mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the effervescent dosage form is an oral dosage form that disintegrates / dissolves in the oral cavity, thereby allowing the contents (e.g., a compound of the present disclosure) to be absorbed through the mucous membrane of the oral cavity and enter the venous circulation there. Because effervescent dosage forms can be reconstituted into an easy-to-swallow liquid or semi-solid dosage form or taken orally, they may be beneficial for treating pediatric / adolescent patients or patients who generally have difficulty swallowing conventional dosage forms, such as regular tablets or capsules.

[0312] When adapted for oral administration, it may be beneficial to formulate the effervescent dosage form with a bioadhesive in addition to the effervescent couple. A "bioadhesive" is a substance that promotes adhesion or attachment to a biological surface, such as a mucous membrane. For example, a bioadhesive can adhere to the biological surface when placed in contact with the surface (e.g., a mucous membrane), thereby allowing the composition of the present disclosure to adhere to the surface and promoting efficient transfer of the contents of the dosage form to the biological surface. Various polymers known in the art can be used as bioadhesives, such as polymeric substances, preferably those having an average (weight-average) molecular weight of greater than 5,000 g / mol. Preferably, such polymeric substances are capable of rapidly swelling when placed in contact with an aqueous medium, such as water or saliva, and / or are substantially insoluble in water at room temperature and atmospheric pressure. Examples of suitable bioadhesives include, but are not limited to, cyclodextrins, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose, modified cellulose gums, and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately crosslinked starch, modified starch, and sodium starch glycolate; acrylic polymers such as carbomer and its derivatives (polycarbophil, Carbopol®, etc.); polyvinylpyrrolidone (PVP); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, and pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride); and croscarmellose (e.g., croscarmellose sodium). Such polymers may be crosslinked. Combinations of two or more bioadhesives may also be used.

[0313] The effervescent couple can be coated with a pharmaceutically acceptable vehicle, such as, for example, a binder, a protective coating, e.g., a solvent protective coating, an enteric coating, an anti-caking agent, and / or a pH adjuster, to prevent premature reaction, e.g., from air, humidity, and / or other components contained in the pharmaceutical composition. Each component of the effervescent couple, e.g., the organic acid agent and / or the carbon dioxide source, can also be individually coated with a pharmaceutically acceptable vehicle, e.g., a binder, a protective coating, e.g., a solvent protective coating, an enteric coating, an anti-caking agent, and / or a pH adjuster, to prevent premature reaction, e.g., from air, humidity, and / or other components contained in the pharmaceutical composition. The effervescent couple can also be mixed with previously lyophilized particles, e.g., one or more pharmaceutically active ingredients coated with a solvent protective coating or an enteric coating.

[0314] Effervescent dosage forms may be made by methods known to those skilled in the art including, but not limited to, slugging, direct compression, roller compaction, dry or wet granulation, melt granulation, melt granulation, vacuum granulation, and fluid bed spray granulation, any of which may optionally be followed by compression / tabletting.

[0315] The pharmaceutical compositions disclosed herein may be formulated as non-effervescent or effervescent granules and powders. The non-effervescent or effervescent granules and powders may be reconstituted into a liquid dosage form or alternatively compressed to form either non-effervescent or effervescent tablet dosage forms, respectively. Pharmaceutically acceptable vehicles used in non-effervescent or effervescent granules or powders include, but are not limited to, binders, granulators, fillers, diluents, sweeteners, wetting agents, stabilizers, solubilizers, anti-caking agents, pH adjusters, or any other pharmaceutical vehicle described herein. In some embodiments, the pharmaceutically acceptable vehicle includes an organic acid, such as glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and / or maleic acid.

[0316] Pharmaceutically acceptable vehicles used in effervescent granules or powders include an effervescent couple, i.e., an organic acid agent and a carbon dioxide source. Effervescent powders can be produced by blending or mixing an organic acid agent and a carbon dioxide source (the effervescent couple) with, optionally, other desired pharmaceutically acceptable vehicles. Effervescent granules can be produced by physically adhering or "gluing" the effervescent couple (organic acid agent and carbon dioxide source) together using an edible or pharmaceutically acceptable binder, including, for example, polyvinylpyrrolidone, polyvinyl alcohol, L-leucine, polyethylene glycol, gum arabic, and combinations thereof. These types of granules are generally made by a process known as "wet granulation." Granulation solvents, such as ethanol and / or isopropyl alcohol, are often used to aid this type of granulation process. Because the effervescent couple is physically bound together in the granules, the gas-generating reaction is usually very vigorous, leading to rapid dissolution. Another type of "wet granulation" product specific to effervescent products is known as a "fused" granule. These granules are formed by reacting an organic acid agent and a carbon dioxide source in a highly controlled manner with small amounts of water (or sometimes a hydroalcoholic granulation solvent, such as various commercial grades of ethanol or isopropyl alcohol). Because the effervescent reaction produces carbon dioxide, fused granules tend to be very porous, which reduces their density and dissolution time. Therefore, effervescent granules prepared by wet granulation or fusion processes may be desirable for making orodispersible dosage forms (ODx) or other dosage forms requiring rapid dissolution / disintegration performance. Effervescent tablet dosage forms prepared by tableting, e.g., compression, of effervescent granules or powders are also included in the present disclosure.

[0317] Further disclosed are pharmaceutical compositions in dosage forms having an immediate-release component and at least one delayed-release component, capable of discontinuously releasing a compound in at least two successive pulses separated by about 0.1 to up to about 24 hours (e.g., about 0.1, 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 10, 22, or 24 hours). The pharmaceutical compositions include a compound disclosed herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof), and one or more controlled-release and / or non-controlled-release vehicles, e.g., excipients or carriers suitable for disruptable semipermeable membranes, and swellable materials.

[0318] Also disclosed herein is a pharmaceutical composition in a dosage form for oral administration to a subject, comprising a compound disclosed herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof), and one or more pharmaceutically acceptable vehicles (e.g., excipients or carriers), encapsulated in an intermediate reactive layer comprising a gastric juice-resistant polymeric layer material that has been partially neutralized with alkali and has cation exchange resin capacity, and a gastric juice-resistant outer layer.

[0319] The dosage form may be an immediate release (IR) dosage form, examples of which include, but are not limited to, immediate release (IR) tablets or immediate release (IR) capsules. In addition to the API, dosage forms adapted for immediate release may contain one or more pharmaceutically acceptable vehicles that readily disperse, dissolve, or disintegrate in the gastric environment so as not to delay or prolong the dissolution / absorption of the API. Examples of pharmaceutically acceptable vehicles for immediate release dosage forms include, but are not limited to, one or more adjuvants, stabilizers, solubilizers, thickeners, lubricants, binders, granulators, fillers, diluents, disintegrants, wetting agents, glidants, anti-caking agents, colorants, sweeteners, dye flow inhibitors, preservatives, antioxidants, cryoprotectants, complexing agents, flavoring agents, matrix formers, dispersing agents, and performance modifiers. In some embodiments, the immediate release (IR) dosage form is an immediate release (IR) tablet comprising one or more of microcrystalline cellulose, sodium carboxymethylcellulose, magnesium stearate, mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the immediate release (IR) dosage form comprises microcrystalline cellulose, sodium carboxymethylcellulose, and magnesium stearate. In some embodiments, the immediate release (IR) dosage form comprises mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the immediate release (IR) dosage form comprises an organic acid agent.

[0320] The pharmaceutical compositions disclosed herein may be disclosed as soft or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs) or powder-filled capsules (PICs), consist of two compartments, one sliding over the other to completely enclose the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methylparaben, propylparaben, and sorbic acid. Liquid, semisolid, and solid dosage forms disclosed herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsules may also be coated as known by those skilled in the art to modify or maintain dissolution of the active ingredient.

