Crystalline salts of T-type calcium channel modulators and methods of use thereof

Abstract

The present disclosure provides Pattern D, i.e., a crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride trihydrate (Compound 1). The present disclosure also provides pharmaceutical compositions comprising the Pattern D form of Compound 1, and methods of treating neurological and psychiatric disorders by administering the Pattern D form of Compound 1 or a pharmaceutical composition comprising the Pattern D form of Compound 1 to a subject in need thereof.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 449,461, filed March 2, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Introduction T-type calcium channels are low-voltage activated ion channels that mediate calcium influx into cells. Abnormal function of these ion channels is associated with several diseases or conditions, including psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremors (e.g., essential tremor), epilepsy, or epilepsy syndromes (e.g., absence seizures and juvenile myoclonic epilepsy). Therefore, compounds that selectively regulate T-type calcium channels in mammals can be useful in treating such diseases. Summary of the Invention [Means for solving the problem]

[0003] Thus, in some embodiments, the present disclosure provides a crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride trihydrate (Compound 1), characterized by an x-ray powder diffraction (XRPD) pattern including at least one peak at a diffraction angle (°2θ) selected from the group consisting of: The peak at approximately 12.0° The peak at about 15.6° Peak at about 16.7°, Peak at about 19.8°, The peak at about 21.2° The peak at about 24.1° The peak at about 25.2° a peak at approximately 27.3°, and Peak at approximately 30.2°.

[0004] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): a peak at approximately 25.2°, and Peak at approximately 27.3°.

[0005] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): The peak at about 24.1° a peak at approximately 25.2°, and Peak at approximately 27.3°.

[0006] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): Peak at about 16.7°, The peak at about 24.1° a peak at approximately 25.2°, and Peak at approximately 27.3°.

[0007] In some embodiments, the crystalline form is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): The peak at approximately 12.0° Peak at about 16.7°, The peak at about 24.1° a peak at approximately 25.2°, and Peak at approximately 27.3°.

[0008] In some embodiments, the crystalline form is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in FIG.

[0009] In some embodiments, the crystalline form has an onset of melting as determined by differential scanning calorimetry (DSC) at about 75.2°C.

[0010] In some embodiments, the crystalline form is of the space group

number

[0011] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a crystalline form of the present disclosure and a pharmaceutically acceptable carrier.

[0012] In some embodiments, the pharmaceutical composition further comprises a release-modifying polymer. In some embodiments, the release-modifying polymer is selected from the group consisting of a hydrophilic matrix polymer, a hydrophobic matrix polymer, and a polyacrylate polymer. In some embodiments, the hydrophilic matrix polymer is hypromellose.

[0013] In some embodiments, the pharmaceutical composition is for oral administration.

[0014] In some embodiments, the present disclosure provides a method of treating a neurological disorder, the method comprising administering to a subject in need thereof a crystalline form of the present disclosure or a pharmaceutical composition of the present disclosure.

[0015] In some embodiments, the neurological disorder is tremor. In some embodiments, the tremor is essential tremor, Parkinson's disease tremor, cerebellar tremor or CACNA1G tremor. In some embodiments, the tremor is essential tremor.

[0016] In some embodiments, the present disclosure provides a method of treating a psychiatric disorder in a subject in need thereof, the method comprising administering to the subject a crystalline form of the present disclosure or a pharmaceutical composition of the present disclosure. [Brief explanation of the drawings]

[0017] [Figure 1]FIG. 1 is an X-ray powder diffraction (XRPD) spectrum of the water activity experiment comparing pattern C and pattern D. [Figure 2] FIG. 2 is an XRPD spectrum of a new crystalline form of Compound 1, i.e., pattern D. [Figure 3] FIG. 3 is a polarized light microscope (PLM) image of pattern D. [Figure 4] FIG. 4 shows the results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis of the new crystalline form of Pattern D. [Figure 5] FIG. 5 shows the XRPD spectrum of Pattern D heated to 90° C. and cooled to room temperature; the XRPD spectrum of Pattern D heated to 150° C. and cooled to room temperature; and an overlay of the reference spectra of Pattern C and Pattern D. [Figure 6] FIG. 6 shows images of Pattern D heated to 90° C. and 150° C. obtained using a hot stage microscope (HSM). [Figure 7] FIG. 7 shows the dynamic vapor sorption (DVS) spectrum collected on pattern D. [Figure 8] FIG. 8 is an XRPD spectrum obtained for pattern D after DVS. [Figure 9] FIG. 9 is a spectrum of a two-week slurry of Pattern D in H2O and the XRPD spectrum of the reference Pattern D. [Figure 10] FIG. 10 is a Thermal Ellipsoid plot of the compound in the crystal of Pattern D. [Figure 11] FIG. 11 shows the hydrogen bond network of pattern D formed by water and chloride anions. [Figure 12] FIG. 12 shows the distances (Angstroms, red) and angles (degrees, blue) of the solvent-anion network. [Figure 13] FIG. 13 shows the unit cell of compound 1, with hydrogen atoms omitted for clarity. [Figure 14]FIG. 14 shows the packing of compound 1 viewed along the b axis. [Figure 15] FIG. 15 shows the intermolecular hydrogen bonds of compound 1, with hydrogen atoms omitted for clarity. DETAILED DESCRIPTION OF THE INVENTION

[0018] Crystalline form of compound 1 (pattern D) In some aspects, the present disclosure provides a crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride trihydrate (Compound 1). In certain embodiments, Compound 1 is represented by the following structure: [ka]

[0019] Compound 1 is a novel selective T-type calcium channel blocker designed to block abnormal neuronal burst firing in the cerebellum-thalamus-cortex (CTC) circuit, which correlates with tremor activity.Cerebello-Thalamo-Cortical (CTC) circuits have been known, and certain crystalline forms of Compound 1 are known, for example, as described in WO / 2021 / 007487.The entire contents of this document are incorporated herein by reference.

[0020] The present disclosure provides novel crystalline forms of Compound 1. As used herein, the terms "crystalline" or "crystalline form" refer to a solid form of Compound 1 in which the atoms are arranged in a regular repeating pattern. In some embodiments, the term "crystalline" encompasses polymorphs or non-amorphous forms of Compound 1 without distinction.

[0021] As used herein, the terms "amorphous" or "amorphous form" refer to a non-crystalline form of a substance, e.g., a solid form, that lacks an ordered arrangement of atoms.

[0022] As used herein, the term "polymorph" or "polymorphic form" refers to an organizational structure that involves only molecules of a solute and has unique crystalline characteristics. These terms may refer to different crystalline forms of the same molecule. Different polymorphs may have different physical properties, such as melting point, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum, as a result of differences in the arrangement or structure of the molecules in the crystal lattice. The differences in physical properties exhibited by different polymorphs may affect parameters important to pharmaceutical substances, such as storage stability, compressibility, and density (important in formulation and product manufacturing), and dissolution rate (an important factor for bioavailability).

[0023] Differences in the stability of different polymorphs can also result from differences in chemical reactivity (e.g., differences in susceptibility to oxidation). Thus, a dosage form composed of one polymorph may discolor more rapidly than a dosage form composed of various polymorphs of the same substance. Differences in the stability of different polymorphs can also result from differences in mechanical properties (e.g., a tablet may disintegrate upon storage as it transforms from a kinetically favored polymorph to a thermodynamically more stable polymorph), or from differences in both chemical and mechanical properties (e.g., a tablet of one polymorph is more susceptible to degradation at high humidity). In extreme cases, differences in solubility / dissolution can result in some polymorphic transformations resulting in a loss of potency or, in other extreme cases, toxicity. Additionally, the physical properties of the crystals can be important in processes. For example, different polymorphs of the same substance may exhibit differences in their tendency to form solvates or may exhibit differences in the shape and size distribution of their particles, which may affect purification (e.g., one polymorph may be more difficult to filter and wash free of impurities than another).

[0024] Polymorphs of molecules can be obtained by many methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy such as IR and Raman spectroscopy, solid-state NMR, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility testing, and dissolution testing. Specifically, XRPD is a technique used to characterize the crystal structure, size, and preferred orientation of polycrystalline or powdered solid samples. It can also be used to characterize heterogeneous solid mixtures to determine the proportion of crystalline compounds present and provide structural information about unknown materials. As used herein, the term "X-ray powder diffraction pattern," which is used interchangeably with the term "XRPD pattern," refers to a graphical representation of the data collected by XRPD analysis.

