Crystalline salts of n-ethyl-(5-fluoro-1h-indol-3-yl)-n-methylene-1-amine

Abstract

The present disclosure relates to a crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt, a pharmaceutical composition comprising the salt, and the use thereof for the treatment of mood disorders, the salt is selected from the group consisting of crystalline n-ethyl-2-(5-fluoro-1h-indol-3-yl)-n-methylethyl-1-amine monophosphate, crystalline n-ethyl-2-(5-fluoro-1h-indol-3-yl)-n-methylethyl-1-amine mono-p-toluenesulfonate, crystalline n-ethyl-2-(5-fluoro-1h-indol-3-yl) The present invention relates to a salt of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemi-malate and to a crystalline salt of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine mono-succinate.

Description

Technical Field

[0001] This disclosure relates to a novel crystalline salt, its preparation method, and its use in treating mood disorders in subjects. Background Technology

[0002] Depression is a common mental health problem, characterized by low mood and aversion to activity. Various symptoms associated with depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism and / or feelings of worthlessness, lethargy, restlessness, irritability, fatigue, loss of interest in pleasurable activities or hobbies, excessive sleep, overeating, loss of appetite, insomnia, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of these symptoms vary depending on the individual case.

[0003] Approximately one-third of patients with major depressive disorder (MDD) fail to achieve symptom relief even after multiple rounds of treatment with several known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs). This high incidence of treatment-resistant depression (TRD) underscores the clear need for new and more effective pharmacological therapies targeting new mechanisms and / or patient populations.

[0004] U.S. Patent No. 11,440,879 describes a class of compounds that can be used to treat depression and mood disorders, the contents of which are incorporated herein by reference. It partially discloses compounds of the following formula:

[0005]

[0006] I

[0007] Or its pharmaceutically acceptable salt, wherein

[0008] R1 is an optionally substituted C1-C4 aliphatic group;

[0009] R2 is an optionally substituted C1-C4 aliphatic group; and

[0010] R 26 Choose from the group consisting of: hydrogen, halogen, -CN, -OH, C1-C3 alkoxy, C1-C3 haloalkyl, OAc, -OPO(OH)2, and NH2.

[0011] These compounds can be used to treat mood disorders, including depressive disorders. An example of such a compound in this class is N-ethyl-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine. However, to date, the free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine has not been prepared or isolated as a crystalline solid. Although it can be used as an active pharmaceutical ingredient in pharmaceutical compositions, the active ingredient of this compound as a crystalline form is preferred for several reasons, including, for example, improved chemical stability, improved ability to remove impurities via recrystallization, improved solubility, improved pharmacokinetic properties, or ease of formulation into pharmaceutical compositions.

[0012] Furthermore, many crystalline compounds can exist in more than one crystal form or polymorph, and these polymorphs exhibit different physical, chemical, and spectroscopic properties relative to each other. For example, some polymorphs of a compound may be chemically more stable, may crystallize more easily, may be more soluble in a particular solvent, may be more or less hygroscopic, may flow more easily, or may be more compressible than other polymorphs. See, for example, “Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development,” edited by Rolf Hilfiker and Markus von Raumer, Wiley‐VCH Verlag GmbH & Co. KGaA, (2018). In the case of pharmaceuticals, some solid forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory perspective, as pharmaceuticals are only approved by government agencies (such as the U.S. Food and Drug Administration) if they meet stringent purity and characterization standards. In fact, regulatory approval of a polymorph of a compound exhibiting certain solubility and physicochemical (including spectral) properties does not necessarily imply the approval of other polymorphs of the same compound. In the pharmaceutical field, it is known that polymorphs of compounds can affect, for example, the solubility, stability, flowability, fracturing, and compressibility of the compound, as well as the safety and efficacy of drug products containing that polymorph. See, for example, Knapman, K. Modern Drug Discoveries, 2000, 53. Therefore, the discovery of new polymorphs of drugs can offer a variety of advantages.

[0013] The search for crystalline salts and polymorphs of pharmaceuticals presents challenges. These challenges are mitigated by employing numerous methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent crystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Polymorphs can be detected, identified, classified, and characterized using well-known techniques such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility, and dissolution rate. The distinct physical properties of polymorphs and / or salts can influence their processing. For example, one polymorph or salt may be more likely to form a solvate than another, or may be more difficult to filter or wash away impurities from than another due to, for example, the shape or size distribution of its particles. However, despite these methods, the challenge of finding suitable conditions for preparing separate crystalline salts and / or polymorphs remains significant.

[0014] The inventors have found such crystalline salts and methods for preparing and crystallizing them. Summary of the Invention

[0015] This disclosure relates to a crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt, a pharmaceutical composition comprising the salt, and its use in treating mood disorders, wherein the salt is selected from crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate. In another embodiment, this disclosure relates to a solid comprising substantially crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt, a pharmaceutical composition comprising the solid, and the use thereof for treating mood disorders, wherein the salt is selected from crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate. In another embodiment, the pharmaceutical composition is a solid dosage form. Attached Figure Description

[0016] From the following detailed description taken in conjunction with the accompanying drawings, the objects, features, and advantages of this disclosure will become apparent to those skilled in the art, in which:

[0017] Figure 1 XRPD diffraction pattern of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate.

[0018] Figure 2 Depicting N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate 1 H NMR spectrum (300MHz, DMSO-d6).

[0019] Figure 3 DSC thermogram of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate.

[0020] Figure 4 XRPD diffraction pattern of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate.

[0021] Figure 5 Describing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate 1 H NMR spectrum (300MHz, DMSO-d6).

[0022] Figure 6 DSC thermogram of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate.

[0023] Figure 7 XRPD diffraction pattern of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate.

[0024] Figure 8 Describing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hememalate 1 H NMR spectrum (300MHz, DMSO-d6).

[0025] Figure 9 DSC thermogram of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate.

[0026] Figure 10 XRPD diffraction pattern of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate.

[0027] Figure 11 Depicting N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate 1 1H NMR spectrum (300MHz, DMSO-d6)

[0028] Figure 12 DSC thermogram of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate.

[0029] Figure 13 The DVS isotherm of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate was plotted graphically.

[0030] Figure 14 The DVS isotherm of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate was plotted graphically.

[0031] Figure 15The DVS isotherm of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate was plotted graphically. Detailed Implementation

[0032] The features and other details of this disclosure will now be described in more detail. Before further describing this disclosure, certain terms used in the specification, embodiments, and appended claims are collected herein. These definitions should be understood in accordance with the remainder of this disclosure and as will be understood by those skilled in the art. 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.

[0033] Unless otherwise indicated, the term "free base" or "free base" refers to N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine, which is a base without any counterions, and can exist as an oil or as an amorphous solid, with a chemical structure falling within the range of Formula I described above.

[0034] As used herein, unless otherwise indicated, the term "salt" itself (without any free base or acid name) refers to crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt selected from crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate.

[0035] As defined herein, the term "solvent" refers to a liquid substance or mixture of liquid substances capable of dissolving another substance (solute) to form a solution, wherein the solute is uniformly dispersed at the molecular or ionic level. For the purposes of this disclosure, a solvent can be a reaction solvent or a crystallization solvent. The solvents mentioned herein are inert solvents relative to the solute or reactants.

[0036] As defined in this article, an "inert solvent" is a solvent that does not react with reactants or products formed in a chemical reaction.

[0037] The term "reaction solvent" or a similar term refers to a solvent in which a chemical reaction occurs. It is an inert solvent, meaning it does not react with the free base or acid or the products formed. In one embodiment, the free base and acid are soluble therein, and the products may be soluble therein or insoluble therein. Further in one embodiment, it is a volatile solvent.

[0038] As used herein, the term "crystallization solvent" or a similar term refers to an inert organic solvent used for the crystallization of salts according to this disclosure, wherein the salt is poorly soluble at room temperature or low temperatures but becomes more soluble when heated to the boiling point of the solvent. Ideally, the salt is practically insoluble or slightly soluble in the solvent at room temperature and readily soluble at the boiling point of the solvent. The crystallization solvent can be a solvent or a mixture of solvents. If it is a mixture of liquid solvents, they can be miscible. In one embodiment, water can be a solvent or a co-solvent. As used herein, the term "recrystallization solvent" is a crystallization solvent, and the two terms are used interchangeably.

[0039] As used throughout this disclosure, the term “crystallization” can refer to crystallization and / or recrystallization, depending on the applicable environment in relation to the preparation of the salts described herein.

[0040] As used in this article for compounds, the term "amorphous" refers to a material that lacks long-range order at the molecular level and can exhibit solid or liquid properties depending on temperature. Typically, such materials do not produce distinctive X-ray diffraction patterns.

[0041] As applied to compounds, the term "crystalline" refers to a solid phase of a material that has a regular, ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with defined peaks. As used herein and unless otherwise stated, the terms "polymorph" and "polymorphic form" refer to the solid crystalline form of a compound or complex. Different polymorphs of the same compound can exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rate (which can affect bioavailability). Differences in stability can be caused by changes in chemical reactivity (e.g., differential oxidation, causing dosage forms to discolor more rapidly when composed of one polymorph than another) or changes in mechanical characteristics (e.g., tablets crumble during storage as a kinetically favorable polymorph transforms into a thermodynamically more stable polymorph) or both (e.g., tablets of a polymorph are more prone to decomposition at high humidity).

[0042] The different physical properties of polymorphs and / or salts can affect their processing. For example, one polymorph may be more likely to form solvates than another, or may be more difficult to filter or wash to remove impurities due to, for example, the shape or size distribution of its particles.

[0043] Polymorphs of molecules can be obtained by a variety of methods known in the art. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent crystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Polymorphs can be detected, identified, classified, and characterized using well-known techniques such as, but not limited to, melting point, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility, and dissolution rate.