[0321] In some embodiments, the pharmaceutical composition is in the form of an immediate release capsule for oral administration and may further comprise cellulose, iron oxide, lactose, magnesium stearate, and sodium starch glycolate.

[0322] In some embodiments, the pharmaceutical composition is in the form of a delayed-release capsule for oral administration and may further comprise cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

[0323] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed-release tablet for oral administration and may further comprise carnauba wax, crospovidone, diacetylated monoglyceride, ethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0324] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed-release tablet for oral administration and may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0325] Any of the pharmaceutical compositions disclosed herein formulated with an organic acid agent may contain an uncoated organic acid agent or an organic acid agent coated with a pharmaceutically acceptable vehicle (coated organic acid agent). Various pharmaceutically acceptable vehicles can be used as coating materials to modify the performance of the organic acid agent and / or to prevent undesired or premature reactions with air, humidity, and / or other components contained in the pharmaceutical composition, for example, without losing the desired functionality of the organic acid agent. A coated organic acid agent may comprise a core of the organic acid agent and a thin film coating, such as a thin film powder coating or a thin film polymer coating. A coated organic acid agent may also be in the form of a core-shell material, comprising a core of the organic acid agent and a protective coating surrounding the core, such as a shell. Any of the organic acid agents disclosed herein may be coated, including, but not limited to, glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and maleic acid.

[0326] In some embodiments, the coated organic acid agent contains a coating weight of at least 0.01 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 1.5 wt%, at least 2 wt%, at least 2.5 wt%, at least 3 wt%, at least 3.5 wt%, and up to 15 wt%, up to 10 wt%, up to 9 wt%, up to 8 wt%, up to 7 wt%, up to 6 wt%, up to 5 wt%, up to 4 wt%, or any range therebetween, based on the total weight of the coated organic acid agent, with the remainder being the organic acid agent when the coated organic acid agent is formulated essentially only with the organic acid agent and the coating.

[0327] In some embodiments, the organic acid agent is coated with a water-soluble polymer, binder, granulator, bulking agent, etc. A non-limiting example of this type of coated organic acid agent is Citric acid DC (available from Jungbunzlauer), which is a directly compressible granular powder type of citric acid coated with a thin layer of maltodextrin.

[0328] In some embodiments, the organic acid agent is coated with an anti-caking agent. Such coated organic acid agents exhibit high moisture spur absorption capacity. A non-limiting example of this type of coated organic acid agent is Citric acid S40 (available from Jungbunzlauer), which is a very fine (carbonized) granular powder of citric acid coated with silicon dioxide.

[0329] In some embodiments, the organic acid agent is coated with a pH adjuster. In some embodiments, the organic acid agent is coated with a salt of the organic acid agent (i.e., a conjugate base salt of the organic acid agent). The salt of the organic acid agent may be an alkali metal salt of the organic acid agent, an alkaline earth salt of the organic acid agent, an ammonium salt of the organic acid agent, or a mixture thereof, including a mixed salt of the organic acid agent (e.g., a mixed salt of sodium and potassium). The salt of the organic acid agent may be monobasic, dibasic, tribasic, etc. When the salt of the organic acid agent is polybasic (dibasic, tribasic, etc.), the salt may be formed from a single cation (e.g., a sodium cation) or two or more different cations (e.g., a mixed salt having both sodium and potassium cations). Examples of salts of organic acid agents that can be used as coating materials include, but are not limited to, sodium citrate (e.g., monosodium citrate, disodium citrate, and / or trisodium citrate), potassium citrate (e.g., monopotassium citrate, dipotassium citrate, and / or tripotassium citrate), sodium tartrate (e.g., monosodium tartrate and / or disodium tartrate), potassium tartrate (e.g., monopotassium tartrate and / or dipotassium tartrate), potassium sodium tartrate, ammonium citrate (e.g., monoammonium citrate, diammonium citrate, and / or tripotassium citrate), Examples of suitable organic acid salts include triammonium citrate, ammonium tartrate (e.g., monoammonium tartrate and / or diammonium tartrate), sodium fumarate (e.g., monosodium fumarate and / or disodium fumarate), potassium fumarate (e.g., monopotassium fumarate and / or dipotassium fumarate), sodium maleate (e.g., monosodium maleate and / or disodium maleate), potassium maleate (e.g., monopotassium maleate and / or dipotassium maleate), sodium lactate, and potassium lactate, including mixtures and / or hydrates thereof. The organic acid agent coated with the salt of the organic acid agent may be in the form of a core-shell material. The organic acid agent (core) and the salt of the organic acid agent (shell) may belong to the same conjugate acid-base pair.For example, the organic acid agent (core) may be citric acid, and the salt of the organic acid agent (shell) may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of citric acid. In another example, the organic acid agent (core) may be tartaric acid, and the salt of the organic acid agent (shell) may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of tartaric acid. In yet another example, the organic acid agent (core) may be fumaric acid, and the salt of the organic acid agent (shell) may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of fumaric acid. Alternatively, the organic acid agent (core) and the salt of the organic acid agent (shell) may belong to different conjugate acid-base pairs. For example, the organic acid agent (core) may be citric acid, and the salt of the organic acid agent (shell) may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of tartaric acid. In another example, the organic acid agent (core) may be citric acid, and the salt of the organic acid agent (shell) may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of fumaric acid. In yet another example, the organic acid agent (core) may be tartaric acid, and the salt of the organic acid agent (shell) may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of citric acid. A non-limiting example of an organic acid agent coated with a salt of an organic acid agent is Citrocoat® N (available from Jungbunzlauer), which is a granular powder made from citric acid as the core material and has a layer of monosodium citrate (1.5-3.5%) as the shell.

[0330] Coated organic acid agents may be utilized in the effervescent dosage forms of the present disclosure, where the effervescent couple may be formed from any of the coated organic acid agents disclosed herein and a carbon dioxide source. In contrast to uncoated organic acid agents, the use of organic acid agents coated with an effervescent couple may provide the effervescent dosage form with improved storage stability without significantly sacrificing reactivity when placed in an aqueous environment, such as in water, juice, or other drinkable fluid, or when placed in an aqueous environment in the oral cavity, such as saliva. A non-limiting example of an effervescent couple formulated with a coated organic acid agent is Citrocoat® EP (available from Jungbunzlauer GmbH), which is an agglomerated granule made by combining Citrocoat® N (a citric acid core coated with a layer of 1.5-3.5% monosodium citrate as a shell) with sodium bicarbonate using gum arabic as a binder.

