Crystal Forms of Neuroactive Steroids

Abstract

The present disclosure relates to a crystalline solid form of Compound 1. The present disclosure also provides a method for preparing the crystalline solid form of Compound 1. In a first aspect, the present disclosure provides a crystalline form of Compound 1, wherein the crystalline form is Crystal Form C, and 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. In a second aspect, the present disclosure provides a solid dosage form comprising Crystal Form C of Compound 1 disclosed herein and at least one pharmaceutically acceptable carrier. JPEG2025523826000018.jpg3067

Description

Technical Field

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

Background Art

[0002] The NMDA receptor is a heteromeric complex composed of NR1, NR2, and / or NR3 subunits and has distinct recognition sites for exogenous and endogenous ligands. These recognition sites include a binding site for glycine and glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity under some circumstances and to excitotoxicity under other circumstances. These receptors are ligand-gated ion channels that accept Ca 2+ upon binding of glutamate and glycine and are essential for excitatory neurotransmission and normal CNS function. Positive modulators may be useful as therapeutic agents with potential clinical use as nootropics and may be useful in the treatment of mental disorders in which glutamatergic transmission is reduced or deficient (see, for example, Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325).

[0003] Compound 1 disclosed in this specification is a positive allosteric modulator (PAM) of the NMDA receptor. For a positive allosteric NMDA modulator to be a useful therapeutic agent, it is necessary to have an appropriate balance of various characteristics including affinity for the NMDA receptor, positive allosteric modulation activity, duration of activity, oral bioavailability, tissue distribution, and stability (e.g., shelf life, formulatability, and crystallizability). An appropriate balance of such a combination of characteristics can lead to an NMDA receptor PAM having improved efficacy, safety, tolerability, patient compliance, manufacturing, etc. Accordingly, large-scale commercial preparations of solid forms of Compound 1 and their corresponding solid dosage forms having appropriate properties (including chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying characteristics, milling characteristics, and stability during tableting) present many challenges. Accordingly, there is a current need for one or more solid forms of an NMDA receptor PAM (e.g., Compound 1) that have an appropriate balance of these characteristics and may be useful in the preparation of its pharmaceutically acceptable solid dosage forms.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0005] This disclosure provides polymorphic forms of Compound 1,

Chemical Formula

[0006] In a first aspect, the present disclosure provides a crystalline form of Compound 1, [Chemical formula] wherein the crystalline form is Crystalline Form C, and 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.

[0007] 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.

[0008] 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 substantially by the XRPD pattern shown in Figure 1A.

[0009] In some embodiments, crystalline Form C has a TGA thermogram substantially as shown in FIG. 1B. In some embodiments, crystalline Form C has a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 1B. In some embodiments, the DSC thermogram includes an endothermic peak at about 204 °C. In some embodiments, the DSC thermogram includes an endothermic peak at about 120 °C.

[0010] In some embodiments, crystalline Form C is characterized by an XRPD pattern substantially as shown in FIG. 1A.

[0011] In a second aspect, the present disclosure provides a solid dosage form comprising crystalline Form C of Compound 1 disclosed herein and at least one pharmaceutically acceptable carrier.

[0012] In a third aspect, the present disclosure provides a method of treating a CNS-related condition in a subject, the method comprising administering to the subject an effective amount of crystalline Form C of Compound 1 disclosed herein or a solid dosage form comprising a crystalline form of Compound 1. In some embodiments, the CNS-related condition is selected from the group consisting of adjustment disorder, 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 depressive states, bipolar disorder, and mood-cycling disorders), 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 with mutations in the Shank protein group), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis), 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 syndrome, etc.), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus.

[0013] In a fourth 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 of compound 1 disclosed herein, or a solid dosage form comprising crystalline form C of compound 1 disclosed herein.

[0014] In a fifth 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: a) dissolving compound 1 in at least one solvent to form a solution; b) adding a poor solvent until a precipitate is formed; and c) isolating 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.

[0015] In some embodiments, the method for preparing crystalline form C of compound 1 comprises: 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.

[0016] In some embodiments, the method for preparing crystalline form C of compound 1 comprises: 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.

[0017] In some embodiments, the method for preparing crystalline form C of compound 1 comprises: 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.

[0018] In some embodiments, a method for preparing crystalline form C of Compound 1 comprises: 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.

[0019] In some embodiments, a method for preparing crystalline form C of Compound 1 comprises: 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

[0020]

Figure 1A

Figure 1B

Figure 1C

[0021] General Definitions The term "herein" means the entire present application.

[0022] Unless defined otherwise herein, scientific and technical terms used in this application have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains. In general, the terms used in connection with the compounds, compositions, and methods described herein are well known and commonly used in the art.

[0023] It should be understood that any of the embodiments described herein, including those described only in the examples and including aspects of the present disclosure and different parts of this specification, can be combined with one or more other embodiments of the present disclosure, unless explicitly denied or inappropriate. Combinations of embodiments are not limited to those specific combinations claimed through the scope of 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. When elements are presented as a list, for example, in Markush group format, each subgroup of the elements is also disclosed and any element(s) can be deleted from the group.

[0024] Throughout this specification, the term "comprise", or variations such as "comprises" or "comprising", is understood to mean including the stated integer (or component) or group of integers (or components), but not meaning the exclusion of any other integer (or component) or group of integers (or components).

[0025] Throughout this specification, when a composition is described as having, including, or comprising (or a variation thereof) a particular component, it is contemplated that the composition may also consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, including, or comprising a particular process step, the process may also consist essentially of or consist of the recited process steps. Further, it should be understood that the order of steps or the order in which a particular operation is performed is not important as long as the compositions and methods described herein remain operable. Additionally, two or more steps or operations can be performed simultaneously.

[0026] As used herein, the term "including" means "including but not limited to". "Including" and "including but not limited to" are used interchangeably. Thus, these terms are understood to mean including the recited integer (or component) or group of integers (or components), but not meaning the exclusion of any other integer (or component) or group of integers (or components).

[0027] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., on the limitations of the measurement system.

[0028] The use of the terms "a", "an", "the", and similar referents in the context of describing an element (particularly in the context of the following claims) is to be construed to cover both the singular and the plural forms unless otherwise indicated herein or clearly contradicted by the context.

[0029] It is to be understood that the term "or" as used herein means "and / or" unless the context clearly dictates otherwise.