[0044] The term "pharmaceuticalally acceptable" (as described in the context of pharmaceutically acceptable excipients or carriers) refers to a material that is compatible with administration to human subjects, for example, that does not cause adverse biological effects. Examples of pharmaceutically acceptable excipients are described in "Handbook of Pharmaceutical Excipients - Ninth Edition, edited by Paul J. Sheskey, Bruno C. Hancock, Gary P. Moss, and David J. Goldfarb (2020)".

[0045] The term “treatment” refers to improving, inhibiting, eradicating, reducing the severity of symptoms, reducing the frequency of symptoms, reducing the risk of symptoms, slowing the progression of damage caused by symptoms, delaying the onset of symptoms, or improving the quality of life of human patients or subjects with symptoms.

[0046] As used herein, the terms “about” or “approximately” mean within an acceptable margin of error for a particular value, which is determined by one of ordinary skill in the art and will depend in part on how the value is measured or determined (i.e., the limitations of the measurement system). For example, according to practice in the art, “about” may mean within three or more standard deviations. Alternatively, “about” may mean a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, particularly for biological systems or processes, the term may mean within an order of magnitude of the value, such as within five times or two times. “About” and “approximately” are used interchangeably herein.

[0047] In the implementation plan, the term "effective amount" or "therapeutic effective amount" refers to the amount of the crystalline salt described herein or a pharmaceutical composition containing the crystalline salt, an agent containing the crystalline salt, or other material containing the crystalline salt that effectively achieves a specific pharmacological and / or physiological effect, including but not limited to reducing sadness or somnolence, depressive mood, anxiety or sadness, decreased interest in all or almost all activities, significant increase or decrease in appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, weakness, inability to concentrate, and the frequency or severity of recurrent thoughts of death or suicide, or effectively providing the desired pharmacological and / or physiological effect, such as reducing, inhibiting, or reversing one or more underlying pathophysiological mechanisms of neurological dysfunction, regulating dopamine levels or signaling, regulating serotonin levels or signaling, regulating norepinephrine levels or signaling, regulating glutamate or GABA levels or signaling, regulating synaptic connectivity or neurogenesis in certain brain regions, or combinations thereof. The precise dosage will vary depending on a number of factors, such as subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.), the disease or condition being treated, and the route of administration and the pharmacokinetics of the agent being administered.

[0048] "Patient" or "subject" refers to an animal and can include any mammal, such as human, rat, mouse, cat, dog, goat, sheep, horse, monkey, ape, rabbit, cow, bear, etc. Mammal subjects can be at any developmental stage, including adults, children, infants, and newborns.

[0049] Unless otherwise indicated, the terms "drug" and "pharmaceutical" are synonymous.

[0050] As used herein, the terms “comprising,” “including,” “having,” or any other variation thereof are intended to cover non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to those elements, but may include other elements not expressly listed or not inherent to such process, method, article, or apparatus. Furthermore, unless expressly stated otherwise, “or” means inclusive “or,” not exclusive “or.” For example, condition A or B is satisfied by either: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); and both A and B are true (or exist).

[0051] When referring to a solid, the term "substantially containing crystals," followed by a compound such as a salt, e.g., N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate, means a solid containing at least 50% by weight of the specified compound / salt in a crystalline state. It may contain other impurities. For example, an amorphous compound may be present, or another polymorphic form or salt form may be present, or other impurities may be present, but the total amount of these impurities shall not exceed 50% by weight. In one embodiment, the substantially crystalline solid may contain at least 55% by weight of a crystalline compound / salt, and in another embodiment, at least 60% by weight of a crystalline compound / salt; and in another embodiment, at least 65% by weight of a crystalline compound / salt; and in yet another embodiment, at least 70% by weight of a crystalline compound / salt, and in yet another embodiment, at least 75% by weight of a crystalline compound / salt, and in yet another embodiment, at least 80% by weight of a crystalline compound / salt; and in yet another embodiment, at least 85% by weight of a crystalline compound / salt, and in yet another embodiment, at least 90% by weight of a crystalline compound / salt, and in yet another embodiment, at least 95% by weight of a crystalline compound / salt; and in yet another embodiment, at least 99% by weight of a crystalline compound / salt. Therefore, the amount of crystalline salt present in the solid can be 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt%, or 100 wt%, or any value in between.

[0052] When the salt being depicted is characterized by or has an XPRD spectrum substantially as shown in the figures above, it should be understood that this means the peak spectrum is substantially as shown, taking into account typical variability in peak position and intensity. In one embodiment, at least 70% of the XPRD spectrum has a peak at the indicated value and a variation of ±0.50 at the 2θ angle; in another embodiment, at least 75% of the XPRD spectrum has a peak at the indicated value and a variation of ±0.50 at the 2θ angle; in yet another embodiment, at least 80% of the XPRD spectrum has a peak at the indicated value and a variation of ±0.50 at the 2θ angle; in yet another embodiment, at least 85% of the XPRD spectrum has a peak at the indicated value and a variation of ±0.50 at the 2θ angle; and in yet another embodiment, at least 90% of the XPRD spectrum has a peak at the indicated value and a variation of ±0.50 at the 2θ angle. Therefore, the peaks observed in the figures and the assignments listed in the various tables and figures herein are intended to cover variations of ±0.50 degrees 2θ and variations of relative peak intensity that are understandable to those skilled in the art. When listing the peaks of XRPD, it should be understood that each value listed is ±0.50 degrees 2θ. o 2θ, even if not mentioned in the list ±0.50 o The same applies at 2θ. Furthermore, when the peak chain list provides ±0.50 at the end of the peak chain... o At 2θ, for the purposes of this disclosure, each value in the peak chain is subject to a variation of ±0.50. o 2θ modifier.

[0053] As used herein, when referring to spectra or data presented in graphical form (e.g., XRPD, DSC, IR, Raman, and NMR spectra), unless otherwise stated, the term "peak" means a peak or other special feature that a person skilled in the art would recognize as not attributable to background noise.

[0054] When listing the peaks of XRPD, it should be understood that each listed value has ±0.50. o Variations of 2θ (or ±0.1, ±0.2, ±0.3, and ±0.4 degrees 2θ), even if ±0.50 is not described in the list. o The same applies to 2θ (±0.1, ±0.2, ±0.3, and ±0.4 degrees 2θ). Furthermore, the list of peak chains provides ±0.50 at the end of the peak chain. o At 2θ, for the purposes of this disclosure, each value in the peak chain is subject to a variation of ±0.50. o Modified by 2θ (±0.1, ±0.2, ±0.3 and ±0.4 degrees 2θ).

[0055] However, it should be understood that the relative intensities and distributions of the salt peaks depicted in these figures can vary depending on many factors, including but not limited to sample preparation, fixation, and the instruments, analytical procedures, and settings used to obtain the spectra. Therefore, the peaks observed in the figures and the distributions listed herein in the various tables and figures are intended to cover variations of plus or minus 0.5 degrees 2θ. However, it should be understood that the tables and figures also cover variations of 0.1, 0.2, 0.3, and 0.4 degrees 2θ.

[0056] In summary, the term "substantially as shown" in XRPD means taking into account the typical variability of a particular method. For example, referring to X-ray diffraction peak positions, the term "substantially as shown" means taking into account the typical variability of peak position and intensity. Those skilled in the art will understand that peak position (2θ) will exhibit some variability, typically ±0.5°. Furthermore, those skilled in the art will understand that relative peak intensities will show variability between devices as well as variability due to crystallinity, preferred orientation, the prepared sample surface, and other factors known to those skilled in the art, and should be considered only as qualitative measurements.

[0057] Regarding the terminology, which is essentially as shown for DSC, consider the variability of values. The shape of the thermogram is as shown, but the peak values ​​can vary, and the peak values ​​should be understood as approximately the values ​​shown.

[0058] As used herein, when referring to spectra or data presented in graphical form (e.g., XRPD and NMR spectra), unless otherwise stated, the term "peak" means a peak or other special feature that a person skilled in the art would recognize as not attributable to background noise.

[0059] Similarly, the terms "a" or "an (kind)" are used to describe the elements and components described herein. This is done merely for convenience and to give a general meaning to the scope of the invention. This description should be understood to include one or at least one.

[0060] Furthermore, unless there is an obvious other meaning, the singular includes the plural, and vice versa.

[0061] Furthermore, unless explicitly stated otherwise, "or" refers to an inclusive "or," not an exclusive "or." For example, condition A or B is satisfied by either of the following: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); and both A and B are true (or exist).

[0062] Furthermore, as used herein, the term “and / or” is synonymous with the term “or”.

[0063] When representing a range of values, the implementation includes the endpoints of the range and all points in between. For example, the range of 6 to 9 includes the values ​​6 and 9, and all values ​​in between. Similarly, when a value is expressed as an approximation using the antecedent “about,” it should be understood that the value is within a range of about the two endpoints, where “about” is as defined herein. All ranges are inclusive and composable. Furthermore, references to values ​​stated within a range include every value within that range.

[0064] 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 invention pertains.

[0065] While similar or equivalent methods and materials described herein may be used in the practice or experimentation of embodiments of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety unless a specific paragraph is cited. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be restrictive.

[0066] Unless otherwise indicated, all percentages are weight percentages.

[0067] This disclosure relates to crystalline salts of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine, methods for preparing the crystalline salts, and their use in treating mood disorders, wherein the crystalline salts are selected from crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate.

[0068] This disclosure not only describes the above-described crystalline salts, but also provides methods for preparing and using these crystalline salts.