[0331] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, and / or I-10) as a free base in crystalline form, and a coated organic acid agent, such as coated citric acid, coated tartaric acid, or coated fumaric acid. For effervescent dosage forms, a carbon dioxide source (e.g., sodium bicarbonate) is also included with the coated organic acid agent. In some embodiments, the compound of Formula (I) is a crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-2,5,6,7-d4-4-ol (I-1), as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-2,5,6,7-d4-4-ol (I-2) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3) as determined by X-ray powder diffraction.In some embodiments, I-3 has the following peaks as determined by XRPD using a CuKα radiation source, for example, as shown in Figures 2A-2C: 7.582°, 8.395°, 9.647°, 10.444°, 11.319°, 12.614°, 13.372°, 14.222°, 15.157°, 16.524°, 16.787°, 17.693°, 19.468°, 19.699°, 20.901°, 21.132°, 21.859°, 22.547°, 23.699°, 24.630°, 25.034°, 26.034°, 27.034°, 28.034°, 29.034°, 30.034°, 31.034°, 32.034°, 33.034°, 34.034°, 35.034°, 36.034°, 37.034°, 38.034°, 39.034°, 40.034°, 41.034°, 42.034°, 43.034°, 44.034°, 45.034°, 46.034°, 47.034°, 48.034°, 49.034°, 50.034°, 51.034°, 52.034°, 53.034°, 54.034°, 55.034°, 56.034°, 57.0 A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 25.264°, 26.867°, 27.399°, 27.929°, 28.219°, 28.871°, 29.430°, 30.120°, 30.675°, 31.373°, 32.365°, 33.880°, 34.418°, 34.792°, 35.884°, 36.254°, 37.156°, 38.200°, and 38.417°. In some embodiments, I-3 has the following peaks as determined by XRPD using a CuKα radiation source, for example, as shown in Figures 88-89: 8.124°, 8.357°, 10.059°, 12.630°, 13.420°, 13.743°, 14.053°, 15.220°, 16.272°, 16.763°, 16.954°, 17.328°, 17.662°, 18.062°, 18.742°, 19.413°, 19.658°, 20.172°, 20.836°, 21.267°, 21.8 A crystalline solid form (Pattern 2) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 33°, 22.213°, 22.504°, 23.334°, 23.701°, 24.385°, 25.431°, 25.721°, 26.049°, 27.291°, 28.368°, 30.349°, 30.656°, 31.337°, 31.538°, 32.091°, 35.870°, 38.514°, and 41.361°.In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol (I-4), as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-5), as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl-2,2-d2)-1H-indol-4-ol (I-6), as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7), as determined by X-ray powder diffraction. In some embodiments, I-7 exhibits the following peaks as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 3C : 7.563°, 8.375°, 12.626°, 13.383°, 15.211°, 16.753°, 17.671°, 19.668°, 21.112°, 21.863°, 22.201°, 22.560°, 23.711°, 24.592°, 25.012°, 26.012°, 27.012°, 28.012°, 29.012°, 30.012°, 31.012°, 32.012°, 33.012°, 34.012°, 35.012°, 36.012°, 37.012°, 38.012°, 39.012°, 40.012°, 41.012°, 42.012°, 43.012°, 44.012°, 45.012°, 46.012°, 47.012°, 48.012°, 49.012°, 50.012°, 51.012°, 52.012°, 53.012°, 54.012°, 55.012°, 56.012°, 57.012°, 58.012°, 59.012°, 60.012°, 61.012°, 62.012°, 63 In some embodiments, the compound of Formula (I) is a crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 5.415°, 26.820°, 27.357°, 27.921°, 28.228°, 29.253°, 30.653°, 31.364°, 32.401°, 33.797°, 34.445°, and 39.867°. In some embodiments, the compound of Formula (I) is a crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indol-4-ol (I-8), as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(dimethylamino)ethyl-1,1-d2)-1H-indol-4-ol (I-9), as determined by X-ray powder diffraction.In some embodiments, the compound of Formula (I) is in the crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol (I-10), as determined by X-ray powder diffraction.

[0332] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, and / or I-10) as the free base in amorphous form, and a coated organic acid agent, such as coated citric acid, coated tartaric acid, or coated fumaric acid. For effervescent dosage forms, a carbon dioxide source (e.g., sodium bicarbonate) is also included with the coated organic acid agent. In some embodiments, the compound of Formula (I) is the amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-2,5,6,7-d4-4-ol (I-1), as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-2,5,6,7-d4-4-ol (I-2) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol (I-4) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(dimethylamino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (1-5) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(dimethylamino)ethyl-2,2-d2)-1H-indol-4-ol (1-6) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (1-7) as determined by X-ray powder diffraction.In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl)-1H-indol-4-ol (1-8) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(dimethylamino)ethyl-1,1-d2)-1H-indol-4-ol (1-9) as determined by X-ray powder diffraction. In some embodiments, the compound of Formula (I) is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol (1-10) as determined by X-ray powder diffraction.

