Hemi-citrate and crystalline form of GABA-A positive allosteric modifier

Abstract

Disclosed herein is the hemi-citrate salt of Compound 1, its crystalline forms, methods for its preparation, pharmaceutical compositions, and methods of its use.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 150,782, filed on 18 February 2021, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to the hemi-citrate of 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one, its crystalline form, a process for preparing such salts and crystalline forms, and a pharmaceutical composition thereof and its use. [Background technology]

[0003] 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one (compound 1) is a synthetic neuroactive steroid. Its primary molecular target is the γ-aminobutyric acid type A (GABA-A) receptor, and it acts as a positive allosteric modulator (PAM) of channel function. The structural formula of compound 1 is shown below. [ka]

[0004] The neurotropic steroid GABA-A PAM has shown clinical efficacy in epilepsy, postpartum depression, and major depressive disorder.

[0005] The synthesis of compound 1 is described in U.S. Patent Publication Nos. 2004 / 0034002 and 2009 / 0118248; the crystalline form of the free base of compound 1 is described in U.S. Patent Publication No. 2006 / 0074059; pharmaceutical compositions containing compound 1 are described in U.S. Patent Publication No. 2009 / 0131383; and the crystalline polymorphs of the salt of compound 1 are described in U.S. Patent Publication No. 2020 / 0071350; all of these are incorporated herein by reference in their entirety for all purposes.

[0006] Compound 1 is insufficiently soluble at the pH observed in the lower GI tube, which may limit its oral bioavailability. To achieve improved solubility, various salt forms of Compound 1 and polymorphs of these salts were developed and tested, for example, as described in U.S. Patent Application Publication 2020 / 0071350. As disclosed in U.S. Patent Application Publication 2020 / 0071350, the mono-citrate of Compound 1 was determined to have favorable overall properties, including improved stability, improved crystalline properties, and improved solubility. The mono-citrate of Compound 1 has a molar ratio of 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one to citrate of 1:1.

[0007] Nevertheless, the formulation of the mono-citrate of compound 1 has proven difficult, particularly as a tablet for oral administration ("mono-citrate tablet"). For successful therapeutic utility, it is crucial that the physicochemical properties of the effective compound are known or reasonably predictable throughout the entire manufacturing and pharmaceutical processing procedure, as well as during storage, shipping, and its final therapeutic use. While some therapeutic compounds may exhibit desirable therapeutic properties, therapeutic compounds may also have undesirable physicochemical properties, such as poor chemical or processing properties, and translating these therapeutic properties into a suitable pharmaceutical composition is not always possible.

[0008] Therefore, there is a need for improved formulations of salts of compound 1 and processes for producing them, as salts of compound 1 possess both desirable therapeutic utility and physicochemical properties. [Overview of the project]

[0009] summary This disclosure provides a hemi-citrate of compound 1, its crystalline form, and methods for preparing and using such salts and crystalline forms. This disclosure also provides pharmaceutical compositions comprising a hemi-citrate of compound 1.

[0010] According to this disclosure, the hemi-citrate form of Compound 1 has now been found to exhibit remarkably improved characteristics compared to other salt forms, including the mono-citrate described in U.S. Patent Application Publication No. 2020 / 0071350. These improved properties include, but are not limited to, enhanced chemical and physical stability, longer shelf life, improved handling properties, and improved solubility. Furthermore, as described herein, the hemi-citrate of Compound 1 is more suitable than other salt forms, including the mono-citrate, for the development of oral formulations, particularly in tablet form.

[0011] In one embodiment, the disclosure provides a substantially pure hemi-citrate of compound 1, with a molar ratio of 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one to citrate of about 2:1. In some embodiments, the disclosure provides a substantially pure hemi-citrate of compound 1 having the following formula: [ka]

[0012] In some embodiments, the hemi-citrate of compound 1 disclosed herein is substantially free of mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 disclosed herein contains less than about 5% by weight of mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 disclosed herein is a hydrate. In some embodiments, the hemi-citrate of compound 1 disclosed herein is a channel hydrate. In some embodiments, the hemi-citrate of compound 1 disclosed herein has a water content of about 0% to about 5% by weight.

[0013] In some embodiments, the hemi-citrate of compound 1 disclosed herein is a monohydrate. In other embodiments, the hemi-citrate of compound 1 disclosed herein contains less than one molecule of water per molecule of compound 1. In some embodiments, the hemi-citrate of compound 1 disclosed herein is an anhydrous hydrate. In other embodiments, the hemi-citrate of compound 1 disclosed herein is an anhydrous. In some embodiments, the hemi-citrate of compound 1 disclosed herein is a sesquihydrate.

[0014] In some embodiments, this disclosure provides a crystalline form of the hemi-citrate of compound 1. In some embodiments, the crystalline form of the hemi-citrate of compound 1 is crystalline form I disclosed herein. In some embodiments, crystalline form I has a water content of about 4.4% by weight, and in some embodiments, crystalline form I exhibits a differential scanning calorimetry (DSC) thermogram having a first peak value of about 65.2 ± 2.0°C and a second peak value of about 126.3 ± 2.0°C. In some embodiments, crystalline form I exhibits a thermogravimetric analysis (TGA) thermogram having a weight loss of about 0.0% to 4.4% in the temperature range of 25 to 125°C.

[0015] In some embodiments, the crystalline form I of the hemi-citrate of compound 1 is the channel hydrate form IA. In some embodiments, crystalline morphology IA exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta that includes at least one of the following peaks: 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, 17.6±0.2, 21.0±0.2, and 25.5±0.2. In some embodiments, crystalline morphology IA exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta that includes at least three of the following peaks: 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, 17.6±0.2, 20.5±0.2, 21.0±0.2, and 25.5±0.2. In some embodiments, crystal morphology IA exhibits an X-ray powder diffraction (XRPD) pattern with the following peaks at a diffraction angle of 2-theta: 5.3±0.2, 14.5±0.2, and 25.5±0.2. In some embodiments, crystal morphology I exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to that of Figure 1 (morphology IA).

[0016] In some embodiments, the crystalline form I of the hemi-citrate salt of Compound 1 is the channel hydrate form IB. In some embodiments, the crystalline form I exhibits an XRPD pattern that is substantially similar to FIG. 2 (form IB). In some embodiments, the crystalline form IB exhibits an XRPD pattern that includes at least one of the following peaks at diffraction angle 2-theta: 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 21.0±0.2, and 25.5±0.2. In some embodiments, the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern that includes at least three of the following peaks at diffraction angle 2-theta: 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 20.3±0.2, 21.0±0.2, and 25.5±0.2. In some embodiments, the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern that includes the following peaks at diffraction angle 2-theta: 5.4±0.2, 14.5±0.2, and 25.5±0.2. Form IB has been found to be surprisingly stable and does not readily revert to a more hydrated form (e.g., form IA) even under high humidity conditions.

[0017] In certain embodiments disclosed herein, the hemi-citrate salt of Compound 1 is defined by unit cell parameters that are substantially similar to the following: a = 34.7 Å, b = 8.3 Å, c = 31.7 Å, α = 90°, β = 108.5°, γ = 90°, space group C2, and molecules / asymmetric unit 2, and the crystalline form is at about 173 K.

[0018] In certain aspects, pharmaceutical compositions comprising the crystalline form I of the hemi-citrate salt of Compound 1 are disclosed herein, and the weight ratio of crystalline form IB to crystalline form IA is greater than about 5:1, greater than about 10:1, greater than about 20:1, greater than about 50:1, or greater than about 100:1. In certain embodiments, the pharmaceutical compositions of the present disclosure comprise the channel hydrate form IB of the hemi-citrate salt of Compound 1 and substantially do not contain the channel hydrate form IA of the hemi-citrate salt of Compound 1.

[0019] The present disclosure relates to the formula: [Chemical] Furthermore provided is a pharmaceutical composition comprising a hemi-citrate salt of Compound 1 having , , and a pharmaceutically acceptable excipient, and the composition substantially does not contain the mono-citrate salt of Compound 1. In certain embodiments, the pharmaceutical composition is an oral dosage form such as a tablet. In some embodiments, the pharmaceutical composition comprises the channel hydrate form IA of the hemi-citrate salt of Compound 1. In other embodiments, the pharmaceutical composition comprises the channel hydrate form IB of the hemi-citrate salt of Compound 1. In other embodiments, the pharmaceutical composition comprises a mixture of the channel hydrate form IA and form IB of the hemi-citrate salt of Compound 1. In certain embodiments, after the pharmaceutical composition is stored at about 40 °C and 75% relative humidity for about 6 months, the chemical purity of the hemi-citrate salt of Compound 1 in the composition is at least about 98%, and in certain embodiments, after the pharmaceutical composition is stored at about 40 °C and 75% relative humidity for about 6 months, the composition comprises no more than about 0.5% by weight of the C-17 epimer of Compound 1 based on the total weight of Compound 1 in the composition.

[0020] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of Compound 1 and a lubricant such as magnesium stearate, and the proportion of the lubricant in the pharmaceutical composition is less than about 4% by weight, for example, less than about 3% by weight, less than about 2.5% by weight, or less than about 2% by weight. In some embodiments, the pharmaceutical composition comprises a lubricant (such as magnesium stearate at about 0.5% by weight, about 1% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, or about 3% by weight) at about 0.5% to about 3% by weight, for example, about 1% to about 2% by weight. In some embodiments, the pharmaceutical composition further comprises crospovidone, and in certain embodiments, the proportion of crospovidone in the pharmaceutical composition is about 3% to about 8% by weight. In certain embodiments, the pharmaceutical composition comprises about 25% by weight of the hemi-citrate salt of Compound 1, about 2% by weight of magnesium stearate, and about 7% by weight of crospovidone.

[0021] In some embodiments, the Disclosure provides pharmaceutical compositions comprising a hemi-citrate of Compound 1 that does not gel or precipitate upon contact with an acidic solution. While not bound by theory, the stability of the hemi-citrate of Compound 1 in an acidic medium is thought to minimize unintended gelation of Compound 1, which can lead to a decrease in bioavailability.

[0022] In some embodiments, the disclosure provides a pharmaceutical composition comprising about 20% to about 30% by weight (e.g., about 20% by weight, about 22% by weight, about 25% by weight, about 27% by weight, about 28% by weight, about 29% by weight, or about 30% by weight) of the hemi-citrate of compound 1 and about 1% to about 3% by weight, about 1.5% to about 2.5% by weight, or about 1.75% to about 2.25% by weight of magnesium stearate. In some embodiments, the hemi-citrate of compound 1 in the pharmaceutical composition is channel hydrate form IA. In other embodiments, the hemi-citrate of compound 1 in the pharmaceutical composition is channel hydrate form IB. In some embodiments, the hemi-citrate of compound 1 in the pharmaceutical composition is a mixture of channel hydrate form IA and channel hydrate form IB. In certain embodiments, the pharmaceutical composition contains less than 5% by weight of the mono-citrate of compound 1.

[0023] In some embodiments, the pharmaceutical compositions disclosed herein are formulated for oral delivery, and in some embodiments, the pharmaceutical compositions are tablets. In some embodiments, the disclosure provides tablets comprising a hemi-citrate of compound 1 and magnesium stearate, wherein the tensile strength of the tablets is at least about 1.7 megapascals (MPa). In some embodiments, the tablets have a tensile strength of about 1.7 MPa to about 4.5 MPa. In some embodiments, the tablets have a tensile strength of about 1.7 MPa to about 3.5 MPa. In some embodiments, the tablets have a disintegration time of less than about 2.5 minutes.

[0024] In other embodiments, the Disclosure provides a method for preparing the hemy-citrate of compound 1. In some embodiments, the method comprises (a) dissolving the mono-citrate of compound 1 in a C1-C2 alcohol to produce a solution; and (b) adding the solution to water to obtain the hemy-citrate of compound 1. In some embodiments, the method comprises (a) suspending the mono-citrate of compound 1 in water; and (b) isolating the hemy-citrate of compound 1. In some embodiments, the method further comprises isolating and drying the hemy-citrate of compound 1. Also disclosed herein are the hemy-citrate of compound 1 prepared according to the method disclosed herein.

[0025] In other embodiments, the Disclosure provides a method for administering the hemi-citrate of Compound 1. In some embodiments, the hemi-citrate of Compound 1 is administered orally. The Disclosure also provides a method for treating a disease, disorder, or condition, comprising administering a therapeutically effective amount of the hemi-citrate of Compound 1 to a patient in need. In certain embodiments, the disease, disorder, or condition is selected from epilepsy, postpartum depression, major depressive disorder, bipolar disorder, treatment-resistant depression, and anxiety. [Brief explanation of the drawing]

[0026] This application can be understood by referring to the following description taken in conjunction with the attached drawings.

[0027] [Figure 1] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of the channel hydrate of compound 1 in hemi-citrate form I at a relative humidity of approximately 90% (form IA) (high humidity pattern).

[0028] [Figure 2] Figure 2 shows the XRPD pattern of the channel hydrate of compound 1 in hemi-citrate form I at a relative humidity of approximately 5% (form IB) (low humidity pattern).

[0029] [Figure 3]Figure 3 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of compound 1 in hemi-citrate form I.

[0030] [Figure 4] Figure 4 shows the dynamic water vapor adsorption (DVS) isotherm plot of compound 1 in hemi-citrate form I.

[0031] [Figure 5] Figure 5 shows a polarized light microscope (PLM) image of the hemi-citrate form I (form IA) sesquihydrate of compound 1.

[0032] [Figure 6] Figure 6 shows the XRPD pattern of compound 1 in hemi-citrate form I, illustrating the bulk product before testing (lower pattern, MeOH_H2O) and after DVS at room temperature (higher pattern).

[0033] [Figure 7] Figure 7 shows the XRPD pattern of compound 1 in hemi-citrate form I, illustrating the bulk product before testing (lower pattern, MeOH_H2O) and after DVS at 40°C (higher pattern).

[0034] [Figure 8] Figure 8 provides the asymmetric unit cell of hemi-citrate form I of compound 1 from a single-crystal X-ray diffraction (SCXRD) solution. The temperature factor ellipsoid is shown with a 50% confidence interval. For clarity, hydrogen atoms have been omitted.

[0035] [Figure 9] Figure 9 shows the solvent-anion interaction and the donor-receptor distance in the hydrogen bonding interaction of compound 1 in hemi-citrate form I.

[0036] [Figure 10]Figure 10 shows the XRPD patterns of compound 1 hemi-citrate form I at various relative humidity (RH) levels (5%RH, 10%RH, 20%RH, 30%RH, 80%RH, and 90%RH). For comparison, the XRPD patterns of compound 1 mono-citrate anhydride ("form IV"), compound 1 mono-citrate ("form A; air-dried"), compound 1 hemi-citrate recrystallized from methanol and water ("form I; MeOH / H2O"), and compound 1 free base are also shown.

[0037] [Figure 11] Figure 11 shows a comparison of the XRPD patterns of compound 1 mono-citrate (form A) (bottom), compound 1 hemi-citrate (form I) (center), and compound 1 mono-citrate anhydride (form IV) (top).

[0038] [Figure 12] Figure 12 is a graph comparing the amount of C17 epimer, a degradation product of compound 1, over time for tablet formulations containing hemi-citrate (Form I; left column in both "1 month" and "2 months") or mono-citrate (Form A; right column in both "1 month" and "2 months") of compound 1 in sealed bottles stored at 40°C / 75%RH.

[0039] [Figure 13] Figure 13 is a graph showing the time course of release of compound 1 from an acidified tablet formulation containing compound 1 in hemi-citrate form I. The tablets were either first used or maintained at 40°C / 75%RH for 2 weeks, 1 month, or 2 months.

[0040] [Figure 14] Figure 14 is a graph showing the time course of release of compound 1 from an acidified tablet formulation containing the mono-citrate (form A) of compound 1. The tablets were either first used or stored at 40°C / 75%RH for 2 weeks, 1 month, or 2 months.

[0041] [Figure 15] Figure 15 is a graph showing the compact tension (MPa) as a function of the average punch pressure (MPa) during tableting of three formulation mixtures of compound 1 hemi-citrate form I.

