Crystalline forms of neuroactive steroids

Abstract

The present disclosure relates to a crystalline solid form # imgabs0 # (Compound 1) of Compound 1. The present disclosure also provides a process for preparing a crystalline solid form of the compound 1.

Description

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 388,323, filed on July 12, 2022, the entire disclosure of which is incorporated herein by reference in its entirety. Background Art

[0002] NMDA receptors are heteromeric complexes composed of NR1, NR2 and / or NR3 subunits and have different recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and CNS, where they participate in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some cases and promotes excitotoxicity in other cases. These receptors are ligand-gated ion channels that accept Ca after glutamate and glycine bind. 2+ , and is the basis of excitatory neurotransmission and normal CNS function. Positive modulators can be used as therapeutic agents, with potential clinical use as cognitive enhancers and for the treatment of psychiatric disorders in which glutamate transmission is reduced or defective (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325).

[0003] Compound 1 disclosed herein is a positive allosteric modulator (PAM) of NMDA receptors. In order to make a positive allosteric NMDA modulator a useful therapeutic agent, it must have a proper balance of various properties, including affinity for NMDA receptors, positive allosteric modulator activity, duration of activity, oral bioavailability, tissue distribution and stability (e.g., shelf life, formulability and crystallinity). The proper balance of such a combination of properties can lead to NMDA receptor PAMs with improved efficacy, safety, tolerance, patient compliance, manufacturing, etc. Therefore, the solid form of compound 1 and its corresponding large-scale commercial preparation of solid dosage forms have appropriate properties (including chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying properties, grinding properties, and stability during tableting) bring many challenges.

[0004] Thus, there is a need for one or more solid forms of NMDA receptor PAMs (eg, Compound 1) that have a suitable balance of these properties and that can be used to prepare pharmaceutically acceptable solid dosage forms thereof. Summary of the invention

[0005] The present disclosure provides polymorphic forms of Compound 1

[0006] (Compound 1), and solid dosage forms containing polymorphic forms of Compound 1 and methods of preparing and using the forms of Compound 1.

[0007] In a first aspect, the present disclosure provides a crystalline form of Compound 1:

[0008]

[0009] (Compound 1),

[0010] Wherein the crystalline form is crystalline Form C, wherein Form C is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ.

[0011] In some embodiments, crystalline Form C is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ. In some embodiments, Form C is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 12.9 ± 0.2, 15.1 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ.

[0012] In some embodiments, the crystalline form is crystalline Form C, characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ. In some embodiments, the XRPD pattern of crystalline Form C further comprises at least one additional peak at a position selected from the group consisting of 12.9 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, and 25.8 ± 0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline Form C, characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline Form C, characterized by an XRPD pattern substantially as Figure 1A XRPD pattern depicted.

[0013] In some embodiments, crystalline Form C has substantially Figure 1B In some embodiments, the crystalline Form C has substantially Figure 1BDepicted is a differential scanning calorimetry (DSC) thermogram. In some embodiments, the DSC thermogram comprises an endothermic peak at about 204°C. In some embodiments, the DSC thermogram comprises an endothermic peak at about 120°C.

[0014] In some embodiments, crystalline Form C is characterized by being substantially as Figure 1A XRPD pattern depicted.

[0015] In a second aspect, the present disclosure provides a solid dosage form comprising crystalline Form C of Compound 1 as disclosed herein and at least one pharmaceutically acceptable carrier.

[0016] In a third aspect, the present disclosure provides a method of treating a CNS-related disorder in a subject, the method comprising administering to the subject an effective amount of crystalline Form C of Compound 1 or a solid dosage form comprising a crystalline form of Compound 1 as disclosed herein. In some embodiments, the CNS-related disorder is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or other psychiatric disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank group of proteins), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis complex), pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (including status epilepticus and monogenic epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus.

[0017] In a fourth aspect, the present disclosure provides a method of inducing sedation or anesthesia in a subject, the method comprising administering to the subject an effective amount of crystalline Form C of Compound 1 as disclosed herein or a solid dosage form comprising crystalline Form C of Compound 1 as disclosed herein.

[0018] In a fifth aspect, the present disclosure provides a method for preparing a crystalline form C of compound 1. In some embodiments, the method for preparing a crystalline form C of compound 1 comprises the following steps: a) dissolving compound 1 in at least one solvent to form a solution; b) adding an anti-solvent until a precipitate is formed; and c) separating the precipitate. In some embodiments, the solvent is selected from the group consisting of EtOH and acetone. In some embodiments, the solvent is EtOH. In some embodiments, the solvent is acetone.

[0019] In some embodiments, the method for preparing crystalline Form C of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent to form a mixture; b) aging the mixture at room temperature to precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is EtOH / H2O.

[0020] In some embodiments, the method of preparing crystalline Form C of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent to form a mixture; b) filtering the mixture to provide a filtrate; c) aging the filtrate at room temperature; d) precipitating a solid; and e) isolating the solid. In some embodiments, the solvent is DME.

[0021] In some embodiments, the method of preparing crystalline Form C of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent to form a mixture; b) adding the mixture to a polymer mixture; c) aging the mixture at room temperature to precipitate a solid; and d) isolating the solid. In some embodiments, the solvent is IPAc.

[0022] In some embodiments, the method of preparing crystalline Form C of Compound 1 comprises the steps of: a) adding Compound 1 to a solvent to form a mixture; b) aging the mixture at about 5° C. to precipitate a solid; and d) isolating the solid. In some embodiments, the solvent is DME / THF.

[0023] In some embodiments, the method of preparing crystalline Form C of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent to form a mixture; b) heating the mixture to about 60° C.; c) filtering the heated mixture to provide a filtrate; d) aging the filtrate at about −20° C. to provide a solid; and e) isolating the solid. In some embodiments, the solvent is DCM. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1A An exemplary XRPD pattern of crystalline Form C is depicted.

[0025] Figure 1B Exemplary TGA (top) and DSC (bottom) thermograms of Form C are depicted.

[0026] Figure 1C Depicted are exemplary XRPD overlays of Form C before and after heating. DETAILED DESCRIPTION

[0027] General Definition

[0028] The term "herein" means the entire application.

[0029] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meaning commonly understood by one of ordinary skill in the art to which the present disclosure belongs. Generally, the nomenclature used in connection with the compounds, compositions and methods described herein are those well known and commonly used in the art.

[0030] It should be understood that any embodiment described herein, including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in examples), can be combined with one or more other embodiments of the disclosure unless expressly denied or inappropriate. The combination of embodiments is not limited to those specific combinations claimed by multiple dependent claims. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same basic claim. In the case where the elements are presented in a list form, such as a Markush group format, each subgroup of the elements is also disclosed, and any one or more elements can be removed from the group.

[0031] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" should be understood to imply the inclusion of a stated integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0032] Throughout the specification, when a composition or device is described as having, including or comprising (or variations thereof) a particular component, it is contemplated that the composition may also consist essentially of or consist of said component. Similarly, where a method or process is described as having, including or comprising a particular method step, the method may also consist essentially of or consist of said processing steps. Further, it should be understood that the order of the steps or the order in which certain actions are performed is immaterial as long as the compositions and methods described herein remain operable. In addition, two or more steps or actions may be performed simultaneously.