[0333] In some embodiments, the pharmaceutical composition comprises a crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I) and a coated organic acid agent, such as coated citric acid, coated tartaric acid, or coated fumaric acid. For effervescent dosage forms, a carbon dioxide source (e.g., sodium bicarbonate) is also included with the coated organic acid agent. In some embodiments, the pharmaceutically acceptable salt is the benzenesulfonate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3a). In some embodiments, I-3a exhibits the following peaks as determined by XRPD using a CuKα radiation source: 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 19.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, as shown, for example, in Figures 63A-63D. 24.187°, 25.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988° (Pattern 1). In some embodiments, the pharmaceutically acceptable salt is the benzenesulfonate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7a).In some embodiments, salt I-7a exhibits peaks of 7.002°, 7.733°, 11.768°, 12.516°, 12.882°, 13.546°, 13.968°, 14.788°, 15.225°, 15.474°, 18.370°, 19.737°, 20.703°, 21.050°, 21.873°, 21.982°, 22.315°, 22.639°, 23.025°, 24.025°, 25.025°, 26.025°, 27.025°, 28.025°, 29.025°, 30.025°, 31.050°, 32.025°, 33.025°, 34.025°, 35.025°, 36.025°, 37.025°, 38.025°, 39.025°, 40.025°, 41.025°, 42.025°, 43.025°, 44.025°, 45.025°, 46.025°, 47.025°, 48.025°, 49.025°, 50.025°, 51.025°, 52.025°, 53.025°, 54.025°, 55.025°, 56.025°, 57.025°, 58.025°, 59.025°, 60. It is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 282°, 23.775°, 24.125°, 25.193°, 25.475°, 25.931°, 26.813°, 27.778°, 28.127°, 30.866°, 31.207°, 32.941°, 33.222°, 33.698°, 36.803°, 38.668°, and 39.289° (Pattern 1). In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3j). In some embodiments, salt I-3j exhibits peaks of 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.831°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.044°, 26.044°, 27.044°, 28.044°, 29.044°, 30.044°, 31.044°, 32.044°, 33.044°, 34.044°, 35.044°, 36.044°, 37.044°, 38.044°, 39.044°, 40.044°, 41.044°, 42.044°, 43.044°, 44.044°, 45.044°, 46.044°, 47.044°, 48.044°, 49.044°, 50.044°, 51.044°, 52.044°, 53.044°, 54.044°, 55.044°, 56.044°, 57.044°, 58.044°, 59.044°, 60.044°, 61.044°, 62.044°, 63.044°, 64 It is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 5.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597° (Pattern 1). In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7j).In some embodiments, salt I-7j has the following peaks as determined by XRPD using a CuKα radiation source, for example, as shown in Figures 53A-53B: 9.492°, 11.011°, 12.391°, 13.440°, 14.609°, 15.432°, 16.394°, 18.259°, 18.967°, 19.356°, 19.827°, 20.843°, 21.476°, 22.062°, 22.805°, 23.862°, 24.96°, 25.96°, 26.96°, 27.96°, 28.96°, 29.96°, 30.96°, 31.96°, 32.96°, 33.96°, 34.96°, 35.96°, 36.96°, 37.96°, 38.96°, 39.96°, 40.96°, 41.96°, 42.96°, 43.96°, 44.96°, 45.96°, 46.96°, 47.96°, 48.96°, 49.96°, 50.96°, 51.96°, 52.96°, 53.96°, 54.96°, 55.96°, 56.96°, 57.96°, 58.96°, 59.96°, 60.96°, 61.96°, 62.96°, 63.96°, 64 3°, 25.734°, 26.170°, 26.992°, 27.738°, 28.593°, 30.073°, 30.746°, 31.041°, 31.799°, 32.794°, 33.551°, 34.480°, 35.430°, 37.685°, and 38.643° (Pattern 1). In some embodiments, the pharmaceutically acceptable salt is the tartrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3b). In some embodiments, salt I-3b is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, for example, as shown in FIG.In some embodiments, salt I-3b has a molecular weight of 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.50°, as determined by XRPD using a CuKα radiation source, as shown, for example, in Figures 69A-69B. 2°, 28.179°, 28.597°, 29.035°, 29.257°, ​​29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049° (Pattern 2). In some embodiments, the pharmaceutically acceptable salt is the tartrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7b). In some embodiments, salt I-7b exhibits the following peaks as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 12 : 6.798°, 11.360°, 12.764°, 13.535°, 14.837°, 15.973°, 16.351°, 17.367°, 18.937°, 20.168°, 20.929°, 21.946°, 22.719°, 23.604°, 23.814°, 24.874°, 25.609°, 26.819°, 27.819°, 28.819°, 29.819°, 30.819°, 31.819°, 32.719°, 33.604°, 34.814°, 35.819°, 36.819°, 37.819°, 38.819°, 39.819°, 40.819°, 41.819°, 42.719°, 43.604°, 44.814°, 45.819°, 46.819°, 47.819°, 48.819°, 49.819°, 50.819°, 51.819°, 52.819°, 53.819°, 54.819°, 55.819°, 56.819°, 57.819°, 58.819°, 59.819°, 60.819°, It is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 26.745°, 27.111°, 27.558°, 28.653°, 29.630°, 31.129°, 31.567°, 32.180°, 33.073°, 34.096°, 34.460°, 36.226°, 37.497°, 38.727°, and 41.126° (Pattern 1).In some embodiments, salt I-7b is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 2, e.g., as shown in Figure 12. In some embodiments, salt I-7b has a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 2, e.g., as shown in Figure 18, as determined by XRPD using a CuKα radiation source, with the following peaks: 6.479°, 10.486°, 10.862°, 11.913°, 12.222°, 12.972°, 13.161°, 13.467°, 14.230°, 15.372°, 15.736°, 16.053°, 17.053°, 18.053°, 19.053°, 20.053°, 21.053°, 22.053°, 23.053°, 24.053°, 25.053°, 26.053°, 27.053°, 28.053°, 29.053°, 30.053°, 31.053°, 32.053°, 33.053°, 34.053°, 35.053°, 36.053°, 37.053°, 38.053°, 39.053°, 40.053°, 41.053°, 42.053°, 43.053°, 44.053°, 45.053°, 46.053°, 47.053°, 48.053°, 49.053°, 50 16.457°, 16.613°, 17.009°, 17.695°, 17.913°, 18.486°, 18.795°, 19.479°, 20.101°, 20.416°, 20.818°, 21.352°, 22.106°, 22.320°, 22.629°, 22.964°, 23.698°, 23.950°, 24.175°, 24.439°, 24.818°, 25.079°, 25.880°, 26.528°, 27.297°, 27.752°, 28.124°, 28.349°, 28.631°, 29.075°, 29.819°, 30.202°, ​​30.562°, 31.025°, 31.207°, 31.650°, 31.953°, 33.721°, 34.362°, 34.651° , 34.994°, 35.512°, 35.982°, 36.450°, 37.476°, 38.287°, 39.699°, 39.980°, 40.951°, and 41.870° (Pattern 3). In some embodiments, the pharmaceutically acceptable salt is the hemifumarate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7c). In some embodiments, salt I-7c is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, 2, 3, or 4, as shown, for example, in Figures 23 and 29.In some embodiments, salt I-7c exhibits the following peaks as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 42 : 8.483°, 8.733°, 11.080°, 11.351°, 11.622°, 12.615°, 13.258, 14.977°, 15.557°, 16.089°, 16.319°, 16.606°, 17.013°, 18.928°, 18.884°, 19.429°, 19.518°, 20.518°, 21.518°, 22.518°, 23.518°, 24.518°, 25.518°, 26.518°, 27.518°, 28.518°, 29.518°, 30.518°, 31.518°, 32.518°, 33.518°, 34.518°, 35.518°, 36.518°, 37.518°, 38.518°, 39.518°, 40.518°, 42.518°, 43.518°, 44.518°, 45.518°, 46.518°, 47.518°, 48.518°, 49.518°, 50.518°, 52.518°, 53.518°, 54.518°, 55.518°, 56.518°, 5 It is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.734°, 20.643°, 21.484°, 22.067°, 23.433°, 24.466°, 24.885°, 26.740°, 27.900°, 28.557°, 29.523°, 32.888°, 34.183°, and 36.808° (Pattern 5). In some embodiments, salt I-7c exhibits the following peaks as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 42: 9.746°, 11.354°, 12.338°, 13.762°, 16.111°, 16.644°, 19.929°, 20.180°, 21.576°, 22.758°, 23.348°, 23.938°, 24.7 I-3c is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 24°, 25.226°, 26.203°, 27.910°, 29.056°, 29.499°, 32.753°, 35.567°, 37.279°, 37.347°, and 39.481° (Pattern 6). In some embodiments, the pharmaceutically acceptable salt is the hemifumarate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3c). In some embodiments, salt I-3c is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, as shown, for example, in Figures 72 and 75A.In some embodiments, salt I-3c exhibits the following peaks as determined by XRPD using a CuKα radiation source, for example, as shown in Figure 75B: 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°. It is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999° (Pattern 2). In some embodiments, the pharmaceutically acceptable salt is the acetate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7d). In some embodiments, salt I-7d is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1 or 2, as shown, for example, in FIG. 32. In some embodiments, the pharmaceutically acceptable salt is the hemimalonate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7f). In some embodiments, salt I-7f is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, as shown in FIG. 39. In some embodiments, the pharmaceutically acceptable salt is the hemisuccinate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7h). In some embodiments, salt I-7h is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, as shown, for example, in FIG. 47. In some embodiments, the pharmaceutically acceptable salt is the oxalate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7i). In some embodiments, salt I-7i is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, 2, 3, 4, 5, or 6, e.g., as shown in Figure 50. In some embodiments, the pharmaceutically acceptable salt is the salicylate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7k). In some embodiments, salt I-7k is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1, 2, or 3, e.g., as shown in Figure 60.

[0334] In some embodiments, the pharmaceutical composition comprises an amorphous form of a pharmaceutically acceptable salt of the compound of Formula (I) and a coated organic acid agent, such as coated citric acid, coated tartaric acid, or coated fumaric acid. For effervescent dosage forms, a carbon dioxide source (e.g., sodium bicarbonate) is also included with the coated organic acid agent. In some embodiments, the pharmaceutically acceptable salt is the citrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3e). In some embodiments, salt I-3e is in the form of an amorphous solid as characterized by X-ray powder diffraction (XRPD). In some embodiments, the pharmaceutically acceptable salt is the citrate salt of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (I-7e). In some embodiments, salt I-7e is in the form of an amorphous solid as characterized by X-ray powder diffraction (XRPD), for example, as shown in Figures 37A-37B.

[0335] When a pharmaceutical composition is formulated containing a pharmaceutically acceptable salt of a compound of Formula (I), the acid used to form the pharmaceutically acceptable salt of the compound of Formula (I) and the organic acid agent (vehicle) may be the same. For example, the pharmaceutical composition may contain a tartrate salt of a compound of Formula (I) (e.g., I-1b, I-2b, I-3b, I-4b, I-5b, I-6b, and / or I-7b) and tartaric acid as the organic acid agent (vehicle). In another example, the pharmaceutical composition may contain a citrate salt of a compound of Formula (I) (e.g., I-1e, I-2e, I-3e, I-4e, I-5e, I-6e, and / or I-7e) and citric acid as the organic acid agent (vehicle).

