Hemi-citrate salt of GABA-A positive allosteric modulator and its crystalline form

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 TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 150,782, filed February 18, 2021, which is incorporated by reference in its entirety.

[0002] The present disclosure relates to the hemi-citrate salt of 3α-hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnan-20-one, crystalline forms thereof, and processes for preparing such salts and crystalline forms, as well as pharmaceutical compositions and methods of use thereof. [Background technology]

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

[0004] The neuroactive steroids GABA-A PAMs have shown clinical efficacy in epilepsy, postpartum depression, and major depression.

[0005] The synthesis of Compound 1 is described in U.S. Patent Application Publication Nos. 2004 / 0034002 and 2009 / 0118248, crystalline forms of Compound 1 free base are described in U.S. Patent Application Publication No. 2006 / 0074059, pharmaceutical compositions containing Compound 1 are described in U.S. Patent Application Publication No. 2009 / 0131383, and crystalline polymorphs of salts of Compound 1 are described in U.S. Patent Application Publication No. 2020 / 0071350, all of which are incorporated by reference in their entireties for all purposes.

[0006] Compound 1 is poorly soluble at the pH found in the lower GI tract, which may limit the oral bioavailability of Compound 1. To achieve improved solubility, various salt forms of Compound 1 and polymorphic forms of these salts have been developed and tested, for example, as described in US Patent Application Publication No. 2020 / 0071350. As disclosed in US Patent Application Publication No. 2020 / 0071350, it has been determined that the mono-citrate salt of Compound 1 has favorable overall properties, including improved stability, improved crystal properties, and improved dissolution. The mono-citrate salt of Compound 1 has a molar ratio of 3α-hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnan-20-one to citric acid of 1:1.

[0007] Nevertheless, formulation of the mono-citrate salt of Compound 1 has proven difficult, especially as a tablet for oral administration ("mono-citrate tablet"). For successful therapeutic utility, it is important that the physicochemical properties of an effective compound are known or reasonably predictable throughout the manufacturing and pharmaceutical processing procedures, as well as during storage, shipping, and its ultimate therapeutic use. Although some therapeutic compounds can exhibit desirable therapeutic properties, it is not always possible to translate these therapeutic properties into a suitable pharmaceutical composition, as the therapeutic compounds may have undesirable physicochemical properties, such as poor chemical or processing properties.

[0008] Thus, there is a need for improved formulations of, and processes for making, salts of Compound 1, which have both desirable therapeutic utility and physicochemical properties. Summary of the Invention

[0009] summary The present disclosure provides a hemi-citrate salt of Compound 1, crystalline forms thereof, and methods of making and using such salts and crystalline forms. The present disclosure also provides pharmaceutical compositions comprising the hemi-citrate salt of Compound 1.

[0010] According to the present disclosure, it has now been discovered that the hemi-citrate form of Compound 1 exhibits surprisingly improved characteristics compared to other salt forms, including the mono-citrate salt described in US Patent Application Publication No. 2020 / 0071350. Such improved properties include, but are not limited to, enhanced chemical and physical stability, longer shelf life, improved processing properties, and improved dissolution properties. Furthermore, as described herein, the hemi-citrate salt of Compound 1 is more suitable for the development of oral formulations, particularly in the form of tablets, than other salt forms, including the mono-citrate salt.

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

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

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

[0014] In some embodiments, the disclosure provides a crystalline form of a hemi-citrate salt of Compound 1. In some embodiments, the crystalline form of the hemi-citrate salt of Compound 1 is crystalline form I as 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 with 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 with a weight loss of about 0.0%-4.4% over a temperature range of 25-125° C.

[0015] In some embodiments, crystalline Form I of the hemi-citrate salt of Compound 1 is channel hydrate Form IA. In some embodiments, crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern comprising at least one of the following peaks at diffraction angles 2-theta: 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, and in some embodiments, crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern comprising at least three of the following peaks at diffraction angles 2-theta: 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, crystalline Form IA exhibits an X-ray powder diffraction (XRPD) pattern comprising the following peaks at diffraction angles 2-theta: 5.3±0.2, 14.5±0.2, and 25.5±0.2. In some embodiments, crystalline Form I exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to FIG. 1 (Form IA).

[0016] In some embodiments, crystalline Form I of the hemi-citrate salt of Compound 1 is channel hydrate Form IB. In some embodiments, crystalline Form I exhibits an XRPD pattern substantially similar to Figure 2 (Form IB). In some embodiments, crystalline form IB exhibits an XRPD pattern that includes at least one of the following peaks at diffraction angles 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, and in some embodiments, crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern that includes at least three of the following peaks at diffraction angles 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, crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern that includes the following peaks at diffraction angles 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 form of increased hydration (e.g., form IA), even under conditions of high humidity.

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

[0018] In certain aspects, disclosed herein are pharmaceutical compositions comprising crystalline Form I of a hemi-citrate salt of Compound 1, wherein 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 disclosure comprise channel hydrate Form IB of the hemi-citrate salt of Compound 1, and are substantially free of channel hydrate Form IA of the hemi-citrate salt of Compound 1.

[0019] The present disclosure provides a compound of the formula: [ka] and a pharmaceutically acceptable excipient, wherein the composition is substantially free of a 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 channel hydrate Form IA of the hemi-citrate salt of Compound 1. In other embodiments, the pharmaceutical composition comprises channel hydrate Form IB of the hemi-citrate salt of Compound 1. In other embodiments, the pharmaceutical composition comprises a mixture of channel hydrate Forms IA and 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 about 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.

[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, wherein the percentage of the lubricant in the pharmaceutical composition is less than about 4% by weight, e.g., 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 about 0.5% to about 3% by weight, e.g., about 1% to about 2% by weight of a lubricant such as magnesium stearate (e.g., 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 of magnesium stearate). In some embodiments, the pharmaceutical composition further comprises crospovidone, and in certain embodiments, the percentage of crospovidone in the pharmaceutical composition is about 3% by weight 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 examples, the present disclosure provides pharmaceutical compositions comprising a hemi-citrate salt of Compound 1 that does not gel or precipitate upon contact with acidic solutions. Without being bound by theory, it is believed that the stability of the hemi-citrate salt of Compound 1 in acidic media minimizes unintended gelation of Compound 1, which can result in reduced bioavailability.

[0022] In some embodiments, the disclosure provides a pharmaceutical composition comprising about 20% to about 30% by weight (e.g., about 20%, about 22%, about 25%, about 27%, about 28%, about 29%, or about 30% by weight) of a hemi-citrate salt 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 salt of Compound 1 in the pharmaceutical composition is channel hydrate form IA. In other embodiments, the hemi-citrate salt of Compound 1 in the pharmaceutical composition is channel hydrate form IB. In some embodiments, the hemi-citrate salt 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 a mono-citrate salt 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 present disclosure provides a tablet comprising a hemi-citrate salt of Compound 1 and magnesium stearate, wherein the tablet has a tensile strength of at least about 1.7 megapascals (MPa). In some embodiments, the tablet has a tensile strength of about 1.7 MPa to about 4.5 MPa. In some embodiments, the tablet has a tensile strength of about 1.7 MPa to about 3.5 MPa. In some embodiments, the tablet has a disintegration time of less than about 2.5 minutes.

[0024] In another aspect, the disclosure provides a method for preparing a hemi-citrate salt of compound 1. In some embodiments, the method includes: (a) reacting C 1 -C 2The method includes dissolving a mono-citrate salt of compound 1 in alcohol to produce a solution; and (b) adding the solution to water to obtain a hemi-citrate salt of compound 1. In some embodiments, the method includes (a) suspending the mono-citrate salt of compound 1 in water; and (b) isolating the hemi-citrate salt of compound 1. In some embodiments, the method further includes isolating and drying the hemi-citrate salt of compound 1. Also disclosed herein are hemi-citrate salts of compound 1 prepared according to the methods disclosed herein.

[0025] In yet another aspect, the disclosure provides a method of administering a hemi-citrate salt of Compound 1. In some embodiments, the hemi-citrate salt of Compound 1 is administered orally. The disclosure also provides a method of treating a disease, disorder, or condition, comprising administering a therapeutically effective amount of a hemi-citrate salt of Compound 1 to a patient in need thereof. 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 description of the drawings]

[0026] The present application can be understood by reference to the following description taken in conjunction with the accompanying drawings.

[0027] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of the channel hydrate of hemi-citrate salt Form I of Compound 1 at about 90% relative humidity (Form IA) (high humidity pattern).

[0028] [Diagram 2] FIG. 2 shows the XRPD pattern of the channel hydrate of hemi-citrate salt Form I of Compound 1 at about 5% relative humidity (Form IB) (low humidity pattern).

[0029] [Diagram 3]FIG. 3 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of hemi-citrate salt Form I of Compound 1.

[0030] [Figure 4] FIG. 4 shows a dynamic vapor sorption (DVS) isotherm plot of hemi-citrate salt Form I of Compound 1.

[0031] [Diagram 5] FIG. 5 shows a polarized light microscopy (PLM) image of the sesquihydrate of hemi-citrate salt Form I (Form IA) of Compound 1.

[0032] [Figure 6] FIG. 6 shows the XRPD patterns of the hemi-citrate salt Form I of Compound 1, showing the bulk product before (lower pattern, MeOH_H2O) and after DVS at room temperature (higher pattern).

[0033] [Figure 7] FIG. 7 shows the XRPD patterns of the hemi-citrate salt Form I of Compound 1, showing the bulk product before (lower pattern, MeOH_H2O) and after DVS at 40° C. (higher pattern).

[0034] [Figure 8] 8 provides the asymmetric unit cell of the hemi-citrate salt form I of Compound 1 from single crystal X-ray diffraction (SCXRD) solution. Temperature factor ellipsoids are shown with 50% confidence intervals. Hydrogen atoms have been omitted for clarity.

[0035] [Figure 9] FIG. 9 shows the solvent and anion interactions in the hemi-citrate salt form I of compound 1, and the distance between the donor and acceptor in the hydrogen bonding interactions.

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

[0037] [Figure 11] FIG. 11 shows a comparison of the XRPD patterns of the mono-citrate salt of Compound 1 (Form A) (bottom), the hemi-citrate salt of Compound 1 (Form I) (middle), and the mono-citrate salt anhydrate of Compound 1 (Form IV) (top).

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

[0039] [Figure 13] 13 is a graph showing the release rate of Compound 1 over time for an acidified tablet formulation containing hemi-citrate salt Form I of Compound 1. The tablets were either used for the first time or kept at 40° C. / 75% RH for 2 weeks, 1 month, or 2 months.

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

[0041] [Figure 15] FIG. 15 is a graph depicting compact tension (MPa) as a function of average punch pressure (MPa) during tableting of three formulation mixtures of hemi-citrate salt Form I of Compound 1.

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

[0043] [Figure 17] FIG. 17 is a graph showing the average punch pressure (MPa) as a function of different ejected solids fraction values ​​during tableting of three formulation mixtures of hemi-citrate salt Form I of Compound 1.

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

[0045] [Figure 19] FIG. 19 is a graph showing the ejected solid fraction as a function of the independent solid fraction during tableting of three formulation mixtures of hemi-citrate salt Form I of Compound 1.