[0025] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, also referred to herein as "Pattern D."

[0026] In some embodiments, the novel crystalline form of Compound 1, i.e., Pattern D, is characterized by an X-ray powder diffraction pattern (XRPD pattern) that includes at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, or nine peaks, at diffraction angles (°2θ) selected from the group consisting of: The peak at approximately 12.0° The peak at about 15.6° Peak at about 16.7°, Peak at about 19.8°, The peak at about 21.2° The peak at about 24.1° The peak at about 25.2° a peak at approximately 27.3°, and Peak at approximately 30.2°.

[0027] As used herein, the term "peak" refers to a peak in an XRPD pattern that has an intensity that is at least 20%, e.g., at least 30%, at least 40%, at least 50%, or at least about 100% greater than the baseline noise.

[0028] As used herein with respect to peaks in an "XRPD pattern," the term "approximately" or "about" refers to an XRPD pattern in which the peak appears within 0.5 °2θ, e.g., within 0.4, 0.3, 0.2, 0.1, 0.05, or 0.01 °2θ, of a given °2θ value.

[0029] In some embodiments, the novel crystalline form of Compound 1, i.e., Pattern D, is characterized by an X-ray powder diffraction pattern (XRPD pattern) that includes at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, or nine peaks, at diffraction angles (°2θ) selected from the group consisting of: Peak at 12.0°±0.2°, Peak at 15.6°±0.2°, Peak at 16.7°±0.2°, Peak at 19.8°±0.2°, Peak at 21.2°±0.2°, Peak at 24.1°±0.2°, Peak at 25.2°±0.2°, a peak at 27.3° ± 0.2°, and Peak at 30.2° ± 0.2°.

[0030] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least two peaks selected from the group of peaks listed above.

[0031] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least three peaks selected from the group of peaks listed above.

[0032] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least four peaks selected from the group of peaks listed above.

[0033] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least five peaks selected from the group of peaks listed above.

[0034] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least six peaks selected from the group of peaks listed above.

[0035] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least seven peaks selected from the group of peaks listed above.

[0036] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least eight peaks selected from the group of peaks listed above.

[0037] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, characterized by an X-ray powder diffraction pattern (XRPD pattern) that includes all nine of the peaks listed above.

[0038] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): a peak at approximately 25.2°, and Peak at approximately 27.3°.

[0039] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): a peak at 25.2° ± 0.2°, and Peak at 27.3° ± 0.2°.

[0040] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): The peak at about 24.1° a peak at approximately 25.2°, and Peak at approximately 27.3°.

[0041] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): Peak at 24.1°±0.2°, a peak at 25.2° ± 0.2°, and Peak at 27.3° ± 0.2°.

[0042] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): Peak at about 16.7°, The peak at about 24.1° a peak at approximately 25.2°, and Peak at approximately 27.3°.

[0043] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): Peak at 16.7°±0.2°, Peak at 24.1°±0.2°, a peak at 25.2° ± 0.2°, and Peak at 27.3° ± 0.2°.

[0044] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): The peak at approximately 12.0° Peak at about 16.7°, The peak at about 24.1° a peak at approximately 25.2°, and Peak at approximately 27.3°.

[0045] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is characterized by an XRPD pattern comprising peaks at the following diffraction angles (°2θ): Peak at 12.0°±0.2°, Peak at 16.7°±0.2°, Peak at 24.1°±0.2°, a peak at 25.2° ± 0.2°, and Peak at 27.3° ± 0.2°.

[0046] In some embodiments, the novel crystalline form of Compound 1, i.e., Pattern D, is characterized by an XRPD pattern substantially identical to the XRPD pattern shown in FIG.

[0047] In some embodiments, the novel crystalline form of Compound 1, ie, Pattern D, has an onset of melting at about 75.2° C. as determined by differential scanning calorimetry (DSC).

[0048] In some embodiments, the novel crystalline form of Compound 1, i.e., pattern D, is represented by the space group

number

[0049] In some embodiments, the novel crystalline form of Compound 1, i.e., Pattern D, has a crystal structure of 1213.0(10) Å 3 and an asymmetric unit cell with 3-D parameters of a = 8.584(3) Å; b = 9.11(4) Å; c = 17.043 Å.

[0050] In some embodiments, the novel crystalline form of Compound 1, i.e., Pattern D, is at least 90% pure, expressed by the weight of Pattern D relative to the weight of a composition containing Pattern D (w / w%). For example, Pattern D may be at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.5% pure, or at least 99% pure. As used herein, the terms "pure" or "purity" refer to a compound that is about 90-100% pure, e.g., about 95-100% pure, 98-100% pure, or about 99-100% pure. In some embodiments, pure Pattern D contains less than about 10%, less than about 5%, less than about 2%, or less than about 1% impurities. Impurities may include, for example, one or more of degradation products, oxidation products, solvents, and / or other undesirable impurities.

[0051] Method for synthesizing the crystalline form of compound 1 (Pattern D) The novel crystalline form of Compound 1 provided by the present disclosure, i.e., Pattern D, may be prepared by crystallizing the amorphous form of Compound 1 from a solvent system characterized by a water activity of greater than about 0.6, e.g., 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1.0. In some embodiments, Pattern D may be prepared by crystallizing the amorphous form of Compound 1 from a solvent system characterized by a water activity of 7.0 or greater. In some embodiments, Pattern D may be prepared by crystallizing the amorphous form of Compound 1 from a solvent system characterized by a water activity of 8.0 or greater.

[0052] As used herein, "water activity (a w The term "water activity (a)" refers to the equilibrium amount of water available for hydration of a substance. w The term "water activity" refers to the ratio of the vapor pressure of water in a solvent system to the vapor pressure of pure water at the same temperature. Water activity is a function of the concentration of water in the solvent system and the nature of the co-solvent, and can be measured by methods known in the art.

[0053] In some embodiments, a solvent system characterized by a water activity of greater than about 0.6, e.g., 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1.0, comprises water. In some embodiments, a solvent system characterized by a water activity of greater than about 0.6, e.g., 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1.0, comprises only water and no organic solvent. In some embodiments, a solvent system characterized by a water activity of greater than about 0.6, e.g., 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1.0, comprises water and an organic solvent, such as, for example, acetone, acetonitrile, benzene, chloroform, cyclohexane, n-hexane, diethyl ether, dimethyl sulfoxide, dimethylformamide, ethyl acetate, methyl t-butyl ether, tetrahydrofuran, or an alcohol (e.g., methanol, ethanol, isopropanol, etc.). In some embodiments, the solvent system comprises water and an organic solvent, such as, for example, acetone, in a water:acetone ratio of greater than 1:3.

[0054] In some embodiments, the present disclosure provides a novel crystalline form of Compound 1, i.e., Pattern D, prepared by the methods described above.

[0055] Compositions containing the crystalline form of Compound 1 (Pattern D) The present disclosure also provides pharmaceutical compositions comprising a novel crystalline salt form, i.e., Pattern D, of Compound 1. The amount of Pattern D form of Compound 1 in the provided compositions is an amount that enables Compound 1 to act as an effective T-type calcium channel blocker. For example, the amount of Pattern D form of Compound 1 in the pharmaceutical composition is an amount that is effective for treating, for example, a neurological disorder, a psychiatric disorder, a generalized epilepsy syndrome, or essential tremor.

[0056] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods include the step of bringing into association Compound 1 in the form of Pattern D with the carrier and / or one or more other accessory ingredients, and then shaping and / or packaging the product into the desired single or multi-dose unit, as necessary and / or desired.

[0057] Pharmaceutically acceptable carriers used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. For example, carriers such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may be present in the compositions.

[0058] Examples of diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0059] Examples of granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0060] Examples of surfactants and emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters, and the like. esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80)), polyoxyethylene esters Examples of suitable oleic acid esters include polyoxyethylene monostearate (Myrj45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol, sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate,Potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0061] Examples of binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of psyllium (isapol husks), carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabinogalactan, alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0062] Examples of preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0063] Examples of antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0064] Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Examples of antibacterial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0065] Examples of antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0066] Examples of alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0067] Examples of acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0068] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0069] Examples of buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, hydroxyapatite, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0070] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, and mixtures thereof.