[0033] As used herein, the term "comprising" means "including but not limited to". "Comprising" and "including but not limited to" are used interchangeably. Thus, these terms will be understood to imply the inclusion of the stated integers (or components) or groups of integers (or components) but not the exclusion of any other integers (or components) or groups of integers (or components).

[0034] As used herein, "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0035] The use of the terms "a" and "an" and "the" and similar referents in the context of describing elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0036] As used herein, the term "or" should be understood to mean "and / or" unless the context clearly indicates otherwise.

[0037] Unless otherwise indicated herein, the description of the range of values ​​herein is intended only to serve as a shorthand method for individually referring to each individual value within the range and including the endpoints, and each individual value is incorporated into this specification as if individually described herein. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein can be performed in any suitable order. Unless otherwise indicated, the use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of the claims. Any language in this specification should not be interpreted as indicating any non-claimed element as necessary.

[0038] All publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In the event of a conflict, this specification (including its specific definitions) will prevail. In addition, any specific embodiment of the present disclosure that falls within the prior art can be explicitly excluded from any one or more of the claims. Since such embodiments are considered to be known to those of ordinary skill in the art, these embodiments can be excluded even if the exclusion is not explicitly stated herein. Any specific embodiment of the present disclosure can be excluded from any claim for any reason, whether or not related to the existence of the prior art.

[0039] The terms "active ingredient," "active agent," and "active substance" refer to a compound that is administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients, for the treatment, prevention, or amelioration of one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient," "active agent," and "active substance" may be an optically active isomer of a compound described herein.

[0040] The terms "drug" and "therapeutic agent" refer to a compound or pharmaceutical composition thereof that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease.

[0041] The term "polymorph" as used herein refers to a crystalline form of a compound or its salt, hydrate or solvate that is in a specific crystal packing arrangement. All polymorphs have the same elemental composition. The term "polymorph" includes pseudopolymorphs, which are generally different solvates of a material, and therefore their properties differ from each other. Therefore, each different polymorph and pseudopolymorph disclosed herein is considered a different single crystal form herein.

[0042] As used herein, the term "crystallization" refers to a solid form composed of an orderly arrangement of structural units. Different crystalline forms of the same compound or its salt, hydrate or solvate are derived from different stacking of solid molecules, which leads to different crystal symmetries and / or unit cell parameters. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability and solubility. See, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton Pa., 173 (1990); United States Pharmacopeia, 23rd edition, 1843-1844 (1995) (incorporated herein by reference). As used herein, the terms "crystalline form", "single crystal form", "crystalline solid form" and "polymorph" are used interchangeably; these terms distinguish crystals with different properties (e.g., different XRPD patterns and / or different DSC scan results).

[0043] The term "substantially pure" refers to a composition of a specific crystalline solid form of Compound 1 that may be free of impurities and / or other solid forms of Compound 1 at least in a specific weight percentage. The specific weight percentage is 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, Compound 1 may be a substantially pure sample of any crystalline solid form described herein. In some embodiments, Compound 1 may be substantially pure Form C.

[0044] Crystalline forms are usually characterized by X-ray powder diffraction (XRPD). XRPD reflection patterns (peaks, usually expressed in 2θ degrees) are usually considered as fingerprints of specific crystalline forms. The relative intensity of XRPD peaks may vary depending on, among other things, sample preparation techniques, crystal size distribution, filters, sample installation procedures, and the specific instrument used. In some cases, there may be more (i.e., new peaks) or fewer (i.e., peaks may disappear) peaks in the XRPD pattern, depending on the instrument type or settings. In some cases, any specific peak in the XRPD pattern may appear as a single peak, double peak, triple peak, quartet peak, or multiple peaks, depending on the type or settings of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystalline form. In some cases, any specific peak in the XRPD may appear in a symmetrical shape or in an asymmetrical shape, such as with a shoulder. In addition, instrument variations and other factors may also affect the 2θ value. A technician who understands these variations is able to use XRPD and other known physicochemical techniques to identify or determine the defining features or characteristics of a specific crystalline form.

[0045] When referring to peaks in an XRPD pattern of a crystalline form of Compound 1, the term "characteristic peaks" refers to a collection of certain peaks whose 2θ values ​​in the range of 0° to 40° are uniquely attributed to one of the crystalline forms of Compound 1 as a whole.

[0046] The term "amorphous" applied to chemical compounds refers to a state in which the material lacks long-range order at the molecular level and, depending on the temperature, can exhibit the physical properties of either a solid or a liquid. Typically, such materials do not give a distinctive X-ray diffraction pattern and, while exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, characterized by a change of state, typically second order ("glass transition").

[0047] The term "solvate" refers to a compound or salt thereof provided herein that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces (e.g., hydrogen bonds). When the solvent is water, the solvate is a hydrate. When the solvent includes ethanol, the compound can be an ethanol solvate.

[0048] The term "stable" in the context of the polymorphic forms disclosed herein refers to the stability of the polymorphic form with respect to heat and / or humidity.

[0049] The crystalline forms of Compound 1 described herein (e.g., Form C) may melt at a specific temperature or within a temperature range. Such a specific temperature or temperature range may be determined by the onset temperature (T) of the melting endotherm in the DSC trace of the crystalline form. 起始). In some embodiments, at such starting temperatures, a sample of the crystalline form of Compound 1 melts and undergoes concurrent side processes, such as recrystallization or chemical decomposition. In some embodiments, at such starting temperatures, the crystalline form of Compound 1 melts in the absence of other concurrent processes.

[0050] The present disclosure provides forms of Compound 1 that have suitable properties for preparing solid dosage forms. Such properties include chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying properties, grinding properties, and stability during tableting.

[0051] In one aspect, the present disclosure relates to a solid form of Compound 1

[0052] (Compound 1).

[0053] In some embodiments, the solid form is crystalline Form C of Compound 1. In some embodiments, the crystalline form is a hydrate.

[0054] Compound 1 and its chemical synthesis are disclosed in US Patent No. 10227375 / PCT Application Publication No. WO2014160480.

[0055] In some embodiments, a crystalline structure of the present disclosure may be identified by having one or more characteristic peaks in an XRPD spectrum, as disclosed herein.

[0056] In some embodiments, the crystalline structures of the present disclosure can be identified by having one or more characteristic endothermic peaks in a differential scanning calorimetry (DSC) thermogram, as disclosed herein.

[0057] In some embodiments, the crystalline structures of the present disclosure can be identified by having one or more characteristic endothermic peaks in a thermogravimetric analysis (TGA) thermogram, as disclosed herein.

[0058] In some embodiments, the crystalline structures of the present disclosure can be identified by having one or more characteristic endothermic peaks in a differential scanning calorimetry (DSC) thermogram or a thermogravimetric analysis (TGA) thermogram, as disclosed herein.

[0059] In some embodiments, the crystalline structures of the present disclosure can be identified by having one or more characteristic peaks in an XRPD spectrum in combination with one or more characteristic endothermic peaks in a differential scanning calorimetry thermogram and / or a thermogravimetric analysis (TGA) thermogram.

[0060] In some embodiments, crystalline Form C of Compound 1 is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ.

[0061] In some embodiments, crystalline Form C of Compound 1 is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ.

[0062] In some embodiments, crystalline Form C of Compound 1 is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 12.9 ± 0.2, 15.1 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ.