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

[0047] [Figure 21] FIG. 21 shows the output pressure of Compound 1 mono-citrate Form A and Compound 1 hemi-citrate Form I.

[0048] [Figure 22]FIG. 22 shows a comparison of output pressure results for Compound 1 mono-citrate Form A and Compound 1 hemi-citrate Form I.

[0049] [Diagram 23] FIG. 23 shows the adhesion force of Compound 1, mono-citrate salt Form A and Compound 1, hemi-citrate salt Form I as a function of compact punch pressure.

[0050] [Figure 24] FIG. 24 shows a plot of the ejection force of Compound 1 mono-citrate salt Form A and Compound 1 hemi-citrate salt Form I, as described in Example 14.

[0051] [Diagram 25] FIG. 25 shows extrusion / detachment force plots for tested Compound 1 mono-citrate salt Form A and Compound 1 hemi-citrate salt Form I formulations described in Example 14.

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

[0053] [Figure 27] FIG. 27 is a graph showing the tabletability of a 20 mg Compound 1 mono-citrate tablet formulation and a 20 mg Compound 1 hemi-citrate tablet formulation, as measured by graphing tensile force (MPa) as a function of upper punch pressure (MPa), as described in Example 14.

[0054] [Figure 28] FIG. 28 is a graph showing the picking index of a 20 mg mono-citrate tablet formulation of Compound 1 and a 20 mg hemi-citrate tablet formulation of Compound 1, measured by graphing the picking index (TS / AS) as a function of tension (MPa), as described in Example 14. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] I. Definition Unless otherwise defined, all technical terms, designations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. In some cases, terms having commonly understood meanings 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 what is commonly understood in the art.

[0056] Throughout this disclosure, various aspects of the claimed subject matter are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and should not be interpreted as an inflexible limitation on the scope of the claimed subject matter. Thus, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, when a range of values ​​is provided, unless the context clearly indicates otherwise, each intervening value to the tenth of the unit of the lower limit between the upper and lower limits of that range, and other stated or intervening values ​​within that stated range, are understood to be encompassed within the disclosure, subject to any specifically excluded limit within the stated range. When a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. In some embodiments, two opposing open-ended ranges are provided for a feature, and such descriptions envision that a combination of those two ranges is provided herein. For example, in some embodiments, a feature may be described as being greater than about 10 units and then described (e.g., in a separate sentence) as being less than about 20 units, and thus a range of about 10 units to about 20 units is described herein.

[0057] The term "about", when immediately preceding a numerical value, means a range (e.g., plus or minus 10% of the value). For example, "about 50" means 45 to 55, and "about 25,000" can mean 22,500 to 27,500, etc., unless the context of this disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range that extends less than half the interval(s) between the preceding value and the following value, e.g., from more than 49.5 to less than 52.5. Furthermore, the phrase "less than about" a value or "greater than about" a value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30", or "about 10 to 30") refers to all values ​​in the series, or to the end points of the range, respectively.

[0058] As used herein, the terms "aprotic solvent", "nonprotic solvent" or "non-protic solvent" refer to an organic solvent or mixture of organic solvents that are not readily deprotonated in the presence of a strongly basic reactant. Non-limiting examples of aprotic solvents include ether, 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, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate, methyl isobutyl ketone, hexachloroacetone, acetone, ethyl methyl ketone, methyl ethyl ketone (MEK), ethyl acetate, acetic acid, and the like. 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, t-butyl methyl ether, and the like.

[0059] As used herein, the term "carrier" encompasses carriers, excipients, and diluents and means a substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is involved in the carrying or transport 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-pregnan-20-one having the following formula: [ka] Compound 1 may be in any form, including amorphous, crystalline, a salt form, a free base, a hydrate, anhydrous, and / or a solvate.

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

[0062] The terms "Compound 1 mono-citrate" and "Compound 1 mono-citrate" are used interchangeably herein and refer to a salt of Compound 1 having a molar ratio of 1:1 3α-hydroxy-3β-methoxymethyl-21-(1'-imidazolyl)-5α-pregnan-20-one to citrate, having the following formula: [ka] The mono-citrate salt of Compound 1 has been previously disclosed, for example, in US Patent Application Publication No. 2020 / 0071350, the entirety of which is incorporated herein by reference. As used herein, "Form A" of the mono-citrate salt of Compound 1 refers to Form A of the mono-citrate salt of Compound 1 disclosed in US Patent Application Publication No. 2020 / 0071350.

[0063] As used herein, the term "polymorphism" refers to a 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 drug substance is chemically identical to any other crystalline polymorph of the drug substance that contains the same atoms bonded together in the same way, but the crystalline forms are different and 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 volume, or channels, into which water molecules can be incorporated. In certain embodiments, the channel hydrate may contain 0% to 5% water by weight, and in certain embodiments, the change in water content (e.g., loss of water) may be fully reversible. In certain embodiments, the channel hydrate may be a sesquihydrate, and in certain embodiments, the channel hydrate may be anhydrous. A crystalline channel hydrate of a given drug substance 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" refers to, and is used interchangeably in this disclosure, with the terms disease, condition, or illness.

[0066] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound, or a salt, solvate or ester thereof, that can obtain the intended result when administered to a patient. For example, an effective amount of the hemi-citrate salt of Compound 1 is the amount necessary to reduce at least one symptom of a disease, disorder, or condition, such as depression, in a patient. The actual amount, including the "effective amount" or "therapeutically effective amount," will vary depending on a number of conditions, including, but not limited to, the severity of the disorder, the size and health of the patient, and the route of administration. Those skilled in the art can easily determine the appropriate amount using methods known in the medical arts.

[0067] As used herein, unless the context clearly indicates otherwise, the terms "in some embodiments," "in other embodiments," or the like, refer to embodiments of all aspects of the present disclosure.

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

[0069] The term "peak" refers to a line having a substantial intensity in an XRPD diffractogram (or pattern) obtained from a sample using standard XRPD collection techniques, where substantial indicates that the peak is distinguishable from the baseline. For example, a peak may be a line in an XRPD diffractogram that has 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 phrase "pharmacologically acceptable" is used herein to refer to those compounds, substances, compositions, and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0071] As used herein, the term "protic solvent" refers to a solvent or mixture of solvents that can function as an acid for the purpose of protonating any unreacted strongly basic reaction intermediates. 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 the like.

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

[0073] As used herein, the term "substantially similar" means that an analytical spectrum, such as an XRPD pattern, DSC thermogram, etc., is highly similar to a reference spectrum. For example, one of ordinary skill in the art would be able to identify two XRPD patterns that are substantially similar by evaluating and comparing the overall patterns of both peak positions and their intensities.

[0074] As used herein with respect to a patient, the term "treating" refers to improving at least one symptom of the patient's disorder. Treatment can improve or at least partially reverse the disorder.

[0075] As used herein, the term "therapeutic effect" refers to a desired or beneficial effect provided by a method and / or composition. For example, a method of treating depression provides a therapeutic effect if the method reduces at least one symptom of depression in a patient.

[0076] As used herein, the symbol "≦" means "less than or equal to," "<" means "less than," "≧" means "greater than or equal to," and ">" means "greater than." Furthermore, when used herein in connection with purity or impurity content, numerical values ​​include not only the exact number, but also the approximate range of numerical values. For example, the phrase "99.0% purity" indicates a purity of about 99.0%.

[0077] II. Hemi-citrate salt of compound 1 The present disclosure relates to a salt of compound 1. In some embodiments, the salt is a hemi-citrate salt of compound 1, and the molar ratio of 3α-hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnan-20-one to citrate salt is about 2:1 ("the hemi-citrate salt of compound 1").

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

[0079] In some embodiments, the hemi-citrate salt of Compound 1 is substantially free of the mono-citrate salt of Compound 1. The mono-citrate salt of Compound 1 has a molar ratio of 3α-hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnan-20-one to citric acid of 1:1. In some examples, the hemi-citrate salt 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, being substantially free of crystalline Form A of the mono-citrate salt of Compound 1 and / or being substantially free of crystalline Form C of the mono-citrate salt of Compound 1. In some embodiments, the hemi-citrate salt 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, or less than about 0.5% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 5% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 4% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 3% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 2% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 1% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 0.5% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains about 1% or less by weight, about 0.9% or less by weight, about 0.8% or less by weight, about 0.7% or less by weight, about 0.6% or less by weight, about 0.5% or less by weight, about 0.4% or less by weight, about 0.3% or less by weight, or about 0.2% or less by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains about 0.2% or less by weight of the mono-citrate salt of compound 1.

[0080] In some embodiments, the hemi-citrate salt of Compound 1 is crystalline form I, as described herein. In some embodiments of the present disclosure, the crystalline form I of the hemi-citrate salt of Compound 1 is a hydrate. In some embodiments, the crystalline form I of the hemi-citrate salt of Compound 1 is a channel hydrate, e.g., a channel hydrate having a water content of about 0% to about 5% by weight, e.g., 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt of Compound 1 is a channel hydrate having a water content of less than about 1% by weight. In some embodiments of the present disclosure, the crystalline form I of the hemi-citrate salt of Compound 1 is a sesquihydrate. In other embodiments, crystalline Form I of the hemi-citrate salt of Compound 1 is a monohydrate. In some embodiments, crystalline Form I of the hemi-citrate salt of Compound 1 is an anhydrous hydrate.

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

[0082] In some embodiments, crystalline forms, including channel hydrates, are characterized by interplanar spacing as determined by X-ray powder diffraction pattern (XRPD). XRPD diffractograms are typically represented by plots of peak intensity versus peak position, i.e., diffraction angle 2θ (two theta) in degrees. Characteristic peaks of a given XRPD diffractogram can be selected according to 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 most intense peak may be expressed as I / Io.

[0083] Those skilled in the art will recognize that measurements of XRPD peak positions and / or intensities for a given crystalline form of the same compound will vary within an error range. The value of degree 2θ will allow for an appropriate error limit. Typically, the error limit is represented by "±". For example, a degree 2θ of about "8.716±0.3" indicates a range of about 8.716+0.3, i.e., about 9.016 to about 8.716-0.3, i.e., about 8.416. Depending on the sample preparation technique, the calibration technique applied to the instrument, human performance variation, etc., those skilled in the art will recognize that appropriate error limits for XRPD may be about ±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 equipment used for the XRPD analysis are provided in the Examples section.

[0085] In some embodiments, the crystalline form is characterized by differential scanning calorimetry (DSC). DSC thermograms are typically represented by a diagram that plots normalized heat flow in units of watts / gram ("W / g") versus measured sample temperature °C. DSC thermograms are usually evaluated for extrapolated onset and end (outset) temperatures, peak temperatures, and heats of fusion. Peak features of the DSC thermogram are often used as signature peaks to distinguish this crystalline structure from others.