[0069] In many cases, the salts of the free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine are isolated from or formed in situ from the reaction of the free base with a suitable acid. For example, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate is prepared by the reaction of the free base with phosphoric acid; N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate is prepared by the reaction of the free base with p-toluenesulfonic acid; N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate is prepared by the reaction of the free base with malic acid; and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate is prepared by the reaction of the free base with succinic acid. Furthermore, in many cases, the reaction between the acid and the free base is carried out in a solvent. In one embodiment, the free base is soluble in the solvent, but the product salt is insoluble in the solvent at room temperature. In another embodiment, the reaction is carried out in a crystallization solvent. In one embodiment, the boiling point of the solvent / co-solvent is lower than the melting point of the crystallized salt.

[0070] The free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine is prepared as described in U.S. Patent No. 11,440,879, the contents of which are incorporated herein by reference. Alternatively, it can be prepared from any salt of Examples 1-3 herein or from the salts described in co-pending applications entitled “Crystal Hydrochloride of N-ethyl-(5-fluoro-1-H-indol-3-yl)-N-methylethyl-1-amine” (SSMP No. 42180) and “Crystal Fumarate of N-ethyl-(5-fluoro-1-H-indol-3-yl)-N-methylethyl-1-amine” (SSMP No. 42468), the contents of which are incorporated herein by reference. The free base is typically prepared by reacting a salt with a base in a suitable solvent system using techniques well known in the art. For example, a free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine is prepared by reacting any salt of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine with a suitable base such as NaOH, KOH, ammonia, NaHCO3, Na2CO3, triethylamine, pyridine, etc. Typically, the alkalization reaction is carried out in an organic solvent immiscible with water. After the reaction of salt and base to form the free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine, the organic phase is washed with water or an aqueous phase to remove the inorganic salts formed in the reaction, residual N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts, or other impurities, leaving the free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine in the organic layer. The organic solvent is then evaporated by heating or under reduced pressure to obtain the free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine as an oily or amorphous solid.

[0071] In one embodiment, the crystalline salts described herein are anhydrous, i.e., they contain less than 5% by weight of water, and in another embodiment, they contain less than 4% by weight of water, and in yet another embodiment, they contain less than 3% by weight of water, and in yet another embodiment, they contain less than 2% by weight of water, and in yet another embodiment, they contain less than 1% by weight of water.

[0072] In one embodiment, the solid described herein may be substantially pure. In another embodiment, it may be polymorphically pure; in yet another embodiment, it may be substantially pure and polymorphically pure. In another embodiment, the solid is anhydrous and substantially pure; in another embodiment, it is polymorphically pure and anhydrous; and in yet another embodiment, it is substantially pure, polymorphically pure, and anhydrous.

[0073] In one embodiment, two or more crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate are mixed together to form a solid using techniques known in the art. The solid may contain any two, any three, or all four crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate. The mixed crystalline salts are present in a large quantity in the solid, i.e., they are present at least 50% by weight of the solid. In another embodiment, the mixed crystalline salts are present at least 75% by weight of the solid, and in another embodiment, they are present at least 90% by weight of the solid, and in yet another embodiment, at least 95% by weight of the solid. In one embodiment, the mixed crystalline salt is present at 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt%, or 100 wt%, or any value between therewith.

[0074] In another embodiment, the solid comprising more than one N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt contains a significant amount of one salt, namely at least 50% by weight of a crystalline salt. In another amount, the solid contains at least 75% by weight of a crystalline salt, and in yet another embodiment, at least 90% by weight of the solid and in yet another embodiment, at least 95% by weight of the solid. Therefore, in one embodiment, in the solid composed of the mixed crystalline salts described herein, a crystalline salt is present in amounts of 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt%, 99 wt%, up to 100 wt%, or any value between therewith.

[0075] example

[0076] The various salts described herein are prepared using techniques known to those skilled in the art. These examples illustrate techniques for preparing crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts. The abbreviations used in this specification are as follows:

[0077] DSC - Differential Scanning Calorimetry

[0078] NMR - Nuclear Magnetic Resonance

[0079] XRPD - X-ray powder diffraction.

[0080] ACN-acetonitrile

[0081] DCM-dichloromethane

[0082] ETOAc - Ethyl acetate

[0083] MEK-Methyl Ethyl Ketone

[0084] MtBE-tert-butylmethyl ether

[0085] MIBK-Methyl Isobutyl Ketone

[0086] IPA-Isopropyl alcohol

[0087] DW - Distilled Water

[0088] iPrOAc-isopropyl acetate

[0089] DMSO-dimethyl sulfoxide

[0090] THF-Tetrahydrofuran

[0091] TSA-p-toluenesulfonic acid

[0092] Volume - typically 1 ml / gram of compound or 1 microliter / mg of compound

[0093] In the examples below, various machines were used to obtain various types of data. For example, XRPD was performed using a RigakuMiniFlex 600 in reflection mode (i.e., Bragg-Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters used for XRPD analysis are as follows:

[0094]

[0095] Alternatively, XRPD was performed in reflection mode (i.e., Bragg-Brentano geometry) using a Bruker D8 Advance equipped with a LYNXEYE detector. Samples were prepared on Si zero-return wafers. The parameters of the XRPD method used are as follows:

[0096]

[0097] 1 ¹H NMR was performed on a Bruker Avance 300MHz or 500MHz spectrometer. The solid was dissolved in 0.75mL of deuterated solvent in a 4mL vial and transferred to an NMR tube (Wilmad 5mm thin-walled 8-cell tube). 2 In 200MHz, 506-PP-8), and based on the following parameters, the analysis was performed:

[0098]

[0099]

[0100] DSC was performed using TA Discovery DSC. Samples (1–5 mg) were weighed directly into a 40 μL sealed aluminum dish with a pinhole and analyzed according to the following parameters:

[0101]

[0102] Dissipative chromatograms (DSC) are an analytical technique that measures the heat absorbed or released when a sample is heated or cooled over a temperature range. It measures not only the thermal properties of a material but also the temperatures at which phase transitions occur, including the glass transition temperature, as well as exothermic events during crystallization and endothermic events during melting. Obviously, the graphs recorded by this instrument are affected by the purity of the sample. Pure compounds melt rapidly, typically within a 1-2°C range, while impure compounds melt earlier, typically 1-3°C lower than pure compounds, and have a wider melting range, such as 3-5°C. The resulting graphs may have both maximum and minimum peaks. The maximum peak represents the exothermic event during crystallization, and the minimum peak represents the endothermic event during melting.

[0103] A. Screening Experiment

[0104] Many methods are known in the art for discovering salts and polymorphs of molecules. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent crystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

[0105] The table below summarizes selected data from screening experiments of salts and polymorphs according to the solvent crystallization method. These experiments were conducted using N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine free base, selected acid, and solvent in the volumes shown in the table. The mixture was stirred until a solid was observed. The solids were collected by filtration and their wet filter cake state was analyzed using XRPD, and in some cases, their dry filter cake state was analyzed after at least 3 hours in a vacuum oven.

[0106]

[0107] The preparation of various salts is described below: N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate, and the accompanying physical data.

[0108] BN-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate

[0109] N-Ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate is prepared by reacting the free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine with phosphoric acid under conditions that effectively form N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate. For example, the preparation is carried out in a polar solvent comprising isopropanol, acetone, or a solvent mixture of isopropanol and water in a ratio of about 9:1 (v / v). In one embodiment, the solvent mixture comprising isopropanol and water may be present in a ratio ranging from about 70:30 to about 99:1 (v / v), such as about 70:30, about 75:25, about 80:20, about 85:15, about 90:10, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1 (v / v) and any values ​​between therebetween. Regardless of which solvent system is used, the reaction is carried out under effective conditions. For example, the reaction is slightly heated with stirring at an effective temperature to form N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate and to completely or partially dissolve it. In one embodiment, for example, the reaction can be carried out under stirring and heating at a temperature ranging from about 30°C to about 60°C, such as about 45°C, to form a gel containing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate. While the gel is forming, it is sonicated to thereby form a flowable slurry containing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate. The slurry is cooled to about room temperature, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate is crystallized from the slurry, for example by crystallization, scraping, or aging, to form a crystalline solid substantially containing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate.

[0110] The following examples further illustrate the subject matter described in this disclosure.

[0111] Example 1: Preparation of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate

[0112] Approximately 0.4 mol equivalents of phosphoric acid were added dropwise to treat the free base N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine in 10 volumes of IPA, followed by stirring for 25 minutes. A grayish-white gel formed at the bottom of the vial. To break up the gel, the vial was sonicated for 5 minutes, at which point a white slurry was observed. Crystals separated from previous screening experiments were introduced into the slurry using a micro-scraper to produce a solid product. An additional 0.7 mol equivalents of phosphoric acid were added dropwise, and gel formation was observed. The vial was sonicated until a flowable white slurry was obtained. The slurry was stirred at 45°C for 2 hours, then cooled to room temperature and stirred for 4 hours. The slurry was filtered, and the filter cake was washed three times with 1 volume of IPA. The resulting solid was vacuum dried overnight at 50°C. The recovered dried solid was crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate.

[0113] The products were analyzed using XPRD based on the parameters described above. Figure 1 The XRPD diffraction pattern of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate is depicted. Peak values ​​and intensities are provided in the table below:

[0114]

[0115]

[0116] Note: The cutoff value for relative intensity is 1.