[0336] When a pharmaceutical composition is formulated containing a pharmaceutically acceptable salt of a compound of Formula (I), the acid used to form the pharmaceutically acceptable salt of the compound of Formula (I) and the organic acid agent (vehicle) may be different. For example, the pharmaceutical composition may contain a benzenesulfonic acid salt of a compound of Formula (I) (e.g., I-1a, I-2a, I-3a, I-4a, I-5a, I-6a, and / or I-7a) and citric acid and / or tartaric acid as the organic acid agent (vehicle). In another example, the pharmaceutical composition may contain a benzoic acid salt of a compound of Formula (I) (e.g., I-1j, I-2j, I-3j, I-4j, I-5j, I-6j, and / or I-7j) and citric acid and / or tartaric acid as the organic acid agent (vehicle).

[0337] The pharmaceutical compositions disclosed herein may be disclosed in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.

[0338] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form (e.g., an effervescent dosage form) disclosed herein into a pharmaceutically acceptable aqueous medium, such as, for example, water, juice, or other drinkable fluid, prior to use.

[0339] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising a compound of Formula (I) (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, and / or I-10) as a crystalline free base in a pharmaceutically acceptable aqueous medium. The solid dosage form may further be formulated with an organic acid agent, including a coated organic acid agent. The effervescent solid dosage form may further be formulated with an organic acid agent, including a coated organic acid agent, and a carbon dioxide source.

[0340] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising a compound of Formula (I) (e.g., I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, and / or I-10) as the free base in amorphous form into a pharmaceutically acceptable aqueous medium. The solid dosage form may further be formulated with an organic acid agent, including a coated organic acid agent. The effervescent solid dosage form may further be formulated with an organic acid agent, including a coated organic acid agent, and a carbon dioxide source.

[0341] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form containing a crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I) in a pharmaceutically acceptable aqueous medium.The solid dosage form may further be formulated with an organic acid, including a coated organic acid.The effervescent solid dosage form may further be formulated with an organic acid, including a coated organic acid, and a carbon dioxide source.

[0342] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising an amorphous form of a pharmaceutically acceptable salt of the compound of Formula (I) in a pharmaceutically acceptable aqueous medium.The solid dosage form may further be formulated with an organic acid, including a coated organic acid.The effervescent solid dosage form may further be formulated with an organic acid, including a coated organic acid, and a carbon dioxide source.

[0343] Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions may contain a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and a water-miscible solvent having one or more hydroxyl groups, e.g., propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, e.g., sucrose, and may contain a preservative. For liquid dosage forms, solutions, e.g., in polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.

[0344] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients disclosed herein and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, and polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weights of the polyethylene glycol. These formulations may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. In some embodiments, examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid.

[0345] Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance delivery of the compositions described herein.

[0346] The pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres, or nanosystems.

[0347] Coloring and flavoring agents may be used in all of the above dosage forms.

[0348] The pharmaceutical compositions disclosed herein can be co-formulated with other active ingredients that do not impair the desired therapeutic action, or with substances that supplement the desired action.

[0349] B. Parenteral Administration The pharmaceutical compositions disclosed herein can be administered parenterally by injection, infusion or implantation for local or systemic administration.As used herein, parenteral administration includes but is not limited to intravenous, intradermal, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

[0350] The pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, supra).

[0351] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable vehicles (e.g., carriers and excipients), including, but not limited to, aqueous solvents, water-miscible solvents, non-aqueous solvents, antimicrobial agents or preservatives against microbial growth, stabilizers, solubilizing agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0352] Suitable aqueous solvents include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous solvents include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil, and medium-chain triglycerides of palm seed oil. Water-miscible solvents include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0353] Suitable antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propylparaben, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citric acid. Suitable antioxidants include those described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, and organic acids (e.g., citric acid, lactic acid, etc.). Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-3-cyclodextrin / hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether-7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

[0354] The pharmaceutical compositions disclosed herein can be formulated for single or multiple dose administration.Single dose preparations are packaged in ampoules, vials or syringes.Multiple dose parenteral preparations must contain antimicrobial agents at bacteriostatic or fungistatic concentrations.All parenteral preparations must be sterile, as is known and practiced in the art.

[0355] In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile solutions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry soluble products, including lyophilized powders and hypodermic tablets, which are reconstituted with a solvent before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile suspensions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry insoluble products, which are reconstituted with a solvent before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile emulsions.

[0356] Pharmaceutical compositions can be formulated as suspension, solid, semi-solid or thixotropic liquid for administration as implanted depot.In some embodiments, pharmaceutical compositions disclosed herein are dispersed in a solid internal matrix that is insoluble in body fluids but is surrounded by an outer polymer membrane that allows the active ingredient in pharmaceutical compositions to diffuse.The fatty acid salt of the compound of formula (I) can be well suited to this dosage form.

[0357] Suitable inner matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0358] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene-propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate copolymers with vinyl chloride, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0359] C. Topical administration The pharmaceutical compositions disclosed herein can be administered topically to the skin, orifices, or mucous membranes. Topical administration as described herein includes, but is not limited to, conjunctival, intracorneal, intraocular, ophthalmic, otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0360] The pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for topical administration for local or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, cleansers, sprays, suppositories, bandages, and skin patches.Topical formulations of the pharmaceutical compositions disclosed herein can contain active ingredients mixed under sterile conditions with a pharmaceutically acceptable vehicle, and with any preservatives, buffers, absorption enhancers, and propellants that may be required.Liposomes, micelles, microspheres, nanosystems, and mixtures thereof can also be used.

[0361] Pharmaceutically acceptable vehicles (e.g., carriers and excipients) suitable for use in the topical formulations disclosed herein include, but are not limited to, aqueous solvents, water-miscible solvents, non-aqueous solvents, antimicrobial agents or preservatives against microbial growth, stabilizers, solubilizing agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, cryoprotectants, thickening agents, and inert gases.

[0362] The ointments, pastes, creams, and gels may contain, in addition to the active ingredient, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0363] Powders and sprays can contain, in addition to the active ingredient, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays, such as those used for nasal (intra)nasal administration, can additionally contain customary propellants, such as fluorohydrocarbons, chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0364] Transdermal delivery devices (e.g., patches) may also be used. Such dosage forms have the additional advantage of providing controlled delivery of active ingredients to the body. That is, the compound of the present disclosure (e.g., compound of formula (I), or its pharmaceutically acceptable salt, polymorph, stereoisomer or solvate) can be administered through transdermal patches at steady-state concentration, thereby gradually administering the active ingredient over time, and avoiding drug spikes and adverse events / toxicity associated with the active ingredient.

[0365] The transdermal patch dosage forms herein may be formulated with various amounts of active ingredient depending on the disease / condition being treated, the active ingredient used, the permeability and size of the transdermal delivery device, the release period, etc. For example, unit dose preparations may be modified or adjusted from, for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg to 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg of a compound of Formula (I) (based on the active form), or otherwise modified or adjusted as may be deemed appropriate using reasonable medical judgment according to the particular application and potency of the compound.

[0366] Transdermal patches formulated with the disclosed compounds may be suitable for microdosing or non-hallucinogenic (also referred to herein as non-psychoactive) administration, which achieves long-term therapeutic benefit with reduced toxicity. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof is administered via a transdermal patch at non-hallucinogenic (yet potentially serotonergic) concentrations for an extended period of time, such as, for example, 8, 24, 48, 72, 84, 96, or 168 hours.