[0063] In some embodiments, the crystalline Form C of Compound 1 is characterized by being substantially as Figure 1A XRPD pattern shown.

[0064] In some embodiments, crystalline Form C of Compound 1 is a hydrate. In some embodiments, crystalline Form C of Compound 1 is a monohydrate.

[0065] In some embodiments, Form C has one or more characteristics selected from the group consisting of:

[0066] a) XRPD pattern of peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ;

[0067] b) Substantially Figure 1A The XRPD pattern shown;

[0068] c) a DSC thermogram comprising an endothermic peak at about 204° C.;

[0069] d) a DSC thermogram comprising an endothermic peak at about 120° C.;

[0070] e) Substantially Figure 1B DSC thermogram shown;

[0071] f) a TGA curve exhibiting at least about 3 wt % loss between about 23°C and about 125°C; and

[0072] g) Substantially Figure 1B TGA curve shown.

[0073] In some embodiments, crystalline Form C of Compound 1 is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ. In some embodiments, Form C is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ, and further comprising at least one additional peak at a position selected from the group consisting of 12.9 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, and 25.8 ± 0.2 degrees 2θ. In some embodiments, Form C is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ. In some embodiments, Form C is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 12.9 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ. In some embodiments, the crystalline Form C of Compound 1 is characterized by substantially Figure 1A XRPD pattern depicted.

[0074] In some embodiments, Form C of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of at least about 3 wt % of Form C between about 23° C. and about 125° C. In some embodiments, Form C of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of about 3 wt % to 4 wt % of Form C between about 23° C. and about 125° C. In some embodiments, Form C of Compound 1 is characterized by substantially Figure 1B Thermogravimetric analysis (TGA) thermogram depicted in .

[0075] In some embodiments, Form C of Compound 1 is characterized by being substantially as Figure 1BThe differential scanning calorimetry (DSC) thermogram depicted in . In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram comprising an endothermic peak at about 204°C. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram comprising an endothermic peak at about 120°C. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram comprising endothermic peaks at about 120°C and about 204°C. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram comprising a dehydration endothermic peak at about 120°C. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram comprising a melting endothermic peak at about 204°C.

[0076] In some embodiments, Form C of Compound 1 is substantially free of other polymorphic forms. In some embodiments, Form C of Compound 1 has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, Form C of Compound 1 has a polymorphic purity of at least 90%. In some embodiments, Form C of Compound 1 has a polymorphic purity of at least 92%. In some embodiments, Form C of Compound 1 has a polymorphic purity of at least 94%. In some embodiments, Form C of Compound 1 has a polymorphic purity of at least 96%. In some embodiments, Form C of Compound 1 has a polymorphic purity of at least 98%. In some embodiments, Form C of Compound 1 has a polymorphic purity of at least 99%.

[0077] Pharmaceutical composition

[0078] In one aspect, the present invention provides a pharmaceutical composition which is a solid dosage form, comprising a solid form of crystalline Form C of Compound 1 as disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of Form C of Compound 1. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Compound 1.

[0079] In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of Compound 1.

[0080] Solid dosage forms suitable for oral administration include solid preparations such as tablets, caplets, capsules, powders, lozenges (including liquid-filled), sachets and the like.

[0081] The solid dosage forms disclosed herein include a carrier, which may include one or more of a pharmaceutically acceptable excipient, including, but not limited to, a binder, a surfactant, a diluent or filler, a buffer, an anti-adherent, a glidant, a hydrophilic or hydrophobic polymer, a retardant, a stabilizer or stabilizer, a disintegrant or super disintegrant, a dispersant, an antioxidant, a defoamer, a filler, a flavoring agent, a colorant, a lubricant, an adsorbent, a preservative, a plasticizer, a coating agent or a sweetener, or a mixture thereof, and other excipients known in the art. For example, one or more excipients may be a binder, such as microcrystalline cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, tragacanth gum, or gelatin; a diluent, such as mannitol, microcrystalline cellulose, maltodextrin, starch, or lactose; a disintegrant, such as alginic acid, PRIMOGEL ® , sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, or corn starch; lubricants such as magnesium stearate, sodium stearyl fumarate, or glyceryl behenate; glidants such as colloidal silicon dioxide; preservatives such as potassium sorbate or methyl paraben; surfactants such as sodium lauryl sulfate, sodium docusate, polysorbate 20, polysorbate 80, cetyl triethylammonium bromide, polyethylene oxide-polypropylene oxide copolymer, or CREMOPHOR ®EL; antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, tocopherol or tocopherol acetate, sodium sulfite or sodium metabisulfite; coatings comprising one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, methacrylate copolymers, cellulose acetate, hydroxypropyl methylcellulose acetate succinate, shellac, etc.; sweeteners such as sucrose, sucralose, acesulfame potassium, aspartame sodium or saccharin sodium; or flavoring agents such as mint, methyl salicylate or orange flavoring. Any well-known pharmaceutical excipients can be incorporated into the dosage form and can be found in the following documents: FDA's Inactive Ingredients Guide, Remington: The Science and Practice of Pharmacy, Twenty-first Edition, (Pharmaceutical Press, 2005); Handbook of Pharmaceutical Excipients, Sixth Edition. (Pharmaceutical Press, 2009), all of which are incorporated by reference. In some embodiments, the solid dosage forms disclosed herein comprise any one or more of the following excipients: low-water microcrystalline cellulose, 90-type silicified low-water microcrystalline cellulose, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate, and Opadry AMB II88A180040 white. In some embodiments, the solid dosage forms disclosed herein comprise low-water microcrystalline cellulose, 90-type silicified low-water microcrystalline cellulose, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate, and Opadry AMB II88A180040 white. In some embodiments, the solid dosage forms disclosed herein comprise low-water microcrystalline cellulose, 90-type silicified low-water microcrystalline cellulose, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate, and Opadry AMB II88A180040 white.

[0082] How to use

[0083] Compound 1 as described herein is generally designed to be a positive allosteric modulator of NMDA function, and thus is useful for treating and preventing, for example, CNS-related disorders in a subject.

[0084] In some embodiments, Compound 1 as described herein is generally designed to penetrate the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). In certain embodiments of the present disclosure, Compound 1 acts as a positive allosteric modulator (PAM) of NMDA and enhances NMDA receptor function.

[0085] In one aspect, the present disclosure provides a method for treating a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject, the method comprising administering to the subject an effective amount of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein.

[0086] In one aspect, the present disclosure provides a method for treating a CNS-related disorder in a subject, the method comprising administering to the subject an effective amount of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein.

[0087] In one aspect, the present disclosure provides a method for preventing a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject, the method comprising administering to the subject an effective amount of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein.

[0088] In one aspect, the present disclosure provides a method for preventing a CNS-related disorder in a subject, the method comprising administering to the subject an effective amount of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein.

[0089] In one aspect, the present disclosure provides a method for inducing sedation or anesthesia in a subject, the method comprising administering to the subject an effective amount of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein.

[0090] In one aspect, the present disclosure provides crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for use in treating a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject.

[0091] In one aspect, the present disclosure provides crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for use in treating a CNS-related disorder in a subject.

[0092] In one aspect, the present disclosure provides crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for use in preventing a disease, disorder or condition requiring positive NMDA modulation in a subject.