[0117] In one embodiment, the X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at 10.99 ± 0.50°, 15.92 ± 0.50°, and 23.88 ± 0.50° at 2θ. In another embodiment, the X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at 10.99 ± 0.50°, 13.34 ± 0.50°, 15.92 ± 0.50°, 23.88 ± 0.50°, and 24.34 ± 0.50° at 2θ. In another embodiment, the X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at 2θ at 10.99 ± 0.50°, 13.34 ± 0.50°, 15.92 ± 0.50°, 16.28 ± 0.50°, 19.24 ± 0.50°, 22.30 ± 0.20°, 23.38 ± 0.50°, 23.88 ± 0.50°, 24.34 ± 0.50°, and 27.22 ± 0.50°. In another embodiment, Cu... The X-ray powder diffraction pattern measured by K-α radiation contains peaks at the following locations: 10.20±0.50, 10.99±0.50, 12.42±0.50, 13.06±0.50, 13.34±0.50, 14.29±0.50, 15.08±0.50, 15.92±0.50, 16.28±0.50, and 16.94±0. 50, 17.64±0.50, 18.44±0.50, 19.24±0.50, 19.75±0.50, 20.11±0.50, 20.46±0.50, 20.68±0.50, 21.51±0.50, 21.78±0.50, 22.06±0.50, 22.30±0.50, 22.67±0.50 23.38±0.50, 23.88±0.50, 24.34±0.50, 25.82±0.50, 26.24±0.50, 26.60±0.50, 27.22±0.50, 27.70±0.50, 28.14±0.50, 28.63±0.50, 29.05±0.50, 29.64±0.50, 3 0.39±0.50, 31.38±0.50, 31.64±0.50, 33.36±0.50, 33.97±0.50, 35.03±0.50, 35.47±0.50, 35.72±0.50, 37.43±0.50, 38.19±0.50, 38.60±0.50, 39.68±0.50 degrees 2θ.

[0118] Also, record the monophosphate products according to the parameters described above. 1 H NMR, results depicted in Figure 2 In the middle. DSC thermograms of the monophosphate products were collected according to the parameters described above, and the results were plotted on... Figure 3 The DSC thermogram shows a sharp temperature peak at approximately 206 °C.

[0119] CN-Ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate

[0120] N-Ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate is prepared by reacting the free base of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine with p-toluenesulfonate under conditions that effectively form N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate. For example, the preparation is carried out in a first polar solvent, such as ethyl acetate, acetone, or a mixture containing ethanol and MtBe in a ratio ranging from about 30:70 to about 70:30 (v / v), such as a 1:1 ratio (v / v). Solvent mixtures containing ethanol and MtBe can exist in ratios ranging from about 70:30 to about 30:70 (v / v), such as about 70:30, about 65:35, about 60:40, about 55:45, about 50:50, about 45:55, about 40:60, about 35:65, or about 30:70 (v / v) and any ratios in between. Regardless of which solvent system is used, the reaction is carried out under effective conditions. For example, the reaction is slightly heated with stirring at an effective temperature to form N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate and to dissolve it completely or partially. For example, the reaction can be carried out under stirring and heating at a temperature ranging from about 30°C to about 60°C, such as about 45°C, to form a slurry containing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate. The slurry is cooled to about room temperature, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate is crystallized from the slurry, for example by crystallization, scraping, or aging, to form a crystalline solid substantially containing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate.

[0121] The following examples further illustrate the subject matter of this disclosure:

[0122] Example 2: Preparation of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate

[0123] One molar equivalent of free base and 1.1 molar equivalents of p-toluenesulfonic acid crystals were stirred in 10 volumes of EtOAc solvent. The mixture was stirred at 45°C until a white slurry was observed. A solid product separated from a previous sample prepared by screening experiments was crystallized into the slurry using a micro-scraper tip, and stirred at room temperature for 4 hours. The slurry was filtered and washed with EtOAc. The resulting white solid was dried under vacuum for approximately 12 hours. The crystallized N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate was collected and analyzed by XRPD according to the parameters described above. Figure 4 The XRPD diffraction pattern of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate is depicted. Peak values ​​and intensities are provided in the table below:

[0124]

[0125]

[0126] Note: The cutoff value for relative intensity is 1.

[0127] In one embodiment, the X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at 17.57 ± 0.50°, 18.77 ± 0.50°, and 23.59 ± 0.50° at 2θ. In another embodiment, the X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at 10.09 ± 0.50°, 14.85 ± 0.50°, 17.57 ± 0.50°, 18.77 ± 0.50°, and 23.59 ± 0.50° at 2θ. In another embodiment, the X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at 2θ at 10.09 ± 0.50°, 11.81 ± 0.50°, 14.85 ± 0.50°, 17.57 ± 0.50°, 18.77 ± 0.50°, 19.27 ± 0.50°, 22.32 ± 0.50°, and 23.59 ± 0.50°. In one embodiment, Cu... The X-ray powder diffraction pattern obtained from K-α radiation measurements contains peaks at the following 2θ angles: 7.44±0.50, 10.99±0.50, 11.52±0.50, 11.81±0.50, 11.96±0.50, 12.11±0.50, 13.70±0.50, 14.56±0.50, 14.85±0.50, 15.81±0.50, 16.03±0.50, 1 7.17±0.50, 17.57±0.50, 18.16±0.50, 18.77±0.50, 19.27±0.50, 20.19±0.50, 20.48±0.50, 21.07±0.50, 21.73±0.50, 22.06±0.50, 22.32±0.50, 22.77±0.50, 23.11±0.50, 23.41±0.5 0, 23.59±0.50, 23.98±0.50, 24.25±0.50, 25.10±0.50, 25.59±0.50, 26.33±0.50, 26.47±0.50, 27.77±0.50, 28.52±0.50, 29.27±0.50, 29.56±0.50, 29.78±0.50, 31.39±0.50, 31.59± 0.50, 32.04±0.50, 34.62±0.50, 34.92±0.50, 35.09±0.50, 35.31±0.50, 35.74±0.50, 36.27±0.50, 36.48±0.50, 36.92±0.50, 37.61±0.50, 37.99±0.50, 38.26±0.50, 39.67±0.50 degrees 2θ.

[0128] Also, record the p-toluenesulfonate products according to the parameters described above. 1H NMR spectra, results described in Figure 5 middle.

[0129] DSC thermograms of the p-toluenesulfonate products were collected based on the parameters described above, and the results were plotted on... Figure 6 The DSC thermogram shows a sharp temperature peak at approximately 137°C.

[0130] DN-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hememalate

[0131] N-Ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate is prepared by reacting N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine with L-malic acid under conditions conducive to the formation of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate. For example, the preparation is carried out in a polar solvent such as isopropanol. The reaction is carried out under conducive conditions. For example, the reaction is slightly heated with stirring at a conducive temperature to form N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and to completely or partially dissolve it. For example, the reaction can be carried out under stirring and heating in the range of about 30°C to about 60°C, such as about 45°C, to form an oily and / or gel-like substance comprising N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate. Optionally, the oily and / or gel-like substance comprising N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate can be sonicated. It is then cooled to about room temperature, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate is crystallized from the oily and / or gel-like substance, for example by crystallization, scraping, or aging, to form a crystalline solid substantially comprising N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate.

[0132] Although the procedure describes the use of L-malic acid as the acid that reacts with N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine, it is also applicable to the reaction of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine with D-malic acid and racemic malic acid.

[0133] The following examples further illustrate the subject matter of this disclosure, using L-malic acid as a representative malic acid for the reaction with N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine:

[0134] Example 3: Preparation of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hememalate

[0135] One molar equivalent of free base was reacted with 0.55 equivalents of L-malic acid in 10 volumes of isopropanol. The mixture was stirred at 45°C for 1 hour, cooled to room temperature, and stirred for 3 days. The resulting slurry was filtered, and the filter cake was washed with isopropanol to give a white solid. The resulting white solid was dried under vacuum overnight. The crystallized N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate was recovered and analyzed by XRPD according to the parameters described above. Figure 7 The XRPD diffraction pattern of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate is depicted. The peak values ​​and intensities of the XRPDs are provided in the table below:

[0136]

[0137]

[0138] Note: The cutoff value for relative intensity is 1.

[0139] As shown, in one embodiment, the X-ray powder diffraction pattern contains peaks at 11.39 ± 0.50 degrees, 15.21 ± 0.50 degrees, and 22.18 ± 0.50 degrees at 2θ. In another embodiment, the X-ray powder diffraction pattern contains peaks at 11.39 ± 0.50 degrees, 15.21 ± 0.50 degrees, 17.11 ± 0.50 degrees, 18.22 ± 0.50 degrees, and 22.18 ± 0.50 degrees at 2θ. In another embodiment, the X-ray powder diffraction pattern includes peaks at 2θ at 5.70±0.50°, 11.39±0.50°, 15.21±0.50°, 17.11±0.50°, 18.22±0.50°, 18.46±0.50°, 19.57±0.50°, 19.64±0.50°, 22.18±0.50°, and 22.94±0.50°. In another embodiment, the X-ray powder diffraction pattern includes peaks at the following locations: 5.70±0.50, 9.80±0.50, 10.87±0.50, 11.39±0.50, 11.92±0.50, 12.62±0.50, 15.21±0.50, 16.31±0.50, 17.11±0.50, 18.22±0.50, 18.46±0.50, 18.78±0.50, 19.57±0.50, 19.64±0.50, 21.12±0.50, 21.62±0.50, 22.18±0.50, 22.94±0.50, 23.35±0.50, 23.94±0.50, 24.19±0.50. 24.74±0.50, 25.36±0.50, 25.89±0.50, 26.50±0.50, 26.81±0.50, 27.45±0.50, 28.31±0.50, 28.93±0.50, 29.55±0.50, 30.07±0.50, 30.75±0.50, 31.60± 0.50, 31.93±0.50, 32.97±0.50, 33.86±0.50, 34.57±0.50, 35.13±0.50, 35.32±0.50, 36.20±0.50, 38.09±0.50, 38.45±0.50, 38.91±0.50 and 39.67±0.50 degrees 2θ.

[0140] Also, record the hemimalate products according to the parameters described above. 1 H NMR spectra, results described in Figure 8 middle.

[0141] DSC thermograms of hemimalate were collected based on the parameters described above, and the results were plotted on... Figure 9 In the middle, a peak temperature of approximately 107°C was observed.