[0367] In addition to the active ingredient(s) and optional pharmaceutically acceptable vehicle, a transdermal patch may comprise one or more of a pressure-sensitive adhesive layer, a backing, and a release liner, as known to those of ordinary skill in the art.

[0368] A transdermal patch dosage form can be prepared by dissolving or dispersing the compound of the present disclosure in a suitable medium. In some embodiments, the compound of the present disclosure may be directly dissolved / dispersed in a polymer matrix forming a pressure-sensitive adhesive layer. Such a transdermal patch is called a drug-adhesive (DIA) patch. A preferred DIA patch form is one in which the active ingredient is uniformly distributed throughout the pressure-sensitive adhesive polymer matrix. In some embodiments, the active ingredient may be provided in a layer comprising the active ingredient and a polymer matrix that is separate from the pressure-sensitive adhesive layer. In either case, the compound of the present disclosure may optionally be formulated with a suitable vehicle, such as a carrier substance, a penetration agent / absorption enhancer, a moisturizer / crystallization inhibitor, etc. It may also be optionally formulated to increase the flux across the skin.

[0369] Examples of carrier agents include C8-C12 fatty acids such as oleic acid, undecanoic acid, valeric acid, heptanoic acid, pelargonic acid, capric acid, lauric acid, and eicosapentaenoic acid. 22 C8-C fatty acids, such as octanol, nonanol, oleyl alcohol, decyl alcohol, and lauryl alcohol 22 C8-C fatty alcohols such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate 22 Lower alkyl esters of fatty acids, C6-C such as diisopropyl adipate 22 C8-C di(lower) alkyl esters of diacids, such as glyceryl monolaurate 22These include, but are not limited to, monoglycerides of fatty acids, tetrahydrofuryl alcohol polyethylene glycol ethers, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monomethyl ether, alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethyl ether, polyethylene oxide dimethyl ether, glycerol, ethyl acetate, acetoacetate esters, N-alkylpyrrolidones, cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or derivatives such as 2-hydroxypropyl-β-cyclodextrin, as well as terpenes / terpenoids such as limonene, linalool, myrcene, pinenes such as α-pinene, caryophyllene, citral, eucoliptol, and mixtures thereof.

[0370] Examples of permeation agents / absorption enhancers include, but are not limited to, sulfoxides such as dodecyl methyl sulfoxide, octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxy-undecyl methyl sulfoxide, 2-hydroxydodecyl methyl sulfoxide; surfactant-lecithin organogel (PLO) formed from an aqueous phase having one or more of poloxamer, CARBOPOL, and PEMULEN, an oily phase formed from one or more of isopropyl palmitate and PPG-2 myristyl ether propionate, and lecithin; fatty acids, esters, and alcohols such as oleic acid and oleyl alcohol; keto acids such as levulinic acid; glycols and glycol ethers, for example, diethylene glycol monoethyl ether; including mixtures thereof.

[0371] Examples of humectants / crystallization inhibitors include, but are not limited to, polyvinylpyrrolidone-co-vinyl acetate, HPMC, polymethacrylate, and mixtures thereof.

[0372] The pressure-sensitive adhesive layer may be formed from polymers including, but not limited to, acrylics (polyacrylates including alkyl acrylics), polyvinyl acetate, natural and synthetic rubbers (e.g., polyisobutylene), ethylene vinyl acetate copolymers, polysiloxanes, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene butadiene rubber block copolymers, and mixtures thereof. The pressure-sensitive adhesive layer used in the transdermal patches of the present disclosure may be formed from an acrylic polymer pressure-sensitive adhesive, preferably an acrylic copolymer pressure-sensitive adhesive. Acrylic copolymer pressure-sensitive adhesives may be obtained by copolymerization of one or more alkyl (meth)acrylates (e.g., 2-ethylhexyl acrylate), aryl (meth)acrylates, arylalkyl (meth)acrylates, and (meth)acrylates with functional groups such as hydroxyalkyl (meth)acrylates (e.g., hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate, and 4-hydroxybutyl methacrylate), carboxylic acid-containing (meth)acrylates (e.g., acrylic acid), and alkoxy (meth)acrylates (e.g., methoxyethyl acrylate), optionally with one or more copolymerizable monomers (e.g., vinylpyrrolidone, vinyl acetate, etc.). Specific examples of acrylic pressure-sensitive adhesives include DURO-TAK 87-900A, DURO-TAK Examples of suitable DURO-TAK products include, but are not limited to, DURO-TAK products (Henkel) such as DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 87-2074, DURO-TAK 87-235A, DURO-TAK 87-2510, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 87-2516, DURO-TAK 387-2052, and DURO-TAK 87-2677.

[0373] The backing used in the transdermal patch of the present disclosure may include flexible backings such as films, nonwoven fabrics, Japanese paper, woven cotton fabrics, knitted fabrics, woven fabrics, and laminated composites of nonwoven fabrics and films. Such backings are preferably made of soft materials that can closely contact the skin and conform to its movements, and that can prevent skin rashes and other discomfort after prolonged use of the patch. Examples of backing materials include, but are not limited to, polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polystyrene, nylon, cotton, rayon acetate, rayon, rayon / polyethylene terephthalate composites, polyacrylonitrile, polyvinyl alcohol, acrylic polyurethane, ester polyurethane, ether polyurethane, styrene-isoprene-styrene copolymer, styrene-butadiene-styrene copolymer, styrene-ethylene-propylene-styrene copolymer, styrene-butadiene rubber, ethylene-vinyl acetate copolymer, or cellophane. Preferred backings do not adsorb or release the active ingredient. In order to prevent the adsorption and release of the active ingredient, improve the percutaneous absorption of the active ingredient, and prevent skin rashes and other discomfort, the backing preferably comprises one or more layers made of the above-mentioned materials and having water vapor permeability.Specific examples of the backing include, but are not limited to, 3M COTRAN products such as 3M COTRAN ethylene vinyl acetate membrane film 9702, 3M COTRAN ethylene vinyl acetate membrane film 9716, 3M COTRAN polyethylene membrane film 9720, and 3M COTRAN ethylene vinyl acetate membrane film 9728.

[0374] The release liner used in the transdermal patch of the present disclosure may include, but is not limited to, polyester film with one or both sides treated with a release coating, polyethylene-laminated high-quality paper treated with a release coating, and glass paper treated with a release coating. The release coating may be a fluoropolymer, silicone, fluorosilicone, or any other release coating known to those skilled in the art. The release liner may have an uneven surface to facilitate easy removal of the transdermal patch from the package. Examples of release liners include, but are not limited to, SCOTCHPAK products from 3M Company, such as 3M SCOTCHPAK 9744, 3M SCOTCHPAK 9755, 3M SCOTCHPAK 9709, and 3M SCOTCHPAK 1022.

[0375] Other layers may also be used, such as an abuse-deterrent layer formulated with one or more irritants (eg, sodium lauryl sulfate, poloxamer, sorbitan monoester, glyceryl monooleate, spices, etc.).

[0376] The methods disclosed herein using transdermal patch dosage forms provide systemic delivery of low amounts of active ingredient, preferably over extended periods of time, such as up to 168 hours, for example, 2 to 96 hours, or 4 to 72 hours, or 8 to 24 hours, or 10 to 18 hours, or 12 to 14 hours. In particular, the compound of formula (I) can be delivered in low, stable, and consistent doses, so as to avoid harmful or undesirable side effects. In some embodiments, the compound of formula (I) is administered transdermally at a concentration that is non-hallucinogenic (yet potentially serotonergic).