[0093] In one aspect, the present disclosure provides crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for use in preventing a CNS-related disorder in a subject.

[0094] In one aspect, the present disclosure provides crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for use in inducing sedation or anesthesia in a subject.

[0095] In one aspect, the present disclosure provides use of a crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for the manufacture of a medicament for treating a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject.

[0096] In one aspect, the present disclosure provides use of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for the manufacture of a medicament for treating a CNS-related disorder in a subject.

[0097] In one aspect, the present disclosure provides use of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for the manufacture of a medicament for preventing a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject.

[0098] In one aspect, the present disclosure provides use of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for the manufacture of a medicament for preventing a CNS-related disorder in a subject.

[0099] In one aspect, the present disclosure provides use of crystalline Form C or a solid dosage form of Compound 1 as disclosed herein for the manufacture of a medicament for inducing sedation or anesthesia in a subject.

[0100] In some embodiments, the disorder is cancer. In some embodiments, the disorder is diabetes. In some embodiments, the disorder is a sterol synthesis disorder. In some embodiments, the disorder is a gastrointestinal (GI) disorder, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis. In some embodiments, the disorder is inflammatory bowel disease.

[0101] In some embodiments, the disorder is S-Lewis syndrome (SLOS). In some embodiments, the disorder is streptosterolemia. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebrotendinous xanthomatosis (CTX). In some embodiments, the disorder is mevalonate kinase deficiency (MKD). In some embodiments, the disorder is SC4MOL gene mutation (SMO deficiency). In some embodiments, the disorder is Niemann-Pick disease. In some embodiments, the disorder is autism spectrum disorder (ASD). In some embodiments, the disorder is associated with phenylketonuria.

[0102] Exemplary conditions associated with positive NMDA modulation include, but are not limited to, gastrointestinal (GI) disorders, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis; and CNS disorders, e.g., as described herein.

[0103] Exemplary CNS disorders associated with positive NMDA modulation include, but are not limited to, adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia)), bipolar disorder, eating disorders, mood disorders (including depression (e.g., puerperal depression), bipolar disorder, dysthymic disorder, suicide), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse disorders, The disease is often related to autoimmune diseases, including schizophrenia, autoimmune diseases, and seizure disorders.

[0104] In certain embodiments, the crystalline Form C or solid dosage form of Compound 1 as disclosed herein can be used to induce sedation or anesthesia. In certain embodiments, the crystalline form or solid dosage form of Compound 1 as disclosed herein can be used to treat or prevent adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other mental disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, sterol synthesis disorders, pain, seizure disorders, stroke, traumatic brain injury, movement disorders and visual impairment, hearing loss and tinnitus. In some embodiments, the disorder is Huntington's disease. In some embodiments, the disorder is Parkinson's disease. In some embodiments, the disorder is an inflammatory disease (e.g., lupus).

[0105] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or suffering from a disorder associated with brain excitability, the method comprising administering to the subject an effective amount of a crystalline form or solid dosage form of Compound 1 as disclosed herein.

[0106] In yet another aspect, the present disclosure provides a combination of a compound of the present disclosure (e.g., crystalline Form C of Compound 1) and another pharmaceutically active agent. The compounds provided herein can be administered as separate active agents, or they can be administered in combination with other active agents. The combined administration can be performed by any technique obvious to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0107] Diseases and disorders

[0108] Movement disorders

[0109] Also described herein are methods for treating movement disorders. As used herein, "movement disorders" refer to a variety of diseases and disorders associated with hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson's disease and Parkinson's syndrome (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff person syndrome, and gait disorders.

[0110] Tremor is an involuntary, sometimes rhythmic contraction and relaxation of muscles that may involve wiggling or jerking of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremors include hereditary, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic disorders (e.g., thyroid, parathyroid, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Ruthie-Levi, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (narcolepsy, tricyclics, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be divided into physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes tremor (ie, rubral tremor), palatal tremor, neurogenic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor.

[0111] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after purposeful movement. Cerebellar tremor is caused by a disorder or injury to the cerebellum, such as a tumor, stroke, or a disease (for example, multiple sclerosis (an inherited degenerative disorder)).

[0112] Dystonic tremor occurs in people with dystonia, a movement disorder in which sustained, involuntary muscle contractions cause twisting and repetitive movements and / or pain and abnormal posture or position. Dystonic tremor may affect any muscle in the body. Dystonic tremor occurs irregularly and is usually relieved by complete rest.

[0113] Essential tremor, or benign essential tremor, is the most common type of tremor. In some people, essential tremor may be mild and non-progressive, or it may be slowly progressive, starting on one side of the body but affecting both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be affected. As a person ages, tremors may become less frequent but may increase in severity. Tremors may be triggered and / or worsened in severity by emotional excitement, stress, fever, physical exhaustion, or low blood sugar. Symptoms often evolve over time and may be noticeable and persistent after an episode.

[0114] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz), rhythmic muscle contractions in the legs and trunk immediately after standing. The patient feels cramps in the thighs and calves, and may shake uncontrollably when asked to stand in one place. Orthostatic tremor may occur in patients with essential tremor.

[0115] Parkinsonian tremors are caused by damage to structures within the brain that control movement. Parkinsonian tremors are often a precursor to Parkinson's disease and usually manifest as a "pill-rolling" motion of the hands, which may also affect the jaw, lips, legs, and trunk. Parkinsonian tremors typically begin after age 60. The movements begin in one limb or side of the body and may progress to include the other side.

[0116] Physiologic tremor may occur in normal individuals and is of no clinical significance. It can be seen in all voluntary muscle groups. Physiologic tremor may be caused by certain medications, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. Tremor typically has a frequency of about 10 Hz.

[0117] Psychogenic or hysterical tremor may occur at rest or during postural or dynamic movement. People with psychogenic tremor may have conversion disorder or other psychiatric disorders.

[0118] Rubral tremor is characterized by a coarse, slow tremor that may occur at rest, in posture, and with intent. This tremor is associated with disorders affecting the red nucleus of the midbrain (typically abnormal stroke).

[0119] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonism has the same symptoms as Parkinson's disease, but it is a symptom complex rather than a progressive neurodegenerative disease.

[0120] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that result in abnormal, often repetitive movements or postures. Dystonic movements may be patterned, distorted, and may be trembling. Dystonia is often triggered or exacerbated by voluntary movements and is associated with excessive muscle activation.

[0121] Chorea is a neurological disorder characterized by sudden involuntary movements that typically affect the shoulders, hips, and face.

[0122] Huntington's disease is a genetic disorder that causes nerve cells in the brain to shrink. Symptoms include uncontrolled movements, clumsiness and balance problems. Huntington's disease can make it harder to walk, talk and swallow.

[0123] Ataxia is the loss of complete control over body movements and can affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0124] Myoclonus and startle are responses to sudden and unexpected stimuli, which may be auditory, tactile, visual, or vestibular.

[0125] A tic is an involuntary movement that usually occurs suddenly, is brief, repetitive but not rhythmic, often mimics normal behavior and often occurs in the context of normal activities. Tics can be classified as motor tics, which are associated with movement, or vocal tics, which are associated with sound. Tics can be classified as simple or complex. For example, a simple motor tic involves only a few muscles limited to a specific body part.

[0126] Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood and characterized by multiple motor tics and at least one vocal tic.