[0142] EN-Ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate

[0143] N-Ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate is prepared by reacting N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine with monosuccinate under conditions that effectively form N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate. For example, the preparation is carried out in a polar solvent such as ethanol. For example, the reaction is slightly heated with stirring at an effective temperature to form N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and to completely or partially dissolve it. For example, the reaction can be carried out with stirring and heating at a temperature in the range of about 30°C to about 60°C, such as about 45°C, to form N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate. A first polar solvent containing ethanol is evaporated to dryness to form an oil containing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate. A crystallization solvent, such as isopropanol, is added to the oil at a temperature ranging from about 30°C to about 60°C, such as 45°C, to form a gel upon cooling to room temperature. Another crystallization solvent, isopropanol, is added to form a slurry, from which N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate is crystallized, for example, by crystallization, scraping, or aging.

[0144] Alternatively, after the ethanol evaporates to form an oil, acetone is added to the oil at a temperature that effectively dissolves the oil (ranging from about 30°C to about 60°C, such as 45°C), and the resulting mixture is then cooled to room temperature. A nonpolar antisolvent, such as n-heptane, is added to the solution while stirring to form a slurry containing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate, for example by crystallization, scraping, or aging, to allow a crystalline solid containing N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate to crystallize from the slurry. The solid is collected by filtration and dried under vacuum. N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate is stable after drying; however, it deliquesces after overnight humidity exposure at 30°C / 90% relative humidity (RH).

[0145] Example 4: Preparation of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate

[0146] The following steps were used to separate N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate from isopropanol.

[0147] One molar equivalent of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine free base was reacted with 1.1 molar equivalent of succinic acid in 10 volumes of ethanol. The solution was stirred in a vial at 45°C for about 2 hours, and then allowed to evaporate to dryness at room temperature. The resulting yellow oily substance was then allowed to dry completely at 50°C under active vacuum for 3 hours.

[0148] Approximately 2 volumes of acetone were added to the dry, oily substance, and the resulting mixture was stirred at 45°C for 2 hours, then cooled to room temperature and stirred overnight. Approximately 1.5 volumes of n-heptane were added dropwise to the clear solution. The contents of the vial were stirred overnight. The next day, a white slurry was observed, and crystals of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate were collected by filtration. The product was analyzed by XRPD according to the parameters described above.

[0149] exist Figure 10 The XRPD diffraction pattern of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate is depicted. The peak values ​​and intensities of the XRPDs are provided in the table below:

[0150]

[0151] Note: The cutoff value for relative intensity is 2.

[0152] In one embodiment, the X-ray powder diffraction pattern includes peaks at 16.96 ± 0.50°, 19.90 ± 0.50°, 21.37 ± 0.50°, and 23.06 ± 0.50° at 2θ. In another embodiment, the monosuccinate is characterized by peaks at 16.96 ± 0.50°, 19.90 ± 0.50°, 21.01 ± 0.50°, 21.37 ± 0.50°, and 23.06 ± 0.50° at 2θ. On the other hand, the X-ray diffraction pattern contains peaks at 2θ at 16.96±0.50°, 17.38±0.50°, 18.23±0.50°, 19.90±0.50°, 21.01±0.50°, 21.37±0.50°, 22.13±0.50°, 23.06±0.50°, and 28.56±0.50°. On the other hand, XRPD is contained in 8.70±0.50, 12.87±0.50, 14.00±0.50, 15.57±0.50, 16.96±0.50, 17.38±0.50, 17.91±0.50, 18.23±0.50, 19.90±0.50, 20.61±0.50, 21.01±0.50, 21 Peaks at 2θ degrees of 0.37±0.50, 22.13±0.50, 23.06±0.50, 23.70±0.50, 24.05±0.50, 24.73±0.50, 25.62±0.50, 25.98±0.50, 26.45±0.50, 27.65±0.50, 28.24±0.50, and 28.56±0.50.

[0153] It also recorded the monosuccinate products. 1 H NMR spectra, results described in Figure 11 middle.

[0154] Record the DSC thermograms of the monosuccinate products, and depict the results on... Figure 12 The DSC thermogram shows an endothermic peak with a peak temperature of approximately 81 °C.

[0155] F. Additional Data

[0156] Dynamic vapor adsorption (DVS) was performed using a Q5000SA. Samples (5-15 mg) were placed in a quartz sample pan, suspended over a microbalance, and exposed to a humidified nitrogen flow. Weight change was measured relative to a matched empty reference pan suspended over the microbalance opposite the sample. Samples were held at each level for at least 10 minutes, and the next humidity level was only performed if a weight change of <0.002% was observed between measurements (interval: 5 seconds), after 45 minutes (for 5%-65% RH), or after 2 hours (for 80% and 95% RH). The following procedure was used:

[0157] 1- Equilibrium at 50% RH

[0158] 2-50% to 5%. (50%, 35%, 20% and 5%)

[0159] 3-5% to 95% (5%, 20%, 35%, 50%, 65%, 80% and 95%)

[0160] 4-95% to 5% (95%, 80%, 65%, 50%, 35%, 20% and 5%)

[0161] 5-5% to 50% (5%, 20%, 35% and 50%)

[0162] 1- Equilibrium at 50% RH

[0163] 2-50% to 2%. (50%, 40%, 30%, 20%, 10% and 2%)

[0164] 3-2% to 75% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70% and 75%)

[0165] 4-75% to 2% (75%, 70%, 60%, 50%, 40%, 30%, 20%, 10% and 2%)

[0166] 5-2% to 50% (2%, 10%, 20%, 30%, 40% and 50%)

[0167] exist Figure 13 The DVS isotherm of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate is depicted graphically.

[0168] exist Figure 14 The DVS isotherm of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate is depicted graphically.

[0169] Regarding N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, Figure 15 The DVS isotherm plot is depicted graphically.

[0170] G. Methods and Compositions

[0171] This document also describes methods and compositions for treating mood disorders by administering crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts to patients in need, the salts being selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate, or mixtures thereof, as disclosed herein. Also provided are pharmaceutical compositions comprising crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate, or mixtures thereof, as disclosed herein.

[0172] In the implementation scheme, the method and composition can be used to treat mood disorders, including depressive disorders such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual affective disorder, seasonal affective disorder, psychotic depression, disruptive mood disorder, substance / drug-induced depressive disorder, and depressive disorder caused by another medical condition.

[0173] In some embodiments, depressive symptoms include major depressive disorder and dysthymia disorder. In some embodiments, depressive symptoms develop under unique circumstances, including but not limited to psychotic depression, postpartum depression, seasonal affective disorder (SAD), mood disorders, depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, post-traumatic stress disorder, and bipolar disorder (or manic-depressive disorder). In some embodiments, depressive symptoms intended to be treated according to this aspect of the disclosure include, but are not limited to, major depressive disorder, dysthymia disorder, psychotic depression, postpartum depression, premenstrual syndrome, premenstrual affective disorder, seasonal affective disorder (SAD), anxiety disorders, mood disorders, depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, post-traumatic stress disorder, and bipolar disorder (or manic-depressive disorder).

[0174] This article also provides methods for treating treatment-resistant depression, such as in patients with depressive disorders who have not responded to and / or have not yet responded to an appropriate course of treatment with at least one or two other antidepressant compounds or therapeutic agents. For example, this article provides a method for treating treatment-resistant depression in patients, the method comprising a) optionally identifying the patient as treatment-resistant and b) administering an effective amount of crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt, the salt being selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate or mixtures thereof, as disclosed herein. In some implementations, treatment-resistant depression occurs in patients with depression who are resistant to both standard pharmacological and non-pharmacological treatments. Standard pharmacological treatments include tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics. Non-pharmacological treatments include psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation. In some implementations, treatment-resistant patients can be identified as those who, despite receiving one or more standard pharmacological or non-pharmacological treatments, have failed to experience a reduction in one or more depressive symptoms (e.g., persistent anxiety or feelings of sadness, helplessness, hopelessness, or pessimism). In some implementations, treatment-resistant patients are those who, despite receiving treatment with two different antidepressants, have failed to experience a reduction in one or more depressive symptoms. In other embodiments, treatment-resistant patients are those who, despite treatment with four different antidepressants other than crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt, selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate, as disclosed herein. In some embodiments, treatment-resistant patients may also be identified as those who are unwilling or unable to tolerate the side effects of one or more standard pharmacological or non-pharmacological treatments.

[0175] In some implementations, symptoms associated with depression include, but are not limited to, persistent anxiety or sadness, helplessness, hopelessness, pessimism and / or worthlessness, lethargy, restlessness, irritability, fatigue, loss of interest in pleasurable activities or hobbies, excessive sleep, overeating, loss of appetite, insomnia, suicidal thoughts or attempts. In some implementations, a variety of anxiety-related symptoms include fear, panic, palpitations, shortness of breath, fatigue, nausea, and headaches. Furthermore, individuals with any form of depression often experience anxiety disorders. Methods for anticipating the current condition can be used to treat anxiety disorders or any of their symptoms. In some implementations, the presence, severity, frequency, and duration of depressive symptoms vary depending on the specific circumstances.

[0176] In the embodiments, the method and composition can be used to treat mood disorders, including bipolar disorder and related disorders, such as type I bipolar disorder, type II bipolar disorder, cyclic psychotic disorder, substance / drug-induced bipolar disorder and related disorders, as well as bipolar disorder and related disorders caused by another medical condition.

[0177] In the implementation scheme, the method and composition can be used to treat mood disorders, including substance-related disorders, such as preventing substance use cravings, reducing substance use cravings, and / or promoting substance use cessation or withdrawal. Substance use disorders involve the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, "substance" is an addictive psychoactive compound such as alcohol, caffeine, cannabis, hallucinogens, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the method and composition can be used to promote smoking cessation or opioid withdrawal.

[0178] In the implementation scheme, the method and composition can be used to treat mood disorders, including anxiety disorders such as separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, and anxiety disorder caused by another medical condition.

