Crystalline salts of 2-phenyl-2-aminocyclohex-1-one derivatives

Abstract

The present disclosure relates to various crystalline salts of (R)-2-(4-fluorophenyl)-2-(methylamino) cyclohex-1-one that are useful in the treatment of psychiatric disorders, including the treatment of mood disorders. These salts include their hydrochloride, sulfate, p-toluenesulfonate, mesylate, maleate, phosphate, tartrate, fumarate, citrate, glycolate, malate, and hippurate.

Description

Technical Field

[0001] This disclosure relates to crystalline salts and polymorphs of 2-phenyl-2-aminocyclohexane-1-one derivatives, which may be used to treat mental disorders. Background Technology

[0002] Depression is a common mental health problem, characterized by low mood and aversion to activity. A variety of 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, binge eating, loss of appetite, insomnia, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of these symptoms vary from person to person.

[0003] Approximately one-third of patients with major depressive disorder (MDD) fail to achieve symptom relief, even after multiple rounds of treatment with various known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) (Rush et al., 2006). The high prevalence of treatment-resistant depression (TRD) underscores the need for novel and more effective pharmacological therapies that target new mechanisms and / or patient populations.

[0004] U.S. Patent No. 11,344,510 (the contents of which are incorporated herein by reference) discloses in part compounds suitable for treating mental disorders, including 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. U.S. patent application with serial number USSN 63 / 471,091 (SSMP file number: 41715) entitled “Synthesis of 2-phenyl-2-aminocyclohexane-1-one derivatives” (the contents of which are incorporated herein by reference) partially discloses polymorphs of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride.

[0005] Many compounds can exist as more than one salt, and these salts can exist in more than one crystalline or polymorphic form. These salts and polymorphs exhibit different physical, chemical, and spectroscopic properties relative to each other. For example, some salts or polymorphs of a compound may have higher chemical stability, be more readily crystallized, be more readily soluble in certain solvents, be more or less hygroscopic, be more readily flowable, or be more readily compressible than other salts or polymorphs. See, for example, P. DiMartino et al., J. Thermal Anal., 48:447-458 (1997). In the case of pharmaceuticals, some solid forms may have higher bioavailability than others, while other solid forms may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory perspective, as pharmaceuticals can only obtain approval from 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 salt or polymorph of a compound exhibiting certain solubility and physicochemical (including spectroscopic) properties does not necessarily imply the approval of other salts or polymorphs of the same compound. In the pharmaceutical field, the salt and polymorphic forms of a compound are known to affect, for example, the compound's solubility, stability, flowability, fractability, and compressibility, as well as the safety and efficacy of drugs containing that compound. See, for example, Knapman, K. Modern Drug Discoveries, 2000, 53. Therefore, the discovery of novel salts and polymorphs of drugs can offer a variety of advantages.

[0006] However, finding the right conditions for preparing novel salts and polymorphs of a particular compound, and for crystallizing them, is tedious and often involves trial and error, as many factors come into play in finding the appropriate conditions for its synthesis and crystallization. For example, all solvents, concentrations, temperatures, heating or cooling rates, stoichiometry of reactants, addition rates, and mixing parameters must be varied to obtain the desired results.

[0007] This disclosure covers polymorphs of certain salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one and their stereoisomers, such as the R isomer. Furthermore, as described below, certain salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one and their stereoisomers, such as ( R Salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one can be prepared and isolated in various crystalline forms. Summary of the Invention

[0008] This disclosure involves ( RVarious crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one are disclosed, which can be used to treat mental disorders, including mood disorders. These salts include hydrochlorides, sulfates, p-toluenesulfonates, methanesulfonates, maleates, phosphates, tartrates, fumarates, citrates, glycolates, malates, and hippurates. Furthermore, this disclosure also relates to polymorphs of the aforementioned salts in crystalline form. Attached Figure Description

[0009] The objectives, features, and advantages of this disclosure will become apparent to those skilled in the art upon referring to the following detailed embodiments in conjunction with the accompanying drawings, wherein: Figure 1 For form 1 (a) and form 2 (b) 1 R ORTEP diagram of the single-crystal X-ray structure of HCl.

[0010] Figure 2 For solid 1 R An exemplary XRPD diffraction pattern of HCl (Form 1).

[0011] Figure 3 For solid 1 R An exemplary PLM image of HCl (Form 1).

[0012] Figure 4 For solid 1 R Exemplary DSC / TGA overlay plot of HCl (Form 1).

[0013] Figure 5 For solid 1 R Exemplary DVS isotherm plot (a) and DVS mass change plot (b) of HCl (Form I).

[0014] Figure 6 For solid 1, which is a mixture of form 1 and form 2 R An exemplary XPRD of HCl.

[0015] Figure 7 Solid 1 generated from single crystal data R Simulated XPRD of HCl (Form 2).

[0016] Figure 8 This is an exemplary XRPD diffraction pattern of sulfate-1.

[0017] Figure 9 This is an exemplary DSC / TGA overlay plot of sulfate-1.

[0018] Figure 10 This is an exemplary XRPD diffraction pattern of sulfate-2.

[0019] Figure 11 This is an exemplary XRPD diffraction pattern of sulfate-3.

[0020] Figure 12 This is an exemplary XRPD diffraction pattern of sulfate-4.

[0021] Figure 13 An exemplary XRPD diffraction pattern of toluenesulfonyl-1.

[0022] Figure 14 An exemplary DSC / TGA overlay diagram of toluenesulfonyl-1.

[0023] Figure 15 An exemplary XRPD diffraction pattern of toluenesulfonyl-2A.

[0024] Figure 16 An exemplary XRPD diffraction pattern of toluenesulfonyl-2B.

[0025] Figure 17 An exemplary DSC / TGA overlay diagram of toluenesulfonyl-2B.

[0026] Figure 18 This is an example XRPD diffraction pattern for MSA-1.

[0027] Figure 19 This is an example DSC / TGA overlay diagram for MSA-1.

[0028] Figure 20 Here is an example XRPD diffraction pattern for Mal-1.

[0029] Figure 21 This is an example DSC / TGA overlay plot for Mal-1.

[0030] Figure 22 Here is an example XRPD diffraction pattern for Mal-2.

[0031] Figure 23 This is an example DSC / TGA overlay plot for Mal-2.

[0032] Figure 24 This is an example XRPD diffraction pattern for Phos-1.

[0033] Figure 25 This is an example DSC / TGA overlay diagram for Phos-1.

[0034] Figure 26 Here is an example XRPD diffraction pattern for Phos-2.

[0035] Figure 27 This is an example DSC / TGA overlay diagram for Phos-2.

[0036] Figure 28 This is an example XRPD diffraction pattern for Tar-1.

[0037] Figure 29 Here is an example XRPD diffraction pattern for Tar-2.

[0038] Figure 30 Here is an example XRPD diffraction pattern for Tar-5.

[0039] Figure 31 This is an example DSC / TGA overlay plot for Tar-5.

[0040] Figure 32 Here is an example XRPD diffraction pattern for Tar-3.

[0041] Figure 33 This is an example DSC / TGA overlay plot for Tar-3.

[0042] Figure 34 This is an example XRPD diffraction pattern for Tar-4.

[0043] Figure 35 This is an example XRPD diffraction pattern for Tar-6.

[0044] Figure 36 This is an example DSC / TGA overlay plot for Tar-6.

[0045] Figure 37 Here is an example XRPD diffraction pattern for Fum-1.

[0046] Figure 38 This is an example DSC / TGA overlay diagram for Fum-1.

[0047] Figure 39 This is an example XRPD diffraction pattern for Fum-2.

[0048] Figure 40 This is an example XRPD diffraction pattern for Cit-1.

[0049] Figure 41 This is an example XRPD diffraction pattern for Cit-2.

[0050] Figure 42 This is an example DSC / TGA overlay plot for Cit-2.

[0051] Figure 43 This is an example XRPD overlay map for Glyc-1.

[0052] Figure 44 This is an example DSC / TGA overlay diagram for Glyc-1.

[0053] Figure 45 Here is an example XRPD diffraction pattern for Mali-1.

[0054] Figure 46 This is an example DSC / TGA overlay plot for Mali-1.

[0055] Figure 47 Here is an example XRPD diffraction pattern for Hip-1.

[0056] Figure 48 This is an example DSC / TGA overlay diagram for Hip-1. Detailed Implementation

[0057] The salts disclosed herein comprise at least one asymmetric center. When a stereoisomer is specifically designated, these centers are specifically indicated by the symbol “R” or “S”, depending on the configuration of the substituents surrounding the chiral atom. However, when no stereochemistry is specified, structures will be drawn without indicating the stereochemistry; these structures are racemic mixtures. As used herein, whether bold or not, italic or non-italic, “R” refers to the R isomer, and as used herein, whether bold or not, italic or non-italic, the term “S” refers to the S isomer.

[0058] In some embodiments, the compositions prepared herein may be enriched with a specific enantiomer of any compound disclosed herein (relative to the corresponding opposite enantiomer of that compound) such that the mixture is not racemic. In such cases, the isomer mixtures of this disclosure should be understood to have an enantiomer excess of >0% and optical purity. The enantiomer excess or optical purity of the isomer mixture may be, for example, >0%, >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%. The enantiomer excess or optical purity of the isomer mixture may be, for example, 5% to 100%, 25% to 100%, 50% to 100%, 75% to 100%, 90% to 100%, 95% to 100%, 97% to 100%, 98% to 100%, or 99% to 100%. Therefore, for example, this document contemplates compositions comprising the S enantiomer of a compound substantially free of the R enantiomer or the R enantiomer substantially free of the S enantiomer. Furthermore, if the mentioned compound comprises more than one chiral center, the scope of this disclosure also includes compositions containing various stereoisomers and diastereomers, including mixtures of various stereoisomers and / or diastereomers in different proportions or pharmaceutically acceptable salts thereof, and compositions comprising one or more stereoisomers and diastereomers substantially free of one or more other stereoisomers and / or diastereomers, respectively. In this context, "substantially free" means that the composition comprises less than, for example, 50%, 25%, 15%, 10%, 8%, 5%, 3%, 2%, or 1% of one or more minor enantiomers or diastereomers. For example, the statement "the compound is enantiomerically pure" means that the compound substantially free of other stereoisomers, including any other enantiomers or diastereomers.

[0059] For clarity, in the context of this disclosure, the chemical structures (defined by wedge and dashed symbols) of compounds having a specific stereochemical orientation at any particular chiral center are intended to indicate that a specified stereoisomer of the compound exists in substantially pure form, or that a mixture is rich in stereoisomers having a specified stereochemical orientation at the defined chiral center, more than stereoisomers having an opposite orientation at the chiral center.

[0060] As used herein, the term "composition substantially free of" (where a polymorph is involved) means that the composition is predominantly present in a particular polymorph relative to other polymorphs. For example, 1 R HCl exists in two solid forms: form 1 and form 2. RThe presence of HCl in form 1, which is substantially free of form 2, means that the form 1 polymorph is present as the predominant polymorph relative to form 2, i.e., the form 1 polymorph is present in excess relative to the form 2 polymorph. "Substantially free of form 2 relative to form 1" means that the composition includes, for example, less than 50%, 25%, 15%, 10%, 8%, 5%, 3%, 2%, or 1% of the form 2 polymorph relative to form 1. Similarly, the use of the term "the composition is substantially free of form 1 relative to form 2" indicates that the composition includes, for example, less than 50%, 25%, 15%, 10%, 8%, 5%, 3%, 2%, or 1% of the form 1 polymorph relative to form 2.

[0061] As used herein, the terms “about” or “approximately” refer to the acceptable margin of error for a particular value as determined by a person skilled in the art, which will depend in part on the method of measurement or determination of that value, i.e., the limitations of the measurement system. For example, “about” may refer to a range of 3 or more standard deviations, based on practice in the art. Alternatively, “about” may refer to a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Additionally, specifically with respect to biological systems or methods, the term may refer to a range within orders of magnitude of the value, such as within 5 times or 2 times. “About” and “approximately” are used interchangeably herein.

[0062] As defined herein, "inert solvent" means a solvent that does not react with reactants or products formed in the reaction. Suitable organic solvents applicable to this disclosure include, but are not limited to: alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, isopropanol, butanol, etc.; ketones having 1 to 6 carbon atoms, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.; ether solvents having 1 to 6 carbon atoms, such as dimethyl ether, diethyl ether, methyl ethyl ether, methyl tert-butyl ether (MTBE), dipropyl ether, diisopropyl ether, etc.; cyclic ethers having 4 to 6 carbon atoms, such as tetrahydrofuran (THF), dioxane, etc.; halogens Suitable solvents include, but are not limited to, dichloroethane, dichloromethane, chloroform, etc.; esters having 2-10 carbon atoms, such as ethyl acetate, isopropyl acetate, n-propyl acetate, etc.; nitriles, such as acetonitrile, propionitrile, etc.; hydrocarbons having 1-10 carbon atoms, including aryl groups, such as toluene, xylene, cyclohexane, heptane, xylene, etc.; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), etc.; and mixtures thereof in various proportions (unrestricted). The use of suitable solvents includes the use of mixtures of solvents. The suitability of a particular solvent for a reaction depends on a variety of factors, such as the type of reaction, reactants, products, and reagents used. Those skilled in the art can determine the suitable solvent for the reactions described herein.

[0063] As used herein, the term "proton" refers to a proton, hydrogen atom, or ion. As used herein, the term "proton solvent" refers to a polar liquid compound having dissociable hydrogen atoms and being able to form hydrogen bonds with oxygen, fluorine, or nitrogen atoms.

[0064] As used herein, the term "proton polar solvent" refers to a solvent having at least one OH or NH bond and being miscible with water. Examples include water, methanol, ethanol, ammonia, etc.

[0065] This document depicts the XRPD spectra of polymorphs. Each polymorph is characterized by having, or substantially having, the XRPD spectra shown in its corresponding foregoing figures, for example, at least 70% of the peaks in the XRPD spectra vary within ±0.50°2θ at the indicated values; in another embodiment, at least 75% of the peaks in the XRPD spectra vary within ±0.50°2θ at the indicated values; in yet another embodiment, at least 80% of the peaks in the XRPD spectra vary within ±0.50°2θ at the indicated values; in yet another embodiment, at least 85% of the peaks in the XRPD spectra vary within ±0.50°2θ at the indicated values; and in yet another embodiment, at least 90% of the peaks in the XRPD spectra vary within ±0.50°2θ at the indicated values. However, it should be understood that the relative intensities and distributions of the peaks in these polymorphic forms depicted in these figures can vary depending on a variety of factors, including but not limited to sample preparation, aspect ratio, particle size, mounting, and the instruments, analytical procedures, and settings used to obtain the spectra. Therefore, the peaks observed in the figures and the allocations listed in the various tables and figures herein are intended to cover variations of ±0.5°2θ and variations of relative peak intensity that are acceptable to those skilled in the art. However, it should be understood that the peaks in the tables and figures also cover variations of ±0.1, ±0.2, ±0.3, and ±0.4°2θ or any values ​​between them. When listing XRPD peaks, it should be understood that each of the listed values ​​is ±0.50°2θ, even when ±0.50°2θ is not listed. Furthermore, when the peak list has a variation (e.g., ±0.50°2θ) at the end of the list for the purposes of this disclosure, each value in the peak list is modified by the listed variation (e.g., ±0.50°2θ). In other embodiments, the depicted or listed XRPD peaks have variations between ±1°2θ and ±0°2θ, such as ±1°2θ, ±0.75°2θ, ±0.20°2θ, or ±0.10°2θ.

[0066] Unless otherwise stated, the term "freebase" or "free base" refers to 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one in its base form (the aproticized form without any counterions) or one of its enantiomers, if specified, either R-freebase or S-freebase. Therefore, as used herein, the term "free base" refers to the structure... Therefore, "R free base" refers to the R isomer of this structure, and "S free base" refers to the S isomer of this structure. Furthermore, the term "deuterated free base" refers to the structure... Therefore, "R-deuterated free base" refers to the R isomer of this structure, and "S-deuterated free base" refers to the S isomer of this structure.

[0067] 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 may be a reaction solvent or a crystallization solvent. Solvents mentioned herein are inert solvents in relation to the solute or reactant.

[0068] As defined herein, "inert solvent" is a solvent that does not react with reactants or products formed in a chemical reaction.

[0069] The term "reaction solvent" or 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, while the product salt may or may not be soluble therein. Furthermore, in one embodiment, it is a volatile solvent. Additionally, in another embodiment, it is a volatile solvent with a boiling point of 90°C or lower at 1 atmosphere.

[0070] As used herein, the term "crystallization solvent" or similar terms refer to an inert solvent used to crystallize the salt of this disclosure, wherein the salt is poorly soluble at room temperature or low temperatures but becomes more soluble when heated to, for example, the boiling point of the solvent. Ideally, the salt is practically insoluble or slightly soluble in the solvent at room temperature, but extremely soluble at the boiling point of the solvent. The crystallization solvent can be a single solvent or a mixture of solvents. If it is a mixture of liquid solvents, it can be miscible. In one embodiment, water can be a solvent or a co-solvent. As used herein, the term "recrystallization solvent" refers to a crystallization solvent, and the two terms are used interchangeably.

[0071] The term "crystallization," when applied to compounds, refers to a solid phase in which the substance has a regular, ordered internal structure at the molecular level and produces a distinctive X-ray diffraction pattern with defined peaks. Essentially, crystallization means that a composition contains more than 50%, or more than 55%, or more than 60%, or more than 65%, or more than 70%, or more than 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95%, or more than 99% of the compound in crystalline form.

[0072] Throughout this disclosure, the term “crystallization” may refer to crystallization and / or recrystallization, depending on the applicable circumstances relating to the preparation of the salts described herein.

[0073] As used herein, unless otherwise stated, the terms “polymorph” and “polycrystalline form” (used synonymously herein) 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., resistance 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 variations in chemical reactivity (e.g., differential oxidation, causing dosage forms containing one polymorph to discolor more quickly than those containing another) or mechanical characteristics (e.g., tablets breaking during storage due to the kinetically favorable transformation of a polymorph into a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more prone to breakage at high humidity).

[0074] The different physical properties of polymorphs and / or salts can affect their processing. For example, due to factors such as particle shape or size distribution, one polymorph may be more likely to form solvates or be more difficult to filter or wash to remove impurities than another polymorph.

[0075] 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, nuclear magnetic resonance (NMR) in the solid state, 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.

[0076] As used herein, "peak" refers to a spectrum or data presented in graphical form (e.g., XRPD, DSC, IR, Raman, and NMR spectra), and unless otherwise specified, 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.

[0077] As used herein, and unless otherwise stated, the term “substantially pure” when used to describe a solid means that the solid form of the compound comprises one or more crystalline polymorphs disclosed herein in an amount of at least 50 wt%; in another embodiment, at least 60 wt%; in another embodiment, at least 70 wt%; in another embodiment, at least 75 wt%; in another embodiment, at least 80 wt%; in another embodiment, at least 90 wt%; in another embodiment, at least 95 wt%; and in yet another embodiment, at least 97 wt%, 98 wt%, 99 wt%, or 100 wt% of solids.

[0078] As used herein and unless otherwise specified, when used to describe a polymorph of a compound, the term "polymorphic pure" refers to a solid form of the compound that contains the polymorph and substantially contains no other polymorphs of the compound. For example, a representative polymorphic pure solid contains more than 80% by weight of one polymorph of the compound and less than 20% by weight of other polymorphs; in another embodiment, more than 90% by weight of one polymorph of the compound and less than 10% by weight of other polymorphs; and in yet another embodiment, more than 95% by weight of one polymorph of the compound and less than 5% by weight of other polymorphs; and in even another embodiment, more than 97% by weight of one polymorph of the compound and less than 3% by weight of other polymorphs.

[0079] When referring to a salt or free base, the term "enantiomerically pure" herein means that the salt or free base is primarily present in one enantiomer and substantially free of the other enantiomer. For example, an enantiomerically pure salt or free base contains more than 80% by weight of one enantiomer of the salt or free base and less than 20% by weight of the other enantiomer of the salt or free base; in another embodiment, more than 90% by weight of one enantiomer and less than 10% by weight of the other enantiomer of the salt or free base; and in yet another embodiment, more than 95% by weight of one enantiomer and less than 5% by weight of the other enantiomer of the salt or free base; and in even another embodiment, more than 97% by weight of one enantiomer and less than 3% by weight of the other enantiomer or salt or free base.

[0080] The term "pharmaceuticalally acceptable" (e.g., when listing pharmaceutically acceptable excipients or carriers) refers to a substance that is compatible with administration to human subjects, meaning that the substance will not cause unwanted biological effects. Examples of pharmaceutically acceptable excipients are described in "Handbook of Pharmaceutical Excipients" (Rowe et al., eds. (Pharmaceutical Press, 7th ed., 2012)).

[0081] The terms “treating” and “treatment” refer to improving symptoms, suppressing symptoms, eradicating symptoms, reducing the severity of symptoms, reducing the frequency of symptoms, reducing the incidence 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.

[0082] The term "effective amount" or "therapeutic effective amount" refers to the amount of the crystalline salt described in this disclosure, a pharmaceutical composition containing the crystalline salt, a pharmaceutical agent containing the crystalline salt, or another substance containing the crystalline salt that can effectively achieve, but is not limited to, the following specific pharmacological and / or physiological effects: reduction of sadness or somnolence, depressive mood, frequency or severity of anxiety or sadness, decreased interest in all or almost all activities, significant increase or decrease in appetite leading to weight gain or loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, inability to concentrate, and recurrent thoughts of death or suicide; or providing the desired pharmacological and / or physiological effects, such as reducing, inhibiting, or reversing one or more of the underlying pathophysiological mechanisms of neurological dysfunction, regulating dopamine levels or transmission, regulating serotonin levels or transmission, regulating norepinephrine levels or transmission, regulating glutamate or GABA levels or transmission, regulating synaptic connectivity or neurogenesis in certain brain regions, or combinations thereof. The precise dosage will vary depending on a variety of factors, such as subject-related variables (e.g., age, immune system health, clinical symptoms, etc.), the disease or disorder being treated, the route of administration, and the pharmacokinetics of the drug being administered.

[0083] The term "therapeutic index" and related therapeutic effects and side effects used in reference to any salt disclosed herein refer to the ratio of the dose of said salt required to induce a specific negative side effect to the dose of said salt required to induce the desired therapeutic effect.

[0084] "Patient" or "subject" refers to an animal and may include any mammal, such as human, rat, mouse, cat, dog, goat, sheep, horse, monkey, ape, rabbit, cow, etc. Mammal subjects may be at any developmental stage, including adults, children, infants, and newborns.

[0085] Unless otherwise stated, the terms "drug" and "medicament" are synonyms.

[0086] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” or any other variations thereof are intended to cover non-exclusive inclusion. For example, a process, method, article, or apparatus that includes a list of elements is not necessarily limited to those elements, but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

[0087] When referring to solids, the term "substantially includes crystalline structures," followed by the name of the compound, such as 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, including stereoisomers, salts, and polymorphs, such as ( R(S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one or (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride, fumarate, sulfate, p-toluenesulfonate, methanesulfonate, maleate, phosphate, tartrate, citrate, malate, or hippurate means a solid having at least 50% by weight in a crystalline state of the specified compound. It may contain other impurities. For example, an amorphous compound may be present, or another polymorph may be present, or other impurities may be present, but the sum of these impurities shall not exceed 50% by weight. In one embodiment, the solid may contain at least 55% by weight of the specified compound in a crystalline state; and in another embodiment, at least 60% by weight of the specified compound in a crystalline state; and in another embodiment, at least 65% by weight of the specified compound in a crystalline state; and in another embodiment, at least 70% by weight of the specified compound in a crystalline state; and in yet another embodiment, at least 75% by weight of the specified compound in a crystalline state; and in another embodiment, at least 80% by weight of the specified compound in a crystalline state; and in yet another embodiment, at least 85% by weight of the specified compound in a crystalline state; and in another embodiment, at least 90% by weight of the specified compound in a crystalline state; and in yet another embodiment, at least 95% by weight of the specified compound in a crystalline state; and in even another embodiment, at least 99% by weight of the specified compound in a crystalline state. Therefore, the amount of a specified compound present in a crystalline state in a 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%.

[0088] When referring to graphical or other graphical representations of data relating to any crystal, solid, polymorph, or mixture thereof described herein, the terms “substantially,” “substantially as depicted,” and “substantially as shown” mean changes in peak intensity or position in an X-ray diffraction pattern resulting from minor variations in the data in the identified graph, such as those attributable to factors like instrumental response, aspect ratio, particle size, experimental error, and variations in sample concentration or purity. Nevertheless, those skilled in the art will be able to readily compare the graphical data in the figures herein with graphical data in a second polymorph, crystal, or solid form and confirm whether the two sets of graphical data characterize the same material or two different materials. It should be understood that all figures therefore represent the inherent properties of the polymorph, crystal, or solid form to which they relate, and the specific data presented are substantially as depicted in the figures, regardless of whether the modifier is substantially explicitly included in any description of the figures.

[0089] The terms “substantially,” “substantially as depicted,” and “substantially as shown” used in DSC thermal analysis plots refer to peak temperatures approximately equal to the shown values ​​and having the same number of peaks as depicted.

[0090] Furthermore, the term "a / an" is used to describe the elements and components described herein. This is done merely for convenience and to broadly define the scope of the invention. This description should be understood to include one or at least one.

[0091] Furthermore, the singular includes the plural, and vice versa, unless there is a clear other meaning.

[0092] Furthermore, unless explicitly stated otherwise, "or" refers to an inclusive "or," not an exclusive "or." For example, either of the following satisfies condition A or condition B: 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).

[0093] Furthermore, as used herein, the term “and / or” is synonymous with the term “or”.

[0094] When representing a range or list of values, the implementation includes the endpoints of the range and / or list, as well as all points in between. For example, a range of 6 to 9 includes the values ​​6 and 9, and all values ​​in between. Similarly, when values ​​are indicated as approximate values ​​using the prefix “about,” it should be understood that the range of values ​​begins at the two endpoints of “about,” where “about” is defined as described herein. All ranges are inclusive and composable. Furthermore, references to values ​​described by range include every value within that range.

[0095] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While similar or equivalent methods and materials to those described herein may be used to practice or test embodiments of this disclosure, 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 disclosure (including its limitations) shall prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be restrictive.

[0096] Unless otherwise stated, all percentages are by weight.

[0097] The terms “salts disclosed herein” or “salt disclosed herein” refer to any of the salts disclosed in the examples, including crystalline salts. These salts are pharmaceutically acceptable.

[0098] This disclosure relates in part to crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, including its stereoisomers, such as ( R (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. These include their hydrochlorides, sulfates, p-toluenesulfonates, methanesulfonates, maleates, phosphates, tartrates, fumarates, citrates, glycolates, malates, and hippurates. These salts exist in various polymorphic forms as described herein and are included in this disclosure.

[0099] In one embodiment, this disclosure relates to any of the disclosed salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, which is substantially crystalline, including its stereoisomers, such as ( R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. The solid may be polymorphically pure, i.e., containing only one of the crystalline polymorphs described herein, or alternatively, may contain a mixture of two or more of the aforementioned crystalline polymorphs. In one embodiment, the solid contains one or more crystalline polymorphs, wherein at least one crystalline polymorph described herein is present in an amount of at least 50% by weight; and in another embodiment, in an amount of at least 55% by weight; and in another embodiment, in an amount of at least 60% by weight; and in another embodiment, in an amount of at least 65% by weight; and in another embodiment, in an amount of at least 70% by weight; and in another embodiment, in an amount of at least 75% by weight; and in another embodiment, in an amount of at least 80% by weight; and in another embodiment, in an amount of at least 85% by weight; and in yet another embodiment, in an amount of at least 90% by weight; and in yet another embodiment, in an amount of at least 95% by weight; and in another embodiment, in an amount of at least 98% by weight; and in yet another embodiment, in an amount of at least 99% by weight. In another embodiment, the solid comprises a mixture of polymorphs.

[0100] In one embodiment, the solid is polymorphically pure. That is, it contains a crystalline polymorph that is substantially free of other crystalline polymorphs. Additionally, regardless of whether the solid is polymorphically pure or contains a mixture, it may contain other materials, such as pharmaceutically acceptable excipients or adjuvants known in the pharmaceutical field, or optionally, non-polymorphic impurities.

[0101] In one embodiment, the solid may be substantially pure. In another embodiment, it may be polymorphically pure; and in yet another embodiment, it may be substantially pure and polymorphically pure. In another embodiment, it may be polymorphically pure and enantiomerically pure. In yet another embodiment, it may be substantially pure, enantiomerically pure, and polymorphically pure.

[0102] In another embodiment, the solid is anhydrous, i.e., contains less than 5% by weight of water. Therefore, in one 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. In yet another embodiment, the solid is substantially pure, enantiomerically pure, polymorphically pure, and anhydrous.

[0103] The salts disclosed herein are prepared by reacting a free base (such as the R isomer of the free base) with an acid to achieve salt formation. Since the reaction does not affect the chiral center of the free base, the resulting salt product retains the stereochemistry of the free base. Examples of acids include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, citric acid, glycolic acid, maleic acid, malic acid, hippuric acid, etc., and are listed in the examples below. The solvent system used for crystallizing the salt is selected based on the solubility of the free base and the selected acid. The solvent can be a single solvent or a mixture of solvents, including mixtures containing water.

[0104] Techniques for salt crystallization are well known to those skilled in the art. These include, but are not limited to, melt recrystallization, melt cooling, solvent crystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. The resulting crystalline product is dried using techniques known in the art, such as air drying, oven drying, vacuum drying, or solvent evaporation (e.g., water). 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.