[0071] Examples of natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, juniper tar oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter oil, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate oil, jojoba oil, kukui seed oil, lavandin oil, lavender oil, and lemon oil. These include mon oil, lily of the valley oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter oil, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Examples of synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, caprylic triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0072] The pharmaceutical compositions provided herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, transmucosally, or in ophthalmic preparations. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In one embodiment, the pharmaceutical compositions provided herein are orally administered in an orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants, such as magnesium stearate, are also often added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0073] The amount of Compound 1 in the Pattern D form that is combined with the carrier materials to produce a single-dosage composition will vary depending on the subject being treated and the particular mode of administration. For example, the specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combinations, the judgment of the treating physician, and the severity of the particular disease being treated. In one embodiment, pharmaceutical compositions may be formulated so that a dosage equivalent to about 0.001 to about 100 mg / kg body weight / day of Compound 1 in the Pattern D form (e.g., about 0.5 to about 100 mg / kg of Compound 1) can be administered to a subject receiving these compositions. Alternatively, dosages equivalent to 1 mg / kg to 1000 mg / kg of Compound 1 every 4 to 120 hours are also acceptable. As used herein, "dose" refers to the amount of Compound 1 in the Pattern D form.

[0074] In some embodiments, Compound 1 in a Pattern D form is formulated for administration at a dose equivalent to about 2 mg to about 3000 mg of Compound 1 in a Pattern D form, e.g., about 5 mg to about 350 mg, about 5 mg to about 200 mg, about 5 mg to about 100 mg, or about 20 mg to about 40 mg of Compound 1 in a Pattern D form. In certain embodiments, the Compound of Formula 1 in a Pattern D form is formulated for administration at a dose equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg of Compound 1 in a Pattern D form.

[0075] In some embodiments, Compound 1 in the Pattern D form is formulated for administration at a dose equivalent to about 2 mg to about 3000 mg of Compound 1 per day, e.g., about 5 mg to about 500 mg, about 5 mg to about 200 mg, or about 20 mg to about 40 mg of Compound 1 per day. In some embodiments, Compound 1 in the Pattern D form is formulated for administration at a dose equivalent to 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 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1 per day. In some embodiments, Compound 1 in the Pattern D form may be administered once daily. In other embodiments, Compound 1 in the Pattern D form may be administered twice daily. In yet other embodiments, Compound 1 in the form of Pattern D may be administered once every other day.

[0076] In some embodiments, Compound 1 in the Pattern D form may be formulated as a tablet composition with a pharmaceutically acceptable carrier. Suitable carriers for use in tablet compositions may be selected from one or more of microcrystalline cellulose, mannitol, croscarmellose sodium, and sodium stearyl fumarate. For example, in some embodiments, the carrier may be microcrystalline cellulose, which may be present in the tablet composition in an amount of about 40% w / w to about 80% w / w, e.g., about 50% w / w to about 70% w / w, or about 55% w / w to about 65% w / w. In some embodiments, the carrier may be mannitol, which may be present in the tablet composition in an amount of 20% w / w to about 45% w / w, e.g., about 20% w / w to about 30% w / w. In some embodiments, the carrier may be croscarmellose sodium, which may be present in an amount of about 1% w / w to about 5% w / w. In some embodiments, the carrier may be stearyl fumarate, which may be present in the tablet composition in an amount of, for example, from about 1% w / w to about 5% w / w.

[0077] In some embodiments, Compound 1 in the Pattern D form may be present in the tablet composition in an amount equivalent to about 1 mg to about 150 mg of Compound 1, e.g., about 1 mg to about 100 mg, about 5 mg to about 50 mg, or about 20 mg to about 40 mg of Compound 1.

[0078] In some embodiments, pharmaceutical compositions provided by the present disclosure may be administered to a subject once a day, or multiple times a day (e.g., twice a day, three times a day, or four times a day).

[0079] In some embodiments, the methods of the present disclosure include administering to a subject in need thereof a set dose of Compound 1 in the form of Pattern D. In some embodiments, the maximum set dose is 60 mg per day or 100 mg per day. In one embodiment, the maximum set dose is 60 mg per day.

[0080] In one aspect, the pharmaceutical composition provided by the present disclosure comprises a single unit dosage form comprising Compound 1 in Pattern D form. In certain embodiments, the single unit dosage form comprises up to 200 mg of Compound 1 in Pattern D form. In some embodiments, the single unit dosage form comprises a length of up to 16 mm, e.g., about 14 mm to about 16 mm, and / or a width of up to 7 mm, e.g., about 5 mm to about 7 mm. In some embodiments, the single unit dosage form is bioequivalent to a reference composition of the same dosage strength administered as multiple dosage forms, such as modified release (MR) formulations comprising Compound 1 in Pattern D form available as round, small-sized (e.g., about 6 mm in diameter) 5 mg and 20 mg tablets. In some embodiments, bioequivalence is demonstrated by (a) a 90% confidence interval for AUC of about 80% to about 125% and (b) a 90% confidence interval for C max The 90% confidence interval for the variance can be established by:

[0081] Modified-Release Dosage Forms and Compositions In some embodiments, the present disclosure also provides a pharmaceutical composition comprising Compound 1 in Pattern D form and an excipient that functions to modify the release rate of Compound 1. In some embodiments, the pharmaceutical composition may be a swellable core technology formulation.

[0082] The compositions of the present disclosure may comprise Compound 1 in the form of Pattern D and a release-modifying polymer. As used herein, the term "release-modifying polymer" refers to any polymer that, when added to a composition comprising Compound 1 in the form of Pattern D, modifies the release rate of Compound 1. The release-modifying polymer may be a hydrophilic polymer, such as a hydroxypropylmethylcellulose (HPMC) polymer, a hydrophobic polymer, such as ethylcellulose or ethocell, or a polyacrylate polymer, such as Eudragit RL100 or Eudragit RS100. In some embodiments, the release-modifying polymer is present in the composition in an amount sufficient to modify the release rate of Compound 1. In some embodiments, the composition is for oral administration.

[0083] In some embodiments, the compositions of the present disclosure comprise a modified release polymer and about 0.9% to about 40% by weight (e.g., about 0.9% to about 30% by weight, about 1% to about 25% by weight, about 2% to about 25% by weight, about 3% to about 20% by weight, about 4% to about 20% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, or about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6% by weight, or about 10% by weight of a modified release polymer. %, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, or about 40 wt% of Compound 1 in the form of Pattern D.

[0084] In some embodiments, the compositions of the present disclosure may include a modified release polymer and an amount of Compound 1 in the form of Pattern D in the amount of about 1 mg to about 40 mg, e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

[0085] In some embodiments, the composition comprises about 55 mg to about 65 mg of a release-modifying polymer (e.g., an HPMC polymer), hi some embodiments, the composition comprises about 10% to about 70% by weight, e.g., about 50% to about 60% by weight, of a release-modifying polymer (e.g., an HPMC polymer).

[0086] In some embodiments, the composition may further comprise a diluent, such as microcrystalline cellulose. In other embodiments, the composition may comprise microcrystalline cellulose in an amount of about 15 mg to about 40 mg, e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, or about 30 mg to about 40 mg. In some embodiments, the composition may comprise microcrystalline cellulose in an amount of about 15% to about 35% by weight, e.g., about 15% to about 20% by weight, about 20% to about 25% by weight, 25% to about 30% by weight, or 30% to about 35% by weight.

[0087] In some embodiments, the composition may further comprise a glidant, such as colloidal silicon dioxide. In some embodiments, the composition may further comprise a lubricant, such as magnesium stearate. In some embodiments, the composition may further comprise a coating.

[0088] In some embodiments, the composition may be administered to a patient once daily or twice daily. In some embodiments, the composition may be in the form of a tablet, capsule, or suspension. In one embodiment, the composition is in the form of a tablet.

[0089] Methods of Treatment Using Compound 1 in Pattern D Form The present disclosure also provides a method for treating a disease, disorder, or condition associated with T-type calcium channel function. The method comprises administering to a subject in need thereof an effective amount of Compound 1 in the Pattern D form described herein, or an effective amount of a pharmaceutical composition comprising Compound 1 in the Pattern D form described herein. The ability of Compound 1 to modulate T-type calcium channels is described, for example, at least in WO2021 / 007487, the entire contents of which are incorporated herein by reference.

[0090] In some embodiments, the methods of the present disclosure comprise administering to a subject in need thereof a single unit dosage form described herein.