[0179] In the implementation scheme, the method and composition can be used to treat mood disorders, including obsessive-compulsive and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), epidermal shedding (skin scratching disorder), substance / drug-induced obsessive-compulsive and related disorders, and obsessive-compulsive and related disorders caused by another medical condition.

[0180] In the implementation scheme, the method and composition can be used to treat mood disorders, including trauma and stressor-related disorders such as reactive attachment disorder, disinhibitory social participation disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

[0181] In the implementation scheme, the method and composition can be used to treat mood disorders, including eating and drinking disorders such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidance / restriction food intake disorder.

[0182] In the implementation scheme, the method and composition can be used to treat mood disorders, including neurocognitive disorders such as delirium, severe neurocognitive disorder, mild neurocognitive disorder, severe or mild neurocognitive disorder due to Alzheimer's disease, severe or mild frontotemporal neurocognitive disorder, severe or mild neurocognitive disorder with Lewy bodies, severe or mild vascular neurocognitive disorder, severe or mild neurocognitive disorder due to traumatic brain injury, substance / drug-induced severe or mild neurocognitive disorder, severe or mild neurocognitive disorder due to HIV infection, severe or mild neurocognitive disorder due to prions, severe or mild neurocognitive disorder due to Parkinson's disease, severe or mild neurocognitive disorder due to Huntington's disease, severe or mild neurocognitive disorder due to another medical condition, and severe or mild neurocognitive disorder due to multiple etiologies.

[0183] In some embodiments, the method and composition can be used to treat mood disorders, including neurodevelopmental disorders such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotyped movement disorder, tic disorders, Tourette syndrome, persistent (chronic) motor or vocal tic disorders, and transient tic disorders. In some embodiments, the method according to this disclosure is intended to treat a variety of other neurological disorders. In some embodiments, neurological conditions include, but are not limited to, learning disabilities, autism, attention deficit hyperactivity disorder, Tourette syndrome, phobias, post-traumatic stress disorder, dementia, AIDS-related dementia, Alzheimer's disease, Parkinson's disease, spasticity, myoclonus, muscle spasms, bipolar disorder, substance abuse disorder, urinary incontinence, and schizophrenia.

[0184] In the implementation scheme, the method and composition can be used to treat mood disorders, including personality disorders such as borderline personality disorder.

[0185] In the implementation scheme, the method and composition can be used to treat mood disorders, including sexual dysfunctions such as delayed ejaculation, erectile dysfunction, female orgasmic disorder, female libido / arousal disorder, perineal-pelvic pain / penetration disorder, male hypoactive sexual desire disorder, premature ejaculation, and substance / drug-induced sexual dysfunction.

[0186] In the implementation plan, the method and composition can be used to treat mood disorders, including gender anxiety.

[0187] In the embodiments, methods and compositions are provided for treating mood disorders by administering an effective amount of a crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt to a subject in need, the salt being selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, as described herein.

[0188] In other embodiments, this document provides methods and compositions for treating migraine, cluster headache, or other headaches by administering crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt to a patient in need, the salt being selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, as disclosed herein.

[0189] In other embodiments, this document provides methods and compositions for treating inflammation by administering crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt to a patient in need, the salt being selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, as disclosed herein.

[0190] In an embodiment, the method includes treating a mood disorder, such as a depressive disorder, by administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising about 0.01 mg to about 400 mg of crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, as disclosed herein.In the embodiments, the dosage may be, for example, in the following ranges: about 0.01 mg to 400 mg, 0.01 mg to 300 mg, 0.01 mg to 250 mg, 0.01 mg to 200 mg, 0.01 mg to 150 mg, 0.01 mg to 100 mg, 0.01 mg to 75 mg, 0.01 mg to 50 mg, 0.01 mg to 25 mg, 0.01 mg to 20 mg, 0.01 mg to 15 mg, 0.01 mg to 10 mg, 0.01 mg to 5 mg, 0.01 mg to 1 mg, 0.01 mg to 0. 5mg, 0.01mg to 0.1mg, 0.1mg to 300mg, 0.1mg to 250mg, 0.1mg to 200mg, 0.1mg to 150mg, 0.1mg to 100mg, 0.1mg to 75mg, 0.1mg to 50mg, 0.1mg to 25mg, 0.1mg to 20mg, 0.1mg to 15mg, 0.1mg to 10mg, 0.1mg to 5mg, 0.1mg to 1mg, 10mg to 300mg, 10mg to 250mg, 10mg to 200mg, 10mg to 15mg 0 mg, 10 mg to 100 mg, 10 mg to 50 mg, 10 mg to 25 mg, 10 mg to 15 mg, 20 mg to 300 mg, 20 mg to 250 mg, 20 mg to 200 mg, 20 mg to 150 mg, 20 mg to 100 mg, 20 mg to 50 mg, 50 mg to 300 mg, 50 mg to 250 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, for example Examples of dosages include approximately 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, and 400 mg.

[0191] In a specific implementation, the dose administered to the patient may include the amount of crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt, selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate ... N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, as disclosed herein, in amounts from, for example, 1 mg to 200 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg The dosage ranges from 0.15 mg to 12.5 mg or 0.2 mg to 10 mg, including 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg. The dosages of 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, and 200 mg are specific examples of dosages.

[0192] Typically, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to patients in need at doses that are daily, every other day, every three days, twice, three times or four times, weekly, twice a month, once a month or three to four times a year. In the implementation scheme, the dosage is approximately, for example, 1-400 mg / day, or 1-300 mg / day, or 1-250 mg / day, or 1-200 mg / day, such as 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, 75 mg / day, 50 mg / day, 40 mg / day, 30 mg / day, 25 mg / day, 20 mg / day, 15 mg / day, 10 mg / day, 5 mg / day, or 1 mg / day.

[0193] In the embodiments, a pharmaceutical composition of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt, for parenteral or inhalation purposes, such as a spray or aerosol, is in a pharmaceutically acceptable liquid carrier at a concentration of about 0.005 mg / mL to about 500 mg / mL. In embodiments, the composition comprises crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof in a pharmaceutically acceptable liquid carrier. -1H-indol-3-yl)-N-methylethyl-1-amine salt, at concentrations of, for example, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 100 mg / mL, about 0.005 mg / mL to about 500 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, or about 0.05 mg / mL to about 1 mg / mL.

[0194] In embodiments, the composition comprises crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof in a pharmaceutically acceptable liquid carrier. The pharmaceutical composition is a fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt, at concentrations of, for example, about 0.05 mg / mL to about 15 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.25 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 7 mg / mL, about 1 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 15 mg / mL, about 5 mg / mL to 25 mg / mL, about 5 mg / mL to 50 mg / mL, or about 10 mg / mL to 100 mg / mL. In embodiments, the pharmaceutical composition is formulated to a total volume of, for example, 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0195] For example, the dosage may be administered to the subject daily, every other day, every three days, twice, three or four times, once a week, twice a month, once a month, or three to four times a year. In an embodiment, a crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monotoluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof is administered to the subject in the pharmaceutical composition once in the morning or once in the evening. In the implementation scheme, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to the subject once in the morning and once in the evening. In the implementation scheme, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to the subject three times daily (e.g., at breakfast, lunch and dinner) at a dose of, for example, 50 mg per administration (e.g., 150 mg per day).

[0196] In the embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to the subject in a pharmaceutical composition at one or more doses of 12.5 mg / day. In the embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to the subject in a pharmaceutical composition at one or more doses of 25 mg / day. In the implementation scheme, a crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof is administered to the subject in a pharmaceutical composition at one or more doses of 35 mg / day. In the implementation scheme, a crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof is administered to the subject in a pharmaceutical composition at one or more doses of 50 mg / day.In the implementation scheme, a crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof is administered to the subject in a pharmaceutical composition at one or more doses of 75 mg / day. In the embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to the subject in a pharmaceutical composition at one or more doses of 100 mg / day. In the embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to the subject in a pharmaceutical composition at one or more doses of 150 mg / day. In the embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to the subject in a pharmaceutical composition at one or more doses of 200 mg / day.In the implementation scheme, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to the subject in a pharmaceutical composition at one or more doses of 250 mg / day.

[0197] In the embodiments, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate as disclosed herein are used. The dosage of crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt and mixtures thereof is 0.0005 mg / kg-5 mg / kg, 0.001 mg / kg-1 mg / kg, 0.01 mg / kg-1 mg / kg or 0.1 mg / kg-5 mg / kg, once, twice, three or four times daily. For example, in the implementation plan, the dosage is 0.0005 mg / kg, 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.025 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 2.5 mg / kg, or 5 mg / kg, once, twice, three times, or four times a day. In the implementation plan, the subject is given a total daily dose of 0.01 mg to 500 mg of crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof once, twice, three or four times daily.In the implementation plan, the total amount administered to the subject over a 24-hour period is, for example, 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In one implementation scheme, subjects may start with a low dose and then increase the dose. In another implementation scheme, subjects may start with a high dose and then decrease the dose.

[0198] In embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof can be administered, for example, by inhalation or oral administration at specified intervals. For example, during treatment, the pharmaceutical composition may be administered to the patient at intervals such as 1 year, 6 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours. N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof as crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts.

[0199] In the embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to a patient in a pharmaceutical composition under the supervision of a healthcare provider.

[0200] In the embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered to patients in the pharmaceutical composition under the supervision of a healthcare provider in a clinic specializing in psychoactive treatment.

[0201] In the embodiments, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemalic acid and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are selected from crystals of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof as disclosed herein. The ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt is administered to a subject in a pharmaceutical composition under the supervision of a healthcare provider at a high dose intended to induce a psychedelic experience in the subject, for example, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, or 150 mg.

[0202] In some implementations, high doses are administered to patients regularly under the supervision of a healthcare provider in order to maintain the therapeutic effect in patients, such as once every three days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year.