[0086] Those skilled in the art will recognize that measurements of DSC thermograms for a given crystalline form of the same compound will vary within error limits. The value of the single peak feature value expressed in °C allows for appropriate error limits. Typically, the error limits are expressed by "±". For example, a single peak feature value of "about 53.09±2.0" indicates a range of about 53.09+2, i.e., about 55.09 to about 53.09-2, i.e., about 51.09. Depending on the sample preparation technique, the calibration technique applied to the device, human performance variation, etc., those skilled in the art will recognize that appropriate limit errors for the 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 equipment used for DSC thermogram analysis are described in the Examples section.

[0088] In some embodiments of the present disclosure, the hemi-citrate salt of Compound 1 is crystalline. In some embodiments, the hemi-citrate salt of Compound 1 is crystalline Form I ("Hemi-citrate salt of Compound 1 (Form I)"). It has been found that Form I of the hemi-citrate salt of Compound 1 can exist in multiple hydration states, which may be determined in part by the relative humidity of the environment. These different hydration forms of the hemi-citrate salt of Compound 1 exhibit different physical properties, some of which may be advantageous for the development of pharmaceutical compositions, as described below. Furthermore, different hydration forms may exhibit different XRPD patterns. For example, FIG. 1 shows the XRPD pattern of the channel hydrate Form IA of the hemi-citrate salt of Compound 1 at 90% relative humidity. As discussed in Example 1, this highly hydrated form was determined to be a sesquihydrate of the hemi-citrate salt of Compound 1, and is referred to herein as the hemi-citrate Form IA of Compound 1. In certain embodiments, the hemi-citrate salt form IA of Compound 1 contains 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 salt form IA of Compound 1 exhibits an XRPD pattern at about 90% 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 5.3±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 salt form IA of Compound 1 exhibits an XRPD pattern at, for example, about 90% relative humidity that includes peaks at 5.3±0.2, 14.5±0.2, and 25.5±0.2 degrees 2-theta. In certain embodiments, the hemi-citrate salt form IA of Compound 1 has an XRPD pattern substantially the same as that shown in FIG. 1.

[0089] In some embodiments, Form I of the hemi-citrate salt of Compound 1 exhibits an XRPD pattern at a high 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 5.2±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 two-theta. In such embodiments, a high percentage relative humidity is greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, or greater than about 90% relative humidity; or from about 30% to about 99%, from about 30% to about 95%, from about 30% to about 90%, from about 40% to about 99%, from about 40% to about 95%, from about 40% to about 90%, from about 50% to about 99%, from about 50% to about 95%, from about 50% to about 90%, from about 60% to about 99%, from about 60% to about 95%, from about 60% to about 90%, from about 70% to about 99%, from about 70% to about 95%, or from about 80% to about 90% relative humidity.

[0090] In some embodiments, the hemi-citrate salt form IA of compound 1 of the present disclosure exhibits an XRPD pattern comprising the peaks shown in Table 1. The percent relative intensity of each peak may be calculated based on height. TIFF2024506942000009.tif245170

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

[0092] As further shown in Figure 10, the peaks in the XRPD pattern shift to the right at relative humidities below about 30%, indicating the presence of Form IB of the hemi-citrate salt of Compound 1. For example, at relative humidities below 20%, a new channel hydrate may become the dominant form, distinct from channel hydrate Form IA of the hemi-citrate salt of Compound 1. Figure 2 shows the XRPD pattern of Form I of the hemi-citrate salt of Compound 1 at very low relative humidity (5%). The less hydrated form is referred to herein as Form IB of the hemi-citrate salt of Compound 1. In some embodiments, the hemi-citrate salt form IB of Compound 1 exhibits an XRPD pattern that includes 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 salt form IB of Compound 1 exhibits an XRPD pattern that includes at least one, at least two, at least three, at least four, or all of the peaks selected from the group consisting of 10.9±0.2, 16.3±0.2, 17.1±0.2, 20.3±0.2, and 21.0±0.2 degrees 2-theta. In some embodiments, the hemi-citrate salt form IB of Compound 1 exhibits an XRPD pattern at about 5% relative humidity that includes peaks at 5.4±0.2, 14.5±0.2, and 25.5±0.2.

[0093] In some embodiments, the hemi-citrate salt 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 two-theta. In such embodiments, a low percentage relative humidity is a 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 a relative humidity of between about 1% and about 30%, between about 5% and about 30%, between about 10% and about 30%, between about 15% and about 30%, between about 20% and about 30%, or between about 25% and 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 an XRPD pattern substantially the same as that shown in Figure 2. In some embodiments, the hemi-citrate form IB of Compound 1 has less than 5% water by weight, e.g., less than 3% by weight, less than 2% by weight, less than 1% by weight, or 0% by weight water. TIFF2024506942000010.tif241170

[0095] In some embodiments, the hemi-citrate salt form IB of compound 1 exhibits an XRPD pattern at about 5% relative humidity substantially similar to FIG.

[0096] In some embodiments, the hemi-citrate salt Form I of Compound 1 exhibits an XRPD pattern at 90% relative humidity (RH) that includes the peaks shown in Table 4. In some embodiments, the hemi-citrate salt Form I of Compound 1 exhibits an XRPD pattern at 80% RH that includes the peaks shown in Table 4. In some embodiments, the hemi-citrate salt Form I of Compound 1 exhibits an XRPD pattern at 30% RH that includes the peaks shown in Table 4. In some embodiments, the hemi-citrate salt Form I of Compound 1 exhibits an XRPD pattern at 20% RH that includes the peaks shown in Table 4. In some embodiments, the hemi-citrate salt Form I of Compound 1 exhibits an XRPD pattern at 10% RH that includes the peaks shown in Table 4. In some embodiments, the hemi-citrate salt Form I of Compound 1 exhibits an XRPD pattern at 5% RH that includes the peaks shown in Table 4. In some embodiments, the hemi-citrate form I of Compound 1 exhibits an XRPD pattern at 90% RH comprising at least the three most intense peaks or at least the five most intense peaks as shown in Table 4. In some embodiments, the hemi-citrate form I of Compound 1 exhibits an XRPD pattern at 80% RH comprising at least the three most intense peaks or at least the five most intense peaks as shown in Table 4. In some embodiments, the hemi-citrate form I of Compound 1 exhibits an XRPD pattern at 30% RH comprising at least the three most intense peaks or at least the five most intense peaks as shown in Table 4. In some embodiments, the hemi-citrate form I of Compound 1 exhibits an XRPD pattern at 20% RH comprising at least the three most intense peaks or at least the five most intense peaks as shown in Table 4. In some embodiments, the hemi-citrate form I of Compound 1 exhibits an XRPD pattern at 10% RH comprising at least the three most intense peaks or at least the five most intense peaks as shown in Table 4. In some embodiments, the hemi-citrate salt Form I of Compound 1 exhibits an XRPD pattern at 5% RH that includes at least the three most intense peaks or at least the five most intense peaks shown in Table 4.

[0097] In some embodiments, crystalline Compound 1 hemi-citrate Form I 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 salt Form I of crystalline Compound 1 has a moisture content of about 4.4% by weight and exhibits a differential scanning calorimetry (DSC) thermogram with a peak value at about 65.2°C with an error limit of about ±2.5°C, e.g., about ±2.0°C, about ±1.5°C, about ±1.0°C, about ±0.5°C or less. In some embodiments, the hemi-citrate salt Form I of crystalline Compound 1 has a moisture content of about 3.70% by weight and exhibits a differential scanning calorimetry (DSC) thermogram with a peak value at about 71°C with an error limit of about ±2.5°C, e.g., about ±2.0°C, about ±1.5°C, about ±1.0°C, about ±0.5°C or less. In another embodiment, the hemi-citrate salt Form I of crystalline Compound 1 exhibits a DSC thermogram with a peak value at about 126.3° C. with a margin of error of about ±2.5° C., e.g., about ±2.0° C., about ±1.5° C., about ±1.0° C., about ±0.5° C. or less. In some embodiments, the hemi-citrate salt Form I of crystalline Compound 1 exhibits a DSC thermogram substantially similar to FIG.

[0099] In some embodiments, the hemi-citrate salt Form I of Compound 1 exhibits a thermogravimetric analysis (TGA) thermogram substantially similar to Figure 3. In some embodiments, the TGA thermogram of the hemi-citrate salt Form I of Compound 1 exhibits a TGA thermogram having a weight loss of about 0.0% to 4.4% in a temperature range of about 25°C to about 125°C, e.g., in a temperature range of about 25°C to about 100°C.

[0100] In some embodiments, the hemi-citrate form I of Compound 1 exhibits a DVS isotherm plot substantially similar to FIG. 4. In some embodiments, the hemi-citrate form I of Compound 1 exhibits a gravimetric water adsorption of about 1.2% (wt%) at about 20% to about 80% RH at 25° C. In some embodiments, the hemi-citrate form I of Compound 1 exhibits a gravimetric water loss of about 4.3% at about 95% to about 0% RH at 25° C. In some embodiments, the hemi-citrate form I of Compound 1 exhibits a gravimetric water adsorption of about 1.8% (wt%) at about 20% to about 80% RH at 40° C. In some embodiments, the hemi-citrate form I of Compound 1 exhibits a gravimetric water loss of about 5.4% at about 95% to about 0% RH at 40° C. In some embodiments, the water loss is fully reversible.

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

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

[0103] III. Methods for Preparing the Hemi-Citrate Salt of Compound 1 The hemi-citrate salt of Compound 1 (and its channel hydrates) may be prepared, for example, by mixing the free base of Compound 1 with citric acid in a suitable solvent to obtain the salt of Compound 1 as a suspension in a suitable solvent. In some embodiments, a ratio of about 1:0.5 of the free base of Compound 1 to citric acid 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 salt of Compound 1 (and its channel hydrates) may be prepared by slow evaporation, slow cooling, or addition of an anti-solvent to a mixture of the free base of Compound 1 and citric acid.

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

[0105] In some embodiments, the method for preparing a hemi-citrate salt of Compound 1 comprises: (a) reacting C 1 -C 3 and (b) adding the solution of step (a) to water to obtain a hemi-citrate salt of compound 1. In some embodiments, the method further comprises step (c) isolating and drying the hemi-citrate salt of compound 1. In some embodiments, the method is used to prepare a crystalline form of the hemi-citrate salt of compound 1. In some embodiments, the crystalline form of the hemi-citrate salt of compound 1 is Form I, including, for example, Form IA or Form IB as disclosed herein.

[0106] In some embodiments, C 1 -C 3 The alcohol is methanol, ethanol or isopropanol. 1 -C 3 The alcohol is methanol or ethanol. 1 -C 3 The alcohol is methanol. 1 -C 3The alcohol is one that has a water activity of greater than about 0.75.

[0107] In some embodiments, the mono-citrate salt of compound 1 is 1 -C 2 In some embodiments, C is dissolved in alcohol. 1 -C 2 The alcohol is methanol. 1 -C 2 The alcohol is ethanol.

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

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

[0110] In some embodiments, the hemi-citrate salt of compound 1 is dissolved in a suitable solvent to obtain a solution, and the crystalline form of the hemi-citrate salt of compound 1 is precipitated from the solution. In some embodiments, the hemi-citrate salt of compound 1 is dissolved by heating a mixture of the hemi-citrate salt of compound 1 and a suitable solvent. In some embodiments, the crystalline form of the hemi-citrate salt of compound 1 is precipitated from the solution by cooling the solution. In some embodiments, the crystalline form of the hemi-citrate salt 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 hemi-citrate salt of compound 1 in the solution) to the solution. In some embodiments, the crystalline form of the hemi-citrate salt 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 hemi-citrate salt is crystalline form I, including, for example, form IA or form IB as disclosed herein. In some embodiments, the suitable solvent comprises water.