[0105] The prepared salt is purified using techniques known in the art, such as chromatography, including column chromatography, HPLC, recrystallization, sublimation, filtration, etc.

[0106] The following non-limiting examples are exemplary embodiments for the preparation and separation of the various salts disclosed herein, but the teachings of this disclosure are not limited thereto. Example

[0107] The following is a list of abbreviations used in this disclosure.

[0108] List of abbreviations <![CDATA[ 1 H NMR / H-1 NMR ]]> 2-Methyltetrahydrofuran dichloromethane N,N-Dimethylformamide Dimethyl sulfoxide Differential scanning calorimetry Dynamic steam adsorption Ethyl acetate ethanol High performance liquid chromatography Hour Isopropanol Isopropyl acetate Acetonitrile methanol Mother liquor, which is the solution remaining after filtration to remove crystalline solids. mg milliliters Methyl tert-butyl ether Methyl isobutyl ketone n-Propanol polarizing microscope Room temperature (20–25 °C) XRPD pattern calculated from single crystal structure Starting materials Thermogravimetric analysis Tetrahydrofuran wet filter cake Powder X-ray diffraction

[0109] The following is a list of the instruments and methods discussed in this article.

[0110] Instruments and methods Powder X-ray diffraction (XRPD) Instrument: Panalytical Empyrean Parameters: X-ray tube Cu (Kα radiation); Power: 45 kV x 40 mA Scan range: 2 to 40 2θ (degrees) Step size: 0.01 degrees Scanning speed: 6.33 degrees (2θ) per minute Proton nuclear magnetic resonance (NMR) 1 H NMR) Instrument: Bruker 400 Ultrashield Solvent: Methanol d 4 Differential scanning calorimetry (DSC) Instrument: TA Instruments DSC 2500 Parameters: Increase at a rate of 5 / 10 / 20 °C per minute, up to 300 °C. Thermogravimetric analysis (TGA) Instrument: TA Instruments TGA 5500 Parameters: 25 to 300 °C, 10 °C / min, N2 purging at 50 mL / min Polarizing microscope (PLM) Instrument: Nikon Eclipse Ci Pol Software: Nikon NIS Elements Dynamic vapor adsorption (DVS) Instruments: DVS Intrinsic, Surface Measurement Systems Parameters: 25 °C, 0-90-0% RH for 2 cycles

[0111] In the embodiments described below, peaks are rounded to the nearest tenths or hundredths place. Therefore, in some cases, several peaks may have the same value. In these cases, conflicting peaks with the same value are rounded to the nearest hundredths place, enclosed in parentheses.

[0112] In the following embodiments, the solid was analyzed by XRPD to determine whether it was crystalline, and if so, the melting point was determined by DSC and whether it was hydrated / solventized by TGA.

[0113] Example 1.

[0114] (a) Preparation ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride form 1 (1R HCl form 1) (Method 1) At room temperature, to ( RA solution of IPA containing 5N HCl (1.5 equivalents) was added dropwise to 10 volumes of MTBE solution of the free base compound 1R, 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, while maintaining the internal temperature below 30°C. After the addition was complete, the formation of a white precipitate was observed. The resulting suspension was aged at 20–30°C for at least 12 hours. The suspension was then filtered, the filter cake was washed with 3 × 3 volumes of MTBE, and dried in a vacuum oven at 35–45°C. A white solid product, 1R HCl, was obtained in 91% yield.

[0115] The product of this embodiment is referred to herein as Form 1 or Form 1 polymorph or 1R HCl Form 1 or 1R HCl polymorph or ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride form 1 or ( R It is available in 1-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride form 1 or HCl-1. These names are synonymous and interchangeable.

[0116] (b) Preparation ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride form 1 (1R HCl form 1) (Method 2) A general procedure for the synthesis of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecane-7-one, 3 In a 1000 mL jacketed reactor equipped with a top-mounted stirrer and a Dean-Stark apparatus, 1,2-cyclohexanedione (50.0 g, 428 mmol) (compound 11), 2,2-dimethylpropane-1,3-diol (54.0 g, 514 mmol), p-TSA (1.66 g, 8.6 mmol), and cyclohexane (200 mL) were added, and the resulting suspension was heated under reflux for 3 hours to achieve complete conversion of the starting material. The mixture was then cooled to room temperature, and 1N NaOH aqueous solution was added, followed by methyl tert-butyl ether (MTBE) and stirring. The phases were separated, and the aqueous phase was further extracted with MTBE. The combined organic phases were washed once with 10% brine and concentrated. The mixture was azeotropically reacted with toluene once to give 113 g (Q-NMR analysis: 66%, yield 87.6%). The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 3.55 (d, J = 11.1 Hz, 1H), 3.32 (d, J= 11.1 Hz,1H), 2.38 – 2.35 (m, 2H), 1.8 – 1.79 (m, 2H), 1.67-1.63 (m, 4H), 1.06 (s,3H), 0.55 (s, 3H).

[0117] synthesis( R,E )-N-(3,3-dimethyl-1,5-dioxane[5.5]undecane-7-ylidene)-2-methylpropane-2-sulfinamide, 5R general procedure At room temperature, compound 3 (33.3 g, 60% by weight, 0.101 mol) was added to a round-bottom flask equipped with a top stirrer. R )-t-Bu-sulfinamide (4) (14.62 g, 0.121 mol), toluene (80 mL), and Ti(OEt4) (25.31 mL, 0.121 mol). The mixture was heated at 80 °C for 5–6 hours and then cooled to room temperature to obtain a dark solution. EDTE (47.5 g) was added to this solution, and the mixture was heated at 55 °C for 60 minutes and then cooled to room temperature. 12% NaCl (aq) was added to the above solution and stirred for about 5 minutes to allow it to settle. The phases were separated, and the aqueous phase was extracted twice more with toluene. The combined organic matter was washed once with water. The organic phase was filtered through an activated carbon plug and SiO2 and concentrated to obtain a crude product as a yellow-orange semi-solid (18.9 g net product wt%, 63% by NMR). The product crystallized into a grayish-white solid upon standing, was filtered, and proceeded to the next step. 1 H NMR (400 MHz, CDCl3) δ 3.83 (d, J = 11.0 Hz, 1H), 3.72 (d, J = 11.0 Hz, 1H), 3.44 – 3.38 (m, 2H), 3.13 – 3.07 (m, 1H), 2.89-2.83 (m, 1H), 1.98-1.85 (m, 1H), 1.81-1.71 (m, 1H), 1.31 (s, 9H), 1.21 (s, 3H), 0.72 (s, 3H).

[0118] synthesis( R )-N-(( R )-7-(4-fluorophenyl)-3,3-dimethyl-1,5-dioxanespiro[5.5]undecane-7-yl)-2-methylpropane-2-sulfinamide, 7R general procedure At -5 °C, a 1 M solution of 4-F-phenylmagnesium bromide in THF (116 mL, 116 mmol, 2 equivalents) was added dropwise to a stirred solution of compound 5R (17.5 g, 58.0 mmol) in THF (70 mL). The resulting reaction mixture was stirred at -5 °C for 4 h, followed by stirring at room temperature for 14 h. TLC (50% EtOAc / hexane) indicated complete conversion of the starting material. The reaction mixture was then cooled to 0 °C, and a saturated aqueous solution of NH4Cl (70 mL) was added dropwise. After warming to room temperature, the aqueous phase was extracted with MTBE, and the combined organic layers were washed with water and then dried over Na2SO4. The solvent was evaporated to give a crude product, which was re-slurryed with heptane and then filtered to give a white solid compound 7R (18.24 g, 79%). 1H NMR (400 MHz, CDCl3) δ7.72 – 7.68 (m, 2H), 6.98 – 6.94 (m, 2H), 4.51 (s, 1H), 3.67-3.60 (m, 2H), 3.35 (dd, J = 11.3 Hz and 2.6 Hz, 1H), 3.27 (dd, J = 11.3 Hz and 2.5 Hz ,1H), 2.70 – 2.63 (m, 1H), 2.33 – 2.27 (m, 1H), 2.05-2.01 (m, 1H), 1.98-1.88(m, 1H), 1.76-1.66 (m, 1H), 1.62-1.45 (m, 2 H), 1.17 (s, 9H), 0.84 (s, 3H), 0.69 (s, 3H).

[0119] synthesis( R The general procedure for )-7-(4-fluorophenyl)-3,3-dimethyl-1,5-dioxane[5.5]undecane-7-amine,8R At 0 °C, a methanol solution containing 3 M HCl (113 mL, 339 mmol, 3 equivalents) was added dropwise to a suspension of compound 7R (45.0 g, 113 mmol) in methanol (180 mL). The resulting reaction mixture was heated to room temperature and stirred for 12–14 hours. After the reaction was complete, the mixture was cooled to 0 °C and a saturated aqueous solution of NaHCO3 (225 mL) was added dropwise. CH2Cl2 (90 mL) was added to the resulting suspension to dissolve the product and separate the phases. The aqueous phase was extracted with CH2Cl2 (2 x 90 mL), the organic matter was combined, washed with brine and dried (Na2SO4), and concentrated to give a white solid crude compound 8R (27.1 g, 82% quantitative), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.52 (m,2H), 6.99 – 6.90 (m, 2H), 3.57 (dd, J = 23.4, 11.4 Hz, 2H), 3.16 (ddd, J = 11.2,8.4, 2.7 Hz, 2H), 2.53 – 2.36 (m, 2H), 1.86 – 1.34 (m, 8H), 0.59 (s, 3H), 0.36 (s, 3H).

[0120] synthesis( R )-N-(7-(4-fluorophenyl)-3,3-dimethyl-1,5-dioxaspiro[5.5]undecane-7-yl)formamide, General Procedure 9R At room temperature, Ac₂O (32 mL, 339.56 mmol, 3 equivalents) and HCO₂H (12.8 mL, 339.56 mmol, 3 equivalents) were added to a reactor equipped with a stirrer, thermocouple, and nitrogen inlet. The reaction mixture was heated to 60 °C and aged for 3 hours, then cooled to 0 °C. At 0 °C, a solution of 8R (26.10 g, 88.96 mmol) in CH₂Cl₂ (125 mL) was added to the mixture using a feeding funnel, and the mixture was stirred at 0 °C for 1.5–2 hours. HPLC and TLC (30% EtOAc / hexane) showed complete conversion of the starting material to the desired product. Subsequently, the reactants were quenched at 0 °C by dropwise addition of a saturated aqueous solution of NaHCO₃ (520 mL) using a feeding funnel. The resulting solution was stirred at 0 °C for 30 minutes and then transferred to a separatory funnel. The phases were separated, and the aqueous phase was extracted with CH₂Cl₂. The organic layers were combined, washed with water, and distilled to a smaller volume. MeOH was then added and distilled to remove residual CH₂Cl₂. The resulting MeOH solution was transferred to a three-necked round-bottom flask, additional MeOH was added, and the mixture was heated at 55°C for 1 hour with stirring. Water was then added dropwise to the stirred solution over 1 hour using a feeding funnel. The resulting off-white suspension was aged at 50°C for 1 hour and cooled to room temperature for 12–14 hours. The suspension was then filtered, and the filter cake was washed with a 1:1 MeOH / water mixture and dried under suction, followed by drying in a vacuum oven at 40°C for 24 hours to give a white solid compound 9R (28.16 g, 98%). 1 H NMR (400 MHz, CDCl3) δ 8.29(d, J = 1.9 Hz, 1H), 8.04 (d, J= 12.5 Hz, 1H), 7.49 – 7.37 (m, 2H), 7.03 – 6.89(m, 2H), 6.43 (d, J = 12.5 Hz, 1H), 6.23 (s, 1H), 3.57 (ddd, J = 24.9, 11.4, 7.2Hz, 2H), 3.24 – 3.13 (m, 2H), 2.91 (dq, J 0.59 (d, 3H), 0.28 (d, J = 23.3 Hz, 3H).

[0121] General procedure for synthesizing 10R Compound 9R (75 g, 0.23 mol) was added to a reactor equipped with a cooler, thermocouples, and a top-mounted stirrer. THF was then added and the mixture was stirred for at least 15 minutes. Next, NaBH4 (26.5 g, 0.7 mmol) was added partically to the reactor. The resulting suspension was cooled to -10°C to 0°C. Iodine (71.1 g, 0.28 mol) in THF was added dropwise to the suspension using a dropping funnel, maintaining the internal temperature between -5°C and 10°C (note: rapid gas escape). After the iodine addition was complete, the mixture was gradually heated to 35°C to 45°C and stirred at this temperature for 2–4 hours. HPLC IPC showed a conversion of 9 to 10. The resulting white suspension was cooled to -5°C to 0°C, and MeOH was added dropwise over 90 minutes, maintaining the internal temperature below 10°C. After the addition was complete, the mixture was heated to 40 to 45°C over 30 minutes and aged at this temperature. 19 F NMR studies were used to monitor the complete decomposition of the intermediate amineborane complex in the reaction mixture.

[0122] In a separate flask, a NaOH(aq) solution was prepared by dissolving 0.930 g of NaOH in 9 mL of water. A portion (20%, 18 mL) of this NaOH(aq) solution was initially added dropwise to the reaction mixture at 40–45 °C and aged at this temperature. The formation of a white precipitate was observed immediately after the addition of the NaOH(aq) solution. The remaining NaOH(aq) solution was then slowly added over 2.5–3 hours at 40–45 °C. After the addition was complete, the internal temperature of the suspension was set to 20–25 °C and aged at this temperature. The suspension was then filtered, the filter cake was washed with a methanol / water (1:1) mixture, and dried under suction. The filter cake was then returned to the reactor, followed by the addition of water. The resulting suspension was heated to 55–65 °C and aged at this temperature. The suspension was then cooled to 20–25 °C and aged for 30 minutes, followed by filtration. The filter cake was then washed with a 1:1 mixture of methanol and water, dried under suction, and then dried in a vacuum oven at 55 to 60 °C. Compound 10R was given as a white solid product in a yield of 71% (54.8 g), with an NMR purity of 93.2 wt%, a KF purity of 3.2%, and an HPLC purity of 99.4 Å. 1 H NMR (400 MHz, CDCl3) δ 7.43 – 7.35 (m, 2H), 7.00 – 6.92 (m, 2H), 3.56 (dd, J = 32.3, 11.1 Hz, 2H), 3.10 (ddd, J = 19.8, 11.1, 2.7 Hz, 2H), 2.51 –2.39 (m, 1H), 2.28 (td, J = 13.3, 3.8 Hz, 1H), 2.04 (s, 3H), 1.87 – 1.58 (m,4H), 1.55 – 1.31 (m, 2H), 0.55 (s, 3H), 0.27 (s, 3H) ppm.

[0123] preparation( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, 1R Compound 10R (50 g, 93.4 wt%, 0.152 mol) was added to a 2 L jacketed reactor equipped with a cooler, thermocouples, and a top-mounted stirrer at room temperature, followed by the addition of HPLC-grade water (4V) and stirring. The resulting suspension was cooled to an internal temperature of 15°C to 25°C. Concentrated HCl (12N, 4 equivalents, 50 mL, 0.76 mol) was slowly added to the suspension, maintaining the temperature below 35°C. The mixture was heated to an internal temperature of 65°C to 75°C and aged at this temperature for at least 12 hours. The completion of the reaction was monitored by HPLC. The mixture was then cooled to 20°C to 30°C, and MTBE was added, with stirring for at least 10 minutes. The phases were separated, and the aqueous phase (bottom) was returned to the reactor. 3NNaOH(aq) solution was then slowly added using a feeding funnel, maintaining the internal temperature below 40°C, to bring the pH of the mixture to 12 to 13 (measured using pH paper). The resulting white suspension was extracted with MTBE. Wash the combined MTBE layers with water. Check the MTBE layers by 1H NMR to see if the neopentyl glycol byproduct has been removed (not exceeding 10%; if >10%, repeat the washing process). Concentrate the MTBE phase to 2V. Add additional MTBE and concentrate again, repeating this process twice. Dilute the resulting MTBE phase with MTBE to obtain KF (KF = not exceeding 0.2%).

[0124] 1R HCl salt formation A solution of 5-6 N HCl in IPA (45.48 mL, 0.228 mol, 1.5 equivalents) was added dropwise to the above MTBE solution containing free alkali compound 1R at room temperature, keeping the internal temperature below 30°C; a white precipitate was observed to form. After the addition was complete, the resulting suspension was aged at 20-30°C for at least 12 hours. The suspension was then filtered, and the filter cake was washed with MTBE (3 V × 3, displacement washing, filter cake washing, and slurry washing), and dried under suction for at least 30 minutes. The filter cake was then dried in a vacuum oven at 35-45°C for at least 12 hours. A product 11R•HCl was obtained as a white solid in a yield of 91% (34.2 g), with an HPLC purity of 99.9 A%, an HPLC purity of 100.1 wt%, and a KF purity of 0.152%. 1 HNMR (400 MHz, DMSO- d 6) δ 9.81 (d, J = 302.4 Hz, 2H), 7.47 – 7.28 (m, 4H), 2.44(p, J = 1.9 Hz, 1H), 2.39 – 2.19 (m, 2H), 2.14 (td, J= 13.5, 3.9 Hz, 1H), 2.06(s, 3H), 1.96 – 1.85 (m, 1H), 1.85 – 1.72 (m, 1H), 1.66 – 1.38 (m, 2H).

[0125] Using HPLC, this product was determined to be greater than 99% pure and anhydrous. Furthermore, it is a crystalline solid.

[0126] Example 2 Preparation of deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride form 1 (1R HCl form 1)

[0127] Synthesis 3 General Program 1,2-cyclohexanedione (50.0 g, 428 mmol) (compound 11), 2,2-dimethylpropane-1,3-diol (54.0 g, 514 mmol), p-toluenesulfonic acid (1.66 g, 8.6 mmol), and cyclohexane (200 mL, 4 V) were added to a jacketed reactor equipped with a stirrer and a Dean-Stark apparatus. The resulting suspension was heated under reflux for 3 hours to obtain complete conversion of the starting material. The suspension was then cooled to 20 °C, and 1 N NaOH aqueous solution was added, followed by the addition of methyl tert-butyl ether (MTBE) and stirring. The phases were separated, and the aqueous phase was further extracted with MTBE. The combined organic phases were washed once with 10% brine and concentrated. The mixture was azeotropically reacted with toluene once to give 113 g (Q-NMR analysis: 66%, yield 87.6%). The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 3.55 (d, J = 11.1 Hz, 1H), 3.32 (d, J = 11.1 Hz,1H), 2.38 – 2.35 (m, 2H), 1.8 – 1.79 (m, 2H), 1.67-1.63 (m, 4H), 1.06 (s,3H), 0.55 (s, 3H).

[0128] Synthesis 5 General Procedure At room temperature, compound 3 (33.3 g, 60% by weight, 0.101 mol) was added to a 1 L round-bottom flask equipped with a stirrer. R(4) 14.62 g, 0.121 mol 1-t-Bu-sulfinamide (40 mL), toluene (80 mL), and Ti(OEt4) (25.31 mL, 0.121 mol). The mixture was heated at 80 °C for 5–6 hours and then cooled to room temperature to obtain a dark solution. EDTE (47.5 g, 2 equivalents) was added to this solution, and the mixture was heated at 55 °C for 60 minutes, followed by cooling to room temperature. 12% NaCl(aq) was added to the above solution and stirred for about 5 minutes to allow it to settle. The phases were separated, and the aqueous phase was extracted again with toluene. The combined organic matter was washed with water. The organic phase was filtered through an activated carbon plug and SiO2 and concentrated to obtain a crude product of yellow-orange semi-solid (18.9 g net product by NMR; 63% by weight). The product crystallized into a grayish-white solid upon standing, was filtered, and proceeded to the next step. 1 H NMR (400 MHz, CDCl3) δ 3.83 (d, J = 11.0 Hz, 1H), 3.72 (d, J = 11.0 Hz,1H), 3.44 – 3.38 (m, 2H), 3.13 – 3.07 (m, 1H), 2.89-2.83 (m, 1H), 1.98-1.85(m, 1H), 1.81-1.71 (m, 1H), 1.31 (s, 9H), 1.21 (s, 3H), 0.72 (s, 3H).

[0129] General procedure for synthesizing 7R At -5 °C, a 1 M solution of 4-fluorophenyl magnesium bromide in tetrahydrofuran (116 mL, 116 mmol, 2 equivalents) was added dropwise to a stirred solution of compound 6 (17.5 g, 58.0 mmol) in tetrahydrofuran (70 mL). The resulting reaction mixture was stirred at -5 °C for 4 h, then at room temperature for 14 h. Thin-layer chromatography (50% ethyl acetate / hexane) showed complete conversion of the starting material. The reaction mixture was then cooled to 0 °C, and a saturated aqueous solution of ammonium chloride (70 mL) was added dropwise. After warming to room temperature, the aqueous phase was extracted with methyl tert-butyl ether, and the combined organic layers were washed with water and then dried over sodium sulfate. The solvent was evaporated to give a crude product, which was re-slurryed with heptane and then filtered to give compound 7 (18.24 g, 79%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.72 – 7.68 (m, 2H), 6.98 – 6.94 (m, 2H), 4.51 (s, 1H), 3.67-3.60 (m, 2H), 3.35 (dd, J= 11.3 Hz and 2.6 Hz, 1H), 3.27 (dd, J = 11.3 Hz and 2.5 Hz , 1H), 2.70 – 2.63 (m, 1H), 2.33 – 2.27 (m, 1H), 2.05-2.01 (m, 1H), 1.98-1.88 (m, 1H), 1.76-1.66 (m, 1H), 1.62-1.45 (m, 2H), 1.17 (s, 9H), 0.84 (s, 3H), 0.69 (s, 3H).

[0130] General procedure for synthesizing 8R At 0 °C, a methanol solution containing 3 M HCl (113 mL, 339 mmol, 3 equivalents) was added dropwise to a suspension of compound 7 (45.0 g, 113 mmol) in methanol (180 mL). The resulting reaction mixture was heated to room temperature and stirred for 12–14 hours. After the reaction was complete, the mixture was cooled to 0 °C and a saturated aqueous solution of NaHCO3 (225 mL) was added dropwise. CH2Cl2 was added to the resulting suspension to dissolve the product and separate the phases. The aqueous phase was extracted with CH2Cl2, and the combined organic phases were washed with brine and dried (Na2SO4). The solution was concentrated to give a white solid crude compound 8 (27.1 g, 82% quantitative), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.62 – 7.52 (m, 2H), 6.99 – 6.90 (m, 2H), 3.57 (dd, J = 23.4, 11.4 Hz, 2H), 3.16 (ddd, J = 11.2, 8.4, 2.7 Hz, 2H), 2.53 –2.36 (m, 2H), 1.86 – 1.34 (m, 8H), 0.59 (s, 3H), 0.36 (s, 3H).

[0131] General procedure for synthesizing [D]-9R Acetic anhydride (1.9 mL, 13.63 mmol) and formic acid- d 3The mixture (0.54 mL, 13.63 mmol) was stirred at 60 °C for 2 hours, then gradually cooled to 0 °C. Subsequently, a solution of compound 8 (1.0 g, 3.41 mmol) in CH₂Cl₂ (5 mL) was added to the mixture at 0 °C, and the mixture was stirred at 0 °C for 2 hours. TLC (30% EtOAc / hexane) indicated complete conversion of the starting material. The mixture was then neutralized by slow addition of an aqueous sodium bicarbonate solution and extracted with CH₂Cl₂. The combined organic matter was washed once with saturated NaHCO₃ (aq) and water, dried (Na₂SO₄), and concentrated to give a grayish-white solid crude [D]-9R (1.1 g, quantitative), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3)δ 7.50 – 7.36 (m, 2H), 7.02 – 6.88 (m, 2H), 6.56 – 6.11 (m, 1H), 3.66 – 3.49(m, 2H), 3.26 – 3.11 (m, 2H), 2.98 – 2.87 (m, 1H), 2.71 – 2.52 (m, 2H), 2.42 – 2.29 (m, 1H), 2.11 – 2.00 (m, 1H), 1.71 – 1.32 (m, 4H), 0.62 – 0.57 (m,3H), 0.33 – 0.23 (m, 3H).

[0132] General procedure for synthesizing [D3]-10R At 0 °C, a solution of iodine (1.13 g, 4.44 mmol) in THF (2 mL) was added dropwise to a stirred suspension of [D]-9R (1.1 g, 3.42 mmol) and NaBD4 (572 mg, 13.66 mmol) in THF (4 mL). The mixture was then heated to room temperature for 14 hours. The mixture was then cooled to 0 °C and quenched by the slow addition of MeOH (2 mL), followed by heating at 40 °C for 1 hour. The resulting clear solution was then concentrated and treated with MTBE, followed by treatment with water and 1N NaOH (aq) to obtain a clear phase separation. MTBE was then separated, and the aqueous phase was further extracted with MTBE. The organic compounds were combined, washed with water, followed by brine, dried (Na2SO4), and concentrated. The crude mixture was purified by SiO2 chromatography (100% hexane to 30-50% EtOAc / hexane) to give a white solid [D3]-10 (710 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.32(m, 2H), 7.02 – 6.90 (m, 2H), 3.56 (dd, J = 32.3, 11.1 Hz, 2H), 3.16 – 3.03 (m,2H), 2.51 – 2.41 (m, 1H), 2.27 (td, J = 13.3, 3.8 Hz, 1H), 1.86 – 1.57 (m, 4H), 1.55 – 1.31 (m, 2H), 0.55 (s, 3H), 0.26 (s, 3H); 19 F NMR (376 MHz, CDCl3) δ -118.7.

[0133] A general procedure for synthesizing [D3]-1R free bases At room temperature, concentrated hydrochloric acid (4 equivalents) was added to a solution of [D3]-10 (640 mg, 2.6 mmol) dissolved in isopropanol (IPA, 4 volumes), and the mixture was heated at 70 °C for 14 hours to obtain complete conversion of the starting material. Subsequently, the mixture was alkalized with 3N sodium hydroxide (NaOH, aqueous solution) and extracted with methyl tert-butyl ether (MTBE). The combined organic phases were washed once with water, dried (Na2SO4), and concentrated to give a colorless, oily crude [D3]-1R (430 mg, 93%), which was used in the next step without further purification.

[0134] As used herein, the terms “deuterated 1R free base” and “[D3]-1R free base” are synonymous and will be used interchangeably.

[0135] A general procedure for synthesizing [D3]-1R-HCl salts At room temperature, a solution of IPA (1.5 equivalents) containing HCl was added dropwise to a solution of crude [D3]-1R free base (430 mg) dissolved in MTBE (5 mL). A white suspension was observed to form during the addition of the HCl solution. The resulting white suspension was then stirred at room temperature for 12–14 hours. It was then filtered and washed with MTBE (3 x 3 V) to give a white solid [D3]-1R-HCl salt (420 mg, 84%). 1 H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 9.34 (s,1H), 7.53 – 7.32 (m, 4H), 3.15 (dt, J= 13.8, 3.0 Hz, 1H), 2.45 – 2.27 (m, 2H), 2.16 – 2.03 (m, 1H), 2.02 – 1.79 (m, 2H), 1.72 – 1.48 (m, 2H).

[0136] As used herein, unless otherwise stated, [D3]-1R-HCl is also referred to as deuterated 1R hydrochloride.

[0137] Example 3 Using the procedure of Example 1, and replacing (S)-t-Bu-sulfinamide with (S)-t-Bu-sulfinamide R )-t-Bu-sulfinamide, to prepare the compounds identified in the above scheme. As defined herein, 1S HCl is also referred to as 1S hydrochloride.

[0138] Example 4 Using the procedure of Example 2, and replacing (S)-t-Bu-sulfinamide with (S)-t-Bu-sulfinamide R )-t-Bu-sulfinamide, to prepare the compounds identified in the above scheme. As defined herein, [D3]-1S HCl is also referred to as deuterated 1S hydrochloride.

[0139] In the following Examples 5, 6, 7 and 8(a)-(l), it should be understood that the data regarding R-deuterated salts, S-salts and S-deuterated salts are exemplary.

[0140] Example 5. Approximate solubility of the HCl salt (Form 1) in Example 1.

[0141] The following method was used to estimate the approximate solubility of the crystalline hydrochloride product (1R HCl form 1) of Example 1 in 20 solvents: Approximately 10 mg of the product of Example 1 was placed in a 4.0 mL vial, and 25 μL of solvent was added to it at room temperature. The vial and its contents were then shaken and stirred. If a clear solution was not obtained, another 25 μL of solvent was added to the vial, followed by shaking and stirring. This process was repeated until 4.0 mL of solvent was added, followed by stirring the vial contents overnight. The results are shown in Table 1 below.

[0142] Table 1. Approximate solubility of the product of Example 1 (1R HCl form 1). entry solvent Solvent categories bp (°C) Solubility (mg / mL) Observation results 1 MeOH 2 64.7 >486 clarify 2 EtOH 3 78.37 215-431 clarify 3 IPA 3 82.5 50-67 clarify 4 iPAc 3 89 <2.4 slurry 5 EtOAc 3 77.1 <2.6 slurry 6 nPA 3 97 51-69 clarify 7 ACN 2 82 32-38 clarify 8 MEK 3 79.64 3.1-3.7 clarify 9 MIBK 2 117-118 <2.7 slurry 10 MTBE 3 55.2 <2.5 slurry 11 THF 2 66 <3.0 slurry 12 1,4-Dioxane 2 101 2.9-3.3 clarify 13 2-MeTHF 2 80.2 <2.6 slurry 14 heptane 3 98.42 <2.7 slurry 15 Toluene 2 110.6 <2.7 slurry 16 water - 100 >464 clarify 17 acetone 3 56 8.8-9.7 clarify 18 DCM 2 39.6 194-388 clarify 19 DMF 2 153 192-384 clarify 20 DMSO 3 189 >395 clarify

[0143] As shown in the results above, the hydrochloride product of Example 1 exhibited solubility >300 mg / mL in water, methanol, ethanol, dichloromethane, N,N-dimethylformamide, and dimethyl sulfoxide. Limited solubility or no solubility was found in esters, ketones, ethers, and alkanes.