[0030] References to ranges of values herein are, unless otherwise indicated herein, intended to function simply as a shorthand method of referring individually to each separate value that falls within the range, with each separate value being incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to clarify the embodiments and does not otherwise limit or delimit the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential.

[0031] All publications, patents, and patent applications cited in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control. Additionally, any particular embodiment of the present disclosure that is relevant to the prior art may be explicitly excluded from any one or more of the claims. Such embodiments may be considered known to those skilled in the art and thus may be excluded even if not explicitly described as such in the present specification. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0032] 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 treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient", "active agent", and "active substance" may be optical isomers of the compounds described herein.

[0033] The terms "drug" and "therapeutic agent" refer to a compound, or a pharmaceutical composition thereof, that is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.

[0034] As used herein, the term "polymorph" refers to a crystalline form of a compound or a salt, hydrate, or solvate thereof in a particular crystal packing arrangement. All polymorphs have the same elemental composition. The term "polymorph" typically includes pseudopolymorphs, which are different solvates of the material, and thus, their properties differ from one another. Accordingly, each distinct polymorph and pseudopolymorph disclosed herein is considered to be a distinct single crystal form disclosed herein.

[0035] As used herein, the term "crystalline" refers to a solid form consisting of an ordered arrangement of structural units. Different crystal forms of the same compound, or a salt, hydrate, or solvate thereof, result from different packings of the molecules in the solid state, which leads to different crystal symmetries and / or unit cell parameters. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. See, for example, Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa., 173 (1990); The United States Pharmacopeia, 23.sup.rd ed., 1843-1844 (1995), which are incorporated herein by reference. As used herein, the terms "crystal form", "single crystal form", "crystalline solid form", and "polymorph" are used interchangeably, and these terms distinguish crystals having different properties (e.g., different XRPD patterns and / or different DSC scan results).

[0036] The term "substantially pure" relates to a composition of a particular crystalline solid form of Compound 1 that may be free of at least a specified weight percentage of impurities and / or other solid forms of Compound 1. The specified 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 of the crystalline solid forms described herein. In some embodiments, Compound 1 may be in substantially pure Form C.

[0037] Crystalline forms are generally characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (peaks, typically expressed in degrees two-theta) is generally regarded as a distinct characteristic of a particular crystalline form. The relative intensities of XRPD peaks can vary depending, inter alia, on sample preparation techniques, crystal size distribution, filters, sample mounting procedures, and the particular instrument used. In some examples, depending on the type or setting of the instrument, more (i.e., new peaks) or fewer (i.e., peaks may disappear) peaks may be present in the XRPD pattern. In some examples, any particular peak in the XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type or setting of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystalline form. In some examples, any particular peak within the XRPD may appear with a symmetric or asymmetric shape, e.g., a shape with a shoulder. Further, instrument variations and other factors can affect the two-theta values. Those skilled in the art to understand these variations can use not only XRPD but also other known physicochemical techniques to identify or confirm the definitive characteristics or features of a particular crystalline form.

[0038] The term "characteristic peak" when referring to a peak in the XRPD pattern of a crystalline form of Compound 1 refers to a particular set of peaks where the values of 2θ over the range of 0° to 40° are uniquely assigned to one of the crystalline forms of Compound 1 as a whole.

[0039] The term "amorphous" as applied to a compound refers to a state in which the material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid depending on temperature. Typically, such materials give a distinctive X-ray diffraction pattern and exhibit the properties of a solid but are more formally described as liquids. When heated, a change of state occurs, typically a change from a solid to a liquid characterized by a secondary change (a "glass transition").

[0040] The term "solvate" refers to a compound or a 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 bonding). When the solvent is water, the solvate is a hydrate. When the solvent includes ethanol, the compound may be an ethanol solvate.

[0041] 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.

[0042] The crystalline form of Compound 1 described herein, e.g., Form C, can melt over a specific temperature or temperature range. Such a specific temperature or temperature range can be represented by the onset temperature (T 開始 ) of the endothermic melting in the DSC trace of the crystalline form. In some embodiments, at such an onset temperature, a sample of the crystalline form of Compound 1 melts and concurrent secondary processes, such as recrystallization or chemical decomposition, occur. In some embodiments, at such an onset temperature, the crystalline form of Compound 1 melts in the absence of other concurrent processes.

[0043] The present disclosure provides forms of Compound 1 having suitable properties for preparing solid dosage forms. Such properties include chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying characteristics, milling characteristics, and stability during tableting.

[0044] In one aspect, the present disclosure relates to a solid form of Compound 1. [Chemical]

[0045] In some embodiments, the solid form is crystalline form C of Compound 1. In some embodiments, the crystalline form is a hydrate.

[0046] Compound 1 and its chemical synthesis are disclosed in U.S. Patent No. 10,227,375 / PCT Application Publication No. 2014 / 160480.

[0047] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic peaks in the XRPD spectrum, as disclosed herein.

[0048] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic endothermic peaks in the differential scanning calorimetry (DSC) thermogram, as disclosed herein.

[0049] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic endothermic peaks in the thermogravimetric analysis (TGA) thermogram, as disclosed herein.

[0050] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic endothermic peaks in the differential scanning calorimetry (DSC) thermogram or the thermogravimetric analysis (TGA) thermogram, as disclosed herein.

[0051] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic peaks in the XRPD spectrum in combination with having one or more characteristic endothermic peaks in the differential scanning calorimetry thermogram and / or the thermogravimetric analysis (TGA) thermogram.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] In some embodiments, crystalline Form C of Compound 1 is characterized by an XRPD pattern substantially as shown in Figure 1A.

[0056] In some embodiments, crystalline Form C of Compound 1 is a hydrate. In some embodiments, crystalline Form C of Compound 1 is a monohydrate.

[0057] In some embodiments, Form C is a) an XRPD pattern comprising peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ, b) an XRPD pattern substantially as shown in Figure 1A, c) a DSC thermogram profile comprising an endothermic peak at about 204 °C, d) a DSC thermogram profile comprising an endothermic peak at about 120 °C, e) a DSC thermogram profile substantially as shown in Figure 1B, f) a TGA profile showing at least about 3 wt% loss between about 23 °C and about 125 °C, and g) has one or more characteristics selected from the group consisting of a TGA profile substantially as shown in Figure 1B.