[0111] In some embodiments, the suitable solvent comprises an aprotic solvent, such as 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, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate, methyl ethyl ketone (MEK), hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethyl The aprotic solvent may include at least one solvent 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, the suitable solvent comprises a protic solvent. In some embodiments, the protic solvent comprises 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 comprises 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 salt of Compound 1 is isolated after preparation. Isolation of the hemi-citrate salt of Compound 1 can be accomplished using methods such as filtration, decantation, centrifugation, or any other suitable separation technique or techniques.

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

[0116] In some embodiments, the hemi-citrate salt of compound 1 prepared by the above embodiment is substantially pure. For example, in some embodiments, the chemical purity of the hemi-citrate salt 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% pure. 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 with detection at a wavelength of 210 nm). In some embodiments, substantial purity is determined based on weight percent. In some embodiments, substantial purity is determined based on area under the curve.

[0117] In some embodiments, the hemi-citrate salt of compound 1 prepared according to the above embodiments is crystalline. In certain embodiments, the crystalline hemi-citrate salt of compound 1 prepared according to the above embodiments is substantially pure. For example, in some embodiments, the polymorphic purity of the crystalline hemi-citrate salt 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% pure. Polymorphic purity may be determined using methods known to those of skill in the art, including, inter alia, X-ray powder 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 its entirety.

[0118] In some embodiments, the hemi-citrate salt of compound 1 prepared according to the above embodiments is epimerically enriched at one or more positions compared to the epimeric purity of the starting material of the free base of compound 1. For example, in some embodiments, the hemi-citrate salt of compound 1 may contain at least 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 of the 17-β:17α epimers of compound 1. In some embodiments, the hemi-citrate salt of compound 1 may contain at least 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 of the 3α-hydroxy:3β-hydroxy of compound 1. In other embodiments, the epimeric purity of the hemi-citrate salt of Compound 1 prepared by the methods described herein is substantially the same as the epimeric purity of the Compound 1 free base starting material.

[0119] IV. Pharmaceutical Compositions In one aspect, the present disclosure provides a hemi-citrate salt of compound 1, as disclosed herein, having the formula: [ka] and a pharma- ceutically acceptable excipient. In some embodiments, the composition is substantially free of compound 1 mono-citrate. 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 compound 1 mono-citrate. In some embodiments, the composition contains less than about 5% by weight of compound 1 mono-citrate. In some embodiments, the composition contains less than about 1% by weight of compound 1 mono-citrate. In some embodiments, the composition contains less than about 0.5% by weight of compound 1 mono-citrate. In some embodiments, the composition contains about 1% or less, about 0.9% or less, about 0.8% or less, about 0.7% or less, about 0.6% or less, about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, or about 0.1% or less by weight of the mono-citrate salt of Compound 1. In some embodiments, the composition contains about 0.2% or less by weight of the mono-citrate salt of Compound 1. In some embodiments, the composition contains about 0.1% or less by weight of the mono-citrate salt of Compound 1.

[0120] In some embodiments, the chemical purity of the hemi-citrate salt of compound 1 in the composition 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% as determined by HPLC analysis after the composition is stored at about 40° C. and about 75% relative humidity for about 6 months. In some embodiments, the chemical purity of the hemi-citrate salt of compound 1 in the composition is at least about 98.0% as determined by HPLC analysis after the composition is stored at about 40° C. and about 75% relative humidity for about 6 months. In some embodiments, the hemi-citrate salt of compound 1 is crystalline form I as disclosed herein.

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

[0122] In some embodiments of the present disclosure, the hemi-citrate salt of compound 1 in the compositions disclosed herein is a channel hydrate. In some embodiments, the hemi-citrate salt 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 salt of compound 1 has a water content of about 5% by weight. In some embodiments, the hemi-citrate salt 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 about 1% by weight. In some embodiments of the present disclosure, the hemi-citrate salt of Compound 1 is a sesquihydrate.

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

[0125] In some embodiments, the composition of the present disclosure is formulated for oral administration.The dosage form for oral administration includes, for example, solid dosage forms (tablets, capsules, pills, granules, etc.) and liquid dosage forms (oral solutions, oral suspensions, syrups, etc.).In some embodiments, the composition of the present disclosure is formulated in the form of tablets.

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

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

[0128] The present disclosure provides pharmaceutical compositions containing the hemi-citrate salt of Compound 1 and one or more pharma- ceutically acceptable excipients or carriers, including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. The pharmaceutical compositions 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. (G.S. Banker & C.T. Rhodes, Eds).

[0129] The pharmaceutical compositions of the present disclosure may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal, and transdermal routes, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhaled agent, or via an impregnated or coated device such as a stent, e.g., or an arterially inserted cylindrical polymer, as described, for example, in these patents and patent applications incorporated herein by reference.

[0130] Oral administration is the preferred route for administering the compounds according to the present disclosure. Administration may be via capsules or enteric coated tablets, etc. In preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material (as described above) that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, troche, sachet, wafer, elixir, suspension, emulsion, solution, syrup, aerosol (in a solid or liquid medium), e.g., ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0131] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation may further include lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl and propylhydroxy-benzoates, sweeteners, and flavoring agents.

[0132] The compositions of the present disclosure can be formulated to provide rapid, sustained, or delayed release of the hemi-citrate salt of Compound 1 after administration to a patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patents Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.

[0133] The composition is preferably formulated in unit dosage form.The term "unit dosage form" refers to a physically separate unit suitable as a unitary dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce desired therapeutic effect in association with suitable pharmaceutical excipients (e.g., tablet, capsule or ampoule).Compound is generally administered in a pharmacologic effective amount.

[0134] Preferably, for oral administration, each dosage unit (e.g., tablet) contains about 5 mg to about 120 mg of the hemi-citrate salt of Compound 1. In some embodiments, each dosage 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 the hemi-citrate salt of Compound 1.

[0135] In some embodiments, the hemi-citrate salt of Compound 1 is present in the oral dosage form (e.g., tablet) at a weight percentage of about 20% to about 40%. In some embodiments, the hemi-citrate salt of Compound 1 is present in the oral dosage form (e.g., tablet) at a weight percentage of about 25% to about 35%. In some embodiments, the hemi-citrate salt of Compound 1 is present in the oral dosage form (e.g., 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 salt of Compound 1 is present in the oral dosage form (e.g., 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 primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the hemi-citrate salt of Compound 1. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0137] The tablets or pills containing the compounds disclosed herein may be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablet or pill may comprise an inner dose and an outer dose component, the latter being in the form of a shell that covers the former.The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact to the duodenum or be delayed in release.Various materials may be used for such enteric layers or coatings, such materials including, for example, many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0138] For example, salt forms of Compound 1, including the mono-citrate salt of Compound 1, may be sticky and therefore may be less suitable for the development of compositions for oral formulations. This can be a significant problem during process scale-up, where the salt forms of Compound 1 tend to stick to metal surfaces. To overcome this problem, formulation development often requires a significant amount of lubricant (e.g., magnesium stearate). It has been found that the hemi-citrate salt 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 high amounts in the composition. Specifically, a greater amount of lubricant (e.g., magnesium stearate) in a tablet containing Compound 1 or a pharma-ceutically acceptable salt thereof can increase the formation of the C17-epimer upon storage. For example, as shown in Figure 26, magnesium stearate appears to play an important role in the formation of the C17 epimer in mono-citrate tablets of Compound 1. Thus, reducing the amount of magnesium stearate that is compatible with the hemi-citrate salt of Compound 1 results in less formation of undesirable impurities such as the C-17 epimer.

[0139] Additionally, reducing the level of magnesium stearate results in a reduction in the compression force required to produce tablets. High compression forces often result in a loss of tablet porosity, thus slowing tablet disintegration and potential dissolution.

[0140] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and a lubricant, wherein the percentage of the lubricant in the pharmaceutical composition is less than about 4% by weight, e.g., 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 present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and a lubricant, wherein the percentage of the lubricant in the pharmaceutical composition is less than about 3% by weight, e.g., 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 present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and a lubricant, wherein the percentage of the lubricant in the pharmaceutical composition is less than about 2% by weight, e.g., 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 present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and a lubricant, wherein the percentage of the lubricant in the pharmaceutical composition is less than about 1.5% by weight. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of Compound 1 and a lubricant, wherein the percentage of the lubricant in the pharmaceutical composition is less than about 1% by weight. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of Compound 1 and a lubricant, wherein the percentage of the lubricant in the pharmaceutical composition is about 2% to about 4% by weight. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of Compound 1 and a lubricant, wherein the percentage of the lubricant in the pharmaceutical composition is about 1.5% to about 3% by weight. Examples of specific lubricants that can be used according to the present disclosure include, but are not limited to, magnesium stearate, sodium stearyl fumarate, stearic acid, talc, silica, and fats (e.g., vegetable stearins). 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 a hemi-citrate salt of compound 1 and magnesium stearate, wherein the percentage of magnesium stearate in the pharmaceutical composition is less than about 4% by weight. In other embodiments, the disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and magnesium stearate, wherein the percentage of magnesium stearate in the pharmaceutical composition is less than about 3% by weight. In other embodiments, the disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and magnesium stearate, wherein the percentage 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 a hemi-citrate salt of compound 1 and magnesium stearate, wherein the percentage of magnesium stearate in the pharmaceutical composition is less than about 2.2% by weight. In other embodiments, the present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and magnesium stearate, wherein the percentage of magnesium stearate in the pharmaceutical composition is less than about 2% by weight, e.g., 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 present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and magnesium stearate, wherein the percentage of magnesium stearate in the pharmaceutical composition is less than about 1% by weight. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 4% by weight of magnesium stearate. In other embodiments, the present disclosure provides a pharmaceutical composition comprising a hemi-citrate salt of compound 1 and magnesium stearate, wherein the percentage of magnesium stearate in the pharmaceutical composition is less than about 1% by weight. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 3% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 2% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 3% by weight magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1% to about 3% by weight magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1% to about 2% by weight magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1% to about 1.5% by weight magnesium stearate.

[0142] In some embodiments, the disclosure provides a pharmaceutical composition comprising a hemi-citrate salt 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 the hemi-citrate salt of Compound 1 and about 1% by weight 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% by weight) of the hemi-citrate salt 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% by weight) of the hemi-citrate salt of Compound 1 and about 1% to about 1.5% by weight of magnesium stearate.