[0144] Example 6. Screening of polymorphs of 1R HCl salt (Form 1) from Example 1.

[0145] Based on the approximate solubility of the product of Example 1 (1R HCl form 1), screening experiments were conducted using various screening techniques to search for possible additional crystalline forms (polymorphs). These techniques included, but were not limited to, slow evaporation, slow cooling, solvent-resistant addition, slurrying at room temperature and 50°C, temperature cycling, diffusion (solid and liquid), and polymer-induced crystallization. Various procedures are outlined below.

[0146] 1. Pulping at room temperature Using a magnetic stirrer at room temperature, approximately 40 mg of the product from Example 1 was slurried in 0.5–1.0 mL of different solvents in a 4.0 mL glass vial. The solids in the slurry were stirred for 7 days.

[0147] 2. Pulping at 50℃ At room temperature (50°C), approximately 40 mg of the product from Example 1 was slurried in 0.5–1.0 mL of different solvents in a 4.0 mL glass vial using a magnetic stirrer. The solids in the slurry were stirred for 3 days.

[0148] 3. Antisolvent addition Approximately 40 mg of the product from Example 1 was dissolved in a solvent to produce a saturated solution, and an antisolvent was added at a volume ratio of up to 10. If present, the solid was collected.

[0149] 4. Slow cooling (thermal circulation) Approximately 40 mg of the product from Example 1 was dissolved in a solvent, heated, and cycled at temperatures of 45°C / 1 hour → 35°C / 4 hours → 25°C / 4 hours → 15°C / 4 hours → 5°C / 4 hours, followed by cooling for 7 days. The resulting solid (if present) was collected after 7 days.

[0150] 5. Slow evaporation Approximately 40 mg of the product from Example 1 was dissolved in a solvent in a vial to produce a saturated solution. The vial opening was sealed with sealing film or aluminum foil (2-hole). The vial was kept at room temperature under a fume hood. The resulting solids (if present) were collected after 7 days.

[0151] 6. Liquid vapor diffusion Approximately 40 mg of the product from Example 1 was dissolved in a solvent to produce a saturated solution in a 4.0 mL glass vial. The vial was then placed in a 20 mL glass vial containing an antisolvent. The resulting solid was collected after 7–10 days.

[0152] 7. Solid vapor diffusion Place approximately 40 mg of the product from Example 1 into a 4.0 mL glass vial; then place this vial into a 20 mL glass vial containing solvent. Collect the solid after 7–10 days.

[0153] 8. Polymer-induced crystallization.

[0154] Approximately 40 mg of the product from Example 1 and 2.0 mg of the listed polymer were added to the solvent and stirred at room temperature. After 7 days, the solids in the slurry or the solids precipitated from the solution were collected.

[0155] The results are provided in Table 2 below.

[0156] Table 2.1 Results of screening for R HCl polymorphs.

[0157] CL = Clear liquid HCl-1 = Form 1 polymorph HCl-2 = a mixture of polymorphs of form 1 and form 2.

[0158] The data above shows that there are at least two polymorphic forms of hydrochloride salts, which will be identified as Form 1 and Form 2 below.

[0159] Various methods were employed in characterizing the polymorphs described herein, including XRPD spectra with a wide range of peaks. The peaks observed in the figures and the assignments listed herein are intended to cover variations within ±0.5°2θ. Therefore, the peaks observed in the figures include given values ​​of ±0.1°2θ, ±0.2°2θ, ±0.3°2θ, ±0.4°2θ, and ±0.5°2θ. Thus, the XRPD spectra are essentially as shown, where the peaks in the figures and / or tables herein are, for example, ±0.5°2θ or other reasonable variations as described above. The entire list of peaks, or its subgroups, is sufficient to characterize the crystalline form or its characteristics by substantially similar spectra that can be identified by those skilled in the art using characterization methods drawn within experimental variations.

[0160] Polymorphic form 1 from each of the above screening experiments was collected, and XRPDs of each were obtained. An exemplary depiction of the XRPD of the HCl form 1 polymorph is shown in [image / description]. Figure 2 middle.

[0161] Figure 2 The peaks are given in Table 3 below.

[0162] Table 3. Figure 2 XRPD peak of (HCl form 1). peak# Pos. [°2θ] strength 1 9.7047 1795.15 2 12.7540 202.56 3 13.1331 1646.90 4 14.2840 431.37 5 14.6188 724.91 6 14.9548 3391.00 7 15.7487 31.84 8 17.1221 480.83 9 18.5553 1709.97 10 19.1878 948.19 11 19.4506 135.76 12 22.3505 349.21 13 22.4833 572.29 14 22.9252 104.22 15 23.0939 23.77 16 23.7509 22.56 17 24.1561 1056.12 18 24.4244 246.14 19 25.0507 586.99 20 25.2516 346.96 21 25.6575 97.26 22 26.2784 93.69 23 26.6406 395.77 24 27.1116 38.58 25 27.3801 171.91 26 28.7633 27.37 27 29.5513 125.52 28 30.1444 109.33 29 30.5425 119.19 30 30.8515 148.52 31 31.5948 513.45 32 32.1302 92.97 33 33.0545 181.05 34 33.6721 144.37 35 33.9668 33.68 36 34.2800 133.34 37 34.6232 10.02 38 35.0265 68.60 39 35.3408 50.07 40 35.7924 15.83 41 36.2865 175.98 42 36.4691 54.14 43 36.8750 78.01 44 37.5893 54.21 45 37.9089 25.48 46 38.0351 49.17 47 38.7831 13.09

[0163] According to the data, the strongest peaks appear at 9.7, 15.0, and 18.6 ± 0.5°2θ. In the second embodiment, the strongest peaks are located at 9.7, 13.1, 15.0, and 18.6 ± 0.5°2θ. In another embodiment, the strongest peaks are located at 9.7, 13.1, 15.0, 18.6, and 24.2 ± 0.5°2θ. In yet another embodiment, the strongest peaks are located at 9.7, 13.1, 14.6, 15.0, 18.6, 19.2, 22.5, 24.2, 25.1, and 31.6 ± 0.5°2θ. In another embodiment, the peaks of form 1 are 9.7, 12.8, 13.1, 14.3, 14.6, 15.0, 15.7, 17.1, 18.6, 19.2, 19.5, 22.4, 22.5, 23.1, 23.8, 24.2, 24.4, 25.1, 25.3, 25.7, 26.3, 26.6, 27.1, 27.4, 28.8, 29.6, 30.1, 30.5, 30.9, 31.6, 32.1, 33.1, 33.7, 34.0, 34.3, 34.6, 35.0, 35.3, 35.8, 36.3, 36.5, 36.9, 37.6, 37.9, 38.0, and 38.8 ± 0.5°2θ. Form 1 crystal has at least 3 peaks described above with minor variations, such as ±0.5°2θ; in another embodiment, Form 1 crystal has at least 4 peaks described above with minor variations, such as ±0.5°2θ; in another embodiment, Form 1 crystal has at least 5 peaks described above with minor variations, such as ±0.5°2θ; in another embodiment, Form 1 crystal has at least 6 peaks described above with minor variations, such as ±0.5°2θ; in yet another embodiment, Form 1 crystal has at least 7 peaks described above with minor variations, such as ±0.5°2θ; in yet another embodiment, Form 1 crystal has at least 10 peaks described above with minor variations, such as ±0.5°2θ; in yet another embodiment, Form 1 crystal has all the peaks described above with minor variations, such as ±0.5°2θ.

[0164] The product of Example 1 was visualized using polarized light microscopy (PLM). Figure 3 The text indicates that form 1R HCl is an irregularly shaped crystalline solid. More specifically, the crystal of form 1 is orthorhombic. Figure 4 The image shows the DSC / TGA overlay for form 1R HCl. The first endothermic peak is approximately 238.0 °C, and the second peak is approximately 270.5 °C. Furthermore, as... Figure 4 As shown, when 1R HCl form 1 is heated from room temperature to 100°C, there is a 0.34% weight loss, indicating that almost no solvent is trapped and the crystals are neither hydrates nor solvates.

[0165] 1R HCl form 1 was analyzed by DVS (0-90-0-90-0% relative humidity, at 25°C). DVS behavior is shown in... Figure 5 In (a) and (b), 1 plots the first-cycle desorption, 2 plots the second-cycle adsorption, 3 plots the second-cycle desorption, 4 plots the first-cycle adsorption, 5 plots the target % P / Po, and 6 plots the dm curve, where P is the vapor pressure, Po is the saturated vapor pressure, and P / Po corresponds to the relative humidity % of water. The data show that 1R HCl form 1 significantly absorbs moisture at relative humidity above approximately 80%, but readily releases moisture at lower humidity. It was observed that after 3 days of DVS at 0% relative humidity, the sample reverted to the same crystalline form as the initial solid.

[0166] Furthermore, the form 1 polymorph can be sublimated from the solid phase to the gas phase without passing through the liquid phase. The form 1 polymorph was heated to 300°C. The substance recovered from sublimation had the same XRPD pattern as 1R HCl form 1.

[0167] Screening of polymorphs of deuterated 1RHCl salt (Form 1) in Example 2.

[0168] Similar XRPD, DSC, and DVS spectra of deuterated 1R HCl as in Example 2 can be obtained. More specifically, subjecting deuterated R hydrochloride to the polymorph screening described above yields results similar to those depicted in Table 2. The XRPD of deuterated R hydrochloride form 1 is substantially the same as that obtained from 1R HCl form 1. Deuterated R hydrochloride form 1 is an irregularly shaped crystalline solid. The DVS behavior of deuterated 1R hydrochloride form 1 is substantially the same as that of 1R HCl. When heated to 300°C, other deuterated 11R hydrochloride forms 1 can sublimate from the solid phase into the gas phase.

[0169] Screening of polymorphs of 1S HCl salt (Form 1) in Example 3.

[0170] XRPD, DSC, and DVS spectra of 1S HCl salts can be obtained. Processing 1S hydrochloride using the polymorphism screening method described above yields results similar to those shown in Table 2. The XRPD of 1S hydrochloride form 1 is essentially the same as that obtained from 1R HCl form 1. 1S hydrochloride form 1 is an irregularly shaped crystalline solid. The DVS behavior of 1S hydrochloride form 1 is essentially the same as that of 1R HCl. When heated to a maximum of 300°C, other deuterated 1R hydrochloride forms 1 can sublimate from the solid phase into the gas phase.

[0171] Screening of polymorphs of deuterated 1S HCl salt (Form 1) in Example 4.

[0172] XRPD, DSC, and DVS spectra of deuterated 1S HCl salts can be obtained. For example, subjecting deuterated 1S hydrochloride to the polymorphism screening described above yields results similar to those shown in Table 2. The XRPD of deuterated 1S hydrochloride form 1 is substantially the same as that obtained from 1R HCl form 1. Deuterated 1S hydrochloride form 1 is an irregularly shaped crystalline solid. The DVS behavior of deuterated 1S hydrochloride form 1 is substantially the same as that of 1R HCl. When heated to a maximum of 300°C, other deuterated 1S hydrochloride forms 1 can sublimate from the solid phase into the gas phase.

[0173] Example 7. Second hydrochloride polymorph.

[0174] The second crystalline form of 1R HCl, form 2, was detected according to the screening procedure described in Table 2. Form 2 of 1R HCl can be obtained at room temperature from approximately 40 mg of 1R HCl (form 1) suspended in 0.5–1.0 mL of acetonitrile or suspended in acetone / H₂O (a… w The form 2 crystal form was recovered and detected in the solid mixture (=0.3). Furthermore, it was also detected in the crystal mixture obtained by dissolving form 1 in dichloromethane in a vial to produce a saturated solution. The vial could be kept in a fume hood at room temperature for one day until a solid was obtained.

[0175] In all three cases, the resulting solids were characterized by XRPD (X-ray powder diffraction). XRPD observations revealed a second polymorph, 1R HCl form 2, as well as 1R HCl form 1. The solids obtained by these methods did not accumulate 1R HCl form 2 over time. However, under a microscope, the crystals of form 2 could be physically separated from form 1 manually by pulling the particles out with tweezers. The XRPD pattern of the mixture of 1R HCl form 1 and form 2 is shown below. Figure 6 middle.

[0176] The availability of chiral separation of single crystals allows for further analysis of Form 2 via single-crystal X-ray analysis. Figure 1 The ORTEP plots of (a) form 1 and (b) form 2 of 1RHCl are shown. Single-crystal X-ray diffraction data are shown in Table 4.

[0177] Table 4.1 Single-crystal X-ray diffraction data of R HCl in forms 1 and 2.

[0178] This data clearly distinguishes these forms. Furthermore, the simulated XRPD spectra generated from single X-ray data demonstrate extremely high fidelity compared to the measured XRPD spectra generated from samples that have undergone XRPD. The simulated XRPD spectra for form 2 are shown below. Figure 7 The peaks are shown in Table 5 below. Figure 7 middle.

[0179] Table 5. Figure 7 Simulated XRPD peaks of (HCl form 2). peak# Pos. [°2θ] strength 1 7.0220 2879.56 2 13.0329 4478.63 3 13.2095 10271.09 4 14.0707 2102.35 5 14.6311 3457.96 6 14.9976 8008.08 7 17.1967 4020.34 8 18.0047 933.85 9 18.4477 7291.67 10 18.7413 7045.31 11 19.5040 983.31 12 21.1734 2347.09 13 22.0389 3362.57 14 22.4898 2489.01 15 23.5588 1105.25 16 24.0017 9742.52 17 24.6028 373.53 18 25.2718 985.16 19 26.0510 593.05 20 26.2297 576.78 21 26.6008 1563.23 22 26.9090 4244.75 23 27.1100 3483.24 24 27.3892 1017.16 25 27.7059 416.05 26 28.3589 220.37 27 28.5878 116.92 28 29.2849 858.52 29 29.5356 665.98 30 29.9144 799.43 31 30.2603 1677.59 32 30.5677 1807.87 33 31.0569 4090.47 34 31.6426 2123.29 35 32.3508 432.41 36 33.0121 891.56 37 33.4441 821.24 38 33.6924 274.89 39 34.0599 1460.84 40 34.7962 577.93 41 35.3807 1024.53 42 35.6908 427.35 43 36.4747 616.41 44 36.9329 238.24 45 37.1642 389.76 46 37.3374 433.24 47 37.7418 337.49 48 38.0096 2734.91 49 38.5620 59.23 50 39.1832 304.65 51 39.4740 392.87 52 39.7977 149.01

[0180] According to the data, the strongest peaks appear at 13.2, 15.0, and 24.0 ± 0.5°2θ. Another group of strong peaks includes 13.2, 15.0, 18.4, 18.7, and 24.0 ± 0.5°2θ. Yet another group of strong peaks includes 13.0, 13.2, 15.0, 17.2, 18.4, 18.7, 24.0, 26.9, 27.1, and 31.1 ± 0.5°2θ. As shown in the table above, the peaks are located at 7.0, 13.0, 13.2, 14.1, 14.6, 15.0, 17.2, 18.0, 18.4, 18.7, 19.5, 21.2, 22.0, 22.5, 23.6, 24.0, 24.6, 25.3, 26.1, 26.3, 26.6, 26.9, 27.1, 27.4, 27.7, and 28.4. At 28.6, 29.3, 29.5, 29.9, 30.3, 30.6, 31.1, 31.6, 32.4, 33.0, 33.4, 33.7, 34.1, 34.8, 35.4, 35.7, 36.5, 36.9, 37.2, 37.3, 37.7, 38.0, 38.6, 39.2, 39.5 and 39.8 ± 0.5°2θ.

[0181] Second-generation 1R hydrochloride polymorph.

[0182] A second polymorph of deuterated 1R hydrochloride, namely form 2, can be detected and is expected to have the same solubility as hydrochloride form 2 described in Table 2. For example, it can be obtained at room temperature by suspending approximately 40 mg of deuterated 1R hydrochloride form 1 in 0.5 to 1.0 mL of acetonitrile or acetone / H2O (a w =0.3) was detected in the solid mixture recovered. Furthermore, the form 2 polymorph was also detected in the crystalline mixture obtained by dissolving deuterated 1R hydrochloride form 1 in dichloromethane in a vial to produce a saturated solution. The vial was kept in a fume hood at room temperature for one day until a solid was obtained.

[0183] The resulting solids were characterized by XRPD. A second polymorph of deuterated 1R hydrochloride, form 2 of deuterated 1R hydrochloride, and form 1 of 1R HCl were generated. However, under a microscope, the crystals of form 2 of deuterated 1R hydrochloride could be physically separated from form 1 by pulling the particles out with tweezers. The XRPD of the mixture of forms 1 and 2 of deuterated 1R hydrochloride was substantially the same as that of the mixture of forms 1 and 2.

[0184] The availability of chiral separation single crystals allows for further analysis of deuterated 1R hydrochloride form 2 via single-crystal X-ray analysis. ORTEP plots of deuterated 1R hydrochloride forms 1 and 2 are compared with... Figure 1 The ORTEP patterns of 1R HCl forms 1 and 2 are essentially the same. The single-crystal X-ray diffraction data for deuterated 1R hydrochloride forms 1 and 2 are substantially the same as those for 1R HCl forms 1 and 2, as shown in Table 4. Furthermore, the simulated XRPD pattern of deuterated 1R hydrochloride form 2 is essentially the same as the simulated XRPD pattern of 1R HCl form 2.

[0185] Second S hydrochloride polymorph.

[0186] The second polymorph of 1S hydrochloride, namely form 2, is expected to have the same solubility as hydrochloride form 2 described in Table 2. For example, it can be suspended from about 40 mg of 1S hydrochloride form 1 in 0.5 to 1.0 mL of acetonitrile or acetone / H2O at room temperature. w =0.3) solid mixture was detected. Furthermore, form 2 polymorph was also detected in a crystalline mixture obtained by dissolving deuterated 1R hydrochloride form 1 in dichloromethane in a vial to produce a saturated solution. The vial was kept in a fume hood at room temperature for one day until a solid was obtained.

[0187] A second polymorph of 1S HCl, namely form 2, has been discovered. For example, its solubility can be assessed at room temperature by suspending approximately 40 mg of 1S HCl form 2 in 0.5 to 1.0 mL of acetonitrile or acetone / H₂O (a w=0.3) was detected in the solid mixture recovered. Furthermore, the 1S hydrochloride form 2 polymorph was also detected in the crystalline mixture obtained by dissolving 1S HCl form 1 in dichloromethane in a vial to produce a saturated solution. The vial was kept in a fume hood at room temperature for one day until a solid was obtained.

[0188] In all cases, the resulting solids were characterized by XRPD (X-ray powder diffraction). XRPD observations revealed the formation of a second polymorph, 1S HCl form 2, as well as 1S HCl form 1. The solids obtained by these methods did not accumulate 1S HCl form 2 over time. However, under a microscope, the crystals of form 2 could be physically separated from form 1 by pulling the particles out with tweezers. The XRPD of the mixture of 1S HCl form 1 and form 2 was substantially the same as that of 1R HCl form 1 and form 2. Furthermore, the simulated XRPD pattern of 1S hydrochloride form 2 was substantially similar to that of 1R hydrochloride form 2.

[0189] Second-generation deuterium S hydrochloride polymorph The second polymorph of deuterated 1S HCl, namely form 2, can be obtained by suspending approximately 40 mg of deuterated 1S HCl form 2 in 0.5 to 1.0 mL of acetonitrile or acetone / H2O at room temperature. w =0.3) solid mixture was detected. Furthermore, the deuterated 1S hydrochloride form 2 polymorph was also detected in a crystalline mixture obtained by dissolving 1S HCl form 1 in dichloromethane in a vial to produce a saturated solution. The vial was kept in a fume hood at room temperature for one day until a solid was obtained.

[0190] In all cases, the resulting solids can be characterized by XRPD (X-ray powder diffraction). According to XRPD, the formation of a second polymorph, deuterated 1S HCl form 2, and deuterated 1S HCl form 1, can be observed. The solids obtained by these methods do not accumulate deuterated 1S HCl form 2 over time. However, under a microscope, the crystals of form 2 can be physically separated from form 1 by pulling the particles out with tweezers. The XRPD of the mixture of deuterated 1S HCl forms 1 and 2 is substantially the same as that of 1R HCl forms 1 and 2. The simulated XRPD pattern of deuterated 1S form 2 is substantially similar to that of 1R hydrochloride form 2.

[0191] Example 8. Preparation of additional salt.

[0192] (a) 1. Preparation of free base ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one and preparation of deuterated free bases (R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Using techniques known in this field, the hydrochloride salt prepared in Example 1 can be treated with alkalis, such as NaHCO3, Na2CO3, LiOH, NaOH, KOH, NH4OH, triethylamine, pyridine, etc. (usually in a solvent), to form ( R The free base of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

[0193] In the following embodiments, the free base is obtained by making ( R It is formed by the reaction of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride with sodium carbonate.

[0194] The above-prepared ( R The hydrochloride salt of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one was mixed with methyl tert-butyl ether (MTBE) in a glass beaker or other reaction vessel at room temperature. A saturated aqueous solution of sodium carbonate was added dropwise with stirring. When the pH of the mixture reached approximately 9 or higher, the addition of the saturated sodium carbonate solution was stopped. Distilled water was added to the additional MTBE, the contents of the glass beaker or reaction vessel were shaken, and then stirred for another hour. The MTBE layer was separated from the aqueous layer and collected. The MTBE was evaporated to give a solid free base (…). R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

[0195] Similarly, using techniques known in this art, when the deuterated R hydrochloride prepared in Example 2 is treated with an alkali (such as NaHCO3, Na2CO3, LiOH, NaOH, KOH, NH4OH, triethylamine, pyridine, etc., usually in a solvent), deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one (hereinafter referred to as deuterated R free base).

[0196] 2. Preparation of the free base (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one and preparation of the deuterated free base (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Using techniques well known to those skilled in the art, when the S hydrochloride prepared in Example 3 is treated with an alkali (such as NaHCO3, Na2CO3, LiOH, NaOH, KOH, NH4OH, triethylamine, pyridine, etc., usually in a solvent), S-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one (hereinafter referred to as S free alkali) will be formed.

[0197] Similarly, using techniques known in the art, when the deuterated S hydrochloride prepared in Example 4 is treated with an alkali (such as NaHCO3, Na2CO3, LiOH, NaOH, KOH, NH4OH, triethylamine, pyridine, etc., usually in a solvent), deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one (hereinafter referred to as deuterated S free base).

[0198] (b)1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate Isopropanol, ethyl acetate, and tetrahydrofuran (0.25 mL) were added separately to a solution containing 40 mg of ( R In three different glass flasks containing the free base of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, 1 mol equivalent of sulfuric acid was added, and the mixture was stirred at room temperature. After observing solid products in each flask, they were collected and dried under vacuum at room temperature. All three products were crystalline, produced the same XRPD pattern, and were designated as (…). R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-1 (sulfate-1). The stoichiometric ratio of base to acid was determined to be 1:1 by proton NMR.

[0199] Figure 8 The XRPD diffraction pattern of sulfate-1 was depicted. The peaks and intensities of the XRPD are provided in Table 6 below.

[0200] Table 6. Figure 8 XRPD peak of (sulfate-1). peak# Pos. [°2θ] strength 1 7.4790 331.22 2 10.2017 828.86 3 11.7857 29.00 4 12.1650 324.51 5 13.5778 37.48 6 13.7202 114.27 7 14.7837 271.60 8 14.9433 46.77 9 16.0334 4916.97 10 16.3952 711.81 11 17.2526 181.82 12 17.5712 974.62 13 18.4892 335.30 14 19.4215 436.90 15 19.5275 147.30 16 19.7448 212.59 17 20.6318 84.30 18 21.0391 300.55 19 21.5076 272.17 20 22.1094 119.42 21 22.4488 363.65 22 22.6134 504.19 23 22.6976 755.39 24 22.8724 100.94 25 23.0018 156.58 26 23.7568 282.92 27 24.3633 238.27 28 24.9654 120.09 29 25.5389 155.14 30 25.8598 92.83 31 26.6447 78.99 32 27.3371 68.95 33 27.7738 198.01 34 28.7141 34.83 35 28.8802 119.63 36 29.2868 92.44 37 29.7158 75.36 38 30.2166 112.26 39 30.4631 45.01 40 30.8000 91.81 41 31.1354 116.83 42 32.1500 27.23 43 32.3314 29.63 44 32.5941 56.57 45 32.8005 30.28 46 33.0382 25.47 47 33.5230 23.71 48 33.9309 62.28 49 34.3486 18.86 50 34.5296 60.66 51 38.2099 6.08 52 39.0983 12.98

[0201] As shown in the figure, in one embodiment, the sulfate-1 salt can be characterized by strong peaks in the X-ray diffraction pattern at 10.2, 16.0, and 17.6 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 10.2, 16.0, 16.4, 17.6, and 22.7 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 7.5, 10.2, 16.0, 16.4, 17.6, 18.5, 19.4, 22.4, 22.6, and 22.7 ± 0.5°2θ. In another embodiment, the salt can be obtained from 7.5, 10.2, 11.8, 12.2, 13.6, 13.7, 14.8, 14.9, 16.0, 16.4, 17.3, 17.6, 18.5, 19.4, 19.5, 19.7, 20.6, 21.0, 21.5, 22.1, 22.4, 22.6, 22.7, 22.9, 23.0, 23 The peaks at 0.8, 24.4, 25.0, 25.5, 25.9, 26.6, 27.3, 27.8, 28.7, 28.9, 29.3, 29.7, 30.2, 30.5, 30.8, 31.1, 32.2, 32.6, 32.8, 33.0, 33.5, 33.9, 34.3, 34.5, 38.2, and 39.1 ± 0.5°2θ are used to characterize the readings.

[0202] This sulfate was analyzed using DSC-TGA according to the method described above. Data are as follows: Figure 9 As shown. The weight loss at 100℃ is approximately 0.08%. Furthermore, the DSC thermal analysis of this sulfate shows two peak temperatures: a small peak at approximately 136.9℃ and a strong peak at approximately 221.3℃. Other polymorphic forms of the sulfate were found as follows.

[0203] One equivalent of free base R was placed in a vial, and approximately 1.0 mol equivalent of sulfuric acid was added to the vial. Approximately 10 volumes of ethyl acetate were then added to dissolve the reactants, and the mixture was stirred at room temperature. After the reaction was complete, the product was collected by filtration.

[0204] The XRPD in the wet filter cake was found to be different from that in sulfate-1, and this new crystalline form was named ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-2 (sulfate-2).

[0205] The XRPD diffraction pattern of wet filter cake sulfate-2 is depicted on Figure 10 The peaks and intensities of XRPD are shown in Table 7 below.

[0206] Table 7. Figure 10 XRPD peak of (sulfate-2). peak# Pos. [°2θ] strength 1 6.3837 680.48 2 6.9482 74.53 3 7.5097 200.51 4 7.8690 54.20 5 10.2270 379.03 6 10.5274 75.93 7 11.8914 48.21 8 12.1819 206.50 9 13.7108 70.68 10 16.0567 1763.62 11 16.4034 419.44 12 17.5980 842.60 13 18.5327 273.47 14 19.1938 409.45 15 19.4467 400.52 16 19.7672 190.09 17 20.6770 131.97 18 21.0767 358.09 19 21.5696 249.26 20 22.1295 118.21 21 22.4677 309.60 22 22.7159 698.27 23 22.9694 86.33 24 23.7830 306.93 25 24.0741 36.65 26 24.4073 200.12 27 25.5485 127.71 28 25.8846 76.07 29 26.7360 43.39 30 27.3535 51.98 31 27.8144 137.75 32 28.4201 54.45 33 28.8910 137.79 34 29.2673 75.09 35 29.7355 61.99 36 30.2398 76.67 37 30.5070 48.54 38 30.8281 75.70 39 31.1794 106.45 40 32.7534 27.59 41 33.9722 35.61 42 34.5470 41.49 43 38.1801 15.03

[0207] As illustrated, in one embodiment, this sulfate-2 salt can be characterized by strong peaks in an X-ray diffraction pattern at 16.1, 17.6, and 22.7 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 6.4, 16.1, 16.4, 17.6, and 22.7 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 6.4, 10.2, 16.1, 16.4, 17.6, 19.2, 19.4, 21.1, 22.5, and 22.7. In another embodiment, this salt can be characterized by peaks at 6.4, 6.9, 7.5, 10.2, 10.5, 11.9, 12.2, 13.7, 16.1, 16.4, 17.6, 18.5, 19.2, 19.4, 19.8, 20.7, 21.1, 21.6, 22.1, 22.5, 22.7, 23.0, 23.8, 24.1, 24.4, 25.5, 25.9, 26.7, 27.4, 27.8, 28.4, 28.9, 29.3, 29.7, 30.2, 30.5, 30.8, 31.2, 32.8, 34.0, 34.5, and 38.2 ± 0.5°2θ. The XRPD spectrum basically matches that of sulfate-1, but with additional peaks.

[0208] Different XRPD diffraction patterns were obtained when the wet filter cake of sulfate-2 was dried at room temperature, such as... Figure 11 As shown, this new crystalline form is designated as ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-3 (sulfate-3). The peak values ​​and intensities of XRPD are provided in Table 8 below.