[0058] 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 comprises peaks at 12.0 ± 0.2, 15.1 ± 0.2, and 21.3 ± 0.2 degrees 2θ and is further characterized by an XRPD pattern 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, crystalline Form C of Compound 1 is characterized by an XRPD pattern substantially as shown in Figure 1A.

[0059] In some embodiments, Form C of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram showing that Form C loses at least about 3 wt% 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 that Form C loses about 3 - 4 wt% between about 23°C and about 125°C. In some embodiments, Form C of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 1B.

[0060] In some embodiments, Form C of Compound 1 is characterized substantially by the differential scanning calorimetry (DSC) thermogram shown in FIG. 1B. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram that includes an endothermic peak at about 204°C. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram that includes an endothermic peak at about 120°C. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram that includes endothermic peaks at about 120°C and about 204°C. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram that includes a desolvation endothermic peak at about 120°C. In some embodiments, Form C of Compound 1 is characterized by a DSC thermogram that includes a melting endothermic peak at about 204°C.

[0061] 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%.

[0062] Pharmaceutical composition In one aspect, the present invention provides a pharmaceutical composition which is a solid dosage form comprising the solid form of Form C of Compound 1 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.

[0063] In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of Compound 1.

[0064] Solid dosage forms suitable for oral administration include solid preparations such as tablets, caplets, capsules, powders, lozenges (including liquid-filled), sachets, and the like.

[0065] The solid dosage forms disclosed herein include a carrier, which may include one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, binders, surfactants, diluents or fillers, buffers, anti-adhesion agents, flow promoters, hydrophilic or hydrophobic polymers, retardants, stabilizers or stabilizers, disintegrants or superdisintegrants, dispersants, antioxidants, defoamers, fillers, fragrances, colorants, lubricants, adsorbents, preservatives, plasticizers, coating agents, or sweeteners, or mixtures thereof, as well as other excipients known in the art. For example, the excipient(s) may be binders such as microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, tragacanth gum or gelatin; diluents such as mannitol, microcrystalline cellulose, maltodextrin, starch or lactose; disintegrants such as alginic acid, PRIMOGEL®, sodium starch glycolate, croscarmellose sodium, crospovidone 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, cetyltriethylammonium bromide, polyethylene oxide - polypropylene oxide copolymer, or CREMOPHOR® EL; antioxidants such as butylhydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid, tocopherol or tocopherol acetate, sodium sulfite, or sodium metabisulfite; coatings including one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, methacrylate copolymer, cellulose acetate, hydroxypropyl methylcellulose acetate succinate, shellac, etc.; sweeteners such as sucrose, sucralose, acesulfame K, sodium aspartame or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor.Any of the well-known pharmaceutical excipients can be incorporated into the dosage form and can be found in the FDA’s Inactive Ingredients Guide, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005), Handbook of Pharmaceutical Excipients, Sixth Ed. (Pharmaceutical Press, 2009), all of which are incorporated by reference. In some embodiments, the solid dosage forms disclosed herein include any one or more of the following excipients: microcrystalline cellulose low humidity, silicified microcrystalline cellulose low humidity type 90, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate, and opadry AMB II 88A180040 white. In some embodiments, the disclosed solid dosage forms include microcrystalline cellulose low humidity, silicified microcrystalline cellulose low humidity type 90, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate, and opadry AMB II 88A180040 white. In some embodiments, the disclosed solid dosage forms include microcrystalline cellulose low humidity, silicified microcrystalline cellulose low humidity type 90, mannitol, sodium starch glycolate, and sodium stearyl fumarate.

[0066] Method of Use As described herein, Compound 1 is generally designed to be a positive allosteric modulator of NMDA function and is thus useful, for example, in the treatment and prevention of CNS-related conditions in a subject.

[0067] In some embodiments, as described herein, Compound 1 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.

[0068] In one aspect, the present disclosure provides a method for treating a disease, disorder, or condition in a subject in need of positive allosteric NMDA modulation, the method comprising administering to the subject an effective amount of crystalline Form C of Compound 1 disclosed herein, or a solid dosage form.

[0069] In one aspect, the present disclosure provides a method for treating a CNS-related condition in a subject, the method comprising administering to the subject an effective amount of crystalline Form C of Compound 1 disclosed herein, or a solid dosage form.

[0070] In one aspect, the present disclosure provides a method for preventing a disease, disorder, or condition in a subject in need of positive allosteric NMDA modulation, the method comprising administering to the subject an effective amount of crystalline Form C of Compound 1 disclosed herein, or a solid dosage form.

[0071] In one aspect, the present disclosure provides a method for preventing a CNS-related condition in a subject, the method comprising administering to the subject an effective amount of crystalline Form C of Compound 1 disclosed herein, or a solid dosage form.

[0072] 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 of Compound 1 disclosed herein, or a solid dosage form.

[0073] In one aspect, the present disclosure provides crystalline form C of Compound 1 disclosed herein, or a solid dosage form, for use in the treatment of a disease, disorder, or condition that requires positive allosteric NMDA modulation in a subject.

[0074] In one aspect, the present disclosure provides crystalline form C of Compound 1 disclosed herein, or a solid dosage form, for use in the treatment of a CNS-related condition in a subject.

[0075] In one aspect, the present disclosure provides crystalline form C of Compound 1 disclosed herein, or a solid dosage form, for use in the prevention of a disease, disorder, or condition that requires positive NMDA modulation in a subject.

[0076] In one aspect, the present disclosure provides crystalline form C of Compound 1 disclosed herein, or a solid dosage form, for use in the prevention of a CNS-related condition in a subject.

[0077] In one aspect, the present disclosure provides crystalline form C of Compound 1 disclosed herein, or a solid dosage form, for use in the induction of sedation or anesthesia in a subject.

[0078] In one aspect, the present disclosure provides the use of crystalline form C of Compound 1 disclosed herein, or a solid dosage form, for the manufacture of a medicament for treating a disease, disorder, or condition that requires positive allosteric NMDA modulation in a subject.

[0079] In one aspect, the present disclosure provides the use of crystalline form C of Compound 1 disclosed herein, or a solid dosage form, for the manufacture of a medicament for treating a CNS-related condition in a subject.

[0080] In one aspect, the present disclosure provides the use of crystalline form C of Compound 1 disclosed herein, or a solid dosage form, for the manufacture of a medicament for preventing a disease, disorder, or condition that requires positive allosteric NMDA modulation in a subject.