[0377] The automatic injection device provides a method of delivering the compositions disclosed herein to a patient. The compositions disclosed herein may be administered to a patient using an automatic injection device via several known devices, a non-limiting list of which includes transdermal, subcutaneous, and intramuscular delivery.

[0378] In some transdermal, subcutaneous or intramuscular applications, the compositions disclosed herein are absorbed through the skin.Passive transdermal patch devices often include an absorption layer or membrane that is placed on the outer layer of the skin.The membrane typically contains a dose of a substance that is allowed to be absorbed through the skin to deliver the composition to the patient.Typically, only substances that are easily absorbed through the outer layer of the skin can be delivered by such transdermal patch devices.

[0379] Other automatic injection devices disclosed herein are configured to provide increased skin permeability to improve delivery of the disclosed compositions. Non-limiting examples of structures used to increase permeability to improve movement of the compositions into, across, or into the muscle include the use of one or more microneedles, which in some embodiments may be coated with the compositions disclosed herein. Alternatively, hollow microneedles may be used to provide a fluid channel for delivery of the disclosed compositions below the outer layer of the skin. Other devices disclosed herein include transdermal delivery via iontophoresis, sonophoresis, reverse iontophoresis, or a combination thereof, and other techniques known in the art for increasing skin permeability to facilitate drug delivery.

[0380] Pharmaceutical compositions can also be administered locally by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection, e.g., POWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, Oreg.).

[0381] The pharmaceutical compositions disclosed herein can be in the form of ointment, cream and gel.Suitable ointment solvents include, for example, oily or hydrocarbon solvents, including lard, benzoated lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsifying or absorbing solvents, such as hydrophilic petrolatum, hydroxystearic sulfate and anhydrous lanolin; water-removing solvents, such as hydrophilic ointments; water-soluble ointment solvents, including polyethylene glycols of various molecular weights; emulsion solvents, including cetyl alcohol, glyceryl monostearate, lanolin, stearic acid, either water-in-oil (W / O) emulsion or oil-in-water (O / W) emulsion (see Remington: The Science and Practice of Pharmacy, supra).These solvents are emollients, but generally require the addition of antioxidants and preservatives.

[0382] Suitable cream bases can be oil-in-water or water-in-oil. Cream vehicles are water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which generally consists of petrolatum and fatty acid alcohols such as cetyl or stearyl alcohol. The aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation can be a nonionic, anionic, cationic, or amphoteric surfactant.

[0383] Gels are semi-solid suspensions. Single-phase gels contain organic polymers dispersed substantially uniformly throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers, such as carbomer, carboxypolyalkylene, Carbopol®; hydrophilic polymers, such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose-based polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate, and gelatin. To prepare a uniform gel, dispersants such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, and / or stirring.

[0384] The pharmaceutical compositions disclosed herein may be administered rectally, urethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, poultice or cataplasm, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, emulsion, tampon, gel, foam, spray, or enema. These dosage forms can be prepared using conventional processes as described in Remington: The Science and Practice of Pharmacy (supra).

[0385] Rectal, urethral, ​​and vaginal suppositories are solids for insertion into bodily orifices; they are solid at normal temperatures but melt or soften at body temperature, releasing the active ingredient into the orifice. Pharmaceutically acceptable carriers used for rectal and vaginal suppositories include bases or solvents, such as stiffening agents, that produce melting points near body temperature when the pharmaceutical compositions disclosed herein are formulated; antioxidants described herein include bisulfite and sodium metabisulfite. Suitable solvents include cocoa butter (theobroma oil), glycerinated gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid; and glycerinated gelatin. Combinations of various solvents may be used, including, but not limited to, cocoa butter (theobroma oil), glycerinated gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid; glycerinated gelatin. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0386] The pharmaceutical compositions disclosed herein may be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solution, gels, intraocular inserts, and implants.

[0387] The pharmaceutical compositions disclosed herein can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical compositions can be disclosed in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to generate a fine mist, or nebulizer, either alone or in combination with a suitable propellant, including, but not limited to, fluorohydrocarbons, chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane, propane, 1,1,1,2-tetrafluoroethane, or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can be disclosed as dry powders for inhalation, alone or in combination with an inert carrier, such as lactose or phospholipids; and as nasal drops. For intranasal use, the powder can contain a bioadhesive agent, including, for example, chitosan and / or cyclodextrin.

[0388] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers can be formulated to contain ethanol, aqueous ethanol, or a suitable substitute for dispersing, solubilizing, or sustaining the release of the active ingredients disclosed herein, a propellant as a solvent; and / or a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0389] The pharmaceutical compositions disclosed herein may be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less, etc. Particles of such sizes may be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0390] Capsules, blisters, and cartridges for use in inhalants or insufflators can be formulated to contain a powder mix of the pharmaceutical compositions disclosed herein; a suitable powder base such as lactose or starch; and a performance modifier such as l-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions disclosed herein for inhalation / intranasal administration can further contain a suitable flavoring agent, such as menthol and levomenthol, or a sweetener, such as saccharin or saccharin sodium.

[0391] The pharmaceutical compositions disclosed herein for topical administration may be formulated to be immediate or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.

[0392] D. Modified release The pharmaceutical compositions disclosed herein can be formulated as modified release dosage forms.As used herein, the term "modified release" refers to a dosage form in which the release rate or release location of active ingredient is different from that of an immediate dosage form when administered by the same route.The pharmaceutical compositions of modified release dosage forms can be prepared using various controlled release devices and methods known to those skilled in the art, including but not limited to matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof.The release rate of active ingredient can also be modified by changing the particle size and polymorphism of active ingredient.

[0393] 1. Matrix controlled release device The pharmaceutical compositions disclosed herein in modified release dosage forms may be prepared using matrix release-controlling devices known to those skilled in the art (see Takada et al., "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz ed., Wiley, 1999).

[0394] In one embodiment, the pharmaceutical compositions disclosed herein in modified controlled dosage form are formulated using a dissolving matrix device that is a water-swellable, erodible, or soluble polymer, including synthetic polymers, natural polymers and derivatives, e.g., polysaccharides and proteins.

[0395] Materials useful for forming a dissolving matrix include chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), and the like. ), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone, polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm Copolymers of L-glutamic acid and ethyl-L-glutamic acid; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride, but are not limited to these.

[0396] In a further embodiment, the pharmaceutical composition is formulated as a non-eluting matrix device. The active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Materials suitable for use as a non-eluting matrix device include insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber. These include, but are not limited to, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer; and hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, cross-linked partially hydrolyzed polyvinyl acetate, aliphatic compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0397] In matrix controlled-release systems, the desired release kinetics can be controlled, for example, through the type of polymer used, the polymer viscosity, the particle size of the polymer and / or the active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0398] The pharmaceutical compositions disclosed herein in modified release dosage forms may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0399] 2. Osmotic Controlled Release Devices The pharmaceutical compositions disclosed herein in modified-release dosage forms can be manufactured using osmotic controlled release devices, including one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient, and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water from an aqueous environment into the core during use, causing drug release by extrusion through the delivery port.

[0400] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that generates a driving force for water transport from the environment of use into the core of the device. Water-swellable hydrophilic polymers, a type of osmotic agent, also referred to as "osmopolymers" and "hydrogels," include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0401] Another type of osmotic agent is an osmogen, which can absorb water and affect the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as glucose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0402] Osmotic agents with different dissolution rates can be used to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can be used to provide more rapid delivery in the first few hours to produce the desired therapeutic effect immediately, with the remaining amount gradually and continuously released to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at a rate that replaces th...