[0209] Table 8. Figure 11 XRPD peak of (sulfate-3). peak# Pos. [°2θ] strength 1 7.0511 346.74 2 7.4899 272.03 3 7.7099 425.27 4 8.4937 397.40 5 10.2096 457.59 6 10.4535 177.10 7 11.8928 580.42 8 12.1831 116.78 9 13.1427 30.14 10 15.5266 112.74 11 16.0330 1383.81 12 16.4004 248.34 13 17.5788 538.76 14 17.7077 178.78 15 18.1195 144.28 16 18.4776 303.14 17 18.7374 714.27 18 19.4360 233.05 19 19.7487 77.80 20 20.0596 27.09 21 20.6677 33.14 22 21.0357 143.47 23 21.2178 184.22 24 21.5028 141.98 25 22.1231 118.43 26 22.4544 258.57 27 22.7117 428.51 28 22.9653 48.02 29 23.5141 162.68 30 23.7909 121.28 31 24.3601 101.31 32 24.8665 72.48 33 25.4786 53.34 34 26.1983 85.72 35 26.6571 174.51 36 27.4506 27.46 37 27.8375 48.96 38 28.4353 36.04 39 28.6771 35.48 40 28.9790 83.58 41 29.3087 73.39 42 29.7644 29.28 43 30.3108 42.16 44 30.7525 29.58 45 31.1530 68.64 46 32.6754 22.21 47 33.7337 24.53 48 34.5529 48.89 49 38.0110 15.69

[0210] As illustrated, in one embodiment, this sulfate-3 salt can be characterized by strong peaks in the X-ray diffraction pattern at 11.9, 16.0, and 18.7 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 10.2, 11.9, 16.0, 17.6, and 18.7 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 7.1, 7.7, 8.5, 10.2, 11.9, 16.0, 17.6, 18.5, 18.7, and 22.7 ± 0.5°2θ. In another embodiment, this salt can be obtained from 7.1, 7.5, 7.7, 8.5, 10.2, 10.5, 11.9, 12.2, 13.1, 15.5, 16.0, 16.4, 17.6, 17.7, 18.1, 18.5, 18.7, 19.4, 19.7, 20.1, 20.7, 21.0, 21.2, 21.5, 22. Peaks at 1, 22.5, 22.7, 23.0, 23.5, 23.8, 24.3, 24.9, 25.5, 26.2, 26.7, 27.5, 27.8, 28.4, 28.7, 29.0, 29.3, 29.8, 30.3, 30.8, 31.2, 32.7, 33.7, 34.6, and 38.0 ± 0.5°2θ are characterized.

[0211] When sulfate-3 crystals were further dried by heating at a set temperature of 40°C, different XRPD diffraction patterns were obtained, such as... Figure 12 As shown, and this novel crystalline form is designated as ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-4 (sulfate-4). The peak values ​​and intensities of XRPD are provided in Table 9 below.

[0212] Table 9. Figure 12 XRPD peak of (sulfate-4). peak# Pos. [°2θ] strength 1 4.5820 270.24 2 7.4799 181.11 3 7.9422 814.28 4 9.5646 55.42 5 10.2038 349.52 6 11.5897 91.81 7 12.1702 157.93 8 13.7585 78.57 9 14.7785 168.34 10 16.0333 1110.38 11 16.4037 228.15 12 16.5881 234.83 13 17.5685 436.17 14 18.4134 128.23 15 19.4277 196.38 16 19.5870 65.29 17 20.8144 102.75 18 21.0645 186.05 19 21.5143 135.19 20 21.7455 33.09 21 22.0847 23.16 22 22.4535 111.64 23 22.7206 364.86 24 22.9611 34.99 25 23.7622 152.80 26 24.3913 89.30 27 25.0074 30.52 28 25.4685 37.62 29 25.8367 24.56 30 26.3156 45.84 31 27.7878 53.47 32 28.1536 32.06 33 28.8833 70.55 34 30.2147 38.25 35 31.2000 24.97 36 32.6173 24.02 37 33.9454 20.23

[0213] As illustrated, in one embodiment, this sulfate-4 salt can be characterized by strong peaks in the X-ray diffraction pattern at 7.9, 16.0, and 17.6 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 7.9, 10.2, 16.0, 17.6, and 22.7 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 4.6, 7.9, 10.2, 16.0, 16.4, 16.6, 17.6, 19.4, 21.1, and 22.7 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 4.6, 7.5, 7.9, 9.6, 10.2, 11.6, 12.2, 13.8, 14.8, 16.0, 16.4, 16.6, 17.6, 18.4, 19.4, 19.6, 20.8, 21.1, 21.5, 21.7, 22.1, 22.5, 22.7, 23.0, 23.8, 24.4, 25.0, 25.5, 25.8, 26.3, 27.8, 28.2, 28.9, 30.2, 31.2, 32.6, and 33.9 ± 0.5°2θ.

[0214] 2. Preparation of deuterated ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate Adding 1 mol equivalent of sulfuric acid to 40 mg of deuterated R free base in an inert solvent (such as isopropanol, ethyl acetate, and tetrahydrofuran, 0.25 mL) generates deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-1 (hereinafter referred to as deuterated R sulfate-1), which has the same properties as ( R The XRPD diffraction pattern of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-1 is essentially the same as that of sulfate-1. The stoichiometric ratio of base to acid is 1:1. The DSC-TGA of deuterated R sulfate-1 is essentially the same as that of sulfate-1. Furthermore, the DVS pattern of deuterated R sulfate-1 is essentially the same as that of sulfate-1. Similarly, the deuterated ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-2 (deuterated R sulfate-2) is formed using the same procedure described above for forming sulfate-2, except that a deuterated R free base is substituted for ( R The free base was 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. The XRPD of the resulting wet filter cake had a substantially identical XRPD diffraction pattern to that of sulfate-2.

[0215] Drying the wet filter cake of deuterated R sulfate-2 at room temperature yields a new crystalline polymorph, namely deuterated ( R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-3 (deuterated R sulfate-3) exhibits essentially the same XRPD diffraction pattern as sulfate-3.

[0216] When the deuterated R sulfate-3 crystals were further dried by heating at a set temperature of 40°C, the product identified in this paper as deuterated ( R Different polymorphs of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-4 (deuterated R sulfate-4). The XRPD diffraction pattern of deuterated R sulfate-4 is essentially the same as that of sulfate-4.

[0217] 3. Preparation of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate and its deuterated analogues Adding 1 mol equivalent of sulfuric acid to 40 mg of free base in an inert solvent (such as isopropanol, ethyl acetate, and tetrahydrofuran, 0.25 mL) yields (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-1 (hereinafter referred to as S sulfate-1). Its XRPD diffraction pattern is similar to that of (…). R The base-to-acid ratio of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-1 is essentially the same as that of sulfate-1. The DSC-TGA of sulfate-1 is essentially the same as that of sulfate-1. In addition, the DVS spectrum of sulfate-1 is essentially the same as that of sulfate-1.

[0218] Similarly, adding 1 mol equivalent of sulfuric acid to 40 mg of deuterated S free base in an inert solvent (such as isopropanol, ethyl acetate, and tetrahydrofuran, totaling 0.25 mL) produces deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-1 (hereinafter referred to as deuterated S sulfate-1), which has the same properties as ( R The XRPD diffraction pattern of 1-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate is essentially the same as that of sulfate-1. The stoichiometric ratio of base to acid is 1:1. The DSC-TGA of deuterated S sulfate-1 is essentially the same as that of sulfate-1. Furthermore, the DVS pattern of deuterated S sulfate-1 is essentially the same as that of sulfate-1.

[0219] Other polymorphic forms of sulfate can be found as follows.

[0220] (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-2 (S sulfate-2) was prepared using the same procedure described above for the formation of sulfate-2, except that the S free base was replaced using (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one free base. The XRPD diffraction pattern of the resulting wet filter cake was substantially the same as that of sulfate-2.

[0221] Drying the wet filter cake of S sulfate-2 at room temperature yielded a new crystalline polymorph, (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-3 (S sulfate-3), which exhibited an XRPD diffraction pattern substantially the same as sulfate-3. Further drying of the S sulfate-3 crystals at a set temperature of 40 °C yielded a different polymorph identified herein as (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-4 (S sulfate-4). The XRPD diffraction pattern of S sulfate-4 was substantially the same as that of sulfate-4.

[0222] Similarly, deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-2 (deuterated S sulfate-2) is prepared by using the same procedure as described above for the formation of sulfate-2, except that ( R The free base of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one was substituted with a deuterated S free base. The XRPD of the resulting wet filter cake of deuterated S sulfate-2 had essentially the same XRPD diffraction pattern as that of sulfate-2.

[0223] Drying the wet filter cake of deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-2 at room temperature yields a new crystalline polymorph, namely deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-3 (deuterated S sulfate-3), which exhibits essentially the same XRPD diffraction pattern as sulfate-3.

[0224] When the deuterated S sulfate-3 crystals were further dried by heating at a set temperature of 40 °C, different polymorphs of deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-4 (deuterated S sulfate-4), which were identified in this paper, were obtained. The XRPD diffraction pattern of deuterated S sulfate-4 was essentially the same as that of sulfate-4.

[0225] (c) 1. ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate and deuterated salt Ethyl acetate and tetrahydrofuran (0.25 mL) were added separately to a container containing 40 mg ( R The free base of ethyl acetate was placed in two separate glass vials. One molar equivalent of p-toluenesulfonic acid was added to each vial, and the mixture was stirred at room temperature. Solid products were observed under their respective conditions, and each solid was collected and dried under vacuum at room temperature. The product separated from ethyl acetate was named (…). R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonyl-1 (p-toluenesulfonate-1, also referred to as p-toluenesulfonyl-1), while the product isolated from tetrahydrofuran (THF) is designated as ( R p-Toluenesulfonyl-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one (p-toluenesulfonate-2, also referred to as p-toluenesulfonyl-2). In both cases, as determined by proton nuclear magnetic resonance (NMR), the stoichiometric ratio of the base to p-toluenesulfonic acid is 1:1.

[0226] XRPD analysis of the toluenesulfonyl-1 sample revealed that its diffraction pattern differed from that of toluenesulfonyl-2. The toluenesulfonyl-1 salt is crystalline. Figure 13 The XRPD diffraction pattern of toluenesulfonyl-1 was depicted. Table 10 below provides the peaks and intensities of the XRPD for toluenesulfonyl-1.

[0227] Table 10. Figure 13 XRPD peak of (p-toluenesulfonyl-1). 1 2.0946 203.60 2 5.9166 109.45 3 6.6266 3356.40 4 10.5845 3310.39 5 12.0444 121.09 6 13.2577 2388.99 7 14.6313 1218.52 8 16.6748 106.61 9 17.3993 237.55 10 17.7858 76.99 11 19.4936 2438.57 12 19.9329 730.40 13 20.1571 890.43 14 20.4393 404.23 15 21.2691 131.48 16 21.9439 222.23 17 22.3835 895.69 18 22.5731 833.82 19 23.7555 132.07 20 24.5947 225.10 21 25.4698 145.34 22 26.2142 994.72 23 26.3131 890.16 24 26.6880 888.60 25 28.1748 84.01 26 28.5466 101.75 27 28.9288 -479.99 28 30.3858 323.63 29 31.0175 29.93 30 31.8172 56.50 31 32.3543 48.34 32 32.8867 104.97 33 33.3568 262.34 34 33.5423 385.90 35 35.0579 33.83 36 36.5213 108.03 37 38.0102 41.21 38 39.4847 39.57

[0228] As shown in the figure, in one embodiment, the p-toluenesulfonyl-1 salt can be characterized by strong peaks in the X-ray diffraction patterns at 6.6, 10.6, and 19.5 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.6, 10.6, 13.3, 14.6, and 19.5 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 6.6, 10.6, 13.3, 14.6, 19.5, 20.2, 22.4, 26.2, 26.3, and 26.7 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 2.1, 5.9, 6.6, 10.6, 12.0, 13.3, 14.6, 16.7, 17.4, 17.8, 19.5, 19.9, 20.2, 20.4, 21.3, 21.9, 22.4, 22.6, 23.8, 24.6, 25.5, 26.2, 26.3, 26.7, 28.2, 28.5, 28.9, 30.4, 31.0, 31.8, 32.4, 32.9, 33.4, 33.5, 35.1, 36.5, 38.0, and 39.5 ± 0.5°2θ.

[0229] p-Toluenesulfonyl-1 was analyzed using DSC-TGA according to the method described above. Data were plotted on... Figure 14 The DSC thermal analysis of this p-toluenesulfonyl-1 salt shows two temperature peaks: a strong peak at approximately 158.9 °C and a smaller peak at approximately 172.3 °C.

[0230] p-Toluenesulfonate-2 was also analyzed by XRPD. p-Toluenesulfonate-2 exhibited different XRPD diffraction patterns in its wet crystalline state compared to its dry filter cake state. The diffraction pattern corresponding to the wet crystals of p-toluenesulfonate-2 is named p-toluenesulfonate-2A, and the diffraction pattern corresponding to the dry crystals is named p-toluenesulfonate-2B. Figure 15 XRPD diffraction patterns of p-toluenesulfonate-2A were depicted. The XRPD peaks and intensities of p-toluenesulfonate-2A are provided in Table 11 below.

[0231] Table 11. Figure 15 XRPD peak of (toluenesulfonyl-2A). peak# Pos. [°2θ] strength 1 5.3752 2478.49 2 6.6275 65.55 3 10.6754 1125.93 4 10.7672 1267.72 5 13.2970 645.47 6 14.6933 987.85 7 16.1413 1034.17 8 16.2000 895.49 9 16.8613 349.17 10 17.1719 175.62 11 19.0644 1069.94 12 19.7012 1889.68 13 19.9607 171.54 14 20.1589 242.70 15 20.8681 1934.33 16 21.5706 1762.95 17 21.6381 1897.64 18 22.5281 90.11 19 22.9033 110.03 20 23.1709 495.09 21 23.3571 546.52 22 23.7044 577.73 23 23.8929 159.13 24 24.0519 248.10 25 24.6488 31.40 26 25.4710 472.20 27 25.7865 123.38 28 26.2837 284.29 29 26.6969 743.23 30 26.7946 596.25 31 27.0530 423.96 32 27.1334 491.01 33 28.2031 36.70 34 28.6418 412.73 35 28.9894 302.55 36 29.8007 57.54 37 30.4933 65.29 38 30.9180 15.31 39 31.5061 125.39 40 32.1803 45.59 41 32.6700 25.73 42 33.1749 106.06 43 33.5120 267.27 44 34.0863 485.61 45 34.1785 489.04 46 34.6128 90.89 47 35.6275 52.15 48 36.2550 33.94 49 36.6607 31.40 50 37.2848 41.24 51 37.7234 27.81 52 38.0742 44.66 53 38.2330 213.24 54 38.3301 239.49 55 38.6720 119.77 56 39.3904 127.58

[0232] As illustrated, in one embodiment, this p-toluenesulfonyl-2A salt can be characterized by strong peaks in an X-ray diffraction pattern at 5.4, 20.9, and 21.6 (21.64) ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 5.4, 19.7, 20.9, 21.6 (21.57), and 21.6 (21.63) ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 5.4, 10.7, 10.8, 14.7, 16.1, 19.1, 19.7, 20.9, 21.6 (21.57), and 21.6 (21.63) ± 0.5°2θ. In another embodiment, this salt can be obtained from 5.4, 6.6, 10.7, 10.8, 13.3, 14.7, 16.1, 16.2, 16.9, 17.2, 19.1, 19.7, 20.0, 20.2, 20.9, 21.6(21.57), 21.6(21.63), 22.5, 23.2, 23.4, 23.7, 23.9, 24.1, 24.6, 25.5, 25.8, 26.3, 26 Peaks at 0.7, 26.8, 27.1 (27.05), 27.1 (27.13), 28.2, 28.6, 29.0, 29.8, 30.5, 30.9, 31.5, 32.2, 32.7, 33.2, 33.5, 34.1, 34.2, 34.6, 35.6, 36.3, 36.7, 37.3, 37.7, 38.1, 38.2, 38.3, 38.7 and 39.4 ± 0.5°2θ are characterized.

[0233] Figure 16 The XRPD diffraction pattern of toluenesulfonyl-2B was depicted. The XRPD peaks and intensities of toluenesulfonyl-2B are provided in Table 12 below.

[0234] Table 12. Figure 16 XRPD peak of (toluenesulfonyl-2B). peak# Pos. [°2θ] strength 1 5.3752 2478.49 2 6.6275 65.55 3 10.6754 1125.93 4 10.7672 1267.72 5 13.2970 645.47 6 14.6933 987.85 7 16.1413 1034.17 8 16.2000 895.49 9 16.8613 349.17 10 17.1719 175.62 11 19.0644 1069.94 12 19.7012 1889.68 13 19.9607 171.54 14 20.1589 242.70 15 20.8681 1934.33 16 21.5706 1762.95 17 21.6381 1897.64 18 22.5281 90.11 19 22.9033 110.03 20 23.1709 495.09 21 23.3571 546.52 22 23.7044 577.73 23 23.8929 159.13 24 24.0519 248.10 25 24.6488 31.40 26 25.4710 472.20 27 25.7865 123.38 28 26.2837 284.29 29 26.6969 743.23 30 26.7946 596.25 31 27.0530 423.96 32 27.1334 491.01 33 28.2031 36.70 34 28.6418 412.73 35 28.9894 302.55 36 29.8007 57.54 37 30.4933 65.29 38 30.9180 15.31 39 31.5061 125.39 40 32.1803 45.59 41 32.6700 25.73 42 33.1749 106.06 43 33.5120 267.27 44 34.0863 485.61 45 34.1785 489.04 46 34.6128 90.89 47 35.6275 52.15 48 36.2550 33.94 49 36.6607 31.40 50 37.2848 41.24 51 37.7234 27.81 52 38.0742 44.66 53 38.2330 213.24 54 38.3301 239.49 55 38.6720 119.77 56 39.3904 127.58

[0235] As illustrated, in one embodiment, this tosylate-2B salt can be characterized by peaks in an X-ray diffraction pattern at 5.4, 19.6, and 21.6 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 5.4, 10.7, 16.1, 19.6, and 21.6 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 5.4, 6.0, 10.5, 10.7, 13.2, 14.7, 16.1, 19.0, 19.3, 19.6, 20.1, 20.8, 21.6, 23.2, 23.4, 24.0, 26.7, 26.8, 27.1, 34.1, and 38.2 ± 0.5°2θ.

[0236] Toluenesulfonyl-2B was analyzed using DSC-TGA, employing the methods described above. Data were plotted on... Figure 17 The DSC thermal analysis of this toluenesulfonyl-2B shows three peak temperatures: a strong peak at approximately 168.7 °C, a small broad peak at approximately 70.7 °C, and a moderate intensity peak at approximately 117.3 °C.

[0237] In the above reaction with p-toluenesulfonic acid, a deuterated R free base was used to replace ( R The free base of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one produced two crystalline salts: deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate-1 (also designated as deuterated R-toluenesulfonyl-1) and ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate-2 (also designated as deuterated R-toluenesulfonyl-2). In both cases, the stoichiometric ratio of base to p-toluenesulfonic acid is 1:1. Furthermore, as described above regarding toluenesulfonyl-2, deuterated R-toluenesulfonyl-2 exhibits a different XRPD diffraction pattern in its wet crystalline state compared to its dry filter cake state. The diffraction pattern corresponding to the wet crystalline state of deuterated R-toluenesulfonyl-2 is designated as deuterated R-toluenesulfonyl-2A (deuterated R-p-toluenesulfonate-2A), while the diffraction pattern corresponding to the dry crystalline state is designated as deuterated R-toluenesulfonyl-2B (deuterated R-p-toluenesulfonate-2B). The XRPD and DSC thermal analysis patterns of deuterated R-toluenesulfonyl-1 are substantially the same as those of toluenesulfonyl-1. In addition, the DVS spectrum of deuterated R tosyl-1 is basically the same as that of tosyl-1.

[0238] The XRPD of deuterated R tosylate-2A is essentially the same as that of tosylate-2A, and the XRPD and DSC-TGA of deuterated R tosylate-2B are essentially the same as those of tosylate-2B, respectively. The DVS spectrum of deuterated R tosylate-2B is essentially the same as that of tosylate-2A.

[0239] 2. Preparation of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate and deuterated salt In the above reaction with p-toluenesulfonic acid, S free base is used to replace ( RUpon removal of the free base, (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one yielded two crystalline salts: (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate-1 (also designated as S-toluenesulfonyl-1) and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate-2 (also designated as S-toluenesulfonyl-2). In both cases, the stoichiometric ratio of base to p-toluenesulfonic acid was 1:1. Furthermore, as described above regarding toluenesulfonyl-2, S-toluenesulfonyl-2 exhibited a different XRPD diffraction pattern in its wet crystalline state compared to its dry filter cake state. The diffraction pattern corresponding to the wet crystals of deuterated S-toluenesulfonyl-2 is named S-toluenesulfonyl-2A (S-p-toluenesulfonate-2A), while the diffraction pattern corresponding to the dry crystals is named S-toluenesulfonyl-2B (S-p-toluenesulfonate-2B). The XRPD and DSC thermal analysis patterns of S-toluenesulfonyl-1 are essentially the same as those of toluenesulfonyl-1. The DVS pattern of S-toluenesulfonyl-1 is substantially identical to that of toluenesulfonyl-1.

[0240] The XRPD of S-toluenesulfonyl-2A is essentially the same as that of toluenesulfonyl-2A, and the XRPD and DSC-TGA of S-toluenesulfonyl-2B are essentially the same as those of toluenesulfonyl-2B, respectively. The DVS spectrum of S-toluenesulfonyl-2B is essentially the same as that of toluenesulfonyl-2B.

[0241] In the above reaction with p-toluenesulfonic acid, a deuterated S free base was used to replace ( RThe free base of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one yielded two crystalline salts: deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate-1 (also designated as deuterated S-toluenesulfonyl-1) and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate-2 (also designated as deuterated S-toluenesulfonyl-2). In both cases, the stoichiometric ratio of base to p-toluenesulfonic acid was 1:1. Furthermore, as described above regarding toluenesulfonyl-2, deuterated S-toluenesulfonyl-2 exhibited an XRPD diffraction pattern in its wet crystalline state that differed from that in its dried filter cake state. The wet crystal form of deuterated S-toluenesulfonyl-2 is designated as deuterated S-toluenesulfonyl-2A (deuterated S-p-toluenesulfonate-2A), and the diffraction pattern of the dry crystal is designated as deuterated R-toluenesulfonyl-2B (deuterated R-p-toluenesulfonate-2B). The XRPD and DSC thermal analysis patterns of deuterated S-toluenesulfonyl-1 are essentially the same as those of toluenesulfonyl-1. The DVS pattern of deuterated S-toluenesulfonyl-1 is essentially the same as that of toluenesulfonyl-1.

[0242] The XRPD of deuterated S-tosylate-2A is essentially the same as that of tosylate-2A, and the XRPD and DSC-TGA of deuterated S-tosylate-2B are essentially the same as those of tosylate-2B, respectively. The DVS spectrum of deuterated S-tosylate-2B is essentially the same as that of tosylate-2B.

[0243] (d) 1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one methanesulfonate and deuterated R analogues Add isopropanol, tetrahydrofuran, and a 9:1 v / v mixture of acetone / water (0.25 mL each solvent) to a solution containing 40 mg of free base. R The methanesulfonic acid was added to three separate glass vials containing 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. An equivalent of methanesulfonic acid was added to each vial, and the contents were stirred at room temperature. Solid products were observed and collected in each vial, and then dried under vacuum at room temperature. The products separated from each solvent were crystals and exhibited the same diffraction pattern on XRPD analysis. In all three cases, as determined by proton NMR, the stoichiometric ratio of methanesulfonic acid to base was 1:1.

[0244] The XRPD diffraction patterns of the three salts are identical, and an exemplary diffraction pattern of one of the samples is depicted on... Figure 18 In this paper, methane sulfonate is named ( RMSA-1 (MSA-1) is a 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. The XRPD peaks and intensities of MSA-1 are provided in Table 13 below.

[0245] Table 13. Figure 18 XRPD peak of (MSA-1). peak# Pos. [°2θ] strength 1 10.1169 2374.71 2 10.9235 564.57 3 11.8151 80.68 4 12.8166 370.89 5 13.4441 1507.95 6 15.0248 712.53 7 15.6709 3037.66 8 16.9353 5044.13 9 17.4458 864.04 10 17.7179 206.00 11 18.0199 62.25 12 18.8497 869.15 13 19.1233 391.01 14 20.4287 1126.51 15 20.8011 736.28 16 21.2100 413.26 17 22.1512 1535.32 18 22.3858 151.48 19 22.6324 2238.04 20 22.7026 926.27 21 23.2912 791.65 22 24.4534 528.23 23 24.5942 708.87 24 24.9046 647.73 25 25.2222 358.89 26 25.7485 286.99 27 26.0453 159.74 28 26.4687 861.60 29 26.9450 363.87 30 27.2675 122.70 31 27.4732 191.07 32 28.4001 205.30 33 28.6138 30.08 34 29.6406 420.10 35 30.2762 264.59 36 30.6101 34.47 37 30.7612 279.11 38 31.0901 104.75 39 31.5990 90.54 40 31.7777 245.98 41 32.2823 87.48 42 32.3925 109.80 43 33.5295 104.20 44 34.5338 46.09 45 35.1949 190.49 46 35.4195 161.86 47 35.8829 29.80 48 36.3435 84.09 49 37.3129 39.81 50 38.2855 15.15 51 39.8988 63.46

[0246] As shown in the figure, in one embodiment, the MSA-1 salt can be characterized by strong peaks in the X-ray diffraction pattern at 10.1, 15.7, and 16.9 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 10.1, 15.7, 16.9, 22.2, and 22.6 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 10.1, 13.4, 15.7, 16.9, 17.4, 18.8, 20.4, 22.2, 22.6, and 22.7 ± 0.5°2θ. In another embodiment, the salt can be obtained from 10.1, 10.9, 11.8, 12.8, 13.4, 15.0, 15.7, 16.9, 17.4, 17.7, 18.0, 18.8, 19.1, 20.4, 20.8, 21.2, 22.2, 22.4, 22.6, 22.7, 23.3, 24.5, 24.6, 24.9, 25.2, 2 The peaks at 5.7, 26.0, 26.5, 26.9, 27.3, 27.5, 28.4, 28.6, 29.6, 30.3, 30.6, 30.8, 31.1, 31.6, 31.8, 32.3, 32.4, 33.5, 34.5, 35.2, 35.4, 35.9, 36.3, 37.3, 38.3, and 39.9 ± 0.5°2θ are used to characterize the values.

[0247] Methane sulfonate was analyzed using DSC-TGA according to the method described above. Data are plotted on... Figure 19 The weight loss at 100°C is approximately 0.01%. Furthermore, the DSC thermal analysis of methane sulfonate shows a strong peak temperature at approximately 228.3°C.

[0248] Deuterium ( R The preparation method of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one methanesulfonate (deuterated R MSA-1) is as described above regarding MSA-1, except that a deuterated R free base is used instead of a free base. R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. The X-ray powder diffraction (XRPD) and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) spectra of deuterated R MSA-1 were essentially the same as those of MSA-1. Furthermore, the dynamic water vapor adsorption (DVS) pattern of deuterated R MSA-1 was essentially the same as that of MSA-1. The stoichiometric ratio of methanesulfonic acid to base was 1:1.

[0249] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one methanesulfonate and deuterated S analogues The preparation method of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one methanesulfonate (SMSA-1) is as described above for MSA-1, except that the free base R is replaced by the free base S. The X-ray powder diffraction (XRPD) and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) results of SMSA-1 are essentially the same as those of MSA-1. Furthermore, the dynamic moisture adsorption (DVS) curve of SMSA-1 is essentially the same as that of MSA-1. The stoichiometric ratio of methanesulfonic acid to base is 1:1.

[0250] The preparation method of deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one methanesulfonate (deuterated S MSA-1) is as described above for MSA-1, except that the free base (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one is replaced by S-deuteration. The X-ray powder diffraction (XRPD) and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) results of deuterated S MSA-1 are essentially the same as those of MSA-1. Furthermore, the dynamic hydrolysis pattern (DVS) of deuterated S MSA-1 is essentially the same as that of MSA-1. The stoichiometric ratio of methanesulfonic acid to base is 1:1.

[0251] (e) 1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one maleate and deuterated analogues Isopropanol, acetonitrile, ethyl acetate, tetrahydrofuran, and a 9:1 v / v mixture of acetone / water (0.25 mL each solvent) were added separately to a mixture containing approximately 40 mg of free base. RFive different glass vials were prepared for the reaction of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. One molar equivalent of maleic acid was added to each vial, and the mixture was stirred at room temperature. Solid products were observed and collected in their respective vials, and then dried under vacuum at room temperature. All products separated from the solvent were crystalline. XRPD analysis revealed two distinct polymorphs; one polymorph, obtained from a mixture of acetonitrile and acetone / water, was identified as (…). R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Mal-1 (maleate-1, also referred to as Mal-1), another polymorph obtained from isopropanol, ethyl acetate and tetrahydrofuran, designated as ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Mal-2 (maleate-2, also referred to as Mal-2). In all cases, as determined by proton NMR, the stoichiometric ratio of the free base to maleic acid is 1:1.

[0252] Mal-1 salt was obtained by XRPD analysis. Figure 20 The XRPD diffraction pattern of Mal-1 was depicted. The XRPD peaks and intensities of the Mal-1 salt are provided in Table 14 below.