[0042] [Figure 16] Figure 16 is a graph showing the compact tension (MPa) as a function of different ejected solid fraction values ​​during tableting of three formulation mixtures of compound 1 hemi-citrate form I.

[0043] [Figure 17] Figure 17 is a graph showing the mean punch pressure (MPa) as a function of different ejected solid fraction values ​​during tableting of three formulation mixtures of compound 1 hemi-citrate form I.

[0044] [Figure 18] Figure 18 is a graph showing the ejection force (kN) as a function of the average punch pressure (MPa) during tableting of three formulation mixtures of compound 1 hemi-citrate form I.

[0045] [Figure 19] Figure 19 is a graph showing the ejected solid fraction as a function of independent solid fractions in tableting of three formulation mixtures of compound 1 hemi-citrate form I.

[0046] [Figure 20] Figure 20 is a graph showing the release force (N) as a function of the average punch pressure (MPa) during tableting of three formulation mixtures of compound 1 hemi-citrate form I.

[0047] [Figure 21] Figure 21 shows the production pressures of the mono-citrate form A and the hemi-citrate form I of compound 1.

[0048] [Figure 22]Figure 22 shows a comparison of the yield pressure results for mono-citrate form A and hemi-citrate form I of compound 1.

[0049] [Figure 23] Figure 23 shows the adhesion force as a function of compact punch pressure for mono-citrate form A and hemi-citrate form I of compound 1.

[0050] [Figure 24] Figure 24 shows plots of the ejection powers of the mono-citrate form A and the hemi-citrate form I of compound 1 as described in Example 14.

[0051] [Figure 25] Figure 25 shows plots of extrusion / release forces for the mono-citrate form A and hemi-citrate form I formulations of compound 1 tested as described in Example 14.

[0052] [Figure 26] Figure 26 is a graph showing the formation of the C17 epimer in mono-citric acid tablet formulations of compound 1 with different amounts of magnesium stearate as a function of time.

[0053] [Figure 27] Figure 27 is a graph showing the tablet properties of 20 mg mono-citrate tablets of compound 1 and 20 mg hemi-citrate tablets of compound 1, measured by graphing the tension (MPa) as a function of upper punch pressure (MPa), as described in Example 14.

[0054] [Figure 28] Figure 28 is a graph showing the picking index (TS / AS) of 20 mg of compound 1 mono-citrate tablet formulation and 20 mg of compound 1 hemi-citrate tablet formulation, measured by graphing the picking index (TS / AS) as a function of tension (MPa), as described in Example 14. [Modes for carrying out the invention]

[0055] I. Definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or vocabulary used herein are intended to have the same meaning as those commonly understood by those skilled in the art in which the claimed subject matter pertains. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from the commonly understood meaning in the art.

[0056] Throughout this disclosure, various aspects of the claimed subject matter are presented in scope form. Naturally, the scope form is for convenience and brevity only and should not be interpreted as an inflexible limitation on the scope of the claimed subject matter. Accordingly, the scope description should be considered to specifically disclose all possible sub-scopes and individual numerical values ​​within that scope. For example, where a range of values ​​is provided, unless the context otherwise explicitly indicates, each intervening value up to one-tenth of the lower limit between the upper and lower limits of that range, and any other stated or intervening values ​​within that stated range, are understood to be included in this disclosure, subject to any particularly excluded limitations within the stated range. Where the stated range includes one or both limits, a range excluding one or both of the limits contained therein is also included in this disclosure. In some embodiments, two opposing open-ended scopes are provided for a feature, and in such descriptions, it is assumed that a combination of those two scopes is provided herein. For example, in some embodiments, it is stated that a feature is greater than about 10 units, and that a feature is less than about 20 units (in another sentence, for instance), and therefore, the range of about 10 units to about 20 units is described herein.

[0057] The term “approximately” when it precedes a number means a range (e.g., plus or minus 10% of that value). For example, “approximately 50” means 45 to 55, and “approximately 25,000” may mean 22,500 to 27,500, etc., unless the context of this disclosure otherwise indicates, or is not consistent with such an interpretation. For example, in a list of numbers such as “approximately 49, approximately 50, approximately 55, ...”, “approximately 50” means a range of less than half the interval (maybe one) between the preceding and succeeding values, e.g., greater than 49.5 to less than 52.5. Furthermore, the phrases “less than approximately” or “greater than approximately” should be understood in light of the definition of the term “approximately” provided herein. Similarly, when the term “approximately” precedes a series of numbers or a range of values ​​(e.g., “approximately 10, 20, 30,” or “approximately 10 to 30”), it refers to all values ​​in the series or the endpoint of the range, respectively.

[0058] As used herein, the terms “aprotic solvent,” “nonprotic solvent,” or “non-protic solvent” refer to organic solvents or mixtures of organic solvents that are not readily deprotonated in the presence of strongly basic reactants. Non-limiting examples of aprotic solvents include ethers, dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, methyl isobutyl ketone, hexachloroacetone, acetone, ethyl methyl ketone, methyl ethyl ketone (MEK), ethyl acetate, and acetic acid. Examples include isopropyl, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide, diethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, tetrahydropyran, diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, and t-butyl methyl ether.

[0059] As used herein, the term “carrier” encompasses carriers, excipients, and diluents and means liquid or solid fillers, diluents, excipients, solvents, or encapsulants involved in the transport or delivery of a pharmaceutical agent from one organ or part of the body to another organ or part of the body.

[0060] As used herein, the term "compound 1" refers to 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one having the following formula: [ka] Compound 1 may be in any form, including amorphous, crystalline, salt form, free base, hydrate, anhydride, and / or solvate.

[0061] The terms "compound 1 hemi-citrate" and "compound 1 hemi-citrate" are used interchangeably herein and refer to a salt of compound 1 having the following formula, with a molar ratio of approximately 2:1 between 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one and citrate. [ka]

[0062] The terms "compound 1 mono-citrate" and "mono-citrate of compound 1" are used interchangeably herein and refer to a salt of compound 1 having the following formula, with a molar ratio of 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one to citrate. [ka] The mono-citrate of Compound 1 has been previously disclosed, for example, in U.S. Patent Application Publication 2020 / 0071350, which is incorporated herein by reference in its entirety. As used herein, “Form A” of the mono-citrate of Compound 1 refers to Form A of the mono-citrate of Compound 1 as disclosed in U.S. Patent Application Publication 2020 / 0071350.

[0063] As used herein, the term “polymorphism” refers to the crystalline form of a chemical substance. Polymorphism can be characterized as the ability of a compound to crystallize into different crystalline forms while maintaining the same structural formula (i.e., the covalent bonds in the compound are the same in different crystalline forms). A crystalline polymorph of a given original compound is chemically identical to any other crystalline polymorph of the original compound that contains the same atoms bonded to each other in the same way, but its crystalline form differs, which may affect one or more physical properties such as stability, solubility, melting point, bulk density, flow properties, or pharmacological properties such as bioavailability.

[0064] As used herein, the term “channel hydrate” refers to a crystalline form of a compound that can incorporate a variable number of water molecules within its crystal lattice. Thus, the crystal lattice contains void volumes or channels into which water molecules can be incorporated. In certain embodiments, the channel hydrate may contain 0% to 5% by weight of water, and in certain embodiments, changes in water content (e.g., water loss) may be completely reversible. In certain embodiments, the channel hydrate may be a sesquihydrate, and in certain embodiments, the channel hydrate may be an anhydrous. A crystalline channel hydrate of a given active ingredient may have the same or similar crystal structure as any other crystalline channel hydrate of the same drug, but may differ in physical properties such as stability, solubility, melting point, bulk density, flow properties, or pharmacological properties such as bioavailability.

[0065] Unless otherwise indicated, the term “disorder” in this disclosure means and is used interchangeably with the terms “disease,” “condition,” or “illness.”

[0066] The terms “effective dose” and “therapeutic dose” are used interchangeably in this disclosure and refer to the amount of a compound, or its salt, solvate, or ester, that, when administered to a patient, can produce the intended result. For example, the effective dose of hemi-citrate of compound 1 is the amount required to reduce at least one symptom of a disease, disorder, or condition, such as depression, in a patient. Actual amounts, including “effective dose” or “therapeutic dose,” will vary depending on a number of factors, including, but not limited to, the severity of the disorder, the patient’s size and health condition, and the route of administration. Those skilled in the art can readily determine an appropriate dose using methods known in the medical art.

[0067] Where used herein, unless the context otherwise clearly indicates, the terms “in some embodiments,” “in other embodiments,” or similar terms refer to embodiments of all aspects of the present disclosure.

[0068] The term "isomer" refers to a compound that has the same chemical formula but may have different stereochemical formulas, structural formulas, or specific arrangements of atoms. Examples of isomers include stereoisomers, diastereomers, enantiomers, rotational isomers, geometric isomers, and atropisomers.

[0069] The term "peak" refers to a line with substantial intensity in an XRPD diffractogram (or pattern) obtained from a sample using standard XRPD acquisition techniques, where "substantial" indicates that the peak is distinguishable from the baseline. For example, a peak may be a line in an XRPD diffractogram having an intensity that is, for example, at least about 10% of the intensity of the largest peak in the XRPD diffractogram.

[0070] As used herein, the term “pharmaceutically acceptable” is used herein to mean those compounds, substances, compositions, and / or drug formulations that are within the bounds of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0071] As used herein, the term “protic solvent” refers to a solvent or solvent mixture that can function as an acid for the purpose of protonating any unreacted strongly basic reaction intermediate. Non-limiting examples of protic solvents include water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, and others.

[0072] If the acid coformer is solid at approximately 23°C (i.e., room temperature) and there is no or only partial proton transfer between compound 1 and the acid coformer, a cocrystal of the coformer and compound 1 is obtained. As used herein, the term “salt” encompasses the cocrystal form of compound 1.

[0073] As used herein, the term “substantially similar” means that an analytical spectrum, such as an XRPD pattern or DSC thermogram, is very similar to a reference spectrum. For example, a person skilled in the art could identify two substantially similar XRPD patterns by evaluating and comparing the overall patterns in both peak location and intensity.

[0074] As used herein in relation to a patient, the term “to treat” means to improve at least one symptom of the patient’s disorder. Treatment can improve or at least partially restore the disorder.

[0075] As used herein, the term “therapeutic effect” refers to a desirable or beneficial effect produced by a method and / or composition. For example, a method for treating depression produces a therapeutic effect if the method reduces at least one symptom of depression in a patient.

[0076] Where used herein, the symbols "≦" means "less than or equal to" or "less than or equal to," "<" means "less than," "≧" means "greater than or equal to" or "greater than or equal to," and ">" means "greater than." Furthermore, where used herein in relation to purity or impurity content, numerical values ​​include not only exact numbers but also approximate ranges of numbers. For example, the phrase "99.0% purity" indicates a purity of approximately 99.0%.

[0077] II. Hemi-citrate of Compound 1 This disclosure relates to a salt of Compound 1. In some embodiments, the salt is the hemi-citrate of Compound 1, with a molar ratio of 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one to citrate of approximately 2:1 ("heme-citrate of Compound 1").

[0078] In some embodiments, the present disclosure provides a substantially pure hemi-citrate of compound 1 having the following formula: [ka]

[0079] In some embodiments, the hemi-citrate of compound 1 is substantially free of the mono-citrate of compound 1. The mono-citrate of compound 1 has a molar ratio of 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnane-20-one to citrate of 1:1. In some examples, the hemi-citrate of compound 1 is substantially free of the crystalline mono-citrate salt forms of compound 1 disclosed in U.S. Patent Application Publication No. 2020 / 0071350, including, for example, substantially free of crystalline form A of the mono-citrate of compound 1 and / or substantially free of crystalline form C of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 15% by weight, less than about 14% by weight, less than about 13% by weight, less than about 12% by weight, less than about 11% by weight, less than about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, or less than about 0.5% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 5% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 4% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 3% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 2% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 1% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 0.5% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains about 1% by weight or less, about 0.9% by weight or less, about 0.8% by weight or less, about 0.7% by weight or less, about 0.6% by weight or less, about 0.5% by weight or less, about 0.4% by weight or less, about 0.3% by weight or less, or about 0.2% by weight or less of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains about 0.2% by weight or less of the mono-citrate of compound 1.

[0080] In some embodiments, the hemi-citrate of compound 1 is crystalline form I as described herein. In some embodiments of this disclosure, crystalline form I of the hemi-citrate of compound 1 is a hydrate. In some embodiments, crystalline form I of the hemi-citrate of compound 1 is a channel hydrate, for example, a channel hydrate having a water content of about 0% to about 5% by weight, for example, about 0%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%, about 4.5%, about 4.75%, or about 5% by weight. In some embodiments, the crystalline form I of the hemi-citrate of compound 1 is a channel hydrate having a water content of about 5% by weight. In some embodiments, the crystalline form I of the hemi-citrate of compound 1 is a channel hydrate having a water content of less than about 5% by weight. In some embodiments, the crystalline form I of the hemi-citrate of compound 1 is a channel hydrate having a water content of less than about 4% by weight. In some embodiments, the crystalline form I of the hemi-citrate of compound 1 is a channel hydrate having a water content of less than about 3% by weight. In some embodiments, the crystalline form I of the hemi-citrate of compound 1 is a channel hydrate having a water content of less than about 2% by weight. In some embodiments, the crystalline form I of the hemi-citrate of compound 1 is a channel hydrate having a water content of less than about 1% by weight. In some embodiments of this disclosure, the crystalline form I of the hemi-citrate of compound 1 is a sesquihydrate. In other embodiments, crystalline form I of the hemi-citrate of compound 1 is a monohydrate. In some embodiments, crystalline form I of the hemi-citrate of compound 1 is an anhydrous hydrate.

[0081] In some embodiments of the present disclosure, crystalline form I of the hemi-citrate of compound 1 is a channel hydrate having a water content of about 2% to about 4% by weight at room temperature and a relative humidity of about 20 to 90%, for example, about 2% by weight, about 2.25% by weight, about 2.5% by weight, about 2.75% by weight, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, or about 4% by weight. In some embodiments of the present disclosure, crystalline form I of the hemi-citrate of compound 1 is a channel hydrate having a water content of about 3% to about 5% by weight at 40°C and a relative humidity of about 20 to 90% by weight, for example, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, about 4% by weight, about 4.25% by weight, about 4.5% by weight, or about 5% by weight. In some embodiments of this disclosure, crystalline form I of the hemi-citrate of compound 1 is form IA as disclosed herein, and in some embodiments of this disclosure, crystalline form I of the hemi-citrate of compound 1 is form IB as disclosed herein.

[0082] In some embodiments, the crystalline form containing channel hydrates is characterized by the interplanar spacing determined by the X-ray powder diffraction pattern (XRPD). The XRPD diffractogram is typically represented by a plot of peak intensity versus peak position, i.e., the diffraction angle 2θ (two theta) in degrees. Characteristic peaks of a given XRPD diffractogram can be selected according to their peak position and their relative intensity to conveniently distinguish a particular crystalline structure from other crystalline forms of the same compound. The % intensity of a peak relative to the strongest peak may be expressed as I / Io.

[0083] Those skilled in the art will recognize that measured XRPD peak positions and / or intensities for a given crystalline form of the same compound will vary within an error range. The degree 2θ value allows for an appropriate error limit. Typically, the error limit is expressed by "±". For example, a degree 2θ of approximately "8.716±0.3" represents a range of approximately 8.716+0.3, i.e., approximately 9.016 to approximately 8.716-0.3, i.e., approximately 8.416. Depending on the sample preparation technique, and the calibration techniques applied to the instrument, human motion variations, etc., those skilled in the art will recognize that an appropriate error limit for XRPD may be approximately ±0.7; ±0.6; ±0.5; ±0.4; ±0.3; ±0.2; ±0.1; ±0.05 or less.

[0084] Further details of the methods and apparatus used for XRPD analysis are described in the Examples section.

[0085] In some embodiments, the crystalline morphology is characterized by differential scanning calorimetry (DSC). A DSC thermogram is typically represented by a graph plotting the heat flow, normalized in watts / grams ("W / g"), against the measured sample temperature in °C. DSC thermograms are usually evaluated for extrapolated start and end (outset) temperatures, peak temperature, and fusion heat. Peak feature values ​​in the DSC thermogram are often used as characteristic peaks to distinguish this crystalline structure from others.