[0127] Restless legs syndrome is a neurological sensorimotor disorder characterized by a strong urge to move the legs while at rest.

[0128] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle rigidity, usually involving the lower back and legs. It usually results in a stiff gait with excess lumbar lordosis of the legs. Characteristic abnormalities in electromyographic recordings of sequential motor unit activity of the paraxial muscles are often observed. Variants include "rigid limb syndrome," which produces focal rigidity, usually affecting the distal legs and feet.

[0129] Gait disorders are abnormalities in the pattern or style of walking caused by neuromuscular, arthritic, or other physical changes. Gaits are classified according to the system responsible for the abnormal movement and include hemiplegic, diplegic, neuropathic, myopathic, parkinsonian, choreiform, ataxic, and sensory gaits.

[0130] Mood disorders

[0131] Also provided herein are methods for treating a mood disorder, such as clinical depression, postpartum or puerperal depression, peripartum depression, atypical depression, melancholic depression, major psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar or manic-depressive disorder, depression due to a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior.

[0132] Clinical depression is also known as major depression, major depressive disorder (MDD), major depressive disorder, unipolar depression, unipolar disorder, and recurrent depression, and 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 pleasurable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel irritable. 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 have difficulty carrying out daily activities and feel that life is not worth living.

[0133] Postpartum depression (PND), also known as puerperal depression (PPD), refers to a type of clinical depression that affects women after childbirth. Symptoms include sadness, fatigue, changes in sleeping and eating habits, decreased libido, crying, anxiety, and irritability. In some embodiments, PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein). In some embodiments, PND is a refractory depression (e.g., a refractory depression as described herein).

[0134] In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy. Such depression is referred to herein as perinatal depression. In one embodiment, subjects experiencing perinatal depression experience an increased risk of PND.

[0135] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and motivation, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or narcolepsy (sleepiness), a feeling of heaviness in the limbs, and severe social impairment due to an oversensitivity to perceived interpersonal rejection.

[0136] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, depressed mood that is more pronounced than sadness or loss, excessive weight loss, or excessive guilt.

[0137] Major psychotic depression (PMD) or psychotic depression refers to a major depressive episode, particularly of a melancholic nature, in which the individual experiences psychotic symptoms, such as delusions and hallucinations.

[0138] Catatonic depression refers to major depressive disorder that involves motor behavior disturbances and other symptoms. The individual may become mute and catatonic, either motionless or making purposeless or bizarre movements.

[0139] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes occurring in the fall or winter.

[0140] Dysthymia refers to conditions related to unipolar depression in which the same physical and cognitive problems are evident. They are less severe and tend to last longer (e.g., at least 2 years).

[0141] Double depression is a period of at least 2 years of fairly depressed mood (dysthymia) interspersed with episodes of major depression.

[0142] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0143] Recurrent brief depressive disorder (RBD) occurs when an individual has depressive episodes approximately once a month, with each episode lasting 2 weeks or less and usually less than 2 to 3 days.

[0144] Minor depressive disorder or minor depression is depression with at least 2 symptoms lasting for 2 weeks.

[0145] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings that include highs (mania or hypomania) and lows (depression). During mania, individuals may feel or act unusually happy, energetic, or irritable. They often make ill-considered decisions with little regard for the consequences. The need for sleep is often reduced. During depression, there may be crying, poor eye contact with others, and a negative attitude toward life. Those with the disorder have a 20-year risk of suicide of more than 6%, and a 30 to 40% risk of self-harm. Other mental health problems such as anxiety disorders and substance abuse disorders are often associated with bipolar disorder.

[0146] Chronic medical-induced depression is depression caused by a chronic medical condition (such as cancer or chronic pain, chemotherapy, chronic stress).

[0147] Treatment-resistant depression refers to a condition in which an individual has been treated for depression but the symptoms have not improved. For example, antidepressants or psychological counseling (psychotherapy) do not relieve depressive symptoms in patients with treatment-resistant depression. In some cases, an individual with treatment-resistant depression has an improvement in symptoms but then relapses. Treatment-resistant depression occurs in patients with depression who are resistant to standard drug treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or antianxiety medications) and non-drug treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0148] Suicide, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts about or an unusual preoccupation with suicide. The range of suicidal ideation varies widely, for example, from fleeting thoughts to extensive contemplation, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social situations, preoccupying oneself with death, feeling trapped or hopeless about a situation, increasing alcohol or drug use, doing dangerous or self-destructive things, and saying goodbye to people as if they were not coming back.

[0149] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, physical challenges, loss of interest in pleasurable activities or hobbies, difficulty concentrating, weakness, poor self-esteem, lack of positive thoughts or plans, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The onset, severity, frequency, and duration of symptoms may vary from case to case. Symptoms of depression and their relief can be determined by a physician or psychologist (e.g., through a mental status examination).

[0150] Anxiety disorders

[0151] Methods for treating anxiety disorders are provided herein. Anxiety disorders are an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a variety of anxiety disorders.

[0152] Generalized anxiety disorder is a common, chronic disorder characterized by persistent anxiety that is not focused on any one object or situation. People with generalized anxiety disorder experience nonspecific, persistent fears and worries and an excessive focus on everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0153] In panic disorder, a person suffers from brief episodes of intense fear and apprehension, often manifested as tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as sudden onset of fear or discomfort that peaks in less than ten minutes, can last for several hours, and can be triggered by stress, fear, or even exercise; but the specific cause is not always obvious. In addition to recurring unexpected panic attacks, the diagnosis of panic disorder requires that the attacks have chronic consequences: either worry about the potential effects of the attack, or persistent worry about future attacks, or significant changes in behavior associated with the attack. Therefore, those with panic disorder experience symptoms even outside of specific panic attacks. Often, panic patients notice normal changes in their heartbeat, leading them to believe that they have a problem with their heart or that another panic attack is about to occur. In some cases, a high level of alertness to bodily functions (hypervigilance) occurs during a panic attack, in which any perceived physiological changes are interpreted as potentially life-threatening illnesses (i.e., extreme hypochondriasis).

[0154] Obsessive-compulsive disorder is an anxiety disorder characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (the urge to perform specific behaviors or rituals). OCD thought patterns may be likened to superstitions because they involve the belief in cause-and-effect relationships when, in fact, no such relationships exist. Often the process is completely illogical; for example, the compulsion to walk in a certain pattern may be used to alleviate distress about an impending injury. And in many cases, the compulsions are completely unexplained and are simply a stress-induced urge to complete a ritual. In a few cases, people with OCD may experience only obsessions without overt compulsions; very rarely, people experience only compulsions.

[0155] The largest category of anxiety disorders is phobias, which include all situations in which a particular stimulus or situation triggers fear and anxiety. The patient usually anticipates a terrible consequence upon encountering the object of the fear, which can be anything from an animal to a place to a bodily fluid.

[0156] Post-traumatic stress disorder, or PTSD, is an anxiety disorder caused by a traumatic experience. Post-traumatic stress can be caused by extreme situations, such as combat, rape, hostage situations, or even serious accidents. It can also be caused by long-term (chronic) exposure to severe stressors, such as a soldier who can withstand individual combat but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0157] epilepsy

[0158] Epilepsy is a brain disease characterized by recurring seizures over time. Types of epilepsy may include, but are not limited to: generalized epilepsy, e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, grand mal seizures with arousal, West syndrome, Lennox-Gastaut syndrome; partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

[0159] Epilepsy

[0160] Epileptogenesis is a gradual process by which the normal brain develops into epilepsy, a chronic disorder in which seizures occur. Epileptogenesis results from neuronal damage caused by an initial insult (e.g., status epilepticus).