[0253] Table 14. Figure 20 XRPD peak of (Mal-1). peak# Pos. [°2θ] strength 1 13.2432 420.32 2 14.3468 3280.48 3 14.9635 79.38 4 15.2352 56.35 5 16.1738 5527.95 6 16.9774 327.00 7 17.5099 232.91 8 18.5575 816.93 9 19.3647 3422.91 10 20.5284 937.16 11 21.4095 598.99 12 21.8730 68.09 13 23.7842 1369.25 14 24.5984 5687.74 15 24.6734 2251.41 16 25.4947 229.49 17 25.7065 431.43 18 26.2574 302.14 19 26.6534 209.26 20 27.3344 351.79 21 28.0112 35.58 22 29.2244 444.57 23 29.3093 164.44 24 30.6864 33.98 25 31.5733 109.81 26 31.8199 1155.78 27 31.9098 474.32 28 32.1809 131.15 29 32.6741 75.43 30 33.1449 87.37 31 33.5895 128.44 32 34.4816 155.99 33 34.5857 98.67 34 34.8459 49.64 35 35.7106 16.47 36 36.0025 67.75 37 36.8268 27.08 38 37.2722 402.52 39 37.3713 188.89 40 38.5350 106.58 41 39.3409 30.08

[0254] As illustrated, in one embodiment, this Mal-1 salt can be characterized by strong peaks in the X-ray diffraction pattern at 14.3, 16.2, 19.4, and 24.6 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 14.3, 16.2, 19.4, 24.6, and 24.7 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 14.3, 16.2, 18.6, 19.4, 20.5, 21.4, 23.8, 24.6, 24.7, and 31.8 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 13.2, 14.3, 15.0, 15.2, 16.2, 17.0, 17.5, 18.6, 19.4, 20.5, 21.4, 21.9, 23.8, 24.6, 24.7, 25.5, 25.7, 26.3, 26.7, 27.3, 28.0, 29.2, 29.3, 30.7, 31.6, 31.8, 31.9, 32.2, 32.7, 33.1, 33.6, 34.5, 34.6, 34.8, 35.7, 36.0, 36.8, 37.3, 37.4, 38.5, and 39.3 ± 0.5°2θ.

[0255] Mal-1 salt was analyzed using DSC-TGA according to the method described above. Data are as follows: Figure 21 As shown, the weight loss at 100°C is approximately 0.16%. Additionally, the DSC thermal analysis of Mal-1 shows a strong peak temperature at approximately 202.0°C.

[0256] Mal-2 salt was also obtained by XRPD analysis. Figure 22 The XRPD diffraction pattern of Mal-2 was depicted. The XRPD peaks and intensities of the Mal-2 salt are provided in Table 15 below.

[0257] Table 15. Figure 22 XRPD peak of (Mal-2). peak# Pos. [°2θ] strength 1 9.2553 461.76 2 11.2370 403.14 3 13.2518 1272.25 4 13.5199 259.72 5 14.7128 927.24 6 14.9777 61.96 7 15.9593 1385.67 8 16.5301 248.15 9 17.9537 843.52 10 18.5771 757.13 11 18.7771 4321.64 12 19.1752 1059.71 13 20.4794 572.16 14 21.0517 464.67 15 21.9470 24.63 16 22.6082 727.67 17 23.2218 162.52 18 24.1143 567.37 19 24.4172 445.74 20 24.8589 518.43 21 25.2863 151.91 22 25.4717 419.34 23 26.7062 130.71 24 26.8939 123.75 25 27.0379 333.24 26 27.2302 450.65 27 28.0588 25.50 28 28.5249 89.73 29 29.3433 29.70 30 29.7942 69.58 31 29.9468 422.03 32 30.2728 68.11 33 30.6787 50.73 34 31.2574 219.14 35 31.5087 132.78 36 31.8671 241.68 37 32.1497 61.29 38 32.3687 69.05 39 33.2868 45.66 40 33.7755 30.81 41 33.9684 112.29 42 34.6040 36.98 43 34.9845 184.90 44 35.3425 27.11 45 35.5566 14.53 46 36.0466 53.03 47 36.7232 19.44 48 37.3013 98.14 49 37.6777 135.03 50 38.1361 34.80

[0258] As shown in the figure, in one embodiment, the Mal-2 salt can be characterized by strong peaks in the X-ray diffraction pattern at 13.3, 16.0, and 18.8 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 13.3, 14.7, 16.0, 18.8, and 19.2 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 13.3, 14.7, 16.0, 18.0, 18.6, 18.8, 19.2, 20.5, 22.6, and 24.1 ± 0.5°2θ. In another embodiment, the salt can be expressed in the following quantities: 9.3, 11.2, 13.3, 13.5, 14.7, 15.0, 16.0, 16.5, 18.0, 18.6, 18.8, 19.2, 20.5, 21.1, 21.9, 22.6, 23.2, 24.1, 24.4, 24.9, 25.3, 25.5, 26.7, 26.9, 27.0. The peaks at 27.2, 28.1, 28.5, 29.3, 29.8, 29.9, 30.3, 30.7, 31.3, 31.5, 31.9, 32.1, 32.4, 33.3, 33.8, 34.0, 34.6, 35.0, 35.3, 35.6, 36.0, 36.7, 37.3, 37.7, and 38.1 ± 0.5°2θ are used to characterize the readings.

[0259] Mal-2 salts were analyzed using DSC-TGA according to the method described above. Data plotted on... Figure 23 The weight loss at 100°C is approximately 0.11%. Additionally, the DSC thermal analysis of Mal-2 shows a strong peak temperature at approximately 198.2°C.

[0260] In the above reaction with maleic acid, a deuterated R free base was used to replace ( R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, yielding two crystalline polymorphs: deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Mal-1 (deuterated R maleate-1, also referred to herein as deuterated RMald-1) and deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Mal-2 (deuterated R maleate-2, also referred to herein as deuterated RMalt-2). In both cases, the stoichiometric ratio of free base to maleic acid is 1:1. The X-ray powder diffraction (XRPD) and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) spectra of deuterated RMalt-1 are substantially identical to those of Mal-1. Furthermore, the dynamic water vapor adsorption (DVS) pattern of deuterated RMalt-1 is substantially identical to that of Mal-1. Similarly, the XRPD and DSC-TGA spectra of deuterated RMalt-2 are substantially identical to those of Mal-2, respectively. In addition, the DVS pattern of deuterated RMalt-2 is substantially identical to that of Mal-2.

[0261] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one maleate and deuterated analogues In the reaction with maleic acid described above, S free base is used to replace ( R Two crystalline polymorphs were produced from (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one: deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Mal-1 ((S)-maleate-1, also referred to herein as S Mal-1) and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Mal-2 ((S)-maleate-2, also referred to herein as S Mal-2). In both cases, the stoichiometric ratio of free base to maleic acid was 1:1. The XRPD and DSC-TGA of S Mal-1 were substantially identical to those of Mal-1, respectively. Furthermore, the DVS spectrum of S Mal-1 was substantially identical to that of Mal-1. Similarly, the XRPD and DSC-TGA of S Mal-2 were substantially identical to those of Mal-2. In addition, the DVS spectrum of S Mal-2 is basically the same as that of Mal-2.

[0262] In the above reaction with maleic acid, a deuterated S free base was used to replace ( RThe reaction of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one yielded two crystalline polymorphs: deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Mal-1 (deuterated S-maleate-1, also referred to herein as deuterated SMal-1) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Mal-2 (deuterated S-maleate-2, also referred to herein as deuterated SMal-2). In both cases, the stoichiometric ratio of free base to maleic acid was 1:1. The XRPD and DSC-TGA spectra of deuterated SMal-1 were substantially identical to those of Mal-1. Furthermore, the DVS spectrum of deuterated SMal-1 was substantially identical to that of Mal-1. Similarly, the XRPD and DSC-TGA of deuterated SMal-2 are essentially the same as those of Mal-2. Furthermore, the DVS spectrum of deuterated SMal-2 is essentially the same as that of Mal-2.

[0263] (f) 1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate and deuterated analogues Isopropanol, acetonitrile, ethyl acetate, tetrahydrofuran, and a 9:1 v / v mixture of acetone / water (0.25 mL each solvent) were added to a solution containing approximately 40 mg of free base. R Five different glass vials containing 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one were prepared. One molar equivalent of 85% by weight phosphoric acid was added to each vial, and the contents were stirred at room temperature. Solid products were observed in each vial, and the solids were collected and then dried under vacuum at room temperature. The products separated from the solvent were crystals. XRPD analysis showed that two different polymorphs were collected; one polymorph was obtained from a mixture of isopropanol, tetrahydrofuran, and acetone / water, and identified as (…). R Phos-1 (phosphate-1, also referred to as Phos-1); another polymorph was obtained from acetonitrile and ethyl acetate, designated as ( R Phos-2 (also referred to as Phos-2), 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. The stoichiometric ratio of the base to phosphoric acid cannot be determined by proton NMR.

[0264] Phos-1 salt obtained by XRPD analysis. Figure 24 The XRPD diffraction pattern of Phos-1 was depicted. The XRPD peaks and intensities of the Phos-1 salt are provided in Table 16 below.

[0265] Table 16. Figure 24XRPD peak of (Phos-1). peak# Pos. [°2θ] strength 1 6.6386 4442.59 2 11.5482 84.45 3 13.4059 654.93 4 14.7275 239.08 5 15.1082 813.72 6 15.5807 357.08 7 17.2142 234.76 8 18.1353 258.84 9 19.0884 818.14 10 19.9530 87.21 11 20.7760 258.26 12 21.0277 2441.43 13 21.4589 85.79 14 22.7954 402.10 15 23.1959 486.71 16 24.1312 999.05 17 24.3218 149.20 18 25.2499 299.86 19 26.7778 347.60 20 26.9501 758.73 21 27.7621 360.05 22 28.4898 96.39 23 29.3072 74.20 24 29.7067 72.73 25 30.0759 90.56 26 31.4393 103.57 27 31.6326 40.81 28 32.1181 47.37 29 32.7531 62.83 30 32.9968 63.61 31 33.5429 191.26 32 33.9549 31.31 33 34.5658 91.37 34 35.9617 59.11 35 36.6269 59.53 36 36.9259 116.94 37 38.6750 32.79 38 39.0339 59.97 39 39.6387 143.88

[0266] As shown in the figure, in one embodiment, the Phos-1 salt can be characterized by peaks in the X-ray diffraction pattern at 6.6, 19.1, 21.0, and 24.1 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.6, 15.1, 19.1, 21.0, and 24.1 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 6.6, 13.4, 15.1, 19.1, 21.0, 22.8, 23.2, 24.1, 27.0, and 27.8 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.6, 11.5, 13.4, 14.7, 15.1, 15.6, 17.2, 18.1, 19.1, 20.0, 20.8, 21.0, 21.5, 22.8, 23.2, 24.1, 24.3, 25.2, 26.8, 27.0, 27.8, 28.5, 29.3, 29.7, 30.1, 31.4, 31.6, 32.1, 32.8, 33.0, 33.5, 34.0, 34.6, 36.0, 36.6, 36.9, 38.7, 39.0, and 39.6 ± 0.5°2θ.

[0267] Phos-1 salts were analyzed using DSC-TGA according to the method described above. Data are presented in... Figure 25 The weight loss at 100°C is approximately 0.11%. Furthermore, the DSC thermal analysis of Phos-1 shows a strong peak temperature at approximately 236.0°C.

[0268] Phos-2 salt obtained by XRPD analysis. Figure 26 The XRPD diffraction pattern of Phos-2 was depicted. The XRPD peaks and intensities of the Phos-2 salt are provided in Table 17 below.

[0269] Table 17. Figure 26 XRPD peak of (Phos-2). peak# Pos. [°2θ] strength 1 3.5187 92.94 2 6.6209 22232.20 3 7.0879 338.85 4 13.3764 441.45 5 14.7087 107.25 6 15.0942 288.93 7 15.5558 258.22 8 17.1973 86.73 9 18.1044 119.76 10 19.0564 291.86 11 19.9230 273.00 12 21.0023 2255.89 13 22.7472 216.14 14 23.1739 219.25 15 24.1072 1012.72 16 25.2430 79.85 17 26.6723 352.86 18 26.7486 299.25 19 26.9246 318.84 20 27.0934 168.28 21 27.7341 189.27 22 28.3871 35.58 23 29.2432 19.19 24 29.6744 21.06 25 30.0561 41.57 26 30.3712 31.38 27 31.4294 51.65 28 31.6452 15.52 29 33.5128 598.48 30 34.5961 22.83 31 35.9402 21.94 32 36.9090 87.29 33 39.6273 56.03

[0270] As shown in the figure, in one embodiment, the Phos-2 salt can be characterized by peaks in the X-ray diffraction pattern at 6.6, 21.0, 24.1, and 33.5 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.6, 13.4, 21.0, 24.1, and 33.5 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 6.6, 7.1, 13.4, 19.1, 21.0, 24.1, 26.7 (26.67), 26.7 (26.75), 26.9, and 33.5 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 3.5, 6.6, 7.1, 13.4, 14.7, 15.1, 15.6, 17.2, 18.1, 19.1, 19.9, 21.0, 22.7, 23.2, 24.1, 25.2, 26.7 (26.67), 26.7 (26.75), 26.9, 27.1, 27.7, 28.4, 29.2, 29.7, 30.1, 30.4, 31.4, 31.6, 33.5, 34.6, 35.9, 36.9, and 39.6 ± 0.5°2θ.

[0271] Phos-2 salts were analyzed using DSC-TGA according to the method described above. Data are as follows: Figure 27 As shown, the weight loss at 100°C is approximately 0.90%. Furthermore, the DSC thermal analysis of Phos-2 shows a broad peak temperature at approximately 224.6°C.

[0272] In the various reactions with 85% phosphoric acid described above, the free base was replaced by a deuterated R free base ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, yielding two polymorphic salts: deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate-1 (deuterated R phosphate-1, also identified as deuterated R Phos-1) and deuterated ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate-2 (deuterated R phosphate-2, also identified as deuterated RPos-2). The XRPD diffraction pattern and DSC-TGA of deuterated R Phos-1 are essentially the same as those of Phos-1. Furthermore, the DVS pattern of deuterated R Phos-1 is essentially the same as that of Phos-1. The XRPD diffraction pattern and DSC-TGA of deuterated R Phos-2 are essentially the same as those of Phos-2. Additionally, the DVS pattern of deuterated R Phos-2 is essentially the same as that of Phos-2.

[0273] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate and deuterated analogues In the various reactions described above with 85% phosphoric acid, S free base was used to replace the free base ( R (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one yielded two polycrystalline salts: (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate-1 (S phosphate-1, also known as S Phos-1) and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate-2 (S phosphate-2, also known as S Phos-2). The XRPD diffraction pattern and DSC-TGA of S Phos-1 are essentially the same as those of Phos-1. The DVS pattern of S Phos-1 is also essentially the same as that of Phos-1. The XRPD diffraction pattern and DSC-TGA of S Phos-2 are also essentially the same as those of Phos-2. Furthermore, the DVS spectrum of S Phos-2 is essentially the same as that of Phos-2.

[0274] In the various reactions described above with 85% phosphoric acid, the free base was replaced by a deuterated S free base ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one yielded two crystalline polymorphic salts: deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate-1 (deuterated S phosphate-1, also identified as deuterated S Phos-1) and deuterated ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate-2 (deuterated S phosphate-2, also identified as deuterated S Phos-2). The XRPD and DSC-TGA patterns of deuterated S Phos-1 are essentially the same as those of Phos-1. The DSC thermal analysis of deuterated S Phos-1 shows a strong peak temperature at approximately 236.0 °C. The XRPD and DSC-TGA patterns of deuterated S Phos-2 are essentially the same as those of Phos-2. Furthermore, the DVS pattern of deuterated S Phos-2 is essentially the same as that of Phos-2.

[0275] (g) ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one L-tartrate and its deuterated analogues Isopropanol, ethyl acetate, tetrahydrofuran, and a 9:1 (v / v) mixture of acetone / water (0.25 mL each solvent) were added to a volume containing approximately 40 mg of free base. RFour different glass vials containing 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one were prepared. A one molar equivalent of L-tartaric acid was added to each vial, and the contents were stirred at room temperature. Solid products were observed and collected in each vial, and dried under vacuum at room temperature. Products separated from the solvent were crystals. Six different crystalline products were collected, as determined by XRPD analysis. One product was obtained from isopropanol and will be identified as (…). R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one L-Tar-1 (tartrate-1, also designated Tar-1). The two products were separated from ethyl acetate and identified as ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Tar-2 (tartrate-2, also identified as Tar-2) and ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Tar-5 (tartrate-5, also identified as Tar-5). As described below, Tar-2 is converted to Tar-5. The fourth product is separated from tetrahydrofuran and identified as ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Tar-3 (tartrate-3, also designated Tar-3). Finally, the two products were separated from the acetone / water mixture and identified as ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Tar-4 (tartrate-4, also known as Tar-4) and ( R Tar-6 (tartrate-6, also known as Tar-6), 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. As described below, Tar-4 is converted to Tar-6. Except for Tar-2 and Tar-5, which have an acid-to-free-base ratio of 1.6:1, and Tar-3, which is a hemi-tartrate, the other polymorphs are identified as 1:1 salts by NMR analysis.

[0276] Tar-1 was isolated from isopropanol and was crystalline. The Tar-1 salt was obtained by XRPD (X-ray powder diffraction) analysis. Figure 28 The XRPD diffraction pattern of Tar-1 is shown. Table 18 below lists the XRPD peaks and intensities of the Tar-1 salt.

[0277] Table 18. Figure 28 XRPD peak of (Tar-1). peak# Pos. [°2θ] strength 1 8.8965 1204.75 2 11.1291 42.39 3 11.8244 420.46 4 12.3506 27.04 5 12.7453 126.01 6 12.9768 288.46 7 14.2488 97.64 8 15.5022 776.09 9 15.7438 1159.01 10 17.5066 596.01 11 17.8461 346.99 12 19.2063 957.63 13 19.7532 269.06 14 20.3499 345.92 15 20.8264 267.13 16 23.0449 486.50 17 23.5694 120.33 18 24.7990 159.59 19 25.6081 28.03 20 26.1047 32.39 21 26.8585 577.59 22 27.1001 517.29 23 28.6658 93.17 24 28.9456 211.34 25 29.2577 91.26 26 29.7721 84.13 27 30.1555 47.90 28 30.4372 49.17 29 31.0068 80.28 30 31.3340 188.41 31 33.6852 94.81 32 36.2154 50.26

[0278] As illustrated, in one embodiment, this Tar-1 salt can be characterized by peaks in an X-ray diffraction pattern at 8.9, 15.7, and 19.2 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 8.9, 15.5, 15.7, 17.5, and 19.2 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 8.9, 11.8, 15.5, 15.7, 17.5, 17.8, 19.2, 23.0, 26.9, and 27.1 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 8.9, 11.1, 11.8, 12.4, 12.7, 13.0, 14.2, 15.5, 15.7, 17.5, 17.8, 19.2, 19.8, 20.3, 20.8, 23.0, 23.6, 24.8, 25.6, 26.1, 26.9, 27.1, 28.7, 28.9, 29.3, 29.8, 30.2, 30.4, 31.0, 31.3, 33.7, and 36.2 ± 0.5°2θ.

[0279] As described above, Tar-2 and Tar-5 are obtained from the reaction of free base with L-tartaric acid in ethyl acetate. Both Tar-2 and Tar-5 are crystalline. Tar-2 is the initial crystal present in the wet filter cake obtained by filtration. After drying in a vacuum oven at room temperature, Tar-2 is converted to Tar-5. The stoichiometric ratio of base to acid in Tar-2 and Tar-5 was determined to be 1:1.6 by proton NMR.

[0280] Tar-2 salts were obtained by XRPD analysis. Figure 29 The XRPD diffraction pattern of Tar-2 was depicted. The XRPD peaks and intensities of the Tar-2 salt are provided in Table 19 below.

[0281] Table 19. Figure 29 XRPD peak of (Tar-2). peak# Pos. [°2θ] strength 1 6.0785 252.38 2 11.6290 702.82 3 11.7515 120.92 4 12.2956 107.05 5 13.2298 87.62 6 14.2661 41.65 7 15.8517 455.11 8 16.5156 99.27 9 17.2952 56.64 10 17.9505 92.57 11 19.0770 91.63 12 19.5051 203.01 13 21.2799 77.30 14 22.3505 52.98 15 24.5158 30.16 16 26.1215 61.06 17 26.8920 33.65 18 27.4691 16.64 19 27.9000 15.51 20 29.0468 19.60 21 29.4672 42.62 22 29.6774 111.60 23 31.5349 24.03 24 33.9501 10.07 25 36.8307 54.74

[0282] As illustrated, in one embodiment, this Tar-2 salt can be characterized by peaks in the X-ray diffraction pattern at 6.1, 11.6, and 15.9 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 6.1, 11.6, 11.8, 15.9, and 19.5 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 6.1, 11.6, 11.8, 12.3, 15.9, 16.5, 18.0, 19.1, 19.5, and 29.7 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 6.1, 11.6, 11.8, 12.3, 13.2, 14.3, 15.9, 16.5, 17.3, 18.0, 19.1, 19.5, 21.3, 22.4, 24.5, 26.1, 26.9, 27.5, 27.9, 26.9, 29.0, 29.5, 29.7, 31.5, 34.0, and 36.8 ± 0.5°2θ.

[0283] XRPD analysis revealed that Tar-5 is a product of the transformation of Tar-2 during drying. Figure 30 The XRPD diffraction pattern of Tar-5 was depicted. The XRPD peaks and intensities of the Tar-5 salt are provided in Table 20 below.

[0284] Table 20. Figure 30 XRPD peak of (Tar-5). peak# Pos. [°2θ] strength 1 9.3116 41.07 2 11.9824 10.08 3 12.4447 29.79 4 14.3398 46.90 5 15.0976 24.16 6 16.5683 128.28 7 19.0470 135.60 8 21.7262 64.67 9 28.8991 12.57

[0285] As illustrated, in one embodiment, this Tar-5 salt can be characterized by peaks in the X-ray diffraction pattern at 16.6, 19.0, and 21.7 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 9.3, 14.3, 16.6, 19.0, and 21.7 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 9.3, 12.0, 12.4, 14.3, 15.1, 16.6, 19.0, 21.7, and 28.9 ± 0.5°2θ.

[0286] Tar-5 salt was analyzed using the above method via DSC-TGA. Data are as follows: Figure 31 As shown, the weight loss at 100°C is approximately 0.26%. Furthermore, the DSC thermal analysis of the Tar-5 salt exhibits two broad peak temperatures at approximately 163.5°C and 187.2°C.

[0287] As described above, Tar-3 free base is isolated by reaction with L-tartaric acid in tetrahydrofuran (THF). The Tar-3 salt is a hemitartaric acid salt because the stoichiometric ratio of base to acid is 1.0:0.5, as determined by proton nuclear magnetic resonance (NMR). Furthermore, the presence of THF solvent was observed in the NMR spectrum of Tar-3 crystals.

[0288] Tar-3 was obtained through XRPD analysis. Figure 32 The XRPD diffraction pattern of Tar-3 was depicted. The XRPD peaks and intensities of the Tar-3 salt are provided in Table 21 below.

[0289] Table 21. Figure 32 XRPD peak of (Tar-3). peak# Pos. [°2θ] strength 1 7.5630 867.18 2 12.1828 543.03 3 13.4211 506.15 4 14.9936 318.17 5 16.7966 953.75 6 18.7729 1013.10 7 19.2377 487.94 8 19.4118 925.01 9 19.9152 350.70 10 20.7353 108.32 11 20.8835 705.82 12 22.3076 171.20 13 22.7566 102.10 14 23.0713 371.78 15 23.5370 140.86 16 24.4799 158.57 17 26.2198 38.19 18 26.9908 108.74 19 28.0381 97.92 20 28.5574 74.21 21 29.6378 30.45 22 29.9618 125.54 23 31.3249 42.15 24 32.0024 44.22 25 32.2733 51.55 26 32.2948 31.30 27 32.5078 43.99 28 33.3784 41.73 29 34.0762 71.89 30 35.9818 37.03

[0290] As shown in the figure, in one embodiment, the Tar-3 salt can be characterized by peaks in the X-ray diffraction pattern at 16.8, 18.8, and 19.4 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 7.6, 16.8, 18.8, 19.4, and 20.9 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 7.6, 12.2, 13.4, 16.8, 18.8, 19.2, 19.4, 19.9, 20.9, and 23.1 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 7.6, 12.2, 13.4, 15.0, 16.8, 18.8, 19.2, 19.4, 19.9, 20.7, 20.9, 22.3, 22.8, 23.1, 23.5, 24.5, 26.2, 27.0, 28.0, 28.6, 29.6, 30.0, 31.3, 32.0, 32.3(32.27), 32.3(32.29), 32.5, 33.4, 34.1, and 36.0 ± 0.5°2θ.

[0291] Tar-3 salts were analyzed using the above method via DSC-TGA. Data are presented in... Figure 33 In the middle. When the temperature rises from room temperature to 125°C, the weight loss is approximately 9.95%. In addition, the DSC thermal analysis of Tar-3 salt shows two peak temperatures, a sharp peak at approximately 176.6°C, and a broader and significantly smaller peak at approximately 110.1°C.

[0292] As described above, Tar-4 and Tar-6 were obtained by reacting free base with L-tartaric acid in a 9:1 (v / v) acetone / water mixture. Tar-4 was present in crystalline form in the filtered wet filter cake and was converted to Tar-6 upon drying in a vacuum oven at room temperature. Both Tar-4 and Tar-6 were found to be crystalline. Proton NMR determined that the stoichiometric ratio of free base to acid in Tar-6 was 1:1.

[0293] Tar-4 salts were obtained by XRPD analysis. Figure 34 The XRPD diffraction pattern of Tar-4 was depicted. The XRPD peaks and intensities of the Tar-4 salt are provided in Table 22 below.

[0294] Table 22. Figure 34 XRPD peak of (Tar-4). peak# Pos. [°2θ] strength 1 6.5058 9249.33 2 8.3075 113.47 3 8.5506 1045.61 4 9.9120 247.89 5 12.8479 644.15 6 13.0470 5111.05 7 14.4629 4297.89 8 15.3086 62.05 9 16.7005 2216.35 10 16.8566 226.74 11 17.1596 2369.47 12 17.3936 425.82 13 19.4248 735.32 14 19.6235 189.28 15 19.9214 401.13 16 20.1720 1395.72 17 20.7392 1279.05 18 21.4973 706.84 19 21.7700 307.66 20 22.6663 74.07 21 23.1997 1151.84 22 23.4493 345.47 23 24.0627 1999.37 24 25.1771 391.70 25 25.6899 154.21 26 25.9534 781.38 27 26.2746 1691.86 28 26.3545 905.14 29 26.8796 193.60 30 27.1902 194.82 31 27.2985 373.29 32 27.6973 272.40 33 28.2061 26.31 34 28.9556 216.91 35 29.8074 133.69 36 30.0939 567.26 37 30.2660 87.79 38 30.8926 105.59 39 31.1510 559.25 40 31.2369 252.62 41 31.5112 132.40 42 31.8663 51.58 43 32.0219 176.25 44 32.6190 109.45 45 32.8287 105.45 46 33.5786 102.32 47 34.1238 87.58 48 35.1511 21.89 49 36.8056 99.53 50 37.4013 20.60 51 39.4354 119.15

[0295] As shown in the figure, in one embodiment, the Tar-4 salt can be characterized by peaks in the X-ray diffraction pattern at 6.5, 13.0, and 14.5 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.5, 13.0, 14.5, 16.7, and 17.2 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 6.5, 8.6, 13.0, 14.5, 16.7, 17.2, 20.2, 20.7, 24.1, and 26.3 ± 0.5°2θ. In another embodiment, the salt can be obtained from concentrations of 6.5, 8.3, 8.6, 9.9, 12.8, 13.0, 14.5, 15.3, 16.7, 16.9, 17.2, 17.4, 19.4, 19.6, 19.9, 20.2, 20.7, 21.5, 21.8, 22.7, 23.2, 23.4, 24.1, 25.2, 25.7, 26.0, 26.3, ... The peaks at 26.4, 26.9, 27.2, 27.3, 27.7, 28.2, 29.0, 29.8, 30.1, 30.3, 30.9, 31.2 (31.15), 31.2 (31.24), 31.5, 31.9, 32.0, 32.6, 32.8, 33.6, 34.1, 35.2, 36.8, 37.4, and 39.4 ± 0.5°2θ are used to characterize the values.

[0296] XRPD analysis revealed that Tar-6 is a product of Tar-4 transformation. Figure 35 The XRPD diffraction pattern of Tar-6 was depicted. The XRPD peaks and intensities of the Tar-6 salt are provided in Table 23 below.

[0297] Table 23. Figure 35XRPD peak of (Tar-6). peak# Pos. [°2θ] strength 1 6.4283 47.19 2 6.5560 254.47 3 13.0946 237.92 4 14.1515 153.37 5 14.5367 306.83 6 15.2000 196.30 7 16.0287 67.32 8 16.7749 158.14 9 17.0962 32.65 10 17.2382 90.88 11 17.4616 47.73 12 18.1697 72.26 13 18.4582 19.31 14 19.2051 37.05 15 19.5147 52.96 16 19.9766 25.99 17 20.2305 111.75 18 20.8001 91.82 19 21.0783 15.81 20 21.3630 13.85 21 21.5568 37.36 22 21.8319 17.43 23 23.2815 129.52 24 23.5098 31.80 25 24.1307 186.45 26 25.2487 62.43 27 26.0262 72.59 28 26.3613 70.45 29 26.7127 22.51 30 26.9751 15.65 31 27.2622 75.92 32 27.8008 17.14 33 28.3020 25.86 34 28.7152 15.13 35 28.9772 34.87 36 29.8602 67.31 37 30.1716 54.81 38 31.2197 45.35 39 31.5938 10.74 40 31.9903 28.98 41 32.9412 17.37

[0298] As shown in the figure, in one embodiment, the Tar-6 salt can be characterized by peaks in the X-ray diffraction pattern at 6.5, 13.1, and 14.5 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.5, 13.1, 14.5, 15.2, and 24.1 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 6.6, 13.1, 14.2, 14.5, 15.2, 16.8, 20.2, 20.8, 23.3, and 24.1 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.4, 6.6, 13.1, 14.2, 14.5, 15.2, 16.0, 16.8, 17.1, 17.2, 17.5, 18.1, 18.5, 19.2, 19.5, 20.0, 20.2, 20.8, 21.1, 21.4, 21.6, 21.8, 23.3, 23.5, 24.1, 25.2, 26.0, 26.3, 26.7, 27.0, 27.3, 27.8, 28.3, 28.7, 29.0, 29.9, 30.2, 31.2, 31.6, 32.0, and 32.9 ± 0.5°2θ.