[0086] Those skilled in the art will recognize that DSC thermogram measurements for a given crystalline form of the same compound will vary within an error limit. A single peak feature value expressed in °C allows for an appropriate error limit. Typically, the error limit is expressed by "±". For example, a single peak feature value of "approximately 53.09 ± 2.0" represents a range of approximately 53.09 + 2, i.e., approximately 55.09 to approximately 53.09 - 2, i.e., approximately 51.09. Depending on the sample preparation technique, and the calibration techniques applied to the instrument, human motion variations, etc., those skilled in the art will recognize that an appropriate limit error for a single peak feature value may be ±2.5; ±2.0; ±1.5; ±1.0; ±0.5 or less.

[0087] Further details of the methods and apparatus used for DSC thermogram analysis are described in the Examples section.

[0088] In some embodiments of this disclosure, the hemi-citrate of compound 1 is crystalline. In some embodiments, the hemi-citrate of compound 1 is crystalline form I ("hemi-citrate of compound 1 (form I)"). It has been found that form I of the hemi-citrate of compound 1 can exist in multiple hydrate states, which can be determined in part by the relative humidity of the environment. These different hydrate states of the hemi-citrate of compound 1 exhibit different physical properties, some of which may be advantageous for the development of pharmaceutical compositions, as described below. Furthermore, different hydrate states may exhibit different XRPD patterns. For example, Figure 1 shows the XRPD pattern of the channel hydrate form IA of the hemi-citrate of compound 1 at a relative humidity of 90%. As discussed in Example 1, this highly hydrated form is determined to be the sesquihydrate of the hemi-citrate of compound 1, and is referred to herein as form IA of the hemi-citrate of compound 1. In certain embodiments, the hemi-citrate form IA of compound 1 includes at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the peaks selected from the group consisting of 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, 17.6±0.2, 20.5±0.2, 21.0±0.2, and 25.5±0.2 degrees 2-theta. In some embodiments, the hemi-citrate form IA of compound 1 exhibits an XRPD pattern at approximately 90% relative humidity, including at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the peaks selected from the group consisting of 5.3±0.2, 10.6±0.2, 15.9±0.2, 17.2±0.2, and 20.5±0.2 degrees 2-theta. In some embodiments, the hemi-citrate form IA of compound 1 exhibits an XRPD pattern at approximately 90% relative humidity, for example, including peaks at 5.3±0.2, 14.5±0.2, and 25.5±0.2 degrees 2-theta. In certain embodiments, the hemi-citrate form IA of compound 1 has substantially the same XRPD pattern as shown in Figure 1.

[0089] In some embodiments, form I of the hemi-citrate of compound 1 exhibits an XRPD pattern at high percentage relative humidity including at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the peaks selected from the group consisting of 5.2±0.2, 10.6±0.2, 14.4±0.2, 15.9±0.2, 17.2±0.2, 20.5±0.2, 22.9±0.2, and 25.5±0.2 degrees 2-theta. In these embodiments, high percentage relative humidity is relative humidity of approximately 30%, 40%, 50%, 60%, 70%, 80%, or 90%; or relative humidity of approximately 30% to 99%, 30% to 95%, 30% to 90%, 40% to 99%, 40% to 95%, 40% to 90%, 50% to 99%, 50% to 95%, 50% to 90%, 60% to 99%, 60% to 95%, 60% to 90%, 70% to 99%, 70% to 95%, or 80% to 90%.

[0090] In some embodiments, the hemi-citrate form IA of compound 1 of this disclosure exhibits an XRPD pattern including the peaks shown in Table 1. The percentage of relative intensity of each peak may be calculated based on height. TIFF0007874887000008.tif245170

[0091] As shown in Figure 10, the hemi-citrate form IA of compound 1 can persist at relative humidity levels below 90%. For example, the hemi-citrate form IA of compound 1 may be the dominant form at relative humidity levels from about 30% to about 90%. Therefore, in some embodiments, the hemi-citrate form IA of compound 1 exhibits XRPD patterns at about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, and / or about 90% relative humidity levels, substantially similar to those in Figure 1.

[0092] As further shown in Figure 10, the peak of the XRPD pattern shifts to the right at relative humidity below approximately 30%, indicating the presence of hemi-citrate form IB of compound 1. For example, at relative humidity below 20%, a new channel hydrate may become the dominant form, distinct from channel hydrate form IA of hemi-citrate of compound 1. Figure 2 shows the XRPD pattern of form I of hemi-citrate of compound 1 at very low relative humidity (5%). The low-hydration form is referred to herein as hemi-citrate form IB of compound 1. In some embodiments, the hemi-citrate form IB of compound 1 exhibits an XRPD pattern containing at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the peaks selected from the group consisting of 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 20.3±0.2, 21.0±0.2, and 25.5±0.2 degrees 2-theta. In some embodiments, the hemi-citrate form IB of compound 1 exhibits an XRPD pattern at approximately 5% relative humidity, including peaks at 5.4±0.2, 14.5±0.2, and 25.5±0.2.

[0093] In some embodiments, the hemi-citrate form IB of compound 1 exhibits an XRPD pattern at low percentage relative humidity that includes at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the peaks selected from the group consisting of 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.4±0.2, 20.3±0.2, 23.5±0.2, and 25.5±0.2 degrees 2-theta. In these embodiments, low percentage relative humidity is relative humidity of less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%; or relative humidity of about 1% to about 30%, about 5% to about 30%, about 10% to about 30%, about 15% to about 30%, about 20% to about 30%, or about 25% to about 30%.

[0094] In some embodiments, the hemi-citrate form IB of compound 1 exhibits an XRPD pattern including the peaks shown in Table 2. In some embodiments, the hemi-citrate form IB of compound 1 exhibits substantially the same XRPD pattern as shown in Figure 2. In some embodiments, the hemi-citrate form IB of compound 1 contains less than 5% by weight of water, e.g., less than 3% by weight, less than 2% by weight, less than 1% by weight, or 0% by weight of water. TIFF0007874887000009.tif241170

[0095] In some embodiments, the hemi-citrate form IB of compound 1 exhibits an XRPD pattern at approximately 5% relative humidity that is substantially similar to that shown in Figure 2.

[0096] In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 90% relative humidity (RH) including the peaks shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 80% RH including the peaks shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 30% RH including the peaks shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 20% RH including the peaks shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 10% RH including the peaks shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 5% RH including the peaks shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 90% RH including at least three or at least five of the strongest peaks, as shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 80% RH including at least three or at least five of the strongest peaks, as shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 30% RH including at least three or at least five of the strongest peaks, as shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 20% RH including at least three or at least five of the strongest peaks, as shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 10% RH including at least three or at least five of the strongest peaks, as shown in Table 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits an XRPD pattern at 5% RH including at least three or at least five strongest peaks, as shown in Table 4.

[0097] In some embodiments, the hemi-citrate form I of crystalline compound 1 exhibits an XRPD pattern including peaks at (1) 5.3–5.5 degrees 2-theta, (2) 10.6–11 degrees 2-theta, and (3) 15.9–16.3 degrees 2-theta.

[0098] In some embodiments, the hemi-citrate form I of crystalline compound 1 has a water content of about 4.4% by weight and shows a differential scanning calorimetry (DSC) thermogram with a peak value at about 65.2°C, with an error limit of about ±2.5°C, for example, about ±2.0°C, about ±1.5°C, about ±1.0°C, and about ±0.5°C. In some embodiments, the hemi-citrate form I of crystalline compound 1 has a water content of about 3.70% by weight and shows a differential scanning calorimetry (DSC) thermogram with a peak value at about 71°C, with an error limit of about ±2.5°C, for example, about ±2.0°C, about ±1.5°C, about ±1.0°C, and about ±0.5°C. In another embodiment, the hemi-citrate form I of crystalline compound 1 shows a DSC thermogram with a peak value at approximately 126.3°C, with error limits of approximately ±2.5°C, for example, approximately ±2.0°C, approximately ±1.5°C, approximately ±1.0°C, and approximately ±0.5°C. In some embodiments, the hemi-citrate form I of crystalline compound 1 shows a DSC thermogram substantially similar to that in Figure 3.

[0099] In some embodiments, the hemi-citrate form I of compound 1 exhibits a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 3. In some embodiments, the TGA thermogram of the hemi-citrate form I of compound 1 exhibits a TGA thermogram with a weight loss of approximately 0.0% to 4.4% in a temperature range of approximately 25°C to approximately 125°C, for example, in a temperature range of approximately 25°C to approximately 100°C.

[0100] In some embodiments, the hemi-citrate form I of compound 1 exhibits a DVS isotherm plot substantially similar to that in Figure 4. In some embodiments, the hemi-citrate form I of compound 1 exhibits approximately 1.2% (wt%) of weight-based water adsorption at approximately 20% to approximately 80% RH at 25°C. In some embodiments, the hemi-citrate form I of compound 1 exhibits approximately 4.3% weight-based water loss at approximately 95% to approximately 0% RH at 25°C. In some embodiments, the hemi-citrate form I of compound 1 exhibits approximately 1.8% (wt%) of weight-based water adsorption at approximately 20% to approximately 80% RH at 40°C. In some embodiments, the hemi-citrate form I of compound 1 exhibits approximately 5.4% weight-based water loss at approximately 95% to approximately 0% RH at 40°C. In some embodiments, the water loss is completely reversible.

[0101] In some embodiments of the present disclosure, the hemi-citrate form I of compound 1 has a moisture content of about 2% to about 4% by weight at room temperature and a relative humidity of about 20 to 90%, for example, about 2% by weight, about 2.25% by weight, about 2.5% by weight, about 2.75% by weight, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, or about 4% by weight. In some embodiments of the present disclosure, the hemi-citrate form I of compound 1 has a moisture content of about 3% to about 5% by weight at 40°C and a relative humidity of about 20 to 90%, for example, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, about 4% by weight, about 4.25% by weight, about 4.5% by weight, or about 5% by weight.

[0102] In some embodiments, the hemi-citrate form I of compound 1 is defined by the following: a=34.7 Å; b=8.3 Å; c=31.7 Å; α=90°; β=108.5°; γ=90°; space group C2; molecular / asymmetric unit 2 substantially similar unit cell parameters, and the crystalline form is at approximately 173 K.

[0103] III. Method for preparing the hemicitrate of compound 1 The hemi-citrate of compound 1 (and its channel hydrate) may be prepared, for example, by mixing the free base of compound 1 with citric acid in a suitable solvent to obtain a salt of compound 1 as a suspension in a suitable solvent. In some embodiments, the free base of compound 1 to citric acid in a ratio of about 1:0.5 is mixed. In some embodiments, the suitable solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether. In some embodiments, the hemi-citrate of compound 1 (and its channel hydrate) may be prepared by slow evaporation, slow cooling, or addition of an antisolvent to a mixture of the free base of compound 1 and citric acid.

[0104] In some embodiments, the hemi-citrate of compound 1 (and its channel hydrate) is prepared from the mono-citrate of compound 1.

[0105] In some embodiments, a method for preparing the hemy-citrate of compound 1 comprises (a) dissolving the mono-citrate of compound 1 in a C1-C3 alcohol; and (b) adding the solution from step (a) to water to obtain the hemy-citrate of compound 1. In some embodiments, the method further comprises step (c) isolating and drying the hemy-citrate of compound 1. In some embodiments, the method is used to prepare the crystalline form of the hemy-citrate of compound 1. In some embodiments, the crystalline form of the hemy-citrate of compound 1 is form I, which includes, for example, form IA or form IB as disclosed herein.

[0106] In some embodiments, the C1-C3 alcohol is methanol, ethanol, or isopropanol. In some embodiments, the C1-C3 alcohol is methanol or ethanol. In some embodiments, the C1-C3 alcohol is methanol. In some embodiments, the C1-C3 alcohol is an alcohol having a water activity greater than about 0.75.

[0107] In some embodiments, the mono-citrate of compound 1 is dissolved in a C1-C2 alcohol. In some embodiments, the C1-C2 alcohol is methanol. In some embodiments, the C1-C2 alcohol is ethanol.

[0108] In some embodiments, a method for preparing the hemy-citrate of compound 1 includes (a) suspending the mono-citrate of compound 1 in water; and (b) isolating the hemy-citrate of compound 1. In some embodiments, the method further includes drying the hemy-citrate of compound 1. In some embodiments, this method is used to prepare the crystalline form of the hemy-citrate of compound 1. In some embodiments, the crystalline form of the hemy-citrate of compound 1 is form I, including, for example, form IA or form IB as disclosed herein.

[0109] In some embodiments, the disclosure further provides a method for preparing the crystalline form of the hemy-citrate of compound 1. For example, in some embodiments, the hemy-citrate of compound 1 is suspended in a suitable solvent for a sufficient time to obtain a suspension of the crystalline form of the hemy-citrate of compound 1.

[0110] In some embodiments, the hemy-citrate of compound 1 is dissolved in a suitable solvent to obtain a solution, and the crystalline form of the hemy-citrate of compound 1 is precipitated from the solution. In some embodiments, the hemy-citrate of compound 1 is dissolved by heating a mixture of the hemy-citrate of compound 1 and a suitable solvent. In some embodiments, the crystalline form of the hemy-citrate of compound 1 is precipitated from the solution by cooling the solution. In some embodiments, the crystalline form of the hemy-citrate of compound 1 is precipitated from the solution by adding an anti-solvent (i.e., a solvent that reduces the solubility of the crystalline form of the hemy-citrate of compound 1 in the solution) to the solution. In some embodiments, the crystalline form of the hemy-citrate of compound 1 is precipitated from the solution by evaporating a portion of the suitable solvent from the solution. In some embodiments, the crystalline form of the hemy-citrate is crystalline form I, including, for example, form IA or form IB as disclosed herein. In some embodiments, the suitable solvent includes water.

[0111] In some embodiments, suitable solvents include aprotic solvents. In some embodiments, aprotic solvents include dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, methyl ethyl ketone (MEK), hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, and N,N-dimethyl The solvent comprises at least one selected from propionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, diethoxymethane, tetrahydrofuran, toluene, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, tetrahydropyran, diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, and t-butyl methyl ether. In some embodiments, the aprotic solvent is acetone. In some embodiments, the aprotic solvent is ethyl acetate. In some embodiments, the aprotic solvent is acetonitrile.

[0112] In some embodiments, suitable solvents include protic solvents. In some embodiments, the protic solvent includes at least one solvent selected from the group consisting of water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, and glycerol. In some embodiments, the protic solvent includes a mixture of 2-propanol and water.

[0113] In some embodiments, the suitable solvent is a single solvent. In some embodiments, the solvent is a mixture of solvents. In some embodiments, the suitable solvent is a mixture of protic and aprotic solvents.

[0114] In certain embodiments, the hemi-citrate of compound 1 is isolated after preparation. Isolation of the hemi-citrate of compound 1 can be achieved using methods such as filtration, decantation, centrifugation, or any other suitable separation technique or a combination of techniques.

[0115] In certain embodiments, the hemi-citrate of isolated compound 1 is optionally washed with a liquid such as an antisolvent, acetonitrile, methanol, ethanol, ethyl acetate, methyl ethyl ketone, acetone, tetrahydrofuran, or a combination thereof.

[0116] In some embodiments, the hemi-citrate of compound 1 prepared by the embodiments described above is substantially pure. For example, in some embodiments, the chemical purity of the hemi-citrate of compound 1 is at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, or about 95%. Chemical purity can be determined using methods known to those skilled in the art (e.g., HPLC chromatography using a suitable solvent and a column that detects a wavelength of 210 nm). In some embodiments, substantial purity is determined on a weight percentage basis. In some embodiments, substantial purity is determined on a curve area basis.