[0091] In some embodiments, the disclosure provides a method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a Pattern D form of Compound 1. In some embodiments, the subject has a mutation in one or both of CACNA1H and CACNA1G of the T-type calcium channel gene. In some embodiments, the neurological disorder is epilepsy. In some embodiments, the epilepsy is juvenile epilepsy. In some embodiments, the epilepsy is genetic epilepsy. In some embodiments, the neurological disorder is absence seizures. In some embodiments, the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain, thalamic pain, or migraine). In some embodiments, the neurological disorder is tremor (e.g., essential tremor or Parkinson's tremor). In some embodiments, the neurological disorder is ataxia (e.g., spinocerebellar ataxia or spinocerebellar ataxia with a CACNA1G mutation). In some embodiments, the neurological disorder is tinnitus. In certain embodiments, the neurological disorder is a disturbance of arousal.

[0092] In some embodiments, the Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising the Pattern D form of Compound 1, is effective for treating tremor (e.g., essential tremor). In some embodiments, the Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising the Pattern D form of Compound 1, is effective for treating epilepsy or an epileptic syndrome, e.g., absence seizures, juvenile myoclonic epilepsy, status epilepticus, or genetic epilepsy. The Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising the Pattern D form of Compound 1, can also modulate all T-type calcium channels, e.g., Cav3.1, Cav3.2, and / or Cav3.3. In some embodiments, the Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising the Pattern D form of Compound 1, is effective for treating a psychiatric disorder, e.g., a mood disorder, e.g., major depressive disorder.

[0093] In some embodiments, the present disclosure also provides a method of treating a psychiatric disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising a Pattern D form of Compound 1. In some embodiments, the psychiatric disorder is a mood disorder. In some embodiments, the mood disorder is major depressive disorder.

[0094] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human" and "patient" may be used interchangeably herein.

[0095] Epilepsy and epilepsy syndromes The pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising the pattern D form of Compound 1, can be useful for treating epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which neuronal activity in the brain is disrupted, resulting in seizures that can manifest as abnormal movements, unusual behavior, sensations, and sometimes periods of loss of consciousness. Epileptic seizure symptoms vary widely, from a simple blank stare for a few seconds to repeated twitching of the arms or legs during an epileptic seizure.

[0096] Epilepsy can include generalized seizures or partial or focal seizures. All areas of the brain are involved in generalized seizures. A person experiencing a generalized seizure may scream or make some noise, stiffen for a few seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are typically open, and the person may not appear to be breathing and may actually turn blue. Consciousness gradually returns, and the person may be confused for several minutes to several hours. The main types of generalized epileptic seizures are: tonic-clonic seizures, tonic-clonic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures, and absence (typical, atypical, myoclonic, lid myoclonic) seizures, as well as epileptic spasms. Partial or focal seizures involve only part of the brain, and therefore affect only part of the body. Symptoms can vary, depending on the part of the brain that has abnormal electrical activity.

[0097] Epilepsy as described herein includes generalized, partial, complex partial (e.g., seizures involving only part of the brain but with impaired consciousness), tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0098] The Pattern D form of Compound 1 described herein, or a pharmaceutical composition containing the Pattern D form of Compound 1, may also be useful for treating epilepsy syndromes. Severe syndromes involving diffuse brain dysfunction caused at least in part by some forms of epilepsy are also called epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive impairment, such as West syndrome.

[0099] In some embodiments, the epilepsy syndrome comprises epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Lennox-Gastaut syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with mutations in genes encoding T-type calcium channels (e.g., CACNA1G, EEF1A2, and GABRG2 for genetic generalized epilepsy (GGE), and LGI1, TRIM3, and GABRG2 for non-acquired focal epilepsy (NAFE)). In some embodiments, the epilepsy syndrome is Doze syndrome or myoclonic-astatic epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spike and wave sleep (CSWS). In some embodiments, the epilepsy syndrome is Landau-Kleffner syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0100] absence seizures Absence seizures are one of the most common seizure types in patients with idiopathic generalized epilepsy (IGE). Absence seizures are relatively brief, nonconvulsive seizures characterized by the sudden onset of loss of consciousness and responsiveness, usually lasting 10–30 seconds, followed by a rapid return to normal consciousness without postictal confusion. Seizures are characterized by the sudden onset and disappearance of generalized 1–6 Hz (e.g., 3 Hz) spike discharges on accompanying EEG recordings. Absence seizures often occur multiple times per day, disrupting learning and psychosocial functioning and presenting a risk of injury due to the frequent episodes of loss of consciousness. Absence seizures typically begin in early childhood and resolve by the late teens. However, in a minority of patients, they persist into adulthood, often becoming drug-resistant, and may be accompanied by other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures, in particular, are usually highly disabling and are associated with significant psychosocial impairment, as the accompanying periods during which the affected individual is unconscious pose a safety risk and disqualify them from obtaining a driver's license or pursuing occupations and hobbies.

[0101] Although absence seizures are generally perceived as relatively "easy" to treat, randomized controlled trials in patients with childhood absence epilepsy showed that even the most effective antiepileptic drugs, ethosuximide and valproate, completely controlled seizures in only 53% and 58% of patients, respectively, at 16 weeks and in 45% and 44% of patients, respectively, at 12 months, as assessed by video-EEG recording. Another commonly used AED, lamotrigine, controlled seizures in only 29% of patients at 16 weeks and 21% at 12 months. Furthermore, both ethosuximide and valproate are commonly associated with intolerable side effects (occurring in 24% of patients treated with either of these medications), and the latter is now generally considered contraindicated in girls and women of childbearing age. Other treatment options for absence seizures are limited; only benzodiazepines have established efficacy, and these are generally poorly tolerated due to sedative and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat, and patients are often treated with multiple medications, resulting in significant side effects, without achieving seizure control.

[0102] A large body of evidence indicates that low-threshold (T-type) calcium channels play a key role in the generation and maintenance of absence seizures and are a key component of the oscillatory burst firing that occurs in thalamocortical neurons during absence seizures. In some embodiments, the present disclosure provides a method of treating absence seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a pattern D form of Compound 1 or a pharmaceutical composition comprising a pattern D form of Compound 1 described herein. In some embodiments, the absence seizures are refractory absence seizures. In some embodiments, the absence seizures are refractory to antiepileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0103] In some embodiments, the subject has epilepsy. In some embodiments, the absence seizures are atypical absence seizures. In some embodiments, the absence seizures include adult absence seizures, juvenile absence seizures, or childhood absence seizures.

[0104] In some embodiments, the methods described herein further comprise identifying a subject having absence seizures.

[0105] In some embodiments, the disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a Pattern D form of Compound 1 described herein or a pharmaceutical composition comprising a Pattern D form of Compound 1. In some embodiments, the method reduces the number of seizures.

[0106] In some embodiments, the present disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein.

[0107] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce the mean or total seizure duration.

[0108] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce seizure frequency, duration, or both as measured by electroencephalogram (EEG).

[0109] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce the mean seizure duration as measured by EEG.

[0110] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce cumulative seizure duration as measured by EEG.

[0111] In some embodiments, the methods of treating generalized epilepsy with absence seizures provided by the present disclosure reduce hyperventilation and the total time with 2.5-4 Hz spike-and-wave discharges following photic stimulation, as measured by EEG.

[0112] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce overall severity as measured by the Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) score. The CGI-S is a 7-point scale test that assesses the severity of a patient's illness at the time of evaluation compared to a clinician's past experience with patients with the same diagnosis. The CGI-I is a 7-point scale test that assesses improvement in a patient's illness compared to baseline.

[0113] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce the number of seizures.

[0114] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce seizure density as measured by electroencephalogram (EEG).

[0115] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce the mean seizure duration as measured by EEG.

[0116] Hereditary epilepsy In some embodiments, the present disclosure provides a method for treating epilepsy or an epilepsy syndrome in a subject in need thereof, the method comprising administering to the subject an effective amount of a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein.

[0117] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. In some embodiments, the epilepsy or epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0118] In some embodiments, the methods described herein include administering a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein to a patient with epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory petit mal with generalized tonic-clonic seizures). and further including identifying a subject with a condition, such as childhood epilepsy, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0119] In one embodiment, the disclosure provides a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, generalized tonic-clonic seizures), comprising administering to a subject in need thereof an effective amount of a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein. The present invention provides methods for treating refractory childhood epilepsy with steroids, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0120] A Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising a Pattern D form of Compound 1, may be used to treat epileptic encephalopathy in a subject in need thereof, wherein the subject is also consuming one or more of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB 1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0121] In some embodiments, the methods described herein include administering any of the following to a patient: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KC The method further includes identifying subjects with a mutation in one or more of NT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H, and CACNA1I.