Claims

1. a compound of formula (I) or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof, and a pharmaceutically acceptable vehicle comprising an organic acid agent, 【Chemical 1】 During the ceremony, R ２ , R ５ , R ６ , and R ７ are independently selected from the group consisting of hydrogen and deuterium; R ８ and R ９ are independently -CH ３- , -CH ２ D -、 -CHD ２- , and -CD ３ is selected from the group consisting of X １ , X ２ , Y １ , and Y ２ are independently selected from the group consisting of hydrogen and deuterium.

2. wherein said compound of formula (I) 【Chemistry 2】 2. The pharmaceutical composition of claim 1, which is at least one selected from the group consisting of: or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof.

3. wherein said compound of formula (I) 【Chemistry 3】 10. The pharmaceutical composition of claim 1, wherein the compound is: or a pharmaceutically acceptable salt, polymorph, stereoisomer, or solvate thereof.

4. The compound of formula (I) is 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ )-1H-indol-4-ol (I-3), (i) 7.582°, 8.395°, 9.647°, 10.444°, 11.319°, 12.614°, 13.372°, 14.222°, 15.157°, 16.524°, 16.787°, 17.693°, 19.468°, 19.699°, 20.901°, 21.132°, 21.859°, 22.547°, 23.699°, 24.630°, 25.034°, 25.264°, 26.867°, 27.399°, 2 or characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 7.929°, 28.219°, 28.871°, 29.430°, 30.120°, 30.675°, 31.373°, 32.365°, 33.880°, 34.418°, 34.792°, 35.884°, 36.254°, 37.156°, 38.200°, and 38.417°; or (ii) 8.124°, 8.357°, 10.059°, 12.630°, 13.420°, 13.743°, 14.053°, 15.220°, 16.272°, 16.763°, 16.954°, 17.328° , 17.662°, 18.062°, 18.742°, 19.413°, 19.658°, 20.172°, 20.836°, 21.267°, 21.833°, 22.213°, 22.504°, 23.334°, 2 2. The pharmaceutical composition of claim 1, characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 3.701°, 24.385°, 25.431°, 25.721°, 26.049°, 27.291°, 28.368°, 30.349°, 30.656°, 31.337°, 31.538°, 32.091°, 35.870°, 38.514°, and 41.361°.

5. 10. The pharmaceutical composition of claim 1, wherein said compound of formula (I) is present as a pharmaceutically acceptable salt of said compound of formula (I).

6. 6. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, hemimalonate, fumarate, hemisuccinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, methanesulfonate, toluenesulfonate, glucuronate, or glutarate salt of the compound of formula (I).

7. The pharmaceutically acceptable salt of the compound of formula (I) is 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ 6. The pharmaceutical composition according to claim 5, wherein the compound is the benzenesulfonate salt of 1H-indol-4-ol (I-3a).

8. 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ The benzenesulfonate salt of )-1H-indol-4-ol (I-3a) is crystalline and has the following peak angles: 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 19.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, 24.187°, 25.022°, 26.022°, 27.023°, 28.022°, 29.022°, 30.022°, 31.022°, 32.007°, 33.022°, 34.022°, 35.022°, 36.022°, 37.022°, 38.022°, 39.022°, 40.022°, 41.022°, 42.022°, 43.022°, 44.022°, 45.022°, 46.022°, 47.022°, 48.022°, 49.022°, 50.022°, 51.022°, 52.022°, 53.022°, 54.022°, 55.022°, 56.022°, 57.022°, 58.022°, 59.022°, 60.022°, 61.022°, 62.022° 8. The pharmaceutical composition of claim 7, characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 5.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988°.

9. The pharmaceutically acceptable salt of the compound of formula (I) is 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ 6. The pharmaceutical composition of claim 5, wherein the compound is the tartrate salt of 1H-indol-4-ol (I-3b).

10. 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ The tartrate salt of )-1H-indol-4-ol (I-3b) is crystalline and has the following peaks: 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.502°, 28.179°, 28.

10. The pharmaceutical composition of claim 9, characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 597°, 29.035°, 29.257°, ​​29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049°.

11. The pharmaceutically acceptable salt of the compound of formula (I) is 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ 6. The pharmaceutical composition of claim 5, wherein the compound is the hemifumarate salt of 1H-indol-4-ol (I-3c).

12. 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ The hemifumarate salt of )-1H-indol-4-ol (I-3c) is crystalline and has the following temperature profiles: 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.262°, 24.262°, 25.262°, 26.262°, 27.262°, 28.262°, 29.262°, 30.262°, 31.262°, 32.262°, 33.262°, 34.262°, 35.262°, 36.262°, 37.262°, 38.262°, 39.262°, 40.262°, 41.262°, 42.262°, 43.262°, 44.262°, 45.262°, 46.262°, 47.262°, 48.262°, 49.262°, 50.262°, 51.262°, 52.262°, 53.262°, 54.262°, 55.262°, 56.262°, 57.262°, 58.262° 12. The pharmaceutical composition of claim 11, characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the following: 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999°.

13. The pharmaceutically acceptable salt of the compound of formula (I) is 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ 6. The pharmaceutical composition of claim 5, wherein the compound is the citrate salt of 1H-indol-4-ol (I-3e).

14. 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ 14. The pharmaceutical composition of claim 13, wherein the citrate salt of 1-(2-methyl-2-propanol)-1H-indol-4-ol (I-3e) is amorphous by X-ray powder diffraction.

15. The pharmaceutically acceptable salt of the compound of formula (I) is 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ 6. The pharmaceutical composition of claim 5, wherein the compound is the benzoate salt of 1H-indol-4-ol (I-3j).

16. 3-(2-(bis(methyl-d ３ ) amino)ethyl-1,1,2,2-d ４ The benzoate salt of )-1H-indol-4-ol (I-3j) is crystalline and has the following peaks: 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.831°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.737°, 26.144° 16. The pharmaceutical composition of claim 15, characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597°.

17. 6. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a fatty acid salt of the compound of formula (I).

18. 2. The pharmaceutical composition of claim 1, wherein the organic acid agent is a hydroxy acid and / or an enedioic acid.

19. 2. The pharmaceutical composition of claim 1, wherein the organic acid agent is at least one selected from the group consisting of glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and maleic acid.

20. 2. The pharmaceutical composition of claim 1, wherein the organic acid agent is citric acid.

21. 21. An oral liquid dosage form prepared by reconstituting the pharmaceutical composition of any one of claims 1 to 20 in solid dosage form in a pharmaceutically acceptable aqueous medium.

22. Serotonin 5-HT ２ 21. A pharmaceutical composition according to any one of claims 1 to 20 for use in a method of treating a subject having a receptor-related disease or disorder.

23. 23. The pharmaceutical composition for use according to claim 22, wherein the disease or disorder is a disorder of the central nervous system (CNS).

24. 24. The pharmaceutical composition for use according to claim 23, wherein the disorder of the central nervous system (CNS) is at least one selected from the group consisting of major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders, eating disorders, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset dysfluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), chronic fatigue syndrome, Lyme disease, gambling disorder, paraphilic disorders, sexual dysfunction, peripheral neuropathy, and obesity.

25. 24. The pharmaceutical composition for use according to claim 23, wherein the central nervous system (CNS) disorder is major depressive disorder (MDD).

26. 24. The pharmaceutical composition for use according to claim 23, wherein the central nervous system (CNS) disorder is treatment-resistant depression (TRD).

27. 24. The pharmaceutical composition for use according to claim 23, wherein the central nervous system (CNS) disorder is a substance use disorder.

28. 28. The pharmaceutical composition for use according to claim 27, wherein the substance use disorder is alcohol use disorder and / or nicotine use disorder.

Images