[0203] In some embodiments, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof are administered by the patient at home or otherwise away from the supervision of a healthcare provider.

[0204] In some embodiments, the preferred formulation is selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate, as disclosed herein. The crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts and mixtures thereof are administered by the patient at home or otherwise away from the supervision of a healthcare provider in low doses intended for extrasensory or threshold psychoactive effects, such as 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, or 9 mg.

[0205] In some implementations, patients administer low doses themselves periodically to maintain the therapeutic effect in the patient, such as daily, every other day, every three days, twice a week, once a week, twice a month, or once a month.

[0206] Selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof as disclosed herein Suitable dosage forms of the crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salt include, but are not limited to, oral forms such as tablets, hard or soft gelatin capsules, powders, granules, and oral solutions, syrups or suspensions, lozenges, and sublingual, buccal, tracheal, intraocular, or intranasal forms, forms suitable for inhalation, topical forms, transdermal forms, or parenteral forms, such as forms suitable for intravenous, intra-arterial, intraperitoneal, intrathecal, intracardiac, intramuscular, or subcutaneous administration. In embodiments, for such parenteral administration, it may be in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salt or glucose, to make the solution isotonic with blood. If necessary, the aqueous solution should be appropriately buffered (preferably to a pH of 3 to 9). The preparation of suitable parenteral formulations under aseptic conditions can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0207] This disclosure also relates in part to pharmaceutical compositions comprising crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, as disclosed herein, as a pharmaceutically acceptable carrier, adjuvant, and / or mediator (collectively referred to as excipients). The pharmaceutical compositions herein may have immediate release, delayed release, prolonged release, or modified release profiles. In embodiments, pharmaceutical compositions with different drug release profiles can be combined to produce two-phase or three-phase release profiles. For example, a pharmaceutical composition may have immediate and prolonged release profiles. In embodiments, a pharmaceutical composition may have prolonged and delayed release profiles. Such compositions can be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc. The composition can be prepared using a pharmaceutically acceptable "carrier" composed of materials deemed safe and effective. A "carrier" includes all components present in the pharmaceutical formulation other than one or more active ingredients. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, flow aids, disintegrants, fillers, and coating compositions.

[0208] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration or via implantation. The compositions can be prepared by any method well known in the pharmaceutical field.

[0209] Such methods include the step of combining the compounds or combinations thereof described in this disclosure with any adjuvants. Adjuvants, also known as auxiliary ingredients, include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, and wetting agents. Such adjuvants are appropriately selected in the intended form and route of administration and in a manner consistent with routine pharmaceutical practice.

[0210] Pharmaceutical compositions suitable for oral administration may be in solid dosage forms for oral administration, as discrete dosage units such as pills, tablets, powders, granules, sugar-coated pills or capsules, or as powders or granules, or as solutions or suspensions. Active ingredients comprising crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, can also be present as pellets or pastes. The compositions can also be formulated into suppositories or enemas for rectal administration.

[0211] The tablets may contain the active ingredient, namely, an N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, as well as suitable binders, lubricants, disintegrants, colorants, flavorings, flow inducers and meltsinks. Gelatin capsules may contain the active ingredient in any salt form disclosed herein and a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Compressed tablets may have a sugar coating or film coating to mask any unpleasant taste and protect the tablet from atmospheric effects, or an enteric coating for selective disintegration in the gastrointestinal tract. For example, for oral administration in dosage units of tablets or capsules, the active pharmaceutical ingredient may be combined with an orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and chlorides. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0212] For oral administration in liquid dosage forms, the oral drug component is combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Examples of liquid dosage forms include, but are not limited to, solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents (including esters), emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent particles, and effervescent formulations reconstituted from effervescent particles. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms intended for oral administration may contain colorants and flavoring agents to increase patient acceptability.

[0213] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile solutions. Generally, water, suitable oils, saline solutions, aqueous solutions of dextran (glucose) and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain water-soluble salts of the active ingredient, suitable stabilizers, and (if necessary) buffers. Antioxidants, alone or in combination, such as sodium bisulfite, sodium sulfite, or ascorbic acid, are suitable stabilizers. Citric acid and its salts, and sodium EDTA are also used. Furthermore, parenteral solutions may contain preservatives such as benzalkonium chloride, methylparaben or propylparaben, and chlorobutanol. Compositions may be presented in single-dose or multi-dose containers, such as sealed vials and ampoules, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water, before use. For transdermal administration, gels, patches, or sprays may be considered. Compositions or formulations suitable for pulmonary administration (e.g., nasal inhalation) include fine dust or mist, which can be generated by a metered-dose pressurized aerosol, nebulizer, or inhaler. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system selected.

[0214] Crystallized N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearamine, or phosphatidylcholine. Crystallized N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof can be applied as a component of tissue-targeting emulsions.

[0215] N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof can also be coupled to a soluble polymer as a targeted drug carrier or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol, or polyoxyethylene-polylysine substituted with palmitoyl residues. Additionally, polymers selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinic acid. Crystallized N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts and mixtures thereof can be coupled with a class of biodegradable polymers that can be used to achieve controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0216] The pharmaceutical compositions described herein may have immediate release, delayed release, prolonged release, or modified release profiles. In some embodiments, pharmaceutical compositions with different drug release profiles may be combined to produce two-phase or three-phase release profiles. For example, a pharmaceutical composition may have immediate and prolonged release profiles. In some embodiments, a pharmaceutical composition may have prolonged and delayed release profiles. Such compositions may be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

[0217] The pharmaceutical compositions described herein can be provided with anti-abuse features using techniques known in the art, such as by preparing tablets that are difficult to crush or poorly soluble in water.

[0218] This disclosure also includes pharmaceutical compositions as described above in combination with packaging materials, the packaging materials including instructions for using the composition for the purposes described above.

[0219] The exact dosage and administration regimen of the composition will necessarily depend on the type and magnitude of the therapeutic or nutritional effect to be achieved, and may vary depending on factors such as: crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monotoluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof, chemical formula, route of administration, or the age or condition of the individual subject to whom the composition is to be administered.

[0220] N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine mono-p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof can be applied in various forms, including those detailed herein. Treatment with N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof may be a component of combination therapy or adjuvant therapy, i.e., the subject or patient requiring this drug receives another drug used for the disease. The present invention comprises a crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof. This combination therapy can be a sequential therapy, wherein the patient is treated first with one drug followed by another drug, or two drugs are administered simultaneously. Depending on the dosage form used, these can be administered independently via the same route or via two or more different routes of administration.

[0221] In some embodiments, the preferred formulations are those selected from N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate. Crystallized N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine salts of aminomonosuccinates and mixtures thereof may be used in combination with one or more other antidepressant treatments, such as tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anti-anxiety medications, for the manufacture of agents for the treatment of depression, anxiety disorders and / or other related conditions, including providing relief of depression or anxiety disorders and preventing relapse of depression or anxiety disorders. In some embodiments, therapeutic agents that can be used in combination with crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate and N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate and mixtures thereof include, but are not limited to, Anafranil. , Adapin, Aventyl, Elavil, Norpramin, Pamelor, Pertofrane, Sinequan, Surmontil, Tofranil, Vivactil, Parnate, Nardil, Marplan, Celexa , Lexapro, Luvox, Paxil, Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel (trazodone), Savella, Fetzima, Pristiq and Ludiomill.

[0222] While certain features of the invention have been described and illustrated herein, many modifications, substitutions, variations, and equivalents will now occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and variations that fall within the true spirit and scope of the invention.

Claims

1. A crystalline salt of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine, said crystalline salt being selected from crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate, crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate, and crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate.

2. The crystalline salt according to claim 1, wherein the crystalline salt is crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monophosphate.

3. The crystalline salt according to claim 2, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at the following 2θ angles: 10.99±0.50°, 13.34±0.50°, 15.92±0.50°, 23.88±0.50°, and 24.34±0.50°.

4. The crystalline salt according to claim 2 or 3, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at the following 2θ angles: 10.99±0.50°, 13.34±0.50°, 15.92±0.50°, 16.28±0.50°, 19.24±0.50°, 22.30±0.20°, 23.38±0.50°, 23.88±0.50°, 24.34±0.50°, and 27.22±0.50°.

5. The crystalline salt according to any one of claims 2 to 4, characterized in that... The X-ray powder diffraction pattern contains peaks at the following locations: 10.20±0.50° 2θ, 10.99±0.50° 2θ, 12.42±0.50° 2θ, 13.06±0.50° 2θ, 13.34±0.50° 2θ, 14.29±0.50° 2θ, 15.08±0.50° 2θ, 15.92±0.50° 2θ, 16.28±0.50° 2θ, 16.94±0.50° 2θ, 17.64±0° 2θ. 0.50°2θ, 18.44±0.50°2θ, 19.24±0.50°2θ, 19.75±0.50°2θ, 20.11±0.50°2θ, 20.46±0.50°2θ, 20.68±0.50°2θ, 21.51±0.50°2θ, 21.78±0.50°2θ, 22.06±0.50°2θ, 22.30±0.50°2θ, 22.67±0.50°2θ, 23.38 ±0.50 degrees 2θ, 23.88±0.50 degrees 2θ, 24.34±0.50 degrees 2θ, 25.82±0.50 degrees 2θ, 26.24±0.50 degrees 2θ, 26.60±0.50 degrees 2θ, 27.22±0.50 degrees 2θ, 27.70±0.50 degrees 2θ, 28.14±0.50 degrees 2θ, 28.63±0.50 degrees 2θ, 29.05±0.50 degrees 2θ, 29.64±0.50 degrees 2θ, 30 0.39±0.50°2θ, 31.38±0.50°2θ, 31.64±0.50°2θ, 33.36±0.50°2θ, 33.97±0.50°2θ, 35.03±0.50°2θ, 35.47±0.50°2θ, 35.72±0.50°2θ, 37.43±0.50°2θ, 38.19±0.50°2θ, 38.60±0.50°2θ, and 39.68±0.50°2θ.