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

[0144] In certain embodiments, a tablet containing the amount of compound 1 hemi-citrate and magnesium stearate described herein may contain less than about 3% by weight of the C17-epimer based on the total weight of the hemi-citrate of compound 1 after about 6 months of storage of the tablet at about 40° C. and about 75% relative humidity. In certain embodiments, a tablet containing the amount of compound 1 hemi-citrate and magnesium stearate described herein may contain less than about 2% by weight of the C17-epimer based on the total weight of the hemi-citrate of compound 1 after about 6 months of storage of the tablet at about 40° C. and about 75% relative humidity. In certain embodiments, a tablet containing the amount of compound 1 hemi-citrate and magnesium stearate described herein may contain less than about 1% by weight of the C17-epimer based on the total weight of the hemi-citrate of compound 1 after about 6 months of storage of the tablet at about 40° C. and about 75% relative humidity. In some embodiments, the tablet may contain less than about 0.75% by weight of the C17-epimer based on the total weight of the hemi-citrate salt of compound 1 after storage of the tablet for about 6 months at about 40° C. and about 75% relative humidity. In other embodiments, the tablet may contain less than about 0.5% by weight of the C17-epimer based on the total weight of the hemi-citrate salt of compound 1 after storage of the tablet for about 6 months at about 40° C. and about 75% relative humidity. In other embodiments, the tablet may contain less than about 0.25% by weight of the C17-epimer based on the total weight of the hemi-citrate salt of compound 1 after storage of the tablet for about 6 months at about 40° C. and about 75% relative humidity. In other embodiments, the tablet may contain from about 0.25% to about 1% by weight of the C17-epimer based on the total weight of the hemi-citrate salt of compound 1 after storage of the tablet for about 6 months at about 40° C. and about 75% relative humidity. In other embodiments, the tablet may contain about 0.5% to less than about 1% by weight of the C17-epimer, based on the total weight of the hemi-citrate salt of Compound 1, after storage of the tablet for about 6 months at about 40° C. and about 75% relative humidity. In certain embodiments, the tablet is stored in the presence of a desiccant. In certain embodiments, the tablet is stored without a desiccant.The percentage of the epimer present in a tablet formulation may vary based on the strength of the dosage form, such that lower strength dosage forms may have a higher percentage of the epimer present than higher strength dosage forms.

[0145] The pharmaceutical composition (e.g., tablet) of the present disclosure may also include 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 the pharmaceutical composition at about 1.5% to about 10% by weight. In some embodiments, the disintegrant (e.g., crospovidone) is present in the pharmaceutical composition at about 3% to about 8% by weight (e.g., about 3%, about 4%, about 5%, about 6%, about 7%, or about 8% by weight). In some embodiments, the pharmaceutical composition comprises an intragranular and an extragranular portion, and the disintegrant (e.g., crospovidone) is present in the intragranular and / or extragranular portion 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] It has been found that tablets containing salt forms other than the hemi-citrate of Compound 1, such as the mono-citrate form, can have an extended disintegration rate after inoculation, even when sufficient amounts of disintegrant are present, which can adversely affect the dissolution and absorption rate of Compound 1. Without intending to be bound by any theory, it is believed that the poor disintegration rate is a result of the stickiness and / or hygroscopicity of the compound, properties that can prevent effective disintegration. The resulting requirement for a higher amount of lubricant (e.g., magnesium stearate) to counter the stickiness and / or hygroscopicity of the compound also adversely affects 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., tablet) comprising a hemi-citrate salt of Compound 1 is measured using a disintegration test according to United States Pharmacopeia (USP) 14.1 without a disk. <701> When performed according to the method described in Chapter 1, the disintegration time of a pharmaceutical composition (e.g., tablet) comprising a hemi-citrate salt of Compound 1 is less than about 3 minutes (see Example 12). In some embodiments, the disintegration time of a pharmaceutical composition (e.g., tablet) comprising a hemi-citrate salt of Compound 1 is measured using a disintegration test according to USP 1366 without a disk. <701> In some embodiments, the disintegration time of a pharmaceutical composition (e.g., tablet) comprising a hemi-citrate salt of Compound 1 is less than about 2.5 minutes when the disintegration test is performed according to the method described in Chapter 1, USP 156112 without a disk. <701> In some embodiments, the disintegration time of a pharmaceutical composition (e.g., tablet) comprising a hemi-citrate salt of Compound 1 is less than about 2 minutes when the disintegration test is performed according to the method described in Chapter 1, USP 156112. <701> In some embodiments, the disintegration time of a pharmaceutical composition (e.g., tablet) comprising a hemi-citrate salt of Compound 1 is less than about 1.5 minutes when the disintegration test is performed according to the method described in Chapter 1, USP 151122 without a disk. <701> In some embodiments, the disintegration time of a pharmaceutical composition (e.g., tablet) comprising a hemi-citrate salt of Compound 1 is about 1.5 minutes to about 3 minutes when the disintegration test is performed according to the method described in Chapter 1, USP 151122 without a disk. <701> In some embodiments, the disintegration time of a pharmaceutical composition (e.g., tablet) comprising a hemi-citrate salt of Compound 1 is about 2 minutes to about 3 minutes when the disintegration test is performed according to the method described in Chapter 1, USP 151122 without a disk. <701> When performed according to the method described in Chapter 1 of the USP, the time required for the elution is about 2 minutes to about 2.5 minutes. <701> The disintegration test described in the chapter is part of the USP No. 1, published on April 26, 2019, with a publication date of May 1, 2020. <701> Refers to the chapter.

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

[0149] In some embodiments, the tablet disclosed herein comprises about 10 mg, about 20 mg, or about 40 mg of compound 1 hemi-citrate, magnesium stearate, and crospovidone. It is understood that the weight of compound 1 hemi-citrate in the tablet refers to the equivalent weight of the free base. In some embodiments, the composition (e.g., tablet) comprises compound 1 hemi-citrate, microcrystalline cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the tablet comprises the following ingredients: TIFF2024506942000013.tif73170

[0150] V. How to use In one aspect, the disclosure provides a method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a hemi-citrate salt of Compound 1, or a composition thereof, as disclosed herein.

[0151] In some embodiments, the hemi-citrate salt of Compound 1 used in the methods disclosed herein is a substantially pure hemi-citrate salt of Compound 1 having the following formula: [ka] In some embodiments, the hemi-citrate salt of compound 1 used in the methods disclosed herein is substantially free of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt 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 salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 5% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 4% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 3% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 2% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 1% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains less than about 0.5% by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of compound 1 contains about 1% or less by weight, about 0.9% or less by weight, about 0.8% or less by weight, about 0.7% or less by weight, about 0.6% or less by weight, about 0.5% or less by weight, about 0.4% or less by weight, about 0.3% or less by weight, about 0.2% or less by weight, or about 0.1% or less by weight of the mono-citrate salt of compound 1. In some embodiments, the hemi-citrate salt of Compound 1 contains about 0.2% by weight or less of the mono-citrate salt of Compound 1. In some embodiments, the mono-citrate salt of Compound 1 is in a crystalline form. In some embodiments, the hemi-citrate salt is substantially free of crystalline Form A of the mono-citrate salt of Compound 1.

[0152] In some embodiments of the present disclosure, the hemi-citrate salt of Compound 1 is a hydrate, such as a channel hydrate. In some embodiments, the hemi-citrate salt 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 salt of Compound 1 has a water content of about 5% by weight. In some embodiments of the present disclosure, the hemi-citrate salt of Compound 1 is a sesquihydrate.

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

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

[0155] In some embodiments, diseases or conditions that may 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 its entirety.

[0157] VI. Manufactured articles Also provided herein is an article of manufacture, comprising a substantially pure hemi-citrate salt of Compound 1 as described herein in suitable packaging. In some embodiments, the hemi-citrate salt of Compound 1 is formulated for oral delivery. In some embodiments, the hemi-citrate salt of Compound 1 is formulated as a tablet. In some of the foregoing embodiments, the article of manufacture further comprises a desiccant. In some embodiments, the packaging is a desiccant bottle. In some embodiments, the packaging is a desiccant blister.

[0158] The present disclosure further provides a kit for carrying out the method disclosed herein. The kit may include a substantially pure hemi-citrate salt of compound 1 described herein in a suitable package. In some embodiments, the kit further includes a desiccant. In some embodiments, the package is a dry bottle. In some embodiments, the package is a dry blister. In some embodiments, the kit further includes a label and / or instructions for use of the substantially pure hemi-citrate salt of compound 1 described herein in the treatment of a disease or disorder described herein. In some embodiments, the kit may include a unit dosage form of the compound. EXAMPLES

[0159] The present disclosure is further illustrated by reference to the following examples, however, as with the above embodiments, it should be noted that these examples are illustrative and should not be construed as limiting the scope of the present disclosure in any way.

[0160] "EtOAc" 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 dimethylsulfoxide. "DI" means distilled. "DSC" means differential scanning calorimetry. "DVS" means dynamic vapor sorption. "eq" means equivalent. "EtOH" means ethyl alcohol. "FaSSIF" means simulated fasted intestinal fluid. "FeSSIF" means simulated fed intestinal fluid. "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 polarized light microscopy. "RH" means relative humidity. "RRT" means relative retention time. "RT" means room temperature. "RT (min)" means retention time. "SGF" means simulated gastric fluid. "TGA" means thermogravimetric analysis. "THF" means tetrahydrofuran. "UPLC" means ultra performance liquid chromatography. "XRPD" means X-ray powder diffractometer or X-ray powder diffraction.

[0161] In some cases, the ratio of Compound 1 to citric acid in the hemi-citrate salt (or crystalline form of the hemi-citrate salt) of Compound 1 described herein was determined by ion chromatography (IC) using the following method: 25 μL of 10.0 μg / mL sample or standard was injected onto 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-4 mm suppressor was set at 38 mA and the column temperature was 30° C. The chromatographic elution was 15 mM KOH and the total run time was 20 minutes.

[0162] XRPD was performed using a 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. XRPD parameters for data collection were as follows: TIFF2024506942000015.tif61170

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

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

[0165] TGA data was collected using a TA Discovery 550 from TA Instruments. The TGA was calibrated using a nickel reference standard. DSC was performed using a TA Q2000 DSC from TA Instruments. The DSC was calibrated with an indium reference standard. Data analysis was performed with TA Universal Analysis software. Parameters for data collection were as follows: TIFF2024506942000016.tif39170

[0166] DVS was measured via SMS (Surface Measurement System) DVS Intrinsic. The parameters for DVS data collection were: TIFF2024506942000017.tif59170

[0167] 1 H-NMR was collected on a Bruker 500 MHz magnet. As known to those skilled in the art, 1 The relative ppm shifts and integrals of H-NMR resonances are given by, for example, d 6 - may vary depending on various sample factors, including the water content in DMSO, ion concentration in the sample, etc. Therefore, the following examples will be reported. 1 H-NMR values ​​should not be considered as characteristic for the salt and / or crystalline form.