[0122] The Pattern D forms of Compound 1 described herein, or pharmaceutical compositions comprising a Pattern D form of Compound 1, may be used to treat epileptic encephalopathy in a subject in need thereof, wherein the subject is also taking any of the following drugs: ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1 ), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L , GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KA NSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, N EXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, REL N, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4,Mutations in one or more of TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0123] In some embodiments, the methods described herein include administering to a patient a compound selected from the group consisting of ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN7, CLN8, CLN9, CLN10, CLN11, CLN12, CLN13, CLN14, CLN15, CLN16, CLN17, CLN18, CLN19, CLN20, CLN21, CLN22, CLN23, CLN24, CLN25, CLN26, CLN27, CLN28, CLN29, CLN30, CLN31, CLN32, CLN33, CLN34, CLN35, CLN36, CLN37, CLN38, CLN39, CLN40, CLN41, CLN42, CLN43, CLN44, CLN45, CLN46, CLN47, CLN48, CLN49 ...9, CLN48, CLN49, CLN49, CLN49, CLN40, CLN41, CLN CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, G ABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1 , KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHL RC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, S CARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2,The method further includes identifying subjects with a mutation in one or more of UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0124] A Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising a Pattern D form of Compound 1, may be used to treat epileptic encephalopathy in a subject in need thereof, wherein the subject is taking any of the following drugs: ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, E EF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KC NH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, ME CP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3.NR2F1, NRXN1, PACS1, PCDH19, PIGA Mutations in one or more of PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0125] In some embodiments, the methods described herein include administering to a patient a compound selected from the group consisting of ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHM, DHK1A, DHK2, DHK3, DHK4, DHK5, DHK6, DHK7, DHK8, DHK9, DHK10, DHK11, DHK12, DHK13, DHK14, DHK15, DHK16, DHK17, DHK18, DHK19, DHK20, DHK21, DHK22, DHK23, DHK24, DHK25, DHK26, DHK27, DHK28, DHK29, DHK30, DHK31, DHK32, DHK33, DHK34, DHK35, DHK36, DHK37, DHK38, DHK40, DHK41, DHK42, DHK43, DHK44, DHK45, DHK46, DHK47, DHK48, DHK49, DHK50, DHK51, DHK52, DH T1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP 2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3.NR2F1, NRXN1, PACS1, PCDH19, PIGA The method further includes identifying subjects with a mutation in one or more of PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0126] A Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising a Pattern D form of Compound 1, may be used to treat epileptic encephalopathy in a subject in need thereof, wherein the subject is also taking one of the following drugs: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRN PU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN 8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0127] In some embodiments, the methods described herein include administering to a patient a pharmaceutical composition comprising Compound 1 in a Pattern D form described herein, the pharmaceutical composition comprising Compound 1 in a Pattern D form, or a combination of ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PI GA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5 , SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0128] Mood disorders In some embodiments, the present disclosure also provides a method of treating a psychiatric disorder, the method comprising administering to a subject in need thereof a Pattern D form of Compound 1 described herein or a pharmaceutical composition comprising a Pattern D form of Compound 1. In some embodiments, the psychiatric disorder can be a mood disorder, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, major psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, dual depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. The method comprises administering to the subject an effective amount of a Pattern D form of Compound 1 described herein or an effective amount of a pharmaceutical composition comprising a Pattern D form of Compound 1. In some embodiments, the methods described herein provide a therapeutic benefit to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0129] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression also experience sleep disturbances, weight loss, and generally agitated and irritable feelings. Clinical depression affects the way an individual feels, thinks, and behaves and can lead to a variety of emotional and physical problems. Individuals with clinical depression may struggle to perform everyday activities and feel that life is not worth living.

[0130] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, emotional withdrawal from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0131] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0132] In some embodiments, the subject with PND also experiences depression or depressive symptoms during pregnancy.This depression is herein referred to as perinatal depression.In embodiments, the subject who experiences perinatal depression is at increased risk of experiencing PND.

[0133] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or drowsiness (hypersomnia), a feeling of heaviness in the legs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0134] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), failure to respond to pleasurable stimuli, depressed mood that is more prominent than sadness or loss, excessive weight loss, or excessive guilt.

[0135] Psychotic major depression (PMD) or psychotic depression refers specifically to a major depressive episode of a melancholic nature in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0136] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. The individual may become silent and stuporous, immobile, or exhibit purposeless or bizarre movements.

[0137] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that fall in the fall or winter.

[0138] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. These tend to be less severe but last longer (e.g., at least two years).

[0139] Dual depression refers to a significant depressed mood (dysthymia) lasting for at least two years and interrupted by periods of major depression.

[0140] Depressive personality disorder (DPD) refers to a personality disorder that has depressive traits.

[0141] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, each lasting less than two weeks, typically less than two to three days.

[0142] Minor depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0143] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may feel or behave unusually happy, energetic, or irritable. They often make decisions with little consideration for the consequences. The need for sleep is usually reduced. During depressive periods, individuals may cry, make little eye contact with others, and have a negative outlook on life. The risk of suicide in those with the disorder is high at over 6% over a 20-year period, while self-harm occurs in 30-40% of cases. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

[0144] Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

[0145] Treatment-resistant depression refers to the state that individuals are treated for depression, but symptoms do not improve.For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression.In some cases, individuals with treatment-resistant depression improve their symptoms, but then relapse.Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatment, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics, and non-pharmacological treatment (for example, psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0146] Postoperative depression refers to feelings of depression after a surgical procedure (e.g., as a result of having to face death). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in normally enjoyable hobbies and activities, or persistent feelings of worthlessness or despair.

[0147] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) that is associated with (e.g., caused by) a women's health condition or disorder (e.g., as described herein).

[0148] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts about suicide or an abnormal preoccupation with suicide. The spectrum of suicidal ideation varies widely, from fleeting thoughts to extensive thinking, detailed plans, role-playing, and abortive attempts. Symptoms include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless in the situation, increased alcohol or drug use, doing risky or self-destructive things, and saying goodbye to people as if they will never see each other again.

[0149] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty exercising, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts.The presence, severity, frequency, and duration of symptoms may vary depending on each individual case.Depression symptoms and their alleviation can be confirmed by a doctor or psychologist (for example, by mental status examination).

[0150] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, dysthymic disorder, anxiety disorder, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0151] In some embodiments, the method includes monitoring the subject using known depression scales, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression-Improvement (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a reduction in the Hamilton Depression (HAM-D) total scale exhibited by the subject. The therapeutic effect can be evaluated over a specific treatment period. For example, the therapeutic effect can be determined by a reduction from baseline in the HAM-D total scale after administration of a composition described herein (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more after administration; or 1 day, 2 days, 14 days, 21 days, or 28 days after administration; or 1 week, 2 weeks, 3 weeks, or 4 weeks after administration; or 1 month, 2 months, 6 months, or 10 months after administration; or 1 year, 2 years, or lifetime).

[0152] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a composition described herein) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is 14 or greater and 18 or less. In some embodiments, the subject's baseline HAM-D total score is 19 or greater and 22 or less. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is 23 or greater. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total score after treatment with a composition described herein is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a composition described herein is less than 10, 7, 5, or 3. In some embodiments, the reduction in HAM-D total score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27), to a HAM-D total score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a composition described herein. In some embodiments, the reduction in HAM-D total score after treatment with a composition described herein from baseline HAM-D total score is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50).In some embodiments, the percentage reduction in the HAM-D total score after treatment with a composition described herein from the baseline HAM-D total score is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in the HAM-D total score after treatment with a composition described herein compared to the baseline HAM-D total score.

[0153] In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as measured by a reduction in the Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within the first or second day of treatment with a composition described herein. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 28 days, e.g., within 21 days, or within 14 days, from the start of treatment with a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein.