[0299] Tar-6 salt was analyzed using the above method via DSC-TGA. Data are as follows: Figure 36 As shown, the weight loss at 100°C is approximately 10.67%. Furthermore, the DSC thermal analysis of the Tar-6 salt reveals two temperature peaks: one at approximately 61.7°C, and a broader and significantly smaller peak at approximately 199.8°C.

[0300] As mentioned above, in various solvents such as isopropanol, ethyl acetate, tetrahydrofuran, and a 9:1 (v / v) mixture of acetone / water, the free base is replaced by a deuterated R free base ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one yielded six polymorphic salts. One product was derived from isopropanol and was identified as deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-L-Tar-1 (deuterated R tartrate-1, also designated as deuterated R Tar-1). Two products were isolated from ethyl acetate and identified as deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-L-Tar-2 (deuterated R tartrate-2, also designated as deuterated R Tar-2) and deuterated ( R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-L-Tar-5 (deuterated R-tartrate-5, also designated as deuterated R-Tar-5). As described below, deuterated R-Tar-2 is converted to deuterated R-tartrate-5. A fourth product was isolated from tetrahydrofuran and identified as deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-L-Tar-3 (deuterated R-tartrate-3, also designated as deuterated R-Tar-3). Finally, the two products were separated from the acetone / water mixture and identified as deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-L-Tar-4 (deuterated R-tartrate-4, also known as deuterated R-Tar-4) and deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-L-Tar-6 (deuterated R-tartrate-6, also known as deuterated R-Tar-6). As described below, deuterated R-Tar-4 is converted to deuterated R-Tar-6. Except for deuterated R-Tar-2 and deuterated R-Tar-5, which have an acid to free base ratio of 1.6:1, and deuterated R-Tar-3, which is a hemi-tartrate, the other polymorphs of deuterated R-tartrates are all 1:1 salts.

[0301] Deuterated R Tar-1 was isolated from isopropanol. The XRPD diffraction pattern of deuterated R Tar-1 was essentially the same as that of Tar-1.

[0302] As described above, deuterated R Tar-2 and deuterated R Tar-5 are obtained by reacting a free base of deuterated R with L-tartaric acid in ethyl acetate. Both deuterated R Tar-2 and deuterated R Tar-5 are crystalline salts. Deuterated R Tar-2 is present in the initial crystals of the wet filter cake obtained by filtration. After drying in a vacuum oven at room temperature, deuterated R Tar-2 is converted to deuterated R Tar-5. The stoichiometric ratio of base to acid in deuterated R Tar-2 to deuterated R Tar-5 is 1:1.6. The XRPD diffraction patterns of deuterated R Tar-2 and deuterated R Tar-5 are substantially the same as those of Tar-2 and Tar-5, respectively. The DSC-TGA pattern of deuterated R Tar-5 is substantially the same as that of Tar-5. The DVS pattern of deuterated R Tar-5 is substantially the same as that of Tar-5.

[0303] Deuterated R Tar-3 is isolated from the reaction of a free deuterated R base with L-tartaric acid in THF. The deuterated R Tar-3 salt is crystalline. It is a hemitartaric acid salt because the stoichiometric ratio of base to acid is 1.0:0.5. The XRPD and DSC-TGA patterns of deuterated R Tar-3 are substantially identical to those of Tar-3. The DVS pattern of deuterated R Tar-3 is also substantially identical to that of Tar-3.

[0304] As described above, deuterated R Tar-4 and deuterated R Tar-6 are obtained by reacting a free base of deuterated R with L-tartaric acid in a 9:1 volume ratio of acetone / water. Deuterated R Tar-4 exists as a crystalline form in a wet filter cake, which is converted to deuterated R Tar-6 upon drying in a vacuum oven at room temperature. Both deuterated R Tar-4 and deuterated R Tar-6 are crystalline. The stoichiometric ratio of the free base to the acid in both deuterated R Tar-4 and deuterated R Tar-6 is 1:1. The XRPD diffraction pattern of deuterated R Tar-4 is substantially the same as that of Tar-4. Furthermore, the XRPD diffraction pattern and DSC-TGA of deuterated R Tar-6 are substantially the same as those of Tar-6. The DVS pattern of the deuterated R Tar-6 salt is substantially the same as that of Tar-6.

[0305] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one tartrate and its deuterated analogues.

[0306] As mentioned above, in various solvents such as isopropanol, ethyl acetate, tetrahydrofuran, and a 9:1 (v / v) mixture of acetone / water, the free base is replaced by S free base ( R (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one and the substitution of L-tartaric acid with D-tartaric acid yield six crystalline polymorphic salts. One product is obtained from isopropanol and will be identified as (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-1 (S tartrate-1, also designated STar-1). Two products are isolated from ethyl acetate and will be identified as (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-2 (S tartrate-2, also designated STar-2) and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-5 (S tartrate-5, also designated STar-5). STar-2 is converted to STar-5 as described below. The fourth product was isolated from tetrahydrofuran and identified as ( R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-3 (S-tartrate-3, also designated STar-3). Finally, the two products were separated from the acetone / water mixture and identified as ( R (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-4 (S tartrate-4, also designated STar-4) and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-6 (S tartrate-6, also designated STar-6). As explained below, STar-4 is converted to STar-6. Except for S Tar-2 and S Tar-5, which have an acid to free base ratio of 1.6:1, and Tar-3, which is a hemi-tartrate, the other S tartrate polymorphs are 1:1 salts.

[0307] S Tar-1 was isolated from isopropanol and is crystalline. The XRPD diffraction pattern of S Tar-1 is basically the same as that of Tar-1.

[0308] As described above, S Tar-2 and S Tar-5 are obtained by reacting a deuterated R free base with D-tartaric acid in ethyl acetate. Both S Tar-2 and S Tar-5 are crystalline salts. S Tar-2 is the initial crystal present in the wet filter cake obtained by filtration. After drying in a vacuum oven at room temperature, S Tar-2 is converted to S Tar-5. The stoichiometric ratio of base to acid in S Tar-2 and S Tar-5 is 1:1.6. The XRPD diffraction patterns of S Tar-2 and S Tar-5 are substantially the same as those of Tar-2 and Tar-5. The DSC-TGA of S Tar-5 is substantially the same as that of Tar-5. The DVS pattern of S Tar-5 is substantially the same as that of Tar-5.

[0309] S Tar-3 was isolated from the reaction of free S base with D-tartaric acid in tetrahydrofuran (THF). The S Tar-3 salt is crystalline. It belongs to the hemitartaric acid salt category because the stoichiometric ratio of base to acid is 1.0:0.5. The X-ray powder diffraction (XRPD) pattern and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) of S Tar-3 are essentially the same as those of Tar-3. The differential spectral density (DVS) pattern of S Tar-3 is also essentially the same as that of Tar-3.

[0310] S Tar-4 and S Tar-6 were obtained by reacting S free base with D-tartaric acid in a 9:1 volume ratio acetone / water mixture. S Tar-4 was converted to S Tar-6 from the crystalline form of the wet filter cake obtained by filtration and dried in a vacuum oven at room temperature. Both S Tar-4 and S Tar-6 are crystalline. The stoichiometric ratio of S free base to acid in S Tar-4 and S Tar-6 is 1:1. The XRPD diffraction pattern of S Tar-4 is substantially the same as that of Tar-4. Furthermore, the XRPD diffraction pattern and DSC-TGA of S Tar-6 are substantially the same as those of Tar-6. The DVS pattern of the S Tar-6 salt is substantially the same as that of Tar-6.

[0311] As mentioned above, in various solvents such as isopropanol, ethyl acetate, tetrahydrofuran, and a 9:1 (v / v) mixture of acetone / water, the free base is replaced by a deuterated S free base. R(S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one and the substitution of L-tartaric acid with D-tartaric acid produce six crystalline polymorphic salts. One product is obtained from isopropanol and will be identified as deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-1 (deuterated S tartrate-1, also designated as deuterated S Tar-1). Two products were isolated from ethyl acetate and identified as deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-2 (deuterated S tartrate-2, also designated as deuterated S Tar-2) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-5 (deuterated S tartrate-5, also designated as deuterated S Tar-5). As described below, deuterated S Tar-2 was converted to deuterated S Tar-5. A fourth product was isolated from tetrahydrofuran and identified as deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-3 (deuterated S tartrate-3, also designated as deuterated S Tar-3). Finally, two products were separated from the acetone / water mixture and identified as deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-4 (deuterated S tartrate-4, also designated as deuterated S Tar-4) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-Tar-6 (deuterated S tartrate-6, also designated as deuterated S Tar-6). As described below, deuterated S Tar-4 is converted to deuterated S Tar-6. Except for deuterated S Tar-2 and deuterated S Tar-5, which have an acid-to-free base ratio of 1.6:1, and deuterated S Tar-3, which is a hemi-tartrate, the other deuterated S tartrate polymorphs are 1:1 salts.

[0312] Deuterated S Tar-1 was isolated from isopropanol and was crystalline. The XRPD diffraction pattern of deuterated S Tar-1 was basically the same as that of Tar-1.

[0313] As described above, deuterated S Tar-2 and deuterated S Tar-5 are obtained by reacting a free base of deuterated S with D-tartaric acid in ethyl acetate. Both deuterated S Tar-2 and deuterated S Tar-5 are crystalline salts. Deuterated S Tar-2 is present in the initial crystals of the wet filter cake obtained by filtration. After drying in a vacuum oven at room temperature, deuterated S Tar-2 is converted to deuterated S Tar-5. The stoichiometric ratio of base to acid in deuterated S Tar-2 and deuterated S Tar-5 is 1:1.6. The XRPD diffraction patterns of deuterated S Tar-2 and deuterated S Tar-5 are essentially the same as those of Tar-2 and Tar-5, respectively. The DSC-TGA pattern of deuterated S Tar-5 is essentially the same as that of Tar-5. The DVS pattern of deuterated S Tar-5 is essentially the same as that of Tar-5.

[0314] Deuterated S Tar-3 was isolated from the reaction of deuterated S free base with D-tartaric acid in tetrahydrofuran (THF). The deuterated S Tar-3 salt is crystalline and, due to its base-to-acid stoichiometric ratio of 1.0:0.5, is a hemitartaric acid salt. The X-ray powder diffraction (XRPD) pattern and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) pattern of deuterated S Tar-3 are essentially the same as those of Tar-3. The dynamic water vapor adsorption (DVS) pattern of deuterated S Tar-3 is also essentially the same as that of Tar-3.

[0315] Deuterated S Tar-4 and deuterated S Tar-6 were obtained by reacting deuterated S free base with D-tartaric acid in an acetone / water mixture at a ratio of 9:1 (v / v). Deuterated S Tar-4 existed as a crystalline form in a wet filter cake, which was converted to deuterated S Tar-6 upon drying in a vacuum oven at room temperature. Both deuterated S Tar-4 and deuterated S Tar-6 were crystalline. The stoichiometric ratio of deuterated S free base to acid was 1:1 relative to deuterated S Tar-4 and deuterated S Tar-6. The XRPD diffraction pattern of deuterated S Tar-4 was substantially identical to that of Tar-4. Furthermore, the XRPD diffraction pattern and DSC-TGA of deuterated S Tar-6 were substantially identical to those of Tar-6, respectively. The DVS diagram of deuterated S Tar-6 salt is basically the same as that of Tar-6.

[0316] (h)1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate and its deuterated analogues Isopropanol, acetonitrile, ethyl acetate, tetrahydrofuran, and a 9:1 v / v mixture of acetone / water (0.25 mL each solvent) were added to a solution containing approximately 40 mg of free base. RFive different glass vials containing 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one were prepared. One molar equivalent of fumaric acid was added to each vial, and the mixture was stirred at room temperature. The solid product from each vial was collected and dried under vacuum at room temperature. X-ray powder diffraction (XRPD) confirmed that the separated products in each vial were crystalline and exhibited identical XRPD diffraction patterns. This product was identified in this paper as (…). R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-1 (Fum-1, also referred to as Fum-1). The stoichiometric ratio of base to acid in Fum-1 was determined to be 1:1 by proton nuclear magnetic resonance (NMR).

[0317] Fum-1 was obtained through XRPD analysis. Figure 37 The XRPD diffraction pattern of Fum-1 was depicted. The XRPD peaks and intensities of the Fum-1 salt are provided in Table 24 below.

[0318] Table 24. Figure 37 XRPD peak of (Fum-1). peak# Pos. [°2θ] strength 1 6.1581 236.76 2 7.3847 509.95 3 9.1154 452.82 4 11.4195 168.82 5 12.2962 332.21 6 13.4078 191.18 7 14.0368 56.65 8 14.7822 918.33 9 15.0745 51.31 10 16.3204 252.88 11 16.6445 123.03 12 16.9340 144.03 13 17.7696 75.43 14 18.2997 384.61 15 19.0686 216.92 16 19.5086 340.04 17 20.7804 77.90 18 21.0042 28.07 19 22.6948 164.50 20 23.8068 346.80 21 24.3575 120.94 22 24.7711 822.17 23 25.0041 143.79 24 25.5451 72.80 25 25.6922 608.20 26 26.6969 148.46 27 27.4101 35.26 28 27.5265 122.68 29 29.6765 80.57 30 31.1132 37.36 31 31.8859 14.76 32 33.9389 -17.92 33 34.0255 20.23 34 35.0150 12.67 35 38.3871 13.83

[0319] As shown in the figure, in one embodiment, the Fum-1 salt can be characterized by peaks in the X-ray diffraction pattern at 14.8, 24.8, and 25.7 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 7.4, 9.1, 14.8, 24.8, and 25.7 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 7.4, 9.1, 12.3, 14.8, 16.3, 18.3, 19.5, 23.8, 24.8, and 25.7 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.2, 7.4, 9.1, 11.4, 12.3, 13.4, 14.0, 14.8, 15.1, 16.3, 16.7, 16.9, 17.8, 18.3, 19.1, 19.5, 20.8, 21.0, 22.7, 23.8, 24.4, 24.8, 25.0, 25.5, 25.7, 27.0, 27.4, 27.5, 29.7, 31.1, 31.9, 33.9, 34.0, 35.0, and 38.3 ± 0.5°2θ.

[0320] Fum-1 salt was analyzed using the above method via DSC-TGA. Data are as follows: Figure 38 As shown, the weight loss at 100°C is approximately 0.66%. Furthermore, the DSC thermal analysis of Fum-1 shows a strong peak temperature at approximately 181.7°C.

[0321] Named in this article (R Different polymorphs of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Fum-2 (fumarate-2, also referred to as Fum-2) were prepared by reacting a free base directly with fumaric acid. Specifically, one equivalent of free base was placed in a vial, and approximately 1.0 mol equivalent of fumaric acid was added to the vial. After initial mixing, approximately 10 volumes of ethyl acetate were added at room temperature to further aid mixing. After the reaction was complete, the product was collected by filtration, dried under vacuum at room temperature, and analyzed by XRPD. The resulting XRPD diffraction pattern differed from that of Fum-1, and this novel form was designated as Fum-2. Figure 39 The XRPD diffraction pattern of Fum-2 was depicted. The peaks and intensities of the XRPD for Fum-2 salt are provided in Table 25 below.

[0322] Table 25. Figure 39 XRPD peak of (Fum-2). peak# Pos. [°2θ] strength 1 6.1540 54.58 2 7.2296 50.16 3 7.3866 294.12 4 7.4479 71.07 5 9.1206 152.11 6 10.1946 127.50 7 11.3762 43.85 8 12.3290 330.04 9 12.4154 840.29 10 13.4500 65.15 11 13.9203 188.62 12 14.7970 534.59 13 16.3114 10165.32 14 16.6661 298.61 15 16.9675 126.38 16 17.4916 681.67 17 17.7000 706.15 18 18.3217 123.64 19 18.8542 239.91 20 19.0963 57.62 21 19.3479 256.85 22 19.5173 114.57 23 19.9167 148.85 24 20.6202 109.77 25 21.3875 589.96 26 22.6954 369.88 27 22.8453 980.12 28 23.0019 88.85 29 23.3932 106.16 30 23.8299 108.69 31 24.5593 688.44 32 24.7886 332.62 33 24.9816 76.90 34 25.3715 298.80 35 25.7410 228.95 36 26.3219 120.96 37 26.7332 56.87 38 27.1135 79.46 39 27.5581 67.00 40 27.6782 296.12 41 27.9552 323.20 42 28.8117 159.66 43 29.2920 103.76 44 29.7591 43.56 45 31.0436 34.47 46 31.6500 20.70 47 32.6959 51.23 48 32.9196 61.90 49 34.1011 33.39 50 34.9384 148.14 51 35.0892 21.33 52 35.4102 21.77 53 35.9672 24.75 54 36.7310 30.00 55 37.7763 90.16

[0323] As shown in the figure, in one embodiment, the Fum-2 salt can be characterized by peaks in the X-ray diffraction pattern at 12.4, 16.3, and 22.8 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 12.4, 16.3, 17.7, 22.8, and 24.6 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 12.4, 14.8, 16.3, 17.5, 17.7, 21.4, 22.7, 22.8, 24.6, and 24.8 ± 0.5°2θ. In another embodiment, the salt can be obtained from 6.2, 7.3, 7.4 (7.39), 7.4 (7.45), 9.1, 10.1, 11.3, 12.3, 12.4, 13.5, 13.9.0 (the original text may be incorrect here; it should be a specific numerical value or descriptive text), 14.8, 16.3, 16.7, 17.0, 17.5, 17.7, 18.3, 18.9, 19.1, 19.3, 19.5, 19.9, 20.6, 21. The peaks at 4, 22.7, 22.8, 23.0, 23.4, 23.8, 24.6, 24.8, 25.0, 25.4, 25.7, 26.3, 26.7, 27.1, 27.6, 27.7, 28.0, 28.8, 29.3, 29.8, 31.0, 31.7, 32.7, 32.9, 33.9, 34.1, 34.9, 35.1, 35.4, 36.0, 36.7, and 37.8 ± 0.5°2θ are used to characterize the readings.

[0324] Therefore, the obtained Fum-2 was determined by proton NMR to have a base:acid stoichiometric ratio of 1:0.65.

[0325] A better sample of Fum-2 was obtained by reacting one molar equivalent of free base with 0.5 molar equivalent of fumaric acid in 5 volumes of ethyl acetate. The mixture in the vial was stirred and the resulting solid was collected. Proton NMR spectra were recorded to confirm a base-to-acid stoichiometric ratio of 2:1. The XRPD of this sample was essentially the same as... Figure 39 The XRPD of Fum-2 described in the text matches.

[0326] The presence of at least two polymorphic salts of deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate. As described above, in the reaction of fumarate with isopropanol, acetonitrile, ethyl acetate, tetrahydrofuran, and a 9:1 (v / v) mixture of acetone / water, the free base is replaced by a deuterated R free base. R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one produces a polymorph, designated as deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-1 (deuterated R fumarate-1, or alternatively identified as deuterated RFum-1). The stoichiometry of the free base to acid in deuterated R is 1:1. The XRPD and DSC-TGA patterns of deuterated Fum-1 are substantially the same as those of Fum-1. Furthermore, the DVS pattern of deuterated RFum-1 is substantially the same as that of Fum-1.

[0327] As mentioned above, in the reaction with fumaric acid, the second polymorph is formed by replacing the free base with a deuterated R free base ( R Obtained by forming a deuterated ( )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-2 (deuterated R fumarate-2, or also deuterated RFum-2). The XRPD diffraction pattern of deuterated RFum-2 is essentially the same as that of Fum-2. The base:acid stoichiometric ratio of deuterated RFum-2 is 2:1.

[0328] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate and its deuterated analogues At least two crystalline polymorph salts exist, namely (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate. As described above, in the reaction with fumaric acid in isopropanol, acetonitrile, ethyl acetate, tetrahydrofuran, and a 9:1 (v / v) mixture of acetone / water, the free base is replaced by a free S base and a deuterated S base. R (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one produces first polymorphs, namely (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-1 (S fumarate-1, also identified as S Fum-1) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-1 (deuterated S fumarate-1, also identified as deuterated S Fum-1). The stoichiometry of the free base to acid of deuterated S relative to the reactions forming S Fum-1 and deuterated S Fum-1 is 1:1. The XRPD diffraction patterns and DSC-TGA of both S Fum-1 and deuterated S Fum-1 are substantially identical to those of Fum-1. In addition, the DVS spectra of S Fum-1 and deuterated S Fum-1 are basically the same as those of Fum-1.

[0329] As mentioned above, in the reaction with fumaric acid, the second polymorph is formed by replacing the free base with S free base and deuterated S free base. R (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one was obtained, forming (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-2 (S fumarate-2, also identified as S Fum-2) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-2 (deuterated S fumarate-2, also identified as deuterated S Fum-2). The XRPD diffraction patterns of S Fum-2 and deuterated S Fum-2 are essentially the same as those of Fum-2. The base:acid stoichiometric ratio of S Fum-2 and deuterated S Fum-2 is 2:1.

[0330] (i) 1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate and its deuterated analogues Add approximately 0.25 mL of ethyl acetate to a volume containing approximately 40 mg of free base ( RThe contents were placed in a glass vial containing 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. One molar equivalent of citric acid was added to the vial, and the contents were stirred at room temperature. The solid product was observed and collected, and dried under vacuum at room temperature. The initially collected wet crystals showed an identification as ( R The XRPD spectrum of )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Cit-1 (citrate-1, also designated as Cit-1) was obtained, but this spectrum was converted to the one identified as ( ) when dried in a vacuum oven at room temperature. R Different XRPD spectra of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one Cit-2 (citrate-2, also designated as Cit-2). As determined by XRPD, both products are crystalline.

[0331] Figure 40 The XRPD diffraction pattern of Cit-1 was depicted. The XRPD peaks and intensities of the Cit-1 salt are provided in Table 26 below.

[0332] Table 26. Figure 40 XRPD peak of (Cit-1). peak# Pos. [°2θ] strength 1 2.0371 334.78 2 6.5825 120.96 3 11.8395 25.15 4 13.5643 39.71 5 14.1277 108.06 6 14.5230 216.73 7 15.9498 46.94 8 16.1700 43.40 9 16.2782 59.24 10 16.5632 101.30 11 17.8589 3260.50 12 18.1133 621.45 13 19.4696 371.40 14 19.8746 47.40 15 21.1769 38.35 16 21.7212 88.04 17 21.8800 66.57 18 22.9451 37.06 19 23.2493 33.26 20 23.8653 218.05 21 24.8723 18.03 22 26.0797 935.09 23 27.4941 41.76 24 28.8328 321.39 25 28.9021 171.17 26 29.8506 17.27 27 31.0629 173.63 28 31.2851 151.20 29 33.6284 136.11 30 34.0054 64.22 31 36.1035 177.65 32 36.3313 33.30 33 36.6836 86.84 34 37.3301 23.25 35 37.6551 29.47 36 39.3146 26.01

[0333] As illustrated, in one embodiment, this Cit-1 salt can be characterized by peaks in the X-ray diffraction pattern at 17.9, 18.1, and 26.1 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 2.0, 17.9, 18.1, 19.5, and 26.1 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 2.0, 17.9, 18.1, 19.5, 23.9, 26.1, 28.8, 28.9, 31.1, and 36.1 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 2.0, 6.6, 11.8, 13.6, 14.1, 14.5, 15.9, 16.2, 16.3, 16.6, 17.9, 18.1, 19.5, 16.7, 17.0, 17.5, 17.8, 18.3, 18.9, 19.1, 19.3, 19.5, 19.9, 21.2, 21.7, 21.9, 22.9, 23.2, 23.9, 24.9, 26.1, 27.5, 28.8, 28.9, 29.9, 31.1, 31.3, 33.6, 34.0, 36.1, 36.3, 36.7, 37.3, 37.7 and 39.3 ± 0.5°2θ.

[0334] As determined by proton NMR, the stoichiometric ratio of base to acid for Cit-2 was found to be 1:1, and it was inferred that the ratio was also 1:1 for Cit-1. Figure 41The XRPD diffraction pattern of Cit-2 was depicted. The XRPD peaks and intensities of the Cit-2 salt are provided in Table 27 below.

[0335] Table 27. Figure 41 XRPD peak of (Cit-2). peak# Pos. [°2θ] strength 1 6.5998 425.57 2 9.6551 24.05 3 9.7957 148.50 4 11.4014 37.20 5 11.8503 169.03 6 13.5554 125.76 7 14.5195 760.83 8 15.0763 139.04 9 15.9444 179.18 10 16.2729 297.32 11 17.3045 22.44 12 17.7152 606.91 13 17.8538 381.10 14 18.1082 27.59 15 18.5099 125.44 16 18.8195 66.29 17 19.6964 64.12 18 19.8697 242.69 19 21.1815 223.83 20 21.8268 157.19 21 21.9332 239.06 22 22.9002 69.82 23 23.2813 130.83 24 24.1037 99.68 25 24.2538 28.89 26 24.6810 87.84 27 26.3792 76.31 28 27.2855 76.35 29 27.5593 130.34 30 28.3165 85.41 31 28.5502 21.61 32 29.2935 48.34 33 29.7160 42.80 34 30.0847 25.69 35 30.7944 28.98 36 31.1373 109.33 37 31.2900 61.91 38 31.4909 25.03 39 31.9655 48.91 40 32.6336 36.25 41 35.5599 22.68 42 36.1405 27.24 43 36.8110 13.28 44 37.8493 22.06 45 38.8677 23.78

[0336] As shown in the figure, in one embodiment, the Cit-2 salt can be characterized by peaks in the X-ray diffraction pattern at 6.6, 14.5, and 17.7 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.6, 14.5, 16.3, 17.7, and 17.9 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 6.6, 11.9, 14.5, 15.9, 16.3, 17.7, 17.9, 19.9, 21.2, and 21.9 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.6, 9.7, 9.8, 11.4, 11.9, 13.6, 14.5, 15.1, 15.9, 16.3, 17.3, 17.7, 17.9, 18.1, 18.5, 18.8, 19.7, 19.9, 21.2, 21.8, 21.9, 22.9, 23.3, 23.9, 24.1, 24.3, 24.7, 26.4, 27.3, 27.6, 28.3, 28.6, 29.3, 29.7, 30.1, 30.8, 31.1, 31.3, 31.5, 32.0, 32.6, 35.6, 36.1, 36.8, 37.8, and 38.9 ± 0.5°2θ.

[0337] Cit-2 salt was analyzed by DSC-TGA using the method described above. Data were plotted on... Figure 42 In the meantime, the weight loss is approximately 1.33% when the temperature increases from room temperature to 100°C. Furthermore, the DSC thermal analysis of the Cit-2 salt shows an extremely broad peak temperature at approximately 173.6°C.

[0338] In the above reaction with citric acid, the free base is replaced by a deuterated R free base ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, to generate deuterated ( R It is a crystalline polymorph salt of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate-1 (deuterated R citrate-1, also designated as deuterated R-Cit-1). The XRPD diffraction pattern of the initially collected wet crystals of deuterated R-Cit-1 is essentially the same as that of Cit-1.

[0339] Similar to Cit-1, deuterated R-Cit-1 transforms into different polymorphic salts upon drying in a vacuum oven at room temperature. The transformed deuterated R-Cit-1 is designated as deuterated ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate-2 (deuterated R citrate-2, also identifiable as deuterated R-Cit-2). The XRPD (X-ray powder diffraction) and DSC-TGA (differential scanning calorimetry-thermogravimetric analysis) spectra of deuterated R-Cit-2 are essentially the same as those of Cit-2. The DVS (dynamic water adsorption) plot of the deuterated R-Cit-2 salt is also essentially the same as that of Cit-2.

[0340] The base-to-acid stoichiometric ratio of deuterated R-Cit-1 and deuterated R-Cit-2 is 1:1.

[0341] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate and its deuterated analogues In the reaction with citric acid described above, the free base is replaced by an S-free base and a deuterated S-free base. R (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one is reacted to produce crystalline polymorphic salts of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate-1 (S citrate-1, also designated as S Cit-1) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate-1 (deuterated S citrate-1, also designated as deuterated S Cit-1). The XRPD diffraction patterns of the initially collected wet crystals of both SCit-1 and deuterated S Cit-1 are essentially the same as those of Cit-1.

[0342] Similar to Cit-1, S Cit-1 and deuterated S Cit-1 transform into different crystalline polymorphic salts upon drying in a vacuum oven at room temperature. The transformed S Cit-1 and deuterated S Cit-1 are designated as (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate-2 (S citrate-2, also known as S Cit-2) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate-2 (deuterated S citrate-2, also known as deuterated S Cit-2), respectively. The X-ray powder diffraction (XRPD) and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) of S-Cit-2 and deuterated R-Cit-2 are essentially the same as those of Cit-2. The dynamic water vapor adsorption (DVS) diagrams of S Cit-2 and deuterated S-Cit-2 salts are basically the same as those of Cit-2.