[0081] In one aspect, the present disclosure provides the use of crystalline form C of compound 1 disclosed herein, or a solid dosage form, for the manufacture of a medicament for preventing a CNS-related condition in a subject.

[0082] In one aspect, the present disclosure provides the use of crystalline form C of compound 1 disclosed herein, or a solid dosage form, for the manufacture of a medicament for inducing sedation or anesthesia in a subject.

[0083] 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 such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), an organic disorder affecting the GI, an anal disorder (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissure, perianal abscess, fistula-in-ano), a colorectal polyp, cancer, colitis. In some embodiments, the disorder is inflammatory bowel disease.

[0084] In some embodiments, the disorder is Smith-Lemli-Opitz syndrome (SLOS). In some embodiments, the disorder is desmosterolosis. 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 related to phenylketonuria.

[0085] Exemplary conditions associated with positive NMDA modulation include, but are not limited to, gastrointestinal (GI) disorders such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), organic disorders affecting the GI, anorectal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissure, perianal abscess, fistula-in-ano), colon polyps, cancer, colitis, and CNS conditions such as those described herein.

[0086] Exemplary CNS conditions 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 types of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, cyclothymic disorder, suicidal tendencies), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance use-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorder (including those related to mutations in the Shank protein family (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, steroid synthesis disorders, pain (acute and chronic pain; headaches, including migraines), seizure disorders (including status epilepticus and monogenic epilepsy, e.g., Dravet syndrome, and tuberous sclerosis complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus.

[0087] In certain embodiments, the crystalline form C of Compound 1 or the solid dosage form disclosed herein can be used to induce sedation or anesthesia. In certain embodiments, the crystalline form or solid dosage form of Compound 1 disclosed herein is useful in the treatment or prevention of adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, steroid synthesis disorders, pain, seizure disorders, stroke, traumatic brain injury, movement disorders, and visual function disorders, 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).

[0088] In another aspect, provided is a method of treating or preventing cerebral excitability in a subject susceptible to or suffering from a condition associated with cerebral excitability, the method comprising administering to the subject an effective amount of the crystalline form or solid dosage form of Compound 1 disclosed herein.

[0089] 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, with another pharmaceutically active agent. The compounds provided herein can be administered as a single active agent or in combination with other agents. The combined administration can be effected by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administrations.

[0090] Diseases and Disorders Movement Disorders Methods for treating movement disorders are also described herein. As used herein, "movement disorder" refers 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 parkinsonism (particularly as defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremors (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders.

[0091] Tremors are involuntary, sometimes rhythmic, muscle contractions and relaxations, which may be accompanied by vibrations or contractions of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremors include, respectively, hereditary, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor; metabolic diseases (e.g., thyroid and parathyroid diseases, liver diseases, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Lévy, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced disorders (narcolepsy, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychiatric disorders. Clinical tremors can be classified into physiological tremors, enhanced physiological tremors, essential tremor syndromes (including classic essential tremor, orthostatic tremor, and task- and position-specific tremors), dystonic tremors, parkinsonian tremors, cerebellar tremors, Holmes tremors (i.e., rubral tremors), palatal tremors, neuropathic tremors, toxic or drug-induced tremors, and psychogenic tremors. Other forms of tremors include cerebellar or intention tremors, dystonic tremors, essential tremors, orthostatic tremors, parkinsonian tremors, physiological tremors, psychogenic tremors, or rubral tremors.

[0092] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after intentional movement. Cerebellar tremor is caused by, for example, lesions or damage to the cerebellum resulting from tumors, strokes, diseases (such as multiple sclerosis, hereditary degenerative disorders).

[0093] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or pain and 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.

[0094] Essential tremor or benign essential tremor is the most common tremor. Essential tremor may be mild and non - progressive, or it may progress slowly. It starts on one side of the body but affects both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. The tremor frequency may decrease with aging, but the severity may increase. Heightened emotion, stress, fever, physical fatigue, or hypoglycemia may trigger and / or increase the severity of the tremor. The symptoms generally progress over time and include both visible and persistent ones after onset.

[0095] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing up. Quivering is felt in the thighs and legs, and the patient may sway uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0096] Parkinsonian tremors are caused by damage to structures in the brain that control movement. Parkinsonian tremors are often a precursor to Parkinson's disease and are typically seen as "pill-rolling" movements of the hands, which can also affect the jaw, lips, legs, and trunk. The onset of Parkinsonian tremors typically begins after the age of 60. Movements usually start in one limb or one side of the body and can progress to include the opposite side.

[0097] Physiological tremors can occur in normal individuals and have no clinical significance. They can be seen in all voluntary muscle groups. Physiological tremors can be caused by certain drugs, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. The tremors classically have a frequency of about 10 Hz.

[0098] Psychogenic or hysterical tremors can occur at rest or during body sway or movement actions. Patients with psychogenic tremors may have conversion disorder or another mental illness.

[0099] Red nuclear tremors are characterized by a coarse, slow tremor that can be present at rest, in a posture, and intentionally. The tremors are associated with conditions that affect the red nucleus of the midbrain, a classical abnormal stroke.

[0100] Parkinson's disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and walking. Parkinsonism is characterized by tremors, bradycardia, rigidity, and postural instability. Parkinsonism shares the symptoms seen in Parkinson's disease but is a syndrome, not a progressive neurodegenerative disease.

[0101] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive movements or postures. Dystonic movements are patterned and can be torsional or tremulous. Dystonia often begins or worsens with voluntary actions and is associated with overflow muscle activation.

[0102] Chorea is a neurological disorder typically characterized by involuntary, jerky movements that affect the shoulders, waist, and face.

[0103] Huntington's disease is a hereditary disorder that weakens the nerve cells in the brain. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, talking, and swallowing.

[0104] Ataxia refers to the inability to fully control body movements and can affect the movements of the fingers, hands, arms, legs, body, speech, and eyes.

[0105] Myoclonus and startle are responses to sudden, unexpected stimuli, which can be auditory, tactile, visual, or vestibular.

[0106] Tics are involuntary movements that usually start suddenly, are repetitive but not rhythmic over a short period of time, typically mimic normal actions, and often occur against the background of normal activities. Tics can be classified as motor or vocal. Motor tics are associated with movement, and vocal tics are associated with sounds. Tics are characterized as simple or complex. For example, simple motor tics involve only some muscles restricted to specific body parts.