[0161] Status epilepticus (SE)

[0162] Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, determined status epilepticus, refractory status epilepticus, and super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic lateralized epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus, and may include early status epilepticus, determined status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Determined status epilepticus is characterized in that despite the administration of first-line therapy and second-line therapy, status epilepticus persists. Refractory status epilepticus is characterized in that despite treatment with first-line therapy and second-line therapy and generally the administration of general anesthesia, status epilepticus persists. Super-refractory status epilepticus is characterized in that despite treatment with first-line therapy, second-line therapy, and general anesthesia for 24 hours or more, status epilepticus persists.

[0163] Non-convulsive status epilepticus may include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, mild non-convulsive status epilepticus; generalized non-convulsive status epilepticus, such as tardive absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0164] attack

[0165] A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A seizure is when a person's body shakes rapidly and uncontrollably. During a seizure, a person's muscles repeatedly contract and relax.

[0166] Based on the type of behavior and brain activity, seizures are divided into two major categories: generalized seizures and partial seizures (also called localized or focal seizures). Classifying seizure types helps doctors diagnose whether a person has epilepsy.

[0167] Generalized seizures are caused by electrical impulses throughout the brain, whereas partial seizures are caused by electrical impulses in a relatively small part of the brain (at least initially). The part of the brain where the seizure occurs is sometimes called the epileptogenic focus.

[0168] There are six types of generalized seizures. The most common, dramatic, and therefore best known is the generalized convulsion, also called a grand mal seizure. During this type of seizure, the person loses consciousness and usually collapses. After the loss of consciousness, the whole body freezes (called the "tonic" phase of the seizure) for 30 to 60 seconds, followed by violent convulsions (the "clonic" phase) for 30 to 60 seconds, after which the person falls into a deep sleep (the "postictal" or post-ictal phase). During a grand mal seizure, injuries and accidents can occur, such as tongue biting and urinary incontinence.

[0169] Absence seizures cause a brief loss of consciousness (only a few seconds) with few symptoms. The person (usually a child) typically stops moving and stares blankly. These seizures begin and end suddenly and may occur several times a day. People are usually unaware that they are having a seizure; they may only be aware of "losing time."

[0170] Myoclonic seizures consist of sporadic twitching, usually on both sides of the body. Patients sometimes describe these twitching as brief electric shocks. When severe, these seizures may cause the person to drop or involuntarily throw objects.

[0171] A clonic seizure is a repetitive, rhythmic twitch that affects both sides of the body at the same time.

[0172] Tonic seizures are characterized by muscle stiffness.

[0173] Atonic seizures are sudden, generalized loss of muscle tone, especially in the arms and legs, which often results in falls.

[0174] Seizures described herein may include epileptic seizures; acute recurrent seizures; cluster seizures; continuous seizures; uninterrupted seizures; prolonged seizures; recurrent seizures; status epilepticus, such as refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign motor seizures; febrile seizures; emotional seizures; focal seizures; convulsive seizures; generalized seizures; infantile spasms; Jackson seizures; massive bilateral myoclonic seizures; multifocal seizures; neonatal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; minor seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female pediatric epilepsy.

[0175] Sterol synthesis disorders

[0176] In one embodiment, methods for treating sterol synthesis disorders are described herein. Cholesterol has important regularities in growth and development. It is a membrane lipid and a precursor of many molecules, playing an important role in cell growth and differentiation, protein glycosylation, and signaling pathways. The biosynthesis of cholesterol involves many enzymes and intermediates. Obstacles caused by any enzyme deficiency involved in cholesterol biosynthesis can lead to the accumulation of intermediates and an imbalance of biomolecules, resulting in disorders including congenital skeletal malformations, facial feature deformities, psychomotor retardation, and developmental disorders. In one embodiment, sterol synthesis disorders or symptoms of sterol synthesis disorders can be treated by administering compounds described herein (such as NMDA receptor modulating compounds as described herein) to subjects suffering from sterol synthesis disorders. Other disorders are described below.

[0177] S-L-O syndrome

[0178] In one embodiment, methods for treating S-L-O syndrome (or SLOS or 7-dehydrocholesterol reductase deficiency) are described herein. SLOS is an inborn error of cholesterol synthesis. In addition to microcephaly, moderate to severe intellectual disability, hyperesthesia, stereotypic movements, dysmorphic facial features, and syndactyly of the second / third toes, one of the characteristics of the disease is a decrease in brain sterol (24(S)-hydroxycholesterol) levels. SLOS is an autosomal recessive genetic disease caused by a deficiency of the final enzyme in the cholesterol synthesis pathway and results in low or subnormal plasma cholesterol levels and elevated levels of 7- and 8-dehydrocholesterol (DHC; 7DHC and 8DHC). Current commonly used therapies include dietary cholesterol supplementation, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoA reductase inhibitors, also known as statins), and treatment with drugs that enhance cholesterol production and / or accumulation; and reduce the accumulation of 7DHC and 8DHC (potentially toxic precursors of cholesterol).

[0179] Streptosterolemia

[0180] Streptosterolemia is a deficiency of the enzyme streptosterol reductase and has a phenotype similar to SLOS. In one embodiment, described herein are methods for treating streptosterolemia using the compounds described herein.

[0181] Sitosterolemia

[0182] Sitosterolemia is a rare autosomal recessive disease caused by mutations in two ATP-binding cassette (ABC) transporter genes (ABCG5 and ABCG8). Sitosterolemia enhances intestinal absorption of plant sterols and cholesterol. Patients often suffer from tendon and tuberous xanthomas and premature coronary artery disease. In one embodiment, methods for treating sitosterolemia using the compounds described herein are described herein.

[0183] Cerebrotendinous xanthomatosis (CTX)

[0184] In one embodiment, methods are described herein for treating cerebrotendinous xanthomas (also known as cerebral cholesterol deposition or Van Bogaert-Scherer-Epstein syndrome) using the compounds described herein. CTX may be caused by mutations in the CYP27A1 gene, which produces sterol 27-hydroxylase. Sterol 27-hydroxylase metabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid), which are very important for the absorption of fats in the intestine. Enzyme dysfunction may lead to the accumulation of cholesterol in tissues. CTX is characterized by diarrhea, cataracts, tendon xanthomas in children, intellectual impairment and movement abnormalities in adults.

[0185] Mevalonate kinase deficiency syndrome (MKD)

[0186] Mevalonate kinase deficiency, also known as mevalonic aciduria (a more severe form of MKD) or hyper-IgD syndrome (HIDS or hyperimmunoglobulinemia D) with menstrual fever syndrome (a more benign form of MKD), results in the accumulation of mevalonic acid in the urine due to insufficient mevalonate kinase activity. MKD may result in developmental delay, low muscle tone, anemia, hepatosplenomegaly, dysmorphic features, mental retardation, and overall developmental impairment. Mevalonic aciduria is characterized by physical and mental retardation, growth retardation, recurrent episodes of fever with vomiting and diarrhea, enlarged liver, spleen, and lymph nodes, microcephaly (small head), cataracts, low muscle tone, short stature, distinct facial features, ataxia, and anemia. HIDS is characterized by recurrent fever with swollen lymph nodes, joint pain, gastrointestinal problems, and rash. In one embodiment, described herein are methods for treating MKD using the compounds described herein.