[0117] In some embodiments, the hemi-citrate of compound 1 prepared by the embodiments described above is crystalline. In certain embodiments, the crystalline hemi-citrate of compound 1 prepared by the embodiments described above is substantially pure. For example, in some embodiments, the polymorphic purity of the crystalline hemi-citrate of compound 1 is at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50%. Polymorphic purity may be determined using methods known to those skilled in the art (in particular, including X-ray crystallography as described in Shah, B., et al., Analytical techniques for quantification of amorphous / crystalline phases in pharmaceutical solids, J. Pharm. Sci. 2006, 95(8), pages 1641-1665, which is incorporated herein by reference in whole).

[0118] In some embodiments, the hemi-citrate of compound 1 prepared by the embodiments described above is epimerically concentrated at one or more positions compared to the epimer purity of the free base of compound 1 from the starting material. For example, in some embodiments, the hemi-citrate of compound 1 may contain at least the 17-β:17α epimer of compound 1 in a ratio of about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, or about 20:1. In some embodiments, the hemi-citrate of compound 1 may contain at least the 3α-hydroxy:3β-hydroxy of compound 1 in a ratio of about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, or about 20:1. In other embodiments, the epimer purity of the hemi-citrate of compound 1 prepared by the method described herein is substantially the same as the epimer purity of the starting material of the free base of compound 1.

[0119] IV. Pharmaceutical Compositions In one embodiment, the present disclosure relates to a hemi-citrate of Compound 1 disclosed herein, having the following formula: [ka] The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient. In some embodiments, the composition is substantially free of mono-citrate of compound 1. In some embodiments, the composition contains less than about 15% by weight, less than about 14% by weight, less than about 13% by weight, less than about 12% by weight, less than about 11% by weight, less than about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, or less than about 0.5% by weight of mono-citrate of compound 1. In some embodiments, the composition contains less than about 5% by weight of mono-citrate of compound 1. In some embodiments, the composition contains less than about 1% by weight of mono-citrate of compound 1. In some embodiments, the composition contains less than about 0.5% by weight of mono-citrate of compound 1. In some embodiments, the composition contains mono-citrate of compound 1 in amounts of about 1% by weight or less, about 0.9% by weight or less, about 0.8% by weight or less, about 0.7% by weight or less, about 0.6% by weight or less, about 0.5% by weight or less, about 0.4% by weight or less, about 0.3% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less. In some embodiments, the composition contains mono-citrate of compound 1 in amounts of about 0.2% by weight or less. In some embodiments, the composition contains mono-citrate of compound 1 in amounts of about 0.1% by weight or less.

[0120] In some embodiments, the chemical purity of the hemi-citrate of compound 1 in the composition is determined by HPLC analysis after the composition has been stored at about 40°C and about 75% relative humidity for about 6 months, and is at least about 99%, at least about 98.0%, at least about 97.0%, at least about 96.0%, at least about 95.0%, at least about 94.0%, at least about 93.0%, at least about 92.0%, at least about 91.0%, or at least about 90.0%. In some embodiments, the chemical purity of the hemi-citrate of compound 1 in the composition is determined by HPLC analysis after the composition has been stored at about 40°C and about 75% relative humidity for about 6 months, and is at least about 98.0%. In some embodiments, the hemi-citrate of compound 1 is crystalline form I disclosed herein.

[0121] In some embodiments, the composition contains about 1% by weight or less, about 0.9% by weight or less, about 0.8% by weight or less, about 0.7% by weight or less, about 0.6% by weight or less, about 0.5% by weight or less, about 0.45% by weight or less, about 0.4% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, or about 0.1% by weight or less of the C-17 epimer of compound 1 after being stored for about 6 months at about 40°C and about 75% relative humidity. The C-17 epimer of compound 1 is represented by the following formula. [ka]

[0122] In some embodiments of this disclosure, the hemi-citrate of compound 1 in the compositions disclosed herein is a channel hydrate. In some embodiments, the hemi-citrate of compound 1 has a water content of about 0% to about 5% by weight, for example, about 0%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%, about 4.5%, about 4.75%, or about 5% by weight. In some embodiments, the hemi-citrate of compound 1 has a water content of about 5% by weight. In some embodiments, the hemi-citrate of compound 1 has a water content of less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, or less than 1% by weight. In some embodiments of this disclosure, the hemi-citrate of compound 1 is a sesquihydrate.

[0123] In some embodiments of this disclosure, the hemi-citrate of compound 1 in the compositions disclosed herein has a moisture content of about 2% to about 4% by weight at room temperature and a relative humidity of about 20 to 90% by weight, for example, about 2% by weight, about 2.25% by weight, about 2.5% by weight, about 2.75% by weight, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, or about 4% by weight. In some embodiments of this disclosure, the hemi-citrate of compound 1 has a moisture content of about 3% to about 5% by weight at 40°C and a relative humidity of about 20 to 90%, for example, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, about 4% by weight, about 4.25% by weight, about 4.5% by weight, or about 5% by weight.

[0124] The compositions disclosed herein may be administered by any suitable route, including, but not limited to, oral, parenteral, rectal, topical, and topical administration. The compositions may be in liquid, semi-liquid, or solid form and may be formulated using methods known to those skilled in the art in a manner suitable for each route of administration.

[0125] In some embodiments, the compositions of the present disclosure are formulated for oral administration. Examples of orally administered dosage forms include solid forms (tablets, capsules, pills, granules, etc.) and liquid forms (oral solutions, oral suspensions, syrups, etc.). In some embodiments, the compositions of the present disclosure are formulated in tablet form.

[0126] In some embodiments, the pharmaceutical composition of the present disclosure comprises a therapeutically effective amount of compound 1 hemi-citrate or a solvate thereof and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of compound 1 hemi-citrate. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of compound 1 hemi-citrate. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of compound 1 hemi-citrate.

[0127] In some embodiments, the pharmaceutical composition of the present disclosure comprises form IA of the hemi-citrate of compound 1. In some embodiments, the pharmaceutical composition comprises form IB of the hemi-citrate of compound 1. In other embodiments, the pharmaceutical composition comprises a mixture of form IA and form IB of the hemi-citrate of compound 1. In certain embodiments, form IB of the hemi-citrate of compound 1 is present in the composition in a greater amount than form IA.

[0128] This disclosure provides a pharmaceutical composition comprising a hemi-citrate of compound 1 and a carrier comprising one or more pharmaceutically acceptable excipients, or an inert solid diluent and filler, a diluent comprising a sterile aqueous solution and various organic solvents, a permeation enhancer, a solubilizer, and an adjuvant. The pharmaceutical composition may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. Rhodes, Eds)).

[0129] The pharmaceutical compositions of this disclosure may be administered in single or multiple doses by any of the acceptable modes of administration of similar useful drugs described in these patents and patent applications incorporated herein by reference, including rectal, oral, nasal, and transdermal routes, intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhaled agents, or via impregnated or coated devices such as stents, or via arterial insertion cylindrical polymers.

[0130] Oral administration is the preferred route for administering the compounds according to this disclosure. Administration may also be via capsules or enteric-coated tablets, etc. When preparing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, sachet, paper, or other container. Where the excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material (as described above) that functions as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in a solid or liquid medium), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0131] Suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further contain smoothing agents, wetting agents, emulsifiers and suspending agents such as talc, magnesium stearate, and mineral oil, as well as preservatives such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents.

[0132] The compositions of this disclosure can be formulated to result in rapid, sustained, or delayed release of the hemi-citrate of compound 1 after administration to a patient. Controlled-release drug delivery systems for oral administration include an osmotic pump system and a dissolution system containing a polymer-coated storage or drug-polymer matrix formulation. Examples of controlled-release systems are given in U.S. Patents No. 3,845,770; No. 4,326,525; No. 4,902,514; and No. 5,616,345.

[0133] The composition is preferably formulated in unit dosage forms. The term “unit dosage form” refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in conjunction with a suitable pharmaceutical excipient (e.g., a tablet, capsule, or ampoule). The compound is generally administered in a pharmaceutically effective amount.

[0134] Preferably, for oral administration, each dose unit (e.g., tablet) contains about 5 mg to about 120 mg of hemi-citrate of compound 1. In some embodiments, each dose unit (e.g., tablet) contains about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg of hemi-citrate of compound 1.

[0135] In some embodiments, the hemi-citrate of compound 1 is present in an oral medication form (e.g., a tablet) at a weight percentage of about 20% to about 40%. In some embodiments, the hemi-citrate of compound 1 is present in an oral medication form (e.g., a tablet) at a weight percentage of about 25% to about 35%. In some embodiments, the hemi-citrate of compound 1 is present in an oral medication form (e.g., a tablet) at a weight percentage of about 20% to about 25% (e.g., about 21%, about 22%, about 23%, about 24%, or about 25%). In some embodiments, the hemi-citrate of compound 1 is present in an oral medication form (e.g., a tablet) at a weight percentage of about 25% to about 30% (e.g., about 25%, about 27%, about 28%, about 29%, or about 30%).

[0136] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid pre-formulation composition containing a homogeneous mixture of the hemi-citrate of compound 1. When these pre-formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into uniformly effective unit dosage forms such as tablets, pills, and capsules.

[0137] Tablets or pills containing the compounds disclosed herein may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-term action or to protect from the acidic conditions of the stomach. For example, a tablet or pill may contain an internal dose and an external dose component, the latter in the form of a shell covering the former. The two components can be separated by an enteric coating that resists disintegration in the stomach and allows the internal component to pass through intact to the duodenum or its release to be delayed. A variety of materials can be used for such enteric coatings or coatings, and such materials include, for example, many high molecular weight acids and mixtures of high molecular weight acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0138] For example, salt forms of compound 1, including the mono-citrate of compound 1, may be sticky and therefore may not be suitable for the development of oral formulations. This can be a significant problem during process scale-up, as salt forms of compound 1 tend to adhere to metal surfaces. To overcome this problem, formulation development often requires a considerable amount of lubricant (e.g., magnesium stearate). It has been found that the hemi-citrate of compound 1 substantially reduces stickiness compared to other salt forms of compound 1, including the mono-citrate salt form. As a result, the amount of lubricant (e.g., magnesium stearate) in the composition can be substantially reduced. Importantly, it has been found that magnesium stearate reduces the chemical stability of compound 1, especially when present in large amounts in the composition. Specifically, a larger amount of lubricant (e.g., magnesium stearate) in tablets containing compound 1 or a pharmaceutically acceptable salt of compound 1 may increase the formation of C17-epimers during storage. For example, as shown in Figure 26, magnesium stearate appears to play a significant role in the formation of the C17 epimer in mono-citrate tablets of compound 1. Therefore, reducing the amount of magnesium stearate compatible with the hemi-citrate of compound 1 reduces the formation of undesirable impurities such as the C17 epimer.

[0139] Furthermore, a decrease in magnesium stearate levels leads to a reduction in the compressive force required to manufacture the tablets. High compressive force often results in a loss of porosity in the tablets, which in turn slows down their disintegration and potential dissolution.

[0140] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a hemi-citrate of compound 1 and a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 4% by weight, for example, less than about 3.75% by weight, less than about 3.5% by weight, or less than about 3.25% by weight. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a hemi-citrate of compound 1 and a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 3% by weight, for example, less than about 2.75% by weight, less than about 2.5% by weight, or less than about 2.25% by weight. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a hemi-citrate of compound 1 and a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 2% by weight, for example, less than about 1.75% by weight, less than about 1.5% by weight, or less than about 1.25% by weight. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a hemi-citrate of compound 1 and a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 1.5% by weight. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a hemi-citrate of Compound 1 and a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 1% by weight. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a hemi-citrate of Compound 1 and a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is about 2% to about 4% by weight. In some embodiments, the Disclosure provides a pharmaceutical composition comprising a hemi-citrate of Compound 1 and a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is about 1.5% to about 3% by weight. Examples of specific lubricants that can be used in accordance with the Disclosure include, but are not limited to, magnesium stearate, sodium stearyl fumarate, stearic acid, talc, silica, and fats (e.g., plant stearin). In some embodiments, the lubricant in the pharmaceutical composition disclosed herein is magnesium stearate.

[0141] In some embodiments, the Disclosure provides a pharmaceutical composition comprising hemi-citrate of compound 1 and magnesium stearate, wherein the proportion of magnesium stearate in the pharmaceutical composition is less than about 4% by weight. In other embodiments, the Disclosure provides a pharmaceutical composition comprising hemi-citrate of compound 1 and magnesium stearate, wherein the proportion of magnesium stearate in the pharmaceutical composition is less than about 3% by weight. In other embodiments, the Disclosure provides a pharmaceutical composition comprising hemi-citrate of compound 1 and magnesium stearate, wherein the proportion of magnesium stearate in the pharmaceutical composition is less than about 2.5% by weight. In other embodiments, the Disclosure provides a pharmaceutical composition comprising hemi-citrate of compound 1 and magnesium stearate, wherein the proportion of magnesium stearate in the pharmaceutical composition is less than about 2.2% by weight. In other embodiments, the disclosure provides a pharmaceutical composition comprising hemi-citrate of compound 1 and magnesium stearate, wherein the proportion of magnesium stearate in the pharmaceutical composition is less than about 2% by weight, for example, less than about 1.75% by weight, less than about 1.5% by weight, or less than about 1.25% by weight. In other embodiments, the disclosure provides a pharmaceutical composition comprising hemi-citrate of compound 1 and magnesium stearate, wherein the proportion of magnesium stearate in the pharmaceutical composition is less than about 1% by weight. In some embodiments, the pharmaceutical composition contains about 0.5% to about 4% by weight of magnesium stearate. In other embodiments, the disclosure provides a pharmaceutical composition comprising hemi-citrate of compound 1 and magnesium stearate, wherein the proportion of magnesium stearate in the pharmaceutical composition is less than about 1% by weight. In some embodiments, the pharmaceutical composition contains about 0.5% to about 3% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition contains about 0.5% to about 2% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition contains about 0.5% to about 3% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition contains about 1% to about 3% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition contains about 1% to about 2% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition contains about 1% to about 1.5% by weight of magnesium stearate.

[0142] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a hemi-citrate of Compound 1 and magnesium stearate, the composition comprising about 20% to about 30% by weight (e.g., about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, or about 30% by weight) of a hemi-citrate of Compound 1 and about 1% to about 3% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 20% to about 30% by weight (e.g., about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%) of the hemi-citrate of compound 1 and about 1% to about 2% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 20% to about 30% by weight (e.g., about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%) of the hemi-citrate of compound 1 and about 1% to about 1.5% by weight of magnesium stearate.

[0143] In the embodiments described above, the weight percentage of the lubricant (e.g., magnesium stearate) represents the total amount of magnesium stearate in the pharmaceutical composition (e.g., a tablet). In some embodiments, the lubricant (e.g., magnesium stearate) in the tablet can be allocated between the intragranular and extragranular sections. For example, in some embodiments where the tablet contains a total of about 2% by weight of magnesium stearate, the intragranular section of the tablet contains about 0.5% by weight of magnesium stearate, and the extragranular section of the tablet contains about 1.5% by weight of magnesium stearate. In some embodiments where the tablet contains a total of about 2% by weight of magnesium stearate, the intragranular section of the tablet contains about 1% by weight of magnesium stearate, and the extragranular section of the tablet contains about 1% by weight of magnesium stearate. In certain embodiments, the intragranular section of the tablet contains 1% by weight or less of magnesium stearate (e.g., about 0.25% by weight, about 0.5% by weight, about 0.75% by weight, or about 1% by weight of magnesium stearate). In some embodiments, the granular section of the tablet contains about 0.5% to about 1% by weight of magnesium stearate (e.g., about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, or about 1% by weight).