[0107] Tourette syndrome is a hereditary neuropsychiatric disorder that begins in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0108] Restless legs syndrome is a sensorimotor disorder characterized by an overwhelming urge to move the legs at rest.

[0109] Generalized dystonia is a progressive movement disorder characterized by involuntary painful seizures and muscle rigidity (usually involving the lumbar region and legs). A typical result is a gait with an exaggerated lumbar lordosis and stiff legs. Characteristic abnormalities in EMG recordings with continuous motor unit activity of paravertebral muscles are typically observed. The variant form includes "limb dystonia syndrome," which typically causes focal dystonia affecting the distal legs and feet.

[0110] Gait disorder refers to an abnormal gait pattern or style resulting from neuromuscular, arthritic, or other physical changes. Gait is classified according to the system causing the abnormal movement, and examples include hemiparetic gait, diparetic gait, neuropathic gait, myopathic gait, parkinsonian gait, chorea-like gait, ataxic gait, and sensory gait.

[0111] Mood disorder Also provided herein are methods for treating mood disorders, which are, for example, clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, bipolar disorder, double depression, dysthymic personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidal tendency, suicidal ideation, or suicidal behavior.

[0112] 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 wide-ranging and persistent low mood accompanied by low self-esteem and loss of interest or pleasure in usually enjoyable activities. Among people with clinical depression, there are those with sleep disorders, weight loss, and generally irritable and excitable individuals. Clinical depression can affect an individual's emotions, thoughts, and actions and can lead to various emotional and physical problems. Individuals with clinical depression may have problems performing daily activities and may feel that life is not worth living.

[0113] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, reduced 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).

[0114] In some embodiments, a subject having PND has also experienced depression, or symptoms of depression, during pregnancy. This depression is referred to herein as peripartum depression. In one embodiment, a subject experiencing peripartum depression is at increased risk of experiencing PND.

[0115] Atypical depression (AD) is characterized by mood reactivity (e.g., anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD may also have significant social impairment as a result of excessive sleep or drowsiness (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0116] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failure to respond to pleasurable stimuli, a depressive mood more prominent than sadness or loss, excessive weight loss, or excessive guilt.

[0117] Psychotic major depression (PMD) or psychotic depression refers to major depressive episodes, particularly of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0118] Catatonic depression refers to major depression accompanied by disturbances in motor behavior. The individual may become mute and stuporous, immobile, or exhibit purposeless or strange movements.

[0119] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter.

[0120] Mood swings refer to a condition related to unipolar depression in which the same physical and cognitive problems manifest. These are less severe and tend to last longer (e.g., at least 2 years).

[0121] Double depression refers to a significant depressive mood (mood swings) that lasts for at least 2 years and is interrupted by periods of major depression.

[0122] Depressive personality disorder (DPD) refers to a personality disorder with depressive characteristics.

[0123] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, and each episode lasts for 2 weeks or less, or typically less than 2 - 3 days.

[0124] Minor depressive disorder or mild depression refers to depression in which at least two symptoms are present for 2 weeks.

[0125] Bipolar disorder or manic - depressive disorder causes extreme mood swings that include elevated (mania or hypomania) and depressed (depression) moods. During a manic episode, an individual may feel unusually happy, energetic, or irritable, or may act in ways that often involve making decisions without much consideration and without adequate deliberation, usually with little regard for the consequences. Typically, the need for sleep is reduced. During a depressive episode, there may be crying, little eye contact with others, and a negative outlook on life. The suicide risk for people with the disorder is as high as over 6% over 20 years, and self - harm occurs in 30 - 40%. Other mental health problems such as anxiety disorders and substance use disorders are commonly associated with bipolar disorder.

[0126] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, etc.

[0127] Treatment-resistant depression refers to a state where an individual has received treatment for depression but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not relieve the depressive symptoms in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression may improve but then relapse. Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0128] Suicidal tendency, suicidal thoughts, and suicidal behavior refer to the tendency of an individual to attempt suicide. Suicidal thoughts are related to thoughts about or abnormal preoccupation with suicide. The scope of suicidal thoughts varies, for example, from momentary thoughts to extensive thoughts, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, obtaining means to attempt suicide, withdrawing from social contact, becoming preoccupied with death, feeling trapped in a situation or hopeless, increasing the use of alcohol or drugs, engaging in dangerous or self-destructive behavior, and saying goodbye to people as if one will never see them again.

[0129] Symptoms of depression include persistent anxiety or a sense of mourning, weakness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, movement problems, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, lack of positive thinking or planning, excessive sleep, overeating, loss of appetite, insomnia, self-harming behavior, suicidal thoughts, and suicidal attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. The symptoms of depression, and their alleviation, can be confirmed by a physician or psychologist (e.g., by a mental state examination).

[0130] Anxiety disorder Methods for treating anxiety disorders are provided herein. Anxiety disorder is an umbrella term covering several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0131] Generalized anxiety disorder is a common chronic disorder characterized by persistent anxiety that is not focused on any one object or situation. People troubled by generalized anxiety experience nonspecific, persistent fears and worries and become overly concerned about everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting the elderly.

[0132] In panic disorder, a person is troubled by brief episodes of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as sudden-onset fear or discomfort that peaks in less than 10 minutes, but can last for hours and can also be triggered by stress, fear, or exercise. However, the specific cause is not always clear. In addition to repeated unexpected panic attacks, a diagnosis of panic disorder also requires the presence of either chronic worry about the potential effects of the attacks, persistent fear of future attacks, or significant changes in behavior related to the attacks. Thus, people with panic disorder experience symptoms even outside of specific panic episodes. In many cases, normal changes in heart rate are noticed by panic patients, leading them to think there is something wrong with their heart or that another panic attack is about to occur. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during a panic attack, and the perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., extreme hypochondriasis).

[0133] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized primarily by repetitive obsessive thoughts (painful, persistent, intrusive thoughts or images) and compulsive impulses (the urge to perform specific actions or rituals). OCD thought patterns can be likened to superstition insofar as they involve beliefs in causal relationships that do not actually exist. Often, this process is not entirely logical; for example, the compulsive impulse to walk in a certain pattern can be used to relieve the obsessive thought of imminent harm. Also often, the compulsive impulse is simply an inexplicable urge to complete a ritual caused by tension. In a few cases, patients with OCD can experience only obsessive thoughts without obvious compulsive impulses, and a much smaller number of patients experience only compulsive impulses.