[0187] SC4MOL gene mutation (SMO deficiency)

[0188] SC4MOL gene deficiency is a genetic disorder in the cholesterol biosynthetic pathway (e.g., mutations in the SC4MOL gene encoding the enzyme neosterol oxidase). SC4MOL deficiency is characterized by the accumulation of dimethyl sterols and monomethyl sterols (which can be detected in blood, skin explants, or primary skin fibroblasts). In one embodiment, described herein are methods for treating SMO deficiency using the compounds described herein.

[0189] Niemann-Pick disease

[0190] Niemann-Pick disease is a lysosomal storage disease caused by a gene mutation that affects metabolism. Niemann-Pick disease results in an abnormal accumulation of cholesterol and other fatty substances (lipids) because the body cannot transport these substances. This accumulation can damage the affected areas.

[0191] Autism

[0192] In one embodiment, the present invention describes a method for treating autism spectrum disorder or autism. Autism spectrum disorder (ASD) and autism refer to a group of complex brain development disorders. The typical characteristics of autism are social interaction difficulties, such as in verbal and non-verbal communication. Individuals with autism also often have repetitive behaviors. Autism may be associated with intellectual disability, motor coordination and attention difficulties, and physical health problems (e.g., sleep and gastrointestinal disorders). Individuals with autism also perform well in visual skills, music, mathematics, and art. Autism may refer to autistic disorder, childhood disintegrative disorder, non-specific pervasive developmental disorder (PDD-NOS) and Asperger's syndrome. Autism also refers to the monogenic causes of autism, such as synaptic diseases, for example, Rett syndrome, fragile X syndrome, Angelman syndrome.

[0193] Disorders associated with phenylketonuria

[0194] In one embodiment, described herein is a method for treating disorders (e.g., cognitive impairment) associated with phenylketonuria using the compounds described herein. Phenylketonuria may lead to hypocholesterolemia and reduced vitamin D status. It has been found that total cholesterol and low-density cholesterol and 25-hydroxyvitamin D in subjects suffering from phenylketonuria are reduced compared to subjects not suffering from phenylketonuria (Clin.Chim.Acta 2013, 416: 54-59). 24S-hydroxycholesterol and 27S-hydroxycholesterol and 7α-hydroxycholesterol (e.g., representing peripheral cholesterol and liver cholesterol elimination, respectively) have been shown to be significantly reduced in subjects suffering from phenylketonuria, while 7β-hydroxycholesterol (e.g., reflecting oxidative stress) is significantly increased in subjects suffering from phenylketonuria. In patients suffering from phenylketonuria, changes in 24S-OHC and 7β-hydroxycholesterol levels are associated with phenylalanine levels, and 27S-hydroxycholesterol levels may be associated with 25-hydroxyvitamin D levels.

[0195] Process for preparing the crystalline form

[0196] In one aspect, the present disclosure provides a method for preparing crystalline Form C of Compound 1. In some embodiments, the method for preparing crystalline Form C of Compound 1 comprises the following steps: a) dissolving Compound 1 in at least one solvent (e.g., acetone, EtOH) to form a solution; b) adding an anti-solvent (e.g., H2O, acetonitrile) until a precipitate is formed; and c) isolating the precipitate. In some embodiments, the solvent is acetone. In some embodiments, the solvent is EtOH. In some embodiments, the anti-solvent is H2O. In some embodiments, the anti-solvent is acetonitrile (ACN).

[0197] In some embodiments, the method of preparing crystalline Form C of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent (e.g., EtOH / H2O) to form a mixture; b) aging the mixture at room temperature to precipitate a solid; and c) isolating the solid.

[0198] In some embodiments, the method for preparing the crystalline form C of compound 1 comprises the following steps: a) adding compound 1 to a solvent (e.g., isopropyl acetate (IPAc), dimethoxyethane (DME)) to form a mixture; b) filtering the mixture to provide a filtrate; c) evaporating the filtrate at room temperature to precipitate a solid; and d) isolating the solid. In some embodiments, the solvent is IPAc. In some embodiments, the solvent is DME.

[0199] In some embodiments, the method for preparing crystalline Form C of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent (e.g., IPAc) to form a mixture; b) adding the mixture to a polymer mixture; c) evaporating the mixture at room temperature to precipitate a solid; and d) isolating the solid. In some embodiments, the solvent is IPAc.

[0200] In some embodiments, the method of preparing crystalline Form C of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent (e.g., dimethoxyethane (DME) / tetrahydrofuran (THF)) to form a mixture; b) aging the mixture at about 5° C. to precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is DME / THF.

[0201] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent (e.g., dichloromethane (DCM)) to form a mixture; b) heating the mixture to about 60° C.; c) filtering the heated mixture to provide a filtrate; d) aging the filtrate at about −20° C. to provide a solid; and d) isolating the solid. In some embodiments, the solvent is DCM.

[0202] Examples

[0203] In order that the invention described herein may be more fully understood, the following examples are set forth. These examples are provided to illustrate the crystalline solid forms provided herein and should not be construed in any way as limiting the scope thereof.

[0204] Example 1. Instruments and methods

[0205] AX-ray powder diffraction (XRPD)

[0206] A PANalytical Empyrean X-ray powder diffractometer was used to collect the X-ray diffraction patterns as described herein. The diffraction peak positions were calibrated using a PANalytical Si reference standard disk. The XRPD parameters used are listed in Table 1.

[0207] Table 1: Parameters used for XRPD testing

[0208]

[0209] B. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0210] TGA data were collected using a TA Discovery 550 / Q500 TGA from TA Instrument. DSC was performed using a TA Q2000 DSC from TA Instrument. The DSC was calibrated using an indium reference standard, and the TGA was calibrated using a nickel reference standard. Detailed parameters are provided in Table 2:

[0211] Table 2: Parameters used for TGA and DSC tests

[0212]

[0213] C. Polarized Light Microscopy (PLM) and Hot Stage

[0214] Polarized light microscopy images were taken at room temperature using a Nikon DS-Fi2 upright microscope. The heating stage was performed on a Linkam.

[0215] D. Chemical purity determination (HPLC)

[0216] Purity analysis and stoichiometry were performed using an Agilent 1100 HPLC as detailed in Table 3:

[0217] Table 3: HPLC purity test method

[0218]

[0219] E. Dynamic Vapor Sorption (DVS)

[0220] DVS was measured using an SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25°C was calibrated based on the deliquescent points of LiCl, Mg(NO3)2, and KCl. The parameters used in the DVS test are listed in Table 4.

[0221] Table 4: Parameters used for DVS testing

[0222]

[0223] F. Nuclear Magnetic Resonance (NMR)

[0224] Solution NMR spectra were collected on a Bruker 400M NMR spectrometer. Samples were prepared in DMSO-d6.

[0225] Example 2. Polymorph Screening

[0226] Polymorph screening experiments were performed using different crystallization or solid phase transformation methods. The methods used to identify Form C are summarized in Table 5.