[0144] In certain embodiments, tablets containing the amounts of hemi-citrate and magnesium stearate of compound 1 described herein may contain less than 3% by weight of C17-epimer based on the total weight of hemi-citrate of compound 1 after the tablets have been stored for about 6 months at about 40°C and about 75% relative humidity. In certain embodiments, tablets containing the amounts of hemi-citrate and magnesium stearate of compound 1 described herein may contain less than 2% by weight of C17-epimer based on the total weight of hemi-citrate of compound 1 after the tablets have been stored for about 6 months at about 40°C and about 75% relative humidity. In certain embodiments, tablets containing the amounts of hemi-citrate and magnesium stearate of compound 1 described herein may contain less than 1% by weight of C17-epimer based on the total weight of hemi-citrate of compound 1 after the tablets have been stored for about 6 months at about 40°C and about 75% relative humidity. In some embodiments, the tablets may contain less than about 0.75% by weight of C17-epimer based on the total weight of the hemi-citrate of compound 1 after the tablets have been stored for about 6 months at about 40°C and about 75% relative humidity. In other embodiments, the tablets may contain less than about 0.5% by weight of C17-epimer based on the total weight of the hemi-citrate of compound 1 after the tablets have been stored for about 6 months at about 40°C and about 75% relative humidity. In other embodiments, the tablets may contain less than about 0.25% by weight of C17-epimer based on the total weight of the hemi-citrate of compound 1 after the tablets have been stored for about 6 months at about 40°C and about 75% relative humidity. In other embodiments, the tablets may contain about 0.25% to less than 1% by weight of C17-epimer based on the total weight of the hemi-citrate of compound 1 after the tablets have been stored for about 6 months at about 40°C and about 75% relative humidity. In other embodiments, the tablets may contain about 0.5% to less than 1% by weight of the C17-epimer, based on the total weight of the hemi-citrate of compound 1, after the tablets have been stored for about 6 months at about 40°C and about 75% relative humidity. In certain embodiments, the tablets are stored in the presence of a desiccant. In certain embodiments, the tablets are stored without a desiccant.The proportion of epimers present in tablet formulations may vary based on the strength of the dosage form, and as a result, lower-strength dosage forms may contain a higher proportion of epimers than higher-strength dosage forms.

[0145] The pharmaceutical compositions of this disclosure (e.g., tablets) may also comprise one or more disintegrants. Suitable disintegrants include, but are not limited to, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and starch. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant (e.g., crospovidone) is present in about 1.5% to about 10% by weight of the pharmaceutical composition. In some embodiments, the disintegrant (e.g., crospovidone) is present in about 3% to about 8% by weight of the pharmaceutical composition (e.g., about 3%, about 4%, about 5%, about 6%, about 7%, or about 8%). In some embodiments, the pharmaceutical composition comprises intragranular and extragranular components, and a disintegrant (e.g., crospovidone) is present in the intragranular and / or extragranular components of the pharmaceutical composition in an amount of about 2% to about 4% by weight (e.g., about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, or about 4% by weight).

[0146] Tablets containing salt forms of compound 1 other than the hemi-citrate, such as the mono-citrate form, have been found to exhibit prolonged disintegration after inoculation, even in the presence of sufficient disintegrants, potentially having a detrimental effect on the dissolution and absorption rate of compound 1. While not intended to be bound by any theory, the poor disintegration rate is thought to be a result of the compound's tackiness and / or hygroscopicity, properties that can hinder effective disintegration. The resulting requirement for a larger amount of lubricant (e.g., magnesium stearate) to counteract the compound's tackiness and / or hygroscopicity also has a detrimental effect on disintegration time. On the other hand, the hemi-citrate of compound 1 disintegrates rapidly from tablets containing one or more disintegrants (e.g., crospovidone).

[0147] In some embodiments, the disintegration time of a pharmaceutical composition (e.g., a tablet) containing the hemi-citrate of compound 1 is determined by a disintegration test without disk, according to the United States Pharmacopeia (USP) No. <701> When performed according to the method described in the chapter, it is less than approximately 3 minutes (see Example 12). In some embodiments, the disintegration time of a pharmaceutical composition (e.g., a tablet) containing the hemi-citrate of compound 1 is less than 3 minutes when the disintegration test is performed without disk, according to USP standards. <701> When performed according to the method described in the chapter, it is less than approximately 2.5 minutes. In some embodiments, the disintegration time of a pharmaceutical composition (e.g., a tablet) containing the hemi-citrate of compound 1 is less than 2.5 minutes when the disintegration test is performed without a disk, according to USP standards. <701> When performed according to the method described in the chapter, it is less than approximately 2 minutes. In some embodiments, the disintegration time of a pharmaceutical composition (e.g., a tablet) containing the hemi-citrate of compound 1 is less than 2 minutes when the disintegration test is performed without disk according to USP standards. <701> When performed according to the method described in the chapter, it is less than approximately 1.5 minutes. In some embodiments, the disintegration time of a pharmaceutical composition (e.g., a tablet) containing the hemi-citrate of compound 1 is less than 1.5 minutes when the disintegration test is performed without a disk, according to USP standards. <701> When performed according to the method described in the chapter, the disintegration time is approximately 1.5 to 3 minutes. In some embodiments, the disintegration time of a pharmaceutical composition (e.g., a tablet) containing the hemi-citrate of compound 1 is determined by the disintegration test without disk, according to USP standards. <701> When performed according to the method described in the chapter, it takes approximately 2 to 3 minutes. In some embodiments, the disintegration time of a pharmaceutical composition (e.g., a tablet) containing the hemi-citrate of compound 1 is determined by the disintegration test without disk, according to USP standards. <701> When performed according to the method described in the chapter, it takes approximately 2 to 2.5 minutes. In all embodiments described herein, the USP is performed without disk. <701> The collapse tests described in this chapter were published on April 26, 2019, and have an official publication date of May 1, 2020, as per the USP's [number missing]. <701> It refers to a chapter.

[0148] Tablets formed according to this disclosure have a tension suitable for scale-up. In some embodiments, this disclosure provides a tablet comprising a hemi-citrate of compound 1 and a lubricant (e.g., magnesium stearate), wherein the tablet has a tension of at least about 1.7 megapascals (MPa). In some embodiments, the tablet has a tension of about 1.7 MPa to about 4.5 MPa. In some embodiments, the tablet has a tension of about 1.7 MPa to about 3.5 MPa. In some embodiments, the tablet has a tension of about 2.0 MPa to about 3.0 MPa.

[0149] In some embodiments, the tablets disclosed herein contain about 10 mg, about 20 mg, or about 40 mg of hemi-citrate of compound 1, magnesium stearate, and crospovidone. It is understood that the weight of hemi-citrate of compound 1 in the tablet refers to the equivalent weight of the free base. In some embodiments, the composition (e.g., the tablet) contains hemi-citrate of compound 1, microcrystalline cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the tablet contains the following components: TIFF0007874887000012.tif73170

[0150] V. How to use In one embodiment, the present disclosure provides a method for treating a disease or condition in a subject requiring such treatment, comprising administering to the subject a therapeutically effective amount of compound 1 hemi-citrate or a composition thereof as disclosed herein.

[0151] In some embodiments, the hemy-citrate of compound 1 used in the methods disclosed herein is a substantially pure hemy-citrate of compound 1 having the following formula: [ka] In some embodiments, the hemi-citrate of compound 1 used in the methods disclosed herein is substantially free of mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 15% by weight, less than about 14% by weight, less than about 13% by weight, less than about 12% by weight, less than about 11% by weight, less than about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, or less than about 0.5% by weight of mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 5% by weight of mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 4% by weight of mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 3% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 2% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 1% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains less than about 0.5% by weight of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains about 1% by weight or less, about 0.9% by weight or less, about 0.8% by weight or less, about 0.7% by weight or less, about 0.6% by weight or less, about 0.5% by weight or less, about 0.4% by weight or less, about 0.3% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less of the mono-citrate of compound 1. In some embodiments, the hemi-citrate of compound 1 contains about 0.2% by weight or less of the mono-citrate of compound 1. In some embodiments, the mono-citrate of compound 1 is in crystalline form. In some embodiments, the hemi-citrate is substantially free of crystalline form A of the mono-citrate of compound 1.

[0152] In some embodiments of this disclosure, the hemy-citrate of compound 1 is a hydrate, such as a channel hydrate. In some embodiments, the hemy-citrate of compound 1 has a water content of about 0% to about 5% by weight, for example, about 0%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%, about 4.5%, about 4.75%, or about 5% by weight. In some embodiments, the hemy-citrate of compound 1 has a water content of about 5% by weight. In some embodiments of this disclosure, the hemi-citrate of compound 1 is a sesquihydrate.

[0153] In some embodiments of the present disclosure, the hemi-citrate of compound 1 has a moisture content of about 2% to about 4% by weight at room temperature and a relative humidity of about 20 to 90%, for example, about 2% by weight, about 2.25% by weight, about 2.5% by weight, about 2.75% by weight, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, or about 4% by weight. In some embodiments of the present disclosure, the hemi-citrate of compound 1 has a moisture content of about 3% to about 5% by weight at about 40°C and a relative humidity of about 20 to 90%, for example, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, about 4% by weight, about 4.25% by weight, about 4.5% by weight, or about 5% by weight.

[0154] In some embodiments of this disclosure, the hemy-citrate of compound 1 is in crystalline form. In some embodiments, the hemy-citrate of compound 1 is in crystalline form I as disclosed herein. In some embodiments, the hemy-citrate of compound 1 is in form IA, and in some embodiments, the hemy-citrate of compound 1 is in form IB.

[0155] In some embodiments, diseases or conditions that can be treated by the methods disclosed herein include, but are not limited to, depression (including treatment-resistant depression and postpartum depression), major depressive disorder, bipolar disorder, epilepsy, and anxiety. In some embodiments, the disease or condition is depression. In some embodiments, the disease or condition is treatment-resistant depression. In some embodiments, the disease or condition is postpartum depression. In some embodiments, the disease or condition is major depressive disorder. In some embodiments, the disease or condition is bipolar disorder. In some embodiments, the disease or condition is epilepsy. In some embodiments, the disease or condition is anxiety.

[0156] Methods for treating such diseases with compound 1 and its salts are disclosed, for example, in US2020 / 0323823 and WO2020 / 180955, each of which is incorporated herein by reference in whole.

[0157] VI. Manufactured articles A manufactured article is also provided herein, which comprises a substantially pure hemi-citrate of compound 1 described herein in appropriate packaging. In some embodiments, the hemi-citrate of compound 1 is formulated for oral delivery. In some embodiments, the hemi-citrate of compound 1 is formulated as a tablet. In some embodiments described above, the manufactured article further comprises a desiccant. In some embodiments, the packaging is a dry bottle. In some embodiments, the packaging is a dry blister.

[0158] This disclosure further provides kits for carrying out the methods disclosed herein. The kit may contain substantially pure hemi-citrate of compound 1 as described herein in appropriate packaging. In some embodiments, the kit further includes a desiccant. In some embodiments, the packaging is a dry bottle. In some embodiments, the packaging is a dry blister. In some embodiments, the kit further includes labels and / or instructions for the use of substantially pure hemi-citrate of compound 1 as described herein in the treatment of the diseases or disorders described herein. In some embodiments, the kit may include a unit dosing form of the compound. This disclosure includes the embodiments described in the following sections. [Section 1] A substantially pure hemi-citrate of compound 1 having the following formula. TIFF0007874887000014.tif50170 [Section 2] The hemi-citrate according to claim 1, wherein the hemi-citrate contains less than about 5% by weight of the mono-citrate of compound 1. [Section 3] The hemi-citrate according to claim 2, wherein the hemi-citrate substantially does not contain the mono-citrate of compound 1. [Section 4] The hemi-citrate according to any one of claims 1 to 3, wherein the hemi-citrate is a hydrate. [Section 5] The hemi-citrate according to any one of claims 1 to 4, wherein the hemi-citrate has a water content of about 0% to about 5% by weight. [Section 6] The hemi-citrate according to any one of claims 1 to 5, wherein the hemi-citrate is a sesquihydrate. [Section 7] The hemi-citrate described in any one of claims 1 to 6, wherein the hemi-citrate is in crystalline form I. [Section 8] The hemi-citrate according to item 7, wherein the crystalline form I has a water content of about 4.4% by weight and exhibits a differential scanning calorimetry (DSC) thermogram having a first peak value of about 65.2 ± 2.0°C and a second peak value of about 126.3 ± 2.0°C. [Section 9] The hemi-citrate according to item 7 or 8, wherein the crystalline form I exhibits a thermogravimetric analysis (TGA) thermogram having a weight loss of approximately 0.0% to 4.4% in the temperature range of 25 to 125°C. [Section 10] The hemi-citrate according to any one of claims 1 to 9, wherein the hemi-citrate is the crystalline form IA of compound 1. [Section 11] The hemi-citrate according to item 10, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta including at least one of the following peaks: 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, 17.6±0.2, 21.0±0.2, and 25.5±0.2. [Section 12] The hemi-citrate according to item 10 or 11, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern at the diffraction angle 2-theta including at least three of the following peaks: 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, 17.6±0.2, 20.5±0.2, 21.0±0.2, and 25.5±0.2. [Section 13] The hemi-citrate according to any one of claims 10 to 12, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern including the following peaks at the diffraction angle 2-theta: 5.3±0.2, 14.5±0.2, and 25.5±0.2. [Section 14] The hemi-citrate according to any one of claims 10 to 13, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 1. [Section 15] The hemi-citrate according to any one of claims 1 to 7, wherein the hemi-citrate is the crystalline form IB of compound 1. [Section 16] The hemi-citrate according to item 15, wherein the crystalline form IB exhibits an XRPD pattern including at least one of the following peaks at the diffraction angle 2-theta: 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 21.0±0.2, and 25.5±0.2. [Section 17] The hemi-citrate according to item 15 or 16, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern at the diffraction angle 2-theta including at least three of the following peaks: 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 20.3±0.2, 21.0±0.2, and 25.5±0.2. [Section 18] The hemi-citrate according to any one of claims 15 to 17, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern including the following peaks at the diffraction angle 2-theta: 5.4±0.2, 14.5±0.2, and 25.5±0.2. [Section 19] The hemi-citrate according to any one of claims 15 to 18, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 2. [Section 20] The above-mentioned form I is as follows: a = 34.7 Å, b = 8.3 Å, c = 31.7 Å, α=90°、 β=108.5°、 γ = 90°, Space group C2, and Defined by unit cell parameters substantially similar to those of molecular / asymmetric unit 2, The hemi-citrate described in item 7, wherein the crystalline form is at approximately 173K. [Section 21] A pharmaceutical composition comprising a hemi-citrate as described in any one of items 1 to 20 and at least one pharmaceutically acceptable excipient. [Section 22] The pharmaceutical composition according to claim 21, wherein after the composition is stored at approximately 40°C and 75% relative humidity for approximately 6 months, the chemical purity of compound 1 in the composition is at least approximately 98%. [Section 23] The pharmaceutical composition according to claim 21 or 22, wherein, after the composition has been stored at approximately 40°C and 75% relative humidity for approximately 6 months, the composition contains approximately 0.5% by weight or less of the C-17 epimer of compound 1, based on the total weight of compound 1 in the composition. [Section 24] A pharmaceutical composition according to any one of claims 21 to 23, further comprising a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 4% by weight. [Section 25] The pharmaceutical composition according to claim 24, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 3% by weight. [Section 26] The pharmaceutical composition according to claim 24, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 2.5% by weight. [Section 27] The pharmaceutical composition according to claim 24, wherein the proportion of the lubricant in the pharmaceutical composition is less than about 2% by weight. [Section 28] The pharmaceutical composition according to item 24, wherein the proportion of the lubricant in the pharmaceutical composition is about 1% by weight to about 2% by weight. [Section 29] The pharmaceutical composition according to any one of claims 24 to 28, wherein the lubricant is magnesium stearate. [Section 30] A pharmaceutical composition according to any one of claims 21 to 29, further comprising crospovidone. [Section 31] The pharmaceutical composition according to claim 30, wherein the proportion of crospovidone in the pharmaceutical composition is about 3% by weight to about 8% by weight. [Section 32] Approximately 25% by weight of the hemi-citrate of compound 1, Approximately 2% by weight of magnesium stearate, and A pharmaceutical composition according to any one of claims 21 to 31, comprising approximately 7% by weight of crospovidone. [Section 33] The pharmaceutical composition according to claim 32, wherein the composition contains less than 5% by weight of the mono-citrate of compound 1. [Section 34] A pharmaceutical composition according to any one of claims 21 to 33, formulated for oral delivery. [Section 35] A pharmaceutical composition as described in item 34, which is in tablet form. [Section 36] The pharmaceutical composition according to item 35, wherein the tensile strength of the tablet is at least 1.7 megapascals (MPa). [Section 37] The pharmaceutical composition according to item 35, wherein the tensile strength of the tablet is approximately 1.7 MPa to approximately 4.5 MPa. [Section 38] The pharmaceutical composition according to any one of claims 35 to 37, wherein the tablet has a disintegration time of less than approximately 2.5 minutes. [Section 39] A method for preparing the hemy-citrate of compound 1 having the following formula, TIFF0007874887000015.tif49170 The method described above is (a) mono-citrate of compound 1 is C 1 -C 2 Dissolving in alcohol to obtain a solution, and (b) A method comprising adding the solution to water to obtain the hemy-citrate of compound 1. [Section 40] The method according to claim 39, further comprising isolating and drying the hemy-citrate of compound 1. [Section 41] A method for preparing the hemy-citrate of compound 1 having the following formula, TIFF0007874887000016.tif49170 The method described above is (a) Suspend the mono-citrate of compound 1 in water, and (b) A method comprising isolating the hemy-citrate of compound 1. [Section 42] The method according to claim 41, further comprising drying the hemi-citrate of compound 1. [Section 43] A hemi-citrate of compound 1, prepared according to the process described in any one of sections 39 to 42. [Section 44] A method for treating a disease or condition, comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition described in any one of paragraphs 21 to 38, wherein the disease or condition is selected from depression, epilepsy, bipolar disorder, or anxiety. [Section 45] The method according to paragraph 44, wherein the depression is selected from major depressive disorder, postpartum depression, or treatment-resistant depression. [Examples]

[0159] This disclosure is further described by reference to the following embodiments. However, as with the embodiments described above, it should be noted that these embodiments are illustrative and should not be construed as limiting the scope of this disclosure in any way.