[0154] In some embodiments, the therapeutic effect is a reduction from baseline in the HAM-D total score after treatment with a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein. In some embodiments, the subject's HAM-D total score before treatment with a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein is at least 18, at least 24, or between 14 and 18. In some embodiments, the methods of treating a depressive disorder described herein result in a reduction in the HAM-D total score of at least 10 or at least 15. In some embodiments, the subject's HAM-D total score after treatment with a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein is 8 or less, e.g., 7 or less, or 6 or less.

[0155] In some embodiments, the methods for treating a depressive disorder provided herein provide a therapeutic effect (e.g., as measured by a reduction in the Clinical Global Impression-Improvement scale (CGI)). In some embodiments, the reduction in the CGI is achieved within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours of initiating treatment with a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein. In some embodiments, the methods for treating a depressive disorder, e.g., major depressive disorder, provide a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in CGI scores at the end of the treatment period (14 days after initiation of administration of a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein).

[0156] In some embodiments, the methods for treating depressive disorders provided herein provide a therapeutic effect (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score presented by the subject). For example, the methods provided by the present disclosure result in a reduction in the MADRS score within 14, 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours after initiation of treatment with a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein. The MADRS is a 10-item diagnostic questionnaire (related to apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of sensation, pessimistic thoughts, and suicidal ideation) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0157] pain The present disclosure also provides a method of treating pain, the method comprising administering to a subject in need thereof Compound 1 in a Pattern D form described herein, or a pharmaceutical composition comprising Compound 1 in a Pattern D form. In some embodiments, the pain comprises acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, the pain comprises acute pain or chronic pain. In some embodiments, the pain comprises neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, the pain comprises central pain (e.g., thalamic pain). In some embodiments, the pain comprises migraine.

[0158] In some embodiments, the methods provided by the present disclosure further include identifying a subject with pain, e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine, prior to administration of Compound 1 in a Pattern D form or a pharmaceutical composition comprising Compound 1 in a Pattern D form described herein.

[0159] Tremor The present disclosure also provides a method of treating tremor, the method comprising administering to a subject in need thereof a Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising a Pattern D form of Compound 1. In some embodiments, the tremor can be cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiologic tremor, or rubral tremor. Tremor may include, for example, genetic, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases; peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (neuroleptic tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproic acid, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and motion-specific and position-specific tremor), dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxin- or drug-induced tremor, and psychogenic tremor. In some embodiments, the tremor may be familial tremor.

[0160] Tremor is an involuntary, rhythmic muscle contraction and relaxation that may involve shaking or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0161] Cerebellar tremor or intention tremor is the slow and widespread tremor of limbs that occurs after purposeful movement.Cerebellar tremor is caused by the lesion or damage to the cerebellum, such as tumor, stroke or other localized lesion disease (such as multiple sclerosis) or neurodegenerative disease.

[0162] Dystonic tremor occurs in individuals with dystonia, and is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions.Dystonic tremor can affect any muscle in the body.Dystonic tremor occurs irregularly, and can often be alleviated by complete rest or certain sensory manipulations.

[0163] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, beginning on one side of the body and progressing slowly, typically affecting both sides. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremors can decrease with age, but the severity may increase. Increased emotion, stress, fever, physical exhaustion, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms generally progress over time and can be visible and persistent after onset.

[0164] Orthostatic tremor is characterized by rapid (greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Spasms can be felt in the thighs and legs, and patients may tremble uncontrollably when asked to stand in one position. Orthostatic tremor can occur in patients with essential tremor.

[0165] Parkinsonism tremor is caused by damage to structures in the brain that control movement. Parkinsonism tremor is typically seen as a "pill-making" movement of the hands that may also affect the jaw, lips, legs, and trunk. The onset of Parkinsonism tremor usually begins after the age of 60. The movement may begin in one leg or one side of the body and progress to involve the other side.

[0166] Rubral tremor is characterized by a coarse, slow tremor that can be present at rest, in position, and with intention. Tremor is associated with conditions that affect the red nucleus in the midbrain, such as stroke.

[0167] In some embodiments, the tremor is selected from essential tremor, Parkinson's tremor, or cerebellar tremor. In some embodiments, the tremor is essential tremor.

[0168] In some embodiments, the present disclosure also provides a method of treating essential tremor, the method comprising administering to a subject in need thereof a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein. In some embodiments, the method results in a reduction in essential tremor as assessed by the Essential Tremor Rating Scale (TETRAS) score. As used herein, the term "Essential Tremor Rating Scale (TETRAS)" refers to a scale developed to quantify the severity of essential tremor and its impact on daily activities. It includes an Activities of Daily Living (ADL) component and a Performance component. The ADL component has 12 items rated from 0 to 4, and the Performance component has 9 items rated from 0 to 4.

[0169] In some embodiments, reduction in essential tremor is assessed by the Essential Tremor Rating Scale (TETRAS) Upper Extremity score.

[0170] In some embodiments, reduction in essential tremor is assessed by the TETRAS Performance subscale score or individual items of the TETRAS Performance.

[0171] In some embodiments, subjects treated by the methods provided herein have moderate essential tremor (i.e., a TETRAS score of 10-15). In some embodiments, subjects treated herein have a TETRAS score of about 10 to about 15, or a TETRAS score of about 12, prior to treatment with the methods of the present disclosure. Treatment with a Pattern D form of Compound 1, or a pharmaceutical composition comprising a Pattern D form of Compound 1, described herein, can reduce a subject's TETRAS score. In some embodiments, subjects treated with a Pattern D form of Compound 1, or a pharmaceutical composition comprising a Pattern D form of Compound 1, described herein, experience a reduction in the mean TETRAS score of about 2 to 5, e.g., about 3. In some embodiments, subjects treated with a Pattern D form of Compound 1, or a pharmaceutical composition comprising a Pattern D form of Compound 1, described herein, experience a reduction in the mean TETRAS score of about 30% to about 50%, e.g., about 40%.

[0172] In some embodiments, the disclosure also provides a method of treating essential tremor, the method comprising administering to a subject in need thereof Compound 1 in a Pattern D form described herein, or a pharmaceutical composition comprising Compound 1 in a Pattern D form. In some embodiments, the method reduces essential tremor as assessed by an accelerometer-based score, e.g., an accelerometer-based upper extremity score. In some embodiments, the method reduces essential tremor as assessed by a CGI score.

[0173] In some embodiments, the essential tremor is upper limb tremor.

[0174] In some embodiments, subjects are selected for treatment with a Pattern D form of Compound 1 compound due to a clinical diagnosis of essential tremor. In some embodiments, subjects selected for treatment with a Pattern D form of Compound 1 have essential tremor but do not have intention tremor.

[0175] The efficacy of the Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising the Pattern D form of Compound 1, for treating essential tremor can be measured by the methods described in the following references: Ferreira, JJ et al., "MDS Evidence-Based Review of Treatments for Essential Tremor." Mov. Disord. 2019 Jul; 34(7): 950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor." Mov. Disord. 2013 Nov; 28(13): 1793-800; Deuschl G. et al. "Treatment of patients with essential tremor." Lancet Neurol. 2011; 10: 148-61; Reich SGet al. "Essential Tremor." Med. Clin. N. Am. 103(2019) 351-356. The disclosures of the references are incorporated herein in their entireties.

[0176] ataxia In some embodiments, the present disclosure also provides a method for treating ataxia, comprising administering to a subject in need thereof a Pattern D form of Compound 1 described herein or a pharmaceutical composition comprising a Pattern D form of Compound 1. Ataxia, including both cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia), is generally accompanied by loss or insufficiency of coordination. Patients with ataxia may have difficulty regulating the force, range, direction, speed, and rhythm involved in posture, balance, and limb movements. Trunk ataxia may, for example, be characterized by increased postural instability and an inability to maintain the center of gravity over the base of support. Ataxia and primary or secondary symptoms of ataxic gait and leg tremor may be accompanied by speech impairment, dysphagia, abnormal ventilation and speech, involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, which may substantially interfere with activities of daily living.