[0134] The single largest category of anxiety disorders is the phobia category, which includes all cases in which fear and anxiety are triggered by specific stimuli or situations. Patients typically encounter objects of fear, from animals to places to body fluids, and anticipate terrible consequences from such encounters.

[0135] Post-traumatic stress disorder (PTSD) is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, rape, hostage situations, or even major accidents. It can also result from being exposed to intense stressors over a long period (chronically), such as soldiers who can withstand individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0136] Epilepsy Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and childhood benign focal epilepsy.

[0137] Epilepsy onset Epilepsy onset is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epilepsy onset is caused by damage to nerve cells precipitated by an initial insult (e.g., status epilepticus).

[0138] Status epilepticus (SE) Status epilepticus (SE) includes, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive seizure activity and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by seizure activity that persists despite treatment with first-line therapy, and second-line therapy is administered. Refractory status epilepticus is characterized by seizure activity that persists despite first- and second-line therapies, and general anesthetics are typically administered. Super-refractory status epilepticus is characterized by seizure activity that persists despite first-line therapy, second-line therapy, and treatment with general anesthetics for 24 hours or more.

[0139] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus, generalized non-convulsive status epilepticus, such as late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0140] Seizure A seizure is a change in physical findings or behavior that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is when a person's body shakes rapidly and uncontrollably. During a convulsion, a person's muscles contract and relax repeatedly.

[0141] Based on the type of behavior and brain activity, seizures are broadly classified into two categories: generalized and partial (also called focal or local). Classifying the type of seizure helps a doctor diagnose whether a patient has epilepsy.

[0142] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that causes the seizure is sometimes called the focus.

[0143] There are six types of generalized seizures. The most common and dramatic, and thus the most well-known, is the generalized convulsion also called a grand mal seizure. In this type of seizure, the patient loses consciousness and usually falls. After the loss of consciousness, there is a 30 - 60 second period of generalized stiffness (called the "tonic" phase of the seizure), followed by a 30 - 60 second period of intense jerking (the "clonic" phase), after which the patient enters a deep sleep (the "postictal" or post-seizure phase). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence may occur.

[0144] Absence seizures cause a short loss of consciousness (only a few seconds) with little or no symptoms. The patient is most often a child and typically interrupts an activity and stares blankly. These seizures start and end suddenly and may occur several times a day. The patient usually does not recognize that a seizure is occurring but may recognize that they are "losing time."

[0145] Myoclonic seizures usually consist of sporadic jerks on both sides of the body. Patients may describe the jerks as brief electric shocks. In severe cases, these seizures can cause a person to drop objects or involuntarily throw things.

[0146] Clonic seizures are repetitive and rhythmic jerks that involve both sides of the body simultaneously.

[0147] Tonic seizures are characterized by muscle rigidity.

[0148] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arm and leg muscles, and often cause a person to fall.

[0149] The seizures described herein include: epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; discontinuous seizures; prolonged seizures; recurrent seizures; seizures of status epilepticus, for example, refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; 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 rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized seizures; infantile convulsions; jacksonian seizures; massive bilateral myoclonic seizures; multiple seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; subtle seizures, sylvian seizures; visual reflex seizures; or dissociative seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0150] Sterol synthesis disorders In one embodiment, methods for treating sterol synthesis disorders are described herein. Cholesterol has essential regulatory roles in growth and development. Cholesterol is a membrane lipid and is a precursor for many molecules that play important roles in cell growth and differentiation, protein glycosylation, and signaling pathways. Cholesterol biosynthesis involves several enzymes and intermediates. Disorders resulting from deficiencies in any of the enzymes involved in cholesterol biosynthesis lead to the accumulation of intermediates and imbalances in biomolecules, which result in disorders that include congenital skeletal malformations, dysmorphic facial features, psychomotor developmental delay, and growth disorders. In one embodiment, sterol synthesis disorders or symptoms of sterol synthesis disorders can be treated by administering to a subject suffering from a sterol synthesis disorder a compound described herein, for example, an NMDA receptor modulating compound described herein. Additional disorders are described below.

[0151] Smith-Lemli-Opitz syndrome In one embodiment, methods for treating Smith-Lemli-Opitz syndrome (or SLOS, or 7-dehydrocholesterol reductase deficiency) are described herein. SLOS is a congenital cholesterol synthesis disorder. In addition to microcephaly, moderate to severe intellectual disability, sensory hypersensitivity, stereotyped behavior, dysmorphic facial features, and syndactyly of the second / third toes, features of the disease are reduced cerebrosterol (24(S)-hydroxycholesterol) levels. SLOS is an autosomal recessive condition resulting from a deficiency in the last enzyme in the cholesterol synthesis pathway, causing low plasma cholesterol levels or low normal plasma cholesterol levels, and increased levels of 7- and 8-dehydrocholesterol (DHC; 7DHC and 8DHC). Current common 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 agents that enhance cholesterol production and / or adhesion, and a reduction in the accumulation of 7DHC and 8DHC, which are potentially toxic precursors of cholesterol.

[0152] Desmosterolosis Desmosterolosis is a deficiency in desmosterol reductase and has a phenotype similar to SLOS. In one embodiment, methods for treating desmosterolosis with the compounds described herein are described herein.

[0153] Sitosterolemia Sitosterolemia is a rare autosomal recessive disorder caused by mutations in two ATP-binding cassette (ABC) transporter genes (ABCG5 and ABCG8). Sitosterolemia enhances the intestinal absorption of plant sterols and cholesterol. Patients typically present with tendon and tuberous xanthomas, as well as premature coronary artery disease. In one embodiment, methods for treating sitosterolemia with the compounds described herein are described herein.

[0154] Cerebrotendinous xanthomatosis (CTX) In one embodiment, methods for treating cerebrotendinous xanthomatosis (also known as cerebral cholesterosis or Van Bogaert-Scherer-Epstein syndrome) with the compounds described herein are described herein. CTX can be caused by mutations in the CYP27A1 gene that produces the sterol 27-hydroxylase enzyme. Sterol 27-hydroxylase metabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid) that are important in the absorption of dietary fat. Enzyme dysfunction can lead to cholesterol accumulation in tissues. CTX is characterized by childhood diarrhea, cataracts, tendon xanthomas, reduced mental ability, and abnormal movements in adults.