6. The crystalline salt according to any one of claims 2 to 5, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation is essentially depicted in Figure 1.

7. The crystalline salt according to any one of claims 2 to 6, characterized in that... The DSC thermogram has at least one endothermic peak with a peak temperature of about 206 °C.

8. The crystalline salt according to any one of claims 2 to 7, characterized in that... The DSC thermogram is basically depicted in Figure 3.

9. The crystalline salt according to claim 1, wherein the crystalline salt is crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine p-toluenesulfonate.

10. The crystalline salt according to claim 9, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at the following 2θ angles: 10.09±0.20°, 14.85±0.50°, 17.57±0.50°, 18.77±0.50°, and 23.59±0.50°.

11. The crystalline salt according to claim 9 or 10, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at the following 2θ angles: 10.09±0.20°, 11.81±0.50°, 14.85±0.50°, 17.57±0.50°, 18.77±0.50°, 19.27±0.50°, 20.19±0.50°, 20.48±0.50°, 22.32±0.50°, and 23.59±0.50°.

12. The crystalline salt according to any one of claims 9 to 11, characterized in that... The X-ray powder diffraction pattern contains peaks at the following locations: 7.44±0.50°2θ, 10.99±0.50°2θ, 11.52±0.50°2θ, 11.81±0.50°2θ, 11.96±0.50°2θ, 12.11±0.50°2θ, 13.70±0.50°2θ, 14.56±0.50°2θ, 14.85±0.50°2θ, 15.81±0.50°2θ, 16.03±0.50°2θ, and 17.17±0.50°2θ. 17.57±0.50 degrees 2θ, 18.16±0.50 degrees 2θ, 18.77±0.50 degrees 2θ, 19.27±0.50 degrees 2θ, 20.19±0.50 degrees 2θ, 20.48±0.50 degrees 2θ, 21.07±0.50 degrees 2θ, 21.73±0.50 degrees 2θ, 22.06±0.50 degrees 2θ, 22.32±0.50 degrees 2θ, 22.77±0.50 degrees 2θ, 23.11±0.50 degrees 2θ, 23.41±0.50 degrees 2θ, 2 3.59±0.50 degrees 2θ, 23.98±0.50 degrees 2θ, 24.25±0.50 degrees 2θ, 25.10±0.50 degrees 2θ, 25.59±0.50 degrees 2θ, 26.33±0.50 degrees 2θ, 26.47±0.50 degrees 2θ, 27.77±0.50 degrees 2θ, 28.52±0.50 degrees 2θ, 29.27±0.50 degrees 2θ, 29.56±0.50 degrees 2θ, 29.78±0.50 degrees 2θ, 31.39±0.50 degrees 2θ, 31. 59±0.50 degrees 2θ, 32.04±0.50 degrees 2θ, 34.62±0.50 degrees 2θ, 34.92±0.50 degrees 2θ, 35.09±0.50 degrees 2θ, 35.31±0.50 degrees 2θ, 35.74±0.50 degrees 2θ, 36.27±0.50 degrees 2θ, 36.48±0.50 degrees 2θ, 36.92±0.50 degrees 2θ, 37.61±0.50 degrees 2θ, 37.99±0.50 degrees 2θ, 38.26 and 39.67±0.50 degrees 2θ.

13. The crystalline salt according to any one of claims 9 to 12, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation is essentially depicted in Figure 4.

14. The crystalline salt according to any one of claims 9 to 13, characterized in that... The DSC thermogram has at least one endothermic peak with a peak temperature of about 137 °C.

15. The crystalline salt according to any one of claims 9 to 14, characterized in that... The DSC thermogram is basically depicted in Figure 6.

16. The crystalline salt according to claim 1, wherein the crystalline salt is crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine hemimalate.

17. The crystalline salt according to claim 16, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at the following 2θ angles: 11.39±0.50°, 15.21±0.50°, 17.11±0.50°, 18.22±0.50°, and 22.18±0.50°.

18. The crystalline salt according to claim 16 or 17, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at the following 2θ angles: 5.70±0.50°, 11.39±0.50°, 15.21±0.50°, 17.11±0.50°, 18.22±0.50°, 18.46±0.50°, 19.57±0.50°, 19.64±0.50°, 22.18±0.50°, and 22.94±0.50°.

19. The crystalline salt according to any one of claims 16 to 18, characterized in that... The X-ray powder diffraction pattern contains peaks at the following locations: 5.70±0.50°2θ, 9.80±0.50°2θ, 10.87±0.50°2θ, 11.39±0.50°2θ, 11.92±0.50°2θ, 12.62±0.50°2θ, 15.21±0.50°2θ, 16.31±0.50°2θ, 17.11±0.50°2θ, 18.22±0.50°2θ, 18... 0.46±0.50°2θ, 18.78±0.50°2θ, 19.57±0.50°2θ, 19.64±0.50°2θ, 21.12±0.50°2θ, 21.62±0.50°2θ, 22.18±0.50°2θ, 22.94±0.50°2θ, 23.35±0.50°2θ, 23.94±0.50°2θ, 24.19±0.50°2θ, 24.74± 0.50°2θ, 25.36±0.50°2θ, 25.89±0.50°2θ, 26.50±0.50°2θ, 26.81±0.50°2θ, 27.45±0.50°2θ, 28.31±0.50°2θ, 28.93±0.50°2θ, 29.55±0.50°2θ, 30.07±0.50°2θ, 30.75±0.50°2θ, 31.60±0.50°2θ 2θ degrees, 31.93±0.50 degrees, 32.97±0.50 degrees, 33.86±0.50 degrees, 34.57±0.50 degrees, 35.13±0.50 degrees, 35.32±0.50 degrees, 36.20±0.50 degrees, 38.09±0.50 degrees, 38.45±0.50 degrees, 38.91±0.50 degrees, and 39.67±0.50 degrees.

20. The crystalline salt according to any one of claims 16 to 19, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation is essentially depicted in Figure 7.

21. The crystalline salt according to any one of claims 16 to 20, characterized in that... The DSC thermogram has at least one endothermic peak with a peak temperature of about 107 °C.

22. The crystalline salt according to any one of claims 16 to 21, characterized in that... The DSC thermogram is basically depicted in Figure 9.

23. The crystalline salt according to claim 1, wherein the crystalline salt is crystalline N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethyl-1-amine monosuccinate.

24. The crystalline salt according to claim 23, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at the following 2θ angles: 16.96±0.50°, 19.90±0.50°, 21.01±0.50°, 21.37±0.50°, and 23.06±0.50°.

25. The crystalline salt according to claim 23 or 24, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation contains peaks at the following 2θ angles: 16.96±0.50°, 17.38±0.50°, 18.23±0.50°, 19.90±0.50°, 21.01±0.50°, 21.37±0.50°, 22.13±0.50°, 23.06±0.50°, 23.70±0.50°, and 28.56±0.50°.

26. The crystalline salt according to any one of claims 23 to 25, characterized in that... The X-ray powder diffraction pattern contains peaks at the following locations: 8.70±0.50°2θ, 12.87±0.50°2θ, 14.00±0.50°2θ, 15.57±0.50°2θ, 16.96±0.50°2θ, 17.38±0.50°2θ, 17.91±0.50°2θ, 18.23±0.50°2θ, 19.90±0.50°2θ, 20.61±0.50°2θ, and 21.01±0.50°2θ. θ, 21.37±0.50 degrees 2θ, 22.13±0.50 degrees 2θ, 23.06±0.50 degrees 2θ, 23.70±0.50 degrees 2θ, 24.05±0.50 degrees 2θ, 24.73±0.50 degrees 2θ, 25.62±0.50 degrees 2θ, 25.98±0.50 degrees 2θ, 26.45±0.50 degrees 2θ, 27.65±0.50 degrees 2θ, 28.24±0.50 degrees 2θ and 28.56±0.50 degrees 2θ.

27. The crystalline salt according to any one of claims 23 to 26, characterized in that... The X-ray powder diffraction pattern measured using Cu K-α radiation is essentially depicted in Figure 10.

28. The crystalline salt according to any one of claims 23 to 27, characterized in that... The DSC thermogram has at least one endothermic peak with a peak temperature of about 81 °C.

29. The crystalline salt according to any one of claims 23 to 28, characterized in that... The DSC thermogram is basically depicted as shown in Figure 12.

30. A solid comprising substantially a crystalline salt according to any one of claims 1 to 29.

31. The solid of claim 30, wherein the crystalline salt is present in at least 90% by weight of the solid.

32. The solid of claim 31, wherein the crystalline salt is present in at least 95% by weight of the solid.

33. A solid comprising a mixture of two or more crystalline salts according to any one of claims 1 to 29, wherein the mixture of the two or more crystalline salts is present in at least 50% by weight of the solid.

34. The solid of claim 33, wherein the mixture of the two or more crystalline salts is present in at least 90% by weight of the solid.

35. The solid of claim 33, wherein the mixture of the two or more crystalline salts is present in at least 95% by weight of the solid.

36. A pharmaceutical composition comprising one or more crystalline salts of any one of claims 1 to 29 and a pharmaceutically acceptable carrier thereof.

37. A pharmaceutical composition comprising a solid according to any one of claims 30 to 35 and a pharmaceutically acceptable carrier thereof.

38. The pharmaceutical composition according to claim 36 or 37, wherein the pharmaceutical composition is in solid dosage form.

39. A method for treating a mood disorder in a subject requiring such treatment, the method comprising administering to the subject a therapeutically effective amount of a crystalline salt of a pharmaceutical composition according to any one of claims 36 to 38.

Images