[0177] As mentioned above, ataxia can result from a wide range of underlying diseases and conditions in a patient, including cerebellar and neurodegenerative disorders and diseases resulting from chronic or long-term exposure to toxins. Ataxic symptoms can result from a wide range of diseases, disorders, and environmental factors, including, among other things, infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplastic diseases, demyelinating diseases, neuromuscular diseases, and diseases resulting from long-term or chronic exposure to toxins (including drugs and alcohol); in one embodiment, for example, ataxia is the result of a metabolic disease, neurodegenerative disease, vascular disease, neuromuscular disease, or disease resulting from long-term or chronic exposure to toxins. Diseases, disorders, syndromes, and conditions that may result in ataxia symptoms that may be treated according to the methods described herein include, among others, amyotrophic lateral sclerosis, benign paroxysmal positional vertigo, cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant pure), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar insufficiency, cerebellar hypoplasia (endosteal sclerosis), cerebellar hypoplasia (pigment epithelial retinal degeneration), cerebellar parenchymal autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar agenesis (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, spinal conditions, autonomic disorders, disequilibrium syndromes, paresthesia, endocrine disorders, diseases caused by chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, neuroleptic drugs), fragile X / ataxia tremens. syndrome, Friedreich's ataxia, frontal lobe dysfunction, genetic disorders, central nervous system granulomatous vasculitis, Hallervorden-Spatz syndrome, hereditary motor and sensory neuropathies, hydrocephalus (e.g., hypotonia or normal pressure), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem response, infantile-onset spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller-Fisher syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonic ataxia, neurodegenerative disorders, olivopontocerebellar atrophy, paraneoplastic disorders, parkinsonism (atypical), peroneal muscular atrophy, phenytoin toxicity, posterior column ataxia with retinitis pigmentosa, post-polio syndrome, severe brain injury (e.g., head injury, brain surgery, multiple sclerosis or cerebral palsy, chronic alcohol / drug abuse, chronic exposure to toxins, viral infection,or those caused by brain tumors), spastic hemiparesis, spastic paraplegia 23, spastic paraplegia, glaucoma, precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular atrophy-hearing loss), spinocerebellar ataxia (dysmorphism), spinocerebellar ataxia 11, spinocerebellar ataxia 17, spinocerebellar ataxia 20, spinocerebellar ataxia 25, spinocerebellar ataxia 29, spinocerebellar ataxia 42, spinocerebellar ataxia 3, spinocerebellar ataxia (autosomal recessive 1), spinocerebellar ataxia (autosomal recessive 3), spinocerebellar ataxia (autosomal recessive) Examples of ataxia include, but are not limited to, spinocerebellar ataxia (autosomal recessive 5), spinocerebellar ataxia (autosomal recessive with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph type II), spinocerebellar ataxia (X-linked 2), spinocerebellar ataxia (X-linked 3), spinocerebellar ataxia (X-linked 4), spinocerebellar degeneration (Book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebrobasilar insufficiency, and diseases caused by vitamin deficiency. In one embodiment, the ataxia is the result of a disease selected from spinocerebellar ataxia, Friedreich's ataxia, and fragile X-associated / tremor ataxia syndrome. In another specific embodiment, the ataxia is the result of spinocerebellar ataxia or fragile X / tremor ataxia.

[0178] Tinnitus In some embodiments, the present disclosure also provides a method for treating tinnitus, comprising administering to a subject in need thereof a Pattern D form of Compound 1 or a pharmaceutical composition comprising a Pattern D form of Compound 1 described herein. Tinnitus is a condition in which an affected individual perceives sound in one or both ears or in the head in the absence of external sound. Often referred to as a "ringing" in the ears, tinnitus occurs intermittently or consistently, with a perceived volume ranging from low to painfully loud. However, objective measurements of tinnitus volume in one patient may be perceived as painful, while in another the same volume may be perceived as inconspicuous; the perceived volume of tinnitus may vary from patient to patient.

[0179] Sleep disorders In some embodiments, the present disclosure also provides a method for treating a sleep disorder, the method comprising administering to a subject in need thereof a Pattern D form of Compound 1 described herein, or a pharmaceutical composition comprising a Pattern D form of Compound 1. For example, the sleep disorder can be central nervous system disorder of excessive sleepiness, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, medication- or substance-induced hypersomnia, hypersomnia associated with a psychiatric disorder, insufficient sleep syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, or circadian rhythm sleep-wake disorder not otherwise specified (NOS).

[0180] Combination therapy In some embodiments, Compound 1 in the Pattern D form described herein, or a pharmaceutical composition comprising Compound 1 in the Pattern D form described herein, may be administered in combination with another agent or therapy. Subjects to be Administered. In some embodiments, the present disclosure also provides a method of treating ataxia, comprising administering Compound 1 in the Pattern D form described herein, or a pharmaceutical composition comprising Compound 1 in the Pattern D form, to a subject in need thereof, where the subject may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. The disease or condition may be related to epilepsy or an epileptic syndrome (e.g., absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy) or tremor (e.g., essential tremor).

[0181] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0182] painkillers Analgesics are therapeutic drugs used to relieve pain.Examples of analgesics include opiates and morphine-like drugs, such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors.Considering the ability of compound 1 to treat pain through the inhibition of T-type calcium channels (for example, Cav3.1, Cav3.2 and Cav3.3), it is particularly contemplated that compound 1 can be used in combination with analgesics.

[0183] Tremor drug treatment Tremor medications include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, Topamax, Neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide. [Example]

[0184] Example 1. Preparation of a novel crystalline form of Compound 1 (Pattern D) The purpose of this experiment was to investigate the polymorphic forms of Compound 1.

[0185] The starting material, Compound 1, was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Characterization showed that the starting material was an anhydrous crystalline solid. DSC showed a single endotherm with an onset at 224.5°C. The crystalline form in the starting material was determined to be Pattern C, which has been previously characterized, for example, as described in WO / 2021 / 007487, the entire contents of which are incorporated herein by reference.

[0186] In this experiment, amorphous material was produced by ball milling with the goal of obtaining a new crystalline form. These experiments led to the discovery of a new crystalline form, classified as Pattern D. Additional experiments were designed starting with crystalline Pattern C and showed that Pattern D crystallized at a water activity of 0.8 or higher. Pattern D was determined to be a channel trihydrate, and the form identity was confirmed by single-crystal XRD. When Pattern D was heated to 90°C, no transformation of form was observed, although some peak broadening was observed. Further heating of the sample containing Pattern D to 150°C resulted in amorphous formation.

[0187] Starting from amorphous ball-milled material, polymorph screening was carried out under four different experimental conditions, resulting in the formation of pattern D. Tables 1 and 2 below show the experimental conditions used in the experiments, and the crystalline forms obtained. [Table 1] [Table 2]

[0188] FIG. 1 is an X-ray powder diffraction (XRPD) spectrum of the water activity experiment comparing pattern C and pattern D.

[0189] Example 2. Characterization of a novel crystalline form of Compound 1 (Pattern D) Pattern D was observed under many conditions at water activities above 0.8 and was characterized by a variety of techniques.

[0190] Figure 2 shows the XRPD spectrum of Pattern D. Table 3 below also shows a list of peaks observed in the XRPD spectrum of Pattern D. [Table 3]

[0191] Figure 3 is a polarized light microscope (PLM) image of Pattern D. Figure 3 shows that Pattern D crystallized as block-like crystals.

[0192] Figure 4 shows the results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis of Pattern D. Figure 4 shows an 11.27% weight loss by 125°C in the TGA (approximately 3.09:1 HO:API) and two broad endotherms in the DSC curve with onsets at 74.5°C and 113.5°C. KF showed a water content of 11.1% (approximately 3:1 HO:API).

[0193] Figure 5 shows the XRPD spectrum of Pattern D heated to 90°C and cooled to room temperature; the XRPD spectrum of Pattern D heated to 150°C and cooled to room temperature; and an overlay of the reference spectra of Pattern C and Pattern D. Figure 5 shows that when Pattern D is heated to 90°C, there is significant peak broadening, but no transformation in form. When Pattern D is further heated to 150°C, the sample becomes amorphous.

[0194] Figure 6 shows images of pattern D obtained using a hot stage microscope (HSM) heated to different temperatures. Figure 6 confirms the results shown in Figure 5.

[0195] Figure 7 is a dynamic vapor sorption (DVS) spectrum collected for pattern D. Figure 7 shows that the material gained approximately 10.45% of its mass at 80% RH. The hydrate desolvated, losing adsorbed water at a RH close to 0, and readsorbed approximately 10.5% of the water molecules at 20% RH.

[0196] Figure 8 is an XRPD spectrum obtained for pattern D after DVS, which showed no obvious shape change.