[0160] ",''" means ethyl acetate. "(m)DSC" means (modulated) differential scanning calorimetry. "ACN" means acetonitrile. "AR" means analytically pure. "DCM" means dichloromethane. "DMF" means dimethylformamide. "DMSO" means dimethyl sulfoxide. "DI" means distillation. "DSC" means differential scanning calorimetry. "DVS" means dynamic vapor adsorption. "eq" means homogeneous. "EtOH" means ethyl alcohol. "FaSSIF" means intestinal fluid simulating fasting. "FeSSIF" means intestinal fluid simulating feeding. "1H-NMR" means proton nuclear magnetic resonance. "IPA" means isopropanol. "IPAC" means isopropyl acetate. "IPE" means diisopropyl ether. "LC" means crystallinity. "MEK" means methyl ethyl ketone. "MeOH" means methyl alcohol. "MIBK" means methyl isobutyl ketone. "MTBE" means methyl tert-butyl ether. "NMR" means nuclear magnetic resonance. "PLM" means polarizing microscope. "RH" means relative humidity. "RRT" means relative retention time. "RT" means room temperature. "RT(min)" means retention time. "SGF" means simulated gastric juice. "TGA" means thermogravimetric analysis. "THF" means tetrahydrofuran. "UPLC" means ultra-high performance liquid chromatography. "XRPD" means X-ray powder diffractometer or X-ray powder diffraction.

[0161] In some cases, the ratio of compound 1 to citrate in the hemi-citrate (or crystalline form of the hemi-citrate) of compound 1 described herein was determined by ion chromatography (IC) using the following method: 25 μL of a 10.0 μg / mL sample or standard was injected into a Dionex IonPac AG18 column at a flow rate of 1.0 mL / min and detected by a Thermo ICS-2100 conductivity detector. The ASRS-4mm inhibitor was set to 38 mA, and the column temperature was 30°C. Chromatographic elution was 15 mM KOH, and the total run time was 20 minutes.

[0162] XRPD was performed using Panalytical X'Pert Powder XRPD on a Si-zero background plate. Analysis was performed using X'Pert HighScore, and graphs were generated using XPert DataViewer. The XRPD parameters used for data collection were as follows: TIFF0007874887000017.tif61170

[0163] Single-crystal X-ray analysis was performed as follows: Selected crystals were immersed in MiTeGen LV5 oil-based antifreeze, mounted on Mylar MiTeGen cryoloops in random orientation, and then placed in an Oxford Cryostream 800 liquid nitrogen stream at 173K. X-ray intensity data were measured by diffraction using a Bruker D8 VENTURE (IμS microfocus X-ray source, Cu Kα, λ=1.54178Å, PHOTON CMOS detector). The acquisition strategy was optimized using Bruker ApexIII software, and frames were integrated with the Bruker SAINT software package. Data were corrected for absorption effects using the multi-scan method (SADABS). Structural refinement and solutions were obtained using the SHELX software suite, and supplementary data analysis was performed using the PLATON software suite. Graphs were generated using Mercury software.

[0164] Polarized light (PLM) images were obtained at room temperature using a Nikon DS-Fi2 upright microscope.

[0165] TGA data was collected using the TA Discovery 550 TA instrument. The TGA was calibrated using a nickel reference standard. DSC was performed using the TA Q2000 DSC instrument. The DSC was calibrated using an indium reference standard. Data analysis was performed using TA Universal Analysis software. The parameters used for data collection were as follows: TIFF0007874887000018.tif39170

[0166] DVS was measured via the SMS (Surface Measurement System) DVS Intrinsic. The parameters for DVS data acquisition were as follows: TIFF0007874887000019.tif59170

[0167] 1 H-NMR was collected on a Bruker 500 MHz magnet. As is known to those skilled in the art, 1 The relative ppm shift and integral values ​​of the H-NMR resonance can vary depending on various sample factors, including, for example, the water content in d6-DMSO and the ion concentration in the sample. Therefore, as reported in the following examples... 1 H-NMR values ​​should not be considered characteristic of the salt and / or crystalline form.

[0168] UPLC data was collected by injecting 0.5 μL of sample or standard into a Waters Acquity UPLC Shield RP18 column at a flow rate of 0.8 mL / min using an Agilent 1290 UPLC (detection wavelength: 210 nm). The column was equilibrated with mobile phase A, consisting of 0.1% H3PO4 in water. Mobile phase B was acetonitrile (ACN). Chromatographic elution was programmed as follows, after further time for re-equilibriumization and with a total run time of 6 minutes: TIFF0007874887000020.tif29170

[0169] The crystalline salts described herein were characterized by polarized light microscopy. In some embodiments, the crystalline salts described herein exhibit birefringence indicating the degree of crystallinity.

[0170] Example 1: Hemi-citrate of Compound 1 preparation The hemi-citrate of compound 1 can be prepared from compound 1 using the following exemplary method.

[0171] Hemi-citrate of compound 1 (form I): A solution of compound 1 mono-citrate (650 g) in methanol (1.95 L) was prepared at room temperature. Complete dissolution using a stirring bar in a 3 L conical flask took about 5 minutes to obtain a pale yellow solution. Water (7.8 L) was added to a 12 L round-bottom flask equipped with a mechanical stirrer, an oil leak port, and a thermocouple. To the stirred aqueous solution, the methanol solution of compound 1 mono-citrate was added via the oil leak port over about 30 minutes while maintaining the temperature at 20–25°C. The hemi-citrate began to precipitate almost immediately after the start of the methanol solution addition. The suspension was aged at 20–25°C for about 30 minutes. The slurry was then filtered through a 2 L Buchner leak channel using a medium-porous frit. The collected solid material was dried on the filter for 24 hours. The yield was about 70%.

[0172] The obtained solid was identified as hemi-citrate form I of compound 1. The ratio of compound 1 to citric acid was determined to be 2:1 by potentiometric titration. The XPRD patterns of the high-humidity form (form IA) and low-humidity form (form IB) are shown in Figures 1 and 2, respectively, the DSC and TGA are shown in Figure 3, and the DVS is shown in Figure 4.

[0173] The hemi-citrate form I of compound 1 in deuterated DMSO 1 Analysis by 1H-NMR yielded the following chemical shifts: 1H NMR(500MHz,DMSO)δ7.75(s,1H),7.11(s,1H),7.00(s,1H),5.01(dd,J=68.5,18.5Hz,2H),3.25(s,3H),3.05(s,2H),2 .81-2.55(m,3H),2.51(d6-DMSO),2.06(dd,J=20.6,10.9Hz,2H),1.76-0.84(m,22H),0.79-0.65(m,4H),0.58(s,3H).

[0174] XRPD, TGA, DSC, and DVS analysis of hemi-citrate form I of compound 1 As shown in Figure 5, the hemi-citrate form I of compound 1 has a thin plate form that is prone to stacking. The TGA of form I (Figure 3) shows a 4.4% weight loss between room temperature and about 100 °C, which suggests a sesquihydrate hemi-citrate (i.e., form IA). DSC shows a desolvation endotherm with a starting temperature of 26.0 °C and a peak at 65.2 °C. Following a second endotherm related to the melting of the dehydrated phase (ΔH: 15.20 J / g) starting at 121.5 °C, rapid decomposition occurred as the temperature continued to rise (Figure 3). Due to the low dehydration starting temperature, DVS was measured at both room temperature and 40 °C to predict the stability of the crystalline phase at 40 °C. At room temperature, it showed a 1.2% water uptake at 20% - 80% RH, indicating that the sample is slightly hygroscopic. A 1.5% weight loss was observed at 95% - 20% RH and a 2.9% weight loss at 20% - 0% RH, with a total weight loss of 4.3% over the entire cycle. This loss appears to be completely reversible as the relative humidity increases. The temperature DVS at 40 °C showed a water absorption rate of 1.8% at 20% - 80% RH, while losing 2.2% water at 95% - 20% RH and 3.2% at 20% - 0% RH, with a total loss of 5.4%. This loss was completely reversible. This indicates that the hemi-citrate form I of compound 1 is slightly hygroscopic and the water in the crystal lattice is more loosely bound than the water in the mono-citrate lattice of compound 1. After measuring the hygroscopicity by DVS, XRPD patterns were collected and found to correspond well to the pattern of the room temperature sample after the DVS temperature cycle compared to the original material (Figure 6). The DVS cycle measured at 40 °C showed a slight change in the XRPD peaks between 2θ values of 14° and 18° (Figure 7).

[0175] Single crystal X-ray structure of the hemi-citrate form I of compound 1 Single crystals of the hemi-citrate form I of compound 1 suitable for X-ray diffraction were selected from samples generated by slow diffusion of water into a saturated solution in methanol.

[0176] The single crystal structure of the hemi-citrate form IA of Compound 1 was collected at -100 °C for structural quality to minimize solvent loss (Figures 8 and 9). The hemi-citrate form IA of Compound 1 crystallized in the C2 monoclinic space group (see Table 3). Additional water within the unit cell decreases the opportunity for API-citrate hydrogen bond formation, thereby reducing the influence of those interactions in the structure. The hydrogen bond network is difficult to fully evaluate because one of the two citrates is present on a center of symmetry, itself being asymmetric and presenting a form of disorder that is not easily resolved. This is further complicated by the possibility of unresolved water molecules. It is difficult to easily distinguish some of the oxygen atoms within that region between a portion of the disordered citrate and the solvent. The interactions between the API and the citrate are few in number but are much stronger as they infer contacts that are essentially ionic rather than electrostatic or van der Waals interactions when measured by interatomic distances. TIFF0007874887000021.tif156170

[0177] Example 2: Characterization of the hemi-citrate sesquihydrate form IA of Compound 1 by X-ray crystal structure analysis Several slurry samples (including solvents such as acetone, water, THF, 2MeTHF, etc.) were submitted for single crystal analysis. After storage at room temperature for several days, cracks were observed in the rod / plate-like crystals and growth of small crystal particles on the surface of the cracked crystals was also observed. Large single crystals with good X-ray diffraction quality were obtained by recrystallizing the slurry samples by heating and then allowing them to cool naturally to room temperature. Data collection was performed at 223 K and 173 K using crystals cooled with a cryostream cryogenic device to reduce crystal decay. The data sets were collected on several newly prepared crystals, thereby consistently obtaining the same unit cell parameters, but the citrate did not decompose in the crystal structures from these data sets. By-products from the screening crystals were those that solved the crystal structure of the normal form of Compound 1 isolated from aqueous acetone.

[0178] The crystal structure of the compound hemi-citrate sesquihydrate (i.e., form IA) was determined from block-like crystals grown from aqueous methanol. The structure was initially determined and partially refined using space group C2, but the resolution of the extremely complex obstacles of citrate proved to be even more difficult. Therefore, the structure was subsequently determined using space group P1 and further refined. [ka] Compound 1: Hemi-citrate sesquihydrate C 26 H 40 N2O3·0.5C6H8O7·1.5H2O 551.71 g / mol

[0179] Example 3: XRPD analysis of hemi-citrate of compound 1 at various relative humidity levels XRPD data were collected for the hemi-citrate form I of compound 1 at 90% RH, 80% RH, 30% RH, 20% RH, 10% RH, and 5% RH (Table 4).

[0180] The pattern shows that the system does not change from 90% to 30% RH, but changes from 30% to 20% RH that persist up to 5% RH (Figure 10). These results show the change from the channel hydrate of compound 1 hemi-citrate from form IA at 90% to 30% RH, and from the channel hydrate of compound 1 hemi-citrate from form IB at RH below 30%. For comparison, Figure 10 also shows the XRPD patterns of compound 1 mono-citrate anhydride ("form IV"), compound 1 mono-citrate ("form A; air-dried"), compound 1 hemi-citrate recrystallized from methanol and water ("form I; MeOH / H2O"), as well as the free base of compound 1.

[0181] The observed shift is similar to the XRPD shift observed in the DVS-posted data shown in Figures 6 and 7.

[0182] Example 4: Comparison of XRPD patterns from hemi-citrate form IA and mono-citrate (form A) of compound 1. The XRPD pattern of hemi-citrate form IA of crystalline compound 1 is shown in Figure 11 (center pattern), and is superimposed on the XRPD patterns of mono-citrate (form A) of compound 1 (bottom pattern) and mono-citrate anhydride ("form IV") of compound 1 (top pattern). A comparison of each XRPD pattern shows that hemi-citrate form IA of compound 1 has a distinct and unique pattern that is easily distinguishable from mono-citrate (form A) of compound 1 and mono-citrate anhydride of compound 1.

[0183] Example 5: Comparison of H-bond interactions between hemi-citrate form IA and mono-citrate form A of compound 1. The hemi-citrate form IA of compound 1 and the mono-citrate (form A) of compound 1 have conformations that are highly dependent on hydrogen bonding interactions. Appropriate hydrogen bonding interactions are listed in Table 5 (mono-citrate form A of compound 1) and Table 6 (hemi-citrate form IA of compound 1). The mono-citrate (form A) of compound 1 exhibits a very distinct set of intermolecular interactions, isolating two water molecules within the citrate network, which then hydrogen-bond with API molecules in one direction and directly interact between citrate anions in the other direction. The APIs act as crosslinking groups between these citrate-water assemblies, resulting in the formation of a two-dimensional pseudopolymer sheet. In contrast, the hydrogen bonding network of the hemi-citrate form IA of compound 1 is primarily a set of interactions between citrate anions and water molecules, but the citrate anions themselves form pseudopolymer chains in one direction. Unlike the mono-citric acid form A of compound 1, water molecules in the hemi-citric acid form IA of compound 1 interact freely with API molecules. Furthermore, while the mono-citric acid form A of compound 1 exhibits a single set of interactions between one citrate and adjacent API molecules, which may be close enough to be considered ionic interactions, the hemi-citric acid form IA of compound 1 exhibits two (3 API ~ 1.5 citrate anions in an asymmetric unit cell) for each citrate. This explains the properties of the hemi-citric acid. The interaction with water is not remarkably uniform, and the presence of hydrogen bonds between water and APIs eliminates opportunities for further citrate-API interactions. However, one of the citrate anions in the hemi-citric acid form IA of compound 1 is located in a special position, but its position is not consistent with the symmetry of its position, resulting in a clear obstruction. This gives rise to a degree of uncertainty in the region, due to the orientation of the citrate or the abundance of oxygen atoms resulting from water molecules dissolving the crystal matrix.