[0227] Table 5: Crystallization methods

[0228]

[0229] A. Antisolvent Addition

[0230] About 15 mg of the starting material (Compound 1) was dissolved in 0.1 to 0.9 mL of solvent to obtain a clear solution. The solution was stirred magnetically and then 0.2 mL of antisolvent was added in each step until precipitation occurred or the total amount of antisolvent reached 15.0 mL. The results in Table 6 (below) show the obtained forms.

[0231] Table 6: Summary of Antisolvent Addition Experiments

[0232]

[0233] B. Slurrying at room temperature

[0234] The slurry conversion experiment was carried out at room temperature in different solvent systems. About 15 mg of the starting material (Compound 1) was suspended in 0.2 mL of solvent in a glass bottle. After the suspension was magnetically stirred at room temperature for 7 days, the remaining solid was separated. The results are summarized in Table 7 below.

[0235] Table 7: Summary of slurry conversion experiments at room temperature

[0236]

[0237] C. Slow evaporation

[0238] Briefly, 15 mg of the starting material (Compound 1) was dissolved in 0.5 to 1.5 mL of solvent in a 3 mL glass vial. If dissolution was not achieved, the suspension was filtered using a PTFE membrane (pore size 0.20 μm) and the filtrate was used for the following step. The visually clear solution was filtered using a PARAFILM ® Cover and evaporate at room temperature. The results are summarized in Table 8:

[0239] Table 8: Summary of slow evaporation experiments

[0240]

[0241] D. Polymer-Induced Crystallization

[0242] Briefly, 7 mg of the starting material (Compound 1) was dissolved in 0.8 to 3.5 mL of solvent in a 3 mL glass vial. If dissolution was not achieved, the suspension was filtered using a PTFE membrane (pore size 0.20 μm) and the filtrate was used in the following step. About 2 mg of the polymer mixture was added to the clear solution. The clear solution was filtered using a PARAFILM ® Cover and evaporate at room temperature. Isolate the solid for XRPD analysis. The results are summarized in Table 9:

[0243] Table 9: Summary of polymer-induced crystallization

[0244]

[0245] E Low temperature pulping

[0246] Low temperature slurry conversion experiments were performed at 5°C in different solvent systems. About 20 mg of the starting material (Compound 1) was suspended in 0.3 mL of solvent in a glass bottle. After the suspension was magnetically stirred at 5°C for 7 days, the remaining solid was separated for XRPD analysis. The results are summarized in Table 10:

[0247] Table 10: Summary of low temperature slurrying

[0248]

[0249] F. Quenching cooling

[0250] Quenching cooling experiments were performed in different solvent systems. About 30 mg of the starting material (Compound 1) was suspended in 0.3 mL of solvent in a 3 mL glass bottle at room temperature. The suspension was then heated to 60°C, equilibrated for about two hours, and filtered using a PTFE membrane (pore size of 0.22 μm). The filtrate was transferred to -20°C. If no precipitation was observed, the solution was evaporated at room temperature. The results are summarized in Table 11:

[0251] Table 11: Quench cooling summary

[0252]

[0253] Example 3: Preparation and characterization of Form C

[0254] Form C was generated by slurrying of Form A in EtOH / H2O at room temperature (0.927 / 0.073, a w =0.4). Figure 1A The XRPD pattern of Form C is provided, and the characteristic peaks are summarized in Table 12. Form C has a chemical purity of about 99% as determined by HPLC. Figure 1B TGA and DSC data for Form C are provided in and show a weight loss of 3.0% up to 125° C. The DSC data show a dehydration endotherm at 119.7° C. (peak temperature) prior to a melting peak at 203.9° C. (peak temperature).

[0255] Heating experiments were performed to further evaluate the DSC thermal events by heating to the desired temperature, then cooling to room temperature under nitrogen, and re-exposure to ambient conditions. Figure 1C In view of these results, Form C is considered to be a hydrate.

[0256] Table 12: XRPD of Crystalline Form C

[0257]

Claims

1. A crystalline form of Compound 1: Compound 1 wherein the crystalline form is Form C, characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ.

2. The crystalline form of claim 1, wherein crystalline Form C is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ.

3. The crystalline form of claim 1, wherein crystalline Form C is characterized by an XRPD pattern comprising peaks at 12.0 ± 0.2, 12.9 ± 0.2, 15.1 ± 0.2, 20.1 ± 0.2, 21.3 ± 0.2, and 25.8 ± 0.2 degrees 2θ.

4. The crystalline form of claim 1, wherein the XRPD pattern further comprises at least one additional peak at a position selected from the group consisting of: 12.9 ± 0.2, 16.3 ± 0.2, 17.5 ± 0.2, 20.1 ± 0.2, and 25.8 ± 0.2 degrees 2θ.

5. The crystalline form according to any one of claims 1 to 4, wherein the crystalline form is a hydrate.

6. The crystalline form of claim 5, wherein the crystalline form is a monohydrate.

7. The crystalline form according to any one of claims 1 to 6, wherein crystalline Form C is characterized by an XRPD pattern substantially as depicted in Figure 1A.

8. The crystalline form of any one of claims 1 to 7, wherein the crystalline Form C has a TGA thermogram substantially as depicted in Figure 1B.

9. The crystalline form of any one of claims 1 to 7, wherein crystalline Form C has a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 1B.

10. The crystalline form of claim 9, wherein the DSC thermogram comprises an endothermic peak at about 204°C.

11. The crystalline form of claim 9 or 10, wherein the DSC thermogram comprises an endothermic peak at about 120°C.

12. A solid dosage form comprising the crystalline form according to any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier.

13. A method of treating a CNS-related disorder in a subject, the method comprising administering to the subject an effective amount of the crystalline form according to any one of claims 1 to 11 or the solid dosage form according to claim 12.

14. The method of claim 13, wherein the CNS-related disorder is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis complex), pain (including acute and chronic pain), encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (including status epilepticus and monogenic epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus.

15. A method of inducing sedation or anesthesia in a subject, the method comprising administering to the subject an effective amount of the crystalline form according to any one of claims 1 to 11 or the solid dosage form according to claim 12.

16. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) dissolving compound 1 in at least one solvent to form a solution; b) adding an anti-solvent until a precipitate is formed; as well as c) isolating the precipitate.

17. The method of claim 16, wherein the solvent is selected from the group consisting of acetone and EtOH.

18. The method of claim 16 or 17, wherein the anti-solvent is acetonitrile.

19. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) aging the mixture at room temperature to precipitate a solid; as well as c) isolating the solid.

20. The method of claim 19, wherein the solvent is EtOH / H2O.

21. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) aging the mixture at room temperature to precipitate a solid; as well as c) isolating the solid.

22. The method of claim 21, wherein the solvent is DME.

23. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) adding the mixture to a polymer mixture; c) aging the mixture at room temperature to precipitate a solid; as well as d) isolating the solid.

24. The method of claim 23, wherein the solvent is IPAc.

25. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) aging the mixture at about 5° C. to precipitate solids; and c) isolating the solid.

26. The method of claim 25, wherein the solvent is DME / THF.

27. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) heating the mixture to about 60° C.; c) filtering the heated mixture to provide a filtrate; d) aging the filtrate at about -20°C to provide a solid; and e) isolating the solid.

28. The method of claim 27, wherein the solvent is DCM.

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