[0197] Pattern D water soluble The water solubility of Pattern D was measured by HPLC to determine the degree of decrease in water solubility between Patterns C and D. To measure the solubility of Pattern D in HO, approximately 150 mg of Pattern D was slurried in 1 mL of HO at room temperature for two weeks. Pattern D was found to be soluble in HO at 77.24 mg / mL, compared to the solubility of over 154 mg / mL observed for Pattern C. Figure 9 is an overlay of the XRPD spectra of the two-week slurry of Pattern D in HO and the reference Pattern D, which showed no shape change.

[0198] Example 3. Crystal structure of pattern D The proposed structure of Form D was verified by single-crystal X-ray structure analysis. Figure 10 shows a thermal ellipsoid plot of the compound from a Form D crystal. Plate-like single crystals with high diffraction quality were immersed in Paratone-N (an oil-based cryoprotectant). The crystals were mounted on mylar loops in random orientation and immersed in a stream of liquid nitrogen at 173 K. X-ray intensity data were measured on a Bruker D8 VENTURE (IμS microfocus X-ray source, Cu Kα, λ = 1.54178 Å, PHOTON CMOS detector) diffractometer. Frames were integrated using the Bruker SAINT software package. Integration of the data using a triclinic unit cell yielded a total of 73,495 reflections to a maximum θ angle of 75.070 (0.83 Å resolution), of which 4,988 were independent (coverage = 99.9%, R int=3.39%), 2σ(F 2 The final lattice parameters were a = 8.584(3) Å, b = 9.11(4) Å, c = 17.043 Å, α = 81.24(3)°, β = 88.90(3)°, γ = 67.176(16)°, and the lattice volume was 1213.0(10) Å. 3 was based on the refinement of 4988 reflections over 20σ(I) between 2.626°<θ<75.070°. The data were corrected for absorption effects using a multiscan method (SADABS). The absorption coefficient μ for this material is 2.761 mm at this wavelength (1.54178 Å). - The calculated minimum and maximum permeability coefficients (based on crystal size) were 0.6649 and 0.7538. The agreement coefficient for averaging was 4.74% based on intensity.

[0199] The structure was elucidated using the ShelXTL structure analysis program using intrinsic phasing to identify the formula unit C 19 H 27 For ClFN3O2·HCl,3(H2O), Z=2 and space group

number

[0200] Structural details and interpretation The structure of compound 1 was obtained as the hydrochloride salt obtained from an acetone / water solvent system. Three water molecules were identified, and their occupancies were refined without restriction, converging to full occupancy. This suggests a highly ordered structure formed by the water molecules. Figure 11 shows the hydrogen-bonding network of pattern D formed by water and chloride anions. The API molecules are connected by nitrogen atoms present on the outer edges. This is further emphasized by the positions of the hydrogen atoms observed in the Fourier peaks, which were assigned as real atoms rather than geometrically ideal positions.

[0201] This level of ordering within a solvent network is highly unusual. Additionally, the distances and angles within the hydrogen-bonding network are nearly ideal, as shown in Figure 12. Specifically, Figure 12 shows the distances (Å, red) and angles (degrees, blue) within the solvent-anion network. Only three solvent molecules and one anion are displayed per API unit, along with their interacting atoms. The donor-acceptor distance of 2.8 Å suggests moderate hydrogen bonding between water molecules. The gap between the water-water and water-chloride hydrogen bonds corresponds to the difference in atomic radii between oxygen and chlorine (approximately 0.3 Å). Furthermore, the Fourier peak is located on N16 of the tertiary amine, which corresponds to a hydrogen, and the contact distance suggests the presence of a hydrogen bond with O102 in the solvent water. Because the hydrogen atoms in the water molecule are directly positioned and assigned, protonation of the amine is suggested and refined accordingly.

[0202] The packing of compound 1 is also interesting. With the hydrogen-bonding network in place, the solvent becomes extremely stable, but it also exists within channels, as shown in Figures 13 and 14. Specifically, Figure 13 shows the unit cell of compound 1, with hydrogen atoms omitted for clarity. Figure 14 shows the packing of compound 1 along the b-axis. Figure 15 shows the intermolecular hydrogen bonds of compound 1, with hydrogen atoms omitted for clarity. Figure 15 shows that the API molecule itself also has a distinct network of short contacts between amide groups (contact distances of 2.899 and 2.922 Å), structuring the API molecule into two-dimensional sheets. These sheets are then paired by slip π-stacking interactions on the disubstituted phenyl rings. Solvent channels exist in the sheet-like structure between these double-sheet formations, connecting them.

[0203] The chloride anions in the solvent channels are bound only by water molecules. There is no direct API-anion contact in this configuration. The water molecules in these channels likely have multiple potential hydrogen-bonding motifs, depending on the amount of water available. Furthermore, the stability of the chloride anion may depend on maintaining some degree of solvation. Although compound 1 crystallizes as a trihydrate, it is highly likely that the mobility of these water molecules is not the same within the channels, a factor that must be considered separately and iteratively. In a fully dehydrated state, the channels are exclusively occupied by the unbound, exposed chloride anions. Several potential pathways for stabilization of this system, such as deprotonation of the API and subsequent loss of unbound HCl gas, could be envisioned. The channels likely rapidly rearrange with some degree of hydration upon exposure to air. Briefly, this crystal form forms as a trihydrate with solvent channels, but could behave as a monohydrate or dihydrate to maintain the level of hydration required for chloride anion stabilization.

[0204] Equal Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the present invention. All patent, patent application, and literature references cited herein are expressly incorporated herein by reference.

Claims

1. A crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride trihydrate (Compound 1), A peak at about 12.0° A peak at about 15.6° A peak at about 16.7° A peak at about 19.8° A peak at about 21.2° A peak at about 24.1° A peak at about 25.2° a peak at about 27.3°, and A crystalline form characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group consisting of: a peak at about 30.2°;

2. Peaks at the following diffraction angles (°2θ): a peak at about 25.2°, and 2. The crystalline form of claim 1, characterized by an XRPD pattern comprising a peak at about 27.3°.

3. Peaks at the following diffraction angles (°2θ): A peak at about 24.1° a peak at about 25.2°, and 2. The crystalline form of claim 1, characterized by an XRPD pattern comprising a peak at about 27.3°.

4. Peaks at the following diffraction angles (°2θ): A peak at about 16.7° A peak at about 24.1° a peak at about 25.2°, and 2. The crystalline form of claim 1, characterized by an XRPD pattern comprising a peak at about 27.3°.

5. Peaks at the following diffraction angles (°2θ): A peak at about 12.0° A peak at about 16.7° A peak at about 24.1° a peak at about 25.2°, and 2. The crystalline form of claim 1, characterized by an XRPD pattern comprising a peak at about 27.3°.

6. 2. The crystalline form of claim 1, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in FIG.

7. 7. The crystalline form of any one of claims 1 to 6, wherein the crystalline form has an onset of melting as determined by differential scanning calorimetry (DSC) at about 75.2°C.

8. The crystalline form is represented by the space group [Equation 4] 8. The crystalline form of any one of claims 1 to 7, having a crystalline structure characterized as follows:

9. The crystal structure has a diameter of 1213.0(10) Å ３ and an asymmetric unit cell with 3-D parameters of a=8.584(3) Å; b=9.11(4) Å; c=17.043 Å.

10. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

11. 11. The pharmaceutical composition of claim 10, further comprising a release-modifying polymer.

12. 12. The pharmaceutical composition of claim 11, wherein the release-modifying polymer is selected from the group consisting of a hydrophilic matrix polymer, a hydrophobic matrix polymer, and a polyacrylate polymer.

13. 13. The pharmaceutical composition of claim 12, wherein the hydrophilic matrix polymer is hypromellose.

14. The pharmaceutical composition according to any one of claims 10 to 13, wherein the pharmaceutical composition is for oral administration.

15. 15. A method of treating a neurological disorder, comprising administering to a subject in need thereof a crystalline form of any one of claims 1 to 9, or a pharmaceutical composition of any one of claims 10 to 14.

16. 16. The method of claim 15, wherein the neurological disorder is tremor.

17. 17. The method of claim 16, wherein the tremor is essential tremor, Parkinson's tremor, cerebellar tremor, or CACNA1G tremor.

18. 18. The method of claim 17, wherein the tremor is essential tremor.

19. 15. A method of treating a psychiatric disorder in a subject in need thereof, comprising administering to the subject a crystalline form of any one of claims 1 to 9 or a pharmaceutical composition of any one of claims 10 to 14.

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