[0155] Mevalonate kinase deficiency syndrome (MKD) Mevalonate kinase deficiency (also known as mevalonic aciduria (more severe form of MKD), or hyper-IgD syndrome (HIDS or hyperglobulinemia D) and periodic fever syndrome (more benign form of MKD)) causes the accumulation of mevalonic acid in the urine as a result of insufficient activity of mevalonate kinase. MKD can lead to developmental delay, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, mental retardation, and overall growth impairment. Mevalonic aciduria is characterized by delays in physical and mental development, growth impairment, recurrent episodes of fever with vomiting and diarrhea, hepatomegaly, splenomegaly and lymphadenopathy, microcephaly (small head size), cataracts, hypotonia, hyporeflexia, characteristic facial features, ataxia, and anemia. HIDS is characterized by recurrent episodes of fever associated with lymphadenopathy, joint pain, gastrointestinal problems, and rashes. In one embodiment, a method for treating MKD with a compound described herein is described herein.

[0156] SC4MOL gene mutation (SMO deficiency) SC4MOL gene deficiency is a hereditary disorder in the cholesterol biosynthesis pathway (e.g., a mutation in the SC4MOL gene encoding a novel sterol oxidase). SC4MOL deficiency is characterized by the accumulation of dimethyl and monomethyl sterols that can be detected in blood, dandruff, or primary skin fibroblasts. In one embodiment, a method for treating SMO deficiency with a compound described herein is described herein.

[0157] Niemann-Pick disease Niemann-Pick disease is a lysosomal storage disorder caused by gene mutations that affect metabolism. Niemann-Pick disease results from the abnormal accumulation of cholesterol and other fatty substances (lipids) due to the body's inability to transport substances. The accumulation damages the affected areas.

[0158] Autism In one embodiment, a method for treating autism spectrum disorder or autism is described herein. Autism spectrum disorder (ASD) and autism refer to a group of complex disorders of brain development. Autism is typically characterized, for example, by difficulties in social interaction, such as difficulties in verbal and non-verbal communication. Repetitive behaviors are also often seen in individuals with autism. Autism can be associated with intellectual disability, motor coordination and attention difficulties, and physical health problems, such as sleep and gastrointestinal disorders. Individuals with autism can also excel in visual skills, music, mathematics, and art. Autism can refer to autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. Autism can also refer to autism of single etiology, such as synaptic degeneration, such as Rett syndrome, fragile X syndrome, Angelman syndrome.

[0159] Disorders associated with phenylketonuria In one embodiment, a method for treating a disorder associated with phenylketonuria (e.g., a cognitive disorder) with a compound described herein is described herein. Phenylketonuria can result in hypocholesterolemia and a decreased vitamin D status. Total and low density cholesterol and 25-hydroxyvitamin D have been found to be decreased in subjects with phenylketonuria compared to subjects without phenylketonuria (Clin. Chim. Acta 2013, 416:54-59). 24S-hydroxy cholesterol and 27S-hydroxy cholesterol, as well as 7α-hydroxy cholesterol (e.g., representing peripheral and hepatic cholesterol elimination, respectively) have been shown to be significantly decreased in subjects with phenylketonuria, while 7β-hydroxy cholesterol (e.g., reflecting oxidative stress) has been significantly increased in subjects with phenylketonuria. Changes in the levels of 24S-OHC and 7β-hydroxy cholesterol correlate with phenylalanine levels, and 27S-hydroxy cholesterol levels may correlate with 25-hydroxyvitamin D levels in subjects with phenylketonuria.

[0160] Method for preparing crystal form 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: a) dissolving Compound 1 in at least one solvent (e.g., acetone, EtOH) to form a solution; b) adding a poor 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 poor solvent is H2O. In some embodiments, the poor solvent is acetonitrile (ACN).

[0161] In some embodiments, the method for preparing crystalline form C of Compound 1 comprises: 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.

[0162] In some embodiments, the method for preparing crystalline form C of Compound 1 comprises: 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.

[0163] In some embodiments, the method for preparing crystalline form C of Compound 1 comprises: 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.

[0164] In some embodiments, the method for preparing crystalline form C of Compound 1 comprises: 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.

[0165] In some embodiments, the method for preparing a crystalline form of Compound 1 comprises: 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 e) isolating the solid. In some embodiments, the solvent is DCM.

Examples

[0166] The following examples are provided so that the present invention described herein can be more fully understood. The examples are provided to illustrate the crystalline solid forms provided herein and should not be construed as limiting their scope in any way.

[0167] Example 1. Means and Methodology A. X-ray Powder Diffraction (XRPD) The X-ray diffraction patterns described herein were collected using a PANalytical Empyrean X-ray powder diffractometer. The diffraction peak positions were calibrated using a PANalytical Si reference standard disk. The XRPD parameters used are listed in Table 1.

Table 1

[0168] B. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) TGA data was collected using a TA Discovery 550 / Q500 TGA from TA Instruments. DSC was performed using a TA Q2000 DSC from TA Instruments. The DSC was calibrated with an indium reference standard, and the TGA was calibrated using a nickel reference standard. Detailed parameters are shown in Table 2.

Table 2

[0169] C. Polarizing Microscope (PLM) and Hot Stage Polarizing microscope photographs were taken at room temperature with a Nikon DS-Fi2 upright microscope. A hot stage was performed with Linkam.

[0170] D. Chemical Purity Determination (HPLC) As detailed in Table 3, purity analysis and stoichiometry were performed using an Agilent 1100 HPLC.

Table 3

[0171] E. Dynamic Vapor Sorption (DVS) DVS was measured using an SMS (Surface Measurement System) DVS Intrinsic. The relative humidity at 25 °C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters used in the DVS test are shown in Table 4.

Table 4

[0172] F. Nuclear Magnetic Resonance (NMR) Solution NMR spectra were collected with a Bruker 400M NMR spectrometer. Samples were prepared in DMSO-d6.

[0173] Example 2. Polymorph Screening Polymorphic screening experiments were conducted using different crystallization or solid transition methods. The methods utilized to identify Form C are summarized in Table 5.

Table 5

[0174] A. Poor solvent addition Approximately 15 mg of the starting material (Compound 1) was dissolved in 0.1 - 0.9 mL of solvent to obtain a clear solution. The solution was magnetically stirred, and 0.2 mL of the poor solvent was added stepwise until a precipitate appeared or the total amount of the poor solvent reached 15.0 mL. The results in Table 6 (below) showed the resulting forms.