[0168] UPLC data was collected by injecting 0.5 μL of sample or standard onto 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 buffered with 0.1% H in water. 3 PO 4 The column was equilibrated with mobile phase A consisting of: Mobile phase B was acetonitrile (ACN). Chromatographic elution was programmed as follows, after an additional time for re-equilibration, and with a total run time of 6 minutes: TIFF2024506942000018.tif29170

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

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

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

[0172] The resulting solid was identified as the hemi-citrate salt Form I of Compound 1. The ratio of Compound 1 to citric acid was 2:1 as determined 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 was dissolved in deuterated DMSO. 1 Analysis by H-NMR gave 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(d 6 -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, compound 1 hemi-citrate form I has a thin plate morphology that is prone to lamination. TGA of form I (Figure 3) shows a weight loss of 4.4% between room temperature and approximately 100 °C, suggesting a sesquihydrate hemi-citrate (i.e., form IA). DSC shows a desolvation endotherm with an onset temperature of 26.0 °C and a peak at 65.2 °C. A second endotherm (starting at 121.5 °C) associated with melting of the dehydrated phase (ΔH: 15.20 J / g) was followed by rapid decomposition as the temperature continued to increase (Figure 3). Due to the low onset temperature of dehydration, DVS was measured at both room temperature and 40 °C to predict the stability of the crystalline phase at 40 °C. At room temperature, the sample showed a water uptake of 1.2% at 20%-80% RH, indicating that the sample is slightly hygroscopic. A weight loss of 1.5% was observed from 95% to 20% RH and a weight loss of 2.9% was observed from 20% to 0% RH for a total weight loss of 4.3% over the entire cycle. This loss appears to be fully reversible as the relative humidity increases. The 40°C temperature DVS showed a water absorption of 1.8% from 20% to 80% RH, while it lost 2.2% water from 95% to 20% RH and 3.2% from 20% to 0% RH for a total loss of 5.4%. This loss was fully reversible. This indicates that the hemi-citrate form I of compound 1 is slightly hygroscopic and the water in the crystalline lattice is more loosely bound than the water in the mono-citrate lattice of compound 1. After the hygroscopicity measurements by DVS, an XRPD pattern was collected and compared to the original material and found to correspond well to the pattern of the room temperature sample after DVS temperature cycling (Figure 6). The DVS cycle measured at 40° C. showed a slight change in the XRPD peak between 14° and 18° 2θ values ​​(FIG. 7).

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

[0176] The single crystal structure of compound 1 hemi-citrate form IA was collected at -100°C for structural quality and to minimize solvent loss (Figures 8 and 9). Compound 1 hemi-citrate form IA was crystallized in the C2 monoclinic space group (see Table 3). The additional water in the unit cell reduces the chances of API-citrate hydrogen bond formation, thus reducing the impact of their interactions in the structure. The hydrogen bond network is difficult to fully evaluate because one of the two citrates resides on the center of symmetry, which is itself asymmetric and results in a disordered form that is not easily resolved. This is further complicated by the possibility of unresolved water molecules. Some of the oxygen atoms in that region are easily differentiated between the disordered citrate portion and the solvent. The interactions between API and citrate are very few in number, but they are much stronger when measured by atomic distances, inferring contacts that are more likely ionic in nature than electrostatic or van der Waals interactions. TIFF2024506942000019.tif156170

[0177] Example 2: Characterization of Compound 1 Hemi-Citrate Sesquihydrate Form IA by X-ray Crystallography Several slurry samples (containing solvents such as acetone, water, THF, 2MeTHF) were submitted for single crystal analysis. After storage at room temperature for several days, cracks were observed in the rod / plate-shaped crystals, and growth of small crystalline 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 them and then naturally cooling them to room temperature. Data collection was performed at 223K and 173K with crystals cooled using a Cryostream cryostat to reduce crystal collapse. Data sets were collected on several freshly prepared crystals, which consistently yielded the same unit cell parameters, but citric acid did not degrade in the crystal structures from these data sets. A by-product from the screening crystals was the solving of the crystal structure of the normal form of compound 1, isolated from aqueous acetone.

[0178] The crystal structure of the hemi-citrate sesquihydrate of the compound (i.e., Form IA) was solved from block-like crystals grown from aqueous methanol. The structure was first solved and partially refined in space group C2, but due to the extra difficulty in resolving the highly complex disorder of the citric acid, the structure was subsequently solved and refined in space group P1. [ka] Compound 1 Hemi-citrate sesquihydrate C 26 H 40 N 2 O 3 0.5C 6 H 8 O 7 1.5H 2 O 551.71 g / mol

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

[0180] The patterns show that the system does not change from 90% to 30% RH, but changes from 30% to 20% that persists up to 5% RH (FIG. 10). These results show the change from a channel hydrate from Form IA of the hemi-citrate salt of Compound 1 at 90% to 30% RH, and from Form IB of the hemi-citrate salt of Compound 1 to a channel hydrate at RH less than 30%. For comparison, FIG. 10 also shows the change from a channel hydrate from Form IV of the mono-citrate salt of Compound 1 to a channel hydrate from Form A of the mono-citrate salt of Compound 1 ("Form A; air dried"), and the hemi-citrate salt of Compound 1 recrystallized from methanol and water ("Form I; MeOH / H 2 0"), as well as the XRPD pattern of the free base of Compound 1.

[0181] The observed shifts are similar to the XRPD shifts observed in the post-DVS data shown in FIGS.

[0182] Example 4: Comparison of XRPD patterns from the hemi-citrate salt of Compound 1, Form IA, and the mono-citrate salt of Compound 1 (Form A) The XRPD pattern of crystalline Compound 1 hemi-citrate Form IA is shown in Figure 11 (middle pattern) and is overlaid with the XRPD patterns of Compound 1 mono-citrate salt (Form A) (bottom pattern) and Compound 1 mono-citrate anhydrate ("Form IV") (top pattern). Comparison of the XRPD patterns shows that Compound 1 hemi-citrate salt Form IA has a separate and unique pattern that is readily distinguishable from Compound 1 mono-citrate salt (Form A) and Compound 1 mono-citrate anhydrate.

[0183] Example 5: Comparison of H-bond interactions in the hemi-citrate salt form IA of Compound 1 and the mono-citrate salt form A of Compound 1 Compound 1 hemi-citrate form IA and compound 1 mono-citrate (form A) have conformations that are highly dependent on hydrogen-bonding interactions. The relevant hydrogen-bonding interactions are listed in Table 5 (compound 1 mono-citrate form A) and Table 6 (compound 1 hemi-citrate form IA). Compound 1 mono-citrate (form A) shows a very distinct set of intermolecular interactions, isolating two water molecules within the citrate network, which then hydrogen-bonds with the API molecule in one direction and a direct interaction between the citrate anion in the other direction. The API acts as a bridging group between these citrate and water assemblies, resulting in the formation of a two-dimensional pseudopolymer sheet. In contrast, the hydrogen-bonding network of compound 1 hemi-citrate form IA is mainly a set of interactions between the citrate anion and water molecules, while the citrate anion itself forms a pseudopolymer chain in one direction. Unlike mono-citrate form A of compound 1, the water molecules in hemi-citrate form IA of compound 1 are free to interact with the API molecules. Furthermore, while mono-citrate form A of compound 1 shows a single set of interactions between one citrate and the adjacent API molecule, which may be close enough to be considered as ionic interactions, hemi-citrate form IA of compound 1 shows two for each citrate (3 API to 1.5 citrate anions in the asymmetric unit cell). This explains the nature of hemi-citrate. The interactions with water are not significantly uniform, and the presence of water-API hydrogen bonds precludes the opportunity for further citrate-API interactions. However, one of the citrate anions in hemi-citrate form IA of compound 1 is located at a special position, but does not match the symmetry of its position, resulting in an obvious obstacle. This gives rise to a degree of uncertainty in the area due to the abundance of oxygen atoms due to the orientation of the citrate, or water molecules dissolving the crystal matrix.

[0184] Example 6: Comparison of Compound 1 Hemi-Citrate Form IA and Compound 1 Mono-Citrate (Form A) Stability As shown in FIG. 12, when formulated as a tablet dosage form using the same formulation ingredients and manufacturing process, the hemi-citrate salt of Compound 1 stored in a sealed bottle for one or two months was observed to produce fewer degradation products (i.e., the C17-epimer) than the mono-citrate salt of Compound 1, and is therefore more chemically stable.

[0185] The hemi-citrate salt of Compound 1 was also observed to be less sensitive than the mono-citrate salt of Compound 1 to slow the dissolution rate of tablets (Figures 13 and 14). The release of Compound 1 from acidified formulations of the hemi-citrate salt of Compound 1 over time is greater than the release of Compound 1 from the same acidified formulations of the mono-citrate salt of Compound 1 under all conditions evaluated (initial and tablets stored in open dishes at 40°C / 75% RH for 2 weeks, 1 month, or 2 months).

[0186] Example 7: Evaluation of the stability of hemi-citrate form I of compound 1 The stability of the hemi-citrate salt Form I of Compound 1 may be evaluated according to the ICH guidelines established for the testing of new substances and products provided below. TIFF2024506942000021.tif59170TIFF2024506942000022.tif250162TIFF2024506942000023.tif73170TIFF2024506942000024.tif67170

[0187] Example 8: Conversion of Compound 1 Hemi-Citrate Form IA to Compound 1 Hemi-Citrate Form IB Hemi-citrate salt form IA of Compound 1 was prepared similarly to Example 1. The wet cake of hemi-citrate form IA of Compound 1 prepared during filtration (before crystallization) was heated at 60° C. under full vacuum (N in Hg). 2 / 30) for 18 hours. Compound 1 hemi-citrate form IA was converted to compound 1 hemi-citrate form IB upon drying.

[0188] Example 9: Gelation Experiments It is noted that during tablet dissolution experiments, significant gelation was observed for the mono-citrate salt of Compound 1 under certain conditions. However, the hemi-citrate salt of Compound 1 was less likely to gel under similar conditions. To confirm these findings, control experiments were performed in which the free base, mono-citrate salt, and hemi-citrate salts of Compound 1 were dissolved in aqueous media at concentrations ranging from 0.5 mg / mL to 10 mg / mL. Dissolution experiments were performed in either 0.1 N HCl, water, or pH 7.4 buffer as the aqueous medium.

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

[0190] Example 10: Tableting test of three granulation formulations of the hemi-citrate salt of Compound 1 The objective of this example was to prepare simulated roller compacted granulations using a compression simulator to investigate three prototype formulation mixtures. All compression testing was performed on a Phoenix hydraulic compression simulator. The formulation batches evaluated are shown in Table 7. TIFF2024506942000025.tif81170

[0191] The intragranular blend of the hemi-citrate salt of Compound 1 was compressed using a compression simulator to produce granules blended into the three final formulations. All three formulations showed good strength during high speed compression, achieving the 1.7 MPa required for a viable formulation.

[0192] Methodology: Preparation of intragranular mixture 60 g of intragranular blend was prepared by blending the materials in a container using a Turbula T2 blender. Compound 1 hemi-citrate salt and excipients were blended for 10 minutes at 30 rpm, sieved magnesium stearate was added, and blended for an additional 2 minutes. The ingredients of the intragranular blend are shown in Table 8. TIFF2024506942000026.tif42170

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

[0194] Determination of actual density by helium pycnometry The instrument used was a Micromeritics AccuPyc II 1340 and the test parameters are listed below: Tests were performed in duplicate (assuming a target variability of <2% was achieved). TIFF2024506942000027.tif42170

[0195] Simulation of Gerteis roller compaction The objective was to compact an initial powder mix 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 replicate the Gerteis roller compactor. The simulation was based on a 250 mm diameter roller operated at 4 rpm. The methodology was based on the reference A. Zinchuk et al., Int. J. Pharm. 269 (2004) 403-415 and was calculated using the formula =sin() (where D is the displacement, R is the radius of the roller (mm), and ω is the rotation frequency of the roller (s -1 ) where t is time (s).