[0343] The base-to-acid stoichiometric ratio of S Cit-1 and deuterated S Cit-1, as well as S Cit-2 and deuterated S Cit-2, is 1:1.

[0344] (j) 1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one glycolate and deuterated analogues Isopropanol, acetonitrile, ethyl acetate, and tetrahydrofuran (0.25 mL each) were added to four separate glass vials, each containing approximately 40 mg of free base. R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. One molar equivalent of glycolic acid was added to each vial, and the mixture was stirred at room temperature. A solid product was observed in each vial, and these were collected and vacuum dried at room temperature. X-ray powder diffraction (XRPD) analysis showed that the product isolated from each vial was crystalline, and all samples exhibited the same XRPD diffraction pattern. This product will be identified as ( ) in this paper. R Glyc-1 (glycolate-1, also referred to as Glyc-1), 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. The stoichiometric ratio of base to acid was determined to be 1:1 by proton nuclear magnetic resonance (NMR).

[0345] Glyc-1 was obtained through XRPD analysis. Figure 43 The XRPD diffraction pattern of Glyc-1 was depicted. Table 28 below lists the XRPD peaks and intensities of the Glyc-1 salt.

[0346] Table 28. Figure 43 XRPD peak of (Glyc-1). peak# Pos. [°2θ] strength 1 7.3781 9286.28 2 9.5595 10460.89 3 12.8368 1735.88 4 13.2781 1880.11 5 14.4115 -626.08 6 14.7740 4919.75 7 16.0860 2362.49 8 16.5106 848.43 9 16.6600 925.80 10 18.7071 182.12 11 19.1661 13246.06 12 19.6151 375.83 13 20.1742 1140.73 14 21.4695 2499.35 15 22.2322 6670.06 16 22.3004 2762.17 17 22.5229 254.88 18 22.6719 186.66 19 22.9726 1369.79 20 23.0401 1013.30 21 23.5351 40.17 22 25.6547 190.90 23 25.8124 63.39 24 26.7756 109.60 25 27.4726 544.78 26 28.0609 55.59 27 28.7794 291.81 28 28.9281 600.97 29 29.7951 5585.26 30 29.8768 2482.86 31 30.8563 416.03 32 31.7534 69.51 33 31.9014 64.41 34 32.4036 252.58 35 32.4965 107.11 36 33.7047 19.35 37 34.4871 132.46 38 34.7451 139.98 39 34.9954 131.40 40 36.2036 174.13 41 36.3003 72.59 42 37.4923 737.45 43 37.5894 298.89 44 38.9064 634.04 45 39.0121 299.56

[0347] As illustrated, in one embodiment, this Glyc-1 salt can be characterized by strong peaks in the X-ray diffraction pattern at 7.4, 9.6, and 19.2 ± 0.5°2θ. In another embodiment, this salt can be characterized by peaks at 7.4, 9.6, 19.2, 22.2, and 29.8 ± 0.5°2θ. In yet another embodiment, this salt can be characterized by peaks at 7.4, 9.6, 14.8, 16.1, 19.2, 21.5, 22.2, 22.3, and 29.8, 29.9 ± 0.5°2θ. In another embodiment, this salt can be obtained from 7.4, 9.6, 12.8, 13.3, 14.4, 14.8, 16.1, 16.5, 16.7, 18.7, 19.2, 19.6, 20.2, 21.5, 22.2, 22.3, 22.5, 22.7, 23.0 (22.97), 23.0 (23.04), 23.5, Peaks at 25.7, 25.8, 26.8, 27.5, 28.1, 28.8, 28.9, 29.8, 29.9, 30.9, 31.8, 31.9, 32.4, 32.5, 33.7, 34.5, 34.7, 35.0, 36.2, 36.3, 37.5, 37.6, 38.9, and 39.0 ± 0.5°2θ are characterized.

[0348] Glyc-1 salt was analyzed using DSC-TGA according to the method described above. Data were plotted on... Figure 44 In the middle, the weight loss was approximately 1.89% when the temperature increased from room temperature to 100°C. Furthermore, the DSC thermal analysis of the Glyc-1 salt showed a strong peak temperature at approximately 118.5°C.

[0349] As mentioned above, in the reaction with glycolic acid, a deuterated R free base is used to replace ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, to generate deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one glycolate-1 (deuterated R glycolate-1, also identified as deuterated R Glyc-1). The XRPD and DSC-TGA patterns of deuterated R Glyc-1 are essentially the same as those of Glyc-1. The DVS pattern of the deuterated R Glyc-1 salt is essentially the same as that of Glyc-1.

[0350] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one glycolate and its deuterated analogues As mentioned above, in the reaction with glycolic acid, S-free base and deuterated S-free base are used to replace ( R(S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one yields (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one glycolate-1 (S glycolate-1, also known as S Glyc-1) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one glycolate-1 (deuterated S glycolate-1, also known as deuterated S Glyc-1). The XRPD diffraction patterns and DSC-TGA of S Glyc-1 and deuterated S Glyc-1 are essentially the same as those of Glyc-1. The DVS patterns of S Glyc-1 and deuterated SGlyc-1 salts are essentially the same as those of Glyc-1.

[0351] (k) 1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-L-malate and its deuterated analogues Add 0.25 mL of ethyl acetate to a volume containing approximately 40 mg of free base. R The product was placed in a glass vial containing 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. One molar equivalent of L-malic acid was added to the vial, and the mixture was stirred at room temperature. The solid product was observed and collected, then dried under vacuum at room temperature. The product separated from the vial was crystalline and is identified herein as (…). R L-Mali-1 (malate-1, also designated as Mali-1), 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. The stoichiometric ratio of base to acid was determined by proton NMR to be 1:1.

[0352] Mali-1 was obtained through XRPD analysis. Figure 45 The XRPD diffraction pattern of Mali-1 is shown. Table 29 below lists the XRPD peaks and intensities of the Mali-1 salt.

[0353] Table 29. Figure 45 XRPD peak of (Mali-1). peak# Pos. [°2θ] strength 1 11.1721 263.82 2 12.1059 67.66 3 13.3822 1374.07 4 14.7302 456.69 5 15.3409 122.29 6 15.7688 1930.08 7 16.4979 70.44 8 17.6293 116.18 9 18.4924 1317.74 10 18.9377 58.50 11 19.3630 375.73 12 20.9303 96.92 13 22.3519 316.01 14 23.6187 140.13 15 24.4159 125.50 16 24.9386 23.34 17 26.7272 108.90 18 26.9167 159.22 19 28.6489 58.21 20 29.4632 40.35 21 29.6955 370.71 22 31.2940 283.92 23 31.8862 338.13 24 33.2404 107.60 25 34.3110 34.06 26 35.7117 35.48 27 36.1274 29.99 28 37.5101 129.37

[0354] As shown in the figure, in one embodiment, the Mali-1 salt can be characterized by peaks in the X-ray diffraction pattern at 13.4, 15.8, and 18.5 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 13.4, 14.7, 15.8, 18.5, and 19.4 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 11.2, 13.4, 14.7, 15.8, 18.5, 19.4, 22.4, 29.7, 31.3, and 31.9 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 11.2, 12.1, 13.4, 14.7, 15.3, 15.8, 16.5, 17.6, 18.5, 18.9, 19.4, 20.9, 22.4, 23.6, 24.4, 24.9, 26.7, 26.9, 28.6, 29.4, 29.7, 31.3, 31.9, 33.2, 34.3, 35.7, 36.1, and 37.5 ± 0.5°2θ.

[0355] Mali-1 salts were analyzed using the above method via DSC-TGA. Data are presented in... Figure 46 The weight loss was approximately 0.70% when the temperature increased from room temperature to 100°C. Furthermore, the DSC thermal analysis of the Mali-1 salt showed two temperature peaks: a broad peak at approximately 196.3°C and a sharp peak at approximately 126.0°C.

[0356] In the reaction with L-malic acid, the free base is replaced by a deuterated R-base ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, to generate deuterated ( R A crystalline polymorph salt of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one malate-1 (deuterated R-malate-1, also identified as deuterated R-Mali-1). The XRPD diffraction pattern of deuterated R-Mali-1 is essentially the same as that of Mali-1, as determined by DSC-TGA. The DVS pattern of deuterated R-Mali-1 is also essentially the same as that of Mali-1.

[0357] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one-D-malate and its deuterated analogues In the above reaction, the free base is replaced by a free S base and a deuterated S base. R(S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one was synthesized by substituting L-malic acid with D-malic acid, resulting in crystalline polymorphic salts of (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one D-malate-1 (also identified as S Mali-1) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one D-malate-1 (deuterated S-malate-1, also identified as deuterated S Mali-1). The XRPD and DSC-TGA patterns of S Mali-1 and deuterated S Mali-1 are essentially the same as those of Mali-1. The DVS patterns of S Mali-1 and deuterated S Mali-1 are also essentially the same as those of Mali-1.

[0358] (l) 1. ( R 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hippurate and its deuterated analogues Isopropanol, ethyl acetate, and tetrahydrofuran (0.25 mL each) were added to a volume containing approximately 40 mg of free base. R The product was placed in three different glass vials containing 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. One equivalent of hippuric acid was added to each vial, and the mixture was stirred at room temperature. Solid products were observed and collected in each vial, and then dried under vacuum at room temperature. X-ray powder diffraction (XRPD) confirmed that the product isolated from each vial was crystalline, and all products exhibited the same XRPD diffraction pattern. This product is identified herein as (…). R Hip-1 (also designated as hippurate-1), 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one. The stoichiometric ratio of base to acid was determined to be 1:1 by proton nuclear magnetic resonance (NMR).

[0359] Hip-1 was obtained through XRPD analysis. Figure 47 The XRPD diffraction pattern of Hip-1 was depicted. The XRPD peaks and intensities of the Hip-1 salt are provided in Table 30 below.

[0360] Table 30. Figure 47 XRPD peak of (Hip-1). peak# Pos. [°2θ] strength 1 6.2305 2211.45 2 8.6362 2257.64 3 12.4614 3087.53 4 13.0098 762.47 5 13.8322 163.90 6 15.0865 205.62 7 15.9754 437.85 8 17.2922 854.62 9 18.7236 1929.06 10 18.8918 692.28 11 19.0590 1370.20 12 19.6755 171.47 13 19.8315 293.95 14 20.2045 1085.04 15 20.9043 1380.78 16 20.9821 1102.20 17 21.4090 214.57 18 21.9261 86.91 19 22.2102 106.70 20 22.4489 476.50 21 23.4805 78.96 22 24.0299 138.50 23 24.5032 56.96 24 25.0452 270.99 25 25.8273 672.63 26 26.1795 233.65 27 26.3063 102.45 28 26.9773 212.90 29 27.8778 253.64 30 28.2464 212.39 31 29.1055 15.85 32 30.4384 54.57 33 30.8096 78.09 34 30.9916 231.09 35 31.7061 103.25 36 32.5413 194.27 37 33.0512 150.10 38 33.1714 67.49 39 33.7479 233.31 40 33.8534 154.87 41 34.2352 33.93 42 35.1513 36.72 43 35.7076 23.37 44 36.4758 44.93 45 38.0252 60.99 46 38.3701 55.99

[0361] As shown in the figure, in one embodiment, the Hip-1 salt can be characterized by strong peaks in the X-ray diffraction patterns at 6.2, 8.6, and 12.5 ± 0.5°2θ. In another embodiment, the salt can be characterized by peaks at 6.2, 8.6, 12.5, 18.7, and 20.9 ± 0.5°2θ. In yet another embodiment, the salt can be characterized by peaks at 6.2, 8.6, 12.5, 13.0, 17.3, 18.7, 19.1, 20.2, 20.9, and 21.0 ± 0.5°2θ. In another embodiment, the salt can be obtained from 6.2, 8.6, 12.5, 13.0, 13.8, 15.1, 16.0, 17.3, 18.7, 18.9, 19.1, 19.7, 19.8, 20.2, 20.9, 21.0, 21.4, 21.9, 22.2, 22.4, 23.5, 24.0.5, 24. The peaks at 5, 25.0, 25.8, 26.2, 26.3, 27.0, 27.9, 28.2, 29.1, 30.4, 30.8, 31.0, 31.7, 32.5, 33.1, 33.2, 33.7, 33.9, 34.2, 35.2, 35.7, 36.5, 38.0, and 38.4 ± 0.5°2θ are used to characterize the readings.

[0362] Hip-1 salt was analyzed using the method described above via DSC-TGA. Data were plotted on... Figure 48 In the meantime, the weight loss is approximately 0.69% when the temperature increases from room temperature to 100°C. Furthermore, the DSC thermal analysis of the Hip-1 salt shows a strong peak temperature at approximately 117.6°C.

[0363] In the reaction with hippuric acid, the free base is replaced by a deuterated R-free base ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, to generate deuterated ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hippurate-1 (deuterated R hippurate-1, also identified as deuterated R Hip-1). The XRPD and DSC-TGA patterns of deuterated R Hip-1 are essentially the same as those of Hip-1. Furthermore, the DVS pattern of the deuterated R Hip-1 salt is substantially similar to that of Hip-1.

[0364] 2. (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hippurate and its deuterated analogues.

[0365] In the above reaction with hippuric acid, S-free base and deuterated S-free base are used to replace the free base ( R(S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one was synthesized to produce (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hippurate-1 (S-hippurate-1, also known as S Hip-1) and deuterated (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hippurate-1 (deuterated S-hippurate-1, also known as deuterated S Hip-1). The XRPD diffraction patterns and DSC-TGA of S Hip-1 and deuterated S Hip-1 are essentially the same as those of Hip-1. Furthermore, the DVS patterns of S Hip-1 and deuterated S Hip-1 salts are essentially the same as those of Hip-1.

[0366] Public utilities and pharmaceutical compositions The salt disclosed herein is applicable to the treatment of mental disorders. Its efficacy is identical to that described in U.S. Patent No. 11,344,510, the contents of which are incorporated herein by reference.

[0367] More specifically, in another aspect, this document provides a method for treating depression or anxiety-depression in a subject in need, the method comprising administering an effective amount of the salt disclosed herein to the subject in need. In some embodiments, the salt is administered orally.

[0368] This salt is applicable to a method of treating mental disorders in patients requiring treatment, the method comprising administering a therapeutically effective amount of the salt disclosed herein or a composition containing the salt to a subject in need. The anticipated mental disorder may include depressive disorders such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, intrusive mood disorders, substance / drug-induced depressive disorder, and depressive disorder due to another medical condition. The salt described in this disclosure is applicable to treating treatment-resistant depression, such as when a patient suffering from depression does not respond to and / or has not yet responded to an appropriate course of treatment with at least one or two other antidepressant compounds or therapeutic agents. In this disclosure, “depression” encompasses treatment-resistant depression. In some embodiments, the salt disclosed herein may be used to treat mental disorders, including bipolar disorder and related disorders, such as type I bipolar disorder, type II bipolar disorder, cyclothymic affective disorder, substance / drug-induced bipolar disorder and related disorders, and bipolar disorder and related disorders attributable to another medical condition. In some embodiments, the salts disclosed herein can be used to treat mental disorders including substance-related disorders, such as preventing substance use addiction, reducing substance use addiction, 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” or “substances” refers to addictive psychoactive compounds such as alcohol, caffeine, cannabis, hallucinogens, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, these methods and compositions can be used to promote smoking cessation or opioid use cessation.

[0369] In some embodiments, the salts disclosed herein can be used to treat mental disorders, including anxiety disorders such as separation anxiety disorder, selective mutism, object phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, and anxiety disorder attributable to another medical condition. In some embodiments, the salts disclosed herein can be used to treat mental disorders, including obsessive-compulsive disorder and related disorders such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), scratching disorder, substance / drug-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder and related disorders attributable to another medical condition. In some embodiments, the salts disclosed herein can be used to treat mental disorders, including trauma and stress-related disorders such as reactive attachment disorder, disinhibitory social participation disorder, post-traumatic stress disorder, acute stress disorder, and dysregulation. In some implementations, the salt disclosed herein can be used to treat mental disorders, including eating and dietary disorders such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidant / restrictive eating disorder.

[0370] In some embodiments, the salts disclosed herein can be used to treat mental disorders including neurocognitive impairments, such as delirium, severe neurocognitive impairment, mild neurocognitive impairment, severe or mild neurocognitive impairment due to Alzheimer's disease, severe or mild frontotemporal neurocognitive impairment, Lewy body severe or mild neurocognitive impairment, severe or mild vascular neurocognitive impairment, severe or mild neurocognitive impairment due to traumatic brain injury, substance / drug-induced severe or mild neurocognitive impairment, severe or mild neurocognitive impairment due to HIV infection, severe or mild neurocognitive impairment due to prion disease, severe or mild neurocognitive impairment due to Parkinson's disease, severe or mild neurocognitive impairment due to Huntington's disease, severe or mild neurocognitive impairment due to another medical condition, and severe or mild neurocognitive impairment due to multiple etiologies. Furthermore, in some embodiments, the salts disclosed herein can be used to treat mental disorders, including neurodevelopmental disorders such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotyped movement disorder, tic disorders, Tourette's disorder, persistent (chronic) motor or vocal tic disorders, and transient tic disorders. Additionally, in some embodiments, the salts disclosed herein can be used to treat mental disorders, including personality disorders such as borderline personality disorder.

[0371] Additionally, in some embodiments, the salts disclosed herein can be used to treat mental disorders, including sexual dysfunctions such as delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest or arousal disorder, genital-pelvic pain or vaginal penetration disorder, male hyposexuality, premature ejaculation, and substance / drug-induced sexual dysfunction. In some embodiments, the salts disclosed herein can be used to treat mental disorders including gender dysphoria, such as gender dysphoria.

[0372] In some embodiments, the method of using the salt disclosed herein includes treating mental disorders by administering a pharmaceutical composition comprising about 0.01 mg to about 400 mg of the salt disclosed herein to a subject in need. In some embodiments, the dosage is, for example, about 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 150 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150 mg, 10 to 100 mg, 10 to 50 mg, 10 to 25 mg, 10 to 15 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 200 mg. The dosage ranges from 50 to 150 mg, 50 to 100 mg, 100 to 300 mg, 100 to 250 mg, and 100 to 200 mg, with doses such as 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.

[0373] In some embodiments, the dosage may include the amount of salt disclosed herein, ranging from approximately, 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 to 15 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, wherein specific examples of the dosage may be 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, 1.5 mg, 1.0 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, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, etc. mg, 8.5 mg, 9 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 and 200 mg.

[0374] Typically, the salts disclosed herein are administered to patients in need once, twice, three or four times daily, every other day, every three days, once weekly, or once monthly. In some embodiments, 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, 25 mg / day, 20 mg / day, 10 mg / day, 5 mg / day, or 1 mg / day.

[0375] In some embodiments, pharmaceutical compositions for non-enteral or inhaled administration, such as sprays or mists of the salts disclosed herein, comprise concentrations of about 0.005 mg / mL to about 500 mg / mL. In some embodiments, the composition comprises the salts disclosed herein 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 0.1 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.

[0376] In some embodiments, the composition comprises, for example, a salt disclosed herein at concentrations of 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, about 10 mg / mL to 100 mg / mL, about 20 mg / mL to 200 mg / mL, or about 30 mg / mL to about 300 mg / mL. In some embodiments, the pharmaceutical composition is prepared to a total volume of about, for example, 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0377] Typically, the dosage may be administered to the subject once, twice, three or four times daily, every other day, every three days, twice weekly, once weekly, twice monthly, once monthly, three times a year, twice a year, or once a year. In some embodiments, the salt disclosed herein is administered to the subject once in the morning or once in the evening. In some embodiments, the salt disclosed herein is administered to the subject once in the morning and once in the evening. In some embodiments, the salt disclosed herein is administered to the subject three times a day (e.g., at breakfast, lunch, and dinner) at a dose of, for example, 50 mg per dose (e.g., 150 mg per day).

[0378] In some embodiments, the salt disclosed herein is administered to the subject at a dose of 25 mg / day, in one or more doses. In some embodiments, the salt disclosed herein is administered to the subject at a dose of 50 mg / day, in one or more doses. In some embodiments, the salt disclosed herein is administered to the subject at a dose of 100 mg / day, in one or more doses. In some embodiments, the salt disclosed herein is administered to the subject at a dose of 150 mg / day, in one or more doses. In some embodiments, the salt disclosed herein is administered to the subject at a dose of 200 mg / day, in one or more doses. In some embodiments, the salt disclosed herein is administered to the subject at a dose of 250 mg / day, in one or more doses.

[0379] In some embodiments, the salt disclosed herein is administered at doses of 0.01-100 mg / kg, 0.5-50 mg / kg, 0.5-10 mg / kg, or 25-50 mg / kg once, twice, three times, or four times daily. For example, in some embodiments, the dose is 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg once, twice, three times, or four times daily. In some embodiments, the subject receives a total daily dose of 0.01 mg to 500 mg of the salt disclosed herein once, twice, three times, or four times daily. In some embodiments, the total dose administered to the subject over a 24-hour period may be, for example, 5 mg, 10 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, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg. In some embodiments, the subject may start with a low dose and increase the dose. In some embodiments, the subject may start with a high dose and decrease the dose.

[0380] In some implementations, the salt disclosed herein is administered to patients under the supervision of a healthcare provider.

[0381] In some implementations, the salt disclosed herein is administered to the patient under the supervision of a healthcare provider at a clinic specializing in the delivery of psychoactive treatments.

[0382] In some implementations, the salt disclosed herein is administered to the patient under the supervision of a healthcare provider at a dose intended to induce a psychotic experience in the subject.

[0383] In some implementations, the medication is administered to the patient periodically under the supervision of a healthcare provider to maintain the therapeutic effect, for example, 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.

[0384] In some implementations, the salt disclosed herein is administered under the supervision of the patient at home or otherwise away from a healthcare provider.

[0385] In some implementations, the patient administers the medication periodically to maintain the therapeutic effect, for example, daily, every other day, every three days, twice a week, once a week, twice a month, or once a month.

[0386] In some implementations, the salt disclosed herein can be administered at specified time intervals. For example, during treatment, the salt disclosed herein can be administered to the patient at time 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.

[0387] In some embodiments, the pharmaceutical composition comprises one or more of the salts disclosed herein. In some embodiments, the salts disclosed herein are used in any of the methods, uses, or compositions described herein.

[0388] Therefore, this disclosure also relates to pharmaceutical compositions comprising the salts disclosed herein mixed with pharmaceutically acceptable adjuvants and optionally other therapeutic agents. The adjuvants must be "acceptable" in the sense that they are compatible with the other components of the composition and harmless to the recipient.

[0389] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including percutaneous, oral, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration or via implantation. The compositions may be prepared by any method well known in the pharmaceutical field.

[0390] Such methods include the step of combining the salt disclosed herein with any excipient. Excipients also include auxiliary components, including those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents. Such excipients are appropriately selected based on the intended form and route of administration, and in accordance with routine pharmaceutical practice.

[0391] Pharmaceutical compositions suitable for oral administration may be presented in dispersible dosage form units, such as pills, tablets, sugar-coated lozenges, or capsules, or in powder or granule form, or in solution or suspension form. The active ingredients comprising the salts disclosed herein may also be presented in bolus or paste form. The compositions may be further processed into suppositories or enemas for rectal administration.

[0392] Salts in pharmaceutical compositions can be administered in solid dosage forms. For example, tablets may contain the salts disclosed herein as active ingredients, combined with suitable binders, lubricants, disintegrants, colorants, flavorings, diluents, and meltsinks. Gelatin capsules may contain the active ingredient salts disclosed herein and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant tastes and protect the tablets from atmospheric effects, or enteric-coated for selective disintegration in the gastrointestinal tract. For example, for oral administration in unit dosage forms of tablets or capsules, the active pharmaceutical ingredient consisting of the salts disclosed herein may be combined with an orally administered, non-toxic, pharmaceutically acceptable inert carrier (e.g., lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, 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. Lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.

[0393] For oral administration in liquid dosage forms, one or more salts disclosed herein are combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water, etc.). Examples of suitable liquid dosage forms include 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-foaming particles, and foaming formulations reconstituted from foaming particles. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms for oral administration may contain colorants and flavoring agents to increase patient acceptability.

[0394] For enteral administration, suitable compositions include aqueous and non-aqueous sterile solutions of one or more salts disclosed herein. Generally, water, suitable oils, physiological saline, aqueous dextran (glucose) and related sugar solutions, and glycols (such as propylene glycol or polyethylene glycol) are suitable carriers for enteral solutions. Solutions for enteral administration preferably contain water-soluble salts of the active ingredient (i.e., salts disclosed herein) and suitable stabilizers and, if necessary, buffering agents. 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. Additionally, enteral solutions may contain preservatives such as benzalkonium chloride, methylparaben or propylparaben, and chlorobutanol. Compositions may also 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 for injection, 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 sprays that may be generated by metered-dose pressurized sprays, nebulizers, or inhalers. Non-enteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

[0395] The salts disclosed herein, used in the methods of this disclosure, can also be administered in the form of liposome delivery systems, such as monolayer microvesicles, monolayer macrovesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearamine, or phosphatidylcholine. The salts disclosed herein can be administered as a component of emulsions targeting tissues.

[0396] The salts disclosed in this disclosure can also be coupled to soluble polymers used as targeted drug carriers or prodrugs. Such polymers may include polyvinylpyrrolidone, piperan copolymers, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethyl-asparagine-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the salts disclosed herein can be coupled to a class of biodegradable polymers suitable for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropiperanone, polycyanoacrylates, and crosslinked or amphoteric block copolymers of hydrogels.

[0397] This document provides information on immediate, delayed, extended, or modified release distributions of pharmaceutical compositions. In some embodiments, pharmaceutical compositions with different drug release profiles can be combined to establish two-phase or three-phase release profiles. For example, a pharmaceutical composition may provide both immediate and extended release distributions. Such compositions may be supplied with pulse-formulated formulations, multilayer tablets, or capsules containing tablets, beads, particles, etc.

[0398] The pharmaceutical compositions described herein can provide abuse deterrence features using techniques known in the art, such as by preparing tablets that are difficult to crush or dissolve in water.

[0399] The pharmaceutical composition described above may be combined with an encapsulation material that includes instructions for using the composition for the purposes described above.

[0400] The precise dosage and regimen of the composition containing the salts disclosed herein will necessarily depend on the type and amount of therapeutic or nutritional effect to be achieved, and may vary depending on factors such as the specific compound, formulation, route of administration, or the age and condition of the subject receiving the composition.

[0401] Furthermore, in some embodiments, the pharmaceutical compositions disclosed herein may include a single enantiomer, diastereomer, or structural isomer of the salt disclosed herein, wherein such stereoisomers are present. In other embodiments, the pharmaceutical compositions disclosed herein may include a mixture of at least one single enantiomer, diastereomer, or structural isomer of the salt disclosed herein with another enantiomer, diastereomer, or structural isomer of the salt disclosed herein. In other embodiments, the mixture is a racemic mixture. In other embodiments, the mixture is a non-racemic mixture (wherein a non-racemic mixture contains one enantiomer or diastereomer). In some embodiments, the salt disclosed herein is substantially pure, or enantiomerically pure, or both, or may contain a polymorph of any of the salts disclosed herein.

[0402] The salts disclosed herein can be administered in various forms, including those detailed herein. Treatment with the disclosed salts can be a component of combination therapy or adjunctive therapy, i.e., the subject or patient requiring medication is treated with another drug for the disease together with one or more of the disclosed salts, or another drug for the disease is administered together with one or more of the disclosed salts. This combination therapy can be sequential therapy, wherein the patient is first treated with one drug, and then other or two drugs may be administered simultaneously thereafter. Depending on the dosage form used, these administrations can be carried out independently via the same route or via two or more different routes of administration.

[0403] Although certain features of this disclosure have been described and illustrated herein, various 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 as belonging to the true spirit of this disclosure.

Claims

1. A kind of ( R Crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one, comprising: crystallization( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexyl-1-one methanesulfonate, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexyl-1-one maleate, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexyl-1-one phosphate, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexyl-1-one tartrate, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexyl-1-one fumarate, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate, crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexyl-1-one malate or crystals ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexyl-1-one hippurate.

2. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride.

3. The crystalline salt according to claim 2, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexyl-1-one hydrochloride form 1.

4. The crystalline salt according to claim 3, characterized in that... The X-ray powder diffraction pattern contains peaks at 9.7, 15.0, and 18.6 ± 0.5°2θ.

5. The crystalline salt according to claim 3, characterized in that... The X-ray powder diffraction pattern contains peaks at 9.7, 13.1, 15.0, 18.6, and 24.2 ± 0.5°2θ.

6. The crystalline salt according to claim 3, characterized in that... The X-ray powder diffraction pattern contains peaks at 9.7, 13.1, 14.6, 15.0, 18.6, 19.2, 22.5, 24.2, 25.1 and 31.6 ± 0.5°2θ.

7. The crystalline salt according to claim 3, characterized in that... The X-ray powder diffraction pattern contains peaks at 9.7, 12.8, 13.1, 14.3, 14.6, 15.0, 15.7, 17.1, 18.6, 19.2, 19.5, 22.4, 22.5, 23.1, 23.8, 24.2, 24.4, 25.1, 25.3, 25.7, 26.3, 26.6, 27.1, 27.4, 28.8, 29.6, 30.1, 30.5, 30.9, 31.6, 32.1, 33.1, 33.7, 34.0, 34.3, 34.6, 35.0, 35.3, 35.8, 36.3, 36.5, 36.9, 37.6, 37.9, 38.0, and 38.8 ± 0.5°2θ.