[0184] Example 6: Comparison of the stability of hemi-citrate form IA and mono-citrate form A of compound 1. As shown in Figure 12, when compounded into tablet form using the same formulation components and manufacturing process, the hemi-citrate of compound 1, when stored in a sealed bottle for one or two months, was observed to produce fewer degradation products (i.e., C17-epimers) than the mono-citrate of compound 1, and is therefore more chemically stable.

[0185] We observed that the hemi-citrate of compound 1 was also less sensitive than the mono-citrate of compound 1 in slowing the dissolution rate of the tablets (Figures 13 and 14). Over time, the release of compound 1 from the acidified formulation of compound 1 hemi-citrate was greater than the release of compound 1 from the same acidified formulation of compound 1 mono-citrate under all conditions evaluated (initial, and tablets stored in an open dish for 2 weeks, 1 month, or 2 months at 40°C / 75%RH).

[0186] Example 7: Evaluation of the stability of hemi-citrate form I of compound 1. The stability of compound 1 in hemi-citrate form I can be evaluated according to the ICH guidelines established for testing new active ingredients and products provided below. TIFF0007874887000023.tif59170TIFF0007874887000024.tif250162TIFF0007874887000025.tif73170TIFF0007874887000026.tif67170

[0187] Example 8: Conversion of compound 1 from hemi-citrate form IA to hemi-citrate form IB The hemi-citrate form IA of compound 1 was prepared in the same manner as in Example 1. The wet cake of the hemi-citrate form IA of compound 1, prepared during filtration (before crystallization), was dried under complete vacuum at 60°C (N2 / 30 in Hg) for 18 hours. The hemi-citrate form IA of compound 1 was converted to the hemi-citrate form IB of compound 1 during drying.

[0188] Example 9: Gelation Experiment Note that significant gelation was observed for the mono-citrate of Compound 1 under specific conditions during the tablet dissolution experiment. However, the hemi-citrate of Compound 1 is less likely to gel under similar conditions. To confirm these findings, a control experiment was conducted by dissolving the free base, mono-citrate, and hemi-citrate of Compound 1 in an aqueous medium at concentrations ranging from 0.5 mg / mL to 10 mg / mL. The dissolution experiment was carried out in either 0.1 N HCl, water, or a pH 7.4 buffer as the aqueous medium.

[0189] The hemi-citrate of Compound 1 did not gel in any of the aqueous media at concentrations up to 10 mg / mL. On the other hand, the mono-citrate of Compound 1 rapidly gelled at a concentration of 5 mg / mL in a 0.1 N HCl medium but did not gel in water or a pH 7.4 buffer. The free base of Compound 1 rapidly gelled at a low concentration of 1 mg / mL in 0.1 N HCl but did not gel in water or a pH 7.4 buffer.

[0190] Example 10: Tableting Test of Three Granulation Formulations of the Hemi-Citrate of Compound 1 The purpose of this example was to prepare simulated roller-compressed granules using a compression simulator to investigate three prototype formulation mixtures. All compression tests were performed on a Phoenix hydraulic compression simulator. The formulated batches evaluated are shown in Table 7. TIFF0007874887000027.tif81170

[0191] The intra-granular mixture of the hemi-citrate of Compound 1 was compressed using a compression simulator to produce granules mixed into three final formulations. All three formulations showed good strength during high-speed tableting and achieved the 1.7 MPa required for a viable formulation.

[0192] Methodology: Manufacture of Intra-Granular Mixture 60 g of the granular mixture was prepared by mixing the materials in a container using a Turbula T2 blender. The hemi-citrate of compound 1 and the excipient were mixed at 30 rpm for 10 minutes, and sifted magnesium stearate was added and mixed for a further 2 minutes. The components of the granular mixture are shown in Table 8. TIFF0007874887000028.tif42170

[0193] The actual density was determined, and the solid fraction was calculated. The objective was to prepare granules with a nominal solid fraction of 0.6.

[0194] Determination of actual density by helium pycnometry The instrument used was the Micromeritics AccuPyc II 1340, and the test parameters are listed below. The test was performed twice (assuming the target variability of <2%) was achieved). TIFF0007874887000029.tif42170

[0195] Simulation of Gerteis roller compression The objective was to compress an initial powder mixture under conditions simulating a roller compactor. The results can be used to understand the compressibility of the material and evaluate manufacturing requirements.

[0196] The punch characteristics were determined to reproduce the Gerteis roller compressor. The simulation was based on a 250 mm diameter roller operated at 4 rpm. The methodology was based on reference A. Zinchuk et al., Int. J. Pharm. 269 (2004) 403-415, using the formula. =sin() (In the formula, D is the displacement, R is the radius of the roller (mm), and ω is the rotational frequency of the roller (s) -1 (where t is time (s)) was used.

[0197] Key test parameters - compression The main test parameters for compression were as follows: TIFF0007874887000030.tif47170

[0198] Equipment used The equipment used in this test was as follows: TIFF0007874887000031.tif32170

[0199] Selecting the settings to use The nominal minimum punch separation value was selected as the starting point (e.g., 3 mm). The resulting solid fraction was calculated. Adjustments were made to the minimum distance between punches to determine the settings necessary to achieve compression with the target solid fraction. A filling depth of 7.3 mm, a filling weight of 300 mg, and a punch separation of 4.3 mm were used. Sufficient compression was performed to complete the formulation. Compression parameters were checked every 10 compressions to ensure that the solid fraction met the target. The average recorded solid fraction was 0.597 SF.

[0200] Crushing The simulated ribbon / compass was ground using a Krupps mini coffee grinder. The granules were screened through a 1.0 mm sieve, and larger fragments were re-ground.

[0201] High-speed tableting of a mixture of three formulations Production of mixtures for tablet manufacturing Small formulation mixtures, as shown in Table 9 below, were prepared using sieved and prepared granules. TIFF0007874887000032.tif37170

[0202] The formulations were mixed for 10 minutes using a Turbula T2 blender, and the screened magnesium stearate was added and mixed for 2 minutes. TIFF0007874887000033.tif63170

[0203] Determination of filling weight The material flowed well, and therefore the mold was filled using a hopper. The starting position of the lower punch (i.e., depth) required to obtain a compact weight was determined experimentally. This was adjusted through testing as needed to ensure that 300 mg was achieved as strictly as possible.

[0204] characteristics The characteristics of the punch's movement were programmed into compression simulation software to define the punch's motion. A single-ended sine wave was used. The base of the sine wave was extended with a flat portion to achieve a target residence time of 10 mS. High speed was chosen to represent the expected manufacturing conditions.

[0205] Selection of Compression Target Thickness The nominal minimum punch separation value was selected as the starting point (e.g., 3.0 mm). The obtained peak force and grinding intensity were recorded. Adjustments were made to the minimum distance between punches, and the results were recorded and plotted to estimate the settings in order to achieve the desired force range. Further compression was performed to obtain compression of different thicknesses. From this, the test conditions were selected to map the material through compression that included a specified force range or to overcompression. The objective was to plot the feasible range of formulations.

[0206] Each setting was repeated, and the reproducibility of each point was evaluated. The data was processed using Phoenix compression analysis software, presented in a table, and exported to Excel for further processing.

[0207] Physical parameters After ejection, the compression was visually examined and its appearance noted. The compressed material was weighed. Occasionally, when capping the compressed material, the top surface may come off and be lost; therefore, the recorded weight may be lower than the actual weight of the compressed material. Thickness and diameter were measured with a handheld caliper. Crushing strength (hardness) was determined using kilopongs. Crushing strength is used as a measure of how strong the bonds are within the compressed material. Tension (MPa) is calculated from the crushing strength to allow for direct comparison of compressed materials of different sizes.

[0208] Calculation The following calculations were used: Average force = average of the upper and lower peak compaction forces (kN) Tensile stress for cylindrical compacts (MPa) = 2 / πDT, where P = crushing strength (hardness), D = compact diameter (mm); and T = compact thickness / height (mm) Punch pressure = average peak force / punch tip area (MPa) Compact volume = Pi × (compact diameter / 2) 2 × compact height (mm 3 ) In the mold, the compact volume was measured from the mold diameter and the minimum punch separation. The compact volume outside the mold was measured from the dimensions of the compact after ejection. Density of the compact [g / cm 3 = mg / mm 3 = mass of the compact (mg) / volume of the compact (mm 3 ) Solid fraction = calculated density (g / cm 3 ) / true density (g / cm 3 )

[0209] Measurement of manufacturability Manufacturability was measured based on the relationship between three different compaction measurements, namely, tableting ability, compressibility, and formability. Tableting ability is the relationship between punch pressure and tensile stress, compressibility is the relationship between punch pressure and solid fraction, and compressibility is the relationship between tensile stress and solid fraction.

[0210] Results Tableting ability The main purpose of plotting the tensile stress against the punch pressure is to understand how the material behaves over the entire range of its compressibility. The force was converted to pressure and normalized with respect to the tablet size. This makes it easier to compare tablets of different sizes. When evaluating the compression characteristics of a material, it is necessary to look for many important indicators.

[0211] In other words, the shape of the plot should be sigmoid. At extremely low compression pressures, the powder undergoes particle recombination, and the compression is too weak for retention and testing. Subsequently, the formulation should have a linear region where there is a good correlation between force and tablet strength. This is a crucial region for tableting. The points should be aligned in a straight line with little variability (scattering) to provide reproducibility and controllability on the tablet press.

[0212] A tension of 1.7 MPa should be achieved within this linear range, as it is considered the minimum strength required for tablet manufacturing [Reference: Powder Tech 238(2013)169-175]. Products with a maximum tension of 1.0–1.7 MPa can be manufactured, but may require careful handling. If a formulation cannot achieve this minimum, it is considered unsuitable for successful scale-up.

[0213] As shown in Figure 15, all three final mixtures exhibited good tablet properties, and all achieved tensile strengths exceeding 1.7 MPa. Formulation 3 was slightly stronger. Formulations 2 and 3 were similar.

[0214] At some point, all formulations become "overcompressed." This occurs when the compressive force exceeds the compressibility of the material. This region can be seen as stagnation with scattering and fluctuations. Sometimes, the strength may peak and then drop. Overcompressed tablets may exhibit visual defects such as capping and lamination. The defects may be internal and only manifest as a decrease in strength in hardness tests. The onset of overcompression should be at a force significantly higher than the force used in production. If production is carried out with a force within the overcompressed region, capping and lamination will be observed as a result, and the yield will decrease. The target strength of this product can be checked against a plot to ensure that it can be manufactured quickly.

[0215] As shown in Figure 15, the formulation becomes overcompressed at approximately 250 MPa. The onset of overcompression varies from formulation to formulation. Batch 1 shows evidence of scattering indicating that internal variation began to occur, which was less evident in the other two batches.

[0216] Overall, all three formulations demonstrated good strength during rapid tableting, achieving the 1.7 MPa required for a viable formulation.

[0217] Compressibility Density was calculated from the measured weight and compressed material dimensions after ejection. The solid fraction was calculated by dividing the compressed material density by the actual density and expressed as the ratio of solid to empty space. The relationship between the solid fraction and tension may be useful for comparing tablet manufacturing parameters with compressed material size.

[0218] The results shown in Figure 16 indicate the solid fraction required to achieve the desired compressive strength. The relationship between the solid fraction and tension is expected to be independent of the punch speed [Reference: Amidon; J. Pharm Sci. Vol 94,3,pp165-472]. Because measurements are taken after the compressed material has been ejected, capped and damaged tablets cause outliers or scattering, making accurate measurements difficult.

[0219] Standard tablet formulations are expected to compress to a solid fraction range of 0.8–0.85. This will result in a compressible strength of approximately 1.5 MPa across the batch. The target strength will depend on other quality characteristics such as dissolution rate and fragility requirements.

[0220] The solid fraction of the granules used was targeted at 0.6 SF. Extrapolating the curve shape, it is estimated that the smallest solid fraction that can be produced from this final formulation is approximately 0.7 SF. Different granule characteristics can be used to obtain different results.

[0221] Compressibility As punch pressure increases, the volume of the compressed material decreases. Density tends to move towards the true density of the material, just as weight remains constant. This information can be used to understand the force required to achieve the desired density and the difference between materials.

[0222] As shown in Figure 17, the formulation achieved a maximum solid fraction of slightly over 0.9 SF. Higher solid fractions are not possible at this rate, but they may be possible at lower compression rates.

[0223] A punch pressure of 100 MPa is required to obtain 0.8 SF, which can be achieved using standard tablet pressure and punch settings.

[0224] Drive power The ejection force is the peak force measurement of the lower punch during tablet ejection. The force is typically kept below 500 N to prevent damage to the compressed material when removing it from the mold. Higher ejection forces promote crack propagation within the compressed material, thus accelerating capping and lamination.

[0225] Because the lubricant was contained within the formulation mixture, the mold was not lubricated externally for this experiment. As shown in Figure 18, the ejection force for all formulations was higher than the recommended level. Formulation 1 produced a squeaking sound during ejection, indicating high friction. The ejection force was highest for formulation 1.

[0226] Changes in density after ejection If elastic recovery is zero, the calculated density of the compressed material remains the same in the mold and after the compressed material is ejected (straight line). As shown in Figure 19, the compressed material exhibits a small amount of elastic recovery.

[0227] The results indicate that the elastic recovery is relatively consistent and therefore predictable. To achieve the desired external solid fraction, a thinner target thickness is required to compensate for the elastic recovery of the compressed material. For example, a target thickness of 0.85 is required to produce a compressed material of 0.80 SF. All batches showed similar results.

[0228] Withdrawal force When ejecting compressed material, it settles into the lower punch and is pushed into the collection chute by an instrumented arm. The packing cell can read the force required to remove the compressed material from the lower punch surface. The baseline reading for non-stick materials (e.g., microcrystalline cellulose (Avicel)) is approximately 0.25 N.

[0229] As shown in Figure 20, the three different formulations exhibited similar levels of interaction with the punch. Approximately half of the compresses showed similar release forces to the baseline, while the others showed a slight increase. This suggests a slightly increased risk of sticking and picking, although no visual evidence of sticking was observed in any of the compresses during the test.

[0230] Example 11: Process-scale production of hemi-citrate tablets of compound 1 Immediate-release tablets containing 10 mg or 20 mg of compound 1 hemi-citrate were prepared. The tablet components are shown in Table 10. TIFF0007874887000034.tif181170

[0231] Hemi-citrate tablets of compound 1 were manufactured using a roller compression granulation process. The hemi-citrate of compound 1 was first mixed with granular portions of microcrystalline cellulose (MCC), lactose, hydroxypropyl methylcellulose (HPMC), crospovidone (CP), and colloidal silicon dioxide (SD). The mixture was then screened by passing it through a conical mill. This powder mixture was then lubricated with magnesium stearate to prepare an intragranular powder mixture. The lubricated intragranular powder mixture was compressed into ribbons using a roller compactor in an in-line granulator.

[0232] Next, the granules were mixed with the granular components of CP and SD, and then lubricated with magnesium stearate to prepare the final powder mixture. This final powder mixture was compressed into the center of a tablet using a rotary tablet press and aesthetically coated using a pan coater.

[0233] Example 12: Evaluation of tablet manufacturing characteristics This example compares the properties of the mono-citrate tablet of compound 1 with those of the hemi-citrate tablet of compound 1. TIFF0007874887000035.tif42170

[0234] All decay tests were conducted without disks, USP No. <701> The procedure was carried out according to the method described in the chapter. Disintegration tests were performed using the LabIndia DT100 FD / DTT / 01 model.

[0235] This example further evaluates the manufacturability of hemi-citrate tablets of compound 1. All formulations listed in the table below contained 2% magnesium stearate, except for formulation #5, which contained 4% magnesium stearate. On average, formulation #5 was observed to require the highest compressive force to reach the same tablet hardness range as the other tablets at the same compression rate. This indicates the effect of increasing the concentration of magnesium stearate. TIFF0007874887000036.tif88170

[0236] Example 13: Compression characterization of mono-citrate form A and hemi-citrate form I salts of compound 1 by Haeckel analysis The purpose of the Haeckel test is to compress a material under controlled conditions and determine the yield pressure of the bulk material. A known weight of material is compressed into a 10 mm diameter mold while a punch with a flat surface is moved at a set speed. The force of the punch is measured accurately at frequent intervals, and the volume of powder is calculated using the punch displacement. The yield pressure is calculated at low and high punch speeds to evaluate the time-dependent component of the material's deformation.