[0197] Primary Test Parameter – Compression The main test parameters for compression were: TIFF2024506942000028.tif47170

[0198] Equipment used The equipment used in this study was as follows: TIFF2024506942000029.tif32170

[0199] Selecting the hitting settings A nominal minimum punch separation was chosen as a starting point (e.g., 3 mm). The resulting solid fraction was calculated. An adjustment to the minimum distance between punches was made to determine the settings necessary to achieve compression with the target solid fraction. A fill depth of 7.3 mm, fill weight of 300 mg, and punch separation of 4.3 mm were used. Sufficient compressions were made to complete the formulation. Compression parameters were checked every 10 compressions to ensure the solid fraction was on 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 the larger pieces were reground.

[0201] High speed tableting of the three formulation mixtures Preparation of mixture for tablet production A small formulation mix as shown in Table 9 below was made using the sieved prepared granules. TIFF2024506942000030.tif37170

[0202] The formulation was blended for 10 minutes using a Turbula T2 blender and the screened magnesium stearate was added and blended for 2 minutes. TIFF2024506942000031.tif63170

[0203] Determining the filling weight The material showed good flow and therefore the hopper was used to fill the mold. The starting position of the lower punch (i.e. depth) required to obtain the compact weight was determined by experiment. This was adjusted as necessary throughout the trial to ensure that the 300 mg was achieved as closely as possible.

[0204] characteristics The punch motion characteristics were programmed into the compression simulation software to define the punch motion. A single ended sine wave was used. The base of the sine wave was extended with a flat section to achieve a target dwell time of 10 mS. A high speed was chosen as it represents the expected production conditions.

[0205] Selection of compression target thickness The nominal minimum punch separation value was selected as a starting point (e.g., 3.0 mm). The resulting peak force and crush strength were recorded. Adjustments to the minimum distance between punches were made and the results were recorded and plotted to set extrapolate to achieve the desired force range. Further compression was performed to obtain different thicknesses of compression. From this, test conditions were selected to include the specified force range or to map the material through compression to overcompression. The objective was to plot the viable range of the formulation.

[0206] Each setup was repeated and each point assessed for reproducibility. Data was processed using Phoenix compression analysis software, tabulated, and exported to Excel for processing.

[0207] Physical parameters After ejection, the compacts were visually inspected and the appearance was noted. The compacts were weighed. Sometimes when the compacts were capped, the top surface may come off and be lost, therefore the weight recorded may be lower than the actual compact weight. Thickness and diameter were measured with a handheld caliper. Crush strength (hardness) was determined in kilopons. Crush strength is used as a measure of how strong the bonds are within the compact. Tensile strength (MPa) is calculated from the crush strength, which allows for a direct comparison of compacts of different sizes.

[0208] calculation The following calculations were used: Mean Force = average of upper and lower peak force (kN) Tension for a cylindrical compression (MPa) = 2 / πDT, During the ceremony, P = crushing strength (hardness), D = compact diameter (mm); and T = Compressed thickness / height (mm) Punch pressure = average peak force / punch tip area (MPa) Volume of compressed product = Pi x (diameter of compressed product / 2) 2 × Compressed height (mm 3 ) In the mold, the compaction volume was determined from the mold diameter and the minimum punch separation. From the dimensions of the compressed product after ejection, the volume of the compressed product outside the mold was measured. Density of compressed material [g / cm 3 = mg / mm 3 ] = mass of compressed product (mg) / volume of compressed product (mm 3 ) Solid fraction = calculated density (g / cm 3 ) / True Density (g / cm 3 )

[0209] Manufacturability measurements Manufacturability was measured based on the relationship between three different compression measurements: tabletability, compressibility, and compactibility. Tabletability is the relationship between punch pressure and tension, compressibility is the relationship between punch pressure and solid fraction, and compressibility is the relationship between tension and solid fraction.

[0210] result Tablet The main purpose of plotting tension against punch pressure is to understand how a material behaves throughout its compressibility range. Force was converted to pressure and normalized to tablet size, which makes it easier to compare tablets of different sizes. There are many important metrics to look for when evaluating the compression properties of a material:

[0211] That is, the shape of the plot should be sigmoidal. At very low compression pressures, the powder undergoes particle rearrangement and the compression is too weak to hold and test. The formulation should then have a linear region where there is a good correlation between force and tablet strength. This is the region that is important for tableting. The points should line up with little variability (scattering) to provide repeatability and control on the tablet press.

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

[0213] All three final blends showed good compression properties, all achieving tensile forces above 1.7 MPa, as shown in Figure 15. Formulation 3 was slightly stronger. Formulations 2 and 3 were similar.

[0214] At some point, all formulations become "over-compressed". This occurs when the force of compression exceeds the compressibility of the material. This region can be seen as a plateau with scattering and fluctuation. Sometimes the strength peaks and falls off. Over-compressed tablets can exhibit visual defects such as capping and lamination. The defects may be internal and only show up as a loss of strength in hardness testing. The onset of over-compression should be at a force significantly higher than that used for production. If production is done with forces within the over-compressed region, the result will be capping and lamination and a loss of yield. The target strength of this product can be checked against the plot to ensure it can be manufactured at high speeds.

[0215] As shown in Figure 15, the formulations become overcompressed at approximately 250 MPa. The onset of overcompression varies from formulation to formulation. Batch 1 has evidence of scattering indicating that internal variations are beginning to occur. This was less evident for the other two batches.

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

[0217] Compressibility Density was calculated from the measured weight and compact dimensions after ejection. Solid fraction was calculated by dividing compact density by actual density and expressed as solid to void ratio. The relationship between solid fraction and tension can be useful for comparing tablet manufacturing parameters and compact size.

[0218] The results shown in Figure 16 indicate the solid fraction required to achieve the desired compact strength. The relationship between solid fraction and tension is expected to be independent of punch speed [Reference: Amidon; J.Pharm Sci. Vol 94,3,pp165-472]. Because the compact is measured after ejection, capped and damaged tablets will cause outliers or scatter, making accurate measurement difficult.

[0219] A standard tablet formulation is expected to compress to a 0.8-0.85 solid fraction range. This will achieve a compressed strength of approximately 1.5 MPa across the range of batches. Target strength is based on dissolution rate and other quality attributes such as friability requirements.

[0220] The solid fraction of the granules used was targeted at 0.6 SF. Extrapolating the shape of the curve estimates that the lowest 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 the punch pressure increases, the volume of the compact decreases. As the weight remains constant, the density tends toward the true density of the material. This information can be used to understand the force required to achieve the desired density and the differences between materials.

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

[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] Driving power Ejection force is the peak force measurement of the lower punch while ejecting the tablet. The force should not typically exceed 500 N to avoid damaging the compact during removal from the die. High forces during ejection promote crack propagation within the compact, thus promoting capping and lamination.

[0225] For this experiment, the mold was not lubricated externally since the lubricant was included in the formulation mixture. As shown in Figure 18, the ejection force for all of the formulations was higher than the recommended level. Formulation 1 produced an audible squeal during ejection, indicating high friction. The ejection force was greatest for Formulation 1.

[0226] Change in density after ejection If the elastic recovery were zero, the calculated density of the compact would be the same after ejection of the compact in the mold (a straight line).As shown in Figure 19, the compact exhibits a small amount of elastic recovery.

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

[0228] Breakaway force As the compact is ejected, it rests against the lower punch and is pushed into a collection chute by an instrumented arm. The loading cell can read the force used to eject the compact from the lower punch surface. The baseline reading for a non-sticky material (e.g., microcrystalline cellulose (Avicel)) is approximately 0.25 N.

[0229] As shown in Figure 20, the three different formulations have similar levels of interaction with the punch, which is lower. Approximately half of the compressions exhibited similar separation forces to the baseline, while the others exhibited slight increases, suggesting a slightly increased risk of sticking and picking, although no compressions showed visual evidence of sticking during testing.

[0230] Example 11: Process Scale Production of Compound 1 Hemi-Citrate Salt Tablets Immediate release tablets were prepared containing 10 mg or 20 mg of the hemi-citrate salt of Compound 1. The tablet ingredients are shown in Table 10. TIFF2024506942000032.tif181170

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

[0232] The granules were then mixed with the extragranular portions of CP and SD and then lubricated with magnesium stearate to prepare the final powder blend. This final powder blend was compressed into tablet centers 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 Compound 1 mono-citrate tablets with Compound 1 hemi-citrate tablets. TIFF2024506942000033.tif42170

[0234] All disintegration tests were performed without discs, using USP <701> The method described in chapter was followed. Disintegration test was carried out using LabIndia DT100 FD / DTT / 01 model.

[0235] This example further evaluates the manufacturability of compound 1 hemi-citrate tablets. All formulations listed in the table below contained 2% magnesium stearate, except for formulation #5, which contained 4% magnesium stearate. It was observed that, on average, formulation #5 required the highest compression force required to reach the same tablet hardness range of other tablets at the same tableting speed. This shows the effect of increasing the concentration of magnesium stearate. TIFF2024506942000034.tif88170

[0236] Example 13: Compression Characterization of Compound 1 Mono-Citrate Form A and Compound 1 Hemi-Citrate Form I Salts by Heckel 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 die using a flat faced punch moving at a set speed. The punch force is precisely measured at frequent intervals and the punch displacement is used to calculate the powder volume. The yield pressure is calculated at slow and fast punch speeds to evaluate the time dependent component to the deformation of the material.

[0237] The real density of the material was determined by Helium Pycnometry. The average real density of the tested batches of Compound 1 mono-citrate salt Form A was 1.2666 g / cm 3 and the average actual density of the tested batches of compound 1 hemi-citrate Form I was 1.2621 g / cm 3 It was.

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

[0239] compression A known weight of pure drug is compressed to theoretical zero porosity using a 10 mm diameter flat faced punch. A compression simulator was used under the following conditions: TIFF2024506942000035.tif43170 During compression, the position of the punch tip was precisely determined and the force measured by the load cell yielded a record of the primary compression parameters. Temperature and humidity were monitored at intervals during the test.

[0240] The data was analyzed by a compression analysis software program to obtain values ​​for yield pressure (Py) using the Haeckel equation.

number

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

number

[0242] result Compression Results for Mono-Citrate Salt Form A of Compound 1 The compression results of Compound 1 mono-citrate salt Form A at low (0.1 mm / sec) and high (300 mm / sec) speeds are provided in Table 13. The laboratory conditions for the low and high speed runs were 21.6° C. / 37.1% RH and 21.7° C. / 38.9% RH, respectively. TIFF2024506942000038.tif72170

[0243] Below is a summary of the results and observations obtained with the batches of Compound 1 mono-citrate salt Form A that were tested. TIFF2024506942000039.tif16170

[0244] The compression results of Compound 1 hemi-citrate Form I at low (0.1 mm / sec) and high (300 mm / sec) speeds are provided in Table 14. The laboratory conditions for the low and high speed runs are 21.9° C. / 38.9% RH and 21.9° C. / 38.6% RH, respectively. TIFF2024506942000040.tif58170

[0245] Below is a summary of the results and observations obtained with this batch of hemi-citrate salt Form I of Compound 1 that was tested. TIFF2024506942000041.tif17170

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

[0247] The yield pressure of both batches of Compound 1 salts increased at higher press speeds, with the mono-citrate salt reaching 109 MPa and the hemi-citrate salt reaching 84 MPa. A comparison of the yield pressure results is shown in FIG.