8. The crystalline salt according to claim 3, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 2.

9. The crystalline salt according to any one of claims 3-8, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 238°C.

10. The crystalline salt according to any one of claims 3-9, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 4.

11. The crystalline salt according to claim 2, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hydrochloride form 2.

12. The crystalline salt according to claim 11, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.2, 15.0, and 24.0 ± 0.5°2θ.

13. The crystalline salt according to claim 11, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.2, 15.0, 18.4, 18.7, and 24.0 ± 0.5°2θ.

14. The crystalline salt according to claim 11, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.0, 13.2, 15.0, 17.2, 18.4, 18.7, 24.0, 26.9, 27.1, and 31.1 ± 0.5°2θ.

15. The crystalline salt according to claim 11, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 7.

16. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate.

17. The crystalline salt according to claim 16, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-1.

18. The crystalline salt according to claim 17, characterized in that... The X-ray powder diffraction pattern contains peaks at 10.2, 16.0, and 17.6 ± 0.5°2θ.

19. The crystalline salt according to claim 17, characterized in that... The X-ray powder diffraction pattern contains peaks at 10.2, 16.0, 16.4, 17.6, and 22.7 ± 0.5°2θ.

20. The crystalline salt according to claim 17, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.5, 10.2, 16.0, 16.4, 17.6, 18.5, 19.4, 22.4, 22.6, and 22.7 ± 0.5°2θ.

21. The crystalline salt according to claim 17, characterized in that... The X-ray powder diffraction patterns include values ​​at 7.5, 10.2, 11.8, 12.2, 13.6, 13.7, 14.8, 14.9, 16.0, 16.4, 17.3, 17.6, 18.5, 19.4, 19.5, 19.7, 20.6, 21.0, 21.5, 22.1, 22.4, 22.6, 22.7, 22.9, 23.0, and 23... Peaks at 0.8, 24.4, 25.0, 25.5, 25.9, 26.6, 27.3, 27.8, 28.7, 28.9, 29.3, 29.7, 30.2, 30.5, 30.8, 31.1, 32.2, 32.6, 32.8, 33.0, 33.5, 33.9, 34.3, 34.5, 38.2, and 39.1 ± 0.5°2θ.

22. The crystalline salt according to claim 17, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 8.

23. The crystalline salt according to any one of claims 17-22, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 221.3°C.

24. The crystalline salt according to any one of claims 17-23, characterized in that... The DSC thermal analysis plot shows at least two endothermic peaks at approximately 136.9°C and approximately 221.3°C.

25. The crystalline salt according to any one of claims 17-24, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 9.

26. The crystalline salt according to claim 16, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-3.

27. The crystalline salt according to claim 26, characterized in that... The X-ray powder diffraction pattern contains peaks at 11.9, 16.0, and 18.7 ± 0.5°2θ.

28. The crystalline salt according to claim 26, characterized in that... The X-ray powder diffraction pattern contains peaks at 10.2, 11.9, 16.0, 17.6, and 18.7 ± 0.5°2θ.

29. The crystalline salt according to claim 26, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.1, 7.7, 8.5, 10.2, 11.9, 16.0, 17.6, 18.5, 18.7 and 22.7 ± 0.5°2θ.

30. The crystalline salt according to claim 26, characterized in that... The X-ray powder diffraction patterns are included in the ranges of 7.1, 7.5, 7.7, 8.5, 10.2, 10.5, 11.9, 12.2, 13.1, 15.5, 16.0, 16.4, 17.6, 17.7, 18.1, 18.5, 18.7, 19.4, 19.7, 20.1, 20.7, 21.0, 21.2, 21.5, and 22. Peaks at 1, 22.5, 22.7, 23.0, 23.5, 23.8, 24.3, 24.9, 25.5, 26.2, 26.7, 27.5, 27.8, 28.4, 28.7, 29.0, 29.3, 29.8, 30.3, 30.8, 31.2, 32.7, 33.7, 34.6, and 38.0 ± 0.5°2θ.

31. The crystalline salt according to claim 26, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 11.

32. The crystalline salt according to claim 16, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one sulfate-4.

33. The crystalline salt according to claim 32, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.9, 16.0, and 17.6 ± 0.5°2θ.

34. The crystalline salt according to claim 32, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.9, 10.2, 16.0, 17.6, and 22.7 ± 0.5°2θ.

35. The crystalline salt according to claim 32, characterized in that... The X-ray powder diffraction pattern contains peaks at 4.6, 7.9, 10.2, 16.0, 16.4, 16.6, 17.6, 19.4, 21.1, and 22.7 ± 0.5°2θ.

36. The crystalline salt according to claim 32, characterized in that... The X-ray powder diffraction pattern contains peaks at 4.6, 7.5, 7.9, 9.6, 10.2, 11.6, 12.2, 13.8, 14.8, 16.0, 16.4, 16.6, 17.6, 18.4, 19.4, 19.6, 20.8, 21.1, 21.5, 21.7, 22.1, 22.5, 22.7, 23.0, 23.8, 24.4, 25.0, 25.5, 25.8, 26.3, 27.8, 28.2, 28.9, 30.2, 31.2, 32.6, and 33.9 ± 0.5°2θ.

37. The crystalline salt according to claim 32, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 12.

38. The crystalline salt according to claim 1, wherein it is ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate.

39. The crystalline salt according to claim 38, wherein it is ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate-1.

40. The crystalline salt according to claim 39, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 10.6, and 19.5 ± 0.5°2θ.

41. The crystalline salt according to claim 39, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 10.6, 13.3, 14.6, and 19.5 ± 0.5°2θ.

42. The crystalline salt according to claim 39, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 10.6, 13.3, 14.6, 19.5, 20.2, 22.4, 26.2, 26.3, and 26.7 ± 0.5°2θ.

43. The crystalline salt according to claim 39, characterized in that... The X-ray powder diffraction pattern contains peaks at 2.1, 5.9, 6.6, 10.6, 12.0, 13.3, 14.6, 16.7, 17.4, 17.8, 19.5, 19.9, 20.2, 20.4, 21.3, 21.9, 22.4, 22.6, 23.8, 24.6, 25.5, 26.2, 26.3, 26.7, 28.2, 28.5, 28.9, 30.4, 31.0, 31.8, 32.4, 32.9, 33.4, 33.5, 35.1, 36.5, 38.0, and 39.5 ± 0.5°2θ.

44. The crystalline salt according to claim 39, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 13.

45. The crystalline salt according to any one of claims 39-44, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 156.9°C.

46. ​​The crystalline salt according to any one of claims 39-45, characterized in that... The DSC thermal analysis plot shows at least two endothermic peaks at approximately 158.9°C and approximately 172.3°C.

47. The crystalline salt according to any one of claims 39-46, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 14.

48. The crystalline salt according to claim 38, wherein it is ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one p-toluenesulfonate-2B.

49. The crystalline salt according to claim 48, characterized in that... The X-ray powder diffraction pattern contains peaks at 5.4, 19.6, and 21.6 ± 0.5°2θ.

50. The crystalline salt according to claim 48, characterized in that... The X-ray powder diffraction pattern contains peaks at 5.4, 10.7, 16.1, 19.6, and 21.6 ± 0.5°2θ.

51. The crystalline salt according to claim 48, characterized in that... The X-ray powder diffraction pattern contains peaks at 5.4, 6.0, 10.5, 10.7, 13.2, 14.7, 16.1, 19.0, 19.3, 19.6, 20.1, 20.8, 21.6, 23.2, 23.4, 24.0, 26.7, 26.8, 27.1, 34.1, and 38.2 ± 0.5°2θ.

52. The crystalline salt according to claim 48, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 16.

53. The crystalline salt according to any one of claims 48-51, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 168.7°C.

54. The crystalline salt according to any one of claims 48-52, characterized in that... The DSC thermal analysis plot shows at least two endothermic peaks at approximately 168.7°C and approximately 117.3°C or approximately 70.7°C.

55. The crystalline salt according to any one of claims 48-53, characterized in that... The DSC thermal analysis plot shows at least three endothermic peaks at approximately 168.7°C, approximately 117.3°C, and approximately 70.7°C.

56. The crystalline salt according to any one of claims 48-54, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 17.

57. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one methanesulfonate.

58. The crystalline salt according to claim 57, characterized in that... The X-ray powder diffraction pattern contains peaks at 10.1, 15.7, and 16.9 ± 0.5°2θ.

59. The crystalline salt according to claim 57, characterized in that... The X-ray powder diffraction pattern contains peaks at 10.1, 15.7, 16.9, 22.2, and 22.6 ± 0.5°2θ.

60. The crystalline salt according to claim 57, characterized in that... The X-ray powder diffraction pattern contains peaks at 10.1, 13.4, 15.7, 16.9, 17.4, 18.8, 20.4, 22.2, 22.6, and 22.7 ± 0.5°2θ.

61. The crystalline salt according to claim 57, characterized in that... The X-ray powder diffraction pattern includes values ​​at 10.1, 10.9, 11.8, 12.8, 13.4, 15.0, 15.7, 16.9, 17.4, 17.7, 18.0, 18.8, 19.1, 20.4, 20.8, 21.2, 22.2, 22.4, 22.6, 22.7, 23.3, 24.5, 24.6, 24.9, 25.2, and 2... Peaks at 5.7, 26.0, 26.5, 26.9, 27.3, 27.5, 28.4, 28.6, 29.6, 30.3, 30.6, 30.8, 31.1, 31.6, 31.8, 32.3, 32.4, 33.5, 34.5, 35.2, 35.4, 35.9, 36.3, 37.3, 38.3 and 39.9 ± 0.5°2θ.

62. The crystalline salt according to claim 57, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 18.

63. The crystalline salt according to any one of claims 57-62, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 228.3°C.

64. The crystalline salt according to any one of claims 57-63, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 19.

65. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one maleate.

66. The crystalline salt according to claim 65, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one maleate-1.

67. The crystalline salt according to claim 66, characterized in that... The X-ray powder diffraction pattern contains peaks at 16.2, 19.4, and 24.6 ± 0.5°2θ.

68. The crystalline salt according to claim 66, characterized in that... The X-ray powder diffraction pattern contains peaks at 14.3, 16.2, 19.4, 24.6, and 24.7 ± 0.5°2θ.

69. The crystalline salt according to claim 66, characterized in that... The X-ray powder diffraction pattern contains peaks at 14.3, 16.2, 18.6, 19.4, 20.5, 21.4, 23.8, 24.6, 24.7 and 31.8 ± 0.5°2θ.

70. The crystalline salt according to claim 66, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.2, 14.3, 15.0, 15.2, 16.2, 17.0, 17.5, 18.6, 19.4, 20.5, 21.4, 21.9, 23.8, 24.6, 24.7, 25.5, 25.7, 26.3, 26.7, 27.3, 28.0, 29.2, 29.3, 30.7, 31.6, 31.8, 31.9, 32.2, 32.7, 33.1, 33.6, 34.5, 34.6, 34.8, 35.7, 36.0, 36.8, 37.3, 37.4, 38.5, and 39.3 ± 0.5°2θ.

71. The crystalline salt according to claim 66, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 20.

72. The crystalline salt according to any one of claims 66-71, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 202.0°C.

73. The crystalline salt according to any one of claims 66-72, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 21.

74. The crystalline salt according to claim 65, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one maleate-2.

75. The crystalline salt according to claim 74, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.3, 16.0, and 18.8 ± 0.5°2θ.

76. The crystalline salt according to claim 74, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.3, 14.7, 16.0, 18.8, and 19.2 ± 0.5°2θ.

77. The crystalline salt according to claim 74, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.3, 14.7, 16.0, 18.0, 18.6, 18.8, 19.2, 20.5, 22.6, and 24.1 ± 0.5°2θ.

78. The crystalline salt according to claim 74, characterized in that... The X-ray powder diffraction pattern includes values ​​at 9.3, 11.2, 13.3, 13.5, 14.7, 15.0, 16.0, 16.5, 18.0, 18.6, 18.8, 19.2, 20.5, 21.1, 21.9, 22.6, 23.2, 24.1, 24.4, 24.9, 25.3, 25.5, 26.7, 26.9, and 27.

0. Peaks at 27.2, 28.1, 28.5, 29.3, 29.8, 29.9, 30.3, 30.7, 31.3, 31.5, 31.9, 32.1, 32.4, 33.3, 33.8, 34.0, 34.6, 35.0, 35.3, 35.6, 36.0, 36.7, 37.3, 37.7 and 38.1 ± 0.5°2θ.

79. The crystalline salt according to claim 74, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 22.

80. The crystalline salt according to any one of claims 74-79, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 198.2°C.

81. The crystalline salt according to any one of claims 74-80, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 23.

82. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate.

83. The crystalline salt according to claim 82, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate-1.

84. The crystalline salt according to claim 83, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 19.1, 21.0, and 24.1 ± 0.5°2θ.

85. The crystalline salt according to claim 83, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 15.1, 19.1, 21.0, and 24.1 ± 0.5°2θ.

86. The crystalline salt according to claim 83, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 13.4, 15.1, 19.1, 21.0, 22.8, 23.2, 24.1, 27.0, and 27.8 ± 0.5°2θ.

87. The crystalline salt according to claim 83, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 11.5, 13.4, 14.7, 15.1, 15.6, 17.2, 18.1, 19.1, 20.0, 20.8, 21.0, 21.5, 22.8, 23.2, 24.1, 24.3, 25.2, 26.8, 27.0, 27.8, 28.5, 29.3, 29.7, 30.1, 31.4, 31.6, 32.1, 32.8, 33.0, 33.5, 34.0, 34.6, 36.0, 36.6, 36.9, 38.7, 39.0, and 39.6 ± 0.5°2θ.

88. The crystalline salt according to claim 83, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 24.

89. The crystalline salt according to any one of claims 83-88, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 236.0°C.

90. The crystalline salt according to any one of claims 83-89, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 25.

91. The crystalline salt according to claim 82, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one phosphate-2.

92. The crystalline salt according to claim 91, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 21.0, 24.1, and 33.5 ± 0.5°2θ.

93. The crystalline salt according to claim 91, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 13.4, 21.0, 24.1, and 33.5 ± 0.5°2θ.

94. The crystalline salt according to claim 91, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 7.1, 13.4, 19.1, 21.0, 24.1, 26.67, 26.75, 26.9 and 33.5 ± 0.5°2θ.

95. The crystalline salt according to claim 91, characterized in that... The X-ray powder diffraction pattern contains peaks at 3.5, 6.6, 7.1, 13.4, 14.7, 15.1, 15.6, 17.2, 18.1, 19.1, 19.9, 21.0, 22.7, 23.2, 24.1, 25.2, 26.67, 26.75, 26.9, 27.1, 27.7, 28.4, 29.2, 29.7, 30.1, 30.4, 31.4, 31.6, 33.5, 34.6, 35.9, 36.9, and 39.6 ± 0.5°2θ.

96. The crystalline salt according to claim 91, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 26.

97. The crystalline salt according to any one of claims 91-96, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 224.6°C.

98. The crystalline salt according to any one of claims 91-97, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 27.

99. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one tartrate.

100. The crystalline salt according to claim 99, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one tartrate-1.

101. The crystalline salt according to claim 100, characterized in that... The X-ray powder diffraction pattern contains peaks at 8.9, 15.7, and 19.2 ± 0.5°2θ.

102. The crystalline salt according to claim 100, characterized in that... The X-ray powder diffraction pattern contains peaks at 8.9, 15.5, 15.7, 17.5, and 19.2 ± 0.5°2θ.

103. The crystalline salt according to claim 100, characterized in that... The X-ray powder diffraction pattern contains peaks at 8.9, 11.8, 15.5, 15.7, 17.5, 17.8, 19.2, 23.0, 26.9, and 27.1 ± 0.5°2θ.

104. The crystalline salt according to claim 100, characterized in that... The X-ray powder diffraction pattern contains peaks at 8.9, 11.1, 11.8, 12.4, 12.7, 13.0, 14.2, 15.5, 15.7, 17.5, 17.8, 19.2, 19.8, 20.3, 20.8, 23.0, 23.6, 24.8, 25.6, 26.1, 26.9, 27.1, 28.7, 28.9, 29.3, 29.8, 30.2, 30.4, 31.0, 31.3, 33.7, and 36.2 ± 0.5°2θ.

105. The crystalline salt according to claim 100, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 28.

106. The crystalline salt according to claim 99, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one tartrate-5.

107. The crystalline salt according to claim 106, characterized in that... The X-ray powder diffraction pattern contains peaks at 16.6, 19.0, and 21.7 ± 0.5°2θ.

108. The crystalline salt according to claim 106, characterized in that... The X-ray powder diffraction pattern contains peaks at 9.3, 14.3, 16.6, 19.0, and 21.7 ± 0.5°2θ.

109. The crystalline salt according to claim 106, characterized in that... The X-ray powder diffraction pattern contains peaks at 9.3, 12.0, 12.4, 14.3, 15.1, 16.6, 19.0, 21.7, and 28.9 ± 0.5°2θ.

110. The crystalline salt according to claim 106, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 30.

111. The crystalline salt according to any one of claims 106-110, characterized in that... The DSC thermal analysis plot has at least one endothermic peak at approximately 163.5°C or approximately 187.2°C.

112. The crystalline salt according to any one of claims 106-111, characterized in that... The DSC thermal analysis plot shows at least two endothermic peaks at approximately 163.5°C and approximately 187.2°C.

113. The crystalline salt according to any one of claims 106-112, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 31.

114. The crystalline salt according to claim 99, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one tartrate-3.

115. The crystalline salt according to claim 114, characterized in that... The X-ray powder diffraction pattern contains peaks at 16.8, 18.8, and 19.4 ± 0.5°2θ.

116. The crystalline salt according to claim 114, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.6, 16.8, 18.8, 19.4, and 20.9 ± 0.5°2θ.

117. The crystalline salt according to claim 114, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.6, 12.2, 13.4, 16.8, 18.8, 19.2, 19.4, 19.9, 20.9, and 23.1 ± 0.5°2θ.

118. The crystalline salt according to claim 114, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.6, 12.2, 13.4, 15.0, 16.8, 18.8, 19.2, 19.4, 19.9, 20.7, 20.9, 22.3, 22.8, 23.1, 23.5, 24.5, 26.2, 27.0, 28.0, 28.6, 29.6, 30.0, 31.3, 32.0, 32.27, 32.29, 32.5, 33.4, 34.1, and 36.0 ± 0.5°2θ.

119. The crystalline salt according to claim 114, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 32.

120. The crystalline salt according to any one of claims 114-119, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 176.6°C.

121. The crystalline salt according to any one of claims 114-119, characterized in that... The DSC thermal analysis plot shows at least two endothermic peaks at approximately 176.6°C and approximately 110.1°C.

122. The crystalline salt according to any one of claims 114-121, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 33.

123. The crystalline salt according to claim 99, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one tartrate-6.

124. The crystalline salt according to claim 123, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 13.1, and 14.5 ± 0.5°2θ.

125. The crystalline salt according to claim 123, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 13.1, 14.5, 15.2, and 24.1 ± 0.5°2θ.

126. The crystalline salt according to claim 123, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 13.1, 14.2, 14.5, 15.2, 16.8, 20.2, 20.8, 23.3, and 24.1 ± 0.5°2θ.

127. The crystalline salt according to claim 123, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.4, 6.6, 13.1, 14.2, 14.5, 15.2, 16.0, 16.8, 17.1, 17.2, 17.5, 18.1, 18.5, 19.2, 19.5, 20.0, 20.2, 20.8, 21.1, 21.4, 21.6, 21.8, 23.3, 23.5, 24.1, 25.2, 26.0, 26.3, 26.7, 27.0, 27.3, 27.8, 28.3, 28.7, 29.0, 29.9, 30.2, 31.2, 31.6, 32.0, and 32.9 ± 0.5°2θ.

128. The crystalline salt according to claim 123, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 35.

129. The crystalline salt according to any one of claims 123-128, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 61.7°C.

130. The crystalline salt according to any one of claims 123-129, characterized in that... The DSC thermal analysis plot shows at least two endothermic peaks at approximately 61.7°C and approximately 199.8°C.

131. The crystalline salt according to any one of claims 123-130, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 36.

132. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate.

133. The crystalline salt according to claim 132, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-1.

134. The crystalline salt according to claim 133, characterized in that... The X-ray powder diffraction pattern contains peaks at 14.8, 24.8, and 25.7 ± 0.5°2θ.

135. The crystalline salt according to claim 133, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.4, 9.1, 14.8, 24.8, and 25.7 ± 0.5°2θ.

136. The crystalline salt according to claim 133, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.4, 9.1, 12.3, 14.8, 16.3, 18.3, 19.5, 23.8, 24.8, and 25.7 ± 0.5°2θ.

137. The crystalline salt according to claim 133, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.2, 7.4, 9.1, 11.4, 12.3, 13.4, 14.0, 14.8, 15.1, 16.3, 16.7, 16.9, 17.8, 18.3, 19.1, 19.5, 20.8, 21.0, 22.7, 23.8, 24.4, 24.8, 25.0, 25.5, 25.7, 27.0, 27.4, 27.5, 29.7, 31.1, 31.9, 33.9, 34.0, 35.0, and 38.3 ± 0.5°2θ.

138. The crystalline salt according to claim 133, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 37.

139. The crystalline salt according to any one of claims 133-138, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 181.7°C.

140. The crystalline salt according to any one of claims 133-139, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 38.

141. The crystalline salt according to claim 132, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one fumarate-2.

142. The crystalline salt according to claim 141, characterized in that... The X-ray powder diffraction pattern contains peaks at 12.4, 16.3, and 22.8 ± 0.5°2θ.

143. The crystalline salt according to claim 141, characterized in that... The X-ray powder diffraction pattern contains peaks at 12.4, 16.3, 17.7, 22.8, and 24.6 ± 0.5°2θ.

144. The crystalline salt according to claim 141, characterized in that... The X-ray powder diffraction pattern contains peaks at 12.4, 14.8, 16.3, 17.5, 17.7, 21.4, 22.7, 22.8, 24.6, and 24.8 ± 0.5°2θ.

145. The crystalline salt according to claim 141, characterized in that... X-ray powder diffraction patterns are included in the following ranges: 6.2, 7.3, 7.4 (7.39), 7.4 (7.45), 9.1, 10.1, 11.3, 12.3, 12.4, 13.5, 13.9.0, 14.8, 16.3, 16.7, 17.0, 17.5, 17.7, 18.3, 18.9, 19.1, 19.3, 19.5, 19.9, 20.6, 21.4, 22.7, 22.

8. Peaks at 23.0, 23.4, 23.8, 24.6, 24.8, 25.0, 25.4, 25.7, 26.3, 26.7, 27.1, 27.6, 27.7, 28.0, 28.8, 29.3, 29.8, 31.0, 31.7, 32.7, 32.9, 33.9, 34.1, 34.9, 35.1, 35.4, 36.0, 36.7, and 37.8 ± 0.5°2θ.

146. The crystalline salt according to claim 141, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 39.

147. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate.

148. The crystalline salt according to claim 147, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one citrate-2.

149. The crystalline salt according to claim 148, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 14.5, and 17.7 ± 0.5°2θ.

150. The crystalline salt according to claim 148, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 14.5, 16.3, 17.7, and 17.9 ± 0.5°2θ.

151. The crystalline salt according to claim 148, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 11.9, 14.5, 15.9, 16.3, 17.7, 17.9, 19.9, 21.2, and 21.9 ± 0.5°2θ.

152. The crystalline salt according to claim 148, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.6, 9.7, 9.8, 11.4, 11.9, 13.6, 14.5, 15.1, 15.9, 16.3, 17.3, 17.7, 17.9, 18.1, 18.5, 18.8, 19.7, 19.9, 21.2, 21.8, 21.9, 22.9, 23.3, 23.9, 24.1, 24.3, 24.7, 26.4, 27.3, 27.6, 28.3, 28.6, 29.3, 29.7, 30.1, 30.8, 31.1, 31.3, 31.5, 32.0, 32.6, 35.6, 36.1, 36.8, 37.8, and 38.9 ± 0.5°2θ.

153. The crystalline salt according to claim 148, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 41.

154. The crystalline salt according to any one of claims 148-153, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 173.6°C.

155. The crystalline salt according to any one of claims 148-154, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 42.

156. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one glycolate.

157. The crystalline salt according to claim 156, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.4, 9.6, and 19.2 ± 0.5°2θ.

158. The crystalline salt according to claim 156, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.4, 9.6, 19.2, 22.2, and 29.8 ± 0.5°2θ.

159. The crystalline salt according to claim 156, characterized in that... The X-ray powder diffraction pattern contains peaks at 7.4, 9.6, 14.8, 16.1, 19.2, 21.5, 22.2, 22.3, 29.8, and 29.9 ± 0.5°2θ.

160. The crystalline salt according to claim 156, characterized in that... X-ray powder diffraction patterns are included in the following ranges: 7.4, 9.6, 12.8, 13.3, 14.4, 14.8, 16.1, 16.5, 16.7, 18.7, 19.2, 19.6, 20.2, 21.5, 22.2, 22.3, 22.5, 22.7, 23.0 (22.97), 23.0 (23.04), 23.

5. Peaks at 25.7, 25.8, 26.8, 27.5, 28.1, 28.8, 28.9, 29.8, 29.9, 30.9, 31.8, 31.9, 32.4, 32.5, 33.7, 34.5, 34.7, 35.0, 36.2, 36.3, 37.5, 37.6, 38.9, and 39.0 ± 0.5°2θ.

161. The crystalline salt according to claim 156, characterized in that... The X-ray powder diffraction pattern is basically as shown in Figure 43.

162. The crystalline salt according to any one of claims 156-161, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 118.5°C.

163. The crystalline salt according to any one of claims 156-162, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 44.

164. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one malate.

165. The crystalline salt according to claim 164, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.4, 15.8, and 18.5 ± 0.5°2θ.

166. The crystalline salt according to claim 164, characterized in that... The X-ray powder diffraction pattern contains peaks at 13.4, 14.7, 15.8, 18.5, and 19.4 ± 0.5°2θ.

167. The crystalline salt according to claim 164, characterized in that... The X-ray powder diffraction pattern contains peaks at 11.2, 13.4, 14.7, 15.8, 18.5, 19.4, 22.4, 29.7, 31.3, and 31.9 ± 0.5°2θ.

168. The crystalline salt according to claim 164, characterized in that... The X-ray powder diffraction pattern contains peaks at 11.2, 12.1, 13.4, 14.7, 15.3, 15.8, 16.5, 17.6, 18.5, 18.9, 19.4, 20.9, 22.4, 23.6, 24.4, 24.9, 26.7, 26.9, 28.6, 29.4, 29.7, 31.3, 31.9, 33.2, 34.3, 35.7, 36.1, and 37.5 ± 0.5°2θ.

169. The crystalline salt according to claim 164, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 45.

170. The crystalline salt according to any one of claims 164-169, characterized in that... The DSC thermal analysis plot has at least one endothermic peak at approximately 196.3°C or approximately 126.0°C.

171. The crystalline salt according to any one of claims 164-170, characterized in that... The DSC thermal analysis plot shows at least two endothermic peaks at approximately 196.3°C and approximately 126.0°C.

172. The crystalline salt according to any one of claims 164-171, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 46.

173. The crystalline salt according to claim 1, wherein it is crystalline ( R )-2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one hippurate.

174. The crystalline salt according to claim 173, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.2, 8.6, and 12.5 ± 0.5°2θ.

175. The crystalline salt according to claim 173, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.2, 8.6, 12.5, 18.7, and 20.9 ± 0.5°2θ.

176. The crystalline salt according to claim 173, characterized in that... The X-ray powder diffraction pattern contains peaks at 6.2, 8.6, 12.5, 13.0, 17.3, 18.7, 19.1, 20.2, 20.9, and 21.0 ± 0.5°2θ.

177. The crystalline salt according to claim 173, characterized in that... The X-ray powder diffraction patterns include values ​​at 6.2, 8.6, 12.5, 13.0, 13.8, 15.1, 16.0, 17.3, 18.7, 18.9, 19.1, 19.7, 19.8, 20.2, 20.9, 21.0, 21.4, 21.9, 22.2, 22.4, 23.5, 24.0.5, and 24.

5. Peaks at 25.0, 25.8, 26.2, 26.3, 27.0, 27.9, 28.2, 29.1, 30.4, 30.8, 31.0, 31.7, 32.5, 33.1, 33.2, 33.7, 33.9, 34.2, 35.2, 35.7, 36.5, 38.0, and 38.4 ± 0.5°2θ.

178. The crystalline salt according to claim 173, characterized in that... The X-ray powder diffraction pattern is basically shown in Figure 47.

179. The crystalline salt according to any one of claims 173-178, characterized in that... The DSC thermal analysis plot shows at least one endothermic peak at approximately 117.6°C.

180. The crystalline salt according to any one of claims 173-179, characterized in that... The DSC thermal analysis diagram is basically as shown in Figure 48.

181. A solid comprising any one of claims 1-180. R One or more crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

182. The solid of claim 181, comprising at least 50% by weight of ( R Any of the crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

183. The solid of claim 181, comprising at least 90% by weight (…). R Any of the crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

184. The solid of claim 181, comprising at least 95% by weight ( ). R Any of the crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

185. The solid of claim 181, comprising at least 97% by weight ( ). R Any of the crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

186. The solid according to claim 181, comprising ( R A mixture of two or more crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

187. A solid comprising substantially chemically pure and polymorphically pure forms as described in any one of claims 1-180. R Any of the crystalline salts of 2-(4-fluorophenyl)-2-(methylamino)cyclohexane-1-one.

188. A pharmaceutical composition comprising one or more of the crystalline salts as described in any one of claims 1-180.

189. A method for treating a mental disorder, comprising administering a therapeutically effective amount of one or more crystalline salts as described in any one of claims 1-180.

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