[0237] The actual density of the material was determined by helium pycnometry. The average actual density of the batch of mono-citrate form A of compound 1 tested was 1.2666 g / cm³. 3 The actual average density of the batch of hemi-citrate form I of compound 1 tested was 1.2621 g / cm³. 3 That was the case.

[0238] Determination of actual density by helium pycnometry The instrument used in this test was the Micromeristics AccuPyc II 1340, and the test parameters were the same as those described in Example 10. The test was performed twice (assuming the target variability of <2%) was achieved).

[0239] compression A known weight of pure chemical agent is compressed to theoretically zero porosity using a punch with a flat surface and a diameter of 10 mm. A compression simulator was used under the following conditions: During compression, the position of the punch tip was precisely determined, and the force measured by the load cell produced a record of the primary compression parameters. Temperature and humidity were monitored at intervals during the test.

[0240] The data was analyzed using compression analysis software, and the yield pressure (Py) was obtained using Haeckel's equation.

number

[0241] Speed-Responsiveness (SRS) For some materials, deformation characteristics change with the rate of applied force. This can be estimated by calculating strain rate sensitivity. The yield pressure at high compression is compared to the yield pressure at low compression using the following formula.

number

[0242] result Compression result of mono-citrate form A of compound 1 The compression results of mono-citrate form A of compound 1 at low speed (0.1 mm / sec) and high speed (300 mm / sec) are provided in Table 13. The laboratory conditions for the low-speed and high-speed runs were 21.6°C / 37.1%RH and 21.7°C / 38.9%RH, respectively. TIFF0007874887000040.tif72170

[0243] The following is a summary of the results and observations obtained from batches of mono-citrate form A of compound 1 that was tested. TIFF0007874887000041.tif16170

[0244] The compression results of hemi-citrate form I of compound 1 at low speed (0.1 mm / sec) and high speed (300 mm / sec) are provided in Table 14. The laboratory conditions for the low-speed and high-speed runs were 21.9°C / 38.9%RH and 21.9°C / 38.6%RH, respectively. TIFF0007874887000042.tif58170

[0245] The following is a summary of the results and observations obtained from this batch of hemi-citrate form I of compound 1 that was tested. TIFF0007874887000043.tif17170

[0246] Observation results The yield pressures of these two batches of salt of compound 1 are compared in Figure 21. As shown in Figure 21, mono-citrate form A of compound 1 had a slow yield pressure of 84 MPa, while hemi-citrate form I of compound 1 had a yield pressure of 69 MPa. These results classify the mono-citrate material as having moderately brittle / ductile compressive properties, and the hemi-citrate material as having soft ductile compressive properties.

[0247] The yield pressures of both batches of the compound 1 salt increased with high press rates, reaching 109 MPa for mono-citrate and 84 MPa for hemi-citrate. A comparison of the yield pressure results is shown in Figure 22.

[0248] Strain rate sensitivity (SRS) measures the change in compression behavior at production compression rates. The SRS was 28.7% for mono-citrate form A of batch compound 1 and 21.4% for hemi-citrate form I of batch compound 1. This indicates that a relatively large increase in force is required to achieve the same level of compression at high speeds, and that some rate-related changes in behavior during scale-up are expected.

[0249] It should be noted that Haeckel analysis is a measure of deformation, not the formation of the compressive material. To understand how residence time affects bonding, compressive strength is observed. The compressed material, formed at low speed, was ejected as a whole, with some chipping at the edges. The grinding strength of a batch of compound 1 mono-citrate form A was 15.6–18 kilopounds at low speed and 5–2.4 kilopounds at high speed. For a batch of compound 1 hemi-citrate form I, the grinding strength at low speed was 14.2–15.2 kilopounds, and the grinding strength at high speed was 4.4–5.6 kilopounds. Ideally, a 10 mm formulation compress should have a strength of 10–12 kilopounds, which is considered low risk. Relatively high concentrations are theoretically possible because the material can contribute to the bonding strength in the final formulation. Compressive strength and bonding decrease at high speed. As the speed increases, there is less time for strong bonding to occur, and the compressed material expands after the force is removed. Therefore, binding strength is affected by residence time. In formulations, for example, the addition of appropriate excipients can increase binding, reduce the rate effect, and limit thinness.

[0250] Furthermore, it should be noted that the test is designed to overcompress the material, and therefore the strength may be improved in terms of tablet-related compressive forces.

[0251] In summary, compound 1 exhibits several differences in compression and compression between two batches of the salt. The grinding strength indicates that the material can impart strength to the compressed object, but due to elasticity, the strength decreases rapidly.

[0252] Example 14: Punch bonding of mono-citrate form A and hemi-citrate form I of compound 1 The objective of this study was to investigate the adhesion of two different salt forms of compound 1 to standard tool steel. Using an adhesive punch with a tool attachment, the force between the upper punch surface and the newly formed tablet was quantified. The compressibility of the powder was also examined, and compression measurements were performed to understand key indicators of product quality. The tests were conducted at room temperature. The formulation mixtures used in this study are shown in Table 15. TIFF0007874887000044.tif58170

[0253] An instrumented adhesive punch was designed to measure the force between the upper punch surface and the top surface of the compact. The punch tip is separate from the punch body. This tip is attached to a force sensor inside the punch body. The compact is compressed in the usual manner. After compression, the punch tip remains attached to the adhesive surface, and when the punch is pulled away, the sensor measures the force. The greater the tensile force required to peel the tablet from the surface, the greater the measured value. The measured value is recorded in bolts, but can be converted to force through an amplifier with proper calibration. A K2 channel amplifier was used in the 50N range.

[0254] A single-ended sine wave was used to simulate the movement of the production punch. To maximize adhesion strength measurement, a dwell was inserted at the bottom of the curve to extend the time the material was in contact with the punch surface. The profile duration was 0.5 seconds, resulting in a residence time of 40-45 mS.

[0255] For compression, the tool surface was cleaned with ethanol before starting. Ten compacts were compressed, and the tool surface was evaluated. The surface was photographed to visually assess the level of adhesion.

[0256] The punch surface was cleaned with alcohol at the start, and ten compacts were compressed in a single set. The punch and die were cleaned and LVDT calibration was performed after every 10 sets. Measurements were expected to start low at the beginning of the test and reach equilibrium as the surface was coated with the mixture. Once the settings were determined in the first test, the test could be repeated to compare different formulation parameters, temperatures, or changes in punch coating. The temperature of the compression simulator was measured using a thermocouple during compression to monitor the tableting conditions. Room temperature and humidity were measured at intervals during the test.

[0257] To ensure consistent test conditions, a control sample was also compressed. An empty mold was used as a baseline check to confirm the absence of friction between the punch tip and the mold. The apparatus was operated without powder, and the force was expected to be virtually zero. Microcrystalline cellulose (MCC, Avicel PH102) is a material with a very low tendency to stick and is therefore used as a negative control, which will result in a low value in the absence of stickiness. Mannitol (Partek 200) is a substance with very high attraction to standard steel and is therefore used as a positive control to confirm that the apparatus exhibits high stickiness.

[0258] Figure 23 shows the adhesion force plotted against compact punch pressure. Adhesion force is the force recorded by the instrumented adhesion punch as the punch is pulled away from the tablet surface. The punch used was from 2019. The results for the control samples were as expected. MCC had a low adhesion force, while mannitol had a high adhesion force. The measurements for empty forms were less than 1N and can be considered baseline. At the lowest compression pressure, both materials were similar. As the compression pressure increased, the interaction with the punch increased, and the measured adhesion force increased. Formulation of compound 1 in hemi-citrate form I had a lower adhesion force compared to formulation of compound 1 in mono-citrate form A.

[0259] Figure 24 shows a plot of the ejection force in this study. The ejection force is the force applied to the lower punch when ejecting the compact. The mold was made of standard steel for all compacts, with only the upper punch surface modified for the surface in question. The ejection force of the hemi-citrate form I formulation of compound 1 was higher than that of the mono-citrate form A formulation of compound 1. Both increased with increasing compression pressure. At the compression force associated with production, the ejection force is higher than the ideal.

[0260] Figure 25 shows a plot of the extrusion / release force of the formulations tested in this study. After ejecting the tablet, it is placed on the lower punch surface until the arm is pushed into the recovery chute. A load cell is attached to the arm to record the force required to remove the sample. Because the load cell can pick up fragments (e.g., loose granules) on the mold table, there is a possibility of false positives, and therefore we look for results that rise at a high frequency rather than individual events indicating adhesion. Baseline measurements using a material known to be non-adhesive (MCC) are shown for comparison.

[0261] The lower punch is made of standard steel. The release force was similar to baseline measurements for both formulations. There is no evidence of significant release force for either salt formulation.

[0262] Tablet properties: Regarding tablet properties, the formulations exhibited good tensile strength exceeding 1.7 MPa, and therefore, the risk of manufacturability issues related to tensile strength was considered low. As shown in Figure 27, the formulation of compound 1 mono-citrate form A had higher tensile strength than the formulation of compound 1 hemi-citrate form I. At faster rates, the formulation strengths were similar, but at longer residence times, differences in strength were observed between the two formulations.

[0263] Picking Index: The picking index was determined for the formulation mixture. The picking index is the ratio between adhesion strength and tension. At the interface between the punch and the compact, particles in this region can either adhere to the compact or adhere to the punch surface. Picking can occur if the punch surface is more attractive than the compact. If the compact is more attractive, the tablet will have a more perfect, undamaged surface. Picking occurs when the two factors coexist and the pull to the punch exceeds the pull from the compact. To reduce the risk of adhesion, the tension of the compact can be increased or the attractive force to the punch surface can be reduced. Tension can be increased by any means known in the art, including, for example, lubricant optimization, modification, and / or process modification. The attractive force of the punch can be reduced by any means known in the art, including, for example, lubricant optimization, selection of coated tools, and / or environmental control.

[0264] As shown in Figure 28, the picking index was plotted as a function of tension. Generally, a lower picking index indicates a higher risk of adhesion. A picking index of less than 20 indicates a high risk of adhesion, a picking index of less than 40 indicates a moderate risk of adhesion, and a picking index greater than 50 indicates a low risk of adhesion. As shown in Figure 28, in the high-risk region (i.e., 0-20), there were 10 compacts of the 20 mg formulation of compound 1 mono-citrate form A mixture, while there were no compacts of the 20 mg formulation of compound 1 hemi-citrate form I mixture in the high-risk region. This indicates that the formulation of compound 1 hemi-citrate form I has a lower risk of adhesion than the formulation of compound 1 mono-citrate form A.

[0265] Reference All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, no reference to any reference, article, publication, patent, patent publication, or patent application cited herein shall be, and should not be, taken in any country of the world as an endorsement or in any form of suggestion that they constitute valid prior art or form part of common general knowledge.

Claims

1. A hemy citrate salt comprising compound 1 having the following formula, and containing less than 5% by weight of mono-citrate salt of compound 1. 【Chemistry 1】

2. The hemy citrate according to claim 1, wherein the hemy citrate contains less than 1% by weight of the mono-citrate of compound 1.

3. The hemi-citrate according to claim 1 or 2, wherein the hemi-citrate is a hydrate.

4. The hemi-citrate according to claim 1, wherein the hemi-citrate has a water content of 0% to 5% by weight.

5. The hemi-citrate according to claim 1, wherein the hemi-citrate is a sesquihydrate.

6. The hemy citrate according to claim 1, wherein the hemy citrate is in crystalline form.

7. The hemi-citrate according to claim 6, wherein the hemi-citrate has a water content of 4.4% by weight and exhibits a differential scanning calorimetry (DSC) thermogram having a first peak value of 65.2 ± 2.0°C and a second peak value of 126.3 ± 2.0°C, and / or the hemi-citrate exhibits a thermogravimetric analysis (TGA) thermogram having a weight loss of 0.0% to 4.4% in the temperature range of 25 to 125°C.

8. The hemi-citrate according to claim 1, wherein the hemi-citrate exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta at 90% relative humidity, comprising at least one of the following peaks: 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, 17.6±0.2, 21.0±0.2, and 25.5±0.

2.

9. The hemi-citrate according to claim 8, wherein the hemi-citrate exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta at 90% relative humidity, comprising at least three of the following peaks: 5.3±0.2, 10.6±0.2, 14.5±0.2, 15.9±0.2, 17.2±0.2, 17.6±0.2, 20.5±0.2, 21.0±0.2, and 25.5±0.

2.

10. The hemi-citrate according to claim 8 or 9, wherein the hemi-citrate exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta including the following peaks: 5.3±0.2, 14.5±0.2, and 25.5±0.2 at a relative humidity of 90%.

11. The hemi-citrate according to claim 1, wherein the hemi-citrate exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta at 5% relative humidity, comprising at least one of the following peaks: 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 21.0±0.2, and 25.5±0.

2.

12. The hemi-citrate according to claim 11, wherein the hemi-citrate exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta including at least three of the following peaks at a relative humidity of 5%: 5.4±0.2, 10.9±0.2, 14.5±0.2, 16.3±0.2, 17.1±0.2, 17.5±0.2, 20.3±0.2, 21.0±0.2, and 25.5±0.

2.

13. The hemi-citrate according to claim 11 or 12, wherein the hemi-citrate exhibits an X-ray powder diffraction (XRPD) pattern at a diffraction angle of 2-theta including the following peaks: 5.4±0.2, 14.5±0.2, and 25.5±0.2 at a relative humidity of 5%.

14. The aforementioned hemi-citrate is a = 34.7 Å, b = 8.3 Å, c = 31.7 Å, α＝９０°、 β＝１０８．５°、 γ = 90°, Space group C2, and Defined by the unit cell parameter of the molecule / asymmetric unit 2, The hemy citrate according to claim 6, wherein the crystalline form is at 173K.

15. A pharmaceutical composition comprising the hemi-citrate according to claim 1 or 2 and at least one pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15, wherein after the composition is stored at 40°C and 75% relative humidity for six months, the chemical purity of compound 1 in the composition is at least 98%.

17. The pharmaceutical composition according to claim 15, wherein after the composition is stored at 40°C and 75% relative humidity for six months, the composition contains 0.5% by weight or less of the C-17 epimer of compound 1, based on the total weight of compound 1 in the composition.

18. The pharmaceutical composition according to claim 15, further comprising a lubricant, wherein the proportion of the lubricant in the pharmaceutical composition is less than 4% by weight.

19. The pharmaceutical composition according to claim 18, wherein the lubricant is magnesium stearate.

20. The pharmaceutical composition according to claim 15, further comprising crospovidone.

21. The pharmaceutical composition according to claim 20, wherein the proportion of crospovidone in the pharmaceutical composition is 3% to 8% by weight.

22. 25% by weight of the hemi-citrate of compound 1, 2% by weight of magnesium stearate, and The pharmaceutical composition according to claim 15, comprising 7% by weight of crospovidone.

23. The pharmaceutical composition according to claim 15, formulated for oral delivery.

24. The pharmaceutical composition according to claim 23, which is in the form of a tablet.

25. The pharmaceutical composition according to claim 24, wherein the tensile strength of the tablet is at least 1.7 megapascals (MPa).

26. The pharmaceutical composition according to claim 24, wherein the tablet has a disintegration time of less than 2.5 minutes.

27. A method for preparing the hemy citrate of compound 1 having the following formula, 【Chemistry 2】 The method described above is (a) The mono-citrate of compound 1 is C １ -C ２ Dissolve in alcohol to obtain a solution. (b) Add the solution to water to obtain the hemy citrate of compound 1, and optionally (c) Isolating and drying the hemy citrate of compound 1. Methods that include...

28. A pharmaceutical composition according to claim 15 for treating a disease or condition, wherein the disease or condition is selected from depression, epilepsy, bipolar disorder, or anxiety.

29. The pharmaceutical composition according to claim 28, wherein the disease or condition is epilepsy.

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