Table 6

[0175] B. Slurry at room temperature Slurry conversion experiments were conducted at room temperature in different solvent systems. Approximately 15 mg of the starting material (Compound 1) was suspended in 0.2 mL of solvent in a glass vial. The suspension was magnetically stirred at room temperature for 7 days, and then the remaining solid was isolated. The results are summarized in Table 7 below.

Table 7

[0176] C. Gentle evaporation Briefly, 15 mg of the starting material (Compound 1) was dissolved in 0.5 - 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 in the subsequent step. The visually clear solution was covered with PARAFILM® having six pinholes and evaporated at room temperature. The results are summarized in Table 8.

Table 8

[0177] D. Polymer - induced crystallization Briefly, 7 mg of the starting material (Compound 1) was dissolved in 0.8 - 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 subsequent steps. Approximately 2 mg of the polymer mixture was added to the clear solution. The clear solution was covered with PARAFILM® having six pinholes and evaporated at room temperature. The solid was isolated for XRPD analysis. The results are summarized in Table 9.

Table 9

[0178] E. Low - temperature slurry The low - temperature slurry conversion experiment was carried out at 5 °C in different solvent systems. Approximately 20 mg of the starting material (Compound 1) was suspended in 0.3 mL of solvent in a glass vial. The suspension was magnetically stirred at 5 °C for 7 days, and then the remaining solid was isolated for XRPD analysis. The results are summarized in Table 10.

Table 10

[0179] F. Quench cooling The quench cooling experiment was carried out in different solvent systems. Approximately 30 mg of the starting material (Compound 1) was suspended in 0.3 mL of solvent in a 3 mL glass vial at room temperature. The suspension was then heated to 60 °C, equilibrated for about 2 hours, and filtered using a PTFE membrane (pore size 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.

Table 11

[0180] Example 3: Preparation and Characterization of Form C Form C was prepared from a slurry of Form A in EtOH / H2O (0.927 / 0.073, a) at room temperature wIt was generated via (where = 0.4). The XRPD pattern of Form C is shown in Figure 1A, and the characteristic peaks are summarized in Table 12. Form C had a chemical purity of approximately 99% as detected by HPLC. The TGA and DSC data of Form C are shown in Figure 1B, showing a 3.0% weight loss up to 125 °C. The DSC data showed an endothermic dehydration at 119.7 °C (peak temperature) prior to the melting peak at 203.9 °C (peak temperature).

[0181] Heating experiments were conducted to further evaluate the DSC thermal events via heating to the desired temperature, then cooling to room temperature under nitrogen protection, and re-exposure to ambient conditions. The results are shown in Figure 1C. Considering these results, Form C was considered to be a hydrate.

Table 12

Claims

1. The crystalline form of compound 1, 【Chemistry 4】 The crystal morphology is characterized by a crystal morphology C, which is characterized by an XRPD pattern including peaks at 12.0±0.2, 15.1±0.2, and 21.3±0.2 degrees 2θ.

2. The crystal morphology according to claim 1, wherein the crystal morphology C is characterized by an XRPD pattern including 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 crystal morphology according to claim 1, wherein the crystal morphology C is characterized by an XRPD pattern including 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 crystal morphology according to claim 1, wherein the XRPD pattern further includes 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 claim 1, wherein the crystalline form is a hydrate.

6. The crystal form according to claim 5, wherein the crystal form is a monohydrate.

7. The crystal morphology according to claim 1, wherein the crystal morphology C is substantially characterized by the XRPD pattern shown in Figure 1A.

8. The crystal morphology according to claim 1, wherein the crystal morphology C substantially has the TGA thermogram shown in Figure 1B.

9. The crystal morphology according to claim 1, wherein the crystal morphology C substantially has a differential scanning calorimetry (DSC) thermogram shown in Figure 1B.

10. The crystal morphology according to claim 9, wherein the DSC thermogram includes an endothermic peak at approximately 204°C.

11. The crystal morphology according to claim 9, wherein the DSC thermogram includes an endothermic peak at approximately 120°C.

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

13. A composition or solid dosage form for treating a CNS-related condition in a subject, wherein the composition comprises a crystalline form according to any one of claims 1 to 11, and the solid dosage form comprises a crystalline form according to any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier.

14. The aforementioned CNS-related conditions include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairments (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression, bipolar disorder, and dysthymia), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorder (Shank The composition or solid dosage form according to claim 13, selected from the group consisting of: (including those involving mutations in a group of proteins), neurodevelopmental disorders (including Rett syndrome and tuberous sclerosis), pain (including acute and chronic pain), encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (including status epilepticus and monogenic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), and tinnitus.

15. A composition or solid dosage form for inducing sedation or anesthesia in a subject, wherein the composition comprises a crystalline form according to any one of claims 1 to 11, and the solid dosage form comprises a crystalline form according to any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier.

16. A method for producing the crystalline form of compound 1, a) The step of dissolving compound 1 in at least one solvent to form a solution, b) Adding a poor solvent until a precipitate is formed, c) A method comprising the step of isolating the precipitate.

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

18. The method according to claim 16 or 17, wherein the poor solvent is acetonitrile.

19. A method for producing the crystalline form of compound 1, a) The step of adding compound 1 to a solvent to form a mixture, b) A step of aging the mixture at room temperature to precipitate the solid, c) A method comprising the step of isolating the solid.

20. The solvent is EtOH / H ２ The method according to claim 19, wherein the result is O.

21. A method for producing the crystalline form of compound 1, a) The step of adding compound 1 to a solvent to form a mixture, b) A step of aging the mixture at room temperature to precipitate the solid, c) A method comprising the step of isolating the solid.

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

23. A method for producing the crystalline form of compound 1, a) The step of adding compound 1 to a solvent to form a mixture, b) The step of adding the mixture to the polymer mixture, c) A step of aging the mixture at room temperature to precipitate the solid, d) A method comprising the step of isolating the solid.

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

25. A method for producing the crystalline form of compound 1, a) The step of adding compound 1 to a solvent to form a mixture, b) A step of aging the mixture at approximately 5°C to precipitate the solid, c) A method comprising the step of isolating the solid.

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

27. A method for producing the crystalline form of compound 1, a) The step of adding compound 1 to a solvent to form a mixture, b) The step of heating the mixture to about 60°C, c) The step of filtering the heated mixture to provide a filtrate, d) A step of aging the filtrate at approximately -20°C to provide a solid, e) A method comprising the step of isolating the solid.

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

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