[0248] Strain rate sensitivity (SRS) measures the change in compression behavior with production compression speed. SRS was 28.7% for the mono-citrate salt form A of batch compound 1 and 21.4% for the hemi-citrate salt 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 higher speeds, and is expected to show some rate-related change in behavior upon scale-up.

[0249] It should be noted that the Haeckel analysis is a measure of deformation, not compact formation. To understand how residence time affects bonding, the compression strength is observed. Compacts produced at low speed were ejected in their entirety with some chipping at the edges. The crush strengths at low speed for batches of Compound 1 mono-citrate form A were 15.6-18 kpounds, and at high speed were 5-2.4 kpounds. For batches of Compound 1 hemi-citrate form I, the crush strengths at low speed were 14.2-15.2 kpounds, and at high speed were 4.4-5.6 kpounds. Ideally, a 10 mm formulation compact should have a strength of 10-12 kpounds, which is considered low risk. Relatively high concentrations are theoretically possible, as materials can contribute bond strength to the final formulation. Compression strength and bonding decrease at high speeds. As the speed increases, there is less time for strong bonds to form and the compact expands after the force is removed. Thus, the strength of the bond is affected by the residence time. In the formulation, for example, the addition of appropriate excipients can increase the bond, reduce the rate effect, and limit the lamellar formation.

[0250] It should also be noted that the test was designed to over-compress the material and therefore strength may improve in tablet-related compression forces.

[0251] In summary, compound 1 shows some differences in compaction and compression between the two batches of salt. The crush strength shows that the material can provide strength in compression, but due to elasticity, the strength decreases rapidly.

[0252] Example 14: Punch adhesion of mono-citrate form A of Compound 1 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. An instrumented adhesion punch was used to quantify the force between the upper punch surface and the freshly formed tablets. The compression properties of the powders were also investigated and compression measurements were performed to understand key indicators of product quality. The studies were performed at room temperature. The formulation mixtures used in this study are shown in Table 15. TIFF2024506942000042.tif58170

[0253] An instrumented adhesive punch was designed to measure the force between the upper punch face and the top surface of the compact. The punch tip is separate from the body of the punch. The tip is attached to a force sensor within the body of the punch. The compact is compressed in the normal manner. After compression, the tip of the punch remains attached to the adhesive surface and as the punch is pulled away the force is measured by the sensor. The more pulling force required to peel the tablet from the surface the larger the measurement. Measurements are recorded in volts but can be converted to force through an amplifier with appropriate calibration. A K2 channel amplifier was used in the 50 N range.

[0254] A single-ended sine wave was used to mimic the motion of the production punch. To maximize adhesion measurements, a dwell is inserted at the bottom of the curve to extend the time the material is in contact with the punch face. The profile duration was 0.5 s, yielding a dwell time of 40-45 mS.

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

[0256] The punch faces were cleaned with alcohol at the start and ten compacts were compressed at one setting. After every ten sets the punches and dies were cleaned and LVDT calibrated. Readings are expected to start low at the beginning of the test and reach an equilibrium amount as the surface becomes coated with the mixture. Once the settings have been determined from the first test, the test can 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] A control sample was also compressed to ensure that the test conditions were consistent. An empty die was used as a baseline check to ensure there was no friction between the punch tip and the die. The device was operated in the absence of powder and the force is expected to be essentially zero. Microcrystalline cellulose (MCC, Avicel PH102) is a material with a very low tendency to stick and is therefore used as a negative control with a low value in the absence of stickiness. Mannitol (Partek 200) is a material with a very high attraction to standard steel and is therefore used as a positive control to ensure that the device exhibits high stickiness.

[0258] FIG. 23 shows adhesion force plotted against compact punch pressure. Adhesion force is the force recorded by an instrumented adhesion punch as the punch is pulled away from the tablet surface. The punch used was from 2019. The results of the control samples were as expected. MCC had low adhesion force and mannitol had high adhesion force. The measurements of the blank mold were less than 1 N and can be considered as the baseline. At the lowest compaction pressure, both materials were similar. As compaction pressure increases, the interaction with the punch increases and the measured adhesion force increases. Formulations of Compound 1 hemi-citrate salt Form I had lower adhesion force compared to formulations of Compound 1 mono-citrate salt Form A.

[0259] FIG. 24 shows a plot of the ejection force in this study. Ejection force is the force exerted on the lower punch as the compact is ejected. The molds were made of standard steel for all compacts, with only the upper punch face modified for the surface in question. The ejection force of the Compound 1 hemi-citrate Form I formulation was higher than that of Compound 1 mono-citrate Form A formulation. Both increased with increasing compression pressure. At production-relevant compression forces, the ejection force is higher than ideal.

[0260] Figure 25 shows the ejection / disengagement force plots for the formulations tested in this study. Once the tablet is ejected, it rests on the lower punch face until the arm is pushed into the collection chute. The arm is fitted with a load cell which records the force applied to remove the sample. There is the potential for false positives as the load cell can pick up debris (e.g. loose granules) on the die table, therefore one is looking for high frequency rising results rather than individual events indicative of sticking. A baseline measurement using a known non-stick material (MCC) is shown for comparison.

[0261] The lower punch was made of standard steel. The separation forces were similar to the baseline measurements for both formulations. There was no evidence of significant separation forces for either salt formulation.

[0262] Tabletability: With regard to tabletability, the formulations had good tensile strength of over 1.7 MPa and therefore were considered to be at low risk for tensile related manufacturability issues. As shown in Figure 27, the formulation of Compound 1 mono-citrate salt Form A had higher tensile strength than the formulation of Compound 1 hemi-citrate salt Form I. At faster rates, formulation strength was similar, but at longer residence times, differences in strength were observed between the two formulations.

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

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

[0265] Incorporation by Reference All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, mention of any references, articles, publications, patents, patent publications, and patent applications cited herein is not, and should not be taken as, an admission or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

1. A substantially pure hemi-citrate salt of Compound 1 having the formula: 【Chemistry 1】

2. 2. The hemi-citrate salt of claim 1, wherein the hemi-citrate salt is substantially free of Compound 1 mono-citrate salt.

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

4. 2. The hemi-citrate salt of claim 1, wherein the hemi-citrate salt has a moisture content of about 0% to about 5% by weight.

5. 2. The hemi-citrate salt of claim 1, wherein the hemi-citrate salt is a sesquihydrate.

6. 2. The hemi-citrate salt of claim 1, wherein the hemi-citrate salt is in crystalline form I.

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

8. 2. The hemi-citrate salt of claim 1, wherein the hemi-citrate salt is crystalline form IA of Compound 1, and the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern including at least one of the following peaks at diffraction angles 2-theta: 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. 9. The hemi-citrate salt of claim 8, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern comprising at least three of the following peaks at the diffraction angle 2-theta: 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. 10. The hemi-citrate salt of claim 8 or 9, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern comprising the following peaks at diffraction angles 2-theta: 5.3±0.2, 14.5±0.2, and 25.5±0.

2.

11. 10. The hemi-citrate salt of claim 8 or 9, wherein the crystalline form IA exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

12. 2. The hemi-citrate salt of claim 1, wherein the hemi-citrate salt is crystalline form IB of Compound 1, and the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern including at least one of the following peaks at diffraction angles 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.

13. 13. The hemi-citrate salt of claim 12, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern comprising at least three 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, 20.3±0.2, 21.0±0.2, and 25.5±0.

2.

14. 14. The hemi-citrate salt of claim 12 or 13, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern comprising the following peaks at the diffraction angles 2-theta: 5.4±0.2, 14.5±0.2, and 25.5±0.

2.

15. 14. The hemi-citrate salt of claim 12 or 13, wherein the crystalline form IB exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

16. The 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 Molecule / asymmetric unit 2, defined by unit cell parameters substantially similar to 7. The hemi-citrate salt of claim 6, wherein the crystalline form is at about 173K.

17. A pharmaceutical composition comprising the hemi-citrate salt of claim 1 or 2 and at least one pharma- ceutically acceptable excipient.

18. 18. The pharmaceutical composition of claim 17, wherein the chemical purity of compound 1 in the composition is at least about 98% after the composition is stored at about 40° C. and 75% relative humidity for about 6 months.

19. 18. The pharmaceutical composition of claim 17, wherein the composition contains about 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, after the composition has been stored at about 40° C. and 75% relative humidity for about 6 months.

20. 18. The pharmaceutical composition of claim 17, further comprising a lubricant, wherein the proportion of said lubricant in said pharmaceutical composition is less than about 4% by weight.

21. 21. The pharmaceutical composition of claim 20, wherein the lubricant is magnesium stearate.

22. 18. The pharmaceutical composition of claim 17, further comprising crospovidone.

23. 23. The pharmaceutical composition of claim 22, wherein the percentage of said crospovidone in said pharmaceutical composition is from about 3% to about 8% by weight.

24. about 25% by weight of the hemi-citrate salt of Compound 1; About 2% by weight of magnesium stearate, and 18. The pharmaceutical composition of claim 17, comprising about 7% by weight of crospovidone.

25. 20. The pharmaceutical composition of claim 17, formulated for oral delivery.

26. 26. The pharmaceutical composition of claim 25, which is a tablet.

27. 27. The pharmaceutical composition of claim 26, wherein the tablet has a tensile strength of at least 1.7 megapascals (MPa).

28. 27. The pharmaceutical composition of claim 26, wherein the tablet has a disintegration time of less than about 2.5 minutes.

29. 1. A method for preparing a hemi-citrate salt of Compound 1 having the formula: 【Chemistry 2】 The method further comprising: (a) Compound 1 mono-citrate salt was added to C １ -C ２ Dissolving in alcohol to obtain a solution; (b) adding said solution to water to obtain said hemi-citrate salt of Compound 1, and optionally (c) isolating and drying the hemi-citrate salt of Compound 1. A method comprising:

30. 1. A method for preparing a hemi-citrate salt of Compound 1 having the formula: 【Chemistry 3】 The method further comprising: (a) suspending the mono-citrate salt of Compound 1 in water; (b) isolating the hemi-citrate salt of Compound 1, and optionally (c) drying the hemi-citrate salt of Compound 1. A method comprising:

31. 31. The hemi-citrate salt of compound 1 prepared according to the process of claim 29 or 30.

32. The pharmaceutical composition of claim 17 for treating a disease or condition, wherein the disease or condition is selected from depression, epilepsy, bipolar disorder, or anxiety.

33. The pharmaceutical composition of claim 32, wherein the disease or condition is epilepsy.

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